Glyhart

Yellow, biconvex, diamond-shaped film-coated tablet with "121" engraved on one side and plain on another side.
Each film-coated tablet contains: Dapagliflozin 10 mg.

Pharmacology: Pharmacodynamics: Dapagliflozin is a potent, reversible and highly selective inhibitor of sodium-glucose co-transporter 2 (SGLT2), a transporter that is expressed in the proximal renal tubules and is responsible for most of the reabsorption of filtered glucose from the tubular lumen. Through inhibition of SGLT2, dapagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose in a dose-dependent manner, leading to increased urinary glucose excretion; increased glucose excretion is independent of insulin secretion.
Dapagliflozin also reduces sodium reabsorption and increases sodium delivery to the distal tubule. This may influence several physiologic functions including lowering cardiac preload and afterload and downregulation of sympathetic activity.
Pharmacokinetics: Dapagliflozin is rapidly absorbed after oral administration with maximum plasma concentration (C_max) occurring within 2 hours under fasting state. The C_max and area under the concentration-time curve (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 time to peak plasma concentration (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 significant. Dapagliflozin may be administered with or without food.
Dapagliflozin is approximately 91% protein bound. Protein binding is not altered in patients with renal or hepatic impairment. The mean steady-state volume of distribution of dapagliflozin is 118 L.
Dapagliflozin is extensively metabolized, primarily to yield dapagliflozin 3-O-glucuronide, an inactive metabolite, via uridine diphosphate-glucuronosyltransferase (UGT) isoenzyme 1A9 in the liver and kidney.
Dapagliflozin and related metabolites are mainly eliminated via the renal pathway. After the administration of a single 50 mg radiolabeled dose of dapagliflozin, 75% and 21% total radioactivity is excreted in urine and feces, respectively, with less than 2% in urine as parent drug and approximately 15% in feces as parent drug. The mean terminal elimination half-life of dapagliflozin is approximately 12.9 hours.
Special Populations: Renal Impairment: Patients with type 2 diabetes mellitus and mild, moderate, or severe renal impairment had mean systemic exposures of dapagliflozin that were 32%, 60% and 87% higher, respectively, compared to patients with type 2 diabetes mellitus and normal renal function.
Hepatic Impairment: In patients with mild or moderate hepatic impairment (Child-Pugh classes A and B), mean C_max and AUC of dapagliflozin were up to 12% and 36% higher, respectively, compared with normal subjects. In patients with severe impairment (Child-Pugh class C), mean C_max and AUC of dapagliflozin were increased up to 40% and 67%, respectively.
Elderly: There is no clinically significant 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.

Type 2 Diabetes Mellitus: As monotherapy in patients with type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycemic control.
In combination with other antidiabetic agents [e.g., metformin and/or a sulfonylurea, a thiazolidinedione, a dipeptidyl peptidase-4 (DPP-4) inhibitor and/or insulin or a glucagon-like peptide 1 (GLP-1) receptor agonist (prolonged-release exenatide)] in patients with type 2 diabetes mellitus as an adjunct to diet and exercise who have not achieved adequate glycemic control.
In patients with type 2 diabetes mellitus and established cardiovascular disease (CVD) or multiple cardiovascular (CV) risk factors to reduce the risk of hospitalization for heart failure.
Limitations of Use: Dapagliflozin is not indicated for patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.
Heart Failure: For the treatment of heart failure in patients with reduced ejection fraction.

General Dosing Recommendations: Volume depletion should be corrected prior to initiation of dapagliflozin therapy. In addition, renal function should be assessed prior to treatment and periodically thereafter.
May be taken with or without food. (See table.)

Click on icon to see table/diagram/image

Dosage in Elderly Patients: No dosage adjustment is required. However, renal function and risk of volume depletion should be taken into consideration.
Dosage in Patients with Renal Impairment: Type 2 Diabetes Mellitus: No dose adjustment is required for patients with estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73 m².
As the glycemic efficacy is dependent on renal function, dapagliflozin should not be initiated to improve glycemic control in patients with an eGFR persistently <60 mL/min/1.73 m² and should be discontinued at eGFR persistently <45 mL/min/1.73 m².
Dapagliflozin is contraindicated in patients with an eGFR <30 mL/min/1.73 m², end-stage renal disease (ESRD) or patients on dialysis.
Heart Failure: No dose adjustment is required based on renal function. Dapagliflozin is contraindicated in patients with an eGFR <30 mL/min/1.73 m², end-stage renal disease (ESRD) or patients on dialysis.
Dosage in Patients with 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. The dose may be increased to 10 mg if well tolerated.
Dosage in Patients at Risk for Volume Depletion: In patients at risk for volume depletion due to coexisting conditions, a starting dose of 5 mg may be appropriate.

Dapagliflozin administered at single doses of up to 500 mg [50 times the maximum recommended human dose (MRHD)] in healthy subjects showed no toxicity. Glucose was detected in the urine of these subjects 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. In addition, no clinically significant effect on QTc interval was observed. The incidence of hypoglycemia was similar to placebo. In clinical studies, dapagliflozin given at once a day doses of up to 100 mg (10 times the MRHD) for 2 weeks in healthy subjects and patients with type 2 diabetes mellitus, had similar rates of adverse events including dehydration or hypotension compared with placebo. There were also no clinically significant dose-related changes in laboratory parameters including serum electrolytes and biomarkers of renal function. The incidence of hypoglycemia was slightly higher than placebo and was not dose-related.
Initiate appropriate supportive treatment dictated by the patient's clinical signs and symptoms if overdose occurs. The removal of dapagliflozin by hemodialysis has not been studied.

Hypersensitivity to dapagliflozin or to any component of the product.
Patients with an estimated glomerular filtration rate (eGFR) less than 30 mL/min/1.73 m², end-stage renal disease (ESRD) or patients on dialysis.

Diabetic Ketoacidosis in Patients with Diabetes: Clinical trial and postmarketing cases of diabetic ketoacidosis (DKA), a serious life threatening condition requiring urgent hospitalization, have been reported in patients with type 2 diabetes mellitus treated with dapagliflozin and other sodium-glucose co-transporter 2 (SGLT2) inhibitors. A number of these cases have been atypical with blood glucose values below 13.9 mmol/L (250 mg/dL). Some cases of DKA have been fatal.
Patients should be assessed for DKA immediately if non-specific symptoms such as difficulty breathing, nausea, vomiting, abdominal pain, confusion, anorexia, excessive thirst and unusual fatigue or sleepiness occur, regardless of blood glucose level. If DKA is suspected or diagnosed, dapagliflozin should be discontinued immediately.
Dapagliflozin should not be used for the treatment of DKA or in patients with a history of DKA.
Dapagliflozin is not indicated, and should not be used, in patients with type 1 diabetes.

Diabetic Ketoacidosis in Patients with Diabetes: The use of SGLT2 inhibitors in patients with type 2 diabetes mellitus may lead to diabetic ketoacidosis (DKA) requiring hospitalization. Fatal cases of diabetic ketoacidosis have been reported in patients receiving dapagliflozin. DKA associated with the use of SGLT2 inhibitors may be present without markedly elevated blood glucose values [e.g., below than 13.9 mmol/L (250 mg/dL)].
DKA must be considered in the event of non-specific symptoms such as difficulty breathing, nausea, vomiting, abdominal pain, confusion, anorexia, excessive thirst, and unusual fatigue or sleepiness. If DKA is suspected, regardless of blood glucose level, patients should discontinue dapagliflozin treatment and be assessed for DKA immediately.
Treatment of ketoacidosis generally requires insulin, fluid, potassium and carbohydrate replacement.
Restarting SGLT2 inhibitor treatment in patients with previous DKA while on SGLT2 inhibitor treatment is not recommended unless another clear precipitating factor is identified and resolved.
Before initiating dapagliflozin, consider factors in the patient history that may predispose to ketoacidosis.
Factors that predispose patients to ketoacidosis include insulin deficiency from any cause (including insulin pump failure, history of pancreatitis or pancreatic surgery), insulin dose reduction, reduced caloric intake or increased insulin requirements due to infections, low carbohydrate diet, acute illness, surgery, a previous ketoacidosis, dehydration and alcohol abuse. Dapagliflozin should be used with caution in these patients. Consider monitoring patients for ketoacidosis and temporarily discontinuing dapagliflozin in clinical situations known to predispose to ketoacidosis.
For patients who will undergo scheduled surgery, consider temporarily discontinuing dapagliflozin for at least 3 days prior to surgery. Treatment with dapagliflozin may be restarted once the patient's condition has stabilized and oral intake is normal.
Volume Depletion and/or Hypotension: Dapagliflozin may cause intravascular volume depletion which may manifest as symptomatic hypotension or acute transient changes in creatinine. Following initiation of dapagliflozin, symptomatic hypotension can occur, particularly in patients with impaired renal function (eGFR <60 mL/min/1.73 m²), elderly patients, or patients receiving loop diuretics. Prior to initiating dapagliflozin in such patients, volume status should be assessed and corrected. Monitor for signs and symptoms of hypotension and renal function after initiating dapagliflozin therapy.
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.
Renal Effects: Dapagliflozin may cause intravascular volume depletion and renal impairment. Dapagliflozin may increase serum creatinine and decrease eGFR; elderly patients and patients with impaired renal function may be more susceptible to these changes. Renal function should be evaluated prior to initiation of dapagliflozin and periodically thereafter.
Monitoring of renal function is recommended as follows: prior to initiation of dapagliflozin and at least yearly thereafter; prior to initiation of concomitant medicines that may reduce renal function and periodically thereafter; for renal function approaching eGFR 45 mL/min/1.73 m², at least 2 to 4 times per year. If renal function falls persistently below eGFR <45 mL/min/1.73 m², treatment with dapagliflozin should be discontinued.
Before initiating dapagliflozin, also consider factors that may predispose patients to acute kidney injury including hypovolemia, chronic renal insufficiency, congestive heart failure and concomitant medications [diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), nonsteroidal anti-inflammatory drugs (NSAIDs)]. Consider temporarily discontinuing dapagliflozin in any setting of reduced oral intake (e.g., acute illness or fasting) or fluid losses (e.g., gastrointestinal illness or excessive heat exposure); monitor patients for signs and symptoms of acute kidney injury. If acute kidney injury occurs, discontinue dapagliflozin promptly and institute treatment.
Concomitant Therapy with Hypoglycemic Agents: Insulin and insulin secretagogues (e.g., sulfonylureas) are known to cause hypoglycemia. The use of dapagliflozin in combination with insulin or an insulin secretagogue may increase the risk of hypoglycemia. Reduction in the dose of insulin or the insulin secretagogue may be necessary to reduce the risk of hypoglycemia when used in combination with dapagliflozin.
Necrotizing Fasciitis of the Perineum (Fournier's Gangrene): There have been postmarketing reports of necrotizing fasciitis of the perineum (Fournier's gangrene), a rare but serious or life-threatening bacterial infection, requiring urgent surgical intervention, in men and women with type 2 diabetes mellitus receiving an SGLT2 inhibitor, including dapagliflozin. Serious outcomes have included hospitalization, multiple surgeries, and death.
Patients receiving dapagliflozin who develop pain or tenderness, erythema, or swelling in the genital or perineal area, with or without to fever or malaise, should be assessed for necrotizing fasciitis. If suspected, dapagliflozin should be discontinued and prompt treatment should be initiated with broad-spectrum antibiotics; surgical debridement should be performed if necessary. Closely monitor blood glucose levels and provide appropriate alternative therapy for glycemic control.
Genital Mycotic Infections: Dapagliflozin may increase the risk of genital mycotic infections in males (e.g., balanitis) and females (e.g., vulvovaginal mycotic infection). In clinical trials, patients with a history of genital mycotic infections were more likely to develop such infections. Patients should be monitored for genital mycotic infections and appropriate treatment should be instituted if these infections occur.
Urinary Tract Infections (including Urosepsis and Pyelonephritis): Dapagliflozin may increase the risk for urinary tract infections. There have been postmarketing reports of serious urinary tract infections, including urosepsis and pyelonephritis, requiring hospitalization in patients treated with dapagliflozin. Assess patients for signs and symptoms of urinary tract infections and treat promptly, if indicated. Temporary interruption of dapagliflozin should be considered when treating pyelonephritis or urosepsis. Discontinuation of dapagliflozin may be considered in cases of recurrent urinary tract infections.
Lower Limb Amputations: An increase in cases of lower limb amputation (primarily of the toe) has been observed in long-term clinical studies with SGLT2 inhibitors. However, it is unknown whether this constitutes a class effect. It is important to regularly examine the feet and advise all patients with diabetes on routine preventative foot care.
Laboratory Test Interferences: SGLT2 inhibitors such as dapagliflozin increase urinary glucose excretion and will result in positive urine glucose tests. Monitoring glycemic control with 1,5-anhydroglucitol (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.
Lactose Intolerance: Dapagliflozin tablet contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this drug product.
Effects on Ability to Drive and Use Machines: There were no studies on the effects on the ability to drive and use machines have been performed with dapagliflozin. Patients should be warned about driving a vehicle or operating machinery under conditions where risk of hypoglycemia is present.
Use in Children: The safety and efficacy of dapagliflozin have not been established in pediatric patients <18 years of age. Therefore, dapagliflozin is not recommended in these patients.
Use in the Elderly: Elderly patients may be at a greater risk for volume depletion and are more likely to be treated with diuretics. They are also more likely to have impaired renal function, and/or to be treated with antihypertensives that may cause changes in renal function (e.g., ACE inhibitors, and ARBs). Caution should be exercised in elderly patients.

Pregnancy: There are no adequate and well-controlled studies with dapagliflozin in pregnant women. Animal data 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 trimesters of pregnancy. When pregnancy is detected, treatment with dapagliflozin should be discontinued.
Lactation: It is not known whether the dapagliflozin is excreted in human milk; the drug is excreted into milk in rats. The risk to the newborns/infants cannot be excluded. Therefore, dapagliflozin is not recommended in breastfeeding women.

The most frequently reported adverse events with dapagliflozin include female genital mycotic infections, nasopharyngitis, and urinary tract infections.
Infections and infestations: Influenza, nasopharyngitis, upper respiratory infection, fungal infection, female genital mycotic infections (including vulvovaginal mycotic infection, vaginal infection, vulvovaginal candidiasis, vulvovaginitis, genital infection, genital candidiasis, fungal genital infection, vulvitis, genitourinary tract infection, vulval abscess, and vaginitis bacterial), male genital mycotic infections (including balanitis, fungal genital infection, balanitis candida, genital candidiasis, genital infection male, penile infection, balanoposthitis, balanoposthitis infective, genital infection and posthitis), necrotizing fasciitis of the perineum (Fournier's gangrene), urinary tract infections (including urinary tract infection, cystitis, Escherichia urinary tract infection, genitourinary tract infection, urosepsis, pyelonephritis, trigonitis, urethritis, kidney infection and prostatitis).
Immune system disorders: Hypersensitivity reactions (e.g., angioedema, urticaria, hypersensitivity), anaphylactic reactions, severe cutaneous adverse reactions.
Metabolism and nutrition disorders: Diabetic ketoacidosis (when used in type 2 diabetes mellitus), hypoglycemia (particularly when used with insulin or sulfonylureas), dyslipidemia, hyperphosphatemia, thirst, volume depletion (including dehydration, hypovolemia, hypotension/orthostatic hypotension).
Nervous system disorders: Dizziness, headache.
Gastrointestinal disorders: Acute pancreatitis, constipation, diarrhea, dry mouth, nausea.
Skin and subcutaneous tissue disorders: Rash (including rash generalized, rash pruritic, rash macular, rash maculopapular, rash pustular, rash vesicular, and rash erythematous).
Musculoskeletal and connective tissue disorders: Back pain, bone fracture, pain in extremity.
Renal and urinary disorders: Acute kidney injury (including acute renal failure), discomfort with urination, dysuria, nocturia, polyuria (including pollakiuria, polyuria, increased urine output).
Reproductive system and breast disorders: Pruritus genital, vulvovaginal pruritus.
Investigations: Increased hematocrit, serum creatinine, blood urea nitrogen (BUN), total cholesterol, LDL- and HDL-cholesterol; decreased triglycerides, creatinine renal clearance, and glomerular filtration rate; increased serum inorganic phosphorus; decreased serum bicarbonate; weight decreased.

The metabolism of dapagliflozin is primarily mediated by uridine diphosphate-glucuronosyltransferase (UGT) isoenzyme 1A9.
In vitro studies have shown that dapagliflozin and dapagliflozin 3-O-glucuronide, an inactive metabolite of dapagliflozin, did not inhibit cytochrome P450 (CYP) isoenzymes 1A2, 2C9, 2C19, 2D6, 3A4. Dapagliflozin also did not induce CYP1A2, 2B6 or 3A4 in vitro. Dapagliflozin is a weak substrate of the P-glycoprotein (P-gp) active transporter and dapagliflozin 3-O-glucuronide is a substrate for the organic anion transport (OAT) 3 active transporter. Dapagliflozin or dapagliflozin 3-O-glucuronide did not significantly inhibit P-gp, OCT2, OAT1, or OAT3 active transporters. Dapagliflozin is unlikely to affect the pharmacokinetics of concurrently administered medications that are P-gp, OCT2, OAT1, or OAT3 substrates.
Insulin and Insulin Secretagogues: Concomitant use may potentially result in hypoglycemia. A lower dose of insulin or insulin secretagogue (e.g., sulfonylurea) may be required to reduce the risk of hypoglycemia.
Bumetanide: Coadministration of dapagliflozin (10 mg once a day for 7 days) and a single dose of bumetanide (1 mg) increased bumetanide AUC and C_max by 13%.
Digoxin: Coadministration of dapagliflozin (20 mg loading dose, then 10 mg once a day for 7 days) and a single dose of digoxin (250 mcg), a P-gp substrate, did not have a clinically significant effect on the AUC or C_max of digoxin.
Glimepiride: Coadministration of a single dose of dapagliflozin (20 mg) and glimepiride (4 mg), a CYP2C9 substrate, increased glimepiride AUC by 13%.
Hydrochlorothiazide: Coadministration of a single dose of dapagliflozin (50 mg) and hydrochlorothiazide (25 mg) did not have a clinically significant effect on the pharmacokinetics of hydrochlorothiazide or dapagliflozin.
Mefenamic Acid: Concurrent use of a single dose of dapagliflozin (10 mg) and mefenamic acid (loading dose of 500 mg, then 250 mg every 6 hours for 14 doses), an inhibitor of UGT1A9, increased dapagliflozin C_max and AUC by 13% and 51%, respectively. No dosage adjustment is necessary.
Metformin: Coadministration of a single dose of dapagliflozin (20 mg) and metformin (1 g), an hOCT-1 and hOCT-2 substrate, did not have a clinically significant effect on the pharmacokinetics of dapagliflozin or metformin.
Pioglitazone: Coadministration of a single dose of dapagliflozin (50 mg) and pioglitazone (45 mg), a CYP2C8 (major) and CYP3A4 (minor) substrate, decreased pioglitazone C_max by 7%.
Rifampicin: Coadministration of a single dose of dapagliflozin (10 mg) and rifampicin (600 mg once a day for 6 days), an inducer of various active transporters and drug-metabolizing enzymes, decreased dapagliflozin C_max and AUC by 7% and 22%, respectively. A clinically relevant effect with other inducers (e.g., carbamazepine, phenytoin, phenobarbital) is not expected.
Simvastatin: Coadministration of a single dose of dapagliflozin (20 mg) and simvastatin (40 mg), a CYP3A4 substrate, increased simvastatin AUC by 19%.
Sitagliptin: Coadministration of a single dose of dapagliflozin (20 mg) and sitagliptin (100 mg), an hOAT-3 and P-gp substrate, did not have a clinically significant effect on the pharmacokinetics of dapagliflozin or sitagliptin.
Valsartan: Coadministration of a single dose of dapagliflozin (20 mg) and valsartan (320 mg) decreased C_max of valsartan and dapagliflozin by 6 and 12%, respectively, and increased valsartan AUC by 5%.
Voglibose: Coadministration of a single dose of dapagliflozin (10 mg) and voglibose (200 mcg three times a day), an α-glucosidase inhibitor, did not have a clinically significant effect on the pharmacokinetics of dapagliflozin.
Warfarin: Concurrent use of dapagliflozin (20 mg loading dose, 10 mg once a day for 7 days) and a single dose of warfarin (25 mg) did not have a clinically significant effect on the pharmacokinetics or anticoagulant activity of warfarin as measured by the prothrombin time [International Normalized Ratio (INR)].

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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