BiDil

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). Keep bottles tightly closed.

Protect from light. Dispense in a light-resistant, tight container.

Manufactured for: Arbor Pharmaceuticals, LLC, Atlanta, GA 30328. Manufactured by: Kremers Urban Pharmaceuticals Inc., Seymour, IN 47274 USA. Revised: Mar 2015

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.

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.

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.

Do not use BiDil in patients who are taking the soluble guanylate cyclase (sGC) stimulator riociguat. Concomitant use can cause hypotension.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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.

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 Is chemic 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 longstanding 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.

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.

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.

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.

SIDE EFFECTS

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: Advers e Reactions Occurring in the A-HeFT Study in ≥ 2% of Patients Treated with BiDil.

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.

DRUG INTERACTIONS

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.

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 longstanding 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.

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: Advers e Reactions Occurring in the A-HeFT Study in ≥ 2% of Patients Treated with BiDil.

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.

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.

The basis for the beneficial clinical effects of BiDil is not known. In a small study of patients with chronic heart failure administered single doses of hydralazine 75 mg, isosorbide dinitrate 20 mg, and the combination, the combination elicited a statistically significant decrease in pulmonary capillary wedge pressure compared to hydralazine alone. The increase in cardiac output, renal blood flow and limb blood flow with the combination, however, was not greater than with hydralazine alone. There is no study of hemodynamic effects following multiple dosing.

Absorption

BiDil: Following a single 75-mg oral dose of hydralazine plus 40 mg of isosorbide dinitrate to 19 healthy adults, peak plasma concentrations of hydralazine (88 ng/mL/65 kg) and isosorbide dinitrate (76 ng/mL/65 kg) were reached in 1 hour. The half-lives were about 4 hours for hydralazine and about 2 hours for isosorbide dinitrate. Peak plasma concentrations of the two active metabolites, isosorbide-2- mononitrate and isosorbide-5-mononitrate, were 98 and 364 ng/mL/65 kg, respectively, at about 2 hours. No information is currently available regarding the effect of food on the bioavailability of hydralazine or isosorbide dinitrate from BiDil tablets.

Hydralazine hydrochloride: About 2/3 of a 50-mg dose of C-hydralazine hydrochloride given in gelatin capsules was absorbed in hypertensive subjects. In patients with heart failure, mean absolute bioavailability of a single oral dose of hydralazine 75 mg varies from 10 to 26%, with the higher percentages in slow acetylators. Administration of doses escalating from 75 mg to 1000 mg three times daily to congestive heart failure patients resulted in an up to 9-fold increase in the dose normalized AUC, indicating non-linear kinetics of hydralazine, probably reflecting saturable first pass metabolism.

Isosorbide dinitrate: Absorption of isosorbide dinitrate from tablets after oral dosing is nearly complete. The average bioavailability of isosorbide dinitrate is about 25%, but is highly variable (10%-90%) because of first-pass metabolism, and increases progressively during chronic therapy. Serum concentrations reach their maximum about one hour after ingestion.

Distribution

Hydralazine hydrochloride: After intravenous administration of hydralazine in a dose of 0.3 mg/kg, the steady-state volume of distribution in patients with congestive heart failure was 2.2 L/kg.

Isosorbide dinitrate: The volume of distribution of isosorbide dinitrate is 2 to 4 L/kg. About 28% of circulating isosorbide dinitrate is protein bound.

Under steady-state conditions, isosorbide dinitrate accumulates significantly in muscle (pectoral) and vein (saphenous) wall relative to simultaneous plasma concentrations.

Metabolism

Hydralazine is metabolized by acetylation, ring oxidation and conjugation with endogenous compounds including pyruvic acid. Acetylation occurs predominantly during the first-pass after oral administration which explains the dependence of the absolute bioavailability on the acetylator phenotype. About 50% of patients are fast acetylators and have lower exposure.

After oral administration of hydralazine, the major circulating metabolites are hydralazine pyruvate hydrazone and methyltriazolophthalazine. Hydralazine is the main pharmacologically active entity; hydralazine pyruvate hydrazone has only minimal hypotensive and tachycardic activity. The pharmacological activity of methyltriazolophthalazine has not been determined. The major identified metabolite of hydralazine excreted in urine is acetylhydrazinophthalazinone.

Isosorbide dinitrate undergoes extensive first-pass metabolism in the liver and is cleared at a rate of 2 to 4 L/minute with a serum half-life of about 1 hour. Isosorbide dinitrate's clearance is primarily by denitration to the 2-mononitrate (15 to 25%) and the 5-mononitrate (75 to 85%). Both metabolites have biological activity, especially the 5-mononitrate which has an overall half-life of about 5 hours. The 5- mononitrate is cleared by denitration to isosorbide, glucuronidation to the 5-mononitrate glucuronides, and by denitration/hydration to sorbitol. The 2-mononitrate appears to participate in the same metabolic pathways with a half-life of about 2 hours.

Elimination

Hydralazine: Metabolism is the main route for the elimination of hydralazine. Negligible amounts of unchanged hydralazine are excreted in urine.

Isosorbide dinitrate: Most isosorbide dinitrate is eliminated renally as conjugated metabolites.