Xenical Information
Xenical () Description
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 CHNO, 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 p 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 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 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 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 the XENDOS study, which included 3304 patients, 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.
Xenical () Indications And Usage
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 or ≥ 27 kg/m in the presence of other risk factors (eg, hypertension, diabetes, dyslipidemia).
Xenical () 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.
Xenical () Precautions
Patients should be advised to adhere to dietary guidelines (see ). Gastrointestinal events (see ) 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 ). 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
Table 10
There have been rare postmarketing reports of severe liver injury with hepatocellular necrosis or acute hepatic failure in patients treated with orlistat 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 orlistat. When these symptoms occur, orlistat and other suspect medications should be discontinued immediately and liver function tests and ALT and AST levels obtained.
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 ).
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.
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/m) basis.
Xenical () Adverse Reactions
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.)
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.
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.
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.
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. 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 ).
Xenical () 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.
Xenical () 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 (see ). The supplement should be taken at least 2 hours before or after the administration of Xenical () , such as at bedtime.
For patients receiving both orlistat and levothyroxine therapy, administer levothyroxine and orlistat at least 4 hours apart.
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 4 years have not been determined at this time.
Xenical () How Supplied
Xenical () is a dark-blue or turquoise, 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).
Xenical () 120 mg Capsules: Turquoise, two-piece, No. 1 opaque hard-gelatin capsule imprinted with ROCHE and Xenical () 120 in black ink — bottle of 90 (NDC 0004-0257-52).
Xenical () Important Patient Information
Please read this information before you start taking Xenical () and each time you renew your prescription. This important information may help you successfully lose weight and maintain your weight loss while taking Xenical () . This patient information is a summary and is not intended to take the place of discussions with your doctor. It does not list all benefits and risks of Xenical () . The medication described here can only be prescribed and dispensed by a licensed health care professional, who has information about your medical condition and more information about the drug, including how to take it, what to expect, and potential side effects. If you have any questions about Xenical () , talk with your doctor.
Xenical () is an oral prescription weight loss medication used to help obese people lose weight and keep this weight off. Xenical () works in your intestines, where it blocks some of the fat you eat from being absorbed. This undigested fat is then eliminated in your bowel movements. Xenical () should be used together with a reduced-calorie diet that your doctor will recommend.
Excess weight has been proven to contribute to an increased risk of developing many medical problems, including high blood pressure, high cholesterol, heart disease, and diabetes. The consumption of excess fatty food and calories plays a significant role in the development of excess weight. While fat is an important component of a balanced diet, the consumption of excess fat contributes to excess body weight, since fat provides twice the number of calories per gram of weight as carbohydrates and protein. Reduction of dietary fat intake is one potential way of losing weight.
If you eat an excess amount of fat or calories, the excess is stored as fat by the body resulting in weight gain. When you eat fat, your body breaks it down into its simplest components so that it can be absorbed. Enzymes in your intestinal tract, called lipases, help digest (or break down) fat. When you take Xenical () with meals, Xenical () attaches to the lipases and blocks them from breaking down some of the fat you have eaten. The undigested fat cannot be absorbed and is eliminated in your bowel movements. By working this way, Xenical () helps block about 30% of the fat eaten in food from being absorbed by your body.
Following one year of treatment, Xenical () in combination with diet was shown to be more effective in reducing weight than diet alone. In most cases, weight loss was gradual. Patients treated with Xenical () and a reduced-calorie diet for one year lost an average of 13.4 pounds while those on a reduced-calorie diet alone lost 5.8 pounds.
Following one year of treatment, Xenical () in combination with diet was shown to be more effective in reducing Body Mass Index (BMI) than diet alone. A reduction in Body Mass Index is a better indicator of weight loss in children because it takes into account changes in weight related to growing children.
A weight loss program that includes a reduced-calorie diet and appropriate physical activity may be adequate in some patients. You should discuss with your doctor or other health care provider whether Xenical () should be added to such a program.
Xenical () may be right for you if you are considerably overweight (at least 30% above ideal weight or a body mass index of 30 or greater). Xenical () may also be right for you if you are overweight (at least 20% above ideal weight or a body mass index of 27 or greater) and also have other risk factors such as high blood pressure, high cholesterol, heart disease, or diabetes.
The chart below illustrates BMI according to a variety of weights and heights. The BMI is calculated by dividing your weight in kilograms by your height in meters squared. To use this chart:
Those who:
Before beginning treatment with Xenical () , make sure your doctor knows if you are:
This information will help you and your physician decide if the expected advantages of Xenical () are greater than any possible disadvantages.
The recommended dose is one 120 mg capsule by mouth with liquid at each main meal that contains fat. You can take Xenical () in conjunction with a mildly reduced-calorie diet up to 3 times a day. Each time you take Xenical () , your meal should contain no more than about 30% of calories from fat. Take Xenical () during meals or up to one hour after a meal. If you occasionally miss a meal or have a meal without fat, you can omit your dose of Xenical () . Doses greater than 120 mg three times a day have not been shown to provide an additional weight loss benefit.
You should use Xenical () together with a nutritionally balanced, mildly reduced-calorie diet that contains no more than about 30% of calories from fat. You should evenly divide your daily intake of fat, carbohydrates, and protein over 3 main meals.
You should try to follow a healthy eating plan such as the one developed by the American Heart Association. Following this eating plan will help you lose weight while decreasing some of the possible gastrointestinal effects you may experience while taking Xenical () .
Be sure to discuss with your doctor all medications (including herbal products) you are currently taking, including medicines you can get without a prescription (over-the-counter), to determine if Xenical () can be taken in addition to these medications. If you are taking cyclosporine, Xenical () and cyclosporine should be taken at least 2 hours apart. If your cyclosporine levels are being measured, more frequent monitoring may be necessary. If you are taking levothyroxine, Xenical () and levothyroxine should be taken at least 4 hours apart.
The use of Xenical () for more than 4 years has not been studied. You and your doctor should discuss how long you should use Xenical () .
Because Xenical () works by blocking the absorption of dietary fat, it is likely that you will experience some changes in bowel habits. These generally occur during the first weeks of treatment; however, they may continue throughout your use of Xenical () . These changes may include oily spotting, gas with discharge, urgent need to go to the bathroom, oily or fatty stools, an oily discharge, increased number of bowel movements, and inability to control bowel movements. Due to the presence of undigested fat, the oil seen in a bowel movement may be clear or have a coloration such as orange or brown.
These bowel changes are a natural effect of blocking the fat from being absorbed and indicate that Xenical () is working. They generally occur early in treatment, particularly after meals containing higher amounts of fat than are recommended. These symptoms are often temporary and may lessen or disappear as you continue treatment and keep to your recommended diet of meals containing no more than about 30% fat. However, these side effects may occur in some individuals over a period of 6 months or longer.
In obese adolescent patients treated with Xenical () , the side effects reported were similar to those observed in adults.
To help you get started on reducing the fat in your diet to around 30%, read the labels on all the foods you buy. You should avoid foods that contain more than 30% fat while you are taking Xenical () .
Xenical () is a registered trademark of Roche Laboratories Inc.
PPI Revised: May 2010
Distributed by:Genentech USA, Inc.A Member of the Roche Group1 DNA WaySouth San Francisco, CA 94080-4990
XLT_180647_PI_092010_KXLT_180647_PPI_032010_N
Revised: December 2010
© 2010 Genentech, Inc. All rights reserved.
Representative sample of labeling (see the section for complete listing):
Xenical () Principal Display Panel - Mg Capsule Bottle Label
NDC 0004-0256-52
Each capsule contains120 mg orlistat.
Xenical () Principal Display Panel - Mg Capsule Bottle Label
NDC 0004-0257-52
Each capsule contains120 mg orlistat.
