Dapafors^® Sita (Tablets) Instructions for Use

Marketing Authorization Holder

Krka d.d., Novo mesto (Slovenia)

ATC Code

A10BD (Oral hypoglycemic drugs in combination)

Active Substances

Dapagliflozin (Rec.INN registered by WHO)

Sitagliptin (Rec.INN registered by WHO)

Dosage Form

Dapafors® Sita

Film-coated tablets 10 mg+100 mg

Dosage Form, Packaging, and Composition

Film-coated tablets

10 pcs. – blisters – cardboard packs (10 pcs.) – By prescription
10 pcs. – blisters (10 pcs.) – cardboard packs (100 pcs.) – By prescription
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 – cardboard packs (14 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
14 pcs. – blisters (6 pcs.) – cardboard packs (84 pcs.) – By prescription
14 pcs. – blisters (7 pcs.) – cardboard packs (98 pcs.) – By prescription

Clinical-Pharmacological Group

Combined hypoglycemic drug

Pharmacotherapeutic Group

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

Pharmacological Action

Combined hypoglycemic agent.

Dapagliflozin is a potent (inhibition constant (Ki) 0.55 nM), selective, reversible inhibitor of SGLT2. Inhibition of SGLT2 by dapagliflozin reduces the reabsorption of glucose from the glomerular filtrate in the proximal renal tubules with a concomitant reduction in sodium reabsorption, leading to urinary glucose excretion and osmotic diuresis. Thus, Dapagliflozin increases sodium delivery to the distal tubules, which enhances tubuloglomerular feedback and reduces intraglomerular pressure. This, combined 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 diastolic function and preserve kidney function. Other effects include an increase in hematocrit and a decrease in body weight.

Dapagliflozin reduces fasting and postprandial plasma glucose concentrations by reducing glucose reabsorption in the renal tubules, promoting urinary 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 entire therapy. The amount of glucose excreted by the kidneys through this mechanism depends on blood glucose concentration and GFR. Thus, in patients with normal blood glucose levels, dapagliflozin has a low tendency to cause hypoglycemia. 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 beta-cell function (HOMA test, homeostasis model assessment) was noted. SGLT2 is selectively expressed in the kidneys. Dapagliflozin does not affect other glucose transporters that transport glucose to peripheral tissues and shows more than 1,400-fold greater selectivity for SGLT2 than for SGLT1, the main transporter in the intestine responsible for glucose absorption.

Sitagliptin is an orally active, highly selective inhibitor of the DPP-4 enzyme, intended for the treatment of type 2 diabetes mellitus. Sitagliptin differs in chemical structure and pharmacological action from analogs of glucagon-like peptide-1 (GLP-1), insulin, sulfonylurea derivatives, biguanides, peroxisome proliferator-activated receptor (PPAR-γ) agonists, alpha-glucosidase inhibitors, and amylin analogs. By inhibiting DPP-4, Sitagliptin increases the concentration of two incretin hormones: GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). Incretin hormones are secreted in the intestine throughout the day, and their concentration increases in response to food intake. Incretins are part of the internal physiological system regulating glucose homeostasis. At normal or elevated blood glucose concentrations, incretin hormones promote an increase in insulin synthesis and its secretion by pancreatic beta-cells through intracellular signaling mechanisms associated with cyclic AMP.

GLP-1 also inhibits the increased secretion of glucagon by pancreatic alpha-cells. The decrease in glucagon concentration against the background of an increase in insulin concentration contributes to a reduction in glucose production by the liver, which ultimately leads to a decrease in glycemia. This mechanism of action differs from that of sulfonylurea derivatives, which stimulate insulin release even at low blood glucose concentrations, which is fraught with the development of sulfated hypoglycemia not only in patients with type 2 diabetes but also in healthy individuals.

At low blood glucose concentrations, the listed effects of incretins on insulin release and reduction of glucagon secretion are not observed. GLP-1 and GIP do not affect the release of glucagon in response to hypoglycemia. Under physiological conditions, incretin activity is limited by the DPP-4 enzyme, which rapidly hydrolyzes incretins to form inactive products.

Pharmacokinetics

Dapagliflozin

After oral administration, Dapagliflozin is rapidly and completely absorbed from the gastrointestinal tract. C_max of dapagliflozin is usually reached within 2 hours after administration on an empty stomach. After administration of dapagliflozin at a dose of 10 mg once daily, the geometric mean values of C_max and AUC at steady state were 158 ng/ml and 628 ng·h/ml, respectively. The absolute bioavailability of oral dapagliflozin at a dose of 10 mg was 78%. Dapagliflozin is approximately 91% bound to proteins. This indicator did not change in patients with various diseases, for example, with impaired renal or liver function. The mean steady-state V_d of dapagliflozin was 118 L. Dapagliflozin is metabolized to form mainly the inactive metabolite dapagliflozin-3-O-glucuronide. Dapagliflozin-3-O-glucuronide and other metabolites do not have a hypoglycemic effect. Dapagliflozin-3-O-glucuronide is formed under the action of the UGT1A9 enzyme, present in the liver and kidneys; cytochrome CYP isoenzymes are less involved in metabolism. The mean T_1/2 of dapagliflozin from plasma was 12.9 hours after a single oral dose of 10 mg dapagliflozin in healthy volunteers. The mean total systemic clearance of dapagliflozin after intravenous administration was 207 ml/min. Dapagliflozin and its metabolites are excreted primarily by the kidneys, with less than 2% of dapagliflozin excreted unchanged. After administration of 50 mg of ¹⁴C-dapagliflozin, 96% of the radioactivity was found, of which 75% was in the urine and 21% in the feces. Approximately 15% of the dose found in the feces was unchanged Dapagliflozin. The exposure of dapagliflozin increased proportionally with the increase in the dapagliflozin dose in the range from 0.1 to 500 mg, and its pharmacokinetic properties did not change over time with repeated daily administration for 24 weeks.

Sitagliptin

In healthy individuals, after oral administration of 100 mg of sitagliptin, its rapid absorption was noted, with C_max reached in the interval from 1 to 4 hours after administration. The AUC increased proportionally to the dose and was 8.52 µmol/L×h in healthy volunteers after oral administration of sitagliptin at a dose of 100 mg, C_max was 950 nmol/L. The plasma AUC of sitagliptin increased by approximately 14% after taking the next 100 mg dose to reach steady state after the first dose. The intra- and inter-subject coefficients of variation for the AUC of sitagliptin were insignificant. The absolute bioavailability of sitagliptin is approximately 87%. The mean V_d at steady state after a single intravenous administration of 100 mg sitagliptin to healthy volunteers was approximately 198 L. The fraction of sitagliptin bound to plasma proteins is relatively low and amounts to 38%. Approximately 79% of sitagliptin is excreted unchanged by the kidneys. Only a small part of the active substance that enters the body is metabolized. After administration of ¹⁴C-sitagliptin orally, approximately 16% of the radioactive sitagliptin was excreted as its metabolites. Traces of 6 metabolites of sitagliptin were found, probably not possessing DPP-4 inhibitory activity. In vitro studies have shown that the primary isoenzymes involved in the limited metabolism of sitagliptin are CYP3A4 and CYP2C8. After oral administration of ¹⁴C-sitagliptin to healthy volunteers, approximately 100% of the administered sitagliptin was excreted: through the intestine (13%) and by the kidneys (87%) within one week after taking the drug. The mean T_1/2 of sitagliptin after oral administration of a 100 mg dose was approximately 12.4 hours; renal clearance was approximately 350 ml/min. The excretion of sitagliptin occurs primarily through renal excretion via the mechanism of active tubular secretion. Sitagliptin is a substrate for the human organic anion transporter type 3 (hOAT-3), which may be involved in the renal excretion of sitagliptin. The clinical involvement of hOAT-3 in the transport of sitagliptin has not been studied. Sitagliptin is also a substrate for P-glycoprotein, which may also be involved in the renal excretion of sitagliptin. However, cyclosporine, a P-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.

Indications

Treatment of type 2 diabetes mellitus – as an adjunct to diet and exercise in patients whose disease is adequately controlled with dapagliflozin and sitagliptin taken as separate tablets in the same dosages as in this combination.

Dosage Regimen

Take one tablet orally once daily.

Administer the fixed-dose combination of 10 mg dapagliflozin and 100 mg sitagliptin as a single daily dose.

Take the tablet with or without food.

Swallow the tablet whole with a glass of water; do not split, crush, or chew.

This regimen is indicated for patients whose type 2 diabetes is adequately controlled on the individual components at these same doses.

Discontinue treatment if the patient’s estimated glomerular filtration rate (eGFR) persistently falls below 45 ml/min/1.73 m².

Do not use in patients with end-stage renal disease requiring dialysis.

No dosage adjustment is required for patients with mild to moderate hepatic impairment; assess patients with moderate impairment before and during therapy.

Use is not recommended in patients with severe hepatic impairment.

No dosage adjustment is required based on age alone; however, consider renal function and the risk of hypovolemia in elderly patients.

Monitor for signs of volume depletion, particularly in patients on diuretics, antihypertensive therapy, or with a history of hypotension.

Temporarily discontinue therapy in patients developing significant hypovolemia until the condition is corrected.

Assess renal function prior to initiation and periodically during treatment.

Consider the potential for hypoglycemia when used concomitantly with insulin or insulin secretagogues; a dose reduction of these agents may be necessary.

Adverse Reactions

Infections and infestations common – vulvovaginitis, balanitis and related genital infections, urinary tract infections; uncommon – fungal infectious diseases; very rare – necrotizing fasciitis of the perineum (Fournier’s gangrene).

Blood and lymphatic system disorders rare – thrombocytopenia

Immune system disorders frequency unknown – hypersensitivity reactions, including anaphylactic reactions.

Metabolism and nutrition disorders very common – hypoglycemia, decreased blood volume; uncommon – thirst; rare – diabetic ketoacidosis.

Nervous system disorders common – dizziness; uncommon – headache.

Respiratory, thoracic and mediastinal disorders frequency unknown – interstitial lung disease.

Gastrointestinal disorders uncommon – constipation, dry oral mucosa; frequency unknown – vomiting, acute pancreatitis, hemorrhagic and necrotizing pancreatitis (with and without fatal outcome).

Skin and subcutaneous tissue disorders common – skin rash; uncommon – pruritus; very rare – angioedema; frequency unknown – urticaria, cutaneous vasculitis, exfoliative skin conditions, including Stevens-Johnson syndrome, bullous pemphigoid.

Musculoskeletal and connective tissue disorders common – back pain; frequency unknown – arthralgia, myalgia, arthropathy.

Renal and urinary disorders common – dysuria, polyuria; uncommon – nocturia; very rare – tubulointerstitial nephritis; frequency unknown – renal impairment, acute renal failure.

Reproductive system and breast disorders uncommon – vulvovaginal pruritus, genital pruritus.

Investigations common – increased hematocrit, decreased creatinine clearance at the initial stage of therapy, dyslipidemia, increased blood creatinine concentration at the initial stage of therapy; uncommon – increased blood urea concentration, weight loss.

Contraindications

Hypersensitivity to dapagliflozin, sitagliptin; type 1 diabetes mellitus; diabetic ketoacidosis; pregnancy, breastfeeding period; children and adolescents under 18 years of age

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Use in Hepatic Impairment

Can be used in patients with mild or moderate hepatic impairment. The condition of patients with moderate hepatic impairment should be assessed before starting and during treatment. Use is not recommended in patients with severe hepatic impairment.

Use in Renal Impairment

Treatment should be discontinued if eGFR remains < 45 ml/min/1.73 m².

Should not be used in patients with end-stage renal disease.

Pediatric Use

Contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

Dosage adjustment of the drug depending on age is not required. Renal function and the risk of hypovolemia should be taken into account.

Special Precautions

The hypoglycemic effect of dapagliflozin depends on renal function; it is reduced in patients with eGFR < 45 ml/min/1.73 m² and may be absent in patients with severe renal failure. Use in this category of patients is not recommended.

Data on use in patients with hepatic impairment are limited.

Use with caution in patients for whom the dapagliflozin-induced decrease in blood pressure may pose a risk, for example, patients receiving antihypertensive therapy, with a history of hypotension episodes, or elderly patients.

In the case of intercurrent conditions that may lead to a decrease in blood volume (e.g., gastrointestinal diseases), careful monitoring of blood volume is recommended (e.g., physical examination, blood pressure measurement, laboratory tests, including hematocrit and electrolyte concentrations). Temporary discontinuation of dapagliflozin treatment is recommended for patients who develop hypovolemia, until it is corrected.

The risk of developing diabetic ketoacidosis should be considered if nonspecific symptoms appear, such as nausea, vomiting, anorexia, abdominal pain, excessive thirst, difficulty breathing, confusion, increased fatigue, or drowsiness. If these symptoms occur, patients should be immediately examined for ketoacidosis, regardless of blood glucose concentration.

In patients with suspected or confirmed diabetic ketoacidosis, treatment with dapagliflozin should be discontinued immediately.

Treatment should be suspended in patients hospitalized for major surgical interventions or acute serious illnesses. In these patients, monitoring of ketone body levels is recommended. Measuring blood ketone body levels is preferable to determining them in urine. Dapagliflozin treatment can be resumed when ketone body levels normalize and the patient’s condition stabilizes.

Before prescribing dapagliflozin, the patient’s history data that may predispose to the development of diabetic ketoacidosis should be taken into account. The group with a possible increased risk of developing diabetic ketoacidosis includes patients with low beta-cell function reserve (e.g., patients with type 2 diabetes with low C-peptide levels or latent autoimmune diabetes in adults (LADA) or patients with a history of pancreatitis); patients with conditions that lead to limited food intake or severe dehydration; patients who have reduced insulin doses; patients with increased insulin requirements due to acute illness, surgery, or alcohol abuse. Caution should be exercised when using SGLT2 inhibitors in such patients.

In patients with diabetic ketoacidosis that occurred during treatment with an SGLT2 inhibitor, resumption of therapy with an SGLT2 inhibitor is not recommended unless another clear precipitating factor has been identified and eliminated.

If Fournier’s gangrene (necrotizing fasciitis of the perineum) is suspected, dapagliflozin should be discontinued and immediate treatment initiated (including antibiotics and surgical debridement).

Urinary glucose excretion may be associated with an increased risk of urinary tract infection. Therefore, when treating pyelonephritis or urosepsis, the possibility of suspending dapagliflozin therapy should be considered.

In elderly patients, the risk of decreased blood volume may be increased, and they are more often prescribed diuretics. Elderly patients more often have impaired renal function and/or are treated with antihypertensive drugs that can cause changes in renal function, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type 1 receptor antagonists (ARBs).

Patients with diabetes should be advised to have constant preventive foot care.

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

If pancreatitis is suspected, sitagliptin and other potentially hazardous drugs should be discontinued.

Hypersensitivity reactions occurred within the first 3 months after starting treatment with sitagliptin, some were observed after the first dose. If hypersensitivity reactions are suspected, sitagliptin should be discontinued, other possible causes of the adverse event should be assessed, and other drug therapy for diabetes should be prescribed.

Patients should be informed of the need to report the development of blisters and/or ulcerations during treatment with sitagliptin. If bullous pemphigoid is suspected, sitagliptin should be discontinued and a dermatologist should be consulted for diagnosis and appropriate treatment.

Drug Interactions

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

Hypoglycemia may develop with the use of insulin and drugs that increase insulin secretion. Therefore, to reduce the risk of hypoglycemia when using dapagliflozin concomitantly with insulin or a drug that increases insulin secretion, a reduction in the dose of insulin or the drug that increases its secretion may be required.

The metabolism of dapagliflozin occurs primarily via glucuronide conjugation mediated by UGT1A9.

Following coadministration of dapagliflozin with rifampicin, an inducer of various active transporters and drug-metabolizing enzymes, a 22% reduction in the systemic exposure (AUC) of dapagliflozin was observed, with no clinically significant effect on 24-hour urinary glucose excretion. No dose adjustment is required.

Following coadministration of dapagliflozin with mefenamic acid (an inhibitor of UGT1A9), a 55% increase in the systemic exposure of dapagliflozin was observed, but without a clinically significant effect on 24-hour urinary glucose excretion. No dose adjustment is required.

Concomitant use of dapagliflozin and lithium preparations may lead to a decrease in serum lithium concentrations due to the potential enhancement of renal lithium excretion. Dose adjustment of the lithium preparation may be required.

Administration of a single 20 mg dose of dapagliflozin with simvastatin (a substrate of the CYP3A4 isoenzyme) resulted in a 19% increase in the AUC of simvastatin and a 31% increase in the AUC of simvastatin acid. The increased exposure of simvastatin and simvastatin acid is not considered clinically significant.

Assessment of glycemic control using 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.

A small increase in the AUC (11%) and mean plasma C_max (18%) of digoxin was observed when coadministered with sitagliptin. This increase is not considered clinically significant. No dose adjustment for either digoxin or sitagliptin is recommended when they are used concomitantly.

An increase in the AUC and C_max of sitagliptin by 29% and 68%, respectively, was observed in patients following coadministration of a single 100 mg oral dose of sitagliptin and a single 600 mg oral dose of cyclosporine, a potent P-glycoprotein inhibitor. The observed changes in the pharmacokinetics of sitagliptin are not considered clinically significant. No dose adjustment for sitagliptin is required when coadministered with cyclosporine and other P-glycoprotein inhibitors (e.g., ketoconazole).

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.