Schedule H

Oral

• Tablets (immediate-release): 10 mg, 20 mg

• Tablets (sustained-release/extended-release): 30 mg, 60 mg, 120 mg

Note: Isosorbide mononitrate (ISMN) is the active metabolite of isosorbide dinitrate. Unlike isosorbide dinitrate, ISMN does not undergo significant first-pass hepatic metabolism, resulting in nearly 100% bioavailability.

INDICATIONS + DOSING — FOR CLINICIAN USE ONLY

Primary Indications (Approved / Standard in India):

1. Chronic Stable Angina Pectoris (Prophylaxis)

Immediate-Release Formulation:

Parameter Dose Clinical Notes

Starting dose 20 mg orally twice daily Give at 8 AM and 2 PM to allow nitrate-free interval

Titration Increase to 20 mg three times daily if needed Maintain asymmetric dosing (e.g., 8 AM, 1 PM, 6 PM)

Usual maintenance dose 20–40 mg twice daily Ensure 10–14 hour nitrate-free interval daily

Maximum dose 120 mg/day in divided doses

Sustained-Release Formulation:

Parameter Dose Clinical Notes

Starting dose 30–60 mg orally once daily in the morning Do NOT crush or chew SR tablets

Titration Increase to 60–120 mg once daily after 1 week if needed Based on symptom control

Usual maintenance dose 60–120 mg once daily Single morning dose preferred

Maximum dose 120 mg/day

Critical Notes:

• ISMN is for prophylaxis only — does NOT abort acute angina attacks (use sublingual GTN for that)

• Nitrate-free interval (10–14 hours daily) is essential to prevent tolerance development

• Morning dosing preferred to provide protection during active daytime hours while allowing nocturnal nitrate-free period

1. Heart Failure with Reduced Ejection Fraction (HFrEF) — Adjunctive Therapy

Parameter Dose Clinical Notes

Starting dose 10–20 mg orally twice daily Start lower if hypotensive

Titration Increase by 10–20 mg/dose every 3–7 days Monitor BP closely

Usual maintenance dose 20–40 mg three times daily Often combined with hydralazine

Maximum dose 120 mg/day

Clinical Note: Isosorbide-hydralazine combination is particularly beneficial in patients intolerant to ACE inhibitors/ARBs (e.g., renal impairment, hyperkalaemia) or as add-on therapy in African American patients (A-HeFT trial evidence; used in Indian specialist practice in selected cases). Specialist-initiated therapy.

Secondary Indications — Adults (Off-label, if any)

1. Variant (Prinzmetal's/Vasospastic) Angina — OFF-LABEL

Parameter Details

Indication Coronary artery spasm causing angina at rest

Dose 20–40 mg twice daily (IR) OR 60 mg once daily (SR)

Duration Long-term prophylaxis

Specialist only Yes — Cardiology

Evidence basis Based on pathophysiology of coronary vasospasm; calcium channel blockers remain first-line; nitrates as adjunct; Indian cardiology practice

1. Achalasia (Symptomatic relief before definitive therapy) — OFF-LABEL

Parameter Details

Indication Lower oesophageal sphincter relaxation for symptom relief

Dose 5–10 mg sublingually (using crushed immediate-release tablet) 15–30 minutes before meals

Duration Short-term; bridge to definitive therapy (pneumatic dilation/surgery)

Specialist only Yes — Gastroenterology

Evidence basis Limited data; used as temporizing measure; isosorbide dinitrate more commonly used for this indication

PAEDIATRIC DOSING (Specialist Only)

Primary Indications:

NOT APPROVED for routine paediatric use in India.

• No standardised paediatric dosing in Indian guidelines

• Safety and efficacy not established in children

• No paediatric-specific formulation available in India

Secondary Indications — Paediatrics (Off-label, if any)

Pulmonary Arterial Hypertension (Adjunct therapy) — OFF-LABEL

Parameter Details

Indication Adjunctive vasodilator therapy in paediatric pulmonary hypertension

Dose 0.5–1 mg/kg/day orally in 1–2 divided doses

Maximum dose 20 mg/day

Specialist only Yes — Paediatric cardiology

Evidence basis Limited international data; used in Indian tertiary centres as adjunct when first-line therapies insufficient

Monitoring:

• Blood pressure (sitting and standing in older children)

• Heart rate

• Oxygen saturation

• Signs of hypotension (dizziness, syncope)

Not recommended below 12 years of age except under specialist paediatric cardiology supervision in tertiary centres with appropriate monitoring facilities.

ISMN bioavailability is already ~100%; hepatic impairment primarily affects elimination rather than activation.

• Known hypersensitivity to isosorbide mononitrate, other nitrates, or any excipient

• Concurrent use with phosphodiesterase-5 (PDE5) inhibitors (sildenafil, tadalafil, vardenafil, avanafil) — risk of severe life-threatening hypotension

• Concurrent use with soluble guanylate cyclase stimulators (riociguat)

• Acute myocardial infarction with low filling pressures (cardiogenic shock, left ventricular failure with low filling pressures)

• Severe hypotension (systolic BP <90 mmHg)

• Acute circulatory failure or shock

• Hypovolaemia

• Severe anaemia

• Raised intracranial pressure (head trauma, cerebral haemorrhage)

• Constrictive pericarditis

• Pericardial tamponade

• Hypertrophic obstructive cardiomyopathy

• Severe aortic or mitral stenosis

• Orthostatic hypotension — particularly in elderly, volume-depleted, or those on antihypertensives

• Tolerance development — ensure nitrate-free interval of 10–14 hours daily

• Alcohol consumption — potentiates hypotension; counsel patients

• Hypertrophic cardiomyopathy (non-obstructive) — may worsen symptoms

• Hypothyroidism or malnutrition — may have exaggerated response

• Glaucoma — theoretically may raise intraocular pressure (minimal clinical significance with oral use)

• Recent use of PDE5 inhibitors — wait at least 24 hours after sildenafil/vardenafil or 48 hours after tadalafil before initiating nitrates

• Abrupt discontinuation — may precipitate rebound angina; taper if stopping

• Concomitant antihypertensive therapy — additive hypotensive effects

Aspect Recommendation

Risk category Limited human data; animal studies show no teratogenicity at therapeutic doses

Use in pregnancy Use only if clearly indicated and benefit outweighs risk

Preferred alternatives Beta-blockers (labetalol, metoprolol) or calcium channel blockers (nifedipine) for angina in pregnancy per Indian obstetric practice

When to use Refractory angina not controlled with preferred agents; specialist cardio-obstetric input

Monitoring Maternal blood pressure (avoid hypotension → uteroplacental insufficiency); fetal growth and wellbeing

Aspect Recommendation

Compatibility Likely compatible; limited data available

Drug levels in milk Expected to be low based on pharmacokinetic properties

Preferred alternatives Beta-blockers (metoprolol, labetalol) preferred if anti-anginal required during lactation

Recommendations May use during lactation if clearly indicated; monitor infant

Infant monitoring Feeding pattern; signs of hypotension (lethargy, poor feeding); weight gain

Aspect Recommendation

Starting dose 10 mg once or twice daily (immediate-release); 30 mg once daily (sustained-release)

Titration Slower titration; increase at weekly intervals

Special considerations Elderly are more susceptible to hypotensive effects; may have impaired baroreceptor reflexes

Extra risks Orthostatic hypotension leading to falls and fractures; dizziness; syncope; impaired cerebral perfusion

Monitoring Blood pressure (sitting and standing); symptoms of postural hypotension; assess fall risk

Drug Interaction Management

Phosphodiesterase-5 inhibitors (sildenafil, tadalafil, vardenafil, avanafil) Severe, potentially life-threatening hypotension due to synergistic vasodilation Contraindicated; wait ≥24 hours after sildenafil/vardenafil or ≥48 hours after tadalafil before using nitrates

Riociguat (sGC stimulator) Severe hypotension Contraindicated

Other nitrates (GTN, ISDN) Additive hypotension; no therapeutic advantage Avoid concurrent use of multiple nitrate preparations

Alpha-blockers (prazosin, terazosin, tamsulosin) Significant additive hypotension Avoid if possible; if combined, use with extreme caution; start nitrate at lowest dose

Drug Interaction Management

Antihypertensives (beta-blockers, CCBs, ACE inhibitors, ARBs, diuretics) Additive hypotensive effect Monitor BP; may need dose adjustment of either drug

Tricyclic antidepressants Enhanced orthostatic hypotension Monitor for postural symptoms

Antipsychotics (phenothiazines) Additive hypotension Monitor BP

Alcohol Potentiates vasodilation and hypotension Counsel patients to avoid or limit alcohol

Dihydropyridine CCBs (amlodipine, nifedipine) Additive vasodilation; may be therapeutic but can cause excessive hypotension Use combination with caution; monitor BP

Heparin Nitrates may reduce anticoagulant effect of heparin (limited clinical significance) Monitor aPTT if concerned

Aspirin (high-dose) May increase nitrate levels; clinical significance uncertain Standard antiplatelet doses unlikely to be problematic

• Headache (most common; up to 60% initially; usually decreases with continued use)

• Dizziness and lightheadedness

• Flushing

• Orthostatic hypotension

• Tachycardia (reflex)

• Nausea

• Weakness and fatigue

• Application site reactions (if using transdermal — not applicable for oral ISMN)

Note: Headache is dose-related and usually diminishes after 1–2 weeks of therapy; paracetamol may be used for symptomatic relief initially.

Adverse Effect Clinical Notes

Severe hypotension May cause syncope, collapse; more likely in volume-depleted, elderly, or with concurrent antihypertensives; discontinue and provide supportive care

Reflex tachycardia May paradoxically worsen angina in some patients

Methemoglobinaemia Very rare; with very high doses or in susceptible individuals (G6PD deficiency); presents as cyanosis, dyspnoea; treat with methylene blue

Syncope May lead to falls and injuries, especially in elderly

Rebound angina Can occur with abrupt discontinuation after prolonged use; taper gradually

Tolerance Loss of antianginal efficacy with continuous exposure; prevented by nitrate-free interval

Action: Discontinue nitrate and provide supportive care (IV fluids, leg elevation) if severe hypotension occurs. Avoid vasopressors if possible.

After initiation/dose change Blood pressure and heart rate within 1–2 weeks; assess headache severity and tolerance; symptom diary for angina frequency

Long-term Regular BP monitoring; assess angina control; ensure adherence to nitrate-free interval; reassess continued need; evaluate for tolerance development

Immediate-Release:

• Monotrate (Sun Pharma)

• Ismo (Pfizer)

• Isomonit (Cipla)

• Imdur IR (Various)

Sustained-Release/Extended-Release:

• Imdur (AstraZeneca) — 30 mg, 60 mg

• Monotrate OD (Sun Pharma)

• Ismo Retard (Pfizer)

• Isonorm SR (Abbott)

• Monit SR (Various)

FDC Note: Some FDCs with aspirin are available but not commonly used.

• Listed in NLEM 2022 (10 mg, 20 mg tablets)

• NPPA price ceiling applicable for scheduled strengths

• Available through government supply at public health facilities

1. Nitrate-free interval is non-negotiable — maintain 10–14 hour nitrate-free period daily (typically overnight) to prevent tolerance. For once-daily SR formulations, give in the morning; for twice-daily IR formulations, use asymmetric dosing (e.g., 8 AM and 2 PM, NOT 8 AM and 8 PM).

1. Headache management — headache is extremely common initially (up to 60%) but typically diminishes within 1–2 weeks; reassure patients and offer paracetamol for symptomatic relief; do not discontinue prematurely.

1. Not for acute angina — ISMN is purely prophylactic; patients must have sublingual GTN for breakthrough/acute attacks. Educate patients on the difference.

1. PDE5 inhibitor timing is critical — if patient uses sildenafil for erectile dysfunction, wait at least 24 hours after sildenafil before nitrate use; 48 hours for tadalafil. Instruct patients to carry medical alert information.

1. Gradual discontinuation — do not stop abruptly after prolonged use due to risk of rebound angina; taper gradually if discontinuing.

1. SR tablets must not be crushed — sustained-release formulations must be swallowed whole; crushing defeats the purpose and may cause dose-dumping.

1. Hydralazine-nitrate combination in HFrEF — useful alternative to ACE inhibitors/ARBs in patients with contraindications (renal failure, hyperkalaemia) or as add-on in select populations; requires specialist initiation.

isosorbide mononitrate; ISMN; nitrate; angina prophylaxis; stable angina; vasodilator; heart failure; nitrate tolerance; PDE5 interaction; NLEM India; Schedule H

RxIndia v1.0 — 06 May 2025

• CDSCO approved prescribing information

• Indian Pharmacopoeia

• NLEM 2022

• API Textbook of Medicine

• AIIMS Drug Policy 2023

• ICMR Guidelines on Cardiovascular Disease Management

• Cardiological Society of India (CSI) Practice Guidelines

• EUROPA, A-HeFT trials (for clinical context)

• Goodman & Gilman's The Pharmacological Basis of Therapeutics (supportive)