Xenical - instructions for use, dose, side effects, contraindications

* pellet composition: orlistat - 120 mg, microcrystalline cellulose - 93.60 mg, sodium carboxymethyl starch (primogel) - 7.20 mg, povidone K-30 - 12.00 mg, sodium lauryl sulfate-7.20 mg; Excipients: talc - 0.24 mg;

Capsule shell composition: gelatin, indigo carmine, titanium dioxide.

Description:

Hard gelatin capsules # 1, opaque, turquoise. On the capsule case there is an inscription "XENICAL 120 ", on the lid - "ROCHE", black color. The contents of the capsules are pellets of white or almost white color.

Pharmacotherapeutic group:GI lipase inhibitor

ATX: & nbsp

A.08.A.B.01 Orlistat

Pharmacodynamics:

Xenical® is a powerful, specific and reversible inhibitor of gastrointestinal lipases, which has a long-lasting effect. Its therapeutic effect is carried out in the lumen of the stomach and small intestine and consists in the formation of a covalent bond with the active serine portion of the gastric and pancreatic lipases. The inactivated enzyme loses its ability to break down the food fats that come in the form of triglycerides, to sucking free fatty acids and monoglycerides. Since uncleaved triglycerides are not absorbed, the resulting decrease in the intake of calories into the body leads to a decrease in body weight.Thus, the therapeutic effect of the drug is carried out without absorption into the systemic bloodstream.

Judging by the results of fat content in feces, the action of orlistat begins 24-48 hours after ingestion. After the drug is withdrawn, the fat content in the stool after 48-72 hours usually returns to the level that occurred before the start of therapy.

Efficiency

Patients with obesity

In clinical trials in patients taking orlistat, there was a large loss of body weight compared with patients on diet therapy. The decrease in body weight began already within the first 2 weeks after the beginning of treatment and lasted from 6 to 12 months even in patients with a negative response to diet therapy. For 2 years, there was a statistically significant improvement in the profile of metabolic risk factors associated with obesity. In addition, compared to taking placebo, there was a significant decrease in the amount of fat in the body. Orlistat It is effective in preventing repeated weight gain. A re-set of body weight, no more than 25% of the lost weight, was observed in about half of the patients, and half of these patients did not observe repeated weight gain or even further decrease.

Patients with obesity and type 2 diabetes mellitus

In clinical studies lasting from 6 months to 1 year in patients with overweight or obesity and type 2 diabetes mellitus orlistat, there was a large loss of body weight compared to patients,

treated only diet. Weight loss occurred in mainly by reducing the amount of fat in the body. It should be noted that up to the beginning of the study, despite the use of hypoglycemic agents, patients often

there was insufficient glycemic control. However, during the treatment with orlistat, statistically and clinically significant improvement in glycemic control was observed. In addition, against the background of orlistat therapy, there was a decrease in doses of hypoglycemic agents, insulin concentrations, and a decrease in insulin resistance.

Reducing the risk of developing type 2 diabetes in obese patients In a 4-year clinical trial, it was shown that orlistat significantly reduces the risk of developing type 2 diabetes mellitus (by about 37% compared with placebo).The degree of risk reduction was even more significant in patients with initial impairment of glucose tolerance (approximately 45%). In the treatment group, orlistat, there was a greater loss of body weight compared to the placebo group. Maintaining the body weight at a new level was observed throughout the study period. Moreover, compared with placebo in patients who received

Orlistat therapy, there was a significant improvement in the profile of metabolic risk factors.

Pubertal obesity

In a clinical study of 1 year duration in adolescents with obesity, with orlistat, a decrease in the body mass index was observed compared to the placebo group, where there was even an increase in the body mass index. In addition, patients of the orlistat group had a decrease in fat mass, as well as waist and hip circumference as compared to the placebo group. Also, patients who received orlistat therapy had a significant reduction in diastolic blood pressure compared with the placebo group.

Pharmacokinetics:

Suction

In volunteers with normal body weight and obesity, the systemic effect of the drug is minimal.After a single oral intake of the drug in a dose of 360 mg unchanged orlistat in plasma it was not possible to determine, which means that its concentrations are below the level of 5 ng / ml.

In general, after taking therapeutic doses, identify unchanged orlistat In plasma it was possible only in rare cases, while its concentrations were extremely small (<10 ng / ml or 0.02 μmol). Signs of cumulation were absent, which confirms that the absorption of the drug is minimal.

Distribution

The volume of distribution can not be determined, since the drug is very poorly absorbed. In vitro orlistat more than 99% associated with plasma proteins (mainly with lipoproteins and albumin). In minimum quantities orlistat can penetrate into erythrocytes.

Metabolism

Judging from the data obtained in the experiment on animals, the metabolism of orlistat occurs mainly in the intestinal wall. In a study in obese individuals found that approximately 42% of the minimum fraction of the drug that undergoes systemic absorption is accounted for by two major metabolites - M1 (four-membered hydrolyzed lactone ring) and M3 (M1 with a split residue N-formleleucine).

Molecules M1 and M3 have an open beta-lactone ring and extremely weakly inhibit lipase (respectively, 1000 and 2500 times weaker than orlistat). Given such low inhibitory activity and low plasma concentrations (an average of 26 ng / mL and 108 ng / mL, respectively) after taking therapeutic doses, these metabolites are considered pharmacologically inactive.

Excretion

Studies in individuals with normal and overweight showed that the main by elimination is the removal of non-sucking drug with feces. With feces about 97% of the dose of the drug was withdrawn, 83% in the form of unchanged orlistat.

The total renal excretion of all substances structurally associated with orlistat is less than 2% of the dose taken. Time to complete elimination of the drug from

body (with feces and urine) is 3-5 days. Proportion of pathways

Orlistat in volunteers with normal and overweight was the same. how orlistat, and metabolites M1 and M3, can be excreted with bile. Pharmacokinetics in special clinical groups

Plasma concentrations of orlistat and its metabolites (M1 and M3) in children do not differ from those in adults when comparing identical doses of the drug. Daily excretion of fat with feces accounted for 27% of intake from food with orlistat therapy and 7% - with placebo.

Preclinical safety data

According to the preclinical data, additional risks for patients concerning the safety profile, toxicity, genotoxicity, carcinogenicity and reproductive toxicity were not revealed. In animal studies,

the teratogenic effect was revealed. In connection with the lack of a teratogenic effect in animals, it is unlikely to be detected in humans.

Indications:

Long-term therapy of obese patients or patients with overweight, including those associated with obesity risk factors, combined with a moderately hypocaloric diet.

In combination with hypoglycemic drugs (metformin, sulfonylureas and / or insulin derivatives) or a moderately hypocaloric diet in patients with type 2 diabetes mellitus with excessive body weight or obesity.

Contraindications:

Syndrome of chronic malabsorption, cholestasis, hypersensitivity to the drug or any other components contained in the capsule.

Pregnancy and lactation:

The drug category B.

In studies of reproductive toxicity in animals teratogenic and embryotoxic effect of the drug was not observed. In the absence of a teratogenic effect in animals, one should not expect a similar effect in humans. but due to lack of clinical data Xenical® should not be given to pregnant women.

Excretion of orlistat with breast milk has not been studied, so it should not be taken during lactation.

Dosing and Administration:

Long-term therapy of obese patients or patients with excessive body weight, including number of obesity-associated risk factors, in combination with moderately hypocaloric diet:

the adults and children over 12 years The recommended dose of orlistat is one 120 mg capsule with each main meal (during meals or not later than an hour after meals).

In combination with hypoglycemic drugs (metformin, derivatives sulfonylureas and / or insulin) or a moderately hypocaloric diet in patients diabetes mellitus type 2 with overweight or obesity:

the of adults The recommended dose of orlistat is one 120 mg capsule with each main meal (during meals or not later than an hour after meals).

If food intake is missed or if the food does not contain fat, Xenical® can also be taken.

The drug should be taken in combination with a balanced, moderately hypocaloric diet containing no more than 30% of calories in the form of fats. The daily intake of fats, carbohydrates and proteins must be divided into three main methods.

Increasing the dose of orlistat more than the recommended (120 mg 3 times a day) does not lead to an increase in its therapeutic effect.

The efficacy and safety of Xenical® in patients with impaired liver and / or kidney function, as well as in elderly and children (under 12 years) have not been studied.

Side effects:

Clinical Trials Data

To describe the frequency of adverse reactions, the following categories are used: very often (> 1/10), often (> 1/100, <1/10), infrequently (> 1/1000, <1/100), rarely (> 1/10000 , <1/1000) and very rarely (<1/10000), including individual cases.

Adverse reactions to orlistat appeared mainly from the gastrointestinal tract and were due to the pharmacological action of the drug, which prevents the absorption of food fats.Often, such phenomena as oily discharges from the rectum, the release of gases with a certain amount of discharge, imperative urges for defecation, steatorrhea, frequent bowel movements, loose stools, flatulence, pain or discomfort in the abdomen were very often noted.

Their frequency increases with an increase in the fat content in the diet. Patients should be informed of the possibility of adverse reactions from the gastrointestinal tract and teach how to eliminate them by better adherence to the diet, especially with regard to the amount of fat contained in it. The use of a low-fat diet reduces the likelihood of side effects from the gastrointestinal tract and thus helps patients to monitor and regulate fat intake.

As a rule, these adverse reactions are mild and transient. They appeared at early stages of treatment (in the first 3 months), and in most patients there was not more than one episode of such reactions.

When treating with Xenical®, the following undesirable gastrointestinal symptoms often occur: "soft" stools, pain or discomfort in the straight line

guts, fecal incontinence, bloating, dental lesions, gum lesions.

There were also very frequent: headaches, upper respiratory tract infections, influenza; often: lower respiratory tract infections, urinary tract infections, dysmenorrhea, anxiety, weakness.

In patients with type 2 diabetes mellitus, the nature and incidence of adverse events were comparable to those in people without diabetes mellitus with excessive body weight and obesity. The only new side effects in patients with type 2 diabetes were hypoglycemic conditions that occurred with a frequency> 2% and incidence> 1% compared with placebo (which could result from improved carbohydrate metabolism compensation), and often bloating.

In a 4-year clinical trial, the overall safety profile did not differ from that obtained in 1- and 2-year studies. At the same time, the overall incidence of adverse events from the gastrointestinal tract decreased annually during the 4-year period of drug intake.

Postmarketing surveillance

Rare cases of allergic reactions are described, the main clinical symptoms of which were pruritus, rash, hives, angioedema, bronchospasm and anaphylaxis.Very rare cases of bullous rash, increased activity of transaminases and alkaline phosphatase, as well as separate, possibly serious, cases of hepatitis development (cause-and-effect relationship with the administration of Xenical® or pathophysiological mechanisms of development have not been established).

With the simultaneous administration of Xenical® and anticoagulants, there have been cases of a decrease in prothrombin, an increase in the values of the international normalized ratio (MNO), and unbalanced anticoagulant therapy, which led to a change in the haemostatic parameters.

Reported cases of rectal bleeding, diverticulitis, pancreatitis, cholelithiasis and oxalate nephropathy (incidence is not known).

With the simultaneous administration of orlistat and antiepileptic drugs, cases of seizures were observed (see section "Interaction with other drugs").

Overdose:

In clinical studies in individuals with normal body weight and obese patients, taking single doses of 800 mg or repeatedly taking the drug 400 mg 3 times a day for 15 days was not accompanied by the appearance of significant adverse events.In addition, patients with obesity have experience of using orlistat 240 mg 3 times a day for 6 months, which was not accompanied by a significant increase in the incidence of adverse events.

In cases of an overdose of Xenical®, either absence was reported. undesirable phenomena, or undesirable phenomena did not differ from those that are observed when taking the drug in therapeutic doses.

In case of severe overdose of Xenical®, it is recommended to observe the patient within 24 hours. According to studies in humans and animals, any systemic effects that could be associated with lipase inhibitory properties of orlistat should be rapidly reversible.

Interaction:

No interaction with amitriptyline, atorvastatin, biguanides, digoxin, fibrates, fluoxetine, losartan, phenytoin, oral contraceptives, phentermine, pravastatin, warfarin, nifedipine GITS (gastrointestinal therapeutic system) and slow release nifedipine, sibutramine or alcohol (based on studies of interactions between drugs).However, it is necessary to monitor the indices of INR with concomitant therapy with warfarin or other oral anticoagulants.

With simultaneous administration with the drug Xenical®, there was a decrease in the absorption of vitamins D, E and beta-carotene. If recommended multivitamins, they should be taken at least 2 hours after taking Xenical® or before bedtime. With the simultaneous administration of the drug Xenical® and cyclosporine, a decrease in plasma concentrations of cyclosporine was noted, therefore, a more frequent determination of plasma cyclosporine concentrations with simultaneous administration of cyclosporine and Xenical® is recommended.

With the oral administration of amiodarone during therapy with Xenical®, the systemic exposure of amiodarone and desethylamiodarone decreased by 25%_;

30%), However, in connection with the complex pharmacokinetics of amiodarone, the clinical significance of this phenomenon is not clear. The addition of Xenical® to prolonged therapy with amiodarone may lead to a decrease in the therapeutic effect of amiodarone (no studies have been conducted).

It is necessary to avoid simultaneous administration of Xenical® and acarbose,due to the lack of pharmacokinetic data.

With the simultaneous administration of orlistat and antiepileptic drugs, cases of seizures developed. Causal relationship between the development of seizures and orlistat therapy is not established. However, patients should be monitored for possible changes in the frequency and / or severity of the convulsive syndrome.

Special instructions:

Xenical® is effective in terms of long-term control of body weight (weight loss and maintenance at a new level, prevention of repeated weight gain).

Treatment with Xenical® leads to an improvement in the profile of risk factors and diseases associated with obesity, including hypercholesterolemia, type 2 diabetes, impaired glucose tolerance, hyperinsulinemia, arterial hypertension, and a reduction in visceral fat.

When used in combination with such hypoglycemic drugs as metformin, sulfonylureas and / or insulin derivatives in patients with type 2 diabetes mellitus with an overweight (body mass index (BMI)> 28 kg / m²) or obesity (BMI> 30 kg / m²), Xenical® in combination with a moderately hypocaloric diet provides an additional improvement in the compensation of carbohydrate metabolism.

In clinical studies in most patients, concentrations of vitamins A, D, E,

K and beta-carotene during the four years of orlistat therapy remained within normal limits.

To ensure adequate supply of all nutrients, you can assign multivitamins.

The patient should receive a balanced, moderately hypocaloric diet containing no more than 30% of calories in the form of fats. We recommend eating rich in fruits and vegetables. The daily intake of fats, carbohydrates and proteins must be divided into three main methods.

The likelihood of gastrointestinal side effects may increase if Xenical® is taken amid a diet rich in fats (for example, 2000 kcal / day, of which more than 30% is fat, which is about 67 g of fat).

Daily intake of fat should be divided into three main methods. If Xenical® is taken with food that is very rich in fat, the likelihood of gastrointestinal reactions increases.

In patients with type 2 diabetes, a decrease in body weight with Xenical® treatment is accompanied by an improvementcompensation of carbohydrate metabolism, which may or may require a reduction in the dose of hypoglycemic drugs (eg, sulfonylurea derivatives).

Form release / dosage:Capsules 120 mg

Packaging:

For 21 pieces in a blister of PVC /AL/ PVDC.

For 1.2 or 4 blisters together with instructions for use are placed in a cardboard box.

Storage conditions:Store at a temperature of no higher than 25 ° C, in the original packaging. Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date printed on the package.

in a cardboard box.

Terms of leave from pharmacies:On prescription

Registration number:П N014903 / 01

Date of registration:18.05.2009

The owner of the registration certificate:Hoffmann-La Roche Ltd.Hoffmann-La Roche Ltd. Switzerland

Manufacturer: & nbsp

F.Hoffmann-La Roche, Ltd. Switzerland

Representation: & nbspF.Hoffmann-La Roche Ltd. F.Hoffmann-La Roche Ltd. Switzerland

Information update date: & nbsp27.02.2013

Illustrated instructions

Instructions

Xenical® (Xenical®)