Lindaxa (Capsules) Instructions for Use

Marketing Authorization Holder

Zentiva, a.s. (Czech Republic)

ATC Code

A08AA10 (Sibutramine)

Active Substance

Sibutramine

Dosage Forms

	Lindaxa	Capsules 10 mg: 30 or 90 pcs.
		Capsules 15 mg: 30 or 90 pcs.

Dosage Form, Packaging, and Composition

Capsules hard gelatin, with a yellow body and a brown cap, marked “10”; capsule contents – white or almost white powder.

Excipients: lactose monohydrate, microcrystalline cellulose, colloidal anhydrous silica, magnesium stearate.

Capsule body composition quinoline yellow, sunset yellow FCF, titanium dioxide, gelatin, black ink 1012 (shellac, black iron oxide, n-butanol, denatured ethanol (industrial methylated spirit), soy lecithin, antifoam DC 1510).

Capsule cap composition black iron oxide, red iron oxide, titanium dioxide, gelatin.

10 pcs. – blisters (3) – carton packs.
10 pcs. – blisters (9) – carton packs.

Capsules hard gelatin, with a yellow body and a blue cap, marked “15”; capsule contents – white or almost white powder.

Excipients: lactose monohydrate, microcrystalline cellulose, colloidal anhydrous silica, magnesium stearate.

Capsule body composition quinoline yellow, sunset yellow FCF, titanium dioxide, gelatin, black ink 1012 (shellac, black iron oxide, n-butanol, denatured ethanol (industrial methylated spirit), soy lecithin, antifoam DC 1510).

Capsule cap composition titanium dioxide, indigo carmine, gelatin.

10 pcs. – blisters (3) – carton packs.
10 pcs. – blisters (9) – carton packs.

Clinical-Pharmacological Group

Drug for the treatment of centrally-acting obesity

Pharmacotherapeutic Group

Remedy for obesity

Pharmacological Action

An anorexiant drug that enhances the feeling of satiety.

In vivo, it exerts its action through metabolites (primary and secondary amines) that inhibit the reuptake of monoamines (serotonin and norepinephrine).

The increased level of neurotransmitters in the synapses enhances the activity of central serotonin 5HT receptors and adrenoceptors, which contributes to decreased appetite and increased thermogenesis.

By indirectly stimulating β₃-adrenoceptors, it affects brown adipose tissue.

Sibutramine and its metabolites do not affect the release of monoamines, do not inhibit MAO, and do not have affinity for a large number of neurotransmitter receptors, including serotonin (5HT₁, 5HT_1A, 5HT_1B, 5HT_2A, 5HT_2C receptors), adrenergic (β₁, β₂, β₃, α₁, α₂ adrenoceptors), dopamine (D₁, D₂ receptors), cholinergic receptors, histamine H₁ receptors, benzodiazepine receptors, and NMDA receptors.

Pharmacokinetics

Absorption

Sibutramine is well absorbed and extensively metabolized during the first-pass effect through the liver.

After oral administration of a 20 mg dose, the T_max of sibutramine is reached in 1.2 hours, and the T_max of the active metabolites M1 and M2 is reached in 3 hours.

Distribution

Protein binding of sibutramine is 97%, and of M1 and M2 is 94%.

It is rapidly and well distributed in tissues.

Metabolism

It is almost completely metabolized in the liver by the CYP3A4 isoenzyme to form mono- (desmethylsibutramine) and di-desmethyl (didesmethylsibutramine) forms of active metabolites (M1 and M2), as well as by hydroxylation and conjugation to form inactive metabolites.

Elimination

The T_1/2 of sibutramine is 1.1 hours, and the T_1/2 of the active metabolites M1 and M2 is 14 hours and 16 hours, respectively.

It is excreted mainly by the kidneys as inactive metabolites.

Pharmacokinetics in special cases

In renal insufficiency, the main pharmacokinetic parameters of sibutramine and its active metabolites do not change significantly.

The pharmacokinetics of sibutramine do not depend on body weight, sex, or age.

Indications

• Alimentary obesity with a body mass index of 30 kg/m² or more;
• Alimentary obesity with a body mass index of 27 kg/m² or more in patients with risk factors associated with excess body weight (type 2 diabetes mellitus, dyslipoproteinemia).

ICD codes

Dosage Regimen

The dose is set individually, depending on tolerance and clinical effectiveness.

The drug is taken once a day, in the morning, regardless of meals (with food or on an empty stomach).

The initial dose is 10 mg.

If the effectiveness is insufficient (weight loss of less than 2 kg over 4 weeks), but provided that tolerance is good, the daily dose can be increased to 15 mg.

If after increasing the dose the drug’s effectiveness remains low (weight loss of less than 2 kg over 4 weeks), continuation of treatment is not advisable.

Treatment should be discontinued after 3 months in those patients who have failed to achieve a 5% reduction in body weight from the initial level during this time.

Treatment should not be continued if, during therapy with the drug, after achieved weight loss, the patient gains 3 kg or more in body weight.

The duration of treatment with sibutramine should not exceed 2 years, as there are no data on the efficacy and safety of use for a longer period of administration.

The capsule should be swallowed whole with a small amount of liquid (a glass of water).

Adverse Reactions

Side effects are most often noted at the beginning of treatment (in the first 4 weeks).

Their severity and frequency decrease over time.

Side effects are usually mild and reversible.

Side effects occur: frequently (>10%), sometimes (1-10%), rarely (<1%).

From the central and peripheral nervous system: frequently – insomnia; sometimes – headache, dizziness, anxiety, paresthesia, taste alteration.

From the cardiovascular system: sometimes – tachycardia (increase in pulse by 3-7 beats/min), palpitation, increased blood pressure (at rest by 1-3 mm Hg), vasodilation (skin redness, flushing); in isolated cases, more pronounced increases in blood pressure and heart rate cannot be excluded.

From the digestive system: frequently – dry mouth, loss of appetite, constipation; sometimes – nausea.

Other: sometimes – increased sweating, exacerbation of hemorrhoids.

In isolated cases, the following clinically significant adverse events have been described: dysmenorrhea, edema, flu-like syndrome, skin itching, back pain, abdominal pain, paradoxical increase in appetite, thirst, rhinitis, depression, drowsiness, emotional lability, anxiety, irritability, nervousness, acute interstitial nephritis, bleeding, Henoch-Schönlein purpura, seizures, thrombocytopenia, transient increase in plasma liver enzyme activity.

One patient with a schizoaffective disorder, which presumably existed before the start of treatment, developed acute psychosis after treatment.

Contraindications

• Organic cause of obesity;
• Serious eating disorders (anorexia or bulimia);
• Mental illness;
• Gilles de la Tourette syndrome (chronic generalized tic);
• Concomitant use of MAO inhibitors (e.g., phentermine, fenfluramine, dexfenfluramine, ethylamphetamine, ephedrine) or their use within 2 weeks prior to prescribing Lindaxa; serotonin reuptake inhibitors, hypnotics, drugs containing tryptophan, other centrally acting drugs for weight loss;
• Cardiovascular diseases, including coronary artery disease, chronic heart failure in the stage of decompensation, congenital heart defects, occlusive peripheral arterial diseases, tachycardia, arrhythmia, cerebrovascular diseases (stroke, transient ischemic attacks);
• Uncontrolled arterial hypertension (blood pressure above 145/90 mm Hg);
• Thyrotoxicosis;
• Severe impairment of liver and/or kidney function;
• Benign prostatic hyperplasia;
• Pheochromocytoma;
• Closed-angle glaucoma;
• Established drug, narcotic or alcohol dependence;
• Pregnancy;
• Lactation period (breastfeeding);
• Childhood and adolescence under 18 years;
• Age over 65 years;
• Hypersensitivity to sibutramine or other components of the drug.

With caution, the drug should be prescribed for a history of arrhythmias, chronic heart failure, cholelithiasis, arterial hypertension (controlled and in history), neurological disorders (including mental retardation and seizures /including in history/), mild to moderate impairment of liver and/or kidney function, history of motor and vocal tics.

Use in Pregnancy and Lactation

The drug is contraindicated for use during pregnancy and breastfeeding.

Use in Hepatic Impairment

The drug is contraindicated in severe hepatic impairment.

With caution, the drug should be prescribed for mild to moderate hepatic impairment.

Use in Renal Impairment

The drug is contraindicated in severe renal impairment.

With caution, the drug should be prescribed for mild to moderate renal impairment.

Special Precautions

Lindaxa should be used only in cases where non-drug measures for weight loss (diet and physical exercise) are ineffective (weight loss over 3 months was less than 5 kg).

Treatment with sibutramine should be carried out within the framework of complex therapy for weight loss under the supervision of a physician with practical experience in the treatment of obesity.

Complex therapy includes both changes in eating habits and lifestyle, as well as increased physical activity.

Patients need to change their lifestyle and habits in such a way as to ensure the maintenance of the achieved weight reduction after completion of treatment.

Patients should clearly understand that failure to comply with these requirements will lead to repeated weight gain and the need for repeated treatment.

During the period of taking Lindaxa, it is necessary to monitor blood pressure and heart rate levels in the first 2 months every 2 weeks, and then monthly.

In patients with arterial hypertension, monitoring should be carried out especially carefully and at shorter intervals.

If during a control measurement the blood pressure twice exceeds the level of 145/90 mm Hg, Lindaxa should be discontinued.

Caution should be exercised when prescribing Sibutramine concomitantly with drugs that prolong the QT interval, including histamine H₁-receptor blockers (astemizole, terfenadine), antiarrhythmic drugs (amiodarone, quinidine, flecainide, mexiletine, propafenone, sotalol), cisapride, pimozide, sertindole and tricyclic antidepressants.

This also applies to conditions that can lead to QT interval prolongation (e.g., hypomagnesemia).

The interval between taking MAO inhibitors (including furazolidone, procarbazine, selegiline) and sibutramine should be at least 2 weeks.

Although a connection between taking sibutramine and the development of primary pulmonary hypertension has not been established, when using the drug, attention should be paid to the appearance of progressive respiratory impairment, chest pain and swelling of the legs.

If a dose of sibutramine is missed, a double dose of the drug should not be taken at the next administration; it is recommended to continue further administration of the drug according to the schedule.

Reactions to drug withdrawal (headache, increased appetite) are rarely observed.

There are no data indicating that a withdrawal syndrome, discontinuation syndrome, or mood disorders are observed after drug withdrawal.

During the period of taking the drug, alcoholic beverages should not be consumed, as alcohol consumption is absolutely incompatible with the dietary measures recommended when taking Lindaxa.

Effect on the ability to drive vehicles and operate machinery

Drugs affecting the CNS may limit mental activity, memory and reaction speed.

During treatment, caution should be exercised when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

There are extremely limited data regarding sibutramine overdose.

Specific signs of overdose are unknown, nevertheless, the possibility of a more pronounced manifestation of side effects should be considered.

Treatment: there is no specific antidote; ensure free breathing, monitor the state of the cardiovascular system, and carry out symptomatic therapy if necessary.

Administration of activated charcoal, gastric lavage is indicated; for increased blood pressure and tachycardia – beta-blockers.

The effectiveness of forced diuresis or hemodialysis has not been established.

Drug Interactions

Concomitant administration of sibutramine with inhibitors of the CYP3A4 isoenzyme (ketoconazole, erythromycin, troleandomycin, cyclosporine) leads to an increase in the concentration of sibutramine metabolites with an increase in heart rate and a clinically insignificant prolongation of the QT interval.

Rifampicin, antibiotics from the macrolide group, phenytoin, carbamazepine, phenobarbital and dexamethasone may accelerate the metabolism of sibutramine.

When sibutramine is used concomitantly with selective serotonin reuptake inhibitors (antidepressants), with drugs for the treatment of migraine (sumatriptan, dihydroergotamine), with potent analgesics (pentazocine, pethidine, fentanyl), with antitussive drugs (dextromethorphan), serotonin syndrome may rarely develop.

The drug interaction of sibutramine with drugs that increase blood pressure and heart rate, with antitussive, antiallergic drugs is currently insufficiently studied.

Sibutramine does not affect the action of oral contraceptives.

No enhancement of the effect of ethanol was observed with simultaneous administration of sibutramine and ethanol.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 30°C (86°F).

Shelf Life

Shelf life – 2 years.

Sibutramine is classified in the List of Potent Substances approved by Decree of the Government of the Russian Federation No. 964 dated December 29, 2007.

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.