BiDil

1 INDICATIONS AND USAGE BiDil is a combination of isosorbide dinitrate, a nitrate vasodilator, and hydralazine hydrochloride, an arteriolar vasodilator, indicated for: the treatment of heart failure as an adjunct therapy to standard therapy in self-identified black patients to improve survival, prolong time to hospitalization for heart failure and to improve patient-reported functional status ( 1.1 ) Limitations of use: There is little experience in patients with NYHA class IV heart failure ( 1.2 ) 1.1 Treatment of Heart Failure in Self-identified Black Patients BiDil is indicated for the treatment of heart failure as an adjunct to standard therapy in self-identified black patients to improve survival, to prolong time to hospitalization for heart failure, and to improve patient-reported functional status. 1.2 Limitations of Use There is little experience in patients with NYHA class IV heart failure.

2 DOSAGE AND ADMINISTRATION BiDil should be initiated at a dose of one BiDil Tablet, three times a day. Titrate to a maximum of two tablets three times daily, if tolerated. Although titration of BiDil can be rapid (3-5 days), some patients may experience side effects and may take longer to reach their maximum tolerated dose. The dosage may be decreased to as little as one-half BiDil Tablet three times a day if intolerable side effects occur. Efforts should be made to titrate up as soon as side effects subside. One tablet three times a day titrated to a maximum tolerated dose up to two tablets three times a day ( 2 ) Dosage may be decreased to as little as one-half tablet three times a day if intolerable side effects occur. Efforts should be made to titrate up as soon as side effects subside ( 2 )

4 CONTRAINDICATIONS BiDil is contraindicated in patients who are allergic to organic nitrates. Do not use BiDil in patients who are taking PDE-5 inhibitors, such as avanafil, sildenafil, tadalafil, or vardenafil. Concomitant use can cause severe hypotension, syncope, or myocardial ischemia [see Drug Interactions (7.1) ] . Do not use BiDil in patients who are taking the soluble guanylate cyclase (sGC) stimulator riociguat. Concomitant use can cause hypotension. Patients who are allergic to organic nitrates ( 4 ) Use of phosphodiesterase type 5 (PDE5) inhibitors, such as avanafil, sildenafil, tadalafil, or vardenafil, or soluble guanylate cyclase (sGC) stimulator (riociguat). ( 4 )

5 WARNINGS AND PRECAUTIONS May cause symptomatic hypotension ( 5.1 ) Symptomatic Lupus Erythematosus Syndromes: Consider discontinuation if clinically appropriate ( 5.2 ) Myocardial ischemia and angina ( 5.3 ) Peripheral Neuritis : May be treated with Pyridoxine ( 5.4 ) 5.1 Hypotension Symptomatic hypotension, particularly with upright posture, may occur with even small doses of BiDil. Hypotension is most likely to occur in patients who have been volume or salt depleted; correct prior to initiation of BiDil [see Adverse Reactions (6.1) ] . 5.2 Systemic Lupus Erythematosus Hydralazine hydrochloride has been reported to cause a drug-induced systemic lupus erythematosus (SLE) syndrome. Symptoms and signs usually regress when hydralazine hydrochloride is discontinued. 5.3 Worsening Ischemic Heart Disease Hydralazine hydrochloride can cause tachycardia and hypotension potentially leading to myocardial ischemia and angina, particularly in patients with hypertrophic cardiomyopathy. 5.4 Peripheral Neuritis Hydralazine hydrochloride has been associated with peripheral neuritis, evidenced by paresthesia, numbness, and tingling, which may be related to an antipyridoxine effect. Pyridoxine should be added to BiDil therapy if such symptoms develop.

7 DRUG INTERACTIONS 7.1 Phosphodiesterase Inhibitors BiDil is contraindicated in patients who are using a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5), PDE5 inhibitors such as avanafil, sildenafil, vardenafil, and tadalafil have been shown to potentiate the hypotensive effects of organic nitrates. Do not use BiDil in patients who are taking the soluble guanylate cyclase (sGC) stimulator riociguat. Concomitant use can cause hypotension [see Contraindications (4) ] .

6 ADVERSE REACTIONS Most common adverse reactions (≥ 5% more on BiDil than on placebo) were headache and dizziness ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Azurity Pharmaceuticals, Inc. at 1-800-461-7449 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. BiDil has been evaluated for safety in 517 heart failure patients in A-HeFT. A total of 317 of these patients received BiDil for at least 6 months, and 220 received BiDil for at least 12 months. In A-HeFT, 21% of the patients discontinued BiDil for adverse reactions compared to 12% who discontinued placebo. Overall, adverse reactions were more common in BiDil -treated than in placebo-treated patients. Table 1 lists adverse reactions reported with an incidence, after rounding, ≥ 2% higher on BiDil than on placebo in A-HeFT, regardless of causality. The most common reasons for discontinuing BiDil in the A-HeFT trial was headache (7%). Table 1. Adverse Reactions Occurring in the A-HeFT Study in ≥ 2% of Patients Treated with BiDil. BiDil (N=517) % Placebo (N=527) % Headache 50 21 Dizziness 32 14 Asthenia 14 11 Nausea 10 6 Hypotension 8 4 Sinusitis 4 2 Ventricular tachycardia 4 2 Paresthesia 4 2 Vomiting 4 2 Amblyopia 3 1 In the V-HeFT I and II clinical studies, a total of 587 patients with heart failure were treated with the combination of isosorbide dinitrate and hydralazine hydrochloride. The type, pattern, frequency and severity of adverse reactions reported in these studies were similar to those reported in A-HeFT, described above and no unusual adverse reactions were reported. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of BiDil. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Use of BiDil: The following adverse reactions have been identified with use of BiDil. Cardiac Disorders: Palpitations Ear and labyrinth disorders: Tinnitus, vertigo Eye Disorders: Eyelid edema, vision blurred Gastrointestinal Disorders: Abdominal discomfort, constipation General Disorders and Administration Site Conditions: Facial pain, flushing, chest discomfort, chest pain, peripheral edema Musculoskeletal and Connective Tissue Disorders: Pain in extremity, myalgia Nervous Disorders: Dysgeusia, hypoaesthesia, migraine, syncope Renal and Urinary Disorders: Chromaturia, pulmonary renal syndrome Respiratory, Thoracic and Mediastinal Disorders: Dyspnea Reproductive System and Breast Disorders: Erectile dysfunction Skin and Subcutaneous Tissue Disorders: Erythema, hyperhidrosis, pruritus, face swelling Use of Hydralazine Hydrochloride or Isosorbide Dinitrate: The following reactions have been reported with use of either hydralazine hydrochloride or isosorbide dinitrate. Blood and Lymphatic System Disorders: Blood dyscrasias, agranulocytosis, purpura, eosinophilia, splenomegaly. Eye Disorders: Lacrimation, conjunctivitis. Gastrointestinal Disorders: Paralytic ileus. Hepatobiliary Disorders: Hepatitis. Psychiatric Disorders: Psychotic reactions, disorientation. Renal and Urinary Disorders: Difficulty in urination.

8.1 Pregnancy Risk Summary There are no data on BiDil use in pregnant women, and insufficient data on its components (hydralazine and isosorbide dinitrate) to assess a drug-associated risk of major birth defects or miscarriage with first trimester use. Available published data on hydralazine use in pregnancy during the second and third trimesters have not shown an association with adverse pregnancy-related outcomes. Hydralazine hydrochloride is teratogenic in mice at 66 mg/kg and possibly in rabbits at 33 mg/kg (2 and 3 times the MRHD of BiDil on a body surface area basis). Isosorbide dinitrate has been shown to cause a dose-related increase in embryo-toxicity (excess mummified pups) in rabbits at 70 mg/kg (12 times the MRHD of BiDil on a body surface area basis). All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Pregnant women with heart failure are at increased risk for preterm birth. Clinical classification of heart disease may worsen with pregnancy and lead to maternal death and/or stillbirth.