Radapex

Light yellow to yellow coloured, diamond shaped, biconvex film-coated tablet, plain on both sides.
Each Film-Coated Tablet contains Dapagliflozin (as Propanediol Monohydrate) USP 10 mg.

Pharmacotherapeutic group: Drugs used in diabetes, sodium-glucose co-transporter 2 (SGLT2) inhibitors. ATC code: A10BK01.
Pharmacology: Pharmacodynamics: Mechanism of action: Dapagliflozin is a highly potent (K_i: 0.55 nM), selective and reversible inhibitor of SGLT2.
Inhibition of SGLT2 by dapagliflozin reduces reabsorption of glucose from the glomerular filtrate in the proximal renal tubule with a concomitant reduction in sodium reabsorption leading to urinary excretion of glucose and osmotic diuresis. Dapagliflozin therefore increases the delivery of sodium to the distal tubule which increases tubuloglomerular feedback and reduces intraglomerular pressure. This combined with osmotic diuresis leads to a reduction in volume overload, reduced blood pressure, and lower preload and afterload, which may have beneficial effects on cardiac remodeling and diastolic function, and preserve renal function. The cardiac and renal benefits of dapagliflozin go beyond the blood glucose-lowering effect and are not limited to patients with diabetes as demonstrated in the DAPA-HF, DELIVER and DAPA-CKD studies. Other effects include an increase in hematocrit and reduction in body weight.
Dapagliflozin improves both fasting and post-prandial plasma glucose levels by reducing renal glucose reabsorption leading to urinary glucose excretion. This glucose excretion (glucuretic effect) is observed after the first dose, is continuous over the 24-hour dosing interval and is sustained for the duration of treatment. The amount of glucose removed by the kidney through this mechanism is dependent upon the blood glucose concentration and GFR. Thus, in subjects with normal blood glucose and/or low GFR, dapagliflozin has a low propensity to cause hypoglycemia, as the amount of filtrated glucose is small and can be reabsorbed by SGLT1 and unblocked SGLT2 transporters. Dapagliflozin does not impair normal endogenous glucose production in response to hypoglycemia. Dapagliflozin acts independently of insulin secretion and insulin action. Improvement in homeostasis model assessment for beta cell function (HOMA beta-cell) has been observed in clinical studies with dapagliflozin.
The SGLT2 is selectively expressed in the kidney. Dapagliflozin does not inhibit other glucose transporters important for glucose transport into peripheral tissues and is >1,400 times more selective for SGLT2 versus the SGLT1, the major transporter in the gut responsible for glucose absorption.
Pharmacodynamic effects: Increases in the amount of glucose excreted in the urine were observed in healthy subjects and in subjects with type 2 diabetes mellitus following the administration of dapagliflozin. Approximately 70 g of glucose was excreted in the urine per day (corresponding to 280 kcal/day) at a dapagliflozin dose of 10 mg/day in subjects with type 2 diabetes mellitus for 12 weeks. Evidence of sustained glucose excretion was seen in subjects with type 2 diabetes mellitus given dapagliflozin 10 mg/day for up to 2 years.
This urinary glucose excretion with dapagliflozin also results in osmotic diuresis and increases in urinary volume in subjects with type 2 diabetes mellitus. Urinary volume increases in subjects with type 2 diabetes mellitus treated with dapagliflozin 10 mg were sustained at 12 weeks and amounted to approximately 375 mL/day. The increase in urinary volume was associated with a small and transient increase in urinary sodium excretion that was not associated with changes in serum sodium concentrations.
Urinary uric acid excretion was also increased transiently (for 3-7 days) and accompanied by a sustained reduction in serum uric acid concentration. At 24 weeks, reductions in serum uric acid concentrations ranged from -48.3 to -18.3 micromoles/L (-0.87 to -0.33 mg/dL).
Pharmacokinetics: Absorption: Dapagliflozin was rapidly and well absorbed after oral administration. Maximum dapagliflozin plasma concentrations (C_max) were usually attained within 2 hours after administration in the fasted state. Geometric mean steady-state dapagliflozin C_max and AUC values following once daily 10 mg doses of dapagliflozin were 158 ng/mL and 628 ng·h/mL, respectively. The absolute oral bioavailability of dapagliflozin following the administration of a 10 mg dose is 78%. Administration with a high-fat meal decreased dapagliflozin C_max by up to 50% and prolonged T_max by approximately 1 hour, but did not alter AUC as compared with the fasted state. These changes are not considered to be clinically meaningful. Hence, dapagliflozin can be administered with or without food.
Distribution: Dapagliflozin is approximately 91% protein bound. Protein binding was not altered in various disease states (e.g. renal or hepatic impairment). The mean steady-state volume of distribution of dapagliflozin was 118 liters.
Biotransformation: Dapagliflozin is extensively metabolized, primarily to yield dapagliflozin 3-O-glucuronide, which is an inactive metabolite. Dapagliflozin 3-O-glucuronide or other metabolites do not contribute to the glucose-lowering effects. The formation of dapagliflozin 3-O-glucuronide is mediated by UGT1A9, an enzyme present in the liver and kidney, and CYP-mediated metabolism was a minor clearance pathway in humans.
Elimination: The mean plasma terminal half-life (t_1/2) for dapagliflozin was 12.9 hours following a single oral dose of dapagliflozin 10 mg to healthy subjects. The mean total systemic clearance of dapagliflozin administered intravenously was 207 mL/min. Dapagliflozin and related metabolites are primarily eliminated via urinary excretion with less than 2% as unchanged dapagliflozin. After administration of a 50 mg [14C]-dapagliflozin dose, 96% was recovered, 75% in urine and 21% in feces. In feces, approximately 15% of the dose was excreted as parent drug.
Linearity: Dapagliflozin exposure increased proportional to the increment in dapagliflozin dose over the range of 0.1 to 500 mg and its pharmacokinetics did not change with time upon repeated daily dosing for up to 24 weeks.
Special populations: Renal impairment: At steady-state (20 mg once-daily dapagliflozin for 7 days), subjects with type 2 diabetes mellitus and mild, moderate or severe renal impairment (as determined by iohexol plasma clearance) had mean systemic exposures of dapagliflozin of 32%, 60% and 87% higher, respectively, than those of subjects with type 2 diabetes mellitus and normal renal function. The steady-state 24-hour urinary glucose excretion was highly dependent on renal function and 85, 52, 18 and 11 g of glucose/day was excreted by subjects with type 2 diabetes mellitus and normal renal function or mild, moderate or severe renal impairment, respectively. The impact of hemodialysis on dapagliflozin exposure is not known.
The effect of reduced renal function on systemic exposure was evaluated in a population pharmacokinetic model. Consistent with previous results, model predicted AUC was higher in patients with chronic kidney disease compared with patients with normal renal function, and was not meaningfully different in chronic kidney disease patients with type 2 diabetes mellitus and without diabetes.
Hepatic impairment: In subjects with mild or moderate hepatic impairment (Child-Pugh classes A and B), mean C_max and AUC of dapagliflozin use up to 12% and 36% higher, respectively, compared to healthy matched control subjects. These differences were not considered to be clinically meaningful. In subjects with severe hepatic impairment (Child-Pugh class C) mean C_max and AUC of dapagliflozin were 40% and 67% higher than matched healthy controls, respectively.
Elderly (≥65 years): There is no clinically meaningful increase in exposure based on age alone in subjects up to 70 years old. However, an increased exposure due to age-related decrease in renal function can be expected. There are insufficient data to draw conclusions regarding exposure in patients >70 years old.
Pediatric population: Pharmacokinetics and pharmacodynamics (glucosuria) in children with type 2 diabetes mellitus aged 10-17 years were similar to those observed in adults with type 2 diabetes mellitus.
Gender: The mean dapagliflozin AUC_ss in females was estimated to be about 22% higher than in males.
Race: There were no clinically relevant differences in systemic exposures between White, Black or Asian races.
Body weight: Dapagliflozin exposure was found to decrease with increased weight. Consequently, low-weight patients may have somewhat increased exposure and patients with high weight somewhat decreased exposure. However, the differences in exposure were not considered clinically meaningful.

Type 2 diabetes mellitus: Dapagliflozin Tablets is indicated in adults and children aged 10 years and above for the treatment of insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise: as monotherapy when metformin is considered inappropriate due to intolerance; in addition to other medicinal products for the treatment of type 2 diabetes.
Heart failure: Dapagliflozin Tablets is indicated in adults for the treatment of symptomatic chronic heart failure with reduced ejection fraction.
Chronic kidney disease: Dapagliflozin Tablets is indicated in adults for the treatment of chronic kidney disease.

Posology: Type 2 diabetes mellitus: The recommended dose is 10 mg dapagliflozin once daily.
When dapagliflozin is used in combination with insulin or an insulin secretagogue, such as a sulphonylurea, a lower dose of insulin or insulin secretagogue may be considered to reduce the risk of hypoglycaemia.
Heart failure: The recommended dose is 10 mg dapagliflozin once daily.
In the DAPA-HF study, dapagliflozin was administered in conjunction with other heart failure therapies.
Chronic kidney disease: The recommended dose is 10 mg dapagliflozin once daily.
In the DAPA-CKD study, dapagliflozin was administered in conjunction with other chronic kidney disease related therapies.
Special populations: Renal impairment: No dose adjustment is required based on renal function.
It is not recommended to initiate treatment with dapagliflozin in patients with an estimated glomerular filtration rate (eGFR) <15 mL/min/1.73 m².
In patients with type 2 diabetes mellitus, the glucose lowering efficacy of dapagliflozin is reduced when eGFR is <45 mL/min/1.73 m², and is likely absent in patients with severe renal impairment. Therefore, if eGFR falls below 45 mL/min/1.73 m², additional glucose lowering treatment should be considered in patients with type 2 diabetes mellitus.
Hepatic impairment: No dose adjustment is necessary for patients with mild or moderate hepatic impairment. In patients with severe hepatic impairment, a starting dose of 5 mg is recommended. If well tolerated, the dose may be increased to 10 mg.
Elderly (≥65 years): No dose adjustment is recommended based on age.
Paediatric population: No dose adjustment is required for the treatment of type 2 diabetes mellitus in children aged 10 years and above. No data are available for children below 10 years of age.
The safety and efficacy of dapagliflozin for the treatment of heart failure or for the treatment of chronic kidney disease in children <18 years have not yet been established. No data are available.
Method of administration: Dapagliflozin tablets can be taken orally once daily at any time of day with or without food. Tablets are to be swallowed whole.

Hypersensitivity to the active substance or to any of the excipients.

Renal impairment: There is limited experience with initiating treatment with dapagliflozin in patients with eGFR <25 mL/min/1.73 m², and no experience with initiating treatment in patients with eGFR <15 mL/min/1.73 m². Therefore, it is not recommended to initiate treatment with dapagliflozin in patients with eGFR <15 mL/min/1.73 m².
The glucose lowering efficacy of dapagliflozin is dependent on renal function, and is reduced in patients with eGFR <45 mL/min/1.73 m² and is likely absent in patients with severe renal impairment.
In patients with moderate renal impairment (eGFR <60 mL/min/1.73 m²), a higher proportion of patients treated with dapagliflozin had adverse reactions of increase in parathyroid hormone (PTH) and hypotension, compared with placebo.
Hepatic impairment: There is limited experience in clinical studies in patients with hepatic impairment. Dapagliflozin exposure is increased in patients with severe hepatic impairment.
Use in patients at risk for volume depletion and/or hypotension: Due to its mechanism of action, dapagliflozin increases diuresis which may lead to the modest decrease in blood pressure observed in clinical studies. It may be more pronounced in patients with very high blood glucose concentrations.
Caution should be exercised in patients for whom a dapagliflozin-induced drop in blood pressure could pose a risk, such as patients on anti-hypertensive therapy with a history of hypotension or elderly patients.
In case of intercurrent conditions that may lead to volume depletion (e.g. gastrointestinal illness), careful monitoring of volume status (e.g. physical examination, blood pressure measurements, laboratory tests including haematocrit and electrolytes) is recommended. Temporary interruption of treatment with dapagliflozin is recommended for patients who develop volume depletion until the depletion is corrected.
Diabetic ketoacidosis: Rare cases of diabetic ketoacidosis (DKA), including life-threatening and fatal cases, have been reported in patients treated with sodium-glucose co-transporter 2 (SGLT2) inhibitors, including dapagliflozin. In a number of cases, the presentation of the condition was atypical with only moderately increased blood glucose values, below 14 mmol/L (250 mg/dL).
The risk of diabetic ketoacidosis must be considered in the event of non-specific symptoms such as nausea, vomiting, anorexia, abdominal pain, excessive thirst, difficulty breathing, confusion, unusual fatigue or sleepiness. Patients should be assessed for ketoacidosis immediately if these symptoms occur, regardless of blood glucose level.
In patients where DKA is suspected or diagnosed, dapagliflozin treatment should be stopped immediately.

Antidiabetic Agents

A10BK01 - dapagliflozin ; Belongs to the class of sodium-glucose co-transporter 2 (SGLT2) inhibitors. Used in the treatment of diabetes.

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