Pharmacology: Mechanism of Action: XIGDUO XR: XIGDUO XR combines two antihyperglycemic agents with complementary mechanisms of action to improve both fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) in patients with type 2 diabetes: dapagliflozin, an SGLT2 inhibitor, and metformin hydrochloride, a member of the biguanide class.
Dapagliflozin:
Dapagliflozin is a highly potent, selective, and reversible inhibitor of sodium glucose cotransporter 2 (SGLT2) that improves glycemic control in patients with type 2 diabetes mellitus by reducing renal glucose reabsorption leading to urinary excretion of excess glucose (glucuresis). Dapagliflozin is orally available and requires once-daily dosing.
SGLT2 is selectively expressed in the kidney with no expression detected in more than 70 other tissues including liver, skeletal muscle, adipose tissue, breast, bladder, and brain. SGLT2 is the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation. Despite the presence of hyperglycemia in type 2 diabetes mellitus, reabsorption of filtered glucose continues. Dapagliflozin reduces maximum tubular glucose transport by 55% and reduces renal glucose reabsorption such that glucose appears in the urine at normal plasma glucose levels. Thus, dapagliflozin improves both fasting and postprandial plasma glucose levels by reducing renal glucose reabsorption leading to urinary excretion of excess glucose. 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 healthy subjects with normal glucose, dapagliflozin has a low propensity to cause hypoglycemia. 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.
Urinary glucose excretion (glucuresis) induced by dapagliflozin is associated with caloric loss and reduction in weight. The majority of weight reduction is 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. Inhibition of glucose and sodium co-transport by dapagliflozin is also associated with mild diuresis and transient natriuresis.
Dapagliflozin does not inhibit other glucose transporters important for glucose transport into peripheral tissues and is greater than 1400 times more selective for SGLT2 versus SGLT1, the major transporter in the gut responsible for glucose absorption.
Metformin hydrochloride:
Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with type 2 diabetes or normal subjects (except in special circumstances, see Precautions) and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.
Pharmacodynamics: General: Dapagliflozin: 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 (Figure 1). 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 patients with type 2 diabetes mellitus for 12 weeks. This glucose elimination rate approached the maximum glucose excretion observed at 20 mg/day of dapagliflozin. Evidence of sustained glucose excretion was seen in patients 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. Urinary volume increases in patients 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 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. (See Figure 1.)
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Cardiac Electrophysiology: Dapagliflozin was not associated with clinically meaningful prolongation of QTc interval at daily doses up to 150 mg (15 times the recommended dose) in a study of healthy subjects. In addition, no clinically meaningful effect on QTc interval was observed following single doses of up to 500 mg (50 times the recommended dose) dapagliflozin in healthy subjects.
Clinical Trial Information: The Co-administration of dapagliflozin and metformin IR or XR has been studied in patients with type 2 diabetes inadequately controlled on metformin. Treatment with dapagliflozin plus metformin at all doses, produced clinically relevant and statistically significant improvements in mean change from baseline at Week 24 in HbA1c, and fasting plasma glucose (FPG) compared to control.
In a dedicated clinical study, decrease in weight was mainly attributable to a reduction in body-fat mass as measured by DXA. Dapagliflozin twice-daily treatment added to metformin was shown to be effective and safe in type 2 diabetic patients.
Additionally, dapagliflozin 10 mg or placebo were studied in type 2 diabetes patients with cardiovascular disease (approximately 37% of patients across 2 studies received dapagliflozin 10 mg or placebo plus metformin alone and type 2 diabetes patients with hypertension (approximately 90% of patients across 2 studies received dapagliflozin 10 mg or placebo plus metformin). In two studies of dapagliflozin 10 mg in type 2 diabetes patients with cardiovascular disease, statistically significant improvements in HbA1c and significant reductions in body weight and seated systolic blood pressure were seen at Week 24 in patients treated with dapagliflozin 10 mg compared to those treated with placebo, and were sustained through Week 104. In two studies of dapagliflozin 10 mg in type 2 diabetes patients with cardiovascular disease, statistically significant improvements in HbA1c and significant reductions in body weight and seated systolic blood pressure were seen at Week 24 in patients treated with dapagliflozin 10 mg compared to those treated with placebo, and were sustained through Week 104. In two studies of dapagliflozin 10 mg in type 2 diabetes patients with hypertension, statistically significant reductions in mean seated systolic blood pressure were also seen in patients treated with dapagliflozin combined with other OADs and antihypertensive treatments (an ACE or ARB in one study and an ACE or ARB plus one additional antihypertensive treatment in another study) compared to those treated with placebo at Week 12.
There have been no clinical efficacy studies conducted with XIGDUO XR/XIGDUO IR; however, XIGDUO XR/XIGDUO IR is considered to be equivalent to co-administered dapagliflozin and metformin hydrochloride extended-release and immediate-release tablets (see Pharmacokinetics as follows).
Addition of dapagliflozin to metformin IR: A total of 546 patients with type 2 diabetes with inadequate glycemic control (HbA1c ≥7% and ≤10%) participated in a 24-week, placebo-controlled study with a 78-week controlled, blinded extension period to evaluate dapagliflozin in combination with metformin. Patients on metformin at a dose of at least 1500 mg/day were randomized after completing a 2-week, single-blind, placebo lead-in period. Following the lead-in period, eligible patients were randomized to dapagliflozin 2.5 mg, 5 mg or 10 mg, or placebo in addition to their current dose of metformin.
As add-on treatment to metformin, dapagliflozin 10 mg provided significant improvements in HbA1c, and FPG, and significant reduction in body weight compared with placebo at week 24 (Table 1). At Week 102, adjusted mean change from baseline in HbA1c (Figure 2), FPG, and body weight was -0.78%, -24.5 mg/dL, and -2.81 kg, respectively, for patients treated with dapagliflozin 10 mg plus metformin and 0.02%, -10.4 mg/dL, and -0.67 kg for patients treated with placebo plus metformin based on the longitudinal repeated measures analysis excluding data after rescue. The proportion of patients who were rescued or discontinued for lack of glycemic control during the 24-week double-blind treatment period (adjusted for baseline HbA1c) was higher in the placebo plus metformin group (15.0%) than in the dapagliflozin 10 mg plus metformin group (4.4%). By week 102 (adjusted for baseline HbA1c), more patients treated with placebo plus metformin (60.1%) required rescue therapy than patients treated with dapagliflozin 10 mg plus metformin (44.0%). (See Table 1 and Figure 2.)
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Click on icon to see table/diagram/image
Dapagliflozin twice-daily add-on to metformin IR: A total of 399 patients with type 2 diabetes and inadequate glycemic control on metformin alone were randomized in this 16-week, placebo-controlled study to evaluate dapagliflozin 2.5 mg twice daily and 5 mg twice daily as add-on therapy to metformin. Recruitment was stratified by HbA1c <7.0% (approximately 15% of patients) and HbA1c ≥7.0% (approximately 85% of patients) at randomization. Patients on metformin at a dose of at least 1500 mg per day were randomized following a 4-week single-blind, placebo lead-in period to dapagliflozin 5 mg, dapagliflozin 2.5 mg or placebo twice daily. An additional double-blind arm of the study included patients received 10 mg dapagliflozin once daily co-administered with metformin as a 'positive control', a measure of assay sensitivity. Efficacy and safety in this dapagliflozin once-daily treatment arm was compared only to placebo co-administered with metformin.
As add-on treatment to metformin, dapagliflozin 5 mg twice daily provided significant improvements in HbA1c and FPG, and significant reduction in body weight compared with placebo twice daily at Week 16 and was consistent with glycemic and body-weight changes seen with dapagliflozin 10 mg once-daily treatment (see Table 2). Dapagliflozin 2.5 mg plus metformin twice-daily treatment also significantly improved HbA1c (-0.52%) compared to placebo plus metformin twice-daily treatment (-0.30%) at Week 16 (p<0.05). (See Table 2.)
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The proportion of patients who were discontinued for lack of glycemic control during the 16- week double-blind treatment period (adjusted for baseline HbA1c) was higher in the placebo twice daily plus metformin group (5.0%) than in the dapagliflozin 2.5 mg twice daily plus metformin group (1%). No patients in the dapagliflozin 5 mg twice daily plus metformin group discontinued due to inadequate glycemic control.
Active Glipizide-Controlled Study Add-On to Metformin Immediate-Release: A total of 816 patients with type 2 diabetes with inadequate glycemic control (HbA1c >6.5% and ≤10%) were randomized in a 52-week, glipizide-controlled non-inferiority study with a 156-week extension period to evaluate dapagliflozin as add-on therapy to metformin. Patients on metformin at a dose of at least 1500 mg per day were randomized following a 2-week placebo lead-in period to glipizide or dapagliflozin (5 mg or 2.5 mg, respectively) and were up titrated over 18 weeks to optimal glycemic effect (FPG <110 mg/dL, <6.1 mmol/L) or to the highest dose level (up to glipizide 20 mg and dapagliflozin 10 mg) as tolerated by patients. Thereafter, doses were kept constant, except for down-titration to prevent hypoglycemia. Rescue for lack of glycemic control was not available in this study through Week 104, but was available between Weeks 105 and 208.
At the end of the titration period, 87% of patients treated with dapagliflozin had been titrated to the maximum study dose (10 mg), versus 73% treated with glipizide (20 mg). Dapagliflozin led to a similar mean reduction in HbA1c from baseline to Week 52, compared with glipizide, thus demonstrating non-inferiority (Table 3). Dapagliflozin treatment led to a significant mean reduction in body weight from baseline to week 52 compared with a mean increase in body weight in the glipizide group.
At Weeks 104 and 208, adjusted mean changes from baseline in HbA1c were -0.32% and -0.10%, and changes in body weight were -3.70 kg and -3.95 kg, respectively, for patients treated with dapagliflozin; adjusted mean changes from baseline in HbA1c were -0.14% and 0.20%, respectively, and changes in body weight were 1.36 kg and 1.12 kg, respectively, for patients treated with glipizide based on the longitudinal repeated measures analysis (Figures 3 and 4). The percent of patients achieving weight loss of ≥5% (adjusted) at Weeks 104 and 208 were 23.8% and 10.2%, respectively, for patients treated with dapagliflozin and 2.8% and 1.8%, respectively, for patients treated with glipizide.
By Weeks 52, 104, and 208, the proportion of patients who discontinued or were rescued for lack of glycemic control (adjusted for baseline HbA1c) were higher for glipizide plus metformin (3.6%, 21.6%, and 44.9%, respectively) than for XIGDUO plus metformin (0.2%, 14.5%, and 39.4%, respectively). At 52, 104, and 208 weeks, respectively, a significantly lower proportion of patients treated with dapagliflozin (3.5%, 4.3%, and 5.0%) experienced at least one event of hypoglycemia, compared to glipizide (40.8%, 47.0%, and 50.0%). (See Table 3, Figure 3 and Figure 4.)
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Click on icon to see table/diagram/image
Click on icon to see table/diagram/image
Dapagliflozin Dual Energy X-ray Absorptiometry in Diabetic Patients: Due to the mechanism of action of dapagliflozin, a study was done to evaluate body composition and bone mineral density in 182 patients with type 2 diabetes. Treatment with dapagliflozin 10 mg added on to metformin IR over a 24-week period provided significant improvements compared with placebo plus metformin, respectively, in body weight (mean change from baseline: -2.96 kg vs. -0.88 kg), waist circumference (mean change from baseline: -2.51 cm vs. -0.99 cm), and body-fat mass as measured by DXA (mean change from baseline -2.22 kg vs. -0.74 kg) rather than lean tissue or fluid loss. Dapagliflozin plus metformin treatment showed a numerical decrease in visceral adipose tissue compared with placebo plus metformin treatment (mean change from baseline: -322.6 cm3 vs. -8.7 cm3 ) in a MRI substudy. Week 24 was analyzed using last observation carried forward (LOCF) analysis including data after rescue.
At Week 24, 2 patients (2.2%) in the placebo plus metformin group and no patients in the dapagliflozin 10 mg plus metformin group were rescued for lack of glycemic control.
At Week 50 and Week 102, improvements were sustained in the dapagliflozin 10 mg added on to metformin group compared with the placebo plus metformin group for body weight (adjusted mean change from baseline at Week 50: -4.39 kg vs. -2.03 kg; adjusted mean change from baseline at Week 102: -4.54 kg vs. -2.12 kg), waist circumference (adjusted mean change from baseline at Week 50: -5.0 cm vs. -3.0 cm; adjusted mean change from baseline at Week 102: -5.0 cm vs. -2.9 cm ), and body-fat mass as measured by DXA at Week 102 (mean change from baseline: -2.80 kg vs. -1.46 kg) based on the longitudinal repeated measures analysis including data after rescue. In an MRI substudy at Weeks 50 and 102, dapagliflozin plus metformin treatment showed a numerical decrease in visceral adipose tissue compared with placebo plus metformin treatment (adjusted mean change from baseline at Week 50: -120.0 cm3 vs. 61.5 cm3; adjusted mean change from baseline at Week 102: -214.9 cm3 vs. -22.3 cm3).
The proportion of patients at Week 50 (unadjusted for baseline HbA1c) and Week 102 (adjusted for baseline HbA1c) who were rescued or discontinued for lack of glycemic control was higher in the placebo plus metformin group (6.6% and 33.2%, respectively) than in the dapagliflozin 10 mg plus metformin group (2.2% and 13.5%, respectively). In an extension of this study to Week 50, there was no change in bone mineral density (BMD) for the lumbar spine, femoral neck, or total hip seen in either treatment group (mean decrease from baseline for all anatomical regions <0.5%). There was also no change in BMD in either treatment group up to Week 102 (mean decrease from baseline for all anatomical regions <1.0%). There were no clinically meaningful changes in markers of bone resorption or bone formation.
Pharmacokinetics: XIGDUO XR combination tablets are considered to be bioequivalent to Co-administration of corresponding doses of dapagliflozin and metformin hydrochloride (XR and IR) administered together as individual tablets.
Interaction with food: XIGDUO XR: The administration of XIGDUO XR in healthy subjects after a standard meal compared to the fasted state results in the same extent of exposure for both dapagliflozin and metformin XR. Compared to the fasted state, the standard meal results in 35% reduction and a delay of 1 to 2 hours in the peak plasma concentrations of dapagliflozin. This effect of food is not considered to be clinically meaningful.
Absorption: Dapagliflozin: Dapagliflozin is rapidly and well absorbed after oral administration and can be administered with or without food. Maximum dapagliflozin plasma concentrations (Cmax) are usually attained within 2 hours after administration in the fasted state. The Cmax and AUC values increase proportionally to the increment in dapagliflozin dose. The absolute oral bioavailability of dapagliflozin following the administration of a 10 mg dose is 78%.
Metformin hydrochloride XR: Following a single oral dose of metformin extended-release, Cmax is achieved with a median value of 7 hours and a range of 4 to 8 hours. At steady state, the AUC and Cmax are less than dose proportional for metformin extended-release within the range of 500 to 2000 mg administered once daily. Peak plasma levels are approximately 0.6, 1.1, 1.4, and 1.8 μg/mL for 500, 1000, 1500, and 2000 mg once-daily doses, respectively.
Distribution: Dapagliflozin: Dapagliflozin is approximately 91% protein-Bound. Protein binding is not altered in various disease states (e.g., renal or hepatic impairment).
Metformin hydrochloride: Distribution studies with extended-release metformin have not been conducted; however, the apparent volume of distribution (V/F) of metformin following single oral doses of immediate-release metformin 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as a function of time.
Metabolism: Dapagliflozin: Dapagliflozin is a C-linked glucoside, meaning the aglycone component is attached to glucose by a carbon-carbon bond, thereby conferring stability against glucosidase enzymes. The mean plasma terminal half-life (t1/2) for dapagliflozin is 12.9 hours following a single oral dose of dapagliflozin 10 mg to healthy subjects. Dapagliflozin is extensively metabolized primarily to yield dapagliflozin 3-O-glucuronide, which is an inactive metabolite. Dapagliflozin 3-O-glucuronide accounts for 61% of a 50 mg [14C]-dapagliflozin dose and is the predominant drug-related component in human plasma, accounting for 42% (based on AUC [0-12 h]) of total plasma radioactivity, similar to the 39% contribution by parent drug. Based on AUC, no other metabolite accounts for >5% of the total plasma radioactivity. 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 is a minor clearance pathway in humans.
Metformin hydrochloride: Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) or biliary excretion.
Metabolism studies with extended-release metformin tablets have not been conducted.
Elimination: Dapagliflozin: Dapagliflozin and related metabolites are primarily eliminated via urinary excretion, of which less than 2% is unchanged dapagliflozin. After administration of 50 mg [14C]-dapagliflozin dose, 96% is recovered, 75% in urine and 21% in feces. In feces, approximately 15% of the dose is excreted as parent drug.
Metformin hydrochloride: Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.
Specific Populations: Renal Impairment: XIGDUO XR: XIGDUO XR should not be used in patients with moderate to severe renal impairment [see Contraindications and Precautions].
Dapagliflozin: For dosing recommendations for patients with moderate to severe renal impairment see Dosage & Administration. 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 once-daily, 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-hour 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.
Metformin hydrochloride: In patients with decreased renal function (based on measured creatinine clearance), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance.
Hepatic Impairment: Dapagliflozin: For dosing recommendations for patients with moderate or severe hepatic impairment see Dosage & Administration. 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 patients with hepatic impairment 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. No dose adjustment is required for patients with severe hepatic impairment. However, the benefit risk for the use of dapagliflozin in patients with severe hepatic impairment should be individually assessed since the safety and efficacy of dapagliflozin have not been specifically studied in this population.
Metformin hydrochloride: No pharmacokinetic studies of metformin have been conducted in patients with hepatic impairment.
Age: Dapagliflozin: No dosage adjustment for dapagliflozin from the dose of 10 mg once daily 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%). These differences in systemic exposure were considered to not be clinically meaningful.
Metformin hydrochloride: Limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and Cmax is increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function.
Pediatric and Adolescent: Dapagliflozin: Pharmacokinetics in the pediatric and adolescent population have not been studied.
Metformin hydrochloride: After administration of a single oral metformin 500 mg tablet with food, geometric mean metformin Cmax and AUC differed less than 5% between pediatric type 2 diabetic patients (12-16 years of age) and gender- and weight-matched healthy adults (20-45 years of age), all with normal renal function.
Gender: Dapagliflozin: 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).
Metformin hydrochloride: Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes when analyzed according to gender (males=19, females=16). Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin was comparable in males and females.
Race: Dapagliflozin: No dosage adjustment from the dapagliflozin dose of 10 mg once daily is recommended on the basis of race. Race (White, Black, 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 subjects (n=43) had 4.9% lower estimated mean dapagliflozin systemic exposures [90% CI range 7.7% lower, 3.7% lower).
Metformin hydrochloride: No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type 2 diabetes, the antihyperglycemic effect was comparable in Whites (n=249), Blacks (n=51), and Hispanics (n=24).
Body Weight: No dose adjustments from the proposed dapagliflozin dose of 10 mg once daily is recommended 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 type 2 diabetes mellitus patients with low body weight (<50 kg) is recommended.
Toxicology: Preclinical safety data: Carcinogenesis, mutagenesis, impairment of fertility: Dapagliflozin: Dapagliflozin did not induce tumors in either mice or rats at any of the doses evaluated in two year carcinogenicity studies. Oral doses in mice consisted of 5, 15, and 40 mg/kg/day in males and 2, 10, and 20 mg/kg/day in females, and oral doses in rats were 0.5, 2, and 10 mg/kg/day for both males and females. The highest doses evaluated in mice were equivalent to AUC exposure multiples of approximately 72x (males) and 105x (females) the human AUC at MRHD of 10 mg/day. In rats, AUC exposures were approximately 131x (males) and 186x (females) the human AUC at the MRHD.
Dapagliflozin was negative in the Ames mutagenicity assay and was positive in an in-vitro clastogenicity assay, but only in the presence of S9 activation and at concentrations ≥ 100 μg/mL. Importantly, dapagliflozin was negative for clastogenicity in vivo in a series of studies evaluating micronuclei or DNA repair in rats at exposure multiples >2100x the human exposure at the MRHD. These studies, along with the absence of tumor findings in the rat and mouse carcinogenicity studies, support that dapagliflozin does not represent a genotoxic risk to humans.
Dapagliflozin-related gene transcription changes were evaluated in kidney, liver, adipose, and skeletal muscle of Zucker Diabetic Fatty (ZDF) rats treated daily with dapagliflozin for 5 weeks. These organs were specifically selected as they represent target organs in the treatment of diabetes. There was no evidence that dapagliflozin caused transcriptional changes that are predictive of tumor promoters.
Dapagliflozin and its primary human metabolite (3-O-glucuronide) did not enhance the in vitro growth of six human urinary bladder transitional cell carcinomas (TCC) cell lines at concentrations ≥100x human Cmax at the MRHD. In a mouse xenograft study, dapagliflozin administered daily to male and female nude mice implanted with human TCC tumors did not significantly enhance the size of tumors at exposures up to 75x and up to 0.9x clinical exposures at the MRHD for dapagliflozin and its 3-O-glucuronide metabolite, respectively.
These studies provide evidence that dapagliflozin and its primary human metabolite do not enhance urinary bladder tumor growth.
In a 15-month phenotyping study, there was no evidence of any difference in survival, body weights, clinical pathology parameters, or histopathologic findings observed between SGLT2 KO mice and their wild-type (WT) counterparts. SGLT2 KO mice had glucosuria, unlike the WT mice. Despite a lifetime of glucosuria, there was no evidence of any alteration of renal function or proliferative changes observed in the kidneys or urinary bladders of SGLT2 KO mice. These data strongly suggest that high levels of urinary glucose do not induce urinary tract tumors or accelerate age-related urinary tract pathology.
In a study of fertility and early embryonic development in rats, doses of 15, 75, or 300/210 mg/kg/day dapagliflozin were administered to males (the 300 mg/kg/day dose was lowered to 210 mg/kg/day after 4 days); and doses of 3, 15, or 75 mg/kg/day were administered to females. Dapagliflozin had no effects on mating, fertility, or early embryonic development in treated males or females at any dose tested (at exposure multiples ≤1708x and 998x the MRHD in males and females, respectively). However, at 300/210 mg/kg/day, seminal vesicle and epididymal weights were reduced; sperm motility and sperm counts were reduced; and there were low numbers of morphologically abnormal sperm.
Metformin hydrochloride: Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1500 mg/kg/day, respectively. These doses are both approximately 4 times the maximum recommended human daily dose of 2000 mg based on body-surface-area comparisons. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day.
There was no evidence of a mutagenic potential of metformin in the following in vitro tests: Ames test (
S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative.
Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately 3 times the maximum recommended human daily dose based on body-surface-area comparisons.
Teratogenicity and impairment of early development: Dapagliflozin: Direct administration of dapagliflozin to weanling juvenile rats, and indirect exposure during late pregnancy and lactation (time periods corresponding to the second and third trimesters of pregnancy with respect to human renal maturation), are each associated with increased incidence and/or severity of renal pelvic and tubular dilatations in progeny.
In a juvenile toxicity study, when dapagliflozin was dosed directly to young rats from postnatal day (PND) 21 until PND 90 at doses of 1, 15, or 75 mg/kg/day, renal pelvic and tubular dilatations were reported at all dose levels; pup exposures at the lowest dose tested were ≥15x the MRHD. These findings were associated with dose-related increases in kidney weight and macroscopic kidney enlargement observed at all doses. The renal pelvic and tubular dilatations observed in juvenile animals did not fully reverse within the approximate 1 month recovery period.
In a separate study of pre-natal and postnatal development, maternal rats were dosed from gestation day (GD) 6 through PND 21 (also at 1, 15, or 75 mg/kg/day), and pups were indirectly exposed in utero and throughout lactation. (A satellite study was conducted to assess dapagliflozin exposures in milk and pups.) Increased incidence or severity of renal pelvic dilatation was again observed in adult offspring of treated dams, although only at 75 mg/kg/day (associated maternal and pup dapagliflozin exposures were 1415x and 137x, respectively, the human values at the MRHD). Additional developmental toxicity was limited to dose-related reductions in pup body weights, and observed only at doses ≥15 mg/kg/day (associated with pup exposures that are ≥29x the human values at the MRHD). Maternal toxicity was evident only at 75 mg/kg/day, and limited to transient reductions in body weight and food consumption at dose initiation. The no-adverse-effect level (NOAEL) for developmental toxicity, 1 mg/kg/day, is associated with a maternal systemic exposure multiple that is approximately 19x the human value at the MRHD.
In additional studies of embryo-fetal development in rats and rabbits, dapagliflozin was administered for intervals coinciding with the major periods of organogenesis in each species. Neither maternal nor developmental toxicities were observed in rabbits at any dose tested (20, 60, or 180 mg/kg/day); 180 mg/kg/day is associated with a systemic exposure multiple of approximately 1191x the MRHD. In rats, dapagliflozin was neither embryo lethal nor teratogenic at doses up to 75 mg/kg/day (1441x the MRHD). Doses ≥150 mg/kg/day (≥2344x the human values at the MRHD) were associated with both maternal and developmental toxicities. Maternal toxicity included mortality, adverse clinical signs, and decrements in body weight and food consumption. Developmental toxicity consisted of increased embryo-fetal lethality, increased incidences of fetal malformations and skeletal variations, and reduced fetal body weights. Malformations included a low incidence of great vessel malformations, fused ribs and vertebral centras, and duplicated manubria and sternal centra. Variations were primarily reduced ossifications.
Metformin hydrochloride: Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about 2 and 6 times the maximum recommended human daily dose of 2000 mg based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.
Animal toxicology: A 3-month rat study was conducted with the combination of dapagliflozin and metformin. No toxicity was observed at AUC exposures 52 and 1.4 times the MRHD for dapagliflozin and metformin, respectively.
Dapagliflozin: Most of the effects observed in pivotal repeat-dose toxicity studies in both rats and dogs were considered to be secondary to pharmacologically mediated increases in urinary glucose and included decreases in body weights and/or body-weight gains, increased food consumption, and increases in urine volumes due to osmotic diuresis. Dapagliflozin was well tolerated when given orally to rats for up to 6 months at doses of ≤25 mg/kg/day (≥346x the human exposures at the MRHD) and in dogs for up to 12 months at doses of ≤120 mg/kg/day (≥3200x the human exposures at the MRHD). Also, single-dose studies with dapagliflozin indicated that the dapagliflozin 3-O-glucuronide metabolite would have been formed in both rat and dog toxicity studies at exposure levels (AUCs) that are greater than or approximately equal to anticipated human dapagliflozin 3-O-glucuronide exposures following administration of dapagliflozin at the MRHD. In rats, the most noteworthy nonclinical toxicity finding of increased trabecular bone and tissue mineralization (associated with increased serum calcium), was only observed at high-exposure multiples (≥2100x based on human exposures at the MRHD). Despite achieving exposure multiples of ≥3200x the human exposure at the MRHD, there was no dose-limiting or target-organ toxicities identified in the 12-month dog study.
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