Dapazin

Yellow colored round, biconvex film coated tablet, debossed with 'C10' on one side and plain on other side.
Each film coated tablet contains: Dapagliflozin 10 mg.

Pharmacotherapeutic group: Drugs used in diabetes, Blood Glucose Lowering Drugs, Excl. Insulins-Sodium-Glucose Co-Transporter 2 (SGLT2) Inhibitors. ATC code: A10BK01.
Pharmacology: Pharmacodynamics: Mechanism of Action: Sodium-Glucose Co-Transporter 2 (SGLT2), expressed in the proximal renal tubules, is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. Dapagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, Dapagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion. Dapagliflozin also reduces sodium reabsorption and increases the delivery of sodium to the distal tubule. This may influence several physiological functions including, but not restricted to, lowering both pre- and afterload of the heart and down regulation of sympathetic activity.
General: Increases in the amount of glucose excreted in the urine were observed in healthy subjects and in patients with type 2 diabetes mellitus following the administration of Dapagliflozin. Dapagliflozin doses of 5 or 10 mg per day in patients with type 2 diabetes mellitus for 12 weeks resulted in excretion of approximately 70 grams of glucose in the urine per day at week 12. A near maximum glucose excretion was observed at the Dapagliflozin daily dose of 20 mg. This urinary glucose excretion with Dapagliflozin also results in increases in urinary volume. After discontinuation of Dapagliflozin, on average, the elevation in urinary glucose excretion approaches baseline by about 3 days for the 10 mg dose.
Pharmacokinetics: Absorption: Following oral administration of Dapagliflozin, the maximum plasma concentration (C_max) is usually attained within 2 hours under fasting state. The C_max and AUC values increase dose proportionally with increase in Dapagliflozin dose in the therapeutic dose range. The absolute oral bioavailability of Dapagliflozin following the administration of a 10 mg dose is 78%. Administration of Dapagliflozin with a high-fat meal decreases its C_max by up to 50% and prolongs T_max by approximately 1 hour, but does not alter AUC as compared with the fasted state. These changes are not considered to be clinically meaningful and Dapagliflozin can be administered with or without food.
Distribution: Dapagliflozin is approximately 91% protein bound. Protein binding is not altered in patients with renal or hepatic impairment.
Metabolism: The metabolism of Dapagliflozin is primarily mediated by UGT1A9; CYP-mediated metabolism is a minor clearance pathway in humans. Dapagliflozin is extensively metabolized, primarily to yield Dapagliflozin 3-o-glucuronide, which is an inactive metabolite. Dapagliflozin 3-o-glucuronide accounted for 61% of a 50 mg [¹⁴C]-Dapagliflozin dose and is the predominant drug-related component in human plasma.
Elimination: Dapagliflozin and related metabolites are primarily eliminated via the renal pathway. Following a single 50 mg dose of [¹⁴C]-Dapagliflozin, 75% and 21% total radioactivity is excreted in urine and feces, respectively. In urine, less than 2% of the dose is excreted as parent drug. In feces, approximately 15% of the dose is excreted as parent drug. The mean plasma terminal half-life (t½) for Dapagliflozin is approximately 12.9 hours following a single oral dose of Dapagliflozin 10 mg.

Type 2 Diabetes Mellitus: Dapagliflozin 10 mg Tablets is indicated: As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Limitations of Use: Dapagliflozin 10 mg is not recommended for patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.

Prior to Initiation of Dapagliflozin: Assess renal function prior to initiation of Dapagliflozin therapy and then as clinically indicated. In patients with volume depletion, correct this condition prior to initiation of Dapagliflozin.
Type 2 Diabetes Mellitus: To improve glycemic control, the recommended starting dose of Dapagliflozin is 5 mg orally once daily, taken in the morning, with or without food. In patients tolerating Dapagliflozin 5 mg once daily who require additional glycemic control, the dose can be increased to 10 mg once daily.
Patients with Renal Impairment: See Table 1.

Click on icon to see table/diagram/image

There were no reports of overdose during the clinical development program for Dapagliflozin. In the event of an overdose, contact the poison control center. It is also reasonable to employ supportive measures as dictated by the patient's clinical status. The removal of Dapagliflozin by hemodialysis has not been studied.

Dapagliflozin 10 mg is contraindicated in patients with: History of a serious hypersensitivity reaction to Dapagliflozin, such as anaphylactic reactions or angioedema.
Patients who are being treated for glycemic control without established CVD or multiple CV risk factors with severe renal impairment, (eGFR less than 30 ml/min/1.73 m²).
Patients on dialysis.

Volume Depletion: Dapagliflozin can cause intravascular volume depletion which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine. There have been post-marketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors, including Dapagliflozin. Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m²), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating Dapagliflozin in patients with one or more of these characteristics, assess volume status and renal function. Monitor for signs and symptoms of hypotension, and renal function after initiating therapy.
Ketoacidosis in Patients with Diabetes Mellitus: Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization have been identified in patients with type 1 and type 2 diabetes mellitus receiving Sodium-Glucose Co-Transporter 2 (SGLT2) Inhibitors, including Dapagliflozin. Fatal cases of ketoacidosis have been reported in patients taking Dapagliflozin. Dapagliflozin is not indicated for the treatment of patients with type 1 diabetes mellitus. Patients treated with Dapagliflozin who present with signs and symptoms consistent with severe metabolic acidosis should be assessed for ketoacidosis regardless of presenting blood glucose levels as ketoacidosis associated with Dapagliflozin may be present even if blood glucose levels are less than 250 mg/dL.
If ketoacidosis is suspected, Dapagliflozin should be discontinued, the patient should be evaluated, and prompt treatment should be instituted. Treatment of ketoacidosis may require insulin, fluid, and carbohydrate replacement. In many of the post-marketing reports, and particularly in patients with type 1 diabetes, the presence of ketoacidosis was not immediately recognized, and the institution of treatment was delayed because the presenting blood glucose levels were below those typically expected for diabetic ketoacidosis (often less than 250 mg/dL). Signs and symptoms at presentation were consistent with dehydration and severe metabolic acidosis and included nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. In some but not all cases, factors predisposing to ketoacidosis, such as insulin dose reduction, acute febrile illness, reduced caloric intake, surgery, pancreatic disorders suggesting insulin deficiency (e.g., type 1 diabetes, history of pancreatitis or pancreatic surgery), and alcohol abuse were identified. Before initiating Dapagliflozin, consider factors in the patient history that may predispose to ketoacidosis, including pancreatic insulin deficiency from any cause, caloric restriction, and alcohol abuse. For patients who undergo scheduled surgery, consider temporarily discontinuing Dapagliflozin for at least 3 days prior to surgery. Consider monitoring for ketoacidosis and temporarily discontinuing Dapagliflozin in other clinical situations known to predispose to ketoacidosis (e.g., prolonged fasting due to acute illness or post-surgery). Ensure risk factors for ketoacidosis are resolved prior to restarting Dapagliflozin. Educate patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue Dapagliflozin and seek medical attention immediately if signs and symptoms occur.
Urosepsis and Pyelonephritis: Serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization have been reported in patients receiving SGLT2 inhibitors, including Dapagliflozin. Treatment with SGLT2 inhibitors increases the risk for urinary tract infections. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated.
Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues: Insulin and insulin secretagogues are known to cause hypoglycemia. Dapagliflozin may increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when these agents are used in combination with Dapagliflozin.
Necrotizing Fasciitis of the Perineum (Fournier's Gangrene): Reports of necrotizing fasciitis of the perineum (fournier's gangrene), a rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, have been identified in post-marketing surveillance in patients with diabetes mellitus receiving SGLT2 inhibitors, including Dapagliflozin. Cases have been reported in both females and males. Serious outcomes have included hospitalization, multiple surgeries, and death. Patients treated with Dapagliflozin presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, should be assessed for necrotizing fasciitis. If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement. Discontinue Dapagliflozin, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control.
Genital Mycotic Infections: Dapagliflozin increases the risk of genital mycotic infections. Patients with a history of genital mycotic infections were more likely to develop genital mycotic infections. Monitor and treat appropriately.
Effects on Ability to Drive and Use Machine: There is no information available for Dapagliflozin for its effects on ability to drive and use machines.

Pregnancy: Based on animal data showing adverse renal effects, Dapagliflozin is not recommended during the second and third trimesters of pregnancy.
Nursing Mothers: Because of the potential for serious adverse reactions in breastfed infants, advise women that use of Dapagliflozin is not recommended while breastfeeding.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Dapagliflozin has been evaluated in clinical trials in patients with type 2 diabetes mellitus. The overall safety profile of Dapagliflozin was consistent across the studied indications. Severe hypoglycemia and Diabetic ketoacidosis (DKA) were observed only in patients with diabetes mellitus.
Clinical Trials in Patients with Type 2 Diabetes Mellitus: Table 2 shows common adverse reactions in published placebo-controlled studies of glycemic control reported in ≥2% of patients treated with Dapagliflozin. These adverse reactions were not present at baseline, occurred more commonly on Dapagliflozin than on placebo, and occurred in at least 2% of patients treated with either Dapagliflozin 5 mg or Dapagliflozin 10 mg. (See Table 2.)

Click on icon to see table/diagram/image

Volume Depletion: Dapagliflozin causes an osmotic diuresis, which may lead to a reduction in intravascular volume. Adverse reactions related to volume depletion (including reports of dehydration, hypovolemia, orthostatic hypotension, or hypotension) in patients with type 2 diabetes mellitus.
Hypoglycemia: The frequency of hypoglycemia by study in patients with type 2 diabetes mellitus is shown in table 3. Hypoglycemia was more frequent when Dapagliflozin was added to sulfonylurea or insulin. (See Table 3.)

Click on icon to see table/diagram/image

Genital Mycotic Infections: The most frequently reported genital mycotic infections were vulvovaginal mycotic infections in females and balanitis in males. Patients with a history of genital mycotic infections were more likely to have a genital mycotic infection during the study than those with no prior history (10.0%, 23.1%, and 25.0% versus 0.8%, 5.9%, and 5.0% on placebo, Dapagliflozin 5 mg, and Dapagliflozin 10 mg, respectively).
Hypersensitivity Reactions: Hypersensitivity reactions (e.g., angioedema, urticaria and hypersensitivity) were reported with Dapagliflozin treatment.
Laboratory Tests: Increases in Serum Creatinine and Decreases in eGFR: Initiation of SGLT2 inhibitors, including Dapagliflozin causes a small increase in serum creatinine and decrease in eGFR. In patients with normal or mildly impaired renal function at baseline, these changes in serum creatinine and eGFR generally occur within weeks of starting therapy and then stabilize. Increases that do not fit this pattern should prompt further evaluation to exclude the possibility of acute kidney injury. The acute effect on eGFR reverses after treatment discontinuation, suggesting acute hemodynamic changes may play a role in the renal function changes observed with Dapagliflozin.
Increase in Hematocrit: In the pool of 13 published placebo-controlled studies of glycemic control, increases from baseline in mean hematocrit values were observed in Dapagliflozin-treated patients starting at week 1 and continuing up to week 16, when the maximum mean difference from baseline was observed. At week 24, the mean changes from baseline in hematocrit were -0.33% in the placebo group and 2.30% in the Dapagliflozin 10 mg group. By week 24, hematocrit values >55% were reported in 0.4% of placebo-treated patients and 1.3% of Dapagliflozin 10 mg-treated patients.
Decrease in Serum Bicarbonate: In a published study of concomitant therapy of Dapagliflozin 10 mg with exenatide extended-release (on a background of metformin), four patients (1.7%) on concomitant therapy had a serum bicarbonate value of less than or equal to 13 meq/L compared to one each (0.4%) in the Dapagliflozin and exenatide extended-release treatment groups.
Seek medical attention immediately at the first sign of any adverse drug reaction.

Positive Urine Glucose Test: Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors as SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests. Use alternative methods to monitor glycemic control.
Interference with 1, 5-anhydroglucitol (1, 5-ag) Assay: Monitoring glycemic control with 1, 5-ag assay is not recommended as measurements of 1, 5-ag are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.

Store at temperatures not exceeding 30°C.

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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