On Tuesday, May 5, the U.S. Food and Drug Administration approved Farxiga (dapagliflozin) oral tablets for adults with heart failure with reduced ejection fraction to reduce the risk of cardiovascular death and hospitalization for heart failure. Heart failure occurs when the heart does not pump enough blood to support the body’s needs, and this type of heart failure happens when the heart’s main pumping chamber, the left ventricle, is weakened. With the approval, Farxiga is the first in this particular drug class, sodium-glucose co-transporter 2 (SGLT2) inhibitors, to be approved to treat adults with New York Heart Association’s functional class II-IV heart failure with reduced ejection fraction.
“Heart failure is a serious health condition that contributes to one in eight deaths in the U.S. and impacts nearly 6.5 million Americans,” said Norman Stockbridge, M.D., Ph.D., director of the Division of Cardiology and Nephrology in the FDA’s Center for Drug Evaluation and Research. “This approval provides patients with heart failure with reduced ejection fraction an additional treatment option that can improve survival and reduce the need for hospitalization.”
Farxiga was shown in a clinical trial to improve survival and reduce the need for hospitalization in adults with heart failure with reduced ejection fraction. Farxiga’s safety and effectiveness were evaluated in a randomized, double-blind, placebo-controlled study of 4,744 participants. The average age of participants was 66 years and more participants were male (77%) than female. To determine the drug’s effectiveness, investigators examined the occurrence of cardiovascular death, hospitalization for heart failure, and urgent heart failure visits. Participants were randomly assigned to receive a once-daily dose of either 10 milligrams of Farxiga or a placebo (inactive treatment). After about 18 months, people who received Farxiga had fewer cardiovascular deaths, hospitalizations for heart failure, and urgent heart failure visits than those receiving the placebo.
Farxiga can cause dehydration, serious urinary tract infections and genital yeast infections. Elderly patients, patients with kidney problems, those with low blood pressure, and patients on diuretics should be assessed for their volume status and kidney function. Patients with signs and symptoms of metabolic acidosis or ketoacidosis (acid buildup in the blood) should also be assessed. Farxiga can cause serious cases of necrotizing fasciitis of the perineum (Fournier’s Gangrene) in people with diabetes and low blood sugar when combined with insulin.
This application received Priority Review designation, meaning the agency planned to take action on the application within six months, because the drug, if approved, would significantly improve the safety or effectiveness of treating, diagnosing or preventing a serious condition.
Farxiga is also FDA-approved to improve glycemic control in adults with type 2 diabetes in addition to diet and exercise, and to reduce the risk of hospitalization for heart failure among adults with type 2 diabetes and known cardiovascular disease or other risk factors.
The FDA granted the approval of Farxiga related to heart failure to AstraZeneca Pharmaceuticals LP Wilmington, DE.
FARXIGA Approved in the US for the Treatment of Heart Failure in Patients with Heart Failure with Reduced Ejection Fraction
PRESS RELEASE
FARXIGA is the first SGLT2 inhibitor proven to significantlyreducethe risk of cardiovascular death and hospitalization for heart failure
AstraZeneca’s FARXIGA®(dapagliflozin) has been approved in the US to reduce the risk of cardiovascular (CV) death and hospitalization for heart failure in adults with heart failure (NYHA class II-IV) with reduced ejection fraction (HFrEF) with and without type 2 diabetes (T2D).
The approval by the Food and Drug Administration (FDA) was based on positive results from the landmark Phase III DAPA-HF trial, which showed FARXIGAachieving a statistically significant and clinically meaningful reduction of CV death or hospitalization for heart failure, compared to placebo.The decision follows thePriority Review designationgranted by the FDA earlier this year and theFast Track designationgranted in September 2019.
FARXIGA is the first sodium glucose co-transporter 2 (SGLT2) inhibitor approved by the US FDA indicated to treat patients with HFrEF (LVEF ≤ 40%).
Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, said: “With the approval ofFARXIGA, we have reached a critical milestone to potentially transform heart failure treatment for the millions of people living with the condition in the US.We are now one step closer to making a significant impact on their lives by providing a much-needed treatment to help reduce their disease burden and live longer.”
John McMurray, MD, Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, UK, said: “The ground-breaking results of the DAPA-HF trial have transformed heart failure therapeutics. Today’s approval provides physicians with a completely novel pharmacological approach that greatly improves outcomes for patients with heart failure with reduced ejection fraction.”
The DAPA-HF trial showed that FARXIGA,in addition to standard of care, reduced the risk of the composite outcome of CV death or the worsening of HF versus placebo by 26% (absolute risk reduction [ARR] = 5% [event rate/100 patient years: 11.6 vs 15.6, respectively]; p<0.0001) in patients with HFrEF. During the trial duration, one CV death or hospitalization for HF or an urgent visit associated with HF could be avoided for every 21 patients treated with FARXIGA.
The safety profile of FARXIGA in the DAPA-HF trial was consistent with the well-established safety profile of the medicine. The data from the DAPA-HF trial were published inThe New England Journal of Medicine.
In October 2019 the US FDAapprovedFARXIGA to reduce the risk of hospitalization for HF in adult patients with T2D and established CV disease or multiple CV risk factors. The approval was based on the DECLARE-TIMI 58 trial.
FARXIGA is also indicated as an adjunct to diet and exercise to improve glycemic control in adults with T2D.
INDICATIONS AND LIMITATIONS 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
- to reduce the risk of hospitalization for heart failure in adults with type 2 diabetes mellitus and established cardiovascular (CV) disease or multiple CV risk factors
- to reduce the risk of cardiovascular death and hospitalization for heart failure in adults with heart failure (NYHA class II-IV) with reduced ejection fraction
FARXIGA is not recommended for patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.
IMPORTANT SAFETY INFORMATION for FARXIGA®(dapagliflozin) 5 mg and 10 mg tablets
Contraindications
- Prior serious hypersensitivity reaction to FARXIGA
- Patients with severe renal impairment (eGFR <30 mL/min/1.73 m2) being treated for glycemic control without established CV disease or multiple CV risk factors
- Patients on dialysis
Warnings and Precautions
- Volume Depletion:FARXIGA can cause intravascular volume depletion which may manifest as symptomatic hypotension or acute transient changes in creatinine. Acute kidney injury requiring hospitalization and dialysis has been reported in patients with type 2 diabetes receiving SGLT2 inhibitors, including FARXIGA. Patients with impaired renal function (eGFR less than 60mL/min/1.73m2), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating FARXIGA in these patients, assess volume status and renal function. After initiating therapy, monitor for signs and symptoms of hypotension and renal function
- Ketoacidosis in Diabetes Mellitushas been reported in patients with type 1 and type 2 diabetes receiving FARXIGA. Some cases were fatal. Assess patients who present with signs and symptoms of metabolic acidosis for ketoacidosis, regardless of blood glucose level. If suspected, discontinue FARXIGA, evaluate and treat promptly. Before initiating FARXIGA, consider risk factors for ketoacidosis. Patients on FARXIGA may require monitoring and temporary discontinuation in situations known to predispose to ketoacidosis
- Urosepsis and Pyelonephritis:SGLT2 inhibitors increase the risk for urinary tract infections (UTIs) and serious UTIs have been reported with FARXIGA. Evaluate for signs and symptoms of UTIs and treat promptly
- Hypoglycemia:FARXIGA can increase the risk of hypoglycemia when coadministered with insulin and insulin secretagogues. Consider lowering the dose of these agents when coadministered with FARXIGA
- Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene):Rare but serious, life-threatening cases have been reported in patients with diabetes mellitus receiving SGLT2 inhibitors including FARXIGA. Cases have been reported in females and males. Serious outcomes have included hospitalization, surgeries, and death. Assess patients presenting with pain or tenderness, erythema, swelling in the genital or perineal area, along with fever or malaise. If suspected, institute prompt treatment and discontinue FARXIGA
- Genital Mycotic Infections:FARXIGA increases the risk of genital mycotic infections, particularly in patients with prior genital mycotic infections. Monitor and treat appropriately
Adverse Reactions
In a pool of 12 placebo-controlled studies, the most common adverse reactions (≥5%) associated 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
- Pregnancy:Advise females of potential risk to a fetus especially during the second and third trimesters
- Lactation:FARXIGA is not recommended when breastfeeding
DOSING
- To improve glycemic control in patients with T2D, the recommended starting dose of FARXIGA is 5 mg orally once daily, taken in the morning. In patients tolerating FARXIGA 5 mg once daily who require additional glycemic control, the dose can be increased to 10 mg once daily
- To reduce the risk of hospitalization for heart failure in patients with T2D and established CV disease or multiple CV risk factors, the recommended dose of FARXIGA is 10 mg orally once daily
- To reduce the risk of CV death and hospitalization for heart failure in patients with HFrEF, the recommended dose of FARXIGA is 10mg orally once daily
Please see accompanyingUSFull Prescribing InformationandMedication Guidefor FARXIGA.
Heart failure
HF is a life-threatening disease in which the heart cannot pump enough blood around the body.It affects approximately 64 million people worldwide (at least half of which have a reduced ejection fraction) and six million in the US.It is a chronic disease where half of patients will die within five years of diagnosis.There are two main categories of HF related to ejection fraction (EF), a measurement of the percentage of blood leaving the heart each time it contracts: HFrEF and heart failure with preserved ejection fraction (HFpEF).HFrEF occurs when the left ventricle (LV) muscle is not able to contract adequately and therefore, expels less oxygen-rich blood in to the body.HF remains as fatal as some of the most common cancers in both men (prostate and bladder cancers) and women (breast cancer).It is the leading cause of hospitalisation for those over the age of 65 and represents a significant clinical and economic burden.
[DAPA-HF]
DAPA-HF (Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure) is an international, multi-center, parallel-group, randomized, double-blinded trial in 4,744 patients with heart failure and reduced ejection fraction (LVEF ≤ 40%), with and without T2D, designed to evaluate the effect ofFARXIGA10mg, compared with placebo, given once daily in addition to standard of care. The primary composite endpoint was time to the first occurrence of a worsening heart failure event (hospitalization or equivalent event; i.e. an urgent heart failure visit), or cardiovascular death. The median duration of follow-up was 18.2 months.
AstraZeneca in CV, Renal & Metabolism (CVMD)
CV, renal and metabolism together form one of AstraZeneca’s main therapy areas and a key growth driver for the Company. By following the science to understand more clearly the underlying links between the heart, kidneys and pancreas, AstraZeneca is investing in a portfolio of medicines to protect organs and improve outcomes by slowing disease progression, reducing risks and tackling co-morbidities. Our ambition is to modify or halt the natural course of CVMD diseases and potentially regenerate organs and restore function, by continuing to deliver transformative science that improves treatment practices and CV health for millions of patients worldwide.
About AstraZeneca
AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines, primarily for the treatment of diseases in three therapy areas - Oncology, Cardiovascular, Renal & Metabolism and Respiratory. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information, please visitwww.astrazeneca-us.comand follow us on Twitter@AstraZenecaUS.
