Side Effects of Xenical (orlistat)

Xenical (orlistat) is a gastrointestinal lipase inhibitor used combined with a reduced-calorie diet to promote weight loss. Xenical also may be used to prevent weight gain after weight has been lost.

Candidates for treatment with Xenical are patients who are obese with a body mass index (a measure of obesity) of more than 30 kg/m2. Candidates also include patients with a body mass index of between 27 and 30 kg/m2 if other risk factors for arteriosclerosis are present such as high blood pressure, diabetes, and elevated blood cholesterol or triglycerides.

Based on several scientific studies, the average weight loss that is achieved when Xenical is taken as recommended for six months to one year is 12.4 to 13.4 pounds.

Common side effects of Xenical include

• oily spotting on underwear,
• gas (flatulence),
• urgent bowel movements,
• fatty or oily stools,
• increased number of bowel movements,
• abdominal pain or discomfort, and
• inability to control stool (incontinence).

Serious side effects of Xenical include

• liver failure (symptoms include loss of appetite, itching, jaundice, dark urine, light colored stools, or right upper abdominal pain),
• serious allergic reactions,
• angioedema, and
• deficiency in fat-soluble vitamins.

Drug interactions of Xenical include warfarin, because its blood thinning effect depends on the amount of vitamin K in the body, and vitamin K is one of the vitamins that binds to fat. Patients receiving warfarin who begin Xenical should have their blood clotting monitored closely because the Xenical may cause levels of vitamin K to decline. This will increase the effects of warfarin and lead to abnormal bleeding from the warfarin.

Xenical may reduce the absorption and blood levels of cyclosporine when both drugs are administered together.

Hypothyroidism has been reported when Xenical and levothyroxine were combined.

Safe use of Xenical during pregnancy has not been established and Xenical is not recommended during pregnancy.

It is unknown if Xenical is secreted in breast milk. Xenical probably should not be taken by breastfeeding mothers.

The most common side effects of orlistat are:

• oily spotting on underwear,
• flatulence,
• urgent bowel movements,
• fatty or oily stools,
• increased number of bowel movements,
• abdominal pain or discomfort, and
• inability to control stool (incontinence).

From 1 in 250 and 1 in 70 patients experienced one or more of these symptoms in the first year. Generally, the side effects occurred within three months of starting therapy.

• In about 50% of patients, the side effects resolved within one to four weeks, but the effects in some patients lasted six months or longer.
• To reduce the occurrence of these side effects, meals should contain no more than 30% fat because it is the unabsorbed fat that causes most of the symptoms. Alli causes fewer side effects because it contains half the dose of prescription-strength orlistat. Patients receiving orlistat with a history of oxalate kidney stones may develop increased levels of oxalate in their urine, which may increase the risk of kidney stones.

Liver failure has been reported in patients treated with orlistat. Orlistat should be discontinued if symptoms of liver failure (loss of appetite, anorexia, itching, jaundice, dark urine, light colored stools, or right upper abdominal pain) occur while taking orlistat.

Other serious side effects of orlistat include:

• Serious allergic reactions
• Angioedema
• Deficiency in fat-soluble vitamins

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 2 : Commonly Observed Adverse Events

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 3 : Other Treatment-Emergent Adverse Events From Seven Placebo-Controlled Clinical Trials

Table 4 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 4 : Incidence of Low Vitamin Values on Two or More Consecutive Visits (Nonsupplemented Adult Patients With Normal Baseline Values - Firs t and Second Year)

Table 5 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 5 : Incidence of Low Vitamin Values on Two or More Consecutive Vis its (Pediatric Patients With Normal Baseline Values*)

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 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.

• 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.
• 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.
• Rare cases of leukocytoclastic vasculitis have been reported. Clinical signs include palpable purpura, maculopapular lesions, or bullous eruption.
• Acute oxalate nephropathy after treatment with Xenical has been reported in patients with or at risk for renal disease.
• 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.

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.

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.

Levothyroxine

Hypothyroidism has been reported in patients treated concomitantly with Xenical and levothyroxine postmarketing. Patients treated concomitantly with Xenical and levothyroxine should be monitored for changes in thyroid function. Administer levothyroxine and Xenical at least 4 hours apart.

Anticoagulants Including Warfarin

Vitamin K absorption may be decreased with Xenical. 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. Patients on chronic stable doses of warfarin or other anticoagulants who are prescribed Xenical should be monitored closely for changes in coagulation parameters.

Amiodarone

A pharmacokinetic study, where amiodarone was orally administered during orlistat treatment, demonstrated a reduction in exposure to amiodarone and its metabolite, desethylamiodarone. A reduced therapeutic effect of amiodarone is possible. The effect of commencing orlistat treatment in patients on stable amiodarone therapy has not been studied.

Antiepileptic Drugs

Convulsions have been reported in patients treated concomitantly with orlistat and antiepileptic drugs. Patients should be monitored for possible changes in the frequency and/or severity of convulsions.

Antiretroviral Drugs

Loss of virological control has been reported in HIV-infected patients taking orlistat concomitantly with antiretroviral drugs such as atazanavir, ritonavir, tenofovir disoproxil fumarate, emtricitabine, and with the combinations lopinavir/ritonavir and emtricitabine/efavirenz/tenofovir disoproxil fumarate.

The exact mechanism for this is unclear, but may include a drug-drug interaction that inhibits systemic absorption of the antiretroviral drug. HIV RNA levels should be frequently monitored in patients who take Xenical while being treated for HIV infection. If there is a confirmed increase in HIV viral load, Xenical should be discontinued.

Drug Abuse And Dependence

Abuse

As with any weight-loss agent, the potential exists for abuse of Xenical in inappropriate patient populations (e.g., patients with anorexia nervosa or bulimia). See prescribing information for recommended prescribing guidelines.