Xenical capsules 120mg, No. 42

long-term therapy of obese or overweight patients, incl. having risk factors associated with obesity, in combination with a moderately hypocaloric diet;

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

Inside, adults - 1 caps. (120 mg) with each main meal (during or no later than 1 hour after meals). If the meal is skipped or the food does not contain fat, then the medication can also be skipped.

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

No dose adjustment is required in elderly patients.

No dose adjustment is required in case of impaired liver or kidney function.

The safety and effectiveness of Xenical in children under 18 years of age has not been established.

Capsules 1 capsule orlistat 120 mg (in the form of pellets * - 240 mg)

* composition of pellets: orlistat; MCC; sodium carboxymethyl starch (primogel); povidone K-30; sodium lauryl sulfate

excipients: talcum powder composition of the capsule shell: gelatin; indigo carmine; titanium dioxide

hypersensitivity to the drug or any other components contained in the capsule;

chronic malabsorption syndrome;

cholestasis.

pharmachologic effect

Xenical is a potent, specific and reversible inhibitor of gastrointestinal lipases with 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 site of gastric and pancreatic lipases. At the same time, the inactivated enzyme loses its ability to break down food fats, which come in the form of triglycerides, into absorbed free fatty acids and monoglycerides. Since the undigested triglycerides are not absorbed, the resulting decrease in caloric intake in the body leads to a decrease in body weight. Thus, the therapeutic effect of the drug is carried out without absorption into the systemic circulation.

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

Efficiency

Obese patients

In clinical studies, patients taking orlistat experienced greater weight loss compared to patients on diet therapy. Weight loss started already within the first 2 weeks after the start 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, there was a significant decrease in body fat compared to taking a placebo. Orlistat is effective in preventing re-weight gain. Re-gaining body weight, no more than 25% of the lost, was observed in about half of the patients,and half of these patients did not regain weight, or even showed further weight gain.

Obese patients with type 2 diabetes
In clinical studies lasting from 6 months to 1 year, overweight or obese patients with type 2 diabetes mellitus taking orlistat experienced greater weight loss compared to patients treated with diet therapy alone. Weight loss was mainly due to a decrease in the amount of body fat. It should be noted that before the start of the study, despite taking hypoglycemic agents, patients often had insufficient glycemic control. However, with orlistat therapy, statistically and clinically significant improvements in glycemic control were observed. In addition, against the background of therapy with orlistat, there was a decrease in the doses of hypoglycemic agents, insulin concentration, as well as a decrease in insulin resistance.

Reducing the risk of developing type 2 diabetes in obese patients

In a 4-year clinical study, orlistat was shown to significantly reduce the risk of type 2 diabetes mellitus (approximately 37% compared to placebo). The degree of risk reduction was even greater in patients with baseline impaired glucose tolerance (approximately 45%). The orlistat group experienced greater weight loss than the placebo group. Maintaining body weight at a new level was observed throughout the study period. Moreover, compared with placebo, patients treated with orlistat showed a significant improvement in the metabolic risk factor profile.

Pubertal obesity

In a clinical study lasting 1 year in obese adolescents, orlistat showed a decrease in body mass index compared to the placebo group, where there was even an increase in body mass index. In addition, the patients in the orlistat group showed a decrease in fat mass, as well as in the circumference of the waist and hips compared with the placebo group. Also, in patients receiving therapy with orlistat, there was a significant decrease in diastolic blood pressure compared with the placebo group.

Preclinical safety data

According to preclinical data, there were no additional risks to patients in terms of safety profile, toxicity, genotoxicity, carcinogenicity and reproductive toxicity. In animal studies, there was also no teratogenic effect. Due to the absence of a teratogenic effect in animals, it is unlikely to be detected in humans.

Pharmacokinetics

Suction

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

In general, after taking therapeutic doses, it was possible to detect unchanged orlistat in plasma only in rare cases, while its concentrations were extremely low (<10 ng / ml or 0.02 ?mol). There were no signs of cumulation, which confirms that the absorption of the drug is minimal.

Distribution

Vd cannot be determined, since the drug is very poorly absorbed. In vitro, more than 99% of orlistat binds to plasma proteins (mainly lipoproteins and albumin). In minimal amounts, orlistat can penetrate into erythrocytes.

Metabolism

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

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

Withdrawal

Studies in persons with normal and overweight have shown that the main route of elimination is the excretion of the unabsorbed drug in the feces. With feces, about 97% of the taken dose of the drug was excreted, with 83% in the form of unchanged orlistat.

The cumulative renal excretion of all substances structurally related to orlistat is less than 2% of the dose taken. The time to complete elimination of the drug from the body (with feces and urine) is 3-5 days. The ratio of the routes of elimination of orlistat in volunteers with normal and overweight was the same. Both orlistat and metabolites M1 and M3 can be excreted in the 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 the same doses of the drug. The daily excretion of fat with feces was 27% of the intake with food with orlistat therapy and 7% with placebo.

Indications for XenicalЃ

• long-term therapy of obese or overweight patients, incl. having risk factors associated with obesity, in combination with a moderately hypocaloric diet;

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

  Side effect

  Clinical trial data

  The following categories are used to describe the frequency of adverse reactions: 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 isolated cases.

  Adverse reactions to orlistat occurred mainly from the gastrointestinal tract and were due to the pharmacological effect of the drug, which prevents the absorption of food fats. Very often, there were such phenomena as oily discharge from the rectum, gas with some discharge, urge to defecate, steatorrhea, increased frequency of bowel movements, loose stools, flatulence, pain or discomfort in the abdomen.

  Their frequency increases with increasing dietary fat content. Patients should be informed of the potential for gastrointestinal adverse reactions and should be taught how to manage them through better adherence to the diet, especially with regard to the amount of fat contained in it. Eating a low-fat diet reduces the likelihood of gastrointestinal side effects and thereby helps patients control and regulate their fat intake.

  As a rule, these side reactions are mild and transient. They occurred in the early stages of treatment (in the first 3 months), and most patients had no more than one episode of such reactions.

  When treating with Xenical, the following adverse events from the gastrointestinal tract often occur: 'soft' stools, pain or discomfort in the rectum, fecal incontinence, bloating, teeth damage, gum damage.

  Were also noted very often: headaches, upper respiratory tract infections, flu; often: lower respiratory tract infections, urinary tract infections, dysmenorrhea, anxiety, weakness.

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

  In a 4-year clinical study, 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 over the 4-year period of taking the drug.

  Post-marketing surveillance

  Rare cases of allergic reactions have been described, the main clinical symptoms of which were itching, rash, urticaria, angioedema, bronchospasm and anaphylaxis.

  Very rare cases of bullous rash, increased activity of transaminases and alkaline phosphatase, as well as individual, possibly serious, cases of the development of hepatitis have been described (a causal relationship with taking XenicalЃ or the pathophysiological mechanisms of development has not been established).

  With the simultaneous administration of the drug Xenical and anticoagulants, cases of a decrease in prothrombin, an increase in the values ??of the international normalized ratio (INR) and unbalanced anticoagulant therapy have been reported, which led to a change in hemostatic parameters.

  Cases of rectal bleeding, diverticulitis, pancreatitis, cholelithiasis and oxalate nephropathy have been reported (incidence not known).

  With the simultaneous administration of orlistat and antiepileptic drugs, there have been cases of seizures (see the section 'Interaction with other drugs').

  Contraindications for use

  • chronic malabsorption syndrome;

  • cholestasis;

  • hypersensitivity to the drug or any other components contained in the capsule.

  Application during pregnancy and lactation

  Category B.

  In studies of reproductive toxicity in animals, the 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. However, due to the lack of clinical data, Xenical should not be administered to pregnant women.

  The excretion of orlistat in breast milk has not been studied, so it should not be taken while breastfeeding.

  special instructions

  Xenical is effective in terms of long-term control of body weight (reducing body weight and maintaining it at a new level, preventing re-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 mellitus, impaired glucose tolerance, hyperinsulinemia, arterial hypertension, and a decrease in the amount of visceral fat.

  When used in combination with hypoglycemic drugs such as metformin, sulfonylureas and / or insulin in type 2 diabetes mellitus patients who are overweight (body mass index (BMI)? 28 kg / m2) or obese (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, the concentrations of vitamins A, D, E, K and beta-carotene remained within the normal range during four years of therapy with orlistat. Multivitamins can be prescribed to ensure an adequate supply of all nutrients.

  The patient should receive a balanced, moderately hypocaloric diet containing no more than 30% of calories as fat. A diet rich in fruits and vegetables is recommended. The daily intake of fats, carbohydrates and proteins must be divided into three main doses.

  The likelihood of adverse reactions from the gastrointestinal tract may increase if Xenical is taken with a diet rich in fats (for example, 2000 kcal / day, of which more than 30% is in the form of fats, which equals about 67 g of fat). The daily fat intake should be divided into three main meals. If Xenical is taken with food that is very rich in fat, the likelihood of gastrointestinal reactions increases.

  In patients with type 2 diabetes mellitus, a decrease in body weight during treatment with Xenical is accompanied by an improvement in the compensation of carbohydrate metabolism, which may allow or require a reduction in the dose of hypoglycemic drugs (for example, sulfonylurea derivatives).

  Overdose

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

  In cases of an overdose of the drug Xenical, either the absence of adverse events was reported, or the adverse events did not differ from those observed when the drug was taken in therapeutic doses.

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

  Drug interactions

  No interactions were found with amitriptyline, atorvastatin, biguanides, digoxin, fibrates, fluoxetine, losartan, phenytoin, oral contraceptives, phentermine, pravastatin, warfarin, nifedipine GITS (gastrointestinal therapeutic system with medication) and nifedolem studies of drug interactions). However, it is necessary to monitor INO indicators with concomitant therapy with warfarin or other oral anticoagulants.

  When taken simultaneously with the drug Xenical, there was a decrease in the absorption of vitamins D, E and beta-carotene. If multivitamins are recommended, they should be taken at least 2 hours after taking Xenical or at bedtime.

  With the simultaneous administration of the drug Xenical and cyclosporine, a decrease in plasma concentrations of cyclosporin was noted, therefore, more frequent determination of the concentrations of cyclosporine in plasma is recommended while taking cyclosporine and the drug Xenical.

  With oral administration of amiodarone during therapy with Xenical, a decrease in the systemic exposure of amiodarone and desethylamiodarone (by 25-30%) was noted, however, due to the complex pharmacokinetics of amiodarone, the clinical significance of this phenomenon is not clear. Adding Xenical to long-term therapy with amiodarone may lead to a decrease in the therapeutic effect of amiodarone (no studies have been conducted).

  Simultaneous administration of the drug Xenical and acarbose should be avoided, due to the lack of data from pharmacokinetic studies.

  With the simultaneous administration of orlistat and antiepileptic drugs, there have been cases of seizures. A causal relationship between the development of seizures and orlistat therapy has not been established. However, patients should be monitored for possible changes in the frequency and / or severity of seizures.