Pharmacy & Therapeutics - June 2008 - (Page 352)

RELISTOR™ (methylnaltrexone bromide) Subcutaneous Injection Brief Summary See package insert for full Prescribing Information. For further product information and current package insert, please visit www.wyeth.com or call our medical communications department toll-free at 1-800-934-5556. INDICATIONS AND USAGE RELISTOR is indicated for the treatment of opioid-induced constipation in patients with advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient. Use of RELISTOR beyond four months has not been studied. CONTRAINDICATIONS RELISTOR is contraindicated in patients with known or suspected mechanical gastrointestinal obstruction. WARNINGS AND PRECAUTIONS Severe or Persistent Diarrhea. If severe or persistent diarrhea occurs during treatment, advise patients to discontinue therapy with RELISTOR and consult their physician. Peritoneal Catheters. Use of RELISTOR has not been studied in patients with peritoneal catheters. ADVERSE REACTIONS Clinical Trial Experience. Because clinical trials are conducted under varying conditions, adverse reaction rates observed in the clinical trials of a drug may not reflect the rates observed in practice. The safety of RELISTOR was evaluated in two, double-blind, placebo-controlled trials in patients with advanced illness receiving palliative care: Study 1 included a single-dose, double-blind, placebo-controlled period, whereas Study 2 included a 14-day multiple dose, double-blind, placebo-controlled period. In both studies, patients had advanced illness with a life expectancy of less than 6 months and received care to control their symptoms. The majority of patients had a primary diagnosis of incurable cancer; other primary diagnoses included end-stage COPD/emphysema, cardiovascular disease/heart failure, Alzheimer’s disease/dementia, HIV/AIDS, or other advanced illnesses. Patients were receiving opioid therapy (median daily baseline oral morphine equivalent dose = 172 mg), and had opioid-induced constipation (either <3 bowel movements in the preceding week or no bowel movement for 2 days). Both the methylnaltrexone bromide and placebo patients were on a stable laxative regimen for at least 3 days prior to study entry and continued on their regimen throughout the study. The adverse reactions in patients receiving RELISTOR are shown in table below. Adverse Reactions from all Doses in Double-Blind, Placebo-Controlled Clinical Studies of RELISTOR* Adverse Reaction Abdominal Pain Flatulence Nausea Dizziness Diarrhea *Doses: 0.075, 0.15, and 0.30 mg/kg/dose RELISTOR N = 165 47 (28.5%) 22 (13.3%) 19 (11.5%) 12 (7.3%) 9 (5.5%) Placebo N = 123 12 (9.8%) 7 (5.7%) 6 (4.9%) 3 (2.4%) 3 (2.4%) PHARMACOKINETIC PARAMETERS OF METHYLNALTREXONE BROMIDE FOLLOWING SINGLE SUBCUTANEOUS DOSES Parameter 0.15 mg/kg 0.30 mg/kg 0.50 mg/kg a 117 (32.7) 239 (62.2) 392 (147.9) Cmax (ng/mL) b tmax (hr) 0.5 (0.25-0.75) 0.5 (0.25-0.75) 0.5 (0.25-0.75) a 175 (36.6) 362 (63.8) 582 (111.2) AUC24 (ng·hr/mL) a Expressed as mean (SD). b Expressed as median (range). Distribution. Methylnaltrexone bromide undergoes moderate tissue distribution. The steady-state volume of distribution (Vss) is approximately 1.1 L/kg. The fraction of methylnaltrexone bromide bound to human plasma proteins is 11.0% to 15.3%, as determined by equilibrium dialysis. Metabolism. In a mass balance study, approximately 60% of the administered radioactivity recovered with 5 distinct metabolites and none of the detected metabolites was in amounts over 6% of administered radioactivity. Conversion to methyl-6-naltrexol isomers (5% of total) and methylnaltrexone sulfate (1.3% of total) appear to be the primary pathways of metabolism. N-demethylation of methylnaltrexone to produce naltrexone is not significant. Excretion. Methylnaltrexone bromide is eliminated primarily as the unchanged drug (85% of administered radioactivity). Approximately half of the dose is excreted in the urine and somewhat less in feces. The terminal half-life (t1/2) is approximately 8 hours. Effect on Cardiac Repolarization. In a randomized, double blind placebo- and (open-label) moxifloxacin-controlled 4-period crossover study, 56 healthy subjects were administered methylnaltrexone bromide 0.3 mg/kg and methylnaltrexone bromide 0.64 mg/kg by IV infusion over 20 minutes, placebo, and a single oral dose of moxifloxacin. At both the 0.3 mg/kg and 0.64 mg/kg methylnaltrexone bromide doses, no significant effect on the QTc interval was detected. CLINICAL STUDIES The efficacy and safety of RELISTOR in the treatment of opioid-induced constipation in advanced illness patients receiving palliative care was demonstrated in two randomized, double-blind, placebo-controlled studies. In these studies, the median age was 68 years (range 21-100); 51% were females. In both studies, patients had advanced illness with a life expectancy of less than 6 months and received care to control their symptoms. The majority of patients had a primary diagnosis of incurable cancer; other primary diagnoses included end-stage COPD/emphysema, cardiovascular disease/heart failure, Alzheimer’s disease/dementia, HIV/AIDS, or other advanced illnesses. Prior to screening, patients had been receiving palliative opioid therapy (median daily baseline oral morphine equivalent dose = 172 mg), and had opioid-induced constipation (either 2 days). Patients were on a stable opioid regimen 3 days prior to randomization (not including PRN or rescue pain medication) and received their opioid medication during the study as clinically needed. Patients maintained their regular laxative regimen for at least 3 days prior to study entry, and throughout the study. Rescue laxatives were prohibited from 4 hours before to 4 hours after taking an injection of study medication. Study 1 compared a single, double-blind, subcutaneous dose of RELISTOR 0.15 mg/kg, or RELISTOR 0.3 mg/kg versus placebo. The double-blind dose was followed by an open-label 4-week dosing period, where RELISTOR could be used as needed, no more frequently than 1 dose in a 24 hour period. Throughout both study periods, patients maintained their regular laxative regimen. A total of 154 patients (47 RELISTOR 0.15 mg/kg, 55 RELISTOR 0.3 mg/kg, 52 placebo) were enrolled and treated in the double-blind period. The primary endpoint was the proportion of patients with a rescue-free laxation within 4 hours of the double-blind dose of study medication. RELISTOR-treated patients had a significantly higher rate of laxation within 4 hours of the double-blind dose (62% for 0.15 mg/kg and 58% for 0.3 mg/kg) than did placebo-treated patients (14%); p < 0.0001 for each dose versus placebo (Figure 1). Study 2 compared double-blind, subcutaneous doses of RELISTOR given every other day for 2 weeks versus placebo. Patients received opioid medication 2 weeks prior to receiving study medication. During the first week (days 1, 3, 5, 7) patients received either 0.15 mg/kg RELISTOR or placebo. In the second week the patient’s assigned dose could be increased to 0.30 mg/kg if the patient had 2 or fewer rescue-free laxations up to day 8. At any time, the patient’s assigned dose could be reduced based on tolerability. Data from 133 (62 RELISTOR, 71 placebo) patients were analyzed. There were 2 primary endpoints: proportion of patients with a rescue-free laxation within 4 hours of the first dose of study medication and proportion of patients with a rescue-free laxation within 4 hours after at least 2 of the first 4 doses of study medication. RELISTOR-treated patients had a higher rate of laxation within 4 hours of the first dose (48%) than placebo-treated patients (16%); p < 0.0001 (Figure 1). RELISTOR-treated patients also had significantly higher rates of laxation within 4 hours after at least 2 of the first 4 doses (52%) than did placebo-treated patients (9%); p < 0.0001. In both studies, in approximately 30% of patients, laxation was reported within 30 minutes of a dose of RELISTOR. Figure 1. Laxation Response Within 4 Hours of the First Dose 100% DRUG INTERACTIONS Drugs Metabolized by Cytochrome P450 Isozymes. In in vitro drug metabolism studies methylnaltrexone bromide did not significantly inhibit the activity of cytochrome P450 (CYP) isozymes CYP1A2, CYP2A6, CYP2C9, CYP2C19 or CYP3A4, while it is a weak inhibitor of CYP2D6. In a clinical drug interaction study in healthy adult male subjects, a subcutaneous dose of 0.30 mg/kg of methylnaltrexone bromide did not significantly affect the metabolism of dextromethorphan, a CYP2D6 substrate. Drugs Renally Excreted. The potential for drug interactions between methylnaltrexone bromide and drugs that are actively secreted by the kidney has not been investigated in humans. USE IN SPECIFIC POPULATIONS Pregnancy. Pregnancy Category B. Reproduction studies have been performed in pregnant rats at intravenous doses up to about 14 times the recommended maximum human subcutaneous dose of 0.3 mg/kg based on the body surface area and in pregnant rabbits at intravenous doses up to about 17 times the recommended maximum human subcutaneous dose based on the body surface area and have revealed no evidence of impaired fertility or harm to the fetus due to methylnaltrexone bromide. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, methylnaltrexone bromide should be used during pregnancy only if clearly needed. Labor and Delivery. Effects of RELISTOR on mother, fetus, duration of labor, and delivery are unknown. There were no effects on the mother, labor, delivery, or on offspring survival and growth in rats following subcutaneous injection of methylnaltrexone bromide at dosages up to 25 mg/kg/day. Nursing Mothers. Results from an animal study using [3H]-labeled methylnaltrexone bromide indicate that methylnaltrexone bromide is excreted via the milk of lactating rats. It is not known whether this drug http://www.wyeth.com http://www.wyeth.com

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Editorial Aliskiren Reduces Plasma Renin Activity Medication Errors Prescription: Washington New Drugs/Drug News/ New Medical Devices Drug Forecast Challenges in Evaluating and Standardizing Medical Devices in Health Care Facilities California e-Pedigree Rules Pose Challenges For Pharmacies Pharmaceutical Approval Update American Psychiatric Association At a Glance: Dermatology Trends in Managed Care

Pharmacy & Therapeutics - June 2008

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