Expiration date: 05/2025

Active substance: orlistat

Pharmachologic effect:

A specific inhibitor of gastrointestinal lipases having prolonged action. Therapeutic action is carried in the lumen of the stomach and small intestine and the card is to form a covalent bond with the serine active site of gastric and pancreatic lipases. Inactivated enzyme thus loses its ability to break down fats from food in the form of triglycerides, for soaked free fatty acids and monoglycerides. Since uncleaved triglycerides are not absorbed, there is a reduction in the number of incoming calories body that leads to a decrease in body weight. Thus, the therapeutic effect is carried out without absorption into the systemic circulation.

Based on the amount of fat in the feces data show that the effect of the drug begins within 24-48 h after administration. After discontinuation of fat content in feces within 48-72 hours usually returns to the level that took place prior to initiating therapy.

Pharmacokinetics:

Suction

In volunteers with normal body weight and obesity, systemic exposure of the drug minimal. After oral administration of orlistat is practically not absorbed from the gastrointestinal tract. After 8 hours, could not be determined after ingestion of an unmodified orlistat in plasma, which means that its concentration in blood plasma below 5 ng / ml.

In general, after receiving therapeutic doses to reveal unchanged orlistat in plasma could only in rare cases, with its concentration were extremely small (t10 ng / ml or 0.02 mM). No signs of accumulation, which confirms that the drug absorption is minimal.

Distribution

Vd can not be set due to the very low systemic absorption of orlistat. Plasma protein binding (mostly to albumin and lipoproteins) in vitr is 99%. The minimum amounts of orlistat can penetrate into erythrocytes.

Metabolism

Based on the data obtained in experimental animal studies carried orlistat metabolism, mainly in the intestinal wall. In obese individuals in the study found that about 42% of the minimum fraction of the preparation, which undergoes systemic absorption, falls into two major metabolite - M1 (four-membered ring lactone hydrolyzed) and M3 (M1 with N-cleaved residue formilleytsina).

The molecules of M1 and M3 have an open beta-lactone ring and extremely weak lipase inhibiting (respectively in 1000 and 2500 times weaker than orlistat). In view of this low inhibitory activity and low plasma concentrations (mean 26 ng / ml and 108 ng / ml, respectively) after administration of therapeutic doses of these metabolites are considered as pharmacologically inactive.

Breeding

Studies in patients with normal and overweight showed that 97% of applied dose of orlistat is excreted in the feces, of which 83% - unchanged. The cumulative renal excretion of substances that are structurally related to orlistat, is less than 2% of the dose. The period of complete elimination of orlistat from the body (in the feces and urine) - 3-5 days. Orlistat and its metabolites are excreted in bile.

The ratio of orlistat elimination pathways in volunteers with normal and overweight was similar.

Pharmacokinetics in special clinical situations

Plasma concentrations of orlistat and its metabolites (M1 and M3) in children do not differ from those of adults compared with similar doses of the drug.

The daily excretion of fat in the feces was 27% of the dietary intake during treatment with orlistat and 7% - placebo.

Testimony:

• Long-term treatment of patients with obesity or patients who are overweight, including associated with obesity risk factors, combined with a moderately hypocaloric diet
  
• In combination with hypoglycemic agents (metformin, sulfonylureas and / or insulin) or mildly hypocaloric diet in patients with type 2 diabetes are overweight or obese.
  

Dosage and administration:

For adults, the recommended dose of Xenical 120 mg (1 capsule) 3 times / day with each main meal (during meals or no later than one hour after a meal). If you miss a meal or the meal contains no fat, the intake of Xenical can also be skipped.

Increasing the dose of Xenical over the recommended (120 mg 3 times / day) does not lead to the strengthening of its therapeutic effect.

For elderly patients, patients with impaired hepatic or renal function dose adjustment is required.

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

Side effects:

Determining the frequency of adverse reactions: very common (ge 1/10), often (ge 1/100 and t 1/10), sometimes (ge 1/1000 and t 1/100), rarely (ge 1/10 000 and t 1 / 1000), very rare (t 1/10 000), including isolated cases.

Adverse reactions to Xenical® arose mainly from the gastrointestinal tract and were due to the pharmacological action of the drug that prevents absorption of fat food.

From the digestive system: very often - oily discharge from the rectum, gassing with a certain amount of discharge, urgency to defecate, steatorrhea, increased frequency of bowel movements, diarrhea, flatulence, pain and abdominal discomfort. The frequency of these adverse effects increase with increasing fat content in food. Patients should be informed about the possibility of adverse reactions, and to teach how to eliminate them through better compliance with a diet low in fat. Typically, these side effects are mild and transient. They appeared early in treatment (during the first three months), and most patients did not have more than one episode of such reactions.

Often - soft stools, pain or discomfort in the abdomen, fecal incontinence, flatulence, loss of teeth, gums defeat.

Very rarely - increased activity of hepatic transaminases and alkaline phosphatase, in some cases - hepatitis (causal connection with taking Xenical or pathophysiological mechanisms of development have not been established.)

The frequency is not known - rectal bleeding, diverticulitis, pancreatitis, cholelithiasis.

Allergic reactions: in some cases - pruritus, rash, urticaria, angioedema, bronchospasm and anaphylactic reactions.

Other: often - headache, infections of the upper respiratory tract, flu often - infections of the lower respiratory tract, dysmenorrhea, anxiety, fatigue, urinary tract infection is very rare - bullous rash.

In patients with type 2 diabetes the nature and frequency of adverse events were comparable to those in patients without diabetes who are overweight and obese. The only new adverse events occur with a frequency and gt2% ge1% compared with placebo, were hypoglycemic state (which could be the result of compensation of carbohydrate metabolism improvement) and flatulence.

When concomitant administration of Xenical and anticoagulants reduce reported cases of prothrombin, increased INR.

Contraindications:

• Chronic malabsorption syndrome
  
• cholestasis
  
• Hypersensitivity to the drug.
  

Pregnancy and lactation:

Category B. Xenical® should not be used during pregnancy due to lack of reliable clinical data supporting its safety of use.

Withdrawal of orlistat in breast milk has not been studied and should not be taken Xenical® during breastfeeding.

In experimental studies in animals have not revealed teratogenic and embryotoxic effect of orlistat.

Special instructions:

Xenical® effective long-term weight control programs (weight loss and its long-term maintenance to a new level, to prevent re-weight gain). The efficacy of Xenical shown to improve the profile of risk factors and diseases associated with obesity (such as high cholesterol, type 2 diabetes mellitus, impaired glucose tolerance, hyperinsulinemia, hypertension) and to reduce the amount of visceral fat.

If concomitant treatment with warfarin or other anticoagulants need to be monitored INR.

When used in combination with hypoglycemic agents such as metformin, sulfonylureas and / or insulin in patients with type 2 diabetes are overweight (BMI ge 28 kg / m2) or obese (BMI ge 30 kg / m2) Xenical®, in combination with a moderately hypocaloric diet, it gives a further improvement in compensation of carbohydrate metabolism.

In clinical studies, the majority of patients treated Xenical® complete within 2 years, the concentration of vitamin A (including betakarotena), D, E and K remained in the normal range.

To ensure an adequate supply of nutrients in the body and may have a multi-vitamin that should be taken at least 2 hours after taking Xenical or at bedtime.

The patient should receive a balanced, moderately hypocaloric diet containing no more than 30% of daily calories as fat. It is recommended to consume food containing plenty of fruits and vegetables. The daily intake of fat, carbohydrate and protein should be distributed into three basic techniques.

The likelihood of adverse reactions from the gastrointestinal tract may increase if Xenical® taken against the background of a diet rich in fat (eg 2000 kcal / day, of which more than 30% - in the form of fat, which equals about 67 grams of fat). The daily intake of fat should be distributed over 3 main reception.

The decrease in body weight associated with Xenical results in an increase in carbohydrate metabolism in diabetes mellitus type 2, which may allow or require a dose reduction of hypoglycemic drugs.

Overdose:

In clinical studies in patients with normal weight and obese patients receiving a single dose of 800 mg or multiple doses of 400 mg 3 times / day for 15 days were not accompanied by the appearance of significant adverse reactions. There is experience with the drug at 240 mg 3 times / day for 6 months, which was not accompanied by a significant increase in the frequency of adverse events.

In the case of Xenical overdose reported about the absence of any adverse events or adverse events did not differ from those observed while taking the drug at therapeutic doses.

Treatment:. In the case of severe overdosage recommended medical observation for 24 hours According to studies in humans and animals is believed that any system effects that could be associated with properties lipazoingibiruyuschimi orlistat should be rapidly reversible.

Drug Interactions:

Not established drug interactions with the concomitant use of Xenical with amitriptyline, atorvastatin, biguanides, digoxin, fibrates, fluoxetine, losartan, phenytoin, warfarin, oral contraceptives, pravastatin, phentermine, nifedipine GITS (gastrointestinal therapeutic system) and nifedipine slow release, sibutramine, ethanol (based on the studies of the interaction between drugs).

In an application Xenical® may reduce the absorption of fat-soluble vitamins A (including betakarotena), D, E and K.

With simultaneous use of Xenical and cyclosporine showed a decrease plasma concentrations of cyclosporine, so if this combination is recommended more frequent determination of cyclosporine concentrations in blood plasma.

In the appointment during amiodarone therapy Xenical observed decrease in the bioavailability of amiodarone and dezetilamiodarona (25-30%), but due to the complex pharmacokinetics of amiodarone the clinical significance of this effect is not clear. Xenical Adding to long-term therapy with amiodarone may lead to a decrease in therapeutic effect of amiodarone.

Xenical simultaneous reception and acarbose be avoided due to the lack of pharmacokinetic studies.

Conditions and terms:

List B. The drug should be stored out of reach of children, dry place at temperatures not above 25 ° C. Shelf life - 3 years. Do not use after the expiration date printed on the package.