Reduxin Forte, 850 mg+15 mg 90 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 regulator of appetite).

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 studies)

In a clinical study in Reduxin® Forte group the percentage of patients who achieved clinically significant weight loss ≥5% during 3 months of therapy (early response rate 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 GI 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, it 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 hours 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 with the formation of 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 individuals (mean age 70 years) is similar to that in young adults.

Renal 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

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

Lactoacidosis

Lactoacidosis is a rare but serious (high mortality in the absence of emergency treatment) complication that can occur due to metformin cumulation. Cases of lactoacidosis when taking metformin have occurred mainly in diabetic patients with severe renal insufficiency.

Other associated risk factors, such as decompensated diabetes mellitus, ketosis, prolonged fasting, alcoholism, liver failure, and any condition associated with severe hypoxia should be considered. This may help reduce the incidence of lactoacidosis.

The risk of lactoacidosis should be considered if nonspecific signs, such as muscle cramps accompanied by dyspeptic symptoms, abdominal pain, and marked asthenia, are present. Lactoacidosis is characterized by acidotic dyspnea, abdominal pain and hypothermia, followed by coma.

The diagnostic laboratory indicators are decreased blood pH (less than 7.25), plasma lactate content over 5 mmol/L, elevated anion gap and lactate/pyruvate ratio. If metabolic acidosis is suspected, discontinue the drug and consult a physician immediately.

Surgical procedures

The use of Reduxin® Forte should be discontinued 48 hours before elective surgical procedures and may be continued up to 48 hours after, provided that renal function has been determined to be normal during evaluation.

Renal function

Because metformin is excreted by the kidneys, CK should be determined before starting Reduxin® Forte and regularly thereafter: At least once a year in patients with normal renal function, and 2-4 times a year in elderly patients, as well as in patients with CK at the lower limit of normal.

Particular caution should be exercised if renal function may be impaired in elderly patients, if hypotensive drugs, diuretics, or nonsteroidal anti-inflammatory drugs are used concomitantly.

Patients are advised to continue on a diet with an even carbohydrate intake throughout the day. Patients who are overweight are recommended to continue on a hypocaloric diet (but at least 1000 kcal/day).

It is recommended that regular standard laboratory tests be performed to control diabetes.

We recommend caution when using Reduxin® Forte in combination with insulin or other hypoglycemic agents (including sulfonylurea derivatives, repaglinide).

The treatment with Reduxin® Forte should be performed within the framework of a complex therapy for weight loss under the supervision of a physician having practical experience in the treatment of obesity. Complex therapy includes both changing diet and lifestyle and increasing physical activity. An important component of therapy is to create the prerequisites for lasting changes in eating habits and lifestyle, which are necessary to maintain the achieved weight loss even after withdrawal of drug therapy. As part of therapy with Reduxin® Forte, patients need to change their lifestyle and habits so that after treatment is completed, to ensure that the achieved weight loss is maintained. Patients should be clear that failure to comply with these requirements will result in repeated weight gain and repeat visits to the attending physician.

In patients taking Reduxin® Forte, blood pressure and heart rate should be measured. In the first 3 months of treatment these parameters should be controlled every 2 weeks, and then monthly. If during two consecutive visits an increase in resting heart rate ≥10 beats per minute or systolic/diastolic pressure ≥10 mm Hg is detected, the treatment should be stopped. In patients with arterial hypertension whose blood pressure is above 145/90 mm Hg during hypotensive therapy, this monitoring should be performed particularly carefully and, if necessary, at shorter intervals. In patients whose blood pressure exceeded 145/90 mmHg twice during repeated measurement, treatment with Reduxin® Forte should be suspended (see section “Adverse effects”, subsections “Cardiac disorders”, “Vascular disorders”).

In patients with sleep apnea syndrome, blood pressure should be monitored particularly closely.

Particular attention is required when concomitant administration of drugs that increase the QT interval. These drugs include H1-histamine receptor blockers (astemizole, terfenadine); antiarrhythmic QT interval prolongers (amiodarone, quinidine, flecainide, mexiletine, propafenone, sotalol); gastrointestinal motility stimulator cisapride; pimozide, sertindol and tricyclic antidepressants. This also applies to conditions that can lead to prolongation of the QT interval, such as hypokalemia and hypomagnesemia (see section “Interaction with other medicinal products”).

The interval between taking MAO inhibitors (including furazolidone, procarbazine, selegiline) and the drug Reduxin® Forte should be at least 2 weeks.

While no association between sibutramine intake and the development of primary pulmonary hypertension has been established, however, given the known risks of this group of drugs, special attention should be paid to symptoms such as progressive dyspnea (breathing problems), chest pain, and edema in the legs during regular medical monitoring.

If a dose of Reduxin® Forte is missed, do not take a double dose of the drug at the next dose; it is recommended to continue further administration of the drug according to the prescribed regimen.

The co-administration of sibutramine and other serotonin reuptake inhibitors may increase the risk of bleeding. Sibutramine should be used with caution in patients prone to bleeding, as well as in patients taking drugs affecting hemostasis or platelet function.

While there are no clinical data on sibutramine addiction, it is necessary to find out whether the patient has a history of drug dependence, and to pay attention to possible signs of drug abuse.

Impact on ability to drive vehicles and machines

Prevention of Reduxin® Forte may limit the ability to drive vehicles and machines. During the period of using Reduxin® Forte drug care should be taken when driving vehicles and engaging in other potentially dangerous activities requiring high concentration and quick psychomotor reactions.

Synopsis

Contraindications

Side effects

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