Xenical - Treatment for Obesity & Overweight

Xenical (Orlistat)

orlistat 120mg capsule

Presentation

XENICAL 12Omg capsules have a turquoise cap and turquoise body with imprint of XENICAL ROCHE 120 on both the cap and body.

Uses

Actions

XENICAL is a potent, specific and long acting 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 site of the gastric and pancreatic lipases. The inactivated enzyme is thus unable to hydrolyse dietary fat, in the form of triglycerides, into absorbable free fatty acids and monoglycerides. As undigested triglycerides are not absorbed, the resulting caloric deficit has a positive effect on weight control Systemic absorption is therefore not needed for activity.

Single and repeated dose toxicity studies in rodents and dogs have demonstrated a similar pattern of dose related effects across species, none of which is considered relevant to the recommended use in man.

No orlistat associated mutagenicity or genotoxicity has been observed in a standard battery of five different short-term assays.

Carcinogenicity studies in rats and mice have not shown a carcinogenic potential for orlistat at doses up to 1000mg/kg/day and 1500mg/kg/day respectively. These doses are 18Z and 125 times the daily human dose calculated on a body surface area (mg/m') basis. There was a decreased incidence of mammary fibroadenoma in female rats in the high dose group. No orlistat associated adverse effects were observed in Segment I, II and III reproductive toxicity studies at doses ranging 62-241 times the recommended clinical dose.

Pharmacokinetics

Absorbtion

Studies in normal weight and obese volunteers have shown that the extent of absorption of orlistat was minimal. Plasma concentrations of intact orlistat were non-measurable ( < 5 mg/ml) eight hours following oral administration of orlistat. In general, at therapeutic doses, detection of intact orlistat in plasma was sporadic and concentrations were extremely low (< 10 mg/ml or 0.02 pM), without evidence of accumulation, and consistent with negligible absorption.

Distribution

The volume of distribution cannot be determined because orlistat is minimally absorbed and has no defined systemic pharmacokinetics. In vitro orlistat is >99'/o bound to plasma proteins (lipoproteins and albumin were the major binding proteins). Orlistat minimally partitions into erythrocytes.

Metabolism

Based on animal data, it is likely that the metabolism of orlistat occurs mainly within the qastrointestinal wall. Based on a study in obese patients, of the minute fraction of the dose that was absorbed systematically, two major metabolites, M1 (4-member lactone ring hydrolysed) and M3 (M1 with N-formyl leucine moiety cleaved), accounted for approximately 42% of the total plasrna concentration. M1 arid M3 have an open E-lactone ring and extremely weak lipase inhibitory activity (1000 and 2500 fold less than orlistat receptively). In view of this low inhibitory activity and the low plasma levels al therapeutic doses (average of 26 mg/ml and 108 mg/ml respectively), these metabolites are considered to be pharmacologically inconsequential.

Elimination

Studies in normal weight and obese subjects have shown that faecal excretion of the unabsorbed substance was the major route of elimination. Approximately 97% of the administered dose was excreted in faeces and 83% of that as unchanged orlistat.
The cumulative renal excretion of total orlistat-related materials was < 2% of the given dose. The time to reach complete excretion (faecal plus urinary) was 3 to 5 days. The disposition of orlistat appeared to be similar between normal weight and obese volunteers. Orlistat, M1 and M3 are all subject to biliary excretion.

Indications

XENICAL is indicated for long-term treatment of significantly obese patients, including patients with risk factors associated with obesity, in conjunction ion with a mildly hypocaloric diet. XENICAL is effective in long-term weight control (weight loss, weight maintenance and prevention of weight regain). Treatment with XENICAL results in an improvement of risk factors and comorbidities associated with obesity, including hypercholesterolemia non-insulin-dependent diabetes mellitus (NIDDM), impaired glucose tolerance, hyperinsulinemia, hypertension and in a reduction of visceral fat.

Dosage and Adminstration

Adults

The recommended dose of XENICAL is one I 20mg capsule with each main meal ( during or up to one hour after the meal). If a meal is missed or contains no fat, the dose of XENICAL may be omitted. The therapeutic benefits of XENICAL (including weight control and improvement of risk factors) are continued with long-term administration.
The patient should be on a nutritionally balanced, mildly hypocaloric diet that contains approximately 30% of calories from fat. It is recommended that the diet should t>e rich in fruit and vegetables The daily intake of fat, carbohydrate and protein should be distributed over three main meals. Doses above 120mg three times daily have not been shown to provide additional benefit. No dose adjustment is necessary for the geriatric patient. Based on faecal fat measurements, the effect of XENICAL is seen as soon as Z4 to 48 hours after dosing. Upon discontinuation of therapy, faecaI fat content usually returns to pre-treatment levels, within 48 to 72 hours.

Hepaticand/or Renal Impariment

Dose adjustment is not required.

Children below the age of 18 years

The safety and efficacy of XENICAL in children have not been established.

Contraindications

XENICAL is contraindicated in patients with chronic malabsorption syndrome and in patients with known hypersensitivity to orlistat or any of the other components contained in the capsule.

Warnings And Precautions

No serious adverse reactions or safety hazards related to the use of XENICAL have been reported to date during large, long-term clinical trials (3300 patients treated with XENICAL for up to 2 years) (see Adverse Effects). Patients should be advised to adhere to dietary guidelines (see Dosage and Administration). The possibility of experiencing gastrointestinal events (see Adverse Effects) may increase when XENICAL is taken with a diet high in fat (e.g. in a 2000 calorie/day diet, >30% of calories from fat equates to >67g of 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 may increase.

Use during pregnancy and lactation

The safety of XENICAL has not been established in pregnant women. In animal reproductive studies no embryotoxic or teratogenic effects were observed that were considered to be associated with XFNICAI. However, because animal studies are not always predictive of human response, XENICAL should not be used during pregnancy unless the potential benefit outweighs the potential risk. XI-NICAI should not be taken by nursing women, because it is not known whether XENICAL is secreted in human milk, unless the potential benefit outweighs the potential risk.

Effect on ability to drive and use machines

No effects on the patient's ability to drive and use machines have been reported.

Adverse Effects

The safety of orlistat has not been established beyond two years. Adverse. reactions to XENICAL are largely gastrointestinal in nature and related to the pharmacological effect of the substance on preventing the absorption of ingested fat (see Actions). Commonly observed events are oily spotting, flatus with discharge, faecal urgency, fatty/oily stool, oily evacuation, increased defecation and faecal incontinence.
The incidence of these increases the higher the fat content of the diet and thus faeces. Patients should be counseled as to the possibility of gastrointestinal effects occurring and how best to handle them such as reinforcing the diet, particularly the percentage of fat it contains. Consumption of a diet low in fat will decrease the likelihood of experiencing adverse gastrointestinal events and this may help patients monitor and regulate their fat intake. In clinical studies, these pharmacological effects were not considered an impediment to continuation of therapy. These adverse reactions are generally mild and transient. Gastrointestinal events occurred early in treatment (within 3 months) and most patients experienced only one episode. On y 3% of patients experienced more than two episodes of any one adverse. event.

In a clinical programme with over 4,000 patients treated for up to Z years, there were a total of 11 reports of breast cancer, all in women 45 years of age or older. There were 10 reports of breast cancer in the XENICAL treated subgroups (N=1063) and 1 in the placebo subgroup (N=579!. The total number of patients reporting breast cancer was small but the, imbalance seen warranted further evaluation. All study patients 45 years of age or older were followed up and all available data were thorough y reviewed by independent clinical experts in the fields of oncology, pathology, radiology and epiderniology. Follow up revealed two more patients with breast cancer in a XENICAL group and two more in the placebo group.

For 6 of the XENICAL patients, mammograms were available from before XENICAL treatment had commenced and in 4 of these 6 it was possible to detect the lesion when the mammogram was re-examined. Most cancers found were 25mm in diameter and, as it takes 8 to 12 years for a cancer to grow from a single cell to 10mm, it is clear that most tumors were pre-existing. A specific marker found in 9 tumors suggests the lesion was at least 5 years old. Of the 1Z patients treated with XENICAL 1ZOmg, 60mg or 30mg found to have breast cancer, 9 had tumors which were proved to have been pre-existing. Of the 3 patients treated with placebo who were found to have breast cancer, one tumor was proven to have been pre-existing.

In summary, there were 3 cases of breast cancer possibly related to therapy in patients in the XFNICAL treatment groups (N=1063) and Z cases possibly related to therapy in patients in the placebo treatment group (N=579). Epidemiological data suggest that if XENICAL were a promoter of cancer, one would expect to see other cancers, and if it were an enhance one would expect to see increased growth around existing tumors. In neither case was this found. A tabulation of the data is as follows:

Breast Cancer Cases

About XENICAL (Orlistat) Capsules

XENICAL (zen´ i-cal)
Generic Name: orlistat

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.

What is XENICAL?

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.

How does XENICAL work?

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 breakdown) 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.

Who should use XENICAL?

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.

Who should not use XENICAL?

Those who:

• consistently have problems absorbing food (chronic malabsorption); or
• have gallbladder problems; or
• are pregnant or are breastfeeding a child; or
• have ever had an allergic reaction to orlistat or any of the inactive ingredients in XENICAL.

What should I tell my doctor before taking XENICAL?

Before beginning treatment with XENICAL, make sure your doctor knows if you are:

• allergic to any medicines, foods, or dyes;
• taking any other weight-loss medication;
• taking cyclosporine;
• taking any other medicines (including those not prescribed by your doctor);
• taking any dietary supplements, including herbal products;
• planning to become pregnant; or
• anorexic or bulimic.

This information will help you and your physician decide if the expected advantages of XENICAL are greater than any possible disadvantages.

How should I take XENICAL?

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.

Should I take a multivitamin with XENICAL?

XENICAL interferes with your body’s absorption of some fat-soluble vitamins. Therefore, when you use XENICAL, you should take a daily multivitamin supplement that contains vitamins D, E, K, and beta-carotene. Take your multivitamin once a day at least 2 hours before or after taking XENICAL, such as at bedtime.

Can I take XENICAL while taking other medications?

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.

How long should I use XENICAL?

The use of XENICAL for more than 2 years has not been studied. You and your doctor should discuss how long you should use XENICAL.

What are the most common side effects of 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.

If you are concerned about these or any other side effects you experience while taking XENICAL, talk to your doctor or pharmacist.

What lifestyle changes should I consider when taking XENICAL?

You must use XENICAL with a recommended mildly reduced-calorie diet. You should also follow a program of regular physical activity, such as walking. However, before you undertake any activity or exercise program, be sure to speak with your doctor or health care professional.

How can I reduce dietary fat?

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.

• When eating meat, poultry or fish, limit your portion to 2 or 3 ounces (roughly the size of a deck of cards). Choose lean cuts of meat and remove the skin from poultry. Fill up your meal plate by including more grains, fruits, and vegetables.
• Replace whole-milk products with nonfat or 1% milk and nonfat, reduced-fat, or low-fat dairy items.
• Cook with less fat. Use vegetable oil spray when cooking. Salad dressings, many baked items, and prepackaged, processed, and fast foods are usually high in fat. Use the low- or non-fat versions and/or cut back on serving sizes.
• When dining out, ask how foods are prepared and request that they be prepared with little or no added fat.