Drug: BiDil

BiDil is a fixed-dose combination of isosorbide dinitrate, a vasodilator with effects on both arteries and veins, and hydralazine hydrochloride, a predominantly arterial vasodilator. Isosorbide dinitrate is described chemically as 1,4:3,6-dianhydro-D-glucitol dinitrate and its structural formula is: Isosorbide dinitrate is a white to off-white, crystalline powder with the empirical formula C6H8N2O8 and a molecular weight of 236.14. It is freely soluble in organic solvents such as alcohol, chloroform and ether, but is only sparingly soluble in water. Hydralazine hydrochloride is described chemically as 1-hydrazinophthalazine monohydrochloride, and its structural formula is: Hydralazine hydrochloride is a white to off-white, crystalline powder with the empirical formula C8H8N4·HCl and a molecular weight of 196.64. It is soluble in water, slightly soluble in alcohol, and very slightly soluble in ether. Each BiDil Tablet for oral administration contains 20 mg of isosorbide dinitrate and 37.5 mg of hydralazine hydrochloride. The inactive ingredients in BiDil tablets include: anhydrous lactose, microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide, magnesium stearate, hypromellose, FD&C Yellow No. 6 aluminum lake, polyethylene glycol, titanium dioxide, polysorbate 80.

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Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. 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 reactions compared to 12% who discontinued placebo. Overall, adverse reactions were more common in BiDil -treated than in placebo-treated patients. Table 1 lists adverse reactions reported with an incidence, after rounding, ≥ 2% higher on BiDil than on placebo in A-HeFT, regardless of causality. The most common reasons for discontinuing BiDil in the A-HeFT trial was headache (7%). Table 1: Adverse Reactions Occurring in the A-HeFT Study in ≥ 2% of Patients Treated with BiDil
  BiDil
(N=517) % Placebo
(N=527) % Headache 50 21 Dizziness 32 14 Asthenia 14 11 Nausea 10 6 Hypotension 8 4 Sinusitis 4 2 Ventricular tachycardia 4 2 Paresthesia 4 2 Vomiting 4 2 Amblyopia 3 1 In the V-HeFT I and II clinical 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 reactions reported in these studies were similar to those reported in A-HeFT, described above and no unusual adverse reactions were reported. Postmarketing Experience The following adverse reactions have been identified during post-approval use of BiDil. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Use of BiDil: The following adverse reactions have been identified with use of BiDil. Cardiac Disorders: Palpitations
Ear and labyrinth disorders: Tinnitus, vertigo
Eye Disorders: Eyelid edema, vision blurred
Gastrointestinal Disorders: Abdominal discomfort, constipation
General Disorders and Administration Site Conditions: Facial pain, flushing, chest discomfort, chest pain, peripheral edema
Musculoskeletal and Connective Tissue Disorders: Pain in extremity, myalgia
Nervous Disorders: Dysgeusia, hypoaesthesia, migraine, syncope
Renal and Urinary Disorders: Chromaturia, pulmonary renal syndrome
Respiratory, Thoracic and Mediastinal Disorders: Dyspnea
Reproductive System and Breast Disorders: Erectile dysfunction
Skin and Subcutaneous Tissue Disorders: Erythema, hyperhidrosis, pruritus, face swelling Use of Hydralazine Hydrochloride or Isosorbide Dinitrate: The following reactions have been reported with use of either hydralazine hydrochloride or isosorbide dinitrate. Blood and Lymphatic System Disorders: Blood dyscrasias, agranulocytosis, purpura, eosinophilia, splenomegaly.
Eye Disorders: Lacrimation, conjunctivitis.
Gastrointestinal Disorders: Paralytic ileus.
Hepatobiliary Disorders: Hepatitis.
Psychiatric Disorders: Psychotic reactions, disorientation.
Renal and Urinary Disorders: Difficulty in urination. Read the BiDil (isosorbide dinitrate and hydralazine hcl) Side Effects Center for a complete guide to possible side effectsLearn More »

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BiDil should be initiated at a dose of one BiDil Tablet, three times a day. Titrate to a maximum of two tablets three times daily, if tolerated. Although titration of BiDil can be rapid (3-5 days), some patients may experience side effects and may take longer to reach their maximum tolerated dose. The dosage may be decreased to as little as one-half BiDil Tablet three times a day if intolerable side effects occur. Efforts should be made to titrate up as soon as side effects subside.

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Phosphodiesterase Inhibitors BiDil is contraindicated in patients who are using a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5), PDE5 inhibitors such as avanafil, sildenafil, vardenafil, and tadalafil have been shown to potentiate the hypotensive effects of organic nitrates. Do not use BiDil in patients who are taking the soluble guanylate cyclase (sGC) stimulator riociguat. Comcomitant use can cause hypotension [see CONTRAINDICATIONS]. Read the BiDil Drug Interactions Center for a complete guide to possible interactions Learn More »

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Treatment Of Heart Failure In Self-identified Black Patients BiDil is indicated for the treatment of heart failure as an adjunct to standard therapy in self-identified black patients to improve survival, to prolong time to hospitalization for heart failure, and to improve patient-reported functional status. Limitations Of Use There is little experience in patients with NYHA class IV heart failure.

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BiDil is contraindicated in patients who are allergic to organic nitrates. Do not use BiDil in patients who are taking PDE-5 inhibitors, such as avanafil, sildenafil, tadalafil, or vardenafil. Concomitant use can cause severe hypotension, syncope, or myocardial ischemia [see DRUG INTERACTIONS]. Do not use BiDil in patients who are taking the soluble guanylate cyclase (sGC) stimulator riociguat. Concomitant use can cause hypotension. Last reviewed on RxList: 4/21/2015
This monograph has been modified to include the generic and brand name in many instances.

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The signs and symptoms of overdosage with BiDil are expected to be those of excessive pharmacologic effect, i.e., vasodilatation, reduced cardiac output and hypotension, and signs and symptoms include headache, confusion, tachycardia, and generalized skin flushing. Complications can include myocardial ischemia and subsequent myocardial infarction, cardiac arrhythmia, and profound shock. Syncope, coma and death may ensue without appropriate treatment. Human Experience: There are no documented cases of overdosage with BiDil. No deaths from acute poisoning have been reported. Treatment: There is no specific antidote. Support of the cardiovascular system is of primary importance. Shock should be treated with plasma expanders, vasopressors, and positive inotropic agents. The gastric contents should be evacuated, taking adequate precautions to prevent aspiration. These manipulations have to be carried out after cardiovascular status has been stabilized, since they might precipitate cardiac arrhythmias or increase the depth of shock. In patients with renal disease or congestive heart failure, therapy resulting in central volume expansion is not without hazard. Treatment of isosorbide dinitrate overdose in these patients may be difficult, and invasive monitoring may be required. No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of the components of BiDil. Dialysis is not effective in removing circulating isosorbide dinitrate. The dialyzability of hydralazine has not been determined. Methemoglobinemia: Nitrate ions liberated during metabolism of isosorbide dinitrate can oxidize hemoglobin into methemoglobin. There are case reports of significant methemoglobinemia in association with moderate overdoses of organic nitrates. Methemoglobin levels are measurable by most clinical laboratories. Methemoglobinemia could be serious in chronic heart failure patients because of already compromised vascular bed-tissue gas exchange dynamics. Classically, methemoglobinemic blood is described as chocolate brown, without color change on exposure to air. When methemoglobinemia is diagnosed, the treatment of choice is methylene blue, 1 to 2 mg/kg intravenously.

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Dosage Forms And Strengths The BiDil (20 mg isosorbide dinitrate and 37.5 mg hydralazine hydrochloride) tablets are orange, biconvex, approximately 8 mm in diameter, scored, film-coated, and debossed with “20” on one side over the score and “N” on the other side. Storage And Handling BiDil Tablets contain 20 mg of isosorbide dinitrate and 37.5 mg of hydralazine hydrochloride. They are 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. NDC 24338-010-18: Bottles of 180 Store at 25°C (77°F), excursions permitted to 15-30°C (59-86°F). [See USP Controlled Room Temperature.] Keep bottles tightly closed. Protect from light. Dispense in a light-resistant, tight container. Manufactured for: Atlanta, GA 30328. Manufactured by: Kremers Urban Pharmaceuticals Inc. Seymour, IN 47274 USA. Revised: Apr 2015 Last reviewed on RxList: 4/21/2015
This monograph has been modified to include the generic and brand name in many instances.

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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. Nonclinical Toxicology 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. 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. Last reviewed on RxList: 4/21/2015
This monograph has been modified to include the generic and brand name in many instances.

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