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FDA Approves Xigduo XR

FDA Approves Xigduo XR (dapagliflozin and metformin hydrochloride) for Type 2 Diabetes

WILMINGTON, Del., October 30, 2014 -- AstraZeneca 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 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 hydrochloride 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

Lactic Acidosis:

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:

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 (greater-than or equal to 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 greater-than or equal to 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.

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.

SOURCE: AstraZeneca

Posted: October 2014

Xigduo XR (dapagliflozin and metformin hydrochloride) FDA Approval History