Xenical Warnings
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.
WARNINGS
Miscellaneous
Organic causes of obesity (eg, 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 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). 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 9 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.
Table9 Incidence of Low Vitamin Values on Two or More Consecutive Visits(Nonsupplemented Adult Patients With Normal Baseline Values - Firstand 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 10 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 10 Incidence of Low Vitamin Values on Two or More ConsecutiveVisits (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% |
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 (eg, sulfonylureas, metformin) or insulin (see CLINICAL STUDIES).
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. In this trial, the incidence of cholelithiasis was similar for
Xenical and placebo at similar amounts of weight loss. An increase in cholelithiasis with
Xenical was not seen in trials that were not evaluating the prevention of type 2 diabetes.
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 INDICATIONS AND USAGE 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 (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
Preliminary data from a
Xenical and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when
Xenical was coadministered with cyclosporine (see WARNINGS).
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.
Levothyroxine
Hypothyroidism has been reported in patients treated concomitantly with
orlistat and levothyroxine postmarketing (see ADVERSE REACTIONS: Other Clinical Studies or Postmarketing Surveillance). Patients treated concomitantly with
orlistat and levothyroxine should be monitored for changes in thyroid function. Administer levothyroxine and
orlistat at least 4 hours apart.
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.
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.
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/m2) 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/m2) 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 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 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
orlistat 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 supplementshould be taken at least 2 hours before or after
Xenical (see CLINICAL PHARMACOLOGY: Other Short-term Studies; CLINICAL STUDIES: Pediatric Clinical Studies; ADVERSE REACTIONS: Pediatric Patients).
Xenical has not been studied in pediatric patients below the age of 12 years.
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 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.)
Table11 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 |
| 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 |
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 12 Other Treatment-Emergent AdverseEvents From Seven Placebo-Controlled Clinical Trials | Year 1 | Year 2 |
|---|
| Body System/Adverse Event | 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 |
|
| GastrointestinalSystem | | | | |
| 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 | – | – |
| RespiratorySystem | | | | |
| 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 | – | – |
| MusculoskeletalSystem | | | | |
| 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 NervousSystem | | | | |
| Headache | 30.6 | 27.6 | – | – |
| Dizziness | 5.2 | 5.0 | – | – |
| Body as aWhole | | | | |
| 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 |
| PsychiatricDisorder | | | | |
| 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 |
| CardiovascularDisorders | | | | |
| 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.
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, bronchospasm and anaphylaxis. Very rare cases of bullous eruption, increase in transaminases and in alkaline phosphatase, and exceptional cases of hepatitis that may be serious have been reported. No causal relationship or physiopathological mechanism between hepatitis and
orlistat therapy has been established. Reports of decreased prothrombin, increased INR and unbalanced anticoagulant treatment resulting in change of hemostatic parameters have been reported in patients treated concomitantly with
orlistat and anticoagulants. Hypothyroidism has been reported in patients treated concomitantly with
orlistat and levothyroxine. 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.
In clinical trials in obese diabetic patients, hypoglycemia and abdominal distension were also observed.
Preliminary data from a
Xenical and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when
Xenical was coadministered with cyclosporine (see WARNINGS).
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.