Goldline^® Combi (Tablet and capsule kit) Instructions for Use

Marketing Authorization Holder

Izvarino Farma, AB (Sweden)

Manufactured By

Izvarino Pharma LLC (Russia)

ATC Codes

A08AA (Centrally acting anti-obesity preparations)

A10BA02 (Metformin)

Active Substances

Sibutramine (Rec.INN registered by WHO)

Metformin (Rec.INN registered by WHO)

Microcrystalline cellulose (Ph.Eur. European Pharmacopoeia)

Dosage Forms

	Goldline® Combi	Kit of prolonged-release tablets and capsules: tab. 500 mg (10-90 pcs.) and caps. 10 mg+158.5 mg (10-90 pcs.)
		Kit of prolonged-release tablets and capsules: tab. 500 mg (10-90 pcs.) and caps. 15 mg+153.5 mg (10-90 pcs.)
		Kit of prolonged-release tablets and capsules: tab. 750 mg (10-90 pcs.) and caps. 10 mg+158.5 mg (10-90 pcs.)
		Kit of prolonged-release tablets and capsules: tab. 750 mg (10-90 pcs.) and caps. 15 mg+153.5 mg (10-90 pcs.)
		Kit of prolonged-release tablets and capsules: tab. 1000 mg (10-90 pcs.) and caps. 10 mg+158.5 mg (10-90 pcs.)
		Kit of prolonged-release tablets and capsules: tab. 1000 mg (10-90 pcs.) and caps. 15 mg+153.5 mg (10-90 pcs.)

Dosage Form, Packaging, and Composition

Kit of prolonged-release tablets and capsules:

Prolonged-release tablets white or almost white, oval, biconvex, with a score on one side and an embossed symbol “f” on the other.

Excipients: low-substituted hydroxypropyl cellulose, hypromellose, colloidal silicon dioxide, sodium stearyl fumarate.

Capsules hard gelatin, size No. 2, yellow body, blue cap; capsule contents – powder or compacted powder mass white or almost white.

Excipients: colloidal silicon dioxide, calcium stearate.

Capsule cap composition: dye azorubine (E122), indigotine (E132), sodium lauryl sulfate, titanium dioxide, gelatin.
Capsule body composition dye sunset yellow FCF (E110), dye quinoline yellow (E104), sodium lauryl sulfate, titanium dioxide, gelatin.

10 pcs. (tab.) + 10 pcs. (caps.) in blister packs.

The kit contains 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 blister packs of tablets (metformin) and capsules (sibutramine + microcrystalline cellulose), packaged in cardboard cartons.

Kit of prolonged-release tablets and capsules:

Prolonged-release tablets, white or almost white, oval, biconvex, with a score on one side and an embossed symbol “f” on the other.

Excipients: low-substituted hydroxypropyl cellulose, hypromellose, colloidal silicon dioxide, sodium stearyl fumarate.

Capsules hard gelatin size No. 2, white or almost white body, blue cap; capsule contents – powder or compacted powder mass white or almost white.

Excipients: colloidal silicon dioxide, calcium stearate.

Capsule cap composition: dye azorubine (E122), indigotine (E132), sodium lauryl sulfate, titanium dioxide, gelatin.
Capsule body composition sodium lauryl sulfate, titanium dioxide, gelatin.

10 pcs. (tab.) + 10 pcs. (caps.) in blister packs.

The kit contains 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 blister packs of tablets (metformin) and capsules (sibutramine + microcrystalline cellulose), packaged in cardboard cartons.

Kit of prolonged-release tablets and capsules:

Prolonged-release tablets white or almost white, oval, biconvex, with a score on one side and an embossed symbol “f” on the other.

Excipients: low-substituted hydroxypropyl cellulose, hypromellose, colloidal silicon dioxide, sodium stearyl fumarate.

Capsules hard gelatin, size No. 2, yellow body, blue cap; capsule contents – powder or compacted powder mass white or almost white.

Excipients: colloidal silicon dioxide, calcium stearate.

Capsule cap composition: dye azorubine (E122), indigotine (E132), sodium lauryl sulfate, titanium dioxide, gelatin.
Capsule body composition dye sunset yellow FCF (E110), dye quinoline yellow (E104), sodium lauryl sulfate, titanium dioxide, gelatin.

10 pcs. (tab.) + 10 pcs. (caps.) in blister packs.

The kit contains 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 blister packs of tablets (metformin) and capsules (sibutramine + microcrystalline cellulose), packaged in cardboard cartons.

Kit of prolonged-release tablets and capsules:

Prolonged-release tablets, white or almost white, oval, biconvex, with a score on one side and an embossed symbol “f” on the other.

Excipients: low-substituted hydroxypropyl cellulose, hypromellose, colloidal silicon dioxide, sodium stearyl fumarate.

Capsules hard gelatin size No. 2, white or almost white body, blue cap; capsule contents – powder or compacted powder mass white or almost white.

Excipients: colloidal silicon dioxide, calcium stearate.

Capsule cap composition: dye azorubine (E122), indigotine (E132), sodium lauryl sulfate, titanium dioxide, gelatin.
Capsule body composition sodium lauryl sulfate, titanium dioxide, gelatin.

10 pcs. (tab.) + 10 pcs. (caps.) in blister packs.

The kit contains 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 blister packs of tablets (metformin) and capsules (sibutramine + microcrystalline cellulose), packaged in cardboard cartons.

Kit of prolonged-release tablets and capsules:

Prolonged-release tablets white or almost white, oval, biconvex, with a score on one side and an embossed symbol “f” on the other.

Excipients: low-substituted hydroxypropyl cellulose, hypromellose, colloidal silicon dioxide, sodium stearyl fumarate.

Capsules hard gelatin, size No. 2, yellow body, blue cap; capsule contents – powder or compacted powder mass white or almost white.

Excipients: colloidal silicon dioxide, calcium stearate.

Capsule cap composition: dye azorubine (E122), indigotine (E132), sodium lauryl sulfate, titanium dioxide, gelatin.
Capsule body composition dye sunset yellow FCF (E110), dye quinoline yellow (E104), sodium lauryl sulfate, titanium dioxide, gelatin.

10 pcs. (tab.) + 10 pcs. (caps.) in blister packs.

The kit contains 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 blister packs of tablets (metformin) and capsules (sibutramine + microcrystalline cellulose), packaged in cardboard cartons.

Kit of prolonged-release tablets and capsules:

Prolonged-release tablets, white or almost white, oval, biconvex, with a score on one side and an embossed symbol “f” on the other.

Excipients: low-substituted hydroxypropyl cellulose, hypromellose, colloidal silicon dioxide, sodium stearyl fumarate.

Capsules hard gelatin size No. 2, white or almost white body, blue cap; capsule contents – powder or compacted powder mass white or almost white.

Excipients: colloidal silicon dioxide, calcium stearate.

Capsule cap composition: dye azorubine (E122), indigotine (E132), sodium lauryl sulfate, titanium dioxide, gelatin.
Capsule body composition sodium lauryl sulfate, titanium dioxide, gelatin.

10 pcs. (tab.) + 10 pcs. (caps.) in blister packs.

The kit contains 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 blister packs of tablets (metformin) and capsules (sibutramine + microcrystalline cellulose), packaged in cardboard cartons.

Clinical-Pharmacological Group

Combined drug for the treatment of osteoporosis

Pharmacotherapeutic Group

Oral hypoglycemic agent of the biguanide group. Anti-obesity agent

Pharmacological Action

A combination of medicinal products containing the oral hypoglycemic agent Metformin, an anti-obesity agent, and microcrystalline cellulose.

Metformin is a biguanide with a hypoglycemic effect, reducing both basal and postprandial plasma glucose concentrations. It does not stimulate insulin secretion and therefore does not cause hypoglycemia. It increases the sensitivity of peripheral receptors to insulin and the utilization of glucose by cells. It reduces glucose production by the liver by inhibiting gluconeogenesis and glycogenolysis. It delays the absorption of glucose in the intestine. Metformin stimulates glycogen synthesis by acting on glycogen synthase. It increases the transport capacity of all types of membrane glucose transporters. During metformin administration, the patient’s body weight either remains stable or moderately decreases. Metformin has a beneficial effect on lipid metabolism: it reduces the concentration of total cholesterol, LDL, and triglycerides.

Sibutramine is a prodrug and exerts its action in vivo through metabolites (primary and secondary amines) that inhibit the reuptake of monoamines (serotonin, noradrenaline, dopamine). The increased content of neurotransmitters in the synapses enhances the activity of central serotonin 5HT-serotonin receptors and adrenoceptors, which contributes to increased satiety and reduced need for food, as well as increased thermogenesis. By indirectly activating β₃-adrenoceptors, sibutramine acts on brown adipose tissue. Weight reduction is accompanied by an increase in serum HDL concentration and a decrease in the amount of triglycerides, total cholesterol, LDL, and uric acid. Sibutramine and its metabolites do not affect the release of monoamines, do not inhibit MAO; they do not have affinity for a large number of neurotransmitter receptors, including serotonin receptors (5HT₁, 5HT_1A, 5HT_1B, 5HT_2C), adrenoceptors (β₁ β₂, β₃, α₁, α₂), dopamine (D₁, D₂), m-cholinergic receptors, histamine H₁ receptors, benzodiazepine and glutamate NMDA receptors.

Microcrystalline cellulose is an enterosorbent, has sorption properties and a nonspecific detoxifying action. It binds and removes from the body various microorganisms, their metabolic products, toxins of exogenous and endogenous nature, allergens, xenobiotics, as well as an excess of some metabolic products and metabolites responsible for the development of endogenous toxicosis.

Pharmacokinetics

Metformin

The time to reach C_max depends on the dosage form and is 5-7 hours. At steady state, identical to the steady state of immediate-release metformin, the maximum concentration (C_max) and AUC increase disproportionately to the dose taken. Plasma protein binding is negligible. The mean V_d ranges from 63-276 L. Metformin penetrates into erythrocytes. Erythrocytes probably represent a secondary distribution compartment for metformin. No metabolites have been detected in humans. Metformin is excreted unchanged by the kidneys. The renal clearance of metformin is > 400 ml/min, indicating that Metformin is eliminated by glomerular filtration and tubular secretion. After oral administration, T_1/2 is about 6.5 hours. In case of impaired renal function, the clearance of metformin decreases proportionally to CCr, and T_1/2 increases, which can lead to an increase in the plasma concentration of metformin.

Sibutramine

After oral administration, it is rapidly absorbed from the gastrointestinal tract by at least 77%. During the “first pass” through the liver, it undergoes biotransformation under the influence of the isoenzyme CYP3A4 to form two active metabolites (monodesmethylsibutramine – M1 and didesmethylsibutramine – M2). After a single dose of 15 mg, C_max of M1 is 4 ng/ml (3.2-4.8 ng/ml), M2 – 6.4 ng/ml (5.6-7.2 ng/ml). C_max is reached after 1.2 hours (sibutramine), 3-4 hours (M1 and M2). Concurrent food intake decreases C_max of metabolites by 30% and increases the time to reach it by 3 hours, without changing AUC. It is rapidly distributed in tissues. Protein binding is 97% (sibutramine) and 94% (M1 and M2). The steady-state plasma concentration of active metabolites is reached within 4 days after the start of use and is approximately 2 times higher than the plasma concentration after a single dose. Active metabolites undergo hydroxylation and conjugation to form inactive metabolites, which are excreted mainly by the kidneys. T_1/2 of sibutramine is 1.1 hours, M1 – 14 hours, M2 -16 hours.

Indications

For weight reduction in alimentary obesity with BMI 27 kg/m² and above in combination with type 2 diabetes mellitus and dyslipidemia.

For weight reduction in alimentary obesity with BMI over 30 kg/m² in patients with prediabetes and additional risk factors for developing type 2 diabetes mellitus, in whom lifestyle changes have not achieved adequate glycemic control.

ICD codes

Dosage Regimen

Take the combination orally once daily as a fixed dose.

Initiate treatment only after confirming inadequate weight loss (less than 5 kg in 3 months) with non-drug measures.

Administer the kit under medical supervision by a physician experienced in obesity management.

Combine therapy with a hypocaloric diet (not less than 1000 kcal/day) and increased physical activity.

Swallow the prolonged-release tablet and capsule whole; do not chew or crush.

Take the dose in the morning, with or without food, to minimize potential gastrointestinal effects.

Regularly monitor blood pressure and heart rate every two weeks for the first three months, then monthly.

Discontinue treatment if, at two consecutive visits, resting heart rate increases by more than 10 beats per minute or blood pressure rises by more than 10 mmHg.

Assess renal function by measuring creatinine clearance before starting and periodically during therapy.

Suspend treatment 48 hours before and after procedures involving iodinated contrast media or major surgery.

Do not exceed a treatment duration of one year.

Re-evaluate therapy if satisfactory weight loss (5% or more of initial body weight) is not achieved within the first 3-4 months.

Use with caution in patients with controlled hypertension or a history of circulatory disorders.

Avoid use in patients with a history of coronary artery disease, congestive heart failure, or cerebrovascular disease.

Do not use concomitantly with other serotonergic drugs, MAO inhibitors, or centrally-acting appetite suppressants.

Adverse Reactions

Metformin

Metabolism and nutrition disorders very rarely – lactic acidosis. With long-term use, decreased absorption of vitamin B₁₂ is possible.

Nervous system disorders often – taste disturbance (metallic taste in the mouth).

Gastrointestinal disorders very often – nausea, vomiting, diarrhea, abdominal pain and loss of appetite.

Hepatobiliary disorders very rarely – impaired liver function tests and hepatitis, which resolve spontaneously after discontinuation of metformin.

Skin and subcutaneous tissue disorders very rarely – skin reactions such as erythema (redness of the skin), itching, urticaria.

Sibutramine

Nervous system disorders very often – dry mouth, insomnia; often – headache, dizziness, anxiety, paresthesia, taste alteration; convulsions, short-term memory impairment are possible.

Cardiac disorders often – tachycardia, palpitations, vasodilation, moderate increase in blood pressure at rest by 1-3 mmHg and a moderate increase in pulse by 3-7 beats/min. In some cases, a more pronounced increase in blood pressure and increase in heart rate cannot be excluded. Clinically significant changes in blood pressure and pulse are recorded mainly at the beginning of treatment (in the first 4-8 weeks). Cases of atrial fibrillation have been described.

Gastrointestinal disorders very often – loss of appetite, constipation, often – nausea, exacerbation of hemorrhoids; diarrhea, vomiting are possible.

Skin and subcutaneous tissue disorders often – increased sweating; alopecia is possible.

Immune system disorders hypersensitivity reactions (from moderate skin rashes and urticaria to angioedema and anaphylaxis).

Psychiatric disorders psychosis, states of suicidally directed thinking, suicide and mania.

Eye disorders blurred vision is possible.

Renal and urinary disorders: urinary retention is possible.

Reproductive system and breast disorders ejaculation/orgasm disorder, impotence, menstrual cycle disorder, uterine bleeding are possible.

In isolated cases 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 (skin hemorrhages), seizures, thrombocytopenia, transient increase in blood liver enzyme activity.

Contraindications

Hypersensitivity to the components of the combination; diabetic ketoacidosis, diabetic precoma, coma; impaired renal function (creatinine clearance less than 45 ml/min); acute conditions with a risk of impaired renal function (including dehydration due to chronic or severe diarrhea, repeated episodes of vomiting, severe infectious diseases, including respiratory tract infections, urinary tract infections); shock; clinically significant manifestations of acute or chronic diseases that may lead to tissue hypoxia (including acute heart failure, chronic heart failure with unstable hemodynamic parameters, respiratory failure, acute myocardial infarction); cardiovascular diseases (in history or present) – coronary artery disease, chronic heart failure in the stage of decompensation, occlusive peripheral arterial diseases, tachycardia, arrhythmia, cerebrovascular diseases (stroke, transient ischemic attacks); uncontrolled arterial hypertension (blood pressure greater than 145/90 mmHg); major surgical operations and trauma when insulin therapy is indicated; severe hepatic impairment; chronic alcoholism, acute alcohol intoxication; established pharmacological or drug dependence; thyrotoxicosis; benign prostatic hyperplasia; pheochromocytoma; angle-closure glaucoma; lactic acidosis (including in history); pregnancy, breastfeeding period; use within less than 48 hours before and within 48 hours after radioisotope or radiological studies with intravascular administration of iodine-containing X-ray contrast agents (e.g., intravenous urography, angiography); adherence to a hypocaloric diet (less than 1000 kcal/day); presence of organic causes of obesity (e.g., hypothyroidism); serious eating disorders – anorexia nervosa or bulimia nervosa; mental illnesses; Gilles de la Tourette syndrome (generalized tics); simultaneous use of MAO inhibitors (e.g., phentermine, fenfluramine, dexfenfluramine, ethylamphetamine, ephedrine) or use within 2 weeks before taking sibutramine and 2 weeks after its discontinuation of other drugs acting on the central nervous system, inhibiting serotonin reuptake (e.g., antidepressants, antipsychotics); hypnotic drugs containing tryptophan, as well as other centrally acting drugs for weight loss or for the treatment of mental disorders; age under 18 years and over 65 years.

With caution

Chronic circulatory failure; coronary artery diseases (including in history), except for coronary artery disease; glaucoma, except for angle-closure glaucoma; cholelithiasis; arterial hypertension (controlled and in history); history of arrhythmia; neurological disorders, including mental retardation and seizures (including in history); epilepsy; mild to moderate hepatic impairment; impaired renal function (creatinine clearance 45-59 ml/min); history of motor and verbal tics; tendency to bleeding; blood clotting disorders; use of drugs affecting hemostasis or platelet function; patients over 60 years of age performing heavy physical work, which is associated with an increased risk of developing lactic acidosis.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Use in Hepatic Impairment

Contraindicated for use in severe hepatic impairment.

Use with caution in mild to moderate hepatic impairment.

Use in Renal Impairment

Contraindicated if creatinine clearance is less than 45 ml/min. Treatment should be suspended in the presence of conditions that may affect renal function.

Pediatric Use

Contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

Contraindicated for use in elderly patients over 65 years of age.

Special Precautions

This combination should be used only in cases where all non-drug measures for weight loss are ineffective – if weight loss within 3 months is less than 5 kg. Treatment with this agent 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. Comprehensive therapy includes both dietary and lifestyle changes, as well as increased physical activity. An important component of therapy is creating the prerequisites for a sustained change in eating behavior and lifestyle, which are necessary to maintain the achieved weight loss even after discontinuation of drug therapy. Patients need to change their lifestyle and habits within the framework of therapy with this agent so that after completion of treatment, the achieved reduction in body weight is maintained. Patients must clearly understand that failure to comply with these requirements will lead to repeated weight gain and repeated visits to the attending physician.

Patients are advised to continue a diet with uniform carbohydrate intake throughout the day. Overweight patients are advised to continue a hypocaloric diet (but not less than 1000 kcal/day). Patients should also exercise regularly.

In case of dehydration (severe diarrhea or vomiting, fever, or reduced fluid intake), treatment with metformin should be temporarily discontinued and a doctor should be consulted.

Patients and/or caregivers should be informed about the risk of lactic acidosis. Lactic acidosis is characterized by acidotic dyspnea, abdominal pain, muscle cramps, severe asthenia, and hypothermia followed by coma. If suspicious symptoms occur, the patient should discontinue the drug and seek immediate medical attention. Doctors should warn patients about the risk and symptoms of lactic acidosis.

The use of this agent must be discontinued 48 hours before the administration of an iodine-containing X-ray contrast agent and resumed no earlier than 48 hours after the study, provided that no impairment of renal function was detected during it.

The use of this agent should be discontinued 48 hours before planned surgical operations under general, spinal, or epidural anesthesia and may be continued no earlier than 48 hours after the surgical intervention, provided that no impairment of renal function was detected during the examination.

Since Metformin is excreted by the kidneys, before starting treatment with this agent and regularly thereafter, it is necessary to determine creatinine clearance: at least once a year in patients with normal renal function; every 3-6 months in patients with creatinine clearance of 45-59 ml/min.

Particular caution should be exercised in case of possible impairment of renal function in elderly patients (due to its asymptomatic nature), with simultaneous use of antihypertensive drugs, diuretics, or NSAIDs.

Patients with heart failure have a higher risk of developing hypoxia and impaired renal function.

Patients with chronic heart failure should regularly monitor cardiac function and renal function during the use of this agent.

Patients should inform the doctor about any ongoing treatment and any infectious diseases, such as colds, respiratory tract infections, or urinary tract infections.

It is recommended to regularly perform standard laboratory tests to monitor diabetes.

Caution is recommended when using this agent in combination with insulin or other oral hypoglycemic agents (including sulfonylurea derivatives or repaglinide).

During treatment, it is necessary to regularly monitor blood pressure and heart rate. During the first 3 months of treatment, these parameters should be monitored every 2 weeks, and then monthly. If during two consecutive visits an increase in resting heart rate > 10 beats/min or systolic/diastolic blood pressure > 10 mmHg is detected, treatment must be discontinued. In patients with arterial hypertension, in whom blood pressure is above 145/90 mmHg against the background of antihypertensive therapy, this control should be carried out especially carefully and, if necessary, at shorter intervals. In patients whose blood pressure exceeded the level of 145/90 mmHg twice upon repeated measurement, treatment with this agent should be suspended.

In patients with sleep apnea syndrome, blood pressure must be monitored especially carefully.

Particular caution should be exercised if the patient has conditions in which there is a risk of increasing the QT interval on the ECG, such as hypokalemia and hypomagnesemia.

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

Although a connection between taking sibutramine and the development of primary pulmonary hypertension has not been established, however, given the well-known risk of drugs in this group, during regular medical monitoring, special attention should be paid to such symptoms as progressive dyspnea (breathing difficulty), chest pain, and leg swelling.

The duration of use should not exceed 1 year.

Although there are no clinical data on addiction to sibutramine, it should be ascertained whether the patient has a history of drug dependence and attention should be paid to possible signs of drug abuse.

The use of this agent in patients with prediabetes is recommended in the presence of additional risk factors for the development of overt type 2 diabetes mellitus, which include: age less than 60 years, BMI greater than 30 kg/m², history of gestational diabetes mellitus, family history of diabetes in first-line relatives, increased triglyceride concentration, decreased HDL cholesterol concentration, arterial hypertension.

Effect on the ability to drive vehicles and machinery

Taking this agent may limit the ability to drive vehicles and machinery. 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.

Drug Interactions

Against the background of functional renal failure in patients with diabetes, radiological examination using iodine-containing X-ray contrast agents can cause the development of lactic acidosis. This combination is contraindicated.

In acute alcohol intoxication, the risk of developing lactic acidosis increases, especially in case of insufficient nutrition, adherence to a low-calorie diet; impaired liver function. During the use of this agent, the use of alcohol and medicines containing ethanol should be avoided.

Some medicines (NSAIDs, including selective COX-2 inhibitors, ACE inhibitors, angiotensin II receptor antagonists, and diuretics, especially “loop” diuretics) can have a negative impact on renal function, which may increase the risk of lactic acidosis. At the beginning and during treatment with such drugs in combination with metformin, careful monitoring of renal function is necessary.

Medicines with indirect hyperglycemic action (e.g., systemic and topical corticosteroids, tetracosactide, beta₂-adrenergic agonists, danazol, chlorpromazine when taken in high doses – 100 mg/day, diuretics): more frequent monitoring of blood glucose concentration may be required, especially at the beginning of treatment. If necessary, the dose of metformin can be adjusted during treatment and after its cessation, based on blood glucose concentration.

With simultaneous use of metformin with sulfonylurea derivatives, insulin, acarbose, salicylates, hypoglycemia may develop.

Nifedipine increases the absorption and C_max of metformin.

Cationic medicines (amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, and vancomycin), secreted in the renal tubules, compete with metformin for tubular transport systems and can lead to an increase in its C_max.

Colesevelam, when used simultaneously with metformin in the form of extended-release tablets, increases the plasma concentration of metformin (increase in AUC without a significant increase in C_max).
The hypoglycemic effect of metformin can be reduced by phenothiazines, glucagon, estrogens, oral contraceptives, phenytoin, sympathomimetics, nicotinic acid, isoniazid, slow calcium channel blockers, levothyroxine sodium.

Simultaneous use with cimetidine reduces the elimination rate of metformin, which can lead to the development of lactic acidosis.

Metformin reduces the C_max and T_1/2 of furosemide.

Metformin may reduce the effect of indirect anticoagulants.

Metformin is a substrate of organic cations OCT1 and OCT2. When used concomitantly with metformin, inhibitors of OCT1 (such as verapamil) may reduce the hypoglycemic effect of metformin; inducers of OCT1 (such as rifampicin) may increase the absorption of metformin in the gastrointestinal tract and enhance its hypoglycemic effect; inhibitors of OCT2 (such as cimetidine, dolutegravir, ranolazine, trimethoprim, vandetanib, isavuconazole) may reduce the renal excretion of metformin and lead to an increase in its plasma concentration; inhibitors of OCT1 and OCT2 (such as crizotinib, olaparib) may reduce the hypoglycemic effect of metformin. In this regard, caution is recommended, especially in patients with impaired renal function, when these drugs are taken simultaneously with metformin, as an increase in the plasma concentration of metformin is possible. If necessary, adjustment of the metformin dose may be considered, as OCT inhibitors/inducers can alter the effectiveness of metformin.

Inhibitors of microsomal oxidation, including inhibitors of the CYP3A4 isoenzyme (including ketoconazole, erythromycin, cyclosporine) increase the plasma concentrations of sibutramine metabolites with an increase in heart rate and a clinically insignificant increase in the QT interval.

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

Simultaneous use of several drugs that increase the serotonin content in blood plasma can lead to the development of a serious interaction. The so-called serotonin syndrome can develop in rare cases with the simultaneous use of sibutramine with selective serotonin reuptake inhibitors (drugs for the treatment of depression), with some drugs for the treatment of migraine (sumatriptan, dihydroergotamine), with potent analgesics (pentazocine, pethidine, fentanyl) or antitussive drugs (dextromethorphan).

No enhancement of the negative effects of alcohol was observed with the simultaneous intake of sibutramine and alcohol. However, alcohol is absolutely incompatible with the dietary measures recommended when taking sibutramine.

With the simultaneous use of sibutramine with other drugs affecting hemostasis or platelet function, the risk of bleeding increases. The drug interaction with the simultaneous use of sibutramine with drugs that increase blood pressure and heart rate has not been sufficiently studied to date. This group of drugs includes decongestants, antitussives, cold and anti-allergy drugs that contain ephedrine or pseudoephedrine. Therefore, in cases of simultaneous use of these drugs with sibutramine, caution should be exercised.

Concomitant use of sibutramine with centrally acting weight loss drugs or drugs for the treatment of mental disorders is contraindicated.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.