Buy Kombiglyze pills 1000 + 5 mg, 28 pcs
  • Buy Kombiglyze pills 1000 + 5 mg, 28 pcs

Kombiglyze®

Bristol-Myers Squibb
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2019-09-19
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Clinical Pharmacology

Combon® Prolong® combines two hypoglycemic drugs with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes mellitus (SD2): saxagliptin, a dipeptilpeptidase 4 inhibitor (DPP-4), and metformin, a representative of the biguanide class.

Saxagliptin:

In response to food ingestion, hormones are released from the small intestine — incretin, such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (HIP). These hormones promote the release of insulin from the beta cells of the pancreas, depending on the concentration of glucose in the blood, but inactivated by the enzyme DPP-4 within a few minutes. GLP-1 also lowers glucagon secretion in pancreatic alpha cells, reducing glucose production in the liver. In patients with T2DM, the concentration of GLP-1 is lowered, but insulin response to GLP-1 is maintained. Saxagliptin, being a competitive inhibitor of DPP-4, reduces the inactivation of hormone incretins, thereby increasing their concentration in the bloodstream and leading to a decrease in fasting glucose concentration and after eating.

Metformin:

Metformin is a hypoglycemic drug that improves glucose tolerance in patients with type 2 diabetes, lowering basal and postprandial glucose concentrations. Metformin reduces the production of glucose by the liver, decreases the absorption of glucose in the intestine, and increases insulin sensitivity, increasing peripheral absorption and utilization of glucose. Unlike sulfonylurea drugs, metformin does not cause hypoglycemia in patients with diabetes mellitus or healthy people (except for special situations, see sections “With caution” and “Special instructions”), and hyperinsulinemia. During metformin therapy, insulin secretion remains unchanged, although fasting insulin concentrations and in response to food intake during the day may decrease.

Indications

Type 2 diabetes in combination with diet and exercise to improve glycemic control.

Composition

active substances: Metformin - 1000 mg; Saxagliptin 2.5 mg.

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Kombiglyze®

Dosage and Administration

Inside, once a day during dinner. pills should be swallowed whole, without chewing, without crushing or breaking. The dose should be selected individually. Usually during therapy with a combination drug containing saxagliptin and metformin, the dose of saxagliptin is 5 mg once a day. The recommended initial dose of metformin modified release is 500 mg once a day, it can be increased to 2000 mg once a day, which is provided by taking 2 pills of 2.5 mg / 1000 mg taken once a day. Metformin dose is increased gradually to reduce the risk of gastrointestinal side effects. The maximum daily dose: Saxagliptin 5 mg and metformin modified release 2000 mg.

No special studies have been conducted on the safety and efficacy of Kombiglyze Prolong in patients previously receiving other hypoglycemic agents and transferred to Prolong Kombiglyze. Changes in the treatment of diabetes mellitus should be made with caution and with appropriate control of the concentration of glucose in the blood. When combined with potent inhibitors of CYP3A4 / 5 isoenzymes (for example, ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir and telithromycin), a dose of saxagliptin should be 2.5 mg once a day.

The inactive ingredients of Commodus Prolong can be excreted through the intestines in the form of a soft, moist mass that can retain the form of an accepted tablet.

Use in special patient groups

Elderly patients

Since saxagliptin and metformin are partially excreted by the kidneys, and in elderly patients the decline in renal function is likely, it should be used with caution in combination with elderly Prolong.

Saxagliptin

There were no differences in the safety or efficacy of the drug in patients ≥ 65 years old and in young patients. Although differences in responses to therapy in elderly patients and young patients have not been established, greater sensitivity in some elderly patients cannot be ruled out. Metformin Controlled clinical trials of metformin did not include a sufficient number of elderly patients to determine differences in response to therapy compared with young patients, although clinical experience has not established differences in response in elderly and young patients. Metformin is known to be largely excreted by the kidneys, and therefore there is a risk of serious adverse events in patients with renal failure. Combination Prolong should be prescribed only to patients with normal renal function. Initial and maintenance doses of metformin should be administered to elderly patients, taking into account the possible reduction of renal function. Any dose adjustment should be carried out after a careful assessment of kidney function.

Children

The safety and efficacy of the drug in patients younger than 18 years has not been studied.

Adverse reactions

Monotherapy and adjunctive therapy

Saxagliptin

Table 1 presents adverse events observed during clinical trials (regardless of the investigator’s assessment of the causal relationship) in ≥ 5% of patients who received saxagliptin 5 mg.

Table 1. Undesirable phenomena

  Number (%) of patients
Saxagliptin 5 mg (N = 882) Placebo (N = 799)
Upper respiratory tract infections 68 (7,7) 61 (7,6)
Urinary tract infections 60 (6,8) 49 (6,1)
Headache 57 (6,5) 47 (5,9)

Five placebo-controlled studies include two monotherapy studies and one combination therapy study with the addition of metformin, thiazolidinedione or glibenclamide each. The table presents the data of the 24-week study, regardless of the use of an additional hypoglycemic drug.

In patients who took saxagliptin at a dose of 2.5 mg, headache (6.5%) was the only adverse event noted with a frequency of ≥ 5% and developed more often than in the placebo group.

Adverse events reported in ≥ 2% of patients taking saxagliptin at a dose of 2.5 mg or saxagliptin at a dose of 5 mg and developing ≥ 1% more often than in the placebo group included sinusitis (2.9% and 2.6%) compared with 1.6%, respectively), abdominal pain (2.4% and 1.7% compared with 0.5%), gastroenteritis (1.9% and 2.3% compared with 0.9 %) and vomiting (2.2% and 2.3% compared with 1.3%).

The incidence of fractures was 1.0 and 0.6 per 100 patient-years, respectively, while taking saxagliptin (combined dose analysis of 2.5 mg, 5 mg and 10 mg) and placebo. The frequency of fractures in patients taking saxagliptin did not increase with time. A causal relationship has not been established, and preclinical studies have not shown undesirable effects of saxagliptin on bone tissue.

During the clinical program, the development of thrombocytopenia was observed, corresponding to the diagnosis of idiopathic thrombocytopenic purpura. The relationship of the development of this phenomenon with taking saxagliptin is not known.

Adverse events associated with co-administration of saxagliptin and metformin in the treatment of patients with type 2 diabetes mellitus (type 2 diabetes) who have not previously received therapy

Saxagliptin

Table 2 presents adverse events noted (regardless of the investigator's assessment of the causal relationship) in ≥ 5% of patients who participated in an additional 24-week, with active control study of the joint use of saxagliptin and metformin in patients who had not previously received therapy.

Table 2. Undesirable effects

  Number (%) of patients
Saxagliptin 5 mg + Metformin * (N = 320) Metformin * (N = 328)
Headache 24 (7,5) 17(5,2)
Nasopharyngitis 22 (6,9) 13 (4,0)

* The initial dose of metformin 500 mg / day was increased to a maximum dosage of 2000 mg / day.

In patients receiving the combination of saxagliptin and metformin, as an additional drug or as the initial combination therapy, diarrhea was the only gastrointestinal adverse event that developed in ≥ 5% of patients in any group. The incidence of diarrhea was 9.9%, 5.8%, and 11.2% in the saxagliptin 2.5 mg, saxagliptin 5 mg and placebo, respectively, in the study of the addition of saxagliptin to metformin; the incidence of diarrhea was 6.9% and 7.3% in the combination group with saxagliptin 5 mg and metformin and the metformin monotherapy group in the study initially combined therapy with metformin.

Hypoglycemia

Saxagliptin

Information on hypoglycemia as an adverse event was collected based on reports of hypoglycemia; no concurrent measurement of glucose concentration was required. The incidence of hypoglycemia with saxagliptin 2.5 mg, saxagliptin 5 mg and placebo (all as monotherapy) was 4%, 5.6% and 4.1%, respectively, and 7.8%, 5.8% and 5 %, respectively, when adding metformin. The incidence of hypoglycemia was 3.4% in previously untreated patients who took saxagliptin 5 mg in combination with metformin and 4% in patients on metformin monotherapy.

Hypersensitivity reactions

Saxagliptin

During the analysis of the five combined studies, adverse events associated with hypersensitivity (such as urticaria and swelling of the face) were observed in 1.5%, 1.5% and 0.4% of patients who received saxagliptin 2.5 mg, saxagliptin 5 mg and placebo, respectively. According to researchers, none of these phenomena in patients treated with saxagliptin required hospitalization and did not threaten the lives of patients. In this analysis of pooled data, one patient who received saxagliptin was excluded from the study due to the development of generalized urticaria and swelling of the face.

Indicators of physiological functions

Saxagliptin

In patients treated with saxagliptin as monotherapy or in combination with metformin, there were no clinically significant changes in the indicators of physiological functions.

Monotherapy

Metformin

During the placebo-controlled studies, the most frequent adverse events noted in> 5% of patients who received modified-release metformin and developed more often than in the placebo group were diarrhea and nausea / vomiting.

Post-marketing application

The following side effects have been reported during post-marketing use of saxagliptin: acute pancreatitis and hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria. It is impossible to reliably estimate the frequency of development of these phenomena, since messages are received spontaneously from a population of an unspecified size (see the sections "Contraindications" and "Special Instructions").

Laboratory research

Absolute lymphocyte count

Saxagliptin

When using saxagliptin, a dose-dependent average decrease in the absolute number of lymphocytes was observed. An analysis of pooled data from five 24-week, placebo-controlled studies showed an average decrease of approximately 100 and 120 cells / μl of the absolute number of lymphocytes from the initial average of 2200 cells / μl with saxagliptin 5 mg and 10 mg, respectively, compared with placebo. A similar effect was observed when taking saxagliptin at a dose of 5 mg in the original combination with metformin compared with metformin monotherapy. There were no differences between saxagliptin therapy at a dose of 2.5 mg and placebo. The proportion of patients whose lymphocyte count was ≤ 750 cells / μl was 0.5%, 1.5%, 1.4%, and 0.4% in the saxagliptin therapy groups at a dose of 2.5 mg, at a dose of 5 mg , at a dose of 10 mg and placebo, respectively. In the majority of patients with repeated use of saxagliptin, no recurrence was observed, although in some patients the number of lymphocytes was again decreased when resuming therapy with saxagliptin, which led to the cancellation of saxagliptin. The decrease in the number of lymphocytes was not accompanied by clinical manifestations.

The reasons for the decrease in the number of lymphocytes during therapy with saxagliptin compared with placebo are unknown. In the case of an unusual or prolonged infection, it is necessary to measure the number of lymphocytes. The effect of saxagliptin on the number of lymphocytes in patients with abnormal lymphocyte counts (for example, human immunodeficiency virus) is unknown.

Platelets

Saxagliptin

Saxagliptin had no clinically significant or consistent effect on platelet count during six double-blind, controlled clinical studies of safety and efficacy.

Vitamin B Concentration12

In controlled clinical trials of metformin with a duration of 29 weeks, approximately in 7% of patients there was a decrease in serum before the normal concentration of vitamin B12 to subnormal values ​​without clinical manifestations. However, such a decrease is very rarely accompanied by the development of anemia and is quickly restored after discontinuation of metformin or an additional intake of vitamin B12.

Contraindications

- increased individual sensitivity to any component of the drug;

- serious hypersensitivity reactions (anaphylaxis or angioedema) to DPP-4 inhibitors;

- diabetes mellitus type 1 (application has not been studied);

- use in conjunction with insulin (not studied);

- congenital intolerance to galactose, lactase deficiency and glucose-galactose malabsorption;

- pregnancy, lactation;

- age up to 18 years (safety and efficacy not studied);

- renal dysfunction (serum creatinine ≥1.5 mg / dl [men], ≥1.4 mg / dl [women] or reduced creatinine clearance), including those caused by acute cardiovascular insufficiency (shock), acute myocardial infarction and septicemia;

- acute diseases at which there is a risk of development of a renal dysfunction: dehydration (vomiting, diarrhea), fever, serious infectious diseases, hypoxia (shock, sepsis, kidney infections, broncho-pulmonary diseases);

- acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma;

- clinically pronounced manifestations of acute and chronic diseases that can lead to the development of tissue hypoxia (respiratory failure, heart failure, acute myocardial infarction);

- serious surgeries and injuries (when insulin therapy is indicated);

- abnormal liver function;

- chronic alcoholism and acute ethanol poisoning;

- lactic acidosis (including in history);

- a period of at least 48 hours before and within 48 hours after conducting radioisotope or radiographic studies with the introduction of iodine-containing contrast media;

- adherence to a low-calorie diet (

Carefully

In persons over the age of 60 who perform heavy physical work (increased risk of developing lactic acidosis) and patients with a history of pancreatitis (the relationship between taking the drug and an increased risk of developing pancreatitis has not been established).

Drug interactions

Metformin

Some drugs increase hyperglycemia (thiazide and other diuretics, glucocorticosteroids, phenothiazines, preparations of iodine-containing thyroid hormones, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, slow calcium channel blockers and isoniazid). When prescribing or canceling such drugs in a patient taking Kombiglyze Prolong, should carefully monitor the concentration of glucose in the blood. The degree of binding of metformin to plasma proteins is small, so it is unlikely that it will interact with drugs that largely bind to plasma proteins, such as salicylates, sulfonamides, chloramphenicol and probenecid (unlike sulfonylurea derivatives, which are largely bound with serum proteins).

Inductors of isoenzymes CYP3A4 / 5

Saxagliptin

Rifampicin significantly reduces the exposure of saxagliptin without changing the AUC of its active metabolite, 5-hydroxy-saxagliptin. Rifampicin does not affect the inhibition of DPP-4 in plasma during the 24-hour treatment interval.

Inhibitors of isoenzymes CYP3A4 / 5

Saxagliptin

Diltiazem enhances the effect of saxagliptin when used together. Increased plasma levels of saxagliptin are expected with amprenavir, aprepitant, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil; however, it is not recommended to adjust the dose of saxagliptin. Ketoconazole significantly increases the concentration of saxagliptin in the plasma. Such a significant increase in plasma concentration of saxagliptin is expected with the use of other potent inhibitors of CYP3A4 / 5 enzymes (for example, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir and telithromycin). When combined with a potent inhibitor of CYP3A4 / 5 isoenzymes, saxagliptin dose should be reduced to 2.5 mg.

Cationic preparations

Metformin

Cationic drugs (for example, amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterone, trimethoprim or vancomycin), which are excreted by the kidneys due to glomerular filtration, can theoretically interact with metformin, competing for common renal tubular transport systems. In the course of studies of drug interactions of metformin and cimetidine with single and repeated intake of the drug, interaction of metformin and cimetidine was observed for oral administration in healthy volunteers; however, a 60% increase in the maximum concentration of metformin in plasma and whole blood and a 40% increase in the AUC of metformin in plasma and whole blood. During the study with a single dose of the drug, no changes in the half-life were observed. Metformin does not affect the parameters of cimetidine pharmacokinetics.It is recommended to carefully monitor patients and, if necessary, adjust the dose in patients taking cationic drugs, which are derived through the system of proximal renal tubules.

Glibenclamide

Metformin

In the study of the interaction with a single dose of the drug in patients with T2DM, the combined use of metformin and glibenclamide does not affect the parameters of pharmacokinetics or pharmacodynamics.

Furosemide

Metformin

In the study of drug interactions of metformin and furosemide with a single dose of the drug, conducted on healthy volunteers, their pharmacokinetic interaction was revealed. Furosemide boosts Cmaxmetformin in plasma and blood by 22% and AUC in blood by 15% without significant changes in the renal clearance of metformin. When taken together with Metformin Cmax and AUC of furosemide are reduced by 31% and 12%, respectively, and the half-life is reduced by 32% without a noticeable change in the kidney clearance of furosemide. There is no data on the interaction of metformin and furosemide with joint long-term use.

Nifedipine

Metformin

During the study of drug interactions of metformin and nifedipine with a single dose of the drug, conducted on healthy volunteers, nifedipine increases Cmax metformin in plasma by 20% and AUC by 9%, and increases renal excretion. Tmax and t1/2 did not change. Nifedipine increases the absorption of metformin. Metformin has virtually no effect on the pharmacokinetics of nifedipine.

Saxagliptin and Metformin

The combined use of single doses of saxagliptin (100 mg) and metformin (1000 mg) has no significant effect on the pharmacokinetics of saxagliptin or metformin in healthy volunteers.

Special pharmacokinetic studies of drug interactions with the use of the drug Kombiglyze Prolong were not conducted, although such studies were conducted with its individual components: saxagliptin and metformin.

Saxagliptin

Effect of other drugs on saxagliptin

Glibenclamide: Joint single use of Saxagliptin (10 mg) and glibenclamide (5 mg), substrate of an isoenzyme CYP2C9, increased Cmaxsaxagliptin at 8%, but the AUC of saxagliptin does not change.

Pioglitazone: The joint repeated use of saxagliptin once a day (10 mg) and pioglitazone (45 mg), the substrate of isoenzyme CYP2C8 (strong) and CYP3A4 (weak), does not affect the parameters of the pharmacokinetics of saxagliptin.

Digoxin: The joint repeated use of saxagliptin once a day (10 mg) and digoxin (0.25 mg), the substrate P-glycoprotein, does not affect the parameters of the pharmacokinetics of saxagliptin.

Simvastatin: The joint repeated use of saxagliptin once a day (10 mg) and simvastatin (40 mg), a substrate of isoenzymes CYP3A4 / 5, increased Cmaxsaxagliptin by 21%, but the AUC of saxagliptin does not change.

Diltiazem: Joint single use of Saxagliptin (10 mg) and diltiazem (360 mg prolonged dosage form in the equilibrium state), a moderate inhibitor of isoenzymes CYP3A4 / 5, increases Cmaxsaxagliptin by 63%, a AUC - 2.1 times. This is accompanied by a corresponding decrease in C.max and AUC of the active metabolite by 44% and 36%, respectively.

Ketoconazole: The combined use of a single dose of saxagliptin (100 mg) and ketoconazole (200 mg every 12 hours in an equilibrium state) increases Cmaxand AUC of saxagliptin 2.4 and 3.7 times, respectively. This is accompanied by a corresponding decrease in C.max and AUC of the active metabolite by 96% and 90%, respectively.

Rifampicin: The combined use of a single dose of saxagliptin (5 mg) and rifampicin (600 mg once a day in equilibrium) lowers Cmax and AUC of saxagliptin by 53% and 76%, respectively, with a corresponding increase in Cmax(39%), but without a significant change in the AUC of the active metabolite.

Omeprazole: The combined repeated use of saxagliptin at a dose of 10 mg once a day and omeprazole at a dose of 40 mg, CYP2C19 isoenzyme substrate (strong) and CYP3A4 isoenzyme (weak), CYP2C19 isoenzyme inhibitor and MRP-3 inducer, does not affect saxagliptin pharmacokinetic.

Aluminum hydroxide + magnesium hydroxide + simethicone: The combined use of single doses of Saxagliptin (10 mg) and a suspension containing aluminum hydroxide (2400 mg), magnesium hydroxide (2400 mg) and simethicone (240 mg), lowers Cmaxsaxagliptin by 26%, however, the AUC of saxagliptin does not change.

Famotidine: Taking single doses of saxagliptin (10 mg) 3 hours after a single dose of famotidine (40 mg), an inhibitor of hOCT-1, hOCT-2, and hOCT-3, increases Cmax saxagliptin by 14%, however, the AUC of saxagliptin does not change.

Pregnancy and Lactation

Due to the fact that the use of the drug Kombiglyze Prolong during pregnancy has not been studied, you should not prescribe the drug during pregnancy.

It is not known whether saxagliptin or metformin passes into breast milk. Since the possibility of penetration of the drug Kombiglyze Prolong into breast milk is not excluded, the use of the drug during lactation is contraindicated.

Special instructions

Lactic acidosis is a rare, serious metabolic complication that can develop as a result of cumulation of metformin during therapy with Kombiglyze Prolong. With the development of lactic acidosis due to administration of metformin, its concentration in the blood plasma exceeds 5 µg / ml.

In patients with diabetes mellitus, lactic acidosis is more likely to develop with severe renal failure, including due to congenital kidney disease and insufficient renal perfusion, especially when taking several drugs. In patients with heart failure, in particular, in patients with unstable angina or acute heart failure and the risk of hypoperfusion and hypoxemia, there is an increased risk of developing lactic acidosis. The risk of developing lactic acidosis increases in proportion to the degree of renal failure and the age of the patient. Regular monitoring of renal function in patients taking metformin should be carried out and a minimum effective dose of metformin should be prescribed. In elderly patients, monitoring renal function is necessary. Metformin should not be prescribed to patients aged 80 years or older if renal function is impaired (according to CC), since these patients are more likely to develop lactic acidosis. In addition, it is necessary to immediately cancel therapy with metformin in the development of conditions accompanied by hypoxemia, dehydration or sepsis. Since hepatic impairment can significantly limit the ability to excrete lactate, do not administer metformin to patients with clinical or laboratory signs of liver disease.

Overdosage

Saxagliptin

With prolonged use of the drug in doses up to 80 times higher than recommended, symptoms of intoxication are not described. In case of overdose, symptomatic therapy should be used. Saxagliptin and its main metabolite are excreted by hemodialysis (elimination rate: 23% of the dose in 4 hours).

Metformin

There have been cases of metformin overdose, including more than 50 g. In approximately 10% of cases, hypoglycemia developed, but its causal relationship with metformin has not been established. In 32% of cases of metformin overdose, patients had lactic acidosis. Metformin is eliminated during dialysis, with clearance reaching 170 ml / min.

  • Brand name: Kombiglyze
  • Active ingredient: Metformin hydrochloride, Saxagliptin

Studies and clinical trials of Kombiglyze (Click to expand)

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