Listata (Tablets) Instructions for Use

Marketing Authorization Holder

Izvarino Pharma LLC (Russia)

Contact Information

IZVARINO PHARMA LLC (Russia)

ATC Code

A08AB01 (Orlistat)

Active Substance

Orlistat (Rec.INN registered by WHO)

Dosage Form

Listata

Film-coated tablets, 120 mg: 10, 20, 30, 40, 60, or 90 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets from light blue to blue with a pearlescent effect, oval, biconvex, with a score on one side and an embossed symbol " f " on the other.

Excipients: sodium lauryl sulfate – 12 mg, acacia gum – 210 mg, mannitol – 580 mg, copovidone – 20 mg, crospovidone – 50 mg, magnesium stearate – 8 mg.

Shell composition shell composition (polyvinyl alcohol – 40%, titanium dioxide – 22.48%, macrogol 3350 – 20.2%, talc – 14.8%, aluminum lacquer blue – 2.28%, iron oxide yellow dye – 0.24%) – 40 mg.

10 pcs. – contour cell packs (1) – cardboard packs.
10 pcs. – contour cell packs (2) – cardboard packs.
10 pcs. – contour cell packs (3) – cardboard packs.
10 pcs. – contour cell packs (4) – cardboard packs.
10 pcs. – contour cell packs (6) – cardboard packs.
10 pcs. – contour cell packs (8) – cardboard packs.
10 pcs. – contour cell packs (9) – cardboard packs.

Clinical-Pharmacological Group

Drug for the treatment of obesity – inhibitor of gastrointestinal lipases

Pharmacotherapeutic Group

Drugs for the treatment of obesity, except dietary products; drugs for the treatment of obesity of peripheral action

Pharmacological Action

Pharmacodynamics

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

The inactivated enzyme thereby loses its ability to break down dietary fats, which come in the form of triglycerides, into absorbable free fatty acids and monoglycerides. Since undigested triglycerides are not absorbed, the resulting reduction in calorie intake leads to a decrease in body weight. Thus, the therapeutic effect of the drug is achieved without absorption into the systemic circulation.

Judging by the results of fecal fat content, the action of orlistat begins 24-48 hours after administration. After discontinuation of orlistat, fecal fat content usually returns to the pre-treatment level within 48-72 hours.

Clinical efficacy

Patients taking Orlistat experience greater weight loss compared to patients on diet therapy alone. Weight loss begins within the first 2 weeks after starting treatment and continues for 6 to 12 months, even in patients who did not respond to diet therapy. Over 2 years, a statistically significant improvement in the profile of metabolic risk factors associated with obesity is observed. Furthermore, compared to placebo, there is a significant reduction in body fat. Orlistat is effective in preventing weight regain. Weight regain, not exceeding 25% of the lost weight, is observed in approximately half of the patients, and half of these patients do not experience weight regain or even show further weight loss.

In patients with overweight or obesity and type 2 diabetes mellitus taking Orlistat for 6 months to 1 year, greater weight loss is observed compared to patients receiving diet therapy alone. Weight loss occurs mainly due to a decrease in body fat. During therapy with orlistat, a statistically and clinically significant improvement in glycemic control is observed. Furthermore, during therapy with orlistat, a reduction in the dose of hypoglycemic agents, insulin concentration, and a decrease in insulin resistance are observed.

When orlistat is used 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 more significant in patients with baseline impaired glucose tolerance (by approximately 45%).

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

When orlistat is used for 1 year in adolescents with obesity, a decrease in BMI, a decrease in fat mass, as well as waist and hip circumference are observed compared to the placebo group. Also, in patients receiving orlistat therapy, a significant decrease in diastolic blood pressure is noted compared to the placebo group.

Pharmacokinetics

Absorption

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

In general, after taking 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 accumulation, confirming that the absorption of orlistat is minimal.

Distribution

V_d 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

The metabolism of orlistat occurs 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 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 beta-lactone ring and are extremely weak inhibitors of lipase (1000 and 2500 times weaker than Orlistat, respectively).

Given such 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.

Excretion

In individuals with normal and overweight, the main 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.

Cumulative renal excretion of all substances structurally related to orlistat is less than 2% of the administered dose. The time to complete elimination of orlistat from the body (through the intestine and kidneys) is 3-5 days. The ratio of excretion pathways of orlistat in volunteers with normal and overweight was the same. Both Orlistat and metabolites M1 and M3 can undergo biliary excretion.

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 fecal fat excretion is 27% of dietary intake during orlistat therapy.

Indications

• Long-term therapy of patients with obesity with a BMI of at least 30 kg/m² or patients with overweight with a BMI of at least 28 kg/m², including those with obesity-associated risk factors, 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 with overweight or obesity.

ICD codes

Dosage Regimen

Orally, with water.

Treatment of patients with obesity with a BMI of at least 30 kg/m² or patients with overweight with a BMI of at least 28 kg/m², including those with obesity-associated risk factors, in combination with a moderately low-calorie diet

Adults and children over 12 years

The recommended dose of Listata is 1 tab. (120 mg) with each main meal (during a meal or no later than 1 hour after a meal).

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

Adults

The recommended dose of Listata is 1 tab. (120 mg) with each main meal (during a meal or no later than 1 hour after a meal).

If a meal is skipped or if the food does not contain fat, the intake of Listata can also be skipped.

Listata should be taken in combination with a balanced, moderately hypocaloric diet containing no more than 30% of calories from fat. Daily intake of fats, carbohydrates, and proteins should be distributed among 3 main meals.

Increasing the dose of Listata above the recommended dose (120 mg 3 times/day) does not lead to an enhancement of its therapeutic effect.

The efficacy and safety of Listata in patients with impaired liver and/or kidney function, as well as in elderly patients and children under 12 years of age have not been studied.

Adverse Reactions

Clinical trial data

Adverse effects of the drug are systematized for each organ system depending on the frequency of occurrence, using the following classification: very common (more than 1/10); common (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 reports (less than 1/10,000). Adverse reactions when using orlistat occurred mainly from the gastrointestinal tract and were due to the pharmacological action of orlistat, which prevents the absorption of dietary fats. Very common phenomena included oily discharge from the rectum, flatus with discharge, imperative urge to defecate, steatorrhea, increased defecation, loose stools, flatulence, abdominal pain or discomfort. Their frequency increases with increasing fat content in the food. Patients should be informed about the possibility of gastrointestinal adverse reactions and taught how to manage them by dietary compliance, especially regarding the amount of fat in the diet. Using a low-fat diet reduces the likelihood of gastrointestinal adverse effects and thereby helps patients control and regulate fat intake.

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

During treatment with orlistat, the following undesirable gastrointestinal phenomena often occur: "soft" stools, rectal pain or discomfort, fecal incontinence, abdominal distension, dental disorders, gum disorders. Also very commonly reported were headache, upper respiratory tract infections, influenza; commonly – 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 non-diabetic individuals with overweight and obesity. The only new adverse events in patients with type 2 diabetes mellitus were hypoglycemic conditions, occurring with a frequency of more than 2% and an incidence of at least 1% compared to placebo (which could occur as a result of improved carbohydrate metabolism compensation), and commonly – abdominal distension.

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 frequency of gastrointestinal adverse events decreased annually over the 4-year period of drug use.

Post-marketing surveillance

Rare cases of allergic reactions have been described, the main clinical manifestations of which were skin rash, itching, urticaria, 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 (a causal relationship with orlistat intake or pathophysiological mechanisms of development have not been established) have been described.

When orlistat was used concomitantly with indirect anticoagulants, cases of decreased prothrombin, increased values of the international normalized ratio (INR), and unbalanced anticoagulant therapy have been registered, leading to changes in hemostatic parameters.

Cases of rectal bleeding, diverticulitis, pancreatitis, cholelithiasis, and oxalate nephropathy have been registered (frequency of occurrence unknown).

Cases of seizures have been observed with the simultaneous use of orlistat and antiepileptic drugs (see section "Drug Interactions")

Contraindications

• Hypersensitivity to orlistat or any other component of the drug;
• Chronic malabsorption syndrome;
• Cholestasis;
• Pregnancy, breastfeeding period;
• Children under 12 years of age.

Use in Pregnancy and Lactation

In reproductive toxicity studies in animals, no teratogenic or embryotoxic effects of the drug orlistat were observed. In the absence of a teratogenic effect in animals, a similar effect in humans is not expected. Since there are no clinical data on the use of orlistat during pregnancy, the use of Listata in pregnant women is contraindicated.

Due to the lack of data on the excretion of orlistat in breast milk, the use of Listata during breastfeeding is contraindicated.

Use in Hepatic Impairment

The efficacy and safety of Listata in patients with impaired liver function.

Use in Renal Impairment

The efficacy and safety of Listata in patients with impaired kidney function.

Pediatric Use

The use of the drug is contraindicated in children under 12 years of age.

Geriatric Use

The efficacy and safety of Listata in elderly patients have not been studied.

Special Precautions

Listata is effective for long-term weight control (weight loss and maintenance, prevention of weight regain). 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 reduction in visceral fat.

When used in combination with hypoglycemic drugs such as metformin, sulfonylurea derivatives and/or insulin in patients with type 2 diabetes mellitus with overweight (BMI of at least 28 kg/m²) or obesity (BMI of at least 30 kg/m²), Listata in combination with a moderately hypocaloric diet contributes to additional improvement in carbohydrate metabolism compensation.

In clinical studies, in most patients, the concentrations of vitamins A, D, E, K and beta-carotene remained within the normal range during 4 years of orlistat therapy. To ensure adequate intake of all minerals, multivitamins can be used.

The patient should receive a balanced, moderately hypocaloric diet containing no more than 30% of calories from fat. A diet rich in fruits and vegetables is recommended. Daily intake of fats, carbohydrates, and proteins should be distributed over three main meals. The likelihood of gastrointestinal adverse reactions may increase if Listata is taken against a background of a diet rich in fats (for example, 2000 kcal/day, of which more than 30% is from fat, which is 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 carbohydrate metabolism compensation, which may allow or require a reduction in the dose of hypoglycemic drugs (e.g., sulfonylurea derivatives).

Effect on ability to drive vehicles and mechanisms

Listata does not affect the ability to drive vehicles and mechanisms. Patients with type 2 diabetes mellitus using Listata in combination with hypoglycemic drugs should exercise caution when driving vehicles and mechanisms due to the possible development of hypoglycemia, accompanied by dizziness and visual disturbances.

Overdose

In individuals with normal body weight and patients with obesity, single doses of 800 mg or multiple doses of orlistat 400 mg 3 times/day for 15 days were not accompanied by the appearance of significant adverse events. Furthermore, in obese patients, there is experience with the use of orlistat 240 mg 3 times/day for 6 months, which was not accompanied by a reliable increase in the frequency 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 significant overdose of orlistat, 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 interaction of orlistat 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 ethanol has been identified (based on drug interaction studies). However, it is necessary to monitor INR indicators during concomitant therapy with warfarin or other indirect anticoagulants.

When taken concomitantly with orlistat, a decrease in the absorption of vitamins D, E, and beta-carotene has been observed. If multivitamins are recommended, they should be taken no less than 2 hours after taking orlistat or at bedtime.

Concomitant administration of orlistat and cyclosporine has been associated with a decrease in plasma cyclosporine concentrations; therefore, more frequent monitoring of plasma cyclosporine concentrations is recommended when cyclosporine and orlistat are taken together.

When amiodarone was administered orally during orlistat therapy, a reduction in the systemic exposure to amiodarone and desethylamiodarone (by 25-30%) was observed; however, due to the complex pharmacokinetics of amiodarone, the clinical significance of this finding is unclear. The addition of orlistat to long-term amiodarone therapy may potentially lead to a reduction in the therapeutic effect of amiodarone (no studies have been conducted).

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

Cases of seizures have been reported with the concomitant use of orlistat and antiepileptic drugs. A causal relationship between the occurrence of seizures and orlistat therapy has not been established. Nevertheless, patients should be monitored for possible changes in the frequency and/or severity of convulsive seizures.

Storage Conditions

The drug should be stored in a place protected from light and out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 2 years.

Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.