Dapafors^® (Tablets) Instructions for Use

Marketing Authorization Holder

Krka d.d., Novo mesto (Slovenia)

ATC Code

A10BK01 (Dapagliflozin)

Active Substance

Dapagliflozin (Rec.INN registered by WHO)

Dosage Form

Dapafors®

Film-coated tablets 10 mg: 14, 28, 30, 45, 56, 60, 90, 98 or 100 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets light brownish-yellow, oval, biconvex, with a score on one side; marked with “1” on one side of the score and “0” on the other side.

Excipients: microcrystalline cellulose PH101, microcrystalline cellulose PH102, lactose monohydrate, hydroxypropyl cellulose, crospovidone, sodium stearyl fumarate, film-forming mixture (polyvinyl alcohol, macrogol 3350, titanium dioxide (E171), talc), iron oxide yellow (E172).

10 pcs. – blisters (3, 6, 9 or 10) – cardboard packs.
14 pcs. – blisters (1, 2, 4 or 7) – cardboard packs.
15 pcs. – blisters (2, 4 or 6) – cardboard packs.

Clinical-Pharmacological Group

Oral hypoglycemic drug – sodium-glucose cotransporter 2 inhibitor

Pharmacotherapeutic Group

Drugs for the treatment of diabetes mellitus; hypoglycemic drugs, other than insulins; sodium-glucose cotransporter 2 (SGLT2) inhibitors

Pharmacological Action

Hypoglycemic agent, selective reversible inhibitor of sodium-glucose cotransporter type 2 (SGLT2).

Inhibition of SGLT2 by dapagliflozin causes a reduction in the reabsorption of glucose from the glomerular filtrate in the proximal renal tubules with a concomitant reduction in sodium reabsorption, leading to renal glucose excretion and osmotic diuresis. Thus, Dapagliflozin increases sodium delivery to the distal tubules, which enhances tubuloglomerular feedback and reduces intraglomerular pressure. This, in combination with osmotic diuresis, leads to a reduction in volume overload, a decrease in blood pressure, and a reduction in preload and afterload, which may have a beneficial effect on cardiac remodeling and preserve kidney function.

Other effects include an increase in hematocrit and a decrease in body weight.

The beneficial effect of dapagliflozin on the cardiovascular system and kidneys is not only due to the reduction in blood glucose concentration and is observed not only in patients with diabetes mellitus. In addition to osmotic diuresis and the associated hemodynamic action arising from SGLT2 inhibition, potential mechanisms providing the beneficial impact of dapagliflozin on the cardiovascular system and kidneys may be secondary effects on myocardial metabolism, ion channels, fibrosis, adipokines, and uric acid.

Dapagliflozin reduces fasting and postprandial plasma glucose concentrations, as well as glycated hemoglobin concentration, by reducing glucose reabsorption in the renal tubules, promoting renal glucose excretion. Glucose excretion (glucosuric effect) is observed after the first dose of the drug, persists for the subsequent 24 hours, and continues throughout the therapy. The amount of glucose excreted by the kidneys via this mechanism depends on blood glucose concentration and GFR. Thus, in patients with normal blood glucose concentration and/or low GFR, there is a low tendency to develop hypoglycemia during dapagliflozin use, because the amount of filtered glucose is small and can be reabsorbed by the SGLT1 transporter and the unblocked SGLT2 transporter.

Dapagliflozin does not impair the normal production of endogenous glucose in response to hypoglycemia. The action of dapagliflozin is independent of insulin secretion and insulin sensitivity. In clinical studies of dapagliflozin, an improvement in β-cell function (HOMA test, homeostasis model assessment) was noted.

SGLT2 is selectively expressed in the kidneys. Dapagliflozin does not affect other glucose transporters responsible for glucose transport to peripheral tissues and exhibits more than 1400-fold greater selectivity for SGLT2 than for SGLT1, the main transporter in the intestine responsible for glucose absorption.

Renal glucose excretion during dapagliflozin use also leads to osmotic diuresis and an increase in urine volume.

Clinical studies have shown that dapagliflozin therapy helps reduce the severity of heart failure symptoms and prevents their worsening.

Furthermore, it has been shown that Dapagliflozin, when added to standard background therapy in patients with chronic kidney disease, contributed to a reduction in the frequency of a sustained decrease in eGFR, development of end-stage renal failure, death due to cardiovascular complications or due to renal complications.

Pharmacokinetics

After oral administration, Dapagliflozin is rapidly and completely absorbed from the gastrointestinal tract. The C_max of dapagliflozin in plasma 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 when taken orally at a dose of 10 mg is 78%. Food had a moderate effect on the pharmacokinetics of dapagliflozin in healthy volunteers. A high-fat meal reduced the C_max of dapagliflozin by 50%, prolonged T_max in plasma by approximately 1 hour, but did not affect AUC compared to administration on an empty stomach. These changes are not clinically significant.

The binding of dapagliflozin to plasma proteins is 91%.

Dapagliflozin is a C-linked glucoside, whose aglycone is linked to glucose by a carbon-carbon bond, which ensures its stability against glucosidases. The mean T_1/2 from plasma in healthy volunteers was 12.9 hours after a single oral dose of 10 mg dapagliflozin. 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 is metabolized to Dapagliflozin-3-O-glucuronide, which accounts for 42% of the total plasma radioactivity (by AUC_{0-12 h}). The unchanged substance accounts for 39% of the total plasma radioactivity. The proportions of other metabolites individually do not exceed 5% of the total plasma radioactivity. Dapagliflozin-3-O-glucuronide and other metabolites have no pharmacological activity. Dapagliflozin-3-O-glucuronide is formed under the action of the enzyme uridine diphosphate glucuronosyltransferase 1A9 (UGT1A9), present in the liver and kidneys; cytochrome CYP isoenzymes are involved to a lesser extent in metabolism.

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.

Indications

Type 2 diabetes mellitus in adult patients as an adjunct to diet and exercise to improve glycemic control as: monotherapy, when metformin use is not possible due to intolerance; as part of combination therapy with metformin, sulfonylurea derivatives (including in combination with metformin), thiazolidinediones, dipeptidyl peptidase-4 (DPP-4) inhibitors (including in combination with metformin), glucagon-like peptide-1 (GLP-1) receptor agonist extended-release exenatide in combination with metformin, insulin preparations (including in combination with one or two oral hypoglycemic drugs) in the absence of adequate glycemic control on this therapy; initial combination therapy with metformin, when this therapy is appropriate.

Type 2 diabetes mellitus in adult patients with established cardiovascular disease or two or more cardiovascular risk factors to reduce the risk of hospitalization for heart failure.

Chronic heart failure (NYHA class II-IV) with reduced ejection fraction in adult patients to reduce the risk of cardiovascular death and hospitalization for heart failure.

Chronic kidney disease in adult patients at risk of its progression to reduce the risk of sustained decline in eGFR, onset of end-stage renal failure, death from cardiovascular disease, and hospitalization for heart failure.

ICD codes

Dosage Regimen

Take the tablet orally once daily at a dose of 10 mg.

Administer the tablet with or without food.

For patients with severe hepatic impairment (Child-Pugh class C), initiate therapy at a dose of 5 mg once daily.

Increase the dose to 10 mg once daily if the lower dose is well tolerated.

Assess renal function (eGFR) before initiating therapy.

Do not initiate therapy in patients with an eGFR less than 25 ml/min/1.73 m².

Discontinue therapy if eGFR falls persistently below 15 ml/min/1.73 m².

For patients with type 2 diabetes and an eGFR between 25 and 45 ml/min/1.73 m², the drug is indicated for heart failure and chronic kidney disease risk reduction, not for glycemic control.

Monitor for signs and symptoms of volume depletion, particularly in elderly patients, those on diuretics, or with renal impairment.

Consider temporary discontinuation during periods of reduced oral intake, such as acute illness or fasting.

No dose adjustment is required for patients with mild or moderate hepatic impairment.

Adverse Reactions

Infections and infestations Common – vulvovaginitis, balanitis and related genital infections, urinary tract infection^_; Uncommon – vulvovaginal pruritus, fungal infectious diseases; Very rare – necrotizing fasciitis of the perineum (Fournier’s gangrene).

Metabolism and nutrition disorders: Very common – hypoglycemia (when used in combination with a sulfonylurea derivative or insulin)^_; Uncommon – decreased blood volume, thirst; Rare – diabetic ketoacidosis (when used in diabetes mellitus)^_.

Nervous system disorders: Common – dizziness.

Gastrointestinal disorders: Uncommon – constipation, dry mouth.

Skin and subcutaneous tissue disorders: Common – rash; Very rare – angioedema.

Musculoskeletal and connective tissue disorders: Common – back pain.

Renal and urinary disorders Common – dysuria, polyuria; Uncommon – nocturia.

Investigations: Common – dyslipidemia, increased hematocrit value, decreased renal creatinine clearance at the initial stage of therapy; Uncommon – increased blood urea concentration, increased blood creatinine concentration at the initial stage of therapy.

Contraindications

Hypersensitivity to dapagliflozin; type 1 diabetes mellitus; diabetic ketoacidosis; renal impairment with eGFR <25 ml/min/1.73 m² (for initiation of therapy), end-stage chronic renal failure requiring dialysis; pregnancy, breastfeeding period; children and adolescents under 18 years of age.

With caution

Severe hepatic failure, urinary tract infections, increased hematocrit value.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Use in Hepatic Impairment

Use with caution in patients with hepatic impairment.

Use in Renal Impairment

Contraindicated for use in patients with renal impairment with eGFR <25 ml/min/1.73 m² (for initiation of therapy), with end-stage chronic renal failure requiring dialysis.

Dose adjustment of dapagliflozin in mild to moderate hepatic impairment is not required.

Pediatric Use

Use with caution in children and adolescents under 18 years of age.

Geriatric Use

No clinically significant increase in exposure was noted in patients under 70 years of age (if other factors besides age are not considered). However, an increase in exposure due to age-related decline in renal function can be expected. Data on exposure in patients over 70 years of age are insufficient.

Special Precautions

Renal function should be assessed before starting therapy with dapagliflozin and thereafter as clinically indicated.

Not recommended for improving glycemic control in adult patients with type 2 diabetes mellitus with eGFR less than 45 ml/min/1.73 m² due to the possible ineffectiveness of dapagliflozin in this population due to its mechanism of pharmacological action.

Not recommended for the treatment of chronic kidney disease in patients with polycystic kidney disease or in patients requiring or recently receiving immunosuppressive therapy for renal failure. Dapagliflozin is not expected to be effective in these patient groups.

In patients with type 2 diabetes mellitus with moderate renal impairment (eGFR < 60 ml/min/1.73 m²), adverse reactions such as increased parathyroid hormone concentration and arterial hypotension were observed in a larger proportion of patients in the dapagliflozin group than in the placebo group.

Dapagliflozin may cause a decrease in blood volume, which can sometimes manifest as symptomatic arterial hypotension or acute transient changes in creatinine concentration.

Cases of acute kidney injury have been noted in patients with type 2 diabetes mellitus, some of which required hospitalization and dialysis. Patients with renal impairment (eGFR less than 60 ml/min/1.73 m²), elderly patients, or patients taking “loop” diuretics may have an increased risk of decreased blood volume or arterial hypotension. Before initiating Dapagliflozin therapy in patients with one or more of these characteristics, blood volume and renal function should be assessed. After initiation of therapy, patients should be monitored for possible signs and symptoms of arterial hypotension, and renal function should be monitored.

According to its mechanism of action, Dapagliflozin enhances diuresis, which can lead to a slight decrease in blood pressure, as noted in clinical studies. The diuretic effect may be more pronounced in patients with very high blood glucose concentrations.

Caution should be exercised in patients for whom dapagliflozin-induced blood pressure reduction may pose a risk, for example, in patients receiving antihypertensive therapy, with a history of hypotension, or in elderly patients.

Patients receiving Dapagliflozin 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. If ketoacidosis is suspected, consideration should be given to discontinuing or temporarily stopping dapagliflozin and the patient should be examined immediately.

Factors predisposing to the development of ketoacidosis include low functional activity of β-cells due to pancreatic dysfunction (e.g., type 1 diabetes mellitus, pancreatitis or history of pancreatic surgery), reduction in insulin dose, reduction in caloric intake, or increased insulin demand due to infections, illness, or surgery, as well as alcohol abuse. Dapagliflozin should be used with caution in these patients.

The patient is advised to consult a doctor if they experience pain, tenderness, erythema, or swelling in the genital or perineal area, accompanied by fever and malaise. It is known that either urogenital infection or perineal abscess can precede necrotizing fasciitis. If Fournier’s gangrene is suspected, dapagliflozin should be discontinued and immediate treatment (including antibiotics and surgical debridement) should be initiated.

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. When treating pyelonephritis or urosepsis, temporary discontinuation of dapagliflozin therapy should be considered.

It is important to recommend constant preventive foot care for diabetic patients taking SGLT2 inhibitors.

Experience with dapagliflozin in patients with chronic heart failure NYHA class IV is limited.

Due to the mechanism of action of dapagliflozin, urine glucose test results in patients receiving Dapagliflozin will be positive.

Assessment of glycemic control by measuring 1,5-anhydroglucitol is not recommended, as the measurement of 1,5-anhydroglucitol is an unreliable method for patients taking SGLT2 inhibitors. Alternative methods should be used to assess glycemic control.

Insulin and insulin secretagogues can cause hypoglycemia. Dapagliflozin may increase the risk of hypoglycemia when used in combination with insulin or insulin secretagogues. A reduction in the dose of insulin or the insulin secretagogue may be required to reduce the risk of hypoglycemia when used concomitantly with dapagliflozin.

Patients with a history of fungal genital infections are more prone to developing these infections. Patients should be monitored and appropriate treatment should be provided in case of such infections.

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 insulin and drugs that increase insulin secretion, hypoglycemia may occur. Therefore, to reduce the risk of hypoglycemia when dapagliflozin is used concomitantly with an insulin preparation or a drug that increases insulin secretion, a reduction in the dose of the insulin preparation or the drug that increases insulin secretion may be required.

The metabolism of dapagliflozin occurs mainly via glucuronide conjugation under the action of UGT1A9.

After concomitant use of dapagliflozin and rifampicin, an inducer of various active transporters and drug-metabolizing enzymes, a 22% reduction in the systemic exposure (AUC) of dapagliflozin was noted, with no clinically significant effect on 24-hour renal glucose excretion. Dose adjustment of dapagliflozin is not required. No clinically significant interaction is expected with other inducers (e.g., carbamazepine, phenytoin, phenobarbital).

After concomitant use of dapagliflozin and mefenamic acid (a UGT1A9 inhibitor), a 55% increase in the systemic exposure of dapagliflozin was noted, but without a clinically significant effect on 24-hour urinary glucose excretion. No dose adjustment of dapagliflozin is required.

Storage Conditions

Store at 15°C (59°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.