Volume 18, Number 8 September 2004 Drugs & Therapy B � U � L � L � E � T � I � N

PRESCRIBING FORMULARY UPDATE The Pharmacy and Therapeutics Acute otitis media — Committee met August 18, 2004. 4 drugs were added in the Formulary and 2 drugs were deleted. 4 drugs No antibiotics does not equal were designated nonformulary and not available. 1 drug was evalu- no treatment! ated and designated a high-priority nonformulary drug. cute otitis media (AOM) is the hours, antibiotics should be instituted A most commonly treated bacterial immediately. infection in children. Treatment ac- Observation of AOM should not ◆ ADDED counts for greater than 50% of pediatric equal no treatment. All patients should Azacitidine (Vidaza® by antibiotic prescriptions and as much receive adequate analgesics, especially Pharmion)* as $5 billion annually.1 Studies show during the fi rst 24 hours after diagno- that the spontaneous resolution rate of sis.3 Although various treatments for Bortezomib (Velcade® by AOM is between 70-90%, and only 1 in otalgia have been used, none are well Millennium Pharmaceuticals)* 7-14 children with AOM benefi ts from studied. Eplerenone (Inspra® by Pfi zer) treatment with antibiotics.2 Acetaminophen and ibuprofen are In May of 2004, The American Acad- the mainstay of treatment for pain Progesterone Suppositories emy of Pediatrics and the American associated with AOM due to their ef- (Compounded) Academy of Family Physicians pub- fective analgesia for mild-to-moderate lished evidence-based clinical practice pain.1 The usual dosage of ibuprofen in *Restricted to chemotherapy guidelines for the diagnosis and man- infants and children in 4-10 mg/kg/dose prescribers AND approval by an agement of AOM in children between orally every 6-8 hours, not to exceed oncology pharmacist 2 months and 12 years of age with 30 mg/kg/day.4 The usual dosage of uncomplicated AOM. The guidelines acetaminophen is 10-15 mg/kg/dose ◆ DELETED recommend that observation without orally given every 4-6 hours as needed Beef Lung Heparin use of antibacterial agents in a child for pain, with a maximum of 5 doses in (Beef Lung Heparin by Upjohn)** with uncomplicated acute otitis media 24 hours. Topical agents such as ben- is an option for selected children based zocaine (Auralgan® otic) have limited Prochlorperazine Syrup on diagnostic certainty, age, illness, se- usefulness, as there is no evidence (Compazine® Syrup by SmithKline verity, and assurance of follow-up. This supporting their use over systemic Beecham)** “observation option” refers to defer- analgesics. Other treatments for otalgia ring antibacterial treatment of selected in AOM include narcotic analgesics, **Nonformulary and not available children for 48-72 hours and limiting which are effective for moderate or management to symptomatic relief. Ap- severe pain. However, these agents ◆ NONFORMULARY AND NOT propriate and adequate management of may be more problematic than acet- AVAILABLE symptoms such as otalgia (ear pain) is aminophen and ibuprofen due to their Hydroxyprogesterone Caproate essential during this time period. adverse effect profi le, which includes Injection (Compounded) Once AOM is diagnosed, the decision respiratory depression, altered men- must be made to observe or treat the tal status, gastrointestinal upset, and Venlafaxine Immediate-Release patient. Based on guideline recommen- constipation.4 Tablets (Generic) dations, observation should be limited (continued on page 3) to otherwise healthy children 6 months ◆ EVALUATED, BUT NOT ADDED to 2 years of age with non-severe ill- Botulism Immune Globulin ness at presentation and an uncertain ® diagnosis, and to children 2 years of (BabyBIG by California Depart- ◆ ment of Health Services)*** age and older without severe symp- toms at presentation or with an un- INSIDE THIS ISSUE ***Cannot be stocked, but designated certain diagnosis. Observation allows a high-priority nonformulary drug the patient time to improve without ◆ P&T Actions instituting antibacterial therapy. If the (continued on next page) patient does not improve within 48-72 Formulary update, from page 1 suggest that bortezomib is a possible larger absolute risk reduction of 11% Azacitidine is a pyrimidine nucleo- option for the outpatient management (NNT= 9). Although approximately side analog that is used in the treat- of refractory multiple myeloma. Bort- 50% of the patients in the RALES trial ment of myelodysplastic syndromes. ezomib plus dexamethasone may offer had ischemic heart failure, these pa- Myelodysplastic syndromes (MDS) benefi t to patients who are refractory tients were not in the immediate post- are a heterogeneous group of clonal to dexamethasone alone. MI setting, like the eplerenone trial. hematological disorders character- The most serious adverse reactions Spironolactone use in males with ized by cytopenia and death from associated with bortezomib include congestive heart failure is associated bleeding, infection, or progression to thrombocytopenia, asthenia, peripheral with gynecomastia in about 10% of acute myelogenous leukemia (AML). neuropathy, neutropenia, anemia, nau- patients. It is also associated with im- There is no standard therapy for sea, vomiting, and diarrhea. Asthenia potence and menstrual irregularities in MDS and treatment options are (fatigue, malaise, weakness) occurs in women. These may be less problem- determined by the patient’s age and most patients. Over 40% of patients atic with eplerenone because of less prognostic factors. Most patients experience thrombocytopenia. affi nity for progesterone and andro- with MDS receive supportive care A typical course of therapy will cost gen receptors, but this has not been (ie, hematopoietic growth factors and approximately $20,000. In August 2003, proven in a head-to-head study. cytokines, transfusions, and antibi- bortezomib was reviewed by the P&T Hyperkalemia is the most trouble- otics). The only curative therapy is Committee and designated nonformu- some adverse effect associated with stem cell transplantation and most lary and not available for inpatient and the use of eplerenone. Excessive patients do not qualify for this option. outpatient use because it was expen- dosages or use with drugs that inhibit Chemotherapy is an alternative to sive and both inpatient and outpatient the metabolism of eplerenone may in- supportive therapy. Azacitidine is the reimbursements did not cover this crease the risk of hyperkalemia. Some only drug with a labeled indication added expense. diseases and drugs (eg, ACE inhibi- for the treatment of MDS. Bortezomib was a reason for a tors) may independently increase the A phase III trial has shown that change in federal reimbursement risk of hyperkalemia. A recent time azacitidine had signifi cantly higher rules. The FDA approved bortezomib, series analysis showed increased mor- response rates, improved quality of yet reimbursement was not provided bidity and mortality associated with life, reduced risk of leukemia trans- for its labeled indication. Regulations hyperkalemia in patients treated with formation, and improved survival now require that all drugs, including spironolactone for heart failure. Similar compared with supportive care. bortezomib, be a covered expense for problems are expected with eplere- Response rates of 60% (7% complete) its labeled indication in the outpatient none unless appropriate monitoring is were dramatically better than with setting. done. supportive care (ie, 5% response rate In the inpatient setting, however, Serum potassium should be mea- and 0% complete response). The reimbursement is “covered” by fi xed sured before the institution of eplere- time to transformation to leukemia reimbursement. Therefore, use should none, within the fi rst week of therapy, or death occurred in a median of 21 be outpatient or in rare instances when and after 1 month after the start of months versus 12 months for sup- a patient is hospitalized and requires therapy. Serum potassium should be portive care. These results were ap- continuation of therapy. Since patients measured “periodically” thereafter. parent despite 53% of the supportive must pay a co-pay in the outpatient set- It should be re-measured within 1 care arm crossing-over to the treat- ting, there is potential for patients to be week and at 1 month after a dosage ment arm because of lack of effect. inappropriately admitted to avoid this change (or the addition of a mediation Myelosuppression is the most expenditure. Thus, an oncology phar- that may decrease the metabolism of common toxicity seen with azaciti- macy specialist must approve inpatient eplerenone). Eplerenone is contrain- dine. Toxicity is diffi cult to assess, use of bortezomib. dicated in patients with a creatinine however, because of the underlying Eplerenone is a selective aldosterone clearance less than 30 mL/min and cytopenias associated with MDS. receptor blocker with labeled indications patients with a serum potassium Azacitidine is expensive. A typical for hypertension and heart failure post greater than 5.5 mEq/mL at initiation 7-day course will cost over $11,000. myocardial infarction (MI). It is similar to of therapy. Usually this drug will be adminis- spironolactone, but pharmacologically it There is insuffi cient evidence to tered as an outpatient; however, is more specifi c for aldosterone recep- support the use of eplerenone for the there will be instances when pa- tors and has less effect on progesterone treatment of hypertension or heart fail- tients will be admitted for complica- and androgen receptors. This may result ure in any other population except in tions of their disease and require in fewer adverse effects. the immediate post-MI setting. Eplere- their scheduled treatment. In order There is 1 large randomized trial none is 14 times more expensive than to avoid cost shifting to the inpatient (EPHESUS) that shows a reduction spironolactone. setting, an oncology pharmacist must in mortality in post-MI patients with Progesterone vaginal supposito- approve the inpatient use of azaciti- congestive heart failure compared with ries were added in the Formulary for dine. placebo (when added to traditional the management of patients at risk Bortezomib is the fi rst proteasome therapy). This study showed an abso- of pre-term delivery when they are inhibitor. It is a cytotoxic drug with a lute risk reduction of 2.3% (ie, number hospitalized. The American College labeled indication for the treatment needed to treat [NNT] of 43). There is no of Obstetrics and Gynecology recom- of multiple myeloma in patients who direct comparison between spironolac- mends that when progesterone is used have failed at least 2 prior therapies tone and eplerenone in the heart failure to prevent preterm labor that it is re- and demonstrated disease progres- population. stricted to women with a documented sion. The absolute benefi t in the RALES history of previous spontaneous birth Bortezomib received accelerated trial, which compared spironolactone to at less than 37 weeks of gestation approval from the FDA based on the placebo in a population of patients with because “unresolved issues remain, favorable results found in 2 Phase II severe congestive heart failure receiving such as optimal route of delivery and trials; however, only 1 of these tri- standard therapy (eg, ACE inhibitors, long-term safety of the drug.” als has been published. These data loop diuretics, and digoxin), showed a (continued on next page) 2 Prescribing, from page 1 parents or guardians believed that their safety-net antibiotic prescription can The impact of appropriate pain con- children had adequate pain control be written and fi lled only if the patient trol on patients and their families was and there was a signifi cant lowering of does not improve after a defi ned period demonstrated in a prospective study antibiotic use compared with previous of time. conducted by Siegel and colleagues.2 episodes. The 55 families that did fi ll It is important to stress that during In this study, parents of children with the antibiotic prescription did so for this observation period, and in any uncomplicated AOM were given pre- the following reasons: continued pain patient with AOM, appropriate pain scriptions for an appropriate “safety (42, 24%), continued fever (19, 11%), control is necessary. Appropriate pain net antibiotic.” Parents were asked to sleep disruption (11, 6%), no reason (8, control not only eases the pain of the not fi ll the prescription unless symp- 5%), missed days of work (6, 3%), and affected child, but the parents and toms worsened or did not improve missed days of child care (5, 3%). families as well. after 48 hours. At the time of diagnosis, Due to the growing rates of antimi- by Gina K. Soliman, PharmD practitioners recommended appro- crobial resistance and growing costs REFERENCES priate pain control medications and of antibiotic prescriptions, the judi- 1. Subcommittee on Management of Acute Otitis Media. cious use of antimicrobials is strongly American Academy of Pediatrics and American Academy dispensed samples of ibuprofen, acet- of Family Physicians Clinical Practice Guideline: Diagno- aminophen, and antipyrine/benzocaine recommended. The American Academy sis and management of acute otitis media. Pediatrics (Auralgan®) otic drops. Of the 175 fami- of Pediatrics and American Academy 2004;113(5):1451-65. 2. Siegel RM, Kiely M, Bien JP, et al. Treatment of otitis me- lies enrolled in the study, 120 (69%; of Family Physicians guidelines on the dia with observation and a safety-net antibiotic prescription. 95% CI=61.7-75.5) families did not fi ll diagnosis and management of AOM Pediatrics 2003;112:527-31. 3. Rovers MM, Schilder AG, Zielhuis GA, et al. Otitis Media. the antibiotic prescription. Of these 120 emphasize the appropriate treatment of Lancet 2004;(363):465-73. families, 117 (97.4%; 95% CI=94.4-100) these patients. The observation period 4. Taketomo CK, Hodding JH, Kraus DM. Pediatric Dosage said that they were willing to use pain is recommended in certain patients Handbook, 10th edition. Lexi-Comp, Ohio: 2003. medication without antibiotics in the with uncomplicated AOM. Depend- future. Furthermore, the majority of ing on the patient and practitioner, a

Formulary update, from page 2 heparin was more expensive than ed-release (ER) tablets remain in the Progesterone suppositories have pork heparin, and there were concerns Formulary and will be recommended been shown to be effective at about Mad Cow Disease. Beef lung as an alternative. The total daily dose decreasing the incidence of preterm heparin was no longer a fi nancially of the immediate-release (IR) tablets birth in a small, randomized pla- viable product and was discontinued should be given once daily as venla- cebo-controlled trial in women with by manufacturers. The supply in the faxine ER. at least 1 previous spontaneous pre- market has now been exhausted. Venlafaxine is an antidepressant term birth. Progesterone supposi- Beef lung heparin was restricted at with a mechanism of action similar to tories reduced the rate of preterm Shands at UF. Restriction was done SSRIs (ie, serotonin reuptake inhibi- births by an absolute percentage because of a higher incidence of throm- tion), but it also inhibits the reuptake of 15.6% (ie, NNT = 6.3). These bocytopenia associated with the use of of norepinephrine and dopamine. favorable results and the availabil- beef lung heparin. It remained in the Venlafaxine is used for various off- ity of a formula to compound these Formulary, but was limited to Hematol- label uses including neuropathic pain. suppositories at Shands at UF make ogy approval for use in patients with a Botulism immune globulin is an this option more desirable than true porcine heparin allergy or patients orphan drug that is the only available other dosage forms (ie, injectable with a religious objection to the use of treatment for infant botulism. Infant hydroxyprogesterone). pork products. botulism is the infectious form of Intramuscular progesterone as Prescribers now must fi nd alterna- human botulism. It is recognized in hydroxyprogesterone caproate has tives to beef lung heparin. The appro- only 80 to 100 patients per year in the also been shown to decrease the priate alternative anticoagulant will United States. It is diffi cult to diag- incidence of preterm birth in a large depend on the indication. A Hematol- nose, and with symptomatic treat- randomized placebo controlled trial. ogy Consult will be recommended to ment patient are usually hospitalized Unfortunately, there is no commer- prescribers to determine the appropri- for more than 5 weeks. Treatment cially available hydroxyprogester- ate alternative. with botulism immune globulin can one injection. Low-molecular-weight heparins are cut the typical hospital course in half. Hydroxyprogesterone caproate is generally not alternatives to unfrac- Botulism immune globulin can- prepared by compounding pharma- tionated porcine heparin. Low-molecu- not be stocked in the hospital and, cies. The risk of complications from lar-weight heparins are fragments of therefore, cannot be listed in the For- noncommercial products discourag- porcine heparin and would be objec- mulary. However, it was designated es its inpatient use at Shands a UF. tionable to patients with religious con- a high-priority nonformulary drug, Thus hydroxyprogesterone caproate cerns. Also, it is unpredictable whether which requires pharmacists to contact was designated nonformulary and a patient with a porcine heparin allergy prescribers immediately to facilitate not available. Patients also may not will tolerate a low-molecular-weight the procurement of this product. use their own supply of this drug. heparin. Botulism immune globulin must be Beef lung heparin is no longer Prochlorperazine syrup has been obtained from the California Depart- manufactured and was deleted discontinued by the manufacturer ment of Health Services. Information from the Formulary and designated and has been deleted from the Formu- on how to acquire botulism im- nonformulary and not available. For lary. This product has not been used mune globulin is available at www. many years, unfractionated heparin recently at Shands at UF. If an alterna- infantbotulism.org. The treating came from 2 animal sources: beef tive is needed, it will depend on the physician must fi rst contact the lung (bovine heparin) and pork indication. manufacturer to determine whether intestine (porcine heparin). The use Venlafaxine immediate-release the patient qualifi es for treatment of beef lung heparin has decreased tablets were designated nonformulary before it can be obtained for nonfor- over the last few years. Beef lung and not available. Venlafaxine extend- mulary use. 3 Drugs & Therapy SHANDS NON-PROFIT ORG. B � U � L � L � E � T � I � N Shands at the University of Florida U.S. POSTAGE DRUG INFORMATION SERVICE PAID GAINESVILLE, FL Volume 18, No. 8 September 2004 PO Box 100316 PERMIT NO. 94 Gainesville, FL 32610-0316 This publication is produced by the Drug Information and Pharmacy Re- source Center under the direction of the Department of Pharmacy Services and the Pharmacy and Therapeutics Committee. EDITOR, DRUGS & THERAPY BULLETIN Randy C. Hatton, PharmD DIRECTOR, PHARMACY SERVICES Alan Knudsen, MS, RPh CHAIRMAN, PHARMACY & THERAPEUTICS COM- MITTEE Ricardo Gonzalez-Rothi, MD EDITING, DESIGN, & PRODUCTION Shands HealthCare’s Publication Svcs. © Copyright 2004. All rights reserved. No portion of the Drugs & Therapy Bul- letin may be reproduced without the written consent of its editor. FOR MORE INFORMATION, VISIT US ONLINE http://shands.org/professional/drugs/ bulletin.htm

NEWS P&T Commitee Action 2003–04 he P&T Committee’s year goes will be placed in the patient’s chart. ■ Strategic Plan for the Anti-Infective T from July to June. Thus, another Drugs that are being used nonfor- Stewardship Program: The strategic productive year was just completed. mulary are reviewed. High volume plan for the Anti-Infective Steward- The P&T Committee is the medical nonformulary drugs are reviewed to ship program and the rationale and staff committee that is the formal line determine whether they should be proposed actions of the program of communication between the medi- added in the Formulary, added with re- were endorsed. The program will cal staff and Shands at UF. Therefore, striction, or designated “not available.” periodically report to the P&T Com- formulary activities, drug use polices, High-priority nonformulary drugs are mittee. adverse drug reaction monitoring, those drugs that a delay could result ■ Vancomycin Guidelines: Guidelines and medication safety are most of the in patient harm, like antibiotics, pain for the use of vancomycin were ap- activities. medications, hypotensive agents, and proved and a program for a clinical 27 new drugs were added in the ophthalmic agents. These agents are pharmacist (as part of the Anti-Infec- Formulary this year.year. There were only reviewed for formulary consideration. tive Stewardship Program) to evalu- 9 new drugs requested, the rest of the As part of the normal function of ate all use of vancomycin at 48-72 additions were the result of reviewing the P&T Committee, several drug use hours implemented. The pharmacist nonformulary drugs, drug category policies were reviewed throughout the will assist in streamlining therapy reviews, and the proactive review of year. The following is a partial list of based on culture and sensitivity new products. policy changes. reports. 16 drugs were deleted from the ■ Policy & Procedure for High-Cost, The Drugs & Therapy Bulletin is the Formulary. 33 drugs were designated Problem-Prone Drugs: A detailed primary method for communicating nonformulary and not available. “Not procedure was established to assure P&T activities throughout the year. In available” drugs cannot be requested appropriate utilization of high-cost most years the P&T Committee meets through the nonformulary process. and problem-prone drugs. This pro- 10 times and a Bulletin is published Several therapeutic interchanges cedure uses “expert panels” to give after each meeting. were approved this year including the P&T guidance in order to make Dr. Gonzalez-Rothi chairs the P&T rosiglitazone for pioglitazone, fenofi - the best “evidence-based” decisions. Committee. This is his 5th year lead- brate tablets for fenofi brate capsules, ■ Ceftriaxone Automatic Dosage ing this medical staff committee. If you albuterol MDI for nebulizations, and ip- Interchange: An Infectious Diseases have questions or comments about the ratropium MDI for nebulizations. When Clinical Pharmacist may automatical- activities of the committee, Dr. Gonza- these changes are made, a new order ly interchange ceftriaxone dosages lez-Rothi can be reached by e-mail at 4 with “P&T Authorized Interchange” based on P&T approved criteria. [email protected]fl .edu.