Kombogliza XR film-coated tablets 5 mg + 1000 mg blister No. 28

Instructions for Kombogliza XR film-coated tablets 5 mg + 1000 mg blister No. 28

Composition

active ingredients: saxagliptin, metformin;

1 film-coated tablet contains 2.79 mg of saxagliptin hydrochloride anhydrous equivalent to 2.5 mg saxagliptin and 1005 mg metformin hydrochloride equivalent to 1000 mg metformin

or 5.58 mg of saxagliptin hydrochloride anhydrous equivalent to 5 mg saxagliptin and 502.5 mg of metformin hydrochloride equivalent to 500 mg metformin;

or 5.58 mg of saxagliptin hydrochloride anhydrous equivalent to 5 mg saxagliptin and 1005 mg of metformin hydrochloride equivalent to 1000 mg metformin;

excipients: carmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose (for 5 mg/500 mg);

dyes for 2.5 mg/1000 mg: Opadry II white, Opadry II yellow, Opacode blue (for inscription);

dyes for 5 mg/500 mg: Opadry II white, Opadry II light brown, Opacode blue (for inscription);

dyes for 5 mg/1000 mg: Opadry II white, Opadry II pink, Opacode blue (for inscription).

Dosage form

Film-coated tablets.

Main physicochemical properties:

2.5 mg/1000 mg tablets: biconvex, capsule-shaped, film-coated tablets; pale yellow to light yellow in color with 2.5/1000 on one side and 4222 on the other side, printed in blue ink;

5 mg/500 mg tablets: biconvex, capsule-shaped, film-coated tablets; light brown to brown in colour with 5/500 on one side and 4221 on the other side in blue ink;

5 mg/1000 mg tablets: biconvex, capsule-shaped, film-coated tablets; pink in colour with 5/1000 on one side and 4223 on the other side in blue ink.

Pharmacotherapeutic group

Combined oral hypoglycemic drugs. Metformin and saxagliptin. ATX code A10BD10.

Pharmacological properties

Pharmacodynamics.

Saxagliptin

In patients with type 2 diabetes, saxagliptin inhibits the activity of the enzyme dipeptidyl peptidase 4 (DPP-4) for 24 hours. Following an oral glucose load or meal, inhibition of DPP-4 resulted in a 2- to 3-fold increase in circulating levels of active glucagon-like peptide-1 (GLP-1) and GIP, decreased glucagon levels, and increased glucose-dependent insulin secretion from pancreatic beta cells. The increased insulin levels and decreased glucagon levels were associated with lower fasting glucose concentrations and reduced glucose concentrations after an oral glucose load or meal.

Treatment with saxagliptin 5 mg and metformin extended-release once daily in the evening with meals for 4 weeks significantly reduced total glucose concentrations over the 24-hour interdose interval compared with placebo plus metformin extended-release.

There was a significant decrease in 2-hour postprandial glucose concentration and 2-day mean fasting glucose.

Cardiac electrophysiology

Saxagliptin

Saxagliptin was not associated with clinically significant prolongation of the QTc interval or increases in heart rate at daily doses up to 40 mg (8 times the maximum recommended human dose).

Pharmacokinetics.

KOMBOGLYZA XR is bioequivalent to concomitant administration of appropriate doses of saxagliptin (Onglyza) and metformin hydrochloride as separate tablets.

Saxagliptin

The pharmacokinetics of saxagliptin and its active metabolite 5-hydroxy saxagliptin were similar in healthy volunteers and patients with type 2 diabetes.

There was no detectable accumulation of either saxagliptin or its active metabolite with repeated once-daily dosing of any dose. The clearance of saxagliptin and its active metabolite was independent of dose and time of administration over 14 days of once-daily dosing with saxagliptin at doses ranging from 2.5 to 400 mg.

Metformin hydrochloride

The median time to reach Cmax of metformin extended-release is 7 hours. The extent of absorption of metformin extended-release tablets is increased by almost 50% when taken with food.

After repeated administration of metformin extended-release, metformin does not accumulate in the blood plasma. Metformin is excreted unchanged in the urine and is not metabolized in the liver.

Absorption

Saxagliptin

The median time to maximum concentration (Tmax) after a 5 mg dose once daily was 2 hours for saxagliptin and 4 hours for its active metabolite. Saxagliptin can be taken with or without food.

Metformin hydrochloride

The extent of metformin absorption (measured by AUC) from metformin extended-release tablets is increased by approximately 50% when administered with food. No effect of food on metformin Cmax or Tmax was observed. Both high- and low-fat meals have similar effects on the pharmacokinetics of metformin extended-release.

Distribution

Saxagliptin

The binding of saxagliptin and its active metabolite to serum proteins in vitro is negligible, therefore changes in blood protein levels in various diseases (e.g., renal or hepatic impairment) should not affect the distribution of saxagliptin.

Metformin hydrochloride

Distribution studies with sustained-release metformin have not been performed. Metformin is poorly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. Metformin penetrates into erythrocytes and this process is likely to increase with time.

Metabolism

Saxagliptin

The metabolism of saxagliptin is mediated primarily by cytochrome P450 3A4/5 (CYP3A4/5). The major metabolite of saxagliptin is also a DPP-4 inhibitor with approximately half the potency of saxagliptin. Therefore, potent inhibitors and inducers of CYP3A4/5 will affect the pharmacokinetics of saxagliptin and its active metabolite.

Metformin hydrochloride

Metabolism studies using metformin extended-release tablets have not been conducted.

Breeding

Saxagliptin

Saxagliptin is eliminated by both the kidneys and the liver. Following a single oral dose of 5 mg saxagliptin to healthy volunteers, the mean terminal plasma half-lives (t1/2) of saxagliptin and its active metabolite were 2.5 and 3.1 hours, respectively.

Metformin hydrochloride

The main route of elimination of metformin is tubular secretion. After oral administration, approximately 90% of the absorbed drug is excreted by the kidneys within the first 24 hours, with a plasma half-life of approximately 6.2 hours. The blood half-life is approximately 17.6 hours.

Certain patient groups

Kidney dysfunction

KOMBOGLYZE XR should not be used in patients with renal impairment.

Saxagliptin

Dose adjustment is not recommended for patients with mild renal impairment.

Metformin hydrochloride

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

Liver dysfunction

Saxagliptin

No dose adjustment is recommended for patients with impaired liver function.

Metformin hydrochloride

Studies of the pharmacokinetics of metformin in patients with hepatic impairment have not been conducted.

Because hepatic dysfunction has been associated with several cases of lactic acidosis, KOMBOGLYZE XR should be avoided in patients with clinical or laboratory evidence of liver disease.

Body mass index

Saxagliptin

Dose adjustment based on body mass index is not recommended.

Sex

Saxagliptin

It is not recommended to adjust the dose based on gender.

Metformin hydrochloride

In studies involving patients with type 2 diabetes, the hypoglycemic effect of metformin was comparable in women and men.

Elderly patients

Saxagliptin

It is not recommended to adjust the dose based on age alone.

Metformin hydrochloride

KOMBOGLYZE XR should not be administered to patients over 80 years of age unless creatinine clearance analysis confirms the absence of renal impairment.

Pediatric patients

Saxagliptin

Studies of the pharmacokinetics of saxagliptin in pediatric patients have not been conducted.

Metformin hydrochloride

After a single oral dose of metformin 500 mg (as tablets) with food, the geometric mean Cmax and AUC of metformin differed by less than 5% in children (12–16 years) with type 2 diabetes and healthy adults (20–45 years) matched for gender and body weight. Renal function was normal in all patient groups.

Race and ethnicity

Saxagliptin

Dose adjustment based on race is not recommended.

Metformin hydrochloride

Studies of metformin pharmacokinetics based on race have not been conducted.

Indication

KOMBOGLYZE XR is indicated as an adjunct to diet and exercise to improve glycemic control in adult patients with type 2 diabetes mellitus when treatment with saxagliptin and metformin is appropriate.

Contraindication

KOMBOGLYZE XR is contraindicated in patients with severe renal impairment (eGFR below 30 mL/min/1.73 m2).

KOMBOGLYZE XR is not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis due to lack of efficacy in these conditions.

This medicinal product should not be used in patients with known hypersensitivity to saxagliptin or metformin hydrochloride. History of a serious hypersensitivity reaction, such as anaphylaxis, anaphylactic shock, anaphylactic reaction, angioedema, or exfoliative skin disease, to any dipeptidyl peptidase-4 (DPP-4) inhibitor.

Acute or chronic metabolic acidosis, including lactic acidosis, diabetic ketoacidosis with or without coma.

Diabetic precoma.

Insulin should be used in diabetic ketoacidosis.

Acute conditions that can affect kidney function, such as:

dehydration,

severe infection,

shock.

Acute or chronic disease that can lead to tissue hypoxia, such as:

heart or lung failure,

recent myocardial infarction,

shock,

liver dysfunction,

acute alcohol intoxication, alcoholism,

breastfeeding period.

KOMBOGLYZA XR should be temporarily discontinued in patients undergoing radiological examinations involving intravascular injection of iodinated contrast agents, as the use of such agents may result in acute deterioration of renal function.

Interaction with other medicinal products and other types of interactions

No specific pharmacokinetic drug interaction studies have been conducted with KOMBOGLYZA XR, although similar studies have been conducted with saxagliptin and metformin alone.

Drug interactions were studied regarding the effectiveness of glucose-lowering activity:

Concomitant use of saxagliptin with metformin extended-release in patients with type 2 diabetes. Adding saxagliptin to metformin.

Combination therapy with saxagliptin with extended-release metformin and glipizide.

Combination therapy with saxagliptin with metformin and a sulfonylurea.

Combination therapy with saxagliptin in combination with insulin (with or without immediate-release metformin).

Saxagliptin as combination therapy with metformin and an SGLT2 inhibitor.

In vitro drug-drug interaction analysis

In in vitro studies, saxagliptin and its active metabolite did not inhibit CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4, and did not induce CYP1A2, 2B6, 2C9, or 3A4. Therefore, saxagliptin is not expected to affect the metabolic clearance of concomitantly administered medicinal products that are metabolized by these enzymes. Saxagliptin is a substrate of P-glycoprotein (P-gp) but is not a significant inhibitor or inducer of P-glycoprotein.

In vivo drug interaction assessment

Table 1

Effect of co-administered medicinal products on the systemic exposure of saxagliptin and its active metabolite (5-hydroxysaxagliptin)

* Single dose unless otherwise stated. Saxagliptin 10 mg is not an approved dosage.

† AUC = AUC(INF) for single-dose drugs and AUC = AUC(TAU) for multiple-dose drugs.

‡ Results exclude data from one patient.

§ Rifampin had no effect on the inhibition of plasma dipeptidyl peptidase-4 (DPP-4) activity over a 24-hour dosing interval.

NB – not determined; QD – once daily; BID – twice daily; LA – long-acting.

Table 2

Effect of saxagliptin on the systemic exposure of co-administered medicinal products

* Single dose unless otherwise stated. Saxagliptin 10 mg is not an approved dosage.

† AUC = AUC(INF) for single-dose drugs and AUC = AUC(TAU) for multiple-dose drugs.

‡ Results include data from all patients.

NB – not determined; QD – once daily; BID – twice daily; LA – long-acting.

Table 3

Effect of co-administered medicinal products on plasma systemic exposure of metformin

* Metformin and concomitant medications were taken once.

† AUC = AUC(INF)

‡ Ratio of arithmetic mean values

Table 4

Effect of metformin on systemic exposure of co-administered medicinal products

* Metformin and concomitant medications were taken once.

† AUC = AUC(INF) unless otherwise noted.

‡ Ratio of arithmetic means, p-value of difference <0.05.

§ AUC(0-24h) is reported.

¶ Ratio of arithmetic mean values.

Potent inhibitors of CYP3A4/5 enzymes

Ketoconazole significantly increased saxagliptin exposure. Similar significant increases in plasma concentrations of saxagliptin are expected with other potent CYP3A4/5 inhibitors (such as atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin). When co-administered with a potent CYP3A4/5 inhibitor, the dose of saxagliptin should not exceed 2.5 mg (see sections 4.2 and 5.2).

Carbonic anhydrase inhibitors

Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide, or dichlorphenamide) frequently cause decreases in serum bicarbonate levels and induce a low anion gap, hypochloremic metabolic acidosis. Concomitant use of these drugs with KOMBIGLYZE XR may increase the risk of lactic acidosis.

Drugs that reduce metformin clearance

Concomitant use of medicinal products that are eliminated by renal tubular secretion involved in the renal elimination of metformin (e.g. organic cation transporter-2 [OCT-2]/multiple drug and toxin extrusion [MAT] inhibitors such as ranolazine, vandetanib, dolutegravir and cimetidine) may lead to increased systemic exposure to metformin and an increased risk of lactic acidosis (see section 5.2). The benefits and risks of concomitant use of these medicinal products should be carefully weighed.

Alcohol

The increased risk of lactic acidosis during alcohol intoxication, especially in the presence of fasting, malnutrition, or impaired liver function, is associated with the presence of metformin in KOMBOGLYZA XR. Alcohol and medications containing alcohol should be avoided.

Use of iodine-containing contrast agents

Intravascular administration of iodinated contrast agents may cause contrast-induced nephropathy, leading to metformin accumulation and an increased risk of lactic acidosis. KOMBOGLYZA XR should be discontinued prior to or at the time of the imaging procedure and not resumed until 48 hours after the procedure, only after re-evaluation and stable renal function.

Insulin secretagogues or insulin

In studies of saxagliptin, hypoglycemia was more common when insulin secretagogues such as sulfonylureas were added compared to placebo. Therefore, when insulin secretagogues (e.g., sulfonylureas) or insulin are used, a reduction in the dose of the insulin secretagogue or insulin may be necessary to minimize the risk of hypoglycemia.

Use of other medicines

Certain medications may predispose to hyperglycemia and may contribute to loss of blood glucose control. These medications include thiazides and other diuretics, corticosteroids, phenothiazines, thyroid hormone preparations, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid. If such medications are prescribed to a patient taking KOMBOGLYZE XR, the patient should be observed closely for signs of loss of glycemic control. If such medications are discontinued in a patient taking KOMBOGLYZE XR, the patient should be observed closely for symptoms of hypoglycemia.

Some medicinal products may have an adverse effect on renal function, which may increase the risk of lactic acidosis, such as NSAIDs, including selective cyclooxygenase (COX) II inhibitors, ACE inhibitors, angiotensin II receptor antagonists and diuretics, especially loop diuretics. Careful monitoring of renal function is necessary at the beginning and during the use of such medicinal products in combination with metformin.

Application features

Lactic acidosis

Lactic acidosis is a very rare but serious metabolic complication, most often occurring in patients with acute renal failure or cardiorespiratory disease or sepsis. Metformin accumulation occurs in acute renal failure with an increased risk of lactic acidosis.

In the post-marketing period, there have been cases of metformin-associated lactic acidosis, including fatal cases. These cases were characterized by an insidious onset and were accompanied by nonspecific symptoms such as malaise, myalgia, abdominal pain, respiratory distress or increased drowsiness; however, hypothermia, hypotension and resistant bradyarrhythmia were observed only in cases of severe acidosis.

Drugs that can rapidly impair renal function (such as antihypertensives, diuretics, and NSAIDs) should be initiated with caution in patients treated with metformin. Other risk factors for lactic acidosis include excessive alcohol consumption, hepatic impairment, poorly controlled diabetes, ketosis, prolonged fasting, and any condition associated with hypoxia, as well as concomitant use of drugs that can induce lactic acidosis.

Metformin-associated lactic acidosis is characterized by elevated blood lactate concentrations (> 5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate/pyruvate ratio, as well as elevated plasma metformin levels, usually > 5 μg/mL. Metformin reduces hepatic lactate uptake, resulting in elevated blood lactate levels, increasing the risk of lactic acidosis, especially in patients at risk.

If metformin-associated lactic acidosis is suspected, general supportive measures should be immediately instituted in a hospital setting and KOMBOGLYZE XR should be discontinued immediately.

Patients taking KOMBOGLYZE XR with diagnosed or reasonably suspected lactic acidosis are recommended to undergo immediate hemodialysis to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable with a clearance of up to 170 mL/minute under satisfactory hemodynamic conditions). Hemodialysis often provides resolution of symptoms and recovery.

Patients and their families should be warned about the symptoms of lactic acidosis and the need to stop taking KOMBOGLYZE XR and consult a doctor if these symptoms occur.

Patients and/or caregivers should be informed of the risk of lactic acidosis. Lactic acidosis is characterized by acidotic dyspnea, abdominal pain, muscle spasms, asthenia, and hypothermia, progressing to coma. If these symptoms are suspected, KOMBOGLYZA XR should be discontinued and medical attention should be sought immediately. Laboratory findings: decreased blood pH (< 7.35), increased plasma lactate concentration above 5 mmol/L, and increased anion gap and lactate/pyruvate ratio.

The following are recommendations for reducing the risk and treating metformin-associated lactic acidosis for each of the known and possible risk factors.

Renal impairment. In the post-marketing period, cases of metformin-associated lactic acidosis have been observed mainly in patients with significant renal impairment. The risk of metformin accumulation and the development of metformin-associated lactic acidosis increases with increasing severity of renal impairment, since metformin is excreted primarily by the kidneys. The following clinical recommendations are given depending on the patient's renal function (see section "Pharmacokinetics").

Before initiating treatment with KOMBOGLYZA XR, determine the estimated glomerular filtration rate (eGFR).

KOMBOGLYZE XR is contraindicated in patients with eGFR <30 mL/min/1.73 m2.

Initiation of KOMBOGLYZA XR in patients with eGFR 30 to 45 mL/min/1.73 m2 is not recommended.

All patients taking KOMBOGLYZE XR should have their eGFR assessed at least annually. In patients at increased risk of developing renal impairment (e.g., elderly patients), renal function should be assessed more frequently.

For patients taking KOMBOGLYZA XR whose eGFR is below 45 mL/min/1.73 m2, the benefits and risks of continuing therapy should be assessed.

Interactions with other medicinal products. Concomitant use of KOMBOGLYZA XR with certain other medicinal products may increase the risk of metformin-associated lactic acidosis; this applies to medicinal products that impair renal function, cause significant changes in blood circulation, affect acid-base balance or increase metformin accumulation (see section 4.5). Therefore, such patients require more frequent monitoring.

Radiographic studies with contrast. Studies with intravascular administration of iodinated contrast agents may result in acute deterioration of renal function and have been associated with lactic acidosis in patients receiving metformin. KOMBOGLYZA XR should be temporarily discontinued during or prior to imaging procedures using iodinated contrast agents in patients with eGFR 30 to 60 mL/min/1.73 m2, liver disease, alcoholism, or a history of heart failure, and in patients who will receive iodinated contrast agents intraarterially. Dose should not be restarted until renal function has been re-evaluated 48 hours after the imaging procedure and renal function has been confirmed to be stable.

Surgery and other procedures. Withholding food and fluids during surgery or other procedures may increase the risk of dehydration, hypotension, and renal impairment. KOMBOGLYZE XR should be temporarily withheld while the patient is on a restricted diet.

Hypoxic conditions. In the post-marketing period, there have been several cases of metformin-associated lactic acidosis in the setting of acute congestive heart failure (accompanied, among other things, by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia are accompanied by the development of lactic acidosis and may also cause prerenal azotemia. In such cases, treatment with KOMBIGLYZE XR should be discontinued.

Alcohol abuse: Alcohol enhances the effects of metformin on lactate metabolism, which may increase the risk of metformin-associated lactic acidosis. Patients should be advised not to abuse alcohol while taking KOMBIGLYZE XR.

Hepatic impairment: Metformin-associated lactic acidosis has been reported in patients with hepatic impairment. This may be due to impaired lactate clearance, resulting in elevated blood lactate levels. Therefore, KOMBIGLYZE XR should be avoided in patients with clinical or laboratory evidence of liver disease.

Acute pancreatitis

Acute pancreatitis has been reported in post-marketing experience. Patients should be advised of the characteristic symptoms of acute pancreatitis, including persistent, severe abdominal pain. If pancreatitis is suspected, the drug should be discontinued; if acute pancreatitis is confirmed, the drug should not be restarted. Caution should be exercised when treating patients with a history of pancreatitis. Acute pancreatitis has been spontaneously reported in the post-marketing setting with saxagliptin. Patients should be monitored for signs and symptoms of pancreatitis after initiation of KOMBOGLYZA XR therapy.

Heart failure

In the SAVOR trial, the incidence of hospitalization for heart failure was higher in patients treated with saxagliptin than in those treated with placebo, although a causal relationship was not established. Patients with a history of heart failure and patients with renal impairment were at higher risk of hospitalization for heart failure regardless of treatment.

The risks and benefits of KOMBOGLYZE XR treatment in patients at increased risk of heart failure should be carefully weighed. During therapy, the patient should be monitored for signs and symptoms of heart failure. Patients should be made aware of the typical symptoms of heart failure and advised to report such symptoms promptly. If heart failure develops, evaluation and treatment according to current standards should be considered; discontinuation of KOMBOGLYZE XR should be considered.