BIDIL
Clinical safety rating: caution
Comprehensive clinical and safety monograph for BIDIL (BIDIL).
Combination of isosorbide dinitrate (a nitric oxide donor) and hydralazine (a direct vasodilator). Isosorbide dinitrate relaxes vascular smooth muscle via NO-mediated cGMP production; hydralazine reduces peripheral resistance and may inhibit DNA synthesis in endothelial cells. Synergy enhances vasodilation and improves cardiac output.
| Metabolism | Isosorbide dinitrate: extensively metabolized by denitration and conjugation in the liver; hydralazine: primarily metabolized by N-acetylation (N-acetyltransferase 2, NAT2) and subsequent glucuronidation. |
| Excretion | Hydralazine: 80% renal (as active drug and metabolites, predominantly N-acetylhydralazine and hydralazine pyruvic acid hydrazone); isosorbide dinitrate: renal (metabolites, primarily isosorbide mononitrates and isosorbide) and fecal (minor). |
| Half-life | Hydralazine: 2-4 hours (fast acetylators), 4-8 hours (slow acetylators); isosorbide dinitrate: 1 hour (parent), 4-5 hours (isosorbide-5-mononitrate, active metabolite). Clinical context: Requires twice-daily dosing for sustained effect. |
| Protein binding | Hydralazine: 87-90% (plasma proteins); isosorbide dinitrate: 30-40% (albumin). |
| Volume of Distribution | Hydralazine: 1.6 L/kg; isosorbide dinitrate: 2-4 L/kg. Clinical meaning: Extensive tissue distribution for both components. |
| Bioavailability | Hydralazine: 30-50% (oral, first-pass effect); isosorbide dinitrate: 20-30% (oral, extensive first-pass metabolism). |
| Onset of Action | Hydralazine: 45-60 minutes (oral); isosorbide dinitrate: 15-30 minutes (oral, sublingual). |
| Duration of Action | Hydralazine: 6-8 hours (oral); isosorbide dinitrate: 4-6 hours (oral), 2-4 hours (sublingual). Clinical note: Combination achieves sustained vasodilation for 12 hours. |
Isosorbide dinitrate 20 mg plus hydralazine 37.5 mg orally three times daily; titrate to target dose of isosorbide dinitrate 40 mg plus hydralazine 75 mg three times daily as tolerated.
| Dosage form | TABLET |
| Renal impairment | No specific dose adjustment recommended; however, hydralazine is cleared renally and may accumulate in severe renal impairment (CrCl <30 mL/min); consider monitoring for adverse effects. |
| Liver impairment | Contraindicated in severe hepatic impairment (Child-Pugh class C). In mild to moderate impairment (Child-Pugh A or B), no specific dose adjustment but caution advised due to potential increased exposure. |
| Pediatric use | Safety and efficacy not established in pediatric patients; no standard dosing recommendations available. |
| Geriatric use | Initiate at lower end of dosing range; titrate slowly due to increased risk of hypotension and dizziness; monitor renal function as hydralazine clearance may decrease. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for BIDIL (BIDIL).
| Breastfeeding | Hydralazine is excreted in breast milk (M/P ratio ~1.2); low levels unlikely to harm infant. Isosorbide dinitrate: No data on excretion. Monitor infant for hypotension. American Academy of Pediatrics considers hydralazine compatible with breastfeeding. |
| Teratogenic Risk | FDA Pregnancy Category C. First trimester: Animal studies show fetal harm; no adequate human studies. Second and third trimesters: Hydralazine crosses placenta; may cause fetal hypotension, thrombocytopenia. Isosorbide dinitrate: Limited data; associated with methemoglobinemia in neonates. Use only if benefit outweighs risk. |
■ FDA Black Box Warning
None.
| Serious Effects |
Hypersensitivity to hydralazine or isosorbide dinitrate, severe hypotension (<100 mmHg systolic), acute myocardial infarction (safety not established), cardiogenic shock, cardiomyopathy with restrictive/obstructive physiology, use with phosphodiesterase-5 inhibitors (e.g., sildenafil, tadalafil) due to risk of severe hypotension.
| Precautions | Hypotension (monitor blood pressure), agranulocytosis (rare; hydralazine may cause neutropenia; monitor CBC), drug-induced lupus-like syndrome (hydralazine; discontinue if symptoms develop), hepatotoxicity (hydralazine; monitor liver enzymes), risk of syncope when initiating or increasing dose, volume depletion (correct before use). |
| Food/Dietary | No specific food interactions. Avoid excessive alcohol intake as it may exacerbate hypotension. |
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| Fetal Monitoring | Monitor maternal blood pressure, heart rate, fluid status, and renal function. Fetal monitoring: serial ultrasound for growth, amniotic fluid index, and nonstress test in third trimester. Assess neonate for hypotension, thrombocytopenia, and methemoglobinemia. |
| Fertility Effects | No known adverse effects on human fertility. Animal studies: hydralazine at high doses caused reduced fertility in male rats; clinical significance unknown. |
| Clinical Pearls | Bidil is a fixed-dose combination of isosorbide dinitrate (20 mg) and hydralazine (37.5 mg), indicated as an adjunct to standard therapy for heart failure in self-identified African American patients (NYHA class III-IV, left ventricular ejection fraction <45%). Dizziness and headache are common due to vasodilation; titrate slowly. Avoid use with phosphodiesterase-5 inhibitors (e.g., sildenafil) due to risk of severe hypotension. Monitor for fluid retention and worsening heart failure. Consider dose reduction in hepatic impairment. |
| Patient Advice | Take this medication exactly as prescribed, usually three times daily with or without food. · Do not take with erectile dysfunction drugs (e.g., Viagra, Cialis, Levitra) as this can cause a dangerous drop in blood pressure. · Common side effects include dizziness and headache, which may improve over time; report severe or persistent symptoms to your doctor. · Avoid sudden position changes to prevent falls. · Do not stop taking this medication abruptly without consulting your healthcare provider. · Inform all healthcare providers you are taking Bidil. · Store at room temperature, away from moisture and heat. |