Combogliz Prolong, 1000 mg+2, 5 mg 56 pcs.

Mechanism of Action

Combogliz Prolong combines two hypoglycemic drugs with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes (T2DM): saxagliptin, a dipeptyl peptidase 4 (DPP-4) inhibitor, and metformin, a class of biguanides.

Saxagliptin

In response to food intake, incretin hormones such as glucagon-like peptide-1 (GFP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released into the bloodstream from the small intestine.

These hormones promote insulin release from pancreatic beta cells, which is dependent on blood glucose concentration, but are inactivated by DPP-4 enzyme within minutes. PPP-1 also decreases glucagon secretion in pancreatic alpha cells, reducing glucose production in the liver. In patients with DM2, the concentration of GFP-1 is reduced, but the insulin response to GFP-1 is maintained. Saxagliptin, as a competitive inhibitor of DPP-4, reduces inactivation of the hormone incretins, thereby increasing their concentrations in the bloodstream and leading to decreased glucose concentrations on an empty stomach and after meals.

Metformin

Metformin is a hypoglycemic drug that improves glucose tolerance in patients with DM2 by lowering basal and postprandial glucose concentrations. Metformin reduces glucose production by the liver, reduces glucose absorption in the intestine, and increases insulin sensitivity by increasing peripheral glucose absorption and utilization. Unlike sulfonylurea drugs, metformin does not cause hypoglycemia in patients with DM2 or healthy people (except in special situations, see sections “Caution” and “Special indications”), and hyperinsulinemia. During therapy with metformin, insulin secretion remains unchanged, although fasting insulin concentrations and in response to meals during the day may decrease.

PHARMACOKINETICS
Saxagliptin

The pharmacokinetics of saxagliptin and its active metabolite, 5-hydroxy-saxagliptin, are similar in healthy volunteers and in patients with DM2. The Cmax values and the area under the AUC curve of saxagliptin and its active metabolite in plasma increased proportionally in the dose range from 2.5 mg to 400 mg. After a single oral dose of 5 mg of saxagliptin in healthy volunteers, the mean AUC values of saxagliptin and its major metabolite were 78 ng*h/mL and 214 ng*h/mL, and plasma Cmax values were 24 ng/mL and 47 ng/mL, respectively. The mean variability of AUC and Cmax of saxagliptin and its active metabolite was less than 25%.

There is no appreciable cumulation of saxagliptin or its active metabolite when the drug is repeated once daily in any dosage. There is no dose and time dependence of clearance of saxagliptin and its active metabolite when used once daily for 14 days in doses from 2.5 mg to 400 mg of saxagliptin.

Metformin

The cmax of modified-release metformin is reached in an average of 7 hours. The absorption rate of metformin from modified-release tablets is increased by approximately 50% when taken with meals. At equilibrium, the AUC and Cmax of modified-release metformin increased disproportionately to the dosage in the dose range from 500 to 2000 mg. After repeated dosing, modified-release metformin did not accumulate in plasma. Metformin is excreted unchanged by the kidneys and is not metabolized in the liver.

Saxagliptin

At least 75% of the administered dose of saxagliptin is absorbed after oral administration. Food intake had no significant effect on the pharmacokinetics of saxagliptin in healthy volunteers. High-fat meal had no effect on the Cmax of saxagliptin, whereas the AUC was increased by 27% compared with fasting meal. The time to reach Cmax (Tmax) for saxagliptin was increased by approximately 0.5 h when the drug was taken with food compared with fasting food intake. However, these changes are not clinically significant.

Metformin

After a single oral administration of modified-release metformin, Cmax is reached after an average of 7 hours, ranging from 4 to 8 hours. The AUC and Cmax of modified-release metformin increased disproportionately to the dosage in the dose range from 500 to 2000 mg. Maximum plasma concentrations of the drug were 0.6, 1.1, 1.4, and 1.8 µg/ml at doses of 500, 1000, 1500, and 2000 mg once daily, respectively. Although the degree of absorption (measured by AUC) of metformin from modified-release metformin tablets is increased by approximately 50% when taken with food, food intake had no effect on the Cmax and Tmax of metformin. Low- and high-fat foods had the same effect on the pharmacokinetic parameters of modified-release metformin.

Distribution

Saxagliptin

. The binding of saxagliptin and its major metabolite to serum proteins is insignificant, so it can be assumed that the distribution of saxagliptin will not be significantly altered by changes in serum proteins noted in hepatic or renal insufficiency.

Metformin

There have been no studies of the distribution of modified-release metformin, but the apparent distribution of metformin after a single oral dose of 850 mg immediate-release metformin tablets averaged 654±358 L. Metformin is slightly bound to plasma proteins.

Metabolism

Saxagliptin

. Saxagliptin is metabolized mainly with the participation of cytochrome P450 isoenzymes of CA4/5 (CYP3A4/5) to form the active main metabolite, whose inhibitory effect against DPP-4 is 2 times weaker than that of saxagliptin.

Metformin

Studies with single intravenous administration of the drug in healthy volunteers show that metformin is excreted unchanged by the kidneys, is not metabolized in the liver (no metabolites have been identified in humans) and is not excreted through the intestine.

Saxagliptin

Saxagliptin is excreted by the kidneys and through the intestine. After a single dose of 50 mg of 14C-labeled saxagliptin, 24% of the dose was excreted by the kidneys as unchanged saxagliptin and 36% as the major metabolite saxagliptin. The total radioactivity detected in the urine corresponded to 75% of the dose taken.

The mean renal clearance of saxagliptin was approximately 230 ml/min, the mean glomerular filtration was approximately 120 ml/min. For the main metabolite, renal clearance was comparable to the average glomerular filtration values. About 22% of the total radioactivity was found in the feces.

Metformin

The renal clearance was approximately 3.5 times the creatinine clearance (CK), indicating that tubular secretion is the major route of metformin excretion. After oral administration, approximately 90% of the absorbed drug is excreted by the kidneys within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, hence the erythrocyte mass may be part of the distribution.

Pharmacokinetics in special clinical situations

Renal impairment

Combogliz Prolong is not recommended in patients with renal impairment.

Saxagliptin

In patients with mild renal impairment, the AUC values of saxagliptin and its active metabolite were 20% and 70% (respectively) higher than the AUC values in patients with normal renal function. Since this increase is not considered clinically significant, it is not recommended to adjust the dose of saxagliptin in patients with mild renal impairment.

Metformin

In patients with impaired renal function (based on CK measurements), the half-life of metformin from plasma and blood is prolonged and renal clearance decreases in proportion to the decrease in CK.

Hepatic impairment

Saxagliptin

In patients with mild, moderate and severe hepatic impairment no clinically significant changes in pharmacokinetic parameters of saxagliptin have been found, so no dose adjustment is required for these patients.

Metformin

There have been no pharmacokinetic studies of metformin in patients with hepatic impairment.

Gender

Saxagliptin

Dose adjustment of saxagliptin according to the gender of patients is not required.

Metformin

In clinical studies in patients with DM2, the hypoglycemic effects of metformin in men and women were comparable.

Elderly patients

Saxagliptin

There were no clinically significant differences in saxagliptin pharmacokinetic parameters in patients 65-80 years old compared with younger patients (18-40 years), so no dose adjustment in elderly patients is required. However, it should be taken into account that in this category of patients it is more likely to decrease renal function (see sections “Dosage and administration” and “Cautions”).

Metformin

Limited data from controlled studies of metformin pharmacokinetics in healthy elderly volunteers suggest that total plasma clearance of metformin is decreased, T1/2 is increased, and Cmax is increased compared to the values of these parameters in healthy young volunteers. According to these data, the change in metformin pharmacokinetic parameters with increasing age is mainly due to changes in renal function. Combogliz Prolong should not be administered to patients over 80 years of age unless normal renal function has been confirmed by CK measurements.

Children

Saxagliptin

No pharmacokinetic studies of saxagliptin have been performed in children.

Metformin

There have been no studies on the pharmacokinetics of modified-release metformin in children.

Race and ethnicity

Saxagliptin

It is not recommended to adjust the dose of saxagliptin according to the race of the patient.

Metformin

There have been no studies of metformin pharmacokinetic parameters depending on the race of patients.

Indications

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

Composition

1 modified-release tablet,

film-coated, contains:
active ingredients:

metformin 1000 mg,

saxagliptin 2.5 mg

How to take, the dosage

To be taken by mouth, once daily with dinner. The tablets should be swallowed whole, without chewing, crushing or breaking. The dose has to be adjusted individually.

In combination therapy with saxagliptin and metformin, the usual dose of saxagliptin is 5 mg once daily. The recommended starting dose of modified-release metformin is 500 mg once daily, which can be increased to 2000 mg once daily, provided by taking 2 tablets of 2.5 mg/1000 mg taken once daily. The dose of metformin is increased gradually to reduce the risk of gastrointestinal side effects. Maximum daily dose: saxagliptin 5 mg and modified-release metformin 2000 mg.

There have been no specific studies of the safety and efficacy of Combogliz Prolong in patients previously treated with other hypoglycemic agents and switched to Combogliz Prolong.

Changes in DM2 therapy should be made with caution and with appropriate monitoring of blood glucose concentrations. When co-administered with potent CYP3A4/5 isoenzyme inhibitors (e.g., ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir and telithromycin) the dose of saxagliptin should be 2.5 mg once daily.

The inactive ingredients in Combogliz Prolong may be excreted through the intestine as a soft, moist mass that may retain the shape of the tablet taken.

Use in special patient groups

Patients in the elderly

Because saxagliptin and metformin are partially excreted by the kidneys, and decreased renal function is likely in elderly patients, Combogliz Prolong should be used with caution in the elderly.

Saxagliptin

No differences in safety or efficacy of the drug have been noted in patients ≥65 years old and younger patients. Although no differences in response to therapy have been established in elderly and younger patients, greater sensitivity in some elderly patients cannot be excluded.

Metformin

Controlled clinical trials of metformin have not included sufficient older patients to determine differences in response to therapy compared with younger patients, although clinical experience has not established differences in response in older and younger 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 impairment.

Combogliz Prolong should only be prescribed in 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 made after careful evaluation of renal function.

Children

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

Interaction

Metformin

. Some drugs increase hyperglycemia (thiazide and other diuretics, glucocorticosteroids, phenothiazines, iodine-containing thyroid hormone preparations, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, “slow” calcium channel blockers and isoniazid).

When such drugs are prescribed or withdrawn in a patient taking Combogliz Prolong, blood glucose concentrations should be carefully monitored. Metformin has low plasma protein binding, so it is unlikely to interact with drugs that bind significantly to plasma proteins, such as salicylates, sulfonamides, chloramphenicol and probenecid (unlike sulfonylurea derivatives, which do bind significantly to serum proteins).

CYP3A4/5 isoenzyme inducers

Saxagliptin

Rifampicin significantly reduces the exposure of saxagliptin without changing the AUC of its active metabolite, 5-hydroxy-saxagliptin. Rifampicin has no effect on plasma inhibition of DPP-4 during the 24-hour therapy interval.

CYP3A4/5 isoenzyme inhibitors

Saxagliptin

Diltiazem enhances the effect of saxagliptin when used together. Increased plasma concentrations of saxagliptin are expected with amprenavir, aprepitant, erythromycin, fluconazole, fosamprenavir, grapefruit juice and verapamil; however, the dose of saxagliptin should not be adjusted. Ketoconazole significantly increases the plasma concentration of saxagliptin. A similar significant increase in plasma concentrations of saxagliptin is expected when using other potent inhibitors of CYP3A4/5 enzymes (e.g., atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir and telithromycin). When co-administered with a potent CYP3A4/5 isoenzyme inhibitor, the dose of saxagliptin should be reduced to 2.5 mg.

Cationic drugs

Metformin

. Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterone, trimethoprim, or vancomycin) that are eliminated by the kidneys via glomerular filtration could theoretically interact with metformin by competing for common renal tubular transport systems. Drug interaction studies of metformin and cimetidine with single and repeated drug administration have observed metformin and cimetidine for oral administration in healthy volunteers, with a 60% increase in maximum metformin concentration in plasma and whole blood and a 40% increase in AUC of metformin in plasma and whole blood. No change in the elimination half-life was observed in the study with single drug administration. Metformin has no effect on the pharmacokinetic parameters of cimetidine. It is recommended that patients should be closely monitored and, if necessary, the dose should be adjusted in patients taking cationic drugs that are excreted through the proximal renal tubule system.

Glibenclamide

Metformin

In a single-dose interaction study in patients with DM2, co-administration of metformin and glibenclamide did not affect pharmacokinetic or pharmacodynamic parameters.

Furosemide

Metformin

The drug interaction study of metformin and furosemide with single drug administration conducted in healthy volunteers revealed their pharmacokinetic interaction. 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 co-administered with metformin, the Cmax and AUC of furosemide are decreased by 31% and 12%, respectively, and the elimination half-life is reduced by 32% without a significant change in renal clearance of furosemide. There are no data on the interaction of metformin and furosemide in long-term coadministration.

Nifedipine

Metformin

In a drug interaction study of metformin and nifedipine with a single dose of the drug conducted in healthy volunteers, nifedipine increased the Cmax of metformin in plasma by 20% and AUC by 9%, and increased renal excretion. Tmax and T1/2 were not altered. Nifedipine increases the absorption of metformin. Metformin has almost no effect on the pharmacokinetics of nifedipine.

Saxagliptin and metformin

The co-administration 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.

There have been no specific pharmacokinetic studies of drug interactions with Combogliz Prolong, although such studies have been performed with its individual components: saxagliptin and metformin.

Saxagliptin

The effect of other drugs on saxagliptin

Glibenclamide: Co-administration of saxagliptin (10 mg) and glibenclamide (5 mg), a substrate of the CYP2C9 isoenzyme, increased the Cmax of saxagliptin by 8%, but the AUC of saxagliptin was not changed.

Pioglitazone: Co-administration of saxagliptin once daily (10 mg) and pioglitazone (45 mg), a substrate of CYP2C8 (strong) and CYP3A4 (weak) isoenzymes, does not affect pharmacokinetic parameters of saxagliptin.

Digoxin: Co-administration of saxagliptin once daily (10 mg) and digoxin (0.25 mg), a substrate of P-glycoprotein, does not affect the pharmacokinetic parameters of saxagliptin.

Simvastatin: Co-administration of saxagliptin once daily (10 mg) and simvastatin (40 mg), a substrate of CYP3A4/5 isoenzymes, increased Cmax of saxagliptin by 21%, but AUC of saxagliptin is not changed.

Diltiazem: Co-administration of saxagliptin (10 mg) and diltiazem (360 mg sustained release form in equilibrium), a moderate inhibitor of CYP3A4/5 isoenzymes, increases Cmax of saxagliptin by 63% and 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: Co-administration of a single dose of saxagliptin (100 mg) and ketoconazole (200 mg every 12 hours in equilibrium), increases Cmax 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: Co-administration of a single dose of saxagliptin (5 mg) and rifampicin (600 mg once daily in equilibrium) decreases the Cmax and AUC of saxagliptin by 53% and 76%, respectively, with a corresponding increase in Cmax(39%) but no significant change in AUC of the active metabolite.

Omeprazole: Co-administration of saxagliptin 10 mg once daily and omeprazole 40 mg, a CYP2C19 (strong) and CYP3A4 (weak) isoenzyme substrate, CYP2C19 isoenzyme inhibitor and MRP-3 inducer, does not affect the pharmacokinetics of saxagliptin.

Aluminum hydroxide+magnesium hydroxide+simethicone: Co-administration of single doses of saxagliptin (10 mg) and suspension containing aluminum hydroxide (2400 mg), magnesium hydroxide (2400 mg) and simethicone (240 mg) decreases the Cmax of saxagliptin by 26%, but the AUC of saxagliptin is not changed.

Famotidine: Taking a single dose 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 the Cmax of saxagliptin by 14%, but the AUC of saxagliptin is not changed.

Special Instructions

Lactoacidosis

Lactoacidosis is a rare, serious metabolic complication that can develop as a result of metformin cumulation during therapy with Combogliz Prolong. When lactoacidosis develops due to metformin administration, its plasma concentration exceeds 5 mcg/ml.

In patients with diabetes mellitus, lactoacidosis more often develops in severe renal insufficiency, including those due to congenital renal disease and insufficient renal perfusion, especially when taking several drugs. In patients with heart failure, in particular, in patients with unstable angina pectoris or acute heart failure and risk of hypoperfusion and hypoxemia, there is an increased risk of lactoacidosis. The risk of lactocidosis increases in proportion to the degree of renal failure and the age of the patient. Regular monitoring of renal function should be performed in patients taking metformin, and the minimum effective dose of metformin should be prescribed. In elderly patients, renal function should be monitored. Metformin should not be administered to patients aged 80 years and older with impaired renal function (according to CK), as these patients are more prone to lactoacidosis. In addition, metformin therapy should be discontinued immediately in case of conditions accompanied by hypoxemia, dehydration or sepsis. Since hepatic impairment may significantly limit the ability to excrete lactate, metformin should not be administered to patients with clinical or laboratory signs of liver disease.

The onset of lactoacidosis is often silent and accompanied by nonspecific symptoms such as malaise, myalgia, respiratory depression, increased drowsiness, and abdominal pain and discomfort. Hypothermia, hypotension, and resistant bradyarrhythmia may be noted. The patient should immediately report all of these symptoms to the physician. If such symptoms are detected, metformin therapy should be stopped, serum electrolytes, ketone bodies, blood glucose, and if indicated, blood pH, lactate concentration, and metformin concentration in blood should be monitored. Gastrointestinal symptoms developing late in metformin therapy may be due to lactoacidosis or other disease.

A fasting plasma lactate concentration above the upper limit of normal but below 5 mmol/L in patients taking metformin may indicate the impending development of lactoacidosis and may also be due to other causes, such as uncompensated diabetes, obesity, and excessive exercise.

The presence of lactoacidosis should be checked in all patients with diabetes mellitus and metabolic acidosis without signs of ketoacidosis (ketonuria and ketonemia). Lactoacidosis requires treatment in a hospital setting. If lactoacidosis is detected in a patient taking metformin, the drug should be discontinued immediately and general supportive measures should be started without delay. Immediate dialysis is recommended to correct acidosis and excretion of cumulated metformin.

Alcohol is known to potentiate the effect of metformin on lactate metabolism, which increases the risk of lactoacidosis. Alcohol consumption should be limited while taking Combogliz Prolong.

Hepatic failure

Combogliz Prolong is not recommended for patients with clinical and laboratory signs of liver disease because of the risk of lactoacidosis.

Renal function evaluation

Renal function should be monitored before initiating therapy with Combogliz Prolong and at least annually thereafter. In patients with suspected renal function impairment, renal function should be assessed more frequently and therapy with Combogliz Prolong should be discontinued if there are signs of renal impairment.

Surgical procedures

The administration of Combogliz Prolong should be temporarily suspended before any surgical procedure (except minor procedures not involving restriction of food and fluids) and should not be resumed until the patient is able to take medication orally and normal renal function is confirmed.

Change in clinical status in patients with previously controlled DM2

In a patient with DM2 who was previously well controlled on therapy with Combogliz Prolong and who shows abnormal laboratory values or develops disease (especially if the diagnosis is unclear), the signs of ketoacidosis or lactoacidosis should be evaluated immediately. Evaluation should include determination of serum electrolytes, ketones, blood glucose, and, if indicated, blood pH, lactate, pyruvate, and metformin concentrations. If any form of acidosis develops, Combogliz Prolong should be stopped immediately and another hypoglycemic drug prescribed.

The use of drugs that may cause hypoglycemia

Saxagliptin

Drugs that stimulate insulin secretion, such as sulfonylurea derivatives, may cause the development of hypoglycemia. Therefore, to reduce the risk of hypoglycemia when combined with saxagliptin, it may be necessary to decrease the dose of the drug that increases insulin secretion.

Metformin

Hypoglycemia does not develop in patients taking metformin alone routinely, but may develop with inadequate carbohydrate intake when vigorous exercise is not compensated by carbohydrate intake, or with concomitant use with other hypoglycemic drugs (such as sulfonylurea derivatives and insulin) or alcohol. Elderly, weakened or malnourished patients and patients with adrenal or pituitary insufficiency or alcohol intoxication are most sensitive to hypoglycemic effects. In the elderly and patients taking beta-adrenoblockers, the diagnosis of hypoglycemia may be difficult.

Companion therapy affecting renal function or metformin distribution

Companion drugs (such as cationic drugs excreted by renal tubular secretion) that may affect renal function, result in significant hemodynamic changes or impair metformin distribution should be administered with caution (see See section “Interaction with other medicinal products”).

In radiological studies with intravascular administration of iodine-containing contrast agents

In radiological studies with intravascular administration of iodine-containing contrast agents, acute renal dysfunction has been identified that may be accompanied by the development of lactoacidosis in patients receiving metformin. Patients scheduled for this study should discontinue therapy with Combogliz Prolong 48 hours prior to this procedure, refrain from taking the drug for 48 hours after the procedure, and resume therapy only after confirmation of normal renal function.

Hypoxic conditions

Cardiovascular collapse (shock) of any origin, acute heart failure, acute myocardial infarction and other conditions accompanied by hypoxia and lactoacidosis may cause prerenal azotemia. If these phenomena develop, therapy with Combogliz Prolong should be stopped immediately.

Disorders of blood glucose concentration

Fever, injury, infection, surgical intervention may lead to abnormal blood glucose concentration, which was previously controlled by Combogliz Prolong. In these cases, temporary withdrawal of therapy and transfer of the patient to insulin therapy may be required. After blood glucose concentration stabilizes and general condition of the patient improves, treatment with Combogliz Prolong may be resumed.

Hypersensitivity reactions

Serious hypersensitivity reactions, including anaphylaxis and angioedema, have been reported during postmarketing use of saxagliptin. If a serious hypersensitivity reaction develops, the drug should be discontinued, other possible causes of the phenomenon should be assessed and an alternative therapy for diabetes mellitus should be prescribed (see sections “Contraindications” and “Side effects”).

Pancreatitis

In postmarketing use of saxagliptin, spontaneous reports of cases of acute pancreatitis have been received. Patients taking Combogliz Prolong should be informed about the characteristic symptoms of acute pancreatitis: prolonged, intense abdominal pain. If pancreatitis is suspected, discontinue the drug Combogliz Prolong (see sections “Caution” and “Side effects”).

Impact on the ability to drive vehicles and operate machinery

There have been no studies investigating the effect of saxagliptin on driving and operating machinery.

It should be noted that saxagliptin may cause headache.

Contraindications

Side effects

Monotherapy and adjunctive combination therapy

Saxagliptin

Table 1 presents adverse events reported in clinical trials (regardless of investigator assessment of causality) in ≥ 5% of patients receiving saxagliptin 5 mg.

Table 1. Adverse events

Number (%) of patientsSaxagliptin 5 mg (N=882)Placebo (N=799)Upper respiratory tract infections68 (7.7)61 (7.6)Urinary tract infections60 (6.8)49 (6.1)Headache57 (6.5)47 (5.9)

The 5 placebo-controlled studies include two monotherapy studies and one study each of combination therapy with the addition of metformin, thiazolidinedione, or glibenclamide. The table shows data from a 24-week study regardless of the use of an additional hypoglycemic drug.

In patients taking 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 frequently than in the placebo group.

. Adverse events noted 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 frequently than in the placebo group included sinusitis (2.9% and 2.6% versus 1.6%, respectively), abdominal pain (2.4% and 1.7% versus 0.5%), gastroenteritis (1.9% and 2.3% versus 0.9%), and vomiting (2.2% and 2.3% versus 1.3%).

The incidence of fracture development was 1.0 and 0.6 per 100 patient-years, respectively, with saxagliptin (combined analysis of 2.5 mg, 5 mg, and 10 mg doses) and placebo. The frequency of fractures in patients taking saxagliptin did not increase over time. No causal relationship has been established, and preclinical studies have shown no adverse effects of saxagliptin on bone tissue.

The development of thrombocytopenia consistent with the diagnosis of idiopathic thrombocytopenic purpura has been observed in a clinical program. The relationship of this phenomenon to saxagliptin administration is not known.

Indications associated with co-administration of saxagliptin and metformin in patients with previously untreated type 2 diabetes mellitus (T2DM)

Saxagliptin

. Table 2 presents adverse events noted (regardless of investigator assessment of causality) in ≥5% of patients participating in an additional 24-week, active-controlled trial of combined use of saxagliptin and metformin in patients who had not previously received therapy.

Table 2. Adverse events

Number (%) of patientsSaxagliptin 5 mg + metformin* (N=320)Metformin* (N=328)Headache24 (7.5)17(5.2)Nasopharyngitis22 (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, either as an adjunctive 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 groups, respectively, in the study of adding saxagliptin to metformin; the incidence of diarrhea was 6.9% and 7.3% in the saxagliptin 5 mg and metformin combination therapy group and metformin monotherapy group in the study of initially combined therapy with metformin.

Hypoglycemia

Saxagliptin

Hypoglycemia as an adverse event was collected based on reports of hypoglycemia; no concomitant 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 metformin was added. The incidence of hypoglycemia was 3.4% in previously untreated patients taking saxagliptin at a dose of 5 mg in combination with metformin and 4% in patients on metformin monotherapy.

Hypersensitivity reactions

Saxagliptin

. In an analysis of five pooled studies, hypersensitivity-related adverse events (such as urticaria and facial edema) were reported in 1.5%, 1.5%, and 0.4% of patients receiving saxagliptin 2.5 mg, saxagliptin 5 mg, and placebo, respectively. According to the researchers, none of these events in patients receiving saxagliptin required hospitalization and were not life-threatening. In this analysis of pooled data, one patient receiving saxagliptin was excluded from the study because of the development of generalized urticaria and facial edema.

Physiologic function parameters

Saxagliptin

Patients receiving saxagliptin as monotherapy or in combination with metformin showed no clinically significant changes in physiologic function parameters.

Monotherapy

Metformin

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

Postmarketing use

The following side effects have been reported during postmarketing use of saxagliptin: acute pancreatitis and hypersensitivity reactions, including anaphylaxis, angioneurotic edema, rash and urticaria. It is not possible to reliably estimate the incidence of these events, because reports have been received spontaneously, from a population of unspecified size (see sections “Contraindications” and “Special Indications”).

Laboratory studies

Limphocyte absolute number

Saxagliptin

A dose-dependent mean decrease in absolute lymphocyte number was observed with saxagliptin administration. In an analysis of pooled data from five 24-week, placebo-controlled studies, a mean reduction of approximately 100 and 120 cells/μL in absolute lymphocyte counts from an initial mean of 2,200 cells/μL was observed with saxagliptin at a dose of 5 mg and 10 mg, respectively, compared with placebo. A similar effect was observed with saxagliptin at a dose of 5 mg in initial combination with metformin compared to metformin monotherapy. No differences were found 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 2.5 mg, 5 mg, 10 mg, and placebo therapy groups, respectively. Most patients did not experience a relapse on repeated saxagliptin use, although some patients had repeatedly decreased lymphocyte counts on resumption of saxagliptin therapy, leading to saxagliptin withdrawal. The decrease in lymphocyte counts was not accompanied by clinical manifestations.

The reasons for the decrease in lymphocyte counts with saxagliptin therapy compared with placebo are unknown. Lymphocyte counts should be measured in cases of unusual or prolonged infection. The effect of saxagliptin on lymphocyte counts in patients with abnormal lymphocyte counts (e.g., human immunodeficiency virus) is unknown.

Platelets

Saxagliptin

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

Vitamin B12 concentrations

In controlled clinical trials of metformin lasting 29 weeks, approximately 7% of patients experienced a decrease in previously normal serum vitamin B12 concentrations to subnormal values without clinical manifestations. However, this decrease is very rarely accompanied by the development of anemia and quickly recovers after discontinuation of metformin or additional vitamin B12 supplementation.

Overdose

Saxagliptin

In long-term administration of the drug in doses up to 80 times higher than recommended, no intoxication symptoms have been described.

In case of overdose symptomatic therapy should be used. Saxagliptin and its main metabolite are excreted from the body by hemodialysis (excretion rate: 23% of the dose in 4 hours).

Metformin

There have been recorded cases of metformin overdose, including administration of more than 50 g. Approximately 10% of cases developed hypoglycemia, but its causal relationship to metformin has not been established. In 32% of cases of metformin overdose patients had lactoacidosis. Metformin is excreted by dialysis, with a clearance of up to 170 ml/min.

Pregnancy use

Because the use of Combogliptin Prolong in pregnancy has not been studied, the drug should not be prescribed during pregnancy.

It is not known whether saxagliptin or metformin passes into the breast milk. Since it is possible that Combogliz Prolong may penetrate into breast milk, the use of the drug during lactation is contraindicated.