Dapagliflozin.

 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 C21H25ClO6•C3H8O2•H2O and the molecular weight is 502.98.

 The structural formula is:

DAPADIET is available as a film-coated tablet for oral administration containing the equivalent of  10 mg dapagliflozin as dapagliflozin propanediol,

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 lowers the renal threshold for glucose, and thereby increases urinary glucose excretion

 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

Dapagliflozin dose of 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

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 Cmax 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-Oglucuronide accounted for 61% of a 50 mg 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 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 DAPADIET 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

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 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 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 (8.7)].

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.

FULL PRESCRIBING INFORMATION

INDICATIONS AND USAGE

DAPADIET (dapagliflozin) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus

 Limitation of Use

DAPADIET is not recommended for patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.

DOSAGE AND ADMINISTRATION

Recommended Dosing

The recommended starting dose of DAPADIET is 10 mg once daily, taken in the morning, with or without food.

In patients with volume depletion, correcting this condition prior to initiation of DAPADIET is recommended Patient Counseling Information (17)].

Patients with Renal Impairment

Assessment of renal function is recommended prior to initiation of DAPADIET therapy and periodically thereafter.

DAPADIET should not be initiated in patients with an eGFR less than 60 mL/min/1.73 m2

No dose adjustment is needed in patients with mild renal impairment (eGFR of

60 mL/min/1.73 m2 or greater).

DAPADIET should be discontinued when eGFR is persistently less than 60 mL/min/1.73 m2

CONTRAINDICATIONS

 History of a serious hypersensitivity reaction to DAPAGLIFLOZIN, Severe renal impairment, end-stage renal disease (ESRD), or patients on dialysis

 WARNINGS AND PRECAUTIONS

Hypotension -  DAPADIET causes intravascular volume contraction. Symptomatic hypotension can occur after initiating DAPADIET  particularly in patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2 ), elderly patients, or patients on loop diuretics. Before initiating DAPADIET in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms of hypotension after initiating therapy.

Impairment in Renal Function -  DAPADIET increases serum creatinine and decreases eGFR. Elderly patients and patients with impaired renal function may be more susceptible to these changes. Adverse reactions related to renal function can occur after initiating DAPADIET.  Renal function should be evaluated prior to initiation of FARXIGA and monitored periodically thereafter.

Hypoglycemia  - with Concomitant Use with Insulin and Insulin Secretagogues Insulin and insulin secretagogues are known to cause hypoglycemia. DAPADIET can increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when these agents are used in combination with DAPADIET.

Genital Mycotic Infections - DAPADIET increases the risk of genital mycotic infections. Patients with a history of genital mycotic infections were more likely to develop genital mycotic infections . Monitor and treat appropriately.

Increases in Low-Density Lipoprotein Cholesterol (LDL-C) -  Increases in LDL-C occur with DAPADIET. Monitor LDL-C and treat per standard of care after initiating DAPADIET.

ADVERSE REACTIONS

The following important adverse reactions are described below

Hypotension

Impairment in Renal Function

Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues

Increases in Low-Density Lipoprotein Cholesterol (LDL-C)

Impairment of Renal Function

Genital Mycotic Infections Genital mycotic infections were more frequent with DAPADIET treatment. Genital mycotic infections were reported in 0.9% of patients on placebo, and 4.8% on DAPADIET 10 mg, in the 12-study placebo-controlled pool. Discontinuation from study due to genital infection occurred in 0% of placebo-treated patients and 0.2% of patients treated with DAPADIET 10 mg. Infections were more frequently reported in females than in males . The most frequently reported genital mycotic infections were vulvovaginal mycotic infections in females and balanitis in males. Patients with a history of genital mycotic infections were more likely to have a genital mycotic infection during the study than those with no prior history (10.0%, 23.1%, and 25.0% versus 0.8%, 5.9%, and 5.0% on placebo, DAPAGLIFLOZIN 10 mg, respectively).

Hypersensitivity Reactions - Hypersensitivity reactions (e.g., angioedema, urticaria, hypersensitivity) were reported with DAPAGLIFLOZIN

USE IN SPECIFIC POPULATIONS

Pregnancy  - Pregnancy Category C There are no adequate and well-controlled studies of DAPADIET in pregnant women. Based on results of reproductive and developmental toxicity studies in animals, dapagliflozin may affect renal development and maturation.

Nursing Mothers  - It is not known whether DAPADIET is excreted in human milk. Dapagliflozin is excreted in rat milk reaching levels 0.49 times that found in maternal plasma.