Dapagliflozin 10 mg Film-Coated Tablet is pale yellow to yellow film-coated tablet, oval-shaped, biconvex, with break line on one side and plain on the other side.
Each film-coated tablet contains: Dapagliflozin 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 (Ki: 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 reduce 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 remodelling and preserve renal function. Other effects include an increase in haematocrit and reduction in body weight. The cardiac and renal benefits of dapagliflozin are not solely dependent on the blood glucose-lowering effect and not limited to patients with diabetes as demonstrated in the DAPA-HF and DAPA-CKD studies.
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 hypoglycaemia, 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 >1.400 is times more selective for SGLT2 versus 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 0.33 mg/dL to 0.87 mg/dL.
Pharmacokinetics: Absorption: Dapagliflozin was rapidly and well absorbed after oral administration. Maximum dapagliflozin plasma concentrations (Cmax) were usually attained within 2 hours after administration in the fasted state. Geometric mean steady-state dapagliflozin Cmax 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 Cmax by up to 50% and prolonged Tmax 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 metabolised, 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 (t1/2) 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 faeces. In faeces, 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 haemodialysis 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 Cmax and AUC of dapagliflozin were 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 Cmax 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 in the paediatric population have not been studied.
Gender: The mean dapagliflozin AUC in females was estimated to be about 22% higher than in males.
Race: There were no clinically relevant differences in systemic exposure between White, Black or Asian race.
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 is indicated in adults 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. For study results with respect to combination of therapies, effects on glycaemic control, cardiovascular and renal events, and the populations studied.
Heart failure: Dapagliflozin is indicated in adults for the treatment of symptomatic chronic heart failure with reduced ejection fraction.
Chronic kidney disease: Dapagliflozin is indicated in adults for the treatment of chronic kidney disease.
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 Population: 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.
Pediatric population: The safety and efficacy of dapagliflozin in children aged 0 to < 18 years have not yet been established. No data are available.
Method of administration: Dapagliflozin can be taken orally once daily at any time of day with or without food. Tablets are to be swallowed whole.
Dapagliflozin did not show any toxicity in healthy subjects at single oral doses up to 500 mg (50 times the maximum recommended human dose).
These subjects had detectable glucose in the urine for a dose-related period of time (at least 5 days for the 500 mg dose), with no reports of dehydration, hypotension or electrolyte imbalance, and with no clinically meaningful effect on QTC interval. The incidence of hypoglycaemia was similar to placebo.
In clinical studies where once-daily doses of up to 100 mg (10 times the maximum recommended human dose) were administered for 2 weeks in healthy subjects and type 2 diabetes subjects, the incidence of hypoglycaemia was slightly higher than placebo and was not dose-related.
Rates of adverse events including dehydration or hypotension were similar to placebo, and there were no clinically meaningful dose-related changes in laboratory parameters, including serum electrolytes and biomarkers of renal function.
In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patient's clinical status.
The removal of dapagliflozin by haemodialysis has not been studied.
Hypersensitivity to the active substance or to any of the excipients.
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 patient's 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 antihypertensive 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 hematocrit 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.
Treatment should be interrupted in patients who are hospitalised for major surgical procedures or acute serious medical illnesses. Monitoring of ketones is recommended in these patients. Measurement of blood ketone levels is preferred to urine. Treatment with dapagliflozin may be restarted when the ketone values are normal and the patient's condition has stabilised.
Before initiating dapagliflozin, factors in the patient history that may predispose to ketoacidosis should be considered.
Patients who may be at higher risk of DKA include patients with a low beta cell function reserve (e.g. type 2 diabetes patients with low C peptide or latent autoimmune diabetes in adults (LADA) or patients with a history of pancreatitis), patients with conditions that lead to restricted food intake or severe dehydration, patients for whom insulin doses are reduced and patients with increased insulin requirements due to acute medical illness, surgery or alcohol abuse. SGLT2 inhibitors should be used with caution in these patients.
Restarting SGLT2 inhibitor treatment in patients experiencing a DKA while on SGLT2 inhibitor treatment is not recommended, unless another clear precipitating factor is identified and resolved. In type 1 diabetes mellitus studies with dapagliflozin, DKA was reported with common frequency. Dapagliflozin should not be used for treatment of patients with type 1 diabetes.
Necrotising fasciitis of the perineum (Fournier's gangrene): Postmarketing cases of necrotising fasciitis of the perineum (also known as Fournier's gangrene) have been reported in female and male patients taking SGLT2 inhibitors. This is a rare but serious and potentially life-threatening event that requires urgent surgical intervention and antibiotic treatment.
Patients should be advised to seek medical attention if they experience a combination of symptoms of pain, tenderness, erythema, or swelling in the genital or perineal area, with fever or malaise. Be aware that either urogenital infection or perineal abscess may precede necrotising fasciitis. If Fournier's gangrene is suspected, Dapagliflozin should be discontinued and prompt treatment (including antibiotics and surgical debridement) should be instituted.
Urinary Tract Infections: Urinary glucose excretion may be associated with an increased risk of urinary tract infection; therefore, temporary interruption of dapagliflozin should be considered when treating pyelonephritis or urosepsis.
Cardiac failure: Experience with dapagliflozin in NYHA class IV is limited.
Chronic kidney disease: There is no experience with dapagliflozin for the treatment of chronic kidney disease in patients without diabetes who do not have albuminuria. Dapagliflozin has not been studied for the treatment of chronic kidney disease in patients with polycystic kidney disease, glomerulonephritis with flares (lupus nephritis or ANCA-Associated vasculitis), ongoing or recent requirements of cytotoxic, immunosuppressive or other immunomodulating renal therapy, or in patients who received an organ transplant.
Lower limb amputations: An increase in cases of lower limb amputations (primarily of the toe) has been observed in long-term, clinical studies in type 2 diabetes mellitus with SGLT2 inhibitors. It is unknown whether this constitutes a class effect. It is important to counsel patients with diabetes on routine preventative foot care.
Urine laboratory assessment: Due to its mechanism of action, patients taking Dapagliflozin will test positive for glucose in their urine.
Lactose: The tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
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 the Elderly: Elderly (≥ 65 years): Elderly patients may be at a greater risk for volume depletion and are more likely to be treated with diuretics. Elderly patients are more like to have impaired renal function, and/or to be treated with antihypertensive medicinal products that may cause changes in renal function such as angiotensin converting enzyme inhibitors (ACE-I) and angiotensin type 1 receptor blockers (ARB). The same recommendations for renal function apply to elderly patients as to all patients.
Pregnancy: There are no data from the use of dapagliflozin in pregnant women. Studies in rats have shown toxicity to the developing kidney in the time period corresponding to the second and third trimesters of human pregnancy. Therefore, the use of dapagliflozin is not recommended during the second and third trimester of pregnancy.
When pregnancy is detected, treatment with dapagliflozin should be discontinued.
Breast-feeding: It is unknown whether dapagliflozin and/or its metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of dapagliflozin/metabolites in milk, as well as pharmacologically-mediated effects in nursing offspring. A risk to the newborns/infants cannot be excluded. Dapagliflozin should not be used while breast-feeding.
Type 2 diabetes mellitus: In the clinical studies in type 2 diabetes, more than 15,000 patients have been treated with dapagliflozin.
The primary assessment of safety and tolerability was conducted in a pre-specified pooled analysis of 13 short-term (up to 24 weeks) placebo-controlled studies with 2,360 subjects treated with dapagliflozin 10 mg and 2,295 treated with placebo. In the dapagliflozin cardiovascular outcomes study in type 2 diabetes mellitus (DECLARE study), 8,574 patients received dapagliflozin 10 mg and 8,569 received placebo for a median exposure time of 48 months. In total, there were 30,623 patient-years of exposure to dapagliflozin.
The most frequently reported adverse reactions across the clinical studies were genital infections.
Heart failure: In the dapagliflozin cardiovascular outcome study in patients with heart failure with reduced ejection fraction (DAPA-HF study), 2,368 patients were treated with dapagliflozin 10 mg and 2,368 patients with placebo for a median exposure time of 18 months.
The patient population included patients with type 2 diabetes mellitus and without diabetes, and patients with eGFR ≥ 30 mL/min/1.73 m
2.
The overall safety profile of dapagliflozin in patients with heart failure was consistent with the known safety profile of dapagliflozin.
Chronic kidney disease: In the dapagliflozin renal outcome study in patients with chronic kidney disease (DAPA_CKD), 2,149 patients were treated were dapagliflozin 10 mg and 2,149 patients with placebo for a median exposure time of 27 months. The patient population included patients with type 2 diabetes mellitus and without diabetes, with eGFR ≥ 25 to ≤ 75 mL/min/1.73 m
2. Treatment was continued if eGFR fell to levels below 25 mL/min/1.73 m
2. The overall safety profile of dapagliflozin in patients with chronic kidney disease was consistent with the known safety profile of dapagliflozin.
Identified adverse reactions in placebo-controlled clinical studies and postmarketing experience: Infections and infestations: Common: Vulvovaginitis, balanitis and related genital infections, Urinary tract infection.
Uncommon: Fungal infection.
Very rare: Necrotising fasciitis of the perineum (Fournier's gangrene).
Metabolism and nutrition disorders: Very common: Hypoglycaemia (when used with SU or insulin).
Uncommon: Volume depletion, Thirst.
Rare: Diabetic ketoacidosis (when used in type 2 diabetes mellitus).
Nervous system disorder: 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.
Reproductive system and breast disorders: Uncommon: Vulvovaginal pruritus, Pruritus genital.
Investigations: Common: Haematocrit increased, Creatinine renal clearance decreased during initial treatment, Dyslipidaemia.
Uncommon: Blood creatinine increased during initial treatment, Blood urea increased, Weight decreased.
Pharmacodynamic interactions: Diuretics: Dapagliflozin may add to the diuretic effect of thiazide and loop diuretics and may increase the risk of dehydration and hypotension.
Insulin and insulin secretagogues: Insulin and insulin secretagogues, such as sulphonylureas, cause hypoglycaemia. Therefore, a lower dose of insulin or an insulin secretagogue may be required to reduce the risk of hypoglycaemia when used in combination with dapagliflozin in patients with type 2 diabetes mellitus.
Pharmacokinetic interactions: The metabolism of dapagliflozin is primarily via glucuronide conjugation mediated by UDP glucuronosyltransferase 1A9 (UGT1A9).
In in vitro studies, dapagliflozin neither inhibited cytochrome P450, (CYP) 1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, nor induced CYP1A2, CYP2B6 or CYP3A4. Therefore, dapagliflozin is not expected to alter the metabolic clearance of coadministered medicinal products that are metabolised by these enzymes.
Effect of other medicinal products on dapagliflozin: Interaction studies conducted in healthy subjects, using mainly a single-dose design, suggest that the pharmacokinetics of dapagliflozin are not altered by metformin, pioglitazone, sitagliptin, glimepiride, voglibose, hydrochlorothiazide, bumetanide, valsartan, or simvastatin.
Following coadministration of dapagliflozin with rifampicin (an inducer of various active transporters and drug-metabolising enzymes) a 22% decrease in dapagliflozin systemic exposure (AUC) was observed, but with no clinically meaningful effect on 24-hour urinary glucose excretion. No dose adjustment is recommended. A clinically relevant effect with other inducers (e.g. carbamazepine, phenytoin, phenobarbital) is not expected. Following coadministration of dapagliflozin with mefenamic acid (an inhibitor of UGT1A9), a 55% increase in dapagliflozin systemic exposure was seen, but with no clinically meaningful effect on 24-hour urinary glucose excretion. No dose adjustment is recommended.
Effect of dapagliflozin on other medicinal products: In interaction studies conducted in healthy subjects, using mainly a single-dose design, dapagliflozin did not alter the pharmacokinetics of metformin, pioglitazone, sitagliptin, glimepiride, hydrochlorothiazide, bumetanide, valsartan, digoxin (a P-gp substrate) or warfarin (S-warfarin, a CYP2C9 substrate), or the anticoagulatory effects of warfarin as measured by INR. Combination of a single dose of dapagliflozin 20 mg and simvastatin (a CYP3A4 substrate) resulted in a 19% increase in AUC of simvastatin and 31% increase in AUC of simvastatin acid. The increase in simvastatin and simvastatin acid exposures are not considered clinically relevant.
Interference with 1,5-anhydroglucitol (1,5-AG) assay: Monitoring glycaemic control with 1,5-AG assay is not recommended as measurements of 1,5-AG are unreliable in assessing glycaemic control in patients taking SGLT2 inhibitors. Use of alternative methods to monitor glycaemic control is advised.
Pediatric population: Interaction studies have only been performed in adults.
Store at temperatures not exceeding 30°C. Protect from light and moisture.
A10BK01 - dapagliflozin ; Belongs to the class of sodium-glucose co-transporter 2 (SGLT2) inhibitors. Used in the treatment of diabetes.
Glifixy FC tab 10 mg
30's
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