WARNINGS AND PRECAUTIONS
Severe Hypotension with Phosphodiesterase Inhibitors
Avoid co-administration of BiDil with phosphodiesterase inhibitors such as sildenafil, vardenafil, or tadalafil because severe hypotension, syncope, or myocardial ischemia may result [see Drug Interactions].
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].
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.
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.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C:
There are no studies using BiDil in pregnant women.
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).
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). There are no animal studies assessing the teratogenicity of BiDil.
A meta-analysis of randomized controlled trials comparing hydralazine hydrochloride with other antihypertensive agents for severe hypertension in pregnancy found that hydralazine hydrochloride was associated with significantly more maternal hypotension, placental abruption, caesarean sections and oliguria, with more adverse effects on fetal heart rate and with lower Apgar scores.
A combination of propranolol and hydralazine hydrochloride was administered to 13 patients with long-standing hypertension during 15 pregnancies. These pregnancies resulted in 14 live births and one unexplained stillbirth. The only neonatal complications were two cases of mild hypoglycemia. Hydralazine hydrochloride and its metabolites have been detected using a non-selective assay in maternal and umbilical plasma in patients treated with the drug during pregnancy.
Isosorbide dinitrate has been used for effective acute and sub-chronic control of hypertension in pregnant women, but there are no studies using it in a chronic regimen and assessing its effects on pregnant women and/or the fetus.
Nursing Mothers
No studies have been performed with BiDil. It is not known if either hydralazine or isosorbide dinitrate is excreted in human milk.
Pediatric Use
The safety and effectiveness of BiDil in children have not been established.
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.
Renal Impairment
There are no studies of renal impairment using BiDil. No dose adjustment is required for hydralazine or isosorbide dinitrite [see Clinical Pharmacology].
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.
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.
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