Farxiga (Dapagliflozin Propanediol) - Description and Clinical Pharmacology

Cardiac Electrophysiology

Dapagliflozin was not associated with clinically meaningful prolongation of QTc interval at daily doses up to 150 mg (15 times the recommended maximum 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 maximum dose) of dapagliflozin in healthy subjects.

Pharmacokinetics

Absorption

Following oral administration of dapagliflozin, the maximum plasma concentration (C_max) is usually attained within 2 hours under fasting state. The C_max and AUC values increase dose proportionally with increase in dapagliflozin dose in the therapeutic dose range. The absolute oral bioavailability of dapagliflozin following the administration of a 10 mg dose is 78%. Administration of dapagliflozin with a high-fat meal decreases its C_max by up to 50% and prolongs T_max by approximately 1 hour, but does not alter AUC as compared with the fasted state. These changes are not considered to be clinically meaningful and dapagliflozin can be administered with or without food.

Distribution

Dapagliflozin is approximately 91% protein bound. Protein binding is not altered in patients with renal or hepatic impairment.

Metabolism

The metabolism of dapagliflozin is primarily mediated by UGT1A9; CYP-mediated metabolism is a minor clearance pathway in humans. Dapagliflozin is extensively metabolized, primarily to yield dapagliflozin 3-O-glucuronide, which is an inactive metabolite. Dapagliflozin 3-O-glucuronide accounted for 61% of a 50 mg [14C]-dapagliflozin dose and is the predominant drug-related component in human plasma.

Elimination

Dapagliflozin and related metabolites are primarily eliminated via the renal pathway. Following a single 50 mg dose of [14C]-dapagliflozin, 75% and 21% total radioactivity is excreted in urine and feces, respectively. In urine, less than 2% of the dose is excreted as parent drug. In feces, approximately 15% of the dose is excreted as parent drug. The mean plasma terminal half-life (t_½) for dapagliflozin is approximately 12.9 hours following a single oral dose of FARXIGA 10 mg.

Specific Populations

Renal Impairment

At steady state (20 mg once-daily dapagliflozin for 7 days), patients with type 2 diabetes with mild, moderate, or severe renal impairment (as determined by eGFR) had geometric mean systemic exposures of dapagliflozin that were 45%, 2.04-fold, and 3.03-fold higher, respectively, as compared to patients with type 2 diabetes with normal renal function. Higher systemic exposure of dapagliflozin in patients with type 2 diabetes mellitus with renal impairment did not result in a correspondingly higher 24-hour urinary glucose excretion. The steady-state 24-hour urinary glucose excretion in patients with type 2 diabetes and mild, moderate, and severe renal impairment was 42%, 80%, and 90% lower, respectively, than patients with type 2 diabetes with normal renal function. The impact of hemodialysis on dapagliflozin exposure is not known. [See Dosage and Administration , Warnings and Precautions , Use in Specific Populations , and Clinical Studies .]

Hepatic Impairment

In subjects with mild and moderate hepatic impairment (Child-Pugh classes A and B), mean C_max and AUC of dapagliflozin were up to 12% and 36% higher, respectively, as compared to healthy matched control subjects following single-dose administration of 10 mg dapagliflozin. These differences were not considered to be clinically meaningful. In patients with severe hepatic impairment (Child-Pugh class C), mean C_max and AUC of dapagliflozin were up to 40% and 67% higher, respectively, as compared to healthy matched controls [see Use in Specific Populations ].

Effects of Age, Gender, Race, and Body Weight on Pharmacokinetics

Based on a population pharmacokinetic analysis, age, gender, race, and body weight do not have a clinically meaningful effect on the pharmacokinetics of dapagliflozin and thus, no dose adjustment is recommended.

Pediatric

Pharmacokinetics in the pediatric population has not been studied.

Drug Interactions

In Vitro Assessment of Drug Interactions

In in vitro studies, dapagliflozin and dapagliflozin 3-O-glucuronide neither inhibited CYP 1A2, 2C9, 2C19, 2D6, or 3A4, nor induced CYP 1A2, 2B6, or 3A4. 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.

Effects of Other Drugs on Dapagliflozin

Table 6 shows the effect of coadministered drugs on the pharmacokinetics of dapagliflozin. No dose adjustments are recommended for dapagliflozin.

Table 6: Effects of Coadministered Drugs on Dapagliflozin Systemic Exposure

Coadministered Drug (Dose Regimen)*	Dapagliflozin (Dose Regimen)*	Effect on Dapagliflozin Exposure (% Change [90% CI])
		Cmax	AUC†
*  Single dose unless otherwise noted. †  AUC = AUC(INF) for drugs given as single dose and AUC = AUC(TAU) for drugs given in multiple doses. ↔ = no change (geometric mean ratio of test:reference within 0.80 to 1.25); ↓ or ↑ = parameter was lower or higher, respectively, with coadministration compared to dapagliflozin administered alone (geometric mean ratio of test:reference was lower than 0.80 or higher than 1.25).
No dosing adjustments required for the following:
Oral Antidiabetic Agents
Metformin (1000 mg)	20 mg	↔	↔
Pioglitazone (45 mg)	50 mg	↔	↔
Sitagliptin (100 mg)	20 mg	↔	↔
Glimepiride (4 mg)	20 mg	↔	↔
Voglibose (0.2 mg three times daily)	10 mg	↔	↔
Other Medications
Hydrochlorothiazide (25 mg)	50 mg	↔	↔
Bumetanide (1 mg)	10 mg once daily for 7 days	↔	↔
Valsartan (320 mg)	20 mg	↓12% [↓3%, ↓20%]	↔
Simvastatin (40 mg)	20 mg	↔	↔
Anti-infective Agent
Rifampin (600 mg once daily for 6 days)	10 mg	↓7% [↓22%, ↑11%]	↓22% [↓27%, ↓17%]
Nonsteroidal Anti-inflammatory Agent
Mefenamic Acid (loading dose of 500 mg followed by 14 doses of 250 mg every 6 hours)	10 mg	↑13% [↑3%, ↑24%]	↑51% [↑44%, ↑58%]

Effects of Dapagliflozin on Other Drugs

Table 7 shows the effect of dapagliflozin on other coadministered drugs. Dapagliflozin did not meaningfully affect the pharmacokinetics of the coadministered drugs.

Table 7: Effects of Dapagliflozin on the Systemic Exposures of Coadministered Drugs

Coadministered Drug (Dose Regimen)*	Dapagliflozin (Dose Regimen)*	Effect on Coadministered Drug Exposure (% Change [90% CI])
		Cmax	AUC†
*  Single dose unless otherwise noted. †  AUC = AUC(INF) for drugs given as single dose and AUC = AUC(TAU) for drugs given in multiple doses. ↔ = no change (geometric mean ratio of test:reference within 0.80 to 1.25); ↓ or ↑ = parameter was lower or higher, respectively, with coadministration compared to dapagliflozin administered alone (geometric mean ratio of test:reference was lower than 0.80 or higher than 1.25).
No dosing adjustments required for the following:
Oral Antidiabetic Agents
Metformin (1000 mg)	20 mg	↔	↔
Pioglitazone (45 mg)	50 mg	↓7% [↓25%, ↑15%]	↔
Sitagliptin (100 mg)	20 mg	↔	↔
Glimepiride (4 mg)	20 mg	↔	↑13% [0%, ↑29%]
Other Medications
Hydrochlorothiazide (25 mg)	50 mg	↔	↔
Bumetanide (1 mg)	10 mg once daily for 7 days	↑13% [↓2%, ↑31%]	↑13% [↓1%, ↑30%]
Valsartan (320 mg)	20 mg	↓6% [↓24%, ↑16%]	↑5% [↓15%, ↑29%]
Simvastatin (40 mg)	20 mg	↔	↑19%
Digoxin (0.25 mg)	20 mg loading dose then 10 mg once daily for 7 days	↔	↔
Warfarin (25 mg)	20 mg loading dose then 10 mg once daily for 7 days	↔	↔

NONCLINICAL TOXICOLOGY

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 approximately 72 times (males) and 105 times (females) the clinical dose of 10 mg per day based on AUC exposure. In rats, the highest dose was approximately 131 times (males) and 186 times (females) the clinical dose of 10 mg per day based on AUC exposure.

Dapagliflozin was negative in the Ames mutagenicity assay and was positive in a series of in vitro clastogenicity assays in the presence of S9 activation and at concentrations ≥100 μg/mL. Dapagliflozin was negative for clastogenicity in a series of in vivo studies evaluating micronuclei or DNA repair in rats at exposure multiples >2100 times the clinical dose.

There was no carcinogenicity or mutagenicity signal in animal studies, suggesting that dapagliflozin does not represent a genotoxic risk to humans.

Dapagliflozin had no effects on mating, fertility, or early embryonic development in treated male or female rats at exposure multiples ≤1708 times and 998 times the maximum recommended human dose in males and females, respectively.

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 a 52-week, glipizide-controlled, noninferiority study to evaluate FARXIGA 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 FARXIGA 10 mg) as tolerated by patients. Thereafter, doses were kept constant, except for down-titration to prevent hypoglycemia.

At the end of the titration period, 87% of patients treated with FARXIGA had been titrated to the maximum study dose (10 mg) versus 73% treated with glipizide (20 mg). FARXIGA led to a similar mean reduction in HbA1c from baseline at Week 52 (LOCF), compared with glipizide, thus demonstrating noninferiority (see Table 12). FARXIGA treatment led to a statistically significant mean reduction in body weight from baseline at Week 52 (LOCF) compared with a mean increase in body weight in the glipizide group. Statistically significant (p<0.0001) mean change from baseline in systolic blood pressure relative to glipizide plus metformin was −5.0 mmHg with FARXIGA plus metformin.

Table 12: Results at Week 52 (LOCF*) in an Active-Controlled Study Comparing FARXIGA to Glipizide as Add-On to Metformin

Efficacy Parameter	FARXIGA + Metformin N=400†	Glipizide + Metformin N=401†
*  LOCF: last observation carried forward. †  Randomized and treated patients with baseline and at least 1 postbaseline efficacy measurement. ‡  Least squares mean adjusted for baseline value. §  Noninferior to glipizide + metformin. ¶  p-value <0.0001.
HbA1c (%)
Baseline (mean)	7.7	7.7
Change from baseline (adjusted mean‡)	−0.5	−0.5
Difference from glipizide + metformin (adjusted mean‡)   (95% CI)	0.0§ (−0.1, 0.1)
Body Weight (kg)
Baseline (mean)	88.4	87.6
Change from baseline (adjusted mean‡)	−3.2	1.4
Difference from glipizide + metformin (adjusted mean‡)   (95% CI)	−4.7¶ (−5.1, −4.2)

Add-On Combination Therapy 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 to evaluate FARXIGA in combination with glimepiride (a sulfonylurea).

Patients on at least half the maximum recommended dose of glimepiride as monotherapy (4 mg) for at least 8 weeks lead-in were randomized to FARXIGA 5 mg, FARXIGA 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, FARXIGA 10 mg provided statistically significant improvement in HbA1c, FPG, and 2-hour PPG, and statistically significant reduction in body weight compared with placebo plus glimepiride at Week 24 (see Table 13). Statistically significant (p<0.05 for both doses) mean changes from baseline in systolic blood pressure relative to placebo plus glimepiride were −2.8 mmHg and −3.8 mmHg with FARXIGA 5 mg and 10 mg plus glimepiride, respectively.

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 to evaluate FARXIGA in combination with pioglitazone (a thiazolidinedione [TZD]) alone. Patients on a stable dose of pioglitazone of 45 mg per day (or 30 mg per day, if 45 mg per day was not tolerated) for 12 weeks were randomized after a 2-week lead-in period to 5 or 10 mg of FARXIGA or placebo in addition to their current dose of pioglitazone. Dose titration of FARXIGA or pioglitazone was not permitted during the study.

In combination with pioglitazone, treatment with FARXIGA 10 mg provided statistically significant improvements in HbA1c, 2-hour PPG, FPG, the proportion of patients achieving HbA1c <7%, and a statistically significant reduction in body weight compared with the placebo plus pioglitazone treatment groups (see Table 13) at Week 24. A statistically significant (p<0.05) mean change from baseline in systolic blood pressure relative to placebo in combination with pioglitazone was −4.5 mmHg with FARXIGA 10 mg in combination with pioglitazone.

Add-On Combination Therapy with a DPP4 Inhibitor

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 to evaluate FARXIGA 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 per day), and within each stratum were randomized to either FARXIGA 10 mg plus sitagliptin 100 mg once daily, or placebo plus sitagliptin 100 mg once daily. Endpoints were tested for FARXIGA 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 FARXIGA, sitagliptin, or metformin was not permitted during the study.

In combination with sitagliptin (with or without metformin), FARXIGA 10 mg provided statistically significant improvements in HbA1c, FPG, and a statistically significant reduction in body weight compared with the placebo plus sitagliptin (with or without metformin) group at Week 24 (see Table 13). These improvements were also seen in the stratum of patients who received FARXIGA 10 mg plus sitagliptin alone (placebo-corrected mean change for HbA1c −0.56%; n=110) compared with placebo plus sitagliptin alone (n=111), and the stratum of patients who received FARXIGA 10 mg plus sitagliptin and metformin (placebo-corrected mean change for HbA1c −0.40; n=113) compared with placebo plus sitagliptin with metformin (n=113).

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 to evaluate FARXIGA 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 to enrollment and on a maximum of 2 oral antidiabetic medications (OADs), including metformin, were randomized after completing a 2-week enrollment period to receive either FARXIGA 5 mg, FARXIGA 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 OAD(s) were not allowed during the treatment phase, with the exception of decreasing OAD(s) 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, FARXIGA 10 mg dose provided statistically significant improvement in HbA1c and reduction in mean insulin dose, and a statistically significant reduction in body weight compared with placebo in combination with insulin, with or without up to 2 OADs (see Table 13); the effect of FARXIGA on HbA1c was similar in patients treated with insulin alone and patients treated with insulin plus OAD. Statistically significant (p<0.05) mean change from baseline in systolic blood pressure relative to placebo in combination with insulin was −3.0 mmHg with FARXIGA 10 mg in combination with insulin.

At Week 24, FARXIGA 5 mg (−5.7 IU, difference from placebo) and 10 mg (−6.2 IU, difference from placebo) once daily resulted in a statistically significant reduction in mean daily insulin dose (p<0.0001 for both doses) compared to placebo in combination with insulin, and a statistically significantly higher proportion of patients on FARXIGA 10 mg (19.6%) reduced their insulin dose by at least 10% compared to placebo (11.0%).

Table 13: Results of 24-Week (LOCF*) Placebo-Controlled Studies of FARXIGA in Combination with Antidiabetic Agents

Efficacy Parameter	FARXIGA 10 mg	FARXIGA 5 mg	Placebo
*  LOCF: last observation (prior to rescue for rescued patients) carried forward. †  Randomized and treated patients with baseline and at least 1 postbaseline efficacy measurement. ‡  Least squares mean adjusted for baseline value. §  p-value <0.0001 versus placebo. ¶  2-hour PPG level as a response to a 75-gram oral glucose tolerance test (OGTT). #  All randomized patients who took at least one dose of double-blind study medication during the short-term, double-blind period. **  p-value <0.05 versus placebo. ††   NT: Not formally tested because of failing to achieve a statistically significant difference in an endpoint that was earlier in the testing sequence.
In Combination with Sulfonylurea (Glimepiride)
Intent-to-Treat Population	N=151†	N=142†	N=145†
HbA1c (%)
Baseline (mean)	8.1	8.1	8.2
Change from baseline (adjusted mean‡)	−0.8	−0.6	−0.1
Difference from placebo + glimepiride (adjusted mean‡) (95% CI)	−0.7§ (−0.9, −0.5)	−0.5§ (−0.7, −0.3)
Percent of patients achieving HbA1c <7% adjusted for baseline	31.7%§	30.3%§	13.0%
FPG (mg/dL)
Baseline (mean)	172.4	174.5	172.7
Change from baseline (adjusted mean‡)	−28.5	−21.2	−2.0
Difference from placebo + glimepiride (adjusted mean‡) (95% CI)	−26.5§ (−33.5, −19.5)	−19.3§ (−26.3, −12.2)
2-hour PPG ¶ (mg/dL)
Baseline (mean)	329.6	322.8	324.1
Change from baseline (adjusted mean‡)	−60.6	–54.5	−11.5
Difference from placebo + glimepiride (adjusted mean‡) (95% CI)	−49.1§ (−64.1, −34.1)	−43.0§ (–58.4, −27.5)
Body Weight (kg)
Baseline (mean)	80.6	81.0	80.9
Change from baseline (adjusted mean‡)	−2.3	−1.6	−0.7
Difference from placebo + glimepiride (adjusted mean‡) (95% CI)	−1.5§ (−2.2, −0.9)	−0.8§ (−1.5, −0.2)
In Combination with Thiazolidinedione (Pioglitazone)
Intent-to-Treat Population	N=140 #	N=141 #	N=139 #
HbA1c (%)
Baseline (mean)	8.4	8.4	8.3
Change from baseline (adjusted mean‡)	−1.0	−0.8	−0.4
Difference from placebo (adjusted mean‡) (95% CI)	−0.6§ (−0.8, −0.3)	−0.4§ (−0.6, −0.2)
Percent of patients achieving HbA1c <7% adjusted for baseline	38.8%**	32.5%**	22.4%
FPG (mg/dL)
Baseline (mean)	164.9	168.3	160.7
Change from baseline (adjusted mean‡)	−29.6	−24.9	−5.5
Difference from placebo (adjusted mean‡) (95% CI)	−24.1§ (−32.2, −16.1)	−19.5§ (−27.5, −11.4)
2-hour PPG ¶ (mg/dL)
Baseline (mean)	308.0	284.8	293.6
Change from baseline (adjusted mean‡)	−67.5	−65.1	−14.1
Difference from placebo (adjusted mean‡) (95% CI)	−53.3§ (−71.1, −35.6)	−51.0§ (−68.7, −33.2)
Body Weight (kg)
Baseline (mean)	84.8	87.8	86.4
Change from baseline (adjusted mean‡)	−0.1	0.1	1.6
Difference from placebo (adjusted mean‡) (95% CI)	−1.8§ (−2.6, −1.0)	−1.6§ (−2.3, −0.8)
In Combination with DPP4 Inhibitor (Sitagliptin) with or without Metformin
Intent-to-Treat Population	N=223†	–	N=224†
HbA1c (%)
Baseline (mean)	7.90	–	7.97
Change from baseline (adjusted mean‡)	−0.45	–	0.04
Difference from placebo (adjusted mean‡) (95% CI)	−0.48§ (−0.62, −0.34)	–
Patients with HbA1c decrease ≥0.7% (adjusted percent)	35.4%	–	16.6%
FPG (mg/dL)
Baseline (mean)	161.7	–	163.1
Change from baseline at Week 24 (adjusted mean‡)	−24.1	–	3.8
Difference from placebo (adjusted mean‡) (95% CI)	−27.9§ (−34.5, −21.4)	–
Body Weight (kg)
Baseline (mean)	91.02	–	89.23
Change from baseline (adjusted mean‡)	−2.14	–	−0.26
Difference from placebo (adjusted mean‡) (95% CI)	−1.89§ (−2.37, −1.40)	–
In Combination with Insulin with or without up to 2 Oral Antidiabetic Therapies
Intent-to-Treat Population	N=194†	N=211†	N=193†
HbA1c (%)
Baseline (mean)	8.6	8.6	8.5
Change from baseline (adjusted mean‡)	−0.9	−0.8	−0.3
Difference from placebo (adjusted mean‡) (95% CI)	−0.6§ (−0.7, −0.5)	−0.5§ (−0.7, −0.4)
FPG (mg/dL)
Baseline (mean)	173.7	NT††	170.0
Change from baseline (adjusted mean‡)	−21.7	NT††	3.3
Difference from placebo (adjusted mean‡) (95% CI)	−25.0§ (−34.3, −15.8)	NT††
Body Weight (kg)
Baseline (mean)	94.6	93.2	94.2
Change from baseline (adjusted mean‡)	−1.7	−1.0	0.0
Difference from placebo (adjusted mean‡) (95% CI)	−1.7§ (−2.2, −1.2)	−1.0§ (−1.5, −0.5)

Use in Patients with Type 2 Diabetes and Renal Impairment

The efficacy of FARXIGA was assessed in a study of diabetic patients with moderate renal impairment (252 patients with mean eGFR 45 mL/min/1.73 m²). FARXIGA did not show efficacy in this study. The placebo-corrected mean HbA1c change at 24 weeks was −0.1% (95% CI [−0.4%, 0.2%]) for both FARXIGA 5 mg (n=83) and 10 mg (n=82).