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.

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.

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%).

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.

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)].

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of BiDil in children have not been established.

8.5 Geriatric Use

Clinical studies of BiDil did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in response between elderly and younger patients. In general, dose selection for an elderly patient should start at the low end of the dosing range, reflecting the greater frequency of decreased hepatic and renal function, and of concomitant disease or other drug therapies.

Isosorbide dinitrate, its active metabolites, and hydralazine may be eliminated more slowly in elderly patients.

8.6 Renal Impairment

There are no studies of renal impairment using BiDil. No dose adjustment is required for hydralazine or isosorbide dinitrite [see Clinical Pharmacology (12.3)].

Dialyzability of hydralazine has not been determined. Dialysis is not an effective method for removing isosorbide dinitrate or its metabolite isosorbide-5-mononitrate from the body.

8.7 Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of hydralazine alone has not been determined. Isosorbide dinitrate concentrations increase in patients with cirrhosis. There are no studies of hepatic impairment using BiDil.

Human Experience: There are no documented cases of overdosage with BiDil. No deaths from acute poisoning have been reported.

Treatment: There is no specific antidote. Support of the cardiovascular system is of primary importance. Shock should be treated with plasma expanders, vasopressors, and positive inotropic agents. The gastric contents should be evacuated, taking adequate precautions to prevent aspiration. These manipulations have to be carried out after cardiovascular status has been stabilized, since they might precipitate cardiac arrhythmias or increase the depth of shock.

In patients with renal disease or congestive heart failure, therapy resulting in central volume expansion is not without hazard. Treatment of isosorbide dinitrate overdose in these patients may be difficult, and invasive monitoring may be required.

No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of the components of BiDil. Dialysis is not effective in removing circulating isosorbide dinitrate. The dialyzability of hydralazine has not been determined.

Methemoglobinemia: Nitrate ions liberated during metabolism of isosorbide dinitrate can oxidize hemoglobin into methemoglobin. There are case reports of significant methemoglobinemia in association with moderate overdoses of organic nitrates. Methemoglobin levels are measurable by most clinical laboratories. Methemoglobinemia could be serious in chronic heart failure patients because of already compromised vascular bed-tissue gas exchange dynamics. Classically, methemoglobinemic blood is described as chocolate brown, without color change on exposure to air. When methemoglobinemia is diagnosed, the treatment of choice is methylene blue, 1 to 2 mg/kg intravenously.

12.1 Mechanism of Action

The mechanism of action underlying the beneficial effects of BiDil in the treatment of heart failure has not been established.

Isosorbide dinitrate is a vasodilator affecting both arteries and veins. Its dilator properties result from the release of nitric oxide and the subsequent activation of guanylyl cyclase, and ultimate relaxation of vascular smooth muscle.

Several well-controlled clinical trials have used exercise testing to assess the anti-anginal efficacy of chronically-delivered nitrates. In the large majority of these trials, active agents were no more effective than placebo after 24 hours (or less) of continuous therapy. Attempts to overcome nitrate tolerance by dose escalation, even to doses far in excess of those used acutely, have consistently failed. Only after nitrates have been absent from the body for several hours is response to nitrates restored.

Hydralazine hydrochloride is a selective dilator of arterial smooth muscle. Animal data suggests that hydralazine may also mitigate tolerance to nitrates.

12.2 Pharmacodynamics

The basis for the beneficial clinical effects of BiDil is not known. In a small study of patients with chronic heart failure administered single doses of hydralazine 75 mg, isosorbide dinitrate 20 mg, and the combination, the combination elicited a statistically significant decrease in pulmonary capillary wedge pressure compared to hydralazine alone. The increase in cardiac output, renal blood flow and limb blood flow with the combination, however, was not greater than with hydralazine alone. There is no study of hemodynamic effects following multiple dosing.

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Placebo-controlled Study: In the multicenter trial V-HeFT I, the combination of hydralazine and isosorbide dinitrate 75 mg/40 mg 4 times daily (n=186) was compared to placebo (n=273) in men with impaired cardiac function and reduced exercise tolerance (primarily NYHA class II and III) and on therapy with digitalis glycosides and diuretics. There was no overall significant difference in mortality between the two treatment groups. There was, however, a trend favoring hydralazine and isosorbide dinitrate, which on retrospective analysis, was attributable to an effect in blacks (n=128). Survival in white patients (n=324) was similar on placebo and the combination treatment.

Active-controlled Study: In a second study of mortality, V-HeFT II, the combination of hydralazine and isosorbide dinitrate 75 mg/40 mg 4 times daily was compared to enalapril in 804 men with impaired cardiac function and reduced exercise tolerance (NYHA class II and III), and on therapy with digitalis glycosides and diuretics. The combination of hydralazine and isosorbide dinitrate was inferior to enalapril overall, but retrospective analysis showed that the difference was observed in the white population (n=574); there was essentially no difference in the black population (n=215).

Based on these retrospective analyses suggesting an effect on survival in black patients, but showing little evidence of an effect in the white population, a third study was conducted among black patients with heart failure.

Placebo-controlled Study: The A-HeFT trial evaluated BiDil vs. placebo among 1,050 self-identified black patients (over 95% NYHA class III) at 169 centers in the United States. All patients had stable symptomatic heart failure. Patients were required to have LVEF ≤ 35% or left ventricular internal diastolic dimension > 2.9 cm/m2 plus LVEF < 45%. Patients were maintained on stable background therapy and randomized to BiDil (n=518) or placebo (n=532). BiDil was initiated at 20 mg isosorbide dinitrate/37.5 mg hydralazine hydrochloride three times daily and titrated to a target dose of 40/75 mg three times daily or to the maximum tolerated dose. Patients were treated for up to 18 months.

The randomized population was 60% male, 1% NYHA class II, 95% NYHA class III and 4% NYHA class IV, with a mean age of 57 years, and was generally treated with standard treatments for heart failure including diuretics (94%, almost all loop diuretics), beta-blockers (87%), angiotensin converting enzyme inhibitors (ACE-I; 78%), angiotensin II receptor blockers (ARBs; 28%), either ACE-I or ARB (93%), digitalis glycosides (62%) and aldosterone antagonists (39%).

The primary endpoint was a composite score consisting of all-cause mortality, first hospitalization for heart failure, and responses to the Minnesota Living with Heart Failure questionnaire. The trial was terminated early, at a mean follow-up of 12 months, primarily because of a statistically significant 43% reduction in all-cause mortality in the BiDil-treated group (p=0.012; see Table 2 and Figure 1). The primary endpoint was also statistically in favor of BiDil (p ≤ 0.021). The BiDil-treated group also showed a 39% reduction in the risk of a first hospitalization for heart failure (p<0.001; see Table 2 and Figure 2) and had statistically significant improvement in response to the Minnesota Living with Heart Failure questionnaire, a self-report of the patient's functional status, at most time points (see Figure 3). Patients in both treatment groups had mean baseline questionnaire scores of 51 (out of a possible 105).

Effects on survival and hospitalization for heart failure were similar in subgroups by age, gender, baseline disease, and use of concomitant medications, as shown in Figure 4.

Patients treated with BiDil in the A-HeFT study had randomly measured blood pressures on average 3/3 mmHg lower than did patients on placebo. The contribution of the difference in blood pressure to the overall outcome difference is unknown. Whether both hydralazine and isosorbide dinitrate contribute to the overall outcome difference has not been studied in outcome trials. Isosorbide dinitrate and hydralazine have not been systematically studied for the treatment of heart failure as separate agents, and neither drug is indicated for heart failure.

Store at 25°C (77°F), excursions permitted to 15-30°C (59-86°F). [See USP Controlled Room Temperature.] Keep bottles tightly closed.

Protect from light. Dispense in a light-resistant, tight container.

Headache

Inform patients that headaches often accompany treatment with BiDil, especially during initiation of treatment. Advise patients to consult a physician to adjust the dose of BiDil if headache continues with repeated dosing.

Hypotension

Warn patients about lightheadedness on standing.

Advise patients that inadequate fluid intake or excessive fluid loss from perspiration, diarrhea or vomiting may lead to an excessive fall in blood pressure and cause lightheadedness or even syncope. If syncope does occur, advise patients to discontinue BiDil and notify their prescribing physician as soon as possible.

Phosphodiesterase-5 Inhibitors

Advise patients to inform their physicians if they are taking, or planning to take, sildenafil, vardenafil, or tadalafil. Bidil should not be taken concomitantly with phosphodiesterase-5 inhibitors.

Worsening Ischemic Heart Disease

Advise patients to inform their physicians of any worsening of symptoms of myocardial ischemia, especially those with hypertrophic cardiomyopathy.

Systemic Lupus Erythematosus-like Symptoms

Advise patients if symptoms suggestive of systemic lupus erythematosus—such as arthralgia, fever, chest pain, prolonged malaise—occur to notify their prescribing physician.

Peripheral Neuritis

Advise patients if symptoms of peripheral neuritis—paresthesia, numbness, and tingling—occur to notify the prescribing physician.