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/m2 or ≥27 kg/m2 in the presence of other risk factors (eg, hypertension, diabetes, dyslipidemia).
Table 1 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″ would have a BMI of 30.
Table 1 Body Mass Index (BMI), kg/m2
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Xenical Dosage and Administration
Recommended Dosing
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 [see Warnings and Precautions (5.1)]. The vitamin supplement should be taken at least 2 hours before or after the administration of Xenical, such as at bedtime.
For patients receiving both Xenical and cyclosporine therapy, administer cyclosporine 3 hours after Xenical.
For patients receiving both Xenical and levothyroxine therapy, administer levothyroxine and Xenical at least 4 hours apart. Patients treated concomitantly with Xenical and levothyroxine should be monitored for changes in thyroid function.
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.
Dosage Forms and Strengths
Xenical 120 mg dark-blue capsules imprinted with Roche and Xenical 120 in light-blue ink or turquoise capsules imprinted with ROCHE and Xenical 120 in black ink
Contraindications
Xenical is contraindicated in:
- Pregnancy [see Use in Specific Populations (8.1)]
- Patients with chronic malabsorption syndrome
- Patients with cholestasis
- Patients with known hypersensitivity to Xenical or to any component of this product
Warnings and Precautions
Concomitant Drug and Vitamin Use
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 simultaneously coadministered. To reduce the chance of a drug-drug interaction, cyclosporine should be taken at least 3 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.
Patients should be strongly encouraged 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 [see Dosage and Administration (2)]. 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 2 illustrates the percentage of adult 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 2 Incidence of Low Vitamin Values on Two or More Consecutive Visits (Nonsupplemented Adult Patients With Normal Baseline Values - First and Second Year)
|
Placebo |
Xenical* |
|---|
|
| Vitamin A |
1.0% |
2.2% |
| Vitamin D |
6.6% |
12.0% |
| Vitamin E |
1.0% |
5.8% |
| Beta-carotene |
1.7% |
6.1% |
Table 3 illustrates the percentage of adolescent patients on Xenical and placebo who developed a low vitamin level on two or more consecutive visits during the 1-year study.
Table 3 Incidence of Low Vitamin Values on Two or More Consecutive Visits (Pediatric Patients With Normal Baseline Values)
|
Placebo |
Xenical† |
|---|
|
| Vitamin A |
0.0% |
0.0% |
| Vitamin D |
0.7% |
1.4% |
| Vitamin E |
0.0% |
0.0% |
| Beta-carotene |
0.8% |
1.5% |
Weight-loss may affect glycemic control in patients with diabetes mellitus. A reduction in dose of oral hypoglycemic medication (eg, sulfonylureas) or insulin may be required in some patients [see Clinical Studies (14)].
Liver Injury
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. Patients should be instructed 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, Xenical and other suspect medications should be discontinued immediately and liver function tests and ALT and AST levels obtained.
Increases in Urinary Oxalate
Some patients may develop increased levels of urinary oxalate following treatment with Xenical. Cases of oxalate nephrolithiasis and oxalate nephropathy with renal failure have been reported. Monitor renal function when prescribing Xenical to patients at risk for renal impairment and use with caution in those with a history of hyperoxaluria or calcium oxalate nephrolithiasis.
Cholelithiasis
Substantial weight loss can increase the risk of cholelithiasis. In a clinical trial of Xenical for the prevention of type 2 diabetes, the rates of cholelithiasis as an adverse event were 2.9% (47/1649) for patients randomized to Xenical and 1.8% (30/1655) for patients randomized to placebo.
Miscellaneous
Organic causes of obesity (eg, hypothyroidism) should be excluded before prescribing Xenical.
Patients should be advised to adhere to dietary guidelines [see Dosage and Administration (2)]. Gastrointestinal events [see Adverse Reactions (6.1)] 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.
Adverse Reactions
Clinical Trials
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.
Commonly Observed (based on first year and second year data)
Gastrointestinal (GI) symptoms were the most commonly observed treatment-emergent adverse events associated with the use of Xenical in the seven 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 4 Commonly Observed Adverse Events
| Adverse Event |
Year 1 |
Year 2 |
|---|
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 |
| Flatus with Discharge |
23.9 |
1.4 |
2.1 |
0.2 |
| Fecal Urgency |
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 |
| Fecal Incontinence |
7.7 |
0.9 |
1.8 |
0.2 |
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 Xenical 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.
Other Adverse Clinical Events
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 5 Other Treatment-Emergent Adverse Events From Seven Placebo-Controlled Clinical Trials
| Body System/Adverse Event |
Year 1 |
Year 2 |
|---|
Xenical % Patients
(N=1913) |
Placebo* % Patients
(N=1466) |
Xenical* % Patients
(N=613) |
Placebo* % Patients
(N=524) |
|---|
| – None reported at a frequency ≥2% and greater than placebo |
|
| Gastrointestinal System |
|
|
|
|
| Abdominal Pain/Discomfort |
25.5 |
21.4 |
– |
– |
| Nausea |
8.1 |
7.3 |
3.6 |
2.7 |
| Infectious Diarrhea |
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 |
| Gingival Disorder |
4.1 |
2.9 |
2.0 |
1.5 |
| Vomiting |
3.8 |
3.5 |
– |
– |
| Respiratory System |
|
|
|
|
| Influenza |
39.7 |
36.2 |
– |
– |
| Upper Respiratory Infection |
38.1 |
32.8 |
26.1 |
25.8 |
| Lower Respiratory Infection |
7.8 |
6.6 |
– |
– |
| Ear, Nose & Throat Symptoms |
2.0 |
1.6 |
– |
– |
| Musculoskeletal System |
|
|
|
|
| Back Pain |
13.9 |
12.1 |
– |
– |
| Pain Lower Extremities |
– |
– |
10.8 |
10.3 |
| Arthritis |
5.4 |
4.8 |
– |
– |
| Myalgia |
4.2 |
3.3 |
– |
– |
| Joint Disorder |
2.3 |
2.2 |
– |
– |
| Tendonitis |
– |
– |
2.0 |
1.9 |
| Central Nervous System |
|
|
|
|
| Headache |
30.6 |
27.6 |
– |
– |
| Dizziness |
5.2 |
5.0 |
– |
– |
| Body as a Whole |
|
|
|
|
| Fatigue |
7.2 |
6.4 |
3.1 |
1.7 |
| Sleep Disorder |
3.9 |
3.3 |
– |
– |
| Skin & Appendages |
|
|
|
|
| Rash |
4.3 |
4.0 |
– |
– |
| Dry Skin |
2.1 |
1.4 |
– |
– |
| Reproductive, Female |
|
|
|
|
| Menstrual Irregularity |
9.8 |
7.5 |
– |
– |
| Vaginitis |
3.8 |
3.6 |
2.6 |
1.9 |
| Urinary System |
|
|
|
|
| Urinary Tract Infection |
7.5 |
7.3 |
5.9 |
4.8 |
| Psychiatric Disorder |
|
|
|
|
| Psychiatric Anxiety |
4.7 |
2.9 |
2.8 |
2.1 |
| Depression |
– |
– |
3.4 |
2.5 |
| Hearing & Vestibular Disorders |
|
|
|
|
| Otitis |
4.3 |
3.4 |
2.9 |
2.5 |
| Cardiovascular Disorders |
|
|
|
|
| Pedal Edema |
– |
– |
2.8 |
1.9 |
In the 4-year XENDOS study, the general pattern of adverse events was similar to that reported for the 1- and 2-year studies with the total incidence of gastrointestinal-related adverse events occurring in year 1 decreasing each year over the 4-year period.
In clinical trials in obese diabetic patients, hypoglycemia and abdominal distension were also observed.
Pediatric Patients
In clinical trials with Xenical in adolescent patients ages 12 to 16 years, the profile of adverse reactions was generally similar to that observed in adults.
Postmarketing Surveillance
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.
- Rare cases of increase in transaminases and in alkaline phosphatase and hepatitis that may be serious have been reported. There have been reports of hepatic failure observed with the use of Xenical in postmarketing surveillance, with some of these cases resulting in liver transplant or death [see Warnings and Precautions (5.2)].
- Cases of reduced concentrations of cyclosporine have been reported when cyclosporine was co-administered with Xenical [see Warnings and Precautions (5.1) and Drug Interactions (7.2)].
- Rare cases of hypersensitivity have been reported with the use of Xenical. Signs and symptoms have included pruritus, rash, urticaria, angioedema, bronchospasm and anaphylaxis. Very rare cases of bullous eruption have been reported.
- Reports of decreased prothrombin, increased INR and unbalanced anticoagulant treatment resulting in change of hemostatic parameters have been reported in patients treated concomitantly with Xenical and anticoagulants [see Drug Interactions (7.4)].
- Hypothyroidism has been reported in patients treated concomitantly with Xenical and levothyroxine [see Drug Interactions (7.3)].
- Acute oxalate nephropathy after treatment with Xenical has been reported in patients with or at risk for renal disease [see Warnings and Precautions (5.3)].
- Pancreatitis has been reported with the use of Xenical in postmarketing surveillance. No causal relationship or physiopathological mechanism between pancreatitis and obesity therapy has been definitively established.
- Lower gastrointestinal bleeding has been reported in patients treated with Xenical. Most reports are nonserious; severe or persistent cases should be investigated further.
Drug Interactions
Cyclosporine
Data from a Xenical and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when Xenical was coadministered with cyclosporine. Xenical and cyclosporine should not be simultaneously coadministered. Cyclosporine should be administered 3 hours after the administration of Xenical [see Dosage and Administration (2), Warnings and Precautions (5.1), and Adverse Reactions (6.2)].
Fat-soluble Vitamin Supplements and Analogues
Data from a pharmacokinetic interaction study showed that the absorption of beta-carotene supplement is reduced when concomitantly administered with Xenical. Xenical inhibited absorption of a vitamin E acetate supplement. The effect of Xenical on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time [see Pharmacokinetics (12.3)].
Levothyroxine
Hypothyroidism has been reported in patients treated concomitantly with Xenical and levothyroxine postmarketing [see Adverse Reactions (6.2)]. Patients treated concomitantly with Xenical and levothyroxine should be monitored for changes in thyroid function. Administer levothyroxine and Xenical at least 4 hours apart [see Dosage and Administration (2)].
Warfarin
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 [see Pharmacokinetics (12.3)].
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category X
Xenical is contraindicated during pregnancy, because weight loss offers no potential benefit to a pregnant woman and may result in fetal harm. A minimum weight gain, and no weight loss, is currently recommended for all pregnant women, including those who are already overweight or obese, due to the obligatory weight gain that occurs in maternal tissues during pregnancy. No embryotoxicity or teratogenicity was seen in animals that received orlistat at doses much higher than the recommended human dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard of maternal weight loss to the fetus.
Animal Data
Reproduction 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/m2) basis for rats and rabbits, respectively.
Nursing Mothers
It is not known if Xenical is present in human milk. Caution should be exercised when Xenical is administered to a nursing woman.
Pediatric Use
Safety and effectiveness in pediatric patients below the age of 12 have not been established.
The safety and efficacy of Xenical have been evaluated in obese adolescent patients aged 12 to 16 years. Use of Xenical in this age group is supported by evidence from adequate and well-controlled studies of Xenical in adults with additional data from a 54-week efficacy and safety study and a 21-day mineral balance study in obese adolescent patients aged 12 to 16 years. Patients treated with Xenical in the 54-week efficacy and safety study (64.8% female, 75% Caucasians, 18.8% Blacks, and 6.3% Other) had a mean reduction in BMI of 0.55 kg/m2 compared with an average increase of 0.31 kg/m2 in placebo-treated patients (p=0.001). In both adolescent studies, adverse effects were generally similar to those described in adults and included fatty/oily stool, oily spotting, and oily evacuation. In a subgroup of 152 Xenical and 77 placebo patients from the 54-week study, changes in body composition measured by DEXA were similar in both treatment groups with the exception of fat mass, which was significantly reduced in patients treated with Xenical compared to patients treated with placebo (-2.5 kg vs -0.6 kg, p=0.033). Because Xenical can interfere with the absorption of fat-soluble vitamins, all patients should take a daily multivitamin that contains vitamins A, D, E, K, and beta-carotene. The vitamin supplement should be taken at least 2 hours before or after Xenical [see Dosage and Administration (2), Warnings and Precautions (5.1), and Clinical Pharmacology (12.2)].
Plasma concentrations of orlistat and its metabolites M1 and M3 were similar to those found in adults at the same dose level. Daily fecal fat excretions were 27% and 7% of dietary intake in Xenical and placebo treatment groups, respectively.
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)].
Drug Abuse and Dependence
Abuse
As with any weight-loss agent, the potential exists for abuse of Xenical in inappropriate patient populations (eg, patients with anorexia nervosa or bulimia). See Indications and Usage (1) for recommended prescribing guidelines.
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 Xenical should be rapidly reversible.
Xenical Description
Xenical (orlistat) is a gastrointestinal 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 C29H53NO5, 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. The structure is:
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 pKa within the physiological pH range.
Xenical is available for oral administration as a dark-blue or turquoise hard-gelatin capsule. The dark blue capsule is imprinted with light blue and the turquoise capsule is imprinted with black. Each capsule contains a pellet formulation consisting of 120 mg of the active ingredient, orlistat, as well as the inactive ingredients microcrystalline cellulose, sodium starch glycolate, sodium lauryl sulfate, povidone, and talc. The dark blue 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. The turquoise capsule shell contains gelatin, titanium dioxide, and FD&C Blue No. 2 with black printing ink containing pharmaceutical grade shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonium solution, potassium hydroxide and black iron oxide.
Xenical - Clinical Pharmacology
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. As undigested triglycerides are not absorbed, the resulting caloric deficit may have a positive effect on weight control.
Pharmacodynamics
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.
Other Short-term Studies
Adults
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.
Pediatrics
In a 3-week study of 32 obese adolescents aged 12 to 16 years, Xenical (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 Xenical and placebo treatment groups, respectively.
Pharmacokinetics
Absorption
Systemic exposure to orlistat is minimal. Following oral dosing with 360 mg 14C-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 14C-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 14C-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 14C-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 Xenical and 40 grams of alcohol (eg, approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat.
Cyclosporine
In a multiple-dose study, coadministration of 50 mg cyclosporine twice daily with 120 mg Xenical three times daily decreased cyclosporine AUC and Cmax by 31 and 25%, respectively. In the same study, administration of 50 mg cyclosporine twice daily three hours after the administration of 120 mg Xenical three times daily decreased cyclosporine AUC and Cmax by 17 and 4%, respectively.
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 Xenical 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.
Levothyroxine
Hypothyroidism has been reported in patients treated concomitantly with Xenical and levothyroxine postmarketing.
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 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving Xenical 120 mg three times a day for 6 days, Xenical did not affect the pharmacokinetics of pravastatin.
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.
Nonclinical Toxicology
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 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/m2) basis.
Clinical Studies
The long-term effects of Xenical 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 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 Xenical on weight regain. These studies included over 2800 patients treated with Xenical and 1400 patients treated with placebo (age range 17-78 years, 80.2% women, 91.0% Caucasians, 5.7% Blacks, 2.3% Hispanics, 0.1% 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 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 F
