Listata, 120 mg 20 pcs.

Pharmacodynamics

Orlistat is a potent, specific and reversible inhibitor of gastrointestinal lipases with prolonged action. Its therapeutic action is carried out in the lumen of the stomach and small intestine and consists in the formation of covalent bonding with the active serine site of gastric and pancreatic lipases.

Inactivated enzyme thereby loses the ability to break down food fats coming in the form of triglycerides, into absorbed free fatty acids and monoglycerides. Since unchecked 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 action of the drug is carried out without absorption into the systemic blood flow.

Judging by the results of fecal fat content the action of orlistat starts 24-48 hours after intake. After discontinuation of orlistat, fecal fat content in 48-72 h usually returns to pre-therapy levels.

Clinical efficacy

Patients taking orlistat show greater weight loss compared to patients on diet therapy. Weight loss begins within the first 2 weeks of starting treatment and continues for 6 to 12 months, even in patients with a negative response to diet therapy. Over 2 years, there is a statistically significant improvement in the profile of metabolic risk factors associated with obesity. In addition, there is a significant decrease in body fat compared to placebo administration. Orlistat is effective in preventing weight gain again. Re-gain of body weight, not more than 25% of the lost weight, is observed in about half of the patients, and in half of these patients re-gain of body weight is not observed or even further weight loss is noted.

In patients with overweight or obesity and type 2 diabetes, taking orlistat for 6 months to 1 year, there is greater weight loss compared to patients receiving diet therapy alone. The weight loss is mainly due to a decrease in body fat. During orlistat therapy, a statistically and clinically significant improvement in glycemic control is observed. In addition, against the background of treatment with orlistat there is a decrease in the dose of hypoglycemic agents, insulin concentration, as well as a decrease in insulin resistance.

When using orlistat for 4 years the risk of developing type 2 diabetes is significantly reduced (by about 37% compared to placebo). The degree of risk reduction is even more significant in patients with initial impaired glucose tolerance (approximately by 45%).

Maintenance of body weight at the new level is observed during the whole period of the drug use.

When orlistat was used for 1 year in adolescents with obesity, a decrease in BMI, fat mass, as well as waist and hip circumference was observed compared to the placebo group. Also, patients treated with orlistat showed a significant decrease in diastolic BP compared to the placebo group.

Pharmacokinetics
Absorption

In volunteers with normal body weight and obesity, the systemic effects of orlistat are minimal. After a single oral dose of 360 mg unchanged orlistat is not detected in plasma, which means that its concentrations are below the limit of quantification (less than 5 ng/ml).

In general, after therapeutic doses unchanged orlistat was detected in plasma only in rare cases, and its concentrations were extremely low (less than 10 ng/ml or 0.02 μmol). There are no signs of cumulation, which confirms that absorption of orlistat is minimal.

Distribution

Vd cannot be determined because orlistat is very poorly absorbed. In vitro orlistat is more than 99% bound to plasma proteins (mainly lipoproteins and albumin). In minimal amounts orlistat can penetrate into erythrocytes.

Metabolism

Metabolism of orlistat is carried out mainly in the intestinal wall. In obese patients, approximately 42% of the minimal fraction of orlistat that undergoes systemic absorption is accounted for by two major metabolites, M1 (a four-member hydrolyzed lactone ring) and M3 (M1 with a detached N-formylleucine residue).

M1 and M3 molecules have an open b-lactone ring and inhibit very weakly lipase (1000 and 2500 times weaker than orlistat, correspondingly).

Given this low inhibitory activity and low plasma concentrations (26 ng/ml and 108 ng/ml on average, respectively) after therapeutic doses, these metabolites are considered pharmacologically inactive.

Excretion

In persons with normal and excess body weight, the major route of excretion is the excretion of unabsorbed orlistat through the intestine. About 97% of the administered dose is excreted through the intestine, with 83% as unchanged orlistat.

The total renal excretion of all substances structurally related to orlistat is less than 2% of the administered dose. The time to complete excretion of orlistat from the body (through the intestine and the kidneys) is 3-5 days. The ratio of orlistat excretion routes in normal and overweight volunteers was similar. Both orlistat and its 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 the same doses of orlistat. Daily excretion of fat with feces is 27% of intake with food during orlistat therapy.

Indications

– long-term therapy of obese patients with a BMI of at least 30 kg/m2 or overweight patients with a BMI of at least 28 kg/m2, 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) and/or a moderately hypocaloric diet in patients with type 2 diabetes mellitus who are overweight or obese.

Pharmacological effect

Pharmacodynamics

Orlistat is a potent, specific and reversible inhibitor of gastrointestinal lipases with a long-lasting effect. Its therapeutic effect occurs in the lumen of the stomach and small intestine and consists of the formation of a covalent bond with the active serine site of gastric and pancreatic lipases.

The inactivated enzyme then loses the ability to break down food fats, which come in the form of triglycerides, into absorbable free fatty acids and monoglycerides. Since unsplit triglycerides are not absorbed, the resulting decrease in caloric intake 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 circulation.

Based on fecal fat results, the effects of orlistat begin 24 to 48 hours after dosing. After discontinuation of orlistat, stool fat content usually returns to pre-therapy levels within 48-72 hours.

Clinical effectiveness

Patients taking orlistat experience greater weight loss compared to patients on diet therapy. Body weight loss begins within the first 2 weeks after the start of treatment and continues from 6 to 12 months, even in patients with a negative response to diet therapy. Over the course of 2 years, there was a statistically significant improvement in the profile of metabolic risk factors associated with obesity. In addition, compared to placebo, there was a significant reduction in body fat. Orlistat is effective in preventing weight gain. Re-gain of body weight, no more than 25% of lost, is observed in approximately half of the patients, and in half of these patients, re-gain of body weight is not observed or even a further decrease is observed.

Overweight or obese patients with type 2 diabetes mellitus treated with orlistat for 6 months to 1 year experienced greater weight loss compared with patients receiving dietary therapy alone. Weight loss occurs mainly due to a decrease in the amount of fat in the body. With orlistat therapy, a statistically and clinically significant improvement in glycemic control is observed. In addition, during therapy with orlistat, there is a decrease in the dose of hypoglycemic agents, insulin concentration, as well as a decrease in insulin resistance.

When using orlistat for 4 years, the risk of developing type 2 diabetes mellitus is significantly reduced (by approximately 37% compared to placebo). The degree of risk reduction is even greater in patients with baseline impaired glucose tolerance (approximately 45%).

Maintaining body weight at a new level is observed throughout the entire period of use of the drug.

When orlistat was used for 1 year in obese adolescents, a decrease in BMI, a decrease in fat mass, and a decrease in waist and hip circumference was observed compared with the placebo group. Also, patients treated with orlistat showed a significant decrease in diastolic blood pressure compared to the placebo group.

Pharmacokinetics
Suction

In normal weight and obese volunteers, systemic exposure to orlistat is minimal. After a single oral dose of 360 mg, unchanged orlistat is undetectable in plasma, which means that its concentrations are below the limit of quantitation (less than 5 ng/ml).

In general, after taking therapeutic doses, it was possible to detect unchanged orlistat in blood plasma only in rare cases, and its concentrations were extremely low (less than 10 ng/ml or 0.02 μmol). There are no signs of accumulation, which confirms that the absorption of orlistat is minimal.

Distribution

Vd cannot be determined because orlistat is very poorly absorbed. In vitro, orlistat is more than 99% bound to plasma proteins (mainly lipoproteins and albumin). In minimal amounts, orlistat can penetrate red blood cells.

Metabolism

Orlistat is metabolized primarily in the intestinal wall. In obese patients, approximately 42% of the minimal fraction of orlistat that is absorbed systemically is accounted for by two main metabolites – M1 (a 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 inhibit lipase extremely weakly (1000 and 2500 times weaker, respectively, than orlistat).

Given this low inhibitory activity and low plasma concentrations (average 26 ng/ml and 108 ng/ml, respectively) after therapeutic doses, these metabolites are considered pharmacologically inactive.

Removal

In individuals with normal and overweight, the main route of elimination is the elimination of unabsorbed orlistat through the intestines. About 97% of the dose taken is excreted through the intestines, 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 administered dose. The time until orlistat is completely eliminated from the body (through the intestines and kidneys) is 3-5 days. The ratio of orlistat elimination routes in volunteers with normal and overweight was the same. Both orlistat and metabolites M1 and M3 can be excreted in 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 orlistat. Daily excretion of fat in feces is 27% of dietary intake during orlistat therapy.

Special instructions

Listata is effective in long-term weight control (weight loss and maintenance, prevention of weight gain). Treatment with Listata 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, sulfonylurea derivatives and/or insulin in patients with type 2 diabetes mellitus who are overweight (BMI not less than 28 kg/m2) or obese (BMI not less than 30 kg/m2), Listata in combination with a moderately hypocaloric diet further improves the compensation of carbohydrate metabolism.

In clinical studies, the majority of patients had concentrations of vitamins A, D, E, K and beta-carotene within the normal range during 4 years of orlistat therapy. Multivitamins can be taken to ensure adequate intake of all minerals.

The patient should receive a balanced, moderately hypocaloric diet containing no more than 30% of calories in the form of fat. A diet rich in fruits and vegetables is recommended. The daily intake of fats, carbohydrates and proteins must be divided into three main meals. The likelihood of adverse reactions from the gastrointestinal tract may increase if Listata is taken on a diet rich in fat (for example, 2000 kcal/day, of which more than 30% in the form of fat, which equals approximately 67 g of fat). If Listata is taken with a meal very rich in fat, the likelihood of gastrointestinal reactions increases.

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

Impact on the ability to drive vehicles and machinery

Listata does not affect the ability to drive vehicles and machines. Patients with type 2 diabetes mellitus using Listata in combination with hypoglycemic drugs should be careful when driving vehicles and machinery due to the possible development of hypoglycemia, accompanied by dizziness and blurred vision.

Active ingredient

Orlistat

Composition

1 tab.

Contraindications

– hypersensitivity, sensitivity to orlistat or any other components of the drug;
— chronic malabsorption syndrome;
– cholestasis;
— pregnancy, breastfeeding period;
— children’s age up to 12 years.

Side Effects

Clinical trial data

Side effects of the drug are systematized in relation to each organ system depending on the frequency of occurrence, using the following classification: very often (more than 1/10); often (more than 1/100, less than 1/10); uncommon (more than 1/1000, less than 1/100); rare (more than 1/10,000, less than 1/1000); very rare, including isolated messages (less than 1/10,000).

Interaction

There was no interaction of orlistat with amitriptyline, atorvastatin, biguanides, digoxin, fibrates, fluoxetine, losartan, phenytoin, oral contraceptives, phentermine, pravastatin, warfarin, nifedipine GITS (gastrointestinal therapeutic system) and nifedipine slow release, sibutramine or ethanol (based on drug interaction studies). However, it is necessary to monitor INR values ​​during concomitant therapy with warfarin or other indirect anticoagulants.

When taken simultaneously with orlistat, a decrease in the absorption of vitamins D, E and beta-carotene was observed. If a multivitamin is recommended, it should be taken at least 2 hours after taking orlistat or at bedtime.

With the simultaneous use of orlistat and cyclosporine, a decrease in the concentration of cyclosporine in the blood plasma was observed, therefore, more frequent determination of the concentration of cyclosporine in the blood plasma is recommended when taking cyclosporine and orlistat simultaneously.

When amiodarone was taken orally during orlistat therapy, a decrease in the systemic exposure of amiodarone and desethylamiodarone was observed (by 25-30%), however, due to the complex pharmacokinetics of amiodarone, the clinical significance of this phenomenon is not clear. Adding orlistat to long-term amiodarone therapy may result in a decrease in the therapeutic effect of amiodarone (not studied).

Concomitant use of orlistat and acarbose should be avoided due to the lack of pharmacokinetic study data.

Cases of seizures have been observed when taking orlistat and antiepileptic drugs simultaneously. A cause-and-effect relationship between the development of seizures and orlistat therapy has not been established. However, patients should be monitored for possible changes in seizure frequency and/or severity.

Overdose

In individuals with normal body weight and obese patients, single doses of 800 mg or repeated doses of orlistat 400 mg 3 times a day for 15 days were not accompanied by the occurrence of significant adverse events. In addition, obese patients have experience 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 orlistat overdose, either no adverse events were reported, or the adverse events did not differ from those observed when taking orlistat in therapeutic doses.

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

Storage conditions

The drug should be stored in a place protected from light and out of reach of children at a temperature not exceeding 25°C.

Shelf life

2 years.

Manufacturer

Izvarino Pharma, Russia