Forxiga

Forxiga

Manufacturer:

AstraZeneca

Distributor:

DKSH
Full Prescribing Info
Contents
Dapagliflozin.
Description
Each film-coated tablet contains 10 mg dapagliflozin as dapagliflozin propanediol.
Dapagliflozin propanediol is described chemically as D-glucitol, 1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-,(1S)-, compounded with (2S)-1,2-propanediol, hydrate (1:1:1). The empirical formula is C21H25ClO6•C3H8O2•H2O and the molecular weight is 502.98.
Excipients/Inactive Ingredients: Microcrystalline cellulose, anhydrous lactose, crospovidone, silicon dioxide, and magnesium stearate.
Film coating: polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and yellow iron oxide.
Action
Pharmacology: Mechanism of Action: 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 (glucoresis).
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 (glucoresis) 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 cotransport 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.
Pharmacodynamics: General: Increases in the amount of glucose excreted in the urine were observed in healthy subjects and in patients with type 2 diabetes mellitus following the administration of dapagliflozin (see 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 FORXIGA 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: More than 28000 patients with type 2 diabetes mellitus had been treated in 22 double-blind, controlled clinical studies conducted to evaluate the safety and efficacy of FORXIGA; more than 15000 patients in these studies were treated with FORXIGA.
FORXIGA has been studied as monotherapy and in combination with metformin with or without a sulfonylurea), sulfonylurea (glimepiride), thiazolidinedione (pioglitazone), sitagliptin (with or without metformin), saxagliptin and metformin or insulin (with or without other oral antidiabetic therapy).
Dedicated studies of the glycemic efficacy and safety of FORXIGA were performed in patients with type 2 diabetes and cardiovascular disease (CVD), with type 2 diabetes and hypertension and with type 2 diabetes and moderate renal impairment (see Pharmacokinetics: Special populations as follows).
A large CV outcomes trial assessed the effect of dapagliflozin on CV and renal outcomes in type 2 diabetes mellitus patients with or without established CV disease.
Clinical efficacy: Glycemic efficacy: Treatment with FORXIGA as monotherapy, as add-on combination therapy with metformin (with or without a sulfonylurea), sulfonylurea (glimepiride), thiazolidinedione (pioglitazone), sitagliptin (with or without metformin), saxagliptin and metformin, or insulin (with or without other oral antidiabetic therapy), produced clinically relevant and statistically significant improvements in mean change from baseline at Week 24 in HbA1c, fasting plasma glucose (FPG), and 2-hour post-prandial glucose (PPG) (where measured) compared to control. Treatment with FORXIGA in concomitant initiation with saxagliptin as add-on to metformin produced clinically relevant and statistically significant improvements in mean change from baseline at Week 24 in HbA1c compared to control.
These clinically relevant glycemic effects were sustained in all long-term extensions up to 208 weeks. HbA1c reductions were seen across subgroups including gender, age, race, duration of disease, and baseline body mass index (BMI).
Additionally at Week 24, clinically relevant and statistically significant reductions in mean changes from baseline in body weight were seen with FORXIGA combination treatments compared to control. Body-weight reductions were sustained in long-term extensions up to 208 weeks. In a dedicated clinical study, decrease in weight was mainly attributable to a reduction in body-fat mass as measured by DXA.
In two studies of FORXIGA 10 mg in type 2 diabetes patients with CVD, 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 FORXIGA 10 mg compared to those treated with placebo, and were sustained through Week 104. In two studies of FORXIGA 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 FORXIGA 10 mg combined with other oral antidiabetic and antihypertensive treatments (an angiotensin-converting enzyme inhibitor (ACE) or angiotensin receptor blocker (ARB) in one study and an ACEi or ARB plus one additional antihypertensive treatment in another study) compared to those treated with placebo at Week 12.
FORXIGA was evaluated at 10 mg once daily in 19 of 21 double-blind glycemic efficacy studies. Doses of dapagliflozin 2.5 mg and FORXIGA 5 mg were also evaluated in some of these studies; 2.5 mg was not consistently effective for glycemic control, and 10 mg had numerically better efficacy and comparable safety to FORXIGA 5 mg.
Monotherapy: A total of 840 treatment-naive patients with inadequately controlled type 2 diabetes participated in two placebo-controlled studies to evaluate the efficacy and safety of monotherapy with FORXIGA.
In one monotherapy study, a total of 558 treatment-naive patients with inadequately controlled diabetes participated in a 24-week study with a 78-week controlled, blinded, extension period. Following a 2-week diet and exercise placebo lead-in period, 485 patients with HbA1c ≥7% and ≤10% were randomized to dapagliflozin 2.5 mg, FORXIGA 5 mg, or 10 mg once daily in either the morning (QAM, main cohort) or evening (QPM), or placebo in the morning only.
At Week 24, treatment with FORXIGA 10 mg QAM provided significant improvements in HbA1c and FPG compared with placebo (Table 1, Figure 2). Overall, the PM administration of FORXIGA had a comparable safety and efficacy profile to FORXIGA administered in the AM. Adjusted mean change from baseline in HbA1c and FPG was -0.61% and -27.0 mg/dL, respectively, at Week 102 in the QAM group for patients treated with FORXIGA 10 mg, and -0.17% and -6.9 mg/dL, respectively, for patients treated with placebo based on the longitudinal repeated measures analysis excluding data after rescue.
The proportion of patients in the main cohort who were rescued or discontinued for lack of glycemic control at Week 24 (adjusted for baseline HbA1c) was higher for placebo (12.0%) than for FORXIGA 10 mg (0.0%). By Week 102 (adjusted for baseline HbA1c), more patients treated with placebo (44.0%) required rescue therapy than patients treated with FORXIGA 10 mg (35.0%). (See Table 1 and Figure 2.)

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Another 24-week study conducted evaluating dapagliflozin 1 mg, 2.5 mg and FORXIGA 5 mg monotherapy versus placebo also showed clinically relevant and statistically significant improvements in glycemic parameters and body weight.
Combination Therapy: FORXIGA was studied as initial combination with metformin, and as add-on to metformin, sulfonylurea (glimepiride), metformin plus a sulfonylurea, thiazolidinedione (pioglitazone), insulin (with or without other oral antidiabetic therapy), sitagliptin (with or without metformin), or saxagliptin plus metformin, as concomitant initiation therapy with saxagliptin added to metformin.
Combination Therapy with Metformin: Four studies were conducted in combination with metformin therapy. Two studies evaluated FORXIGA added to metformin as initial combination therapy, one study evaluated the effect of FORXIGA added to metformin in patients already on metformin, and one study evaluated the effect of FORXIGA added to metformin versus sulfonylurea added to metformin.
Initial Combination Therapy with Metformin: A total of 1236 treatment-naive patients with inadequately controlled type 2 diabetes (HbA1c ≥7.5% and ≤12%) participated in two active-controlled studies of 24-weeks duration to evaluate the efficacy and safety of initial therapy with FORXIGA 5 mg or 10 mg in combination with metformin extended-release formulation (XR).
In one study, 638 patients were randomized to one of three treatment arms following a 1-week lead-in period: FORXIGA 10 mg plus metformin XR (up to 2000 mg per day), FORXIGA 10 mg plus placebo, or metformin XR (up to 2000 mg per day) plus placebo. Metformin XR dose was up-titrated weekly in 500 mg increments, as tolerated, with a median dose achieved of 2000 mg.
The combination treatment of FORXIGA 10 mg plus metformin XR provided significant improvements in HbA1c and FPG compared with either of the monotherapy treatments and significant reductions in body weight compared with metformin XR alone. (Table 2, Figures 3 and 4). FORXIGA 10 mg as monotherapy also provided significant improvements in FPG and significant reduction in body weight compared with metformin XR alone and was non-inferior to metformin XR monotherapy in lowering HbA1c. 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 on treatment with metformin XR plus placebo (13.5%) than on FORXIGA 10 mg plus placebo and FORXIGA 10 mg plus metformin XR (7.8% and 1.4%, respectively). (See Table 2, Figures 3 and 4.)

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Another 24-week study evaluating FORXIGA 5 mg plus metformin XR showed clinically relevant and statistically significant improvements in glycemic parameters versus FORXIGA 5 mg monotherapy and metformin XR monotherapy.
Add-on to Metformin: 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 FORXIGA in combination with metformin. Patients on metformin at a dose of at least 1500 mg per 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, FORXIGA 5 mg, or 10 mg, or placebo in addition to their current dose of metformin.
As add-on treatment to metformin, FORXIGA 10 mg provided significant improvements in HbA1c and FPG, and significant reduction in body weight compared with placebo at Week 24 (Table 3). At Week 102, adjusted mean change from baseline in HbA1c (see Figure 5), FPG, and body weight was -0.78%, -24.5 mg/dL, and -2.81 kg, respectively, for patients treated with FORXIGA 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 (Figure 5). 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 FORXIGA 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 FORXIGA 10 mg plus metformin (44.0%). (See Table 3 and Figure 5.)

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Active Glipizide Controlled Study Add-on to Metformin: A total of 816 patients with type 2 diabetes with inadequate glycemic control (HbA1c >6.5% and ≤10%) were randomized in this a 52-week, glipizide-controlled, non-inferiority study with a 156-week extension period to evaluate FORXIGA 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 FORXIGA 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 FORXIGA had been titrated to the maximum study dose (10 mg) versus 73% treated with glipizide (20 mg). FORXIGA led to a similar mean reduction in HbA1c from baseline at Week 52, compared with glipizide, thus demonstrating non-inferiority (Table 4). FORXIGA treatment led to a significant mean reduction in body weight from baseline at 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 -0.1% and changes in body weight were -3.70 kg and -3.95 kg, respectively, for patients treated with FORXIGA; 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 6 and 7). The percent of patients achieving weight loss of ≥5% (adjusted) at Weeks 104 and 208 were 23.8% and 51.0%, respectively, for patients treated with FORXIGA and 2.8% and 9.9%, 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 FORXIGA 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 FORXIGA (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 4, Figures 6 and 7.)

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Add-On Combination with Other Antidiabetic Agents: Add-on Combination Therapy with a Sulfonylurea: A total of 597 patients with type 2 diabetes and inadequate glycemic control (HbA1c ≥7% and ≤10%) were randomized in this 24-week, placebo-controlled study with a 24-week extension period to evaluate FORXIGA in combination with glimepiride (a sulfonylurea).
Patients on at least half the maximum recommended dose of a glimepiride as monotherapy (4 mg) for at least 8 weeks lead-in were randomized to dapagliflozin 2.5 mg, FORXIGA 5 mg, or 10 mg, or placebo in addition to glimepiride 4 mg per day. Down-titration of glimepiride to 2 mg or 0 mg was allowed for hypoglycemia during the treatment period; no up-titration of glimepiride was allowed.
In combination with glimepiride, treatment with FORXIGA 10 mg provided significant improvement in HbA1c, FPG, 2-hour PPG, and significant reduction in body weight compared with placebo plus glimepiride at Week 24 (Tables 5a, 5b and Figure 8). At Week 48, adjusted mean change from baseline in HbA1c, FPG, and body weight were -0.73%, -28.8 mg/dL, and -2.41 kg, respectively, for patients treated with FORXIGA 10 mg plus glimepiride, and -0.04%, 2.6 mg/dL, and -0.77 kg for patients treated with placebo plus glimepiride at Week 48 based on the longitudinal repeated measures analysis excluding data after rescue.
At week 24, the proportion of patients who were rescued or discontinued for lack of glycemic control (adjusted for baseline HbA1c) was higher for placebo plus glimepiride (16.2%) than for FORXIGA 10 mg plus glimepiride (2.0%). By Week 48 (adjusted for baseline HbA1c), more patients on placebo plus glimepiride (52.1%) required rescue therapy than patients on FORXIGA 10 mg plus glimepiride (18.4%).
Add-on combination therapy with metformin and a sulfonylurea: A total of 218 patients with type 2 diabetes and inadequate glycemic control (HbA1c ≥7% and ≤10.5%) participated in a 24-week, placebo-controlled study with a 28-week extension period to evaluate FORXIGA in combination with metformin and a sulfonylurea. Patients on a stable dose of metformin (immediate- or extended-release formulations) ≥1500 mg/day plus maximum tolerated dose, which must be at least half maximum dose, of a sulfonylurea for at least 8 weeks prior to enrollment were randomized after an 8-week placebo lead-in period to FORXIGA 10 mg or placebo. Dose-titration of FORXIGA or metformin was not permitted during the 24-week treatment period. Down-titration of sulfonylurea was permitted to prevent hypoglycemia, but no up-titration was permitted.
As add-on treatment to combined metformin and a sulfonylurea, treatment with FORXIGA 10 mg provided significant improvements in HbA1c and FPG and significant reductions in body weight compared with placebo at Week 24 (Tables 5a and 5b). Significant reduction in seated systolic blood pressure at Week 8 was also observed in patients treated with FORXIGA 10 mg compared to placebo. The effects in HbA1C, FPG and body weight observed at Week 24 were sustained at Week 52.
At Week 24, no patients treated with FORXIGA 10 mg combined with metformin and a sulfonylurea and 10 patients (9.3%) treated with placebo combined with metformin and a sulfonylurea were rescued or discontinued for lack of glycemic control (adjusted for baseline HbA1c). By week 52 (adjusted for baseline HbA1c) more patients on placebo combined with metformin and a sulfonylurea (42.7%) were rescued for lack of glycemic control than patients on FORXIGA (10.1%). No patient was discontinued from study medication due to inadequate glycemic control.
Add-on Combination Therapy with a Thiazolidinedione: A total of 420 patients with type 2 diabetes with inadequate glycemic control (HbA1c ≥7% and ≤10.5%) participated in a 24-week, placebo-controlled study with a 24-week extension period to evaluate FORXIGA in combination with pioglitazone (a thiazolidinedione) alone. Patients on a stable dose of pioglitazone of 45 mg/day (or 30 mg/day, if 45 mg/day not tolerated) for 12 weeks were randomized after a 2-week lead-in period to 5 mg or 10 mg of FORXIGA or placebo in addition to their current dose of pioglitazone. Dose titration of FORXIGA or pioglitazone was not permitted during the study.
In combination with pioglitazone, treatment with FORXIGA 10 mg provided significant improvements in HbA1c, 2-hour PPG, FPG, the proportion of patients achieving HbA1c <7% and a significant reduction in body weight compared with the placebo plus pioglitazone treatment groups (Tables 5a, 5b and Figure 9) at Week 24. Treatment with FORXIGA 10 mg plus pioglitazone also led to a significant reduction in waist circumference compared with the placebo plus pioglitazone group. At Week 48, adjusted mean change from baseline in HbA1c, FPG, and body weight were -1.21%, -33.1 mg/dL, and 0.69 kg, respectively, for patients treated with FORXIGA 10 mg plus pioglitazone, and -0.54%, -13.1 mg/dL, and 2.99 kg for patients treated with placebo 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 (adjusted for baseline HbA1c) was higher in the placebo plus pioglitazone group (11.6%) than in the FORXIGA 10 mg plus pioglitazone group (3.7%) at Week 24. By Week 48 (adjusted for baseline), more patients treated with placebo plus pioglitazone (33.8%) required rescue therapy than patients treated with FORXIGA 10 mg plus pioglitazone (11.8%).
Add-on Combination Therapy with Insulin: A total of 808 patients with type 2 diabetes who had inadequate glycemic control (HbA1c ≥7.5% and ≤10.5%) were randomized in a 24-week, placebo-controlled study with an 80-week extension period to evaluate FORXIGA as add-on therapy to insulin. Patients on a stable insulin regimen, with a mean dose of at least 30 IU of injectable insulin per day, for a period of at least 8 weeks prior and on a maximum of two OADs including metformin, were randomized after completing a 2-week enrollment period to receive dapagliflozin 2.5 mg, FORXIGA 5 mg, or 10 mg, or placebo in addition to their current dose of insulin and other OADs, if applicable. Patients were stratified according to the presence or absence of background OADs. Up- or down-titration of insulin was only permitted during the treatment phase in patients who failed to meet specific glycemic goals. Dose modifications of blinded study medication or OADs were not allowed during the treatment phase, with the exception of decreasing OADs where there were concerns over hypoglycemia after cessation of insulin therapy.
In this study, 50% of patients were on insulin monotherapy at baseline, while 50% were on 1 or 2 OADs in addition to insulin. At Week 24, FORXIGA 10 mg dose provided significant improvement in HbA1c, and mean insulin dose, and a significant reduction in body weight compared with placebo in combination with insulin, with or without up to 2 OADs (Tables 5a and 5b); the effect of FORXIGA on HbA1c was similar in patients on insulin alone and patients on insulin plus OADs.
At Weeks 48 and 104, adjusted mean changes from baseline in HbA1c were -0.93% and -0.71%, changes in FPG were -21.5 mg/dL and -18.2 mg/dL, and changes in body weight were -1.79 kg and -1.97 kg, respectively, for patients treated with FORXIGA 10 mg plus insulin; adjusted mean changes from baseline in HbA1c were -0.43% and -0.06%, changes in FPG were -4.4 mg/dL and -11.2 mg/dL, and changes in body weight were -0.18 kg and 0.91 kg, respectively, for patients treated with placebo plus insulin (see Figure 10).
At Week 24, a significantly higher proportion of patients on FORXIGA 10 mg reduce their insulin dose by at least 10% compared to placebo. The proportion of patients who required up-titration of their insulin dose or discontinued due to lack of glycemic control (adjusted for baseline HbA1c) was higher for placebo plus insulin (29.2%) than for FORXIGA 10 mg plus insulin (9.7%). By Weeks 48 and 104, the insulin dose remained stable in patients treated with FORXIGA 10 mg at an average dose of 76 IU/day, but continued to increase (mean increase 10.5 IU and 18.3 IU, respectively, from baseline) in placebo-treated patients. By Weeks 48 and 104 (adjusted for baseline HbA1c), more patients treated with required up-titration with insulin to maintain glycemic levels or discontinued due to lack of glycemic control (42.8% and 50.4%, respectively) compare with patients treated with FORXIGA 10 mg (15.3% and 25.5%, respectively). (See Tables 5a and 5b, Figures 8, 9 and 10.)

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Add-on to Sitagliptin Alone or in Combination with Metformin: A total of 452 patients with type 2 diabetes who were drug naive, or who were treated at entry with metformin or a DPP4 inhibitor alone or in combination, and had inadequate glycemic control (HbA1c ≥7.0% and ≤10.0% at randomization), participated in a 24-week, placebo-controlled study with a 24-week extension period to evaluate FORXIGA in combination with sitagliptin (a DPP4 inhibitor) with or without metformin.
Eligible patients were stratified based on the presence or absence of background metformin (≥1500 mg/day) and within each stratum were randomized to either FORXIGA 10 mg plus sitagliptin 100 mg once daily or placebo plus sitagliptin 100 mg once daily. Endpoints were tested for FORXIGA 10 mg versus placebo for the total study group (sitagliptin with and without metformin) and for each stratum (sitagliptin alone or sitagliptin with metformin). Thirty-seven percent (37%) of patients were drug naive, 32% were on metformin alone, 13% were on a DPP4 inhibitor alone, and 18% were on a DPP4 inhibitor plus metformin. Dose titration of FORXIGA, sitagliptin or metformin was not permitted during the study.
In combination with sitagliptin (with and without metformin), FORXIGA 10 mg provided significant improvements in HbA1c, HbA1c in patients with baseline HbA1c ≥8%, and FPG, and significant reduction in body weight compared with the placebo plus sitagliptin (with or without metformin) group at Week 24 (Table 6). These improvements were also seen in the stratum of patients who received FORXIGA 10 mg plus sitagliptin alone (n=110) compared with placebo plus sitagliptin alone (n=111), and the stratum of patients who received FORXIGA 10 mg plus sitagliptin and metformin (n=113) compared with placebo plus sitagliptin with metformin (n=113) (Table 6).
At Week 48, adjusted mean change from baseline in HbA1c, HbA1c in patients with HbA1c ≥8% at baseline, FPG, PPG, and body weight were -0.30%, -0.72%, -19.7 mg/dL, -43.0 mg/dL, and -2.03 kg, respectively, for patients treated with FORXIGA 10 mg plus sitagliptin with or without metformin, and 0.38%, 0.26%, 13.4 mg/dL, -12.1 mg/dL, and 0.18 kg for patients treated with placebo plus sitagliptin with or without metformin based on the longitudinal repeated measures analysis excluding data after rescue. At Week 48, for the stratum of patients without metformin, adjusted mean change from baseline in HbA1c for patients treated with FORXIGA 10 mg plus sitagliptin was 0.00% and placebo plus sitagliptin was 0.85%; and for the stratum of patients with metformin, adjusted mean change from baseline in HbA1c for patients treated with FORXIGA 10 mg plus sitagliptin was -0.44% and placebo plus sitagliptin was 0.15% based on the longitudinal repeated measures analysis excluding data after rescue.
The proportion of patients at Week 24 and Week 48 who were rescued or discontinued for lack of glycemic control (adjusted for baseline HbA1c) was higher for sitagliptin with or without metformin (41.5% and 56.6%, respectively) than for FORXIGA with or without metformin (18.8% and 32.7%, respectively). (See Table 6.)

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Concomitant Initiation of Saxagliptin and FORXIGA in Patients Inadequately Controlled on Metformin: A total of 534 adult patients with type 2 diabetes mellitus and inadequate glycemic control on metformin alone (HbA1c ≥8% and ≤12%), participated in this 24-week randomized, double blind, active comparator-controlled superiority trial to compare the combination of saxagliptin and FORXIGA added concurrently to metformin, versus saxagliptin (DPP4 inhibitor) or FORXIGA added to metformin. Patients were randomized to one of three double-blind treatment groups to receive saxagliptin 5 mg and FORXIGA 10 mg added to metformin XR, saxagliptin 5 mg and placebo added to metformin XR, or FORXIGA 10 mg and placebo added to metformin XR.
The saxagliptin and FORXIGA combination group achieved significantly greater reductions in HbA1c versus either saxagliptin group or FORXIGA group at 24 weeks. Forty-one percent (41%) of patients in the saxagliptin and FORXIGA combination group achieved HbA1c levels of less than 7% compared to 18% patients in the saxagliptin group and 22% patients in the FORXIGA group. (See Table 7.)

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The adjusted mean change in body weight at 24 weeks was -2.05 kg (95% CI [-2.52, -1.58]) in the saxagliptin and FORXIGA plus metformin group and -2.39 kg (95% CI [-2.87, -1.91]) in the FORXIGA plus metformin group. The adjusted mean change for body weight in the saxagliptin plus metformin group had no change 0.00 kg (95% CI [-0.48, 0.49]).
Add-on therapy with FORXIGA in patients inadequately controlled on saxagliptin plus metformin: A 24-week randomized, double-blind, placebo-controlled study compared the sequential addition of 10 mg FORXIGA to 5 mg saxagliptin and metformin to the addition of placebo to 5 mg saxagliptin (DPP4 inhibitor) and metformin in patients with type 2 diabetes mellitus and inadequate glycaemic control (HbA1c ≥7% and ≤10.5%). 320 subjects were randomized equally into either the FORXIGA added to saxagliptin plus metformin treatment group or placebo plus saxagliptin plus metformin treatment group.
The group with FORXIGA sequentially added to saxagliptin and metformin achieved statistically significant (p-value <0.0001) greater reductions in HbA1c versus the group with placebo sequentially added to saxagliptin plus metformin group at 24 weeks (see Table 8).

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The proportion of patients achieving HbA1c <7.0% at Week 24 was higher in the FORXIGA plus saxagliptin plus metformin group 38.0% (95% CI [30.9, 45.1]) compared to the placebo plus saxagliptin plus metformin group 12.4% (95% [7.0, 17.9]).
The adjusted changes from baseline at Week 24 in body weight were -1.91 kg (95% CI [-2.34, -1.48]), in the FORXIGA plus saxagliptin plus metformin group and -0.41 kg (95% CI [-0.86, -0.04]), in the placebo plus saxagliptin plus metformin group.
The effects in HbA1C, FPG and body weight observed at Week 24 were sustained at Week 52. Adjusted mean change from baseline in HbA1c, FPG, and body weight were -0.74% (95% CI [-0.90, -0.57]), -26.8 mg/dL (95% CI [-34.2, -19.4]) and -2.13 kg (95% CI [-2.70, 1.56]), respectively, for patients treated with FORXIGA 10 mg plus saxagliptin with metformin, and 0.07% (95% CI [-0.13, 0.27]), 10.2 mg/dL (95% CI [1.6, 18.8]) and -0.37 kg (95% CI [-1.01, 0.26]) for patients treated with placebo plus saxagliptin with metformin based on the longitudinal repeated measures analysis excluding data after rescue.
Supportive Studies: Dual Energy X-ray Absorptiometry in Type 2 Diabetic Patients: Due to the mechanism of action of FORXIGA, a study was done to evaluate body composition and bone mineral density in 182 patients with type 2 diabetes. Treatment with FORXIGA 10 mg added on to metformin over a 24-week period provided significant improvements compared with placebo plus metformin, respectively, in body weight (mean change from baseline: -2.96 kg versus -0.88 kg); waist circumference (mean change from baseline: -2.51 cm versus -0.99 cm), and body-fat mass as measured by DXA (mean change from baseline -2.22 kg versus -0.74 kg) rather than lean tissue or fluid loss. FORXIGA plus metformin treatment showed a numerical decrease in visceral adipose tissue compared with placebo plus metformin treatment (change from baseline -322.6 cm3 versus -8.7 cm3) in an 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 FORXIGA 10 mg plus metformin group were rescued for lack of glycemic control.
At Week 50 and Week 102, improvements were sustained in the FORXIGA 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 versus -2.03 kg; adjusted mean change from baseline at Week 102: -4.54 kg versus -2.12 kg), waist circumference (adjusted mean change from baseline at Week 50: -5.0 cm versus -3.0 cm; adjusted mean change from baseline at Week 102: -5.0 cm versus -2.9 cm), and body-fat mass as measured by DXA at Week 102 (mean change from baseline: -2.80 kg versus -1.46 kg) based on the longitudinal repeated measures analysis including data after rescue. In an MRI sub-study at Weeks 50 and 102, FORXIGA 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 versus 61.5 cm3; adjusted mean change from baseline at Week 102: -214.9 cm3 versus -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 FORXIGA 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 change 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.
Clinical Safety: Volume depletion: Events suggestive of volume depletion (including reports of dehydration, hypovolemia, or hypotension) were reported in 1.1% and 0.7% of patients who received FORXIGA 10 mg, and placebo, respectively, in the 13-study short-term, placebo-controlled pool. Serious events occurred in ≤0.2% of patients across the 21 active- and placebo-controlled studies and were balanced between FORXIGA 10 mg and comparator. In subgroup analyses of patients on loop diuretics or ≥65 years of age in the 13-study placebo-controlled pool, the proportion of patients with events related to volume depletion were slightly higher in patients treated with FORXIGA 10 mg than in those treated with placebo (events in patients on loop diuretics: 2.5% versus 1.5%; events in patients ≥65 years of age: 1.7% versus 0.8%, respectively).
In the CV outcomes study, the numbers of patients with events suggestive of volume depletion were balanced between treatment groups: 213 (2.5%) and 207 (2.4%) in the FORXIGA and placebo groups, respectively. Serious adverse events were reported in 81 (0.9%) and 70 (0.8%) in the FORXIGA and placebo group, respectively. Events were generally balanced between treatment groups across subgroups of age, diuretic use, blood pressure and ACEi/ARB use. In patients with eGFR <60 mL/min/1.73 m2 at baseline, there were 19 events of SAEs suggestive of volume depletion in the FORXIGA group and 13 events in the placebo group.
Hypoglycemia: The incidence of hypoglycemia as seen in controlled clinical studies with dapagliflozin in different combinations is shown in Table 9. (See Table 9.)

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Events related to decreased renal function: In the 13-study, short-term, placebo-controlled pool, mean serum creatinine levels increased a small amount at Week 1 (mean change from baseline: 0.041 mg/dL FORXIGA 10 mg versus 0.008 mg/dL placebo) and decreased toward baseline by Week 24 (mean change from baseline: 0.019 mg/dL FORXIGA 10 mg versus 0.008 mg/dL placebo). There were no further changes through Week 102.
In the CV outcomes study, there were fewer patients with marked laboratory abnormalities of creatinine, creatinine clearance, eGFR, and UACR in the FORXIGA group compared with the placebo group. Fewer renal events (e.g., decreased renal creatinine clearance, renal impairment, increased blood creatinine, and decreased glomerular filtration rate) were reported in the FORXIGA group compared with the placebo group: 422 (4.9%) and 526 (6.1%), respectively. There were fewer patients with events reported as acute kidney injury in the FORXIGA group compared with the placebo group: 125 (1.5%) and 175 (2.0%), respectively. There were fewer patients with SAEs of renal events in the FORXIGA group compared with the placebo group: 80 (0.9%) and 136 (1.6%), respectively.
Laboratory Findings: Hematocrit: In the pool of 13 placebo-controlled studies, increases from baseline in mean hematocrit values were observed in FORXIGA-treated patients starting at Week 1 and continuing up to Week 16, when the maximum mean difference from baseline was observed. At Week 24, the mean changes from baseline in hematocrit were 2.30% in the FORXIGA 10 mg group versus -0.33% in the placebo group. At Week 102, the mean changes were 2.68% versus -0.46% respectively. By Week 24, hematocrit values >55% were reported in 1.3% of FORXIGA 10 mg-treated patients versus 0.3% of placebo-treated patients. Results were similar during the short-term plus long-term phase (the majority of patients were exposed to treatment for more than one year).
Serum Inorganic Phosphorus: In the pool of 13 placebo-controlled studies, increases from baseline in mean serum phosphorus levels were reported at Week 24 in FORXIGA 10 mg-treated patients compared with placebo-treated patients (mean increases of 0.13 mg/dL versus 0.04 mg/dL, respectively). Similar results were seen at Week 102. Higher proportions of patients with marked laboratory abnormalities of hyperphosphatemia (≥5.6 mg/dL if age 17-65 or ≥5.1 mg/dL if age ≥66) were reported in FORXIGA 10 mg group versus placebo at Week 24 (1.7% versus 0.9%, respectively) and during the short-term plus long-term phase (3.0% versus 1.6%, respectively). The clinical relevance of these findings is unknown.
Lipids: In the pool of 13 placebo-controlled studies, small changes from baseline in mean lipid values were reported at Week 24 in FORXIGA 10 mg-treated patients compared with placebo-treated patients. Mean percent change from baseline at Week 24 for FORXIGA 10 mg versus placebo, respectively, was as follows: total cholesterol, 2.5% versus 0.0%; HDL cholesterol, 6.0% versus 2.7%; LDL cholesterol, 2.9% versus -1.0%; triglycerides, -2.7% versus -0.7%. Mean percent change from baseline at Week 102 for FORXIGA 10 mg versus placebo, respectively, was as follows: total cholesterol, 2.1% versus -1.5%; HDL cholesterol, 6.6% versus 2.1%; LDL cholesterol, 2.9% versus -2.2%; triglycerides, -1.8% versus -1.8%. The ratio between LDL cholesterol and HDL cholesterol decreased for all treatment groups at Week 24.
In the CV outcomes study, no clinical important differences in total cholesterol, HDL cholesterol, LDL cholesterol or triglycerides were seen.
Glycemic control in special populations: Use in patients with type 2 diabetes and hypertension: In two 12-week, placebo-controlled studies, a total of 1062 patients with inadequately controlled type 2 diabetes and hypertension were treated with FORXIGA 10 mg or placebo. Patients with inadequately controlled hypertension (seated systolic blood pressure ≥140 and <165 mmHg, seated diastolic blood pressure ≥85 and <105 mmHg, and a 24-hour mean blood pressure of ≥130/80 mmHg) despite pre-existing stable treatment with an ACEi or ARB (alone [Study 1] or in combination with an additional antihypertensive [Study 2]) as well as inadequate glycemic control (HbA1c ≥7.0% and ≤10.5%) despite pre-existing stable treatment with OADs or insulin (alone or in combination) prior to entry, were eligible for these studies. During the studies, no adjustments in antidiabetic and antihypertensive medications were allowed. Across the 2 studies, 527 patients were treated with FORXIGA 10 mg and 535 with placebo. Patients treated with FORXIGA 10 mg or placebo also received the following medications for blood pressure control, which were balanced between treatment groups: ACEs (64%), ARBs (36%), thiazide diuretics (16%), calcium channel blockers (9%), and beta-blockers (6%).
At Week 12 for both studies, FORXIGA 10 mg plus usual treatment provided significant improvement in HbA1c and significant reduction in seated systolic blood pressure compared with placebo plus usual treatment (see Table 10). Consistent reductions were seen in mean 24-hour ambulatory systolic blood pressure in patients treated with FORXIGA 10 mg treatment compared with placebo. There was a small reduction in mean seated diastolic blood pressure in patients treated with FORXIGA 10 mg that was not statistically significant compared with placebo. (See Table 10.)

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Use in patients with type 2 diabetes and cardiovascular disease: In two 24-week, placebo-controlled studies with 80-week extension periods, a total of 1887 patients with type 2 diabetes and CVD were treated with FORXIGA 10 mg or placebo.
Patients with established CVD and inadequate glycemic control (HbA1c ≥7.0% and ≤10.0%), despite pre-existing, stable treatment with OADs or insulin (alone or in combination) prior to entry, were eligible for these studies and were stratified according to age (<65 years or ≥65 years), insulin use (no or yes), and time from most recent qualifying cardiovascular event (>1 year or <1 year prior to enrollment). Across the 2 studies, 942 patients were treated with FORXIGA 10 mg and 945 with placebo. Ninety-six percent (96%) of patients treated with FORXIGA 10 mg across the 2 studies had hypertension at entry, the majority for more than 10 years duration; the most common qualifying cardiovascular events were coronary heart disease (76%) or stroke (20%). Approximately 19% of patients received loop diuretics at entry and 15% had congestive heart failure (2% had NYHA Class III). Approximately 37% of patients treated with FORXIGA 10 mg also received metformin plus one additional OAD (sulfonylurea, thiazolidinedione, DPP4-inhibitor, or other OAD with or without insulin at entry), 39% received insulin plus at least one OAD, and 18% received insulin alone.
At Week 24 for both studies, when added to pre-existing antidiabetic treatments, treatment with FORXIGA 10 mg provided significant improvement to coprimary endpoints of HbA1c and composite clinical benefit compared with placebo. Composite clinical benefit was defined as the proportion of patients with an absolute drop from baseline of 0.5% in HbA1c, and a relative drop from baseline of at least 3% in total body weight, and an absolute drop from baseline of at least 3 mmHg in seated SBP (Table 11). Significant reductions in total body weight and seated systolic blood pressure were also seen in patients treated with FORXIGA 10 mg compared with placebo. At Week 52 and Week 104 for Study 1, adjusted mean change from baseline in HbA1c, seated systolic blood pressure, and adjusted percent change from baseline in body weight were -0.44% and -0.41%, -3.40 mmHg and -2.64 mmHg, and -2.89% and -3.53%, respectively, for patients treated with FORXIGA 10 mg plus usual treatment based on the longitudinal repeated measures analysis. Corresponding numbers for patients treated with placebo plus usual treatment were 0.22% and 0.50%, 0.18 mmHg and 1.54 mmHg, and -0.29% and -0.02%. At Week 52 and Week 104, percent composite clinical benefit was still higher in the FORXIGA 10 mg group (6.6% and 3.8%) than in the placebo group (0.7% and 0.5%).
At Week 24, Week 52, and Week 104 for Study 1, the proportion of patients who were rescued for lack of glycemic control (adjusted for baseline HbA1c) was higher in the placebo plus usual treatment group (24.0%, 51.8%, and 57.3%, respectively) than in the FORXIGA 10 mg plus usual treatment group (7.9%, 24.6%, and 31.8%, respectively).
At Week 52 and Week 104 for Study 2, adjusted mean change from baseline in HbA1c, seated systolic blood pressure, and adjusted percent change from baseline in body weight were -0.47% and -0.37%, -3.56 mmHg and -1.96 mmHg, and -3.20% and -3.51%, respectively, for patients treated with FORXIGA 10 mg plus usual treatment based on the longitudinal repeated measures analysis. Corresponding numbers for patients treated with placebo plus usual treatment were 0.03% and -0.18%, -0.91 mmHg and -0.37 mmHg, and -1.12% and -0.65%. At Week 52 and Week 104, percent composite clinical benefit was still higher in the FORXIGA 10 mg group (10.6% and 4.2%) than in the placebo group (3.1% and 1.1%).
At Week 24, Week 52, and Week 104 for Study 2, the proportion of patients who were rescued for lack of glycemic control (adjusted for baseline HbA1c) was higher in the placebo plus usual treatment group (22.3%, 43.6%, and 50.5%, respectively) than in the FORXIGA 10 mg plus usual treatment group (7.6%, 18.7%, and 27.5%, respectively). (See Table 11.)

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At week 24, patients treated with FORXIGA 10 mg in the predefined age groups (<65 and ≥65 years of age) also showed significant improvements in the coprimary endpoints of HbA1c and composite clinical benefit compared with placebo in both studies. A significant reduction in total body weight was also seen in both age groups and a significant reduction of seated SBP in patients <65 years treated with FORXIGA 10 mg compared with placebo at Week 24. These effects were maintained at Week 52 and Week 104.
The safety profile of FORXIGA in these studies was consistent with that of FORXIGA in the general clinical study population through 104 weeks of treatment (see Adverse Reactions).
Use in patients with type 2 diabetes and renal impairment: Patients with mild renal impairment (eGFR ≥60 to <90 mL/min/1.73 m2): In the clinical trial program more than 3000 patients with mild renal impairment were treated with dapagliflozin. Efficacy was assessed in a pooled analysis across 9 clinical studies consisting of 2226 patients with mild renal impairment. The mean change from baseline in hemoglobin A1c (HbA1c) and the placebo-corrected mean HbA1c change at 24 weeks was -1.03% and -0.54%, respectively, for FORXIGA 10 mg (n=562). The safety profile in patients with mild renal impairment is similar to that in the overall population.
Patients with moderate renal impairment (eGFR ≥30 to <60 mL/min/1.73 m2): The glycemic efficacy and safety of FORXIGA was evaluated in two dedicated studies of patients with moderate renal impairment and in two subgroup analyses of pooled clinical studies.
In a randomized, double blind, placebo-controlled trial a total of 321 adult patients with type 2 diabetes mellitus and eGFR ≥45 to <60 mL/min/1.73 m2 (moderate renal impairment subgroup CKD 3A), with inadequate glycemic control on current treatment regimen, were treated with FORXIGA 10 mg or placebo. At Week 24, FORXIGA 10 mg (n=159) provided significant improvements in HbA1c, FPG, Body Weight and SBP compared with placebo (n=161) (Table 12). The mean change from baseline in HbA1c and the placebo-corrected mean HbA1c change was -0.37% and -0.34%, respectively. The mean change from baseline in FPG and the placebo-corrected mean FPG was -21.46 mg/dL and -16.59 mg/dL, respectively. The mean body weight reduction (percentage) and the placebo-corrected mean body weight reduction was -3.42% and -1.43%, respectively. The mean reduction in seated systolic blood pressure (SBP) and the placebo-corrected mean reduction in SBP was -4.8 mmHg and -3.1 mmHg, respectively. (See Table 12.)

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The safety profile of dapagliflozin in the study was consistent with that in the general population of patients with type 2 diabetes. Mean eGFR decreased initially during the treatment period in the dapagliflozin group and subsequently remained stable during the 24-week treatment period (FORXIGA: -3.39 mL/min/1.73 m2 and placebo: -0.90 mL/min/1.73 m2). At 3 weeks after termination of FORXIGA, the mean change from baseline in eGFR in the dapagliflozin group was similar to the mean change in the placebo group (FORXIGA: 0.57 mL/min/1.73 m2 and placebo: -0.04 mL/min/1.73 m2).
Efficacy in patients with moderate renal impairment was assessed in a pooled analysis across 9 clinical studies (366 patients, 87% with eGFR ≥45 to <60 mL/min/1.73 m2) ; this pool did not include the two dedicated studies of diabetic patients with moderate renal impairment. The mean change from baseline in HbA1c and the placebo-corrected mean HbA1c change at 24 weeks was -0.87% and -0.39%, respectively, for FORXIGA 10 mg (n=85).
Safety in patients with moderate renal impairment was assessed in a pooled analysis of 12 clinical studies (384 patients, 88% with eGFR ≥45 to <60 mL/min/1.73 m2); this pool does not include the dedicated study of diabetic patients with moderate renal impairment. At Week 24, safety was similar to that seen in the overall program of clinical studies except for a higher proportion of patients reporting at least one event related to renal impairment or failure (7.9% FORXIGA 10 mg versus 5.6% placebo). Of these events, increased serum creatinine was the most frequently reported (6.7% FORXIGA 10 mg versus 2.8% placebo). Increases in mean parathyroid hormone (PTH) and serum phosphorus observed with FORXIGA in the overall program of clinical studies were also seen in the pooled analysis. No imbalance in bone fractures was observed in this analysis. In the short-term plus long-term safety pool up to 102 weeks, the safety profile remained similar.
The efficacy and safety of FORXIGA was also assessed in a study of 252 diabetic patients with eGFR ≥30 to <60 mL/min/1.73 m2 (moderate renal impairment subgroup CKD 3A and CKD 3B). FORXIGA treatment did not show a significant placebo corrected change in HbA1c in the overall study population (CKD 3A and CKD 3B combined) at 24 weeks. In an additional analysis of the subgroup CKD 3A, FORXIGA 10 mg (n=32) provided a placebo-corrected mean HbA1c change at 24 weeks of -0.33%. At Week 52, FORXIGA was associated with changes from baseline in mean eGFR (FORXIGA 10 mg -4.46 mL/min/1.73 m2 and placebo -2.58 mL/min/1.73 m2). At Week 104, these changes persisted (eGFR: FORXIGA 10 mg -3.50 mL/min/1.73 m2 and placebo -2.38 mL/min/1.73 m2). With FORXIGA 10 mg, this eGFR reductions were evident at Week 1 and remained stable through Week 104, while placebo-treated patients had a slow continuous decline through Week 52 that stabilized through Week 104.
At Week 52 and persisting through Week 104, greater increases in mean PTH and serum phosphorus were observed in this study with FORXIGA 10 mg compared to placebo, where baseline values of these analytes were higher. Elevations of potassium of ≥6 mEq/L were more common in patients treated with placebo (12.0%) than those treated with FORXIGA 5 mg and 10 mg (4.8% for both groups) during the cumulative 104-week treatment period. The proportion of patients discontinued for elevated potassium, adjusted for baseline potassium, was higher for the placebo group (14.3%) than for the FORXIGA groups (6.9% and 6.7% for the 5 mg and 10 mg groups, respectively).
Overall, there were 13 patients with an adverse event of bone fracture reported in this study up to Week 104 of which 8 occurred in the FORXIGA 10 mg group, 5 occurred in the FORXIGA 5 mg group, and none occurred in the placebo group. Eight (8) of these 13 fractures were in patients who had eGFR 30 to 45 mL/min/1.73 m2 and 10 of the 13 fractures were reported within the first 52 weeks. There was no apparent pattern with respect to the site of fracture. No imbalance in bone fractures was observed in the safety analysis of the 12-study pool data and no bone fractures were reported in the dedicated study of patients with eGFR ≥45 to <60 mL/min/1.73 m2 (CKD 3A).
Use in elderly patients with type 2 diabetes: A total of 2403 (26%) of 9339 treated patients were 65 years and older and 327 (5%) patients were 75 years and older in a pool of 21 double-blind, controlled, clinical studies of FORXIGA assessing the safety and efficacy of FORXIGA in improving glycemic control. After controlling for level of renal function (eGFR), there was no conclusive evidence suggesting that age is an independent factor affecting efficacy. Overall, the proportion of patients reporting adverse events was consistent between those ≥65 and <65 years of age.
Pharmacokinetics: 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 proportionally 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 (eg, renal or hepatic impairment).
Metabolism: 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 (t½) for dapagliflozin was 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 was the predominant drug-related component in human plasma, accounting for 42% (based on AUC [0-12 hour]) of total plasma radioactivity, similar to the 39% contribution by parent drug. Based on AUC, no other metabolite accounted 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 was a minor clearance pathway in humans.
Elimination: 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% was recovered; 75% in urine and 21% in feces. In feces, approximately 15% of the dose was excreted as parent drug.
Special Populations: No dosage adjustments based on pharmacokinetic analyses are recommended for mild to moderate renal impairment; mild, or moderate 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 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 were 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.
Hepatic impairment: 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.
Age: 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.
Pediatric and adolescent patients: 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, 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).
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 did not induce tumors in either mice or rats at any of the doses evaluated in 2-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 131× (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 ≥100× 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. This data strongly suggests 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.
Teratogenicity and impairment of early development: 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 prenatal 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 embryolethal 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.
Animal toxicology: 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.
Indications/Uses
Type 2 diabetes mellitus: FORXIGA is indicated in adults with type 2 diabetes mellitus for: the treatment of diabetes as an adjunct to diet and exercise. FORXIGA can be given as monotherapy or in combination with other medicinal products indicated for the treatment of type 2 diabetes mellitus (see Pharmacology: Pharmacodynamics under Actions); the prevention of new or worsening heart failure or cardiovascular death (see Pharmacology: Pharmacodynamics under Actions); the prevention of new or worsening nephropathy (see Pharmacology: Pharmacodynamics under Actions).
Limitations of Use: FORXIGA is not indicated for use in patients with type 1 diabetes.
FORXIGA should not be used for the treatment of diabetic ketoacidosis.
Dosage/Direction for Use
Recommended Dosage: The recommended dose of FORXIGA is 10 mg taken orally once daily at any time of the day regardless of meals.
Monotherapy and Add-On Combination Therapy: The recommended dose of FORXIGA is 10 mg once daily as monotherapy or as add-on to combination therapy with metformin (with or without a sulfonylurea), a thiazolidinedione, a sulfonylurea, a DPP4-inhibitor (with or without metformin), or insulin (with or without oral antidiabetic therapy, either metformin plus insulin dual therapy or metformin plus sulfonylurea plus insulin triple therapy).
Initial Combination Therapy: The recommended starting doses of FORXIGA and metformin when used as initial combination therapy are 10 mg FORXIGA plus 500 mg metformin once daily. Patients with inadequate glycemic control on this dose should further have their metformin dose increased according to approved local label guidelines.
Special Populations: Patients with renal impairment: No dosage adjustment for FORXIGA is required based on renal function.
FORXIGA is not recommended for the treatment of diabetes in patients where eGFR is persistently <45 mL/min/1.73 m2 as the glycemic efficacy is dependent on renal function see Precautions, Adverse Reactions and Pharmacology: Pharmacodynamics under Actions).
Patients with hepatic impairment: No dosage adjustment for FORXIGA is necessary for patients with mild, moderate or severe hepatic impairment (see Pharmacology: Pharmacokinetics under Actions).
Pediatric and adolescent patients: Safety and effectiveness of FORXIGA in pediatric and adolescent patients have not been established.
Geriatric Patients: No dosage adjustment for FORXIGA is required based on age (see Pharmacology: Pharmacodynamics under Actions). Older patients are more likely to have impaired renal function. The renal function recommendations provided for all patients also apply to elderly patients (see Precautions).
Patients at risk for volume depletion: For patients at risk for volume depletion due to co-existing conditions, a 5-mg starting dose of FORXIGA may be appropriate (see Precautions and Pharmacology: Pharmacodynamics under Actions).
Overdosage
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 for patients treated with dapagliflozin was similar to placebo. In clinical studies where once-daily doses of up to 100 mg (10 times the MRHD) of dapagliflozin were administered for 2 weeks in healthy subjects and type 2 diabetes patients, the incidence of hypoglycemia for subjects administered dapagliflozin was slightly higher than placebo and was not dose related. Rates of adverse events including dehydration or hypotension for patients treated with dapagliflozin 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.
Contraindications
FORXIGA is contraindicated in patients with a history of any serious hypersensitivity reaction to the active substance or to any of the excipients.
Special Precautions
Use in patients with renal impairment: FORXIGA is not recommended for the treatment of diabetes when eGFR is persistently below 45 mL/min/1.73 m2 as the glycaemic efficacy of dapagliflozin is dependent on renal function. Renal function should be evaluated prior to initiation of FORXIGA and periodically thereafter.
FORXIGA has not been studied in patients with severe renal impairment (eGFR <30 mL/min/1.73 m2) or end-stage renal disease (ESRD).
Use in patients at risk for volume depletion: Due to its mechanism of action, FORXIGA induces osmotic diuresis which may lead to the modest decrease in blood pressure observed in clinical studies (see Pharmacology: Pharmacodynamics under Actions). For patients at risk for volume depletion due to co-existing conditions, a 5-mg starting dose of FORXIGA may be appropriate. Temporary interruption of FORXIGA should be considered for patients who develop volume depletion.
Ketoacidosis: Predisposing factors to ketoacidosis include a low beta-cell function reserve resulting from pancreatic disorders (e.g., type 1 diabetes, history of pancreatitis or pancreatic surgery), insulin dose reduction, reduced caloric intake or increased insulin requirements due to infections, illness or surgery and alcohol abuse. FORXIGA should be used with caution in these patients.
Patients treated with FORXIGA 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, discontinuation or temporary interruption of FORXIGA should be considered and the patient should be promptly evaluated.
There have been reports of ketoacidosis, including diabetic ketoacidosis (DKA), in patients with type 2 diabetes mellitus taking FORXIGA and other SGLT2 inhibitors.
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 FORXIGA (see Pharmacology: Pharmacodynamics under Actions).
Urinary tract infections: Urinary glucose excretion may be associated with an increased risk of urinary tract infection; therefore, temporary interruption of dapagliflozin should be considered when treating pyelonephritis or urosepsis.
Effects on ability to drive and use machines: No studies on the effects on the ability to drive and use machines have been performed.
Use In Pregnancy & Lactation
Pregnancy: FORXIGA must not be used in the second and third trimesters of pregnancy. In the time period corresponding to the second and third trimesters of pregnancy with respect to human renal maturation, maternal exposure to dapagliflozin in rat studies was associated with increased incidence and/or severity of renal pelvic and tubular dilatations in progeny (see Pharmacology: Toxicology: Preclinical safety data: Carcinogenesis, Mutagenesis, Impairment of Fertility under Actions).
In conventional studies of embryo-fetal development in rats and rabbits, dapagliflozin was administered for intervals coinciding with the first trimester period of nonrenal organogenesis in humans. No developmental toxicities were observed in rabbits at any dose tested (1191x the maximum recommended human dose [MRHD]). In rats, dapagliflozin was neither embryolethal nor teratogenic (1441x the MRHD) in the absence of maternal toxicity.
There are no adequate and well-controlled studies of FORXIGA in pregnant women. When pregnancy is detected, FORXIGA should be discontinued.
Lactation: FORXIGA must not be used by a nursing woman. Studies in rats have shown excretion of FORXIGA in milk. Direct and indirect exposure of FORXIGA 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, although 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, FORXIGA-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 FORXIGA must be avoided during the first 2 years of life (see Pharmacology: Toxicology: Preclinical safety data under Actions).
It is not known whether FORXIGA and/or its metabolite are excreted in human milk.
Adverse Reactions
Clinical Trials: The safety profile of dapagliflozin has been evaluated in clinical development programs for type 2 diabetes mellitus. This includes more than 15000 subjects treated with dapagliflozin for type 2 diabetes. For further information about the clinical studies, see Pharmacology: Pharmacodynamics under Actions.
The incidence of adverse reactions was determined using a pre-specified pool of patients from 13 short-term (mean duration 22 weeks), placebo-controlled studies in type 2 diabetes. Across these 13 studies, 2360 patients were treated once daily with FORXIGA 10 mg and 2295 were treated with placebo (either as monotherapy or in combination with other antidiabetic therapies).
Additionally, FORXIGA 5 mg was evaluated in a 12-study, short-term, placebo-controlled pool of type 2 diabetes patients that included 1145 patients treated with FORXIGA 5 mg (mean exposure = 22 weeks) and 1393 patients treated with placebo (mean exposure = 21 weeks), either as monotherapy or in combination with other antidiabetic therapies.
In the dedicated cardiovascular (CV) outcomes study in patients with type 2 diabetes mellitus, 8574 patients received FORXIGA 10 mg and 8569 received placebo for a median exposure time of 48 months. In total, there were 30623 patient-years of exposure to FORXIGA.
Adverse reactions: The adverse reactions in patients treated with FORXIGA 10 mg in clinical trials and postmarketing are shown in Table 13. (See Table 13.)

Click on icon to see table/diagram/image

Description of selected adverse events observed in studies in type 2 diabetes mellitus: Genital Infections: Events of genital infections were reported in 5.5% and 0.6% of patients who received FORXIGA 10 mg and placebo, respectively, in the 13-study short-term, placebo-controlled pool. The events of genital infections reported in patients treated with FORXIGA 10 mg were all mild to moderate. Most events of genital infection responded to an initial course of standard treatment and rarely resulted in discontinuation from the study (0.2% FORXIGA 10 mg versus 0% in placebo). Infections were reported more frequently in females (8.4% FORXIGA 10 mg versus 1.2% placebo) than in males (3.4% FORXIGA 10 mg versus 0.2% placebo). The most frequently reported genital infections were vulvovaginal mycotic infections in females, and balanitis in males.
Overall, treatment with FORXIGA 5 mg was similar to treatment with FORXIGA 10 mg.
In the CV outcomes study, the number of patients with serious adverse events (SAE) of genital infections were few and balanced: 2 (<0.1%) patients in each of the FORXIGA and placebo groups.
Urinary tract infections: Events of urinary tract infections (UTI) were reported in 4.7% and 3.5% of patients who received FORXIGA 10 mg and placebo, respectively, in the 13-study short-term, placebo-controlled pool. Most events of urinary tract infections reported in patients treated with FORXIGA 10 mg were mild to moderate. Most patients responded to an initial course of standard treatment, and urinary tract infections rarely caused discontinuation from the study (0.2% FORXIGA 10 mg versus 0.1% placebo). Infections were more frequently reported in females (8.5% FORXIGA 10 mg versus 6.7% placebo) than in males (1.8% FORXIGA 10 mg versus 1.3% placebo).
In the CV outcomes study there were fewer patients with SAEs of UTI in the FORXIGA group compared with the placebo group: 79 (0.9%) and 109 (1.3%), respectively.
Diabetic ketoacidosis (DKA): Type 2 diabetes mellitus: In the CV outcomes study with a median exposure time of 48 months, events of DKA were reported in 27 patients in the FORXIGA 10 mg group and 12 patients in the placebo group. The events occurred evenly distributed over the study period. Of the 27 patients with DKA events in the FORXIGA group, 22 had concomitant insulin treatment at the time of the event. Precipitating factors for DKA were as expected in a type 2 diabetes mellitus population (see Precautions).
Drug 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 and dapagliflozin 3-O-glucuronide neither inhibited CYP1A2, 2C9, 2C19, 2D6, 3A4, nor induced CYP1A2, 2B6 or 3A4. Therefore, dapagliflozin is not expected to alter the metabolic clearance of coadministered drugs that are metabolized by these enzymes, and drugs that 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 P-gp, 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.
Effect of other drugs on dapagliflozin: 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 inhibitor would not be expected.
Following coadministration 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.
Coadministration of dapagliflozin and bumetanide did not meaningfully change the pharmacodynamic effect of dapagliflozin to increase urinary glucose excretion in healthy subjects.
Effect of dapagliflozin on other drugs: In interaction studies conducted in healthy subjects, using mainly a single dose design, dapagliflozin did not alter the pharmacokinetics of metformin, pioglitazone, sitagliptin, glimepiride, hydrochlorothiazide, bumetanide, valsartan, 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.
Coadministration of dapagliflozin and bumetanide did not meaningfully alter the steady-state pharmacodynamic responses (urinary sodium excretion, urine volume) to bumetanide in healthy subjects.
Dapagliflozin did not affect the anticoagulant activity of warfarin as measured by the prothrombin time (International Normalized Ratio [INR]).
Other interactions: The effects of smoking, diet, herbal products, and alcohol use on the pharmacokinetics of dapagliflozin have not been specifically studied.
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.
Caution For Usage
Incompatibilities: Not applicable.
Storage
Store below 30°C.
Shelf-Life: 24 months.
MIMS Class
ATC Classification
A10BK01 - dapagliflozin ; Belongs to the class of sodium-glucose co-transporter 2 (SGLT2) inhibitors. Used in the treatment of diabetes.
Presentation/Packing
FC tab 10 mg (yellow, biconvex, diamond-shaped, with "10" debossed on one side and "1428" debossed on the other side) x 3 x 10's.
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