FDA approves Farxiga tablets to improve glycemic control in adults with type 2 diabetes mellitus

AstraZenecaJan 13 2014

AstraZeneca (NYSE:AZN) and Bristol-Myers Squibb Company (NYSE:BMY) announced the U.S. Food and Drug Administration (FDA) approved Farxiga™ [far-SEE-ga] (dapagliflozin), a once-daily oral treatment indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Farxiga should not be used for the treatment of patients with type 1 diabetes or diabetic ketoacidosis.

The recommended starting dose of Farxiga is 5 mg once daily, taken in the morning, with or without food. In patients tolerating Farxiga 5 mg once daily who require additional glycemic control, the dose can be increased to 10 mg once daily. Farxiga is part of a newer class of medicines called sodium-glucose cotransporter 2 (SGLT2) inhibitors, which remove glucose via the kidneys.

"With the diabetes epidemic escalating and many people with type 2 diabetes struggling to reach their blood sugar goals, Farxiga offers an important new option for healthcare professionals and adult patients," said Brian Daniels, senior vice president, global development and medical affairs, Bristol-Myers Squibb. "In clinical trials, Farxiga helped improve glycemic control, and offered additional benefits of weight and blood pressure reductions."

Farxiga is contraindicated in patients with a history of a serious hypersensitivity reaction to Farxiga or with severe renal impairment, end stage renal disease, or patients on dialysis.

"The addition of Farxiga to our U.S. treatment portfolio is a step forward as we work to help reduce the burden of type 2 diabetes by offering a range of treatment options with different modes of action," said Briggs Morrison, M.D., executive vice president, Global Medicines Development and chief medical officer, AstraZeneca. "We aim to help adults with type 2 diabetes, and their doctors, create individualized treatment programs that will help patients lower their glucose levels."

Dapagliflozin (marketed outside of the United States as Forxiga^®) is approved for the treatment of adults with type 2 diabetes, along with diet and exercise, in 40 countries, including European Union countries and Australia.

Farxiga Clinical Development Program

The robust Farxiga clinical development program included 24 clinical studies evaluating safety and efficacy. The studies included more than 11,000 adults with type 2 diabetes, including more than 6,000 patients treated with Farxiga.

Farxiga causes intravascular volume contraction. Symptomatic hypotension can occur after initiating Farxiga 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 Farxiga 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. Farxiga 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 Farxiga. Renal function should be evaluated prior to initiation of Farxiga and monitored periodically thereafter.

In a 24-week, add-on to metformin clinical trial, adult patients with type 2 diabetes treated with Farxiga 5 mg>Farxiga 5 mg (baseline 84.7 kg) and -2.0 kg with 10 mg (baseline 86.3 kg). Also, mean changes from baseline in systolic blood pressure relative to placebo plus metformin were -4.5 mmHg and -5.3 mmHg with Farxiga 5 mg or 10 mg plus metformin, respectively. No major episodes of hypoglycemia were seen in any of the treatment arms. Minor episodes of hypoglycemia were reported in 1.5%, 0.7%, and 0% with Farxiga 5 mg, 10 mg, and placebo plus metformin, respectively.

In addition to the clinical development program, the AstraZeneca/Bristol-Myers Squibb Diabetes Alliance has initiated DECLARE, a large, randomized, placebo-controlled study of more than 17,000 adult patients with type 2 diabetes designed to determine the effect of Farxiga, when added to the patients' current anti-diabetes therapy, on the risk of CV events, such as CV death, myocardial infarction or ischemic stroke, compared with placebo. The study, which will also provide additional data on the long-term safety profile, initiated enrollment in April 2013 and has an anticipated completion date of 2019.

INDICATION AND LIMITATION OF USE FOR FARXIGA™ (dapagliflozin)

Farxiga is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

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

IMPORTANT SAFETY INFORMATION FOR FARXIGA

Contraindications

• History of a serious hypersensitivity reaction to Farxiga

• Severe renal impairment, end stage renal disease, or patients on dialysis

Warnings and Precautions

• Hypotension: Farxiga causes intravascular volume contraction. Symptomatic hypotension can occur after initiating Farxiga, particularly in patients with impaired renal function (eGFR <60 mL/min/1.73 m²), elderly patients, or patients on loop diuretics. Before initiating Farxiga in patients with one or more of these characteristics, assess and correct volume status. After initiating therapy, monitor for signs and symptoms of hypotension.

• Impairment in Renal Function: Farxiga 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 Farxiga. Before initiating Farxiga, evaluate renal function and monitor periodically thereafter. Discontinue Farxiga when eGFR is persistently <60 mL/min/1.73 m².

• Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues: Insulin and insulin secretagogues are known to cause hypoglycemia. Farxiga 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 Farxiga.

• Genital Mycotic Infections: Farxiga 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 Farxiga. After initiating Farxiga, 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% of Farxiga -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 Farxiga 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 Farxiga.

There are insufficient data to determine whether Farxiga has an effect on pre-existing bladder tumors. Farxiga should not be used in patients with active bladder cancer. Use with caution in patients with a prior history of bladder cancer.

Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Farxiga or any other antidiabetic drug.

Adverse Reactions

• In a pool of 12 placebo-controlled studies, the most common adverse reactions (≥5%) treated with Farxiga 5 mg, 10 mg, and placebo respectively were female genital mycotic infections (8.4% vs 6.9% vs 1.5%), nasopharyngitis (6.6% vs 6.3% vs 6.2%), and urinary tract infections (5.7% vs 4.3% vs 3.7%).

Use in Specific Populations

• Pregnant Women: There are no adequate and well-controlled studies of Farxiga in pregnant women. Consider appropriate alternative therapies, especially during the second and third trimesters.

• Nursing Mothers: It is not known whether Farxiga is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Farxiga, discontinue nursing or discontinue Farxiga.

• Geriatric Use: A higher proportion of patients ≥65 years treated with Farxiga had adverse reactions related to volume depletion and renal impairment or failure compared to patients treated with placebo. No Farxiga dose change is recommended based on age.