Volume X, No. I January/February 2007 Mandy C. Leonard, Pharm.D., BCPS Assistant Director, Drug Information Service Editor Use of Inhaled Human in Patients with Mellitus Meghan K. Lehmann, Pharm.D., BCPS by Linda Ghobrial, Pharm.D. Drug Information Specialist Editor I ntroduction: Diabetes mellitus is a concentration >200 mg/dL in the pres- Dana L. Travis, R.Ph. Drug Information Pharmacist metabolic disease characterized by ence of symptoms, or a 2-hour OGTT 2 Editor hyperglycemia and abnormal carbo- value of >200 mg/dL. The diagnosis hydrate, fat, and protein metabolism. is then confirmed by measuring any David A. White, B.S., R.Ph. Diabetes has a very high prevalence one of the three criteria on a subse- Restricted Drug Pharmacist 2 Associate Editor worldwide. There are approximately quent day. 20.8 million (7%) people in the 1 Marcia J. Wyman, Pharm.D. United States who have diabetes. Classification: Most patients with D rug Information Pharmacist Diabetes results from defects in insu- diabetes mellitus are classified as hav- A ssociate Editor lin secretion, sensitivity, or both. Al- ing either type 1 or type 2. Type 1

Amy T. Sekel, Pharm.D. though the exact cause remains un- diabetes (previously known as juve- D rug Information Pharmacist clear, genetics and environmental fac- nile diabetes) accounts for about 10% AInss otchiaiste IEsdsituoer tors such as obesity and lack of exer- of all diabetes cases and is usually cise appear to be involved. diagnosed in children and young David Kvancz, M.S., R.Ph., FASHP 2 Chief Pharmacy Officer adults. In these patients, insulin is Diagnosis: The diagnosis of diabetes not produced because of immune- Morton Goldman, Pharm.D., BCPS mellitus is based on one of three crite- mediated destruction of pancreatic Director, Pharmacotherapy Services ria: fasting plasma (FPG), cells. In comparison, ,

In This Issue: casual elevated glucose levels that which accounts for almost 90% of • Inhaled Insulin occur in conjunction with symptoms, diabetes cases, is characterized by or an abnormal oral glucose tolerance both insulin resistance and insuffi- • Formulary Update 2 2 test (OGTT). Fasting plasma glucose cient insulin production. There are is defined as the glucose level taken other uncommon causes of diabetes after no caloric intake for at least which include endocrine disorders 2 Drug Information Service 8 hours. Casual glucose levels are (e.g., Cushing’s syndrome), gesta- (216) 444-6456, option #1 defined as the glucose level taken at tional diabetes mellitus, disease of the any time of the day without regard to (e.g., pancreatitis) and some Comprehensive information about meals. In the OGTT test, blood medications (e.g., glucocorticoids,

medications, biologics, nutrients, glucose levels are measured 2 hours pentamidine, and interferon alfa).2 and drug therapy after drinking a glucose-rich beverage

that contains 75 grams of glucose. Complications: It is well known that Formulary Information This test is completed after a fast with the long-term complications of diabe-

normal FPG defined as <100 mg/dL tes include both microvascular and Medication Inservices 3 and impaired fasting glucose (IFG) macrovascular complications. Exam- between 100 and 125 mg/dL.2 ples of microvascular complications Diabetes mellitus is defined as FPG include retinopathy, neuropathy, and >126 mg/dL, a casual plasma glucose nephropathy. Macrovascular compli-

cations include coronary heart disease, stroke, and periph- lease a constant amount of insulin over a 24-hour period.4 eral vascular disease.3 Good glycemic control has been There are also insulin mixtures available that contain fixed shown to decrease the risk of long-term complications in ratios of rapid- or short-acting insulin with intermediate insu- both type 1 and type 2 diabetic patients.3 lin (e.g., Novolin® 70/30) to reduce the number of injections patients may need to take each day.4 However, in an effort to Management: The goal of treatment is to ameliorate mimic normal physiologic insulin response in the body, insu- symptoms of hyperglycemia, reduce the onset and progres- lin mixtures are used less often resulting in more daily insulin sion of microvascular and macrovascular complications, injections. Attempts to treat diabetes by delivering insulin reduce mortality, and improve quality of life. The Ameri- through non-invasive means have led to the development of a can Diabetes Association (ADA) recommends a hemo- new formulation of insulin. globin A1c (HbA1c) of <7%, preprandial plasma glucose of 90-130 mg/dL, and postprandial glucose <180 mg/dL.4 Inhaled Insulin: Since its first use in 1922, there have been These goals can be difficult to achieve in type 1 diabetics as numerous efforts towards painless administration of insulin.7 well as in type 2 diabetics who do not respond to non- Until now, alternative insulin administration routes have pharmacologic and oral antihyperglycemic therapy and re- failed to deliver insulin in a reproducible and dose-dependent quire multiple daily insulin injections. Diabetic patients manner.7 The concept of pulmonary insulin administration requiring exogenous insulin have traditionally received it has become a reality with advances in technology and drug by either with disposable needles, formulation.8 Exubera®, insulin human [rDNA origin] inha- pen devices, or insulin pumps (i.e., portable devices that lation powder (Pfizer), was approved by the Food and Drug deliver rapid-acting insulin). Administration (FDA) on January 27, 2006, for the treatment of children aged 6 years or older and adult patients with Type 1 and some type 2 diabetic patients require both long- type 1 or type 2 diabetes mellitus.9 In patients with type 1 and short-acting to provide basal insulin coverage diabetes, Exubera® is used in combination with a long-acting as well as coverage required during meal times. Over the insulin.9 In patients with type 2 diabetes, Exubera® can be last 2 decades, there has been an increase in the number of used as monotherapy or in combination with oral agents or insulin analogues available for patients with diabetes (see long-acting insulin.9 This article will review the background Table 1).4 Rapid-acting insulins have a faster onset of ac- of inhaled insulin, its efficacy and tolerability, as well as its tion and more predictable duration of action than regular directions for use and place in therapy. insulin and have been used more frequently to provide meal time insulin requirements. (Apidra®) was Pharmacology: The primary action of insulin, a polypeptide, recently approved as a rapid-acting insulin. Likewise, insu- is to regulate glucose metabolism. Insulin lowers blood glu- lin glargine (Lantus®) and (Levemir®) have cose concentrations by stimulating peripheral glucose uptake been introduced for basal insulin coverage since they re- by skeletal muscle and fat, and by inhibiting hepatic glucose

Table 1. Insulin and Insulin Analogues5,6,9

Generic Brand Name Manufacturer Classification Onset Duration AWP Inhaled insulin Exubera®NF Pfizer Rapid 10-20 min 6-8 h $180.00† Humalog®NF Eli Lilly Rapid 10-20 min 3-4 h $80.35‡ Novolog®NF Rapid 10-20 min 3-5 h $83.70‡ Insulin glulisine Apridra®F Sanofi Aventis Rapid 10-20 min 3-4 h $77.63‡ Humulin R®NF Eli Lilly $54.24‡ Insulin regular Short 30 min 6-8 h Novolin R®F Novo Nordisk $56.55‡

Humulin N®NF Eli Lilly $54.24‡ Insulin NPH Intermediate 1-2 h 18-24 h Novolin N®F Novo Nordisk $56.55‡ Insulin detemir Levemir®F Novo Nordisk Long 3-4 h 6-23 h $83.70‡ Lantus®F Sanofi Aventis Long 3-4 h 24 h $76.98‡ F= Formulary NF= Non-formulary AWP= Average Wholesale Price † = Kit (inhaler, chamber and release unit, 90- 1 mg blisters and 180- 3 mg blisters) ‡=10 mL vial

production. Insulin also inhibits lipolysis and proteolysis, and (Cmax) were reduced by approximately 20 and 30%, respec- enhances protein synthesis.4 Once inside the gastrointestinal tively.9 In patients with unstable or poorly controlled lung tract, insulin is denatured. This is why insulin has only been disease, there are wide variations in lung function that could administered by either subcutaneous (SC) injection or intrave- affect absorption and increase the risk of or nous infusion in the past.7 hyperglycemia.9 In asthmatic patients, absorption of inhaled insulin in the absence of treatment with a bronchodilator is Pharmacokinetics: The absorption of inhaled insulin a pproximately 20% lower than absorption noted in subjects depends on many factors. Each alveolus has a diameter of without asthma.9 Systemic insulin concentrations are ap- 0.06 to 0.2 mm and healthy adult lungs consist of about proximately 2-fold higher in patients with chronic obstructive 400 million alveoli, thus forming a surface area of approxi- pulmonary disease (COPD) compared to normal subjects.9 mately 100 m2.7 In order for a drug to reach the alveoli, the inhalation system must generate the optimal aerodynamic di- Select Clinical Trials: The efficacy of inhaled insulin was ameter of 1-3 µm.7 Particles larger than 5 µm linger in the studied in both type 1 and type 2 diabetic patients with oropharynx and upper airway whereas smaller particles are primary endpoints of changes in HbA1c, FPG, and postpran- lost during exhalation.7 The rate of drug absorption varies at dial glucose. Type 1 diabetic patients who were stable on different sites within the lung because of the variable thickness their current treatment were studied in two 24-week trials.11,12 of mucosal surfaces.7 The alveolar regions of the lungs are so Both studies compared the regimens of preprandial inhaled densely perfused with capillaries that five liters of blood pass insulin to preprandial administered SC. All through the lung each minute.7 These alveolar membranes patients established basal insulin coverage with either once or allow the passage of proteins, such as insulin, with less degra- twice daily SC intermediate- or long-acting insulin. dation by proteolytic enzymes.7 Quattrin and colleagues conducted an open-label, 24-week, In a Phase II randomized, cross-over study (n = 17), 6 mg of randomized, multi-center comparative trial (n = 334) to study inhaled insulin demonstrated a faster onset of action than an the efficacy and safety of preprandial inhaled insulin in com- equivalent dose of SC administered regular insulin.10 When bination with a single SC injection of com- insulin is inhaled, the onset of glucose-lowering activity in pared to a conventional SC insulin regimen.11 The conven- healthy volunteers occurs within 10 to 20 minutes and is com- tional SC insulin regimen consisted of NPH and regular insu- parable to insulin lispro (see Table 1). The maximum effect lin before breakfast, regular insulin before dinner, and NPH on glucose-lowering occurs approximately 2 hours after inha- insulin either before dinner or at bedtime. The objective of lation.9 The 6-hour duration of glucose-lowering activity of the trial was to show that inhaled insulin was non-inferior to inhaled insulin is longer than insulin lispro and comparable to the conventional SC insulin regimen in the change in HbA1c regular insulin (see Table 1).10 Since recombinant human in- at 24 weeks with a non-inferiority margin of 0.5%. For the sulin is identical to endogenous insulin, the systemic distribu- primary objective, inhaled insulin was non-inferior to the tion and elimination are expected to be the same.9 conventional SC insulin regimen in the mean decrease of HbA1c (adjusted treatment group difference 0.16% [95% CI Special populations in which inhaled insulin has been studied, -0.01 to 0.32]) and had a greater reduction for both FPG include pediatric, geriatric, and obese patients, those with renal (adjusted mean change difference -25.17 mg/dl [95% CI or hepatic impairment, smokers, and/or those with underlying -43.39 to -6.95]) and postprandial plasma glucose (adjusted lung disease. The time to peak insulin administration for mean change difference -30.28 mg/dl [95% CI -54.58 to patients aged 6-11 years old is consistent with findings from -5.97]). Hypoglycemic events were lower for inhaled insulin the adult population. Likewise, there are no differences in (risk ratio 0.96 [95% CI 0.93 to 0.99]). Other adverse events the pharmacokinetics of inhaled insulin in patients older than were comparable between the two groups. Cough, however, 65 years of age.9 For obese patients, the absorption of inhaled occurred more frequently in the inhaled insulin group and insulin is independent of body mass index (BMI), unlike SC decreased as therapy continued. There were no differences in administered insulin where absorption declines with increasing pulmonary function tests besides carbon monoxide diffusing 9 BMI. The effect of renal or hepatic impairment on the phar- capacity (DLCO). There were increased insulin antibodies macokinetics of inhaled insulin has not been studied. observed in the inhaled insulin group. Finally, treatment sat- isfaction measured by a validated questionnaire, known as the Systemic absorption of inhaled insulin varies significantly in Diabetes Quality of Life and Treatment Satisfaction Ques- smokers and those with underlying lung disease. The systemic tionnaire, was greater in the inhaled insulin group. The au- insulin exposure of inhaled insulin is 2- to 5-fold higher in thors concluded that inhaled insulin is effective, well- smokers.9 Smokers also have a more rapid onset of action, tolerated, and accepted in patients with and greater maximum effect, and a greater total glucose-lowering provides glycemic control comparable to that of a conven- effect (particularly during the first 2-3 hours after dosing) tional insulin regimen. compared to non-smokers.9 In contrast to the increase in insu- lin exposure following active smoking, when non-smokers Skyler and colleagues conducted an open-label, 24-week, were exposed to 2 hours of passive cigarette smoke, insulin randomized, multi-center outpatient comparative trial area-under-the-cure (AUC) and maximum concentration (n = 328) to compare a basal/bolus insulin regimen involving preprandial inhaled insulin with twice-daily SC NPH insulin to weeks of treatment and did not progress over the 2-year treat- regular preprandial SC insulin with twice-daily SC NPH insu- ment period. lin injections.12 The objective of the trial was to show that the inhaled insulin group was non-inferior to the SC administered Drug Interactions:9 There are a number of medications insulin group in the change in HbA1c at 24 weeks with a non- known to affect glucose metabolism leading to insulin dose inferiority margin of 0.5%. Results demonstrated that inhaled adjustment and monitoring. These drug interactions are simi- insulin was non-inferior (adjusted difference -0.16% [95% CI lar to those noted with injectable insulin, with one notable -0.34 to 0.01]) to the SC insulin regimen in the mean decrease difference. Bronchodilators and other inhaled products may of HbA1c. Inhaled insulin was associated with a statistically alter the absorption of inhaled human insulin. Therefore, significant reduction in FPG (adjusted difference -39.5 mg/dl consistent timing of bronchodilator administration relative to [95% CI -57.5 to -21.6]) compared to the SC insulin regimen inhaled insulin administration, close monitoring of blood glu- group. There was no statistically significant difference be- cose concentrations, and dose titration as appropriate are rec- tween the two groups in the 2-hour postprandial concentration. ommended by the manufacturer. Although, the overall hypoglycemia rate was lower in the in- haled insulin group (risk ratio 0.94 [95% CI 0.91 to 0.97]), the and Lactation:9 Inhaled insulin absorption in rate of severe hypoglycemia was higher in the inhaled insulin pregnant patients with gestational or pre-gestational type 2 group (risk ratio 2.00 [95% CI 1.28 to 3.12]). There were no diabetes is consistent with that of non-pregnant patients with differences in pulmonary function tests except for DLCO. This type 2 diabetes. Since animal reproduction studies have not trial also demonstrated increased insulin antibodies in the in- been conducted with inhaled insulin, it is unknown whether haled insulin group as well as an increased incidence of cough. inhaled insulin can cause fetal harm when administered to a The authors concluded that in combination with twice-daily pregnant woman. Exubera® is classified as a pregnancy-risk basal injections of NPH insulin, both inhaled and SC insulin category C, defined as either animal studies have revealed regimens provided comparable glycemic control over a d v erse effects on the fetus or there are no controlled studies 6 months in terms of HbA1c reduction. in pregnant women, which is why it should be given only if the potential benefit justifies the potential risk to the fetus. The use of inhaled insulin was also studied in patients with However, SC insulin is classified as a pregnancy-risk cate- type 2 diabetes in comparison to SC insulin, oral thiazo- gory B and is the drug of choice for the control of diabetes lidinediones, oral and oral or repag- mellitus in pregnancy.17 Human insulin is excreted in breast linide in combination with metformin or a milk and caution should be taken when insulin is admin- (see Table 2).13-16 istered to a nursing woman. However, since the gastro- intestinal tract destroys insulin, systemic absorption of the Contraindications:9 Exubera® is contraindicated in patients lactating infant is not expected. Patients with diabetes who with hypersensitivity to any one of its excipients, smokers or are lactating may require adjustments in insulin dose, meal those who have discontinued smoking less than 6 months prior plan, or both. to starting therapy, and in patients with unstable or poorly con- trolled lung disease since wide variations in lung function af- Dose and Administration:7,9 The dry-powder formulation of fect absorption and lead to an increased risk of hypoglycemia insulin described in this review is a mix of human insulin or hyperglycemia. If a patient starts or resumes smoking, ther- (rDNA origin), mannitol (stabilizing agent), glycine, and so- apy must be discontinued immediately because of increased dium citrate. The insulin powder is available in single-dose risk of hypoglycemia, and an alternative treatment must be blister packs of 1- or 3-mg. Directions for use must be ade- utilized. There are also warnings and precautions associated quately explained to patients initiated on inhaled insulin to with the use of inhaled insulin, which are described in Table 3. reduce administration errors. The insulin blisters are placed into a slot on the inhaler device. Once pierced, the contents Adverse Drug Reactions:9 The safety of inhaled insulin alone are dispersed by compressed air into a visible aerosol cloud, and in combination with SC insulin or oral agents, has been which is captured in a holding chamber. The patient inhales evaluated in approximately 2500 adult patients with type 1 or from this chamber at the beginning of a deep, slow breath. If type 2 diabetes.9 Reported non-respiratory adverse events in- the insulin dose is not exactly 1- or 3-mg, the patient will clude hypoglycemia, chest pain (4.7%), dry mouth (2.4%), and need to inhale the contents of multiple blisters. Bioavailabil- otitis media (6.5% in type 1 pediatric diabetics). Cough (4.2%) ity does not appear to be enhanced by holding the breath at occurs more frequently with inhaled insulin and usually within the end of inspiration.7 seconds to minutes after insulin inhalation. The described cough is predominantly mild in severity, rarely productive, As with other insulins designed for mealtime use, the dosage and has a decreased incidence with continued inhaled insulin of inhaled insulin must be titrated to the needs of individual use. There are also reports of mild-to-moderate dyspnea with patients. Any changes to the insulin dose should be made inhaled insulin use. Patients treated with inhaled insulin cautiously and under medical supervision. Because of the demonstrated a greater decline in pulmonary function, specifi- rapid onset of action, the dose should be given within 10 min- cally FEV1 and DLCO, than comparator-treated patients. Dif- utes before a meal to prevent hypoglycemia. In patients with ferences in FEV1 and DLCO, were noted within the first several type 2 diabetes, concomitant oral antihyperglycemic therapy

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2 ( 2 D R T R * Table 3. Warnings and Precautions for Inhaled Insulin Use9 Include rash, shortness of breath, wheezing, reduction in blood pressure, Allergic Reactions rapid pulse, or sweating Caution in patients with long duration of diabetes, diabetic nerve disease, Hypoglycemia use of medications such as beta-blockers, or intensified diabetes control Assess prior to initiating therapy, use not recommended in patients with Pulmonary Function baseline FEV1 or DLCO < 70% Acute Illness Insulin requirements may be altered Bronchospasm Discontinue therapy and seek medical attention Renal/Hepatic Impairment Insulin dose may need to be reduced Insulin Antibodies Clinical consequences unknown may need to be adjusted after initiating inhaled insulin ther- recommended after the first 6 months of therapy, and annu- apy. Finally, adjustment of insulin dosage may be necessary ally thereafter, even in the absence of pulmonary symp- for changes in physical activity or meal plans. toms. The use of inhaled insulin with an FEV1 or DLCO less than 70% of normal is not recommended. In patients who An FDA-approved medication guide must be distributed have a decline of ≥20% in FEV1 from baseline, pulmonary when dispensing an outpatient prescription for Exubera® and function tests should be repeated. If the ≥20% decline from can be found at http://www.fda.gov/cder/Offices/ODS/ baseline FEV1 is confirmed, therapy should be discontin- medication_guides.htm. The Exubera® Release Unit in the ued. The presence of pulmonary symptoms and lesser de- inhaler should be changed every 2 weeks, which requires clines in pulmonary function may require more frequent manual dexterity. The Exubera® inhaler must be cleaned monitoring of pulmonary function and consideration of dis- weekly and allowed to air dry, since moisture in the chamber continuation of inhaled insulin. During respiratory illness, absorbs the insulin powder. The inhaler may be used c lose monitoring of glucose levels are required and the in- for 1 year. There are two release units packaged with every haled insulin dose may need to be adjusted. Patients should refill kit. also be made aware that the use of bronchodilators may alter inhaled insulin absorption. The initial preprandial dose is 0.05 mg/kg, rounded down to the nearest whole number based on the findings of clinical Cost/Formulary Status: The cost of inhaled insulin is trials in which patients consumed three meals per day. If the significantly higher than SC administered insulin (see Table patient is being switched from regular SC insulin, dose con- 1).6 However, the benefit of treatment satisfaction and the versions should be made based on Table 4. The foil blisters potential positive impact on treatment adherence may offset should be combined so that the smallest possible number of the additional cost of inhaled insulin.19 Since patient satis- blisters are used for each dose. For example, if a patient has faction declines in patients with diabetes who require multi- been taking 10 units of SC regular insulin and is switched to ple daily SC injections, resulting in decreased patient com- inhaled insulin, the units should be rounded to 11 units. pliance, any non-invasive therapy that delivers the same Therefore, the patient would begin inhaled insulin treatment therapeutic benefit is likely to be of considerable interest with a total of 4 mg which is equivalent to one 3 mg and one from a patient acceptability and compliance point of view. 1 mg blister. The patient would then have to closely self- This is true regardless if the drug is more costly, as shown monitor blood glucose. by a Canadian study.19 Inhaled insulin is not on the inpa- tient Formulary at Cleveland Clinic. Although there are no specific guidelines on how to round SC insulin units to equal inhaled insulin doses, inhaled insulin Summary: The benefit of an intensive insulin regimen has doses should match as closely as possible to the original SC been demonstrated in the Diabetes Control and Complica- dose. It should be noted that three consecutive 1 mg doses of tions Trial. Despite these advantages, there are barriers to inhaled insulin provide more insulin than a 3 mg blister and insulin use because of decreased patient acceptance as a should therefore not be substituted for the 3 mg dose. This result of multiple daily injections. Inhaled insulin has a information has been addressed in an Institutes of Safe Medi- unique place in the treatment of diabetes to achieve glyce- cation Practices (ISMP) Safety Alert and can be reviewed at mic control and thereby reduce the risk and slow the pro- http://www.ismp.org/Newsletters/acutecare/articles/ gression of long-term complications in patients who are A4Q06Action.asp. averse to insulin injections and have good lung function. Traditionally, patients have used intermediate- to long- 9 Monitoring : Before initiating therapy with inhaled insulin, acting insulin to provide basal insulin as well as short- all patients should have spirometry performed as well as an acting insulin at mealtime when physiologic requirements assessment of DLCO. The monitoring of lung function is also of insulin were increased. Patients now have an inhaled

Table 4. Approximate Equivalent Doses of Inhaled Human Insulin (Exubera®) and Subcutaneous (SC) Regular Human Insulin9

Approximate equivalent dose Dose of inhaled Number of 1 mg blisters Number of 3 mg blisters of of SC regular insulin (units) insulin (mg) of inhaled insulin inhaled insulin 3 1 1 6 2 2 8 3 1 11 4 1 1 14 5 2 1 16 6 2 Adapted from package labeling insulin formulation to use for mealtime insulin requirements. The disadvantages of using inhaled insulin include variations in absorption that are age-related or due to respiratory tract infections and smoking, as well as cost. Patients should be made aware that inhaled insulin is not a comprehensive replacement of SC insulin since there is still a need for daily injections of basal insu- lin requirements, but it will certainly reduce the number of insulin injections required each day.

References: 1. American Diabetes Association. www.diabetes.org. Accessed October 10, 2006. 2. Oki JC, Isley WL. Diabetes Mellitus. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM. Pharmacotherapy: a pharmacologic approach. New York: McGraw-Hill; 2002. p. 1335-8. 3. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications and insulin-dependent diabetes mellitus. N Engl J Med 1993;329(14):977-86. 4. The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Standards of medical care in diabetes. Diabetes Care 2006;29 Suppl 1:S1-42. 5. Inhaled insulin. In: DRUGDEX System [Internet database]. Greenwood Village, CO: Thomson Micromedex. Updated periodically. Ac- cessed October 10, 2006. 6. Red Book. Pharmacy’s Fundamental Reference. Montvale, NJ: October 2006. 7. Owens DR, Zinman B, Bolli G. Alternative routes of insulin delivery. Diabet Med 2003;20(11):886-98. 8. Laube BL. Treating diabetes with aerosolized insulin. Chest 2001;120(3 Suppl):99S-106S. 9. Exubera® package insert. New York, NY: Pfizer Labs; 2006 May. 10. Rave K, Bott S, Heinemann L, Sha S, Becker RH, Willavize SA, et al. Time-action profile of inhaled insulin in comparison with subcuta- neously injected insulin lispro and regular human insulin. Diabetes Care 2005;28(5):1077-82. 11. Quattrin T, Belanger A, Bohannon NJ, Schwartz SL. Efficacy and safety of inhaled insulin (Exubera) compared with subcutaneous insu- lin therapy in patients with type 1 diabetes: results of a 6-month, randomized, comparative trial. Diabetes Care 2004;27(11):2622-7. 12. Skyler JS, Weinstock RS, Raskin P, Yale JF, Barrett E, Gerich JE, et al. Use of inhaled insulin in a basal/bolus insulin regimen in type 1 diabetic subjects: a 6-month, randomized, comparative trial. Diabetes Care 2005;28(7):1630-5. 13. Hollander PA, Blonde L, Rowe R, Mehta AE, Milburn JL, Hershon KS, et al. Levin SR. Efficacy and safety of inhaled insulin (Exubera®) compared with subcutaneous insulin therapy in patients with type 2 diabetes: results of a 6-month, randomized, comparative trial. Diabetes Care 2004;27(10):2356-2. 14. DeFronzo RA, Bergenstal RM, Cefalu WT, Pullman J, Lerman S, Bode BW, et al. Efficacy of inhaled insulin in patients with type 2 dia- betes not controlled with diet and exercise: a 12-week, randomized, comparative trial. Diabetes Care 2005;28(8):1922-8. 15. Barnett AH, Dreyer M, Lange P, Serdarevic-Pehar M. An open, randomized, parallel-group study to compare the efficacy and safety pro- file of inhaled human insulin (Exubera®) with as adjunctive therapy in patients with type 2 diabetes poorly controlled on metformin. Diabetes Care 2006;29(8):1818-25. 16. Rosenstock J, Zinman B, Murphy LJ, Clement SC, Moore P, Bowering CK, et al. Inhaled insulin improves glycemic control when substi- tuted for or added to oral combination therapy in type 2 diabetes: a randomized, controlled trial. Ann Intern Med 2005;143(8):549-58. 17. Briggs GC. Drugs in pregnancy and lactation. Seventh Edition. Philadephia: Lippincott Williams and Wilkins; 2005. p 834-5. 18. Sadri H, MacKeigan LD, Leiter LA, Einarson TR. Willingness to pay for inhaled insulin: a contingent valuation approach. Pharma- coeconomics 2005;23(12):1215-27.

Formulary Additions

The Cleveland Clinic Pharmacy and Therapeutics Committee met on Tuesday, January 9, 2007, and the following decisions were made:

1. Carvedilol CR (Coreg CR™): Carvedilol 10-, 20-, 40-, and 80-mg extended-release capsules are intended for once daily administration. Please refer to product labeling for dose conversions between immediate-release and extended-release carvedilol formulations. These capsules will become commercially available by the end of the first quarter of 2007 and will be stocked in addition to immediate-release carvedilol tablets.

2. Conivaptan (Vaprisol®): Conivaptan is the first in a new class of diuretics that block antidiuretic hormone or vasopressin receptors V1A and V2. By binding to the V1A receptor it blocks the effect of vasopressin, whereas its aquaretic effects are due to its binding at the V2 receptor. It is indicated for the treatment of euvolemic hyponatremia in hospitalized patients. Conivaptan use is restricted as follows: • Restricted to intensive care unit patients with: · Severe hyponatremia <120 mmol/L and · Symptoms attributed to hyponatremia not responsive to standard treatment • Patients must fail standard therapies for treating hyponatremia: · Adequate free water restriction in appropriate patients · Furosemide diuresis in appropriate patients · Saline infusion in appropriate patients · Demeclocycline in appropriate patients

A loading dose of 20 mg should be administered intravenously over 30 minutes. The maintenance dose is a continuous infusion of 20 mg administered over 24 hours for 4 days maximum. The continuous infusion may be titrated to 40 mg daily if the serum sodium is not increasing as desired. However, the total duration of the infusion should not exceed 4 days. It is recommended that conivaptan be infused via a large vein and that the infusion site be changed every 24 hours to decrease the risk of vascular irritation. Because a rapid rise in serum sodium (i.e., >12 mEq/L per day) may result in negative sequelae, serum sodium, vol- ume, and neurologic status should be monitored frequently during treatment. In addition, patients should be monitored for infu- sion site reactions including phlebitis, inflammation, and thrombosis. Conivaptan is available as 5 mg/mL (4 mL) vials.

3. Decitabine (Dacogen™): Decitabine, an antimetabolite (pyrimidine), is FDA-approved for the treatment of patients with myelodysplastic syndrome (MDS) including previously treated and untreated de novo and secondary MDS of all French- American-British (FAB) subtypes, Intermediate-1, Intermediate-2, and high-risk International Prognostic Scoring System Groups. Decitabine use is restricted to the Department of Hematology and Medical Oncology for both outpatient and inpatient administration.

4. Insulin detemir (Levemir®): Insulin detemir is a long-acting insulin analogue indicated for once or twice daily subcutaneous administration for the treatment of adult and pediatric patients with type 1 diabetes mellitus or adult patients with type 2 diabetes mellitus who require basal insulin control for hyperglycemia. Its use is restricted to patients who currently receive insulin detemir at home or initiation of therapy in inpatients as prescribed by Endocrinology. To help distinguish this insulin from other insulin products, please write orders as "insulin detemir (Levemir®)".

5. Panitumumab (Vectibix™): The monoclonal antibody, panitumumab, is FDA-approved for the treatment of epidermal growth factor receptor-expressing metastatic colorectal carcinoma with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing regimens. Panitumumab use is restricted to the Department of Hematology and Medical Oncology for outpatient use only.

6. Rifaximin (Xifaxan™): Rifaximin is FDA-approved for the treatment of travelers’ diarrhea; however, there are data for us- ing it to treat hepatic encephalopathy. The most commonly used dose for hepatic encephalopathy is 400 mg orally three times daily; however, doses ranging from 600 mg to 2400 mg/day have been studied. Rifaximin is available as 200 mg tablets and its use is restricted to patients with hepatic encephalopathy who have failed first-line therapies, such as lactulose or neomycin.

7. (Januvia™): Sitagliptin is in a new class of agents known as dipeptidyl peptidase-IV inhibitors. It is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. It can be used alone or in combination with metformin or a peroxisome proliferator-activated receptor gamma agonist (e.g., ). Sitaglip- tan is available as 25-, 50-, and 100-mg tablets. The recommended dose is 100 mg orally once daily with dosage adjustments recommended in patients with renal impairment.

Restriction Changes: 1. The recombinant Factor VIIa (NovoSeven®) restriction has been changed to include Departments of Hematology/Medical Oncology, Vascular Medicine, Neurology, Neurosurgery, and Medical Staff from the Liver Transplant Team for the following hepatology patients: • Fulminant Hepatic Failure: to permit insertion of an intracranial pressure (ICP) monitor in patients with coagulo- pathy who are either unresponsive to conventional measures or unable to tolerate the volume load that would result from administration of multiple units of fresh frozen plasma. The decision to administer should be determined by a multidisciplinary team including the Liver Transplant Surgeon, Critical Care Staff, Neurosurgery Staff, and Staff Hepatologist. • “Rescue Therapy” During Liver Transplantation: in patients with life-threatening bleeding and severe coagulopa- thy unresponsive to conventional measures and exhaustive surgical control attempts. Due to the risk of throm- boembolic phenomena, the decision to administer should be determined by both the Liver Transplant Surgeon and Staff Anesthesiologist.

The initial dose is 80 mcg/kg (based on actual body weight or adjusted body weight if patient is 25% over their ideal body weight) rounded to the nearest vial size and given as an IV push. The dose may be repeated once after 2 hours if bleeding con- tinues despite adequate amounts of blood products as determined by the Liver Transplant Surgeon/Staff Anesthesiologist.

2. The iron sucrose (Venofer®) restriction has been changed to include the Department of Adult Nephrology for outpatient use only and Pediatric Nephrology.

Formulary Deletions: 1. Injectable ziprasidone (Geodon®)

Automatic Therapeutic Interchanges: 1. 5HT3 Receptor Antagonists for Chemotherapy Induced Nausea and Vomiting (CINV) and Postoperative Nausea and Vomiting (PONV) Automatic Therapeutic Interchange: a. Beginning Tuesday, January 30th, 2007, all inpatient CINV orders for granisetron (Kytril®) and dolasetron (Anzemet®) will be automatically converted to generic ondansetron. Dose Conversions of Dolasetron IV and Granisetron IV to Generic Ondansetron IV for CINV (Adults)

Dolasetron 100 mg IV daily = Ondansetron 8 mg IV daily

Granisetron 1 mg IV daily = Ondansetron 8 mg IV daily

For inpatient palonosetron orders for CINV, treat these orders as non-formulary (i.e., no automatic interchange to ondansetron). Contact physician and state that palonosetron is non-formulary for inpatients and ask if they will to the Department of Hematology and Medical Oncology for both outpatient and consider changing the order to ondansetron 8 mg IV daily.

Dose Conversions of Dolasetron PO and Granisetron PO to Ondansetron PO for CINV (Adults)

Dolasetron 100 mg PO daily = Ondansetron 16 mg PO daily

Granisetron 2 mg PO daily= Ondansetron 16 mg PO daily

b. Beginning Tuesday, January 30th, 2007, all inpatient and outpatient PONV orders for granisetron (Kytril®), dolasetron (Anzemet®), and palonosetron (Aloxi®) will be automatically converted to generic ondansetron.

Dose Conversions of Dolasetron IV to Ondansetron IV for PONV (Adults) Dolasetron 12.5 mg IV x 1 dose = Ondansetron 4 mg IV x 1 dose

Dolasetron 12.5 mg IV Q 8 hours prn x 24 hours = Ondansetron 4 mg IV Q 6 hours prn x 24 hours

Dose Conversions of Dolasetron PO to Ondansetron PO for PONV (Adults) Dolasetron 50 mg PO x 1 dose = Ondansetron 8 mg PO x 1 dose

Dolasetron 100 mg PO (120 minutes prior to induction of anesthesia) x 1 dose = Ondansetron 16 mg PO (60 minutes prior to induction of anesthesia) x 1 dose

2. Rapid-Acting Insulin Analogue Automatic Therapeutic Interchange: Within the next month or so, Cleveland Clinic will transition to a single rapid-acting insulin analogue. All orders written for in- sulin aspart (Novolog®) or insulin lispro (Humalog®) will be automatically converted to insulin glulisine (Apidra®). Additional communications regarding this interchange will be sent in the near future.

For more detailed information on the above medications, please consult the Formulary on the Intranet (under Clinical Resources/ Drug Information), specifically under Lexi-Drugs Online. Furthermore, please call the Drug Information Center at 4-6456, op- tion #1 if you have any questions.

Cleveland Clinic Department of Pharmacy/Hb-03 Drug Information Center