Dapafors^® Met (Tablets) Instructions for Use

Marketing Authorization Holder

Krka d.d., Novo mesto (Slovenia)

ATC Code

A10BD15 (Metformin and dapagliflozin)

Active Substances

Metformin (Rec.INN registered by WHO)

Dapagliflozin (Rec.INN registered by WHO)

Dosage Forms

	Dapafors® Met	Film-coated tablets 5 mg+850 mg
		Film-coated tablets 5 mg+1000 mg

Dosage Form, Packaging, and Composition

Film-coated tablets

10 pcs. – blisters (3 pcs.) – cardboard packs (30 pcs.) – By prescription
10 pcs. – blisters (6 pcs.) – cardboard packs (60 pcs.) – By prescription
10 pcs. – blisters (9 pcs.) – cardboard packs (90 pcs.) – By prescription
14 pcs. – blisters (2 pcs.) – cardboard packs (28 pcs.) – By prescription
14 pcs. – blisters (4 pcs.) – cardboard packs (56 pcs.) – By prescription
15 pcs. – blisters (2 pcs.) – cardboard packs (30 pcs.) – By prescription
15 pcs. – blisters (4 pcs.) – cardboard packs (60 pcs.) – By prescription
15 pcs. – blisters (6 pcs.) – cardboard packs (90 pcs.) – By prescription

Film-coated tablets

10 pcs. – blisters (3 pcs.) – cardboard packs (30 pcs.) – By prescription
10 pcs. – blisters (6 pcs.) – cardboard packs (60 pcs.) – By prescription
10 pcs. – blisters (9 pcs.) – cardboard packs (90 pcs.) – By prescription
14 pcs. – blisters (2 pcs.) – cardboard packs (28 pcs.) – By prescription
14 pcs. – blisters (4 pcs.) – cardboard packs (56 pcs.) – By prescription
15 pcs. – blisters (2 pcs.) – cardboard packs (30 pcs.) – By prescription
15 pcs. – blisters (4 pcs.) – cardboard packs (60 pcs.) – By prescription
15 pcs. – blisters (6 pcs.) – cardboard packs (90 pcs.) – By prescription

Clinical-Pharmacological Group

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

Pharmacotherapeutic Group

Drugs for the treatment of diabetes mellitus; hypoglycemic drugs, other than insulins; combinations of oral hypoglycemic drugs

Pharmacological Action

A combined hypoglycemic agent containing two hypoglycemic drugs with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes mellitus (T2DM): dapagliflozin, a selective reversible inhibitor of sodium-glucose cotransporter 2 (SGLT2), and metformin, a representative of the biguanide class.

Dapagliflozin. SGLT2 is expressed in the proximal renal tubules and is the main transporter involved in the process of glucose reabsorption. By inhibiting SGLT2, dapagliflozin reduces glucose reabsorption and lowers the renal threshold for glucose, leading to increased urinary glucose excretion.

When dapagliflozin was administered at a dose of 5 mg/day or 10 mg/day for 12 weeks to patients with T2DM, approximately 70 g of glucose was excreted in the urine per day. When dapagliflozin was administered at a dose of 20 mg per day, glucose excretion almost reached its maximum. Urinary glucose excretion with dapagliflozin also leads to an increase in urine volume.

Metformin increases glucose tolerance in patients with T2DM by reducing fasting plasma glucose concentration and postprandial glucose concentration. Metformin reduces hepatic glucose production, decreases intestinal glucose absorption, and increases insulin sensitivity by increasing peripheral glucose uptake and utilization. Metformin does not cause hypoglycemia in patients with T2DM or healthy individuals and does not cause hyperinsulinemia. During metformin therapy, insulin secretion does not change, although fasting insulin concentrations and insulin response to meals throughout the day may decrease.

Studies have shown that when dapagliflozin was added to immediate-release metformin therapy, there was a reduction in the mean HbA1c concentration by week 52 of treatment. A marked reduction in mean body weight by week 52 of treatment and a reduction in systolic blood pressure by 5 mm Hg were also observed.

Pharmacokinetics

Dapagliflozin

After oral administration of dapagliflozin in the fasted state, C_max is typically reached within 2 hours. C_max and AUC values increase proportionally to the dapagliflozin dose within the therapeutic dose range. The absolute bioavailability of dapagliflozin after oral administration of a 10 mg dose is 78%.

The plasma protein binding of dapagliflozin is approximately 91%.

The metabolism of dapagliflozin occurs mainly via the enzyme uridine diphosphate glucuronosyltransferase 1A9 (UGT1A9); CYP isoenzymes are involved in human metabolism to a lesser extent. 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.

Dapagliflozin and its metabolites are excreted primarily by the kidneys, with less than 2% excreted unchanged. After administration of 50 mg of ¹⁴C-dapagliflozin, 96% of the radioactivity was recovered – 75% in urine and 21% in feces. Approximately 15% of the radioactivity recovered in feces was unchanged dapagliflozin. The plasma T_1/2 after a single dose of 10 mg dapagliflozin is approximately 12.9 hours.

Metformin

The apparent V_d of metformin after a single oral dose of 850 mg immediate-release metformin tablets averages 654±358 L. Metformin is negligibly bound to plasma proteins. It penetrates into erythrocytes.

Studies with single intravenous administration of metformin to 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 via the intestines.

The renal clearance of metformin is approximately 3.5 times higher than the creatinine clearance, indicating that tubular secretion is the main route of metformin elimination. After oral administration, approximately 90% of the absorbed metformin is excreted by the kidneys within the first 24 hours, with a plasma T_1/2 of approximately 6.2 hours. The blood T_1/2 is approximately 17.6 hours, so the erythrocyte mass may be part of the distribution.

In patients with impaired renal function (based on creatinine clearance measurements), the plasma and blood T_1/2 of metformin is prolonged, and renal clearance is reduced.

Indications

Type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycemic control in adult patients for whom combination therapy with dapagliflozin and metformin is appropriate.

ICD codes

Dosage Regimen

Select the dose individually based on efficacy and tolerability.

Initiate therapy with one tablet twice daily.

Administer with meals to reduce gastrointestinal adverse reactions associated with metformin.

Use the 5 mg/850 mg strength for initial combination therapy.

For patients switching from separate components of dapagliflozin and metformin, select the strength that provides an equivalent or lower dose of metformin.

Gradually increase the dose to minimize metformin-related gastrointestinal effects.

The maximum recommended daily dose is 10 mg for dapagliflozin and 2000 mg for metformin.

Do not exceed two tablets of the 5 mg/1000 mg strength per day.

For patients requiring a dose of metformin 2000 mg/day and dapagliflozin 10 mg/day, use two tablets of the 5 mg/1000 mg strength.

Divide the total daily dose for administration twice daily.

Assess renal function before initiation and periodically during treatment.

Do not initiate therapy if eGFR is below 60 mL/min/1.73 m².

Discontinue therapy if eGFR falls below 45 mL/min/1.73 m² during treatment.

Monitor for signs and symptoms of volume depletion, especially in elderly patients and those on diuretics.

Suspend therapy for conditions that may lead to volume depletion or acute renal impairment.

Temporarily discontinue at least 48 hours before scheduled surgical procedures or radiographic studies with intravascular iodinated contrast media.

Resume therapy only after stable renal function is confirmed 48 hours post-procedure.

Adverse Reactions

Infections and infestations Common – fungal genital infections, urinary tract infections.

Urinary system disorders Common – polyuria. Adverse reactions associated with impaired renal function, including renal failure and increased serum creatinine concentration, were more frequently reported in patients taking dapagliflozin, and were more frequently reported in elderly patients and in patients with impaired renal function. A persistent decrease in eGFR was observed in patients with moderate renal impairment (60>eGFR>30 ml/min/1.73 m²).

Metabolism and nutrition disorders: Hyperphosphatemia; Common – increased LDL-C concentration; Possible decrease in serum vitamin B₁₂

Allergic reactions Rare – serious anaphylactic reactions, severe skin reactions, and angioedema.

Laboratory investigations Very common – increased hematocrit.

Contraindications

Type 1 diabetes mellitus; moderate to severe renal impairment (eGFR<60 ml/min/1.73 m²), end-stage renal disease or patients receiving hemodialysis; use of “loop” diuretics, reduced blood volume (including due to acute conditions such as gastrointestinal diseases); hepatic impairment; acute conditions with a risk of renal impairment (including dehydration /due to vomiting, diarrhea/, fever, severe infectious diseases, hypoxic conditions /shock, sepsis, kidney infections, bronchopulmonary diseases/); acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma; clinically significant manifestations of acute and chronic diseases that can lead to tissue hypoxia (respiratory failure, heart failure, acute myocardial infarction); major surgical operations and trauma (when insulin therapy is indicated); chronic alcoholism and acute ethanol intoxication; lactic acidosis (including history); period at least 48 hours before and 48 hours after radioisotope or X-ray studies with the administration of iodine-containing contrast agents; adherence to a hypocaloric diet (<1000 kcal/day); pregnancy, breastfeeding period; elderly patients 75 years and older; children under 18 years of age; hypersensitivity to the components of the combination.

With caution

Urinary tract infections; risk of reduced blood volume; elderly patients; elevated hematocrit value; patients over 60 years of age performing heavy physical labor.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Use in Hepatic Impairment

The drug is contraindicated for use in hepatic impairment.

Use in Renal Impairment

The drug is contraindicated for use in renal impairment.

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age.

Special Precautions

If lactic acidosis is suspected in a patient taking metformin, general supportive measures should be initiated promptly in a hospital setting and the drug containing this combination should be discontinued immediately.

In case of probable or confirmed lactic acidosis while taking this combination, hemodialysis is recommended to be initiated immediately to correct the acidosis and remove accumulated metformin (metformin is removed by hemodialysis, with a clearance of up to 170 ml/min under good hemodynamic conditions). Hemodialysis often led to resolution of symptoms and recovery.

Lactic acidosis associated with metformin use in post-marketing experience most often occurred in patients with significant renal impairment. Metformin is primarily excreted by the kidneys, so the risk of metformin accumulation and lactic acidosis increases with the severity of renal impairment.
EGFR should be assessed in all patients taking the drug containing this combination at least annually. In patients at risk of renal impairment (e.g., elderly patients), renal function should be monitored more frequently.

Concomitant use of this combination with drugs that may affect renal function may lead to significant hemodynamic changes, cause changes in acid-base balance, or contribute to the accumulation of metformin (e.g., cationic drugs). Therefore, such patients should be monitored more frequently.

The risk of metformin-associated lactic acidosis increases with age, as the risk of hepatic impairment, renal impairment, or heart failure is higher in elderly patients compared to younger patients. Renal function in elderly patients should be monitored more frequently.

Cases of acute renal impairment and lactic acidosis have been identified in patients receiving metformin during radiological studies with intravascular administration of iodine-containing contrast agents. Therapy with drugs containing metformin should be suspended 48 hours before such a procedure, eGFR should be determined 48 hours after the procedure, and administration should be resumed only after stable renal function is confirmed.

Restriction of food and fluid intake during surgical or other procedures may increase the risk of reduced blood volume, arterial hypotension, and renal impairment. This combination should be suspended when food and fluid intake is restricted.

Several cases of lactic acidosis associated with post-marketing use of metformin occurred against a background of acute heart failure (especially in combination with hypoperfusion and hypoxemia). Vascular collapse (shock), acute myocardial infarction, sepsis, and other conditions characterized by hypoxemia are associated with lactic acidosis and can also cause prerenal azotemia. If such conditions occur, the use of this combination should be discontinued.

Alcohol potentiates the effect of metformin on lactate metabolism and may contribute to the development of lactic acidosis.

The use of metformin by patients with hepatic impairment has in some cases led to lactic acidosis, probably due to impaired lactate utilization in the liver and an increase in its concentration in the blood.

Dapagliflozin contributes to a reduction in blood volume. After initiation of dapagliflozin therapy, symptomatic arterial hypotension may occur, especially in patients with impaired renal function (eGFR less than 60 ml/min/1.73 m²), elderly patients, and patients taking “loop” diuretics. Before using this combination in patients, blood volume should be assessed and corrected, and after initiation of therapy, monitoring should be performed to detect symptoms of arterial hypotension.

If a patient receiving this combination develops signs and symptoms of severe metabolic acidosis, ketoacidosis should be ruled out, regardless of blood glucose concentration, as blood glucose concentration during ketoacidosis while taking this combination may be less than 13.9 mmol/L. If ketoacidosis is suspected, this combination should be discontinued, necessary examination should be performed, and appropriate treatment should be prescribed.

Before starting this combination, risk factors for ketoacidosis should be assessed, including insufficient insulin production by the pancreas due to various causes, reduced caloric intake, and alcohol abuse.

Renal function should be assessed before starting this combination and periodically during therapy.

Before starting this combination, possible risk factors for acute renal failure should be assessed, such as hypovolemia, chronic renal failure, chronic heart failure, and concomitant medication use (diuretics, ACE inhibitors, angiotensin II receptor blockers, NSAIDs). When food and fluid intake is restricted (e.g., during acute illness or fasting), or fluid loss occurs (e.g., due to gastrointestinal illness or exposure to high temperatures), temporary discontinuation of therapy with this combination and monitoring of the patient for possible symptoms of acute renal failure should be considered. If acute renal failure develops, this combination should be discontinued immediately and appropriate treatment initiated.

Patients should be monitored for possible symptoms of urinary tract infection and, if necessary, treatment should be initiated promptly.

Hematological parameters should be assessed annually in patients receiving this combination, and if changes are detected, appropriate examination and treatment should be performed.

Some patients (e.g., those with insufficient dietary intake or impaired absorption of vitamin B₁₂ and calcium) are predisposed to a decrease in vitamin B₁₂ concentration to subnormal values. In such patients, it may be advisable to determine serum vitamin B₁₂ concentration every 2-3 years of therapy.

Patients receiving dapagliflozin may have an increased risk of fungal genital infections. The risk of genital infections is higher in patients who had episodes of a similar infection before starting the drug. Patients should be monitored for possible symptoms and appropriate treatment should be provided in case of such an infection.

This combination should not be used in patients with bladder cancer. There are no data to assess the possible effect of dapagliflozin on a pre-existing bladder tumor.

In patients receiving SGLT2 inhibitors, the use of the 1,5-anhydroglucitol assay for glycemic monitoring is not recommended. Alternative monitoring methods should be used.

SGLT2 inhibitors increase urinary glucose excretion. Therefore, urine glucose test results in patients taking this combination will be positive. Alternative monitoring methods should be used.

Drug Interactions

Carbonic anhydrase inhibitors: Topiramate and other carbonic anhydrase inhibitors (such as zonisamide, acetazolamide, or diclofenamide) often cause a decrease in serum bicarbonate concentrations and non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with the dapagliflozin+metformin combination may increase the risk of lactic acidosis. Such patients require more frequent monitoring.

Drugs that slow the elimination of metformin: Concomitant use of drugs that affect the renal tubular transport systems involved in the renal excretion of metformin (OCT2 and MATE inhibitors, such as ranolazine, vandetanib, dolutegravir, and cimetidine) may increase the systemic exposure to metformin and the risk of lactic acidosis. The expected benefit and possible risk of concomitant use of these drugs should be assessed.

The use of certain medications, such as diuretics (including thiazides), corticosteroids, phenothiazines, thyroid hormones, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid, may predispose to the development of hyperglycemia and worsening of glycemic control. When these drugs are used concomitantly with this combination, careful monitoring of glycemia is necessary, and upon their discontinuation, observation of the patient is required due to the possibility of hypoglycemia.

Hypoglycemia does not develop in patients taking only metformin in the usual regimen, but may develop with a hypocaloric diet, or if intense physical exertion is not compensated by caloric intake, or when used concomitantly with other hypoglycemic agents (such as sulfonylurea derivatives and insulin) or alcohol.

In elderly patients and patients taking beta-blockers, the diagnosis of hypoglycemia may be difficult.

Alcohol potentiates the effect of metformin on lactate metabolism. Patients should be informed about the inadmissibility of consuming large doses of alcohol while undergoing therapy with drugs containing this combination.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°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.