Kombogliz Prolong - instructions for use, dose, side effects, contraindications

Active substanceMetformin + SaxagliptinMetformin + Saxagliptin

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Dosage form: & nbspPills.

Composition:One modified release tablet coated with a film coating of 1000 mg + 2.5 mg contains:
Active substances: metformin hydrochloride 1000 mg + saxagliptin 2.5 mg tablet core: metformin hydrochloride in a mixture with 0.5% magnesium stearate 1005.0 mg (1000.0 mg metformin hydrochloride + 5.0 mg magnesium stearate), carmellose sodium 50.0 mg , hypromellose 2208 393.0 mg, magnesium stearate 2.0 mg; the first coat layer (protective): Opadrai II white (% m / m) 130.5 mg [polyvinyl alcohol partially hydrolysed 40.00%, titanium dioxide 25.00%, macrogol 3350 20.20%, talc 14.80% ], 1 M hydrochloric acid solution to a pH of 2.0 ± 0.3 *; the second layer of the coating (active): saxagliptin 2.5 mg, Opadrai II white 20.0 mg, 1 M hydrochloric acid solution to pH 2.0 ± 0.3 *; film cover (third layer of coating color (color)): Opadrai II yellow (% m / m) 48.0 mg [polyvinyl alcohol partially hydrolysed 40.00%, titanium dioxide 24.25%, macrogol 3350 20.20%, talcum powder 14.80%, yellow iron oxide dye 0.75%], 1M hydrochloric acid solution to pH 2.0 ± 0.3 *, inscription ink: Opacod blue ink ** (% m / m) 0.03 mg [indigo carmine aluminum varnish 16.00%, shellac ~ 45% (20% esterified) in ethanol 55.40%, butanol 15.00%, propylene glycol 10.50%, isopropanol 3.00%28% ammonium hydroxide solution 0.10%].
One modified release tablet coated with a film coating of 500 mg + 5 mg contains:
Active substances: metformin hydrochloride 500 mg + saxagliptin 5 mg Core tablet: metformin hydrochloride in a mixture with 0.5% magnesium stearate 502.5 mg (500.0 mg metformin hydrochloride + 2.5 mg magnesium stearate), carmellose sodium 50.0 mg, hypromellose 2208 358.0 mg, hypromellose 2910 10.0 mg, microcrystalline cellulose 102.0 mg, magnesium stearate 1.0 mg; the first coat layer (protective): Opadrai II white (% m / m) 99.0 mg [polyvinyl alcohol partially hydrolysed 40.00%, titanium dioxide 25.00%, macrogol 3350 20.20%, talc 14.80% ], 1 M hydrochloric acid solution to a pH of 2.0 ± 0.3 *; the second layer of the coating (active): saxagliptin 5.0 mg, Opadrai II white 20.0 mg, 1 M hydrochloric acid solution to pH 2.0 ± 0.3 *; film layer (third layer of coating color (color)): Opadrai II yellowish brown (% m / m) 33.0 mg [polyvinyl alcohol partially hydrolysed 40.00%, macrogol 3350 20.20%, titanium dioxide 19.58%, talcum powder 14.80%, iron oxide yellow dye 5.00% and iron oxide red dye 0.42%], 1M hydrochloric acid solution to pH 2.0 ± 0.3 *; ink for inscription: ink Opacode blue ** (% m / m) 0.03 mg [indigo carmine aluminum varnish 16.00%Shellac ~ 45% (20% esterified) in ethanol 55.40%, butanol 15.00%, propylene glycol 10.50%, isopropanol 3.00%, 28% ammonium hydroxide solution 0.10%].
One modified release tablet coated with a film coating of 1000 mg + 5 mg contains:
Active substances: metformin hydrochloride 1000 mg + saxagliptin 5 mg Core tablet: metformin hydrochloride in a mixture with 0.5% magnesium stearate 1005.0 mg (1000.0 mg metformin hydrochloride + 5.0 mg magnesium stearate), carmellose sodium 50.0
mg, hypromellose 2208 393.0 mg, magnesium stearate 2.0 mg; the first coat layer (protective): Opadrai II white (% m / m) 130.5 mg [polyvinyl alcohol partially hydrolysed 40.00%, titanium dioxide 25.00%, macrogol 3350 20.20%, talc 14.80% ], 1 M hydrochloric acid solution to a pH of 2.0 ± 0.3 *; the second layer of the coating (active): saxagliptin 5.0 mg, Opadrai II white 20.0 mg, 1 M hydrochloric acid solution to pH 2.0 ± 0.3 *; film cover (third layer of coating coating (color)): Opadrai II pink (% m / m) 48.0 mg [polyvinyl alcohol partially hydrolyzed 40.00%, titanium dioxide 24.25%, macrogol 3350 20.20%, talcum powder 14.80%, iron oxide red dye 0.75%], 1 M hydrochloric acid solution to a pH of 2.0 ± 0.3 *; ink for inscription: ink Opacode blue ** (% m / m) 0.03 mg [indigo carmine aluminum varnish 16.00%Shellac ~ 45% (20% esterified) in ethanol 55.40%, butanol 15.00%, propylene glycol 10.50%, isopropanol 3.00%, 28% ammonium hydroxide solution 0.10%].
* If necessary, 1 M sodium hydroxide solution can be used to adjust the pH.
** If necessary, alcohol isopropanol is added to the ink during the inscription process. Trace amounts of indigo carmine aluminum lacquer and shellac remain on the tablets when applying the inscription. Solvents that form part of the ink are removed during production during drying.

Pharmacotherapeutic group:Hypoglycemic agent for oral administration (dipeptidyl peptidase 4 inhibitor + biguanide).

ATX: & nbsp

A.10.B.D Combination of biguanides and sulfonylurea derivatives

A.10.B.D.10 Metformin and saxagliptin

Pharmacodynamics:Mechanism of action
Kombogliz Prolong® combines two hypoglycemic drugs with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes mellitus (DM2): saxagliptin, an inhibitor of dipeptidyl peptidase 4 (DPP-4), and metformin, a representative of the biguanide class.
Saxaglyptine
In response to food from the small intestine, hormones-incretins such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (HIP) are released into the bloodstream. These hormones contribute to the release of insulin from the pancreatic beta cells, depending on the concentration of glucose in the blood, but are inactivated by the DPP-4 enzyme for several minutes. GLP-1 also lowers the secretion of glucagon in the alpha-cells of the pancreas, reducing the production of glucose in the liver. In patients with CD2, the concentration of GLP-1 is lowered, but the insulin response to GLP-1 is maintained. Saxaglyptine, as a competitive inhibitor of DPP-4, reduces the inactivation of hormone-incretins, thereby increasing their concentrations in the bloodstream and leading to a decrease in fasting and postprandial glucose.
Metformin
Metformin is a hypoglycemic drug that improves glucose tolerance in patients with CD2, lowering basal and postprandial glucose concentrations.
Metformin reduces glucose production by the liver, reduces glucose uptake in the intestine and increases insulin sensitivity, increasing peripheral uptake and utilization of glucose.Unlike sulfonylurea preparations, metformin does not cause hypoglycemia in patients with CD2 or healthy people (except for special situations, see the sections "With caution" and "Special instructions"), and hyperinsulinemia. During metformin therapy, the secretion of insulin remains unchanged, although fasting insulin concentrations and in response to food intake during the day may decrease.
Clinical efficacy and safety
Saxaglyptine
In double-blind, randomized, controlled clinical trials, saxagliptin therapy received more than 17,000 patients with CD2. Cardiovascular outcomes In the SAVOR study (Evaluation of cardiovascular outcomes in patients with diabetes mellitus taking saxagliptin) cardiovascular outcomes were studied in 16492 patients with CD2 (12959 patients with confirmed cardiovascular diseases (CVD), 3533 patients with multiple risk factors for cardiovascular complications) and 6.5% ≤ HbAlc <12%. Patients were randomized into two groups to receive saxagliptin (8280 patients) or placebo (8212 patients), in addition to the standard for each region of therapy aimed at controlling glycosylated hemoglobin and cardiovascular risk factors.
It was shown that saxagliptin does not increase the risk of cardiovascular complications (such as death from CVD, nonfatal myocardial infarction, nonfatal ischemic stroke) compared with placebo when added to standard base therapy (relative risk [RR] 1.00, 95% confidence interval [CI] 0 , 89, 1.12). It has also been shown that the addition of saxagliptin to basic therapy does not increase the risk of a combined endpoint, including death from CVD, nonfatal myocardial infarction, nonfatal ischemic stroke, hospitalization for chronic heart failure, unstable angina, or coronary artery revascularization compared with placebo RR 1.02, 95% CI 0.94, 1.11). Overall mortality was comparable in the saxagliptin and placebo groups (RR 1.11, 95% CI 0.96, 1.27).
In the study, there was an increase in the hospitalization rate for chronic heart failure in the saxagliptin group (3.5%, 289 patients) compared to the placebo group (2.8%, 228 patients) with nominal statistical significance (i.e., without correction for multiple end points) (RR 1.27, 95% CI 1.07, 1.51, P = 0.007). In patients with chronic heart failure or renal insufficiency who received saxagliptin, there was no higher incidence of the primary endpoint, secondary endpoint, and overall mortality compared to the placebo group.
In the saxagliptin group, the dynamics of the HbAlc value was significantly more pronounced, and the percentage of patients achieving the target HbAlc value was higher than in the placebo group. In this case, the intensification of hypoglycemic therapy or the addition of insulin in the saxagliptin group was required in significantly fewer patients than in the placebo group.

Carefully:In persons over the age of 60 years, performing heavy physical work (increased risk of lactic acidosis); in patients with pancreatitis in the anamnesis (the relationship between taking the drug and an increased risk of pancreatitis is not established); in patients with a history of heart failure; In patients with moderate and severe renal insufficiency in the anamnesis.

Dosing and Administration:Inside, once a day during dinner. Tablets should be swallowed whole, not chewing, not crushing and not breaking. The dose should be selected individually. Usually, with combined therapy 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 achieved by taking 2 tablets of 2.5 mg / 1000 mg taken once a day. The dose of metformin is increased gradually to reduce the risk of side effects from the gastrointestinal tract. The maximum daily dose: saxagliptin 5 mg and modified release metformin 2000 mg.
No special safety and efficacy studies of Kombogliz Prolong® were performed in patients who had previously received other hypoglycemic agents and who had been switched to Kombogliz Prolong®. It is necessary to make changes to the therapy of CD2 with caution and with appropriate control of the concentration of glucose in the blood.
When combined with powerful inhibitors of CYP3A4 / 5 isoenzymes (for example, ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir and telithromycin), the dose of saxagliptin should be 2.5 mg once daily.
Inactive ingredients of Kombogliz Prolong® can be excreted through the intestines in the form of a soft, moist mass that can retain the shape of the taken tablet.
Use in special patient groups
Elderly patients
As saxagliptin and metformin are partially excreted by the kidneys, and in elderly patients the kidney function is likely to decrease, caution should be exercised with Combogenty Prolong® in the elderly.
Saxaglyptine
There were no differences in safety or efficacy of the drug in patients aged ≥65 years, ≥75 years and young patients.
Metformin
Controlled clinical studies of metformin did not include a sufficient number of elderly patients to determine differences in response to therapy compared to younger patients, although clinical experience did not establish differences in response in the elderly and in young patients. As is known, metformin is largely excreted by the kidneys, and therefore there is a risk of developing serious adverse events in patients with renal insufficiency.
Kombogliz Prolong® should be given only to patients with normal renal function. Initial and maintenance doses of metformin should be administered to elderly patients, taking into account the possible decrease in renal function.Any dose adjustment should be performed after careful assessment of kidney function.
Children
The safety and efficacy of the drug in patients under the age of 18 years has not been studied.

Side effects:Undesirable reactions in studies of glycemic control during
the use of saxagliptin in monotherapy and when added to other drugs
Saxaglyptine
Table 1 presents the undesirable effects observed in clinical trials (regardless of the causative agent's assessment) in> 5% of patients who received saxagliptin 5 mg, and with a greater frequency than in the placebo group, according to a combined analysis of 24-week studies.
Table 1. Adverse events

	Number (%) of patients
	Saxaglyptine 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 trials included in this analysis are two monotherapy studies and one study of combination therapy with the addition of saxagliptin to metformin, thiazolidinediones or glibenclamide.
In patients who took saxagliptin in a dose of 2.5 mg, headache (6.5%) was the only adverse event noted with a frequency of ≥ 5%, and developing more often than in the placebo group.
According to this same pooled analysis, adverse events noted in ≥ 2% of patients taking saxagliptin in a dose of 2.5 mg or saxagliptin in a dose of 5 mg, and those developing at ≥ 1% more often than in the placebo group included sinusitis (2.9% and 2.6% compared to 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 fracture was 1.0 and 0.6 per 100 patient-years, respectively, when taking saxagliptin (combined dose analysis of 2.5 mg, 5 mg and 10 mg) and placebo.
Frequency of fractures in patients taking saxagliptin, did not increase in time. There is no causal relationship, and preclinical studies have shown no undesirable effects of saxagliptin on bone tissue.
During the clinical program, there was a development of thrombocytopenia corresponding to the diagnosis of idiopathic thrombocytopenic purpura. The association of the development of this phenomenon with the administration of saxagliptin is not known.
The undesirable phenomena associated with the joint administration of saxagliptin and metformin in the treatment of patients with CD2,previously untreated, in studies of glycemic control Saxagliptin
Table 2 shows the adverse events noted (regardless of the causative agent's assessment) in ≥5% of patients participating in an additional 24-week, active control study of the combined use of saxagliptin and metformin in patients who had not previously received therapy.
Table 2. Undesirable phenomena

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

* The initial dose of metformin 500 mg / day was raised to a maximum dosage of 2000 mg / day.
In patients who received saxagliptin in addition to metformin therapy or as an initial combination therapy, diarrhea was the only gastrointestinal adverse event that occurred in> 5% of patients in any group. The incidence of diarrhea was 9.9%, 5.8%, and 11.2% in the 2.5 mg saxagliptin group, 5 mg saxagliptin, 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 therapy group of 5 mg saxagliptin and metformin and the metformin monotherapy group in a study of initially combination therapy with metformin.
Hypoglycaemia
Saxaglyptine
Information on hypoglycemia as an undesirable phenomenon was collected on the basis of reports of hypoglycemia; no concomitant measurement of glucose concentration was required. The incidence of hypoglycemia when applying 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, with the addition of metformin. The incidence of hypoglycemia was 3.4% in previously untreated patients taking saxagliptin in a dose of 5 mg in combination with metformin, and 4% in patients on monotherapy with metformin.
Hypersensitivity reactions
Saxaglyptine
In the analysis of five pooled studies adverse events associated with hypersensitivity (such as urticaria and facial edema) were observed in 1.5%, 1.5% and 0.4% of patients receiving saxagliptin in a dose of 2.5 mg, saxagliptin in a dose of 5 mg and placebo, respectively. According to the researchers, none of these phenomena in patients who received saxagliptin, did not require hospitalization and did not endanger the lives of patients. In this pooled data analysis, one patient who received saxagliptin, was excluded from the study because of the development of generalized urticaria and edema of the face.
Indicators of physiological functions
Saxaglyptine
In patients who received saxagliptin in the form of monotherapy or in combination with metformin, there were no clinically significant changes in the indices of physiological functions.
Monotherapy
Metformin
In placebo-controlled studies, the most frequent adverse events noted in> 5% of patients who received metformin modified release, and developed more often than in the placebo group, were diarrhea and nausea / vomiting.
Undesirable effects of saxagliptin in the SAVOR trial
In the SAVOR study, 8240 patients received saxagliptin in a dose of 2.5 mg or 5 mg once a day, and 8173 patients received a placebo. The average duration of therapy with saxagliptin, regardless of interruptions in treatment, was 1.8 years. In 3698 patients (45%), the duration of therapy with saxagliptin was 2-3 years. The overall incidence of adverse events in this study in the group of patients taking saxagliptin (72.5%) was comparable with the incidence of adverse events in the placebo group (72.2%).The frequency of cancellation of therapy due to adverse events was comparable in patients taking saxagliptin (4.9%) and placebo (5%).
The SAVOR study evaluated the effect of saxagliptin on the incidence of cardiovascular complications. It has been shown that the addition of saxagliptin to therapy does not increase the risk of cardiovascular complications (such as cardiovascular mortality, nonfatal myocardial infarction, nonfatal ischemic stroke) in patients with DM2 compared with placebo (RR 1.00, 95% CI 0.89, 1.12, P <0.001 for the hypothesis of comparability of saxagliptin and placebo).
The incidence of pancreatitis confirmed in accordance with the study protocol was 0.3% in the saxagliptin and placebo groups in the population of all randomized patients.
The incidence of hypersensitivity reactions was 1.1% in the saxagliptin and placebo groups.
Hypoglycaemia
The overall incidence of hypoglycemia (noted in patient diaries) in the SAVOR trial was 17.1% in the saxagliptin group and 14.8% in the placebo group.
The proportion of patients who had severe hypoglycaemia (hypoglycaemia requiring third-party care) was higher in the group of saxagliptin compared to placebo (2.1% and 1.6%, respectively).The increased risk of hypoglycemia in general, as well as severe hypoglycemia in the saxagliptin group, was mainly observed in patients receiving sulfonylurea preparations, but not in patients receiving insulin or metformin as a basic therapy.
The increased risk of hypoglycemia in general, as well as severe hypoglycemia, is mainly observed in patients with a baseline HbAlc <7%.
Postmarketing application
During the post-marketing use of saxagliptin, the following adverse reactions were recorded: acute pancreatitis, arthralgia, and hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria. It is impossible to estimate the frequency of development of these phenomena reliably, since messages were received spontaneously from a population of an unidentified size (see the sections "Contraindications" and "Special instructions").
Laboratory research
Absolute number of lymphocytes
Saxaglyptine
With the use of saxagliptin, a dose-dependent mean decrease in the absolute number of lymphocytes was observed. When analyzing the pooled data of five 24-week, placebo-controlled studies, an average decrease of approximately 100 and 120 cells / μlof the absolute number of lymphocytes from the initial average of 2200 cells / μl when using saxagliptin at a dose of 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 initial combination with metformin compared with metformin monotherapy. There was no difference between saxagliptin 2.5 mg and placebo. The proportion of patients with a lymphocyte count of <750 cells / μl was 0.5%, 1.5%, 1.4%, and 0.4% in the saxaggliptin 2.5 mg dose group, at a dose of 5 mg , in a dose of 10 mg and placebo, respectively. In most patients with repeated use of saxagliptin, there was no relapse, although in some patients the number of lymphocytes was re-lowered with the resumption of saxagliptin therapy, which led to the elimination of saxagliptin. The decrease in the number of lymphocytes was not accompanied by clinical manifestations.
In the SAVOR study, a decrease in the number of lymphocytes in the saxagliptin group was observed in 0.5% of patients, in the placebo group in 0.4% of patients.
The causes of a decrease in the number of lymphocytes with saxagliptin compared with placebo are unknown. If an unusual or prolonged infection develops, the number of lymphocytes must be measured.
The effect of saxagliptin on the number of lymphocytes in patients with deviations in the number of lymphocytes (eg, human immunodeficiency virus) is unknown.
Platelets
Saxaglyptine
Saxagliptin did not have a clinically significant or sequential effect on the number of platelets in six double-blind, controlled clinical trials of safety and efficacy.
Concentration of vitamin B₁₂
In controlled clinical trials of metformin lasting for 29 weeks, approximately 7% of patients had a decrease in serum before the normal concentration of vitamin B₁₂ to subnormal values without clinical manifestations. However, this reduction is very rarely accompanied by the development of anemia and is quickly restored after the withdrawal of metformin or supplemental intake of vitamin B₁₂.

Interaction:Saxaglyptine
The metabolism of saxagliptin is predominantly mediated by the cytochrome P450 isoenzyme system of Z4 / 5 (CYP3A4 / 5). In in vitro studies, it was shown that saxagliptin and its main metabolite do not inhibit the isoenzymes CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4 and do not induce isoenzymes CYP1A2, 2B6, 2C9, and 3A4.Therefore, it is not expected that saxagliptin will influence the metabolic clearance of drugs whose metabolism involves these isoenzymes when they are used together. Saxaglyptine is not a significant inhibitor or inducer of P-gp.
Metformin
Some drugs increase hyperglycemia (thiazide and other diuretics, glucocorticosteroids, phenothiazines, preparations of iodine-containing thyroid hormones, estrogens, oral contraceptives, phenytoin, a nicotinic acid, sympathomimetics, blockers of "slow" calcium channels and isoniazid). When prescribing or removing such medications, the patient taking Comboglize Prolong® should carefully monitor the concentration of glucose in the blood. The degree of binding of metformin to blood plasma proteins is low, so it is unlikely that it will interact with drugs that largely bind to plasma proteins, such as salicylates, sulfonamides, chloramphenicol and probenecid (in contrast to sulfonylurea derivatives, which largely bind to serum proteins).
Inductors of isoenzymes CYP3A4 / 5
Saxaglyptine
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 blood plasma during the 24-hour interval of therapy. Inhibitors of isoenzymes CYP3A4 / 5
Saxaglyptine
Diltiazem enhances the effect of saxagliptin in a joint application. Saxagliptin Increased plasma concentrations are expected in the application of amprenavir, aprepitant, erythromycin, fluconazole, fosamprenavir, grapefruit juice and verapamil; however, the dose of saxagliptin should not be adjusted.
Ketoconazole significantly increases the concentration of saxagliptin in plasma. This significant increase saxagliptin plasma concentrations are expected in the application of other potent inhibitors of CYP3A4 / 5 isoenzymes (e.g., atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir and telithromycin). When combined with a potent inhibitor of CYP3A4 / 5 isoenzymes, the dose of saxagliptin should be reduced to 2.5 mg.
Cationic preparations
Metformin
Cationic preparations (for example, amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim or vancomycin), which are excreted by the kidneys due to glomerular filtration, can theoretically interact with metformin, competing for common transport systems of the renal tubules. During the studies of the drug interaction of metformin and cimetidine with a single and repeated administration of the drug, there was interaction of metformin and cimetidine with ingestion in healthy volunteers; with a 60% increase in the maximum concentration of metformin in plasma and whole blood and a 40% increase in metformin AUC in plasma and whole blood. During the study with a single dose of the drug, there was no change in the half-life period. Metformin does not affect the pharmacokinetics of cimetidine. It is recommended to carefully monitor patients and, if necessary, adjust the dose in patients taking cationic drugs that are excreted through the system of proximal renal tubules.
Glibenclamide
Metformin
In the study of interaction with a single dose of the drug in patients with diabetes, the combined use of metformin and glibenclamide does not affect the parameters of pharmacokinetics or pharmacodynamics.
Furosemide
Metformin
During the study of the drug interaction of metformin and furosemide with a single dose of the drug, performed on healthy volunteers, their pharmacokinetic interaction was revealed. Furosemide increases Cmax of metformin in plasma and blood by 22% and AUC in blood by 15% without a significant change in renal clearance of metformin. When combined with metformin, Cmax and AUC, furosemide is reduced by 31% and 12%, respectively, and the half-life is reduced by 32% without noticeable changes in furosemide renal clearance. There is no data on the interaction of metformin and furosemide in a joint long-term use.
Nifedipine
Metformin
In the study of the drug interaction of metformin and nifedipine with a single dose of the drug, conducted with the participation of healthy volunteers, nifedipine increases Cmax of metformin in plasma by 20% and AUC by 9%, and increases excretion by the kidneys. Tmax and half-life did not change. Nifedipine increases the absorption of metformin. Metformin practically does not affect the pharmacokinetics of nifedipine.
Saxagliptin and metformin
The combined use of single doses of saxagliptin (100mg) and metformin (1000 mg) had no significant effect on the pharmacokinetics of saxagliptin or metformin in healthy volunteers.
No special pharmacokinetic studies of drug interactions with the use of Kombogliz Prolong®, although such studies have been conducted with its individual components: saxagliptin and metformin.
The effect of other drugs on saxagliptin
Glibenclamide: The combined single application of saxagliptin (10 mg) and glibenclamide (5 mg), the substrate of the isoenzyme CYP2C9, increased the C max of saxagliptin by 8%, but the aux of saxagliptin did not change.
Pioglitazone: The simultaneous re-use of saxagliptin once daily (10 mg) and pioglitazone (45 mg), the substrate of the isoenzyme CYP2C8 (strong) and CYP3A4 (weak), does not affect the parameters of the pharmacokinetics of saxagliptin.
Digoxin: The simultaneous re-use of saxagliptin once daily (10 mg) and digoxin (0.25 mg), the P-glycoprotein substrate, does not affect the parameters of the pharmacokinetics of saxagliptin.
Simvastatin: The simultaneous re-use of saxagliptin once daily (10 mg) and simvastatin (40 mg), the substrate of the CYP3A4 / 5 isoenzymes, increased the C max of saxagliptin by 21%, but the aux of saxagliptin did not change.
Diltiazem: The combined single use of saxagliptin (10 mg) and diltiazem (360 mg prolonged drug in equilibrium), a moderate inhibitor of isoenzymes CYP3A4 / 5, increases the C max of saxagliptin by 63%, and the AUC by 2.1 times. This is accompanied by a corresponding decrease in Cmax 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 the equilibrium state) increases the C max and AUC of saxagliptin by 2.4 and 3.7 times, respectively. This is accompanied by a corresponding decrease in Cmax 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 Cax and AUC of saxagliptin by 53% and 76%, respectively, with a corresponding increase in Cmax (39%), but without a significant change in AUC active metabolite.
Omeprazole: The simultaneous multiple use of saxagliptin 10 mg once daily and omeprazole 40 mg, the substrate of the isoenzyme CYP2C19 (strong) and the isoenzyme CYP3A4 (weak), the inhibitor of the isoenzyme CYP2C19 and the MRP-3 inductor, does not affect the pharmacokinetics of saxagliptin.
Aluminum hydroxide + magnesium hydroxide + simethicone: The combined use of single doses of saxagliptin (10 mg) and a suspension containing aluminum hydroxide (2,400 mg), magnesium hydroxide (2,400 mg) and simethicone (240 mg), lowers the C max of saxagliptin by 26%, but the AUC of saxagliptin does not change.
Famotidine: The administration of single doses of saxagliptin (10 mg) 3 hours after a single dose of famotidine (40 mg), inhibitor hOCT-1, hOCT-2, and hOCT-3, increases C max of saxagliptin by 14%, but the aux of saxagliptin does not change.

Special instructions:Lactic acidosis
Lactic acidosis is a rare, serious metabolic complication that can develop as a result of cumulation of metformin during therapy with Kombogliz Prolong®. With the development of lactic acidosis due to the use of metformin, its concentration in the blood plasma exceeds 5 μg / ml.
In patients with diabetes more likely to develop lactic acidosis with severe renal insufficiency, including those due to congenital renal disease and renal hypoperfusion, especially when taking multiple medications. In patients with heart failure, particularly 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. Kidney function should be monitored regularly in patients taking metformin, and prescribe the minimum effective dose of metformin. Older patients need control of kidney function. Do not assign metformin patients aged 80 years and older, if renal function is impaired (according to CC), as these patients are more likely to develop lactic acidosis. In addition, it is necessary to immediately cancel metformin therapy in the development of conditions accompanied by hypoxemia, dehydration or sepsis. Since liver failure can significantly limit the ability to excrete lactate, one should not prescribe metformin patients with clinical or laboratory signs of liver disease.
The onset of lactic acidosis often goes unnoticed and is accompanied by nonspecific symptoms, such as malaise, myalgia, respiratory failure, increased drowsiness, pain and discomfort in the abdomen. Hypothermia, hypotension and resistant bradyarrhythmia can be noted.The patient should immediately report all of these symptoms to the doctor. If such symptoms are detected, metformin therapy should be canceled, serum electrolytes, ketone bodies, blood glucose should be monitored, and if indicated, blood pH, lactate concentrations and metformin concentrations in the blood.
Gastrointestinal symptoms, developing at the late stage of metformin therapy, can be caused by lactic acidosis or another disease. The concentration of lactate in the plasma of venous blood on an empty stomach, exceeding the upper limit of the norm, but below 5 mmol / l, in patients taking metformin, can indicate the approaching development of lactic acidosis, and can also be explained by other causes, such as uncompensated diabetes mellitus, obesity, excessive physical exertion. The presence of lactic acidosis should be checked in all patients with diabetes mellitus and metabolic acidosis without signs of ketoacidosis (ketonuria and ketonemia). Lactic acidosis requires treatment in a hospital. In detecting lactic acidosis in a patient receiving metformin, the drug should be discontinued immediately and the generalsupporting activities. It is recommended to begin dialysis immediately to correct acidosis and excrete cumulated metformin. As you know, alcohol potentiates the effect of metformin on the metabolism of lactate, which increases the risk of lactic acidosis. It is necessary to limit the use of alcohol during the intake of Kombogliz Prolong®.
Liver failure
The use of Kombogliz Prolong® is contraindicated in patients with clinical and laboratory signs of liver disease due to the risk of developing lactic acidosis.
Evaluation of kidney function
Before starting therapy with Kombogliz Prolong® and at least annually, it is necessary to check the kidney function afterwards. In patients with suspected renal dysfunction, kidney function should be assessed more frequently and Kombogliz Prolong® therapy should be discontinued if there is evidence of renal failure.
Surgical procedures
It is necessary to temporarily stop the use of Kombogliz Prolong® before any surgical procedure (except for small procedures not related to the restriction of food and liquids), and do not resume its use until the patient is able to take medication inside and the normal function is not confirmed kidney.
Changes in the clinical state of patients with previously controlled CD2
In a patient with CD2 who had previously been well-controlled with Kombogliz Prolong® and who had laboratory abnormalities or developed a disease (especially in the case of an unclear diagnosis), it is necessary to immediately assess the signs of ketoacidosis or lactic acidosis. The evaluation should include the determination of electrolytes in blood serum, ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate and metformin concentrations. If any form of acidosis develops, immediately discontinue Kombogliz Prolong® and prescribe another hypoglycemic drug.
The use of drugs that can cause hypoglycemia
Saxaglyptine
Derivatives of sulfonylureas and insulin can cause hypoglycemia. Therefore, in order to reduce the risk of hypoglycemia when used simultaneously with saxagliptin, a dose reduction of the sulfonylurea or insulin derivatives may be required.
Metformin
Hypoglycemia does not develop in patients taking only metformin in normal mode, but can develop with insufficient intake of carbohydrates,when the active physical load is not compensated by the intake of carbohydrates, or with concomitant use with other hypoglycemic drugs (such as sulfonylureas and insulin derivatives) or alcohol. Elderly, impaired or malnourished patients and patients with adrenal insufficiency or pituitary gland or alcohol intoxication are most sensitive to hypoglycemic effects. In elderly people and patients taking beta-adrenoblockers, the diagnosis of hypoglycemia can be difficult.
Concomitant therapy, which affects the function of the kidneys or the distribution of metformin
Caution is advisable to use concomitant medications (such as cationic drugs released by secretion in the renal tubules) that can affect kidney function, lead to significant hemodynamic changes, or disrupt the distribution of metformin (see section "Interaction with other drugs"). Radiological studies with intravascular injection of iodine-containing contrast agents Radiological studies with intravascular administration of iodine-containing contrast agents revealed acutedisorders of kidney function, which may be accompanied by the development of lactic acidosis in patients receiving metformin. Patients who are scheduled for this study should be withdrawn from Combigliz ProLong® before 48 hours after the procedure, refrain from taking the drug within 48 hours after the procedure, and resume therapy only after confirming the normal function of the kidneys.
Hypoxic states
Cardiovascular collapse (shock) of any origin, acute heart failure, acute myocardial infarction and other conditions accompanied by hypoxia and lactic acidosis, can cause prerenal azotemia. In the development of such phenomena, it is necessary to immediately cancel the therapy with Kombogliz Prolong®.
The change in the concentration of glucose in the blood
Fever, trauma, infection, surgery can lead to a change in the concentration of glucose in the blood, which previously could be controlled with Kombogliz Prolong®. In these cases, it may be necessary to temporarily discontinue therapy and transfer the patient to insulin therapy.After stabilizing the concentration of glucose in the blood and improving the general condition of the patient, treatment with Kombogliz Prolong® can be resumed.
Hypersensitivity reactions
During the post-marketing use of saxagliptin, severe hypersensitivity reactions were noted, including anaphylaxis and angioedema. If you develop a serious hypersensitivity reaction, stop using the drug, evaluate other possible causes of the phenomenon and prescribe an alternative therapy for diabetes mellitus (see the sections "Contraindications" and "Side effect").
Pancreatitis
Spontaneous reports of cases of acute pancreatitis were obtained in the framework of post-marketing use of saxagliptin. Patients taking Kombogliz Prolong® should be informed of the characteristic symptoms of acute pancreatitis: prolonged, intense pain in the abdomen. If suspected development of pancreatitis should stop taking Kombogliz Prolong® (see sections "With caution" and "Side effect").
The frequency of pancreatitis in the SAVOR study, confirmed in accordance with the study protocol,was 0.3% in the saxagliptin and placebo groups in the population of all randomized patients.
Elderly patients
Of the 16492 patients randomized to the SAVOR study, 8561 patients (51.9%) were 65 years of age or older, and 2330 patients (14.1%) were aged 75 years and older. Of these, 4,290 patients aged 65 years and over and 1,169 patients aged 75 and over received saxagliptin.
According to clinical studies, the efficacy and safety indices in patients aged 65 years and over, 75 years and older did not differ from those in younger patients.
Heart failure
In the SAVOR study, there was an increase in the hospitalization rate for heart failure in the saxagliptin group compared with the placebo group, although a cause-and-effect relationship was not established. Caution should be exercised when using Kombogliz Prolong® in patients with risk factors for developing heart failure, such as heart failure or a history of moderate and severe renal failure. Patients should be informed of the characteristic symptoms of heart failure andthe need to immediately report such symptoms (see the section "Pharmacodynamics", Clinical efficacy and safety).
Arthralgia
Post-marketing reports describe joint pain, including severe pain, with the use of DPP-4 inhibitors. Patients experienced symptom relief after discontinuation, and individual patients experienced a relapse of symptoms with the resumption of the same or another inhibitor of DPP-4. The appearance of symptoms after the start of the drug can be rapid or marked against a background of prolonged therapy. With the development of severe pain in the joints, it should be evaluated whether it is advisable to continue taking the drug in each individual case (see the "Side effect" section).

Form release / dosage:Tablets with modified release, film-coated.

Packaging:Tablets with modified release, film-coated 1000 mg + 2.5 mg.
7 tablets per aluminum foil blister; for 4 or 8 blisters with instructions for use in a cardboard box with the control of the first opening.
Modified-release tablets coated with a film coat 500 mg + 5 mg
7 tablets per aluminum foil blister; 4 blisters with instructions for use in a cardboard box with the control of the first opening.
Modified-release tablets coated with a film coat 1000 mg + 5 mg
7 tablets per aluminum foil blister; 4 blisters with instructions for use in a cardboard box with the control of the first opening.

Storage conditions:At a temperature not exceeding 30 FROM.

Shelf life:3 years.

Terms of leave from pharmacies:On prescription

Registration number:LP-002068

Date of registration:14.05.2013 / 05.09.2016

Expiration Date:14.05.2018

The owner of the registration certificate:AstraZeneca UK LtdAstraZeneca UK Ltd United Kingdom

Manufacturer: & nbsp

ASTRAZENECA UK, Ltd. United Kingdom

Representation: & nbspAstraZeneca Pharmaceuticals Ltd.AstraZeneca Pharmaceuticals Ltd.

Information update date: & nbsp2016-09-26

Illustrated instructions

Instructions

Kombogliz Prolong® (Kombiglyce Prolong)