Janumet, 850 mg+50 mg 56 pcs.

Janumet is a combination of two hypoglycemic drugs with a complementary mechanism of action designed to improve glycemic control in patients with type 2 diabetes: sitagliptin, an inhibitor of the dipeptidyl peptidase-4 enzyme (DPP-4), and metformin, a representative of the biguanide class.

Sitagliptin is an orally active, highly selective DPP-4 inhibitor for the treatment of type 2 diabetes. Pharmacological effects of the class of DPP-4 inhibitor drugs are mediated by the activation of insectins.

Inhibiting DPP-4, sitagliptin increases the concentration of two known active hormones of the incretin family: glucagon-like peptide 1 (GFP-1) and glucose-dependent insulinotropic polypeptide (GIP). Incretins are part of the internal physiological system of glucose homeostasis regulation. At normal or elevated blood glucose concentrations, GFP-1 and GIP contribute to increased insulin synthesis and secretion by pancreatic beta cells. GFP-1 also suppresses glucagon secretion by pancreatic alpha cells, thereby reducing glucose synthesis in the liver.

This mechanism of action differs from the mechanism of action of sulfonylurea derivatives which stimulate insulin release even at low concentrations of blood glucose and this causes development of sulfonyl-induced hypoglycemia not only in patients with type 2 diabetes but also in healthy individuals.

As a highly selective and effective inhibitor of DPP-4 enzyme, sitagliptin in therapeutic concentrations does not inhibit activity of related enzymes DPP-8 or DPP-9.

Sitagliptin differs in chemical structure and pharmacological action from GFP-1 analogues, insulin, sulfonylurea or meglitinide derivatives, biguanides, peroxisome proliferator-activated receptor gamma agonists (PPARy), alpha-glycosidase inhibitors and amylin analogues.

Metformin is a hypoglycemic drug that increases glucose tolerance in patients with type 2 diabetes by reducing basal and postprandial blood glucose concentrations. Its pharmacological mechanisms of action are different from the mechanisms of action of oral hypoglycemic drugs of other classes. Metformin reduces glucose synthesis in the liver, reduces glucose absorption in the intestine and increases insulin sensitivity through glucose capture and utilization.

Indications

Janumet is indicated as an adjunct to diet and exercise regimen to improve glycemic control in patients with type II diabetes who have not achieved adequate control on monotherapy with metformin or sitagliptin, or after unsuccessful combination treatment with both drugs.

Janumet is indicated in combination with sulfonylurea derivatives (three-drug combination) as an adjunct to diet and exercise regimens to improve glycemic control in patients with type II diabetes who have not achieved adequate control after treatment with two of the following three drugs: metformin, sitagliptin, or sulfonylurea derivatives.

Janumet is indicated in combination with PPAR-agonists? (e.g., thiazolidinediones) as an adjunct to diet and exercise regimens to improve glycemic control in patients with type II diabetes who have not achieved adequate control after treatment with two of the following three drugs: metformin, sitagliptin, or a PPAR-? agonist.

Janumet is indicated for patients with type II diabetes (a combination of the three drugs) as an adjunct to diet and exercise regimens to improve glycemic control in combination with insulin.

Active ingredient

Composition

One film-coated tablet contains:

Sitagliptin phosphate monohydrate 50 mg;

Metformin hydrochloride 850 mg.

Auxiliary substances:

Microcrystalline cellulose 59.30 mg;

Povidone 48.23 mg;

Sodium stearyl fumarate 13.78 mg;

Sodium lauryl sulfate 3.445 mg.

The Opadray II Pink tablet sheath, 85 F 94203 (17.23 mg) contains:

Polyvinyl alcohol 47.800%;

Titanium dioxide (E 171) 6.000%;

Macrogol 3350 23.500%;

Talc 22.590 %;

Iron oxide black (E 172) 0.005 %;

Iron oxide red (E 172) 0.105 %.

How to take, the dosage

The dosing regimen of Janumet should be chosen individually, based on current therapy, efficacy and tolerability, but not exceeding the maximum recommended daily dose of sitagliptin 100 mg.

Janumet is usually prescribed as a twice-daily regimen with meals, with gradual dose increases to minimize possible gastrointestinal (GI) side effects characteristic of metformin. The initial dose of the drug Janumet depends on the current hypoglycemic therapy.

Interaction

Sitagliptin and metformin

. Simultaneous administration of multiple doses of sitagliptin (50 mg twice daily) and metformin (1000 mg twice daily) was not accompanied by significant changes in the pharmacokinetic parameters of sitagliptin or metformin in patients with type 2 diabetes.

There have been no studies of interdrug effects on the pharmacokinetic parameters of Janumet, but a sufficient number of such studies have been performed for each of the drug components, sitagliptin and metformin.

Sitagliptin

In studies on interactions with other drugs, sitagliptin had no clinically significant effect on the pharmacokinetics of the following drugs: metformin, rosiglitazone, glibenclamide, simvastatin, warfarin, and oral contraceptives. Based on these data, sitagliptin does not inhibit the CYP isoenzymes of the cytochrome system CYP3A4,2C8 or 2C9. In vitro data indicate that sitagliptin also does not inhibit the CYP2D6,1A2,2C19, and 2B6 isoenzymes and does not induce CYP3A4. According to population pharmacokinetic analysis of patients with type 2 diabetes mellitus, concomitant therapy had no clinically significant effect on sitagliptin pharmacokinetics.

The study evaluated a number of drugs most commonly used by patients with type 2 diabetes, including: hypocholesterolemic drugs (statins, fibrates, ezetimibe), antiaggregants (clopidogrel), hypotensive drugs (ACE inhibitors, angiotensin II receptor antagonists, beta-adrenoblockers, “slow” calcium channel blockers, hydrochlorothiazide, analgesics and non-steroidal anti-inflammatory drugs (naproxen, diclofenac, celecoxib), antidepressants (bupropion, fluoxetine, sertraline), antihistamines (cetirizine), proton pump inhibitors (omeprazole, lansoprazole) and drugs to treat erectile dysfunction (sildenafil).

Augmentation of the AUC (11%) as well as the mean C mah (18%) of digoxin when coadministered with sitagliptin has been noted. This increase is not considered clinically significant, but patient monitoring is recommended when concomitant administration of digoxin. There was an increase in AUC and C mah of sitagliptin by 29% and 68%, respectively, when co-administering a single oral dose of JANUVIA at 100 mg and cyclosporine (a potent inhibitor of p-glycoprotein) at a dose of 600 mg. These changes in the pharmacokinetic parameters of sitagliptin are not clinically significant.

Metformin

Gliburide – no changes in the pharmacokinetic and pharmacodynamic parameters of metformin were observed in an interdrug interaction study of single doses of metformin and glyburide in patients with type 2 diabetes. Changes in the AUC and Stach values of glyburide were highly variable. Insufficient information (single administration) and inconsistency of the plasma concentration of glyburide with the observed pharmacodynamic effects call into question the clinical significance of this interaction.

Furosemide – In an interdrug interaction study of single-dose metformin and furosemide in healthy volunteers, changes in the pharmacokinetic parameters of both drugs were observed. Furosemide increased the value of metformin C mah concentration in plasma and whole blood by 22%, the AUC value of metformin in whole blood by 15%, without changing renal clearance of the drug. The C mah and AUC values of furosemide, in turn, decreased by 31% and 12%, respectively, and the elimination half-life decreased by 32%, without significant changes in renal clearance of furosemide. There is no information on interdrug interactions between the two drugs in long-term concomitant use.

Nifedipine – a study of interdrug interaction between nifedipine and metformin after a single dose of the drugs in healthy volunteers showed an increase in plasma C mah and AUC of metformin by 20% and 9%, respectively, as well as an increase in metformin renal excretion. T mah and metformin elimination half-life were unchanged. The basis is an increase in metformin absorption in the presence of nifedipine. The effect of metformin on the pharmacokinetics of nifedipine is minimal.

Cationic drugs are cationic drugs (ie. amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) excreted by tubular secretion could theoretically interact with metformin by competing for the shared renal tubular transport system. Such competition was observed when metformin and cimetidine were administered simultaneously to healthy volunteers in single- and multiple-dose studies, with a 60% increase in plasma and whole blood C mah concentration of metformin and a 40% increase in plasma and whole blood AUC of metformin. The metformin elimination half-life was not altered in the single-dose study. Metformin did not affect the pharmacokinetics of cimetidine. Although the above interdrug interactions are mainly theoretical (with the exception of cimetidine), close patient monitoring and dose adjustment of Janumet and/or the above cationic drugs excreted by proximal renal tubules are recommended in cases of concomitant administration.

Some drugs have hyperglycemic potential and may interfere with established glycemic control. These include thiazide and other diuretics, glucocorticosteroids, phenothiazines, thyroid medications, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, slow calcium channel blockers, and isoniazid. When prescribing the above drugs, a patient receiving Janumet is recommended to closely monitor the parameters of glycemic control. No changes in the pharmacokinetic parameters of these drugs were observed when metformin and propranolol or metformin and ibuprofen were administered simultaneously in healthy volunteers.

. Only a small proportion of metformin binds to plasma proteins; therefore, interdrug interactions between metformin and drugs that actively bind to plasma proteins (salicylates, sulfonamides, chloramphenicol and probenecid) are unlikely, unlike sulfonylurea derivatives, which also actively bind to plasma proteins.

Special Instructions

Application in the elderly with Janumet: Since the kidneys are the main route of excretion of sitagliptin and metformin, and since renal excretory function decreases with age, the precautions for prescribing Janumet increase in proportion to age.

Elderly patients should be carefully dosed and renal function monitored regularly.

Contraindications

Hypersensitivity to sitagliptin phosphate, metformin hydrochloride or any other component of the drug;

Acute conditions that may affect renal function: Dehydration, severe infections, shock;

Acute or chronic conditions that may lead to tissue hypoxia, such as heart or respiratory failure, recent myocardial infarction, shock;

Moderate or severe renal function impairment (creatinine clearance

Impaired liver function;

Acute alcohol intoxication, alcoholism;

Breastfeeding period;

Type I diabetes mellitus;

Acute or chronic metabolic acidosis, including diabetic ketoacidosis (with or without coma);

Radiology studies (intravascular administration of iodine-containing contrast agents).

Side effects

Gastrointestinal system disorders:at the beginning of treatment – anorexia, diarrhea, nausea, vomiting, flatulence, abdominal pain (reduced with meals); metallic taste in the mouth (3%).

Cardiovascular system and blood (hematopoiesis, hemostasis):in single cases – megaloblastic anemia (result of impaired absorption of vitamin B12 and folic acid).

From the metabolic side: hypoglycemia; in rare cases, lactate acidosis (weakness, drowsiness, hypotension, resistant bradyarrhythmia, respiratory disorders, abdominal pain, myalgia, hypothermia).

Skin side:rash, dermatitis.

Overdose

Sitagliptin: In healthy volunteers, single doses up to 800 mg were generally well tolerated. When using 800 mg in a clinical trial, a slight prolongation of the Q-Tc interval was observed, which was not considered to be clinically significant. There is no experience of using the drug in doses greater than 800 mg.

There have been no dose-related adverse reactions reported in studies when using 600 mg/day for 10 days and 400 mg for 28 days. Sitagliptin is poorly dialyzed: according to clinical studies, only 13.5% of the dose was excreted during a 3-4-hour hemodialysis session. Prolonged hemodialysis is prescribed in case of clinical necessity. There are no data on the effectiveness of peritoneal dialysis of sitagliptin.

Metformin: There have been cases of metformin overdose, including administration in amounts greater than 50 g. Hypoglycemia was detected in about 10% of all overdoses, but a causal association with metformin overdose has not been established. Lactacidosis has been reported in about 32% of all metformin overdoses.

Hemodialysis should be performed urgently (metformin is dialyzed at up to 170 mL/min under good hemodynamic conditions) to expedite the excretion of excess metformin if an overdose is suspected. In case of Janumet overdose, standard supportive measures should be initiated: removal from the GI tract of residual drug that has not yet been absorbed, monitoring of vital signs, including ECG, hemodialysis, and administration of supportive therapy if necessary.

Pregnancy use

No adequately controlled studies of the drug Janumet or its components have been conducted in pregnant women; therefore, there are no data on the safety of its use in pregnant women.

The drug Janumet, like other oral hypoglycemic drugs, is not recommended for use during pregnancy.

There have been no experimental studies of the combined drug Janumet to evaluate its effect on reproductive function.

Only data available from studies of sitagliptin and metformin are cited.

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