WARNINGS
Augmentation of the vasodilatory effects of isosorbide dinitrate by phosphodiesterase inhibitors such as sildenafil, vardenafil, or tadalafil could result in severe hypotension. The time course and dose dependence of this interaction have not been studied. Reasonable supportive care should consist of those measures used to treat a nitrate overdose with elevation of the extremities and central volume expansion.
PRECAUTIONS
General
The precautions that need to be taken when using BiDil are those appropriate to each of its components.
Treatment with hydralazine hydrochloride may produce a clinical picture simulating systemic lupus erythematosus including glomerulonephritis.
If systemic lupus erythematosus-like symptoms occur in patients treated with BiDil, discontinuation of BiDil should be considered only after a thorough benefit-to-risk assessment. Symptoms and signs of systemic lupus erythematosus usually regress when hydralazine hydrochloride is discontinued but residua have been detected many years later. Long-term treatment with steroids may be necessary. (See PRECAUTIONS Laboratory Tests.)
Symptomatic hypotension, particularly with upright posture, may occur with even small doses of BiDil. Therefore, BiDil should be used with caution in patients who may be volume depleted or who, for whatever reason, are already hypotensive.
Hydralazine hydrochloride can cause tachycardia potentially leading to myocardial ischemia and anginal attacks.
Careful clinical and hemodynamic monitoring is recommended when BiDil is administered to patients with acute myocardial infarction to avoid the hazards of hypotension and tachycardia.
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.
Isosorbide dinitrate therapy may aggravate angina associated with hypertrophic cardiomyopathy.
Information for Patients
Patients should be informed of possible side effects and advised to take the medication regularly and continuously as directed.
Patients should be told that headaches often accompany treatment with BiDil, especially during initiation of treatment. Headaches tend to subside even with continued dosing. Patients should be instructed to consult a physician to adjust the dose of BiDil if headache continues with repeated dosing. Treatment of emerging headache was managed with acetaminophen in some clinical trial patients .
Treatment with BiDil may be associated with lightheadedness on standing, especially after rising from a recumbent or seated position.
Patients should be cautioned 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, BiDil should be discontinued, and the prescribing physician should be notified as soon as possible.
Patients should be cautioned about the increased risk of hypotension especially if they are taking antihypertensive drugs concomitantly.
Patients should be cautioned against concomitant use of BiDil with phosphodiesterase-5 inhibitor drugs used for the treatment for erectile dysfunction or pulmonary hypertension such as sildenafil citrate (Viagra®; Revatio™), vardenafil (Levitra®) or tadalafil (Cialis®). Use of BiDil may produce an extreme drop in blood pressure that may result in fainting or may provoke chest pain or a heart attack.
Laboratory Tests
If symptoms suggestive of systemic lupus erythematosus occur, such as arthralgia, fever, chest pain, prolonged malaise, or other unexplained signs or symptoms, complete blood counts and antinuclear antibody titer determinations should be performed. A positive antinuclear antibody titer requires that the physician carefully weigh the benefits and risks of continued therapy with BiDil.
Drug/Drug Interactions
Due to the hydralazine component of BiDil, monoamine-oxidase inhibitors should be used with caution in patients receiving BiDil.
Patients treated with BiDil who receive any potent parenteral antihypertensive agent should be continuously observed for several hours for excessive fall in blood pressure.
The effects of BiDil on vasodilators including alcohol may be additive.
Sildenafil: See WARNINGS.
Vardenafil: See WARNINGS.
Tadalafil: See WARNINGS.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Hydralazine Hydrochloride
An increased incidence of lung tumors (adenomas and adenocarcinomas) was observed in a lifetime study in Swiss albino mice given hydralazine hydrochloride continuously in their drinking water at a dosage of about 250 mg/kg per day (6 times the MRHD provided by BiDil on a body surface area basis). In a 2-year carcinogenicity study of rats given hydralazine hydrochloride by gavage at dose levels of 15, 30, and 60 mg/kg/day (up to 3 times the MRHD of BiDil on a body surface area basis), microscopic examination of the liver revealed a small, but statistically significant increase in benign neoplastic nodules in males (high-dosage) and females (both high and intermediate dosage groups). Benign interstitial cell tumors of the testes were also significantly increased in the high-dose group.
Hydralazine hydrochloride is mutagenic in bacterial systems, and is positive in rat and rabbit hepatocyte DNA repair studies in vitro. Additional in vivo and in vitro studies using lymphoma cells, germinal cells, fibroblasts from mice, bone marrow cells from Chinese hamsters and fibroblasts from human cell lines did not demonstrate any mutagenic or clastogenic potential for hydralazine hydrochloride.
Isosorbide Dinitrate
No long-term animal studies have been performed to evaluate the mutagenic or carcinogenic potential of isosorbide dinitrate. A modified two-litter reproduction study among rats fed isosorbide dinitrate at 25 or 100 mg/kg/day (up to 9 times the Maximum Recommended Human Dose of BiDil on a body surface area basis) revealed no evidence of altered fertility or gestation.
Pregnancy Category C
Isosorbide dinitrate has been shown to cause a dose-related increase in embryotoxicity (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.
There are no studies using BiDil in pregnant women. Therefore, BiDil should be used with caution during pregnancy and only if the potential benefit justifies the potential risk to the fetus.
Nursing mothers
The possible excretion of hydralazine in breast milk has not been determined. It is also not known whether isosorbide dinitrate is excreted in human milk. No studies have been performed with BiDil. Caution should be exercised when BiDil is administered to a nursing woman.
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 be cautious, usually starting 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.
|
