BiDil tablets contain Isosorbide dinitrate and Hydralazine. Both the drugs act as direct vasodilators and are used in patients with heart failure.
Isosorbide dinitrate and hydralazine Uses:
-
Heart failure with reduced ejection fraction (HFrEF):
- Used as an adjunct to standard therapy for the treatment of heart failure in self-identified African-American patients.
Note:
- Based on the American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guidelines for the management of heart failure, a combination of isosorbide dinitrate & hydralazine is effective and recommended as additional therapy to optimal medical therapy for self-identified African-American patients with persistent NYHA class III or IV HFrEF or for patients who are intolerant to an ACE inhibitor or an ARB.
- Some experts have recommended isosorbide dinitrate and hydralazine in combination in addition to optimal guideline-directed medical therapy for black and nonblack patients with persistent NYHA class III or IV HFrEF, particularly for those who are in a state of low output or hypertension, or for patients who become intolerant to an ACE inhibitor, ARB, or angiotensin II-neprilysin inhibitor.
Isosorbide dinitrate and Hydralazine (BiDil) Dose in Adults:
Isosorbide dinitrate and Hydralazine (BiDil) Dose in the treatment of Heart failure with reduced ejection fraction (HFrEF):
Note: As an additional therapy for persistent NYHA class III or IV HFrEF despite optimal medical therapies or for patients who become intolerant to an ACE inhibitor, ARB, or angiotensin II-neprilysin inhibitor.
- Oral: Initial: One tablet (containing 20 mg of isosorbide dinitrate and 37.5 mg of hydralazine) thrice a day; dose should be titrated in 2 to 4 weeks to a maximum of 2 tablets (containing a total of 40 mg of isosorbide dinitrate and 75 mg of hydralazine) thrice a day.
Note: Use of hydralazine thrice a day and isosorbide dinitrate thrice a day as separate components may also be considered rather than this combination tablet.
Use in Children:
Not indicated.
Pregnancy Risk Category: C
- Hydralazine crosses the placenta.
Use during breastfeeding:
- Breast milk contains hydralazine.
- The manufacturer suggests that the risks of infant exposure, benefits of breastfeeding to the baby, and the benefits to the mother be considered when making decisions about breastfeeding during therapy.
- For more information, see individual monographs.
Dose in Kidney Disease:
No dosage adjustments are provided in the manufacturer’s labeling (has not been studied).
Dose in Liver disease:
No dosage adjustments are provided in the manufacturer’s labeling (has not been studied).
In the A-HeFT Study using the combination isosorbide dinitrate/hydralazine product, the following events were reported. See individual drug monographs for additional information.
Common Side Effects of Isosorbide dinitrate and hydralazine (BiDil):
-
Cardiovascular:
- Chest pain
-
Central nervous system:
- Headache
- Dizziness
-
Neuromuscular & skeletal:
- Weakness
Less Common Side Effects of Isosorbide dinitrate and hydralazine (BiDil):
-
Cardiovascular:
- Hypotension
- Palpitations
- Ventricular Tachycardia
- Tachycardia
-
Central Nervous System:
- Paresthesia
- Drowsiness
- Malaise
-
Dermatologic:
- Alopecia
- Diaphoresis
-
Endocrine & Metabolic:
- Hyperglycemia
- Hyperlipidemia
- Hypercholesterolemia
-
Gastrointestinal:
- Nausea
- Vomiting
- Cholecystitis
-
Hypersensitivity:
- Angioedema
- Hypersensitivity Reaction
-
Neuromuscular & Skeletal:
- Arthralgia
- Myalgia
- Tendon Disease
-
Ophthalmic:
- Amblyopia
-
Respiratory:
- Bronchitis
- Rhinitis
- Sinusitis
Contraindications to Isosorbide dinitrate and hydralazine (BiDil):
- Hypersensitivity to organic nitrates
- Hypersensitivity to any ingredient in the formulation
- Use of phosphodiesterase-5 inhibitors in conjunction with avanafil (eg sildenafil), tadalafil and vardenafil).
- Use of riociguat concurrently
Warnings and precautions
-
Drug-induced lupus-like symptoms:
- Hydralazine may cause a drug-induced lupus-like condition. This is more common with higher doses and a longer duration of treatment.
-
Fluid/sodium retention:
- Hydralazine can cause fluid retention and sodium retention, which may require an increased or additional dosage of diuretics.
-
Hypotension/bradycardia:
- Hypotension can be severe; hypotension can also cause paradoxical bradycardia or increased angina pectoris.
- Avoid excessive salt or volume loss and/or hypotension.
- It is important to exercise extreme caution when using it with inferior-wall MI or suspected right ventricular Infarctions.
- Even small amounts can cause hypotension, which is more severe in upright positions.
-
The intracranial pressure rose:
- An increase in intracranial pressure could be caused by nitrates, or worsen the clinical outcome for patients with neurologic injuries (eg intracranial hemorhage, trauma brain injury).
-
Peripheral neuritis:
- Hydralazine's anti-pyridoxine action has been linked to peripheral neuritis, such as paresthesia, numbness and tingling.
- These symptoms should be accompanied by pyridoxine therapy.
-
Cardiovascular disease
- Patients with coronary artery disease (CAD) should be cautious. Hydralazine can cause tachycardia or hypotension, which can lead to myocardial ischemia.
-
Hypertrophic cardiomyopathy, (HCM)
- Patients with HCM should avoid nitrates. They can reduce preload, which can lead to hypotension, syncope, and/or worsening heart failure.
-
Hypertension in the lungs:
- It is important to exercise caution when using it for pulmonary hypertension because of the possibility of hypotension.
Isosorbide dinitrate and hydralazine: Drug Interaction
|
Risk Factor C (Monitor therapy) |
|
|
Alcohol (Ethyl) |
May enhance the vasodilatory effect of Vasodilators (Organic Nitrates). |
|
Alfuzosin |
May enhance the hypotensive effect of Blood Pressure Lowering Agents. |
|
Amphetamines |
May diminish the antihypertensive effect of Antihypertensive Agents. |
|
Antipsychotic Agents (Second Generation [Atypical]) |
Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). |
|
Aprepitant |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
|
Barbiturates |
May enhance the hypotensive effect of Blood Pressure Lowering Agents. |
|
Benperidol |
May enhance the hypotensive effect of Blood Pressure Lowering Agents. |
|
Blood Pressure Lowering Agents |
May enhance the hypotensive effect of HypotensionAssociated Agents. |
|
Bosentan |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). |
|
Brigatinib |
May diminish the antihypertensive effect of Antihypertensive Agents. Brigatinib may enhance the bradycardic effect of Antihypertensive Agents. |
|
Brimonidine (Topical) |
May enhance the hypotensive effect of Blood Pressure Lowering Agents. |
|
Clofazimine |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
|
CYP3A4 Inducers (Moderate) |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). |
|
CYP3A4 Inhibitors (Moderate) |
May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). |
|
Dapoxetine |
May enhance the orthostatic hypotensive effect of HydrALAZINE. |
|
Dapsone (Topical) |
May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. |
|
Deferasirox |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). |
|
Dexmethylphenidate |
May diminish the therapeutic effect of Antihypertensive Agents. |
|
Diazoxide |
May enhance the hypotensive effect of Blood Pressure Lowering Agents. |
|
DULoxetine |
Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. |
|
Duvelisib |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
|
Erdafitinib |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). |
|
Erdafitinib |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
|
Fosaprepitant |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
|
Fosnetupitant |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
|
Herbs (Hypertensive Properties) |
May diminish the antihypertensive effect of Antihypertensive Agents. |
|
Herbs (Hypotensive Properties) |
May enhance the hypotensive effect of Blood Pressure Lowering Agents. |
|
Hypotension-Associated Agents |
Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. |
|
Ivosidenib |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). |
|
Larotrectinib |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
|
Levodopa-Containing Products |
Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Containing Products. |
|
Local Anesthetics |
Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Local Anesthetics. Specifically, the risk for methemoglobinemia may be increased. |
|
Lormetazepam |
May enhance the hypotensive effect of Blood Pressure Lowering Agents. |
|
Methylphenidate |
May diminish the antihypertensive effect of Antihypertensive Agents. |
|
Molsidomine |
May enhance the hypotensive effect of Vasodilators (Organic Nitrates). |
|
Molsidomine |
May enhance the hypotensive effect of Blood Pressure Lowering Agents. |
|
Naftopidil |
May enhance the hypotensive effect of Blood Pressure Lowering Agents. |
|
Netupitant |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
|
Nicergoline |
May enhance the hypotensive effect of Blood Pressure Lowering Agents. |
|
Nicorandil |
May enhance the hypotensive effect of Blood Pressure Lowering Agents. |
|
Nitric Oxide |
May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Combinations of these agents may increase the likelihood of significant methemoglobinemia. |
|
Nitroprusside |
Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. |
|
Nonsteroidal Anti-Inflammatory Agents |
May diminish the antihypertensive effect of HydrALAZINE. |
|
Palbociclib |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
|
Pentoxifylline |
May enhance the hypotensive effect of Blood Pressure Lowering Agents. |
|
Pholcodine |
Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. |
|
Prilocaine |
Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Prilocaine. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Management: Monitor patients for signs of methemoglobinemia (e.g., hypoxia, cyanosis) when prilocaine is used in combination with other agents associated with development of methemoglobinemia. Avoid lidocaine/prilocaine in infants receiving such agents. |
|
Prostacyclin Analogues |
May enhance the hypotensive effect of Blood Pressure Lowering Agents. |
|
Quinagolide |
May enhance the hypotensive effect of Blood Pressure Lowering Agents. |
|
Rilmenidine |
Vasodilators (Organic Nitrates) may enhance the hypotensive effect of Rilmenidine. |
|
Rosiglitazone |
Vasodilators (Organic Nitrates) may enhance the adverse/toxic effect of Rosiglitazone. Specifically, a greater risk of ischemia and other adverse effects has been associated with this combination in some pooled analyses. |
|
Sarilumab |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). |
|
Siltuximab |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). |
|
Simeprevir |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
|
Sodium Nitrite |
Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Sodium Nitrite. Combinations of these agents may increase the likelihood of significant methemoglobinemia. |
|
Tocilizumab |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). |
|
Yohimbine |
May diminish the antihypertensive effect of Antihypertensive Agents. |
|
Risk Factor D (Consider therapy modification) |
|
|
Amifostine |
Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. |
|
CYP3A4 Inducers (Strong) |
May increase the metabolism of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. |
|
CYP3A4 Inhibitors (Strong) |
May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). |
|
Dabrafenib |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). |
|
Enzalutamide |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. |
|
Lorlatinib |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. |
|
MiFEPRIStone |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. |
|
Mitotane |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. |
|
Obinutuzumab |
May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. |
|
Stiripentol |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. |
|
Risk Factor X (Avoid combination) |
|
|
Bromperidol |
Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Bromperidol may diminish the hypotensive effect of Blood Pressure Lowering Agents. |
|
Conivaptan |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
|
Fusidic Acid (Systemic) |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
|
Idelalisib |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
|
Phosphodiesterase 5 Inhibitors |
May enhance the vasodilatory effect of Vasodilators (Organic Nitrates). |
|
Riociguat |
Vasodilators (Organic Nitrates) may enhance the hypotensive effect of Riociguat. |
Monitoring parameters:
- Blood pressure (standing and sitting/supine)
- Pulse rate
- Blood CP
- Antinuclear antibody (ANA) titers (in case of symptoms of SLE)
How to administer Isosorbide dinitrate and Hydralazine (BiDil)?
Heart failure with reduced ejection fraction (HFrEF):
- Used in the treatment of heart failure as an adjunct to standard therapy in self-identified African-American patients.
- Based on the American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guidelines for the management of heart failure, a combination of isosorbide dinitrate & hydralazine is effective and recommended as additional therapy to optimal medical therapy for self-identified African-American patients with persistent NYHA class III or IV HFrEF or for patients who are intolerant to an ACE inhibitor or an ARB.
- Some experts have recommended isosorbide dinitrate and hydralazine in combination in addition to optimal guideline-directed medical therapy for black and nonblack patients with persistent NYHA class III or IV HFrEF, particularly for those who are in a state of low output or hypertension, or for patients who become intolerant to an ACE inhibitor, ARB, or angiotensin II-neprilysin inhibitor.
Mechanism of action of Isosorbide dinitrate and Hydralazine (BiDil):
Hydralazine causes Direct arteriolar vasodilation (with little effect on veins) resulting in decreased systemic resistance.
Isosorbide Dinitrate:
- It stimulates intracellular cyclic–GMP, which results in relaxation of the vascular smooth muscles of both the arterial and the venous vasculature.
- However, it has more significant effects on the veins.
- It reduces cardiac oxygen demand by decreasing preload (left-ventricular end-diastolic tension); it may also cause a slight reduction in afterload.
- The collateral flow to the ischemic areas is also improved by dilation of coronary arteries.
- These values were obtained from healthy adults who received isosorbide diuretrate 40 mg and hydralazine 75m mg.
Also see individual drug monographs.
Half-life elimination:
- Hydralazine: 4 hours; Isosorbide dinitrate: 2 hours
Time to peak, plasma:
- 1 hour (both hydralazine and isosorbide dinitrate)
International Brand Names of Isosorbide dinitrate and hydralazine:
- BiDil
Isosorbide dinitrate and hydralazine Brand Names in Pakistan:
No Brands Available in Pakistan.
