Isosorbide Dinitrate and Hydralazine Hcl (BiDil)
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Isosorbide Dinitrate and Hydralazine Hcl (BiDil)

BiDil®
(isosorbide dinitrate and hydralazine hydrochloride) Tablets

DRUG DESCRIPTION

BiDil (isosorbide dinitrate and hydralazine hcl) 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-2,5-dinitrate and its structural formula is:

Isosorbide dinitrate Structural Formula Illustration

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 monohy-drochloride,and its structural formula is:

Hydralazine hydrochloride Structural Formula Illustration

Hydralazine HCl 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 (isosorbide dinitrate and hydralazine hcl) Tablet for oral administration contains 20 mg of isosorbide dinitrate and 37.5 mg of hydralazine hydrochloride.

The inactive ingredients in BiDil (isosorbide dinitrate and hydralazine hcl) tablets include: anhydrous lactose, microcrystalline cellu-lose, sodium starch glycolate,colloidal silicon dioxide, magnesium stearate,hypromellose, FD&C Yellow No.6 aluminum lake,polyethylene glycol,titanium dioxide,polysorbate 80.

What are the possible side effects of hydralazine and isosorbide dinitrate (BiDil)?

If you experience any of the following serious side effects, stop taking hydralazine and isosorbide dinitrate and seek emergency medical attention:

  • an allergic reaction (difficulty breathing; closing of your throat; swelling of your lips, tongue, or face; or hives);
  • blurred vision and dry mouth;
  • irregular heartbeat; or
  • blood in your urine or stools;
  • numbness, tingling, pain, or weakness of your arms or legs;
  • fainting.

Other, less serious side effects may be more likely to occur. If you experience any of the...

Read All Potential Side Effects and See Pictures of BiDil »

What are the precautions when taking isosorbide dinitrate and hydralazine hcl (BiDil)?

Before taking this medication, tell your doctor or pharmacist if you are allergic to either isosorbide dinitrate or hydralazine; or to similar drugs (such as nitroglycerin); or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: other heart problems (such as recent heart attack, rheumatic heart disease of the mitral valve), previous stroke, low blood pressure, blood vessel problems, loss of too much body water (dehydration), recent head injury, anemia, kidney problems.

This drug may make you dizzy. Do not drive, use machinery, or do any activity that...

Read All Potential Precautions of BiDil »

Last reviewed on RxList: 10/7/2008
This monograph has been modified to include the generic and brand name in many instances.

INDICATIONS

BiDil (isosorbide dinitrate and hydralazine hcl) 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.There is little experience in patients with NYHA class IV heart failure.Most patients in the clinical trial supporting effectiveness (A-HeFT) received a loop diuretic, an angiotensin con-verting enzyme inhibitor or an angiotensin II receptor blocker,and a beta blocker, and many also received a cardiac glycoside or an aldosterone antagonist.

DOSAGE AND ADMINISTRATION

Treatment with BiDil (isosorbide dinitrate and hydralazine hcl) should be initiated at a dose of one BiDil (isosorbide dinitrate and hydralazine hcl) Tablet,3 times a day.BiDil (isosorbide dinitrate and hydralazine hcl) may be titrated to a maximum tolerated dose,not to exceed two BiDil (isosorbide dinitrate and hydralazine hcl) Tablets, 3 times a day.

There is no adequate experience in heart failure with doses of BiDil (isosorbide dinitrate and hydralazine hcl) other than those recommended and no experience with use of individual components.

Although titration of BiDil (isosorbide dinitrate and hydralazine hcl) 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 (isosorbide dinitrate and hydralazine hcl) Tablet 3 times a day if intolerable side effects occur. Efforts should be made to titrate up as soon as side effects subside.

HOW SUPPLIED

BiDil (isosorbide dinitrate and hydralazine hcl) Tablets contain 20 mg of isosorbide dinitrate plus 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 12948-001-01 bottle of 12.
NDC 12948-001-12 bottle of 180.

Keep bottles tightly closed.

Store at 25°C (77°F),excursions permitted to 15-30°C (59-86°F). [See USP Controlled Room Temperature.]

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

Manufactured for: NitroMed, Inc. Lexington,MA 02421, USA. By Schwarz Pharma Mfg.,Inc. Seymour, IN 47274, USA. FDA Rev date: 6/23/2005

Last reviewed on RxList: 10/7/2008
This monograph has been modified to include the generic and brand name in many instances.

SIDE EFFECTS

BiDil (isosorbide dinitrate and hydralazine hcl)

BiDil (isosorbide dinitrate and hydralazine hcl) has been evaluated for safety in 517 heart failure patients in A-HeFT. A total of 317 of these patients received BiDil (isosorbide dinitrate and hydralazine hcl) for at least 6 months,and 220 received BiDil (isosorbide dinitrate and hydralazine hcl) for at least 12 months. In A-HeFT, 21% of the patients discontinued BiDil (isosorbide dinitrate and hydralazine hcl) for adverse experiences compared to 12% who discontinued placebo.Overall, adverse events were more common in BiDil (isosorbide dinitrate and hydralazine hcl) -treated than in placebo-treated patients. Table 2 lists adverse events reported with an incidence of ≥ 2% in patients treated with BiDil (isosorbide dinitrate and hydralazine hcl) 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 (isosorbide dinitrate and hydralazine hcl) group. The most common reasons for discontinuing BiDil (isosorbide dinitrate and hydralazine hcl) 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 (isosorbide dinitrate and hydralazine hcl) .

  BiDil (isosorbide dinitrate and hydralazine hcl)
(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 (isosorbide dinitrate and hydralazine hcl) , 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 treat-ed 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 (isosorbide dinitrate and hydralazine hcl) components

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

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.

Read the BiDil (isosorbide dinitrate and hydralazine hcl) Side Effects Center for a complete guide to possible side effects »

DRUG INTERACTIONS

Drug/Drug Interactions

Due to the hydralazine component of BiDil (isosorbide dinitrate and hydralazine hcl) ,monoamine-oxidase inhibitors should be used with caution in patients receiving BiDil (isosorbide dinitrate and hydralazine hcl) .

Patients treated with BiDil (isosorbide dinitrate and hydralazine hcl) who receive any potent parenteral antihypertensive agent should be continuously observed for several hours for excessive fall in blood pressure.

The effects of BiDil (isosorbide dinitrate and hydralazine hcl) on vasodilators including alcohol may be additive.

Sildenafil: See WARNINGS.

Vardenafil: See WARNINGS.

Tadalafil: See WARNINGS.

Last reviewed on RxList: 10/7/2008
This monograph has been modified to include the generic and brand name in many instances.

WARNINGS

Augmentation of the vasodilatory effects of isosorbide dinitrate by phosphodi-esterase 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 (isosorbide dinitrate and hydralazine hcl) 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 (isosorbide dinitrate and hydralazine hcl) , discontinuation of BiDil (isosorbide dinitrate and hydralazine hcl) 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 (isosorbide dinitrate and hydralazine hcl) .Therefore,BiDil (isosorbide dinitrate and hydralazine hcl) 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 (isosorbide dinitrate and hydralazine hcl) 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 (isosorbide dinitrate and hydralazine hcl) therapy if such symptoms develop.

Isosorbide dinitrate therapy may aggravate angina associated with hypertrophic cardiomyopathy.

Laboratory Tests

If symptoms suggestive of systemic lupus erythematosus occur,such as arthral-gia,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 (isosorbide dinitrate and hydralazine hcl) .

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 (isosorbide dinitrate and hydralazine hcl) on a body surface area basis). In a 2-year car-cinogenicity 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 (isosorbide dinitrate and hydralazine hcl) 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 (isosorbide dinitrate and hydralazine hcl) 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 embryo-toxicity (excess mummified pups) in rabbits at 70 mg/kg (12 times the MRHD of BiDil (isosorbide dinitrate and hydralazine hcl) 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 (isosorbide dinitrate and hydralazine hcl) on a body surface area basis).There are no animal studies assessing the teratogenicity of BiDil (isosorbide dinitrate and hydralazine hcl) .

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 preg-nancies 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 (isosorbide dinitrate and hydralazine hcl) in pregnant women. Therefore,BiDil (isosorbide dinitrate and hydralazine hcl) 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 (isosorbide dinitrate and hydralazine hcl) .Caution should be exercised when BiDil (isosorbide dinitrate and hydralazine hcl) is admin-istered to a nursing woman.

Pediatric use

The safety and effectiveness of BiDil (isosorbide dinitrate and hydralazine hcl) in children have not been established.

Geriatric use

Clinical studies of BiDil (isosorbide dinitrate and hydralazine hcl) 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.

Last reviewed on RxList: 10/7/2008
This monograph has been modified to include the generic and brand name in many instances.

OVERDOSE

There are no documented cases of overdosage with BiDil (isosorbide dinitrate and hydralazine hcl) .The signs and symptoms of overdosage with BiDil (isosorbide dinitrate and hydralazine hcl) are expected to be those of excessive pharmaco-logic effect and those that may occur with overdosage of either isosorbide dini-trate or hydralazine hydrochloride administered alone.

Acute toxicity: No deaths due to acute poisoning have been reported.

Signs and Symptoms: The signs and symptoms of overdosage with BiDil (isosorbide dinitrate and hydralazine hcl) 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.

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 (isosorbide dinitrate and hydralazine hcl) . 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.

CONTRAINDICATIONS

BiDil (isosorbide dinitrate and hydralazine hcl) is contraindicated in patients who are allergic to organic nitrates.

Last reviewed on RxList: 10/7/2008
This monograph has been modified to include the generic and brand name in many instances.

CLINICAL PHARMACOLOGY

Mechanism of Action

The mechanism of action underlying the beneficial effects of BiDil (isosorbide dinitrate and hydralazine hcl) in the treatment of heart failure has not been established.

Isosorbide dinitrate is a vasodilator affecting both arteries and veins. Its dilator properties result from the release of nitric oxide and the subsequent activation of guanylyl cyclase, and ultimate relaxation of vascular smooth muscle.

Several well-controlled clinical trials have used exercise testing to assess the anti-anginal efficacy of chronically-delivered nitrates.In the large majority of these trials,active agents were no more effective than placebo after 24 hours (or less) of continuous therapy. Attempts to overcome nitrate tolerance by dose escalation,even to doses far in excess of those used acutely,have consistently failed.Only after nitrates have been absent from the body for several hours has response to nitrates been restored.

Hydralazine is a selective dilator of arterial smooth muscle.Animal data suggests that hydralazine may also mitigate tolerance to nitrates.

Pharmacokinetics

Hydralazine

Absorption and Distribution: About 2/3 of a 50-mg dose of 14C-hydralazine HCl 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 (See Metabolism and Elimination). Administration of doses escalating from 75 mg to 1000 mg tid 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.

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.

Metabolism and Elimination: Metabolism is the main route for the elimination of hydralazine. Negligible amounts of unchanged hydralazine are excreted in urine. Hydralazine is metabolized by acetylation,ring oxidation and conjugation with endoge-nous 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

Absorption and Distribution: 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%) due to first-pass metabolism and increases pro-gressively during chronic therapy. Serum concentrations reach their maximum about one hour after ingestion.

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 and Elimination: 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.

Most isosorbide dinitrate is eliminated renally as conjugated metabolites.

BiDil (isosorbide dinitrate and hydralazine hcl)

Absorption and Bioavailability: 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,isosor-bide-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 (isosorbide dinitrate and hydralazine hcl) tablets.

Special Populations

Pediatric: The pharmacokinetics of hydralazine and isosorbide dinitrate,alone or in combination,have not been determined in patients below the age of 18 years.

Geriatric: The pharmacokinetics of hydralazine and isosorbide dinitrate,alone or in combination,have not been determined in patients over 65 years of age.

Renal Impairment: The effect of renal impairment on the pharmacokinetics of hydralazine has not been determined.In a study with 49 hypertensive patients on chronic therapy with hydralazine in daily doses of 25-200 mg,the daily dose of hydralazine in 19 subjects with severely impaired renal function (creatinine clearance 5- 28 mL/min) and in 17 subjects with normal renal function (creatinine clearance >100 mL/min) was not different,suggesting no need for dose adjustment in patients with renal impairment.The dialyzability of hydralazine has not been determined.In three studies,renal insufficiency did not affect the pharmacokinetics of isosorbide dinitrate. 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 (isosorbide dinitrate and hydralazine hcl) .

Gender: There are no studies of gender-dependent effects with hydralazine.In a single dose study with isosorbide dinitrate,no gender-dependent differences in the pharmaco-kinetics of isosorbide dinitrate and its mononitrate metabolites were found.

No pharmacokinetic studies in special populations were conducted with BiDil (isosorbide dinitrate and hydralazine hcl) .

Pharmacokinetic Drug-Drug Interactions

Hydralazine

Administration of hydralazine can increase the exposure to a number of drugs including beta blockers.

In healthy males administered a single oral dose of hydralazine 50 mg and propranolol 1 mg/kg,the Cmax and AUC for propranolol increased by about 143% and 77%, respectively.In healthy subjects administered a single oral dose of hydralazine 50 mg and metoprolol 100 mg,the Cmax and AUC for metoprolol increased by about 50% and 30%,respectively.In pre-eclamptic women,multiple doses of hydralazine 25 mg bid and metoprolol 50 mg bid increased the Cmax and AUC for metoprolol by 88% and 38%,respectively.

In healthy males administered single oral doses of hydralazine 25 mg and either lisino-pril 20 mg or enalapril 20 mg,Cmax and AUC for lisinopril were each increased by about 30%,but enalapril concentrations were unaffected.

Intravenous co-administration of 0.2 mg/kg hydralazine HCl and 40 mg furosemide in Japanese patients with congestive heart failure resulted in a 21% increase in the clearance of furosemide.

Isosorbide Dinitrate

A single dose of 20 mg of isosorbide dinitrate was administered to healthy subjects after pretreatment with 80 mg propranolol tid for 48 hours, resulting in no impact on the pharmacokinetics of isosorbide dinitrate and isosorbide 5-mononitrate.

When single 100-mg oral doses of atenolol were administered 2 hours before isosor-bide dinitrate at a 10-mg dose no differences in the pharmacokinetics of isosorbide dinitrate or its mononitrates were observed.

The vasodilating effects of coadministered isosorbide dinitrate may be additive to those of other vasodilators,especially alcohol when administered concomitantly with isosorbide dinitrate.

BiDil (isosorbide dinitrate and hydralazine hcl)

No pharmacokinetic drug-drug interaction studies were conducted with BiDil (isosorbide dinitrate and hydralazine hcl) .

Pharmacodynamics

The basis for the beneficial clinical effects of BiDil (isosorbide dinitrate and hydralazine hcl) 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.

Clinical Trials

BiDil or a combination of isosorbide dinitrate and hydralazine hydrochloride was studied in two placebo-controlled clinical trials in 1,692 patients with mild to severe heart failure (mostly NYHA class II and III) and one active control trial (vs.enalapril) in 804 patients.

In the multicenter trial V-HeFT I, the combination of hydralazine and isosorbide dinitrate 75 mg/40 mg qid (n=186) was compared to placebo (n=273) in men with impaired cardiac function and reduced exercise tolerance (primarily NYHA class II and III),and on therapy with digitalis glycosides and diuretics. There was no overall significant difference in mortality between the two treatment groups.There was,however,a trend favoring hydralazine and isosorbide dinitrate,which on retrospective analysis, was attributable to an effect in blacks (n=128). Survival in white patients (n=324) was similar on placebo and the combination treatment.

In a second study of mortality,V-HeFT II,the combination of hydralazine and isosorbide dinitrate 75 mg/40 mg qid was compared to enalapril in 804 men with impaired cardiac function and reduced exercise tolerance (NYHA class II and III), and on therapy with digitalis glycosides and diuretics. The combination of hydralazine and isosorbide dini-trate was inferior to enalapril overall,but retrospective analysis showed that the difference was observed in the white population (n=574); there was essentially no difference in the black population (n=215).

Based on these retrospective analyses suggesting an effect on survival in black patients, but showing little evidence of an effect in the white population,a third study was conducted among black patients with heart failure.

The A-HeFT trial evaluated BiDil (isosorbide dinitrate and hydralazine hcl) vs.placebo among 1,050 self-identified black patients (over 95% NYHA class III) at 169 centers in the United States.All patients had stable symptomatic heart failure.Patients were required to have LVEF ≤ 35% or left ventricular internal diastolic dimension > 2.9 cm/m2 plus LVEF < 45%.Patients were maintained on stable background therapy and randomized to BiDil (isosorbide dinitrate and hydralazine hcl) (n=518) or placebo (n=532). BiDil (isosorbide dinitrate and hydralazine hcl) was initiated at 20 mg isosorbide dinitrate/37.5 mg hydralazine hydrochloride three times daily and titrated to a target dose of 40/75 mg three times daily or to the maximum tolerated dose. Patients were treated for up to 18 months.

The randomized population was 60% male,1% NYHA class II, 95% NYHA class III and 4% NYHA class IV,with a mean age of 57 years,and was generally treated with standard treatments for heart failure including diuretics (94%,almost all loop diuretics), beta-blockers (87%), angiotensin converting enzyme inhibitors (ACE-I; 78%), angiotensin II receptor blockers (ARBs; 28%),either ACE-I or ARB (93%),digitalis gly-cosides (62%) and aldosterone antagonists (39%).

The primary end point was a composite score consisting of all-cause mortality,first hospitalization for heart failure,and responses to the Minnesota Living with Heart Failure questionnaire,with the individual components of the composite examined as separate endpoints.The trial was terminated early,at a mean follow-up of 12 months,primarily because of a statistically significant 43% reduction in all-cause mortality in the BiDil (isosorbide dinitrate and hydralazine hcl) -treated group (p=0.012; see Table 1 and Figure 1).The primary endpoint was also statistically in favor of BiDil (isosorbide dinitrate and hydralazine hcl) (p ≤ 0.021).The BiDil (isosorbide dinitrate and hydralazine hcl) -treated group also showed a 39% reduction in the risk of a first hospitalization for heart failure (p<0.001; see Table 1 and Figure 2) and had statistically significant improvement in response to the Minnesota Living with Heart Failure questionnaire,a self-report of the patient's functional status,at most time points (see Figure 3).Patients in both treatment groups had mean baseline questionnaire scores of 51 (out of a possible 105).

Table 1. Results of A-HeFT (Intent-To-Treat Population)

End point BiDil®
N=518
Placebo
N=532
Hazard Ratio
(95% CI)
Risk Reduction with BiDil P-value
Composite score -0.16±1.93 -0.47±2.04 N/A N/A ≤ 0.021
All-cause mortality 6.2% 10.2% 0.57
(0.37,0.89)
43% 0.012
First hospitalization for heart failure 16.4% 24.4% 0.61
(0.46,0.80)
39% <0.001

Kaplan-Meier Plot of Time to Death by All Cause in Black Patietns (A-HeFT) - Illustration

 

Kaplan-Meier Plot of Time to First Hospitalization for Heart Failure In Black Patietns (A-HeFT) - Illustration

Change in Minnesota Living with Heart Failure Score - Illustration

Effects on survival and hospitalization for heart failure were similar in subgroups by age,gender,baseline disease,and use of concomitant medications,as shown in Figure 4.

Figure 4: Results for Demographic, Baseline Medication and Clinical Charateristic Subgroups In Black Patients (A-HeFT)

Results for Demographic, Baseline Medication and Clinical Charateristic Subgroups In Black Patients - Illustration

Patients treated with BiDil (isosorbide dinitrate and hydralazine hcl) in the A-HeFT study had randomly measured blood pressures on average 3/3 mmHg lower than did patients on placebo.The contri-bution of the difference in blood pressure to the overall outcome difference is unknown.Whether both hydralazine and isosorbide dinitrate contribute to the overall outcome difference has not been studied in outcome trials. Isosorbide dinitrate and hydralazine have not been systematically studied for the treatment of heart failure as separate agents,and neither drug is indicated for heart failure.

Last reviewed on RxList: 10/7/2008
This monograph has been modified to include the generic and brand name in many instances.

PATIENT INFORMATION

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 (isosorbide dinitrate and hydralazine hcl) , 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 (isosorbide dinitrate and hydralazine hcl) if headache continues with repeated dosing. Treatment of emerging headache was managed with acetaminophen in some clinical trial patients.

Treatment with BiDil (isosorbide dinitrate and hydralazine hcl) 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 (isosorbide dinitrate and hydralazine hcl) 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 (isosorbide dinitrate and hydralazine hcl) 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 (isosorbide dinitrate and hydralazine hcl) may produce an extreme drop in blood pressure that may result in fainting or may provoke chest pain or a heart attack.

Last reviewed on RxList: 7/14/2005
This monograph has been modified to include the generic and brand name in many instances.

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PATIENT INFORMATION

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 (isosorbide dinitrate and hydralazine hcl) , 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 (isosorbide dinitrate and hydralazine hcl) if headache continues with repeated dosing. Treatment of emerging headache was managed with acetaminophen in some clinical trial patients.

Treatment with BiDil (isosorbide dinitrate and hydralazine hcl) 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 (isosorbide dinitrate and hydralazine hcl) 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 (isosorbide dinitrate and hydralazine hcl) 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 (isosorbide dinitrate and hydralazine hcl) may produce an extreme drop in blood pressure that may result in fainting or may provoke chest pain or a heart attack.

Last reviewed on RxList: 7/14/2005
This monograph has been modified to include the generic and brand name in many instances.

Disclaimer

BiDil Consumer

IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

ISOSORBIDE DINITRATE/HYDRALAZINE - ORAL

(EYE-soe-SOR-bide dye-NYE-trate/hye-DRAL-a-zeen)

COMMON BRAND NAME(S): Bidil

USES: This medication contains 2 drugs (hydralazine and isosorbide dinitrate) and is used with other medications to treat heart failure. Both drugs are known as vasodilators. They work by relaxing and widening blood vessels so blood can flow more easily to the heart.

HOW TO USE: Take this medication by mouth, usually 3 times daily or as directed by your doctor.

The dosage is based on your medical condition and response to treatment. Your doctor may start you at a low dose and gradually increase your dose. Follow your doctor's instructions carefully.

Use this medication regularly to get the most benefit from it. To help you remember, take it at the same times each day.

Do not stop taking this medication without consulting your doctor. Some conditions may become worse when the drug is suddenly stopped. Your dose may need to be gradually decreased.

Tell your doctor if your condition worsens.

Disclaimer

BiDil Consumer (continued)

SIDE EFFECTS: Headache, dizziness, lightheadedness, nausea, and flushing may occur as your body adjusts to the medication. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Headache is often a sign that this medication is working. Your doctor may recommend treating headaches with an over-the-counter pain reliever (such as acetaminophen). If the headaches continue or become severe, tell your doctor promptly.

To reduce the risk of dizziness and lightheadedness, get up slowly when rising from a sitting or lying position.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

This medication may infrequently cause nerve problems. Tell your doctor promptly if you experience numbness or tingling. Your doctor may recommend a vitamin B6 supplement (pyridoxine).

Tell your doctor immediately if any of these unlikely but serious side effects occur: severe tiredness, aching/swollen joints, rash on nose and cheeks, swollen glands, change in the amount of urine, bloody/pink urine, signs of infection (such as fever, chills, persistent sore throat), easy bruising/bleeding, fainting, fast/irregular/pounding heartbeat.

Seek immediate medical attention if this rare but serious side effect occurs: chest/jaw/left arm pain.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any of the following symptoms of a serious allergic reaction: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US -

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

Read the BiDil (isosorbide dinitrate and hydralazine hcl) Side Effects Center for a complete guide to possible side effects »

PRECAUTIONS: Before taking this medication, tell your doctor or pharmacist if you are allergic to either isosorbide dinitrate or hydralazine; or to similar drugs (such as nitroglycerin); or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: other heart problems (such as recent heart attack, rheumatic heart disease of the mitral valve), previous stroke, low blood pressure, blood vessel problems, loss of too much body water (dehydration), recent head injury, anemia, kidney problems.

This drug may make you dizzy. Do not drive, use machinery, or do any activity that requires alertness until you are sure you can perform such activities safely. Limit alcoholic beverages.

Before having surgery, tell your doctor or dentist that you are using this medication.

Older adults may be more sensitive to the side effects of this drug, especially dizziness and lightheadedness, which could increase the risk of falls.

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

It is not known whether this drug passes into breast milk or if it may harm a nursing infant. Consult your doctor before breast-feeding.

Disclaimer

BiDil Consumer (continued)

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

This drug should not be used with the following medications because very serious (possibly fatal) interactions may occur: drugs to treat erectile dysfunction (such as sildenafil, tadalafil, vardenafil).

If you are currently using any of these medications listed above, tell your doctor or pharmacist before starting this medication.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: rosiglitazone, certain drugs to treat migraine headaches (ergot alkaloids such as ergotamine), drugs that lower blood pressure (including alpha blockers such as tamsulosin), MAO inhibitors (isocarboxazid, linezolid, methylene blue, moclobemide, phenelzine, procarbazine, rasagiline, selegiline, tranylcypromine).

Check the labels on all your medicines (such as cough-and-cold products, diet aids, or NSAIDs such as ibuprofen, naproxen) because they may contain ingredients that could worsen your heart failure. Ask your pharmacist for more details.

This medication may interfere with certain laboratory tests (including blood cholesterol levels), possibly causing false test results. Make sure laboratory personnel and all your doctors know you use this drug.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: slow heartbeat, vision changes, severe nausea/vomiting, sweating, cold/clammy skin, bluish fingers/toes/lips, chest/jaw/left arm pain.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (such as complete blood count, blood pressure monitoring) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

Lifestyle changes such as exercise and dietary changes may help this drug work better. Talk to your doctor or pharmacist about lifestyle changes that might benefit you.

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature at 77 degrees F (25 degrees C) away from light and moisture. Brief storage between 59-86 degrees F (15-30 degrees C) is permitted. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For information about enrolling in MedicAlert, call 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised March 2012. Copyright(c) 2012 First Databank, Inc.

BiDil Patient Information Including Side Effects

Brand Names: BiDil

Generic Name: hydralazine and isosorbide dinitrate (Pronunciation: hi dral LA zeen and I so zor bi da din eye treyt)

What is hydralazine and isosorbide dinitrate (BiDil)?

Hydralazine is a vasodilator. It relaxes (widens) veins and arteries, which makes it easier for your heart to pump.

Isosorbide dinitrate is in a class of drugs called nitrates. Isosorbide dinitrate dilates (widens or relaxes) blood vessels (arteries and veins). When blood vessels are dilated, it is easier for the heart to pump. Also, more blood, which is rich in oxygen, can flow to the heart.

Hydralazine and isosorbide dinitrate is used to treat heart failure.

Hydralazine and isosorbide dinitrate may also be used for purposes other than those listed in this medication guide.

What are the possible side effects of hydralazine and isosorbide dinitrate (BiDil)?

If you experience any of the following serious side effects, stop taking hydralazine and isosorbide dinitrate and seek emergency medical attention:

  • an allergic reaction (difficulty breathing; closing of your throat; swelling of your lips, tongue, or face; or hives);
  • blurred vision and dry mouth;
  • irregular heartbeat; or
  • blood in your urine or stools;
  • numbness, tingling, pain, or weakness of your arms or legs;
  • fainting.

Other, less serious side effects may be more likely to occur. If you experience any of the following side effects, continue to take isosorbide and talk to your doctor:

  • headache or dizziness;
  • flushing (redness of the face, neck and chest);
  • nausea or vomiting;
  • fast heartbeat;
  • swollen ankles; or
  • weakness.

Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome. You may report side effects to FDA at 1-800-FDA-1088.

Read the BiDil (isosorbide dinitrate and hydralazine hcl) Side Effects Center for a complete guide to possible side effects »

What is the most important information I should know about hydralazine and isosorbide dinitrate (BiDil)?

You may develop a headache because of this medicine, but do not stop taking it. Take aspirin or acetaminophen to treat the headache. Ask your doctor which is best for you. This side effect usually goes away with continued hydralazine and isosorbide dinitrate treatment.

Do not stop taking hydralazine and isosorbide dinitrate suddenly. Talk to your doctor before you stop taking the drug completely.

Do not drink alcohol while taking this medication.

Use caution when driving, operating machinery, or performing other hazardous activities. Hydralazine and isosorbide dinitrate may cause dizziness. If you experience dizziness, avoid these activities.

Side Effects Centers

BiDil Patient Information including How Should I Take

What should I discuss with my healthcare provider before taking hydralazine and isosorbide dinitrate (BiDil)?

Before taking this medication, tell your doctor if you

  • have low blood pressure;
  • have had a stroke, a transient ischemic attack (TIA, or mini-stroke), or a serious head injury;
  • have anemia;
  • have an allergy to nitrates;
  • have closed-angle glaucoma;
  • suffer from migraines;
  • have systemic lupus erythematosus;
  • have high levels of cholesterol or triglycerides (types of fat) in your blood;
  • have pulmonary hypertension;
  • have kidney disease; or
  • have liver disease.

You may not be able to take hydralazine and isosorbide dinitrate, or you may require a dosage adjustment or special monitoring during therapy.

Hydralazine and isosorbide dinitrate is in the FDA pregnancy category C. This means that it is not known whether hydralazine and isosorbide dinitrate will harm an unborn baby. Do not take this medication without first talking to your doctor if you are pregnant.

It is also not known whether hydralazine or isosorbide dinitrate pass into breast milk. Do not take this medication without first talking to your doctor if you are breast-feeding a baby.

If you are over 60 years of age, you may be more likely to experience dizziness from hydralazine. You may require a lower dose or special monitoring during therapy.

How should I take hydralazine and isosorbide dinitrate (BiDil)?

Take hydralazine and isosorbide dinitrate exactly as directed by your doctor. If you do not understand these directions, ask your pharmacist, nurse, or doctor to explain them to you.

Take each dose with a full glass of water.

Do not stop taking hydralazine and isosorbide dinitrate suddenly. Talk to your doctor before you stop taking the drug completely.

Store this medication at room temperature away from moisture and heat.

Side Effects Centers

BiDil Patient Information including If I Miss a Dose

What happens if I miss a dose (BiDil)?

Take the missed dose as soon as you remember. If your next regularly scheduled dose is within 2 hours, skip the dose you missed and take only the next dose. Do Not take a double dose of this medication.

What happens if I overdose (BiDil)?

Seek emergency medical attention.

Symptoms of an hydralazine and isosorbide dinitrate overdose include a severe throbbing headache, difficult or slow breathing, muscle cramps, nausea, vomiting, diarrhea, fever, dizziness, fainting, an irregular or slow heart beat, changes in vision, confusion, flushing, and seizures.

What should I avoid while taking hydralazine and isosorbide dinitrate (BiDil)?

Use caution when driving, operating machinery, or performing other hazardous activities. Hydralazine and isosorbide dinitrate may cause dizziness. If you experience dizziness, avoid these activities. Also, stand up slowly from a lying or sitting position.

Avoid alcohol. Alcohol also widens your blood vessels, and it can cause very low blood pressure, dizziness, and drowsiness. If you consume alcohol, you could endanger yourself or others.

Do not stop taking hydralazine and isosorbide dinitrate suddenly. Talk to your doctor before you stop taking the drug completely.

What other drugs will affect hydralazine and isosorbide dinitrate (BiDil)?

Before taking hydralazine and isosorbide dinitrate, tell your doctor if you are taking any of the following medicines:

  • dihydroergotamine (D.H.E. 45); or
  • any other heart medicines, especially those used to treat high blood pressure or irregular heartbeats.

You may require a dosage adjustment or special monitoring during your treatment if you are taking any of the medicines listed above.

Drugs other than those listed here may also interact with hydralazine and isosorbide dinitrate or affect your condition. Talk to your doctor and pharmacist before taking any prescription or over-the-counter medicines.

Where can I get more information?

Your pharmacist has additional information about hydralazine and isosorbide dinitrate written for health professionals that you may read.


Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

Copyright 1996-2012 Cerner Multum, Inc. Version: 2.03. Revision date: 12/15/2010.

Your use of the content provided in this service indicates that you have read,understood and agree to the End-User License Agreement,which can be accessed by clicking on this link.

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Side Effects Centers

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