Xenical

General characteristics. Structure:

Active agent: орлистат 120 mg (in the form of pellets * 240 mg);

* structure of pellets: орлистат — 120 mg, cellulose microcrystallic — 93.60 mg, sodium carboxymethylstarch (примогель) — 7.20 mg, K-30 povidone — 12.00 mg, sodium lauryl sulfate — 7.20 mg;

Excipients: talc — 0.24 mg;
structure of a cover of the capsule: gelatin, indigo carmine, titanium dioxide.

Pharmacological properties:

Ксеникал® — the powerful, specific and reversible inhibitor of gastrointestinal lipases possessing long action. Its therapeutic action is carried out in a gleam of a stomach and small intestine and consists in formation of a covalent bond with the active serinovy site of gastric and pancreatic lipases. The inactivated enzyme at the same time loses ability to split the food fats arriving in the form of triglycerides on the soaking-up free fatty acids and monoglycerides. As not split triglycerides are not soaked up, arising thereof reduction of receipt of calories in an organism leads to a body degrowth. Thus, therapeutic effect of drug is carried out without absorption in a system blood stream.
Judging by results of content of fat to Calais, action of an orlistat begins in 24–48 hours after reception. After drug withdrawal the content of fat in 48–72 hours usually is returned to Calais to the level taking place prior to therapy.
Efficiency
Patients with obesity
In clinical trials at the patients accepting орлистат big loss of body weight in comparison with the patients who are on a dietotherapy was observed. Decrease in body weight began within the first 2 weeks after an initiation of treatment and continued from 6 to 12 months even at patients with the negative answer to a dietotherapy. For 2 years statistically significant improvement of a profile of the metabolic risk factors accompanying obesity was observed. Besides, in comparison with reception of placebo considerable reduction of amount of fat in an organism was noted. Orlistat is effective concerning prevention of a repeated increase of body weight. A repeated set of body weight, no more than 25% of lost, was observed approximately at a half of patients, and at a half of these patients of repeated set of body weight was not observed or even its further decrease was noted.
Patients with obesity and a diabetes mellitus 2 types
In clinical trials lasting from 6 months till 1 year at patients with the excess body weight or obesity and a diabetes mellitus 2 types accepting орлистат big loss of body weight in comparison with the patients undergoing treatment only a dietotherapy was observed. Loss of body weight happened generally due to reduction of amount of fat in an organism. It should be noted that prior to the research, despite reception of hypoglycemic means, at patients insufficient control of a glycemia was often noted. However, when performing therapy orlistaty also clinically significant improvement of control of a glycemia was observed statistically. Besides, against the background of therapy orlistaty decrease in doses of hypoglycemic means, concentration of insulin, and also insulin resistance reduction was observed.
Reduction of risk of development of a diabetes mellitus 2 types at patients with obesity
In 4-year-old clinical trial it was shown what орлистат considerably reduces risk of development of a diabetes mellitus of the 2nd type (approximately for 37% in comparison with placebo). Extent of reduction of risk was even more considerable at patients with initial disturbance of tolerance to glucose (approximately for 45%). In group of therapy orlistaty more considerable loss of body weight in comparison with group of placebo was noted. Maintenance of body weight at the new level was observed during the entire period of a research. Moreover, in comparison with placebo at the patients receiving therapy orlistaty considerable improvement of a profile of metabolic risk factors was observed.
Pubertal obesity
In clinical trial lasting 1 year at teenagers with obesity, at reception of an orlistat reduction of an index of body weight in comparison with group of placebo where even increase in an index of body weight was noted was observed. Besides, at patients of group of an orlistat reduction of fatty weight, and also a circle of a waist and hips in comparison with group of placebo was noted. Also at the patients receiving therapy orlistaty considerable decrease in diastolic arterial pressure in comparison with group of placebo was noted.

Pharmacokinetics. Absorption
At volunteers with the normal body weight and obesity system influence of drug is minimum. After single oral administration of drug in a dose of 360 mg not changed орлистат in plasma it was not succeeded to define what means that its concentration are lower than the level of 5 ng/ml.
In general, after reception of therapeutic doses it was possible to reveal not changed орлистат in plasma only in rare instances, at the same time its concentration were extremely small (<10 ng/ml or 0.02 µmol). Signs of cumulation were absent that confirms that absorption of drug is minimum.
Distribution
The volume of distribution cannot be determined as drug is very badly soaked up. In vitro орлистат more than for 99% contacts proteins of plasma (generally with lipoproteins and albumine). In the minimum quantities орлистат can get into erythrocytes.
Metabolism
Judging by the data obtained in an experiment on animals, metabolism of an orlistat is carried out mainly in an intestines wall. In a research at persons with obesity it is established that about 42% of that minimum fraction of drug which is exposed to system absorption are the share of two main metabolites — M1 (the four-membered hydrolyzed lactonic ring) and M3 (M1 with the chipped-off N-formilleytsina rest).
The molecules M1 and M3 have an open β-lactone ring and extremely poorly inhibit a lipase (respectively, in 1000 and 2500 times are weaker, than орлистат). Taking into account such low inhibiting activity and low plasma concentration (on average, 26 ng/ml and 108 ng/ml, respectively) after reception of therapeutic doses, these metabolites are considered as pharmacological inactive.
Removal
Researches at persons with normal and excess body weight showed that the main way of elimination is removal of not soaked up drug with a stake. With a stake about 97% of the accepted drug dose, and 83% — in the form of not changed orlistat were removed.
Cumulative renal excretion of all substances which are structurally connected with orlistaty makes less than 2% of the accepted dose. Time before full elimination of drug from an organism (with a stake and urine) equals to 3-5 days. The ratio of ways of removal of an orlistat at volunteers with normal and excess body weight was identical. As орлистат, and metabolites of M1 and M3, can be exposed to excretion with bile.
Pharmacokinetics in special clinical groups
Plasma concentration of an orlistat and its metabolites (M1 and M3) at children do not differ from those at adults when comparing identical doses of drug. Daily excretion of fat with a stake made 27% of reception with food at therapy of orlistaty and 7% — at placebo reception.
Preclinical data on safety
According to preclinical data, additional risks for the patients concerning a profile of safety, toxicity, genotoxicity, carcinogenicity and reproductive toxicity it was not revealed. In researches on animals the teratogenic effect was also not revealed. Due to the lack of teratogenic effect at animals, its identification at people is improbable.

Indications to use:

Long therapy of patients with obesity or the patients with excess body weight including having the risk factors associated with obesity in combination with moderately hypocaloric diet.
In a combination with hypoglycemic drugs (Metforminum, derivatives of sulphonylurea and/or insulin) or moderately hypocaloric diet at patients with a diabetes mellitus 2 types with the excess body weight or obesity.

Route of administration and doses:

Long therapy of patients with obesity or the patients with excess body weight including having the risk factors associated with obesity in combination with moderately hypocaloric diet:
at adults and children 12 years are more senior the recommended dose of an orlistat makes one capsule in 120 mg with each main meal (during food or not later than in an hour after food).
In a combination with hypoglycemic drugs (Metforminum, derivatives of sulphonylurea and/or insulin) or moderately hypocaloric diet at patients with a diabetes mellitus 2 types with the excess body weight or obesity:
at adults the recommended dose of an orlistat makes one capsule in 120 mg with each main meal (during food or not later than in an hour after food).
If meal is missed or if food does not contain fat, then administration of drug of Ksenikal® can also be missed.
Drug should be accepted in a combination to the balanced, moderately hypocaloric diet containing no more than 30% of a kalorazh in the form of fats. Daily consumption of fats, carbohydrates and proteins it is necessary to distribute on three the main reception.
Increase in a dose of an orlistat over recommended (120 mg 3 times a day) does not lead to strengthening of its therapeutic effect.
Efficiency and safety of the drug Ksenikal® at patients with an abnormal liver function and/or kidneys, and also at patients of advanced and children's age (12 years are younger) were not investigated.

Features of use:

Ксеникал® it is effective in respect of long control of body weight (decrease in body weight and its maintenance at the new level, prevention of a repeated increase of body weight). Treatment by the drug Ksenikal® leads to improvement of a profile of the risk factors and diseases accompanying obesity including a hypercholesterolemia, a diabetes mellitus 2 types, disturbance of tolerance to glucose, a giperinsulinemiya, arterial hypertension, and to reduction of amount of visceral fat.
When using in a combination with such hypoglycemic drugs as Metforminum, derivatives of sulphonylurea and/or insulin at patients with a diabetes mellitus 2 types with the excess body weight (the body weight index (BWI) of ≥28 kg/sq.m) or obesity (IMT of ≥30 kg/sq.m), Ksenikal® in combination with moderately hypocaloric diet gives additional improvement of compensation of carbohydrate metabolism.
In clinical trials during four years of therapy orlistaty remained with most of patients of concentration of A, D, E, K vitamins and beta carotene within norm. For ensuring adequate intake of all nutrients it is possible to appoint polyvitamins.
The patient has to receive the balanced, moderately hypocaloric diet containing no more than 30% of a kalorazh in the form of fats. The food rich with fruit and vegetables is recommended. Daily consumption of fats, carbohydrates and proteins it is necessary to distribute on three the main reception.
The probability of side reactions from digestive tract can increase if Ksenikal® accept against the background of the food rich with fats (for example, 2000 kcal/days, from them more than 30% in the form of fats that about 67 g of fat equal). Daily consumption of fats has to be distributed on three main receptions. If Ksenikal® accept with food, very fat-rich, the probability of gastrointestinal reactions increases.
At patients with a diabetes mellitus 2 types the body degrowth at treatment with the drug Ksenikal® is followed by improvement of compensation of carbohydrate metabolism that is able to afford or to demand a dose decline of hypoglycemic drugs (for example, sulphonylurea derivatives).

Side effects:

Data of clinical trials
For the description of frequency of side reactions the following categories are used: very often (≥1/10), it is frequent (≥1/100, <1/10), infrequently (≥1/1000, <1/100), is rare (≥1/10000, <1/1000) and is very rare (<1/10000), including separate cases.
Side reactions on орлистат arose mainly from digestive tract and were caused by pharmacological effect of the drug interfering absorption of fats of food. Such phenomena as oily allocations from a rectum, release of gases with a quantity separated, imperative desires on defecation, a steatorrhea, defecation increase, a liquid chair, a meteorism, pains or discomfort in a stomach were very often noted.
Their frequency increases at increase in content of fat in food. Patients should be informed on possibility of side reactions from digestive tract and to train how to eliminate them by the best observance of a diet, especially concerning amount of the fat which is contained in it. Use of a diet with the low content of fat reduces probability of side effects from digestive tract and by that helps patients to control and regulate consumption of fats.
As a rule, the specified side reactions are poorly expressed and tranzitorny. They arose at early stages of treatment (in the first 3 months), and most of patients had no more than one episode of such reactions.
At treatment the following undesirable phenomena from digestive tract arise the drug Ksenikal® often: "soft" chair, pains or discomfort in a rectum, incontience calla, abdominal distention, damage of teeth, damage of gums.
Were noted also very often: headaches, upper respiratory tract infections, flu; often: lower respiratory tract infections, infections of urinary tract, dysmenorrhea, alarm, weakness.
Patients with a diabetes mellitus have 2 types character and frequency of the undesirable phenomena were comparable to those at persons without diabetes mellitus with the excess body weight and obesity. The only new by-effects at patients with a diabetes mellitus 2 types were the hypoglycemic states arising with a frequency> 2% and incidence of ≥1% in comparison with placebos (which could result from improvement of compensation of carbohydrate metabolism), and is frequent — abdominal distention.
In 4-year-old clinical trial the general profile of safety did not differ from that, received in 1-and 2-year researches. At the same time the general frequency of emergence of the undesirable phenomena from digestive tract annually decreased throughout the 4-year period of administration of drug.

Post-marketing observation
Exceptional cases of allergic reactions which main clinical symptoms were an itch, rash, urticaria, a Quincke's disease, a bronchospasm and an anaphylaxis are described.
Very exceptional cases of violent rash, increase in activity of transaminases and alkaline phosphatase, and also separate, perhaps serious, cases of development of hepatitis are described (relationship of cause and effect with administration of drug Ksenikal® or pathophysiological mechanisms of development are not established).
At co-administration of the drug Ksenikal® and anticoagulants cases of decrease in a prothrombin, increase in values of the international normalized relation (MNO) and unbalanced therapy are registered by anticoagulants that led to change of haemo static parameters.
Cases of rectal bleeding, diverticulitis, pancreatitis, cholelithiasis and oxalic nephropathy are registered (frequency of emergence is not known).
At a concomitant use of an orlistat and antiepileptic drugs cases of development of spasms were observed (see the section "Interaction with Other Medicines").

Interaction with other medicines:

Interaction with amitriptyline, atorvastatiny, guanyl guanidines, digoxin, fibrata, fluoxetine, lozartany, Phenytoinum, oral contraceptives, phentermine, pravastatiny, warfarin, nifedipine GTS (gastrointestinal therapeutic system) and nifedipine with slow release, sibutraminy or alcohol is not revealed (on the basis of researches of interactions between medicines). However it is necessary to watch MNO indicators at the accompanying therapy by warfarin or other peroral anticoagulants.
At a concomitant use with the drug Ksenikal® reduction of absorption of vitamins D, E and beta carotene was noted. If polyvitamins are recommended, it is necessary to accept them not less than in 2 hours after administration of drug of Ksenikal® or before going to bed.
At a concomitant use of the drug Ksenikal® and cyclosporine decrease in plasma concentration of cyclosporine therefore more frequent definition of concentration of cyclosporine in plasma at a concomitant use of cyclosporine and the drug Ksenikal® is recommended was noted.
At peroral purpose of Amiodaronum during therapy the drug Ksenikal® noted decrease in system exposure of Amiodaronum and dezetilamiodaron (for 25–30%), however in connection with difficult pharmacokinetics of Amiodaronum, the clinical importance of this phenomenon is not clear. Addition of the drug Ksenikal® to long therapy by Amiodaronum will perhaps lead to decrease in therapeutic effect of Amiodaronum (researches were not conducted).
It is necessary to avoid a concomitant use of the drug Ksenikal® and acarbose, due to the lack of these pharmacokinetic researches.
At a concomitant use of an orlistat and antiepileptic drugs cases of development of spasms were observed. Relationship of cause and effect between development of spasms and therapy orlistaty is not established. Nevertheless, it is necessary to monitorirovat a condition of patients regarding possible changes in frequency and/or weight of a convulsive syndrome.

Contraindications:

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

Pregnancy and period of feeding by a breast
Category B drug.
In researches of reproductive toxicity on animals of teratogenic and embriotoksichesky effect of drug it was not observed. For lack of teratogenic effect at animals it is not necessary to expect similar effect at the person. However due to the lack of clinical data Ksenikal® it is not necessary to appoint pregnant.
Removal of an orlistat with breast milk was not studied therefore it should not be accepted during feeding by a breast.

Overdose:

In clinical trials at persons with normal body weight and patients with obesity reception of single doses of 800 mg or multiple dose of drug on 400 mg 3 times a day within 15 days was not followed by emergence of the essential undesirable phenomena. Besides, patients with obesity have an experience of use of an orlistat on 240 mg 3 times a day within 6 months that was not followed by reliable increase in frequency of the undesirable phenomena.
In cases of overdose of the drug Ksenikal® it was reported or about lack of the undesirable phenomena, or the undesirable phenomena did not differ from those which are observed at administration of drug in therapeutic doses.
In case of the expressed overdose of the drug Ksenikal® it is recommended to observe the patient within 24 hours. According to researches at the person and animals, any system effects which could be connected with lipazoingibiruyushchy properties of an orlistat have to be quickly reversible.

Storage conditions:

To store at a temperature not above 25 °C in the place protected from moisture.
To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Capsules of 120 mg
On 21 pieces in the blister from PVH/AL/PVDH.
On 1, 2 or 4 blisters together with the application instruction place in a cardboard pack.