1 INDICATIONS AND USAGE Isosorbide dinitrate and hydralazine hydrochloride tablets are 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 Isosorbide dinitrate and hydralazine hydrochloride tablets are 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.

6 ADVERSE REACTIONS Most common adverse reactions (≥ 5% more on isosorbide dinitrate and hydralazine hydrochloride tablets than on placebo) were headache and dizziness ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Wilshire Pharmaceuticals, Inc.

at 1-877-495-6856 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.

Isosorbide dinitrate and hydralazine hydrochloride tablets have been evaluated for safety in 517 heart failure patients in A-HeFT.

A total of 317 of these patients received isosorbide dinitrate and hydralazine hydrochloride tablets for at least 6 months, and 220 received isosorbide dinitrate and hydralazine hydrochloride tablets for at least 12 months.

In A-HeFT, 21% of the patients discontinued isosorbide dinitrate and hydralazine hydrochloride tablets for adverse reactions compared to 12% who discontinued placebo.

Overall, adverse reactions were more common in isosorbide dinitrate and hydralazine hydrochloride tablets-treated than in placebo-treated patients.

Table 1 lists adverse reactions reported with an incidence, after rounding, ≥ 2% higher on isosorbide dinitrate and hydralazine hydrochloride tablets than on placebo in A-HeFT, regardless of causality.

The most common reasons for discontinuing isosorbide dinitrate and hydralazine hydrochloride tablets in the A-HeFT trial was headache (7%).

Table 1.

Adverse Reactions Occurring in the A-HeFT Study in ≥ 2% of Patients Treated with isosorbide dinitrate and hydralazine hydrochloride tablets.

Isosorbide dinitrate and hydralazine hydrochloride tablets (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 isosorbide dinitrate and hydralazine hydrochloride tablets .

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 Isosorbide dinitrate and hydralazine hydrochloride tablets: The following adverse reactions have been identified with use of isosorbide dinitrate and hydralazine hydrochloride tablets.

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.