AstraZeneca
(NYSE:AZN) today announced that the U.S. Food and Drug
Administration has approved once-daily XIGDUO™ XR (dapagliflozin and
metformin hydrochloride extended-release) for the treatment of adults
with type 2 diabetes.
XIGDUO XR combines two anti-hyperglycemic agents with complementary
mechanisms of action, dapagliflozin (trade name in the U.S. FARXIGA™),
an inhibitor of sodium-glucose cotransporter 2 (SGLT2), and metformin
hydrochloride (HCl) extended-release, a biguanide, in a once-daily oral
tablet. SGLT2 inhibitors are a relatively new class of medicines that
remove glucose from the body via the kidneys.
XIGDUO XR is the first and only once-daily combination tablet of an
SGLT2 inhibitor and metformin HCl extended-release to be approved in the
United States. XIGDUO XR is indicated as an adjunct therapy to diet and
exercise to improve glycemic control in adults with type 2 diabetes
mellitus when treatment with both dapagliflozin and metformin is
appropriate.
XIGDUO XR is not recommended for patients with type 1 diabetes or
diabetic ketoacidosis. The product label for XIGDUO XR contains a boxed
warning for lactic acidosis, a rare, but serious metabolic complication
that can occur due to metformin accumulation during treatment with
XIGDUO XR.
XIGDUO XR is contraindicated in patients with moderate to severe renal
impairment; a history of a serious hypersensitivity to dapagliflozin or
to metformin HCl; or with metabolic acidosis, including diabetic
ketoacidosis.
“The addition of XIGDUO XR to our U.S. diabetes portfolio is further
evidence of AstraZeneca’s commitment to develop new treatment options
for patients with type 2 diabetes,” said Elisabeth Björk, Head of
Cardiovascular & Metabolism, Global Medicines Development, AstraZeneca.
“The approval of once-daily XIGDUO XR provides prescribers and adult
patients with another treatment choice, supporting a more personalized
approach to disease management.”
XIGDUO XR is already approved in Australia for the treatment of adults
with type 2 diabetes, along with diet and exercise. XIGDUO
(dapagliflozin and metformin hydrochloride), which uses an
immediate-release form of metformin, is approved in the European Union.
XIGDUO XR Dosing
XIGDUO XR is approved with multiple dosage strengths of dapagliflozin
and metformin HCl extended-release, respectively, including 5 mg/500 mg,
5 mg/1000 mg, 10 mg/500 mg, and 10 mg/1000 mg, and the starting dose
should be individualized based on each patient’s current treatment
regimen. XIGDUO XR should be taken once daily in the morning with food
with gradual dose escalation to reduce the risk of gastrointestinal (GI)
side effects due to metformin. The maximum daily recommended dose is 10
mg for dapagliflozin and 2,000 mg for metformin HCl. Dapagliflozin
causes intravascular volume contraction. Symptomatic hypotension can
occur after initiating dapagliflozin, particularly in patients with
impaired renal function (eGFR <60 mL/min/1.73 m2), elderly
patients, or patients on loop diuretics. Before initiating XIGDUO XR in
patients with one or more of these characteristics, assess and correct
volume status. After initiating therapy, monitor for signs and symptoms
of hypotension. Dapagliflozin 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 XIGDUO XR. Before initiation of
XIGDUO XR therapy, and at least annually thereafter, renal function
should be assessed. Discontinue XIGDUO XR if evidence of moderate to
severe renal impairment is present.
Clinical Development Program
The co-administration of dapagliflozin and metformin has been studied in
adults with type 2 diabetes. The FDA approved once-daily XIGDUO XR based
upon four Phase III clinical trials, which provided clinical evidence
for the efficacy and safety of dapagliflozin and metformin IR or XR
tablets in treatment-naïve patients, in patients inadequately controlled
on metformin, as well as compared to a sulfonylurea (glipizide) plus
metformin. There have been no clinical studies conducted with XIGDUO XR
combination tablets. Bioequivalence was demonstrated in healthy adults
between XIGDUO XR and dapagliflozin plus metformin XR as separate
tablets.
INDICATION AND LIMITATIONS OF USE
XIGDUO XR is indicated as an adjunct to diet and exercise to improve
glycemic control in adults with type 2 diabetes mellitus when treatment
with both dapagliflozin and metformin is appropriate.
XIGDUO XR is not recommended for patients with type 1 diabetes mellitus
or diabetic ketoacidosis.
IMPORTANT SAFETY INFORMATION
WARNING: LACTIC ACIDOSIS
Lactic acidosis is a rare, but serious, complication that can occur
due to metformin accumulation. The risk increases with conditions such
as sepsis, dehydration, excess alcohol intake, hepatic impairment, renal
impairment, and acute congestive heart failure.
The onset of lactic acidosis is often subtle, accompanied only by
nonspecific symptoms such as malaise, myalgias, respiratory distress,
increasing somnolence, and nonspecific abdominal distress.
Laboratory abnormalities include low pH, increased anion gap, and
elevated blood lactate.
If acidosis is suspected, XIGDUO XR should be discontinued and the
patient hospitalized immediately. [See Warnings and Precautions]
Contraindications
-
Moderate to severe renal impairment (eg, serum creatinine levels ≥1.5
mg/dL for men, ≥1.4 mg/dL for women, or eGFR <60 mL/min/1.73 m2
or CrCl <60 mL/min), which may also result from conditions such as
cardiovascular collapse (shock), acute myocardial infarction, and
septicemia
-
History of a serious hypersensitivity reaction to dapagliflozin or
hypersensitivity to metformin hydrochloride
-
Acute or chronic metabolic acidosis, including diabetic ketoacidosis,
with or without coma
Warnings and Precautions
Lactic Acidosis:
-
The reported incidence of lactic acidosis in patients receiving
metformin is very low (approximately 0.03 cases/1000 patient-years).
When it occurs, it is fatal in approximately 50% of cases. Reported
cases of lactic acidosis have occurred primarily in diabetic patients
with significant renal insufficiency.
-
Patients with congestive heart failure requiring pharmacologic
management, in particular those with unstable or acute congestive
heart failure who are at risk of hypoperfusion and hypoxemia, are at
increased risk of lactic acidosis.
-
Lactic acidosis risk increases with the degree of renal dysfunction
and patient age. The risk may be significantly decreased by use of
minimum effective dose of metformin and regular monitoring of renal
function. Careful renal monitoring is particularly important in the
elderly. XIGDUO XR should not be initiated in patients ≥80 years of
age unless measurement of creatinine clearance demonstrates that renal
function is not reduced.
-
Withhold XIGDUO XR in the presence of any condition associated with
hypoxemia, dehydration, or sepsis.
Hypoxic States: Cardiovascular collapse (shock), acute congestive
heart failure, acute myocardial infarction, and other conditions
characterized by hypoxemia have been associated with lactic acidosis and
may also cause prerenal azotemia. When such events occur in patients on
XIGDUO XR, the drug should be promptly discontinued.
Renal Impairment: Dapagliflozin 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 XIGDUO XR. Before
initiation of XIGDUO XR therapy, and at least annually thereafter, renal
function should be assessed. Discontinue XIGDUO XR if evidence of
moderate to severe renal impairment is present.
Hypotension: Dapagliflozin causes intravascular volume
contraction. Symptomatic hypotension can occur after initiating
dapagliflozin, particularly in patients with impaired renal function
(eGFR <60 mL/min/1.73 m2), elderly patients, or patients
on loop diuretics. Before initiating XIGDUO XR in patients with one or
more of these characteristics, assess and correct volume status. After
initiating therapy, monitor for signs and symptoms of hypotension.
Impaired Hepatic Function: XIGDUO XR is not recommended in
patients with hepatic impairment.
Alcohol Intake: Warn patients against excessive alcohol intake
while receiving XIGDUO XR.
Surgical Procedures: XIGDUO XR should be suspended for any
surgical procedure (except minor procedures not associated with
restricted intake of food and fluids), and should not be restarted until
patient's oral intake has resumed and renal function is normal or mildly
impaired.
Use with Medications Known to Cause Hypoglycemia:
-
Dapagliflozin: Insulin and
insulin secretagogues are known to cause hypoglycemia. Dapagliflozin
can increase the risk of hypoglycemia when combined with these agents.
Consider a lower dose of insulin or the insulin secretagogue to reduce
the risk of hypoglycemia when used in combination with XIGDUO XR.
-
Metformin: Hypoglycemia
does not occur in patients receiving metformin alone under usual
circumstances of use, but could occur when caloric intake is
deficient, when strenuous exercise is not compensated by caloric
supplementation, during concomitant use with other glucose-lowering
agents (such as sulfonylureas or insulin), or with use of ethanol.
Elderly, debilitated, or malnourished patients and those with adrenal
or pituitary insufficiency or alcohol intoxication are particularly
susceptible to hypoglycemic effects.
Concomitant Medications Affecting Renal Function or Metformin
Disposition: Use caution with concomitant medication(s) that may
affect renal function or result in significant hemodynamic change or may
interfere with the disposition of metformin, such as cationic drugs that
are eliminated by renal tubular secretion.
Radiologic Studies with Intravascular Iodinated Contrast Materials: Temporarily
discontinue XIGDUO XR at the time of or prior to any procedure with
intravascular administration of iodinated contrast study materials and
withhold for 48 hours subsequent to the procedure. XIGDUO XR should be
reinstituted only after renal function has been re-evaluated and found
to be normal or mildly impaired.
Vitamin B12 Concentrations: Metformin may lower vitamin B12
levels. Measure hematological parameters annually.
Genital Mycotic Infections: Dapagliflozin 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 dapagliflozin. After initiating XIGDUO XR, monitor
LDL-C and treat per standard of care.
Bladder Cancer: Across 22 clinical studies, newly diagnosed cases
of bladder cancer were reported in 0.17% dapagliflozin-treated patients
and 0.03% of placebo/comparator-treated patients. After excluding
patients in whom exposure to study drug was <1 year at the time of
diagnosis of bladder cancer, there were 4 cases with dapagliflozin and
no cases with placebo/comparator. Bladder cancer risk factors and
hematuria (a potential indicator of pre-existing tumors) were balanced
between treatment arms at baseline. There were too few cases to
determine whether the emergence of these events is related to
dapagliflozin.
There are insufficient data to determine whether dapagliflozin has an
effect on pre-existing bladder tumors. XIGDUO XR should not be used in
patients with active bladder cancer. Use with caution in patients with
prior history of bladder cancer.
Macrovascular Outcomes: There have been no clinical studies
establishing conclusive evidence of macrovascular risk reduction with
XIGDUO XR or any other antidiabetic drug.
Adverse Reactions
Most common adverse reactions (≥5%) with dapagliflozin (5mg or 10mg)
plus metformin vs placebo plus metformin were female genital mycotic
infection (9.4%, 9.3%, 1.5%), nasopharyngitis (6.3%, 5.2%, 5.9%),
urinary tract infection (6.1%, 5.5%, 3.6%), diarrhea (5.9%, 4.2%, 5.6%),
and headache (5.4%, 3.3%, 2.8%), respectively. Adverse reactions
reported in >5% of patients treated with metformin XR and more commonly
than in patients treated with placebo were diarrhea (9.6% vs 2.6%) and
nausea/vomiting (6.5% vs 1.5%).
Use in Specific Populations
Pregnant Women: There are no adequate and well-controlled studies
of XIGDUO XR or its individual components in pregnant women. During
pregnancy, consider appropriate alternative therapies, especially during
the second and third trimesters.
Nursing Mothers: It is not known whether XIGDUO XR is excreted in
human milk. Because of the potential for serious adverse reactions in
nursing infants from dapagliflozin, discontinue nursing or discontinue
XIGDUO XR.
Geriatric Use: A higher proportion of patients ≥65 years treated
with dapagliflozin had adverse reactions related to volume depletion and
renal impairment or failure compared to patients treated with placebo.
No XIGDUO XR dosage change is recommended based on age.
Please click
here for US Full Prescribing Information, including Boxed
WARNING about lactic acidosis, and Medication Guide for XIGDUO XR.
About Type 2 Diabetes
Diabetes is estimated to affect 29.1 million people in the U.S. and more
than 382 million people worldwide. The prevalence of diabetes is
projected to reach more than 592 million people worldwide by 2035. Type
2 diabetes accounts for approximately 90-95 percent of all cases of
diagnosed diabetes in the U.S. Type 2 diabetes is a chronic
disease characterized by pathophysiologic defects leading to elevated
glucose levels. Significant unmet needs still exist, as many patients
remain inadequately controlled on their current glucose-lowering regimen.
About SGLT2 Inhibition
The kidney plays a contributing role in maintaining normal glucose
balance, in part by filtering and subsequently reabsorbing glucose back
into circulation. SGLT2, a sodium-glucose cotransporter found
predominantly in the kidney, is responsible for the majority of glucose
reabsorption. Selective inhibition of SGLT2 reduces the reabsorption of
glucose and enables its removal via the urine.
About AstraZeneca
AstraZeneca is a global, innovation-driven biopharmaceutical business
that focuses on the discovery, development and commercialization of
prescription medicines, primarily for the treatment of cardiovascular,
metabolic, respiratory, inflammation, autoimmune, oncology, infection
and neuroscience diseases. AstraZeneca operates in over 100 countries
and its medicines are used by millions of patients worldwide. For more
information please visit: www.astrazeneca.com.
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