ODS Customary Specialty Medication Review Criteria Effective 10/01/2008

ODS HEALTH PLANS, INC. MR Criteria

PA Description: Endocrine and Metabolic Agents

Generic Name (Brand): Abarelix (Plenaxis)

DISTRIBUTION Limited Distribution. For safety reasons, abarelix is approved with marketing restrictions. Abarelix will be provided to physicians enrolled in the Plenaxis PLUS Program. To enroll in the abarelix prescribing program, call (866) PLENAXIS (866-753-6294) or visit http://www.plenaxisplus.com.

FDA APPROVED INDICATIONS Prostate cancer: For the palliative treatment of men with advanced symptomatic prostate cancer in whom LHRH agonist therapy is not appropriate, who refuse surgical castration, and have 1 or more of the following: 1) Risk of neurological compromise because of metastases, 2) ureteral or bladder outlet obstruction caused by local encroachment or metastatic disease, or 3) severe bone pain from skeletal metastases persisting on narcotic analgesia

TREATMENT DOSE / DURATION / REGIMEN Dose: The recommended dose of abarelix is 100 mg IM to the buttock on days 1, 15, 29 (week 4), and every 4 weeks thereafter.

EFFECTIVENESS MONITORING PARAMETERS Suppression of serum testosterone below 50 ng/dL. Treatment failure can be detected by measuring serum testosterone concentrations just prior to abarelix administration, beginning on day 29 and every 8 weeks thereafter.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08.

Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 2 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Orencia

Generic Name (Brand): Abatacept (Orencia)

QUANTITY LIMIT: The following quantity limits apply to approved Prior Authorizations. 16 vials during initial 60 days of approval and 4 vials per 30 day period thereafter if renewal is approved. Orencia is dosed at 2 and 4 weeks following the initial infusion, and then once every 4 weeks thereafter.

DESCRIPTION: Orencia is a recombinant soluble fusion protein classified as a costimulation modulator. Orencia inhibits T cell activation by binding to CD80 and CD86, which blocks the interaction with CD28. This in-turn prevents full activation of the T lymphocytes attenuating the inflammatory cascade at earlier stages.

PRODUCT AVAILABILITY: Orencia (Abatacept) – 250 mg in a 15 mL vial

INDICATION: As monotherapy or concomitantly with DMARDs other than TNF- or IL-1 receptor antagonists for reducing signs and symptoms, inducing major clinical response, slowing the progression of structural damage, and improving physical function in adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more DMARDs such as methotrexate or TNF antagonists.

GUIDELINES FOR USE: 1) Is Orencia prescribed by a rheumatologist? a) If yes, go to #2. b) If no, denied.

2) Has the patient had a NEGATIVE tuberculin skin test, or if positive, has treatment for latent TB been initiated prior to Orencia therapy? a) If yes, go to #3. b) If no, denied.

3) Will the patient be using Orencia with Humira®, Remicade®, Enbrel®, Rituxan® or Kineret®? a) If yes, denied. b) If no, go to #4 for induction therapy with Orencia. c) If no, go to #6 for maintenance therapy with Orencia.

4) Is the patient being treated for moderately- to severely-active rheumatoid arthritis with documented evidence of at least four of the following for at least 6 weeks duration: i) Prolonged morning stiffness in the joints (≥ 45 minutes duration) ii) Arthritis of 3 or more joint areas: wrist, elbow, knee, subtalar, MTP or hands (MCP or PIP) iii) Arthritis of hand joints iv) Symmetric arthritis v) Rheumatoid nodules under the skin vi) Elevated levels of serum rheumatoid factor vii) Radiographic changes in the joints a) If yes, go to #5.

ODS Health Plan Customary Specialty MR Criteria Page 3 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

b) If no, denied.

5) Has the patient met at least two of the following criteria: i) Documented failure of optimal dosing/adequate duration of methotrexate ii) Documented failure of optimal dosing/adequate duration of a DMARD other than methotrexate iii) Contraindication or intolerance to methotrexate iv) Documented failure of Humira, Enbrel or Remicade a) If yes, approved for 3 months induction therapy. b) If no, denied.

RENEWAL CRITERIA: 6) Has the patient had: i) ≥ 20% improvement in the number of tender joints AND ii) ≥ 20% improvement in the number of swollen joints AND iii) ≥ 20% improvement in three of the following five measures: (1) Pain (2) Global assessment of disease activity by the physician (3) Global assessments of disease activity by the patient (4) Patient assessment of physical function (5) Levels of acute phase reactant (ESR or CRP) iv) OR achieved an equivalent therapeutic response as indicated by scoring using the DAS28, SDAI or CDAI indices. a) If yes, approved for 12 months for maintenance therapy. b) If no, denied.

Special Instructions Clinical Information: Dosing for RA • 500 mg if weight <60 kg (132 lbs) 750 mg if 60 to 100 kg (132 to 220 lbs) 1 g if >100 kg (> 220 lbs) Administered as a 30 minute IV infusion at 0, 2, and 4 weeks then every 4 weeks thereafter.

Pregnancy Category: C

Trial Data • Infections occurred in 54% of Orencia-treated pts and 48% of placebo-treated pts. • Serious infections occurred in 3% of Orencia-treated pts and 1.9% in placebo- treated pts. • Pts receiving concomitant Orencia and TNF antagonists experienced more infections (63%) and serious infections (4.4%) compared to pts treated with only TNF antagonists (43% and 0.8% respectively). Precautions • Before initiating Orencia therapy, pts should be screened for latent tuberculosis (TB) with a skin test. Patients testing positive during TB screening should treated prior to therapy with Orencia. • COPD pts treated with Orencia developed adverse events more frequently than those treated with placebo and thus should be monitored for worsening of respiratory status.

Storage

ODS Health Plan Customary Specialty MR Criteria Page 4 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

• Orencia must be refrigerated at 2°C to 8°C (36°F to 46°F) before use. Must be used within 24 hours of reconstitution. • Once diluted, may be stored at room temp or refrigerated before use.

Adverse Events Seen in Trials: • The most commonly reported adverse events (occurred in ≥ 10% of pts with Orencia compared to placebo) were headache, upper respiratory tract infection, nasopharyngitis and nausea.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 5 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Humira

Generic Name (Brand): Adalimumab (Humira)

GUIDELINES FOR USE INITIAL CRITERIA (NOTE: FOR RENEWAL CRITERIA SEE BELOW) 1. Does the patient have active rheumatoid arthritis, psoriatic arthritis or ankylosing spondylitis? If yes, continue to #2. If no, continue to #5. 2. Has this drug been prescribed by or is it currently being supervised by a rheumatologist or dermatologist? If yes, continue to #3. If no, do not approve. 3. Has the patient tried and failed, or experienced intolerable side effects to at least one of the following DMARDs: methotrexate, leflunomide, azathioprine, cyclosporine, hydroxychloroquine, minocycline, penicillamine, sulfasalazine gold sodium thiomalate, aurothioglucose or auranofin? If yes continue to #4. If no, do not approve and recommend use of a DMARD. 4. Is the patient taking Humira with Kineret OR Orencia? If yes, do not approve. If no, continue to #10. 5. Does the patient have a diagnosis of moderate to severe Crohn’s Disease? If yes, continue to #6. If no, do not approve. 6 Is therapy being initiated or recommended by a gastroenterologist? If yes, continue to #7 If no, do not approve. 7. Has the patient tried one or more conventional therapies for Crohn’s Disease such as: corticosteroids, azathioprine, mercaptopurine, methotrexate, or mesalamine? If yes, continue to #8. If no, do not approve. 8. Has the patient failed treatment with infliximab? If yes, continue to #9 If no, recommend infliximab

CONTINUED ON NEXT PAGE

ODS Health Plan Customary Specialty MR Criteria Page 6 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Humira (continued)

INITIAL CRITERIA (CONTINUED) NOTE: FOR RENEWAL CRITERIA SEE BELOW 9. Crohn’s Disease: Approve Crohn’s Disease Starter Package (contains 6 x 40mg syringes) x 1, then approve 1 kit (#2 syringes/vials) per month x 3 months. 10. Rheumatoid Arthritis, Ankylosing Spondylitis, Psoriatic Arthritis: Approve for one kit (#2 syringes/vials) per month x 3 months.

RENEWAL CRITERIA 1. Does the patient have active rheumatoid arthritis, psoriatic arthritis? If yes, continue to #3. If no, continue to #2. 2. Does the patient have ankylosing spondylitis? If yes, continue to #4. If no, continue to #10. 3. Has the patient experienced 20% or greater improvement in tender joint count and swollen joint count? If yes, continue to #5. If no, do not approve. 4. Has the patient experienced an improvement of at least 50% or 2 units (scale of 1-10) in the Bath ankylosing spondylitis disease activity Index (BASDAI)? If yes, continue to #7. If no, do not approve 5. Is the dose of Humira 40mg every other week? If yes, continue to #7. If no, continue to #6. 6. Has the patient tried and failed at least a 3-month trial of Humira 40mg every other week? If yes, continue to #8. If no, continue to #7. 7. Approve one kit (#2 syringes/vials) per month x 1 year. 8. Is the dose of Humira 40mg every week? If yes, continue to #9. If no, do not approve.

CONTINUED ON NEXT PAGE

ODS Health Plan Customary Specialty MR Criteria Page 7 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Humira (continued)

RENEWAL CRITERIA (CONTINUED) NOTE: FOR INITIAL CRITERIA SEE ABOVE 9. Approve two kits (#4 syringes/vials) per month x 1 year. 10. Does the patient have Crohn’s Disease? If yes, continue to #11. If no, do not approve. 11. Has the patient experienced a ≥ 70 point decrease in the Crohn’s Disease Activity Index (CDAI) score? If yes, continue to #12. If no, do not approve. 12. Approve one kit (#2 syringes/vials) per month x 1 year.

FDA APPROVED INDICATIONS 1. Reducing the signs and symptoms, inducing major clinical response, improving physical function, and helping to keep the joint damage from getting worse in adult patients with moderate to severe rheumatoid arthritis. 2. Reducing the signs and symptoms of active arthritis, improving physical function, and helping to keep the joint damage from getting worse in patients with psoriatic arthritis, used alone or with methotrexate or other DMARDs. Reducing signs and symptoms in patients with active ankylosing spondylitis. 3. Reducing the signs and symptoms and inducing and maintaining clinical remission in adults with moderately to severely active Crohn's disease who have had an inadequate response to conventional therapy. HUMIRA is also indicated for reducing the signs and symptoms and inducing clinical remission in these patients if they have also lost response to or are intolerant to infliximab, the only other approved biologic for treatment of Crohn's disease.

REFERENCES 1. Humira Product Information, Abbott Laboratories. February 2007. 2. Mease P, Gladman D, Ritchlin C, Ruderman E, Steinfeld S, Choy E, et al. Adalimumab for the treatment of patients with moderately to severely active psoriatic arthritis. Arthritis and Rheumatism 2005;52:3279-89. 3. Anti-Tumor Necrosis Factor Agents. MedImpact P&T monograph, May 2006.

Effective: 10/01/08

Created: 09/01/05 Updated: 07/24/06, 02/28/07 11/14/07 Reviewed: _____

ODS Health Plan Customary Specialty MR Criteria Page 8 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Hepsera

Generic Name (Brand): Adefovir (Hepsera)

INDICATIONS: HEPSERA is indicated for the treatment of chronic hepatitis B in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease/

This indication is based on histological, virological, biochemical, and serological responses in adults with HBeAg+ and HBeAg- chronic hepatitis B with compensated liver function, and in adults with clinical evidence of lamivudine-resistant hepatitis B virus with either compensated or decompensated liver function.

PRODUCT AVAILABILITY: • Adefovir (Hepsera®) 10mg tablets

GUIDELINES FOR USE: 1) Is the drug prescribed by a gastroenterologist, infectious disease specialist or physician specializing in the treatment of HBV? a) If yes, go to #2. b) If no, do not approve.

2) Is the patient ≥ 18years old? a) If yes, go to #3. b) If no, do not approve.

3) Is the patient pregnant or of childbearing age? a) If yes, please verify counseling of pregnancy risk has been given to the patient, go to #4. b) If no, go to #4.

4) Has Hepsera been prescribed for this patient before? a) If yes go to #20. b) If no, go to #5.

5) Has the patient tried and failed Epivir-HBV or have a contraindication to the use of Epivir- HBV? a) If yes, go to #6. b) If no, do not approve.

6) Documentation of serum HBV DNA. i) ______copies/mL ______Date ii) Go to #7.

7) Documentation of recent ALT level and documentation of liver biopsy if available. i) ______units/L ______Date ii) Go to #8.

8) Is the patient HIV postive? a) If yes, go to #9. b) If no or unknown, go to #10.

ODS Health Plan Customary Specialty MR Criteria Page 9 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

9) Will the patient be taking Hepsera with concomitant HAART? a) If yes, go to #10. b) If no, do not approve.

10) Is this patient a Hepatitis B carrier requesting antiviral prophylaxis while receiving immunosuppressive or cytotoxic therapy? a) If yes, go to #19. b) If no, go to #11.

11) Does the patient have decompensated cirrhosis? a) If yes, go to #19. b) If no, go to #12.

12) Is the patient HBeAg positive or negative and how long has the patient had persistence of HBeAg (i.e. > or < 6 months)? a) If positive and patient has HBeAg persistence for > 6 months, go to #13. b) If positive and patient hasn’t had HBeAg persistence for > 6 months, deny therapy and continue to monitor patient. c) If negative and patient has HBeAg persistence for > 6 months, go to #16. d) If negative and patient hasn’t had HBeAg persistence for > 6 months, deny therapy and continue to monitor patient.

13) Does the patient have a HBV DNA < 20,000 copies/mL? a) If yes, deny therapy. b) If no, go to #14.

14) Does the patient have persistently elevated ALT [> 30 IU/L (men) or >19 IU/L (women)] observed for 3 to 6 months? a) If yes and prescribing go to #19. b) If no, go to #15.

15) Does the patient have moderate-severe hepatitis evidenced by recent biopsy (i.e. Ishak necroinflammatory score > 4)? a) If yes, go to #19. b) If no, deny therapy.

16) Does the patient have a HBV DNA < 2000 copies/ml? a) If yes, deny therapy. b) If no, go to #17.

17) Does the patient have persistently elevated ALT [> 30 IU/L (men) or >19 IU/L (women)] observed for 3 to 6 months? a) If yes, go to #19. b) If no, go to #18.

18) Does the patient have moderate-severe hepatitis evidenced by recent biopsy (i.e. Ishak necroinflammatory score > 4)? a) If yes, go to #19. b) If no, deny therapy

19) Approve for 12 months.

RENEWAL AFTER INITIAL THERAPY: 20) Is the patient HBeAg positive? a) If yes, go to #21. b) If not go to #22.

ODS Health Plan Customary Specialty MR Criteria Page 10 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

21) Has the patient been treated with Hepsera for 12 months beyond seroconversion? a) If yes, Do Not approve b) If No, the end point of treatment is seroconversion from HBeAg to anti HBe or undetectable HBV DNA levels and recommended duration is as follows – Approve for 12 months as typically therapy should continue for 6-12 months after HBeAg seroconversion. 22) If HBeAG negative, end point of treatment is achievement of sustained normalization of ALT and undetectable HBV DNA and recommended duration is as followed: Approve for 1 year. (Long- term treatment usually required unless HBsAg seroconversion).

Special Instructions: Pregnancy Risk Factor: C

Clinical Information: Severe acute exacerbations of hepatitis have been seen in patients who have discontinued anti-hepatitis B therapy, including Epivir HBV, Hepsera, Tyzeka, and Baraclude. Hepatic function should be monitored closely for at least several months in patients who discontinue therapy.

DOSING: Hepsera -10 mg PO once daily

References: 1. Lok A, McMahon B. AASLD Practice Guideline, Chronic Hepatitis B: Update of Recommendations. Hepatology, 2004; 39:1-5. 2. Lok A, McMahon B. AASLD Practice Guidelines, Chronic Hepatitis B, Revised on December 9, 2003. available at: https://www.aasld.org/eweb/DynamicPage.aspx?Site=AASLD3&webcode=ViralHepatitis. 3. Keeffe E et al. A Treatment Algorithm for the Management of Chronic Hepatitis B Virus Infection in the United States. Clinical Gastroenterology and Hepatology 2004;2:87-106. 4. Marcellin P et al. Peginterferon Alfa-2a Alone, Lamivudine Alone and the Two in Combinations in Patients with HBeAg-Negative Chronic Hepatitis B. NEJM 2004;351:12:1206-17. 5. Hui A et al. Systematic Review: Treatment of Chronic Hepatitis B Virus Infection by Pegylated Interferon. Aliment Pharmacol Ther. 2005;22(6):519-28. 6. Tung B, Kowdley K. Hepatitis B and Liver Transplantation. Clinical Infectious Diseases. 2005;41:1461-6. 7. Kanwal F et al. Treatment Alternatives for Chronic Hepatitis B Virus Infection: A Cost-Effectiveness Analysis. Annals of Internal Medicine. 2005;142:821-31. 8. Chang T et al. A comparison of entecavir and lamivudine for HBeAg-Positive chronic hepatitis B. NEJM 2006;354:1001-10. 9. Lai C et al. Entecavir versus lamivudine for patients with HBeAg-Negative chronic hepatitis B. NEJM 2006;354:1011-20. 10. Pallier C. Dynamics of Hepatitis B resistance to lamivudine. J Virol 2006; 80: 643-53. 11. Keeffe E et al. A Treatment Algorithm for the Management of Chronic Hepatitis B Virus Infection in the United States: an Update. Clinical Gastroenterology and Hepatology 2006;4(8): published online July 16, 2006 at http://www.natap.org/. 12. Hepsera. Product Information. Gilead Sciences, Inc. Revised on April 2006, available at http://www.hepsera.com/. 13. Supplement to the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and 14. Adolescents - October 10, 2006. Issued April 30, 2007.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 11 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Endocrine and Metabolic Agents

Generic Name (Brand): Agalsidase Beta (Fabrazyme)

FDA APPROVED INDICATIONS For use in patients with Fabry disease. Agalsidase beta reduces globotriasylceramide (GL-3) deposition in capillary endothelium of the kidney and certain other cell types.

TREATMENT DOSE / DURATION / REGIMEN 1 mg/kg body weight infused every 2 weeks as an IV infusion.

EFFECTIVENESS MONITORING PARAMETERS Reduction of GL-3 inclusions to normal or near normal levels (0 score) in the capillary endothelium of the kidney, heart, and skin.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08.

Effective: 10/01/08

Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 12 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Aldesleukin (Proleukin)

GUIDELINES FOR USE 1. What is the patient’s diagnosis? If the diagnosis is an FDA approved indication, continue to #2. If not, do not approve. 2. What is the treatment dose? If treatment dose is within the approved dosing range, continue to #3. If not, do not approve. 3. What is the expected treatment duration? If submitted duration is an approved treatment duration, continue to #4. If not, do not approve. 4. What other antineoplastic agents will be included in the treatment regimen? If an approved treatment regimen, continue to #5. If not, do not approve. 5. What clinical parameters will be monitored to establish treatment effectiveness? If submitted monitoring plan is consistent with effectiveness monitoring, continue to #6. If not, do not approve. 6. Will the medication be administered by a trained healthcare professional? If submitted administration plan for injectable agent is consistent with recommended administration, continue to #7. If not, do not approve. 7. Approve for 6 months.

FDA APPROVED INDICATIONS 1. Metastatic renal cell carcinoma: For the treatment of adults with metastatic renal cell carcinoma (metastatic RCC). 2. Metastatic melanoma: For the treatment of adults with metastatic melanoma.

TREATMENT DOSE / DURATION / REGIMEN The recommended aldesleukin for injection treatment regimen is administered by a 15-minute IV infusion every 8 hours. Before initiating treatment, carefully review the entire monograph, particularly regarding patient selection, possible serious adverse events, patient monitoring, and withholding dosage. The following schedule has been used to treat adult patients with metastatic renal cell carcinoma (metastatic RCC) or metastatic melanoma. Each course of treatment consists of two 5-day treatment cycles separated by a rest period. Dosage is 600,000 units/kg (0.037 mg/kg) dose administered every 8 hours by a 15-minute IV infusion for a maximum of 14 doses. Following 9 days of rest, the schedule is repeated for another 14 doses, for a maximum of 28 doses per course, as tolerated. During clinical trials, doses were frequently withheld for toxicity. Metastatic RCC patients treated with this schedule received a median of 20 of the 28 doses during the first course of therapy. Metastatic melanoma patients received a median of 18 doses during the first course of therapy.

ODS Health Plan Customary Specialty MR Criteria Page 13 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

EFFECTIVENESS MONITORING PARAMETERS Clinical and pathologic response.

INJECTABLE ADMINISTRATION REQUIREMENTS Administer aldesleukin in a hospital setting under the supervision of a qualified physician experienced in the use of anticancer agents. An intensive care facility and specialists skilled in cardiopulmonary or intensive care medicine must be available.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 14 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Endocrine and Metabolic Agents

Generic Name (Brand): Alglucerase (Ceredase)

FDA APPROVED INDICATIONS Type 1 Gaucher disease: For use as long-term enzyme replacement therapy for children, adolescents, and adults with a confirmed diagnosis of type 1 Gaucher disease who exhibit signs and symptoms that are severe enough to result in 1 or more of the following conditions: moderate to severe anemia, thrombocytopenia with bleeding tendency, bone disease, significant hepatomegaly, or splenomegaly. TREATMENT DOSE / DURATION / REGIMEN Alglucerase is administered by intravenous (IV) infusion over 1 to 2 hours. Dosage should be individualized for each patient. Initial dosage may be as little as 2.5 units/kg of body weight 3 times a week and as much as 60 units/kg administered as frequently as once a week or as infrequently as every 4 weeks. Most data are available for the dosage of 60 units/kg every 2 weeks. Disease severity may dictate that the drug be initiated with relatively high doses or relatively frequent administration. After patient response is well-established, a reduction in dosage may be attempted for maintenance therapy. Progressive reductions can be made at intervals of 3 to 6 months while carefully monitoring response parameters. Relatively low toxicity, combined with the extended time course of response, allows small dosage adjustments to be made occasionally to avoid discarding partially used bottles. Thus, the dosage administered in individual infusions may be slightly increased or decreased to fully utilize each bottle, as long as the monthly administered dosage remains substantially unaltered. EFFECTIVENESS MONITORING PARAMETERS Hematologic improvements, reduced cachexia and wasting, improved mineralization of bone. REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08. Effective: 10/01/08

Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 15 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Respiratory Agents

Generic Name (Brand): Alpha 1-protease inhibitor (Aralast, Prolastin, Zemaira)

FDA APPROVED INDICATIONS Congenital alpha1-proteinase inhibitor (alpha1-PI; alpha1-antitrypsin) deficiency: For chronic augmentation therapy in patients having congenital deficiency of alpha1-PI with clinically evident emphysema. Clinical data demonstrating the long-term effects of chronic augmentation or replacement therapy of individuals with alpha1-PI are not available. Aralast and Zemaira are not indicated as therapy for lung disease patients in whom congenital alpha1-PI deficiency has not been established. Prolastin is not indicated for use in patients other than those with PiZZ, PiZ(null), or Pi(null)(null) phenotypes

TREATMENT DOSE / DURATION / REGIMEN DOSAGE: The recommended dosage is 60 mg/kg/body weight administered once weekly by IV infusion.

EFFECTIVENESS MONITORING PARAMETERS Trough serum alpha1-PI levels.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08.

Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 16 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Amevive

Generic Name (Brand): Alefacept (Amevive)

GUIDELINES FOR USE 1. Is the prescription written by a dermatologist with experience using Amevive? If yes, continue to #2. If no, do not approve. 2. Is this the initial request for treatment with alefacept? If yes, continue to #5. If no, continue to #3. 3. Has the patient already received two 3-month courses of alefacept treatment? If yes, do not approve. If no, continue to #4. 4. Has there been a 3-month interval since the end of the patient’s previous 3-month course of treatment with alefacept AND did the patient receive clinical benefit on the therapy as measured by Psoriasis Area and Severity Index (PASI 50:≥ 50% improvement in PASI score) or a significant improvement in Quality of Life observed by the physician and patient (i.e., Dermatology Life Quality Index)? If yes, continue to #7. If no, do not approve. 5. Does the patient have generalized severe plaque psoriasis (psoriasis involving ≥ 10% of body surface area? If yes, continue to #6. If no, do not approve. 6. Has the patient failed or does the patient have a contraindication to 2 or more forms of preferred therapy (PUVA, UVB, acitretin, methotrexate or cyclosporine)? If yes, continue to #7. If no, do not approve. 7. Does the patient have an active infection (including, but not limited to histoplasmosis, cytomegalovirus, tuberculosis and human immunodeficiency virus infection), a history of recurring infections or a history of systemic malignancy? If yes, do not approve. If no, continue to #8. 8. Are the patient’s liver function tests (LFTs) within normal limits? If yes, continue to #9. If no, do not approve.

CONTINUED ON NEXT PAGE

ODS Health Plan Customary Specialty MR Criteria Page 17 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Amevive (continued)

Generic Name (Brand): Alefacept (Amevive)

GUIDELINES FOR USE (CONTINUED) 9. Has the physician submitted documentation indicating that the current CD4+ T-lymphocyte count is above 250 cells/uL If yes, continue to #10. If no, do not approve. 10. Approve for 3 months.

Quantity limit: 4 vials per 30 days.

FDA APPROVED INDICATIONS Amevive is indicated for the treatment of adult patients with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy.

REFERENCES 1. Amevive product information, Biogen, Inc. Oct 2006. 2. Amevive. MedImpact P&T monograph, May 2003.

Effective: 10/01/08 Created: 01/01/06 Updated: 11/14/07 Reviewed: 01/05/07

ODS Health Plan Customary Specialty MR Criteria Page 18 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Alemtuzumab (Campath)

FDA APPROVED INDICATIONS B-cell chronic lymphocytic leukemia (B-CLL): As a single agent for the treatment of B-CLL.

TREATMENT DOSE / DURATION / REGIMEN Administration: Adminiter as an intravenous (IV) infusion over 2 hours. Do not administer as an IV push or bolus. Gradually escalate to the maximum recommended single dose of 30 mg. Escalation is required at initiation of dosing or if dosing is withheld for at least 7 days during treatment. Escalation to 30 mg ordinarily can be accomplished in 3 to 7 days. Dose modifications may be required Escalation strategy: • Administer 3 mg daily until infusion reactions are grade 2 or less. • Then administer 10 mg daily until infusion reactions are grade 2 or less. • Then administer 30 mg/day 3 times per week on alternate days (eg, Monday, Wednesday, Friday). The total duration of therapy, including dose escalation, is 12 weeks.

ODS Health Plan Customary Specialty MR Criteria Page 19 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

• Single doses of more than 30 mg or cumulative doses of more than 90 mg per week increase the incidence of pancytopenia. EFFECTIVENESS MONITORING PARAMETERS Progression-free survival.

INJECTABLE ADMINISTRATION REQUIREMENTS Administration should be supervised by medical professional experienced in the use of anticancer agents and the treatment of infusion reactions.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 20 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Altretamine (Hexalen)

FDA APPROVED INDICATIONS Ovarian cancer: For use as a single agent in the palliative treatment of patients with persistent or recurrent ovarian cancer following first-line therapy with a cisplatin- or alkylating agent-based combination.

TREATMENT DOSE / DURATION / REGIMEN Altretamine is administered orally. Calculate doses on the basis of body surface area. Altretamine may be administered either for 14 or 21 consecutive days in a 28 day cycle at a dose of 260 mg/m2/day. Give the total daily dose as 4 divided oral doses after meals and at bedtime.

EFFECTIVENESS MONITORING PARAMETERS Clinical or pathologic response including tumor regression. INJECTABLE ADMINISTRATION REQUIREMENTS None. REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 21 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Treatment of Pulmonary Arterial Hypertension

Generic Name (Brand): Ambrisentan (Letairis), Bosentan (Tracleer)

PURPOSE: To ensure the safe and effective use of endothelin receptor antagonists to treat pulmonary arterial hypertension.

Indication: TRACLEER and LETAIRIS are indicated for the treatment of pulmonary arterial hypertension (WHO Group I) in patients with WHO functional class III or IV symptoms, to improve exercise ability and decrease the rate of clinical worsening.

Product Availability: Tracleer 62.5 mg and 125 mg tablets Letairis 5 mg and 10 mg tablets.

Quantity Limitations: Tracleer is limited to 2 tablets per day. Letairis is limited to 1 tablet per day.

GUIDELINES FOR USE INITIAL CRITERIA (FOR RENEWAL CRITERIA SEE BELOW)

1. Is requested drug being prescribed by a cardiologist or pulmonologist specializing in the treatment of Pulmonary Arterial Hypertension (PAH)? a. If yes, go to #2. b. If no, Do not approve.

2. Does the patient have a diagnosis for severe pulmonary arterial hypertension (WHO functional status Class III-IV)? a. If yes, go to #3. b. If no, do not approve.

3. What is patients 6-minute walk distance?______a. Go to #4.

4. What is patient’s “Borg” dyspnea score?______a. Go to #5.

5. What is the patient’s Hemoglobin and hematocrit?______a. Go to #6.

6. Has requested drug been prescribed for this patient before?

a. If yes, go to #12. b. If no, go to #7.

ODS Health Plan Customary Specialty MR Criteria Page 22 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

7. Has the patient tried and failed an adequate course (four weeks) of sildenafil (Revatio) 20mg t.i.d.? a. If yes, go to #8. b. If no, do not approve.

8. Will Tracleer be prescribed in combination with Cyclosporine or glyburide?

a. If yes, Do not Approve. b. If no, go to #9

9. Is the prescription for a female patient of child bearing potential, that has had a negative pregnancy test within last 15 days, been counseled on the teratogenic effects of the therapy, and is willing to practice contraception methods in addition to hormonal contraception during and for 6 months after completion of therapy?

a. If Yes or NA, go to #11. b. If Male, go to #10.

10. Is the prescription for a male patient of child bearing potential, that has been counseled on the teratogenic effects of the therapy and is willing to practice contraception methods in addition to hormonal contraception during and for 6 months after completion of therapy?

a. If Yes or NA, go to #11. b. If No, deny therapy.

11. Does the patient have moderate to sever liver impairment or ALT/AST ≥ 3 x ULN?

a. If yes, do not approve. b. If no, Approve c. Tracleer 62.5 mg b.i.d. for 5 weeks d. Letairis 5mg q.d. for 5 weeks.

RENEWAL CRITERIA

12. Is female of child bearing age that has had a negative pregnancy test within last 15 days? a. If yes or NA, go to #13. b. If no, do not approve (negative urine/serum pregnancy required monthly prior to treatment approval).

13. Has patient demonstrated improvement over baseline 6 minute walk distance or improvement in the Borg dyspnea score? a. If yes, go to #14. b. If no and patient taking Tracleer for less than 8 weeks, go to #14. c. If no and patient taking Tracleer for > 8 weeks, do not approve. d. If no and patient taking Letairis less than 12 weeks go to #14. e. If no and patient taking Letairis > 12 weeks, do not approve.

14. What is the patients ALT/AST level measured within previous 2 weeks? a. < 3 times ULN, go to #17. b. ≥ 3 and ≤8 times ULN go to #15. c. 8 times ULN, Do Not Approve. ODS Health Plan Customary Specialty MR Criteria Page 23 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

15. Has the patient’s bilirubin increased ≥2 x ULN? a. If yes, do not approve. b. If no, go to #16.

16. Is the patient Hbg <12 if a female or < 14 if a male? a. If yes, do not approve. b. If no, go to #18.

17. Approve a. Tracleer 125mg b.i.d. for 5 weeks. b. Approve Letairis 5mg or 10mg q.d. for 5 weeks.

18. Has the patient ceased therapy or reduced his or her dose for at least 2 weeks? a. If yes, do not approve. ALT/AST should be reevaluated in 2 weeks. b. If no and patient currently taking Tracleer 62.5 mg b.i.d, or Letairis 5mg q.d., do not approve. ALT/AST should be reevaluated in 2 weeks. c. If no and patient taking Tracleer 125 mg b.i.d., approve Tracleer 62.5 mg b.i.d. for 3 weeks. ALT/AST should be reevaluated in 2 weeks. d. If no and patient taking Letairis 10mg q.d., approve Letairis 5mg q.d. for 3 weeks. ALT/ASST should be reevaluated in 2 weeks.

Special Instructions: Clinical Information: • Dosing ◊ Tracleer: 62.5 mg b.i.d. for 4 weeks then increase to 125 mg b.i.d. Increasing the dose above 125 mg b.i.d. does not improve efficacy sufficient to offset the increased risk of hepatic injury. ◊ Letairis: 5 mg q.d. for 4 weeks then increase to 10 mg q.d. if patient can tolerate dose. Doses above 10 mg q.d. does not improve efficacy sufficient to offset the increased risk of hepatic injury.

Pregnancy Category: X • Tracleer and Letairis will cause significant birth defects. Pregnancy must be excluded prior to initiation of therapy with monthly serum or urine follow-up tests. Men and women need to use 2 methods of contraception one including primary methods.

• Laboratory Values

ALT: Optimal Adult Reading 24 U/L (Range 0 - 48 U/L) AST: Optimal Adult Reading 21 U/L (Range 0 - 42 U/L) Bilirubin: Optimal Adult Reading 0.65 mg/dl; (Range 0-1.3 mg/dl) Hematocrit (HCT): Optimal Female Reading 42% (Range 37%-47%); Optimal Male Reading 47% (Range 40%-54%) Hemoglobin (HGB): Optimal Female Reading 14 g/dl (Range 12 – 16 g/dl); Optimal Male Reading 16 g/dl (Range 14-16 g/dl

ODS Health Plan Customary Specialty MR Criteria Page 24 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Amifostine (Ethyol)

FDA APPROVED INDICATIONS Renal toxicity: Reduction of cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced ovarian cancer or non-small cell lung cancer.

Xerostomia: Reduction of the incidence of moderate-to-severe xerostomia in patients undergoing postoperative radiation treatment for head and neck cancer, where the radiation port includes a substantial portion of the parotid glands.

TREATMENT DOSE / DURATION / REGIMEN Reduction of cumulative renal toxicity with chemotherapy: Recommended starting dose is 910 mg/m2 administered once daily as a 15-minute IV infusion, starting 30 minutes prior to chemotherapy. The 15-minute infusion is better tolerated than more extended infusions. Reduction of moderate-to-severe xerostomia from radiation of the head and neck: 200 mg/m2 administered once daily as a 3-minute IV infusion 15 to 30 minutes prior to standard fraction radiation therapy (1.8 to 2 Gy).

EFFECTIVENESS MONITORING PARAMETERS Clinical resonse.

ODS Health Plan Customary Specialty MR Criteria Page 25 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

INJECTABLE ADMINISTRATION REQUIREMENTS Administration should be supervised by medical professional experienced in the use of anticancer agents.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 26 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Hematological Agents

Generic Name (Brand): Aminocaproic Acid (Amicar)

FDA APPROVED INDICATIONS Excessive bleeding: Aminocaproic acid is useful in enhancing hemostasis when fibrinolysis contributes to bleeding. In life-threatening situations, fresh whole blood transfusions, fibrinogen infusions, and other emergency measures may be required.

TREATMENT DOSE / DURATION / REGIMEN Plasma levels: An initial dose of 5 g, followed by 1 to 1.25 g hourly, should achieve and sustain drug plasma levels at 0.13 mg/mL. This is the concentration apparently necessary for inhibition of fibrinolysis. Administration of more than 30 g/24 hours is not recommended. Tablets and Syrup: If the patient is able to take medication by mouth, an identical dosage regimen may be followed by administering aminocaproic acid tablets or aminocaproic acid syrup, 25% as follows: For the treatment of acute bleeding syndromes due to elevated fibrinolytic activity, it is suggested that 10 tablets (5 g) or 4 teaspoonfuls of syrup (5 g) of aminocaproic acid be administered during the first hour of treatment, followed by a continuing rate of 2 tablets (1 g) or 1 teaspoonful of syrup (1.25 g) per hour. This method of treatment would ordinarily be continued for about 8 hours or until the bleeding situation has been controlled.

EFFECTIVENESS MONITORING PARAMETERS Clinical and laboratory response.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08.

Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 27 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Kineret

Generic Name (Brand): Anakinra (Kineret)

GUIDELINES FOR USE INITIAL CRITERIA (NOTE: FOR RENEWAL CRITERIA SEE BELOW) 1. Has the treatment been prescribed or is it currently being supervised by a Rheumatologist? If yes, continue to #5. If no, continue to #2. 2. Does the patient have diagnosis of moderate to severe rheumatoid arthritis? If yes, continue to #3. If no, do not approve. 3. Is the patient 18 years of age or older? If yes, continue to #4. If no, do not approve. 4. Has the patient tried and failed or experienced intolerable side effects to at least one of the following DMARD agents: methotrexate, leflunomide, azathioprine, cyclosporine, hydroxychloroquine, minocycline, penicillamine, sulfasalazine gold sodium thiomalate, aurothioglucose or auranofin? If yes, continue to #5. If no, do not approve. 5. Is the current absolute neutrophil count (ANC) in the range of 2,500 to 10,000? If yes, continue to #6. If no, do not approve. 6. Is patient using Kineret with Enbrel, Remicade or Humira? If yes, do not approve. If no, continue to #7. 7. Approve for 3 months with a quantity limit of 28 syringes per 28 days.

RENEWAL CRITERIA 1. Has the patient experienced 20% or greater improvement in tender joint count or swollen joint count? If yes, continue to #2. If no, do not approve. 2. Approve for 1 year with a quantity limit of 28 syringes per 30 days.

ODS Health Plan Customary Specialty MR Criteria Page 28 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Kineret (continued)

Generic Name (Brand): Anakinra (Kineret)

FDA APPROVED INDICATION Moderate to severe rheumatoid arthritis in patients 18 years or older who have failed 1 or more DMARDs. Kineret can be used alone or in combination with DMARDs other than Tumor Necrosis Factor (TNF) blocking agents.

REFERENCES Kineret Product Information, Amgen. 12/15/2006.

Effective: 10/01/08 Created: 01/01/06 Updated: 11/14/07 Reviewed: 01/05/07

ODS Health Plan Customary Specialty MR Criteria Page 29 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Anastrozole (Arimidex)

FDA APPROVED INDICATIONS 1. For adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer. 2. The effectiveness of anastrozole in early breast cancer is based on an analysis of recurrence-free survival in patients treated for a median of 31 months. Further follow-up of study patients will be required to determine long-term outcomes. 3. For the first-line treatment of postmenopausal women with hormone receptor positive or hormone receptor unknown locally advanced or metastatic breast cancer. 4. For the treatment of advanced breast cancer in postmenopausal women with disease progression following tamoxifen therapy. 5. Patients with estrogen receptor-negative disease and patients who did not respond to previous tamoxifen therapy rarely responded to anastrozole.

TREATMENT DOSE / DURATION / REGIMEN Recommended dosage: 1 mg orally once a day. For patients with advanced breast cancer, anastrozole should be continued until tumor progression. Duration of therapy: For adjuvant treatment of early breast cancer in postmenopausal women, the optimal duration of therapy is unknown. The median duration of therapy at the time of data analysis was 31 months; the ongoing ATAC trial is planned for 5 years of treatment.

ODS Health Plan Customary Specialty MR Criteria Page 30 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

EFFECTIVENESS MONITORING PARAMETERS Tumor progression.

INJECTABLE ADMINISTRATION REQUIREMENTS None.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 31 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Asparaginase (Elspar)

FDA APPROVED INDICATIONS Acute lymphocytic leukemia: Therapy of patients with acute lymphocytic leukemia. This agent is useful primarily in combination with other chemotherapeutic agents in the induction of remissions of the disease in pediatric patients. Asparaginase should not be used as the sole induction agent unless combination therapy is deemed inappropriate. Asparaginase is not recommended for maintenance therapy.

TREATMENT DOSE / DURATION / REGIMEN As a component of selected multiple agent induction regimens, asparaginase may be administered by either the intravenous or the intramuscular route. When administered intravenously, this enzyme should be given over a period of not less than thirty minutes through the side arm of an already running infusion of Sodium Chloride Injection or Dextrose Injection 5% (D5W). When administering asparaginase intramuscularly, the volume at a single injection site should be limited to 2 ml.

INJECTABLE ADMINISTRATION REQUIREMENTS It is recommended that asparaginase be administered to patients only in a hospital setting under the supervision of a physician who is qualified by training and experience to administer cancer

ODS Health Plan Customary Specialty MR Criteria Page 32 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

chemotherapeutic agents, because of the possibility of severe reactions, including anaphylaxis and sudden death. The physician must be prepared to treat anaphylaxis at each administration of the drug.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 33 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Hematological Agents

Generic Name (Brand): Anti-inhibitor coagulant complex (Feiba VH)

FDA APPROVED INDICATIONS Hemorrhage: For the control of spontaneous bleeding episodes or to cover surgical interventions in hemophilia A and B patients with inhibitors. In addition, the use of anti-inhibitor coagulant complex (AICC) has been described in a few nonhemophiliacs with acquired inhibitors to factors VIII, XI, and XII. One case has been reported in which AICC was effective in a patient with von Willebrand disease with an inhibitor. Clinical experience suggests that patients with a factor VIII inhibitor titer of less than 5 Bethesda units (BU) may be successfully treated with antihemophilic factor. Patients with titers ranging between 5 and 10 BU may either be treated with antihemophilic factor or AICC, vapor-heated. Cases with factor VIII inhibitor titers more than 10 BU have generally been refractory to treatment with antihemophilic factor

TREATMENT DOSE / DURATION / REGIMEN Recommended dose: As a general guideline, a dosage range of 50 to 100 units of AICC per kg of body weight is recommended. However, care should be taken to distinguish between the following 4 indications, all of which have undergone careful clinical evaluation

EFFECTIVENESS MONITORING PARAMETERS Bleeding episodes and complications.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08. Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 34 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Anticoagulants

Generic Name (Brand): Antithrombin III (Atryn)

FDA APPROVED INDICATIONS Antithrombin III deficiency: Antithrombin III (human) is indicated for the treatment of patients with hereditary antithrombin III (AT-III) deficiency in connection with surgical or obstetrical procedures or when they suffer from thromboembolism.

TREATMENT DOSE / DURATION / REGIMEN Determine dosage on an individual basis based on the pretherapy plasma AT-III level, in order to increase plasma AT-III levels to the level found in normal human plasma (100%). Dosage of antithrombin III (human) can be calculated from the following formula: The international units required equals the difference between the desired and baseline AT-III level (expressed as % normal level based on functional AT-III assay) times the patient's weight in kg divided by 1.4.

The formula is based on an expected incremental in vivo recovery above baseline levels for antithrombin III (human), of 1.4% per Unit per kg administered. Thus, if a 70 kg individual has a baseline AT-III level of 57%, in order to increase plasma AT-III to 120%, the initial antithrombin III (human) dose would be [(120−57) × 70]/1.4 = 3,150 Units total.

EFFECTIVENESS MONITORING PARAMETERS AT-III assays.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08. Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 35 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Central Nervous System Agents

Generic Name (Brand): Apomorphine (Apokyn)

DISTRIBUTION Limited distribution

FDA APPROVED INDICATIONS Parkinson disease: Apomorphine injection is indicated for the acute, intermittent treatment of hypomobility, “off” episodes (“end-of-dose wearing off” and unpredictable “on/off” episodes) associated with advanced Parkinson’s disease. Apomorphine injection has been studied as an adjunct to other medications.

TREATMENT DOSE / DURATION / REGIMEN The prescribed dose of apomorphine injection should always be expressed in mL to avoid confusion and doses greater than 0.6 mL (6 mg) are not recommended. Patients and caregivers must receive detailed instructions in the preparation and injection of doses, with particular attention paid to the correct use of the dosing pen. Apomorphine injection is indicated for subcutaneous administration only. Apomorphine injection should not be initiated without use of a concomitant antiemetic. At the recommended doses of apomorphine, severe nausea and vomiting can be expected. Most antiemetic experience is with trimethobenzamide and this should generally be used. Trimethobenzamide (300 mg 3 times daily orally) should be started 3 days prior to the initial dose of apomorphine and continued at least during the first 2 months of therapy. Based on reports of profound hypotension and loss of consciousness when apomorphine was administered with ondansetron, the concomitant use of apomorphine with drugs of the 5HT3 antagonist class (including, for example, ondansetron, granisetron, dolasetron, palonosetron, and alosetron) is contraindicated. The dose of apomorphine injection must be titrated on the basis of effectiveness and tolerance, starting at 0.2 mL (2 mg) and up to a maximum recommended dose of 0.6 mL (6 mg) as follows: Patients in an “off” state should be given a 0.2 mL (2 mg) test dose in a setting where blood pressure can be closely monitored by medical personnel. Both supine and standing blood pressure should be checked predose and at 20, 40, and 60 minutes post dose. Patients who develop clinically significant orthostatic hypotension in response to this test dose of

ODS Health Plan Customary Specialty MR Criteria Page 36 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

apomorphine should not be considered candidates for treatment with apomorphine injection. If the patient tolerates the 0.2 mL (2 mg) dose, and responds, the starting dose should be 0.2 mL (2 mg) used on an as needed basis to treat existing “off” episodes. If needed, the dose can be increased in 0.1 mL (1 mg) increments every few days on an outpatient basis.

EFFECTIVENESS MONITORING PARAMETERS Clinical response.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08. Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 37 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Azacitidine (Vidaza)

FDA APPROVED INDICATIONS Myelodysplastic syndrome (MDS) subtypes: For the treatment of patients with the following MDS subtypes: refractory anemia (RA) or refractory anemia with ringed sideroblasts (RARS) (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMMoL).1

TREATMENT DOSE / DURATION / REGIMEN First treatment cycle: The recommended starting dose for the first treatment cycle, for all patients regardless of baseline hematology laboratory values, is 75 mg/m2 subcutaneously or intravenously (IV), daily for 7 days. Patients should be premedicated for nausea and vomiting.1

Subsequent treatment cycles: Cycles should be repeated every 4 weeks. The dose may be increased to 100 mg/m2 if no beneficial effect is seen after 2 treatment cycles and if no toxicity other than nausea and vomiting has occurred. It is recommended that patients be treated for a minimum of 4 cycles. However, complete or partial response may require more than 4 treatment cycles. Treatment may be continued as long as the patient continues to benefit.

EFFECTIVENESS MONITORING PARAMETERS

ODS Health Plan Customary Specialty MR Criteria Page 38 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

INJECTABLE ADMINISTRATION REQUIREMENTS Administration should be supervised by medical professional experienced in the use of anticancer agents.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 39 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Immunologic Agents

Generic Name (Brand): Basiliximab (Simulect)

FDA APPROVED INDICATIONS Organ rejection: For the prophylaxis of acute organ rejection in patients receiving renal transplantation when used as part of an immunosuppressive regimen that includes cyclosporine and corticosteroids. The efficacy of basiliximab for the prophylaxis of acute rejection in recipients of other solid organ allografts has not been demonstrated.

TREATMENT DOSE / DURATION / REGIMEN Administration: Basiliximab is used as part of an immunosuppressive regimen that includes cyclosporine (modified) and corticosteroids. Basiliximab is for central or peripheral intravenous administration only.

EFFECTIVENESS MONITORING PARAMETERS Prevent acute rejection episode.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08. Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 40 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Bendamustine (Treanda)

FDA APPROVED INDICATIONS For the treatment of patients with Chronic lymphocytic leukemia (CLL).

TREATMENT DOSE / DURATION / REGIMEN Recommended dosage: 100 mg/m2 administered intravenously (IV) on days 1 and 2 of a 28-day cycle, up to 6 cycles. Bendamustine is intended for administration as an IV infusion over 30 minutes. EFFECTIVENESS MONITORING PARAMETERS Efficacy end points of objective response rate and progression-free survival were calculated using a prespecified algorithm based on National Cancer Institute (NCI) working group criteria for CLL. INJECTABLE ADMINISTRATION REQUIREMENTS Administration should be supervised by medical professional experienced in the use of anticancer agents. REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 41 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Avastin

Generic Name (Brand): Bevacizumab (Avastin)

DESCRIPTION: Avastin is a full-length recombinant humanized monoclonal antibody directed against vascular endothelial growth factor (VEGF).

PRODUCT AVAILABILITY: • Avastin (Bevacizumab) – 25 mg/mL in a 4 mL vial (100 mg) o 25 mg/mL in a 16 mL vial (400 mg)

INDICATIONS:: Approved in combination with IV 5-fluoroacil-based chemotherapy as first- or second-line treatment of metastatic carcinoma of the colon or rectum

GUIDELINES FOR USE: 1) Is the drug prescribed for an oncologic diagnosis? a) If yes, approved for 12 months. b) If no, denied. If prescribed for other diagnosis, collect information and forward to plan for review. (NOTE: If prescribed for macular degeneration, please note that Lucentis® (ranibizumab), a humanized anti-VEGF antibody fragment derived from bevacizumab, is available.)

Special Instructions Off-Label Uses for Oncology • Breast cancer, malignant mesothelioma, prostate cancer, lung cancer (non-small cell), renal cell cancer Other Off-Label Uses • Macular degeneration Clinical Information • Administered IV • Avastin must be refrigerated and protected from light. • Store in original carton until time of use. Do not freeze or shake. • Avastin’s use outside of a clinical trial was not recommended by investigators for treatment of AMD due to the potential of fatal thromboembolic events and small number of patients treated with only limited follow-up Pregnancy Category: C Boxed Warnings: Gastrointestinal Perforations/Wound Healing Complications – Gastrointestinal perforation and wound dehiscence which have resulted in fatality occurred with Avastin administration. Hemorrhage – Serious and some fatal cases of hemoptysis have occurred in patients with non-small cell lung cancer treated with chemotherapy and Avastin.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 42 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Bexarotene (Targretin)

FDA APPROVED INDICATIONS Cutaneous T-cell lymphoma (CTCL): Bexarotene capsules are indicated for the treatment of cutaneous manifestations of CTCL in patients who are refractory to at least 1 prior systemic therapy.

TREATMENT DOSE / DURATION / REGIMEN Initial dose: The recommended initial dose of bexarotene capsules is 300 mg/m2/day (see table below). Bexarotene capsules should be taken as a single oral daily dose with a meal.

Bexarotene Capsule Initial Dose Calculation According to Body Surface Area Initial dose level (300 mg/m2/day) Number of 75 mg Body surface Total daily dose bexarotene capsules area (m2) (mg/day) 0.88 to 1.12 300 4 1.13 to 1.37 375 5 1.38 to 1.62 450 6 1.63 to 1.87 525 7 1.88 to 2.12 600 8 2.13 to 2.37 675 9 2.38 to 2.62 750 10

ODS Health Plan Customary Specialty MR Criteria Page 43 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

Dose modification guidelines: The 300 mg/m2/day dose level of bexarotene capsules may be adjusted to 200 mg/m2/day then to 100 mg/m2/day, or temporarily suspended, if necessitated by toxicity. When toxicity is controlled, doses may be carefully readjusted upward. If there is no tumor response after 8 weeks of treatment and if the initial dose of 300 mg/m2/day is well tolerated, the dose may be escalated to 400 mg/m2/day with careful monitoring. Duration of therapy: In clinical trials in CTCL, bexarotene capsules were administered for up to 97 weeks. Bexarotene capsules should be continued as long as the patient is deriving benefit.

EFFECTIVENESS MONITORING PARAMETERS Tumor response was assessed in both studies by observation of up to 5 baseline-defined index lesions using a Composite Assessment of Index Lesion Disease Severity (CA). This endpoint was based on a summation of the grades, for all index lesions, of erythema, scaling, plaque elevation, hypopigmentation or hyperpigmentation, and area of involvement. Also considered in response assessment was the presence or absence of cutaneous tumors and extracutaneous disease manifestations. All tumor responses required confirmation over at least 2 assessments separated by at least 4 weeks. A partial response was defined as an improvement of at least 50% in the index lesions without worsening, or development of new cutaneous tumors or non-cutaneous manifestations. A complete clinical response required complete disappearance of all manifestations of disease, but did not require confirmation by biopsy.

INJECTABLE ADMINISTRATION REQUIREMENTS None.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 44 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Bicalutamide (Casodex)

FDA APPROVED INDICATIONS Prostate cancer: For use in combination therapy with a luteinizing hormone-releasing hormone (LHRH) analog for the treatment of Stage D2 metastatic carcinoma of the prostate.

TREATMENT DOSE / DURATION / REGIMEN The recommended dose for bicalutamide therapy, in combination with an LHRH analog, is one 50 mg tablet once daily (morning or evening), with or without food. It is recommended that bicalutamide be taken at the same time each day. Treatment with bicalutamide should be started at the same time as treatment with an LHRH analog.

EFFECTIVENESS MONITORING PARAMETERS Objective tumor progression was defined as the appearance of any bone metastases or the worsening of any existing bone metastases on bone scan attributable to metastatic disease, or an increase by 25% or more of any existing measurable extraskeletal metastases. The hazard ratio for time to progression of bicalutamide plus LHRH analog to that of flutamide plus LHRH analog was 0.93 (95% confidence interval, 0.79 to 1.1).

INJECTABLE ADMINISTRATION REQUIREMENTS None.

ODS Health Plan Customary Specialty MR Criteria Page 45 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 46 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Bortezomib (Velcade)

FDA APPROVED INDICATIONS 1. Mantle Cell Lymphoma: VELCADE (bortezomib) for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy. 2. Multiple Myeloma: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myloma.. On June 20, the FDA approved an expanded indication for bortezomib intravenous injection (Velcade; Millennium Pharmaceuticals, Inc), allowing its use in patients with previously untreated multiple myeloma. VISTA) trial: Results at a median follow-up of 16.3 months showed that that the addition of bortezomib to melphalan plus prednisone yielded significantly improved response rates, both complete (30% vs 4%) and partial (40% vs 30%; P < 10-10). The addition of bortezomib significantly increased time to disease progression (20.7 vs 15.0 months; hazard ratio [HR], 0.54; P = .000002), overall survival (HR, 0.61; P = .000782), and progression-free survival (HR, 0.61; P = .00001).

TREATMENT DOSE / DURATION / REGIMEN Recommended dosage: 1.3 mg/m2/dose administered as a 3- to 5-second bolus intravenous (IV) injection twice weekly for 2 weeks (days 1, 4, 8, and 11) followed by a 10-day rest period (days 12 to 21). For extended therapy of more than 8 cycles, bortezomib may be administered on the standard schedule or on a maintenance schedule of once weekly for 4 weeks (days 1, 8,

ODS Health Plan Customary Specialty MR Criteria Page 47 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

15, and 22) followed by a 13-day rest period (days 23 to 35). At least 72 hours should elapse between consecutive doses of bortezomib. Dose modification and reinitiation of therapy: Bortezomib should be withheld at the onset of any grade 3 nonhematological or grade 4 hematological toxicities, excluding neuropathy. Once the symptoms of the toxicity have resolved, bortezomib may be reinitiated at a 25% reduced dose (1.3 mg/m2/dose reduced to 1 mg/m2/dose; 1 mg/m2/dose reduced to 0.7 mg/m2/dose).

EFFECTIVENESS MONITORING PARAMETERS Response and progression were assessed using the European Group for Blood and Marrow Transplantation (EBMT) criteria. Complete response (CR) required less than 5% plasma cells in the marrow, 100% reduction in M protein, and a negative immunofixation test (IF−). Partial response (PR) requires a 50% or more reduction in serum myeloma protein and a 90% or more reduction of urine myeloma protein on at least 2 occasions for a minimum of at least 6 weeks along with stable bone disease and normal calcium. Near complete response (nCR) was defined as meeting all the criteria for complete response, including 100% reduction in M protein by protein electrophoresis; however, M protein was still detectable by immunofixation (IF+).

INJECTABLE ADMINISTRATION REQUIREMENTS Administration should be supervised by medical professional experienced in the use of anticancer agents.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 48 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Botox

Generic Name (Brand): Botulinum Toxin Type A and Type B (Botox))(Myobloc)

GUIDELINES FOR USE 1. Does patient have a diagnosis related to cosmetic treatment? If yes, do not approve. If no, continue to #2. 2. Does patient have an FDA approved diagnosis? If yes, continue to #3. If no, do not approve. 3. Approve for 12 months.

FDA APPROVED INDICATIONS 1. Botox is indicated for the treatment of cervical dystonia in adults to decrease the severity of abnormal head position and neck pain associated with cervical dystonia. 2. Botox is indicated for the treatment of severe primary axillary hyperhidrosis that is inadequately managed with topical agents. 3. Botox is indicated for the treatment of strabismus and blepharospasm associated with dystonia, including benign essential blepharospasm or VII nerve disorders in patients 12 years of age and above.

REFERENCES Botox product information. Solstice Neurosciences. 2004.

Effective: 10/01/08 Created: 04/01/07 Updated: 11/14/07 Reviewed:______

ODS Health Plan Customary Specialty MR Criteria Page 49 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Busulfan (Busulfex, Myleran)

FDA APPROVED INDICATIONS CML: Oral Busulfan is indicated for the palliative treatment of chronic myelogenous (myeloid, myelocytic, granulocytic) leukemia. Injections of busulfan are indicated as a component of the busulfan/cyclophosphamide conditioning regimen prior to bone marrow or peripheral blood progenitor cell replacement.

TREATMENT DOSE / DURATION / REGIMEN The usual adult dose of oral busulfan for remission induction is 4 to 8 mg, total dose, daily. Dosing on a weight basis is the same for children and adults, approximately 60 mcg/kg of body weight or 1.8 mg/m2 of body surface, daily. Because the rate of fall of the leukocyte count is dose related, reserve daily doses exceeding 4 mg daily for patients with the most compelling symptoms; the greater the total daily dose, the greater the possibility of inducing bone marrow aplasia. The usual IV adult dosage is 0.8 mg/kg of ideal body weight (IBW) or actual body weight (ABW), whichever is lower, administered every 6 hours for 4 days (a total of 16 doses). For obese or severely obese patients, busulfan should be administered based on adjusted ideal body weight (AIBW). IBW should be calculated as follows (height in cm, and weight in kg): IBW (kg; men) = 50 + 0.91 × (height in cm − 152) IBW (kg; women) = 45 + 0.91 × (height in cm − 152)

ODS Health Plan Customary Specialty MR Criteria Page 50 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

EFFECTIVENESS MONITORING PARAMETERS Although not curative, busulfan reduces the total granulocyte mass, relieves symptoms of the disease, and improves the clinical state of the patient.

INJECTABLE ADMINISTRATION REQUIREMENTS Administration of injectible busulfan should be supervised by medical professional experienced in the use of anticancer agents.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 51 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Cadribine (Leustatin) GUIDELINES FOR USE 1. What is the patient’s diagnosis? If the diagnosis is an FDA approved indication, continue to #2. If not, do not approve. 2. What is the treatment dose? If treatment dose is within the approved dosing range, continue to #3. If not, do not approve. 3. What is the expected treatment duration? If submitted duration is an approved treatment duration, continue to #4. If not, do not approve. 4. What other antineoplastic agents will be included in the treatment regimen? If an approved treatment regimen, continue to #5. If not, do not approve. 5. What clinical parameters will be monitored to establish treatment effectiveness? If submitted monitoring plan is consistent with effectiveness monitoring, continue to #6. If not, do not approve. 6. Will the medication be administered by a trained healthcare professional? If submitted administration plan for injectable agent is consistent with recommended administration, continue to #7. If not, do not approve. 7. Approve for 6 months.

FDA APPROVED INDICATIONS Hairy cell leukemia: For the treatment of active hairy cell leukemia as defined by clinically significant anemia, neutropenia, thrombocytopenia or disease-related symptoms.

TREATMENT DOSE / DURATION / REGIMEN Usual dose: The recommended dose and schedule of cladribine for active hairy cell leukemia is as a single course given by continuous infusion for 7 consecutive days at a dose of 0.09 mg/kg/day. Deviations from this dosage regimen are not advised.

EFFECTIVENESS MONITORING PARAMETERS A clinical relapse was defined as the recurrence of cytopenias, specifically, decreases in hemoglobin greater than or equal to 2 g/dL, ANC greater than or equal to 25% or platelet counts greater than or equal to 50,000. pathologic relapse was defined as an increase in bone marrow hairy cells to 25% of pretreatment levels. If the patient does not respond to the initial course of cladribine for hairy cell leukemia, it is unlikely that they will benefit from additional courses.

INJECTABLE ADMINISTRATION REQUIREMENTS Administration should be supervised by medical professional experienced in the use of anticancer agents.

ODS Health Plan Customary Specialty MR Criteria Page 52 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 53 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Xeloda

Generic Name (Brand): Capecitabine (Xeloda)

DESCRIPTION: Capecitabine is a fluoropyrimidine carbamate with antineoplastic activity. It is an orally administered systemic prodrug of 5’-deoxy-5-5fluorouridine which is converted to 5-fluorouracil.

PRODUCT AVAILABILITY: 150mg and 500mg tablets

INDICATION: Breast Cancer: Capecitabine in combination with docetaxel is indicated for the treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing chemotherapy.

Capecitabine monotherapy is indicated for the treatment of patients with metastatic breast cancer resistant to both paclitaxel and an anthracycline–containing chemotherapy regimen or resistant to paclitaxel and for whom further anthracycline therapy is not indicated (eg, patients who have received cumulative doses of 400 mg/m2 of doxorubicin or doxorubicin equivalents). Resistance is defined as progressive disease while on treatment, with or without an initial response, or relapse within 6 months of completing treatment with an anthracycline-containing adjuvant regimen.

Colon Cancer: Capecitabine is indicated as a single agent for adjuvant treatment in patients with Duke’s C colon cancer who have undergone complete resection of the primary tumor when treatment with fluoropyrimidine therapy alone is preferred.

Capecitabine is indicated as first-line treatment of patients with metastatic colorectal carcinoma when treatment with fluoropyrimidine therapy alone is preferred.

GUIDELINES FOR USE: 1) Has the patient received Capecitabine previously? a) If yes, do not approve. b) If no, continue to #2.

2) Does the patient have an ECOG performance status of 0 – 2? a) If yes, continue to #2. b) If no, do not approve

3) Does the patient have breast cancer or colon cancer? a) If Breast Cancer, continue to #4. b) If Colon Cancer, continue to #12.

4) Does patient have measurable (lesions 15mm-19mm in diameter as assessed by means other than spiral CT) metastatic or advanced breast cancer (T4 tumor and stage IIIB or IIIC of disease). a) If yes, continue to #5 b) If no, do not approve.

ODS Health Plan Customary Specialty MR Criteria Page 54 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

5) Is the tumor positive for over expression of HER2 (3+ staining intensity by means of immunohistochemical analysis or 2+ staining intensity by means of immunohistochemical analysis with gene amplification)? a) If yes, go to #6. b) If no, do not approve.

6) Does patient have decreased left ventricular ejection fraction ≥ Grade 2 by National Cancer Institute (NCI) Common Terminology? a) If yes, do not approve. b) If no, go to #7.

7) Has the patient tried at least 4 cycles of an taxanes, or 2 cycles with disease progression during treatment? a) If yes, continue to #8. b) If no, do not approve.

8) Has the patient tried at least 4 cycles of an anthracycline, or 2 cycles with disease progression during treatment, and/or are anthracyclines no longer indicated (cumulative dose 400mg/m2 of doxorubicin or doxorubicin equivalents)? a) If yes, continue to #9. b) If no, do not approve.

9) Has the patient tried trastuzumab (Herceptin) for at least 6 weeks and disease continued to progress while taking trastuzumab? a) If yes, go to #10. b) If no, do not approve.

10) Has the patient tried at least 4 cycles of a taxane (paclitaxel or docetaxol), or 2 cycles with disease progression during treatment? a) If yes, continue to #11. b) If no, do not approve.

11) Will the patient be taking docetaxol in combination with capecitabine or is docetaxol contraindicated? a) If yes, approve for 24 weeks. b) If no, do not approve.

Colon Cancer: 12) Does the patient have Duke’s C colon cancer or metastatic colorectal cancer? a) If Duke’s C, continue to #13. b) If metastatic colorectal cancer, continue to #14.

13) Has the patient undergone complete resection of the primary tumor without macroscopic or microscopic evidence of remaining tumor? a) If yes, go to #14. b) If no, do not approve.

14) Will Capecitabine be administered in combination with leukovorin? a) If yes, do not approve. b) If no, approve for 24 weeks. ODS Health Plan Customary Specialty MR Criteria Page 55 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

References: 1. Capecitabine Product Information. Roche. Revised: April 2006.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 56 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Carboplatin

FDA APPROVED INDICATIONS Advanced ovarian carcinoma: For the initial treatment of advanced ovarian carcinoma in established combination with other approved chemotherapeutic agents. Carboplatin is indicated for the palliative treatment of patients with ovarian carcinoma recurrent after prior chemotherapy, including patients who have been previously treated with cisplatin.

TREATMENT DOSE / DURATION / REGIMEN Single agent therapy: Carboplatin, as a single agent, has been shown to be effective in patients with recurrent ovarian carcinoma at a dosage of 360 mg/m2 IV on day 1 every 4 weeks (alternately, see Formula dosing). In general, however, single intermittent courses of carboplatin should not be repeated until the neutrophil count is at least 2000 and the platelet count is at least 100,000. Combination therapy with cyclophosphamide: In the chemotherapy of advanced ovarian cancer, an effective combination for previously untreated patients consists of:Carboplatin 300 mg/m2 IV on day 1 every 4 weeks for 6 cycles (alternately, see Formula dosing). Cyclophosphamide 600 mg/m2 IV on day 1 every 4 weeks for 6 cycles. Intermittent courses of carboplatin in combination with cyclophosphamide should not be repeated until the neutrophil count is at least 2000 and the platelet count is at least 100,000. ODS Health Plan Customary Specialty MR Criteria Page 57 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

EFFECTIVENESS MONITORING PARAMETERS Clinical and pathologic response.

INJECTABLE ADMINISTRATION REQUIREMENTS Carboplatin should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of therapy and complications is possible only when adequate treatment facilities are readily available.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 58 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Carmustine (Gliadel)

FDA APPROVED INDICATIONS As palliative therapy as a single agent or in established combination therapy with other approved chemotherapeutic agents in the following: 1. Brain tumors (glioblastoma, brainstem glioma, medulloblastoma, astrocytoma, ependymoma, and metastatic brain tumors). 2. Multiple myeloma in combination with prednisone. 3. Hodgkin's disease as secondary therapy in combination with other approved drugs in patients who relapse while being treated with primary therapy, or who fail to respond to primary therapy. 4. Non-Hodgkin's lymphomas as secondary therapy in combination with other approved drugs for patients who relapse while being treated with primary therapy, or who fail to respond to primary therapy.

TREATMENT DOSE / DURATION / REGIMEN The recommended dose of carmustine for injection as a single agent in previously untreated patients is 150 to 200 mg/m2 intravenously every 6 weeks. This may be given as a single dose or divided into daily injections such as 75 to 100 mg/m2 on 2 successive days. When carmustine for injection is used in combination with other myelosuppressive drugs or in patients in whom bone marrow reserve is depleted, the doses should be adjusted accordingly.

ODS Health Plan Customary Specialty MR Criteria Page 59 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

Doses subsequent to the initial dose should be adjusted according to the hematologic response of the patient to the preceding dose.

EFFECTIVENESS MONITORING PARAMETERS Clinical and pathologic response.

INJECTABLE ADMINISTRATION REQUIREMENTS Administration should be supervised by medical professional experienced in the use of anticancer agents.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 60 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Cimzia

Generic Name (Brand): Certolizumab Pegol (Cimzia)

GUIDELINES FOR USE

1. Is the drug prescribed by a gastroenterologist? If Yes, go to 2. If No, denied. Refer to plan.

2. Is the patient being treated for moderate to severe Crohn’s Disease? If Yes, go to 3. If No, denied. Refer to plan.

3. Is the patient concurrently on anakinra or other TNF blocking therapy (i.e., infliximab)? If Yes, denied. If No, go to 4.

4. Has the patient had a NEGATIVE tuberculin skin test, or if positive, has treatment for latent TB been initiated prior to Cimzia therapy? If Yes, go to 5. If No, denied. Refer to plan.

5. Is the prescribed Cimzia dose greater than 400mg initially and at weeks 2 and 4 for induction therapy and 400mg every 4 weeks for maintenance therapy? If Yes, denied. Refer to plan. If No, go to 6.

6. Does the patient have a clinically important active infection? If Yes, denied. Refer to plan. If No, go to 7. (It is relatively contraindicated for patients with a chronic or recurrent infection to receive TNF antagonists. These medications may place patients at greater risk for developing serious infections).

7. Is the drug being administered for induction therapy (not maintenance)? If Yes and diagnosed with moderate to severe Crohn’s Disease, go to 8. If No and maintenance, go to 11.

8. Has the patient failed or is intolerant to optimal dosing and adequate duration of mesalamine or sulfasalazine? If Yes, go to 9. If No, denied. Refer to plan.

9. Has the patient failed or is intolerant to optimal dosing and adequate duration of corticosteroids? If Yes, go to 10. If No, denied. Refer to plan.

10. Has the patient failed or is intolerant to optimal dosing and adequate duration of an immunomodulator (i.e., methotrexate, 6-mercaptopurine or azathioprine)? If Yes, go to 11. If No, denied. Refer to plan.

11. Has the patient failed or is intolerant to optimal dosing and adequate duration of alternate tumor necrosis factor (TNF) antagonists (i.e., adalimimab, etanercept)? If Yes, approved for 1 year.

ODS Health Plan Customary Specialty MR Criteria Page 61 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

If No, denied. Refer to plan.

GUIDELINES FOR RENEWAL

12. Has the patient shown clinical improvement (i.e. decreased number of draining fistulas, decreased rectal bleeding, diarrhea and abdominal pain; maintenance of remission) after induction therapy with Cimzia as documented in medical records of treating physician? If Yes, approved for 1 year. If No, denied. Refer to plan.

Special Instructions Duration of Approvals: 12 months Clinical Information: Dosing: ◊ Induction: 400mg initially and at Weeks 2 and 4 ◊ Maintenance: 400mg every 4 weeks

Special Warnings/Considerations: • Pregnancy category B • Safety and efficacy has not been established in children • Serious infections, sepsis and fatalities have been reported with the use of TNF antagonists. These medications should not be initiated in patients with clinically important, active infections. • Patients who are carriers of Hepatitis B and require treatment with certolizumab pegol should be closely monitored for clinical and laboratory signs of active HBV infection throughout therapy and for several months following termination of therapy. Patients with active Hepatitis B infections should not receive certolizumab pegol therapy. • Patients receiving certolizumab pegol therapy should not receive live or attenuated vaccines.

RATIONALE Ensure the safe and effective use of Cimzia in appropriate populations with moderately to severely active Crohn’s disease who have demonstrated inadequate response to conventional therapy including alternative FDA APPROVED INDICATIONS Cimzia is used for reducing signs and symptoms of Crohn disease and maintaining clinical response in adult patients with moderately to severely active disease who have had an inadequate response to conventional therapy.

REFERENCES 1. Egan LJ, Sandborn W. Advances in the treatment of Crohn's disease. Gastroenterology 2004;126:1574-81. 2. Hanauer SB, Sandborn W. Management of Crohn's disease in adults. Am J Gastroenterol 2001; 96(3):635-43. 3. Human Anti-Tumor Necrosis Factor Monoclonal Antibody (adalimumab) in Chron’s Disease: the CLASSIC-1 Trial. Gastroenterology 2006; 130:323-333. 4. Cimzia. Product Information. UCB, Inc. Revised April 2008. Information available at www.Cimzia.com.

Effective: 10/01/08 Created: 07/11/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 62 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Fertility Agents

Generic Name (Brand): Cetrorelix Acetate (Cetrotide)

FDA APPROVED INDICATIONS Infertility treatment: Cetrorelix is indicated for the inhibition of premature luteinizing hormone (LH) surges in women undergoing controlled ovarian stimulation.

TREATMENT DOSE / DURATION / REGIMEN Start ovarian stimulation therapy with gonadotropins (follicle-stimulating hormone [FSH], human menopausal gonadotropin [HMG]) on cycle day 2 or 3. Adjust the dose of gonadotropins according to individual response. Cetrorelix may be administered subcutaneously once daily (0.25 mg dose) or once (3 mg dose) during the early- to midfollicular phase.

EFFECTIVENESS MONITORING PARAMETERS Clinical response.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08. Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 63 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Cetuximab (Erbitux)

FDA APPROVED INDICATIONS 1. Colorectal cancer: Cetuximab, as a single agent, is indicated for the treatment of epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based regimens. Cetuximab, as a single agent, is also indicated for the treatment of EGFR-expressing metastatic colorectal cancer in patients who are intolerant to irinotecan-based regimens. Cetuximab, in combination with irinotecan, is indicated for the treatment of EGFR-expressing metastatic colorectal carcinoma in patients who are refractory to irinotecan-based chemotherapy. The effectiveness of cetuximab in combination with irinotecan is based on objective response rates. Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with cetuximab in combination with irinotecan for the treatment of EGFR-expressing, metastatic colorectal carcinoma. 2. Squamous cell carcinoma of the head and neck (SCCHN): In combination with radiation therapy for the initial treatment of locally or regionally advanced SCCHN. Cetuximab, as a single agent, is indicated for the treatment of patients with recurrent or metastatic SCCHN for whom prior platinum-based therapy has failed.1

TREATMENT DOSE / DURATION / REGIMEN

ODS Health Plan Customary Specialty MR Criteria Page 64 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

Colorectal cancer:The recommended initial dose of cetuximab, either as monotherapy or in combination with irinotecan, is 400 mg/m2 administered as a 120-minute intravenous (IV) infusion (maximum infusion rate, 10 mg/min). The recommended subsequent weekly dose, either as monotherapy or in combination with irinotecan, is 250 mg/m2 infused over 60 minutes (maximum infusion rate, 10 mg/min) until disease progression or unacceptable toxicity occurs. SCCHN: Combination with radiation therapy: The recommended initial dose is 400 mg/m2 administered 1 week prior to initiation of radiation therapy as a 120-minute IV infusion (maximum infusion rate, 10 mg/min). The recommended subsequent weekly dose (all other infusions) is 250 mg/m2 infused over 60 minutes (maximum infusion rate, 10 mg/min) for the duration of radiation therapy (6 to 7 weeks). Complete cetuximab administration 1 hour prior to radiation therapy. 1 Monotherapy: The recommended initial dose is 400 mg/m2 administered as a 120-minute IV infusion (maximum infusion rate, 10 mg/min). The recommended subsequent weekly dose (all other infusions) is 250 mg/m2 infused over 60 minutes (maximum infusion rate, 10 mg/min) until disease progression or unacceptable toxicity occurs.

EFFECTIVENESS MONITORING PARAMETERS Clinical and pathologic response.

INJECTABLE ADMINISTRATION REQUIREMENTS Administration should be supervised by medical professional experienced in the use of anticancer agents and the treatment of infusion reactions.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 65 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Chlorambucil (Leukeran)

FDA APPROVED INDICATIONS Leukemia/Lymphomas: For the treatment of chronic lymphatic (lymphocytic) leukemia, malignant lymphomas including lymphosarcoma, giant follicular lymphoma, and Hodgkin disease. It is not curative in any of these disorders but may produce clinically useful palliation.

TREATMENT DOSE / DURATION / REGIMEN Initial and short courses of therapy: The usual oral dosage is 0.1 to 0.2 mg/kg body weight daily for 3 to 6 weeks as required. This usually amounts to 4 to 10 mg/day for the average patient. The entire daily dose may be given at one time. These dosages are for initiation of therapy or for short courses of treatment. The dosage must be carefully adjusted according to the response of the patient and must be reduced as soon as there is an abrupt fall in the white blood cell count. Patients with Hodgkin disease usually require 0.2 mg/kg/day, whereas patients with other lymphomas or chronic lymphocytic leukemia usually require only 0.1 mg/kg/day. When lymphocytic infiltration of the bone marrow is present, or when the bone marrow is hypoplastic, the daily dose should not exceed 0.1 mg/kg (about 6 mg for the average patient). Alternate schedules for the treatment of chronic lymphocytic leukemia employing intermittent, biweekly, or once-monthly pulse doses of chlorambucil have been reported. Intermittent schedules of chlorambucil begin with an initial single dose of 0.4 mg/kg. Doses are generally increased by 0.1 mg/kg until control of lymphocytosis or toxicity is observed. Subsequent doses

ODS Health Plan Customary Specialty MR Criteria Page 66 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

are modified to produce mild hematologic toxicity. It is felt that the response rate of chronic lymphocytic leukemia to the biweekly or once-monthly schedule of chlorambucil administration is similar or better to that previously reported with daily administration and that hematologic toxicity was less than or equal to that encountered in studies using daily chlorambucil. Radiation and cytotoxic drugs render the bone marrow more vulnerable to damage, and chlorambucil should be used with particular caution within 4 weeks of a full course of radiation therapy or chemotherapy. However, small doses of palliative radiation over isolated foci remote from the bone marrow will not usually depress the neutrophil and platelet count. In these cases chlorambucil may be given in the customary dosage. Maintenance: It is presently felt that short courses of treatment are safer than continuous maintenance therapy, although both methods have been effective. It must be recognized that continuous therapy may give the appearance of “maintenance” in patients who are actually in remission and have no immediate need for further drug. If maintenance dosage is used, it should not exceed 0.1 mg/kg/day and may well be as low as 0.03 mg/kg/day. A typical maintenance dose is 2 to 4 mg/day, or less, depending on the status of the blood counts. It may, therefore, be desirable to withdraw the drug after maximal control has been achieved, since intermittent therapy reinstituted at time of relapse may be as effective as continuous treatment

EFFECTIVENESS MONITORING PARAMETERS Clinical and pathologic response.

INJECTABLE ADMINISTRATION REQUIREMENTS None.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 67 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Fertility Agents

Generic Name (Brand): Choriogonadotripin Alfa (Ovidrel) GUIDELINES FOR USE 1. What is the patient’s diagnosis? If the diagnosis is an FDA approved indication, continue to #2. If not, do not approve. 2. What is the treatment dose? If treatment dose is within the approved dosing range, continue to #3. If not, do not approve. 3. What clinical parameters will be monitored to establish treatment effectiveness? If submitted monitoring plan is consistent with effectiveness monitoring, continue to #4. If not, do not approve. 4. Approve for 6 months.

FDA APPROVED INDICATIONS Final follicular maturation: Choriogonadotropin alfa for injection is indicated for the induction of final follicular maturation and early luteinization in infertile women who have undergone pituitary desensitization and who have been appropriately pretreated with follicle-stimulating hormones (FSH) as part of an assisted reproductive technology (ART) program such as in vitro fertilization and embryo transfer. Ovulation induction: Choriogonadotropin alfa is also indicated for the induction of ovulation (OI) and pregnancy in anovulatory infertile patients in whom the cause of infertility is functional and not caused by primary ovarian failure.

TREATMENT DOSE / DURATION / REGIMEN Infertile women undergoing ART: Administer choriogonadotropin alfa 250 mcg 1 day following the last dose of the follicle-stimulating agent. Do not administer choriogonadotropin alfa until adequate follicular development is indicated by serum estradiol and vaginal ultrasonography. Withhold administration in situations where there is an excessive ovarian response, as evidenced by clinically significant ovarian enlargement or excessive estradiol production. Infertile women undergoing OI: Do not administer choriogonadotropin alfa until adequate follicular development is indicated by serum estradiol and vaginal ultrasonography. Administer choriogonadotropin alfa 250 mcg 1 day following the last dose of the follicle- stimulating agent.

EFFECTIVENESS MONITORING PARAMETERS Clinical response.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08.

Effective: 10/01/08

Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 68 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Anti-Infective Agents

Generic Name (Brand): Cidofovir (Vistide)

FDA APPROVED INDICATIONS CMV retinitis: Treatment of cytomegalovirus (CMV) retinitis in patients with AIDS. The safety and efficacy of cidofovir have not been established for treatment of other CMV infections (such as pneumonitis or gastroenteritis), congenital or neonatal CMV disease, or CMV disease in non- HIV-infected individuals.

TREATMENT DOSE / DURATION / REGIMEN Dosage: The recommended dosage, frequency, or infusion rate must not be exceeded. Cidofovir must be diluted in 100 mL 0.9% (normal) saline prior to administration. To minimize potential nephrotoxicity, probenecid, and IV saline prehydration must be administered with each cidofovir infusion. Induction treatment: The recommended induction dose of cidofovir for patients with a serum creatinine of ≤ 1.5 mg/dL, a calculated creatinine clearance > 55 mL/min, and a urine protein < 100 mg/dL (equivalent to < 2+ proteinuria) is 5 mg/kg body weight (given as an IV infusion at a constant rate over 1 hour) administered once weekly for 2 consecutive weeks. Because serum creatinine in patients with advanced AIDS and CMV retinitis may not provide a complete picture of the patient's underlying renal status, it is important to utilize the Cockcroft-Gault formula to more precisely estimate creatinine clearance (Ccr). As creatinine clearance is dependent on serum creatinine and patient weight, it is necessary to calculate clearance prior to initiation of cidofovir. Ccr (mL/min) should be calculated according to the following formula: Ccr males = [140 - age (in years)] × [body weight (in kg)]/72 × [serum creatinine (mg/dL)]. Ccr females = 0.85 × [140 - age (in years)] × [body weight (in kg)]/72 × [serum creatinine (mg/dL)]. Maintenance treatment: The recommended maintenance dose of cidofovir is 5 mg/kg body weight (given as an IV infusion at a constant rate over 1 hour), administered once every 2 weeks. Probenecid: Probenecid must be administered orally with each cidofovir dose. Two grams must be administered 3 hours prior to the cidofovir dose and 1 g administered at 2 and again at 8 hours after completion of the 1 hour cidofovir infusion (for a total of 4 g).

EFFECTIVENESS MONITORING PARAMETERS

ODS Health Plan Customary Specialty MR Criteria Page 69 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

Microbiological suppression of CMV replication.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08.

Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 70 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Endocrine and Metabolic Agents

Generic Name (Brand): Corticotropin (HP Acthar)

FDA APPROVED INDICATIONS For diagnostic testing of adrenocortical function. Repository corticotropin injection has limited therapeutic value in those conditions responsive to corticosteroid therapy; in such cases, corticosteroid therapy is considered to be the treatment of choice. Repository corticotropin injection may be employed in the following disorders: Endocrine disorders: Nonsuppurative thyroiditis; hypercalcemia associated with cancer. Nervous system diseases: Acute exacerbations of multiple sclerosis. Rheumatic disorders: As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in the following: Psoriatic arthritis; rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy); ankylosing spondylitis; acute and subacute bursitis; acute nonspecific tenosynovitis; acute gouty arthritis; posttraumatic arthritis; synovitis of osteoarthritis; epicondylitis. Collagen diseases: During an exacerbation or as maintenance therapy in selected cases of the following: Systemic lupus erythematosus; systemic dermatomyositis (polymyositis); acute rheumatic carditis. Dermatologic diseases: Pemphigus; bullous dermatitis herpetiformis; severe erythema multiforme (Stevens-Johnson syndrome); exfoliative dermatitis; severe psoriasis; severe seborrheic dermatitis; mycosis fungoides. Allergic states: Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment, such as the following: Seasonal or perennial allergic rhinitis; bronchial asthma; contact dermatitis; atopic dermatitis; serum sickness. Ophthalmic diseases: Severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa, such as the following: Allergic conjunctivitis; keratitis; herpes zoster ophthalmicus; iritis and iridocyclitis; diffuse posterior uveitis and choroiditis; optic neuritis; sympathetic ophthalmia; chorioretinitis; anterior segment inflammation; allergic corneal marginal ulcers. Respiratory diseases: Symptomatic sarcoidosis; Loeffler syndrome not manageable by other means; berylliosis; fulminating or disseminated pulmonary tuberculosis when used concurrently with antituberculous chemotherapy; aspiration pneumonitis. Hematologic disorders: Acquired (autoimmune) hemolytic anemia; secondary thrombocytopenia

ODS Health Plan Customary Specialty MR Criteria Page 71 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

in adults; erythro-blastopenia (RBC anemia); congenital (erythroid) hypoplastic anemia. Neoplastic diseases: For palliative management of leukemias and lymphomas in adults or acute leukemia of childhood. Edematous state: To induce a diuresis or a remission of proteinuria in the nephrotic syndrome without uremia of the idiopathic type or that due to lupus erythematosus. GI diseases: To tide the patient over a critical period of the disease in ulcerative colitis or regional enteritis. Miscellaneous: Tuberculous meningitis with subarachnoid block or impending block when used concurrently with appropriate antituberculous chemotherapy; trichinosis with neurologic or myocardial involvement.

TREATMENT DOSE / DURATION / REGIMEN Verification test: Standard tests for verification of adrenal responsiveness to corticotropin may utilize as much as 80 units as a single injection or 1 or more injections of a lesser dosage. Verification tests should be performed prior to treatment with corticotropins. The test should utilize the route(s) of administration proposed for treatment. Following verification, dosage should be individualized according to the disease under treatment and the general medical condition of each patient. Frequency and dose of the drug should be determined by considering severity of the disease, plasma and urine corticosteroid levels, and the initial response of the patient. Only gradual change in dosage schedules should be attempted after full drug effects have become apparent. Dosage reduction: When reduction in dosage is indicated, this should be done gradually by either reducing the amount of each injection, administering injections at longer intervals or by a combination of both of the above. During reduction of dosage, careful consideration should be given to the disease being treated, the general medical conditions of the patient, and the duration over which corticotropin was administered. Usual dose: The usual dose of repository corticotropin injection is 40 to 80 units given IM or subcutaneous every 24 to 72 hours. The chronic administration of greater than 40 units daily may be associated with uncontrollable adverse reactions. Acute exacerbations of multiple sclerosis: In the treatment of acute exacerbations of multiple sclerosis, daily IM doses of 80 to 120 units for 2 to 3 weeks may be administered.

EFFECTIVENESS MONITORING PARAMETERS Clinical and laboratory response to adrenal cortex stimulation.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08.

Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 72 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Cyclophosphamide (Cytoxan)

FDA APPROVED INDICATIONS Cyclophosphamide, although effective alone in susceptible malignancies, is more frequently used concurrently or sequentially with other antineoplastic drugs. The following malignancies are often susceptible to cyclophosphamide treatment: Malignant diseases: Malignant lymphomas (stages III and IV of the Ann Arbor staging system), Hodgkin's disease, lymphocytic lymphoma (nodular or diffuse), mixed-cell type lymphoma, histiocytic lymphoma, Burkitt's lymphoma, neuroblastoma (disseminated disease), adenocarcinoma of the ovary, retinoblastoma, carcinoma of the breast. Multiple myeloma: Treatment of multiple myeloma Leukemias: Chronic lymphocytic leukemia, chronic granulocytic leukemia (it is usually ineffective in acute blastic crisis), acute myelogenous and monocytic leukemia, acute lymphoblastic (stem-cell) leukemia in children (cyclophosphamide given during remission is effective in prolonging its duration). Mycosis fungoides: Advanced disease. Nonmalignant disease-biopsy proven “minimal change” nephrotic syndrome in children: Cyclophosphamide is useful in carefully selected cases of biopsy proven “minimal change” nephrotic syndrome in children but should not be used as primary therapy. In children whose disease fails to respond adequately to appropriate adrenocorticosteroid therapy or in whom the adrenocorticosteroid therapy produces or threatens to produce intolerable side effects,

ODS Health Plan Customary Specialty MR Criteria Page 73 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

cyclophosphamide may induce a remission. Cyclophosphamide is not indicated for the nephrotic syndrome in adults or for any other renal disease.

TREATMENT DOSE / DURATION / REGIMEN Malignant diseases (adults and children): IV: When used as the only oncolytic drug therapy, the initial course of cyclophosphamide for patients with no hematologic deficiency usually consists of 40 to 50 mg/kg given IV in divided doses over a period of 2 to 5 days. Other intravenous regimens include 10 to 15 mg/kg given every 7 to 10 days or 3 to 5 mg/kg twice weekly. Oral: Oral cyclophosphamide dosing is usually in the range of 1 to 5 mg/kg/day for both initial and maintenance dosing. Many other regimens of intravenous and oral cyclophosphamide have been reported. Dosages must be adjusted in accord with evidence of antitumor activity or leukopenia. The total leukocyte count is a good, objective guide for regulating dosage.

EFFECTIVENESS MONITORING PARAMETERS Clinical and pathologic response.

INJECTABLE ADMINISTRATION REQUIREMENTS Administration of injectable cyclophosphamide should be supervised by medical professional experienced in the use of anticancer agents.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 74 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Immunologic Agents

Generic Name (Brand): Cyclosporine (Gengraf, Sandimmune))

FDA APPROVED INDICATIONS Allogeneic transplants: For prophylaxis of organ rejection in kidney, liver, and heart allogeneic transplants. Gengraf and Neoral have been used in combination with azathioprine and corticosteroids. Sandimmune always is to be used with adrenal corticosteroids. Sandimmune also may be used in the treatment of chronic rejection in patients previously treated with other immunosuppressive agents. Because of the risk of anaphylaxis, reserve Sandimmune injection for patients who are unable to take the soft gelatin capsule or oral solution. Psoriasis: Neoral and Gengraf are indicated for the treatment of adult, nonimmunocompromised patients with severe (ie, extensive and/or disabling), recalcitrant, plaque psoriasis who have failed to respond to at least 1 systemic therapy (eg, PUVA, retinoids, methotrexate) or in patients for whom other systemic therapies are contraindicated or cannot be tolerated. While rebound rarely occurs, most patients will experience relapse with Neoral or Gengraf as with other therapies upon cessation of treatment.1 2 RA: Neoral and Gengraf are indicated for the treatment of patients with severe, active, RA where the disease has not adequately responded to methotrexate. Neoral and Gengraf can be used in combination with methotrexate in RA patients who do not respond adequately to methotrexate alone.

TREATMENT DOSE / DURATION / REGIMEN Bioequivalency: Because Sandimmune is not bioequivalent to Neoral or Gengraf, conversion from Neoral or Gengraf to Sandimmune using a 1:1 ratio (mg/kg/day) may result in lower cyclosporine blood concentration. Conversion from Neoral or Gengraf to Sandimmune should be made with increased blood concentration monitoring to avoid the potential of underdosing.

Sandimmune, parenteral: For infusion only. Sandimmune injection is administered at one-third the oral dose. Give the initial dose 4 to 12 hours prior to transplantation as a single IV dose of 5 to 6 mg/kg/day. This single dose is continued postoperatively until the patient can tolerate oral therapy. Switch patients to oral therapy as soon as possible after surgery.

ODS Health Plan Customary Specialty MR Criteria Page 75 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

Sandimmune, oral: Give the initial dose of Sandimmune 4 to 12 hours prior to transplantation as a single dose of 15 mg/kg. Although a single daily dose of 14 to 18 mg/kg was used in most clinical trials, few centers continue to use the highest dose, most favoring the lower end of the scale. There is a trend towards use of even lower initial doses for renal transplantation in the ranges of 10 to 14 mg/kg/day. The initial single daily dose is continued postoperatively for 1 to 2 weeks and then tapered by 5% per week to a maintenance dose of 5 to 10 mg/kg/day. Some centers have successfully tapered the maintenance dose to as low as 3 mg/kg/day in selected renal transplant patients without an apparent rise in rejection rate. Neoral and Gengraf: Always give the daily dosage of Neoral and Gengraf in 2 divided doses (bid) on a consistent schedule with regard to time of day and relation to meals. Newly transplanted patients: Give the initial dose of Neoral and Gengraf 4 to 12 hours prior to transplantation or postoperatively. The initial dose of Neoral and Gengraf varies depending on the transplanted organ and the other immunosuppressive agents included in the immunosuppressive protocol. In newly transplanted patients, the initial oral dose of Neoral and Gengraf are the same as the initial dose of Sandimmune. The mean approximate initial doses were 9 mg/kg/day for renal transplant patients, 8 mg/kg/day for liver transplant patients, and 7 mg/kg/day for heart transplant patients. Total daily doses were divided into equal daily doses. The Neoral and Gengraf dose is subsequently adjusted to achieve a predefined cyclosporine blood concentration. Using the same trough concentration target for Neoral and Gengraf as for Sandimmune results in greater cyclosporine exposure when Neoral and Gengraf are administered. Titrate dosing based on clinical assessments of rejection and tolerability. Lower Neoral and Gengraf doses may be sufficient as maintenance therapy. Conversion from Sandimmune: In transplanted patients who are considered for conversion to Neoral or Gengraf from Sandimmune, start Neoral or Gengraf with the same daily dose as was previously used with Sandimmune (1:1 dose conversion). Subsequently, adjust the Neoral or Gengraf dose to attain the preconversion cyclosporine blood trough concentration. Using the same trough concentration target range for Neoral and Gengraf as for Sandimmune results in greater cyclosporine exposure when Neoral and Gengraf are administered. Patients with suspected poor absorption of Sandimmune require different dosing strategies. In some patients, the increase in blood trough concentration is more pronounced and may be of clinical significance. Until the blood trough concentration attains the preconversion value, it is strongly recommended that the cyclosporine blood-trough concentration be monitored every 4 to 7 days after conversion to Neoral or Gengraf. In addition, monitor clinical safety parameters such as serum creatinine and blood pressure every 2 weeks during the first 2 months after conversion. If the blood trough concentrations are outside the desired range and/or if the clinical safety parameters worsen, adjust the dosage of Neoral or Gengraf accordingly. Exercise particular caution when converting patients to Neoral or Gengraf at doses greater than 10 mg/kg/day. Individually titrate the dose of Neoral or Gengraf based on cyclosporine trough concentrations, tolerability, and clinical response. In this population, measure the cyclosporine trough concentrations more frequently, at least twice a week (daily, if initial dose exceeds 10 mg/kg/day), until the concentration stabilizes within the desired range.

Adjunct therapy: Adjunct therapy with adrenal corticosteroids is recommended initially. Different tapering dosage schedules of prednisone appear to achieve similar results. A representative dosage schedule based on the patient's weight started with 2 mg/kg/day for the first 4 days tapered to 1 mg/kg/day by 1 week, 0.6 mg/kg/day by 2 weeks, 0.3 mg/kg/day by 1 month, and 0.15 mg/kg/day by 2 months and thereafter as a maintenance dose. Steroid doses may be further tapered on an individualized basis depending on status of patient and function of graft. Adjustments in dosage of prednisone must be made according to the clinical situation. Psoriasis: The initial dose of Neoral or Gengraf should be 2.5 mg/kg/day. Take Neoral or ODS Health Plan Customary Specialty MR Criteria Page 76 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

Gengraf twice daily, as a divided (1.25 mg/kg BID) oral dose. Keep patients at that dose for at least 4 weeks, barring adverse events. Increase dosage at 2-week intervals if significant clinical improvement has not occurred by that time. Based on patient response, make dose increases of approximately 0.5 mg/kg/day to a maximum of 4 mg/kg/day. Make dose decreases by 25% to 50% at any time to control adverse events, such as hypertension, serum creatinine elevations (greater than or equal to 25% above the patient's pretreatment level), or clinically significant laboratory abnormalities. If dose reduction is not effective in controlling abnormalities, or if the adverse event or abnormality is severe, discontinue Neoral or Gengraf therapy. Patients generally show some improvement in the clinical manifestations of psoriasis in 2 weeks. Satisfactory control and stabilization of the disease may take 12 to 16 weeks to achieve. Discontinue treatment if satisfactory response cannot be achieved after 6 weeks at 4 mg/kg/day or the patient's maximum tolerated dose. Once a patient is adequately controlled and appears stable, lower the dose of Neoral or Gengraf. Doses below 2.5 mg/kg/day may also be equally effective. Upon stopping treatment with cyclosporine, relapse will occur in approximately 6 weeks (50% of patients) to 16 weeks (75% of patients). In the majority of patients, rebound does not occur after cessation of treatment with cyclosporine. Continuous treatment for extended periods longer than 1 year is not recommended. Consider alternating with other forms of treatment in the long-term management of patients with life-long disease. RA: The initial dose of Neoral or Gengraf is 2.5 mg/kg/day, taken twice daily as a divided (bid) oral dose. Salicylates, NSAIDs, and oral corticosteroids may be continued. Onset of action generally occurs between 4 and 8 weeks. If sufficient clinical benefit is seen and tolerability is good (including serum creatinine less than 30% above baseline), the dose may be increased by 0.5 to 0.75 mg/kg/day after 8 weeks and again after 12 weeks to a maximum of 4 mg/kg/day. If no benefit is seen by 16 weeks of therapy, discontinue Neoral or Gengraf therapy. Make dose decreases by 25% to 50% at any time to control adverse events, such as hypertension, serum creatinine elevations (greater than or equal to 25% above the patient's pretreatment level), or clinically significant laboratory abnormalities. If dose reduction is not effective in controlling abnormalities, or if the adverse event or abnormality is severe, discontinue Neoral or Gengraf. Use with methotrexate: Use the same initial dose and dosage range if Neoral or Gengraf is combined with the recommended dose of methotrexate. Most patients can be treated with Neoral or Gengraf doses of 3 mg/kg/day or less when combined with methotrexate doses of up to 15 mg/week.

EFFECTIVENESS MONITORING PARAMETERS Clinical and laboratory response.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08. Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 77 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Cytarabine (Tarabine PFS)

FDA APPROVED INDICATIONS Conventional cytarabine: Cytarabine solution for injection and cytarabine powder for injection, in combination with other approved anticancer drugs, is indicated for remission induction in acute nonlymphocytic leukemia of adults and pediatric patients. It has also been found useful in the treatment of acute lymphocytic leukemia and the blast phase of chronic myelocytic leukemia. Intrathecal administration of cytarabine injection (preservative-free preparations only) is indicated in the prophylaxis and treatment of meningeal leukemia. Liposome injection: For the intrathecal treatment of lymphomatous meningitis. This indication is based on demonstration of increased complete response rate compared to unencapsulated cytarabine. There are no controlled trials that demonstrate a clinical benefit resulting from this treatment, such as improvement in disease-related symptoms, or increased time to disease progression, or increased survival.

TREATMENT DOSE / DURATION / REGIMEN Acute nonlymphocytic leukemia: In the induction therapy of acute nonlymphocytic leukemia, the usual cytarabine dose in combination with other anticancer drugs is 100 mg/m2/day by continuous IV infusion (days 1 to 7) or 100 mg/m2 IV every 12 hours (days 1 to 7).

ODS Health Plan Customary Specialty MR Criteria Page 78 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

The literature should be consulted for the current recommendations for use in acute lymphocytic leukemia. Meningeal leukemia: Cytarabine injections have been used intrathecally in acute leukemia in doses ranging from 5 mg/m2 to 75 mg/m2 of body surface area. The frequency of administration varied from once a day for 4 days to once every 4 days. The most frequently used dose was 30 mg/m2 every 4 days until cerebrospinal fluid findings were normal, followed by 1 additional treatment. The dosage schedule is usually governed by the type and severity of central nervous system manifestations and the response to previous therapy. If used intrathecally, do not use a diluent containing benzyl alcohol. Many clinicians reconstitute with autologous spinal fluid or preservative-free 0.9% sodium chloride injection, and use immediately.

EFFECTIVENESS MONITORING PARAMETERS Clinical and hematological response.

INJECTABLE ADMINISTRATION REQUIREMENTS Administration should be supervised by medical professional experienced in the use of anticancer agents.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 79 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Immunologic Agents

Generic Name (Brand): Cytomegalovirus Immune Globulin (CytoGam)

FDA APPROVED INDICATIONS Cytomegalovirus prophylaxis: For the prophylaxis of cytomegalovirus disease associated with transplantation of kidney, lung, liver, pancreas, and heart. In transplants of these organs other than kidney from CMV seropositive donors into seronegative recipients, prophylactic CMV-IGIV should be considered in combination with ganciclovir.

TREATMENT DOSE / DURATION / REGIMEN The maximum recommended total dosage per infusion is 150 mg/kg, administered according to the following schedule:

Cytomegalovirus Infusion Schedule Administer Type of transplant within: Kidney Liver, pancreas, lung, heart 72 hours of transplant 150 mg/kg 150 mg/kg 2 weeks post-transplant 100 mg/kg 150 mg/kg 4 weeks post-transplant 100 mg/kg 150 mg/kg 6 weeks post-transplant 100 mg/kg 150 mg/kg 8 weeks post-transplant 100 mg/kg 150 mg/kg 12 weeks post-transplant 50 mg/kg 100 mg/kg 16 weeks post-transplant 50 mg/kg 100 mg/kg

EFFECTIVENESS MONITORING PARAMETERS Prevention of CMV infection.

ODS Health Plan Customary Specialty MR Criteria Page 80 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08.

Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 81 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Immunologic Agents

Generic Name (Brand): Daclizumab (Zenapax)

FDA APPROVED INDICATIONS Renal rejection prophylaxis: For the prophylaxis of acute organ rejection in patients receiving renal transplants. It is used as part of an immunosuppressive regimen that includes cyclosporine and corticosteroids. The efficacy of daclizumab for the prophylaxis of acute rejection in recipients of other solid organ allografts has not been demonstrated.

TREATMENT DOSE / DURATION / REGIMEN Daclizumab is used as part of an immunosuppressive regimen that includes cyclosporine and corticosteroids. The recommended dose for daclizumab is 1 mg/kg. The calculated volume of daclizumab should be mixed with 50 mL of sterile 0.9% sodium chloride solution and administered via a peripheral or central vein over a 15-minute period. Based on the clinical trials, the standard course of daclizumab therapy is 5 doses. The first dose should be given no more than 24 hours before transplantation. The 4 remaining doses should be given at intervals of 14 days.

EFFECTIVENESS MONITORING PARAMETERS Prevent acute rejection episode.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08.

Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 82 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Dactinomycin (Cosmegen)

FDA APPROVED INDICATIONS 1. Wilm's tumor, rhabdomyosarcoma, Ewing's sarcoma, nonseminomatous testicular cancer: As part of a combination chemotherapy and/or multi-modality treatment regimen for the treatment of Wilms’ tumor, childhood rhabdomyosarcoma, Ewing’s sarcoma and metastatic, nonseminomatous testicular cancer. 2. Gestational trophoblastic neoplasia: As a single agent or as part of a combination chemotherapy regimen for the treatment of gestational trophoblastic neoplasia. 3. Solid malignancies: As a component of regional perfusion for the palliative and/or adjunctive treatment of locally recurrent or locoregional solid malignancies.

TREATMENT DOSE / DURATION / REGIMEN The IV dosage of dactinomycin varies depending on the tolerance of the patient, the size, and location of the neoplasm, and the use of other forms of therapy. It may be necessary to decrease the usual dosages suggested below when other chemotherapy or radiation therapy is used concomitantly or has been used previously. The dosage for dactinomycin is calculated in micrograms (mcg). The dose intensity per 2-week cycle adults or children should not exceed 15 mcg/kg/day or 400 to 600 mcg/m2/day IV for 5 days. Calculation of the dosage for obese or edematous patients should be performed on the basis of surface area in an effort to more closely relate dosage to lean body mass.

ODS Health Plan Customary Specialty MR Criteria Page 83 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

A wide variety of single agent and combination chemotherapy regimens with dactinomycin may be employed. Because chemotherapeutic regimens are constantly changing, dosing and administration should be performed under the direct supervision of physicians familiar with current oncologic practices and new advances in therapy. The following suggested regimens are based upon a review of current literature concerning therapy with dactinomycin and are on a per cycle basis. Wilms’ tumor, childhood rhabdomyosarcoma and Ewing’s sarcoma: Regimens of 15 mcg/kg intravenously daily for 5 days administered in various combinations and schedules with other chemotherapeutic agents have been utilized in the treatment of Wilms’ tumor, rhabdomyosarcoma and Ewing’s sarcoma. Metastatic nonseminomatous testicular cancer: 1000 mcg/m2 intravenously on Day 1 as part of a combination regimen with cyclophosphamide, bleomycin, vinblastine, and cisplatin. Gestational trophoblastic neoplasia: 12 mcg/kg intravenously daily for 5 days as a single agent. 500 mcg intravenously on Days 1 and 2 as part of a combination regimen with etoposide, methotrexate, folinic acid, vincristine, cyclophosphamide and cisplatin. Regional perfusion in locally recurrent and locoregional solid malignancies: The dosage schedules and the technique itself vary from one investigator to another; the published literature, therefore, should be consulted for details. In general, the following doses are suggested:50 mcg (0.05 mg) per kilogram of body weight for lower extremity or pelvis. 35 mcg (0.035 mg) per kilogram of body weight for upper extremity.

Reduced doses: It may be advisable to use lower doses in obese patients, or when previous chemotherapy or radiation therapy has been employed.

EFFECTIVENESS MONITORING PARAMETERS Clinical and pathologic response.

INJECTABLE ADMINISTRATION REQUIREMENTS Administration should be supervised by medical professional experienced in the use of anticancer agents.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 84 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Anticoagulants

Generic Name (Brand): Dalteparin (Fragmin), Enoxaparin (Lovenox), Tinzaparin (Innohep)

GUIDELINES FOR USE 1. Is the patient currently on warfarin and is scheduled for a minor procedure (such as dental procedure) or a major surgery? If yes, continue to #6. If no, continue to #2. 2. Is the patient receiving dalteparin, enoxaparin, or tinzaparin for prevention of thrombosis following surgery (abdominal, knee or hip replacement) or prevention of ischemic complications of unstable angina and non-Q-wave MI ? If yes, continue to #7. If no, continue to #3. 3. Is the patient receiving dalteparin, enoxaparin, or tinzaparin for outpatient treatment of acute deep vein thrombosis (DVT), without pulmonary embolism (PE), and administered in conjunction with warfarin? If yes, continue to #5. If no, continue to #4. 4. Does the patient have cancer and requires dalteparin (Fragmin) to reduce the reccurrence of VTE (venous thromboembolism: DVT and/or PE)? If yes, Approve for lifetime. If no, continue to #5 5. Is patient currently stabilized on oral warfarin (INR greater than 2)? If yes, continue to #6. If no, continue to #8. 6. Has the patient been therapeutic (INR greater than 2) for at least 2 days? If yes, do not approve. If no, continue to #8. 7. Approve one time for the quantity requested.

CONTINUED ON NEXT PAGE

ODS Health Plan Customary Specialty MR Criteria Page 85 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

GUIDELINES FOR USE (CONTINUED) 8. Approve for maximum of 10 days with the following quantity limits: Dalteparin (Fragmin): 2,500u per 0.2ml syringe: 2.0ml per 30 days or per copay 5,000u per 0.2ml syringe: 2.0ml per 30 days or per copay 7,500u per 0.3ml syringe: 3.0ml per 30 days or per copay 10,000u per 1.0ml syringe: 10.0ml per 30 days or per copay 10,000u/ml 9.5ml vial: 9.5ml per 30 days or per copay 25,000u/ml 3.8ml vial: 11.4ml per 30 days or per copay

Enoxaparin (Lovenox): 30mg per 0.3ml syringe: 6.0ml per 30 days or per copay 40mg per 0.4ml syringe: 8.0ml per 30 days or per copay 60mg per 0.6ml syringe: 12.0ml per 30 days or per copay 80mg per 0.8ml syringe: 16.0ml per 30 days or per copay 100mg per 1.0ml syringe: 20.0ml per 30 days or per copay 120mg per 0.8ml syringe: 16.0ml per 30 days or per copay 150mg per 1.0ml syringe: 20.0ml per 30 days or per copay 100mg/ml 3.0ml vial: 20.0ml per 30 days or per copay

Tinzaparin (Innohep): 20,000iu/ml 2ml vial: 12mls per 30 days or per copay.

FDA APPROVED INDICATIONS Dalteparin (Fragmin): 1. Prophylaxis of deep vein thrombosis (DVT). 2. Prophylaxis of ischemic complications in unstable angina and non-Q-wave myocardial infarction. 3. Extended treatment of symptomatic venous thrombolism to reduce the recurrence of VTE in patients with cancer.

Enoxaparin (Lovenox): 1. Prophylaxis of deep vein thrombosis (DVT). 2. For DVT/Pulmonary embolism (PE) treatment in conjunction with warfarin for inpatient treatment of acute DVT with and without PE or outpatient treatment of acute DVT without PE. 3. For the prevention of ischemic complications of unstable angina and non-Q-wave MI when co-administered with aspirin.

Tinzaparin (Innohep): 1. Treatment of acute symptomatic deep vein thrombosis with or without pulmonary embolism when administered in conjunction with warfarin sodium.

ODS Health Plan Customary Specialty MR Criteria Page 86 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

REFERENCES 1. Injectable Anticoagulants. MedImpact P&T Monograph, May 2005. 2. Fragmin Product Information, Pfizer, April 2007. 3. Innohep Product Information, LEO Pharmaceuticals, January 2007. 4. Lovenox Product Information, Sanofi-Aventis, September 2006. 5. MICROMEDEX® Healthcare Series. 6. Dramitsaris, G, Vincent, M Cronther, M, Dalteparin verus warfarin for the prevention of recurrent venous thromboembolism events in cancer patients: a pharmacoeconomic analysis. Pharmacoeconomics:2006;24 (6):593-607.

Effective:10/01/08 Created: 04/01/07 Updated: 11/14/07 Reviewed:______

ODS Health Plan Customary Specialty MR Criteria Page 87 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Erythropoiesis Stimulating Agents

Generic Name (Brand): Darbepoetin Alfa (Aranesp) Epoetin Alfa (Epogen) (Procrit)

QUANTITY LIMITS: See # 5 under Guidelines For Use for appropriate quantity limits.

POLICY: 1) An ESA agent will be approved only if both of the following criteria are met: a) It is being used to manage anemia associated with one of the following: i) Chronic kidney disease (both dialysis and non-dialysis patients) ii) Chemotherapy in cancer patients with non-myeloid malignancies iii) Zidovudine therapy in patients infected with human immunodeficiency virus (HIV) (epoetin only) iv) Reduction of allogeneic blood transfusion in surgery patients (epoetin only) b) The following laboratory parameters have been documented: i) Hgb < 12g/dL monitored monthly ii) Adequate iron stores: transferring saturation > 20% and ferritin > 100ng/mL at initiation of therapy and every other month while on ESA therapy iii) Adequate blood pressure control

GUIDELINES FOR USE: 1) Is the request for Aranesp? a) If yes, go to #3. b) If no, go to #2.

2) Is epoetin being used to manage anemia associated with one of the following: i) Chronic kidney disease (both dialysis and non-dialysis patients) ii) Chemotherapy in cancer patients with non-myeloid malignancies iii) Zidovudine therapy in patients infected with human immunodeficiency virus (HIV) iv) Reduction of allogeneic blood transfusion in surgery patients a) If yes, go to #4. b) If no, do not approve.

3) Is Aranesp being used to manage anemia associated with one of the following: i) Chronic kidney disease (both dialysis and non-dialysis patients) ii) Chemotherapy in cancer patients with non-myeloid malignancies a) If yes, go to #4. b) If no, do not approve.

4) Does the patient meet the following laboratory parameters? i) Hgb < 12 g/dL

ODS Health Plan Customary Specialty MR Criteria Page 88 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

ii) Transferrin saturation > 20% iii) Ferritin > 100 ng/mL iv) Adequate blood pressure control a) If yes; go to #5. b) If no; do not approve.

5) Approve for the following agents and quantities depending on diagnosis: a) Renal failure i) Aranesp approve #4 vials per 30 days ii) Epogen or Procrit (1) 2,000U, 3,000U, 4,000U and 10,000U vials: 12 vials per 30 days. (2) 20,000U and 40,000U vials: 4 vials per 30 days. b) Cancer chemotherapy i) Aranesp approve #4 vials per 30 days ii) Epogen or Procrit (1) 2,000U, 3,000U, 4,000U and 10,000U vials: 12 vials per 30 days. (2) 20,000U and 40,000U vials: 4 vials per 30 days c) Anemia due to zidovudine therapy (do not approve Aranesp) i) Epogen or Procrit (1) 2,000U, 3,000U, 4,000U and 10,000U vials: 12 vials per 30 days (2) 20,000U and 40,000U vials: 4 vials per 30 days d) Surgery (Do not approve Aranesp) i) Epogen or Procrit (1) 2,000U, 3,000U, 4,000U and 10,000U vials: 12 vials per 14 days. (2) 20,000U and 40,000U vials: 4 vials per 14 days e) Approve for 1 year with the following quantity limits (applies only to renal failure,

chemotherapy, and anemia associated with zidovudine):

• 2,000U, 3,000U, 4,000U and 10,000U vials: 12 vials per 30 days. • 20,000U and 40,000U vials: 4 vials per 30 days.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 89 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Dasatinib (Sprycel)

FDA APPROVED INDICATIONS 1. Acute lymphoblastic leukemia (ALL): For the treatment of adults with Philadelphia chromosome–positive (Ph+) ALL with resistance or intolerance to prior therapy. 2. Chronic myeloid leukemia (CML): For the treatment of adults with chronic, accelerated, or myeloid or lymphoid blast phase CML with resistance or intolerance to prior therapy, including imatinib.

TREATMENT DOSE / DURATION / REGIMEN ALL: 140 mg/day administered orally in 2 divided doses (70 mg twice daily), 1 in the morning and 1 in the evening with or without a meal. CML: Accelerated/myeloid/lymphoid blast phase: 140 mg/day administered orally in 2 divided doses (70 mg twice daily), 1 in the morning and 1 in the evening with or without a meal. Chronic phase: 100 mg administered orally once daily, either in the morning or in the evening. Duration of treatment: In clinical studies, treatment of dasatinib was continued until disease progression or until no longer tolerated by the patient. The effect of stopping treatment after the achievement of a complete cytogenetic response has not been investigated.

Dose modification:

ODS Health Plan Customary Specialty MR Criteria Page 90 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

Concomitant strong CYP3A4 inducers: The use of concomitant strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital) may decrease dasatinib plasma concentrations and should be avoided. St. John's wort may decrease dasatinib plasma concentrations unpredictably and should be avoided. If patients must be coadministered a strong CYP3A4 inducer, based on pharmacokinetic studies, a dasatinib dose increase should be considered. If the dose of dasatinib is increased, the patient should be monitored carefully for toxicity. Concomitant strong CYP3A4 inhibitors: CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase dasatinib plasma concentrations. Grapefruit juice may also increase plasma concentrations of dasatinib and should be avoided. Selection of an alternate concomitant medication with no or minimal enzyme inhibition potential is recommended. If dasatinib must be administered with a strong CYP3A4 inhibitor, a dose decrease to 20 mg daily should be considered. If 20 mg/day is not tolerated, either the strong CYP3A4 inhibitor must be discontinued, or dasatinib should be stopped until treatment with the inhibitor has ceased. When the strong inhibitor is discontinued, a washout period of approximately 1 week should be allowed before the dasatinib dose is increased.

EFFECTIVENESS MONITORING PARAMETERS The effectiveness of dasatinib is based on hematologic and cytogenetic response rates. There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival

INJECTABLE ADMINISTRATION REQUIREMENTS None.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 91 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Decitabine (Dacogen)

FDA APPROVED INDICATIONS Myelodysplastic syndromes (MDS): For treatment of patients with MDS, including previously treated and untreated, de novo and secondary MDS of all French-American-British (FAB) subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System (IPSS) groups.

TREATMENT DOSE / DURATION / REGIMEN First treatment cycle: 15 mg/m2 administered by continuous intravenous (IV) infusion over 3 hours, repeated every 8 hours for 3 days. Subsequent treatment cycles: The above cycle should be repeated every 6 weeks. It is recommended that patients be treated for a minimum of 4 cycles; however, a complete or partial response may take longer than 4 cycles. Treatment may be continued as long as the patient continues to benefit.1

ODS Health Plan Customary Specialty MR Criteria Page 92 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

EFFECTIVENESS MONITORING PARAMETERS Coprimary end points of the study were overall response rate (complete response plus partial response) and time to AML or death. Responses were classified using the MDS International Working Group criteria; patients were required to be RBC and platelet transfusion independent during the time of response.

INJECTABLE ADMINISTRATION REQUIREMENTS Administration should be supervised by medical professional experienced in the use of anticancer agents.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 93 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Chelating Agents

Generic Name (Brand): Deferasirox (Exjade)

DISTRIBUTION Limited distribution FDA APPROVED INDICATIONS Chronic iron overload: For the treatment of chronic iron overload caused by blood transfusions (transfusional hemosiderosis) in patients 2 years of age and older. TREATMENT DOSE / DURATION / REGIMEN Initial dose: 20 mg/kg body weight daily. Maintenance dose: After commencing initial therapy, it is recommended that serum ferritin be monitored every month and the dose of deferasirox adjusted if necessary every 3 to 6 months based on serum ferritin trends. Dose adjustments should be made in increments of 5 or 10 mg/kg and should be tailored to the individual patient's response and therapeutic goals (maintenance or reduction of body iron burden). Maximum dose: Doses of deferasirox should not exceed 30 mg/kg/day because there is limited experience with doses above this level.

EFFECTIVENESS MONITORING PARAMETERS The decision to remove accumulated iron should be individualized based on the anticipated clinical benefits and risks of deferasirox therapy. In patients who are in need of iron chelation therapy, it is recommended that therapy with deferasirox start when a patient has evidence of chronic iron overload, such as the transfusion of approximately 100 mL/kg of packed red blood cells (approximately 20 units for a 40 kg patient) and a serum ferritin level consistently greater than 1,000 mcg/L. During therapy, if the serum ferritin falls consistently below 500 mcg/L, consideration should be given to temporarily interrupting therapy.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08.

Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 94 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Endocrine and Metabolic Agents

Generic Name (Brand): Desmopressin (DDAVP, Stimate)

FDA APPROVED INDICATIONS Oral Desmopressin: Central diabetes insipidus: As antidiuretic replacement therapy in the management of central diabetes insipidus and for the management of the temporary polyuria and polydipsia following head trauma or surgery in the pituitary region. Desmopressin is ineffective for the treatment of nephrogenic diabetes insipidus. Continued response to desmopressin can be monitored by measuring urine volume and osmolality. Primary nocturnal enuresis: For the management of primary nocturnal enuresis. Desmopressin may be used alone or as an adjunct to behavioral conditioning or other nonpharmacologic intervention.

Injectable Desmopressin: Hemophilia A: For patients with hemophilia A with factor VIII coagulant activity levels more than 5%. Desmopressin will often maintain hemostasis in patients with hemophilia A during surgical procedures and postoperatively when administered 30 minutes prior to the scheduled procedure. Desmopressin will also stop bleeding in hemophilia A patients with episodes of spontaneous or trauma-induced injuries, such as hemarthroses, intramuscular (IM) hematomas, or mucosal bleeding. Desmopressin is not indicated for the treatment of hemophilia A with factor VIII coagulant activity levels of 5% or less, for the treatment of hemophilia B, or in patients who have factor VIII antibodies. In certain clinical situations, it may be justified to try desmopressin in patients with factor VIII levels between 2% and 5%; however, carefully monitor these patients. von Willebrand Disease (type I): For patients with mild to moderate classic von Willebrand disease (type I) with factor VIII levels more than 5%. Desmopressin will often maintain hemostasis in patients with mild to moderate von Willebrand disease during surgical procedures and postoperatively when administered 30 minutes prior to the scheduled procedure. Desmopressin will usually stop bleeding in mild to moderate von Willebrand patients with episodes of spontaneous or trauma-induced injuries, such as hemarthroses, IM hematomas, or mucosal bleeding. Those von Willebrand disease patients who are least likely to respond are those with severe homozygous von Willebrand disease with factor VIII coagulant activity and factor VIII von Willebrand factor antigen levels less than 1%. Other patients may respond in a

ODS Health Plan Customary Specialty MR Criteria Page 95 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

variable fashion depending on the type of molecular defect they have. Desmopressin is not indicated for the treatment of severe classic von Willebrand disease (type I) and when there is evidence of an abnormal molecular form of factor VIII antigen. Diabetes insipidus: As antidiuretic replacement therapy in the management of central (cranial) diabetes insipidus and for the management of the temporary polyuria and polydipsia following head trauma or surgery in the pituitary region. Desmopressin is ineffective for the treatment of nephrogenic diabetes insipidus.

Nasal Desmopressin: Primary nocturnal enuresis: For the management of primary nocturnal enuresis. May be used alone or adjunctive to behavioral conditioning or other nonpharmacological intervention. Efficacy has been shown in some cases that are refractory to conventional therapies. Central cranial diabetes insipidus: As antidiuretic replacement therapy in the management of central cranial diabetes insipidus and for management of the temporary polyuria and polydipsia following head trauma or surgery in the pituitary region. It is ineffective for the treatment of nephrogenic diabetes insipidus.

TREATMENT DOSE / DURATION / REGIMEN Oral Desmopressin: CENTRAL DIABETES INSIPIDUS: The dosage of desmopressin must be determined for each individual patient and adjusted according to the diurnal pattern of response. Response should be estimated by 2 parameters: adequate duration of sleep and adequate, not excessive, water turnover. Patients previously on intranasal desmopressin therapy should begin tablet therapy 12 hours after the last intranasal dose. During the initial dose titration period, patients should be observed closely and appropriate safety parameters measured to ensure adequate response. Patients should be monitored at regular intervals during the course of desmopressin therapy to ensure adequate antidiuretic response. Modifications in dosage regimen should be implemented as necessary to ensure adequate water turnover. Adults and children: It is recommended that patients be started on doses of 0.05 mg (1/2 of the 0.1 mg tablet) 2 times a day and individually adjusted to their optimum therapeutic dose. Most patients in clinical trials found that the optimal dosage range is 0.1 to 0.8 mg daily, administered in divided doses. Each dose should be separately adjusted for an adequate diurnal rhythm of water turnover. Total daily dosage should be increased or decreased in the range of 0.1 to 1.2 mg divided into 2 or 3 daily doses as needed to obtain adequate antidiuresis. Primary nocturnal enuresis: The dosage of desmopressin must be determined for each individual patient and adjusted according to response. Patients previously on intranasal desmopressin therapy can begin tablet therapy the night following (24 hours after) the last intranasal dose. The recommended initial dosage for patients at least 6 years of age is 0.2 mg at bedtime. The dose may be titrated up to 0.6 mg to achieve the desired response.

Injectable Desmopressin: Hemophilia A and von Willebrand Disease (type I): Administered as an intravenous (IV) infusion at a dose of desmopressin 0.3 mcg/kg body weight diluted in sterile physiological saline and infused slowly over 15 to 30 minutes. In adults and children weighing more than 10 kg, 50 mL of diluent is recommended; in children weighing 10 kg or less, 10 mL of diluent is recommended. Blood pressure and pulse should be monitored during infusion. If desmopressin is used preoperatively, it should be administered 30 minutes prior to the scheduled procedure. The necessity for repeat administration of desmopressin or use of any blood products for hemostasis should be determined by laboratory response as well as the clinical condition of the patient. The tendency toward tachyphylaxis (lessening of

ODS Health Plan Customary Specialty MR Criteria Page 96 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

response) with repeated administration given more frequently than every 48 hours should be considered in treating each patient. Diabetes insipidus: This formulation is administered subcutaneously or by direct IV injection. Desmopressin dosage must be determined for each patient and adjusted according to the pattern of response. Response should be estimated by 2 parameters: adequate duration of sleep and adequate, not excessive, water turnover. The usual dosage range in adults is 0.5 mL (2 mcg) to 1 mL (4 mcg) daily, administered IV or subcutaneously, usually in 2 divided doses. The morning and evening doses should be separately adjusted for an adequate diurnal rhythm of water turnover. For patients who have been controlled on intranasal desmopressin and who must be switched to the injection form, either because of poor intranasal absorption or because of the need for surgery, the comparable antidiuretic dose of the injection is about one tenth the intranasal dose.

Intranasal Desmopressin: Primary nocturnal enuresis: Dosage should be adjusted according to the individual. The recommended initial dose for patients 6 years of age and older is 20 mcg or 0.2 mL solution intranasally at bedtime. Some patients may respond to 10 mcg, and adjustment to the lower dose may be done if the patient has shown a response to 20 mcg. It is recommended that one half of the dose be administered per nostril. An adjustment up to 40 mcg is suggested if the patient does not respond. Adequately controlled studies have not been conducted beyond 4 to 8 weeks. Nasal spray: For patients receiving 10 mg, the dose should be administered in 1 nostril. Central cranial diabetes insipidus: Desmopressin dosage must be determined for each individual patient and adjusted according to the diurnal pattern of response. Response should be estimated by 2 parameters: adequate duration of sleep and adequate, not excessive, water turnover. Patients with nasal congestion and blockage have often responded well to desmopressin. The usual dosage range in adults is 0.1 to 0.4 mL daily, either as a single dose or divided into 2 or 3 doses. Most adults require 0.2 mL daily in 2 divided doses.

EFFECTIVENESS MONITORIG PARAMETERS Bleeding time and factor VIII coagulant activity, ristocetin cofactor activity, and von Willebrand factor antigen should be checked during administration of desmopressin to ensure that adequate levels are being achieved.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08. Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 97 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Didanosine (Videx)

FDA APPROVED INDICATIONS HIV infection: The treatment of HIV-1 infection in combination with other antiretroviral agents.

TREATMENT DOSE / DURATION / REGIMEN All didanosine formulations should be administered on an empty stomach, at least 30 minutes before or 2 hours after eating. For either a once-daily or twice-daily regimen, patients must take at least 2 of the appropriate strength tablets at each dose to provide adequate buffering and prevent gastric acid degradation of didanosine. Because of the need for adequate buffering, the 200 mg strength tablet should only be used as a component of a once-daily regimen. To reduce the risk of GI side effects, patients should take no more than 4 tablets at each dose. Adults: The preferred dosing frequency of didanosine is twice daily because there is more evidence to support the effectiveness of this dosing regimen. Once-daily dosing should be considered only for adult patients whose management requires once-daily dosing of didanosine. The daily dose in adult patients is dependent on weight as outlined in the table below.

Didanosine Adult Dosing Patient weight Didanosine tabletsa Didanosine buffered powderb Preferred dosing ≥ 60 kg 200 mg twice daily 250 mg twice daily < 60 kg 125 mg twice daily 167 twice daily Dosing for patients whose management requires once-daily frequency ≥ 60 kg 400 mg once daily b < 60 kg 250 mg once daily b aThe 200 mg strength tablet should only be used as a component of a once-daily regimen. bNot suitable for once-daily dosing except for patients with renal impairment. See table below (recommended dosage of didanosine in renal impairment). Children: The recommended dose of didanosine in pediatric patients is 120 mg/m2 twice a day. ODS Health Plan Customary Specialty MR Criteria Page 98 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

There are no data on once-daily dosing of didanosine in pediatric patients. Didanosine delayed-release capsules: Didanosine delayed-release capsules should be administered on an empty stomach; the capsules should be swallowed intact. The recommended daily dose is dependent on body weight and is administered as one capsule given on a once-daily schedule as follows.

Dosing of Didanosine Delayed-Release Capsules Patient weight Dosage ≥ 60 kg 400 mg once daily < 60 kg 250 mg once daily

EFFECTIVENESS MONITORING PARAMETERS Clinical response.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08.

Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 99 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antinausea Agents

Generic Name (Brand): Dolasetron (Anzemet), Granisetron (Kytril) Ondansetron (Zofran)

GUIDELINES FOR USE 1. What is the intended use of the drug? (Refer to 4 bullet points listed below) • Prevention of chemotherapy-induced nausea and vomiting – answer the following three questions and then continue to #4.

A. How many cycles/treatments are being requested? B. What is the duration of each cycle/treatment C. How many tablets per cycle/treatment are being requested?

• Prevention of radiation-therapy induced nausea and vomiting – answer the following three questions and then continue to #5.

A. How many cycles/treatments are being requested? B. What is the duration of each cycle/treatment C. How many tablets per cycle/treatment are being requested?

• Prevention of post-operative nausea and vomiting (i.e., intra-abdominal procedures, major gynecologic surgery, orthopedic surgery, ear-nose-throat surgery, laparoscopic surgery, adenotonsillectomy, or strabismus surgery), continue to #6

• Pregnancy related nausea and vomiting, continue to #7

4. Has patient tried and failed generic ondansetron? If yes, approve up to: • (#8) 1mg Kytril tablets, or • 60ml of Kytril solution, or • 400mg total of Anzemet (either (#8) 50mg or (#4) 100mg), or Approve per chemo cycle for as many cycles as requested. The requester may choose the strengths to use. If no, please consider formulary alternative generic ondansetron. It may be approved up to: • 72mg total of ondansetron tablets (either (#18) 4mg, (#9) 8mg or (#3) 24mg)

5. Has patient tried and failed generic ondansetron? If yes, approve up to: • (#2) 1mg Kytril tablets, or • 30ml of Kytril solution ONLY. Do not approve Anzemet Approve per radiation treatment for as many treatments as requested. The requester may choose trengths to use. If no, please consider formulary alternative generic ondansetron. It may be approved up to: • 24mg total of ondansetron tablets (either (#1) 24mg, (#3) 8mg or (#6) 4mg ODS Health Plan Customary Specialty MR Criteria Page 100 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

6. Has patient tried and failed ondansetron (brand name Zofran)? If yes, approve up to: • (#2) 1mg Kytril tablets, or • 30ml of Kytril solution, or • 100mg total of Anzemet (either (#2) 50mg or (#1) 100mg) Approve one time only post surgery. The requester may choose strengths to use. If no, please consider formulary alternative generic ondansetron. It may be approved up to: 16mg total of ondansetron tablets (either (#2) 8mg or (#4) 4mg)

7. Has the patient tried and failed pyridoxine (vitamin B6), promethazine or metoclopramide? If yes, approve generic ondansetron 4mg or 8mg tablets up to #3/day or ondansetron oral solution 900ml (4mg/5ml). Do not approve Kytril or Anzemet. If no, do not approve. Please consider a trial of formulary alternatives pyridoxine, promethazine or metoclopramide.

ODS Health Plan Customary Specialty MR Criteria Page 101 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

FDA APPROVED INDICATIONS The oral forms of Zofran, Kytril and Anzemet are indicated for prevention of nausea and vomiting associated with initial and repeat courses of cancer chemotherapy (CINV) and for prevention of post-operative nausea and vomiting (PONV). Zofran and Kytril are also currently approved for prevention of nausea and vomiting associated with radiation therapy. Only intravenous Anzemet is indicted for treatment of post-operative nausea and vomiting.

REFERENCES 1. Zofran® (ondansetron) prescribing information. Glaxo Smith Kline. Research Triangle Park, NC. Feb 2006. 2. Kytril® (granisetron) prescribing information Roche Laboratories Inc. Nutley NJ. Nov 2005. 3. Anzemet® (dolasetron) prescribing information. Sanofi Aventis. Kansas City MO. Jun 2005.

Effective: 10/01/06 Created: 01/01/06 Updated: 01/05/07, 11/14/07 Reviewed:______

ODS Health Plan Customary Specialty MR Criteria Page 102 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Immunologic Agents

Generic Name (Brand): Eculizumab (Soliris)

FDA APPROVED INDICATIONS Paroxysmal nocturnal hemoglobinuria (PNH): For the treatment of patients with PNH to reduce hemolysis.

TREATMENT DOSE / DURATION / REGIMEN DOSAGE: Eculizumab therapy consists of 600 mg every 7 days for the first 4 weeks, followed by 900 mg for the fifth dose 7 days later, then 900 mg every 14 days thereafter. Eculizumab should be administered at the recommended dosage regimen time points or within 2 days of these time points.

Eculizumab increases the risk of meningococcal infections. Vaccinate patients with a meningococcal vaccine at least 2 weeks prior to receiving the first dose of eculizumab; revaccinate according to current medical guidelines for vaccine use. Monitor patients for early signs of meningococcal infections; evaluate immediately if infection is suspected and treat with antibiotics if necessary.

EFFECTIVENESS MONITORING PARAMETERS Monitor RBC count and clinical response.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08. Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 103 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Baraclude

Generic Name (Brand): Entecavir (Baraclude)

INDICATIONS: BARACLUDE is indicated for the treatment of chronic hepatitis B virus infection in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease. This indication is based on histologic, virologic, biochemical, and serologic responses in nucleoside-treatment-naive and lamivudine-resistant adult subjects with HBeAg-positive or HBeAg-negative chronic HBV infection with compensated liver disease and on more limited data in adult subjects with HIV/HBV co-infection who have received prior lamivudine therapy.

PRODUCT AVAILABILITY: • Entecavir (Baraclude®) 0.05 mg/mL (210 mL) oral solution; 0.5 mg, 1 mg tablets

GUIDELINES FOR USE: 1) Is the drug prescribed by a gastroenterologist, infectious disease specialist or physician specializing in the treatment of HBV? a) If yes, go to #2. b) If no, Do Not Approve.

2) Is the patient ≥ 16 years old? a) If yes, go to #3. b) If no, do not approve.

3) Is the patient pregnant or of childbearing age? a) If yes, please verify counseling of pregnancy risk has been given to the patient, go to #4. b) If no, go to #4.

4) Has Baraclude been prescribed for this patient before? a) If yes go to #21. b) If no, go to #5.

5) Has the patient tried and failed Epivir-HBV or have a contraindication to the use of Epivir- HBV? a) If yes, go to #6. b) If no, do not approve.

6) Documentation of serum HBV DNA. a) ______copies/mL ______Date b) Go to #7.

7) Documentation of recent ALT level and documentation of liver biopsy if available. a) ______units/L ______Date b) Go to #8.

8) Is the patient HIV postive? a) If yes, go to #9. b) If no or unknown, go to #10.

9) Will the patient be taking Baraclude with concomitant HAART? a) If yes, go to #10. b) If no, do not approve.

ODS Health Plan Customary Specialty MR Criteria Page 104 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

10) Is this patient a Hepatitis B carrier requesting antiviral prophylaxis while receiving immunosuppressive or cytotoxic therapy? a) If yes, go to #19. b) If no, go to #11.

11) Does the patient have decompensated cirrhosis? a) If yes, go to #19. b) If no, go to #12.

13) Does the patient have a HBV DNA < 20,000 copies/mL? a) If yes, deny therapy. b) If no, go to #14.

14) Does the patient have persistently elevated ALT [> 30 IU/L (men) or >19 IU/L (women)] observed for 3 to 6 months? a) If yes and prescribing go to #19. b) If no, go to #15. 15) 15) Does the patient have moderate-severe hepatitis evidenced by recent biopsy (i.e. Ishak necroinflammatory score > 4)? a) If yes, go to #19. b) If no, deny therapy.

16) Does the patient have a HBV DNA < 2000 copies/ml? a) If yes, deny therapy. b) If no, go to #17.

17) Does the patient have persistently elevated ALT [> 30 IU/L (men) or >19 IU/L (women)] observed for 3 to 6 months? a) If yes, go to #19. b) If no, go to #18.

18) Does the patient have moderate-severe hepatitis evidenced by recent biopsy (i.e. Ishak necroinflammatory score > 4)? a) If yes, go to #19. b) If no, deny therapy

19) Approve the following for: a) Neucleoside treatment naïve Adults: Baraclude 0.5mg once daily for 12 months. b) Patients taking concurrent lamivudine or have lamivudine resistance: Baraclude 1mg once daily for 12 months.

RENEWAL AFTER INITIAL THERAPY:

20) Is the patient HBeAg positive? a) If yes, go to #21.

ODS Health Plan Customary Specialty MR Criteria Page 105 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

b) If not go to #22.

21) Has the patient been treated with Baraclude for 12 months beyond seroconversion? a) If yes, do not approve b) If no, the end point of treatment is seroconversion from HBeAg to anti HBe or undetectable HBV DNA levels and recommended duration is as follows – Approve for 12 months as typically therapy should continue for 6-12 months after HBeAg seroconversion.

22) If HBeAG negative, end point of treatment is achievement of sustained normalization of ALT and undetectable HBV DNA and recommended duration is as followed: a) Approve for 1 year (Long-term treatment usually required unless HBsAg seroconversion).

Special Instructions:

Pregnancy Risk Factor: C

Clinical Information  Dosing adjustments in renal impaired patients are recommended.  Severe acute exacerbations of hepatitis have been seen in patients who have discontinued anti-hepatitis B therapy. Hepatic function should be monitored closely for at least several months in patients who discontinue therapy.  Baraclude should not be used in HIV co-infected patients not on concomitant HAART to avoid the development of drug-resistant HIV mutations.

DOSING: Baraclude -0.5 mg PO once daily (nucleoside-naïve patients) -1 mg PO once daily (lamivudine-refractory patients)

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 106 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Denileukin diftitox (Ontak)

FDA APPROVED INDICATIONS Cutaneous T-cell lymphoma (CTCL): Persistent or recurrent CTCL whose malignant cells express the CD25 component of the interleukin-2 (IL-2) receptor. The safety and efficacy of denileukin diftitox in patients with CTCL whose malignant cells do not express the CD25 component of the IL-2 receptor have not been examined.

TREATMENT DOSE / DURATION / REGIMEN Denileukin diftitox is for intravenous (IV) use only. The recommended treatment regimen (1 treatment cycle) is 9 or 18 mcg/kg/day administered IV for 5 consecutive days every 21 days. Denileukin diftitox should be infused over at least 15 minutes. If infusional adverse reactions occur, the infusion should be discontinued or the rate should be reduced depending on the severity of the reaction. There is no clinical experience with prolonged infusion times (longer than 80 minutes). Duration of therapy: The optimal duration of therapy has not been determined; however, only 2% (1/51) of patients who did not demonstrate a 25% or more decrease in tumor burden prior to the fourth course of treatment subsequently responded.

EFFECTIVENESS MONITORING PARAMETERS

ODS Health Plan Customary Specialty MR Criteria Page 107 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

Objective tumor response, partial response and complete response (50% reduction in tumor burden that was sustained for at least 6 weeks, 4 months, 9 months respectively)

INJECTABLE ADMINISTRATION REQUIREMENTS Administration should be supervised by medical professional experienced in the use of anticancer agents.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 108 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Dexrazoxane (Zinecard)

FDA APPROVED INDICATIONS Cardiomyopathy associated with doxorubicin use (except Totect): For reducing the incidence and severity of cardiomyopathy associated with doxorubicin administration in women with metastatic breast cancer who have received a cumulative doxorubicin dose of 300 mg/m2 and who will continue to receive doxorubicin therapy to maintain tumor control. It is not recommended for use with the initiation of doxorubicin therapy. Extravasation resulting from intravenous (IV) anthracycline chemotherapy (Totect only): For the treatment of extravasation resulting from IV anthracycline chemotherapy.

TREATMENT DOSE / DURATION / REGIMEN Cardiomyopathy associated with doxorubicin use (except Totect): Dose: The recommended dose ratio of dexrazoxane:doxorubicin is 10:1 (eg, dexrazoxane 500 mg/m2:doxorubicin 50 mg/m2). Renal function impairment: In patients with moderate to severe renal function impairment (creatinine clearance [CrCl] values less than 40 mL/min), the recommended dose ratio of dexrazoxane:doxorubicin is 5:1 (eg, dexrazoxane 250 mg/m2:doxorubicin 50 mg/m2).

EFFECTIVENESS MONITORING PARAMETERS

ODS Health Plan Customary Specialty MR Criteria Page 109 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

None.

INJECTABLE ADMINISTRATION REQUIREMENTS Administration should be supervised by medical professional experienced in the use of anticancer agents.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 110 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Docetaxel (Taxotere)

FDA APPROVED INDICATIONS 1. Breast cancer: For the treatment of patients with locally advanced or metastatic breast cancer after failure of prior chemotherapy. In combination with doxorubicin and cyclophosphamide for the adjuvant treatment of patients with operable node-positive breast cancer. 2. Gastric adenocarcinoma: In combination with cisplatin and fluorouracil for the treatment of patients with advanced gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, who have not received prior chemotherapy for advanced disease. 3. Head and neck cancer: In combination with cisplatin and fluorouracil for the induction treatment of patients with inoperable locally advanced squamous cell carcinoma of the head and neck (SCCHN). 4. NSCLC: As a single agent for the treatment of patients with locally advanced or metastatic NSCLC after failure of prior platinum-based chemotherapy. In combination with cisplatin for the treatment of patients with unresectable, locally advanced, or metastatic NSCLC who have not previously received chemotherapy for this condition. 5. Prostate cancer: In combination with prednisone for the treatment of patients with androgen-independent (hormone-refractory) metastatic prostate cancer.1

ODS Health Plan Customary Specialty MR Criteria Page 111 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

TREATMENT DOSE / DURATION / REGIMEN Breast cancer: 60 to 100 mg/m2 administered intravenously (IV) over 1 hour every 3 weeks. Adjuvant treatment of breast cancer: 75 mg/m2 administered 1 hour after doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 every 3 weeks for 6 courses. Gastric adenocarcinoma: 75 mg/m2 as 1-hour IV infusion, followed by cisplatin 75 mg/m2, as a 1- to 3-hour IV infusion (both on day 1 only), followed by fluorouracil 750 mg/m2/day given as a 24-hour continuous IV infusion for 5 days, starting at the end of the cisplatin infusion. Treatment is repeated every 3 weeks. Head and neck cancer: 75 mg/m2 as a 1-hour IV infusion, followed by cisplatin 75 mg/m2 IV over 1 hour, on day 1, followed by fluorouracil as a continuous IV infusion at 750 mg/m2/day for 5 days. This regimen is administered every 3 weeks for 4 cycles. Following chemotherapy, patients should receive radiotherapy. Patients must receive premedication with antiemetics and appropriate hydration (prior to and after cisplatin administration). All patients on the docetaxel- containing arm of the TAX 323 study received prophylactic antibiotics. NSCLC: After failure of prior platinum-based chemotherapy: For treatment after failure of prior platinum-based chemotherapy, docetaxel was evaluated as monotherapy, and the recommended dose of docetaxel is 75 mg/m2 administered IV over 1 hour every 3 weeks. A dose of 100 mg/m2 in patients who had been previously treated with chemotherapy was associated with increased hematologic toxicity, infection, and treatment-related mortality in randomized, controlled trials. Chemotherapy-naïve patients: For chemotherapy-naïve patients, docetaxel was evaluated in combination with cisplatin. The recommended dose of docetaxel is 75 mg/m2 administered IV over 1 hour, immediately followed by cisplatin 75 mg/m2 over 30 to 60 minutes every 3 weeks.1 Prostate cancer: 75 mg/m2 every 3 weeks as a 1-hour infusion. Prednisone 5 mg orally twice daily is administered continuously.1

EFFECTIVENESS MONITORING PARAMETERS Clinical and pathologic response.

INJECTABLE ADMINISTRATION REQUIREMENTS Administration should be supervised by medical professional experienced in the use of anticancer agents.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 112 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Doxorubicin (Doxil)

FDA APPROVED INDICATIONS AIDS-related Kaposi sarcoma (KS): For the treatment of AIDS-related KS in patients with disease that has progressed on prior combination chemotherapy or in patients who are intolerant to such therapy. The treatment of patients with AIDS-related KS is based on objective tumor response rates. No results are available from controlled trials that demonstrate a clinical benefit resulting from this treatment, such as improvement in disease-related symptoms or increased survival. Multiple myeloma: In combination with bortezomib for the treatment of patients with multiple myeloma who have not previously received bortezomib and have received at least 1 prior therapy. Ovarian cancer: For the treatment of patients with ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy.

TREATMENT DOSE / DURATION / REGIMEN AIDS-related KS: Doxorubicin hydrochloride liposome injection should be administered intravenously (IV) at a dose of 20 mg/m2 (doxorubicin hydrochloride equivalent). An initial rate of 1 mg/min should be used to minimize the risk of infusion-related reactions. If no infusion-related adverse reactions are observed, the infusion rate should be increased to complete the

ODS Health Plan Customary Specialty MR Criteria Page 113 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

administration of the drug over 1 hour. The dose should be repeated once every 3 weeks for as long as patients respond satisfactorily and tolerate treatment. Multiple myeloma: Bortezomib is administered at a dose of 1.3 mg/m2 as an IV bolus on days 1, 4, 8, and 11 every 3 weeks. Liposomal doxorubicin 30 mg/m2 should be administered as a 1- hour IV infusion on day 4 following bortezomib. With the first liposomal doxorubicin dose, an initial rate of 1 mg/min should be used to minimize the risk of infusion-related reactions. If no infusion-related adverse reactions are observed, the infusion rate should be increased to complete the administration of the drug over 1 hour. Patients may be treated for up to 8 cycles, until disease progression or the occurrence of unacceptable toxicity. Ovarian cancer: Doxorubicin hydrochloride liposome injection should be administered IV at a dose of 50 mg/m2 (doxorubicin hydrochloride equivalent) at an initial rate of 1 mg/min to minimize the risk of infusion reactions. If no infusion-related adverse reactions are observed, the rate of infusion can be increased to complete administration of the drug over 1 hour. The patient should be dosed once every 4 weeks, for as long as the patient does not progress, shows no evidence of cardiotoxicity, and continues to tolerate treatment. A minimum of 4 courses is recommended because the median time to response in clinical trials was 4 months.

EFFECTIVENESS MONITORING PARAMETERS Clinical and pathologic response.

INJECTABLE ADMINISTRATION REQUIREMENTS Administration should be supervised by medical professional experienced in the use of anticancer agents.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 114 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Raptiva

Generic Name (Brand): Efalizumab (Raptiva)

GUIDELINES FOR USE 1. Is the prescription written by a dermatologist or a rheumatologist? If yes, continue to #2. If no, do not approve. 2. Does the patient have generalized moderate to severe plaque psoriasis (involving ≥ 10% of body surface area or with a PASI score of at least 12)? If yes, continue to #3. If no, do not approve. 3. Has the patient failed or does the patient have a contraindication to 2 or more forms of preferred therapy (PUVA, UVB, acitretin, methotrexate or cyclosporine)? If yes, continue to #4. If no, do not approve. 4. Does the patient have an active infection (including, but not limited to histoplasmosis, cytomegalovirus, tuberculosis and HIV), a history of recurring infections or a history of systemic malignancy, or is the patient currently receiving other immunosuppressive agents (i.e., cyclosporine, methotrexate, etanercept, alefacept, infliximab)? If yes, do not approve. If no, continue to #5. 5. Approve for 1 year with a quantity limited to #4 vials/month.

FDA APPROVED INDICATION Raptiva is indicated for the treatment of adult patients (18 years or older) with chronic moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

REFERENCES 1. Raptiva product information, Genentech June 2005. 2. Lebwohl M, Tyring SK, Hamilton TK, Toth D, Glazer S, Tawfik NH, et al. A novel targeted T- cell modulator, efalizumab, for plaque psoriasis. NEJM 2003; 349(21): 2004-2013. 3. Gordon KB, Papp KA, Hamilton TK, Walicke PA, Dummer W, Li N, et al. Efalizumab for patients with moderate to severe plaque psoriasis: a randomized controlled trial. JAMA 2003; 290(23): 3073-3080. 4. Raptiva. MedImpact P&T monograph, February 2004.

Effective: 10/01/08 Created: 01/01/06 Updated: ______Reviewed: 01/05/07, 11/14/07

ODS Health Plan Customary Specialty MR Criteria Page 115 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Epirubicin (Ellence)

FDA APPROVED INDICATIONS Breast cancer: Epirubicin HCl injection is indicated as a component of adjuvant therapy in patients with evidence of axillary node tumor involvement following resection of primary breast cancer. TREATMENT DOSE / DURATION / REGIMEN The recommended starting dose of epirubicin HCl is 100 to 120 mg/m2 The following regimens were used in the trials supporting use of epirubicin HCl as a component of adjuvant therapy in patients with axillary-node positive breast cancer:

Epirubicin Regimens in Adjuvant Therapy CEF-120 Cyclophosphamide 75 mg/m2 orally days 1 to 14 Epirubicin 60 mg/m2 IV days 1, 8 5-flourouracil (repeated every 500 mg/m2 IV days 1, 8 28 days for 6 cycles) FEC-100* 5-fluorouracil 500 mg/m2 Epirubicin 100 mg/m2 Cyclophosphamide 500 mg/m2 *All drugs were administered intravenously on day 1 and repeated every 21 days for 6 cycles.

ODS Health Plan Customary Specialty MR Criteria Page 116 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

EFFECTIVENESS MONITORING PARAMETERS Clinical and pathologic response.

INJECTABLE ADMINISTRATION REQUIREMENTS Administration should be supervised by medical professional experienced in the use of anticancer agents.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 117 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Flolan

Generic Name (Brand): Epoprostenol (Flolan)

INDICATIONS: FLOLAN is indicated for the long-term intravenous treatment of primary pulmonary hypertension and pulmonary hypertension associated with the scleroderma spectrum of disease in NYHA Class III and Class IV patients who do not respond adequately to conventional therapyI or IV symptoms, to improve exercise ability and decrease the rate of clinical worsening.

GUIDELINES FOR USE: 1) Is requested drug being prescribed by a cardiologist or pulmonologist specializing in the treatment of Pulmaonary Arterial Hypertension (PAH)? a) If yes, go to #2. b) If no, do not approve.

2) Does the patient have a diagnosis for severe pulmonary arterial hypertension (WHO functional status Class III-IV)? a) If yes, go to #3. b) If no, do not approve.

3) What is patients 6-minute walk distance?______a) Go to #4.

4) What is patient’s “Borg” dyspnea score?______a) Go to #5.

5) Has requested drug been prescribed for this patient before? a) If yes, go to #7. b) If no, go to #6.

6) Has the patient tried and failed an adequate course (four weeks) of sildenafil (Revatio) 20mg t.i.d.? a) If yes, Approve Ventavis for 12 weeks. b) If no, do not approve.

Renewal Criteria: 7) Has patient maintained or demonstrated improvement over baseline 6 minute walk distance or improvement in the Borg dyspnea score? a) If yes, go to #8. b) If no do not approve.

8) Approve Flolan for 12 months.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 118 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Tarceva

Generic Name (Brand): Erlotinib (Tarceva)

NOTE: This prior authorization edit will apply to NEW STARTS ONLY and will not apply to beneficiaries transitioning to the plan on this medication.

GUIDELINES FOR USE 1. Does patient have a diagnosis of locally advanced or metastatic Non-Small Cell Lung Cancer (NSCLC)? If yes, continue to #3. If no, continue to #2. 2. Does patient have a diagnosis of locally advanced, unrescetable or metastatic pancreatic cancer? If yes, continue to #4. If no, do not approve. 3. Has patient failed at least on prior chemotherapy regimen? If yes, continue to #4. If no, do not approve. 4. Approve for 12 months.

FDA APPROVED INDICATIONS 1. Tarceva monotherapy is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen. 2. Tarceva in combination with gemcitabine is indicated for the first-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer.

REFERENCES Tarceva product information. OSI Pharmaceuticals, Inc. and Genentech Inc. 2007.

Effective:10/01/08 Created: 04/01/07 Updated:______Reviewed: 11/14/07

ODS Health Plan Customary Specialty MR Criteria Page 119 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Estramustine (Emcyte)

FDA APPROVED INDICATIONS Metastatic/Progressive prostate cancer: Palliative treatment of metastatic and/or progressive carcinoma of the prostate.

TREATMENT DOSE / DURATION / REGIMEN Recommended daily oral dosage: 14 mg/kg/day (ie, one 140 mg capsule for each 10 kg or 22 lb) given in 3 or 4 divided doses (dosage range, 10 to 16 mg/kg/day).Take with water at least 1 hour before or 2 hours after meals. Milk, milk products, and calcium-rich foods or drugs (such as calcium-containing antacids) must not be taken simultaneously with estramustine phosphate sodium. Duration of therapy: Treat for 30 to 90 days before assessing the possible benefits of continued therapy. Continue therapy as long as response is favorable. Some patients have been maintained on therapy for more than 3 years at doses ranging from 10 to 16 mg/kg/day. Storage / Stability: Refrigerate at 2° to 8°C (36° to 46°F). Capsules may be left out of the refrigerator for 24 to 48 hours without affecting potency.

EFFECTIVENESS MONITORING PARAMETERS Clinical and pathologic response.

ODS Health Plan Customary Specialty MR Criteria Page 120 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

INJECTABLE ADMINISTRATION REQUIREMENTS None.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 121 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Enbrel

Generic Name (Brand): Etanercept (Enbrel)

GUIDELINES FOR USE INITIAL CRITERIA: (NOTE: FOR RENEWAL CRITERIA SEE BELOW) 1. Does the patient have active rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis or juvenile arthritis? If yes, continue to #2. If no, continue to #4. 2. Has the treatment been prescribed by or is it currently being supervised by a Rheumatologist? If yes, continue to #3. If no, do not approve. 3. Has the patient tried and failed, or experienced intolerable side effects to at least one of the following DMARD agents: methotrexate, leflunomide, azathioprine, cyclosporine, hydroxychloroquine, minocycline, penicillamine, sulfasalazine, gold sodium thiomalate, aurothioglucose or auranofin? If yes, continue to #7. If no, do not approve. Recommend a formulary DMARD. 4. Is the patient ≥ 18 years of age with chronic moderate to severe plaque psoriasis of greater than 10% body surface area (BSA)? If yes, continue to #5. If no, do not approve. 5. Has the treatment been prescribed or is it currently being supervised by a Dermatologist? If yes, continue to #6. If no, do not approve. 6. Has the patient failed or does the patient have a contraindication to 2 or more forms of preferred therapy (PUVA, UVB, acitretin, methotrexate or cyclosporine)? If yes, continue to #7. If no, do not approve.

CONTINUED ON NEXT PAGE

ODS Health Plan Customary Specialty MR Criteria Page 122 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

INITIAL CRITERIA (CONTINUED): NOTE: FOR RENEWAL CRITERIA SEE BELOW 7. Is the patient taking Enbrel with Kineret OR Orencia or Humira? If yes, do not approve. If no, continue to #8. 8. Total initial approval equal to 3 months: a. Active rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis or juvenile arthritis: 8 x 25mg kits per month x 3 months or 4 x 50mg kits per month x 3 months. b. Chronic plaque psoriasis: 16 x 25mg kits per month x 3 months or 8 x 50mg kits per month x 3 months.

RENEWAL CRITERIA (NOTE: FOR INITIAL CRITERIA SEE ABOVE) 1. Does the patient have active rheumatoid arthritis, psoriatic arthritis, or juvenile arthritis? If yes, continue to #2. If no, continue to #3. 2. Has the patient experienced 20% or greater improvement in tender joint count or swollen joint count? If yes, continue to #7. If no, do not approve. 3. Does the patient have chronic plaque psoriasis? If yes, continue to #4. If no, continue to #5. 4. Has the patient experienced a Psoriasis Area and Severity index (PASI 50: improvement > 50% in PASI score) or a significant improvement in Quality of Life observed by the physician and patient (i.e., Dermatology Life Quality Index)? If yes, continue to #7. If no, do not approve.

CONTINUED ON NEXT PAGE

ODS Health Plan Customary Specialty MR Criteria Page 123 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Enbrel (continued)

Generic Name (Brand): Etanercept (Enbrel)

RENEWAL CRITERIA (CONTINUED) NOTE: FOR INITIAL CRITERIA SEE ABOVE 5. Does the patient have ankylosing spondylitis? If yes, continue to #6. If no, do not approve 6. Has the patient experienced an improvement of at least 50% or 2 units (scale of 1-10) in the Bath ankylosing spondylitis disease activity Index (BASDAI)? If yes, continue to #7. If no, do not approve 7. Approve 8 x 25mg kits per month x 1 year or 4 x 50mg kits per month x 1 year.

FDA APPROVED INDICATION Rheumatoid arthritis, psoriatic arthritis, chronic moderate to severe plaque psoriasis, ankylosing spondylitis and juvenile rheumatoid arthritis.

REFERENCES 1. Enbrel product information. Immunex Corporation. 2. Anti-Tumor Necrosis Factor Agents. MedImpact P&T Monograph, May 2006. 3. Braun J, Davis J et al.. First update of the international ASAS consensus statement for the use of anti-TNF agents in patients with ankylosing spondylitis. Ann Rheum Dis. 2006;65(3):316-20.

Created: 09/01/05 Updated:10/12/05, 02/07/07, 11/14/07 Reviewed: _____

ODS Health Plan Customary Specialty MR Criteria Page 124 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Endocrine and Metabolic Agents

Generic Name (Brand): Etonogestrel (Implanon)

DISTRIBUTION Limited distribution.

FDA APPROVED INDICATIONS Contraception: For the prevention of pregnancy.

TREATMENT DOSE / DURATION / REGIMEN All health care providers performing insertions and/or removals of the etonogestrel implant must receive instruction and training and, where appropriate, supervision prior to inserting or removing the etonogestrel implant. Insert the etonogestrel implant subdermally in the inner side of the upper arm (nondominant arm) about 6 to 8 cm (2½ to 3 inches) above the elbow crease overlying the groove between the biceps and the triceps. The etonogestrel implant must be inserted by the expiration date stated on the packaging. The etonogestrel implant must be removed by the end of the third year and may be replaced by a new implant at the time of removal if continued contraceptive protection is desired.

EFFECTIVENESS MONITORING PARAMETERS Clinical response.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08. Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 125 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Etoposide (VePesid)

FDA APPROVED INDICATIONS 1. Refractory testicular tumors: Adequate data on the use of etoposide capsules in the treatment of testicular cancer are not available. 2. Small cell lung cancer: In combination with other approved chemotherapeutic agents, as first-line treatment in patients with small cell lung cancer.

TREATMENT DOSE / DURATION / REGIMEN Small cell lung cancer: 2 times the IV dose rounded to the nearest 50 mg (ie, two times 35 mg/m2/day for 4 days to 50 mg/m2/day for 5 days).The dosage, by either route, should be modified to take into account the myelosuppressive effects of other drugs in the combination or the effects of prior x-ray therapy or chemotherapy which may have compromised bone marrow reserve.

EFFECTIVENESS MONITORING PARAMETERS Clinical and pathologic response.

INJECTABLE ADMINISTRATION REQUIREMENTS Administration of injectable etoposide should be supervised by medical professional experienced in the use of anticancer agents.

ODS Health Plan Customary Specialty MR Criteria Page 126 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 127 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Exemestane (Aromasin)

FDA APPROVED INDICATIONS Breast cancer: For the treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy.

TREATMENT DOSE / DURATION / REGIMEN The recommended dose of exemestane tablets is 25 mg once daily after a meal. Treatment with exemestane should continue until tumor progression is evident.

EFFECTIVENESS MONITORING PARAMETERS Exemestane 25 mg administered once daily was evaluated in a randomized double-blind, multicenter, multinational comparative study and in 2 multicenter single-arm studies of postmenopausal women with advanced breast cancer who had disease progression after treatment with tamoxifen for metastatic disease or as adjuvant therapy. Some patients also have received prior cytotoxic therapy, either as adjuvant treatment or for metastatic disease. The primary purpose of the 3 studies was evaluation of objective response rate (complete response [CR] and partial response [PR]). Time to tumor progression and overall survival were also assessed in the comparative trial. Response rates were assessed based on World Health Organization (WHO) criteria, and in the comparative study

ODS Health Plan Customary Specialty MR Criteria Page 128 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

INJECTABLE ADMINISTRATION REQUIREMENTS None.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 129 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Hematological Agents

Generic Name (Brand): Factor IX (BeneFix), Factor VIIa (NovoSeven) Factor VIII (Advate)

FDA APPROVED INDICATIONS Factor IX (BeneFix) Factor IX deficiency (hemophilia B [Christmas disease]): For the control or prevention of bleeding episodes. Do not use in mild factor ΙX deficiency if fresh frozen plasma is effective. (See individual package inserts for product specifications.) Factor VIIa (NovoSeven) Bleeding episodes: For the treatment of bleeding episodes in hemophilia A or B patients with inhibitors to factor VIII or factor IX and in patients with acquired hemophilia. For the prevention of bleeding in surgical interventions or invasive procedures in hemophilia A or B patients with inhibitors to factor VIII or factor IX and in patients with acquired hemophilia. For the treatment of bleeding episodes in patients with congenital factor VII deficiency. For the prevention of bleeding in surgical interventions or invasive procedures in patients with congenital factor VII deficiency Factor VIII (Advate) In hemophilia A (classical hemophilia) for the prevention and control of bleeding episodes. Antihemophilic factor (recombinant) (Advate rAHF-PFM) is also indicated in the perioperative management of patients with hemophilia A. Antihemophilic factor (recombinant) (Advate rAHF- PFM) can be of therapeutic value in patients with Factor VIII inhibitors not exceeding 10 Bethesda units (BU) per mL. However, in patients with a known or suspected inhibitor to Factor VIII, the plasma Factor VIII level should be monitored frequently and the dose of antihemophilic factor (recombinant) (Advate rAHF-PFM) should be adjusted accordingly.

Antihemophilic factor (recombinant) (Advate rAHF-PFM) is not indicated for the treatment of von Willebrand's disease.

TREATMENT DOSE / DURATION / REGIMEN Factor IX (BeneFix) Dosage: Dosage and duration of treatment for all factor IX products depend on the severity of the factor IX deficiency, the location and extent of bleeding, and the patient's clinical condition,

ODS Health Plan Customary Specialty MR Criteria Page 130 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

age, and recovery of factor IX. To ensure that the desired factor IX activity level has been achieved, precise monitoring using the factor IX assay is advised. Doses should be titrated using the factor IX activity and pharmacokinetic parameters, such as half-life and recovery, as well as taking the clinical situation into Factor VIIa (NovoSeven) Evaluation of hemostasis should be used to determine the effectiveness of coagulation factor VIIa and to provide a basis for modification of the coagulation factor VIIa treatment schedule; coagulation parameters do not necessarily correlate with or predict the effectiveness of coagulation factor VIIa Factor VIII (Advate) The expected in vivo peak increase in Factor VIII level expressed as units/dL of plasma or percent of normal can be estimated by multiplying the dose administered per kg body weight (units/kg) by 2.

EFFECTIVENESS MONITORING PARAMETERS Although dose can be estimated by the calculations above, it is highly recommended that, whenever possible, appropriate laboratory tests including serial activity assays be performed on the patient's plasma at suitable intervals to ensure that adequate levels have been reached and are maintained.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08. Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 131 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Fludarabine (Fludara)

FDA APPROVED INDICATIONS B-cell chronic lymphocytic leukemia: For the treatment of patients with B-cell chronic lymphocytic leukemia (CLL) who have not responded to or whose disease has progressed during treatment with at least 1 standard alkylating-agent containing regimen. The safety and effectiveness of fludarabine in previously untreated or non-refractory patients with CLL have not been established.

TREATMENT DOSE / DURATION / REGIMEN Usual dose: 25 mg/m2 administered intravenously over a period of approximately 30 minutes daily for 5 consecutive days. Each 5 day course of treatment should commence every 28 days. Dosage may be decreased or delayed based on evidence of hematologic or nonhematologic toxicity. Physicians should consider delaying or discontinuing the drug if neurotoxicity occurs. Duration: The optimal duration of treatment has not been clearly established. It is recommended that 3 additional cycles of fludarabine be administered following the achievement of a maximal response and then the drug should be discontinued.

EFFECTIVENESS MONITORING PARAMETERS response rates were obtained using standardized response criteria developed by the National Cancer Institute CLL Working Group and were achieved in heavily pretreated patients. The

ODS Health Plan Customary Specialty MR Criteria Page 132 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

ability of fludarabine to induce a significant rate of response in refractory patients suggests minimal cross-resistance with commonly used anti-CLL agents.

INJECTABLE ADMINISTRATION REQUIREMENTS Administration should be supervised by medical professional experienced in the use of anticancer agents.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 133 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Fertility Agents

Generic Name (Brand): Follitropin Alfa (Gonal-f), Follitropin Beta (Follistim)

FDA APPROVED INDICATIONS Follitropin Alfa (Gonal-f) Ovulation induction: For the induction of ovulation and pregnancy in oligo-anovulatory infertile patients in whom the cause of infertility is functional and not primary ovarian failure. Multifollicular development during assisted reproductive technology (ART): To stimulate the development of multiple follicles in ovulatory patients participating in an ART program (eg, in vitro fertilization). Male infertility (except prefilled pen): For the induction of spermatogenesis in men with primary and secondary hypogonadotropic hypogonadism in whom the cause of infertility is not primary testicular failure. Follitropin Beta (Follistim) Follicle stimulation: For the development of multiple follicles in ovulatory patients participating in an assisted reproductive technology (ART) program. OI: For the induction of ovulation and pregnancy in anovulatory infertile patients in whom the cause of infertility is functional and not due to primary ovarian failure.

TREATMENT DOSE / DURATION / REGIMEN Follitropin Alfa (Gonal-f) Ovulation induction: The initial dose for the first cycle is 75 units/day subcutaneous. An incremental adjustment in dose of up to 37.5 units may be considered after 14 days. Further dose increases of the same magnitude can be made, if necessary, every 7 days. Do not exceed a treatment duration of 35 days unless an estradiol rise indicates imminent follicular development. To complete follicular development and effect ovulation in the absence of an endogenous luteinizing hormone surge, give 5,000 units human chorionic gonadotropin (hCG) 1 day after the last dose of follitropin alfa. Withhold hCG if the serum estradiol is greater than 2,000 pg/mL. If the ovaries are abnormally enlarged or abdominal pain occurs, discontinue follitropin alfa treatment, do not administer hCG, and advise the patient not to have intercourse; this may reduce the chance of developing Ovarian Hyperstimulation Syndrome (OHSS) and, should spontaneous ovulation occur, reduce the chance of multiple gestations. Conduct a follow-up visit in the luteal phase.

ODS Health Plan Customary Specialty MR Criteria Page 134 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

Individualize initial dose in subsequent cycles for each patient based on response in the preceding cycle. Doses larger than 300 units/day of follicle stimulating hormone are not routinely recommended. As in the initial cycle, 5,000 units of hCG must be given 1 day after the last dose of follitropin alfa to complete follicular development and induce ovulation. Follow the above precautions to minimize the chances of developing OHSS Use the lowest dose consistent with the expectation of good results. Over the course of treatment, doses of follitropin alfa may range up to 300 units/day depending on patient response. Give until adequate follicular development is indicated by serum estradiol and vaginal ultrasonography. A response is generally evident after 5 to 7 days. Base subsequent monitoring intervals on patient response.

Multifollicular development during ART: Initiate in the early follicular phase (cycle day 2 or 3) at a dose of 150 units/day, until sufficient follicular development is attained. In most cases, therapy should not exceed 10 days. In patients undergoing ART under 35 years of age, whose endogenous gonadotropin levels are suppressed, initiate follitropin alfa prefilled pens at a dose of 150 units/day. In patients undergoing ART 35 years of age and older, whose endogenous gonadotropin levels are suppressed, initiate follitropin alfa prefilled pens at a dose of 225 units/day. Continue treatment until adequate follicular development is indicated as determined by ultrasound in combination with measurement of serum estradiol levels. Consider dose adjustments after 5 days based on the patient's response; adjust subsequent dosage no more frequently than every 3 to 5 days and by no more than 75 to 150 units additionally at each adjustment. Doses greater than 450 units/day are not recommended. Once adequate follicular development is evident, administer hCG (5,000 to 10,000 units) to induce final follicular maturation in preparation for oocyte retrieval. Withhold hCG in cases where the ovaries are abnormally enlarged on the last day of therapy to reduce the risk of developing OHSS.

Male infertility: The dose of follitropin alfa to induce spermatogenesis must be individualized for each patient. Give follitropin alfa in conjunction with hCG. Prior to concomitant therapy with follitropin alfa and hCG, pretreatment with hCG alone (1,000 to 2,250 units 2 to 3 times/week) is required. Continue treatment for a period sufficient to achieve serum testosterone levels within the normal range. Such pretreatment may require 3 to 6 months and the dose of hCG may need to be increased to achieve normal testosterone levels. After normal serum testosterone levels are reached, the recommended dose of follitropin alfa is 150 units administered subcutaneous 3 times/week and the recommended dose of hCG is 1,000 units (or the dose required to maintain serum testosterone levels within the normal range) 3 times/week. Use the lowest dose of follitropin alfa that induces spermatogenesis. If azoospermia persists, the dose may be increased to a maximum of 300 units 3 times/week. Follitropin alfa may need to be administered for up to 18 months to achieve adequate spermatogenesis.

Follitropin Beta (Follistim) Dose conversion of follitropin beta administered with the Follistim Pen: Consider a lower starting dose for gonadotropin stimulation and dose adjustments during gonadotropin stimulation for each patient. For that purpose, the following dose conversion table might be a useful reference.

Follitropin Beta Administered with the Follistim Pen Dose Conversion Tablea1 Lyophilized recombinant Follitropin beta dosing FSH with the Follistim Pen

ODS Health Plan Customary Specialty MR Criteria Page 135 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

dosing in ampules or vials, using conventional syringe 75 units 50 units 150 units 125 units 225 units 175 units 300 units 250 units 375 units 300 units 450 units 375 units aEach value represents an 18% difference rounded to the nearest 25 unit increment.

EFFECTIVENESS MONITORING PARAMETERS Laboratory and clinical response.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08. Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 136 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Arixtra

Generic Name (Brand): Fondaparinux (Arixtra)

GUIDELINES FOR USE 1. Is this for prevention (prophylaxis) of deep vein thrombosis (DVT) after hip fracture surgery, hip replacement surgery, knee replacement surgery or prevention of venous thromboembolism (VTE) in patients undergoing abdominal surgery? If yes, continue to #3. If no, continue to #2. 2. Is the patient receiving fondaparinux for outpatient treatment of acute deep vein thrombosis (DVT) or acute pulmonary edema (PE) administered in conjunction with warfarin? If yes, continue to #3. If no, do not approve. 3. Is the patient currently stabilized on oral warfarin (INR greater than 2)? If yes, continue to #4. If no, continue to #5. 4. Has the patient been at a therapeutic INR level (INR greater than 2) for at least 2 days? If yes, do not approve. If no, continue to #5. 5. Approve for quantity of #10 syringes.

FDA APPROVED INDICATION • Prevention of DVT in patients undergoing hip fracture surgery, hip replacement surgery, or knee replacement surgery or treatment of acute DVT and PE. • Treatment of acute DVT when administered in conjunction with warfarin. Treatment of acute PE when administered in conjunction with warfarin when initial therapy is administered in the hospital. • Use in patients undergoing abdominal surgery who are at risk for thromboembolic complications.

REFERENCES Arixtra Product Information, Organon Sanofi-Synthelabo. 2007.

Effective: 10/01/06 Created: 01/01/06 Updated: 11/14/07 Reviewed: 01/05/07

ODS Health Plan Customary Specialty MR Criteria Page 137 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Fulvestrant (Faslodex)

FDA APPROVED INDICATIONS Breast cancer: For the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy.

TREATMENT DOSE / DURATION / REGIMEN Adults: 250 mg administered intramuscularly into the buttock at intervals of 1 month as either a single 5 mL injection or 2 concurrent 2.5 mL injections. EFFECTIVENESS MONITORING PARAMETERS The effectiveness endpoints were response rates (RR), based on the Union Internationale Contre le Cancer (UICC) criteria, and time to progression (TTP). Survival time was also determined. INJECTABLE ADMINISTRATION REQUIREMENTS Administration should be supervised by medical professional experienced in the use of anticancer agents. REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 138 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Endocrine and Metabolic Agents

Generic Name (Brand): Galsulfase (Naglazyme)

DISTRIBUTION Limited distribution. A clinical surveillance program has been established in order to better understand the variability and progression of the disease in the population as a whole, and to monitor and evaluate long-term treatment effects of galsulfase. The clinical surveillance program will also monitor the effect of galsulfase on pregnant women and their offspring, and determine if galsulfase is excreted in breast milk. Encourage patients to participate and advise them that their participation is voluntary and may involve long-term follow-up. For more information, visit http://www.MPSVI.com or call 1-866-906-6100.

FDA APPROVED INDICATIONS Mucopolysaccharidosis VI: For patients with mucopolysaccharidosis VI (MPS VI; Maroteaux-Lamy syndrome).

TREATMENT DOSE / DURATION / REGIMEN Dosage: 1 mg/kg of body weight administered once weekly as an intravenous (IV) infusion.

EFFECTIVENESS MONITORING PARAMETERS Galsulfase has been shown to improve walking and stair-climbing capacity.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08. Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 139 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Anti-Infective Agents

Generic Name (Brand): Ganciclovir (Vitraset intraocular)

FDA APPROVED INDICATIONS Cytomegalovirus (CMV) retinitis: For the treatment of CMV retinitis in patients with acquired immune deficiency syndrome (AIDS).

TREATMENT DOSE / DURATION / REGIMEN The ganciclovir implant is for intravitreal implantation only. Each ganciclovir implant contains a minimum of 4.5 mg ganciclovir and is designed to release the drug over a 5– to 8–month period of time. Following depletion of ganciclovir from the ganciclovir implant, as evidenced by progression of retinitis, the ganciclovir implant may be removed or replaced

EFFECTIVENESS MONITORING PARAMETERS Clinical response.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08. Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 140 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Fertility Agents

Generic Name (Brand): Ganirelix Acetate (Ganirelix)

FDA APPROVED INDICATIONS Infertility treatment: For the inhibition of premature luteinizing hormone (LH) surges in women undergoing controlled ovarian hyperstimulation.

TREATMENT DOSE / DURATION / REGIMEN Infertility treatment: After initiating follicle-stimulating hormone (FSH) therapy on day 2 or 3 of the cycle, ganirelix 250 mcg may be administered subcutaneously once daily during the early- to-mid follicular phase. By taking advantage of endogenous pituitary FSH secretion, the requirement for exogenously administered FSH may be reduced. Continue treatment with ganirelix daily until the day of chorionic gonadotropin (hCG) administration. When a sufficient number of follicles of adequate size are present, as assessed by ultrasound, final maturation of follicles is induced by administering hCG. Withhold the administration of hCG in cases where the ovaries are abnormally enlarged on the last day of FSH therapy to reduce the chance of developing ovarian hyperstimulation syndrome (OHSS).

EFFECTIVENESS MONITORING PARAMETERS Laboratory and clinical response.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08. Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 141 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Gefitinib (Iressa)

FDA APPROVED INDICATIONS Non-small cell lung cancer: As monotherapy for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of both platinum-based and docetaxel chemotherapies. Results from 2 large, controlled, randomized trials in first-line treatment of non-small cell lung cancer showed no benefit from adding gefitinib to doublet, platinum-based chemotherapy. Therefore, gefitinib is not indicated for use in this setting.

TREATMENT DOSE / DURATION / REGIMEN The recommended daily dose of gefitinib is one 250 mg tablet with or without food. Higher doses do not give a better response and cause increased toxicity.

EFFECTIVENESS MONITORING PARAMETERS The effectiveness of gefitinib is based on objective response rates. There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival.

INJECTABLE ADMINISTRATION REQUIREMENTS None.

ODS Health Plan Customary Specialty MR Criteria Page 142 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 143 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Gemcitabine (Gemzar)

FDA APPROVED INDICATIONS 1. Breast cancer: In combination with paclitaxel as first-line treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing adjuvant chemotherapy, unless anthracyclines were clinically contraindicated. 2. Non-small cell lung cancer (NSCLC): In combination with cisplatin as first-line treatment of patients with inoperable, locally advanced (stage IIIA or IIIB), or metastatic (stage IV) NSCLC. 3. Ovarian cancer: In combination with carboplatin for treatment of patients with advanced ovarian cancer that has relapsed at least 6 months after completion of platinum-based therapy. 4. Pancreatic cancer: As first-line treatment for patients with locally advanced (nonresectable stage II or stage III) or metastatic (stage IV) adenocarcinoma of the pancreas. Gemcitabine is indicated for patients previously treated with 5-fluorouracil (5-FU).

TREATMENT DOSE / DURATION / REGIMEN Breast cancer: Combination use: Gemcitabine should be administered IV at a dose of 1,250 mg/m2 over 30 minutes on days 1 and 8 of each 21-day cycle. Paclitaxel should be administered at 175 mg/m2 on day 1 as a 3-hour IV infusion before gemcitabine administration. Patients should be monitored prior to each dose with a complete blood cell count (CBC),

ODS Health Plan Customary Specialty MR Criteria Page 144 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

including differential counts. Patients should have an absolute granulocyte count (AGC) at least 1,500 × 106/L and a platelet count at least 100,000 × 106/L prior to each cycle.

NSCLC: Combination use: Two schedules have been investigated, and the optimum schedule has not been determined. With the 4-week schedule, gemcitabine should be administered IV at 1,000 mg/m2 over 30 minutes on days 1, 8, and 15 of each 28-day cycle. Cisplatin should be administered IV at 100 mg/m2 on day 1 after the infusion of gemcitabine. With the 3-week schedule, gemcitabine should be administered IV at 1,250 mg/m2 over 30 minutes on days 1 and 8 of each 21-day cycle. Cisplatin should be administered at a dose of 100 mg/m2 IV after the infusion of gemcitabine on day 1. See the cisplatin monograph for cisplatin administration and hydration guidelines.

Ovarian cancer: Combination use: Gemcitabine should be administered IV at a dosage of 1,000 mg/m2 over 30 minutes on days 1 and 8 of each 21-day cycle. Carboplatin area under the curve (AUC) 4 should be administered IV on day 1 after gemcitabine administration. Patients should be monitored prior to each dose with a CBC, including differential counts. Patients should have an AGC of 1,500 × 106/L or greater and a platelet count of 100,000 × 106/L or greater prior to each cycle.

Pancreatic cancer: Single-agent use: Gemcitabine should be administered by IV infusion at a dose of 1,000 mg/m2 over 30 minutes once weekly for up to 7 weeks (or until toxicity necessitates reducing or holding a dose), followed by 1 week of rest from treatment. Subsequent cycles should consist of infusions once weekly for 3 consecutive weeks out of every 4 weeks.

EFFECTIVENESS MONITORING PARAMETERS Clinical and pathologic response.

INJECTABLE ADMINISTRATION REQUIREMENTS Administration should be supervised by medical professional experienced in the use of anticancer agents.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 145 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Gemtuzumab (Mylotarg)

FDA APPROVED INDICATIONS Acute myeloid leukemia (AML): For the treatment of patients with CD33-positive AML in first relapse who are 60 years of age and older and not considered candidates for other cytotoxic chemotherapy.

TREATMENT DOSE / DURATION / REGIMEN Dosage: 9 mg/m2 infused over a 2-hour period. Consider leukoreduction with hydroxyurea or leukapheresis to reduce the peripheral white blood cell (WBC) count to below 30,000/mcL prior to administration of gemtuzumab. Appropriate measures (eg, hydration, allopurinol) must be taken to prevent hyperuricemia. Monitor vital signs during infusion and for 4 hours following infusion. The recommended treatment course with gemtuzumab is a total of 2 doses with 14 days between the doses. Full recovery from hematologic toxicities is not a requirement for administration of the second dose.

EFFECTIVENESS MONITORING PARAMETERS Clinical and pathologic response.

ODS Health Plan Customary Specialty MR Criteria Page 146 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

INJECTABLE ADMINISTRATION REQUIREMENTS Administration should be supervised by medical professional experienced in the use of anticancer agents.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 147 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Medications for Multiple Sclerosis

Generic Name (Brand): Glatiramer (Copaxone) Interferon beta-1a (Avonex) (Rebif) Interferon beta-1b (Betaseron)

DESCRIPTION: Avonex, Betaseron and Rebif are recombinant agents that have been shown to slow the progression of multiple sclerosis (MS) and reduce the incidence and severity of relapses. They also reduce the development of lesions in the brain due to MS. Copaxone is a synthetic protein immunomodulator that appears to block damage to the myelin sheath of nerves which results in a reduction of the attack rate in Relapsing-Remitting Multiple Sclerosis (RRMS) patients and a beneficial effect on MRI measures of disease severity. Copaxone may also slow sustained disability progression in RRMS patients.

PRODUCT AVAILABILITY: • Avonex (Interferon beta-1a): 30 mcg/0.5 mL in a pre-filled syringe, - 30 mcg powder for reconstitution injection • Betaseron (Interferon beta-1b): 0.3 mg powder for reconstitution injection • Copaxone (Glatiramer acetate): 20mg/mL in a pre-filled syringe • Rebif (Interferon beta-1a): 22 mcg/0.2 mL in a pre-filled syringe - 22 mcg/0.5 mL in a pre-filled syringe - 44 mcg/0.2 mL in a pre-filled syringe - 44 mcg/0.5 mL in a pre-filled syringe - Titration Pack (six 8 mcg pre-filled syringes and six 22 mcg pre-filled syringes)

INDICATIONS:

• Avonex, Betaseron, and Rebif - treatment of relapsing forms of MS • Betaseron - early stage MS patients who have experienced a first clinical episode and have MRI features consistent with MS. • Copaxone - treatment of relapsing-remitting type MS

GUIDELINES FOR USE: 1) Is the drug prescribed by a neurologist? a) If yes, go to #2. b) If no, denied.

2) Is Copaxone being prescribed? a) If yes, go to #3. b) If no, go to #4.

3) Does the patient have relapsing-remitting multiple sclerosis? a) If yes, go to #6. b) If no, denied.

4) Does the patient have a relapsing form of multiple sclerosis or experienced a first clinical demyelinating event with MRI evidence consistent with multiple sclerosis? a) If yes, go to #5.

ODS Health Plan Customary Specialty MR Criteria Page 148 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

b) If no, denied.

5) Does the patient have a history of or currently being treated for severe psychiatric disorders, suicidal ideations or severe depression which is currently not well controlled? a) If yes, deny therapy. b) If no, go to #6.

6) Will the patient be using combination therapy of any 2 of these products together: Copaxone, Novantrone, Betaseron, Avonex or Rebif? a) If yes, denied. b) If no and renewing, go to #7. c) If no and induction, approved for 6 months of therapy.

7) Has the patient had a poor response to therapy as indicated by at least one of the following: i) Increase of ≥ 1 point on the Expanded Disability Status Scale (EDSS) ii) Multiple relapses in a short time span (ie. ≥ 2 relapses in 6 months after 1 year of therapy) iii) Development of new neurologic deficits iv) Deterioration evident on MRI a) If yes, deny therapy. b) If no, approve for 12 months.

Special Instructions: • Approval lengths: Initial - 6 months Renewal - 12 months • Recommended for use in > 18 years of age Clinical Information: • Avonex, Rebif and Betaseron - Pregnancy Category C • Copaxone - Pregnancy Category B DOSING: • Avonex 30 mcg IM once weekly • Rebif Initiate at 20% of prescribed dose SQ three times weekly and increase over a 4-week period to the targeted dose of 22 mcg or 44 mcg three times weekly • Betaseron Initially 0.0625 mg SQ every other day; Increase over 6 weeks to 0.25 mg every other day • Copaxone 20 mg SQ daily

References: 1. Goodin DS et al. Disease modifying therapies in multiple sclerosis: report of the therapeutics and technology assessment subcommittee of the American Academy of Neurology and the MS council for clinical practice guidelines. Neurology 2002; 58(2):169- 78. 2. Rizvi SA, Agius MA. Current approved options for treating patients with multiple sclerosis. Neurology 2004;63(Suppl 6):S8-S14. 3. Wingerchuk D, Noseworthy J. Randomized controlled trials to assess therapies for multiple sclerosis. Neurology 2002;58(Suppl 4)S40-8.

ODS Health Plan Customary Specialty MR Criteria Page 149 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

4. Ebers GC et al. Randomized double-blind placebo-controlled study of interferon 1a in relapsing/remitting multiple sclerosis (PRISMS). Lancet 1998;352:1498-1504. 5. King J et al. PRISMS-4: long-term efficacy of interferon-β-1a in relapsing MS Neurology 2001;56:1628-36. 6. Disease management consensus statement from the Medical Advisory Board of the National Multiple Sclerosis Society [online]. Available at: http://www.nationalmssociety.org/pdf/forpros/Exp_Consensus.pdf. Accessed September 12, 2005. 7. Jacobs LD et al. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis (CHAMPS). NEJM 2000; 343(13):898-904. 8. Comi G et al. Effect of early treatment on conversion to definite multiple sclerosis: a randomised study ETOMS. Lancet 2001; 357(9268):1576-82. 9. Rich SJ et al. Stepped-care approach to treating MS: A managed care treatment algorithm. J Manag Care Pharm 2004;10(3)(suppl S-b):S26-32. 10. Avonex. Product Information. Biogen, Inc., May 2006. Available on-line at www.avonex.com 11. Betaseron. Product Information. Berlex Laboratories. Revised October 2006. Available on-line at www.betaseron.com 12. Copaxone. Product Information. Teva Pharmaceuticals, Inc., Revised February 2004. Available on-line at www.copaxone.com 13. Rebif. Product Information. Serono, Inc., September 2005. Available on-line at www.rebif.com 14. CHAMPIONS Study Group. IM interferon beta-1a delays definite multiple sclerosis 5 years after a first demyelinating event. Neurology 2006;66:678-684. 15. Polman CH, Kappos L, Freedman MS, et al; BENEFIT Study Group. Betaseron in Newly Emerging Multiple Sclerosis for Initial Treatment (BENEFIT): subgroup analyses. Program and abstracts of the American Academy of Neurology 58th Annual Meeting; April 1-8, 2006; San Diego, California. Abstract S02.002 16. Freedman MS, Kappos L, Polman CH, et al; BENEFIT Study Group. Betaseron in Newly Emerging Multiple Sclerosis for Initial Treatment (BENEFIT): clinical outcomes. Program and abstracts of the American Academy of Neurology 58th Annual Meeting; April 1-8, 2006; San Diego, California. Abstract S02.001. 17. 2. Multiple Sclerosis Disease State Management Review. MedImpact P&T Monograph, February 2005.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 150 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Goserelin (Zoladex)

FDA APPROVED INDICATIONS 1. Advanced breast cancer (3.6 mg only): For use in the palliative treatment of advanced breast cancer in pre- and postmenopausal women. The estrogen and progesterone receptor values may help to predict whether goserelin therapy is likely to be beneficial. 2. Endometrial thinning (3.6 mg only): For use as an endometrial-thinning agent prior to endometrial ablation for dysfunctional uterine bleeding. 3. Endometriosis (3.6 mg only): For the management of endometriosis, including pain relief and reduction of endometriotic lesions for the duration of therapy. Experience with goserelin for the management of endometriosis has been limited to women 18 years of age and older treated for 6 months. 4. Prostatic carcinoma: In the palliative treatment of advanced carcinoma of the prostate. In controlled studies of patients with advanced prostatic cancer comparing 3.6 mg goserelin with orchiectomy, the long-term endocrine responses and objective responses were similar between the 2 treatment arms. Additionally, duration of survival was similar between the 2 treatment arms in a major comparative trial. In controlled studies of patients with advanced prostatic cancer, 10.8 mg goserelin implant produced pharmacodynamically similar effect in terms of suppression of serum testosterone to that achieved with 3.6 mg goserelin implant. Clinical outcome similar to that produced with the use of the 3.6 mg goserelin implant

ODS Health Plan Customary Specialty MR Criteria Page 151 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

administered every 28 days is predicted with the 10.8 mg goserelin implant administered every 12 weeks. 5. Stage B2 to C prostatic carcinoma: For use in combination with flutamide for the management of locally confined stage T2b to T4 (stage B2-C) carcinoma of the prostate. Treatment with goserelin and flutamide should start 8 weeks prior to initiating radiation therapy and continue during radiation therapy.

TREATMENT DOSE / DURATION / REGIMEN Monthly (3.6 mg) implant: Administer 3.6 mg goserelin subcutaneously every 28 days into the anterior abdominal wall below the navel line using an aseptic technique under the supervision of a physician. 3-Month (10.8 mg) implant: Administer 10.8 mg goserelin subcutaneously every 12 weeks into the upper abdominal wall using an aseptic technique under the supervision of a physician. Advanced breast cancer (3.6 mg only): For the management of advanced breast cancer, goserelin is intended for long-term administration unless clinically inappropriate. Endometrial thinning (3.6 mg only): For use as an endometrial-thinning agent prior to endometrial ablation, the dosing recommendation is 1 or 2 depots (with each depot given 4 weeks apart). When 1 depot is administered, perform surgery at 4 weeks. When 2 depots are administered, perform surgery within 2 to 4 weeks following administration of the second depot Endometriosis (3.6 mg only): For the management of endometriosis, the recommended duration of administration is 6 months. Retreatment cannot be recommended for the management of endometriosis because safety data for retreatment are not available. If the symptoms of endometriosis recur after a course of therapy, and further treatment with goserelin is contemplated, consider monitoring bone mineral density. Prostatic carcinoma: For the management of advanced prostate cancer, goserelin is intended for long-term administration unless clinically inappropriate. Stage B2 to C prostatic carcinoma: When goserelin is given in combination with radiotherapy and flutamide for patients with stage T2b to T4 (stage B2 to C) prostatic carcinoma, start treatment 8 weeks prior to initiating radiotherapy and continue during radiation therapy. Administer a treatment regimen using one 3.6 mg goserelin depot 8 weeks before radiotherapy, followed in 28 days by one 10.8 mg goserelin depot. Alternatively, 4 injections of 3.6 mg depot can be administered at 28-day intervals, 2 depots preceding and 2 during radiotherapy.

EFFECTIVENESS MONITORING PARAMETERS Clinical response.

INJECTABLE ADMINISTRATION REQUIREMENTS Administration should be supervised by medical professional experienced in the use of anticancer agents.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 152 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Histrelin (Supprelin LA, Vantas) )

FDA APPROVED INDICATIONS 1. Advanced prostate cancer (Vantas only): For the palliative treatment of advanced prostate cancer. 2. Central precocious puberty (Supprelin LA only): For the treatment of children with central precocious puberty.

TREATMENT DOSE / DURATION / REGIMEN Recommended dosage: The recommended dose is 1 implant every 12 months. The implant is inserted subcutaneously in the inner aspect of the upper arm and provides continuous release of histrelin (65 mcg/day for Supprelin LA and 50 to 60 mcg/day for Vantas) for 12 months of hormonal therapy.

EFFECTIVENESS MONITORING PARAMETERS Clinical and laboratory response.

INJECTABLE ADMINISTRATION REQUIREMENTS Administration of the device should be supervised by medical professional.

REFERENCES

ODS Health Plan Customary Specialty MR Criteria Page 153 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 154 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Fertility Agents

Generic Name (Brand): Human Chorionic Gonadotropin (Pregnyl)

FDA APPROVED INDICATIONS Prepubertal cryptorchidism: Prepubertal cryptorchidism not caused by anatomic obstruction. In general, chorionic gonadotropin is thought to induce testicular descent in situations when descent would have occurred at puberty. Chorionic gonadotropin thus may help to predict whether or not orchiopexy will be needed in the future. Although, in some cases, descent following chorionic gonadotropin administration is permanent, in most cases the response is temporary. Therapy is usually instituted between the ages of 4 and 9. Hypogonadism: Selected cases of hypogonadotropic hypogonadism (hypogonadism secondary to a pituitary deficiency) in males. Ovulation induction: Induction of ovulation and pregnancy in the anovulatory, infertile woman in whom the cause of anovulation is secondary and not caused by primary ovarian failure, and who has been appropriately pretreated with human menotropins.

TREATMENT DOSE / DURATION / REGIMEN IM use only: The dosage regimen to be used will depend upon the indication for use, the age and weight of the patient, and the physician's preference. The following regimens have been advocated by various authorities. Prepubertal cryptorchidism not caused by anatomical obstruction: Therapy is usually instituted between the ages of 4 and 9. 1. 4,000 units 3 times weekly for 3 weeks. 2. 5,000 units every second day for 4 injections. 3. 15 injections of 500 to 1,000 units over a period of 6 weeks. 4. 500 units 3 times weekly for 4 to 6 weeks. If this course of treatment is not successful, another is begun 1 month later, giving 1,000 units/injection. Selected cases of male hypogonadism secondary to pituitary failure: 1. 500 to 1,000 units 3 times a week for 3 weeks, followed by the same dose twice a week for 3 weeks. 2. 4,000 units 3 times weekly for 6 to 9 months, following which the dosage may be reduced to 2,000 units 3 times weekly for an additional 3 months.

ODS Health Plan Customary Specialty MR Criteria Page 155 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

Induction of ovulation and pregnancy: 1. Induction of ovulation and pregnancy in the anovulatory, infertile woman in whom the cause of anovulation is secondary and not caused by primary ovarian failure and who has been appropriately pretreated with human menotropins. 2. 5,000 to 10,000 units 1 day following the last dose of menotropins. A dosage of 10,000 units is recommended in the labeling for menotropins.

EFFECTIVENESS MONITORING PARAMETERS Laboratory and clinical response.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08.

Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 156 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description Hyaluronic Acid Derivatives

Generic Name (Brand): Hyaluronic Acid Derivatives (Hyalagan) (Supartz) (Synvisc)

QUANTITY LIMIT: • Synvisc 1 vial per week (if treatment is bilateral, up to 2 vials per week) • Hyalagan/Supartz 1 vial per week (if treatment is bilateral, up to 2 vials per week) POLICY: 1) Grandfathering is allowed when an enrollee has a claim for requested drug within the previous 180 days

DESCRIPTION: Hyaluronic acid derivatives are used for viscosupplementation in osteoarthritis of the knee. These derivatives increase the viscosity of fluid in the joints and act as lubricants and shock absorbers to provide pain relief and increase mobility.

PRODUCT AVAILABILITY: • Euflexxa® (Sodium Hyaluronate): o 10 mg/mL in a 2 mL syringe • Hyalgan® (Sodium Hyaluronate): o 10 mg/mL in a 2 mL vial o 10 mg/mL in a 2 mL syringe • Orthovisc® (high molecular weight Hyaluronan):15 mg/mL in a 2mL PFS • Supartz® (Sodium Hyaluronate): 10 mg/mL in a 2.5 mL syringe • Synvisc® (Hylan G-F 20): 8 mg/mL in a 2 mL syringe INDICATIONS: Treatment of pain in osteoarthritis of the knee in patients with inadequate response to conservative nonpharmacologic therapy and simple analgesics. GUIDELINES FOR USE: 1) Is the patient being treated for documented osteoarthritis of the knee? a) If yes, go to #2. b) If no, denied.

2) Which knee is being treated? a) Please indicate: Left, Right, or both then go to #3.

3) Has the patient previously been treated with Euflexxa, Hyalgan, Orthovisc, Supartz or Synvisc? a) If yes, go to #7. b) If no, go to #4.

4) Has the patient failed an adequate trial of ( > 6 weeks duration) non-pharmacologic therapy (e.g., education, exercise, insoles, braces, weight reduction, physical therapy)? a) If yes, go to #5. b) If no, denied.

5) Does the patient have therapeutic failure ( > 21 day trial), intolerance of or contraindication to at least 1 of the following: i) Acetaminophen ii) Opioid Analgesics iii) Topical applications - ie. Capsaicin, NSAIDs

ODS Health Plan Customary Specialty MR Criteria Page 157 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

a) If yes, go to #6. b) If no, denied.

6) Has the patient failed maximal anti-inflammatory dosing/adequate duration (> 3 weeks) of at least 2 different NSAIDS or a COX-2 inhibitor (if unable to take NSAIDS) or does the patient have contraindication to or intolerance of NSAIDS/COX -2 inhibitor? a) If yes, approve therapy (see instructions below for duration) b) If no, denied.

7) Has it been at least 6 months since the last treatment with Euflexxa, Hyalgan, Supartz, Orthovisc or Synvisc? a) If yes, go to #8. b) If no, denied.

8) Did the patient experience a positive response (i.e. adequate pain relief, increased or maintenance of function) with the last treatment with Euflexxa, Hyalgan, Supartz, Orthovisc or Synvisc as documented in medical records of treating physician? a) If yes, approve therapy (see instructions below for duration). b) If no, denied. Special Instructions: • Approval lengths: Euflexxa for 3 weeks Hyalgan for 5 weeks Orthovisc for 4 weeks Supartz for 5 weeks Synvisc for 3 weeks Clinical Information: • Dosing: Euflexxa- 20 mg (2 mL) injected once weekly for 3 weeks Hyalgan - 20mg (2 mL) injected once weekly for 5 weeks; some patients may benefit from 3 injections Orthovisc - 30 mg (2 mL) injected once weekly for a total of three or four injections Supartz - 25 mg (2.5 mL) injected once weekly for 3 to 5 weeks Synvisc- 16 mg (2 mL) injected once weekly for a total of three injections

• One treatment cycle of a hyaluronic acid derivative may provide up to 6 months relief. • Pregnancy Category C • Joint fluid or effusions should be removed prior to injection with hyaluronic acids

ODS Health Plan Customary Specialty MR Criteria Page 158 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Hydroxyurea (Droxia)

FDA APPROVED INDICATIONS 1. Droxia: To reduce the frequency of painful crises and to reduce the need for blood transfusions in adult patients with sickle cell anemia with recurrent moderate to severe painful crises (generally at least 3 during the preceding 12 months). 2. Hydrea: Significant tumor response to Hydrea (hydroxyurea capsules, USP) has been demonstrated in melanoma, resistant chronic myelocytic leukemia, and recurrent, metastatic, or inoperable carcinoma of the ovary. 3. Hydroxyurea used concomitantly with irradiation therapy is intended for use in the local control of primary squamous cell (epidermoid) carcinomas of the head and neck, excluding the lip.

TREATMENT DOSE / DURATION / REGIMEN The initial dose of Droxia is 15 mg/kg/day as a single dose. If blood counts are in an acceptable range, the dose may be increased by 5 mg/kg/day every 12 weeks until a maximum tolerated dose (the highest dose that does not produce toxic blood counts over 24 consecutive weeks), or 35 mg/kg/day, is reached. If blood counts are between the acceptable range and toxic (see parameters for acceptable and toxic below) the dose is not increased. If blood counts are considered toxic, Droxia should be discontinued until hematologic recovery. Treatment may then be resumed after reducing the

ODS Health Plan Customary Specialty MR Criteria Page 159 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

dose by 2.5 mg/kg/day from the dose associated with hematologic toxicity. Droxia may then be titrated up or down, every 12 weeks in 2.5 mg/kg/day increments, until the patient is at a stable dose that does not result in hematologic toxicity for 24 weeks. Any dosage on which a patient develops hematologic toxicity twice should not be tried again.

EFFECTIVENESS MONITORING PARAMETERS Clinical and hematological response.

INJECTABLE ADMINISTRATION REQUIREMENTS None.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 160 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Boniva

Generic Name (Brand): Ibandronate (Boniva)

PRODUCT AVAILABILITY: Injection: 1 mg/mL (as base) In 5 mL single-use prefilled syringe

FDA APPROVED INDICATIONS Treatment of osteoporosis in postmenopausal women. Ibandronate increases bone mineral density (BMD) and reduces the incidence of vertebral fractures.

TREATMENT DOSE / DURATION / REGIMEN The recommended dose for the treatment of postmenopausal osteoporosis is 3 mg every 3 months administered over a period of 15 to 30 seconds.

INJECTABLE ADMINISTRATION REQUIREMENTS Ibandronate injection must be administered by a health care provider. Ibandronate must only be administered intravenously (IV).

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 161 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Idarubicin (Idamycin)

FDA APPROVED INDICATIONS Acute myeloid leukemia: In combination with other approved antileukemic drugs for the treatment of acute myeloid leukemia (AML) in adults. This includes French-American-British (FAB) classifications M1 through M7.

TREATMENT DOSE / DURATION / REGIMEN Induction therapy in adult patients with AML: Idarubicin hydrochloride 12 mg/m2 daily for 3 days by slow (10 to 15 minute) IV injection in combination with cytarabine. The cytarabine may be given as 100 mg/m2 daily by continuous infusion for 7 days or as cytarabine 25 mg/m2 IV bolus followed by cytarabine 200 mg/m2 daily for 5 days continuous infusion. In patients with unequivocal evidence of leukemia after the first induction course, a second course may be administered. Administration of the second course should be delayed in patients who experience severe mucositis, until recovery from this toxicity has occurred, and a dose reduction of 25% is recommended. In patients with hepatic or renal impairment, a dose reduction of idarubicin HCl should be considered. Idarubicin HCl should not be administered if the bilirubin level exceeds 5 mg/dL. The benefit of consolidation in prolonging the duration of remissions and survival is not proven. There is no consensus regarding optional regimens to be used for consolidation.

EFFECTIVENESS MONITORING PARAMETERS

ODS Health Plan Customary Specialty MR Criteria Page 162 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

Clinical and pathologic response.

INJECTABLE ADMINISTRATION REQUIREMENTS Administration should be supervised by medical professional experienced in the use of anticancer agents.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 163 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Endocrine and Metabolic Agents

Generic Name (Brand): Idursulfase (Elaprase)

DISTRIBUTION Limited distribution. A Hunter Outcome Survey has been established to better understand the variability and progression of Hunter syndrome in the population as a whole, and to monitor and evaluate long-term treatment effects of idursulfase. Patients and their health care providers are encouraged to participate in this program. For more information, visit http://www.elaprase.com or call OnePath at 1-866-888-0660.1

FDA APPROVED INDICATIONS Hunter syndrome: For patients with Hunter syndrome (mucopolysaccharidosis type II).

TREATMENT DOSE / DURATION / REGIMEN Dosage: 0.5 mg/kg of body weight administered every week as an intravenous (IV) infusion.

EFFECTIVENESS MONITORING PARAMETERS Idursulfase has been shown to improve walking capacity in these patients.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08. Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 164 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Ifosfamide (Ifex)

FDA APPROVED INDICATIONS Germ cell testicular cancer: In combination with certain other approved antineoplastic agents for third-line chemotherapy of germ cell testicular cancer. It should ordinarily be used in combination with a prophylactic agent for hemorrhagic cystitis, such as mesna.

TREATMENT DOSE / DURATION / REGIMEN Ifosfamide should be administered IV at a dose of 1.2 g/m2/day for 5 consecutive days. Treatment is repeated every 3 weeks or after recovery from hematologic toxicity (platelets greater than or equal to 100,000/mcL, WBC greater than or equal to 4000/mcL). In order to prevent bladder toxicity, ifosfamide should be given with extensive hydration consisting of at least 2 L of oral or IV fluid per day. A protector, such as mesna, should also be used to prevent hemorrhagic cystitis. Ifosfamide should be administered as a slow IV infusion lasting a minimum of 30 minutes.

EFFECTIVENESS MONITORING PARAMETERS Clinical and pathologic response.

INJECTABLE ADMINISTRATION REQUIREMENTS Administration should be supervised by medical professional experienced in the use of anticancer agents.

ODS Health Plan Customary Specialty MR Criteria Page 165 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 166 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Vantavis

Generic Name (Brand): Iloprost (Vantavis)

INDICAITONS: VENTAVIS is indicated for the treatment of pulmonary arterial hypertension (WHO Group I) in patients with WHO functional class III or IV symptoms, to improve exercise ability and decrease the rate of clinical worsening.

PRODUCT AVAILABILITY: 10mcg/ml iloprost formulated for inhalation via either two pulmonary drug delivery devices the I-neb AAD® (Adaptive Aerosol Delivery) system or the Prodose® ADD® system.

GUIDELINES FOR USE 1) Is requested drug being prescribed by a cardiologist or pulmonologist specializing in the treatment of Pulmaonary Arterial Hypertension (PAH)? a) If yes, go to #2. b) If no, do not approve.

2) Does the patient have a diagnosis for severe pulmonary arterial hypertension (WHO functional status Class III-IV)? a) If yes, go to #3. b) If no, do not approve.

3) What is patients 6-minute walk distance?______a) Go to #4

4) What is patient’s “Borg” dyspnea score______a) Go to #5.

5) Has requested drug been prescribed for this patient before? a) If yes, go to #7. b) If no, go to #6.

6) Has the patient tried and failed an adequate course (four weeks) of sildenafil (Revatio) 20mg t.i.d.? a) If yes, Approve Ventavis for 12 weeks. b) If no, do not approve.

Renewal Criteria

7) Has patient maintained or demonstrated improvement over baseline 6 minute walk distance or improvement in the Borg dyspnea score? a) If yes, go to #8. b) If no do not approve.

8) Approve Ventavis for 12 months.

ODS Health Plan Customary Specialty MR Criteria Page 167 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

Special Instructions: Clinical Information: • Dosing ◊ Ventavis 2.5mcg – 5mcg, 6 to 9 inhalations per day.

Pregnancy Category: C

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 168 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Gleevec

Generic Name (Brand): Imatinib (Gleevec)

POLICY 1) Grandfathering is allowed when an enrollee has a claim for Gleevec® within the previous 180 days.

GUIDELINES FOR USE: 1) Does patient have Philadelphia positive CML, gastrointestinal stromal tumors, acute lymphoblastic leukemia (ALL), aggressive systemic mastocytosis (ASM), dermatofibrosarcoma protuberans (DFSP), hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL), myelodysplastic/myeloproliferative diseases (MDS/MPD)? a) If yes, continue to #2. b) If no, do not approve.

2) Approve for one year.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 169 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Medications for Gaucher Disease

Generic Name (Brand): Imiglucerase (Cerezyme) (Zavesca)

DESCRIPTION: Patients with Gaucher Disease are deficient in the enzyme glucocerebrosidase which results in accumulation of a fatty substance (glucocerebroside) in the liver, spleen, lungs, bone marrow and sometimes brain.

PRODUCT AVAILABILITY: • Cerezyme (Imiglucerase- 200 Units and 400 Units in vials for injection • Zavesca (Miglustat- 100 mg Capsules (Distribution limited to CuraScript Pharmacy)

INDICATIONS:

• Cerezyme- Long-term enzyme replacement therapy for adults and pediatrics with Type 1 Gaucher Disease which can cause anemia, thrombocytopenia, bone disease, hepatomegaly and splenomegaly. • Zavesca- Treatment of adults with mild to moderate Type 1 Gaucher disease in whom enzyme replacement therapy is not an option (i.e. allergy, hypersensitivity, and/or poor venous access).

POLICY: 1) Grandfathering is allowed when an enrollee has a claim for Cerezyme or Zavesca® within the previous 180 days.

GUIDELINES FOR USE: 1) Is the patient being treated for type 1 (non-neuropathic) Gaucher Disease? a) If yes, and initiating therapy go to #2. b) If yes, and continuing therapy go to #3. c) If no, denied.

2) For initial therapy, does the patient exhibit one or more of the following: symptomatic disease (i.e. abdominal or bone pain, fatigue, exertional limitations, hepatomegaly, splenomegaly, weakness and cachexia), evidence of skeletal involvement, decreased platelet count (≤ 60,000 mm3), low hemoglobin (≥ 2 g/dL below lower limit of normal for age and weight), growth failure, or impaired quality of life due to Gaucher Disease? a) If yes, go to #3. b) If no, denied.

3) Was the patient prescribed Cerezyme or Zavesca? a) If Cerezyme, go to #4. b) If Zavesca, go to #6.

4) Is the patient at least 2 years of age or older? a) If yes, go to #5. b) If no, denied.

5) Has the patient been tested and is negative for IgG antibodies to Ceredase or Cerezyme? a) If yes, approved for Cerezyme for 12 months.

ODS Health Plan Customary Specialty MR Criteria Page 170 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

b) If no, approved for Cerezyme for 12 months but note caution with use. (Note:Patients with IgG antibodies to Ceredase or Cerezyme have a higher risk of hypersensitivity reactions. [See clinical information below)]

6) Is the patient at least 18 years of age or older? a) If yes, go to #7. b) If no, denied. (See clinical information below)

7) Is the patient intolerant to or not a candidate for enzyme replacement therapy? a) If yes, go to #8 for females; go to #9 for males. b) If no, denied. (See clinical information below)

8) Is the patient pregnant? a) If yes, denied b) If no, women with reproduction potential have been advised on use of effective contraception during therapy and for 3 months after discontinuation, go to #9.

9) Has physician advised patient and patient’s partner not to conceive while taking Zavesca and for 3 months after discontinuation? a) If yes, go to #10. b) If no, denied.

10) Will Cerezyme be prescribed with Zavesca? a) If yes, denied. (Note:Combination therapy is not FDA approved, may increase the clearance of Cerezyme, and has not been shown to significantly impact efficacy.) b) If no, approved for Zavesca for 12 months.

Special Instructions: Pharmacist Information • Approval length: 12 months

Clinical Information Cerezyme • Dosing: Initial Dosing Range 30 to 60 units/kg infused every 2 weeks Avg. Dose 60 units/kg infused every 2 weeks • Pregnancy Category C • Pediatrics: Safety and efficacy has not been established in children < 2 years old. • Monitoring: CBC, platelets, LFTs, IgG, liver and spleen scan • Antibodies: Approximately 15% of patients have developed IgG antibodies to Cerezyme during the first year of therapy, mainly within 6 months of treatment and rarely after 12 months of therapy. Approximately 46% of patients with detectable IgG antibodies experienced symptoms of hypersensitivity. Patients with antibody have a higher risk of hypersensitivity reaction. Conversely, not all patients with symptoms of hypersensitivity have detectable IgG antibody. Most patients with IgG antibodies are able to continue treatment after rate of infusion is reduced and pretreatment with antihistamines and/or corticosteroids.

Zavesca • Dosing: 100 mg three times daily; administered orally at about the same time each day; give with or without food ODS Health Plan Customary Specialty MR Criteria Page 171 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

• Pregnancy category X: Risk of impaired fertility in females and males. • Pediatrics: Safety and efficacy has not been established in patients < 18 years of age. • Monitoring: neurologic evaluations at baseline and every 6 months, weight

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 172 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Immunologic Agents

Generic Name (Brand): Immune Globulin (Octagam IV/SC, GamaSTAN IM)

FDA APPROVED INDICATIONS Immune Globulin IV/SC (Octagam) Primary immune deficiency diseases: For the treatment of primary immune deficient diseases, such as congenital agammaglobulinemia and hypogammaglobulinemia, common variable immunodeficiency, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies.

Immune Globulin IM (GamaSTAN) Hepatitis A: The prophylactic value of immune globulin intramuscular (IM) is greatest when given before or soon after exposure to hepatitis A. Immune globulin IM is not indicated in individuals with clinical manifestations of hepatitis A or in those who were exposed more than 2 weeks previously. Immunoglobulin deficiency: In patients with immunoglobulin deficiencies, immune globulin IM may prevent serious infection. However, it may not prevent chronic infections of the external secretory tissues, such as the respiratory and GI tracts. Prophylactic therapy, especially against infections caused by encapsulated bacteria, is effective in Bruton-type, sex-linked, congenital agammaglobulinemia, agammaglobulinemia associated with thymoma, and acquired agammaglobulinemia. Measles (Rubeola): Prevention or modification of measles in a susceptible person (one who has not been vaccinated and has not had measles previously) exposed fewer than 6 days previously. Immune globulin IM may be especially indicated for susceptible household contacts of measles patients, particularly those contacts younger than 1 year of age, for whom the risk of complications is highest. Do not give immune globulin IM with measles vaccine. If a child older than 12 months of age has received immune globulin IM, give measles vaccine about 3 months later, when the measles antibody titer will have disappeared. If a susceptible child exposed to measles is immunocompromised, administer immune globulin IM immediately. Do not give children who are immunocompromised the measles vaccine or any other live viral vaccine. Rubella: The routine use of immune globulin IM for prophylaxis of rubella in early pregnancy is of dubious value and cannot be justified. Some studies suggest that the use of immune globulin IM in exposed, susceptible women can lessen the likelihood of infection and fetal damage;

ODS Health Plan Customary Specialty MR Criteria Page 173 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

therefore, immune globulin IM may benefit those women who will not consider a therapeutic abortion. Varicella: Passive immunization against varicella in immunosuppressed patients is best accomplished by use of varicella-zoster immune globulin (VZIG). If VZIG is unavailable, immune globulin IM, promptly given, may also modify varicella.

TREATMENT DOSE / DURATION / REGIMEN Immune Globulin IV/SC (Octagam) Primary immunodeficiency diseases: As there are significant differences in the half-life of IgG among patients with primary immunodeficiencies, the frequency and amount of immunoglobulin therapy may vary from patient to patient. The proper amount can be determined by monitoring clinical response. The usual dose for replacement therapy in primary immunodeficiency diseases is 300 to 600 mg/kg body weight administered every 3 to 4 weeks. Doses may be adjusted over time to achieve the desired trough levels and clinical responses.

Immune Globulin IM (GamaSTAN) Hepatitis A: The recommended dose is 0.02 mL/kg (0.01 mL/lb) for household and institutional hepatitis A case contacts. The following doses are recommended for persons who plan to travel in areas where hepatitis A is common.

Immune Globulin IM Dose for Common Hepatitis A Areas1 Length of stay Dose < 3 months 0.02 mL/kg Prolonged (> 3 months) 0.06 mL/kg (repeat every 4 to 6 months)

Immunoglobulin deficiency: The recommended dosage is 0.66 mL/kg (at least 100 mg/kg) given every 3 to 4 weeks. A double dose is given at the onset of therapy; some patients may require more frequent injections. Immune globulin IM may prevent serious infection in patients with immunoglobulin deficiencies if circulating immunoglobulin G (IgG) levels of approximately 200 mg per 100 mL plasma are maintained. Measles (Rubeola): The recommended dose is 0.25 mL/kg (0.11 mL/lb) to prevent or modify measles in a susceptible person exposed fewer than 6 days previously. A susceptible child who is exposed to measles and who is immunocompromised should receive an immune globulin IM dose of 0.5 mL/kg (maximum dose, 15 mL) immediately. Rubella: A dose of 0.55 mL/kg may benefit those women who will not consider a therapeutic abortion. Varicella: If VZIG is unavailable, immune globulin IM at a dose of 0.6 to 1.2 mL/kg, promptly given, may also modify varicella.

EFFECTIVENESS MONITORING PARAMETERS Clinical and laboratory response.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08.

Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 174 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Immune Globulin SC

Generic Name (Brand): Immune Globulin Subcutaneous (Vivaglobin)

FDA APPROVED INDICATION: • Primary immune deficiency

STANDARD DOSING: • Approximately 100-200 mg/kg weekly • Package size is 10mL (concentration 160mg/mL) • Approximate dose for 70 kg individual is 45 mL, based on 400 mg/month dose.

(FDA approved and off-label indications for intravenous immune globulin are listed below for informational purposes only.) FDA Labeled Indications for Intravenous Immune Globulin (IVIG): • Bacterial infectious disease; Prophylaxis - B-cell chronic lymphocytic leukemia • Hepatitis A; Prophylaxis • Idiopathic thrombocytopenic purpura • Kawasaki disease • Measles; Prophylaxis • Primary immune deficiency disorder • Rubella contact in pregnancy; Prophylaxis • Varicella, when varicella-zoster immune globulin is unavailable; Prophylaxis

Off-Label Uses of IVIG: Acquired epidermolysis bullosa Cytomegalovirus infection; Prophylaxis - Acquired thrombocytopenia Hemopoietic stem cell transplant; Prophylaxis Alopecia universalis Cytomegalovirus infection; Treatment and Antiphospholipid syndrome Prophylaxis Asthma Dermatomyositis, Systemic Autoimmune hemolytic anemia Diabetic amyotrophy Autoimmune neutropenia Disorder of nervous system Bone marrow transplant; Adjunct Disseminated encephalomyelitis, acute Bullous pemphigoid Enteritis due to rotavirus; Prophylaxis Burn, Severe; Adjunct Epilepsy Cerebellar ataxia - Epstein-Barr virus Gastroenteritis disease Guillain-Barre syndrome Chronic fatigue syndrome Haemophilus influenzae infection; Clostridium difficile colitis Prophylaxis - Hemopoietic stem cell Crohn's disease; Adjunct transplant; Prophylaxis Cystic fibrosis; Adjunct Hemolytic disease of fetus OR newborn due to RhD isoimmunization; Prophylaxis Hemolytic uremic syndrome

ODS Health Plan Customary Specialty MR Criteria Page 175 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

Hemophagocytic syndrome Neonatal jaundice Hemophilia A; Adjunct - Hemophilia B; Ocular cicatricial pemphigoid Adjunct Otitis media Hemopoietic stem cell transplant; Paraneoplastic syndrome - Visual Prophylaxis - Streptococcal infectious disturbance disease; Prophylaxis Pemphigoid nodularis Hemopoietic stem cell transplant - Pemphigus vulgaris Streptococcal infectious disease Polyarteritis nodosa Herpes gestationis Polymyositis HIV infection Post-transplant lymphoproliferative disorder Immunization education - Immunosuppression Pure red cell aplasia Infectious disease; Prophylaxis Pyoderma gangrenosum Inflammatory demyelinating Renal transplant rejection polyradiculoneuropathy, chronic Respiratory syncytial virus infection In vitro fertilization; Adjunct Rheumatoid arthritis; Adjunct Isaacs syndrome Sepsis Japanese encephalitis virus disease Spontaneous abortion; Prophylaxis Juvenile rheumatoid arthritis Stevens-Johnson syndrome Kidney disease Stiff-man syndrome Linear IgA dermatosis Systemic lupus erythematosus Lysinuric protein intolerance Systemic onset juvenile chronic arthritis Malaria; Prophylaxis Systemic vasculitis Motor neuropathy with multiple conduction Thrombocytopenia, Antenatal and neonatal block Toxic shock syndrome Multiple myeloma Transplantation of heart Multiple sclerosis Uveitis Myasthenia gravis von Willebrand disorder Myocarditis Wegener's granulomatosis Neonatal infectious disorder, High-risk, preterm AND low-birthweight; Adjunct GUIDELINES FOR USE: 1) Does patient have one of the following diseases: a primary immune deficiency such as common variable immunodeficiency (CVID), X-linked agammaglobulinemia, other hypo- or agammaglobulinemia, IgG subclass deficiency, or severe combined immunodeficiency (SCID)? a) If yes, continue to #2. b) If no, do not approve.

2) Has the patient shown intolerance to, adverse effects from or poor venous access for intravenous immune globulin? a) If yes, go to #3. b) If no, do not approve.

3) Approve indefinitely.

ODS Health Plan Customary Specialty MR Criteria Page 176 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

References: . Berger M. Subcutaneous immunoglobulin replacement in primary immunodeficiencies. Clin Immunol. 2004;112(1):1-7. . Gardulf A, Nicolay U, Asensio O, et al. Rapid subcutaneous IgG replacement therapy is effective and safe in children and adults with primary immunodeficiencies--a prospective, multi-national study. J Clin Immunol. 2006;26(2):177-85. . Gardulf A. Immunoglobulin treatment for primary antibody deficiencies: advantages of the subcutaneous route. BioDrugs. 2007;21(2):105-16. . Micromedex Healthcare Series, accessed December 19, 2007. . Ochs HD, Gupta S, Kiessling P, et al. Safety and efficacy of self-administered subcutaneous immunoglobulin in patients with primary immunodeficiency diseases. J Clin Immunol. 2006;26(3):265-73. . Vivaglobin package insert. www.vivaglobin.com

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 177 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Remicade

Generic Name (Brand): Infliximab (Remicade)

DESCRIPTION: Tumor necrosis factor (TNF) antagonists inhibit binding of tumor necrosis factor alpha which results in a decrease of circulating pro-inflammatory cytokines involved in inflammatory responses in rheumatoid arthritis (RA), ankylosing spondylitis, psoriasis, and psoriatic arthritis.

INDICATIONS: • Treatment in combination with methotrexate, of moderately to severely active RA. • Treatment of psoriatic arthritis. • Treatment of active ankylosing spondylitis • Use of Remicade off-label in psoriasis • Reduction of signs and symptoms and inducement and maintenance of clinical remission in patients with moderately to severely active Crohn's disease. • Reduction in the number of fistulas and maintenance of fistula closure in patients with fistulizing Crohn's disease. • Reduction in signs and symptoms, promotion of clinical remission, mucosal healing, and elimination of corticosteroid use in patients with moderately to severely active UC with an inadequate response to conventional therapy.

POLICY: 1) Exclude endorsing providers. 2) Grandfathering is allowed when an enrollee has a claim for the requested prescription within the previous 180 days.

QUANTITY LIMITS: • Crohn’s disease, ulcerative colitis, plaque psoriasis or psoriatic arthritis: 15 x 100mg vials per 6 weeks x 1, then 5 x 100mg vials per 8 weeks. • Rheumatoid arthritis: 9 x 100mg vials per 6 weeks x 1, then 5 x 100mg vials per 8 weeks • Ankylosing spondylitis: 15 x 100mg vials per 6 weeks x 1, then 3 x 100mg vials per 6 weeks for 2 months

GUIDELINES FOR USE: 1) Has the treatment been prescribed by or is it being supervised by a dermatologist, gastroenterologist or rheumatologist? a) If yes, go to #2. b) If no, do not approve.

2) Does the patient have a clinically important active infection? a) If yes, denied. b) If no, go to #3. (It is relatively contraindicated for patients with a chronic or recurrent infection to receive TNF antagonists. These medications may place patients at greater risk for developing serious infections.)

3) Has the patient had a NEGATIVE tuberculin skin test, or if positive, has treatment for latent TB been initiated prior to anti-TNF therapy? a) If yes go to #4. ODS Health Plan Customary Specialty MR Criteria Page 178 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

b) If no, do not approve.

4) Has the patient previously been treated with Remicade? a) If yes go to #31. b) If no, go to #5.

5) Will the patient be using the Remicade drug with Rituxan, Orencia, Kineret, Amevive, Raptiva, or Enbrel? a) If yes, denied. b) If no, go to #6.

6) Does the patient have moderate to severe congestive heart failure (ie. NYHA Functional Class III or IV)? a) If yes, go to #7. b) If no, go to #8.

7) Is the prescribed Remicade dose greater than 5 mg/kg? a) If yes, denied. b) If no, go to #8. - Caution prescriber about risks of cardiovascular adverse events, hospitalizations and death with doses > 5 mg/kg in patients with Class III or IV heart failure. Must consider whether benefits outweigh risks and be aware not to increase dose > 5 mg/kg.

8) What is the indication for use? i) Rheumatoid Arthritis, go to #9. ii) Psoriasis, go to #12. iii) Psoriatic Arthritis, go to #16. iv) Ankylosing Spondylitis, go to #18. v) Crohn’s Disease, go to #23. vi) Ulcerative Colitis, go to #29. vii) None of the above, DO NOT APPROVE.

Rheumatoid Arthritis: 9) Does the patient have at least four of the following for at least 6 weeks duration: i) Prolonged morning stiffness in the joints ( ≥ 45 minutes duration) ii) Arthritis of 3 or more joint areas- wrist, elbow, knee, subtalar, MTP, or hands (MCP or PIP) iii) Arthritis of hand joints iv) Symmetric arthritis v) Rheumatoid nodules under the skin vi) Elevated levels of serum rheumatoid factor vii) Radiographic changes in the joints a) If yes, go to #10 b) If no, denied.

10) Has the patient met at least two of the following criteria: i) Failure of optimal dosing/adequate duration of methotrexate (at least 3 months) ii) Failure of optimal dosing/adequate duration of a DMARD other than methotrexate iii) Contraindication or intolerance to methotrexate

a) If yes, go to #11 b) If no, denied.

11) Is Remicade being co-prescribed with methotrexate? a) If yes, go to #30. b) If no, Denied.

ODS Health Plan Customary Specialty MR Criteria Page 179 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

Psoriais: 12) Does the patient have documented chronic (>12 months) plaque psoriasis which covers > 10% of the body surface area or involves areas of the face, ears, hands, feet or genitalia? a) If yes, go to #13. b) If no, denied.

13) Is the patient at least 18 years of age? a) If yes, go to #14. b) If no, denied.

14) Is the patient a candidate for systemic therapy and/or phototherapy? a) If yes, go to #15. b) If no, denied.

15) Does the patient have documented relative contraindication to or failure/intolerance of optimal dosing/adequate duration of systemic therapy (i.e. methotrexate, cyclosporine, acitretin) and/or phototherapy (i.e. PUVA, UVB)? a) If yes, go to #30 b) If no, denied.

Psoriatic Arthritis 16) Has the patient received > 1,000 joules cumulative dosage of PUVA? a) If yes, go to # 17 (Note: Patients have a 6-fold increased risk of nonmelanoma skin cancer if they have received > 1,000 joules cumulative dosage of PUVA and are treated with anti-TNF agents. It is recommended that these patients receive annual skin checks from a dermatologist.) b) If no, go to #17.

17) Does the patient have active disease and failed optimal dosing or an adequate trial duration of at least two different DMARDs? i) Adequate trial: (1) Treatment for ≥ 6 months, of which 2 months is at standard target dose OR (2) Treatment for < 6 months where treatment was withdrawn because of intolerance, toxicity, or contraindicated OR (3) If treatment is withdrawn because of drug intolerance or toxicity after > 2 months, at least 2 months should have been at therapeutic doses a) If yes, go to #30. b) If no, denied.

Ankylosing Spondylitis 18) Does the patient have: i) Active disease defined by BASDAI score ≥ 4 cms AND spinal pain VAS (within last week) ≥ 4 cms, both having been measured on two occasions at least 4 weeks apart without a change in treatment AND ii) Radiologic evidence of Sacroiliitis ≥ grade II bilaterally or grade III to IV unilaterally AND iii) One of the following three criteria: (1) Low back pain and stiffness for > 3 months that improves with exercise but is not relieved by rest (2) Limitation of motion of the lumbar spine in both the sagital and frontal planes (3) Limitation of chest expansion relative to normal values correlated for age and sex a) If yes, go to #19. b) If no, denied.

ODS Health Plan Customary Specialty MR Criteria Page 180 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

19) Has the patient failed adequate trial of at least two different NSAID treatments? i) Adequate trial: (1) Treatment for ≥ 3 months of maximal recommended or tolerated anti-inflammatory dose unless contraindicated OR (2) Treatment for < 3 months where treatment was withdrawn because of intolerance, toxicity, or contraindicated a) If yes, go to #20. b) If no, denied.

20) Is the disease manifested as axial disease, peripheral arthritis or enthesitis? a) If enthesitis or axial disease, go to #30. b) If peripheral arthritis, go to #21.

21) Has patient failed intra-articular corticosteroid treatment (at least one injection)? a) If yes, go to #22. b) If no, denied.

22) Has the patient failed three months trial of at least 2 g/day oral sulfasalazine, unless contraindicated? a) If yes, go to #30. b) If no, denied.

Crohn’s Disease 23) Is the patient being treated for: a) Moderate to Severe Crohn’s Disease, go to #24. b) Fistulizing Crohn’s Disease go to #27.

24) Has the patient failed or is intolerant to optimal dosing and adequate duration of corticosteroids? a) If yes, go to #25. b) If no, denied.

25) Has the patient failed or is intolerant to optimal dosing and adequate duration of mesalamine or sulfasalazine? a) If yes, go to #26. b) If no, denied.

26) Has the patient failed or is intolerant to optimal dosing and adequate duration of an immunomodulator (i.e., methotrexate, 6-mercaptopurine or azathioprine)? a) If yes, go to #28 b) If no, denied.

27) Has the patient failed or is intolerant to optimal dosing and adequate duration of corticosteroids or an immunomodulator (6-mercaptopurine and/or azathioprine)? a) If yes, go to #30 b) If no, denied.

Ulcerative Colitis: 28) Is the patient being treated for moderate to severe ulcerative colitis? a) If yes, go to 3. b) If no, denied.

ODS Health Plan Customary Specialty MR Criteria Page 181 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

29) Does the patient have a documented failure of an aminosalicylate, corticosteroid, and/or immunomodulator (i.e., mesalamine, sulfasalazine, balsalazide, mercaptopurine, or azathioprine) at optimal dosing/adequate duration? (1) If yes, go to #30 (2) If no, denied.

30) Initial Approval - Approve 8 weeks initial therapy

RENEWAL CRITERIA 31) What is the indication for use? i) Rheumatoid Arthritis, go to #32. ii) Psoriasis, go to #33. iii) Psoriatic Arthritis, go to #34. iv) Ankylosing Spondylitis, go to #34. v) Crohn’s Disease, go to #36. vi) Ulcerative Colitis, go to #39. vii) None of the above, do not approve.

Rheumatoid Arthritis 32) Has the patient had: i) ≥ 20% improvement in the number of tender joints AND ii) ≥ 20% improvement in the number of swollen joints AND iii) ≥ 20% improvement in three of the following five measures: iv) Pain v) Global assessment of disease activity by the physician vi) Global assessments of disease activity by the patient vii) Patient assessment of physical function viii) Levels of acute phase reactant (ESR or CRP) ix) OR achieved an equivalent therapeutic response as indicated by scoring using the DAS28, SDAI or CDAI indices. a) If yes, approved for 12 months for maintenance therapy. b) If no, denied.

Psoriasis Renewal 33) Did the patient receive clinical benefit on the therapy as measured by PASI improvement (> 50% improvement in PASI score) or a significant improvement in Quality of Life observed by the physician and patient (i.e. Dermatology Life Quality Index)? a) If yes approve 50 mg subcutaneously once weekly for 12 months. b) If no, denied.

Psoriatic Arthritis Renewal 34) For Psoriatic Arthritis, has the patient had: i) ≥ 20% improvement in the number of tender joints AND ii) ≥ 20% improvement in the number of swollen joints AND iii) ≥ 20% improvement in three of the following five measures: (1) Pain (2) Global assessment of disease activity by the physician (3) Global assessments of disease activity by the patient (4) Patient assessment of physical function (5) Levels of acute phase reactant (ESR or CRP) a) If yes, approved for 12 months of maintenance therapy. b) If no, denied.

Ankylosing Spondylitis Renewal

ODS Health Plan Customary Specialty MR Criteria Page 182 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

35) For Ankylosing Spondylitis, have the patient’s symptoms improved ≥ 50% relative to baseline or experienced an absolute change of 2 points (scale 0-10) in the BASDAI score? a) If yes, approved for 12 months of maintenance therapy. b) If no, denied.

Crohn’s Disease Renewal 36) Has the patient shown clinical improvement (i.e. decreased number of draining fistulas, decreased rectal bleeding, diarrhea and abdominal pain; maintenance of remission) after induction therapy with Remicade as documented in medical records of treating physician? a) If yes, go to #37 b) If no, denied.

37) Has it been at least 8 weeks since the last Remicade treatment? a) If yes, approved 12 months for maintenance therapy. Refer to guide below for appropriate number of vials to dispense. b) If no, go to #38.

38) Is the prescribed dose an increase from the last dose? If it has been less than 8 weeks from the last dosage signifying inadequate response, the dosage should be increased from 5 mg/kg. a) If yes, approve for 12 months of maintenance therapy. Refer to guide below for appropriate number of vials to dispense. b) If no, denied

Ulcerative Colitis 39) Did the patient experience a positive response (i.e. decreased rectal bleeding, mucosal healing, corticosteroid discontinuation) post-induction or during maintenance therapy as documented in medical records of treating physician? a) If yes, go to #40. b) If no, denied.

40) Has it been at least 8 weeks since the last Remicade treatment? a) If yes, approved for 12 months maintenance therapy. Refer to guide below for appropriate number of vials to dispense. b) If no, denied.

ODS Health Plan Customary Specialty MR Criteria Page 183 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

Remicade Appropriate Vial Provision Guide If prescribed dose is within 10% of an incremental vial size, the pharmacist may round down to the nearest vial size to provide cost-savings while not compromising clinical efficacy. ie. Pt = 66kg. MD writes for 5 mg/kg = 330mg; Round down to give 300 mg (3 vials) Patient Weight Range Remicade dose (# vials) (based on 5 mg/kg ± 10%) < 40 kg 5 mg/kg (up to 2 vials) 40 kg to 44 kg 200 mg (2 vials) > 44 kg to 60 kg 5 mg/kg (up to 3 vials) 60 kg to 66 kg 300 mg (3 vials) > 66 kg to 80 kg 5 mg/kg (up to 4 vials) > 80 kg to 88 kg 400 mg (4 vials) > 88 kg to 100 kg 5 mg/kg (up to 5 vials) > 100 kg to 110 kg 500 mg (5 vials) > 110 kg to 120 kg 5 mg/kg (up to 6 vials) > 120 kg to 132 kg 600 mg (6 vials) > 132 kg to 140 kg 5 mg/kg (up to 7 vials) > 140 kg to 154 kg 700 mg (7 vials) > 154 kg to 160 kg 5 mg/kg (up to 8 vials) > 160 kg to 176 kg 800 mg (8 vials)

Special Instructions: • Duration of Approvals: Induction – 2 months Maintenance - 12 months • Dosing: (RA) 3 mg/kg IV infusion at 0, 2, and 6 weeks then q 8 wks, in combination with methotrexate. (AS) 5 mg/kg IV infusion at 0, 2, and 6 weeks then q 6 wks. With/Without methotrexate. (PsA) 5mg/kg IV infusion at 0, 2, and 6 weeks then q 8 wks. With/Without methotrexate. (CD) Induction: 5 mg/kg at 0, 2 and 6 weeks as an IV infusion Maintenance: 5 mg/kg IV every 8 weeks thereafter induction For responders that lose response: consider 10mg/kg If patient has not responded by week 14, consider discontinuing medication since response is unlikely. (UC) Induction: 5 mg/kg IV at 0, 2 and 6 weeks Maintenance: 5 mg/kg IV every 8 weeks thereafter induction

• Pregnancy category B • Remicade is indicated for adults (≥ 18 years of age) • Treatment with Remicade in patients with moderate to severe heart failure (NYHA Class III or IV) has resulted increased cardiovascular adverse events, hospitalizations and death. • Serious infections, sepsis and fatalities have been reported with the use of anti- TNF agents. These medications should not be initiated in patients with clinically important, active infections • Monitoring - LFTs; D/C if > 5x upper limit of normal

Optimal Dosing and Duration Sulfasalazine 4 to 6 g/day PO 4 weeks Mesalamine 2 to 4.8 g/day PO or PR 4 weeks ODS Health Plan Customary Specialty MR Criteria Page 184 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

Balsalazide 6.75 g/day PO 4 weeks Prednisone 40 to 60 mg/day PO 8 to 12 weeks Azathioprine 1.5 to 2.5 mg/kg/day PO 3 to 6 months Mercaptopurine individualized 3 to 6 months

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 185 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Clinical

Generic Name (Brand): Interferon (Intron A)

GUIDELINES FOR USE 1. Is the medication being used to treat an FDA approved indication? If yes, continue to #3. If no, continue to #2. 2. Is there supporting evidence from medical literature that substantiates the use of this medication for the condition being treated and the treatment is not investigational in nature? If yes, continue to #3. If no, do not approve. 3. Approve for 9 months.

REFERENCES Product Information. 2006.

Effective: 10/01/08 Created: 01/01/06 Updated: 01/05/07 Reviewed: 11/14/07

ODS Health Plan Customary Specialty MR Criteria Page 186 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Immunologic Agents

Generic Name (Brand): Interferon Alfa-N3 (Alferon N)

FDA APPROVED INDICATIONS Condylomata acuminata: For the intralesional treatment of refractory or recurring external condylomata acuminata in patients 18 years of age or older.

TREATMENT DOSE / DURATION / REGIMEN Recommended dose: 0.05 mL (250,000 IU) per wart. Interferon alfa-n3 (human leukocyte derived) should be administered twice weekly for up to 8 weeks. The maximum recommended dose per treatment session is 0.5 mL (2.5 million IU). Interferon alfa-n3 (human leukocyte derived) should be injected into the base of each wart, preferably using a 30 gauge needle. For large warts, interferon alfa-n3 (human leukocyte derived) may be injected at several points around the periphery of the wart, using a total dose of 0.05 mL per wart. The minimum effective dose of interferon alfa-n3 (human leukocyte derived) for the treatment of condylomata acuminata has not been established. Moderate to severe adverse experiences may require modification of the dosage regimen or, in some cases, termination of therapy with interferon alfa-n3 (human leukocyte derived). Duration of therapy: Genital warts usually begin to disappear after several weeks of treatment with interferon alfa-n3 (human leukocyte derived). Treatment should continue for a maximum of 8 weeks. In clinical trials with interferon alfa-n3 (human leukocyte derived), many patients who had partial resolution of warts during treatment experienced further resolution of their warts after cessation of treatment. Of the patients who had complete resolution of warts due to treatment, half the patients had complete resolution of warts by the end of the treatment and half had complete resolution of warts during the 3 months after cessation of treatment. Thus, it is recommended that no further therapy (interferon alfa-n3 [human leukocyte derived] or conventional therapy) be administered for 3 months after the initial 8-week course of treatment unless the warts enlarge or new warts appear.

EFFECTIVENESS MONITORING PARAMETERS Clinical response. Studies to determine the safety and efficacy of a second course of treatment with interferon alfa-n3 (human leukocyte derived) have not been conducted.

REFERENCES ODS Health Plan Customary Specialty MR Criteria Page 187 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

Product Information. Facts and Comparisons 4.0. Accessed 09/15/08.

Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 188 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antiviral Agents

Generic Name (Brand): Interferon Alfacon-1 (Infergen), Peg-Interferon Alfa-2A (Pegasys), Peg-Interferon Alfa-2B (Peg-Intron), Ribavirin (Copegus, Rebetol, Ribapak, Ribasphere, Ribatab)

GUIDELINES FOR USE INITIAL CRITERIA (NOTE: FOR RENEWAL CRITERIA SEE BELOW) 1. Is the patient being treated for chronic Hepatitis C and is the patient currently being supervised by a gastroenterologist, infectious disease specialist or a physician specializing in the treatment of hepatitis (e.g., hepatologist)? If yes, continue to #2. If no, do not approve. 2. Is the patient 18 years or older? If yes, continue to #3. If no, .do not approve 3. Does the patient have a detectable pretreatment HCV RNA level/viral load of ≥ 50 IU/mL? If yes, continue to #4. If no, do not approve. 4. Is ribavirin being used in combination with PEG-Intron, or Pegasys? If yes, continue to #6. If no, continue to #5. 5. Is there a contraindication to combination (ribavirin + interferon) therapy? If yes, continue to #6 If no, do not approve 6. Is the patient infected with genotype 1,4,5,6 hepatitis C? If yes, continue to #7 If no, continue to #8. 7. Does the patient’s liver biopsy show chronic hepatitis with significant fibrosis (Metavir score ≥ 2 or Ishak score ≥ 3)? If yes, continue to #9. If no, do not approve. 8. Is the patient infected with genotype 2 or genotype 3 hepatitis C? If yes, continue to #10. If no, do not approve. 9. Approve for 16 weeks (4 months) Recommend HCV RNA level at approximately 12 weeks to determine if the patient has achieved an early virologic response and if therapy will be continued. 10. Approve for 24 weeks (6 months)

RENEWAL CRITERIA (NOTE: FOR INITIAL CRITERIA SEE ABOVE) 1. Unless there is a contraindication to combination therapy, is the request for continuing treatment for combination therapy with ribavirin (i.e., Copegus/Rebetol/Ribasphere) and an interferon (i.e., Pegasys, Peg-Intron)? If yes, continue to #2. If no, do not approve. ODS Health Plan Customary Specialty MR Criteria Page 189 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

2. Did the patient achieve a≥ 2 log reduction in HCV RNA from baseline value in the first 12 weeks of treatment? If yes, continue to #3. If no, do not approve 3. Is the patient infected with genotype 1,4,5,6 hepatitis C? 4. Approve for 32 If yes, continue to #4. If no, do not approve 5. Approve for 32 weeks (8 months).

RATIONALE • Ensure that ribavirin and interferon are used for combination treatment of chronic hepatitis C. • Combination drug therapy with an interferon (preferably a pegylated form) and ribavirin results in a better clinical response than monotherapy. • The 4-month initial approval for hepatitis C allow a sufficient length of time for the 12-week HCV RNA result (EVR) to be reported and evaluated by the physician.

FDA APPROVED INDICATIONS 1. COPEGUS (ribavirin) is indicated in combination with PEGASYS (peg-interferon alfa 2-a), for the treatment of adults (>18 yrs) with chronic hepatitis C in patients who have compensated liver disease who have not been previously treated with interferon alfa. 2. REBETOL and RIBASPHERE (ribavirin) are indicated in combination with PEG-INTRON (peg-interferon alfa-2b, recombinant) Injection for the treatment of chronic hepatitis C in patients 18 years of age and older with compensated liver disease previously untreated with alfa interferon. 3. PEGASYS (peg-interferon alfa-2a) alone or in combination with COPEGUS (ribavirin) is indicated for the treatment of adults with chronic hepatitis C virus infection who have compensated liver disease and have not been previously treated with interferon alpha. PEGASYS is also indicated for treatment of adults with HBeAg positive and negative chronic hepatitis B who have compensated liver disease and evidence of viral replication and inflammation. 4. PEG-INTRON (peg-interferon alfa-2b) is indicated for use alone or in combination with REBETOL (ribavirin), for the treatment of chronic hepatitis C in patients at least 18 years of age with compensated liver disease who have not been previously treated with interferon alpha. 5. INFERGEN is indicated for the treatment of chronic HCV infection in patients 18 years of age or older with compensated liver disease who have anti-HCV serum antibodies and/or the presence of HCV RNA.

REFERENCES 1. Anon. National Institutes of Health Consensus Development Conference Statement. Management of Hepatitis C:2002. Available at http://consensus.nih.gov/2002/2002HepatitisC2002116html.htm. (5/15/07) 2. Strader D et al. AASLD Practice Guidelines. Diagnosis, Management, and Treatment of Hepatitis C. Hepatology 2004, 39(4) 1147-71.Fried MW et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus 3. Infection. NEJM 2002, 347(13):975-82.

ODS Health Plan Customary Specialty MR Criteria Page 190 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

4. Chung R et al. Peginterferon Alfa-2a plus Ribavirin versus Interferon Alfa-2a plus 5. Ribavirin for Chronic Hepatitis C in HIV-Coinfected Persons. NEJM 2004, 351(5): 45 6. Sulkowski MS. Treatment Algorithm for the Management of Hepatitis C in HIV-coinfected Persons. J Hepatol. In press January 2006. 7. Brau, N. Chronic Hepatitic C in Patients with HIV/AIDS: A New Challenge in Antiviral Therapy. JAC 2005;56:991-5. 8. Management and Treatment of Hepatitis C Virus Infection in HIV-Infected Adults: Recommendations from the Veterans Affairs Hepatitis C Resource Center Program and National Hepatitis C Program Office. September 1, 2005. http://hepatitis.va.gov/vahep?page=prtop04-00-rr (5/15/07) and Am J Gastroenterol 2006;101:2360-78. 9. Shiffman ML/ Management of Patients with Chronic Hepatitis C Virus Infection and Previous Nonresponse. Rev Gastroenterol Disord 2004;4(suppl1):S22-30. 10. Shiffman M et al. 2006. Peginterferon alfa-2a (PEGASYS) plus ribavirin (COPEGUS) for 16 or 24 weeks in patients with HCV genotype 2 or 3 [abstract]. In: 41st Annual Meeting of The European Association for the Study of the Liver; 2006 April 26-30; Vienna, Austria. 11. PEG-Intron. Product Information. Schering Corporation. Revised February 2005. Available on-line at www.pegintron.com, Kenilworth, N.J. May 2007 12. Pegasys. Product Information. Roche Pharmaceuticals. Revised January 2004. Available on-line at www.rocheusa.com/products/pegasys/pi.pdf Nutley, N.J. May 2007 13. Infergen. Product Information. InterMune, Inc. Revised February 2003. Available at: http://www.infergen.com/pdf/infergen_pi.pdf. , Costa Mesa, CA May 2007 14. HCV Treatment Algorithm available on line at http://clinicaloptions.com/Hepatitis May 2007

Effective: 10/01/08 Created: 01/01/06 Updated: 11/14/07 Reviewed: 01/05/07

ODS Health Plan Customary Specialty MR Criteria Page 191 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Immunologic Agents

Generic Name (Brand): Interferon Gamma-1B (Actimmune)

DISTRIBUTION Limited distribution.

FDA APPROVED INDICATIONS Chronic granulomatous disease: For reducing the frequency and severity of serious infections associated with chronic granulomatous disease. Malignant osteopetrosis: For delaying time to disease progression in patients with severe, malignant osteopetrosis.

TREATMENT DOSE / DURATION / REGIMEN Recommended dose: 50 mcg/m2 (1 million units/m2) for patients whose body surface area (BSA) is more than 0.5 m2, and 1.5 mcg/kg/dose for patients whose BSA is 0.5 m2 or less. Injections should be administered subcutaneously 3 times a week (ie, Monday, Wednesday, Friday). Note that the above activity is expressed in international units (1 million units per 50 mcg). This is equivalent to what was previously expressed as units (1.5 million units per 50 mcg). Higher doses are not recommended. Safety and efficacy have not been established for interferon gamma-1b given in doses more than or less than the recommended dose of 50 mcg/m2. The minimum effective dose of interferon gamma-1b has not been established. EFFECTIVENESS MONITORING PARAMETERS Osteopetrosis: Treatment failure was considered to be disease progression, as defined by the following: death, significant reduction in hemoglobin or platelet counts, a serious bacterial infection requiring antibiotics, or a 50-decibel decrease in hearing or progressive optic atrophy. Chronic granulomatous disease: Reduction in primary infections and other clinical indicators. REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08. Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 192 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Ixabepilone (Ixempra)

FDA APPROVED INDICATIONS Breast cancer: In combination with capecitabine for the treatment of patients with metastatic or locally advanced breast cancer resistant to treatment with an anthracycline and a taxane, or in patients whose cancer is taxane-resistant and for whom further anthracycline therapy is contraindicated; as monotherapy for the treatment of metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and capecitabine. Anthracycline resistance is defined as progression while on therapy or within 6 months in the adjuvant setting or 3 months in the metastatic setting. Taxane resistance is defined as progression while on therapy or within 12 months in the adjuvant setting or 4 months in the metastatic setting.1

TREATMENT DOSE / DURATION / REGIMEN Dosage: 40 mg/m2 administered intravenously (IV) over 3 hours every 3 weeks. Doses for patients with body surface area greater than 2.2 m2 should be calculated based on 2.2 m2.

EFFECTIVENESS MONITORING PARAMETERS Progression-free survival (PFS), defined as time from randomization to radiologic progression as determined by Independent Radiologic Review (IRR), clinical progression of measurable skin

ODS Health Plan Customary Specialty MR Criteria Page 193 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

lesions, or death from any cause. Other study end points included objective tumor response based on Response Evaluation Criteria in Solid Tumors (RECIST), time to response, response duration, and overall survival. The data for overall survival analysis are not mature.

INJECTABLE ADMINISTRATION REQUIREMENTS Administration should be supervised by medical professional experienced in the use of anticancer agents.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 194 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Anti-Infective Agents

Generic Name (Brand): Lamivudine (Epivir-HBV)

FDA APPROVED INDICATIONS Chronic hepatitis B (lamivudine-HBV): For the treatment of chronic hepatitis B associated with evidence of hepatitis B viral replication and active liver inflammation. This indication is based on 1-year histologic and serologic responses in adult patients with compensated chronic hepatitis B and more limited information from a study in children 2 to 17 years of age. HIV infection (lamivudine): In combination with other antiretroviral agents, for the treatment of HIV infection. TREATMENT DOSE / DURATION / REGIMEN If lamivudine is administered to a patient dually infected with HIV and HBV, the dosage indicated for HIV therapy should be used as part of an appropriate combination regimen. The formulation and dosage of lamivudine-HBV are not appropriate for patients dually infected with HBV and HIV. Chronic hepatitis B: Adults: 100 mg once daily. Safety and efficacy of treatment beyond 1 year have not been established, and the optimum duration of treatment is not known. Children (2 to 17 years of age): 3 mg/kg once daily up to a maximum daily dose of 100 mg. Safety and efficacy of treatment beyond 1 year have not been established, and the optimum duration of treatment is not known.

EFFECTIVENESS MONITORING PARAMETERS Histologic and serologic responses in adult patients with compensated chronic hepatitis B and HIV.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08.

Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 195 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Endocrine and Metabolic Agents

Generic Name (Brand): Lanreotide (Somatuline)

FDA APPROVED INDICATIONS Acromegaly: For the long-term treatment of acromegalic patients who have had an inadequate response to surgery and/or radiotherapy, or for whom surgery and/or radiotherapy is not an option. TREATMENT DOSE / DURATION / REGIMEN Dosage: Begin treatment with lanreotide 90 mg given via the deep subcutaneous route, at 4-week intervals for 3 months. After 3 months, the dosage may be adjusted as follows: Lanreotide Dosage Recommendations1 GHa levels (ng/mL) Lanreotide dose GH > 1 to ≤ 2.5 ng/mL, Maintain the lanreotide dose at IGF-1 normal, and 90 mg every 4 weeks. clinical symptoms controlled GH > 2.5 ng/mL, Increase the lanreotide dose to IGF-1 elevated, and/or 120 mg every 4 weeks. clinical symptoms uncontrolled GH ≤ 1 ng/mL, Reduce the lanreotide dose to IGF-1 normal, and 60 mg every 4 weeks. clinical symptoms controlled aGH = growth hormone. Thereafter, the dose should be adjusted according to the response of the patient, as judged by a reduction in serum GH and/or IGF-1 levels, and/or changes in symptoms of acromegaly.

EFFECTIVENESS MONITORING PARAMETERS The goal of treatment in acromegaly is to reduce growth hormone (GH) and insulin growth factor-1 (IGF-1) levels to normal.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08.

Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 196 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Endocrine and Metabolic Agents

Generic Name (Brand): Levonorgestrel (Mirena)

DISTRIBUTION Limited distribution.

FDA APPROVED INDICATIONS Contraception: The levonorgestrel-releasing intrauterine system is indicated for intrauterine contraception for up to 5 years. Thereafter, if continued contraception is desired, the system should be replaced. Recommended patient profile: Levonorgestrel-releasing intrauterine system is recommended for women who have had at least one child, are in a stable, mutually monogamous relationship, have no history of pelvic inflammatory disease, and have no history of ectopic pregnancy or condition that would predispose to ectopic pregnancy.

TREATMENT DOSE / DURATION / REGIMEN Directions for use: Note: Healthcare providers are advised to become thoroughly familiar with the insertion instructions before attempting insertion of the levonorgestrel-releasing intrauterine system.Insertion instructions: The levonorgestrel-releasing intrauterine system is inserted with the provided inserter into the uterine cavity within 7 days of the onset of menstruation or immediately after first trimester abortion by carefully following the insertion instructions. It can be replaced by a new system at any time during the menstrual cycle.

EFFECTIVENESS MONITORING PARAMETERS Clinical response.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08.

Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 197 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Fertility Agents

Generic Name (Brand): Lutropin Alfa (Luveris)

FDA APPROVED INDICATIONS Follicle stimulation: Lutropin alfa coadministered with follitropin alfa (Gonal-F) is indicated for stimulation of follicular development in infertile, hypogonadotropic, hypogonadal women with profound luteinizing hormone (LH) deficiency (LH less than 1.2 units/L). A definitive effect on pregnancy in this population has not been demonstrated. The safety and efficacy of concomitant administration of lutropin alfa with any other preparation of recombinant human follicle stimulating hormone (FSH) or urinary human FSH is unknown.

TREATMENT DOSE / DURATION / REGIMEN Dosage: It is recommended that lutropin alfa 75 units be coadministered subcutaneously with follitropin alfa 75 to 150 units as 2 separate injections in the initial treatment cycle.

EFFECTIVENESS MONITORING PARAMETERS Laboratory and clinical response.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08.

Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 198 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Immunologic Agents

Generic Name (Brand): Lymphocyte Immune Globulin (Atgam)

FDA APPROVED INDICATIONS Renal transplantation: For the management of allograft rejection in renal transplant patients. When administered with conventional therapy at the time of rejection, it increases the frequency of resolution of the acute rejection episode. The drug has also been administered as an adjunct to other immunosuppressive therapy to delay the onset of the first rejection episode. Data accumulated to date have not consistently demonstrated improvement in functional graft survival associated with therapy to delay the onset of the first rejection episode. Aplastic anemia: For the treatment of moderate-to-severe aplastic anemia in patients who are unsuitable for bone marrow transplantation. When administered with a regimen of supportive care, lymphocyte immune globulin may induce partial or complete hematologic remission. In a controlled trial, patients receiving lymphocyte immune globulin showed a statistically significantly higher improvement rate compared with standard supportive care at 3 months. Improvement was defined in terms of sustained increase in peripheral blood counts and reduced transfusion needs.

TREATMENT DOSE / DURATION / REGIMEN Skin testing: Before the first infusion of lymphocyte immune globulin, the manufacturer strongly recommends that patients be tested with an intradermal injection of 0.1 mL of a 1:1000 dilution (5 mcg horse IgG) of lymphocyte immune globulin in sodium chloride injection, USP and a contralateral sodium chloride injection control. Use only freshly diluted lymphocyte immune globulin for skin testing. The patient, and specifically the skin test, should be observed every 15 to 20 minutes over the first hour after intradermal injection. A local reaction of ≥ 10 mm with a wheal or erythema, or both, with or without pseudopod formation and itching or a marked local swelling should be considered a positive test. A systemic reaction such as a generalized rash, tachycardia, dyspnea, hypotension, or anaphylaxis precludes any additional administration of lymphocyte immune globulin. Note: The predictive value of this test has not been proved clinically. Allergic reactions such as anaphylaxis have occurred in patients whose skin test is negative. In the presence of a locally positive skin test to lymphocyte immune globulin, serious consideration to alternative forms of

ODS Health Plan Customary Specialty MR Criteria Page 199 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

therapy should be given. The risk to benefit ratio must be carefully weighed. If therapy with lymphocyte immune globulin is deemed appropriate following a locally positive skin test, treatment should be administered in a setting where intensive life support facilities are immediately available and with a physician familiar with the treatment of potentially life- threatening allergic reactions in attendance. Renal allograft recipients: Adult renal allograft patients have received lymphocyte immune globulin sterile solution at the dosage of 10 to 30 mg/kg of body weight daily. The few children studied received 5 to 25 mg/kg daily. Lymphocyte immune globulin has been used to delay the onset of the first rejection episode and at the time of the first rejection episode. Most patients who received lymphocyte immune globulin for the treatment of acute rejection had not received it starting at the time of transplantation. Usually, lymphocyte immune globulin is used concomitantly with azathioprine and corticosteroids, which are commonly used to suppress the immune response. Exercise caution during repeat courses of lymphocyte immune globulin; carefully observe patients for signs of allergic reactions. Delaying the onset of allograft rejection: Give a fixed dose of 15 mg/kg/day for 14 days, then every other day for 14 days for a total of 21 doses in 28 days. Administer the first dose within 24 hours before or after the transplant. Treatment of rejection: The first dose of lymphocyte immune globulin can be delayed until the diagnosis of the first rejection episode. The recommended dose is 10 to 15 mg/kg/day for 14 days. Additional alternate-day therapy up to a total of 21 doses can be given. Aplastic anemia: 10 to 20 mg/kg/day for 8 to 14 days. Additional alternate-day therapy up to a total of 21 doses can be administered. Because thrombocytopenia can be associated with the administration of lymphocyte immune globulin, patients receiving it for the treatment of aplastic anemia may need prophylactic platelet transfusions to maintain platelets at clinically acceptable levels.

EFFECTIVENESS MONITORING PARAMETERS Clinical response.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08. Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 200 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Endocrine and Metabolic Agents

Generic Name (Brand): Mecasermin (Increlex, Iplex)

FDA APPROVED INDICATIONS Growth failure: For the long-term treatment of growth failure in children with severe primary insulin-like growth factor-1 (IGF-1) deficiency (primary IGFD) or with growth hormone (GH) gene deletion who have developed neutralizing antibodies to GH. Severe primary IGFD is defined by: • height standard deviation score less than or equal to −3, • basal IGF-1 standard deviation score less than or equal to −3, and • normal or elevated GH.

Severe primary IGFD includes patients with mutations in the GH receptor (GHR), post-GHR signaling pathway, and IGF-1 gene defects; they are not GH deficient; therefore, they cannot be expected to respond adequately to exogenous GH treatment. Mecasermin is not intended for use in subjects with secondary forms of IGF-1 deficiency, such as GH deficiency, malnutrition, hypothyroidism, or chronic treatment with pharmacologic doses of anti-inflammatory steroids. Correct thyroid and nutritional deficiencies before initiating mecasermin treatment The FDA has awarded orphan drug status to Insmed Inc. for Iplex for the treatment of myotonic muscular dystrophy (MMD). Iplex is a complex recombinant human insulin-like growth factor-I (IGF-I) currently approved for the treatment of children with growth failure caused by severe primary IGF-I deficiency. In addition to its potential use as treatment for MMD, Iplex is being investigated as a treatment for several serious medical conditions, including amyotrophic lateral sclerosis (Lou Gehrig disease).

TREATMENT DOSE / DURATION / REGIMEN Dosage: The dosage of mecasermin should be individualized for each patient. The recommended starting dose of mecasermin is 0.04 to 0.08 mg/kg (40 to 80 mcg/kg) twice daily by subcutaneous injection. If well-tolerated for at least 1 week, the dose may be increased by 0.04 mg/kg per dose, to the maximum dose of 0.12 mg/kg given twice daily. Doses greater than 0.12 mg/kg given twice daily have not been evaluated in children with primary IGFD and, because of potential hypoglycemic effects, should not be used. If hypoglycemia occurs with recommended doses, despite adequate food intake, the dose should be reduced.

ODS Health Plan Customary Specialty MR Criteria Page 201 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

EFFECTIVENESS MONITORING PARAMETERS Clinical response including height velocity.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08.

Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 202 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Endocrine and Metabolic Agents

Generic Name (Brand): Megestrol (Megace)

FDA APPROVED INDICATIONS Tablets: For the palliative treatment of advanced carcinoma of the breast or endometrium ( recurrent, inoperable, or metastatic disease). It should not be used in lieu of currently accepted procedures such as surgery, radiation, or chemotherapy. Oral suspension: For the treatment of anorexia, cachexia, or an unexplained, significant weight loss in patients with a diagnosis of acquired immunodeficiency syndrome (AIDS).

TREATMENT DOSE / DURATION / REGIMEN Tablets: Breast cancer: For breast cancer 160 mg/day (40 mg 4 times a day). Endometrial carcinoma: For endometrial carcinoma 40 to 320 mg/day in divided doses. At least 2 months of continuous treatment is considered an adequate period for determining the efficacy of megestrol acetate. Oral suspension: The recommended adult initial dosage of megestrol acetate oral suspension, is 800 mg/day (20 mL/day). Shake container well before using. In clinical trials evaluating different dose schedules, daily doses of 400 and 800 mg/day were found to be clinically effective. Extra strength oral suspension: The recommended adult initial dosage of megestrol acetate extra strength oral suspension is 625 mg/day (5 mL/day or one teaspoon daily). Please refer to the table below for correct dosing and administration. Shake container well before using.

Megestrol Oral Suspension Product Differences Megestrol extra strength oral Megestrol oral suspension suspension mg/mL 125 mg/mL 40 mg/mL Recommended daily dose 625 mg 800 mg Daily volume 5 mL 20 mL

ODS Health Plan Customary Specialty MR Criteria Page 203 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

intake (teaspoon) (dosing cup) Formulation Concentrated formula Regular formula

In clinical trials evaluating the different dose schedules, daily doses of 400 and 800 mg/day of megestrol oral suspension (800 mg/20 mL equivalent to 625 mg/5 mL of megestrol extra strength oral suspension) were found to be clinically effective.

EFFECTIVENESS MONITORING PARAMETERS Clinical response including improved appitite and increase in nonwater body weight.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08.

Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 204 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Fertility Agents

Generic Name (Brand): Menotropin (Repronex)

FDA APPROVED INDICATIONS Repronex: Menotropins, in conjunction with human chorionic gonadotropin (hCG), is indicated for multiple follicular development (controlled ovarian stimulation) and ovulation induction in patients who have previously received pituitary suppression.

TREATMENT DOSE / DURATION / REGIMEN Dosage: Assisted reproductive technologies (Menopur and Repronex): The recommended initial dose of menotropins for patients who have received gonadotropin- releasing hormone (GnRH) agonist pituitary suppression is 225 units. Based on clinical monitoring (including serum estradiol levels and vaginal ultrasound results), subsequent dosing should be adjusted according to individual patient response. Adjustments in dose should not be made more frequently than once every 2 days and should not exceed more than 75 to 150 units/adjustment for Repronex or 150 units/adjustment for Menopur. The maximum daily dose of menotropins given should not exceed 450 units, and dosing beyond 12 days for Repronex and 20 days for Menopur is not recommended. Once adequate follicular development is evident, hCG (5,000 to 10,000 units) should be administered to induce final follicular maturation in preparation for oocyte retrieval. The administration of hCG must be withheld in cases in which the ovaries are abnormally enlarged on the last day of therapy. Infertile patients with oligoanovulation (Repronex only): The dose of menotropins to stimulate development of ovarian follicles must be individualized for each patient. The lowest dose consistent with achieving good results based on clinical experience and reported clinical data should be used.

EFFECTIVENESS MONITORING PARAMETERS Clinical response.

REFERENCES

ODS Health Plan Customary Specialty MR Criteria Page 205 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

Product Information. Facts and Comparisons 4.0. Accessed 09/15/08.

Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 206 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Immunologic Agents

Generic Name (Brand): Muromonab CD3 (Orthoclone OKT3) GUIDELINES FOR USE 1. What is the patient’s diagnosis? If the diagnosis is an FDA approved indication, continue to #2. If not, do not approve. 2. What is the treatment dose? If treatment dose is within the approved dosing range, continue to #3. If not, do not approve. 3. What clinical parameters will be monitored to establish treatment effectiveness? If submitted monitoring plan is consistent with effectiveness monitoring, continue to #4. If not, do not approve. 4. Approve for 6 months.

FDA APPROVED INDICATIONS Renal allograft rejection: Treatment of acute allograft rejection in renal transplant patients. Cardiac/Hepatic allograft rejection: Treatment of steroid-resistant acute allograft rejection in cardiac and hepatic transplant patients.

TREATMENT DOSE / DURATION / REGIMEN Administer as an IV bolus in < 1 minute. Do not give by IV infusion or in conjunction with other drug solutions. Renal allograft rejection, acute: 5 mg/day for 10 to 14 days. Begin treatment once acute renal rejection is diagnosed. Cardiac/hepatic allograft rejection, steroid resistant: 5 mg/day for 10 to 14 days. Begin treatment when it is determined that a rejection has not been reversed by an adequate course of corticosteroid therapy.

EFFECTIVENESS MONITORING PARAMETERS Clinical response.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08. Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 207 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Immunologic Agents

Generic Name (Brand): Mycophenolate (CellCept IV)( Myfortic Tablets)

FDA APPROVED INDICATIONS Renal, cardiac, and hepatic transplant: For the prophylaxis of organ rejection in patients receiving allogeneic renal, cardiac, or hepatic transplants. Use mycophenolate concomitantly with cyclosporine and corticosteroids.

TREATMENT DOSE / DURATION / REGIMEN Mycophenolate intravenous (IV) is an alternative dosage form to mycophenolate capsules, tablets, and oral suspension. Administer mycophenolate IV within 24 hours following transplantation. Mycophenolate IV can be administered for up to 14 days; switch patients to oral mycophenolate as soon as they can tolerate oral medication. Renal transplantation: Adults: 1 g administered IV (over no less than 2 hours) twice a day (daily dose of 2 g). Although a dose of 1.5 g administered twice a day (daily dose of 3 g) was used in clinical trials and was shown to be safe and effective, no efficacy advantage could be established for renal transplant patients. Patients receiving mycophenolate 2 g/day demonstrated an overall better safety profile than patients receiving mycophenolate 3 g/day. Cardiac transplantation: 1.5 g twice a day administered IV (over no less than 2 hours).

Renal transplantation: Adults: 1 g administered orally twice a day (daily dose of 2 g). Although a dose of 1.5 g administered twice a day (daily dose of 3 g) was used in clinical trials and was shown to be safe and effective, no efficacy advantage could be established for renal transplant patients. Patients receiving mycophenolate 2 g/day demonstrated an overall better safety profile than patients receiving mycophenolate 3 g/day. Children (3 months to 18 years of age): The recommended dose of mycophenolate oral suspension is 600 mg/m2 administered twice a day (up to a maximum daily dose of 2 g per 10 mL oral suspension). Patients with a body surface area (BSA) of 1.25 to 1.5 m2 may be dosed with mycophenolate capsules at a dose of 750 mg twice a day (1.5 g daily dosage). Patients with a BSA greater than 1.5 m2 may be dosed with mycophenolate capsules or tablets at a dose of 1 g twice a day (2 g daily dosage). Cardiac transplantation: 1.5 g twice a day administered orally (daily dose of 3 g) in adults. Hepatic transplantation: 1.5 g twice a day administered orally (daily dose of 3 g) in adults. ODS Health Plan Customary Specialty MR Criteria Page 208 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

EFFECTIVENESS MONITORING PARAMETERS Clinical response.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08. Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 209 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Endocrine and Metabolic Agents

Generic Name (Brand): Nafarelin Acetate (Synarel)

FDA APPROVED INDICATIONS Endometriosis: Nafarelin acetate is indicated for management of endometriosis, including pain relief and reduction of endometriotic lesions. Experience with nafarelin acetate for the management of endometriosis has been limited to women 18 years of age and older treated for 6 months. Central precocious puberty: Nafarelin acetate is indicated for treatment of central precocious puberty (CPP) (gonadotropin-dependent precocious puberty) in children of both sexes.

TREATMENT DOSE / DURATION / REGIMEN Endometriosis: For the management of endometriosis, the recommended daily dose of nafarelin acetate is 400 mcg. This is achieved by one spray (200 mcg) into one nostril in the morning and one spray into the other nostril in the evening. Treatment should be started between days 2 and 4 of the menstrual cycle. In an occasional patient, the 400 mcg daily dose may not produce amenorrhea. For these patients with persistent regular menstruation after 2 months of treatment, the dose of nafarelin acetate may be increased to 800 μg daily. The 800 mcg dose is administered as one spray into each nostril in the morning (a total of 2 sprays) and again in the evening. The recommended duration of administration is 6 months. Retreatment cannot be recommended since safety data for retreatment are not available. Central Precocious Puberty: For the treatment of central precocious puberty (CPP), the recommended daily dose of nafarelin acetate is 1,600 mcg. The dose can be increased to 1,800 mcg daily if adequate suppression cannot be achieved at 1,600 mcg/day. The 1,600 mcg dose is achieved by 2 sprays (400 mcg) into each nostril in the morning (4 sprays) and 2 sprays into each nostril in the evening (4 sprays), a total of 8 sprays daily. The 1,800 mcg dose is achieved by 3 sprays (600 mcg) into alternating nostrils 3 times a day, a total of 9 sprays per day. The patient's head should be tilted back slightly, and 30 seconds should elapse between sprays. If the prescribed therapy has been well tolerated by the patient, treatment of CPP with nafarelin acetate should continue until resumption of puberty is desired.

EFFECTIVENESS MONITORING PARAMETERS

ODS Health Plan Customary Specialty MR Criteria Page 210 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

Clinical and laboratory response.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08. Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 211 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Endocrine and Metabolic Agents

Generic Name (Brand): Naltrexone (Vivitrol)

DISTRIBUTION Limited distribution.

FDA APPROVED INDICATIONS Alcohol dependence: For the treatment of alcohol dependence in patients who are able to abstain from alcohol in an outpatient setting prior to initiation of treatment. Patients should not be actively drinking at the time of initial naltrexone administration. Treatment with naltrexone should be part of a comprehensive management program that includes psychosocial support.

TREATMENT DOSE / DURATION / REGIMEN Dosage: 380 mg delivered intramuscularly (IM) every 4 weeks or once a month. The injection should be administered by a health care provider as an IM gluteal injection, alternating buttocks, using the carton components provided. Naltrexone must not be administered intravenously (IV). If patients miss doses, they should be instructed to receive the next dose as soon as possible. Pretreatment with oral naltrexone is not required before using naltrexone injection. Reinitiation of treatment in patients previously discontinued: There are no data to specifically address reinitiation of treatment. Switching from oral naltrexone for alcohol dependence: There are no systematically collected data that specifically address the switch from oral naltrexone to naltrexone injection.

EFFECTIVENESS MONITORING PARAMETERS Abstinence from alcohol.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08.

Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 212 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Endocrine and Metabolic Agents

Generic Name (Brand): Octreotide (Sandostatin)

FDA APPROVED INDICATIONS Acromegaly: To reduce blood levels of growth hormone (GH) and insulin-like growth factor 1 (IGF-1) (somatomedin C) in acromegaly patients who have had inadequate response to or cannot be treated with surgical resection, pituitary irradiation, and bromocriptine mesylate at maximally tolerated doses (solution); for long-term maintenance therapy in acromegalic patients who have had an inadequate response to surgery and/or radiotherapy, or for whom surgery and/or radiotherapy is not an option (suspension). The goal is to achieve normalization of GH and IGF-1 (somatomedin C) levels. In patients with acromegaly, octreotide solution reduces GH to within normal ranges in 50% of patients and reduces IGF-1 (somatomedin C) to within normal ranges in 50% to 60% of patients. Since the effects of pituitary irradiation may not become maximal for several years, adjunctive therapy with octreotide solution to reduce blood levels of GH and IGF-1 (somatomedin C) offers potential benefit before the effects of irradiation are manifested. Improvement in clinical signs and symptoms or reduction in tumor size or rate of growth were not shown in clinical trials performed with octreotide solution; these trials were not optimally designed to detect such effects. Carcinoid tumors: For the symptomatic treatment of patients with metastatic carcinoid tumors where it suppresses or inhibits the severe diarrhea and flushing episodes associated with the disease (solution); for long-term treatment of the severe diarrhea and flushing episodes associated with metastatic carcinoid tumors (suspension). Octreotide studies were not designed to show an effect on the size, rate of growth, or development of metastases. Vasoactive intestinal peptide tumors (VIPomas): For the treatment of the profuse watery diarrhea associated with VIP-secreting tumors (solution); for long-term treatment of the profuse watery diarrhea associated with VIP-secreting tumor (suspension). Octreotide studies were not designed to show an effect on the size, rate of growth, or development of metastases.

TREATMENT DOSE / DURATION / REGIMEN Solution: The initial dosage is usually 50 mcg administered 2 or 3 times daily. Upward dose titration is frequently required. Doses more than 300 mcg/day seldom result in additional

ODS Health Plan Customary Specialty MR Criteria Page 213 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

biochemical benefit, and if an increase in dose fails to provide additional benefit, the dose should be reduced Dosage information for patients with specific tumors follows. Acromegaly: Dosage may be initiated at 50 mcg 3 times daily. Beginning with this low dose may permit adaptation to adverse GI reactions for patients who will require higher doses. IGF-1 (somatomedin C) levels every 2 weeks can be used to guide titration. Alternatively, multiple GH levels at 0 to 8 hours after octreotide administration permit more rapid titration of dose. The goal is to achieve GH levels less than 5 ng/mL or IGF-1 (somatomedin C) levels less than 1.9 units/mL in men and less than 2.2 units/mL in women. The dosage most commonly found to be effective is 100 mcg 3 times daily, but some patients require up to 500 mcg 3 times daily for maximum effectiveness.. IGF-1 (somatomedin C) or GH levels should be reevaluated at 6 month intervals. Octreotide should be withdrawn yearly for approximately 4 weeks from patients who have received irradiation to assess disease activity. If GH or IGF-1 (somatomedin C) levels increase and signs and symptoms recur, octreotide therapy may be resumed. Carcinoid tumors: The suggested daily dose during the first 2 weeks of therapy ranges from 100 to 600 mcg/day in 2 to 4 divided doses (mean daily dosage, 300 mcg). In the clinical studies, the median daily maintenance dose was approximately 450 mcg, but clinical and biochemical benefits were obtained in some patients with as little as 50 mcg, while others required doses of 1,500 mcg/day or less. However, experience with doses more than 750 mcg/day is limited. VIPomas: Daily doses of 200 to 300 mcg in 2 to 4 divided doses are recommended during the initial 2 weeks of therapy (range, 150 to 750 mcg) to control symptoms of the disease. On an individual basis, dosage may be adjusted to achieve a therapeutic response, but doses more than 450 mcg/day are usually not required. Suspension: Octreotide suspension is indicated in patients in whom initial treatment with octreotide solution has been shown to be effective and tolerated. Acromegaly: Patients not currently receiving octreotide solution: Patients not currently receiving octreotide should begin therapy with octreotide solution given subcutaneously in an initial dosage of 50 mcg 3 times daily, which may be titrated. Most patients require dosages of 100 to 200 mcg 3 times daily for maximum effect, but some patients require up to 500 mcg 3 times daily. Patients should be maintained on octreotide solution subcutaneously for at least 2 weeks to determine tolerance to octreotide. Patients who are considered to be “responders” to the drug, based on GH and IGF-1 levels, and who tolerate the drug, can then be switched to octreotide suspension in the dosage scheme described in the following section.Patients currently receiving octreotide solution: Patients currently receiving octreotide solution can be switched directly to octreotide suspension in a dose of 20 mg given intramuscularly (IM) intragluteally at 4-week intervals for 3 months. At the end of 3 months, octreotide suspension dosage may be adjusted as follows. GH 2.5 ng/mL or less, IGF-1 normal, and clinical symptoms controlled: Maintain dosage at 20 mg every 4 weeks. GH more than 2.5 ng/mL, IGF-1 elevated, and/or clinical symptoms uncontrolled: Increase dosage to 30 mg every 4 weeks. GH 1 ng/mL or less, IGF-1 normal, and clinical symptoms controlled: Reduce dosage to 10 mg every 4 weeks. Patients whose GH, IGF-1, and symptoms are not adequately controlled at a dose of 30 mg may have the dosage increased to 40 mg every 4 weeks. Doses more than 40 mg are not recommended. In patients who have received pituitary irradiation, octreotide suspension should be withdrawn yearly for approximately 8 weeks to assess disease activity. If GH or IGF-1 levels increase and signs and symptoms recur, octreotide suspension therapy may be resumed. Carcinoid tumors and VIPomas: Patients not currently receiving octreotide solution: Patients not currently receiving octreotide should begin therapy with octreotide solution given subcutaneously. The suggested daily dosage for carcinoid tumors during the first 2 weeks of

ODS Health Plan Customary Specialty MR Criteria Page 214 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

therapy ranges from 100 to 600 mcg/day in 2 to 4 divided doses (mean daily dose, 300 mcg). Some patients may require doses up to 1,500 mcg/day. The suggested daily dose for VIPomas is 200 to 300 mcg in 2 to 4 divided doses (range, 150 to 750 mcg); dose may be adjusted on an individual basis to control symptoms, but doses more than 450 mcg/day are usually not required. Octreocide solution should be continued for at least 2 weeks. Thereafter, patients who are considered “responders” to octreotide and who tolerate the drug may be switched to octreotide suspension in the dosage regimen described in the following section. Patients currently receiving octreotide solution: Patients currently receiving octreotide solution can be switched to octreotide suspension in a dose of 20 mg given IM intragluteally at 4-week intervals for 2 months. Because of the need for serum octreotide to reach therapeutically effective levels following initial injection of octreotide suspension, carcinoid tumor and VIPoma patients should continue to receive octreotide solution subcutaneously for at least 2 weeks in the same dosage they were taking before the switch. Failure to continue subcutaneous injections for this period may result in exacerbation of symptoms. Some patients may require 3 or 4 weeks of such therapy. After 2 months, the dosage may be adjusted as follows. If symptoms are adequately controlled, consider a dose reduction to 10 mg for a trial period. If symptoms recur, the dosage should then be increased to 20 mg every 4 weeks. Many patients can, however, be satisfactorily maintained at a 10 mg dose every 4 weeks. If symptoms are not adequately controlled, increase octreotide suspension to 30 mg every 4 weeks. Patients who achieve good control on a 20 mg dose may have their dose lowered to 10 mg for a trial period. If symptoms recur, the dosage should be increased to 20 mg every 4 weeks. Doses higher than 30 mg are not recommended. Despite good overall control of symptoms, patients with carcinoid tumors and VIPomas often experience periodic exacerbation of symptoms (regardless of whether they are being maintained on octreotide solution or suspension). During these periods, they may be given octreotide solution subcutaneously for a few days at the dosage they were receiving prior to switch to octreotide suspension. When symptoms are again controlled, the octreotide solution can be discontinued.1

EFFECTIVENESS MONITORING PARAMETERS Patients should be maintained on octreotide solution subcutaneously for at least 2 weeks to determine tolerance to octreotide. Patients who are considered to be “responders” to the drug, based on GH and IGF-1 levels, and who tolerate the drug, can then be switched to octreotide suspension.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08. Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 215 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Hematological Agents

Generic Name (Brand): Oprelvekin (Neumega)

FDA APPROVED INDICATIONS Thrombocytopenia, prevention: For the prevention of severe thrombocytopenia and the reduction of the need for platelet transfusions following myelosuppressive chemotherapy in adult patients with nonmyeloid malignancies who are at high risk of severe thrombocytopenia. Efficacy was demonstrated in patients who had experienced severe thrombocytopenia following the previous chemotherapy cycle. Oprelvekin is not indicated following myeloablative chemotherapy. The safety and efficacy of oprelvekin have not been established in children.

TREATMENT DOSE / DURATION / REGIMEN Dosage: 50 mcg/kg given once daily. A safe and effective dose has not been established in children. Initiate dosing 6 to 24 hours after the completion of chemotherapy. In controlled clinical studies, doses were administered in courses of 10 to 21 days. Dosing beyond 21 days per treatment course is not recommended. Discontinue treatment with oprelvekin at least 2 days before starting the next planned cycle of chemotherapy.

EFFECTIVENESS MONITORING PARAMETERS Monitor platelet counts periodically to assess the optimal duration of therapy. Continue dosing until the postnadir platelet count is at least 50,000/mcL.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08.

Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 216 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Immunologic Agents

Generic Name (Brand): Palifermin (Kepivance)

DISTRIBUTION Limited distribution.

FDA APPROVED INDICATIONS Oral mucositis: Palifermin is indicated to decrease the incidence and duration of severe oral mucositis in patients with hematologic malignancies who are receiving myelotoxic therapy requiring hematopoietic stem cell support. TREATMENT DOSE / DURATION / REGIMEN Recommended dose: The recommended dosage of palifermin is 60 mcg/kg/day, administered as an intravenous (IV) bolus injection for 3 consecutive days before and 3 consecutive days after myelotoxic therapy, for a total of 6 doses. Premyelotoxic therapy: Administer the first 3 doses prior to myelotoxic therapy, with the third dose 24 to 48 hours before myelotoxic therapy. Postmyelotoxic therapy: Administer the last 3 doses following myelotoxic therapy; administer the first of these doses after, but on the same day of, hematopoietic stem cell infusion and at least 4 days after the most recent administration of palifermin.

EFFECTIVENESS MONITORING PARAMETERS Clinical response.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08.

Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 217 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Endocrine and Metabolic Agents

Generic Name (Brand): Pamidronate (Aredia)

FDA APPROVED INDICATIONS Hypercalcemia of malignancy: Pamidronate, in conjunction with adequate hydration, is indicated for the treatment of moderate or severe hypercalcemia associated with malignancy, with or without bone metastases. Patients who have either epidermoid or nonepidermoid tumors respond to treatment with pamidronate. Initiate vigorous saline hydration, an integral part of hypercalcemia therapy, promptly and attempt to restore the urine output to about 2 L/day throughout treatment. Mild or asymptomatic hypercalcemia may be treated with conservative measures (ie, saline hydration, with or without loop diuretics). Patients should be hydrated adequately throughout the treatment, but overhydration, especially in those patients who have cardiac failure, must be avoided. Do not employ diuretic therapy prior to correction of hypovolemia. The safety and efficacy of pamidronate in the treatment of hypercalcemia associated with hyperparathyroidism or with other nontumor-related conditions have not been established. Paget disease: Pamidronate is indicated for the treatment of patients with moderate to severe Paget disease of bone. The effectiveness of pamidronate was demonstrated primarily in patients with serum alkaline phosphatase greater than or equal to 3 times the upper limit of normal. Pamidronate therapy in patients with Paget disease has been effective in reducing serum alkaline phosphatase and urinary hydroxyproline levels by greater than or equal to 50% in at least 50% of patients, and by greater than or equal to 30% in at least 80% of patients. Pamidronate therapy has also been effective in reducing these biochemical markers in patients with Paget disease who failed to respond, or no longer responded to, other treatments Osteolytic bone metastases of breast cancer and osteolytic lesions of multiple myeloma: Pamidronate is indicated, in conjunction with standard antineoplastic therapy, for the treatment of osteolytic bone metastases of breast cancer and osteolytic lesions of multiple myeloma. The pamidronate treatment effect appeared to be smaller in the study of breast cancer patients receiving hormonal therapy than in the study of those receiving chemotherapy; however, overall evidence of clinical benefit has been demonstrated.

TREATMENT DOSE / DURATION / REGIMEN Hypercalcemia of malignancy: Consider the severity and the symptoms of hypercalcemia. Vigorous saline hydration alone may be sufficient for treating mild, asymptomatic

ODS Health Plan Customary Specialty MR Criteria Page 218 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

hypercalcemia. Avoid overhydration in patients who have potential for cardiac failure. In hypercalcemia associated with hematologic malignancies, the use of glucocorticoid therapy may be helpful. Moderate hypercalcemia: The recommended dose of pamidronate in moderate hypercalcemia (corrected serum calcium [albumin-corrected serum calcium (CCa, mg/dL) = serum calcium, mg/dL + 0.8 (4-serum albumin, g/dL)] of approximately 12 to 13.5 mg/dL) is 60 to 90 mg given as a single dose, intravenous infusion over at least 2 to 24 hours. Longer infusions (ie, greater than 2 hours) may reduce the risk for renal toxicity, particularly in patients with preexisting renal insufficiency. Severe hypercalcemia: The recommended dose of pamidronate in severe hypercalcemia (corrected serum calcium [albumin-corrected serum calcium (CCa, mg/dL) = serum calcium, mg/dL + 0.8 (4-serum albumin, g/dL)] greater than 13.5 mg/dL) is 90 mg given as a single dose, intravenous infusion over 2 to 24 hours. Longer infusions (ie, greater than 2 hours) may reduce the risk for renal toxicity, particularly in patients with preexisting renal insufficiency. Retreatment: A limited number of patients have received more than 1 treatment with pamidronate for hypercalcemia. Retreatment with pamidronate in patients who show complete or partial response initially may be carried out if serum calcium does not return to normal or remain normal after initial treatment. It is recommended that a minimum of 7 days elapse before retreatment, to allow for full response to the initial dose. The dose and manner of retreatment is identical to that of the initial therapy. Paget disease: The recommended dosage of pamidronate in patients with moderate to severe Paget disease of bone is 30 mg/day, administered as a 4-hour infusion on 3 consecutive days for a total dose of 90 mg. Retreatment: A limited number of patients with Paget disease have received more than 1 treatment of pamidronate in clinical trials. When clinically indicated, patients should be retreated at the dose of initial therapy. Osteolytic bone lesions of multiple myeloma: The recommended dosage of pamidronate in patients with osteolytic bone lesions of multiple myeloma is 90 mg administered as a 4-hour infusion given on a monthly basis. Give patients with marked Bence-Jones proteinuria and dehydration adequate hydration prior to pamidronate infusion. Limited information is available on the use of pamidronate in multiple myeloma patients with a serum creatinine greater than or equal to 3 mg/dL. The optimal duration of therapy is not yet known, however, in a study of patients with myeloma, final analysis after 21 months demonstrated overall benefits. Osteolytic bone metastases of breast cancer: The recommended dosage of pamidronate in patients with osteolytic bone metastases is 90 mg administered over a 2-hour infusion given every 3 to 4 weeks.

EFFECTIVENESS MONITORING PARAMETERS Serum calcium levels.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08. Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 219 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Ophthalmic Agents

Generic Name (Brand): Pegaptanib (Macugen)

DISTRIBUTION Limited distribution.

FDA APPROVED INDICATIONS Neovascular age-related macular degeneration (AMD): For the treatment of neovascular (wet) AMD.

TREATMENT DOSE / DURATION / REGIMEN Administer pegaptanib 0.3 mg once every 6 weeks by intravitreous injection into the eye to be treated

EFFECTIVENESS MONITORING PARAMETERS Clinical response.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08.

Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 220 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Clinical

Generic Name (Brand): Pegvisomant (Somavert)

GUIDELINES FOR USE 1. Does the patient have a confirmed diagnosis of acromegly? If yes, continue to #2. If no, do not approve. 2. Has the patient had an inadequate response to surgery or radiation therapy? If yes, continue to #3. If no, request further documention on contraindication for surgery. 3. Has the patient had an adequate trial of Sandostatin, cabergoline or bromocriptine? If yes, continue to #4. If no, do not approve. 4. Approve for 12 months.

FDA APPROVED INDICATION Somavert is indicated for the treatment of acromegaly in patients who have had an inadequate response to surgery and/or radiation therapy and/or other medical therapies, or for whom these therapies are not appropriate. The goal of treatment is to normalize serum insulin-like growth factor-I (IGF-I) levels.

REFERENCES Product Information. 2006.

Effective: 10/01/08 Created: 04/01/07 Updated:______Reviewed: 11/14/07

ODS Health Plan Customary Specialty MR Criteria Page 221 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Lenalidomide (Revlimid)

strategy FOR USE 1. What is the patient’s diagnosis? If the diagnosis is an FDA approved indication, continue to #2. If not, do not approve. 2. What is the treatment dose? If treatment dose is within the approved dosing range, continue to #3. If not, do not approve. 3. What is the expected treatment duration? If submitted duration is an approved treatment duration, continue to #4. If not, do not approve. 4. What other antineoplastic agents will be included in the treatment regimen? If an approved treatment regimen, continue to #5. If not, do not approve. 5. What clinical parameters will be monitored to establish treatment effectiveness? If submitted monitoring plan is consistent with effectiveness monitoring, continue to #6. If not, do not approve. 6. Will the medication be administered by a trained healthcare professional? If submitted administration plan for injectable agent is consistent with recommended administration, continue to #7. If not, do not approve. 7. Approve for 6 months.

APPROVED INDICATIONS 1. MDS: For the treatment of patients with transfusion-dependent anemia due to low- or intermediate-1–risk MDS associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities. 2. Multiple myeloma: In combination with dexamethasone for the treatment of multiple myeloma patients who have received at least 1 prior therapy.

TREATMENT DOSE / DURATION / REGIMEN MDS: 10 mg daily with water. Patients should not break, chew, or open the capsules. Dosing is continued or modified based upon clinical and laboratory findings. Multiple myeloma: 25 mg/day with water orally administered as a single 25 mg capsule on days 1 through 21 of repeated 28-day cycles. Patients should not break, chew, or open the capsules. The recommended dosage of dexamethasone is 40 mg/day on days 1 through 4, 9 through 12, and 17 through 20 of each 28-day cycle for the first 4 cycles of therapy and then 40 mg/day orally on days 1 through 4 every 28 days. Dosing is continued or modified based upon clinical and laboratory findings. The effect of substituting lesser strengths of lenalidomide to achieve a 25 mg capsule dose is unknown.

EFFECTIVENESS MONITORING PARAMETERS

ODS Health Plan Customary Specialty MR Criteria Page 222 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

Clinical and pathologic response. ` INJECTABLE ADMINISTRATION REQUIREMENTS None.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 223 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Letrozole (Femara)

FDA APPROVED INDICATIONS 1. Adjuvant treatment of early breast cancer: For the adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer. The efficacy of letrozole in early breast cancer is based on an analysis of disease-free survival in patients treated for a median of 24 months and followed for a median of 26 months. Follow-up analyses will determine long-term outcomes for both safety and efficacy. 2. Advanced or metastatic breast cancer: For first-line treatment of postmenopausal women with hormone receptor–positive or hormone receptor–unknown locally advanced or metastatic breast cancer. Letrozole is indicated for the treatment of advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy. 3. Extended adjuvant treatment of early breast cancer: For the extended adjuvant treatment of early breast cancer in postmenopausal women who have received 5 years of adjuvant tamoxifen therapy. The efficacy of letrozole in extended adjuvant treatment of early breast cancer is based on an analysis of disease-free survival in patients treated for a median of 24 months. Further data is required to determine a long-term outcome.

TREATMENT DOSE / DURATION / REGIMEN

ODS Health Plan Customary Specialty MR Criteria Page 224 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

Adults: The recommended oral dosage of letrozole is 2.5 mg administered once daily, without regard to meals. Patients treated with letrozole do not require glucocorticoid or mineralocorticoid replacement therapy. Duration: In patients with advanced disease, continue treatment with letrozole until tumor progression is evident. In the extended adjuvant setting, the optimal treatment duration with letrozole is not known. The planned duration of treatment in the study was 5 years. However, at the time of the analysis, the median treatment duration was 24 months; 25% of patients were treated for at least 3 years, and less than 1% of patients were treated for the planned duration of 5 years. The median duration of follow-up was 28 months. Treatment should be discontinued at tumor relapse. In the adjuvant setting, the optimal duration of treatment with letrozole is unknown. The planned duration of treatment in the study is 5 years. However, at the time of analysis, the median duration of treatment was 24 months, median duration of follow-up was 26 months, and 16% of the patients had been treated for 5 years. Treatment should be discontinued at relapse.

EFFECTIVENESS MONITORING PARAMETERS Clinical and pathologic response.

INJECTABLE ADMINISTRATION REQUIREMENTS None.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 225 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Lomustine (CeeNU)

FDA APPROVED INDICATIONS Lomustine has been shown to be useful as a single agent in addition to other treatment modalities, or in established combination therapy with other approved chemotherapeutic agents in the following: 1. Brain Tumors: Both primary and metastatic, in patients who have already received appropriate surgical and/or radiotherapeutic procedures. 2. Hodgkin's Disease: Secondary therapy in combination with other approved drugs in patients who relapse while being treated with primary therapy, or who fail to respond to primary therapy.

TREATMENT DOSE / DURATION / REGIMEN Adults and children: The recommended dose in adults and children as a single agent in previously untreated patients is 130 mg/m2as a single oral dose every 6 weeks. In individuals with compromised bone marrow function, the dose should be reduced to 100 mg/m2 every 6 weeks. When lomustine is used in combination with other myelosuppressive drugs, the doses should be adjusted accordingly.

EFFECTIVENESS MONITORING PARAMETERS Clinical and pathologic response.

ODS Health Plan Customary Specialty MR Criteria Page 226 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

INJECTABLE ADMINISTRATION REQUIREMENTS None.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 227 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Mechlorethamine (Mustargen)

FDA APPROVED INDICATIONS 1. Leukemia/Lymphomas/Polycythemia vera/Mycosis fungoides/Bronchogenic carcinoma (IV only): For the palliative treatment of Hodgkin's disease (stages III and IV), lymphosarcoma, chronic myelocytic or chronic lymphocytic leukemia, polycythemia vera, mycosis fungoides, and bronchogenic carcinoma. 2. Metastatic carcinoma: Intrapleurally, intraperitoneally, or intrapericardially for the palliative treatment of metastatic carcinoma resulting in effusion.

TREATMENT DOSE / DURATION / REGIMEN The dosage of mechlorethamine varies with the clinical situation, the therapeutic response, and the magnitude of hematologic depression. A total dose of 0.4 mg/kg of body weight for each course usually is given either as a single dose or in divided doses of 0.1 to 0.2 mg/kg/day. Base dosage on ideal dry body weight. The presence of edema or ascites must be considered so that dosage will be based on actual weight unaugmented by these conditions. The margin of safety in therapy with mechlorethamine is narrow, and considerable care must be exercised in the matter of dosage. Repeated examinations of blood are mandatory as a guide to subsequent therapy.

EFFECTIVENESS MONITORING PARAMETERS

ODS Health Plan Customary Specialty MR Criteria Page 228 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

Clinical and pathologic response.

INJECTABLE ADMINISTRATION REQUIREMENTS Administration should be supervised by medical professional experienced in the use of anticancer agents.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 229 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Melphalan (Alkeran)

FDA APPROVED INDICATIONS 1. Epithelial ovarian cancer: For the palliation of nonresectable epithelial carcinoma of the ovary. 2. Multiple myeloma: For the palliative treatment of multiple myeloma

TREATMENT DOSE / DURATION / REGIMEN Epithelial ovarian cancer: 0.2 mg/kg/day for 5 days as a single course. Courses are repeated every 4 to 5 weeks depending upon hematologic tolerance. Multiple myeloma: Initial dosage: The usual oral dose is 6 mg (3 tablets) daily. The entire daily dose may be given at 1 time. The dose is adjusted, as required, on the basis of blood cell counts done at approximately weekly intervals. After 2 to 3 weeks of treatment, the drug should be discontinued for up to 4 weeks, during which time the blood cell count should be followed carefully. Maintenance dosage: When the white blood cell count (WBC) and platelet count are rising, a maintenance dose of 2 mg daily may be instituted. Because of the patient-to-patient variation in melphalan plasma levels following oral administration of the drug, several investigators have recommended that the dosage of melphalan be cautiously escalated until some myelosuppression is observed in order to ensure that potentially therapeutic levels of the drug have been reached.

ODS Health Plan Customary Specialty MR Criteria Page 230 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

Alternative regimens: Investigators in one study have used an initial course of 10 mg/day for 7 to 10 days. They report that maximal suppression of the leukocyte and platelet counts occurs within 3 to 5 weeks and recovery within 4 to 8 weeks. Continuous maintenance therapy with 2 mg/day is instituted when the WBC is more than 4,000 cells/mcL and the platelet count is more than 100,000 cells/mcL. Dosage is adjusted to between 1 and 3 mg/day, depending upon the hematological response. It is desirable to try to maintain a significant degree of bone marrow depression so as to keep the leukocyte count in the range of 3,000 to 3,500 cells/mcL. One study reports starting treatment with 0.15 mg/kg/day for 7 days. This is followed by a rest period of at least 14 days, but it may be as long as 5 to 6 weeks. Maintenance therapy is started when the WBC and platelet count are rising. The maintenance dose is 0.05 mg/kg/day or less and is adjusted according to the blood cell count. Available evidence suggests that about one-third to one-half of patients with multiple myeloma show a favorable response to oral administration of the drug. Response may be very gradual over many months. It is important that repeated courses or continuous therapy be given because improvement may continue slowly over many months, and the maximum benefit may be missed if treatment is abandoned too soon

EFFECTIVENESS MONITORING PARAMETERS Clinical and pathologic response.

INJECTABLE ADMINISTRATION REQUIREMENTS Administration of IV melphalan should be supervised by medical professional experienced in the use of anticancer agents.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 231 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Mercaptopurine (Purinethol)

FDA APPROVED INDICATIONS 1. Acute lymphatic leukemia: For remission induction and maintenance therapy of acute lymphatic leukemia. The response to this agent depends upon the particular subclassification of acute lymphatic leukemia and the age of the patient (pediatric patient or adult). Given as a single agent for remission induction, mercaptopurine induces complete remission in approximately 25% of pediatric patients and approximately 10% of adults. However, reliance upon mercaptopurine alone is not justified for initial remission induction of acute lymphatic leukemia, since combination chemotherapy with vincristine, prednisone, and L-asparaginase results in more frequent complete remission induction than with mercaptopurine alone or in combination. The duration of complete remission induced in acute lymphatic leukemia is so brief without the use of maintenance therapy that some form of drug therapy is considered essential. Mercaptopurine, as a single agent, is capable of significantly prolonging complete remission duration; however, combination therapy has produced remission duration longer than that achieved with mercaptopurine alone. 2. Acute myelogenous (and acute myelomonocytic) leukemia: As a single agent, mercaptopurine will induce complete remission in approximately 10% of pediatric patients and adults with acute myelogenous leukemia or its subclassifications. These results are inferior to those achieved with combination chemotherapy employing optimum treatment schedules.

ODS Health Plan Customary Specialty MR Criteria Page 232 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

3. CNS leukemia: Mercaptopurine is not effective for prophylaxis or treatment of CNS leukemia.

Other neoplasms: Mercaptopurine is not effective in chronic lymphatic leukemia, the lymphomas (including Hodgkin's disease), or solid tumors.

TREATMENT DOSE / DURATION / REGIMEN Induction therapy: The dosage which will be tolerated and effective varies from patient to patient, and, therefore, careful titration is necessary to obtain the optimum therapeutic effect without incurring excessive, unintended toxicity. The usual initial dosage for pediatric patients and adults is 2.5 mg/kg of body weight per day (100 to 200 mg in the average adult and 50 mg in an average 5-year-old child). Pediatric patients with acute leukemia have tolerated this dose without difficulty in most cases; it may be continued daily for several weeks or more in some patients. If, after 4 weeks at this dosage, there is no clinical improvement and no definite evidence of leukocyte or platelet depression, the dosage may be increased up to 5 mg/kg daily. A dosage of 2.5 mg/kg/day may result in a rapid fall in leukocyte count within 1 to 2 weeks in some adults with acute lymphatic leukemia and high total leukocyte counts. The total daily dosage may be given at 1 time. It is calculated to the nearest multiple of 25 mg. The dosage of mercaptopurine should be reduced to one-third to one-fourth of the usual dose if allopurinol is given concurrently. Because the drug may have a delayed action, it should be discontinued at the first sign of an abnormally large or rapid fall in the leukocyte or platelet count. If subsequently the leukocyte count or platelet count remains constant for 2 or 3 days, or rises, treatment may be resumed. Maintenance therapy: Once a complete hematologic remission is obtained, maintenance therapy is considered essential. Maintenance doses will vary from patient to patient. A usual daily maintenance dose of mercaptopurine is 1.5 to 2.5 mg/kg/day as a single dose. It is to be emphasized that in pediatric patients with acute lymphatic leukemia in remission, superior results have been obtained when mercaptopurine has been combined with other agents (most frequently with methotrexate) for remission maintenance. Mercaptopurine should rarely be relied upon as a single agent for the maintenance of remissions induced in acute leukemia.

EFFECTIVENESS MONITORING PARAMETERS Clinical and pathologic response.

INJECTABLE ADMINISTRATION REQUIREMENTS None.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 233 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Mesna (Mesnex)

FDA APPROVED INDICATIONS Ifosfamide-induced hemorrhagic cystitis: Mesna has been shown to be effective as a prophylactic agent in reducing the incidence of ifosfamide-induced hemorrhagic cystitis.

TREATMENT DOSE / DURATION / REGIMEN IV and oral dosing: Mesna injection is given as IV bolus injections in a dosage equal to 20% of the ifosfamide dosage (w/w) at the time of ifosfamide administration. Mesna tablets are given orally in a dosage equal to 40% of the ifosfamide dose 2 and 6 hours after each dose of ifosfamide. The total daily dose of mesna is 100% of the ifosfamide dose.

EFFECTIVENESS MONITORING PARAMETERS Prevention of hematuria. INJECTABLE ADMINISTRATION REQUIREMENTS Administration should be supervised by medical professional experienced in the use of anticancer agents. REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08. Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 234 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Relistor

Generic Name (Brand): Methylnaltrexone (Relistor)

PRODUCT AVAILABILITY: • Relistor o 1 kit contains 7 unit-of-use vials, syringes, and needles

INDICATIONS: • Relistor is indicated for the treatment of opioid-induced constipation in patients with advanced illness receiving palliative care with inadequate response to conventional laxative regimens.

POLICY: GUIDELINES FOR USE 1) Is the patient receiving palliative care for advanced illness? a) If yes, continue to #2. b) If no, do not approve. 2) Is the patient experiencing opioid-induced constipation that is not responsive to stimulant laxatives or newer agents listed in Table 1? a) If yes, continue to #3. b) If no, do not approve. 3) Has a known or suspected mechanical gastrointestinal obstruction been ruled- out? a) If yes, continue to #4. b) If no, do not approve.

4) Approve 4 vials per month or 1 kit (NDC: 00008-2513-02) per month for up to 4 months

TABLE 1: Medications for the Treatment of Constipation Laxative Common Adult Dose Onset of Action Possible Side Effects Bulk-forming laxatives Impaction above strictures, Psyllium (OTC) Up to 1 tablespoon 3 times/day 12 to 72 h fluid overload, gas and bloating Impaction above strictures, Methylcellulose (OTC) Up to 1 tablespoon 3 times/day 12 to 72 h fluid overload, gas and bloating Impaction above strictures, Calcium polycarbophil (OTC) 2 to 4 tabs/day 24 to 48 h fluid overload, gas and bloating Emollients (stool softeners) Docusate sodium (OTC) 100 mg 2 times/day 24 to 72 h Skin rash Decreased absorption of Mineral oil (OTC) 15 to 45 mL/day 6 to 8 h vitamins, and medications Osmolar agents Polyethylene glycol (Rx, OTC) 8.5-34 g in 240 mL liquids 2 to 4 days Nausea, bloating, cramping 15 to 30 mL every other day, or Lactulose (Rx) 24 to 48 h Abdominal bloating 2 times/day Sorbitol (OTC) 120 mL of 25 percent solution 24 to 48 h Abdominal bloating

ODS Health Plan Customary Specialty MR Criteria Page 235 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

1 time/day Glycerine (OTC) 3g suppository 1 time/day 15 to 60 min Rectal irritation Magnesium toxicity (with renal Magnesium sulfate (OTC) 15 g 1 time/day 0.5 to 3 h insufficiency) Magnesium toxicity (with renal Magnesium citrate (OTC) 200 mL 1 time/day 0.5 to 3 h insufficiency) Stimulant laxatives Bisacodyl (oral) (OTC) 10-30 mg po 1 time/day 6 to 10 h Gastric irritation Bisacodyl (suppository) (OTC) 10 mg suppository 1 time/day 15 to 60 min Gastric irritation Senna (OTC) 2 to 4 Tabs 1 time/day 6 to 12 h Melanosis coli Newer Agents Lubiprostone (Rx) 24 micrograms 2 times/day 1 to 2 days Nausea, diarrhea 1 injection dose (weight based) Nausea, bloating, cramping, Methylnaltrexone (Rx) 15 to 60 min every other day diarrhea

How Supplied: 12mg/0.6ml solution for subcutaneous injection in a single use vial.

Patient Weight Pounds Kilograms Injection Volume Dose Less than 84 Less than 38 See Below * 0.15mg/kg 84 to less than 136 38 to less than 62 0.4ml 8mg 126 to 251 62 to 114 0.6ml 12mg More than 251 More than 114 See Below* 0.15mg/kg *The injection volume for these patients should be calculated using one of the following: o Multiply the patient weight in pounds by 0.0034 and round up the volume to the nearest 0.1ml. o Multiply the patient weight in kilograms by 0.0075 and round up the volume to the nearest 0.1ml. A dose reduction of one-half should occur in patients with severe renal impairment (creatinine clearance less than 30ml/min)

References:

1. Relistor Package Insert, Wyeth Pharmaceuticals, April 2008. Prescribing information available at http://www.wyeth.com (access date June 5, 2008). 2. Chronic Constipation Task Force. An evidence-based approach to the management of chronic constipation in North America. AM J Gastroenterol 2005;100 Suppl 1:S1-4.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 236 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Mitotane (Lysodrin)

FDA APPROVED INDICATIONS Adrenal cortical carcinoma: Mitotane is indicated in the treatment of inoperable adrenal cortical carcinoma of both functional and nonfunctional types.

TREATMENT DOSE / DURATION / REGIMEN Recommended dosage: The recommended treatment schedule is to start the patient at 2 to 6 g of mitotane per day in divided doses, either 3 or 4 times a day. Doses are usually increased incrementally to 9 to 10 g/day. If severe side effects appear, the dose should be reduced until the maximum tolerated dose is achieved. If the patient can tolerate higher doses and improved clinical response appears possible, the dose should be increased until adverse reactions interfere. Experience has shown that the maximum tolerated dose (MTD) will vary from 2 to 16 g/day, but has usually been 9 to 10 g/day. The highest dose used in the studies to date were 18 to 19 g/day. Duration of therapy: Treatment should be continued as long as clinical benefits are observed. Maintenance of clinical status or slowing of growth of metastatic lesions can be considered clinical benefits if they can clearly be shown to have occurred. If no clinical benefits are observed after 3 months at the maximum tolerated dose, the case would generally be considered a clinical failure. However, 10% of the patients who showed a measurable response required more than 3 months at the MTD. Early diagnosis and prompt

ODS Health Plan Customary Specialty MR Criteria Page 237 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

institution of treatment improve the probability of a positive clinical response. Clinical effectiveness can be shown by reduction in tumor mass; reduction in pain, weakness or anorexia; and reduction of symptoms and signs due to excessive steroid production. A number of patients have been treated intermittently with treatment being restarted when severe symptoms have reappeared. Patients often do not respond after the third or fourth such course. Experience accumulated to date suggests that continuous treatment with the maximum possible dosage of mitotane is the best approach.

EFFECTIVENESS MONITORING PARAMETERS Clinical and pathologic response.

SPECIAL ADMINISTRATION REQUIREMENTS Treatment should be instituted in the hospital until a stable dosage regimen is achieved.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 238 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Mitoxantrone (Novantrone)

FDA APPROVED INDICATIONS 1. ANLL: In combination with other approved drug(s), is indicated in the initial therapy of ANLL in adults. This category includes myelogenous, promyelocytic, monocytic, and erythroid acute leukemias. 2. MS: For reducing neurologic disability and/or the frequency of clinical relapses in patients with secondary (chronic) progressive, progressive relapsing, or worsening relapsing- remitting MS (ie, patients whose neurologic status is significantly abnormal between relapses). Mitoxantrone is not indicated in the treatment of patients with primary progressive MS. The clinical patterns of MS in the studies were characterized as follows: secondary progressive and progressive relapsing disease were characterized by gradual increasing disability with or without superimposed clinical relapses, and worsening relapsing-remitting disease was characterized by clinical relapses, resulting in a stepwise worsening of disability. 3. Prostate cancer: In combination with corticosteroids, as initial chemotherapy for the treatment of patients with pain related to advanced hormone-refractory prostate cancer.

TREATMENT DOSE / DURATION / REGIMEN MS: 12 mg/m2 given as a short (approximately 5 to 15 minutes) IV infusion every 3 months. LVEF should be evaluated by echocardiogram or MUGA prior to administration of the initial

ODS Health Plan Customary Specialty MR Criteria Page 239 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

dose of mitoxantrone and all subsequent doses. In addition, LVEF evaluations are recommended if signs or symptoms of CHF develop at any time during treatment with mitoxantrone. Mitoxantrone should not be administered to MS patients with an LVEF less than 50%, with a clinically significant reduction in LVEF, or to those who have received a cumulative lifetime dose of greater than or equal to 140 mg/m2. Prostate cancer: 12 to 14 mg/m2 given as a short IV infusion every 21 days. ANLL: Adults: Induction therapy, the recommended dosage is 12 mg/m2 of mitoxantrone daily on days 1 to 3 given as an IV infusion, and 100 mg/m2 of cytarabine for 7 days given as a continuous 24-hour infusion on days 1 to 7. Most complete remissions will occur following the initial course of induction therapy. In the event of an incomplete antileukemic response, a second induction course may be given. Mitoxantrone should be given for 2 days and cytarabine for 5 days using the same daily dosage levels. If severe or life-threatening nonhematologic toxicity is observed during the first induction course, the second induction course should be withheld until toxicity resolves. Consolidation therapy: 12 mg/m2 of mitoxantrone given by IV infusion daily on days 1 and 2 and cytarabine, 100 mg/m2 for 5 days given as a continuous 24-hour infusion on days 1 to 5. The first course was given approximately 6 weeks after the final induction course, the second was generally administered 4 weeks after the first. Severe myelosuppression occurred

EFFECTIVENESS MONITORING PARAMETERS MS: Neurological disability based on the Kurtzke Expanded Disability Status Scale (EDSS). The EDSS is an ordinal scale with 0.5-point increments ranging from 0 to 10 (increasing score indicates worsening) and based largely on ambulatory impairment in its middle range (EDSS 4.5 to 7.5 points). Relapse defined by corticosteroid treatment required and MRI Gd-enhancing lesions.

INJECTABLE ADMINISTRATION REQUIREMENTS Mitoxantrone for injection concentrate should be administered under the supervision of a physician experienced in the use of cytotoxic chemotherapy agents. Mitoxantrone should be given slowly into a freely flowing intravenous (IV) infusion. It must never be given subcutaneously, intramuscularly (IM), or intra-arterially. Severe local tissue damage may occur if there is extravasation during administration.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 240 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Tysabri

Generic Name (Brand): Natalizumab (Tysabri)

QUANTITY LIMIT: • 1 x 300mg vial per 30 days

DESCRIPTION: Tysabri is a monoclonal antibody to the alpha-4 subunit of integrin molecules which are important to adhesion and migration of cells from the vasculature into inflamed tissue. Tysabri blocks integrin association with vascular receptors, limiting adhesion and transmigration of leukocytes. Efficacy may be related to the blockade of T-lymphocyte migration into the central nervous system.

PRODUCT AVAILABILITY: • Tysabri concentrate is supplied as 300 mg in a sterile, single-use vial free of preservatives.

INDICATIONS: Tysabri is indicated as monotherapy for the treatment of patients with relapsing forms of multiple sclerosis to delay the accumulation of physical disability and reduce the frequency of clinical exacerbations. Tysabri is generally recommended for patients who have failed or are unable to tolerate alternate therapies for multiple sclerosis. The safety and efficacy beyond two years is not known.

POLICY: 1) Grandfathering is allowed when an enrollee has a claim for Tysabri® within the previous 180 days.

GUIDELINES FOR USE: 1) Did the patient have an inadequate response to, or is unable to tolerate one of the interferons for MS (Avonex, Betaseron, or Rebif) or Copaxone? a) If yes, go to #2. b) If no, do not approve.

2) Will the patient be taking Tysabri with any of the interferons for MS (Avonex, Betaseron, or Rebif) or Copaxone? a) If yes, deny therapy. b) If no, go to #3

3) Approve for 12 months with a quantity level limit of 1 x 300mg vial per 30 days.

Special Instructions: Boxed Warnings: • Tysabri increases the risk of progressive multifocal leukoencephalopathy (PML), a viral infection of the brain that usually leads to death or severe disability. Due to the risk of PML, Tysabri is available only through a special restricted distribution

ODS Health Plan Customary Specialty MR Criteria Page 241 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

program called the TOUCH prescribing program. Only prescribers, infusion centers and pharmacies associated with the infusion centers registered with the program are able to prescribe, distribute or infuse Tysabri. Only patients who are enrolled in and meet all the conditions of the TOUCH prescribing program are able to receive the medication. • Healthcare professionals should monitor patients on Tysabri for any new sign or symptom that may be suggestive of PML. For diagnosis, an evaluation that includes a gadolinium-enhanced MRI scan of the brain and, when indicated, cerebrospinal fluid analysis for JC viral DNA are recommended.

Warnings: • Tysabri has been associated with hypersensitivity reactions, including serious systemic reactions (i.e. anaphylaxis) which occurred in <1% or people taking Tysabri. These reactions usually occur within 2 hours of the start of the infusion. Symptoms associated with these reactions can include urticaria, dizziness, fever, rash, rigors, pruritus, nausea, flushing, hypotension, dyspnea and chest pain. • Immune system effects of Tysabri may increase the risk for infections such as pneumonias, urinary tract infections, gastroenteritis, vaginal infections, tooth infections, tonsillitis and herpes infection. • Concurrent use of antineoplastic, immunosuppressant or immunomodulating agents may further increase the risk of infections, including PML and other opportunistic infections, over the risk observed with use of Tysabri alone. • Concurrent use of short courses of corticosteroids was associated with an increase in infections.

Clinical Information: • Pregnancy Category C • If a woman becomes pregnant while taking Tysabri, consider enrolling her in the Tysabri Pregnancy Exposure Registry 1-800-456-2255. • Persistently-positive antibodies (antibodies detected at ≥ 2 different time points which are ≥ 42 days apart) occur in about 6% of people taking Tysabri and are associated with substantial decrease in efficacy, decrease in serum Tysabri levels and increase in infusion and hypersensitivity reactions. Dosing: • 300 mg IV infusion every four weeks • Recommended for use in > 18 years of age Common Side Effects (>10%) • Headache, urinary tract infection, fatigue, arthralgia, depression, lower respiratory tract infection, pain in extremity, rash, gastroenteritis, abdominal discomfort, vaginitis, diarrhea NOS Storage: • Tysabri single-use vials must be refrigerated between 2-8 degrees C (36-46 degrees F). Protect from light. Do not shake or freeze.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 242 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Tasigna

Generic Name (Brand): Nilotinib (Tasigna)

QUANTITY LIMIT: Prior Authorization will be approved up to 120 capsules per 30 days

GUIDELINES FOR USE: 1. Does patient have Philadelphia positive CML? a. If yes, continue to #2. b. If no, do not approve.

2. Has the patient tried and failed or is intolerant to Imitinab (Gleevec)? a. If yes, approve for one year with maximum quantity 120 capsules per 30 days. b. If no, do not approve.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 243 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Nilutamide (Nilandron)

FDA APPROVED INDICATIONS Metastatic prostate cancer: For use in combination with surgical castration for the treatment of metastatic prostate cancer (stage D2). For maximum benefit, nilutamide treatment must begin on the same day as or on the day after surgical castration.

TREATMENT DOSE / DURATION / REGIMEN The recommended oral dosage is 300 mg once a day for 30 days, followed thereafter by 150 mg once a day.

EFFECTIVENESS MONITORING PARAMETERS Clinical and pathologic response. INJECTABLE ADMINISTRATION REQUIREMENTS None.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 244 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Xolair

Generic Name (Brand): Omalizumab (Xolair)

GUIDELINES FOR USE INITIAL CRITERIA (NOTE FOR RENEWAL CRITERIA SEE BELOW) 1. Is a physician specializing in Allergy or Pulmonary Medicine currently prescribing or supervising treatment? If yes, continue to #2. If no, do not approve. 2. Is the patient 12 years of age or older? If yes, continue to #3. If no, do not approve. 3. Does the patient currently smoke cigarettes? If yes, do not approve. If no, continue to #4. 4. Does the patient have at least one of the following criteria to meet the diagnosis of moderate to severe asthma? Daily asthma symptoms, or

Daily use of inhaled short-acting beta2 agonist (e.g., albuterol) , or Exacerbations ≥ 2 times a week, or Nighttime symptoms > 1 time a week, or

FEV1 or PEF < 80% predicted, or PEF variability > 30%. If yes, continue to #5. If no, do not approve. 5. Does the patient have a positive skin prick or RAST test to a perennial aeroallergen? If yes, continue to #6. If no, do not approve. 6. Does the patient have a history of therapeutic failure, intolerance or contraindication to specific immunotherapy (allergy shots)? If yes, continue to #7. If no, do not approve. CONTINUED ON NEXT PAGE

ODS Health Plan Customary Specialty MR Criteria Page 245 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Xolair (continued)

GUIDELINES FOR USE INITIAL CRITERIA (CONTINUED) 7. Does the patient have a measured FEV1 of < 80%? If yes, continue to #8. If no, do not approve. 8. Has the patient demonstrated therapeutic failure to an inhaled or oral corticosteroid product combined with a second asthma controller agent such as a long-acting inhaled beta2-agonist (Serevent, Foradil or Advair), leukotriene modifier (Singulair or Accolate), or theophylline? If yes, continue to #9. If no, do not approve. 9. Does the patient have a history of intubation secondary to an asthma exacerbation? If yes, continue to #11. If no, continue to #10. 10. In the past year, has the patient had an emergency room visit or required hospitalization directly related to and/or for an asthma exacerbation, or required one or more pulses of oral corticosteroid use for the treatment of an asthma exacerbation? If yes, continue to #11. If no, do not approve. 11. Is the patient’s baseline IgE serum level ≥ 30IU/ml? If yes, continue to #12. If no, do not approve. 12. Approve for 1 year with a quantity limit of 6 vials/30 days.

RENEWAL CRITERIA (FOR INITIAL CRITERIA SEE ABOVE) 1. In the previous year, has the patient experienced at least a 25% reduction in asthma exacerbations (e.g., hospitalizations, urgent or emergent care visits, use of rescue medications, etc.) from their pre-Xolair baseline? If yes, continue to #5. If no, continue to #2. 2. Was the patient receiving maintenance therapy with an oral corticosteroid prior to initiation of Xolair? If yes, continue to #3. If no, continue to #4. 3. Has the patient been able to reduce their oral corticosteroid dose by 75% from their pre- Xolair baseline or to ≤ 5mg daily? If yes, continue to #5. If no, do not approve. CONTINUED ON NEXT PAGE

ODS Health Plan Customary Specialty MR Criteria Page 246 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Xolair (continued)

GUIDELINES FOR USE (CONTINUED) 4. Has the patient been able to reduce their inhaled corticosteroid dose by at least 25% from their pre-Xolair dose? If yes, continue to #5. If no, do not approve. 5. Approve for 1 year with a quantity limit of #6 vials/30 days.

FDA APPROVED INDICATIONS Adults and adolescents (12 years of age and above) with moderate to severe persistent asthma who have a positive skin test or in vitro reactivity to a perennial aeroallergen and whose symptoms are inadequately controlled with inhaled corticosteroids.

REFERENCES 1. Busse W, Corren J, Lanier BQ, McAlary MA, Fowler-Tayler A, et al. Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma. J Allergy Clin Immunol 2001;108:184-90. 2. Global Initiative for Asthma: Global Strategy for Asthma Management and Prevention. Bethesda, MD: National Institutes of Health;2002:Publication No. 02-3659. 3. Holgate S, Bousquet J, Wenzel S, Fox H, Liu J, et al. Efficacy of omalizumab, an anti- immunoglobulin E antibody in patients with allergic asthma at high risk of serious asthma- related morbidity and mortality. Curr Med Res Opin 2001;17(4):233-240. 4. NAEPP Expert Panel Report: Guidelines for the diagnosis and management of asthma- update on selected topics 2002. Bethesda, MD: National Institutes of Health;2002:Publication No. 02-5075. 5. Soler M, Matz J, Townley R, Buhl R, O’Brien J, et al. The anti-IgE antibody omalizumab reduces exacerbations and steroid requirement in allergic asthmatics. Eur Respir J 2001;18(2):254-61. 6. Xolair product information, Genentech/Novartis. Aprill 2006.

Effective: 10/01/08 Created: 01/01/06 Updated: ______Reviewed: 01/05/07, 11/14/07

ODS Health Plan Customary Specialty MR Criteria Page 247 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Oxaliplatin (Eloxatin)

FDA APPROVED INDICATIONS Adjuvant treatment of stage III colon cancer: In combination with infusional 5-fluorouracil/leucovorin for adjuvant treatment of stage III colon cancer patients who have undergone complete resection of the primary tumor. The indication is based on an improvement in disease-free survival (DFS), with no demonstrated benefit in overall survival after a median follow-up of 4 years. Advanced carcinoma of the colon or rectum: In combination with infusional 5- fluorouracil/leucovorin for the treatment of advanced carcinoma of the colon or rectum.

TREATMENT DOSE / DURATION / REGIMEN Adjuvant treatment in stage III colon cancer: Recommended for a total of 6 months (ie, 12 cycles, every 2 weeks), according to the dose schedule for previously treated patients with advanced colorectal cancer. Advanced colorectal cancer (previously untreated and previously treated patients): • Day 1: oxaliplatin 85 mg/m2 intravenous (IV) infusion in 5% dextrose in water (D5W) 250 to 500 mL and leucovorin 200 mg/m2 IV infusion in D5W both given over 120 minutes at the same time in separate bags using a Y-line, followed by 5-fluorouracil 400 mg/m2 IV bolus given over 2 to 4 minutes, followed by 5-fluorouracil 600 mg/m2 IV infusion in D5W 500 mL (recommended) as a 22-hour continuous infusion.

ODS Health Plan Customary Specialty MR Criteria Page 248 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

• Day 2: leucovorin 200 mg/m2 IV infusion over 120 minutes, followed by 5-fluorouracil 400 mg/m2 IV bolus given over 2 to 4 minutes, followed by 5-fluorouracil 600 mg/m2 IV infusion in D5W 500 mL (recommended) as a 22-hour continuous infusion.1 Repeat cycle every 2 weeks.

EFFECTIVENESS MONITORING PARAMETERS Clinical and pathologic response.

INJECTABLE ADMINISTRATION REQUIREMENTS Administration should be supervised by medical professional experienced in the use of anticancer agents.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 249 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Paclitaxel (Taxol)

FDA APPROVED INDICATIONS Taxol: Ovarian cancer: As first-line and subsequent therapy for the treatment of advanced carcinoma of the ovary. As first-line therapy, paclitaxel is indicated in combination with cisplatin. Breast cancer: Adjuvant treatment of node-positive breast cancer administered sequentially to standard doxorubicin-containing combination chemotherapy. In the clinical trial, there was an overall favorable effect on disease-free and overall survival in the total population of patients with receptor-positive and receptor-negative tumors, but the benefit has been specifically demonstrated by available data (median follow-up, 30 months) only in the patients with estrogen and progesterone receptor-negative tumors. Indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Previous therapy should have included an anthracycline unless clinically contraindicated. Non-small cell lung cancer (NSCLC): In combination with cisplatin, for the first-line treatment of NSCLC in patients who are not candidates for potentially curative surgery or radiation therapy. AIDS-related Kaposi sarcoma: For the second-line treatment of AIDS-related Kaposi sarcoma. Onxol: Ovarian cancer: As subsequent therapy for the treatment of advanced carcinoma of the ovary.

ODS Health Plan Customary Specialty MR Criteria Page 250 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

Breast cancer: For the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Previous therapy should have included an anthracycline unless clinically contraindicated.2 Abraxane: Breast cancer: For the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Previous therapy should have included an anthracycline unless clinically contraindicated.3

TREATMENT DOSE / DURATION / REGIMEN Ovarian cancer: 1. For previously untreated patients with carcinoma of the ovary, 1 of the following recommended regimens may be given every 3 weeks. In selecting the appropriate regimen, consider differences in toxicities. a. Paclitaxel 175 mg/m2 administered intravenously (IV) over 3 hours followed by cisplatin 75 mg/m2. b. Paclitaxel 135 mg/m2 administered IV over 24 hours followed by cisplatin 75 mg/m2. 2. In patients previously treated with chemotherapy for carcinoma of the ovary, paclitaxel has been used at several doses and schedules; however, the optimal regimen is not yet clear. The recommended regimen is paclitaxel 135 or 175 mg/m2 administered IV over 3 hours every 3 weeks. Breast cancer: 1. For the adjuvant treatment of node-positive breast cancer, the recommended regimen is paclitaxel 175 mg/m2 IV over 3 hours every 3 weeks for 4 courses administered sequentially to doxorubicin-containing combination chemotherapy. The clinical trial used 4 courses of doxorubicin and cyclophosphamide. 2. After failure of initial chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy, paclitaxel 175 mg/m2 administered IV over 3 hours every 3 weeks has been shown to be effective. NSCLC: Given every 3 weeks, paclitaxel 135 mg/m2 is administered IV over 24 hours followed by cisplatin 75 mg/m2. Repeated course: For the therapy of patients with solid tumors (ovary, breast, and NSCLC), do not repeat courses of Taxol until neutrophil count is at least 1,500 cells/mm3 and the platelet count is at least 100,000 cells/mm3 AIDS-related Kaposi sarcoma: Do not give Taxol to patients with AIDS-related Kaposi sarcoma if the baseline or subsequent neutrophil count is less than 1,000 cells/mm3. Paclitaxel 135 mg/m2 given IV over 3 hours every 3 weeks or at a dose of 100 mg/m2 given IV over 3 hours every 2 weeks is recommended (dose intensity 45 to 50 mg/m2/week). In the 2 clinical trials evaluating these schedules, the former schedule (135 mg/m2 every 3 weeks) was more toxic than the latter. In addition, all patients with low performance status were treated with the latter schedule (100 mg/m2 every 2 weeks). EFFECTIVENESS MONITORING PARAMETERS Clinical and pathologic response. INJECTABLE ADMINISTRATION REQUIREMENTS Administration should be supervised by medical professional experienced in the use of anticancer agents. REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 251 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Synagis

Generic Name (Brand): Palivizumab (Synagis)

DESCRIPTION: Synagis is used in the prevention of severe respiratory syncytial virus (RSV) in certain high risk infants and children younger than 24 months. Synagis exhibits neutralizing and fusion-inhibitory activity against RSV. These activities inhibit RSV replication in laboratory experiments and clinical studies. The typical RSV season in the Northern Hemisphere is November – March. The season starts in October to December and terminates in March to May but regional differences exist. The onset of the season is earlier in southern states followed by the northern states, western states and last the Midwest states. The 2006 AAP Red Book Guidelines cite that in recent years, the national median duration of the RSV season has been 15 weeks; in the south it is 16 weeks with a range of 13-20 weeks. The 2006 AAP Red Book Guidelines suggest 5 monthly doses of Synagis may be adequate for coverage of the RSV season (Nov- April), however please see the CDC Regional RSV Surveillance Data at the end of the criteria to determine the trends and appropriate duration in your region.

PRODUCT AVAILABILITY: Synagis (Palivizumab) IM soln 100 mg/ml -0.5mL vial (50 mg) -1 mL vial (100 mg)

INDICATIONS: Synagis is indicated for the prevention of serious lower respiratory tract disease caused by RSV in pediatric patients at high risk of RSV disease.

GUIDELINES FOR USE: 1) Is treatment being administered at the start or within the RSV season? (Season to be determined by plan: Nov- March, Oct- April, Nov- April, Oct- March, etc. BioScrip’s general recommendation is Nov- April.) a) If Yes, go to 2. b) If No, deny therapy.

2) Is the patient < 2 years of age at the start of the RSV season with chronic lung disease (CLD) that has required treatment (supplemental oxygen, bronchodilator, diuretic or corticosteroid) for CLD within 6 months before the start of the RSV season? a) If Yes, approve therapy for the duration of current RSV season. b) If No, go to 3.

3) Is the patient born < 28 weeks gestation and is < 12 months of age at the start of the RSV season? (a) If yes, approve therapy for the duration of current RSV season. (b) If no, go to #4.

4) Is the patient born between 29-32 weeks gestation and is < 6 months of age at the start of the RSV season? a) If yes, approve therapy for the duration of current RSV season. b) If no, go to #5.

5) Is the patient born between 32-35 weeks gestation, < 6 months at the start of the RSV season AND has two or more of the following risk factors? i) Child care attendance

ODS Health Plan Customary Specialty MR Criteria Page 252 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

ii) School-aged siblings iii) Exposure to environmental air pollutants (e.g. tobacco smoke. Note the AAP Guidelines recommend that a less costly option than Synagis is avoidance of tobacco smoke by the family of an infant at risk for RSV) iv) Congenital abnormalities of the airways v) Severe neuromuscular disease a) If yes, approve therapy for the duration of current RSV season. b) If no, go to #6.

6) Is the patient < 24 months of age at the start of the RSV season with hemodynamically significant congenital heart disease, including one of the following? i) Receiving medication to control congestive heart failure; or ii) With moderate to severe pulmonary artery hypertension; or iii) With cyanotic congenital heart disease a) If yes, approve therapy for the duration of current RSV season. b) If no, go to #7.

7) For patients that do not meet the above criteria, please collect information and forward to the plan for review.

Special Instructions: Approval length: for the duration of current RSV season (typically November through April) but specific time will be determined by the plan. The typical RSV season in the Northern Hemisphere is November – March; the season starts in October to December and terminates in March to May but regional differences exist. The onset of the season is earlier in southern states followed by the northern states, western states and last the Midwest states. See the CDC Regional RSV Surveillance Data at the end of the criteria to determine the trends in your region

Dosing: The recommended monthly IM dose of Synagis is 15 mg/kg of body weight. Patients, including those who develop an RSV infection, should continue to receive monthly doses throughout the RSV season. The first dose should be administered prior to commencement of RSV season.

Gestational Age: For the purpose of this recommendation, 32 weeks gestation refers to an infant born on or before the 32nd week of gestation (ie, 32 weeks, 0 days).

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 253 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Aloxi

Generic Name (Brand): Palonosetron (Aloxi)

GUIDELINES FOR USE 1. Is the patient receiving a chemotherapy agent considered to be of moderate to high emetic risk (see attachment for list of agents and their levels)? If yes, continue to #2. If no, do not approve. 2. Approve up to 1 mg IV per month for up to 6 months.

FDA APPROVED INDICATIONS Aloxi is indicated for prevention of acute nausea and vomiting associated with initial and repeat courses of moderately and highly emetogenic cancer therapy, as well as for the prevention of delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy.

REFERENCES 1. Aloxi Package Insert, Helsinn Blrex, Pharmaceuticals, January 2006. Prescribing information available at www.aloxi.com (access date March, 13, 2007). 2. NCCN Practice Guidelines in Oncology-Antiemetics-v.1.2007 available @www.nccn.org/professionals/physicians gls/PDF/antiemesis.pdf (access date March 13, 2007).

Effective: 10/01/06 Created: 01/01/06 Updated: 01/05/07, 11/14/07 Reviewed: ______

SEE NEXT PAGE FOR LIST OF CHEMOTHERAPY AGENTS

ODS Health Plan Customary Specialty MR Criteria Page 254 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Aloxi (Continued)

Generic Name (Brand): Palonosetron (Aloxi)

Emetogenicity of Chemotherapeutic Agents

High emetic risk (> 90% frequency of emesis) AC combination defined as either doxorubicin or epirubicin with cyclophosphamide Altretamine Carmustine > 250 mg/m2 Cisplatin > 50 mg/ m2 Cyclophosphamide > 1,500 mg/m2 Dacarbazine Mechlorethamine Procarbazine (oral) Streptozocin

Moderate emetic risk (30-90% frequency of emesis) Aldesleukin >12-15 million units/m2 Amifostine > 300 Arsenic trioxide Azacitidine Busulfan > 4 mg/d Carboplatin Carmustine ≤ 250 mg/m2 Cisplatin < 50 mg/m2 Cyclophosphamide < 1,500 mg/m2 Cyclophosphamide (oral) Cytarabine > 1 gm/m2 Dactinomycin Daunorubicin Doxorubicin Epirubicin Etoposide (oral) Idarubicin Ifosfamide Imatinib (oral) Irinotecan Lomustine Melphalan > 50 mg/m2 Methotrexate 250 - > 1,000 mg/m2

CONTINUED ON NEXT PAGE

ODS Health Plan Customary Specialty MR Criteria Page 255 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

Pa Description: Aloxi (Continued)

Generic Name (Brand): Palonosetron (Aloxi)

Emetogenicity of Chemotherapeutic Agents (continued)

Moderate emetic risk (30-90% frequency of emesis) Oxaliplatin > 75 mg/m2 Temozolomide (oral) Vinorelbine (oral)

Low emetic risk (10-30% frequency of emesis) Amifostine < 300 mg Bexarotene Capecitabine Cetuximab Cytarabine (low dose) 100-200 mg/m2 Docetaxel Doxorubicin (liposomal) Etoposide Fludarabine (oral) 5-Fluorouracil Gemcitabine Methotrexate > 50 mg/m2 < 250 mg/m2 Mitomycin Mitoxantrone Paclitaxel Paclitaxel-albumin Pemetrexed Topotecan

Minimal emetic risk (< 10% frequency of emesis) Alemtuzumab Alpha Interferon Asparaginase Bevacizumab Bleomycin Bortezomib Busulfan Chlorambucil (oral) Cladribine 2-Chlorodeoxyadenosine Cladribine Denileukin diftitox Dexrazoxane CONTINUED ON NEXT PAGE

ODS Health Plan Customary Specialty MR Criteria Page 256 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Aloxi (continued)

Generic Name (Brand): Palonosetron (Aloxi)

Emetogenicity of Chemotherapeutic Agents (continued)

Minimal emetic risk (< 10% frequency of emesis) Erlotinib Fludarabine Gefitinib Gentuzumab ozogamicin Hydroxyurea (oral) Melphalan (oral low-dose) Methotrexate < 50 mg/m2 Nelarabine Pentostatin Rituximab Thalidomide Thioguanine (oral) Trastuzumab Valrubicin Vinblastine Vincristine Vinorelbine

ODS Health Plan Customary Specialty MR Criteria Page 257 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Panitumumab (Vectibix)

FDA APPROVED INDICATIONS Colorectal carcinoma: As a single agent for the treatment of EGFR-expressing, metastatic colorectal carcinoma with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens.

TREATMENT DOSE / DURATION / REGIMEN Dosage: 6 mg/kg administered over 60 minutes as an intravenous (IV) infusion through a peripheral line or indwelling catheter every 14 days. Doses higher than 1,000 mg should be administered over 90 minutes.

EFFECTIVENESS MONITORING PARAMETERS Clinical and pathologic response. The efficacy of panitumumab for the treatment of EGFR- expressing, metastatic colorectal carcinoma is based on progression-free survival (PFS). Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with panitumumab

ODS Health Plan Customary Specialty MR Criteria Page 258 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

INJECTABLE ADMINISTRATION REQUIREMENTS Administration should be supervised by medical professional experienced in the use of anticancer agents.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 259 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Pemetrexed (Alimta)

FDA APPROVED INDICATIONS 1. Malignant pleural mesothelioma: In combination with cisplatin for the treatment of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery. 2. Non-small cell lung cancer (NSCLC): As a single-agent for the treatment of patients with locally advanced or metastatic NSCLC after prior chemotherapy. The efficacy of pemetrexed in second-line NSCLC was based on the surrogate end point, response rate. There are no controlled trials demonstrating a clinical benefit, such as a favorable survival effect or improvement of disease-related symptoms

TREATMENT DOSE / DURATION / REGIMEN Malignant pleural mesothelioma: The recommended dose of pemetrexed is 500 mg/m2 administered as an IV infusion over 10 minutes on day 1 of each 21-day cycle. The recommended dose of cisplatin is 75 mg/m2 infused over 2 hours beginning approximately 30 minutes after the end of pemetrexed administration. NSCLC: The recommended dose of pemetrexed is 500 mg/m2 administered as an IV infusion over 10 minutes on day 1 of each 21-day cycle.

ODS Health Plan Customary Specialty MR Criteria Page 260 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

EFFECTIVENESS MONITORING PARAMETERS Objective tumor response rate.

INJECTABLE ADMINISTRATION REQUIREMENTS Administration should be supervised by medical professional experienced in the use of anticancer agents.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 261 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Pentostatin (Nipent)

FDA APPROVED INDICATIONS Hairy-cell leukemia: Single-agent treatment for both untreated and alpha-interferon-refractory hairy-cell leukemia patients with active disease as defined by clinically significant anemia, neutropenia, thrombocytopenia, or disease-related symptoms.

TREATMENT DOSE / DURATION / REGIMEN Usual dosage: 4 mg/m 2 every other week. Pentostatin may be administered intravenously by bolus injection or diluted in a larger volume and given over 20 to 30 minutes. Response to treatment: All patients receiving pentostatin at 6 months should be assessed for response to treatment. If the patient has not achieved a complete or partial response, treatment with pentostatin should be discontinued. If the patient has achieved a partial response, pentostatin treatment should be continued in an effort to achieve a complete response. At any time thereafter that a complete response is achieved, 2 additional doses of pentostatin are recommended. Pentostatin treatment should then be stopped. If the best response to treatment at the end of 12 months is a partial response, it is recommended that treatment with pentostatin be stopped.

ODS Health Plan Customary Specialty MR Criteria Page 262 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

EFFECTIVENESS MONITORING PARAMETERS A complete response (CR) required clearing of the peripheral blood and bone marrow of all hairy cells, normalization of organomegaly and lymphadenopathy by physical examination, and recovery of hemoglobin to at least 12 g/dL, platelet count to at least 100,000/mm3, and granulocyte count to at least 1500/mm3. A partial response (PR) required that the percentage of hairy cells in the blood and bone marrow decrease by more than 50%, enlarged organs and lymph nodes decrease by more than 50% by physical examination, and hematologic parameters had to meet the same criteria as for complete response.

INJECTABLE ADMINISTRATION REQUIREMENTS Administration should be supervised by medical professional experienced in the use of anticancer agents.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 263 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Porfimerpo (Photofrin)

FDA APPROVED INDICATIONS Photodynamic therapy (PDT) with porfimer sodium is indicated for the following: 1. Esophageal cancer: Palliation of patients with completely obstructing esophageal cancer, or of patients with partially obstructing esophageal cancer who, in the opinion of their physician, cannot be satisfactorily treated with Nd:YAG laser therapy. 2. Endobronchial nonsmall cell lung cancer (NSCLC): The reduction of obstruction and palliation of symptoms in patients with completely or partially obstructing endobronchial NSCLC. 3. Microinvasive endobronchial NSCLC: The treatment of microinvasive endobronchial NSCLC in patients for whom surgery and radiotherapy are not indicated. 4. Barrett's esophagus: Ablation of high-grade dysplasia in Barrett's esophagus patients who do not undergo esophagectomy

TREATMENT DOSE / DURATION / REGIMEN Photodynamic therapy with porfimer sodium is a 2-stage process requiring administration of both drug and light. The first stage of PDT is the IV injection of porfimer sodium at 2 mg/kg. Illumination with laser light 40 to 50 hours following injection with porfimer sodium constitutes the second stage of therapy. A second laser light application may be given 96 to 120 hours after injection, preceded by gentle debridement of residual tumor (see Administration of laser light.

ODS Health Plan Customary Specialty MR Criteria Page 264 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

Esophageal/Endobronchial cancer: For the treatment of esophageal and endobronchial cancer, patients may receive a second course of PDT a minimum of 30 days after the initial therapy; up to 3 courses of PDT (each separated by a minimum of 30 days) can be given. Before each course of treatment, patients with esophageal cancer should be evaluated for the presence of a tracheoesophageal or bronchoesophageal fistula. Porfimer sodium is also contraindicated in the presence of this condition. Barrett's esophagus: For the ablation of high-grade dysplasia in Barrett’s esophagus, patients may receive an additional course of PDT at a minimum of 90 days after the initial therapy; up to 3 courses of PDT (each injection separated by a minimum of 90 days) can be given to a previously treated segment which still shows high-grade dysplasia, low-grade dysplasia, or Barrett’s metaplasia, or to a new segment if the initial Barrett’s segment was greater than 7 cm in length.

EFFECTIVENESS MONITORING PARAMETERS Clinical and pathologic response.

INJECTABLE ADMINISTRATION REQUIREMENTS Administration should be supervised by medical professional experienced in the use of anticancer agents.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 265 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Procarbazine (Matulane)

FDA APPROVED INDICATIONS Hodgkin's disease: Procarbazine hydrochloride is indicated for use in combination with other anticancer drugs for the treatment of Stage III and IV Hodgkin's disease. Procarbazine hydrochloride is used as part of the MOPP (nitrogen mustard, vincristine, procarbazine, prednisone) regimen.

TREATMENT DOSE / DURATION / REGIMEN The following doses are for administration of the drug as a single agent. When used in combination with other anticancer drugs, the procarbazine hydrochloride dose should be appropriately reduced (eg, in the MOPP regimen, the procarbazine hydrochloride dose is 100 mg/m2 daily for 14 days). All dosages are based on the patient's actual weight. However, the estimated lean body mass (dry weight) is used if the patient is obese or if there has been a spurious weight gain due to edema, ascites or other forms of abnormal fluid retention. Adults: To minimize the nausea and vomiting experienced by a high percentage of patients beginning procarbazine hydrochloride therapy, single or divided doses of 2 to 4 mg/kg/day for the first week are recommended. Daily dosage should then be maintained at 4 to 6 mg/kg/day until maximum response is obtained or until the white blood count falls below 4000/cmm or the platelets fall below 100,000/cmm. When maximum response is obtained, the dose may be maintained at 1 to 2 mg/kg/day. Upon evidence of hematologic or other toxicity, the drug should

ODS Health Plan Customary Specialty MR Criteria Page 266 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

be discontinued until there has been satisfactory recovery. Prompt cessation of therapy is recommended if any one of the following occurs: • CNS signs or symptoms such as paresthesias, neuropathies or confusion. • Leukopenia (white blood count under 4000). • Thrombocytopenia (platelets under 100,000). • Hypersensitivity reaction. • Stomatitis (the first small ulceration or persistent spot soreness around the oral cavity is a signal for cessation of therapy). • Diarrhea (frequent bowel movements or watery stools). • Hemorrhage or bleeding tendencies. After toxic side effects have subsided, therapy may then be resumed at the discretion of the physician, based on clinical evaluation and appropriate laboratory studies, at a dosage of 1 to 2 mg/kg/day. Pediatric patients: Very close clinical monitoring is mandatory. Undue toxicity, evidenced by tremors, coma and convulsions, has occurred in a few cases. Dosage, therefore, should be individualized. The following dosage schedule is provided as a guideline only. Fifty (50) mg per square meter of body surface per day is recommended for the first week. Dosage should then be maintained at 100 mg per square meter of body surface per day until maximum response is obtained or until leukopenia or thrombocytopenia occurs. When maximum response is attained, the dose may be maintained at 50 mg per square meter of body surface per day. Upon evidence of hematologic or other toxicity, the drug should be discontinued until there has been satisfactory recovery, based on clinical evaluation and appropriate laboratory tests. After toxic side effects have subsided, therapy may then be resumed.

EFFECTIVENESS MONITORING PARAMETERS Clinical and pathologic response.

INJECTABLE ADMINISTRATION REQUIREMENTS None.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 267 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Ophthalmic Agents

Generic Name (Brand): Ranibizumab (Lucentis)

DISTRIBUTION Limited distribution.

FDA APPROVED INDICATIONS Macular degeneration: For the treatment of patients with neovascular (wet) age- related macular degeneration (AMD).

TREATMENT DOSE / DURATION / REGIMEN Dosage: Administer 0.5 mg (0.05 mL) by intravitreal injection once a month.

EFFECTIVENESS MONITORING PARAMETERS Clinical response.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08.

Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 268 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Rasburicase (Elitek)

FDA APPROVED INDICATIONS Hyperuricemia: For the initial management of plasma uric acid levels in pediatric patients with leukemia, lymphoma, and solid tumor malignancies who are receiving anti-cancer therapy expected to result in tumor lysis and subsequent elevation of plasma uric acid.

TREATMENT DOSE / DURATION / REGIMEN Dosage: 0.15 or 0.2 mg/kg as a single daily dose for 5 days. Because the safety and effectiveness of other schedules have not been established, dosing beyond 5 days or administration of more than 1 course of rasburicase is not recommended. Chemotherapy should be initiated 4 to 24 hours after the first dose of rasburicase. Do not administer as a bolus infusion. Rasburicase should be administered as an intravenous infusion over 30 minutes.

EFFECTIVENESS MONITORING PARAMETERS Uric acid levels.

INJECTABLE ADMINISTRATION REQUIREMENTS Administration should be supervised by medical professional experienced in the use of anticancer agents.

ODS Health Plan Customary Specialty MR Criteria Page 269 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 270 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Immunologic Agents

Generic Name (Brand): Respiratory Syncytial Virus Immune Globulin (RespiGam)

FDA APPROVED INDICATIONS Respiratory syncytial virus (RSV): Prevention of serious lower respiratory tract infection caused by RSV in children < 24 months of age with bronchopulmonary dysplasia (BPD) or a history of premature birth (≤ 35 weeks gestation). RSV-IGIV is safe and effective in reducing the incidence and duration of RSV hospitalization and the severity of RSV illness in these high-risk infants. TREATMENT DOSE / DURATION / REGIMEN Recommended dose: The maximum recommended total dosage per monthly infusion is 750 mg/kg, administered according to the following schedule:

RSV-IGIV Infusion Schedule1 Rate of infusion Time after start of infusion (mL/kg of body mass per hour) 0 to 15 minutes 1.5 mL/kg/hr 15 minutes to end of infusion 3.6 mL/kg/hr

EFFECTIVENESS MONITORING PARAMETERS Clinical response.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08.

Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 271 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Anti-Infective Agents

Generic Name (Brand): Ribavirin Inhalation (Virazole)

FDA APPROVED INDICATIONS Severe respiratory syncytial virus (RSV) infection: For the treatment of hospitalized infants and young children with severe lower respiratory tract infection due to RSV. Treatment early in the course of severe lower respiratory tract infection may be necessary to achieve efficacy.

TREATMENT DOSE / DURATION / REGIMEN Dosage: Ribavirin 20 mg/mL as the starting solution in the drug reservoir of the SPAG-2 unit, with continuous aerosol administration for 12 to 18 hours per day for 3 to 7 days. Using the recommended drug concentration of 20 mg/mL, the average aerosol concentration for a 12-hour delivery period would be 190 mcg/L of air. Aerosolized ribavirin should not be administered in a mixture for combined aerosolization or simultaneously with other aerosolized medications.

EFFECTIVENESS MONITORING PARAMETERS Clinical response.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08.

Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 272 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Immunologic Agents

Generic Name (Brand): Rilonacept (Arcalyst)

FDA APPROVED INDICATIONS Cryopyrin-associated periodic syndromes: For the treatment of cryopyrin-associated periodic syndromes, including familial cold autoinflammatory syndrome and Muckle- Wells syndrome in adults and children 12 years of age and older.

TREATMENT DOSE / DURATION / REGIMEN Dosage: Adults (18 years of age and older): Treatment should be initiated with a loading dose of 320 mg delivered as two, 2 mL, subcutaneous injections of 160 mg each given on the same day at 2 different sites. Dosing should be continued with a once-weekly injection of 160 mg administered as a single, 2 mL, subcutaneous injection. Rilonacept should not be given more often than once weekly. Children (12 to 17 years of age): Treatment should be initiated with a loading dose of 4.4 mg/kg, up to a maximum of 320 mg, delivered as 1 or 2 subcutaneous injections, with a maximum single-injection volume of 2 mL. Dosing should be continued with a once-weekly injection of 2.2 mg/kg, up to a maximum of 160 mg, administered as a single subcutaneous injection, up to 2 mL. If the initial dose is given as 2 injections, they should be given on the same day at 2 different sites. Rilonacept should not be given more often than once weekly.1 EFFECTIVENESS MONITORING PARAMETERS Using a daily diary questionnaire, patients rated the following 5 signs and symptoms of cryopyrin-associated periodic syndromes: joint pain, rash, feeling of fever/chills, eye redness/pain, and fatigue, each on a scale of 0 (none, no severity) to 10 (very severe). REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08.

Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 273 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Rituxan

Generic Name (Brand): Rituximab (Rituxan)

DESCRIPTION: Rituximab is a murine/human monoclonal antibody that specifically targets the CD20 antigen found on the surface of normal and malignant B lymphocytes. B-cells are believed to play a role in rheumatoid arthritis by producing rheumatoid factor, activating T-cells and pro-inflammatory cytokines.

PRODUCT AVAILABILITY: • Rituximab (Rituxan®) – 10 mg/mL in a 10 mL vial (100 mg) o 10 mg/mL in a 50 mL vial (500 mg)

INDICATIONS: In combination with methotrexate, to reduce signs and symptoms in adult patients with moderately- to severely- active rheumatoid arthritis who have had an inadequate response to one or more TNF antagonists

GUIDELINES FOR USE: 1) Is the drug prescribed by a rheumatologist? a) If yes, go to #2. b) If no, denied.

2) Is Rituxan being co-prescribed with methotrexate? a) If yes and initial therapy, go to #3 b) If yes and requesting re-treatment, go to #5. c) If no, denied. (Note: Rituxan must be administered in combination with methotrexate for RA.)

3) Is the patient being treated for moderately- to severely-active rheumatoid arthritis with documented evidence of at least four of the following for at least 6 weeks duration: i) Prolonged morning stiffness in the joints (≥ 45 minutes duration) ii) Arthritis of 3 or more joint areas: wrist, elbow, knee, subtalar, MTP or hands (MCP or PIP) iii) Arthritis of hand joints iv) Symmetric arthritis v) Rheumatoid nodules under the skin vi) Elevated levels of serum rheumatoid factor vii) Radiographic changes in the joints a) If yes, go to #4. b) If no, denied.

4) Has the patient failed optimal dosing/adequate duration or does the patient have intolerance/ contraindication to at least one tumor necrosis factor antagonist? a) If yes, approve for one month (one course of two-1000 mg IV infusions of Rituxan). b) If no, denied.

5) All retreatment requests will be denied and forwarded to plan for review. Safety and efficacy of retreatment have not been established in controlled trials.

Special Instructions

ODS Health Plan Customary Specialty MR Criteria Page 274 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

Clinical Information: Other FDA approved indications for Rituxan: • First-line treatment of diffuse large B-cell, CD20-positive, non-Hodgkin’s lymphoma in combination with CHOP or other anthracycline-based chemotherapy regimens • Treatment of patients with relapsed or refractory, low-grade or follicular, 20-positive, B-cell, non-Hodgkin’s lymphoma.

Dosing for RA: • Rituxan is dosed as two-1000 mg infusions, separated by two weeks. • Initial infusion should be administered IV at an initial rate of 50 mg/hr and may be escalated in 50 mg/hr increments every 30 minutes to a max of 400 mg/hr. The infusion may be temporarily slowed or interrupted in a hypersensitivity or infusion reaction occurs. Upon improvement of symptoms, the infusion may continue at ½ the previous rate. • Subsequent infusions can be administered at an initial rate of 100 mg/hr (if initial rate was tolerated) and increased by 100 mg/hr increments at 30-minute intervals to a max of 400 mg/hr. • Rituxan for RA must be administered in combination with methotrexate. • Administration of methylprednisolone 100 mg IV or an equivalent glucocorticoid 30 minutes prior to each infusion reduces infusion reactions. • In trials, pts also received APAP and antihistamines prior to Rituxan infusions. • Safety and efficacy of retreatment have not been established in controlled trials. A limited number of patients have received two to five courses in an uncontrolled setting. In trials of patients with RA, retreatment averaged 24 weeks with a second course being no sooner than 16 weeks. • Most patients in trials failed 2.5 DMARDS and 1.5 TNF antagonists before trial of Rituxan.

Adverse Events Seen in Trials: • Acute infusion reactions (27% vs. 19% placebo) – fever, chills, pruritus, rigors, rash, angioedema, throat irritation, w/ or w/o hypertension or hypotension • Serious acute infusion reactions were <1% in either group (Rituxan or placebo)

Pregnancy Category: C

Boxed Warnings: Fatal Infusion Reactions – Deaths have occurred within 24 hours of the first dose of Rituxan after a complex of reactions including hypoxia, acute respiratory distress syndrome, MI, or cardiogenic shock. Patients who develop severe infusion reactions should have Rituxan infusion discontinued and receive medical treatment. Tumor Lysis Syndrome (TLS) – Acute renal failure requiring dialysis with instances of fatal outcome has been reported in TLS following treatment of non-Hodgkin’s lymphoma. Severe Mucocutaneous Reactions – Some mucocutaneous reactions have been fatal.

Other Warnings: Hepatitis B Reactivation with fulminant Hepatitis and infections have occurred in patients receiving Rituxan. Cardiac events and immunogenicity also occurred. Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 275 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Endocrine and Metabolic Agents

Generic Name (Brand): Sapropterin (Kuvan) GUIDELINES FOR USE 1. What is the patient’s diagnosis? If the diagnosis is an FDA approved indication, continue to #2. If not, do not approve. 2. What is the treatment dose? If treatment dose is within the approved dosing range, continue to #3. If not, do not approve. 3. What clinical parameters will be monitored to establish treatment effectiveness? If submitted monitoring plan is consistent with effectiveness monitoring, continue to #4. If not, do not approve. 4. Approve for 6 months.

FDA APPROVED INDICATIONS Hyperphenylalaninemia: To reduce blood phenylalanine (Phe) levels in patients with hyperphenylalaninemia caused by tetrahydrobiopterin (BH4)-responsive phenylketonuria. Sapropterin is to be used in conjunction with a Phe-restricted diet.

TREATMENT DOSE / DURATION / REGIMEN Dosage: The recommended starting dosage is 10 mg/kg/day once daily. Doses higher than 20 mg/kg/day have not been evaluated in clinical trials. Response to therapy: Response to therapy is determined by change in blood Phe following treatment with sapropterin at 10 mg/kg/day for a period of up to 1 month. Blood Phe levels should be checked after 1 week of sapropterin treatment and periodically for up to a month. If blood Phe does not decrease from baseline at 10 mg/kg/day, the dose may be increased to 20 mg/kg/day. Patients whose blood Phe does not decrease after 1 month of treatment at 20 mg/kg/day are nonresponders, and treatment with sapropterin should be discontinued in these patients. Dosage adjustments: Once responsiveness to sapropterin has been established, the dose may be adjusted within the range of 5 to 20 mg/kg/day, according to response to therapy.1

EFFECTIVENESS MONITORING PARAMETERS Patients whose blood Phe does not decrease after 1 month of treatment at 20 mg/kg/day are nonresponders, and treatment with sapropterin should be discontinued in these patients.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08.

Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 276 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Hematological Agents

Generic Name (Brand): Sargramostim (Leukine)

FDA APPROVED INDICATIONS Following induction chemotherapy in acute myelogenous leukemia: For use following induction chemotherapy in older adult patients with acute myelogenous leukemia (AML) to shorten time to neutrophil recovery and to reduce the incidence of severe and life-threatening infections and infections resulting in death. The safety and efficacy of sargramostim have not been assessed in patients with AML under 55 years of age. The term acute myelogenous leukemia, also referred to as acute non-lymphocytic leukemia (ANLL), encompasses a heterogeneous group of leukemias arising from various non-lymphoid cell lines that have been defined morphologically by the French-American-British (FAB) system of classification. Mobilization and following transplantation of autologous peripheral blood progenitor cells: For the mobilization of hematopoietic progenitor cells into peripheral blood for collection by leukapheresis. Mobilization allows for the collection of increased numbers of progenitor cells capable of engraftment as compared with collection without mobilization. After myeloablative chemotherapy, the transplantation of an increased number of progenitor cells lead to more rapid engraftment, which result in a decreased need for supportive care. Myeloid reconstitution is further accelerated by administration of sargramostim following peripheral blood progenitor cell transplantation. Myeloid reconstitution after autologous bone marrow transplantation (BMT): For acceleration of myeloid recovery in patients with non-Hodgkin lymphoma (NHL), acute lymphoblastic leukemia (ALL), and Hodgkin disease undergoing autologous BMT. After autologous BMT in patients with NHL, ALL, or Hodgkin disease, sargramostim has been found to be safe and effective in accelerating myeloid engraftment, decreasing median duration of antibiotic administration, reducing the median duration of infectious episodes, and shortening the median duration of hospitalization. Hematologic response to sargramostim can be detected by complete blood count (CBC) with differential performed twice per week. Myeloid reconstitution after allogeneic bone marrow transplantation: For acceleration of myeloid recovery in patients undergoing allogeneic BMT from HLA-matched related donors. Sargramostim has been found to be safe and effective in accelerating myeloid engraftment,

ODS Health Plan Customary Specialty MR Criteria Page 277 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

reducing the incidence of bacteremia and other culture positive infections, and shortening the median duration of hospitalization. Bone marrow transplantation failure or engraftment delay: In patients who have undergone allogeneic or autologous BMT in whom engraftment is delayed or has failed. Sargramostim has been found to be safe and effective in prolonging survival of patients who are experiencing graft failure or engraftment delay, in the presence or absence of infection, following autologous or allogeneic BMT. Survival benefit may be relatively greater in those patients who demonstrate one or more of the following characteristics: Autologous BMT failure or engraftment delay, no previous total body irradiation, malignancy other than leukemia or a multiple organ failure (MOF) score of 2 or less. Hematologic response to sargramostim can be detected by CBC with differential performed twice weekly.

TREATMENT DOSE / DURATION / REGIMEN Neutrophil recovery following chemotherapy in acute myelogenous leukemia: 250 mcg/m2/day administered intravenously over a 4-hour period starting approximately on day 11 or 4 days following the completion of induction chemotherapy, if the day 10 bone marrow is hypoplastic with less than 5% blasts. If a second cycle of induction chemotherapy is necessary, sargramostim should be administered approximately 4 days after the completion of chemotherapy if the bone marrow is hypoplastic with less than 5% blasts. Sargramostim should be continued until an ANC more than 1,500/mm3 for 3 consecutive days or a maximum of 42 days. Sargramostim should be discontinued immediately if leukemic regrowth occurs. If a severe adverse reaction occurs, the dose can be reduced 50% or temporarily discontinued until the reaction abates. In order to avoid potential complications of excessive leukocytosis (WBC more than 50,000 cells/mm3 or ANC more than 20,000 cells/mm3) a CBC with differential is recommended twice a week during sargramostim therapy. Sargramostim treatment should be interrupted or the dose reduced 50% if the ANC exceeds 20,000 cells/mm3. Mobilization of peripheral blood progenitor cells: 250 mcg/m2/day administered IV over 24 hours or subcutaneously once daily. Dosing should continue at the same dose through the period of peripheral blood progenitor cells (PBPC) collection. The optimal schedule for PBPC collection has not been established. In clinical studies, collection of PBPC was usually begun by day 5 and performed daily until protocol specified targets were achieved. If WBC more than 50,000 cells/mm3, the sargramostim dose should be reduced 50%. If adequate numbers of progenitor cells are not collected, other mobilization therapy should be considered. Post-PBPC transplantation: 250 mcg/m2/day administered IV over 24 hours or subcutaneously once daily beginning immediately following infusion of progenitor cells and continuing until an ANC greater than 1,500/mm3 for 3 consecutive days is attained. Myeloid reconstitution after autologous or allogeneic bone marrow transplantation: 250 mcg/m2/day administered IV over a 2–hour period beginning 2 to 4 hours after bone marrow infusion, and not less than 24 hours after the last dose of chemotherapy or radiotherapy. Patients should not receive sargramostim until the post-marrow infusion ANC is less than 500 cells/mm3. Sargramostim should be continued until an ANC greater than 1,500/mm3 for 3 consecutive days is attained. If a severe adverse reaction occurs, the dose can be reduced 50% or temporarily discontinued until the reaction abates. Sargramostim should be discontinued immediately if blast cells appear or disease progression occurs. Bone marrow transplantation failure or engraftment delay: 250 mcg/m2/day for 14 days as a 2-hour IV infusion. The dose can be repeated after 7 days off therapy if engraftment has not occurred. If engraftment still has not occurred, a third course of 500 mcg/m2/day for 14 days may be tried after another 7 days off therapy. If there is still no improvement, it is unlikely that further dose escalation will be beneficial. If a severe adverse reaction occurs, the dose can be

ODS Health Plan Customary Specialty MR Criteria Page 278 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

reduced 50% or temporarily discontinued until the reaction abates. Sargramostim should be discontinued immediately if blast cells appear or disease progression occurs.

EFFECTIVENESS MONITORING PARAMETERS In order to avoid potential complications of excessive leukocytosis (WBC more than 50,000 cells/mm3, ANC greater than 20,000 cells/mm3) a CBC with differential is recommended twice weekly during sargramostim therapy. Sargramostim treatment should be interrupted or the dose reduced by half if the ANC exceeds 20,000 cells/mm3.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08.

Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 279 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Immunologic Agents

Generic Name (Brand): Sirolimus (Rapamune)

FDA APPROVED INDICATIONS Renal transplant: For the prophylaxis of organ rejection in patients 13 years of age or older receiving renal transplants. It is recommended that sirolimus be used initially in a regimen with cyclosporine and corticosteroids. In patients at low to moderate immunological risk, cyclosporine should be withdrawn 2 to 4 months after transplantation, and the sirolimus dosage should be increased to reach recommended blood concentrations. The safety and efficacy of sirolimus have not been established in children younger than 13 years of age, or in pediatric (younger than 18 years of age) renal transplant recipients considered at high immunologic risk.

TREATMENT DOSE / DURATION / REGIMEN Sirolimus is to be administered orally once daily. It is recommended that sirolimus be used in a regimen with cyclosporine and corticosteroids. Cyclosporine withdrawal is recommended 2 to 4 months after transplantation in patients at low to moderate immunological risk. The safety and efficacy of cyclosporine withdrawal in high-risk patients have not been adequately studied; therefore, use is not recommended. High-risk patients include those with Banff grade III acute rejection or vascular rejection prior to cyclosporine withdrawal, those who are dialysis- dependent, those with serum creatinine greater than 4.5 mg/dL, black patients, retransplant patients, multiorgan transplant patients, and patients with a high panel of reactive antibodies. Bioequivalence: The sirolimus 2 mg oral solution has been demonstrated to be clinically equivalent to sirolimus 2 mg oral tablets; therefore, they are interchangeable on a mg to mg basis. However, it is not known whether higher dosages of sirolimus oral solution are therapeutically equivalent to higher dosages of tablets on a mg to mg basis. Sirolimus and cyclosporine combination therapy: The initial dose of sirolimus should be administered as soon as possible after transplantation. For de novo transplant recipients, a loading dose of sirolimus of 3 times the maintenance dose should be given. A daily maintenance dose of 2 mg is recommended for use in renal transplant patients, with a loading dose of 6 mg. Although a daily maintenance dose of 5 mg with a loading dose of 15 mg was used in clinical trials of the oral solution and was shown to be safe and effective, no efficacy advantage over the 2 mg dose could be established for renal transplant patients. Patients

ODS Health Plan Customary Specialty MR Criteria Page 280 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

receiving sirolimus 2 mg oral solution per day demonstrated an overall better safety profile than patients receiving sirolimus 5 mg oral solution per day. Sirolimus following cyclosporine withdrawal: Initially, patients considered for cyclosporine withdrawal should be receiving sirolimus and cyclosporine combination therapy. At 2 to 4 months following transplantation, cyclosporine should be discontinued progressively over 4 to 8 weeks, and the sirolimus dosage should be adjusted to obtain whole blood trough concentrations within the range of 12 to 24 ng/mL (chromatographic method). Therapeutic drug monitoring should not be the sole basis for adjusting sirolimus therapy. Careful attention should be made to clinical signs/symptoms, tissue biopsy, and laboratory parameters. Cyclosporine inhibits the metabolism and transport of sirolimus; consequently, sirolimus concentrations will decrease when cyclosporine is discontinued unless the sirolimus dosage is increased. The sirolimus dosage will need to be approximately 4-fold higher to account for the absence of the pharmacokinetic interaction (approximately 2-fold increase) and the augmented immunosuppressive requirement in the absence of cyclosporine (approximately 2-fold increase). Frequent sirolimus dosage adjustments based on non–steady-state sirolimus concentrations can lead to overdosing or underdosing because sirolimus has a long half-life (t½). Once the sirolimus maintenance dosage is adjusted, patients should be retained on the new maintenance dosage at least for 7 to 14 days before further dosage adjustment with concentration monitoring. In most patients, dosage adjustments can be based on a simple proportion: new sirolimus dose = current dose × (target concentration / current concentration) . A loading dose should be considered in addition to a new maintenance dosage when it is necessary to considerably increase sirolimus trough concentrations: sirolimus loading dose = 3 × (new maintenance dosage − current maintenance dosage) . The maximum sirolimus dose administered on any day should not exceed 40 mg. If an estimated daily dose exceeds 40 mg because of the addition of a loading dose, the loading dose should be administered over 2 days. Sirolimus trough concentrations should be monitored at least 3 to 4 days after a loading dose(s).

EFFECTIVENESS MONITORING PARAMETERS Clinical and laboratory response

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08.

Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 281 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Central Nervous System Agents

Generic Name (Brand): Sodium Oxybate (Xyrem)

DISTRIBUTION Limited distribution. Sodium oxybate is available through the Xyrem Success Program, using a centralized pharmacy (1-866-997-3688). The Success Program provides educational materials to the prescriber and the patient explaining the risks and proper use of sodium oxybate and the required prescription form. Once it is documented that the patient has read and/or understands the materials, the drug will be shipped to the patient. The Xyrem Success Program also recommends patient follow-up every 3 months. Health care providers are expected to report all serious adverse reactions to the manufacturer.

FDA APPROVED INDICATIONS Excessive daytime sleepiness/cataplexy: For the treatment of excessive daytime sleepiness and cataplexy in patients with narcolepsy. In sodium oxybate clinical trials, approximately 80% of patients maintained concomitant stimulant use.

TREATMENT DOSE / DURATION / REGIMEN Dosage: Sodium oxybate is required to be taken at bedtime while in bed and again 2.5 to 4 hours later. The dose of sodium oxybate should be titrated to effect. The recommended starting dose is 4.5 g/night divided into 2 equal doses of 2.25 g. The starting dose then can be increased to a maximum of 9 g/night in increments of 1.5 g/night (0.75 g/dose). One to 2 weeks are recommended between dosage increases to evaluate clinical response and minimize adverse reactions. The effective dose range of sodium oxybate is 6 to 9 g/night. The efficacy and safety of sodium oxybate at doses higher than 9 g/night have not been investigated.

EFFECTIVENESS MONITORING PARAMETERS Clinical response.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08.

Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed: ODS Health Plan Customary Specialty MR Criteria Page 282 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Somatropin

Generic Name (Brand): Somatropin (Genotropin, Humatrope, Norditropin, Nutropin, Saizen, Serostim,Tev-Tropin, Zorbtive)

GUIDELINES FOR USE (NOTE INITIAL AND RENEWAL CRITERIA ARE WITHIN THE FOLLOWING CRITERIA) 1. Does the patient have AIDS related cachexia, defined as profound involuntary weight loss of more than 10% of baseline body weight, plus either chronic diarrhea (equal or greater than 2 loose stools a day) for more than 30 days or chronic weakness and documented fever (intermittent or constant), for more than 30 days in the absence of a concurrent illness or condition other than HIV infection that could explain these symptoms (e.g., cancer, tuberculosis, etc)? If yes, continue to #2. If no, continue to #5. 2. Is this an initial PA request? If yes, continue to #3. If no, continue to #4. 3. Has the member tried and failed any of the following medications? Dronabinol, or Oxandrolone, or Megestrol If yes, continue to #17. If no, do not approve and recommend one of the above agents. 4. Has the member experienced a significant weight gain while on growth hormone (significant weight gain defined as + 0.5kg/month)? If yes, continue to #17. If no, do not approve. 5. Is the member less than 18 years old? If yes, continue to #6. If no, continue to #14.

ODS Health Plan Customary Specialty MR Criteria Page 283 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

6. Is this an initial prior authorization request? If yes, continue to #7. If no, continue to #11. 7. Is the prescriber a pediatric endocrinologist or a pediatric nephrologist? If yes, continue to #8. If no, do not approve and respond with the following: Guidelines require initiation of therapy and monitoring by pediatric endocrinologists or nephrologists. If this request is a continuation of recommendations from a specialist, please contact MedImpact or provide documentation. 8. Does the member have ONE of the following diagnoses? Growth hormone deficiency, or Small for Gestational age (defined as a standard deviation score of 2 or more below the mean for weight and/or length at preterm or term birth), or Prader-Willi syndrome, or Pre-transplant chronic renal insufficiency, or Neonatal hypoglycemia associated with growth hormone deficiency. If yes, continue to #9. If no, continue to #13. 9. If male, is bone age less than 16 years old OR if female, is bone age less than 14 years old and is there evidence of non-closure of the epiphyseal plate? If yes, continue to #10. If no, do not approve. 10. Does the member meet at least ONE of the following criteria? Lack of response to growth hormone stimulation tests. [serum growth hormone level of < 10ngm/ml to at least two stimuli (insulin, levodopa, arginine, clonidine, or glucagons)], or IGF-1 is -2 standard deviations (SD) below the normal range for age and sex, or IGFBG-3 level is -2 SD below the normal range for age and sex. If yes, continue to #17. If no, do not approve.

11. Is the growth velocity of at least 0.25 SD score within the first year? If yes, continue to #12. If no, do not approve. 11. If male, is bone age less than 16 years old OR if female, is bone age less than 14 years old and is there evidence of non-closure of the epiphyseal plate? If yes, continue to #17. If no, do not approve. 13. Does the member have a diagnosis of Turner’s syndrome or neonatal hypoglycemia (not associated with growth hormone deficiency)? If yes, continue to #17. If no, do not approve.

ODS Health Plan Customary Specialty MR Criteria Page 284 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

14. Does the member have growth hormone deficiency that is from an organic cause (i.e., pituitary hormone deficiency)? If yes, continue to #17. If no, continue to #15. 15. Does the member have growth hormone deficiency that is idiopathic in nature? If yes, continue to #16. If no, do not approve. 16. Does the member meet at least ONE of the following criteria? a. Lack of response to growth hormone stimulation tests. [serum growth hormone level of < 5ngm/ml to at least two stimuli (insulin, levodopa, arginine, or glucagons)], or b. IGF-1 is -2 SD below the normal range for age and sex, or c. IGFBG-3 level is -2 SD below the normal range for age and sex. If yes, continue to #17. If no, do not approve. 17. Approve for 12 months according to the dosing table below. Dosage Recommendations for GH Clinical condition Dose (mcg/kg/day) GHD children 25-50 GHD adolescents 25-100 GHD adults 6-25 Chronic renal insufficiency 50 Turner Syndrome 50 Small for gestational age 50-70 Prader-Willi Syndrome 35-50 AIDS related cachexia 100

FDA APPROVED INDICATIONS Growth hormone deficiency in children and in adults, chronic renal insufficiency, Turner Syndrome, small for gestational age, Prader-Willi Syndrome, AIDS-related cachexia, and idiopathic short stature.

REFERENCES 1. Consensus guidelines for the diagnosis and treatment of adults with growth hormone deficiency: summary statement of the Growth Hormone Research Society Workshop on Adult Growth Hormone Deficiency. J Clin Endocrinol Metab. 1998;83(2):379-381. 2. Wilson TA, Rose SR, Cohen P, Rogol AD, Backeljauw P, Brown R, et al. Update of guidelines for the use of growth hormone in children: the Lawson Wilkins Pediatric Endocrinology Society Drug and Therapeutics Committee. J Pediatr. 2003;143(4):415-421. 3. The American Association of Clinical Endocrinologists and The American College of Endocrinology. AACE clinical practice guidelines for growth hormone use in adults and children. Endocr Pract. 1998;4(3):165-173.

Effective: 10/01/08 Created: 01/01/06 Updated: ______Reviewed: 01/05/07, 11/14/07

ODS Health Plan Customary Specialty MR Criteria Page 285 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Sorafenib tosylate (Nexavar)

FDA APPROVED INDICATIONS 1. Advanced renal cell carcinoma: For the treatment of patients with advanced renal cell carcinoma. 2. Hepatocellular carcinoma: For the treatment of patients with unresectable hepatocellular carcinoma.

TREATMENT DOSE / DURATION / REGIMEN Recommended dosage: Sorafenib 400 mg (two 200 mg tablets) taken twice daily, without food (at least 1 hour before or 2 hours after eating). Treatment should continue until the patient is no longer clinically benefiting from therapy or until unacceptable toxicity occurs.

EFFECTIVENESS MONITORING PARAMETERS Clinical and pathologic response including progression-free survival, defined as the time from randomization to progression or death from any cause, whichever occurred earlier, was evaluated by blinded independent radiological review using Response Evaluation Criteria in Solid Tumors (RECIST) criteria.

INJECTABLE ADMINISTRATION REQUIREMENTS None.

ODS Health Plan Customary Specialty MR Criteria Page 286 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 287 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Streptozocin (Zanosar)

FDA APPROVED INDICATIONS Metastatic islet cell carcinoma of the pancrease: For the treatment of metastatic islet cell carcinoma of the pancreas. Responses have been obtained with both functional and nonfunctional carcinomas. Because of its inherent renal toxicity, therapy with this drug should be limited to patients with symptomatic or progressive metastatic disease.

TREATMENT DOSE / DURATION / REGIMEN Streptozocin sterile powder should be administered intravenously by rapid injection or short/prolonged infusion. It is not active orally. Although it has been administered intra-arterially, this is not recommended pending further evaluation of the possibility that adverse renal effects may be evoked more rapidly by this route of administration. Dosage schedules: Two different dosage schedules have been employed successfully with streptozocin. Daily schedule: The recommended dose for daily intravenous administration is 500 mg/m2 of body surface area for 5 consecutive days every 6 weeks until maximum benefit or until treatment-limiting toxicity is observed. Dose escalation on this schedule is not recommended. Weekly schedule: The recommended initial dose for weekly intravenous administration is 1000 mg/m2of body surface area at weekly intervals for the first 2 courses (weeks). In subsequent courses, drug doses may be escalated in patients who have not achieved a therapeutic

ODS Health Plan Customary Specialty MR Criteria Page 288 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

response and who have not experienced significant toxicity with the previous course of treatment. However, a single dose of 1500 mg/m2body surface area should not be exceededas a greater dose may cause azotemia. When administered on this schedule, the median time to onset of response is about 17 days and the median time to maximum response is about 35 days. The median total dose to onset of response is about 2000 mg/m2 body surface area and the median total dose to maximum response is about 4000 mg/m2 body surface area. Maintenance: The ideal duration of maintenance therapy with streptozocin has not yet been clearly established for either of the above schedules. Response to therapy: For patients with functional tumors, serial monitoring of fasting insulin levels allows a determination of biochemical response to therapy. For patients with either functional or nonfunctional tumors, response to therapy can be determined by measurable reductions of tumor size (reduction of organomegaly, masses, or lymph nodes).

EFFECTIVENESS MONITORING PARAMETERS Clinical and pathologic response.

INJECTABLE ADMINISTRATION REQUIREMENTS Administration should be supervised by medical professional experienced in the use of anticancer agents.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 289 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Sunitinib (Sutent)

FDA APPROVED INDICATIONS 1. Advanced renal cell carcinoma: For the treatment of advanced renal cell carcinoma. 2. GI stromal tumor (GIST): For the treatment of GIST after disease progression on or intolerance to imatinib.

TREATMENT DOSE / DURATION / REGIMEN The recommended dose for GIST and advanced renal cell carcinoma is one 50 mg oral dose taken once daily on a schedule of 4 weeks on treatment followed by 2 weeks off. It may be taken with or without food. Dose modification: Dose increase or reduction in 12.5 mg increments is recommended based on individual safety and tolerability. Concomitant therapy: Strong CYP3A4 inhibitors, such as ketoconazole, may increase sunitinib plasma concentrations. Selection of an alternative concomitant medication with no or minimal enzyme inhibition potential is recommended. A dosage reduction for sunitinib to a minimum of 37.5 mg daily should be considered if sunitinib must be coadministered with a strong CYP3A4 inhibitor. CYP3A4 inducers, such as rifampin, may decrease sunitinib plasma concentrations. Selection of an alternative concomitant medication with no or minimal enzyme induction potential is recommended. A dosage increase for sunitinib to a maximum of 87.5 mg

ODS Health Plan Customary Specialty MR Criteria Page 290 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

daily should be considered if sunitinib must be coadministered with a CYP3A4 inducer. If the dose is increased, the patient should be monitored carefully for toxicity.

EFFECTIVENESS MONITORING PARAMETERS Clinical and pathologic response.

INJECTABLE ADMINISTRATION REQUIREMENTS None.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 291 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Immunologic Agents

Generic Name (Brand): Tacrolimus (Prograf)

FDA APPROVED INDICATIONS Organ rejection prophylaxis: For the prophylaxis of organ rejection in patients receiving allogeneic liver, kidney, or heart transplants. It is recommended that tacrolimus be used concomitantly with adrenal corticosteroids. Because of the risk of anaphylaxis, reserve tacrolimus injection for patients unable to take tacrolimus capsules orally. In heart transplant recipients, it is recommended that tacrolimus be used in conjunction with azathioprine or mycophenolate mofetil. The safety and efficacy of the use of tacrolimus with sirolimus have not been established.

TREATMENT DOSE / DURATION / REGIMEN For intravenous (IV) infusion: In patients unable to take the capsules, therapy may be initiated with the injection. Administer the initial dose no sooner than 6 hours after transplantation. The recommended starting dose is 0.01 mg/kg/day (heart) or 0.03 to 0.05 mg/kg/day(liver, kidney) as a continuous IV infusion. Give adult patients doses at the lower end of the dosing range. Concomitant adrenal corticosteroid therapy is recommended early posttransplantation. Continue continuous IV infusion only until the patient can tolerate oral administration.

Tacrolimus Oral Dose Recommendations and Typical Whole Blood Trough Concentrations1 Patient population Recommended Typical whole blood initial oral dosea trough concentrations Adult kidney 0.2 mg/kg/day Month 1 through 3: 7 to 20 ng/mL transplant Month 4 through 12: 5 to 15 ng/mL patients Adult liver 0.1 to 0.15 mg/kg/day Month 1 through 12: 5 to 20 ng/mL transplant patients Pediatric liver 0.15 to 0.2 mg/kg/day Month 1 to 12: 5 to 20 ng/mL transplant

ODS Health Plan Customary Specialty MR Criteria Page 292 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

patients Adult heart 0.075 mg/kg/day Month 1 through 3: 10 to 20 ng/mL transplant Month ≥4: 5 to 15 ng/mL patients aTwo divided doses every 12 hours. Heart transplantation: The recommended starting oral dose is 0.075 mg/kg/day administered every 12 hours in 2 divided doses. If possible, initiating oral therapy with tacrolimus capsules is recommended. If IV therapy is necessary, conversion from IV to oral tacrolimus is recommended as soon as oral therapy can be tolerated. This usually occurs within 2 to 3 days. The initial dose of tacrolimus should be administered no sooner than 6 hours after transplantation. In a patient receiving an IV infusion, the first dose of oral therapy should be given 8 to 12 hours after discontinuing the IV infusion. Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower tacrolimus dosages may be sufficient as maintenance therapy. Adjunct therapy with adrenal corticosteroids is recommended early posttransplant. Kidney transplantation: The recommended starting oral dose of tacrolimus is 0.2 mg/kg/day administered every 12 hours in 2 divided doses. The initial dose of tacrolimus may be administered within 24 hours of transplantation but should be delayed until renal function has recovered (as indicated, for example, by a serum creatinine less than or equal to 4 mg/dL). Black patients may require higher doses to achieve comparable blood concentrations. The data in kidney transplant patients indicate that black patients required a higher dose to attain comparable trough concentrations compared with white patients.

Tacrolimus Dosing Recommendations by Race Time after White (n = 114) Black (n = 56) transplant Dose Trough Dose Trough (mg/kg) concentrations (mg/kg) concentrations (ng/mL) (ng/mL) Day 7 0.18 12 0.23 10.9 Month 1 0.17 12.8 0.26 12.9 Month 6 0.14 11.8 0.24 11.5 Month 12 0.13 10.1 0.19 11

Liver transplantation: It is recommended that patients initiate oral therapy with tacrolimus capsules if possible. If intravenous (IV) therapy is necessary, conversion from IV to oral tacrolimus is recommended as soon as oral therapy can be tolerated. This usually occurs within 2 to 3 days. The initial dose of tacrolimus should be administered no sooner than 6 hours after transplantation. In a patient receiving an IV infusion, the first dose of oral therapy should be given 8 to 12 hours after discontinuing the IV infusion. The recommended starting oral dose of tacrolimus capsules is 0.1 to 0.15 mg/kg/day administered in 2 divided daily doses every 12 hours. Coadministered grapefruit juice has been reported to increase tacrolimus blood trough concentrations in liver transplant patients. Grapefruit juice affects CYP3A-mediated metabolism and should be avoided. Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower tacrolimus dosages may be sufficient as maintenance therapy. Adjunct therapy with adrenal corticosteroids is recommended early posttransplant. Children: Pediatric liver transplantation patients without preexisting renal or hepatic dysfunction have required and tolerated higher doses than adults to achieve similar blood concentrations. Therefore, it is recommended that therapy be initiated in children at a starting oral dose of 0.15

ODS Health Plan Customary Specialty MR Criteria Page 293 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

to 0.2 mg/kg/day. Dose adjustments may be required. Experience in pediatric kidney and heart transplantation patients is limited.

EFFECTIVENESS MONITORING PARAMETERS Laboratory and clinical response.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08.

Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 294 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Tamoxifen (Soltamox)

FDA APPROVED INDICATIONS Adjuvant treatment of breast cancer: For the treatment of node-positive breast cancer in postmenopausal women following total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation. In some tamoxifen adjuvant studies, most of the benefit to date has been in the subgroup with 4 or more positive axillary nodes. For the treatment of axillary node-negative breast cancer in women following total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation. The ER- and progesterone-receptor values may help to predict whether adjuvant tamoxifen therapy is likely to be beneficial. DCIS: In women with DCIS, following breast surgery and radiation, tamoxifen is indicated to reduce the risk of invasive breast cancer. Base the decisions regarding therapy with tamoxifen for the reduction in breast cancer incidence upon an individual assessment of the benefits and risks of tamoxifen therapy. Current data from clinical trials support 5 years of adjuvant tamoxifen therapy for patients with breast cancer. Metastatic breast cancer: Effective in the treatment of metastatic breast cancer in women and men. In premenopausal women with metastatic breast cancer, tamoxifen is an alternative to oophorectomy or ovarian irradiation. Available evidence indicates that patients whose tumors are estrogen receptor (ER) positive are more likely to benefit from tamoxifen therapy.

ODS Health Plan Customary Specialty MR Criteria Page 295 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

Reduction of breast cancer incidence in high-risk women: To reduce the incidence of breast cancer in women at high risk for breast cancer. This effect was shown in a study of 5 years planned duration, with a median follow-up of 4.2 years. Twenty-five percent of the participants received the drug for 5 years. The longer-term effects are not known. In this study, there was no impact of tamoxifen on overall or breast cancer–related mortality. Tamoxifen is indicated only for high-risk women. “High risk” is defined as women at least 35 years of age with a 5-year predicted risk of breast cancer greater than or equal to 1.67%, as calculated by the Gail model.

TREATMENT DOSE / DURATION / REGIMEN Breast cancer: 20 to 40 mg; dosages greater than 20 mg/day should be given in divided doses (morning and evening) DCIS: 20 mg/day for 5 years. Reduction of breast cancer incidence in high-risk women: 20 mg/day for 5 years; there are no data to support the use of tamoxifen for other than for 5 years.

EFFECTIVENESS MONITORING PARAMETERS Clinical and pathologic response.

INJECTABLE ADMINISTRATION REQUIREMENTS None.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 296 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Temodar

Generic Name (Brand): Temozolomide (Temodar)

INDICATIONS • Indicated for treatment of adult patients with refractory anaplastic astrocytoma, specifically, patients at first relapse who have experienced disease progression on a drug regimen containing a nitrosourea and procarbazine. • Indicated for the treatment of adult patients with newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and then as maintenance treatment.

OFF-LABEL USE: Metastatic melanoma

POLICY: 1) Grandfathering is allowed when an enrollee has a claim for Temodar within the previous 180 days.

GUIDELINES FOR USE: 1) Is the patient 18 years of age or older? a) If yes, continue to #2. b) If no, do not approve.

2) Is the requested drug being prescribed or supervised by an oncologist? a) If yes, continue to #3. b) If no, do not approve.

3) What is the indication for use? a) Anaplastic astrocytoma, go to # 4. b) Gliobastoma multiforme or brain cancer, go to # 5. c) If none of the above, do not approve. Anaplastic Astrocytoma: 4) Has the patient failed a drug regimen containing a nitrosourea and Procarbazine? a) If yes, continue to # 7. b) If no, do not approve.

Glioblastoma Multiforme: 5) Is this a newly diagnosed brain cancer/tumer-gliobastoma multiforme? a) If yes, continue to #6. b) If no, continue to #7

6) Will Temodar be used in combination with radiotherapy? a) If yes, continue to #7. b) If no, do not approve.

7) Approve for 1 year. Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 297 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Temsirolimus (Torisel)

FDA APPROVED INDICATIONS Advanced renal cell carcinoma: For the treatment of advanced renal cell carcinoma

TREATMENT DOSE / DURATION / REGIMEN The recommended dose is 25 mg infused over a 30- to 60-minute period once a week. Treatment should continue until disease progression or unacceptable toxicity occurs

EFFECTIVENESS MONITORING PARAMETERS Evaluations of progression-free survival (time from randomization to disease progression or death) and objective response rates, based on blinded independent radiologic assessment of tumor response. INJECTABLE ADMINISTRATION REQUIREMENTS Administration should be supervised by medical professional experienced in the use of anticancer agents. REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 298 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Teniposide (Vumon)

FDA APPROVED INDICATIONS Acute lymphoblastic leukemia: In combination with other approved anticancer agents for induction therapy in patients with refractory childhood acute lymphoblastic leukemia (ALL).

TREATMENT DOSE / DURATION / REGIMEN Dosage: In 1 study, childhood acute lymphoblastic leukemia (ALL) patients failing induction therapy with a cytarabine-containing regimen were treated with the combination of teniposide 165 mg/m2 and cytarabine 300 mg/m2 IV, twice weekly for 8 to 9 doses. In another study, patients with childhood ALL refractory to vincristine/prednisone-containing regimens were treated with the combination of teniposide 250 mg/m2 and vincristine 1.5 mg/m2 IV, weekly for 4 to 8 weeks and prednisone 40 mg/m2 orally for 28 days.

EFFECTIVENESS MONITORING PARAMETERS Clinical and pathologic response.

INJECTABLE ADMINISTRATION REQUIREMENTS Administration should be supervised by medical professional experienced in the use of anticancer agents.

ODS Health Plan Customary Specialty MR Criteria Page 299 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 300 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Forteo

Generic Name (Brand): Teriparatide (Forteo)

GUIDELINES FOR USE 1. Does the patient have a diagnosis of severe osteoporosis at a high risk for fracture (T ≤ 2.5 with a history of fragility fractures), or does the patient have multiple risk factors for fracture (e.g., history of multiple recent low trauma fractures, history of corticosteroid use, use of GnRH analogues such as nafarelin, etc.)? If yes, continue to #2. If no, do not approve. 2. Has patient failed an adequate trial of bisphosphonates (Fosamax, Actonel) or is the patient intolerant or does the patient have a contraindication to these medications for the treatment of osteoporosis? If yes, continue to #3. If no, do not approve. 3. Does patient have a diagnosis of Paget’s disease, a history of radiation therapy, bone malignancy, a history of hypercalcemia or hyperparathyroidism? If yes, do not approve. If no, continue to #4. 4. Approve for 12 months with a quantity limit of 1 pen per month.

FDA APPROVED INDICATIONS 1. For the treatment of postmenopausal women with osteoporosis who are at high risk for fracture, such as women with a history of osteoporotic fracture, or who have multiple risk factors for fracture, or who have failed or are intolerant to previous osteoporosis therapy. In postmenopausal women with osteoporosis, teriparatide can increase bone mineral density and reduce the risk of vertebral and non-vertebral fractures. 2. Teriparatide is also indicated to increase bone mass in men with primary or hypogonadal osteoporosis who are at high risk of fracture such as men with a history of osteoporotic fracture, or who have multiple risk factors for fracture, or who have failed or are intolerant to previous osteoporosis therapy. In men with osteoporosis, teriparatide increases bone mineral density but the effects of this drug on the risk for fracture in men has not been studied. REFERENCES 1. Forteo Product Information, Eli Lilly. June 2006. 2. Forteo. MedImpact P&T Monograph, May 2003.

Effective: 10/01/08

Created: 01/01/06 Updated: ______Reviewed: 01/05/07, 11/14/07

ODS Health Plan Customary Specialty MR Criteria Page 301 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Endocrine and Metabolic Agents

Generic Name (Brand): Testosterone Cypionate (Depo-Testosterone), Testosterone Enanthate (Delatestryl)

FDA APPROVED INDICATIONS Testosterone Cypionate (Depo-Testosterone) Replacement therapy: Testosterone cypionate injectable sterile solution is indicated for replacement therapy in the male in conditions associated with symptoms of deficiency or absence of endogenous testosterone. Primary hypogonadism (congenital or acquired): Primary hypogonadism (congenital or acquired)-testicular failure caused by cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome; or orchidectomy. Hypogonadotropic hypogonadism (congenital or acquired): Hypogonadotropic hypogonadism (congenital or acquired)-idiopathic gonadotropin or LHRH deficiency, or pituitary- hypothalamic injury from tumors, trauma, or radiation.

Testosterone Enanthate (Delatestryl) Males: Testosterone enanthate injection is indicated for replacement therapy in conditions associated with a deficiency or absence of endogenous testosterone. Primary hypogonadism (congenital or acquired): Testicular failure due to cryptorchidism; bilateral torsion, orchitis, vanishing testis syndrome, or orchidectomy. Hypogonadotropic hypogonadism (congenital or acquired): Idiopathic gonadotropin or luteinizing hormone-releasing hormone (LHRH) deficiency, or pituitary-hypothalamic injury from tumors, trauma, or radiation. (Appropriate adrenal cortical and thyroid hormone replacement therapy are still necessary, however, and are actually of primary importance.) If the above conditions occur prior to puberty, androgen replacement therapy will be needed during the adolescent years for development of secondary sexual characteristics. Prolonged androgen treatment will be required to maintain sexual characteristics in these and other males who develop testosterone deficiency after puberty. Delayed puberty: Testosterone enanthate injection may be used to stimulate puberty in carefully selected males with clearly delayed puberty. These patients usually have a familial pattern of delayed puberty that is not secondary to a pathological disorder; puberty is expected to occur

ODS Health Plan Customary Specialty MR Criteria Page 302 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

spontaneously at a relatively late date. Brief treatment with conservative doses may occasionally be justified in these patients if they do not respond to psychological support. The potential adverse effect on bone maturation should be discussed with the patient and parents prior to androgen administration. An x-ray of the hand and wrist to determine bone age should be obtained every 6 months to assess the effect of treatment on the epiphyseal centers (see Warnings). Females: Metastatic mammary cancer: Testosterone enanthate injection may be used secondarily in women with advancing inoperable metastatic (skeletal) mammary cancer who are 1 to 5 years postmenopausal. Primary goals of therapy in these women include ablation of the ovaries. Other methods of counteracting estrogen activity are adrenalectomy, hypophysectomy, or antiestrogen therapy. This treatment has also been used in premenopausal women with breast cancer who have benefited from oophorectomy and are considered to have a hormone- responsive tumor. Judgment concerning androgen therapy should be made by an oncologist with expertise in this field.

TREATMENT DOSE / DURATION / REGIMEN Testosterone Cypionate (Depo-Testosterone) Testosterone cypionate sterile solution is for intramuscular use only. IM injections should be given deep in the gluteal muscle. It should not be given IV. Testosterone cypionate should not be used interchangeably with testosterone propionate because of differences in duration of action. The suggested dosage for testosterone cypionate sterile solution varies depending on the age, sex, and diagnosis of the individual patient. Dosage is adjusted according to the patient's response and the appearance of adverse reactions. Various dosage regimens have been used to induce pubertal changes in hypogonadal males; some experts have advocated lower dosages initially, gradually increasing the dose as puberty progresses, with or without a decrease to maintenance levels. Other experts emphasize that higher dosages are needed to induce pubertal changes and lower dosages can be used for maintenance after puberty. The chronological and skeletal ages must be taken into consideration, both in determining the initial dose and in adjusting the dose. For replacement in the hypogonadal male, 50 to 400 mg should be administered every 2 to 4 weeks.

Testosterone Enanthate (Delatestryl) Dosage and duration of therapy with testosterone enanthate injection will depend on age, sex, diagnosis, patient's response to treatment, and appearance of adverse effects. When properly given, injections of testosterone enanthate are well tolerated. Care should be taken to inject the preparation deeply into the gluteal muscle following the usual precautions for IM administration. In general, total doses above 400 mg monthly are not required because of the prolonged action of the preparation. Injections more frequently than every 2 weeks are rarely indicated. Male hypogonadism: As replacement therapy (ie, for eunuchism) the suggested dosage is 50 to 400 mg every 2 to 4 weeks. In males with delayed puberty: Various dosage regimens have been used; some call for lower dosages initially with gradual increases as puberty progresses, with or without a decrease to maintenance levels. Other regimens call for higher dosage to induce pubertal changes and lower dosage for maintenance after puberty. The chronological and skeletal ages must be taken into consideration, both in determining the initial dose and in adjusting the dose. Dosage is within the range of 50 to 200 mg every 2 to 4 weeks for a limited duration, for example, 4 to 6 months. X-rays should be taken at appropriate intervals to determine the amount of bone maturation and skeletal development (see Indications and Warnings). Palliation of inoperable mammary cancer in women: A dosage of 200 to 400 mg every 2 to 4 weeks is recommended. Women with metastatic breast carcinoma must be followed closely because androgen therapy occasionally appears to accelerate the disease.

ODS Health Plan Customary Specialty MR Criteria Page 303 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

EFFECTIVENESS MONITORING PARAMETERS Clinical response and testosterone serum levels.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08. Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 304 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Thalidomide (Thalomid)

DISTRIBUTION Limited Distribution. Thalidomide must only be administered in compliance with all of the terms outlined in the S.T.E.P.S. program. Thalidomide may only be prescribed by health care providers registered with the S.T.E.P.S. program and dispensed by pharmacists registered with the S.T.E.P.S. program. Prescribing thalidomide to women of childbearing potential is contingent upon initial and continued confirmed negative results of pregnancy testing.

FDA APPROVED INDICATIONS 1. Multiple myeloma: In combination with dexamethasone, for the treatment of patients with newly diagnosed multiple myeloma. Efficacy is based on response rates. There are no controlled trials demonstrating a clinical benefit, such as an improvement in survival. 2. Erythema nodosum leprosum: Acute treatment: Acute treatment of the cutaneous manifestations of moderate to severe erythema nodosum leprosum. Not indicated as monotherapy for such erythema nodosum leprosum treatment in the presence of moderate to severe neuritis. Maintenance therapy: For prevention and suppression of the cutaneous manifestations of erythema nodosum leprosum recurrence.

ODS Health Plan Customary Specialty MR Criteria Page 305 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

TREATMENT DOSE / DURATION / REGIMEN Multiple myeloma: Administered in combination with dexamethasone in 28-day treatment cycles. Administer 200 mg orally, once daily with water, preferably at bedtime, and at least 1 hour after the evening meal. The dosage of dexamethasone is 40 mg daily administered orally on days 1 to 4, 9 to 12, and 17 to 20 every 28 days. Erythema nodosum leprosum: Initiate dosing at 100 to 300 mg/day, once daily with water, preferably at bedtime, and at least 1 hour after the evening meal. Start patients weighing less than 50 kg (110 lb) at the low end of the dose range. In patients with a severe cutaneous erythema nodosum leprosum reaction, or in those who have previously required higher doses to control the reaction, thalidomide dosing may be initiated at higher doses, up to 400 mg/day once daily at bedtime or in divided doses with water at least 1 hour after meals. In patients with moderate to severe neuritis associated with a severe erythema nodosum leprosum reaction, corticosteroids may be started concomitantly with thalidomide. Steroid usage can be tapered and discontinued when the neuritis has ameliorated. Duration: Continue dosing with thalidomide until signs and symptoms of active reaction have subsided, usually at least 2 weeks. Patients then may be tapered off medication in 50 mg decrements every 2 to 4 weeks. Maintain patients who have a documented history of requiring prolonged maintenance treatment to prevent the recurrence of cutaneous erythema nodosum leprosum or who flare during tapering on the minimum dose necessary to control the reaction. Attempt tapering of medication every 3 to 6 months in decrements of 50 mg every 2 to 4 weeks.

EFFECTIVENESS MONITORING PARAMETERS Clinical and pathologic response.

INJECTABLE ADMINISTRATION REQUIREMENTS Thalidomide must only be administered in compliance with all of the terms outlined in the S.T.E.P.S. program. Thalidomide may only be prescribed by health care providers registered with the S.T.E.P.S. program and dispensed by pharmacists registered with the S.T.E.P.S. program.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 306 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Thioguanine (Tabloid)

FDA APPROVED INDICATIONS Acute nonlymphocytic leukemias: For remission induction and remission consolidation treatment of acute nonlymphocytic leukemias. However, it is not recommended for use during maintenance therapy or similar long-term continuous treatments because of the high risk of liver toxicity. Reliance upon thioguanine alone is seldom justified for initial remission induction of acute nonlymphocytic leukemias because combination chemotherapy including thioguanine results in more frequent remission induction and longer duration of remission than thioguanine alone. Other neoplasms: Thioguanine is not effective in chronic lymphocytic leukemia, Hodgkin lymphoma, multiple myeloma, or solid tumors. Although thioguanine is one of several agents with activity in the treatment of the chronic phase of chronic myelogenous leukemia, more objective responses are observed with busulfan, and therefore busulfan is usually regarded as the preferred drug.1

TREATMENT DOSE / DURATION / REGIMEN Dosage: On those occasions when single-agent chemotherapy with thioguanine may be appropriate, the usual initial dosage for pediatric patients and adults is approximately 2 mg/kg of body weight per day. If, after 4 weeks on this dosage, there is no clinical improvement and no

ODS Health Plan Customary Specialty MR Criteria Page 307 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

leukocyte or platelet depression, the dosage may be cautiously increased to 3 mg/kg/day. The total daily dose may be given at one time. Administration: The dosage that will be tolerated and effective varies according to the stage and type of neoplastic process being treated. Because the usual therapies for adult and pediatric acute nonlymphocytic leukemias involve the use of thioguanine in combination with other agents, physicians responsible for administering these therapies should be experienced in the use of cancer chemotherapy and in the chosen protocol.

EFFECTIVENESS MONITORING PARAMETERS Clinical and pathologic response.

INJECTABLE ADMINISTRATION REQUIREMENTS None.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 308 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Thiotepa (Thioplex)

FDA APPROVED INDICATIONS adenocarcinoma of the ovary; for controlling intracavitary effusions secondary to diffuse or localized neoplastic diseases of various serosal cavities; for the treatment of superficial papillary carcinoma of the urinary bladder. While now largely superseded by other treatments, thiotepa has been effective against other lymphomas, such as lymphosarcoma and Hodgkin's disease.

TREATMENT DOSE / DURATION / REGIMEN Dosage must be carefully individualized. A slow response to thiotepa does not necessarily indicate a lack of effect. Therefore, increasing the frequency of dosing may only increase toxicity. After maximum benefit is obtained by initial therapy, it is necessary to continue the patient on maintenance therapy (1- to 4-week intervals). In order to continue optimal effect, maintenance doses should not be administered more frequently than weekly in order to preserve correlation between dose and blood counts.

EFFECTIVENESS MONITORING PARAMETERS Clinical and pathologic response.

INJECTABLE ADMINISTRATION REQUIREMENTS

ODS Health Plan Customary Specialty MR Criteria Page 309 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

Administration should be supervised by medical professional experienced in the use of anticancer agents.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 310 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Diagnostic Agents

Generic Name (Brand): Thyrotropin Alfa (Thyrogen)

DISTRIBUTION Limited distribution.

FDA APPROVED INDICATIONS Adjunctive diagnostic tool for serum thyroglobulin (Tg) testing: For use as an adjunctive diagnostic tool for serum Tg testing with or without radioiodine imaging in the follow-up of patients with well-differentiated thyroid cancer. Adjunctive treatment for radioiodine ablation of thyroid tissue remnants: For use as an adjunctive treatment for radioiodine ablation of thyroid tissue remnants in patients who have undergone a near-total or total thyroidectomy for well-differentiated thyroid cancer and who do not have evidence of metastatic thyroid cancer. Potential clinical uses: May be used in patients with an undetectable Tg on thyroid hormone suppressive therapy to exclude the diagnosis of residual or recurrent thyroid cancer. May be used in combination with radioiodine (iodine-131 [131I]) to ablate thyroid remnants following near-total thyroidectomy in patients without evidence of metastatic disease. May be used in patients requiring serum Tg testing and radioiodine imaging who are unwilling to undergo thyroid hormone withdrawal testing and whose treating physician believes that use of a less sensitive test is justified. May be used in patients who are either unable to mount an adequate endogenous thyroid- stimulating hormone response to thyroid hormone withdrawal or in whom withdrawal is medically contraindicated.

TREATMENT DOSE / DURATION / REGIMEN Adults (16 years of age and older): Usual dosage: A 2-injection regimen is recommended for thyrotropin alfa administration. The 2-injection regimen is thyrotropin alfa 0.9 mg (1 mL) intramuscularly (IM) into the buttock, followed by a second 0.9 mg (1 mL) IM injection 24 hours later.

EFFECTIVENESS MONITORING PARAMETERS

ODS Health Plan Customary Specialty MR Criteria Page 311 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

Clinical and laboratory response. For serum Tg testing, the serum sample should be obtained 72 hours after the final injection of thyrotropin alfa.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08.

Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 312 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Topotecan (Hycamtin)

FDA APPROVED INDICATIONS 1. Cervical cancer (in combination with cisplatin): For the treatment of stage IVB, recurrent, or persistent carcinoma of the cervix that is not amenable to curative treatment with surgery and/or radiation therapy. 2. Ovarian cancer: For the treatment of metastatic carcinoma of the ovary after failure of initial or subsequent chemotherapy. 3. Small cell lung cancer (SCLC): For the treatment of SCLC-sensitive disease after failure of first-line chemotherapy. In clinical studies submitted to support approval, sensitive disease was defined as disease responding to chemotherapy but subsequently progressing at least 60 days (in the phase 3 study) or at least 90 days (in the phase 2 studies) after chemotherapy.

TREATMENT DOSE / DURATION / REGIMEN Cervical cancer: Dosage: 0.75 mg/m2 by intravenous (IV) infusion over 30 minutes on days 1, 2, and 3, followed by cisplatin 50 mg/m2 by IV infusion on day 1, repeated every 21 days (21- day course). Ovarian cancer and SCLC: Dosage: 1.5 mg/m2 daily by IV infusion over 30 minutes for 5 consecutive days, starting on day 1 of a 21-day course. In the absence of tumor progression, a minimum of 4 courses is recommended because tumor response may be delayed. The median

ODS Health Plan Customary Specialty MR Criteria Page 313 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

time to response in 3 ovarian cancer clinical trials was 9 to 12 weeks, and the median time to response in 4 SCLC trials was 5 to 7 weeks.

EFFECTIVENESS MONITORING PARAMETERS Clinical and pathologic response.

INJECTABLE ADMINISTRATION REQUIREMENTS Administration of IV topotecan should be supervised by medical professional experienced in the use of anticancer agents.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 314 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Toremifene (Fareston)

FDA APPROVED INDICATIONS Breast cancer: For the treatment of metastatic breast cancer in postmenopausal women with estrogen-receptor positive or unknown tumors.

TREATMENT DOSE / DURATION / REGIMEN The dosage of toremifene citrate is 60 mg, once daily, orally. Treatment is generally continued until disease progression is observed.

EFFECTIVENESS MONITORING PARAMETERS Clinical and pathologic response.

INJECTABLE ADMINISTRATION REQUIREMENTS None.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 315 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Hematological Agents

Generic Name (Brand): Tranexamic Acid (Cyklokapron)

FDA APPROVED INDICATIONS Hemorrhage: In patients with hemophilia for short-term use (2 to 8 days) to reduce or prevent hemorrhage and reduce the need for replacement therapy during and following tooth extraction.

TREATMENT DOSE / DURATION / REGIMEN Parenteral therapy, 10 mg per kg body weight 3 to 4 times daily can be used for patients unable to take oral medication. Dental extraction in patients with hemophilia: Immediately before dental extraction in patients with hemophilia, administer 10 mg per kg body weight of tranexamic acid intravenously together with replacement therapy.

EFFECTIVENESS MONITORING PARAMETERS Clinical response.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08.

Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 316 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Trastuzumab (Herceptin)

FDA APPROVED INDICATIONS

Breast cancer: • For the adjuvant treatment of patients with human epidermal growth factor receptor 2 (HER2)–overexpressing, node-positive breast cancer as part of a treatment regimen containing doxorubicin, cyclophosphamide, and paclitaxel. • As a single agent for the treatment of patients with metastatic breast cancer whose tumors overexpress the HER2 protein and who have received 1 or more chemotherapy regimens for their metastatic disease. • In combination with paclitaxel for treatment of patients with metastatic breast cancer whose tumors overexpress the HER2 protein and who have not received chemotherapy for their metastatic disease.1

TREATMENT DOSE / DURATION / REGIMEN Recommended dose: Administer as an intravenous (IV) infusion once every 7 days. The recommended dose for the first infusion is 4 mg/kg administered as a 90-minute IV infusion. Do not administer as an IV push or bolus. The recommended subsequent weekly dose of 2 mg/kg can be administered as a 30-minute IV infusion if the first infusion was well tolerated. Metastatic breast cancer: Trastuzumab is administered until tumor progression.

ODS Health Plan Customary Specialty MR Criteria Page 317 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

Adjuvant treatment of metastatic breast cancer: Do not coadminister with doxorubicin and cyclophosphamide. Following completion of doxorubicin and cyclophosphamide, trastuzumab is administered weekly for 52 weeks. During the first 12 weeks, trastuzumab is coadministered with paclitaxel

EFFECTIVENESS MONITORING PARAMETERS Clinical and pathologic response.

INJECTABLE ADMINISTRATION REQUIREMENTS Administration should be supervised by medical professional experienced in the use of anticancer agents.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 318 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Treatment of Pulmonary Arterial Hypertension

Generic Name (Brand): Treprostinil (Remodulin)

DISTRIBUTION Limited distribution.

FDA APPROVED INDICATIONS Pulmonary arterial hypertension (PAH): As a continuous subcutaneous or intravenous (IV) infusion (for those not able to tolerate a subcutaneous infusion) for the treatment of PAH in patients with New York Heart Association (NYHA) class II to IV symptoms to diminish symptoms associated with exercise. Transition from epoprostenol: To diminish the rate of clinical deterioration in patients requiring transition from epoprostenol.

TREATMENT DOSE / DURATION / REGIMEN Treprostinil can be administered as supplied or diluted for IV infusion with sterile water for injection or sodium chloride 0.9% injection prior to administration. Initial dose: Treprostinil is administered by continuous infusion. Treprostinil is preferably infused subcutaneously but can be administered by a central IV line if the subcutaneous route is not tolerated because of severe site pain or reaction. The infusion rate is initiated at 1.25 ng/kg/min. If this initial dose cannot be tolerated because of systemic effects, the infusion rate should be reduced to 0.625 ng/kg/min. Dosage adjustments: The goal of chronic dosage adjustments is to establish a dose at which PAH symptoms are improved, while minimizing excessive pharmacologic effects of treprostinil (eg, anxiety, emesis, headache, infusion-site pain or reaction, nausea, restlessness). The infusion rate should be increased in increments of no more than 1.25 ng/kg/min per week for the first 4 weeks and then no more than 2.5 ng/kg/min per week for the remaining duration of infusion, depending on clinical response. There is little experience with doses greater than 40 ng/kg/min. Abrupt cessation of infusion should be avoided. Abrupt withdrawal or sudden large reductions in dosage of treprostinil may result in the worsening of PAH symptoms and should be avoided. Transition from epoprostenol to treprostinil: Transition from epoprostenol to treprostinil is accomplished by initiating the infusion of treprostinil and increasing it while simultaneously reducing the dose of IV epoprostenol. The transition to treprostinil should take place in a

ODS Health Plan Customary Specialty MR Criteria Page 319 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

hospital with constant observation of response (eg, signs and symptoms of disease progression, walk distance). During the transition, treprostinil is initiated at a recommended dose of 10% of the current epoprostenol dose and then escalated as the epoprostenol dose is decreased. Patients are individually titrated to a dose that allows transition from epoprostenol therapy to treprostinil while balancing prostacylin-limiting adverse reactions. Increases in the patient's symptoms of PAH should be first treated with increases in the dose of treprostinil. Adverse reactions normally associated with prostacylin and prostacylin analogs are to be first treated by decreasing the dose of epoprostenol.

Recommended Transition Dose Changes for Treprostinil1 Step Epoprostenol dose Treprostinil dose 1 Unchanged 10% starting epoprostenol dose 2 80% starting epoprostenol dose 30% starting epoprostenol dose 3 60% starting epoprostenol dose 50% starting epoprostenol dose 4 40% starting epoprostenol dose 70% starting epoprostenol dose 5 20% starting epoprostenol dose 90% starting epoprostenol dose 6 5% starting epoprostenol dose 110% starting epoprostenol dose 7 0% 110% starting epoprostenol dose + additional 5% to 10% increments as needed

Administration: Subcutaneous infusion: Treprostinil is administered subcutaneously by continuous infusion, via a self-inserted subcutaneous catheter, using an infusion pump designed for subcutaneous drug delivery. To avoid potential interruptions in drug delivery, the patient must have immediate access to a backup infusion pump and subcutaneous infusion sets. The ambulatory infusion pump used to administer treprostinil should be small and lightweight; be adjustable to approximately 0.002 mL/h; have occlusion/no delivery, low battery, programming error, and motor malfunction alarms; have delivery accuracy of ± 6% or better; and be positive-pressure driven. The reservoir should be made of polyvinyl chloride, polypropylene, or glass. For subcutaneous infusion, treprostinil is delivered without further dilution at a calculated subcutaneous infusion rate (mL/h) based on a patient's dose (ng/kg/min), weight (kg), and the vial strength (mg/mL) of treprostinil being used. During use, a single reservoir (syringe) of undiluted treprostinil can be administered up to 72 hours at 37°C (98.6°F). The subcutaneous infusion rate is calculated using the dose (ng/kg/min) × weight (kg) × 0.00006 following formula: Subcutaneous infusion rate (mL/h) = /treprostinil vial strength (mg/mL) In the above formula, conversion factor of 0.00006 = 60 min/h × 0.000001 mg/ng Example calculations for subcutaneous infusion: Example 1: For a 60 kg person at the recommended initial dose of 1.25 ng/kg/min using the treprostinil 1 mg/mL vial strength, the infusion rate would be calculated as follows: 1.25 ng/kg/min × 60 kg × 0.00006 Subcutaneous infusion rate (mL/h) = /1 mg/mL = 0.005 mL/h. Example 2: For a 65 kg person at a dose of 40 ng/kg/min using the treprostinil 5 mg/mL vial strength, the infusion rate would be calculated as follows: 40 ng/kg/min × 65 kg × 0.00006 Subcutaneous infusion rate (mL/h) = /5 mg/mL = 0.031 mL/h.

IV infusion: Treprostinil must be diluted with either sterile water for injection or sodium chloride 0.9% injection and is administered IV by continuous infusion via a surgically placed, indwelling, central venous catheter, using an infusion pump designed for IV drug delivery. To avoid

ODS Health Plan Customary Specialty MR Criteria Page 320 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

potential interruptions in drug delivery, the patient must have immediate access to a backup infusion pump and infusion sets. The ambulatory infusion pump used to administer treprostinil should be small and lightweight; have occlusion/no delivery, low battery, programming error, and motor malfunction alarms; have delivery accuracy of ± 6% or better of the hourly dose; and be positive pressure driven. The reservoir should be made of polyvinyl chloride, polypropylene, or glass. Diluted treprostinil has been shown to be stable at ambient temperature for up to 48 hours at concentrations as low as 0.004 mg/mL (4,000 ng/mL). When using an appropriate infusion pump and reservoir, a predetermined IV infusion rate should first be selected to allow for a desired infusion period length of up to 48 hours between system changeovers. Typical IV infusion system reservoirs have volumes of 50 or 100 mL. With this selected IV infusion rate (mL/h) and the patient's dose (ng/kg/min) and weight (kg), the diluted IV treprostinil concentration (mg/mL) can be calculated using the following formula: Step 1: Diluted IV treprostinil concentration (mg/mL) = dose (ng/kg/min) × weight (kg) × 0.00006 /IV infusion rate (mL/h). The amount of treprostinil injection needed to make the required diluted IV treprostinil concentration for the given reservoir size can then be calculated using the following formula: Step 2: Amount of treprostinil injection (mL) = diluted IV treprostinil concentration (mg/mL) /treprostinil vial strength (mg/mL) × total volume of diluted treprostinil solution in reservoir (mL) The calculated amount of treprostinil injection is then added to the reservoir along with the sufficient volume of diluent (sterile water for injection or sodium chloride 0.9% injection) to achieve the desired total volume in the reservoir. EFFECTIVENESS MONITORING PARAMETERS Clinical response.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08.

Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 321 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Triptorelin (Trelstar)

FDA APPROVED INDICATIONS Advanced prostate cancer: As palliative treatment of advanced prostate cancer. They offer an alternative treatment for prostate cancer when orchiectomy or estrogen administration are either not indicated or unacceptable to the patient.

TREATMENT DOSE / DURATION / REGIMEN Triptorelin depot injection: 3.75 mg incorporated in a depot formulation and administered monthly as a single intramuscular (IM) injection EFFECTIVENESS MONITORING PARAMETERS Castration levels of serum testosterone (less than or equal to 1.735 nmol/L). INJECTABLE ADMINISTRATION REQUIREMENTS Administration should be supervised by medical professional experienced in the use of anticancer agents.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 322 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Fertility Agents

Generic Name (Brand): Urofollitropin (Bravelle)

FDA APPROVED INDICATIONS Ovulation induction: In conjunction with human chorionic gonadotropin (hCG) for ovulation induction in patients who previously have received pituitary suppression. Multifollicular development during ART: In conjunction with hCG for multiple follicular development (controlled ovarian stimulation) during assisted reproductive technologies (ART) cycles in patients who have previously received pituitary suppression.

TREATMENT DOSE / DURATION / REGIMEN

The dose to stimulate development of ovarian follicles must be individualized for each patient. Use the lowest dose consistent with achieving good results based on clinical experience and reported clinical data. The recommended initial dose for patients who have received gonadotropin-releasing hormone (GnRH) agonist or antagonist suppression is 150 units/day subcutaneous or IM for the first 5 days of treatment. Based on clinical monitoring (including serum estradiol levels and vaginal ultrasound results), adjust subsequent dosing according to individual patient response. Do not make adjustments in dose more frequently than once every 2 days and do not exceed more than 75 to 150 units/adjustment. The maximum daily dose should not exceed 450 units and, in most cases, dosing beyond 12 days is not recommended. If patient response is appropriate, give hCG (5,000 to 10,000 units) 1 day following the last dose of urofollitropin. Withhold the hCG if the serum estradiol is greater than 2,000 pg/mL, if the ovaries are abnormally enlarged, or if abdominal pain occurs, and advise the patient to refrain from intercourse. These precautions may reduce the risk of Ovarian Hyperstimulation Syndrome (OHSS) and multiple gestations. Follow patients closely for at least 2 weeks after hCG administration. If there is inadequate follicle development or ovulation without subsequent pregnancy, the course of treatment may be repeated. ART: The recommended initial dose of urofollitropin for patients undergoing in vitro fertilization (IVF) and donor egg patients who have received GnRH agonist or antagonist pituitary suppression is 225 units daily administered subcutaneous for the first 5 days of treatment. Based on clinical monitoring (including serum estradiol levels and vaginal ultrasound results) subsequent dosing should be adjusted according to individual patient response. Adjustments in

ODS Health Plan Customary Specialty MR Criteria Page 323 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

dose should not be made more frequently than once every 2 days and should not exceed more than 75 to 150 units per adjustment. The maximum daily dose of urofollitropin given should not exceed 450 units and in most cases dosing beyond 12 days is not recommended.

EFFECTIVENESS MONITORING PARAMETERS Clinical and laboratory response.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08. Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 324 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Ophthalmic Agents

Generic Name (Brand): Verteporfin (Visudyne)

DISTRIBUTION Limited distribution

FDA APPROVED INDICATIONS For the treatment of patients with predominantly classic subfoveal choroidal neovascularization due to age-related macular degeneration, pathologic myopia or presumed ocular histoplasmosis. There is insufficient evidence to indicate verteporfin for the treatment of predominately occult subfoveal choroidal neovascularization.

TREATMENT DOSE / DURATION / REGIMEN A course of verteporfin therapy is a 2-step process requiring administration of both drug and light. The first step is the intravenous infusion of verteporfin. The second step is the activation of verteporfin with light from a nonthermal diode laser. Lesion size determination: The greatest linear dimension (GLD) of the lesion is estimated by fluorescein angiography and color fundus photography. All classic and occult choroidal neovascularization (CNV), blood and/or blocked fluorescence, and any serous detachments of the retinal pigment epithelium should be included for this measurement. Fundus cameras with magnification within the range of 2.4 to 2.6X are recommended. The GLD of the lesion on the fluorescein angiogram must be corrected for the magnification of the fundus camera to obtain the GLD of the lesion on the retina. Spot size determination: The treatment spot size should be 1,000 microns larger than the GLD of the lesion on the retina to allow a 500 micron border, ensuring full coverage of the lesion. The maximum spot size used in the clinical trials was 6400 microns. The nasal edge of the treatment spot must be positioned at least 200 microns from the temporal edge of the optic disc, even if this will result in lack of photoactivation of CNV within 200 microns of the optic nerve. Verteporfin administration: Reconstitute each vial of verteporfin with 7 mL of Sterile Water for Injection to provide 7.5 mL containing 2 mg/mL. Reconstituted verteporfin must be protected from light and used within 4 hours. It is recommended that reconstituted verteporfin be inspected visually for particulate matter and discoloration prior to administration. Reconstituted

ODS Health Plan Customary Specialty MR Criteria Page 325 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

verteporfin is an opaque dark green solution. The volume of reconstituted verteporfin required to achieve the desired dose of 6 mg/m2 body surface area is withdrawn from the vial and diluted with 5% Dextrose for Injection to a total infusion volume of 30 mL. The full infusion volume is administered intravenously over 10 minutes at a rate of 3 mL/min, using an appropriate syringe pump and in-line filter. The clinical studies were conducted using a standard infusion line filter of 1.2 microns.

EFFECTIVENESS MONITORING PARAMETERS The physician should re-evaluate the patient every 3 months and if choroidal neovascular leakage is detected on fluorescein angiography, therapy should be repeated.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08.

Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 326 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Vinblastine (Velban)

FDA APPROVED INDICATIONS Palliative treatment of the following: 1. Frequently responsive malignancies: Generalized Hodgkin's disease (stages III and IV, Ann Arbor modification of Rye staging system), lymphocytic lymphoma (nodular and diffuse, poorly and well differentiated); histiocytic lymphoma; mycosis fungoides (advanced stages); advanced testicular carcinoma; Kaposi's sarcoma and Letterer-Siwe disease (histiocytosis X). 2. Less frequently responsive malignancies: Choriocarcinoma resistant to other chemotherapy; breast cancer unresponsive to endocrine surgery and hormonal therapy. 3. Multiple drug protocols: Vinblastine, effective as a single agent, is usually administered with other antineoplastics. Combination therapy enhances therapeutic effect without additive toxicity when agents with different dose-limiting toxicities and mechanisms of action are selected. 4. Hodgkin's disease: Vinblastine used as a single agent; advanced Hodgkin's disease also has been successfully treated with multiple-drug regimens that included vinblastine. 5. Advanced testicular germinal-cell cancers (embryonal carcinoma, teratocarcinoma, and choriocarcinoma): Advanced testicular germinal-cell cancers are sensitive to vinblastine alone, but better clinical results are achieved with combination therapy. Vinblastine enhances the effect of bleomycin if given 6 to 8 hours prior to bleomycin

ODS Health Plan Customary Specialty MR Criteria Page 327 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

administration; this schedule permits more cells to be arrested during metaphase, the stage in which bleomycin is active.

TREATMENT DOSE / DURATION / REGIMEN Leukopenic responses vary following therapy. For this reason, do not administer drug more than once weekly. Initiate therapy for adults with a single IV dose of 3.7 mg/m2 of body surface. Thereafter, measure WBC counts to determine patient's sensitivity. A 50% dose reduction is recommended for patients having a direct serum bilirubin value > 3 mg/dlL. Because metabolism and excretion are primarily hepatic, no modification is recommended for patients with impaired renal function.

EFFECTIVENESS MONITORING PARAMETERS Clinical and pathologic response.

INJECTABLE ADMINISTRATION REQUIREMENTS Administration should be supervised by medical professional experienced in the use of anticancer agents.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 328 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Antineoplastic Agents

Generic Name (Brand): Vinorelbine (Navelbine)

FDA APPROVED INDICATIONS Non-small cell lung cancer: As a single agent or in combination with cisplatin for the first-line treatment of ambulatory patients with unresectable, advanced nonsmall cell lung cancer (NSCLC). In patients with stage IV NSCLC, vinorelbine tartrate is indicated as a single agent or in combination with cisplatin. In stage III NSCLC, vinorelbine tartrate is indicated in combination with cisplatin.

TREATMENT DOSE / DURATION / REGIMEN Single-agent vinorelbine tartrate: 30 mg/m2 administered weekly. The recommended method of administration is an intravenous injection over 6 to 10 minutes. In controlled trials, single- agent vinorelbine tartrate was given weekly until progression or dose-limiting toxicity. Vinorelbine tartrate in combination with cisplatin: Vinorelbine tartrate may be administered weekly at a dose of 25 mg/m2 in combination with cisplatin given every 4 weeks at a dose of 100 mg/m2. Blood counts should be checked weekly to determine whether dose reductions of vinorelbine tartrate or cisplatin are necessary. In the SWOG study, most patients required a 50% dose reduction of vinorelbine tartrate at day 15 of each cycle and a 50% dose reduction of cisplatin by cycle 3. Vinorelbine tartrate may also be administered weekly at a dose of 30 mg/m2 in combination with cisplatin, given on days 1 and 29, then every 6 weeks at a dose of 120 mg/m2.

ODS Health Plan Customary Specialty MR Criteria Page 329 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

Dose modifications for vinorelbine tartrate: The dosage should be adjusted according to hematologic toxicity or hepatic insufficiency, whichever results in the lower dose for the corresponding starting dose of vinorelbine tartrate (see table below). Hematologic toxicity: Granulocyte counts should be greater than or equal to 1000 cells/mm3 prior to the administration of vinorelbine tartrate. Adjustments in the dosage of vinorelbine tartrate should be based on granulocyte counts obtained on the day of treatment

EFFECTIVENESS MONITORING PARAMETERS Clinical and pathologic response.

INJECTABLE ADMINISTRATION REQUIREMENTS Administration should be supervised by medical professional experienced in the use of anticancer agents.

REFERENCES Product Information. 2008. Facts and Comparisons 4.0. Accessed 08/27/08.

Effective: 10/01/08 Created: 08/01/08 Updated: Reviewed: ______

ODS Health Plan Customary Specialty MR Criteria Page 330 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Central Nervous System Agents

Generic Name (Brand): Ziconotide (Prialt)

DISTRIBUTION Limited distribution. FDA APPROVED INDICATIONS Analgesia: For the management of severe chronic pain in patients for whom intrathecal (IT) therapy is warranted, and who are intolerant of or refractory to other treatment, such as systemic analgesics, adjunctive therapies, or IT morphine. TREATMENT DOSE / DURATION / REGIMEN Initiate ziconotide IT at no more than 2.4 mcg/day (0.1 mcg/h) and titrate to patient response. Doses may be titrated upward by up to 2.4 mcg/day (0.1 mcg/h) at intervals of no more than 2 to 3 times per week, up to a recommended maximum of 19.2 mcg/day (0.8 mcg/h) by day 21. Dose increases in increments of less than 2.4 mcg/day (0.1 mcg/h) and increases in dose less frequently than 2 to 3 times per week may be used. For each dose titration, assess the dosing requirements and adjust the pump infusion flow rate as required to achieve the new dosing. Although 977 patients have been treated with ziconotide IT in long-term, open-label trials, controlled studies of pain relief have not been conducted for longer than 3 weeks duration. Adjust the dose of ziconotide IT according to the patient's severity of pain, their response to therapy, and the occurrence of adverse reactions. The effective dose of ziconotide for analgesia is variable. The average dose level at the end of the 21-day titration used in the slow titration clinical trial was 6.9 mcg/day (0.29 mcg/h) and the maximum dose was 19.2 mcg/day (0.8 mcg/h) on day 21. Because of the frequency of adverse reactions, 19.2 mcg/day (0.8 mcg/h) is the maximum recommended dose.

EFFECTIVENESS MONITORING PARAMETERS Clinical response.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08.

Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 331 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

PA Description: Endocrine and Metabolic Agents

Generic Name (Brand): Zoledronic Acid (Reclast, Zometa)

FDA APPROVED INDICATIONS Zometa: Hypercalcemia of malignancy: For the treatment of hypercalcemia of malignancy. The safety and efficacy of zoledronic acid in the treatment of hypercalcemia associated with hyperparathyroidism or with other non–tumor-related conditions have not been established. Multiple myeloma and bone metastases from solid tumors: For the treatment of patients with multiple myeloma and patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least 1 hormonal therapy. Reclast: Paget disease: For the treatment of Paget disease of bone in men and women. Treatment is indicated in patients with Paget disease of bone with elevations in serum alkaline phosphatase of 2 times or higher than the upper limit of the age-specific normal reference range, or those who are symptomatic, or those at risk for complications from their disease, to induce remission (normalization of serum alkaline phosphatase). Postmenopausal osteoporosis: For treatment of osteoporosis in postmenopausal women. In postmenopausal women with osteoporosis, zoledronic acid reduces the incidence of fractures (eg, hip, vertebral, nonvertebral osteoporosis-related fractures).

TREATMENT DOSE / DURATION / REGIMEN Zometa: Hypercalcemia of malignancy: Consider the severity of, as well as the symptoms of, tumor- induced hypercalcemia when considering use of zoledronic acid for injection. Vigorous saline hydration alone may be sufficient to treat mild, asymptomatic hypercalcemia. Dose: The maximum recommended dose of zoledronic acid in hypercalcemia of malignancy (albumin-corrected serum calcium is at least 12 mg/dL [3 mmol/L]) is 4 mg. Albumin-corrected serum calcium (Cca, mg/dL) = Ca + 0.8 (mid-range albumin-measured albumin in mg/dL). The 4 mg dose must be given as a single-dose intravenous (IV) infusion over no less than 15 minutes. Hydration: Adequately rehydrate patients prior to administration of zoledronic acid. Promptly initiate vigorous saline hydration, an integral part of hypercalcemia therapy, and make an

ODS Health Plan Customary Specialty MR Criteria Page 332 of 333 Revision Date: 09/24/2008 ODS HEALTH PLANS, INC. MR Criteria

attempt to restore the urine output to about 2 L/day throughout treatment. Mild or asymptomatic hypercalcemia may be treated with conservative measures (eg, saline hydration, with or without loop diuretics). Adequately hydrate patients throughout the treatment, but overhydration, especially in those patients who have cardiac failure, must be avoided. Do not employ diuretic therapy prior to correction of hypovolemia. Re-treatment: Re-treatment with zoledronic acid 4 mg may be considered if serum calcium does not return to normal or remain normal after initial treatment. It is recommended that a minimum of 7 days elapse before re-treatment to allow for full response to the initial dose. Renal function must be carefully monitored in all patients receiving zoledronic acid, and possible deterioration in renal function must be assessed prior to re-treatment with zoledronic acid. Multiple myeloma and bone metastases from solid tumors: The recommended dose of zoledronic acid in patients with multiple myeloma and metastatic bone lesions from solid tumors for patients with creatinine clearance (CrCl) greater than 60 mL/min is 4 mg infused over no less than 15 minutes every 3 or 4 weeks. The optimal duration of therapy is not known. Calcium/Vitamin D supplementation: Administer patients an oral calcium supplement of 500 mg and a multiple vitamin containing 400 units of vitamin D daily.

EFFECTIVENESS MONITORING PARAMETERS Clinical and laboratory response including serum calcium levels.

REFERENCES Product Information. Facts and Comparisons 4.0. Accessed 09/15/08.

Effective: 10/01/08 Created: 09/15/08 Updated: Reviewed:

ODS Health Plan Customary Specialty MR Criteria Page 333 of 333 Revision Date: 09/24/2008