Orlistat 120 Mg Oral Capsule

Recommended Dosage and Administration

The recommended dosage of XENICAL is one 120 mg capsule taken orally three times a day with each main meal containing fat (during or up to 1 hour after the meal). Dosages above 120 mg three times a day have not been shown to provide additional benefit.

Serious outcomes due to the loss of effect of cyclosporine, levothyroxine, warfarin, amiodarone, antiepileptic drugs, antiretroviral drugs, certain fat-soluble vitamins, and beta carotene have been reported with coadministration of XENICAL. Do not coadminister XENICAL simultaneously with cyclosporine or levothyroxine [see Drug Interactions (7)]. Administer cyclosporine 3 hours after the administration of XENICAL. Administer levothyroxine and XENICAL at least 4 hours apart. Administer a multivitamin supplement at least 2 hours before or 2 hours after the administration of XENICAL, or at bedtime. Monitor the effectiveness of cyclosporine, levothyroxine, warfarin, amiodarone, antiepileptic drugs, antiretroviral drugs, certain fat-soluble vitamins, and beta carotene, as clinically indicated [see Drug Interactions (7) and Clinical Pharmacology (12.3 )].

There have been rare postmarketing reports of severe liver injury with hepatocellular necrosis or acute hepatic failure in patients treated with XENICAL, with some of these cases resulting in liver transplant or death [see Adverse Reactions (6.2 )]. Instruct patients to report any symptoms of hepatic dysfunction (anorexia, pruritus, jaundice, dark urine, light-colored stools, or right upper quadrant pain) while taking XENICAL. When these symptoms occur, immediately discontinue XENICAL and other suspected medications and obtain liver function tests, including ALT and AST levels.

XENICAL may increase levels of urinary oxalate. Cases of oxalate nephrolithiasis and oxalate nephropathy with renal failure have been reported [see Adverse Reactions (6.2)]. Monitor renal function when prescribing XENICAL to patients at increased risk for oxalate nephropathy, including patients with renal impairment and in those with a history of hyperoxaluria or calcium oxalate nephrolithiasis. Discontinue XENICAL in patients who develop oxalate nephropathy.

Acute events of gallbladder disease such as cholelithiasis, have been reported in clinical trials and during the postmarketing experience with XENICAL. In a 4-year clinical trial of XENICAL, cholelithiasis was reported in 2.9% (47/1649) of XENICAL-treated patients versus 1.8% (30/1655) of placebo-treated patients. If cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated.

Gastrointestinal events may increase when XENICAL is taken with a diet high in fat (>30% total daily calories from fat) [see Adverse Reactions (6.1)]. Advise patients receiving XENICAL to adhere to dietary guidelines [see Dosage and Administration (2 )]. The daily intake of fat should be distributed over three main meals. If XENICAL is taken with any one meal very high in fat, the possibility of gastrointestinal effects increases.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in patients.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of XENICAL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to XENICAL exposure.

Table 4 describes the clinically significant drug and dietary supplement interactions with XENICAL.

Table  4               Clinically Significant Drug and Dietary Supplement Interactions with XENICAL

8.1 Pregnancy

8.2 Lactation

Risk Summary

There are no data on the presence of XENICAL or its metabolite in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for XENICAL and any potential adverse effects on the breastfed infant from XENICAL or from the underlying maternal condition.

8.4 Pediatric Use

The safety and effectiveness of XENICAL in combination with a reduced calorie diet and increased physical activity to reduce excess body weight and maintain weight reduction long term have been established in pediatric patients aged 12 years and older with obesity. Use of XENICAL in this indication is supported by a 54-week randomized, placebo-controlled trial in 539 pediatric patients aged 12 years and older with obesity (defined as a baseline BMI that was 2 units greater than the US weighted mean for the 95^th percentile based on age and sex) [see Clinical Pharmacology (12.2), Clinical Studies (14.2)] and from trials in adult patients with obesity [see Clinical Studies (14.1)]. Adverse reactions with XENICAL treatment in pediatric patients aged 12 years and older were generally similar to those reported in adults [see Adverse Reactions (6.1)].

The safety and effectiveness of XENICAL have not been established in pediatric patients less than 12 years of age.

8.5 Geriatric Use

Clinical studies of XENICAL did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients [see Clinical Studies (14.1)] .

12.1 Mechanism 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. Undigested triglycerides are not absorbed, resulting in a caloric deficit.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In two-year carcinogenicity studies, orlistat was given to rats and mice at doses up to 1,000 mg/kg/day and 1,500 mg/kg/day, respectively. Orlistat was not carcinogenic up to the highest doses tested in rats and mice, representing 46 times and 38 times the maximum recommended human dose, respectively, based on area under concentration vs time curve 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.

No effects on fertility were observed in male and female rats given orlistat oral doses up to 400 mg/kg/day corresponding to 12 times MRHD, based on body surface area (mg/m²).

14.1 Weight Reduction and Long-term Maintenance Trials in Adults with Obesity or Overweight

Overview of Clinical Trials in Adults

The effects of XENICAL 120 mg administered orally three times a day on weight reduction and long-term maintenance of body weight in conjunction with a reduced calorie diet that provided approximately 30% of calories from fat were assessed in seven multicenter, double-blind, placebo-controlled clinical trials of 1- to 2-years duration, and in a 4-year trial. The seven trials included 1,466 patients treated with placebo, 1,913 patients treated with XENICAL 120 mg orally three times a day, and 809 patients treated with unapproved dosages of XENICAL. Patients were 17 to 78 years of age; 80% were female, 91% White, 6% Black or African American, 2% were of Hispanic or Latino ethnicity, and 1% were of other races. Six of the trials enrolled patients without type 2 diabetes mellitus (Trials 1-6) and one of the trials enrolled a population of patients with type 2 diabetes mellitus (Trial 7). The 4-year trial (Trial 8) included 3,304 patients; age range 30 to 58 years; 55% were female; 99% were White and 1% other races. This trial included a subset of patients with abnormal glucose at baseline.

Effect of XENICAL on Body Weight After 1 Year of Treatment

A total of 2,680 obese patients were randomly assigned to receive either placebo (n = 1,119) or XENICAL 120 mg orally three times a day (n = 1,561) for at least one year in five clinical trials. Baseline mean body weight was approximately 100 kg in the pool of Trials 1-5. A total of 1,072 (69%) patients treated with XENICAL and 701 (63%) patients treated with placebo completed 1 year of treatment. After 1 year of treatment, the mean percent weight loss difference between XENICAL-treated patients and placebo-treated patients was 3%. Greater proportions of patients treated with XENICAL achieved 5% and 10% weight loss than those treated with placebo as shown in Table 5.

Table 5              Percentage of Patients Losing ≥ 5% and ≥ 10% of Body Weight from Randomization After 1 Year of Treatment^a

^a modified intent to treat – last observation carried forward (MITT-LOCF)

^b All trials, with the exception of Trial 4, were conducted at centers specialized in treating obesity and complications of obesity. Trial 4 was conducted with primary care physicians.

Effect of XENICAL on Anthropometry and Cardiometabolic Parameters

The changes in anthropometry and cardiometabolic parameters at the end of the 1-year treatment period in the all trials population (Trials 1-5) are presented in Table 6.

Table 6              Mean Changes in Anthropometry and Cardiometabolic Parameters from Randomization Following 1 Year of Treatment^a,bin the All Trials Population of Clinical Trials 1 – 5

^a modified intent to treat – last observation carried forward (MITT-LOCF)

^b Change from baseline at 1 year of treatment.

Effect of XENICAL on Body Weight After 2 Years of Treatment

The treatment effects of XENICAL were examined for 2 years in four trials (Trials 2-5). The 2-year analysis population included a total of 1,122 patients who were randomly assigned to receive either placebo (n = 516) or XENICAL (n = 606). Patients were included only if they had been randomly assigned to receive the same treatment for both years – either placebo, or XENICAL 120 mg orally three times a day– and only if they had completed the first year of treatment. At the end of year 1, the patients’ diets were reviewed and changed where necessary. The diet prescribed in the second year was designed to maintain a patient’s current weight. The mean baseline body weight was 99 kg.

The proportion of patients (pooled from four clinical trials) who completed 1 year of treatment and went on to complete a second year of therapy was 74% for XENICAL (n = 450) and 76% for placebo (n = 392). Pooled data from four clinical trials indicate that the mean weight loss difference between XENICAL 120 mg three times a day and placebo treatment groups at year 2 in those patients who completed 1 year of treatment (LOCF) was 3% The percentages of patients achieving a ≥5% and ≥10% weight loss after 2 years are shown in Table 7.

Table 7              Percentage of Patients Losing ≥ 5% and ≥ 10% of Body Weight from Randomization After 2 Years of Treatment^a

^a modified intent to treat – last observation carried forward (MITT-LOCF)

^b All trials, with the exception of Trial 4, were conducted at centers specializing in treating obesity or complications of obesity. Trial 4 was conducted with primary care physicians.

The relative differences in anthropometry and cardiometabolic parameters between treatment with XENICAL and placebo were similar to the results following 1 year of therapy for total cholesterol, LDL-cholesterol, triglycerides, diastolic blood pressure, and waist circumference. The relative differences between treatment groups for HDL cholesterol and systolic blood pressure were less than that observed in the year one results.

Effect of XENICAL on Body Weight After 4 Years of Treatment

In the 4-year double-blind, placebo-controlled trial (Trial 8), the effects of XENICAL on body weight were compared to placebo in 3,304 patients with obesity who had either normal or impaired blood glucose tolerance at baseline. Mean baseline body weight was 110.5 kg and mean BMI was 37.4 kg/m². A total of 564 patients (34%) of the 1,655 patients, who were randomized to the placebo group, and 850 patients (52%) of the 1,649 patients, who were randomized to the XENICAL group, completed the 4-year study.

At the end of the study, the mean percent weight loss in the placebo group was -2.75% compared with -5.17% in the XENICAL group (p<0.001). Figure 2 presents mean percent change from baseline body weight observed for patients completing each study visit.

Forty-five percent of the placebo patients and 73% of the XENICAL patients lost ≥5% of their baseline body weight, and 21% of the placebo patients and 41% of the XENICAL patients lost ≥10% of their baseline body weight following the first year of treatment. Following 4 years of treatment, 28% of the placebo patients and 45% of the XENICAL patients lost ≥5% of their baseline body weight and 10% of the placebo patients and 21% of the XENICAL patients lost ≥10% of their baseline body weight. After 4 years of treatment, the mean percent difference in weight loss between XENICAL-treated patients and placebo was 2.5%.

Figure 2             Mean Change from Baseline Body Weight (%) Over Time ^a

^a Observed values for patients completing each scheduled visit.

Effect of XENICAL on Body Weight in Adults with Type 2 Diabetes Mellitus and Obesity or Overweight

A 1-year double-blind, placebo-controlled trial in patients with type 2 diabetes mellitus with obesity or overweight (n = 321) stabilized on sulfonylureas was conducted (Trial 7). Mean baseline body weight was 99.7 kg and mean BMI was 34.3 kg/m². Following 1 year of treatment, the mean change in body weight was 6.19 kg with XENICAL and 4.31 kg with placebo (p≤0.05). Thirty percent (30%) of patients treated with XENICAL achieved at least a 5% or greater reduction in body weight from randomization compared to 13% of the placebo-treated patients (p<0.001).

The changes in HbA1c and cardiometabolic parameters at the end of the 1-year treatment period in Trial 7 are presented in Table 8.

Table 8              Mean Changes in HbA1c and Cardiometabolic Parameters from Randomization Following 1 Year of Treatment^a

^a modified intent to treat – last observation carried forward (MITT-LOCF)

14.2 Weight Reduction and Long-term Maintenance Trial in Pediatric Patients Aged 12 Years and Older with Obesity

The effects of XENICAL on weight reduction and long-term maintenance were assessed in a 54-week multicenter, double-blind, placebo-controlled study in 539 pediatric patients aged 12 years and older with obesity (357 receiving XENICAL 120 mg three times a day, 182 receiving placebo). A similar percentage of patients in each treatment group (placebo 64%, XENICAL 65%) completed the study. The mean baseline BMI was 36 kg/m² in both treatment groups, and the mean baseline body weight was 98 kg among XENICAL-treated patients and 95 kg for placebo-treated patients. All study participants had a baseline BMI that was 2 units greater than the US weighted mean for the 95^th percentile based on age and sex. The primary endpoint was percent change from baseline BMI. The mean age was 13.5 years. Most of the patients were White (XENICAL 75%, placebo 78%), Black or African American (XENICAL 19%, placebo 14%) and females (XENICAL 65%, placebo 71%).

During the study, all patients were instructed to take a multivitamin containing fat-soluble vitamins at least 2 hours before or after ingestion of XENICAL. Patients were instructed to maintain a reduced-calorie diet that provided 30% of calories from fat, 50% of calories from carbohydrate, and 20% of calories as protein. In addition, all patients were enrolled in a behavior modification program and offered counseling on physical activity.

At week 54, the least squared mean change from baseline in BMI was -0.55 kg/m² in XENICAL-treated patients and +0.31 kg/m² in placebo-treated patients (p=0.001).

The percentages of patients achieving ≥5% and ≥10% reduction in BMI and body weight after 52 weeks of treatment for the intent-to-treat population are presented in Table 9.

Table 9              Percentages of Patients with ≥5% and ≥10% Decrease in Body Mass Index and Body Weight After 1 Year of Treatment^a

^a modified intent to treat – last observation carried forward (MITT-LOCF)

Storage and Handling

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Keep bottle tightly closed.