XENICAL (orlistat) is a lipase inhibitor for obesity management that acts by inhibiting the absorption of dietary fats.

Orlistat is (S)-2-formylamino-4-methyl-pentanoic acid (S)-1-[[(2S, 3S)-3-hexyl-4-oxo-2-oxetanyl] methyl]-dodecyl ester. Its empirical formula is C 29 H 53 NO 5 , and its molecular weight is 495.7. It is a single diastereomeric molecule that contains four chiral centers, with a negative optical rotation in ethanol at 529 nm.

Orlistat is a white to off-white crystalline powder. Orlistat is practically insoluble in water, freely soluble in chloroform, and very soluble in methanol and ethanol. Orlistat has no p K a within the physiological pH range.

XENICAL is available for oral administration in dark-blue, hard-gelatin capsules, with light-blue imprinting. Each capsule contains 120 mg of the active ingredient, orlistat. The capsules also contain the inactive ingredients microcrystalline cellulose, sodium starch glycolate, sodium lauryl sulfate, povidone, and talc. Each capsule shell contains gelatin, titanium dioxide, and FD&C Blue No. 1, with printing of pharmaceutical glaze NF, titanium dioxide, and FD&C Blue No. 1 aluminum lake.

Mechanism of Action:   Orlistat is a reversible inhibitor of 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. Systemic absorption of the drug is therefore not needed for activity. At the recommended therapeutic dose of 120 mg three times a day, orlistat inhibits dietary fat absorption by approximately 30%.

   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.

The average absolute bioavailability of intact orlistat was assessed in studies with male rats at oral doses of 150 and 1000 mg/kg/day and in male dogs at oral doses of 100 and 1000 mg/kg/day and found to be 0.12%, 0.59% in rats and 0.7%, 1.9% in dogs, respectively.

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 animal data, it is likely that the metabolism of orlistat occurs mainly within the gastrointestinal wall. Based on an oral 14 C-orlistat mass balance study in obese patients, two metabolites, M1 (4-member lactone ring hydrolyzed) and M3 (M1 with N-formyl leucine moiety cleaved), accounted for approximately 42% of total radioactivity in plasma. M1 and M3 have an open (beta)-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 disappeared at a slower rate (half-life approximately 13.5 hours). In obese patients, steady-state plasma levels of M1, but not M3, increased in proportion to orlistat doses.

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.

Special Populations:   Because the drug is minimally absorbed, studies in special populations (geriatric, pediatric, different races, patients with renal and hepatic insufficiency) were not conducted.

Drug-Drug Interactions:   Drug-drug interaction studies indicate that XENICAL had no effect on pharmacokinetics and/or pharmacodynamics of alcohol, digoxin, glyburide, nifedipine (extended-release tablets), oral contraceptives, phenytoin, or warfarin. XENICAL induced a modest increase of the bioavailability and lipid-lowering effect of pravastatin (see CLINICAL STUDIES and PRECAUTIONS ). Alcohol did not affect the pharmacodynamics of orlistat.

Other Short-term Studies:   In several studies of up to 6-weeks duration, the effects of therapeutic doses of XENICAL on gastrointestinal and systemic physiological processes were assessed in normal-weight and obese subjects. Postprandial cholecystokinin plasma concentrations were lowered after multiple doses of XENICAL 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 XENICAL in these studies. In a 3-week study of 28 healthy male volunteers, XENICAL (120 mg three times a day) did not significantly affect the balance of calcium, magnesium, phosphorus, zinc, copper, and iron.

Dose-response Relationship:   A simple maximum effect (E max ) model was used to define the dose-response curve of the relationship between XENICAL daily dose and fecal fat excretion as representative of gastrointestinal lipase inhibition. The dose-response curve demonstrated a steep portion for doses up to approximately 400 mg daily, followed by a plateau for higher doses. At doses greater than 120 mg three times a day, the percentage increase in effect was minimal.

CLINICAL STUDIES

Observational epidemiologic studies have established a relationship between obesity and visceral fat and the risks for cardiovascular disease, type 2 diabetes, certain forms of cancer, gallstones, certain respiratory disorders, and an increase in overall mortality. These studies suggest that weight loss, if maintained, may produce health benefits for obese patients who have or are at risk of developing weight-related comorbidities. The long-term effects of orlistat on morbidity and mortality associated with obesity have not been established.

The effects of XENICAL on weight loss, weight maintenance, and weight regain and on a number of comorbidities (eg, type 2 diabetes, lipids, blood pressure) were assessed in seven long-term (1- to 2-years duration) multicenter, double-blind, placebo-controlled clinical trials. During the first year of therapy, weight loss and weight maintenance were assessed. 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 XENICAL and 1400 patients treated with placebo. The majority of these patients had obesity-related risk factors and comorbidities. In these 7 studies, treatment with XENICAL and placebo designates treatment with XENICAL 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.

One-year Results: Weight Loss, Weight Maintenance, and Risk Factors:   Weight loss was observed within 2 weeks of initiation of therapy and continued for 6 to 12 months.

Pooled data from five clinical trials indicated that the overall mean weight loss from randomization to the end of 6 months and 1 year of treatment in the intent-to-treat population were 12.4 lbs and 13.4 lbs in the patients treated with XENICAL and 6.2 lbs and 5.8 lbs in the placebo-treated patients, respectively. During the 4-week placebo lead-in period of the studies, an additional 5 to 6 lb weight loss was also observed in the same patients. Of the patients who completed 1 year of treatment, 57% of the patients treated with XENICAL (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 1.

Table 1. Percentage of Patients Losing >/=5% and >/=10% of
Body Weight From Randomization After 1-Year Treatment *
Intent-to-Treat Population **
>/=5% Weight Loss >/=10% Weight Loss
Study No. XENICAL n Placebo n p-value XENICAL n Placebo n p-value
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 *** 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 diet utilized during year 1 was a reduced-calorie diet.
* Treatment designates XENICAL 120 mg three times a day plus diet or placebo plus diet
** Last observation carried forward
*** 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.

The relative changes in risk factors associated with obesity following 1 year of therapy with XENICAL 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' risk factor status at randomization, are presented in Table 2. One year of therapy with XENICAL resulted in relative improvement in several risk factors.

Table 2. Mean Change in Risk Factors From
Randomization Following 1-Year Treatment * -
Population as a Whole
XENICAL
120 mg **
Placebo **
Total Cholesterol
-2.0% +5.0%
LDL-Cholesterol
-4.0% +5.0%
HDL-Cholesterol
+9.3% +12.8%
LDL/HDL
-0.37% -0.20
Triglycerides
+1.34% +2.9%
Fasting Glucose, mmol/L
-0.04 +0.0
Fasting Insulin, pmol/L
-6.7 +5.2
-1.01 +0.58
-1.19 +0.46
-6.45 -4.04
Hip Circumference, cm
-5.31 -2.96
* Treatment designates XENICAL 120 mg three times a day plus diet or placebo plus diet
** Intent-to-treat population at week 52, observed data based on pooled data from 5 studies

Population With Abnormal Risk Factors at Randomization: The changes from randomization following 1-year treatment in the population with abnormal lipid levels (LDL >/=130 mg/dL, LDL/HDL >/=3.5, HDL <35 mg/dL) were greater for XENICAL compared to placebo with respect to LDL-cholesterol (-7.83% vs +1.14%) and the LDL/HDL ratio (-0.64 vs -0.46). HDL increased in the placebo group by 20.1% and in the XENICAL group by 18.8%. In the population with abnormal blood pressure at baseline (systolic BP >/=140 mm Hg), the change in SBP from randomization to 1 year was greater for XENICAL (-10.89 mm Hg) than placebo (-5.07 mm Hg). For patients with a diastolic blood pressure >/=90 mm Hg, XENICAL patients decreased by -7.9 mm Hg while the placebo patients decreased by -5.5 mm Hg. Fasting insulin decreased more for XENICAL than placebo (-39 vs -16 pmol/L) from randomization to 1 year in the population with abnormal baseline values (>/=120 pmol/L). A greater reduction in waist circumference for XENICAL vs placebo (-7.29 vs -4.53 cm) was observed in the population with abnormal baseline values (>/=100 cm).

Effect on Weight Regain:   Three studies were designed to evaluate the effects of XENICAL compared to placebo in reducing weight regain after a previous weight loss achieved following either diet alone (one study, 14302) or prior treatment with XENICAL (two studies, 14119C and 14185). The diet utilized during the 1-year weight regain portion of the studies was a weight-maintenance diet, rather than a weight-loss diet, and patients received less nutritional counseling than patients in weight-loss studies. For studies 14119C and 14185, patients' previous weight loss was due to 1 year of treatment with XENICAL in conjunction with a mildly hypocaloric diet. Study 14302 was conducted to evaluate the effects of 1 year of treatment with XENICAL on weight regain in patients who had lost 8% or more of their body weight in the previous 6 months on diet alone.

In study 14119C, patients treated with placebo regained 52% of the weight they had previously lost while the patients treated with XENICAL regained 26% of the weight they had previously lost (p<0.001). In study 14185, patients treated with placebo regained 63% of the weight they had previously lost while the patients treated with XENICAL regained 35% of the weight they had lost (p<0.001). In study 14302, patients treated with placebo regained 53% of the weight they had previously lost while the patients treated with XENICAL regained 32% of the weight that they had lost (p<0.001).

Two-year Results:  Long-term Weight Control and Risk Factors: The treatment effects of XENICAL were examined for 2 years in four of the five 1-year weight management clinical studies previously discussed (see Table 1). 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 patient' current weight. XENICAL was shown to be more effective than placebo in long-term weight control in four large, multicenter, 2-year double-blind, placebo-controlled studies.

Pooled data from four clinical studies indicate that 40% of all patients treated with 120 mg three times a day of XENICAL and 24% of patients treated with placebo who completed 2 years of the same therapy had >/=5% loss of body weight from randomization. Pooled data from four clinical studies indicate that the relative weight loss advantage between XENICAL 120 mg three times a day and placebo treatment groups was the same after 2 years as for 1 year, indicating that the pharmacologic advantage of XENICAL was maintained over 2 years. In the same studies cited in the One-year Results (see Table 1), the percentages of patients achieving a >/=5% and >/=10% weight loss after 2 years are shown in Table 3.

Table 3. Percentage of Patients Losing >/=5% and >/=10% of
Body Weight From Randomization After 2-Year Treatment *
Intent-to-Treat Population **
  
>/=5% Weight Loss >/=10% Weight Loss
Study No.
XENICAL n Placebo n p-value XENICAL n Placebo n p-value
14119C
45.1% 133 23.6% 123 <0.001 24.8% 133  6.5% 123 <0.001
14149
43.3% 178 27.2% 158 0.002 18.0% 178  9.5% 158 0.025
14161 ***
25.0% 148 15.0% 113 0.049 16.9% 148  3.5% 113 0.001
14185
34.0% 147 27.9% 122 0.279 17.7% 147 11.5% 122 0.154
The diet utilized during year 2 was designed for weight maintenance and not weight loss.
* Treatment designates XENICAL 120 mg three times a day plus diet or placebo plus diet
** Last observation carried forward
*** All studies, with the exception of 14161 were conducted at centers specializing in treating obesity or complications of obesity. Study 14161 was conducted with primary care physicians.

The relative changes in risk factors associated with obesity following 2 years of therapy were also assessed in the population as a whole and the population with abnormal risk factors at randomization.

Population as a Whole:   The relative differences in risk factors between treatment with XENICAL and placebo were similar to the results following 1 year of therapy for total cholesterol, LDL-cholesterol, LDL/HDL ratio, triglycerides, fasting glucose, fasting insulin, diastolic blood pressure, waist circumference, and hip circumference. The relative differences between treatment groups for HDL cholesterol and systolic blood pressure were less than that observed in the year one results.

Population With Abnormal Risk Factors at Randomization: The relative differences in risk factors between treatment with XENICAL and placebo were similar to the results following 1 year of therapy for LDL- and HDL-cholesterol, triglycerides, fasting insulin, diastolic blood pressure, and waist circumference. The relative differences between treatment groups for LDL/HDL ratio and isolated systolic blood pressure were less than that observed in the year one results.

Study of Patients With Type 2 Diabetes:    A 1-year double-blind, placebo-controlled study in type 2 diabetics (N=321) stabilized on sulfonylureas was conducted. Thirty percent 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). Table 4 describes the changes over 1 year of treatment with XENICAL compared to placebo, in sulfonylurea usage and dose reduction as well as in hemoglobin HbA1c, fasting glucose, and insulin.

Table 4. Mean Changes in Body Weight and Glycemic
Control From Randomization Following 1-Year
Treatment in Patients With Type 2 Diabetes
 
XENICAL
120 mg *
(n=162)
Placebo *
(n=159)
Statistical
Significance
% patients who discontinued
   dose of oral sulfonylurea
11.7% 7.5% **
% patients who decreased dose
    of oral sulfonylurea
31.5% 21.4%  
Average reduction in sulfonylurea
   medication dose
-22.8% -9.1% **
-8.9 -4.2 **
HbA1c
-0.18% +0.28% **
Fasting glucose, mmol/L
-0.02 +0.54 **
Fasting insulin, pmol/L
-19.68 -18.02 ns
Statistical significance based on intent-to-treat population, last observation carried forward.
* Treatment designates XENICAL 120 mg three times a day plus diet or placebo plus diet
** Statistically significant (p</=0.05) based on intent-to-treat, last observation carried forward
ns nonsignificant, p>0.05

In addition, XENICAL (n=162) compared to placebo (n=159) was associated with significant lowering for total cholesterol (-1.0% vs +9.0%, p</=0.05), LDL-cholesterol (-3.0% vs +10.0%, p</=0.05), LDL/HDL ratio (-0.26 vs -0.02, p</=0.05) and triglycerides (+2.54% vs +16.2%, p</=0.05), respectively. For HDL cholesterol, there was a +6.49% increase on XENICAL and +8.6% increase on placebo, p>0.05. Systolic blood pressure increased by +0.61 mm Hg on XENICAL and increased by +4.33 mm Hg on placebo, p>0.05. Diastolic blood pressure decreased by -0.47 mm Hg for XENICAL and by -0.5 mm Hg for placebo, p>0.05.

Glucose Tolerance in Obese Patients:   Two-year studies that included oral glucose tolerance tests were conducted in obese patients not previously diagnosed or treated for type 2 diabetes and whose baseline oral glucose tolerance test (OGTT) status at randomization was either normal, impaired, or diabetic.

The progression from a normal OGTT at randomization to a diabetic or impaired OGTT following 2 years of treatment with XENICAL (n=251) or placebo (n=207) were compared. Following treatment with XENICAL, 0.0% and 7.2% of the patients progressed from normal to diabetic and normal to impaired, respectively, compared to 1.9% and 12.6% of the placebo treatment group, respectively.

In patients found to have an impaired OGTT at randomization, the percent of patients improving to normal or deteriorating to diabetic status following 1 and 2 years of treatment with XENICAL compared to placebo are presented. After 1 year of treatment, 45.8% of the placebo patients and 73% of the XENICAL patients had a normal oral glucose tolerance test while 10.4% of the placebo patients and 2.6% of the XENICAL patients became diabetic. After 2 years of treatment, 50% of the placebo patients and 71.7% of the XENICAL patients had a normal oral glucose tolerance test while 7.5% of placebo patients were found to be diabetic and 1.7% of XENICAL patients were found to be diabetic after treatment.

XENICAL is indicated for obesity management including weight loss and weight maintenance when used in conjunction with a reduced-calorie diet. XENICAL is also indicated to reduce the risk for weight regain after prior weight loss. XENICAL is indicated for obese patients with an initial body mass index (BMI) >/=30 kg/m 2 or >/=27 kg/m 2 in the presence of other risk factors (e.g., hypertension, diabetes, dyslipidemia).

Table 5 illustrates body mass index (BMI) according to a variety of weights and heights. The BMI is calculated by dividing weight in kilograms by height in meters squared. For example, a person who weighs 180 lbs and is 5'5[Prime ] would have a BMI of 30.

images/76/92062001.jpg

CONTRAINDICATIONS

XENICAL is contraindicated in patients with chronic malabsorption syndrome or cholestasis, and in patients with known hypersensitivity to XENICAL or to any component of this product.

Miscellaneous:   Organic causes of obesity (e.g., hypothyroidism) should be excluded before prescribing XENICAL.

Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Therefore, XENICAL and cyclosporine should not be coadministered. To reduce the chance of a drug-drug interaction, cyclosporine should be taken at least 2 hours before or after XENICAL in patients taking both drugs. In addition, in those patients whose cyclosporine levels are being measured, more frequent monitoring should be considered.

PRECAUTIONS

General:   Patients should be advised to adhere to dietary guidelines (see DOSAGE AND ADMINISTRATION ). Gastrointestinal events (see ADVERSE REACTIONS ) may increase when XENICAL is taken with a diet high in fat (>30% total daily calories from fat). 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.

Patients should be counseled to take a multivitamin supplement that contains fat-soluble vitamins to ensure adequate nutrition because XENICAL has been shown to reduce the absorption of some fat-soluble vitamins and beta-carotene. In addition, the levels of vitamin D and beta-carotene may be low in obese patients compared with non-obese subjects. The supplement should be taken once a day at least 2 hours before or after the administration of XENICAL, such as at bedtime.

Table 6 illustrates the percentage of patients on XENICAL and placebo who developed a low vitamin level on two or more consecutive visits during 1 and 2 years of therapy in studies in which patients were not previously receiving vitamin supplementation.

Table 6. Incidence of Low Vitamin Values on
Two or More Consecutive Visits (Nonsupplemented
Patients With Normal Baseline Values -
First and Second Year)
 
Placebo * XENICAL *
1.0%  2.2%
6.6% 12.0%
1.0%  5.8%
Beta-carotene
1.7%  6.1%
*Treatment designates placebo plus diet or XENICAL plus diet

Some patients may develop increased levels of urinary oxalate following treatment with XENICAL. Caution should be exercised when prescribing XENICAL to patients with a history of hyperoxaluria or calcium oxalate nephrolithiasis.

Weight-loss induction by XENICAL may be accompanied by improved metabolic control in diabetics, which might require a reduction in dose of oral hypoglycemic medication (e.g., sulfonylureas, metformin) or insulin (see CLINICAL STUDIES ).

Misuse Potential:   As with any weight-loss agent, the potential exists for misuse of XENICAL in inappropriate patient populations (eg, patients with anorexia nervosa or bulimia). See for recommended prescribing guidelines.

Information for Patients:   Patients should read the Patient Information before starting treatment with XENICAL and each time their prescription is renewed.

Drug Interactions:    Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL 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.

Cyclosporine    Preliminary data from XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine (see ).

Digoxin   In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL 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 absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time.

Glyburide:   In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide.

Nifedipine (extended-release tablets):   In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets).

Oral Contraceptives:    In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives.

Phenytoin   In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin.

Pravastatin:   In a parallel study of 24 normal-weight, mildly hypercholesterolemic subjects receiving XENICAL 120 mg three times a day for 10 days, the effect of XENICAL was additive to the lipid-lowering effect of pravastatin. Modest increases (approximately 30%) in pravastatin plasma concentrations were observed during coadministration with XENICAL.

Warfarin:   In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters.

Carcinogenesis, 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 times 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.

Pregnancy:   Teratogenic Effects: Pregnancy Category B. Teratogenicity studies were conducted in rats and rabbits at doses up to 800 mg/kg/day. Neither study showed embryotoxicity or teratogenicity. This dose is 23 and 47 times the daily human dose calculated on a body surface area (mg/m 2 ) basis for rats and rabbits, respectively.

The incidence of dilated cerebral ventricles was increased in the mid- and high-dose groups of the rat teratology study. These doses were 6 and 23 times the daily human dose calculated on a body surface area (mg/m 2 ) basis for the mid- and high-dose levels, respectively. This finding was not reproduced in two additional rat teratology studies at similar doses.

There are no adequate and well-controlled studies of XENICAL in pregnant women. Because animal reproductive studies are not always predictive of human response, XENICAL is not recommended for use during pregnancy.

Nursing Mothers:   It is not known if orlistat is secreted in human milk. Therefore, XENICAL should not be taken by nursing women.

Pediatric Use:   The safety and efficacy of XENICAL in pediatric patients have not been established.

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.

ADVERSE REACTIONS

Commonly Observed (based on first year and second year data -- XENICAL 120 mg three times a day versus placebo):

Gastrointestinal (GI) symptoms were the most commonly observed treatment-emergent adverse events associated with the use of XENICAL in double-blind, placebo-controlled clinical trials and are primarily a manifestation of the mechanism of action. (Commonly observed is defined as an incidence of >/=5% and an incidence in the XENICAL 120 mg group that is at least twice that of placebo.)

Table 7. Commonly Observed Adverse Events
 
Year 1 Year 2
Adverse Event
XENICAL *
% Patients
(N=1913)
Placebo *
% Patients
(N=1466)
XENICAL *
% Patients
(N=613)
Placebo *
% Patients
(N=524)
Oily Spotting
26.6 1.3 4.4 0.2
23.9 1.4 2.1 0.2
22.1 6.7 2.8 1.7
Fatty/Oily Stool
20.0 2.9 5.5 0.6
Oily Evacuation
11.9 0.8 2.3 0.2
Increased Defecation
10.8 4.1 2.6 0.8
 7.7 0.9 1.8 0.2
*Treatment designates XENICAL three times a day plus diet or placebo plus diet

These and other commonly observed adverse reactions were generally mild and transient, and they decreased during the second year of treatment. In general, the first occurrence of these events was within 3 months of starting therapy. Overall, approximately 50% of all episodes of GI adverse events associated with orlistat treatment lasted for less than 1 week, and a majority lasted for no more than 4 weeks. However, GI adverse events may occur in some individuals over a period of 6 months or longer.

Discontinuation of Treatment:   In controlled clinical trials, 8.8% of patients treated with XENICAL discontinued treatment due to adverse events, compared with 5.0% of placebo-treated patients. For XENICAL, the most common adverse events resulting in discontinuation of treatment were gastrointestinal.

Incidence in Controlled Clinical Trials:   The following table lists other treatment-emergent adverse events from seven multicenter, double-blind, placebo-controlled clinical trials that occurred at a frequency of >/=2% among patients treated with XENICAL 120 mg three times a day and with an incidence that was greater than placebo during year 1 and year 2, regardless of relationship to study medication.

Table 8. Other Treatment-Emergent Adverse Events From
Seven Placebo-Controlled Clinical Trials
  Year 1 Year 2
Body System/
Adverse Events
XENICAL *
% Patients
(N=1913)
Placebo *
% Patients
(N=1466)
XENICAL *
% Patients
(N=613)
Placebo *
% Patients
(N=524)
  Abdominal Pain/Discomfort
25.5
21.4 -- --
  Nausea
8.1
7.3 3.6 2.7
5.3
4.4 -- --
  Rectal Pain/Discomfort
5.2
4.0 3.3 1.9
  Tooth Disorder
4.3
3.1 2.9 2.3
4.1
2.9 2.0 1.5
3.8
3.5 -- --
39.7
36.2 -- --
38.1
32.8 26.1 25.8
7.8
6.6 -- --
  Ear, Nose & Throat Symptoms
2.0
1.6 -- --
  Back Pain
13.9
12.1 -- --
  Pain Lower Extremities
--
-- 10.8 10.3
5.4
4.8 -- --
  Myalgia
4.2
3.3 -- --
2.3
2.2 -- --
--
-- 2.0 1.9
Central Nervous System
30.6
27.6 -- --
5.2
5.0 -- --
Body as a Whole
  Fatigue
7.2
6.4 3.1 1.7
3.9
3.3 -- --
Skin & Appendages
  Rash
4.3
4.0 -- --
  Dry Skin
2.1
1.4 -- --
  Menstrual Irregularity
9.8
7.5 -- --
3.8
3.6 2.6 1.9
7.5
7.3 5.9 4.8
4.7
2.9 2.8 2.1
--
-- 3.4 2.5
Hearing & Vestibular Disorders
  Otitis
4.3
3.4 2.9 2.5
Cardiovascular Disorders
--
-- 2.8 1.9
* Treatment designates XENICAL 120 mg three times a day plus diet or placebo plus diet
-- None reported at a frequency >/=2% and greater than placebo

Other Clinical Studies or Postmarketing Surveillance: Rare cases of hypersensitivity have been reported with the use of XENICAL. Signs and symptoms have included pruritus, rash, urticaria, angioedema, and anaphylaxis.

Preliminary data from XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine (see ).

OVERDOSAGE

Single doses of 800 mg XENICAL and multiple doses of up to 400 mg three times a day for 15 days have been studied in normal weight and obese subjects without significant adverse findings.

Should a significant overdose of XENICAL occur, it is recommended that the patient be observed for 24 hours. Based on human and animal studies, systemic effects attributable to the lipase-inhibiting properties of orlistat should be rapidly reversible.

DOSAGE AND ADMINISTRATION

The recommended dose of XENICAL is one 120 mg capsule three times a day with each main meal containing fat (during or up to 1 hour after the meal).

The patient should be on a nutritionally balanced, reduced-calorie diet that contains approximately 30% of calories from fat. The daily intake of fat, carbohydrate, and protein should be distributed over three main meals. If a meal is occasionally missed or contains no fat, the dose of XENICAL can be omitted.

Because XENICAL has been shown to reduce the absorption of some fat-soluble vitamins and beta-carotene, patients should be counseled to take a multivitamin containing fat-soluble vitamins to ensure adequate nutrition. The supplement should be taken at least 2 hours before or after the administration of XENICAL, such as at bedtime.

Doses above 120 mg three times a day have not been shown to provide additional benefit.

Based on fecal fat measurements, the effect of XENICAL is seen as soon as 24 to 48 hours after dosing. Upon discontinuation of therapy, fecal fat content usually returns to pretreatment levels within 48 to 72 hours.

The safety and effectiveness of XENICAL beyond 2 years have not been determined at this time.

HOW SUPPLIED

XENICAL is a dark-blue, hard-gelatin capsule containing pellets of powder.

XENICAL 120 mg Capsules: Dark-blue, two-piece, No. 1 opaque hard-gelatin capsule imprinted with Roche and XENICAL 120 in light-blue ink -- bottle of 90 (NDC 0004-0256-52).

Storage Conditions:    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.

XENICAL should not be used after the given expiration date.

Roche Pharmaceuticals

Roche Laboratories Inc.

340 Kingsland Street

Nutley, New Jersey 07110-1199

Copyright © by Roche Laboratories Inc.

All rights reserved.

                          Revised: September 1999

PRODUCT PHOTO(S):

NOTE: These photos can be used only for identification by shape, color, and imprint. They do not depict actual or relative size.

The product samples shown here have been supplied by the manufacturer and reproduced in full color by PDR as a quick-reference identification aid. While every effort has been made to assure accurate reproduction, please remember that any visual identification should be considered preliminary. In cases of poisoning or suspected overdosage, the drug' identity should be verified by chemical analysis.

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