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warnings and cautions
5 WARNINGS AND PRECAUTIONS XENICAL can decrease cyclosporine exposure. ( 5.1 ) Take a multivitamin supplement that contains fat-soluble vitamins to ensure adequate nutrition. ( 5.1 ) Rare cases of severe liver injury with hepatocellular necrosis or acute hepatic failure have been reported. ( 5.2 ) Patients may develop increased levels of urinary oxalate following treatment with XENICAL. Monitor renal function in patients at risk for renal insufficiency. ( 5.3 ) Substantial weight loss can increase the risk of cholelithiasis. ( 5.4 ) Exclude organic causes of obesity (eg, hypothyroidism) before prescribing XENICAL. ( 5.5 ) Gastrointestinal events may increase when XENICAL is taken with a diet high in fat (>30% total daily calories from fat). ( 5.5 ) 5.1 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 Treatment designates placebo plus diet or XENICAL plus diet 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 All patients were treated with vitamin supplementation throughout the course of the study ) Placebo Treatment designates placebo plus diet or XENICAL plus diet 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 (e.g., sulfonylureas) or insulin may be required in some patients [see Clinical Studies (14) ] . 5.2 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. 5.3 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. 5.4 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. 5.5 Miscellaneous Organic causes of obesity (e.g., 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.
warnings and cautions table
<table ID="table2" width="75%"> <caption>Table 2 Incidence of Low Vitamin Values on Two or More Consecutive Visits (Nonsupplemented Adult Patients With Normal Baseline Values - First and Second Year)</caption> <col width="40%" align="left" valign="top"/> <col width="30%" align="center" valign="top"/> <col width="30%" align="center" valign="top"/> <thead> <tr> <th styleCode="Lrule"/> <th>Placebo<footnote ID="table2a">Treatment designates placebo plus diet or XENICAL plus diet</footnote> </th> <th styleCode="Rrule">XENICAL<footnoteRef IDREF="table2a"/> </th> </tr> </thead> <tbody> <tr> <td styleCode="Lrule">Vitamin A</td> <td>1.0%</td> <td styleCode="Rrule">2.2%</td> </tr> <tr> <td styleCode="Lrule">Vitamin D</td> <td>6.6%</td> <td styleCode="Rrule">12.0%</td> </tr> <tr> <td styleCode="Lrule">Vitamin E</td> <td>1.0%</td> <td styleCode="Rrule">5.8%</td> </tr> <tr> <td styleCode="Lrule">Beta-carotene</td> <td>1.7%</td> <td styleCode="Rrule">6.1%</td> </tr> </tbody> </table>
warnings and cautions table
<table ID="table3" width="75%"> <caption>Table 3 Incidence of Low Vitamin Values on Two or More Consecutive Visits (Pediatric Patients With Normal Baseline Values<footnote ID="table3a">All patients were treated with vitamin supplementation throughout the course of the study</footnote>)</caption> <col width="40%" align="left" valign="top"/> <col width="30%" align="center" valign="top"/> <col width="30%" align="center" valign="top"/> <thead> <tr> <th styleCode="Lrule"/> <th>Placebo<footnote ID="table3b">Treatment designates placebo plus diet or XENICAL plus diet</footnote> </th> <th styleCode="Rrule">XENICAL<footnoteRef IDREF="table3b"/> </th> </tr> </thead> <tbody> <tr> <td styleCode="Lrule">Vitamin A</td> <td>0.0%</td> <td styleCode="Rrule">0.0%</td> </tr> <tr> <td styleCode="Lrule">Vitamin D</td> <td>0.7%</td> <td styleCode="Rrule">1.4%</td> </tr> <tr> <td styleCode="Lrule">Vitamin E</td> <td>0.0%</td> <td styleCode="Rrule">0.0%</td> </tr> <tr> <td styleCode="Lrule">Beta-carotene</td> <td>0.8%</td> <td styleCode="Rrule">1.5%</td> </tr> </tbody> </table>
6 ADVERSE REACTIONS Most common treatment emergent adverse reactions (≥5% and at least twice that of placebo) include oily spotting, flatus with discharge, fecal urgency fatty/oily stool, oily evacuation, increased defecation and fecal incontinence. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 Treatment designates XENICAL three times a day plus diet or placebo plus diet % Patients (N=1913) Placebo % Patients (N=1466) XENICAL % Patients (N=613) Placebo % Patients (N=524) Oily Spotting Oily discharge may be clear or have a coloration such as orange or brown. 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 Treatment designates XENICAL 120 mg three times a day plus diet or placebo plus diet % 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. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of XENICAL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to XENICAL exposure. 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 (7.1) ] . 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. Convulsions have been reported in patients treated concomitantly with orlistat and antiepileptic drugs [see Drug Interactions (7.5) ].