Reduxin Forte, 850 mg+10 mg 30 pcs

Pharmacotherapeutic group
Hypoglycemic agent of oral biguanide group. An agent for the treatment of obesity.

ATX code: A08A and A10BA02

Pharmacodynamics

Metformin
. An oral hypoglycemic drug of the biguanide group, reduces hyperglycemia without resulting in hypoglycemia. Unlike sulfonylurea derivatives, it does not stimulate insulin secretion and does not cause hypoglycemic effect in healthy people. Increases the sensitivity of peripheral receptors to insulin and glucose utilization by cells. Inhibits gluconeogenesis in the liver. Delays absorption of carbohydrates in the intestine and stimulates the production of GTP-1 (physiological appetite regulator). Metformin stimulates glycogen synthesis by acting on glycogen synthase. It increases transport capacity of all types of membrane glucose transporters. In addition, it has a favorable effect on lipid metabolism: it decreases concentrations of total cholesterol, low-density lipoproteins and triglycerides.

During metformin administration body weight remains stable or decreases moderately.

Sibutramine
It is a prodrug and shows its effect in vivo due to metabolites (primary and secondary amines) that inhibit monoamine reuptake (serotonin, noradrenaline and dopamine). The increase of neurotransmitters in synapses increases the activity of central 5NT-serotonin and adrenergic receptors and contributes to the physiological regulation of appetite by increasing the feeling of satiety and reducing the need for food, as well as increasing thermoproduction (internal energy expenditure). By activating β-adrenoceptors indirectly, sibutramine affects brown adipose tissue. Reduction of body weight when taking sibutramine is accompanied by an increase in serum concentration of high density lipoproteins (HDL) and a decrease in triglycerides, total cholesterol, low density lipoproteins (LDL) and uric acid.

Sibutramine and its metabolites do not affect the release of monoamines, do not inhibit monoamine oxidase (MAO); They have no affinity to a large number of neurotransmitter receptors, including serotonin receptors (5-HT1, 5-HT1A, 5-HT1B, 5-HT2C), adrenergic (β1, β2, β3, α1, α2), dopamine (D1, D2), muscarinic, histamine (H1), benzodiazepine and glutamate NMDA receptors.
Simultaneous use of metformin and sibutramine increases the effectiveness of therapy in obese patients. By regulating appetite, reducing hunger, increasing energy expenditure and regulating lipid and carbohydrate metabolism, Reduxin® Forte reduces human body weight and restores metabolic health.

Clinical efficacy and safety (Results of clinical trials)
In a clinical trial in Reduxin® Forte group the percentage of patients who achieved clinically significant weight loss ≥5% during 3 months of therapy (early responders to therapy) exceeded 90%. During 6 months of therapy 91.67% of patients in the Reduxin® Forte group achieved a weight loss of 10% or more. The decrease of body weight was accompanied by clinically significant reduction of waist circumference and improvement of lipid profile, which proves the effectiveness of the drug in reducing the risk of complications and meets the main objectives of treatment of obesity.

No negative effect of Reduxin® Forte on the cardiovascular system parameters was observed during the study in patients with obesity.

Pharmacokinetics

absorption
After oral administration metformin is completely absorbed from the gastrointestinal tract. With concomitant food intake, metformin absorption is reduced and delayed. Absolute bioavailability is 50-60%. Maximum plasma concentration (Cmax) is approximately 2 µg/ml or 15 µmol and is reached after 2.5 hours.

Distribution
Metformin is rapidly distributed in body tissues. Virtually not bound to plasma proteins.

Metabolism
Subject to little metabolism.

Elimation
It is excreted by the kidneys. Metformin clearance in healthy subjects is 400 ml/min (4 times higher than creatinine clearance (CK)), indicating active tubular secretion.

The half-life (T1/2) is approximately 6.5 h.

Pharmacokinetics in special clinical cases
In patients with renal insufficiency T1/2 is increased, there is a risk of metformin cumulation in the body.

Sibutramine

absorption
After oral administration is rapidly absorbed from the GI tract by at least 77 %. During “primary passage” through the liver, it undergoes biotransformation under the influence of CYP3A4 isoenzyme to form two active metabolites (monodesmethylsibutramine (M1) and didesmethylsibutramine (M2)). After a single dose of 15 mg, maximum blood concentration (Cmax) of monodesmethylsibutramine (M1) is 4 ng/ml (3.2-4.8 ng/ml), didesmethylsibutramine (M2) – 6.4 ng/ml (5.6-7.2 ng/ml). Cmax is reached in 1.2 h (sibutramine), 3-4 h (active metabolites). Simultaneous intake of food decreases Cmax of metabolites by 30% and increases the time to reach it by 3 h without changing the area under the curve “concentration-time” (AUC).

Distribution
Rapidly distributed in tissues. Protein binding is 97% (sibutramine) and 94% (M1 and M2). Equilibrium concentration of active metabolites in blood is reached within 4 days after the start of treatment and is approximately 2 times higher than the concentration in plasma after a single dose.

Metabolism and excretion
Active metabolites undergo hydroxylation and conjugation to form inactive metabolites, which are excreted mainly by the kidneys. The half-life of sibutramine is 1.1 h, M1 – 14 h, M2 – 16 h.

Pharmacokinetics in special clinical cases
The currently available data do not indicate the existence of clinically significant differences in pharmacokinetics in men and women.

Pharmacokinetics in the elderly
Pharmacokinetics in elderly healthy subjects (mean age 70 years) are similar to those in young adults.

Kidney failure
Renal failure has no effect on the AUC of active metabolites M1 and M2, except for metabolite M2 in patients with end-stage renal failure on dialysis.

Hepatic failure
Patients with moderate hepatic failure after a single dose of sibutramine have a 24% higher AUC of active M1 and M2 metabolites than in healthy subjects.

Indications

Active ingredient

Composition

Each 850 mg + 10 mg tablet contains:

Active ingredients:

metformin hydrochloride, 850.0 mg; sibutramine hydrochloride monohydrate, 10.0 mg;

Auxiliary substances:

Microcrystalline cellulose, croscarmellose sodium, povidone K-25, magnesium stearate;

Sheet film excipients:

Prepared coating system Opadray II 85F30656 blue (polyvinyl alcohol, macrogol, titanium dioxide, talc, brilliant blue dye with aluminum varnish, indigo carmine dye with aluminum varnish, iron oxide yellow dye).

Each tablet with a dosage of 850 mg + 15 mg containsit:

Active ingredients:

metformin hydrochloride, 850.0 mg; sibutramine hydrochloride monohydrate, 15.0 mg;

Auxiliary substances:

Microcrystalline cellulose, croscarmellose sodium, povidone K-25, magnesium stearate;

Sheet film excipients:

Prepared coating system Opadray II 85F48105 white (polyvinyl alcohol, macrogol, talc, titanium dioxide).

How to take, the dosage

Interaction

Metformin

Contraindicated combinations

Iodine-containing radiopaque agents: Against a background of functional renal insufficiency in diabetic patients, radiological examination with iodine-containing radiopaque contrast agents may cause the development of lactoacidosis. Metformin should be discontinued depending on renal function 48 hours before or at the time of radiology with iodine-containing radiopaque agents and not resumed until 48 hours after the study, provided that renal function has been assessed as normal during the examination.

Unrecommended combinations

Alcohol: acute alcohol intoxication increases the risk of lactoacidosis, especially in cases:

Alcohol and medications containing ethanol should be avoided while taking the drug.

Combinations requiring caution

Danazol: Simultaneous administration of danazol is not recommended to avoid the hyperglycemic effects of the latter. If treatment with danazolol is necessary and after discontinuation of the latter, metformin dose adjustment is required with monitoring of blood glucose concentrations.

Chlorpromazine: when taken in high doses (100 mg per day) increases blood glucose concentration, reducing insulin release. When treating with neuroleptics and after discontinuation of the latter it is required to correct the dose of the drug under control of blood glucose concentration.

Glucocorticosteroids (GCS) of systemic and local action decrease glucose tolerance and increase blood glucose concentration, sometimes causing ketosis. Metformin dose adjustment is required during treatment with GCS and after discontinuation of GCS under control of blood glucose concentration.

Diuretics: concomitant use of “loop” diuretics may lead to lactoacidosis due to possible functional renal failure. Metformin should not be administered if IQ is below 60 mL/min.

Beta2-adrenomimetics administered as injections: increase blood glucose concentration due to beta2-adrenoreceptor stimulation. In this case it is necessary to control blood glucose concentration. If necessary, the prescription of insulin is recommended.

In case of concomitant use of the above drugs, more frequent monitoring of blood glucose concentrations may be required, especially at the beginning of treatment. If necessary, the dose of metformin may be adjusted during treatment and after discontinuation.

Angiotensin-converting enzyme inhibitors and other hypotensive drugs may decrease blood glucose concentration. If necessary, the dose of metformin should be adjusted.

Phenothiazides, glucagon, estrogens, oral contraceptives, phenytoin, sympathomimetics, nicotinic acid, isoniazid, “slow” calcium channel blockers, levothyroxine sodium may decrease the hypoglycemic effect of metformin. Concomitant use with cimetidine reduces the excretion rate of metformin, which may lead to lactoacidosis. In healthy volunteers, concomitant use of metformin and propranolol, as well as when using metformin and ibuprofen, no changes in their pharmacokinetic parameters were observed. Metformin may decrease the effect of indirect anticoagulants.

Organic cation transporter substrates 1 and 2 (OCT1 AND OCT2)

Metformin is a substrate of organic cations OCT1 and OCT2. When co-administered with metformin:

OCT1 and OCT2 inhibitors (such as crizotinib, olaparide) may decrease the hypoglycemic effects of metformin.

Concomitant use of metformin with sulfonylurea derivatives, insulin, acarbose, salicylates may cause hypoglycemia.

Nifedipine increases absorption and Cmax of metformin.

Cationic drugs (amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim and vancomycin) that are secreted in the renal tubules compete with metformin for tubular transport systems and may increase its Cmax.

Sibutramine

Microsomal oxidation inhibitors, including CYP3A4 isoenzyme inhibitors (ketoconazole, erythromycin, cyclosporine, etc.) increase plasma concentrations of sibutramine metabolites with increased heart rate and clinically insignificant increase of QT interval.

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

The simultaneous use of several drugs that increase serotonin plasma levels can lead to serious interactions. So-called serotonin syndrome may develop in rare cases with concomitant use of sibutramine with selective serotonin reuptake inhibitors (drugs for treatment of depression), with some drugs for treatment of migraine (sumatriptan, dihydroergotamine), with potent analgesics (pentazocine, pethidine, fentanyl), or anti-cough drugs (dextromethorphan). Sibutramine does not affect the effect of oral contraceptives.

In concomitant use of sibutramine and alcohol no increase in the negative effects of alcohol has been noted. However, alcohol is absolutely not combined with the recommended dietary measures when taking sibutramine.

When concomitant use with sibutramine of other drugs affecting hemostasis or platelet function, the risk of bleeding increases. Drug interaction when using sibutramine concomitantly with drugs that increase blood pressure and heart rate has not been fully studied. This group of drugs includes decongestants, anti-cough, anti-inflammatory and anti-allergic drugs containing ephedrine or pseudoephedrine. Therefore, caution should be exercised when taking these drugs concomitantly with sibutramine.

The co-administration of sibutramine with weight loss drugs acting on the central nervous system or drugs for the treatment of mental disorders is contraindicated.

Special Instructions

Synopsis

Contraindications

Side effects

Definition of frequency of side effects: very frequently (³1/10), frequently (³1/100, < 1/10), infrequently (³1/1000, < 1/100), rarely (³1/10 000,

< 1/1000), very rarely (< 1/10 000). Side effects are presented in decreasing order of importance.

Metformin

Metabolic and nutritional disorders: very rare – lactoacidosis; with prolonged use, decreased absorption of vitamin B12 is possible. Decrease of concentration of vitamin B12 must be taken into account in patients with megaloblastic anemia.

Nervous system disorders: often – disorders of taste.

Gastrointestinal disorders: very often – nausea, vomiting, diarrhea, abdominal pain, lack of appetite. These symptoms most often occur during the initial period of treatment and in most cases spontaneously disappear. Slowly increasing the dose may improve gastrointestinal tolerance.

Hepatic and biliary tract disorders: very rare – hepatic impairment, hepatitis, after cancellation of metformin these adverse events disappear completely.

Skin and subcutaneous tissue disorders: very rare – skin reactions such as erythema, itching, rash.

Sibutramine

The most frequent side effects occur at the beginning of treatment (in the first 4 weeks). Their severity and frequency lessen over time. Side effects are generally mild and reversible.

Nervous system disorders: very often – dry mouth and insomnia, often – headache, dizziness, anxiety, paresthesia, as well as changes in taste.

Chronic disorders: often – tachycardia, palpitations.

Vascular disorders: increase in blood pressure, vasodilation. A moderate increase of resting blood pressure by 1-3 mm Hg and a moderate increase of pulse by 3-7 beats per minute are observed. In some cases, a more pronounced increase in blood pressure and increased heart rate are not excluded. Clinically significant changes in blood pressure and pulse are mostly registered at the beginning of treatment (during the first 4-8 weeks). Gastrointestinal tract disorders: very often – loss of appetite and constipation, often – nausea and exacerbation of hemorrhoids. With a tendency to constipation in the first few days you need to monitor the evacuatory function of the intestine. If constipation occurs, stop taking it and take a laxative.

Skin and subcutaneous tissue disorders: often – increased sweating.

In single cases during treatment with sibutramine the following adverse clinically significant events have been described: Dysmenorrhea, edema, flu-like syndrome, skin itching, back pain, abdominal pain, paradoxical increase in appetite, thirst, rhinitis, depression, somnolence, emotional lability, anxiety, irritability, nervousness, acute interstitial nephritis, bleeding, Schoenlein-Henoch purpura (skin hemorrhages), seizures, plateletopenia, transient increase in activity of “liver” enzymes in blood.

The use of Reduxin® Forte in patients with high blood pressure: see sections “Contraindications” and “Cautions”.

In post-marketing studies of sibutramine, additional adverse reactions have been described, listed below by organ system:

Immune system disorders: hypersensitivity reactions (from mild skin rashes and urticaria to angioedema (Quincke’s edema) and anaphylaxis).

Mental disorders: psychosis, suicidal ideation, suicide and mania. If these conditions occur, the drug should be discontinued.

Nervous system disorders: convulsions, short-term memory disorders. Visual disorders: blurred vision (“shroud before eyes”). Cardiac disorders: atrial fibrillation.

Gastrointestinal disorders: diarrhea, vomiting.

Skin and subcutaneous tissue disorders: alopecia.

Renal and urinary tract disorders: urinary retention.

Gender and mammary gland disorders: disorders of ejaculation/orgasm, impotence, menstrual cycle disorders, uterine bleeding.

Overdose

Metformin

Symptoms: At a dose of 85 g of metformin (42.5 times the maximum daily dose) no hypoglycemia was observed, but the development of lactoacidosis was noted.

Significant overdose or associated risk factors can lead to the development of lactoacidosis.

Treatment: In case of signs of lactocidosis the drug treatment should be stopped immediately, the patient should be urgently hospitalized and, after determining the lactate concentration, the diagnosis should be confirmed. The most effective measure for elimination of lactate and metformin from the body is hemodialysis. Asymptomatic treatment is also carried out.

Sibutramine

There are extremely limited data on sibutramine overdose. The most common adverse reactions associated with overdose are: tachycardia, increased blood pressure, headache, dizziness. It is necessary to inform your attending physician in case of suspected overdose.

Treatment: there is no specific treatment or antidotes. It is necessary to perform general measures: to ensure free breathing, to monitor the state of the cardiovascular system, as well as, if necessary, to carry out supportive symptomatic therapy. Timely use of activated charcoal, as well as gastric lavage can reduce sibutramine intake into the body. Patients with high blood pressure and tachycardia may be prescribed β-adrenoblockers. The effectiveness of forced diuresis or hemodialysis has not been established. In case of overdose, the drug Reduxin® Forte should be stopped immediately.

Pregnancy use