Bidil Generic Name & Formulations
BiDil supplied as:
- biconvex, approximately 8 mm in diameter, scored, film-coated, orange tablets debossed "20" on one side over the score and "N" on the other side.
Store at 25° C (77° F), excursions permitted to 15-30° C (59-86° F).
Protect from light.
Limitations of Use
There is little experience in patients with NYHA class IV heart failure.
Bidil Dosage and Administration
Bidil Boxed Warnings
- 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.
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.
Worsening Ischemic Heart Disease
- Hydralazine hydrochloride can cause tachycardia and hypotension potentially leading to myocardial ischemia and angina, particularly in patients with hypertrophic cardiomyopathy.
- 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.
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.
Nursing Mother Considerations
There is no data on the presence of BiDil in human or animal milk, the effects on the breastfed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for BiDil and any potential adverse effects on the breastfed child from BiDil or from the underlying maternal condition.
The safety and effectiveness of BiDil in children have not been established.
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.
Following a single 75-mg oral dose of hydralazine plus 40 mg of isosorbide dinitrate to 19 healthy adults, peak plasma concentrations of hydralazine (88 ng/mL/65 kg) and isosorbide dinitrate (76 ng/mL/65 kg) were reached in 1 hour.
Hydralazine hydrochloride: After intravenous administration of hydralazine in a dose of 0.3 mg/kg, the steady-state volume of distribution in patients with congestive heart failure was 2.2 L/kg.
Isosorbide dinitrate: The volume of distribution of isosorbide dinitrate is 2 to 4 L/kg. About 28% of circulating isosorbide dinitrate is protein bound.
Hydralazine: Metabolism is the main route for the elimination of hydralazine. Negligible amounts of unchanged hydralazine are excreted in urine.
Isosorbide dinitrate: Most isosorbide dinitrate is eliminated renally as conjugated metabolites.
Bidil Adverse Reactions
Bidil Clinical Trials
BiDil or a combination of isosorbide dinitrate and hydralazine hydrochloride was studied in two placebo-controlled clinical trials in 1,692 patients with mild to severe heart failure (mostly NYHA class II and III) and one active control trial (vs. enalapril) in 804 patients.
- 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.
- 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.
- 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 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 (HR: 0.57 [95% CI, 0.37-0.89]; P =0.012). 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 (HR: 0.61 [95% CI, 0.46-0.80]; P <0.001) 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 full labeling). Patients in both treatment groups had mean baseline questionnaire scores of 51 (out of a possible 105).
Bidil Patient Counseling
- 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.
- 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 physician as soon as possible.
- 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 (eg arthralgia, fever, chest pain, prolonged malaise) occur to notify their physician.
- Advise patients if symptoms of peripheral neuritis (eg, paresthesia, numbness, and tingling) occur to notify their physician.