Orlistat 120 mg Capsule, 90-count — NDC 61269-565-90 (Billing 61269-0565-90)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Orlistat is a reversible inhibitor of gastrointestinal lipases. It exerts its therapeutic activity in the lumen of the stomach and small intestine by forming a covalent bond with the active serine residue site of gastric and pancreatic lipases. The inactivated enzymes are thus unavailable to hydrolyze dietary fat in the form of triglycerides into absorbable free fatty acids and monoglycerides.

As undigested triglycerides are not absorbed, the resulting caloric deficit may have a positive effect on weight control.

12.2Pharmacodynamics Dose-response Relationship The dose-response relationship for orlistat in human volunteers is shown in Figure 1 . The effect is the percentage of ingested fat excreted, referred to as fecal fat excretion percentage. Both individual data (open circles) and the curve predicted for the population with the maximum-effect model (continuous line) are shown in Figure 1 .

Figure 1 Dose-Response Relationship for Orlistat in Human Volunteers At the recommended therapeutic dose of 120 mg three times a day, orlistat inhibits dietary fat absorption by approximately 30%. Ethanol does not affect orlistat's effect on preventing the absorption of fat. Figure 1 Other Short-term Studies Adults In several studies of up to 6-weeks duration, the effects of therapeutic doses of ORLISTAT on gastrointestinal and systemic physiological processes were assessed in normal weight and obese subjects.

Postprandial cholecystokinin plasma concentrations were lowered after multiple doses of ORLISTAT in two studies but not significantly different from placebo in two other experiments. There were no clinically significant changes observed in gallbladder motility, bile composition or lithogenicity, or colonic cell proliferation rate, and no clinically significant reduction of gastric emptying time or gastric acidity. In addition, no effects on plasma triglyceride levels or systemic lipases were observed with the administration of ORLISTAT in these studies.

In a 3-week study of 28 healthy male volunteers, ORLISTAT (120 mg three times a day) did not significantly affect the balance of calcium, magnesium, phosphorus, zinc, copper, and iron. Pediatrics In a 3-week study of 32 obese adolescents aged 12 to 16 years, ORLISTAT (120 mg three times a day) did not significantly affect the balance of calcium, magnesium, phosphorus, zinc, or copper. The iron balance was decreased by 64.7 µmole/24 hours and 40.4 µmole/24 hours in ORLISTAT and placebo treatment groups, respectively.

12.3Pharmacokinetics Absorption Systemic exposure to orlistat is minimal. Following oral dosing with 360 mg 14 C-orlistat, plasma radioactivity peaked at approximately 8 hours; plasma concentrations of intact orlistat were near the limits of detection (<5 ng/mL). In therapeutic studies involving monitoring of plasma samples, detection of intact orlistat in plasma was sporadic and concentrations were low (<10 ng/mL or 0.02 µM), without evidence of accumulation, and consistent with minimal absorption.

Distribution In vitro orlistat was >99% bound to plasma proteins (lipoproteins and albumin were major binding proteins). Orlistat minimally partitioned into erythrocytes. Metabolism Based on an oral 14 C-orlistat mass balance study in obese patients, two metabolites, M1 ((the hydrolyzed β-lactone ring product of orlistat) and M3 (sequential metabolite after M1's cleavage of the N-formyl leucine side-chain), accounted for approximately 42% of total radioactivity in plasma.

M1 and M3 have an open β-lactone ring and extremely weak lipase inhibitory activity (1000- and 2500-fold less than orlistat, respectively). In view of this low inhibitory activity and the low plasma levels at the therapeutic dose (average of 26 ng/mL and 108 ng/mL for M1 and M3, respectively, 2 to 4 hours after a dose), these metabolites are considered pharmacologically inconsequential. The primary metabolite M1 had a short half-life (approximately 3 hours)… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Orlistat is a reversible inhibitor of gastrointestinal lipases. It exerts its therapeutic activity in the lumen of the stomach and small intestine by forming a covalent bond with the active serine residue site of gastric and pancreatic lipases. The inactivated enzymes are thus unavailable to hydrolyze dietary fat in the form of triglycerides into absorbable free fatty acids and monoglycerides.

As undigested triglycerides are not absorbed, the resulting caloric deficit may have a positive effect on weight control.

12.3Pharmacokinetics Absorption Systemic exposure to orlistat is minimal. Following oral dosing with 360 mg 14 C-orlistat, plasma radioactivity peaked at approximately 8 hours; plasma concentrations of intact orlistat were near the limits of detection (<5 ng/mL). In therapeutic studies involving monitoring of plasma samples, detection of intact orlistat in plasma was sporadic and concentrations were low (<10 ng/mL or 0.02 µM), without evidence of accumulation, and consistent with minimal absorption.

Distribution In vitro orlistat was >99% bound to plasma proteins (lipoproteins and albumin were major binding proteins). Orlistat minimally partitioned into erythrocytes. Metabolism Based on an oral 14 C-orlistat mass balance study in obese patients, two metabolites, M1 ((the hydrolyzed β-lactone ring product of orlistat) and M3 (sequential metabolite after M1's cleavage of the N-formyl leucine side-chain), accounted for approximately 42% of total radioactivity in plasma.

M1 and M3 have an open β-lactone ring and extremely weak lipase inhibitory activity (1000- and 2500-fold less than orlistat, respectively). In view of this low inhibitory activity and the low plasma levels at the therapeutic dose (average of 26 ng/mL and 108 ng/mL for M1 and M3, respectively, 2 to 4 hours after a dose), these metabolites are considered pharmacologically inconsequential. The primary metabolite M1 had a short half-life (approximately 3 hours) whereas the secondary metabolite M3 eliminated at a slower rate (half-life approximately 13.5 hours).

Elimination Following a single oral dose of 360 mg 14 C-orlistat in both normal weight and obese subjects, fecal excretion of the unabsorbed drug was found to be the major route of elimination. Orlistat and its M1 and M3 metabolites were also subject to biliary excretion. Approximately 97% of the administered radioactivity was excreted in feces; 83% of that was found to be unchanged orlistat.

The cumulative renal excretion of total radioactivity was <2% of the given dose of 360 mg 14 C-orlistat. The time to reach complete excretion (fecal plus urinary) was 3 to 5 days. The disposition of orlistat appeared to be similar between normal weight and obese subjects.

Based on limited data, the half-life of the absorbed orlistat is in the range of 1 to 2 hours. Specific Populations No pharmacokinetic study was conducted for specific populations such as geriatric, different races, and patients with renal and hepatic impairment. Drug Interactions Alcohol In a multiple-dose study in 30 normal-weight subjects, coadministration of ORLISTAT and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat.

Amiodarone In a pharmacokinetic study conducted in healthy volunteers who received 120 mg orlistat three times daily for 13 days and a single dose of 120 mg orlistat on the morning of Day 14 co-administered with a single dose of 1200 mg amiodarone on Day 4, a 23 – 27% reduction in the systemic exposure to amiodarone and desethylamiodarone was observed [see Drug Interactions (7.5) ] . The effect of commencing orlistat treatment in patients on stable amiodarone therapy has not been studied. Cyclosporine In a multiple-dose study, coadministration of 50 mg cyclosporine twice daily with 120 mg ORLISTAT three times daily decreased cyclosporine AUC and C max by 31% and 25%, respectively.

In the same study, administration of 50 mg cyclosporine twice daily three hours after the administration of 120 mg ORLISTAT three times daily decreased cyclosporine AUC and C max by 17% and 4%, respectively. Digoxin In 12 normal-weight subjects receiving ORLISTAT 120 mg three times a day for 6 days, ORLISTAT did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorpti… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Dose-response Relationship The dose-response relationship for orlistat in human volunteers is shown in Figure 1 . The effect is the percentage of ingested fat excreted, referred to as fecal fat excretion percentage. Both individual data (open circles) and the curve predicted for the population with the maximum-effect model (continuous line) are shown in Figure 1 .

Figure 1 Dose-Response Relationship for Orlistat in Human Volunteers At the recommended therapeutic dose of 120 mg three times a day, orlistat inhibits dietary fat absorption by approximately 30%. Ethanol does not affect orlistat's effect on preventing the absorption of fat. Figure 1 Other Short-term Studies Adults In several studies of up to 6-weeks duration, the effects of therapeutic doses of ORLISTAT on gastrointestinal and systemic physiological processes were assessed in normal weight and obese subjects.

Postprandial cholecystokinin plasma concentrations were lowered after multiple doses of ORLISTAT in two studies but not significantly different from placebo in two other experiments. There were no clinically significant changes observed in gallbladder motility, bile composition or lithogenicity, or colonic cell proliferation rate, and no clinically significant reduction of gastric emptying time or gastric acidity. In addition, no effects on plasma triglyceride levels or systemic lipases were observed with the administration of ORLISTAT in these studies.

In a 3-week study of 28 healthy male volunteers, ORLISTAT (120 mg three times a day) did not significantly affect the balance of calcium, magnesium, phosphorus, zinc, copper, and iron. Pediatrics In a 3-week study of 32 obese adolescents aged 12 to 16 years, ORLISTAT (120 mg three times a day) did not significantly affect the balance of calcium, magnesium, phosphorus, zinc, or copper. The iron balance was decreased by 64.7 µmole/24 hours and 40.4 µmole/24 hours in ORLISTAT and placebo treatment groups, respectively.

14 CLINICAL STUDIES The long-term effects of ORLISTAT on morbidity and mortality associated with obesity have not been established. The effects of ORLISTAT on weight loss, weight maintenance, and weight regain and on a number of comorbidities (e.g., type 2 diabetes, lipids, blood pressure) were assessed in the 4-year XENDOS study and in seven long-term (1- to 2-years duration) multicenter, double-blind, placebo-controlled clinical trials. During the first year of therapy, the studies of 2-year duration assessed weight loss and weight maintenance.

During the second year of therapy, some studies assessed continued weight loss and weight maintenance and others assessed the effect of ORLISTAT on weight regain. These studies included over 2800 patients treated with ORLISTAT and 1400 patients treated with placebo (age range 17-78 years, 80.2% women, 91.0% Caucasians, 5.7% Blacks, 2.3% Hispanics, 0.9% Other). The majority of these patients had obesity-related risk factors and comorbidities.

In the XENDOS study, which included 3304 patients (age range 30-58 years, 55% women, 99% Caucasians, 1% other), the time to onset of type 2 diabetes was assessed in addition to weight management. In all these studies, treatment with ORLISTAT and placebo designates treatment with ORLISTAT plus diet and placebo plus diet, respectively. During the weight loss and weight maintenance period, a well-balanced, reduced-calorie diet that was intended to result in an approximate 20% decrease in caloric intake and provide 30% of calories from fat was recommended to all patients.

In addition, all patients were offered nutritional counseling.

14.1One-year Results: Weight Loss, Weight Maintenance, and Risk Factors Pooled data from five clinical trials indicated that the overall mean weight loss from randomization to the end of 1 year of treatment in the intent-to-treat population was 13.4 lbs in the patients treated with ORLISTAT and 5.8 lbs in the placebo-treated patients. After 1 year of treatment, the mean percent weight loss difference between ORLISTAT-treated patients and placebo-treated patients was 3%. One thousand seventy two (69%) patients treated with ORLISTAT and 701 (63%) patients treated with placebo completed 1 year of treatment.

Of the patients who completed 1 year of treatment, 57% of the patients treated with ORLISTAT (120 mg three times a day) and 31% of the placebo-treated patients lost at least 5% of their baseline body weight. The percentages of patients achieving ≥5% and ≥10% weight loss after 1 year in five large multicenter studies for the intent-to-treat populations are presented in Table 6 . Table 6 Percentage of Patients Losing ≥5% and ≥10% of Body Weight From Randomization After 1-Year Treatment Treatment designates ORLISTAT 120 mg three times a day plus diet or placebo plus diet Study No.

Intent-to-Treat Population Last observation carried forward ≥5% Weight Loss ≥10% Weight Loss Orlistat n Placebo n p-value Orlistat n Placebo n p-value The diet utilized during year 1 was a reduced-calorie diet. 14119B 35.5% 110 21.3% 108 0.021 16.4% 110 6.5% 108 0.022 14119C 54.8% 343 27.4% 340 <0.001 24.8% 343 8.2% 340 <0.001 14149 50.6% 241 26.3% 236 <0.001 22.8% 241 11.9% 236 0.02 14161 All studies, with the exception of 14161, were conducted at centers specialized in treating obesity and complications of obesity.

Study 14161 was conducted with primary care physicians. 37.1% 210 16.0% 212 <0.001 19.5% 210 3.8% 212 <0.001 14185 42.6% 657 22.4% 223 <0.001 17.7% 657 9.9% 223 0.006 The relative changes in risk factors associated with obesity following 1 year of therapy with ORLISTAT and placebo are presented for the population as a whole and for the population with abnormal values at randomization. Population as a Whole The changes in metabolic, cardiovascular and anthropometric risk factors associated with obesity based on pooled data for five clinical studies, regardless of the patient's risk factor status at randomization, are presented in Table… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies in rats and mice did not show a carcinogenic potential for orlistat at doses up to 1000 mg/kg/day and 1500 mg/kg/day, respectively. For mice and rats, these doses are 38 and 46 times the daily human dose calculated on an area under concentration vs time curve basis of total drug-related material. Orlistat had no detectable mutagenic or genotoxic activity as determined by the Ames test, a mammalian forward mutation assay (V79/HPRT), an in vitro clastogenesis assay in peripheral human lymphocytes, an unscheduled DNA synthesis assay (UDS) in rat hepatocytes in culture, and an in vivo mouse micronucleus test.

When given to rats at a dose of 400 mg/kg/day in a fertility and reproduction study, orlistat had no observable adverse effects. This dose is 12 times the daily human dose calculated on a body surface area (mg/m 2 ) basis.