Kutern (Tablets) Instructions for Use

Marketing Authorization Holder

AstraZeneca AB (Sweden)

Manufactured By

AstraZeneca Pharmaceuticals LP (USA)

Labeled By

ASTRAZENECA, AB (Sweden)

ATC Code

A10BD21 (Saxagliptin and dapagliflozin)

Active Substances

Saxagliptin (Rec.INN registered by WHO)

Dapagliflozin (Rec.INN registered by WHO)

Dosage Form

Kutern

Film-coated tablets, 10 mg+5 mg: 30 pcs.

Dosage Form, Packaging, and Composition

Modified-release film-coated tablets from light brown to brown in color, round, biconvex, with the inscriptions “5/10” on one side and “1122” on the other side.

Film coating composition Opadry^® II yellowish-brown³ – 7 mg, hydrochloric acid 1M solution q.s., sodium hydroxide q.s., purified water q.s.; printing ink – Opacode^® blue ink⁴ q.s.

10 pcs. – blisters made of aluminum foil (3) – cardboard packs with first-opening control.

_{¹ Opadry^® II white contains polyvinyl alcohol (40%) (E1203), titanium dioxide (25%) (E171), macrogol/PEG (20.2%) (E1521), talc (14.8%) (E553b).
² The tablet contains Saxagliptin in the form of saxagliptin hydrochloride in an amount of 5.95 mg.
³ Opadry^® II yellowish-brown contains polyvinyl alcohol (40%) (E1203), titanium dioxide (19.6%) (E171), macrogol/PEG (20.2%) (E1521), talc (14.8%) (E553b), yellow iron oxide (5%) (E172), red iron oxide (0.42%) (E172).
⁴ Opacode^® blue printing ink contains shellac 45% in ethanol 55.4% (w/w), FD&C blue No.2/indigo carmine aluminum lake 16% (w/w) (E132), ammonium hydroxide 0.1% (28%, E527). A mixture of isopropyl alcohol 3%, n-butyl alcohol 15% and propylene glycol 10.5% (E1520) is used as the ink base; the specified solvents are removed during the drying process.}

Clinical-Pharmacological Group

Hypoglycemic agent for oral administration (sodium-glucose cotransporter 2 inhibitor + biguanide)

Pharmacotherapeutic Group

Oral hypoglycemic agent (sodium-glucose cotransporter 2 inhibitor + biguanide)

Pharmacological Action

Combined hypoglycemic agent.

Dapagliflozin is a potent, selective, and reversible inhibitor of SGLT2. SGLT2 is expressed in the proximal renal tubules and is responsible for the reabsorption of glucose from the glomerular filtrate back into the bloodstream. By inhibiting SGLT2, dapagliflozin reduces glucose reabsorption and lowers the renal threshold for glucose, thereby enhancing its excretion by the kidneys. As a result, the concentration of glucose in the blood plasma on an empty stomach and after a meal is reduced. Dapagliflozin does not impair the normal production of endogenous glucose in response to hypoglycemia. Renal glucose excretion induced by dapagliflozin is accompanied by calorie loss and a reduction in body weight, mainly due to a decrease in adipose tissue mass, including visceral fat.

Saxagliptin is a potent, selective, reversible, competitive inhibitor of the DPP-4 enzyme, which is responsible for the breakdown of incretin hormones. When blood glucose concentration increases, the incretin hormones, glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide, enhance insulin synthesis and its release from pancreatic beta cells. Glucagon-like peptide-1 also reduces glucagon secretion by pancreatic alpha cells, leading to decreased glucose production in the liver. By increasing and prolonging the concentration of active incretins, Saxagliptin increases insulin release and reduces glucagon concentration in the bloodstream, thereby reducing fasting and postprandial glucose concentrations in patients with type 2 diabetes.

Pharmacokinetics

Dapagliflozin

After oral administration, dapagliflozin is rapidly and completely absorbed and can be taken regardless of food intake. C_max is usually reached within 2 hours after administration on an empty stomach. C_max and AUC values increase proportionally to the dapagliflozin dose. The absolute bioavailability of dapagliflozin after oral administration of a 10 mg dose was 78%. The drug is approximately 91% bound to proteins. This indicator does not change in various diseases (e.g., renal or hepatic impairment). Dapagliflozin is metabolized to form mainly the inactive metabolite dapagliflozin-3-O-glucuronide. After oral administration of 50 mg of ¹⁴C-dapagliflozin, 61% of the administered dose was metabolized to dapagliflozin-3-O-glucuronide, which accounted for 42% of the total plasma radioactivity (by AUC_{0-12 h}), while unchanged dapagliflozin accounted for 39% of the total plasma radioactivity. Dapagliflozin-3-O-glucuronide or other metabolites do not have a hypoglycemic effect. Dapagliflozin-3-O-glucuronide is formed under the action of the enzyme uridine-5′-diphospho-glucuronosyltransferase 1A9 (UGT1A9), present in the liver and kidneys, and cytochrome P450 (CYP) isoenzymes are involved in metabolism in humans to a lesser extent. Dapagliflozin and its metabolites are excreted primarily by the kidneys, and less than 2% is excreted unchanged. After administration of 50 mg of ¹⁴C-dapagliflozin, 96% of the radioactivity was found: 75% in urine and 21% in feces. Approximately 15% of the radioactivity found in feces was attributed to unchanged dapagliflozin.

Saxagliptin

Saxagliptin is rapidly absorbed after oral administration on an empty stomach, with C_max of saxagliptin and its major metabolite reached within 2 and 4 hours (T_max), respectively. With increasing saxagliptin dose, a proportional increase in C_max and AUC values of saxagliptin and its major metabolite is observed; dose-dependency was observed up to a dose of 400 mg. After a single oral dose of 5 mg saxagliptin in healthy volunteers, the mean plasma AUC values for saxagliptin and its major metabolite were 78 ngh/mL and 214 ngh/mL, and the plasma C_max values were 24 ng/mL and 47 ng/mL, respectively. The intra-individual variability coefficients for C_max and AUC of saxagliptin were less than 12%. After oral administration, at least 75% of the saxagliptin dose is absorbed. The binding of saxagliptin and its major metabolite to plasma proteins in vitro was below the detection limit, so it can be assumed that changes in blood protein composition in various diseases (e.g., renal or hepatic impairment) will not affect the distribution of saxagliptin. Drug metabolism occurs mainly under the action of the CYP3A4/5 isoenzyme. The major metabolite of saxagliptin, 5-hydroxysaxagliptin, is also a selective, reversible, competitive inhibitor of DPP-4, whose action against DPP-4 is 2 times weaker than that of saxagliptin. It is excreted by the kidneys and liver. After a single dose of 50 mg of ¹⁴C-saxagliptin, 24% of the dose was excreted by the kidneys as saxagliptin and 36% as the major metabolite. The total radioactivity found in urine corresponded to 75% of the administered saxagliptin dose. The mean renal clearance of saxagliptin (approximately 230 mL/min) was higher than the mean estimated GFR (approximately 120 mL/min), indicating active renal excretion. About 22% of the total radioactivity was found in feces.

Indications

Type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycemic control in adult patients with inadequate glycemic control on dapagliflozin therapy or in patients who were already receiving a combination of dapagliflozin and saxagliptin as monocomponent preparations.

ICD codes

Dosage Regimen

Administer orally as one 10 mg+5 mg tablet once daily.

Take the tablet at any time of day, with or without food.

Swallow the tablet whole; do not split, crush, or chew.

This fixed-dose combination is indicated for patients inadequately controlled on dapagliflozin monotherapy or already stabilized on the individual components.

Assess renal function before initiation. Do not initiate if eGFR is below 60 mL/min/1.73 m².

Monitor renal function periodically during therapy. Discontinue if eGFR falls persistently below 60 mL/min/1.73 m².

When used concomitantly with insulin or a sulfonylurea, a dose reduction of the insulin or sulfonylurea may be required to mitigate the risk of hypoglycemia.

Ensure adequate fluid intake to reduce the risk of volume depletion and urinary tract infections.

Do not use in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.

Adverse Reactions

Infectious and parasitic diseases: very common – upper respiratory tract infection; common – urinary tract infection, vulvovaginitis, balanitis and other genital infections, gastroenteritis; uncommon – fungal infection.

Immune system disorders uncommon – hypersensitivity reactions; rare – anaphylactic reactions, including anaphylactic shock.

Metabolism and nutrition disorders : very common – hypoglycemia (when used in combination with sulfonylurea derivatives); common – dyslipidemia; uncommon – decreased blood volume, thirst; rare – diabetic ketoacidosis.

Nervous system disorders common – headache, dizziness.

Gastrointestinal disorders common – abdominal pain, diarrhea, dyspepsia, gastritis, nausea, vomiting; uncommon – constipation, dry mouth, pancreatitis.

Renal and urinary disorders common – dysuria, polyuria; uncommon – nocturia, renal impairment.

Skin and subcutaneous tissue disorders common – skin rash; uncommon – dermatitis, pruritus, urticaria; rare – angioedema.

Musculoskeletal and connective tissue disorders: common – arthralgia, back pain, myalgia.

Reproductive system and breast disorders uncommon – erectile dysfunction, genital itching, vulvovaginal itching.

General disorders and administration site conditions: common – increased fatigue, peripheral edema.

Investigations common – decreased creatinine renal clearance, increased hematocrit value; uncommon – increased blood creatinine concentration, increased blood urea concentration, decreased body weight.

Contraindications

Serious hypersensitivity reaction, including anaphylactic reaction, anaphylactic shock and angioedema, to DPP-4 inhibitors; type 1 diabetes mellitus; diabetic ketoacidosis; severe hepatic impairment; moderate and severe renal impairment (eGFR<60 mL/min/1.73 m² or CrCl<60 mL/min), end-stage renal disease; patients taking “loop” diuretics, or with reduced circulating blood volume, for example, due to acute illnesses (such as gastrointestinal diseases); elderly patients aged 75 years and older; pregnancy and breastfeeding period; age under 18 years.

With caution

Urinary tract infections; risk of decreased blood volume; in elderly patients (aged > 65 years and less than 75 years); chronic heart failure; elevated hematocrit value; history of pancreatitis; in patients with a history of cardiovascular disease; receiving antihypertensive therapy or with a history of hypotension episodes; in patients with moderate hepatic impairment.

Use in Pregnancy and Lactation

Use is contraindicated during pregnancy and breastfeeding.

Use in Hepatic Impairment

Use is contraindicated in severe hepatic impairment.

Use in Renal Impairment

Use is contraindicated in moderate and severe renal impairment (eGFR<60 mL/min/1.73 m² or CrCl<60 mL/min), end-stage renal disease.

Pediatric Use

Use is contraindicated in children under 18 years of age.

Geriatric Use

Use is contraindicated in elderly patients aged 75 years and older.

Special Precautions

The efficacy of dapagliflozin depends on renal function. The efficacy of the drug is reduced in patients with moderate renal impairment and is likely absent in patients with severe renal impairment. If renal function decreases below CrCl<60 mL/min or eGFR<60 mL/min/1.73 m², it is necessary to discontinue the use of this combination.

When taking the drug, careful monitoring of blood volume status (e.g., physical examination, blood pressure measurement, laboratory tests, including hematocrit) and electrolyte concentrations is recommended against the background of concomitant conditions that may lead to a decrease in blood volume.

Patients with signs and symptoms suggestive of ketoacidosis, including nausea, vomiting, abdominal pain, malaise, and shortness of breath, should be tested for ketoacidosis, even if blood glucose concentration is below 14 mmol/L (250 mg/dL). If ketoacidosis is suspected, consideration should be given to discontinuing or temporarily stopping the use of this combination and the patient should be examined immediately.

Saxagliptin and dapagliflozin individually may increase the risk of hypoglycemia when used in combination with insulin or an insulin secretagogue. To reduce the risk of hypoglycemia, a reduction in the dose of insulin or the insulin secretagogue may be required when used concomitantly.

Therapy with SGLT2 inhibitors increases the risk of urinary tract infections. Patients should be monitored for possible signs and symptoms of urinary tract infections and, if indicated, treatment should be initiated promptly.

If a serious hypersensitivity reaction occurs, the use of this combination should be discontinued, other possible causes of the event should be assessed, and alternative therapy for diabetes should be prescribed.

Spontaneous reports of acute pancreatitis have been received during post-marketing use of saxagliptin. Patients should be informed of the characteristic symptom of acute pancreatitis.

Since renal impairment is more common in elderly patients, caution should be exercised when prescribing this combination to this category of patients depending on renal function.

Caution should be exercised when using saxagliptin in patients with risk factors for hospitalization for heart failure, such as a history of heart failure or moderate and severe renal impairment. Patients should be informed about the characteristic symptoms of heart failure and the need to report such symptoms immediately.

If severe joint pain develops, the advisability of continuing saxagliptin should be assessed on a case-by-case basis.

An increase in hematocrit has been observed with the use of dapagliflozin, therefore caution should be exercised in patients with elevated hematocrit.

Effect on ability to drive vehicles and operate machinery

Given the reported cases of dizziness while taking this combination, caution should be exercised when driving vehicles or operating machinery, or when performing work that requires concentration and speed of psychomotor reactions.

Drug Interactions

Dapagliflozin may enhance the diuretic effect of thiazide and “loop” diuretics and increase the risk of dehydration and arterial hypotension.

When used with drugs that increase insulin secretion (sulfonylurea derivatives), a reduction in the dose of the sulfonylurea derivative may be required to reduce the risk of hypoglycemia.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.