Relistor Methylnaltrexone bromide 12 mg/.6mL Injection, Solution, 1 vial — NDC 65649-551-02 (Billing 65649-0551-02)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Methylnaltrexone is a selective antagonist of opioid binding at the mu-opioid receptor. As a quaternary amine, the ability of methylnaltrexone to cross the blood-brain barrier is restricted. This allows methylnaltrexone to function as a peripherally-acting mu-opioid receptor antagonist in tissues such as the gastrointestinal tract, thereby decreasing the constipating effects of opioids without impacting opioid-mediated analgesic effects on the central nervous system (CNS).

12.2Pharmacodynamics Cardiac Electrophysiology 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 intravenous infusion over 20 minutes (RELISTOR is not approved for intravenous use), placebo, and a single oral dose of moxifloxacin. At a dose approximately 4.3 times the maximum recommended dose (7.5 times the mean peak plasma concentration for RELISTOR injection and 22 times the peak plasma concentration for RELISTOR tablets), methylnaltrexone does not prolong the QTc interval to any clinically relevant extent.

12.3Pharmacokinetics Between the oral dosage range of 150 mg to 450 mg for RELISTOR tablets and the subcutaneous dosage range of 0.15 mg/kg to 0.50 mg/kg for RELISTOR injection, the mean C max and area under the plasma concentration-time curve (AUC) of methylnaltrexone increased in a dose-proportional manner. There was no significant accumulation of methylnaltrexone following once-daily oral dosing of 450 mg RELISTOR tablets or subcutaneous dosing of 12 mg RELISTOR injection for seven consecutive days in healthy subjects.

Absorption Tablets Following administration of a single 450 mg dose of RELISTOR tablets in OIC patients or healthy subjects, peak concentrations (C max ) of methylnaltrexone were observed at approximately 1.5 hours. The absolute bioavailability of oral methylnaltrexone bromide has not been determined. The C max and AUC in healthy subjects were 48.1 ng/mL and 382 ng·hr/mL, respectively, following a single 450 mg dose of RELISTOR tablets.

Exposure in the OIC patient population was approximately 27% lower than in healthy subjects. Food Effect Administration of a single 450 mg dose of RELISTOR tablets to healthy subjects with a high-fat breakfast (containing approximately 800 to 1000 total calories, with 60%, 25% and 15% of calories derived from fat, carbohydrate and protein, respectively) resulted in a decrease in the C max of methylnaltrexone by 60%, the AUC by 43% and delayed the T max by 2 hours [see Dosage and Administration ( 2.1 )] . Injection Following administration of RELISTOR injection subcutaneously, methylnaltrexone achieved peak concentrations (C max ) at approximately 0.5 hours (see Table 7 ).

Table 7: Pharmacokinetic Parameters of Methylnaltrexone Following Subcutaneous Doses Parameter 0.15 mg/kg Single Dose 12 mg Single Dose 12 mg at Steady-State C max (ng/mL) i 117 (32.7) 140 (35.6) 119 (27.2) T max (hr) ii 0.5 (0.25 to 0.75) 0.25 (0.25 to 0.5) 0.25 (0.25 to 0.5) AUC 24 (ng·hr/mL) i 175 (36.6) 218 (28.3) 223 (28.2) ⁱ Expressed as mean (SD). ⁱⁱ Expressed as median (range). Distribution The steady-state volume of distribution (Vss) of methylnaltrexone is approximately

1.1L/kg. The fraction of methylnaltrexone bound to human plasma proteins is 11% to 15%, as determined by equilibrium dialysis. Elimination Following oral administration of a single 450 mg dose of RELISTOR tablets, concentrations of methylnaltrexone declined in multiphasic manner with a terminal half-life (t 1/2 ) of approximately 15 hours.

Metabolism In an intravenous mass balance study, approximately 44% of the administered radioactivity was recovered in the urine over 24 hours with 5 distinct metabolites. None of the detected metabolites was in amounts over 6% of administered radioactivity. Conversion to methyl-6-naltrexol isomers (5% of… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Methylnaltrexone is a selective antagonist of opioid binding at the mu-opioid receptor. As a quaternary amine, the ability of methylnaltrexone to cross the blood-brain barrier is restricted. This allows methylnaltrexone to function as a peripherally-acting mu-opioid receptor antagonist in tissues such as the gastrointestinal tract, thereby decreasing the constipating effects of opioids without impacting opioid-mediated analgesic effects on the central nervous system (CNS).

12.3Pharmacokinetics Between the oral dosage range of 150 mg to 450 mg for RELISTOR tablets and the subcutaneous dosage range of 0.15 mg/kg to 0.50 mg/kg for RELISTOR injection, the mean C max and area under the plasma concentration-time curve (AUC) of methylnaltrexone increased in a dose-proportional manner. There was no significant accumulation of methylnaltrexone following once-daily oral dosing of 450 mg RELISTOR tablets or subcutaneous dosing of 12 mg RELISTOR injection for seven consecutive days in healthy subjects.

Absorption Tablets Following administration of a single 450 mg dose of RELISTOR tablets in OIC patients or healthy subjects, peak concentrations (C max ) of methylnaltrexone were observed at approximately 1.5 hours. The absolute bioavailability of oral methylnaltrexone bromide has not been determined. The C max and AUC in healthy subjects were 48.1 ng/mL and 382 ng·hr/mL, respectively, following a single 450 mg dose of RELISTOR tablets.

Exposure in the OIC patient population was approximately 27% lower than in healthy subjects. Food Effect Administration of a single 450 mg dose of RELISTOR tablets to healthy subjects with a high-fat breakfast (containing approximately 800 to 1000 total calories, with 60%, 25% and 15% of calories derived from fat, carbohydrate and protein, respectively) resulted in a decrease in the C max of methylnaltrexone by 60%, the AUC by 43% and delayed the T max by 2 hours [see Dosage and Administration ( 2.1 )] . Injection Following administration of RELISTOR injection subcutaneously, methylnaltrexone achieved peak concentrations (C max ) at approximately 0.5 hours (see Table 7 ).

Table 7: Pharmacokinetic Parameters of Methylnaltrexone Following Subcutaneous Doses Parameter 0.15 mg/kg Single Dose 12 mg Single Dose 12 mg at Steady-State C max (ng/mL) i 117 (32.7) 140 (35.6) 119 (27.2) T max (hr) ii 0.5 (0.25 to 0.75) 0.25 (0.25 to 0.5) 0.25 (0.25 to 0.5) AUC 24 (ng·hr/mL) i 175 (36.6) 218 (28.3) 223 (28.2) ⁱ Expressed as mean (SD). ⁱⁱ Expressed as median (range). Distribution The steady-state volume of distribution (Vss) of methylnaltrexone is approximately

1.1L/kg. The fraction of methylnaltrexone bound to human plasma proteins is 11% to 15%, as determined by equilibrium dialysis. Elimination Following oral administration of a single 450 mg dose of RELISTOR tablets, concentrations of methylnaltrexone declined in multiphasic manner with a terminal half-life (t 1/2 ) of approximately 15 hours.

Metabolism In an intravenous mass balance study, approximately 44% of the administered radioactivity was recovered in the urine over 24 hours with 5 distinct metabolites. 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% of total) appear to be the primary pathways of metabolism.

N-demethylation of methylnaltrexone to produce naltrexone is not significant. Systemic exposure of methylnaltrexone metabolites after oral administration of a single 450 mg dose of RELISTOR tablets are greater than the systemic exposure of methylnaltrexone metabolites after subcutaneous administration of a single 12 mg dose of RELISTOR injection. Subcutaneous administration is not subject to first-pass hepatic metabolism prior to appearance in the systemic circulation.

After 12 mg subcutaneous once daily dosing the mean AUC 0-24 ratio of metabolites to methylnaltrexone at steady-state was 30%, 19%, and 9% for methylnaltrexone sulfate, methyl-6α-naltrexol, and methyl-6β-naltrexol, respectively. After 450 mg oral once daily dosing, the ratio of the mean AUC 0-24 of metabolites to methylnaltrexone at steady-state was 79%, 38%, and 21% for methylnaltrexone sulfate, methyl-6α-naltrexol, and methyl-6β-naltrexol, respectively. Methylnaltrexone sulfate is a weak mu-opioid receptor antagonist; methyl-6α-naltrexol, and methyl-6β-naltrexol are active mu-opioid receptor antagonists.

Methylnaltrexone is conjugat… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Cardiac Electrophysiology 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 intravenous infusion over 20 minutes (RELISTOR is not approved for intravenous use), placebo, and a single oral dose of moxifloxacin. At a dose approximately 4.3 times the maximum recommended dose (7.5 times the mean peak plasma concentration for RELISTOR injection and 22 times the peak plasma concentration for RELISTOR tablets), methylnaltrexone does not prolong the QTc interval to any clinically relevant extent.

14 CLINICAL STUDIES

14.1Opioid-Induced Constipation in Adult Patients with Chronic Non-Cancer Pain RELISTOR Tablets The efficacy of RELISTOR tablets in the treatment of OIC in patients with chronic non-cancer pain was evaluated in a randomized, double-blind, placebo-controlled study (Study 1). This study compared 4-week treatment of RELISTOR tablets 450 mg orally once daily with placebo. A total of 401 patients (200 RELISTOR, 201 placebo) were enrolled and treated in the double-blind period.

Patients had a history of chronic non-cancer pain for which they were taking opioids. The most common pain condition requiring opioid use was back pain. Other frequently reported primary pain conditions were arthritis, neurologic/neuropathic pain, joint/extremity pain, and fibromyalgia.

Prior to screening, patients were receiving opioid therapy for pain for 1 month or longer (median daily baseline oral morphine equivalent dose of 156 mg) and had OIC (less than 3 spontaneous bowel movements per week during the screening period). Constipation due to opioid use had to be associated with 1 or more of the following: A Bristol Stool Form Scale score of 1 or 2 for at least 25% of the bowel movements (BM), straining during at least 25% of the BMs or a sensation of incomplete evacuation after at least 25% of the BMs.

Patients were required to be on a stable opioid regimen (daily dose 50 mg or more of oral morphine equivalents per day) a minimum of 2 weeks prior to the screening visit and received their opioid medication during the study as clinically needed. The median duration of OIC at baseline was 53 months (4 years). The mean patient age was 52 years (range 23 to 78 years), 64% were female, and 84% of patients were Caucasian.

Eligible patients were required to discontinue all previous laxative therapy and use only the study-permitted rescue laxative (bisacodyl tablets). If patients did not have a bowel movement for 3 consecutive days during the study, they were permitted to use rescue medication (up to 3 bisacodyl tablets taken orally once during a 24-hour period). Bisacodyl tablets were taken 5 hours or longer and up to 8 hours after study drug administration.

If rescue treatment with bisacodyl tablets did not result in a bowel movement, a second dose of bisacodyl or an enema 24 hours after rescue was permitted. Enema use was permitted after rescue with bisacodyl tablets had failed at least once. A responder analysis was performed which defined the proportion of patients with 3 or more spontaneous bowel movements (SBMs)/week, with an increase of 1 or more SBM/week over baseline, for 3 or more out of the first 4 weeks of the treatment period.

A SBM was defined as a bowel movement that occurred without laxative use during the previous 24 hours. Table 8 presents the proportion of patients who responded during the double-blind treatment period in the intent-to-treat (ITT) population, which included all randomized patients who received at least one dose of double-blind study medication. Table 8: Proportion of Responders* in the ITT Population in Study 1 of RELISTOR Tablets for the Treatment of OIC in Patients with Chronic Non-Cancer Pain Treatment N n (%) Percent Difference a (2-sided 95% CI) RELISTOR Tablets 450 mg Once Daily 200 103 (52%) 13% (3%, 23%) Placebo 201 77 (38%) CI = confidence interval; ITT = intent-to-treat; a Difference for active treatment vs. placebo; * A responder is defined as a patient with 3 or more SBMs/week, with an increase of 1 or more SBM/week over baseline, for 3 or more out of the first 4 weeks of the treatment period.

RELISTOR Injection The efficacy of RELISTOR injection in the treatment of OIC in patients with chronic non-cancer pain were evaluated in a randomized, double-blind, placebo-controlled study (Study 2). This study compared 4-week treatment of RELISTOR injection 12 mg administered subcutaneously once daily with placebo. A total of 312 patients (150 RELISTOR, 162 placebo) were enrolled and treated in the dou… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Two-year oral carcinogenicity studies have been conducted with methylnaltrexone bromide in CD-1 mice at doses up to 200 mg/kg/day (about 81 times the subcutaneous maximum recommended human dose (MRHD) of 12 mg/day based on body surface area) in males and 400 mg/kg/day (about 162 times the subcutaneous MRHD of 12 mg/day) in females and in Sprague Dawley rats at oral doses up to 300 mg/kg/day (about 243 times the subcutaneous MRHD of 12 mg/day). The 200 mg/kg/day and 400 mg/kg/day doses in male and female mice are about 2.2 and 4.4 times, respectively, the oral MRHD of 450 mg/day, and the 300 mg/kg/day dose in rats is about 6.5 times the oral MRHD of 450 mg/day, based on body surface area.

Oral administration of methylnaltrexone bromide for 104 weeks did not produce tumors in mice and rats. Mutagenesis Methylnaltrexone bromide was negative in the Ames test, chromosome aberration tests in Chinese hamster ovary cells and human lymphocytes, in the mouse lymphoma cell forward mutation tests and in the in vivo mouse micronucleus test. Impairment of Fertility Methylnaltrexone bromide at subcutaneous doses up to 150 mg/kg/day (about 122 times the subcutaneous MRHD of 12 mg/day; about 3.3 times the oral MRHD of 450 mg/day) was found to have no adverse effect on fertility and reproductive performance of male and female rats.

13.2Animal Toxicology and/or Pharmacology In an in vitro human cardiac potassium ion channel (hERG) assay, methylnaltrexone caused concentration-dependent inhibition of hERG current (1%, 12%, 13% and 40% inhibition at 30, 100, 300 and 1000 micromolar concentrations, respectively). Methylnaltrexone had a hERG IC 50 of more than 1000 micromolar. In isolated dog Purkinje fibers, methylnaltrexone caused prolongations in action potential duration (APD).

The highest tested concentration (10 micromolar) in the dog Purkinje fiber study was about 18 and 37 times the C max at human subcutaneous doses of 0.3 and 0.15 mg/kg, respectively. In isolated rabbit Purkinje fibers, methylnaltrexone (up to 100 micromolar) did not have an effect on APD, compared to vehicle control. The highest methylnaltrexone concentration (100 micromolar) tested was about 186 and 373 times the human C max at subcutaneous doses of 0.3 and 0.15 mg/kg, respectively.

In anesthetized dogs, methylnaltrexone bromide caused decreases in blood pressure, heart rate, cardiac output, left ventricular pressure, left ventricular end diastolic pressure, and +dP/dt at 1 mg/kg or more. In conscious dogs, methylnaltrexone bromide caused a dose-related increase in QTc interval. After a single intravenous dosage of 20 mg/kg to beagle dogs, predicted C max and AUC values were approximately 482 and 144 times, respectively, the exposure at human subcutaneous dose of 0.15 mg/kg and 241 times and 66 times, respectively, the exposure at a human subcutaneous dose of 0.3 mg/kg.

In conscious guinea pigs, methylnaltrexone bromide caused mild prolongation of QTc (4% over baseline) at 20 mg/kg, intravenous. A thorough QTc assessment was conducted in humans [see Clinical Pharmacology ( 12.2 )] . In juvenile rats administered intravenous methylnaltrexone bromide for 13 weeks, adverse clinical signs such as convulsions, tremors and labored breathing occurred at dosages of 3 and 10 mg/kg/day (about 2.4 and 8 times, respectively, the subcutaneous MRHD of 12 mg/day; about 0.06 and 0.22 times, respectively, the oral MRHD of 450 mg/day).

Similar adverse clinical signs were seen in adult rats at 20 mg/kg/day (about 16 times the subcutaneous MRHD of 12 mg/day; about 0.43 times the oral MRHD of 450 mg/day). Juvenile rats were found to be more sensitive to the toxicity of methylnaltrexone bromide when compared to adults. The no observed adverse effect levels (NOAELs) in juvenile and adult rats were 1 and 5 mg/kg/day, respectively (about 0.8 and 4 times, respectively, the subcutaneous MRHD of 12 mg/… [Excerpted — this section continues on DailyMed.]