Contrave Extended-Release naltrexone hydrochloride and bupropion 8 mg; 90 mg Tablet, Extended Release, 120-count — NDC 51267-890-99 (Billing 51267-0890-99) · Product 51267-890

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action CONTRAVE has two components: naltrexone, an opioid antagonist, and bupropion, a relatively weak inhibitor of the neuronal reuptake of dopamine and norepinephrine. Nonclinical studies suggest that naltrexone and bupropion have effects on two separate areas of the brain involved in the regulation of food intake: the hypothalamus (appetite regulatory center) and the mesolimbic dopamine circuit (reward system). The exact neurochemical effects of CONTRAVE leading to weight loss are not fully understood.

12.2Pharmacodynamics Combined, bupropion and naltrexone increased the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons in vitro, which are associated with regulation of appetite. The combination of bupropion and naltrexone also reduced food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, an area associated with regulation of reward pathways. Cardiac Electrophysiology At the recommended dose, CONTRAVE does not prolong the QTc interval to any clinically relevant extent.

12.3Pharmacokinetics Absorption Naltrexone Following single oral administration of CONTRAVE (two 8 mg naltrexone/90 mg bupropion tablets) to healthy subjects, mean peak naltrexone concentration (C max ) was 1.4 ng/mL, time to peak concentration (T max ) was 2 hours, and extent of exposure (AUC 0-inf ) was 8.4 ng∙hr/mL. Bupropion Following single oral administration of CONTRAVE (two 8 mg naltrexone/90 mg bupropion tablets) to healthy subjects, mean peak bupropion concentration (C max ) was 168 ng/mL, time to peak concentration (T max ) was three hours, and extent of exposure (AUC 0-inf ) was 1,607 ng∙hr/mL.

Food Effect on Absorption When CONTRAVE was administered with a high-fat meal, the AUC and C max for naltrexone increased 2.1-fold and 3.7-fold, respectively, and the AUC and C max for bupropion increased 1.4-fold and 1.8-fold, respectively. At steady state, the food effect increased AUC and C max for naltrexone by 1.7-fold and 1.9-fold, respectively, and increased AUC and C max for bupropion by 1.1-fold and 1.3-fold, respectively. Thus, CONTRAVE should not be taken with high-fat meals because of the resulting significant increases in bupropion and naltrexone systemic exposure.

Distribution Naltrexone Naltrexone is 21% plasma protein bound. The mean apparent volume of distribution at steady state for naltrexone (V ss /F) is 5,697 liters. Bupropion Bupropion is 84% plasma protein bound.

The mean apparent volume of distribution at steady state for bupropion (V ss /F) is 880 liters. Metabolism and Excretion Naltrexone The major metabolite of naltrexone is 6-beta-naltrexol. The activity of naltrexone is believed to be the result of both the parent and the 6-beta-naltrexol metabolite.

Though less potent, 6-beta-naltrexol is eliminated more slowly and thus circulates at much higher concentrations than naltrexone. Naltrexone and 6-beta-naltrexol are not metabolized by cytochrome P450 enzymes and in vitro studies indicate that there is no potential for inhibition or induction of important isozymes. Naltrexone and its metabolites are excreted primarily by the kidney (53% to 79% of the dose).

Urinary excretion of unchanged naltrexone accounts for less than 2% of an oral dose. Urinary excretion of unchanged and conjugated 6-beta-naltrexol accounts for 43% of an oral dose. The renal clearance for naltrexone ranges from 30 to 127 mL/min, suggesting that renal elimination is primarily by glomerular filtration.

The renal clearance for 6-beta-naltrexol ranges from 230 to 369 mL/min suggesting an additional renal tubular secretory mechanism. Fecal excretion is a minor elimination pathway. Following single oral administration of CONTRAVE tablets to healthy subjects, mean elimination half-life (T 1/2 ) was approximately 5 hours for naltrexone.

Following twice daily administration of CONTRAVE, naltrexone did not accumulate and its kinetics appeared linear. However, in comp… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action CONTRAVE has two components: naltrexone, an opioid antagonist, and bupropion, a relatively weak inhibitor of the neuronal reuptake of dopamine and norepinephrine. Nonclinical studies suggest that naltrexone and bupropion have effects on two separate areas of the brain involved in the regulation of food intake: the hypothalamus (appetite regulatory center) and the mesolimbic dopamine circuit (reward system). The exact neurochemical effects of CONTRAVE leading to weight loss are not fully understood.

12.3Pharmacokinetics Absorption Naltrexone Following single oral administration of CONTRAVE (two 8 mg naltrexone/90 mg bupropion tablets) to healthy subjects, mean peak naltrexone concentration (C max ) was 1.4 ng/mL, time to peak concentration (T max ) was 2 hours, and extent of exposure (AUC 0-inf ) was 8.4 ng∙hr/mL. Bupropion Following single oral administration of CONTRAVE (two 8 mg naltrexone/90 mg bupropion tablets) to healthy subjects, mean peak bupropion concentration (C max ) was 168 ng/mL, time to peak concentration (T max ) was three hours, and extent of exposure (AUC 0-inf ) was 1,607 ng∙hr/mL.

Food Effect on Absorption When CONTRAVE was administered with a high-fat meal, the AUC and C max for naltrexone increased 2.1-fold and 3.7-fold, respectively, and the AUC and C max for bupropion increased 1.4-fold and 1.8-fold, respectively. At steady state, the food effect increased AUC and C max for naltrexone by 1.7-fold and 1.9-fold, respectively, and increased AUC and C max for bupropion by 1.1-fold and 1.3-fold, respectively. Thus, CONTRAVE should not be taken with high-fat meals because of the resulting significant increases in bupropion and naltrexone systemic exposure.

Distribution Naltrexone Naltrexone is 21% plasma protein bound. The mean apparent volume of distribution at steady state for naltrexone (V ss /F) is 5,697 liters. Bupropion Bupropion is 84% plasma protein bound.

The mean apparent volume of distribution at steady state for bupropion (V ss /F) is 880 liters. Metabolism and Excretion Naltrexone The major metabolite of naltrexone is 6-beta-naltrexol. The activity of naltrexone is believed to be the result of both the parent and the 6-beta-naltrexol metabolite.

Though less potent, 6-beta-naltrexol is eliminated more slowly and thus circulates at much higher concentrations than naltrexone. Naltrexone and 6-beta-naltrexol are not metabolized by cytochrome P450 enzymes and in vitro studies indicate that there is no potential for inhibition or induction of important isozymes. Naltrexone and its metabolites are excreted primarily by the kidney (53% to 79% of the dose).

Urinary excretion of unchanged naltrexone accounts for less than 2% of an oral dose. Urinary excretion of unchanged and conjugated 6-beta-naltrexol accounts for 43% of an oral dose. The renal clearance for naltrexone ranges from 30 to 127 mL/min, suggesting that renal elimination is primarily by glomerular filtration.

The renal clearance for 6-beta-naltrexol ranges from 230 to 369 mL/min suggesting an additional renal tubular secretory mechanism. Fecal excretion is a minor elimination pathway. Following single oral administration of CONTRAVE tablets to healthy subjects, mean elimination half-life (T 1/2 ) was approximately 5 hours for naltrexone.

Following twice daily administration of CONTRAVE, naltrexone did not accumulate and its kinetics appeared linear. However, in comparison to naltrexone, 6-beta-naltrexol accumulates to a larger extent (accumulation ratio ~3). Bupropion Bupropion is extensively metabolized with three active metabolites: hydroxybupropion, threohydrobupropion and erythrohydrobupropion.

The metabolites have longer elimination half-lives than bupropion and accumulate to a greater extent. Following bupropion administration, more than 90% of the exposure is a result of metabolites. In vitro findings suggest that CYP2B6 is the principal isozyme involved in the formation of hydroxybupropion whereas cytochrome P450 isozymes are not involved in the formation of the other active metabolites.

Bupropion and its metabolites inhibit CYP2D6. Plasma protein binding of hydroxybupropion is similar to that of bupropion (84%) whereas the other two metabolites have approximately half the binding. Following oral administration of 200 mg of 14 C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively.

The fraction of the oral dose of bupropion excreted unchanged was 0.5%, a finding consistent… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Combined, bupropion and naltrexone increased the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons in vitro, which are associated with regulation of appetite. The combination of bupropion and naltrexone also reduced food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, an area associated with regulation of reward pathways. Cardiac Electrophysiology At the recommended dose, CONTRAVE does not prolong the QTc interval to any clinically relevant extent.

14 CLINICAL STUDIES The effects of CONTRAVE on weight reduction and long-term maintenance in conjunction with reduced caloric intake and increased physical activity was studied in double-blind, placebo-controlled trials (BMI range 27 to 45 kg/m 2 ) with study durations of 16 to 56 weeks randomized to naltrexone and/or bupropion or placebo. Effect on Weight Reduction and Long-Term Maintenance Four 56-week multicenter, double-blind, placebo-controlled obesity trials (CONTRAVE Obesity Research, or COR-I, COR-II, COR-BMOD, and COR-Diabetes) were conducted to evaluate the effect of CONTRAVE on weight reduction in conjunction with lifestyle modification in 4,536 patients randomized to CONTRAVE or placebo.

The COR-I, COR-II, and COR-BMOD trials enrolled patients with obesity (BMI 30 kg/m 2 or greater) or overweight (BMI 27 kg/m 2 or greater) and at least one comorbidity (hypertension or dyslipidemia). The COR-Diabetes trial enrolled patients with BMI greater than 27 kg/m 2 with type 2 diabetes with or without hypertension and/or dyslipidemia. Treatment was initiated with a three-week dose-escalation period followed by approximately 1 year of continued therapy.

Patients were instructed to take CONTRAVE with food. COR-I and COR-II included a program consisting of a reduced-calorie diet resulting in an approximate 500 kcal/day decrease in caloric intake, behavioral counseling, and increased physical activity. COR-BMOD included an intensive behavioral modification program consisting of 28 group counseling sessions over 56 weeks as well as a prescribed diet and exercise regimen.

COR-Diabetes evaluated patients with type 2 diabetes not achieving glycemic goal of a HbA1c less than 7% either with oral antidiabetic agents or with diet and exercise alone. Of the overall population from these four trials, 24% had hypertension, 54% had dyslipidemia at study entry, and 10% had type 2 diabetes. Apart from COR-Diabetes, which only enrolled patients with type 2 diabetes, the demographic characteristics of patients were similar across all four trials.

For the four trial populations combined, the mean age was 46 years, 83% were female, 77% were Caucasian, 18% were black, and 5% were other races. At baseline, mean BMI was 36 kg/m 2 and mean waist circumference was 110 cm. A substantial percentage of randomized patients withdrew from the trials prior to Week 56: 45% for the placebo group and 46% for the CONTRAVE group.

The majority of these patients discontinued within the first 12 weeks of treatment. Approximately 24% of patients treated with CONTRAVE and 12% of patients treated with placebo discontinued treatment because of an adverse reaction [see Adverse Reactions (6.1) ] . The co-primary endpoints were percent change from baseline body weight and the proportion of patients achieving at least a 5% reduction in body weight.

In the 56-week COR-I trial, the mean change in body weight was -5.4% among patients assigned to CONTRAVE 32 mg/360 mg compared with -1.3% among patients assigned to placebo (Intent-To-Treat [ITT] population), as shown in Table 6 and Figure 1. In this trial, the achievement of at least a 5% reduction in body weight from baseline occurred more frequently for patients treated with CONTRAVE 32 mg/360 mg compared with placebo (42% vs 17%; Table 6 ). Results from COR-BMOD and COR-Diabetes are shown in Table 6 and Figures 2 and 3.

Table 6. Changes in Weight in 56-Week Trials with CONTRAVE (ITT/LOCF Based on last observation carried forward (LOCF) in all randomized subjects who had a baseline body weight measurement and at least one post baseline body weight measurement during the defined treatment phase. All available body weight data during the double-blind treatment phase are included in the analysis, including data collected from subjects who discontinued study drug. ) COR-I COR-BMOD COR-Diabetes CONTRAVE 32 mg/360 mg Placebo CONTRAVE 32 mg/360 mg Placebo CONTRAVE 32 mg/360 mg Placebo N 538 536 565 196 321 166 Type 1 error was control… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Studies to evaluate carcinogenesis, mutagenesis, or impairment of fertility with the combined products in CONTRAVE have not been conducted. The following findings are from studies performed individually with naltrexone and bupropion. The potential carcinogenic, mutagenic and fertility effects of the metabolite 6-beta-naltrexol are unknown.

Safety margins were estimated using body surface area exposure (mg/m 2 ) based on a body weight of 100 kg. In a two-year carcinogenicity study in rats with naltrexone, there were small increases in the numbers of testicular mesotheliomas in males and tumors of vascular origin in males and females. The incidence of mesothelioma in males given naltrexone at a dietary dose of 100 mg/kg/day (approximately 50 times the recommended therapeutic dose on a mg/m 2 basis for the naltrexone maintenance dose for CONTRAVE) was 6%, compared with a maximum historical incidence of 4%.

The incidence of vascular tumors in males and females given dietary doses of 100 mg/kg/day was 4%, but only the incidence in females was increased compared with a maximum historical control incidence of 2%. There was no evidence of carcinogenicity in a two-year dietary study with naltrexone in male and female mice. Lifetime carcinogenicity studies of bupropion were performed in rats and mice at doses up to 300 and 150 mg/kg/day, respectively.

These doses are approximately 14 and 3 times the maximum recommended human dose (MRHD) of the bupropion component in CONTRAVE, respectively, on a mg/m 2 basis. In the rat study there was an increase in nodular proliferative lesions of the liver at doses of 100 to 300 mg/kg/day (approximately 5 to 14 times the MRHD of the bupropion component in CONTRAVE on a mg/m 2 basis); lower doses were not tested. The question of whether or not such lesions may be precursors of neoplasms of the liver is currently unresolved.

Similar liver lesions were not seen in the mouse study, and no increase in malignant tumors of the liver and other organs was seen in either study. There was limited evidence of a weak genotoxic effect of naltrexone in one gene mutation assay in a mammalian cell line, in the Drosophila recessive lethal assay, and in non-specific DNA repair tests with E. coli . However, no evidence of genotoxic potential was observed in a range of other in vitro tests, including assays for gene mutation in bacteria, yeast, or in a second mammalian cell line, a chromosomal aberration assay, and an assay for DNA damage in human cells.

Naltrexone did not exhibit clastogenicity in an in vivo mouse micronucleus assay. Bupropion produced a positive response (two to three times control mutation rate) in two of five strains in the Ames bacterial mutagenicity test and an increase in chromosomal aberrations in one of three in vivo rat bone marrow cytogenetic studies. Naltrexone administered orally to rats caused a significant increase in pseudopregnancy and a decrease in pregnancy rates in rats at 100 mg/kg/day (approximately 50 times the MRHD of the naltrexone component in CONTRAVE on a mg/m 2 basis).

There was no effect on male fertility at this dose level. The relevance of these observations to human fertility is not known. A fertility study of bupropion in rats at doses up to 300 mg/kg/day (approximately 14 times the MRHD of the bupropion component in CONTRAVE on a mg/m 2 basis) revealed no evidence of impaired fertility.