BiDil Side Effects

Please note - some side effects for BiDil may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of BiDil - for the Consumer

BiDil

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using BiDil:

Dizziness; headache; lightheadedness; nausea; vomiting.

Seek medical attention right away if any of these SEVERE side effects occur when using BiDil:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); change in the amount of urine produced; chest pain; difficult urination; fainting; fast or irregular heartbeat; fever, chills, or sore throat; joint pain; numbness or tingling of the skin; persistent fatigue or weakness; runny nose; severe or persistent headache or dizziness; vision changes.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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BiDil Side Effects - for the Professional

BiDil

BiDil

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 experiences compared to 12% who discontinued placebo. Overall, adverse events were more common in BiDil-treated than in placebo-treated patients. Table 2 lists adverse events reported with an incidence of ≥ 2% in patients treated with BiDil in A-HeFT, and, after rounding to the nearest 1%, occurring more frequently than in the placebo group, regardless of causality. Headache and dizziness were the two most frequent adverse events and were more than twice as frequent in the BiDil group. The most common reasons for discontinuing BiDil in the A-HeFT trial were headache (7%) and dizziness (4%).  

Table 2.       Adverse Events Occurring in the A-HeFT Study in ≥2% of Patients Treated with BiDil

				BiDil (N=517) (% of patients)				Placebo (N=527) (% of patients)
Headache				50				21
Dizziness				32				14
Chest pain				16				15
Asthenia				14				11
Nausea				10				6
Bronchitis				8				7
Hypotension				8				4
Sinusitis				4				2
Ventricular tachycardia				4				2
Palpitations				4				3
Hyperglycemia				4				3
Rhinitis				4				3
Paresthesia				4				2
Vomiting				4				2
Amblyopia				3				1
Hyperlipidemia				3				2
Tachycardia				2				1

The following adverse events were reported in A-HeFT in at least 1% but less than 2% of patients treated with BiDil, and also occurred in at least 0.5% more patients than in placebo-treated patients; all such events are included unless they are too non-specific to be meaningful or appear to reflect underlying disease.

Body as a Whole: Allergic reaction, malaise.

Central nervous system: Somnolence.

Gastrointestinal: Cholecystitis.

Metabolic: Hypercholesteremia.

Musculoskeletal: Arthralgia, myalgia, tendon disorder.

Skin: Alopecia, angioedema, sweating.

In the V-HeFT I and II 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 experiences reported in these studies were similar to those reported in A-HeFT, and no unusual adverse experiences were reported. 

Prior experience with BiDil components

The following additional adverse events have been reported with hydralazine hydrochloride or isosorbide dinitrate but not necessarily with BiDil:

Digestive: paralytic ileus.

Cardiovascular: paradoxical pressor response, crescendo angina.

Neurologic: peripheral neuritis, numbness, tingling, muscle cramps, psychotic reactions, disorientation.

Genitourinary: difficulty in urination.

Hematologic: blood dyscrasias, agranulocytosis, purpura, splenomegaly.

Hypersensitive Reactions: eosinophilia, hepatitis.

Other: nasal congestion, flushing, lacrimation, conjunctivitis. 

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Side Effects by Body System - for Healthcare Professionals

Nervous system

Nervous system side effects associated with the combination product have included headache (50%), dizziness (32%), asthenia (14%), and paresthesia (4%). Somnolence has been reported in less than 2% of patients.

Nervous system side effects associated with hydralazine as a single agent have included peripheral neuropathy, which appears to be dose-related and is more common in slow acetylators. The neuropathy usually first presents as paresthesias, numbness, and tingling in the extremities. It is probably the result of pyridoxine deficiency, perhaps because formation of a pyridoxal-hydralazine complex inactivates the coenzyme, and can, therefore, be treated by administration of pyridoxine. Headache or dizziness have been reported in approximately 5% of patients receiving hydralazine.

A 61-year-old man with hypertension developed ataxia, numbness, and lower extremity weakness approximately six months after beginning hydralazine (up to 300 mg per day) and reserpine therapy. The neuropathy partially resolved after reduction of the hydralazine dosage to 60 mg daily. A complete evaluation revealed that this man was a slow acetylator of hydralazine.

Cardiovascular

Cardiovascular side effects associated with the combination product have included chest pain (16%), hypotension (8%), ventricular tachycardia (4%), and palpitations (4%).

Cardiovascular side effects associated with hydralazine as a single agent are related to its vasodilatory properties. Reflex tachycardia is commonly observed. Palpitations, flushing, edema, or chest pain have been reported in less than 5% of patients. The use of hydralazine in patients with severe chronic heart failure has been associated with ischemia, including episodes of myocardial infarction. In patients with pulmonary hypertension (PH) and chronic obstructive pulmonary disease (COPD), hydralazine may increase pulmonary artery hypertension, especially during periods of hypoxia. The use of hydralazine in these patients may, on rare occasions, result in profound hypotension, tachycardia, and even death. Rare cases of bradycardia or cardiac tamponade (associated with hydralazine-induced lupus) have been reported. Hydralazine does not have a deleterious effect on the lipid profile, and, in fact, has been shown to decrease total and LDL cholesterol.

Cardiovascular side effects associated with isosorbide dinitrate as a single agent have included flushing, hypotension, diaphoresis, weakness, sinus bradycardia, and unusual case reports of AV heart block. Unusual cases of edema have also been reported.

Gastrointestinal

Gastrointestinal side effects associated with the combination product have included nausea (10%) and vomiting (4%).

Gastrointestinal side effects associated with isosorbide dinitrate as a single agent include mild nausea and constipation.

Hematologic

A 71-year-old man with hypertension developed anorexia, weight loss, petechiae, and a microcytic anemia during therapy with hydralazine and oxprenolol. Evaluation for iron deficiency, hemolysis, or marrow depression was negative. The patient was found to have fecal blood loss, anti-DNA antibodies, decreased complement levels, a normal upper GI series, and biopsy-proven vasculitis. The syndrome resolved within two weeks after discontinuation of hydralazine.

Hematologic abnormalities have been associated with the hydralazine-induced lupus-like syndrome. Anemia may be caused by one of at least four hydralazine-associated problems; hemolysis, the formation of a circulating anticoagulant, thrombocytopenia, and vasculitis. Rare cases of leukopenia and agranulocytosis have been reported.

Hematologic side effects associated with isosorbide dinitrate as a single agent are rare and include methemoglobinemia and at least one case of isosorbide dinitrate-induced hemolytic anemia.

Immunologic

The lupus syndrome may present as arthralgias (most common), myalgias, lethargy, malaise, a typical erythematous rash, weight loss, or dyspnea, but may be found incidentally in asymptomatic patients by urinalysis (proteinuria, hematuria), blood chemistry (elevated ESR, antinuclear antibody), or chest X-ray (interstitial lung disease, rare). Hypocomplementemia is an extremely rare finding in hydralazine-induced lupus.

Immunologic side effects associated with hydralazine as a single agent have included the development of a lupus-like syndrome, which is more likely in patients who receive 400 mg or more of hydralazine per day, in female patients, or in patients who are slow acetylators. Of patients who receive less than 200 mg or 400 mg or more per day of hydralazine, 40% and 50%, respectively, develop a positive ANA titer, and up to 6% and 14%, respectively, develop a lupus-like syndrome.

Renal

In one study, rapidly progressive glomerulonephritis (RPGN) is described in 4 of 444 patients, all of whom were men who were treated for 5 to 11 years with daily hydralazine doses of 100 to 250 mg. In three of the four cases, biopsy revealed a focal and segmental glomerular necrosis with crescents and positive immunofluorescence. The antinuclear antibody titer became positive in three. Renal function improved in all but one after the withdrawal of hydralazine and institution of corticosteroid therapy. A number of other cases of RPGN are reported. It appears to be far more common in patients who are slow acetylators.

Renal side effects including rare cases of rapidly progressive and focal glomerulonephritis associated with the hydralazine-induced lupus syndrome have been reported and are often accompanied by anemia, a positive anti-DNA antibody titer, and a positive ANA titer.

Isosorbide dinitrate can cause a reduction of glomerular filtration rate and free water clearance associated with significant increases in plasma renin and aldosterone in patients with liver cirrhosis. The changes are most remarkable in patients with ascites.

Metabolic

Metabolic side effects associated with the combination product have included hyperglycemia (4%) and hyperlipidemia (3%). Hypercholesterolemia has been reported in less than 2% of patients.

Respiratory

Respiratory side effects associated with the combination product have included bronchitis (8%), sinusitis (4%), and rhinitis (4%).

Respiratory side effects associated with hydralazine as a single agent have included nasal stuffiness (seen in approximately 3% of patients). A case of "hydralazine lung" associated with hydralazine-induced lupus has been reported.

A 48-year-old woman with hypertension developed dyspnea, hemoptysis, pleurisy, proteinuria, and hematuria one year after beginning hydralazine (150 mg per day), polythiazide, and atenolol therapy. Other associated findings included an elevated ESR, antinuclear factor, anti-DNA titer, a positive LE test, and radiographic findings of diffuse interstitial lung disease. Two weeks after stopping hydralazine, the signs and symptoms of lupus with pulmonary involvement disappeared.

Hypersensitivity

Hypersensitivity reactions including allergic reaction have been reported rarely in patients receiving the combination product. Angioedema has been reported in less than 2% of patients.

Hypersensitivity reactions associated with hydralazine as a single agent are rare. Many of the rare cases of hepatitis are believed to be due to hypersensitivity. A case of retroperitoneal fibrosis and of occupational asthma are believed to be due to hypersensitivity.

Hypersensitivity reactions associated with isosorbide dinitrate as a single agent including rare cases of pruritus and drug rash have been reported.

A 44-year-old woman with hypertension and acute sinusitis developed acute renal failure, edema, and a generalized maculopapular erythematous rash during therapy with ampicillin (for sinusitis), hydrochlorothiazide, and hydralazine. A complete evaluation revealed bilateral hydronephrosis and hydroureters secondary to ureteral obstruction due to retroperitoneal fibrosis. Renal function returned to baseline after oral prednisone therapy. It is unclear whether this problem was due to one or more of her medications.

Ocular

Ocular side effects associated with the combination product have included amblyopia (3%).

Musculoskeletal

Musculoskeletal side effects including arthralgia, myalgia, and tendon disorder have been reported in less than 2% of patients receiving the combination product.

Dermatologic

A 65-year-old man with ischemic cardiomyopathy developed a pruritic, erythematous, generalized rash within two months after beginning hydralazine (200 mg per day) therapy. There were no clinical or laboratory signs of lupus. The rash persisted upon gradual withdrawal of the patient's other medications, but cleared only after discontinuation of hydralazine. Rechallenge resulted in a recurrent pruritic rash.

Dermatologic side effects including alopecia and sweating have been reported in less than 2% of patients receiving the combination product.

Dermatologic manifestations of hydralazine-induced lupus-like syndrome include cutaneous vasculitis. A generalized, pruritic rash without evidence of lupus has been associated with hydralazine. Rare cases of Sweet's syndrome (neutrophilic dermatosis) have been associated with hydralazine.

Genitourinary

Genitourinary side effects rarely associated with hydralazine as a single agent have included impotence.

At least two cases of male impotence associated with hydralazine are reported. The mechanism is unclear. There was no evidence of a neuropathy in either case.

Hepatic

Hepatic reactions associated with hydralazine as a single agent are rare. Less than ten cases of hepatitis have been reported, many of which were believed to be due to hypersensitivity. Histological findings include hepatocellular, cholestatic, mixed hepatocellular-cholestatic, and granulomatous patterns.

A 59-year-old woman with hypertension and cholecystic gallbladder disease developed abdominal pain, nausea, vomiting, painful hepatomegaly, elevated serum transaminases, direct hyperbilirubinemia, and liver biopsy findings of subacute hepatitis (with bridging necrosis) within two days after hydralazine was added to her medical regimen. The signs and symptoms of hepatitis resolved after all medications were withheld, but returned upon rechallenge with hydralazine.

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