DFLOZ

(Dapagliflozin propanediol monohydrate)

 Film Coated Tablets 
 
 
PRESENTATION Each Film – Coated Tablets Contains: Dapagliflozin propanediol monohydrate 5/10 mg Pack Size: 3*10  Packing: Blister 
 
CLINICAL PARTICULARS 
Therapeutic Indications:

 Type 2 diabetes mellitus

 Glycemic control 
 
Dfloz Is Indicated In Adults With Type 2 Diabetes Mellitus:

 As monotherapy as an adjunct to diet and exercise in patients for whom metformin is otherwise indicated but was not tolerated.  As initial combination therapy with metformin, as an adjunct to diet and exercise, to improve glycemic control when diet and exercise have failed to provide adequate glycemic control and there are poor prospects for response to metformin monotherapy (for example, high initial hemoglobin A1c [HbA1c] levels).

 In combination with other anti-hyperglycemic agents to improve glycemic control, when these together with diet and exercise, do not provide adequate glycemic control (see Pharmacodynamics properties – Clinical trials and Special warnings and precautions for use for available data on different add-on combination therapies). 
 
Prevention of Hospitalization for Heart Failure

DFLOZ is indicated in adults with type 2 diabetes mellitus and established cardiovascular disease or risk factors for cardiovascular disease to reduce the risk of hospitalization for heart failure (see Pharmacodynamics properties – Clinical trials). 
 
Heart Failure

DFLOZ is indicated in adults for the treatment of symptomatic heart failure with reduced ejection fraction, as an adjunct to standard of care therapy (see Pharmacodynamics properties). 
 
Chronic Kidney Disease

DFLOZ is indicated to reduce the risk of progressive decline in kidney function in adults with proteinuric chronic kidney disease (CKD Stage 2, 3 or 4 and urine ACR ≥ 30 mg/g) 
 
DOSE AND METHOD OF ADMINISTRATION 

Type 2 Diabetes Mellitus

The recommended dose of DFLOZ is 10 mg taken orally once daily at any time of the day regardless of meals. When DFLOZ is used as an add-on therapy with insulin or an insulin secretagogue (e.g., sulfonylurea), a lower dose of insulin or an insulin secretagogue may be considered to reduce the risk of hypoglycemia. The recommended starting doses of DFLOZ and metformin when used as initial combination therapy are 10 mg DFLOZ plus 500 mg metformin once daily. Patients with inadequate glycemic control on this starting dose should have their metformin dose increased according to approved metformin Product Information. 
 
Heart Failure

The recommended dose of DFLOZ is 10 mg taken orally once daily at any time of the day regardless of meals. DFLOZ should be used in conjunction with individualized standard of care therapy. 
 
Chronic Kidney Disease

The recommended dose of DFLOZ is 10 mg taken orally once daily at any time of the day regardless of meals. 
 
Special Populations 

Renal Impairment

No dose adjustment is required based on renal function. Initiating treatment with DFLOZ in patients with eGFR <25 mL/min/1.73 m2 is not recommended (see Special warnings and precautions for use). The glucose lowering efficacy of DFLOZ is reduced in patients with estimated glomerular filtration rate (eGFR) below 45 mL/min/1.73 m2 (see Special warnings and precautions for use, and Pharmacodynamics properties – Clinical Trials). 
Therefore, if eGFR falls below 45 mL/min/1.73 m2, additional glucose lowering treatment should be considered in patients with diabetes mellitus. 
Hepatic Impairment

No dosage adjustment for DFLOZ is necessary for patients with mild or moderate hepatic impairment. DFLOZ should not be used in patients with severe hepatic impairment (see Special warnings and precautions for use). 
Pediatric and Adolescent Safety and effectiveness of DFLOZ in pediatric and adolescent patients have not been established. 
 
Elderly

No dosage adjustment is recommended based on age (see Pharmacodynamics properties). 
 

CONTRAINDICATIONS

 Known hypersensitivity to any of the ingredients. 
 
SPECIAL WARNINGS AND PRECAUTIONS FOR USE

DFLOZ should not be used in patients with type 1 diabetes (see Therapeutic Indications) or for the treatment of diabetic ketoacidosis (see Special Warnings and Precautions for Use – Ketoacidosis). 
 
Use in Renal Impairment

There is limited experience with initiating treatment with DFLOZ in patient’s eGFR <25 mL/min/1.73 m2 Dapagliflozin increases serum creatinine and decreases eGFR (see adverse effects (Undesirable effects)). Renal function abnormalities can occur after initiating dapagliflozin. 
Patients with hypovolemia may be more susceptible to these changes. The glucose lowering efficacy of dapagliflozin is dependent on renal function and is reduced where eGFR is <45 mL/min/1.73 m2. (See Dose and method of administration). 

Use in Hepatic Impairment

There is limited experience in clinical trials in patients with hepatic impairment. Dapagliflozin exposure is increased in patients with severe hepatic impairment. DFLOZ should not be used in patients with severe hepatic impairment (see Dose and method of administration and Pharmacokinetic properties– Special Populations). 

Use in Patients at Risk for Volume depletion and or hypotension

The diuretic effect of Dapagliflozin is a potential concern for volume depleted patients. Due to its mechanism of action, Dapagliflozin induces osmotic diuresis which may lead to the modest decrease in blood pressure observed in clinical studies (see Pharmacodynamics properties – Clinical trials). When considering initiating dapagliflozin, there may be patients for whom the additional diuretic effect of dapagliflozin is a potential concern either due to acute illness (such as gastrointestinal illness) or a history of hypotension or dehydration with diuretic therapy for patients who may become volume depleted. Initiation of therapy with dapagliflozin is therefore not recommended in these patients. 
In case of undercurrent conditions that may lead to volume depletion, such as gastrointestinal illness, heat stress or severe infections, careful monitoring of volume status (e.g. physical examination, blood pressure measurements, and laboratory tests including electrolytes) is recommended. Temporary interruption of Dapagliflozin is recommended for patients who develop volume depletion until the depletion is corrected (see adverse effects (Undesirable effects)). 
Caution should be exercised in patients for whom a dapagliflozin-induced drop in blood pressure could pose a risk, such as patients with known cardiovascular disease, patients on antihypertensive therapy with a history of hypotension or elderly patients. 
 
Ketoacidosis in Patients with Diabetes Mellitus

Dapagliflozin should not be used for the treatment of diabetic ketoacidosis (DKA). There have been reports of ketoacidosis, including DKA, a serious life-threatening condition requiring urgent hospitalization in patients taking dapagliflozin and other sodium-glucose co-transporter 2 (SGLT2) inhibitors. Fatal cases of ketoacidosis have been reported in patients taking dapagliflozin. Patients treated with Dapagliflozin who present with signs and symptoms consistent with ketoacidosis, including nausea, vomiting, abdominal pain, malaise and shortness of breath, should be assessed for ketoacidosis, even if blood glucose levels are below 14 mmol/L (250 mg/dL). If ketoacidosis is suspected, Dapagliflozin should be suspended, the patient should be evaluated and prompt treatment initiated. 

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. 
Surgery Treatment with Dapagliflozin should be ceased prior to major surgery. An increase in other glucose lowering agents may be required during this time. Patients scheduled for non-urgent surgery who have not ceased dapagliflozin should be assessed and consideration should be given to postponing the procedure. Treatment with Dapagliflozin may be restarted once the patient’s condition has stabilized and oral intake is normal.

 
Urinary Tract Infections

There have been post-marketing reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization in patients receiving SGLT2 inhibitors, including Dapagliflozin. Urinary tract infections were more frequently reported for dapagliflozin 10 mg compared to control in a placebo-pooled analysis up to 24 weeks (4.7% vs. 3.5%, respectively). Urinary glucose excretion may be associated with an increased risk of urinary tract infection. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated (see adverse effects (Undesirable effects)). 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; see adverse effects (Undesirable effects). 
Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) Post-marketing cases of necrotizing fasciitis of the perineum (also known as Fournier’s gangrene), a rare, but serious and potentially life-threatening necrotizing infection, have been reported in female and male patients with diabetes mellitus treated with SGLT2 inhibitors, including dapagliflozin (see (Adverse effects (Undesirable effects)). Serious outcomes have included hospitalization, multiple surgeries, and death. Patients treated with Dapagliflozin who present with pain or tenderness, erythema, swelling in the genital or perineal area, fever, and malaise should be evaluated for necrotizing fasciitis. If suspected, Dapagliflozin should be discontinued and prompt treatment should be instituted (including broad-spectrum antibiotics and surgical debridement if necessary). 
Lower Limb Amputations In one long-term clinical study with another SGLT2 inhibitor, an increase in cases of lower limb amputation (primarily of the toe) has been observed. The medicine in that study is not dapagliflozin. However, it is unknown whether this constitutes a class effect. It is important to regularly examine the feet and counsel all patients with diabetes on routine preventative foot care. 
 
Use with Medications Known to Cause Hypoglycemia Insulin and insulin secretagogues, such as sulfonylureas, cause hypoglycemia. Therefore, a lower dose of insulin or the insulin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with Dapagliflozin (see adverse effects (Undesirable effects)). 
 
Pediatric Use

Safety and effectiveness of Dapagliflozin in pediatric patients have not been established. Delayed growth and metabolic acidosis in rats were observed in both sexes at higher doses (greater than or equal to 15 mg/kg/day). The developmental age of animals in this study approximately correlates to 2 to 16 years in humans. 
Use in the Elderly No dosage adjustment for Dapagliflozin is required based on age (see Dose and administration). Older patients are more likely to have impaired renal function. The renal function recommendations provided for all patients also apply to elderly patients (see Special warnings and precautions for use). 
 
Cardiac Failure

There is limited clinical experience in patients with NYHA class IV. 
 
Effects on Laboratory Tests

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. Haematocrit In the pool of 13 short-term placebo-controlled studies (see adverse effects (Undesirable effects)), increases from baseline in mean hematocrit values were observed in Dapagliflozintreated patients starting at Week 1. 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. In the pool of 9 placebo-controlled studies with short-term and long-term data, at week 102, the mean changes in hematocrit values were 2.68% vs. -0.46%, respectively. Results for hematocrit values >55% during the short-term plus long-term phase (the majority of patients were exposed to treatment for more than one year), were similar to week 24. Most patients with marked abnormalities of elevated hematocrit or hemoglobin had elevations measured a single time that resolved at subsequent visits. 
 
Serum Inorganic Phosphorus In the pool of 13 short-term placebo-controlled studies, increases from baseline in mean serum phosphorus levels were reported at Week 24 in Dapagliflozin-treated patients compared with placebo-treated patients (mean increase of 0.042 mmol/L versus -0.0013 mmol/L, respectively). Higher proportions of patients with marked laboratory abnormalities of hyperphosphataemia (≥1.81 mmol/L for age 17-65 years or ≥1.65 mmol/L for age ≥66 years) were reported on DFLOZ at Week 24 (0.9% versus 1.7% for placebo and Dapagliflozin 10 mg, respectively). In the pool of 9 placebo-controlled studies with short-term and long-term data, at week 102, reported increases in mean serum phosphorus were similar to week 24 results. During the shortterm plus long-term phase laboratory abnormalities of hyperphosphataemia were reported in a higher proportion of patients in the Dapagliflozin group compared to placebo (3.0% vs. 1.6%, respectively). The clinical relevance of these findings is unknown. 
Lipids In the 13-study short-term placebo-controlled pool, small changes from baseline in mean lipid values were reported at week 24 in Dapagliflozin 10 mg treated patients compared with placebo (see Adverse effects (Undesirable effects)). Mean percent change from baseline at week 24 for Dapagliflozin 10 mg vs. placebo, respectively was as follows: total cholesterol 2.5% vs. 0.0%; HDL cholesterol 6.0% vs. 2.7%; LDL cholesterol 2.9% vs. -1.0%; triglycerides -2.7% vs. -0.7%. The ratio between LDL cholesterol and HDL cholesterol decreased for both treatment groups at week 24. In the pool of 9 placebo-controlled studies with short-term and long-term data, the mean percent change from baseline at week 102 for Dapagliflozin 10 mg vs. placebo, respectively was as follows: total cholesterol 2.1% vs.-1.5%; HDL cholesterol 6.6% vs. 2.1%; LDL cholesterol 2.9% vs. -2.2%; triglycerides -1.8% vs. -1.8%. 

In the cardiovascular outcomes study, no clinical important differences in total cholesterol, HDL cholesterol, LDL cholesterol or triglycerides were seen. 
Liver Function Tests In the 21-study active and placebo-controlled pool (see adverse effects (Undesirable effects)), there was no imbalance across treatment groups in the incidence of elevations of ALT or AST. ALT >3 x ULN was reported in 1.2% of patients treated with Dapagliflozin 10 mg and 1.6% treated with comparator. ALT or AST >3 x ULN and bilirubin >2 x ULN was reported in 0.1% of patients on any dose of dapagliflozin, 0.2% of patients on Dapagliflozin, and 0.1% of patients on comparator. 
 
INTERACTIONS WITH OTHER MEDICINES AND OTHER FORMS OF INTERACTIONS 
The metabolism of dapagliflozin is primarily mediated by UGT1A9-dependent glucuronide conjugation. The major metabolite, dapagliflozin 3-O-glucuronide, is not an SGLT2 inhibitor. 
In in-vitro studies, dapagliflozin neither inhibited CYP 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4, nor induced CYP1A2, 2B6 or 3A4. Therefore, dapagliflozin is not expected to alter the metabolic clearance of co-administered drugs that are metabolized by these enzymes and drugs which inhibit or induce these enzymes are not expected to alter the metabolic clearance of dapagliflozin. Dapagliflozin is a weak substrate of the P-glycoprotein (P-gp) active transporter and dapagliflozin 3-O-glucuronide is a substrate for the OAT3 active transporter. Dapagliflozin or dapagliflozin 3-O-glucuronide did not meaningfully inhibit Pgp, OCT2, OAT1, or OAT3 active transporters. Overall, dapagliflozin is unlikely to affect the pharmacokinetics of concurrently administered medications that are P-gp, OCT2, OAT1, or OAT3 substrates. 
In interaction studies conducted in healthy subjects, using mainly single dose design, the pharmacokinetics of dapagliflozin were not altered by metformin (an hOCT-1 and hOCT-2 substrate), pioglitazone (a CYP2C8 [major] and CYP3A4 [minor] substrate), sitagliptin (an hOAT-3 substrate, and P-glycoprotein substrate), glimepiride (a CYP2C9 substrate), voglibose, hydrochlorothiazide, bumetanide, valsartan, or simvastatin (a CYP3A4 substrate). 
Therefore, meaningful interaction of dapagliflozin with other substrates of hOCT-1, hOCT-2, hOAT-3, P-gp, CYP2C8, CYP2C9, CYP3A4, and other α-glucosidase inhibitors would not be expected. 
Concomitant use of dapagliflozin and lithium may lead to a reduction in serum lithium concentrations due to a possible increased urinary clearance of lithium. The dose of lithium may need to be adjusted. 
Dapagliflozin also did not alter the pharmacokinetics of metformin, pioglitazone, sitagliptin, glimepiride, hydrochlorothiazide, bumetanide, valsartan, simvastatin, digoxin (a P-gp substrate), or warfarin (S-warfarin is a CYP2C substrate). Therefore, dapagliflozin is not a clinical meaningful inhibitor of hOCT-1, hOCT-2, hOAT-3, P-gp transporter pathway, and CYP2C8, CYP2C9, CYP2C19 and CYP3A4 mediated metabolism. 

Following co-administration of dapagliflozin with rifampicin (an inducer of various active transporters and drug-metabolizing enzymes) or mefenamic acid (an inhibitor of UGT1A9), a 22% decrease and a 51% increase, respectively, in dapagliflozin systemic exposure was seen, but with no clinically meaningful effect on 24-hour urinary glucose excretion in either case. 
No dose adjustment of dapagliflozin is recommended when dapagliflozin is co-administered with either rifampicin or mefenamic acid. 
Other Interactions The effects of smoking, diet, herbal products, and alcohol use on the pharmacokinetics of dapagliflozin have not been specifically studied. 
 
FERTILITY, PREGNANCY AND LACTATION

Effects on Fertility In a study of fertility in rats, no effects on mating, fertility, or early embryonic development were seen when males received oral doses up to 210 mg/kg/day or when females received oral doses up to 75 mg/kg/day (yielding plasma AUC values at least 1000 times the clinical exposure at the maximum recommended human dose [MRHD] of 10 mg/day). However, at 210 mg/kg/day, a dose associated with profound toxicity (including mortality), seminal vesicle and epididymal weights were reduced; sperm motility and sperm counts were reduced; and there were increased numbers of morphologically abnormal sperm. No adverse effects on sperm or male reproductive organs were seen at 75 mg/kg/day (700 times the clinical exposure at the MRHD). 

Use in Pregnancy – Category D

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 (see Special warnings and precautions for use). Therefore, Dapagliflozin must not be used during the second and third trimesters of pregnancy. When pregnancy is detected, treatment with Dapagliflozin should be discontinued. In conventional studies of embryofoetal development in rats and rabbits, dapagliflozin was administered for intervals coinciding with the period of organogenesis in humans. An increased incidence of embryofoetal lethality, decreased fetal weight and an increased incidence of fetal visceral and skeletal anomalies were seen in rats at maternotoxic doses (oral doses greater than or equal to 150 mg/kg/day). The no observed effect level for embryofoetal effects in rats was an oral dose of 75 mg/kg/day (1530 times the exposure in patients at the maximum recommended human dose [MRHD]). No developmental toxicities were observed in rabbits at oral doses up to 180 mg/kg/day (1265 times the exposure in patients at the MRHD). 

Use in Lactation

Dapagliflozin must not be used by breastfeeding women. It is not known whether dapagliflozin or its metabolites are excreted in human milk. Studies in rats have shown excretion of dapagliflozin in milk. Direct and indirect exposure of dapagliflozin to weanling juvenile rats and during late pregnancy are each associated with increased incidence and/or severity of renal pelvic and tubular dilatations in progeny. The long-term functional consequences of these effects are unknown. These periods of exposure coincide with a critical window of renal maturation in rats. As functional maturation of the kidneys in humans continues in the first 2 years of life, dapagliflozin-associated dilated renal pelvis and tubules noted in juvenile rats could constitute potential risk for human renal maturation during the first 2 years of life. Additionally, the negative effects on body weight gain associated with lactational exposure in weanling juvenile rats suggest that Dapagliflozin must be avoided during the first 2 years of life. 

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES

No studies on the effects on the ability to drive and use machines have been performed. Patients should be alerted to the risk of hypoglycemia when dapagliflozin is used in combination with a sulfonylurea or insulin. 

ADVERSE EFFECTS (UNDESIRABLE EFFECTS) 
 
Infections and Infestations

 Genital Infection

 Urinary tract infection 
 
Musculoskeletal and Connective Tissue Disorders

 Back pain  

 Renal and Urinary disorders

 Polyuria 
 
Metabolism and Nutrition Disorders

 Hypoglycemia 
 
Genital infection includes the preferred terms, listed in order of frequency reported: vulvovaginal mycotic infection, vaginal infection, balanitis, genital infection fungal, vulvovaginal candidiasis, vulvovaginitis, and balanitis candida, genital candidiasis, genital infection, genital infection male, penile infection, vulvitis, vaginitis bacterial, and vulval abscess. 

Urinary tract infection includes the following preferred terms, listed in order of frequency reported: urinary tract infection, cystitis, Escherichia urinary tract infection, genitourinary tract infection, pyelonephritis, trigonitis, urethritis, kidney infection, and prostatitis. 

Metabolism and Nutrition Disorders – Ketoacidosis 

Infections And Infestations – Pyelonephritis, urosepsis, necrotizing fasciitis of the perineum (Fournier’s gangrene) 
Skin And Subcutaneous Tissue Disorders – Rash, angioedema 

OVERDOSE

Orally administered dapagliflozin has been shown to be safe and well tolerated in healthy subjects at single doses up to 500 mg (50 times the MRHD). 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 hypoglycemia was similar to placebo. In clinical studies where once-daily doses of up to 100 mg (10 times the MRHD) were administered for 2 weeks in healthy subjects and patients with type 2 diabetes, the incidence of hypoglycemia 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 hemodialysis has not been studied. 
 
PHARMACOLOGICAL PROPERTIES 

PHARMACODYNAMIC PROPERTIES 

Mechanism of Action

Dapagliflozin is a reversible competitive inhibitor of sodium glucose co-transporter 2 (SGLT2) with Nano molar potency that improves glycemic control in patients with type 2 diabetes mellitus and provides cardio-renal benefits. 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 intra glomerular 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 preserve renal function. Other effects include an increase in hematocrit and reduction in body weight. 
The cardio-renal benefits of dapagliflozin are not solely dependent on the blood glucose lowering effect and not limited to patients with diabetes. In addition to the osmotic diuretic and related hemodynamic actions of SGLT2 inhibition, potential secondary effects on myocardial metabolism, ion channels, fibrosis, adipokines and uric acid may be mechanisms underlying the cardio-renal beneficial effects of dapagliflozin. 
Dapagliflozin improves both fasting plasma glucose (FPG) and post-prandial plasma glucose (PPG) 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 eGFR, 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. Over time, improvement in beta cell function (HOMA-2) has been observed in clinical studies with dapagliflozin. 
The majority of the weight reduction was body fat loss, including visceral fat rather than lean tissue or fluid loss as demonstrated by dual energy X-ray absorptiometry (DXA) and magnetic resonance imaging. 
SGLT2 is selectively expressed in the kidney. Dapagliflozin does not inhibit other glucose transporters important for glucose transport into peripheral tissues and is approximately 10003000 times more selective for SGLT2 vs. SGLT1, the major transporter in the gut responsible for glucose absorption. 

PHARMACOKINETIC PROPERTIES 

Absorption

Dapagliflozin was rapidly and well absorbed after oral administration and can be administered with or without food. Maximum dapagliflozin plasma concentrations (Cmax) were usually attained within 2 hours after administration in the fasted state. The Cmax and AUC values increased proportional to the increment in dapagliflozin dose. The absolute oral bioavailability of dapagliflozin following the administration of a 10 mg dose is 78%. Food had relatively modest effects on the pharmacokinetics of dapagliflozin in healthy subjects. 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. 

Distribution

Dapagliflozin is approximately 91% protein bound. Protein binding was not altered in various disease states (e.g., renal or hepatic impairment). 
 
Metabolism

Dapagliflozin is extensively metabolized, primarily to yield dapagliflozin 3-O-glucuronide. Dapagliflozin 3-O-glucuronide, with a molar plasma AUC 52% higher than that of dapagliflozin itself at the clinical dose, is an inactive metabolite and does 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. 

Excretion

Dapagliflozin and related metabolites are primarily eliminated via urinary excretion, of which less than 2% is unchanged dapagliflozin. After oral administration of 50 mg [14C]-dapagliflozin dose, 96% was recovered, 75% in urine and 21% in faces. In faces, approximately 15% of the dose was excreted as parent drug. The mean plasma terminal half-life (t1/2) for dapagliflozin was 12.9 hours following a single oral dose of DFLOZ 10 mg to healthy subjects. 
 

Special Populations No dosages adjustments based on pharmacokinetic analyses are recommended for mild, moderate and severe renal impairment, mild, moderate, and severe hepatic impairment, age, gender, race and body weight. 
 
Renal Impairment

At steady-state (20 mg once-daily dapagliflozin for 7 days), patients with type 2 diabetes and mild, moderate or severe renal impairment (as determined by iohexol clearance) had mean systemic exposures of dapagliflozin that were 32%, 60% and 87% higher, respectively, than those of patients with type 2 diabetes and normal renal function. At dapagliflozin 20 mg oncedaily, higher systemic exposure to dapagliflozin in patients with type 2 diabetes mellitus and renal impairment did not result in a correspondingly higher renal glucose clearance or 24 hour glucose excretion. The renal glucose clearance and 24 hour glucose excretion was lower in patients with moderate or severe renal impairment as compared to patients with normal and mild renal impairment. The steady-state 24-h urinary glucose excretion was highly dependent on renal function and 85, 52, 18 and 11 g of glucose/day was excreted by patients with type 2 diabetes mellitus and normal renal function or mild, moderate or severe renal impairment, respectively. There were no differences in the protein binding of dapagliflozin between renal impairment groups or compared to healthy subjects. 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

A single dose (10 mg) dapagliflozin clinical pharmacology study was conducted in patients with mild, moderate or severe hepatic impairment (Child-Pugh classes A, B, and C, respectively) and healthy matched controls in order to compare the pharmacokinetic characteristics of dapagliflozin between these populations. There were no differences in the protein binding of dapagliflozin between hepatic impairment groups or compared to healthy subjects. In patients with mild or moderate hepatic impairment 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 and no dose adjustment from the proposed usual dose of 10 mg once daily for dapagliflozin is proposed for these populations. In patients with severe hepatic impairment (Child-Pugh class C) mean Cmax and AUC of dapagliflozin were up to 40% and 67% higher than matched healthy controls, respectively. DFLOZ should not be used in patients with severe hepatic impairment (see Special warnings and precautions for use). Age No dosage adjustment for dapagliflozin is recommended on the basis of age. The effect of age (young: ≥18 to <40 years [n=105] and elderly: ≥65 years [n=224]) was evaluated as a covariate in a population pharmacokinetic model and compared to patients ≥40 to <65 years using data from healthy subject and patient studies). The mean dapagliflozin systemic exposure (AUC) in young patients was estimated to be 10.4% lower than in the reference group [90% CI: 87.9, 92.2%] and 25% higher in elderly patients compared to the reference group [90% CI: 123, 129%]. 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 and Adolescent

Pharmacokinetics in the pediatric and adolescent population have not been studied. 
 
Gender

No dosage adjustment from the dose of 10 mg once daily is recommended for dapagliflozin on the basis of gender. Gender was evaluated as a covariate in a population pharmacokinetic model using data from healthy subject and patient studies. The mean dapagliflozin AUCss in females (n=619) was estimated to be 22% higher than in males (n=634) [90% CI: 117,124]. 
 
Race

No dosage adjustment from the dapagliflozin dose of 10 mg once daily is recommended on the basis of race. Race (white, black [African descent] or Asian) was evaluated as a covariate in a population pharmacokinetic model using data from healthy subject and patient studies. Differences in systemic exposures between these races were small. Compared to whites (n=1147), Asian subjects (n=47) had no difference in estimated mean dapagliflozin systemic exposures [90% CI range 3.7% lower, 1% higher]. Compared to whites, black (African descent) subjects (n=43) had 4.9% lower estimated mean dapagliflozin systemic exposures [90% CI range 7.7% lower, 3.7% lower]. 

Body Weight

No dose adjustment from the proposed dapagliflozin dose of 10 mg once daily is recommended in patients with diabetes mellitus or in patients without diabetes on the basis of weight. In a population pharmacokinetic analysis using data from healthy subject and patient studies, systemic exposures in high body weight subjects (≥120 kg, n=91) were estimated to be 78.3% [90% CI: 78.2, 83.2%] of those of reference subjects with body weight between 75 and 100 kg. This difference is considered to be small, therefore, no dose adjustment from the proposed dose of 10 mg dapagliflozin once daily in type 2 diabetes mellitus patients with high body weight (≥120 kg) is recommended. 
Subjects with low body weights (<50 kg) were not well represented in the healthy subject and patient studies used in the population pharmacokinetic analysis. Therefore, dapagliflozin systemic exposures were simulated with a large number of subjects. The simulated mean dapagliflozin systemic exposures in low body weight subjects were estimated to be 29% higher than subjects with the reference group body weight. This difference is considered to be small and based on these findings no dose adjustment from the proposed dose of 10 mg dapagliflozin once daily in patients with type 2 diabetes mellitus with low body weight (<50 kg) is recommended. 
 

PRECLINICAL SAFETY DATA 
Genotoxicity

Dapagliflozin was positive in an in-vitro clastogenicity assay in the presence of metabolic activation. However, dapagliflozin was negative in the Ames mutagenicity assay and in a series of in-vivo clastogenicity studies evaluating micronuclei or DNA repair in rats at exposure multiples at least 2100 times the human exposure at the MRHD. The weight of evidence from these studies, along with the absence of tumor findings in the rat and mouse carcinogenicity studies, support that dapagliflozin is not genotoxic. 
 
Carcinogenicity

Dapagliflozin did not induce tumors in two-year carcinogenicity studies in mice or rats at oral doses up to 40 mg/kg/day and 10 mg/kg/day respectively. These doses correspond to AUC exposure levels at least 78 times the human AUC at the MRHD of 10 mg/day. 
 
SPECIAL PRECAUTIONS FOR STORAGE

The tablets should be stored below 30°C.