Contents
Dapagliflozin and Metformin
Description
Each caplet contains 10 mg of Dapagliflozin and Metformin hydrochloride
( Extended release) 500 mg
Presentation/Packing
Caplet (Film-coated, rectangle, yellow colour)
Shelf-Life: 2 years.
Storage
Store below 30°C, protected from light
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
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.