Composition, form of production and packaging
Capsules hard gelatinous, в„–1, turquoise color, opaque; on the body of the inscription is black "XENICAL 120", on the lid - "ROCHE"; the contents of the capsules are pellets of white or almost white color.
Orlistat 120 mg
(in the form of pellets * 240 mg)
Excipients: talcum - 0.24 mg.
* Pellet composition: microcrystalline cellulose - 93.6 mg, sodium carboxymethyl starch (primogel) - 7.2 mg, povidone K-30 - 12 mg, sodium lauryl sulfate - 7.2 mg.
The composition of the capsule shell: gelatin, indigocarmine, titanium dioxide.
21 pcs. - blisters (1) - packs of cardboard.
21 pcs. - blisters (2) - packs of cardboard.
21 pcs. - blisters (4) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2011.
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 After the drug is withdrawn, the fat content in the stool after 48-72 hours usually returns to the level that occurred before the start of therapy.
Patients with obesity
In clinical trials, patients taking orlistat had a greater weight loss compared to 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 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 taking orlistat, there was a large loss of body weight compared to patients treated only with diet therapy. The loss of body weight occurred mainly due to a decrease in the amount of fat in the body. It should be noted that before the study, despite the use of hypoglycemic agents, patients often had insufficient glycemic control. However, during the treatment with orlistat, a 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 study, orlistat significantly reduced the risk of developing type 2 diabetes (approximately 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 receiving orlistat therapy, there was a significant improvement in the profile of metabolic risk factors.
In a 1-year clinical trial in adolescents with obesity, 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.
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 studies on animals, there was also no teratogenic effect. In connection with the lack of a teratogenic effect in animals, it is unlikely to be detected in humans.
In volunteers with normal body weight and obesity, the systemic effect of the drug is minimal. After a single oral intake of the drug at a dose of 360 mg unchanged orlistat in the plasma could not be determined, which means that its concentrations are below 5 ng / ml.
In general, after administration of therapeutic doses, unchanged orlistat in plasma was detected only rarely, and its concentrations were extremely small (<10 ng / ml or 0.02 Ојmol). Signs of cumulation were absent, which confirms that the absorption of the drug is minimal.
V d can not be determined, because the drug is very poorly absorbed. In vitro orlistat more than 99% is associated with plasma proteins (mainly lipoproteins and albumin). In minimal quantities orlistat can penetrate into the erythrocytes.
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, it was found that about 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 the cleaved residue of N-formylleucine).
M1 and M3 molecules have an open b-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.
Studies in individuals with normal and overweight showed that the main way of elimination is to remove the 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 the body (with feces and urine) is 3-5 days. The ratio of pathways for orlistat in volunteers with normal and overweight was the same. Both 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.
- Long-term therapy of obese patients or patients with excessive body weight, incl. associated with obesity risk factors, combined with a moderately hypocaloric diet;
- in combination with hypoglycemic drugs (metformin, sulfonylureas and / or insulin derivatives) or moderately hypocaloric diet in patients with type 2 diabetes with excess body weight or obesity.
Long-term therapy for obese patients or overweight patients, including those who are associated with obesity risk factors, in combination with a moderately hypocaloric diet in adults and children over 12 years of age, the recommended dose of orlistat is one 120 mg capsule with each major meal time of meal or not later than an hour after a meal).
In combination with hypoglycemic drugs (metformin, sulfonylureas and / or insulin derivatives) or moderately hypocaloric diet in patients with type 2 diabetes with overweight or obesity : in adults, the recommended dose of orlistat is one 120 mg capsule with each main meal time of meal or not later than an hour after a meal).
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 over the recommended (120 mg 3 times / day) does not lead to an increase in its therapeutic effect.
The effectiveness 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.
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 arose primarily 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 about the possibility of occurrence of adverse reactions from the gastrointestinal tract and teach how to eliminate them by better adherence to the diet, especially regarding the amount of fat contained in it. The use of a low-fat diet reduces the likelihood of side effects on the part of the gastrointestinal tract and thereby helps patients to monitor and regulate the consumption of fats.
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 rectum, stool incontinence, bloating, dental damage, gum lesion.
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 of> 2% and incidence of в‰Ґ 1% compared to 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.
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 isolated, possibly serious, cases of hepatitis development (cause-and-effect relationship with XenicalВ® or pathophysiological mechanisms of development have not been established).
With the simultaneous administration of Xenical's anticoagulant, there have been cases of a decrease in prothrombin, an increase in the values вЂ‹вЂ‹of the international normalized ratio (MNO), and unbalanced anticoagulant therapy, which led to a change in 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 the section "Interaction with other drugs").
- Syndrome of chronic malabsorption;
- 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, 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 given to pregnant women.
Excretion of orlistat with breast milk has not been studied, so it should not be taken during breastfeeding.
Xenical is effective in terms of long-term control of body weight (reduction in body weight and its 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 in patients with type 2 diabetes, overweight (BMI = 28 kg / m2 ) or obesity (BMI = 30 kg / m 2 ), 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 betakaren for four years of orlistat therapy remained within normal limits. To ensure adequate intake of all nutrients, multivitamins can be prescribed.
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 GI adverse reactions 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, very rich in fat, the likelihood of gastrointestinal reactions increases.
In patients with type 2 diabetes, a decrease in body weight when treated with Xenical is accompanied by an improvement in the compensation of carbohydrate metabolism, which may or may require a reduction in the dose of hypoglycemic drugs (eg, sulfonylurea derivatives).
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 / day for 15 days was not accompanied by the appearance of significant adverse events. In addition, patients with obesity have experience with orlistat 240 mg 3 times / day for 6 months, which was not accompanied by a significant increase in the incidence of adverse events.
In cases of Xenical overdose, either the absence of adverse events was reported, or the undesirable events did not differ from those observed when taking the drug 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 lipase inhibitory properties of orlistat should be quickly reversible.
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, you need to monitor the performance MNO with concomitant therapy with warfarin or other oral anticoagulants.
Together with the admission drug Xenical was a decrease in absorption of vitamins D, E and betakarotena. If the recommended multivitamins, they should take no less than 2 hours after administration of the drug Xenical or at bedtime.
When simultaneous administration of the drug Xenical and cyclosporine showed a decrease of plasma concentrations of cyclosporine, it is recommended that more frequent determination of cyclosporin plasma concentrations while receiving cyclosporine and Xenical drug.
Upon oral administration of amiodarone during therapy with Xenical It marked reduction of systemic exposure and dezetilamiodarona amiodarone (25-30%), but due to the difficult pharmacokinetics of amiodarone, the clinical significance of this phenomenon is not clear. Adding to Xenical drug amiodarone prolonged therapy may lead to a decrease in therapeutic effect of amiodarone (studies have been conducted).
Avoid the simultaneous administration of the drug Xenical and acarbose, due to the lack of pharmacokinetic studies.
At the same time taking orlistat and antiepileptic drugs cases of seizures have been observed. The causal relationship between the development of seizures, and orlistat therapy has not been established. However, you should monitor the condition of patients for possible changes in the frequency and / or severity of seizures.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored at a temperature not higher than 25 В° C, protected from moisture, the reach of children.
Shelf life - 3 years. Do not use after the expiration date printed on the package.