WILMINGTON, Del., Oct 30, 2014 (BUSINESS WIRE) –
currently announced that a U.S. Food and Drug
Administration has authorized once-daily XIGDUO™ XR (dapagliflozin and
metformin hydrochloride extended-release) for a diagnosis of adults
with form 2 diabetes.
XIGDUO XR combines dual anti-hyperglycemic agents with complementary
mechanisms of action, dapagliflozin (trade name in a 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 comparatively new category of medicines that
mislay glucose from a physique around a kidneys.
XIGDUO XR is a initial and usually once-daily mixed inscription of an
SGLT2 inhibitor and metformin HCl extended-release to be authorized in the
United States. XIGDUO XR is indicated as an accessory therapy to diet and
practice to urge glycemic control in adults with form 2 diabetes
mellitus when diagnosis with both dapagliflozin and metformin is
XIGDUO XR is not endorsed for patients with form 1 diabetes or
diabetic ketoacidosis. The product tag for XIGDUO XR contains a boxed
warning for lactic acidosis, a rare, though critical metabolic complication
that can start due to metformin accumulation during diagnosis with
XIGDUO XR is contraindicated in patients with assuage to critical renal
impairment; a story of a critical hypersensitivity to dapagliflozin or
to metformin HCl; or with metabolic acidosis, including diabetic
“The further of XIGDUO XR to a U.S. diabetes portfolio is further
justification of AstraZeneca’s joining to rise new diagnosis options
for patients with form 2 diabetes,” pronounced Elisabeth Björk, Head of
Cardiovascular Metabolism, Global Medicines Development, AstraZeneca.
“The capitulation of once-daily XIGDUO XR provides prescribers and adult
patients with another diagnosis choice, ancillary a some-more personalized
proceed to illness management.”
XIGDUO XR is already authorized in Australia for a diagnosis of adults
with form 2 diabetes, along with diet and exercise. XIGDUO
(dapagliflozin and metformin hydrochloride), that uses an
immediate-release form of metformin, is authorized in a European Union.
XIGDUO XR Dosing
XIGDUO XR is authorized with mixed sip 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 a starting dose
should be individualized formed on any patient’s stream treatment
regimen. XIGDUO XR should be taken once daily in a morning with food
with light sip escalation to revoke a risk of gastrointestinal (GI)
side effects due to metformin. The limit daily endorsed sip is 10
mg for dapagliflozin and 2,000 mg for metformin HCl. Dapagliflozin
causes intravascular volume contraction. Symptomatic hypotension can
start after initiating dapagliflozin, quite in patients with
marred renal duty (eGFR 60 mL/min/1.73 m2), elderly
patients, or patients on loop diuretics. Before initiating XIGDUO XR in
patients with one or some-more of these characteristics, cruise and correct
volume status. After initiating therapy, guard for signs and symptoms
of hypotension. Dapagliflozin increases serum creatinine and decreases
eGFR. Elderly patients and patients with marred renal duty might be
some-more receptive to these changes. Adverse reactions compared to renal
duty can start after initiating XIGDUO XR. Before arising of
XIGDUO XR therapy, and during slightest annually thereafter, renal function
should be assessed. Discontinue XIGDUO XR if justification of assuage to
critical renal spoil is present.
Clinical Development Program
The co-administration of dapagliflozin and metformin has been complicated in
adults with form 2 diabetes. The FDA authorized once-daily XIGDUO XR based
on 4 Phase III clinical trials, that supposing clinical evidence
for a efficiency and reserve of dapagliflozin and metformin IR or XR
tablets in treatment-naïve patients, in patients insufficiently controlled
on metformin, as good as compared to a sulfonylurea (glipizide) plus
metformin. There have been no clinical studies conducted with XIGDUO XR
mixed tablets. Bioequivalence was demonstrated in healthy adults
between XIGDUO XR and dapagliflozin and metformin XR as separate
INDICATION AND LIMITATIONS OF USE
XIGDUO XR is indicated as an accessory to diet and practice to improve
glycemic control in adults with form 2 diabetes mellitus when treatment
with both dapagliflozin and metformin is appropriate.
XIGDUO XR is not endorsed for patients with form 1 diabetes mellitus
or diabetic ketoacidosis.
IMPORTANT SAFETY INFORMATION
WARNING: LACTIC ACIDOSIS
Lactic acidosis is a rare, though serious, snarl that can occur
due to metformin accumulation. The risk increases with conditions such
as sepsis, dehydration, additional ethanol intake, hepatic impairment, renal
impairment, and strident congestive heart failure.
The conflict of lactic acidosis is mostly subtle, accompanied usually by
nonspecific symptoms such as malaise, myalgias, respiratory distress,
increasing somnolence, and nonspecific abdominal distress.
Laboratory abnormalities embody low pH, increasing anion gap, and
elevated blood lactate.
If acidosis is suspected, XIGDUO XR should be dropped and the
patient hospitalized immediately. [See Warnings and Precautions]
Moderate to critical renal spoil (eg, serum creatinine levels greater-than or equal to 1.5
mg/dL for men, greater-than or equal to 1.4 mg/dL for women, or eGFR 60 mL/min/1.73 m2
or CrCl 60 mL/min), that might also outcome from conditions such as
cardiovascular fall (shock), strident myocardial infarction, and
History of a critical hypersensitivity greeting to dapagliflozin or
hypersensitivity to metformin hydrochloride
Acute or ongoing metabolic acidosis, including diabetic ketoacidosis,
with or though coma
Warnings and Precautions
The reported occurrence of lactic acidosis in patients receiving
metformin is really low (approximately 0.03 cases/1000 patient-years).
When it occurs, it is deadly in approximately 50% of cases. Reported
cases of lactic acidosis have occurred essentially in diabetic patients
with poignant renal insufficiency.
Patients with congestive heart disaster requiring pharmacologic
management, in sold those with inconstant or strident congestive
heart disaster who are during risk of hypoperfusion and hypoxemia, are at
increasing risk of lactic acidosis.
Lactic acidosis risk increases with a grade of renal dysfunction
and studious age. The risk might be significantly decreased by use of
smallest effective sip of metformin and unchanging monitoring of renal
function. Careful renal monitoring is quite critical in the
elderly. XIGDUO XR should not be instituted in patients greater-than or equal to 80 years of
age unless dimensions of creatinine clearway demonstrates that renal
duty is not reduced.
Withhold XIGDUO XR in a participation of any condition compared with
hypoxemia, dehydration, or sepsis.
Hypoxic States: Cardiovascular fall (shock), strident congestive
heart failure, strident myocardial infarction, and other conditions
characterized by hypoxemia have been compared with lactic acidosis and
might also means prerenal azotemia. When such events start in patients on
XIGDUO XR, a drug should be soon discontinued.
Renal Impairment: Dapagliflozin increases serum creatinine and
decreases eGFR. Elderly patients and patients with marred renal
duty might be some-more receptive to these changes. Adverse reactions
compared to renal duty can start after initiating XIGDUO XR. Before
arising of XIGDUO XR therapy, and during slightest annually thereafter, renal
duty should be assessed. Discontinue XIGDUO XR if justification of
assuage to critical renal spoil is present.
Hypotension: Dapagliflozin causes intravascular volume
contraction. Symptomatic hypotension can start after initiating
dapagliflozin, quite in patients with marred renal function
(eGFR 60 mL/min/1.73 m2), aged patients, or patients
on loop diuretics. Before initiating XIGDUO XR in patients with one or
some-more of these characteristics, cruise and scold volume status. After
initiating therapy, guard for signs and symptoms of hypotension.
Impaired Hepatic Function: XIGDUO XR is not endorsed in
patients with hepatic impairment.
Alcohol Intake: Warn patients opposite extreme ethanol intake
while receiving XIGDUO XR.
Surgical Procedures: XIGDUO XR should be dangling for any
surgical procession (except teenager procedures not compared with
limited intake of food and fluids), and should not be restarted until
patient’s verbal intake has resumed and renal duty is normal or mildly
Use with Medications Known to Cause Hypoglycemia:
- Dapagliflozin: Insulin and
insulin secretagogues are famous to means hypoglycemia. Dapagliflozin
can boost a risk of hypoglycemia when total with these agents.
Consider a reduce sip of insulin or a insulin secretagogue to reduce
a risk of hypoglycemia when used in mixed with XIGDUO XR.
- Metformin: Hypoglycemia
does not start in patients receiving metformin alone underneath usual
resources of use, though could start when caloric intake is
deficient, when eager practice is not compensated by caloric
supplementation, during consequent 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 ineptitude or ethanol intoxication are particularly
receptive to hypoglycemic effects.
Concomitant Medications Affecting Renal Function or Metformin
Disposition: Use counsel with consequent medication(s) that may
impact renal duty or outcome in poignant hemodynamic change or may
meddle with a showing of metformin, such as cationic drugs that
are separated by renal tubular secretion.
Radiologic Studies with Intravascular Iodinated Contrast Materials: Temporarily
pause XIGDUO XR during a time of or before to any procession with
intravascular administration of iodinated contrariety investigate materials and
secrete for 48 hours successive to a procedure. XIGDUO XR should be
reinstituted usually after renal duty has been re-evaluated and found
to be normal or softly impaired.
Vitamin B12 Concentrations: Metformin might reduce vitamin B12
levels. Measure hematological parameters annually.
Genital Mycotic Infections: Dapagliflozin increases a risk of
genital mycotic infections. Patients with a story of genital mycotic
infections were some-more expected to rise genital mycotic infections.
Monitor and provide appropriately.
Increases in Low-Density Lipoprotein Cholesterol (LDL-C): Increases
in LDL-C start with dapagliflozin. After initiating XIGDUO XR, monitor
LDL-C and provide per customary 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 bearing to investigate drug was 1 year during a 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 intensity indicator of pre-existing tumors) were balanced
between diagnosis arms during baseline. There were too few cases to
establish either a presentation of these events is compared to
There are deficient information to establish either dapagliflozin has an
outcome on pre-existing bladder tumors. XIGDUO XR should not be used in
patients with active bladder cancer. Use with counsel in patients with
before story of bladder cancer.
Macrovascular Outcomes: There have been no clinical studies
substantiating decisive justification of macrovascular risk rebate with
XIGDUO XR or any other antidiabetic drug.
Most common inauspicious reactions (greater-than or equal to 5%) with dapagliflozin (5mg or 10mg)
and metformin vs remedy and metformin were womanlike 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 some-more commonly
than in patients treated with remedy 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 a particular components in profound women. During
pregnancy, cruise suitable choice therapies, generally during
a second and third trimesters.
Nursing Mothers: It is not famous either XIGDUO XR is excreted in
tellurian milk. Because of a intensity for critical inauspicious reactions in
nursing infants from dapagliflozin, pause nursing or discontinue
Geriatric Use: A aloft suit of patients greater-than or equal to 65 years treated
with dapagliflozin had inauspicious reactions compared to volume lassitude and
renal spoil or disaster compared to patients treated with placebo.
No XIGDUO XR sip change is endorsed formed on age.
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 impact 29.1 million people in a U.S. and more
than 382 million people worldwide. The superiority of diabetes is
projected to strech some-more than 592 million people worldwide by 2035. Type
2 diabetes accounts for approximately 90-95 percent of all cases of
diagnosed diabetes in a U.S.Type 2 diabetes is a chronic
illness characterized by pathophysiologic defects heading to elevated
glucose levels. Significant unmet needs still exist, as many patients
sojourn insufficiently tranquil on their stream glucose-lowering regimen.
About SGLT2 Inhibition
The kidney plays a contributing purpose in progressing normal glucose
balance, in partial by filtering and subsequently reabsorbing glucose back
into circulation. SGLT2, a sodium-glucose cotransporter found
essentially in a kidney, is obliged for a infancy of glucose
reabsorption. Selective predicament of SGLT2 reduces a reabsorption of
glucose and enables a dismissal around a urine.
AstraZeneca is a global, innovation-driven biopharmaceutical business
that focuses on a discovery, growth and commercialization of
medication medicines, essentially for a diagnosis of cardiovascular,
metabolic, respiratory, inflammation, autoimmune, oncology, infection
and neuroscience diseases. AstraZeneca operates in over 100 countries
and a medicines are used by millions of patients worldwide. For more
information greatfully visit: www.astrazeneca.com.
Esra Erkal-Paler, +44 20 7604
Vanessa Rhodes, +44 20 7604 8037
Ayesha Bharmal, +44 20 7604 8034 (UK/Global)
Lund, +46 8 553 260 20 (Sweden)
+ 1 302 885 6351 (US)
+44 20 7604 8199
mob: +44 7818 524185
Karl Hård, +44
20 7604 8123
mob: +44 7789 654364
Jens Lindberg, mob:
+44 7557 319729
Anthony Brown, +44 20 7604 8067
+44 7585 404943
Eugenia Litz, +44 20 7604 8233
+44 7884 735627
Copyright Business Wire 2014