Xenalten^® (Capsules) Instructions for Use

ATC Code

A08AB01 (Orlistat)

Active Substance

Orlistat (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Drug for the treatment of obesity – inhibitor of gastrointestinal lipases

Pharmacotherapeutic Group

Gastrointestinal lipase inhibitor

Pharmacological Action

A specific inhibitor of gastrointestinal lipases. It forms a covalent bond with the active serine site of gastric and pancreatic lipases in the lumen of the stomach and small intestine. The inactivated enzyme loses its ability to break down dietary fats supplied in the form of triglycerides (TG). Undigested TGs are not absorbed, and the resulting reduction in calorie intake leads to a decrease in body weight. It increases the concentration of fat in feces 24-48 hours after administration. It provides effective control of body weight and reduction of fat depots.

Systemic absorption of orlistat is not required for its activity; at the recommended therapeutic dose (120 mg 3 times/day), it inhibits the absorption of dietary fats by approximately 30%.

Pharmacokinetics

Absorption is low; unchanged Orlistat is not detected in plasma 8 hours after oral administration (concentration below 5 ng/ml).

The systemic exposure to orlistat is minimal. After oral administration of 360 mg of radioactively labeled ¹⁴C-orlistat, the peak of radioactivity in plasma was reached in about 8 hours; the concentration of unchanged orlistat was close to the limit of detection (less than 5 ng/ml). In therapeutic studies involving monitoring of patient plasma samples, unchanged Orlistat was detected sporadically in plasma, and its concentrations were low (less than 10 ng/ml), with no signs of accumulation, which is consistent with minimal absorption of the drug.

In vitro, Orlistat is more than 99% bound to plasma proteins, mainly lipoproteins and albumin. Orlistat minimally penetrates into erythrocytes. It is metabolized mainly in the wall of the gastrointestinal tract (GIT) to form pharmacologically inactive metabolites M1 (hydrolyzed four-membered lactone ring) and M3 (M1 with the N-formylleucine residue cleaved off). In a study in obese patients who took ¹⁴C-Orlistat orally, these two metabolites, M1 and M3, accounted for about 42% of the total plasma radioactivity. M1 and M3 have an open beta-lactone ring and exhibit extremely weak inhibitory activity against lipases (1000 and 2500 times weaker than orlistat, respectively). Given the low activity and low plasma concentrations of the metabolites (about 26 ng/ml and 108 ng/ml for M1 and M3, respectively, 2-4 hours after administration of orlistat in therapeutic doses), these metabolites are considered pharmacologically insignificant. The main metabolite M1 has a short half-life (T_1/2) (about 3 hours), the second metabolite is eliminated more slowly (T_1/2 — 13.5 hours). In obese patients, the steady-state concentration (Css) of metabolite M1 (but not M3) increases proportionally to the orlistat dose. After a single oral dose of 360 mg of ¹⁴C-orlistat to patients with normal body weight and obese patients, the excretion of unabsorbed orlistat through the intestine was the main route of elimination. Orlistat and its metabolites M1 and M3 are also subject to biliary excretion. About 97% of the administered radioactively labeled substance was excreted in the feces, including 83% unchanged.

Cumulative renal excretion of total radioactivity after administration of 360 mg of ¹⁴C-orlistat was less than 2%. The time for complete elimination via feces and urine is 3-5 days. The elimination of orlistat was similar in patients with normal body weight and obese patients. Based on limited data, the T_1/2 of absorbed orlistat ranges from 1-2 hours.

Indications

Treatment of obesity, including reduction and maintenance of body weight, in combination with a hypocaloric diet.

Orlistat is also indicated to reduce the risk of regaining weight after its initial loss.

Orlistat is indicated for patients with obesity with a body mass index (BMI) >30 kg/m² or >28 kg/m² in the presence of other risk factors (diabetes mellitus, arterial hypertension, dyslipidemia).

(BMI calculation: BMI = M/P², where M is body weight, kg; P is height, m.)

ICD codes

Dosage Regimen

Take one 120 mg capsule three times daily with each main meal containing fat.

Administer the capsule during the meal or up to one hour after its completion.

Omit the dose if a meal is missed or if it contains no fat.

Adhere to a nutritionally balanced, hypocaloric diet where fat provides no more than 30% of total daily calories.

Distribute daily intake of fats, carbohydrates, and proteins across three main meals.

Take a multivitamin supplement containing fat-soluble vitamins (A, D, E, K) daily.

Administer the multivitamin at least 2 hours before or 2 hours after taking Xenalten^®, such as at bedtime.

Do not exceed the recommended dose of one capsule three times daily, as higher doses provide no additional therapeutic benefit.

Assess treatment efficacy after 12 weeks; discontinue therapy if weight loss is less than 5% of initial body weight.

Do not continue treatment for more than 2 years.

Adverse Reactions

The frequency of adverse reactions listed below was determined as follows: very common >1/10; common > 1/100, < 1/10; uncommon > 1/1000, <1/100; rare > 1/10 000, <1/1000; very rare < 1/10 000, including isolated reports.

Gastrointestinal disorders very common – oily discharge from the rectum, flatus with discharge, imperative urge to defecate, steatorrhea, increased defecation, loose stools, flatulence, abdominal pain or discomfort. As a rule, these adverse reactions are mild and transient, occurring in the early stages of treatment (the first 3 months). The frequency of these undesirable reactions increases with an increase in the fat content in the diet. Patients should be informed about the possibility of these side effects and taught how to eliminate them by better adherence to the diet, especially regarding its fat content. Common – soft stools, rectal pain or discomfort, fecal incontinence, abdominal distension, tooth disorder, gum disorder.

Respiratory, thoracic and mediastinal disorders very common – upper respiratory tract infections; common – lower respiratory tract infections.

Immune system disorders rare – pruritus, urticaria, rash, angioedema, bronchospasm, anaphylaxis.

Nervous system disorders very common – headache.

Hepatobiliary disorders very rare – increased transaminase and alkaline phosphatase activity, hepatitis.

Renal and urinary disorders common – urinary tract infections.

Other very common – influenza; common – dysmenorrhea, anxiety, fatigue.

If any of the side effects listed in the instructions get worse, or you notice any other side effects not listed in the instructions, tell your doctor.

Contraindications

• Hypersensitivity to orlistat or other components of the drug;
• Malabsorption syndrome;
• Cholestasis;
• Concomitant use with cyclosporine;
• Pregnancy;
• Breastfeeding;
• Age under 18 years.

With caution in the presence of a history of hyperoxaluria, nephrolithiasis (calcium oxalate stones).

Use in Pregnancy and Lactation

Orlistat is contraindicated during pregnancy due to the lack of reliable clinical data confirming its safety.

It has not been established whether Orlistat passes into breast milk, therefore the use of Xenalten^® during breastfeeding is not recommended.

Pediatric Use

Xenalten^® is not intended for use in pediatric practice.

Special Precautions

During treatment, it is necessary to follow a balanced, low-calorie diet containing no more than 30% of calories in the form of fats and enriched with fruits and vegetables (additional prescription of multivitamins may be necessary to compensate for reduced absorption of fat-soluble vitamins).

Before prescribing orlistat, an organic cause of obesity, such as hypothyroidism, should be excluded.

The likelihood of developing gastrointestinal side effects increases with a high fat content in food (more than 30% of daily calories). The daily intake of fats, carbohydrates and proteins should be distributed among three main meals. Since Orlistat reduces the absorption of some fat-soluble vitamins, to ensure their adequate intake, patients should take multivitamin preparations containing fat-soluble vitamins. Furthermore, the levels of vitamin D and beta-carotene in obese patients may be lower than in non-obese individuals. Multivitamins should be taken 2 hours before or 2 hours after taking orlistat, for example, at bedtime. Taking orlistat in doses exceeding 120 mg 3 times/day does not provide an additional effect.

If concomitant administration of orlistat with cyclosporine cannot be avoided, constant monitoring of cyclosporine plasma levels is necessary.

In patients who did not receive prophylactic vitamin supplements, a decrease in plasma vitamin levels was recorded at two or more consecutive visits during the first and second years of orlistat treatment.

In some patients, orlistat may increase the oxalate content in the urine.

As with other weight loss drugs, there is a possibility of orlistat abuse in some groups of patients (e.g., with anorexia nervosa or bulimia).

Since the absorption of vitamin K may decrease when taking orlistat, in patients receiving Orlistat against the background of long-term constant warfarin intake, blood coagulation parameters should be monitored.

Induction of weight loss by orlistat may be combined with improved metabolic control of diabetes mellitus, which may require a reduction in the doses of oral hypoglycemic agents (sulfonylurea derivatives, metformin, etc.) or insulin.

If after 12 weeks of therapy with Xenalten^® the weight loss is less than 5% of the initial weight, a doctor’s consultation is necessary to decide on the need to continue treatment with orlistat.

Treatment should not be continued for more than 2 years.

Xenalten^® is not intended for use in pediatric practice.

Effect on the ability to drive vehicles and operate machinery

Does not affect the ability to drive vehicles and operate moving machinery.

Overdose

Cases of overdose have not been described.

A single dose of 800 mg of orlistat or its multiple administration in a dose of up to 400 mg 3 times/day for 15 days in people with normal body weight and obesity was not accompanied by significant side effects.

If a significant overdose of orlistat is identified, the patient should be observed for 24 hours. According to studies in animals and humans, systemic effects associated with the lipase-inhibiting properties of orlistat should be rapidly reversible.

Drug Interactions

Orlistat does not affect the pharmacokinetics of ethanol, digoxin (administered as a single dose) and phenytoin (administered as a single dose of 300 mg), or the bioavailability of nifedipine (extended-release tablets). Ethanol does not affect the pharmacodynamics (excretion of fats in feces) and systemic exposure of orlistat.

With simultaneous use of orlistat and cyclosporine, the plasma level of the latter decreases (Orlistat and cyclosporine should not be taken simultaneously; to reduce the likelihood of drug interaction, cyclosporine should be taken 2 hours before or 2 hours after taking orlistat).

With simultaneous use of warfarin or other indirect anticoagulants with orlistat, the prothrombin level may decrease and the value of the international normalized ratio (INR) may change, therefore INR monitoring is necessary.

Orlistat reduces the absorption of beta-carotene contained in dietary supplements by 30% and inhibits the absorption of vitamin E (in the form of tocopheryl acetate) by approximately 60%.

It increases the bioavailability and hypolipidemic effect of pravastatin, increasing its plasma concentration by 30%.

When taken simultaneously with orlistat, the absorption of vitamins A, D, E and K is reduced. If multivitamins are recommended, they should be taken at least 2 hours after taking Xenalten^® or at bedtime.

Weight loss may improve metabolism in patients with diabetes mellitus, which may require a reduction in the dose of oral hypoglycemic drugs.

Concomitant use with acarbose is not recommended due to the lack of data on pharmacokinetic interactions.

When used concomitantly with orlistat, a decrease in the plasma level of amiodarone after a single dose was noted. Concomitant use of orlistat and amiodarone is possible only on the recommendation of a doctor.

Orlistat may indirectly reduce the bioavailability of oral contraceptives, which may lead to unwanted pregnancy. It is recommended to use additional methods of contraception in case of acute diarrhea.

Clinically significant interactions with digoxin, amitriptyline, phenytoin, fluoxetine, sibutramine, atorvastatin, pravastatin, nifedipine, losartan, glibenclamide, furosemide, captopril, atenolol, and ethanol have not been noted.

Storage Conditions

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

Shelf Life

Shelf life – 2 years. Do not use after the expiration date printed on the package.

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.