FARXIGA (Page 4 of 13)

8.7 Hepatic Impairment

No dose adjustment is recommended for patients with mild, moderate, or 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 [see Clinical Pharmacology (12.3)].

10 OVERDOSAGE

There were no reports of overdose during the clinical development program for FARXIGA.

In the event of an overdose, contact the Poison Control Center. It is also reasonable to employ supportive measures as dictated by the patient’s clinical status. The removal of dapagliflozin by hemodialysis has not been studied.

11 DESCRIPTION

Dapagliflozin 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 C21 H25 ClO6 •C3 H8 O2 •H2 O and the molecular weight is 502.98. The structural formula is:

Dapagliflozin Chemical Structure
(click image for full-size original)

FARXIGA is available as a film-coated tablet for oral administration containing the equivalent of 5 mg dapagliflozin as dapagliflozin propanediol or the equivalent of 10 mg dapagliflozin as dapagliflozin propanediol, and the following inactive ingredients: microcrystalline cellulose, anhydrous lactose, crospovidone, silicon dioxide, and magnesium stearate. In addition, the film coating contains the following inactive ingredients: polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and yellow iron oxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Sodium-glucose cotransporter 2 (SGLT2), expressed in the proximal renal tubules, is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. Dapagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, dapagliflozin reduces reabsorption of filtered glucose and thereby promotes urinary glucose excretion. Dapagliflozin also reduces sodium reabsorption and increases the delivery of sodium to the distal tubule. This may influence several physiological functions including, but not restricted to, lowering both pre- and afterload of the heart and downregulation of sympathetic activity, and decreased intraglomerular pressure which is believed to be mediated by increased tubuloglomerular feedback.

12.2 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). Dapagliflozin doses of 5 or 10 mg per day in patients with type 2 diabetes mellitus for 12 weeks resulted in excretion of approximately 70 grams of glucose in the urine per day at Week 12. A near maximum glucose excretion was observed at the dapagliflozin daily dose of 20 mg. This urinary glucose excretion with dapagliflozin also results in increases in urinary volume [see Adverse Reactions (6.1)]. After discontinuation of dapagliflozin, on average, the elevation in urinary glucose excretion approaches baseline by about 3 days for the 10 mg dose.

Figure 1: Scatter Plot and Fitted Line of Change from Baseline in 24-Hour Urinary Glucose Amount versus Dapagliflozin Dose in Healthy Subjects and Subjects with Type 2 Diabetes Mellitus (T2DM) (Semi-Log Plot)

Figure 1
(click image for full-size original)

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.

12.3 Pharmacokinetics

Absorption

Following oral administration of dapagliflozin, the maximum plasma concentration (Cmax ) is usually attained within 2 hours under fasting state. The Cmax 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 Cmax by up to 50% and prolongs Tmax 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 [14 C]-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 [14 C]-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 (t½ ) 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%, 100%, and 200% higher, respectively, as compared to patients with type 2 diabetes mellitus with normal renal function. There was no meaningful difference in exposure between patients with chronic kidney disease with and without type 2 diabetes. 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 mellitus and mild, moderate, and severe renal impairment was 42%, 80%, and 90% lower, respectively, than in patients with type 2 diabetes mellitus with normal renal function.

The impact of hemodialysis on dapagliflozin exposure is not known [see Dosage and Administration (2.2), Warnings and Precautions (5.2), Use in Specific Populations (8.6), and Clinical Studies (14)].

Hepatic Impairment

In subjects with mild and moderate hepatic impairment (Child-Pugh classes A and B), mean Cmax 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 Cmax and AUC of dapagliflozin were up to 40% and 67% higher, respectively, as compared to healthy matched controls [see Use in Specific Populations (8.7)].

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