Schedule H

Oral, Sublingual

• Tablets (Immediate-release): 5 mg, 10 mg, 20 mg

• Sublingual Tablets: 5 mg, 10 mg

• Extended-release Tablets: 40 mg

Note: Fixed-dose combinations with hydralazine available but not widely used in India

INDICATIONS + DOSING — FOR CLINICIAN USE ONLY

Primary Indications (Approved / Standard in India)

1. Chronic Stable Angina — Prophylaxis

Parameter Recommendation

Starting dose 5–10 mg orally twice daily

Titration Increase by 5–10 mg per dose at weekly intervals based on anginal control and tolerability

Usual maintenance dose 10–20 mg two to three times daily

Maximum dose 80 mg/day in divided doses

Clinical notes Schedule doses to allow 10–14 hour nitrate-free interval daily (e.g., morning and afternoon dosing, avoid evening dose) to prevent tolerance development

1. Acute Anginal Attack — Sublingual Use

Parameter Recommendation

Starting dose 5 mg sublingually at onset of chest pain

Titration Not applicable for acute use

Usual maintenance dose 5–10 mg sublingually as needed

Maximum dose 3 doses (up to 30 mg total) within 15 minutes

Clinical notes If no relief after 3 doses within 15 minutes, suspect acute coronary syndrome — urgent evaluation required; advise patient to sit during sublingual administration to avoid syncope

1. Heart Failure with Reduced Ejection Fraction (HFrEF) — As adjunct therapy

Parameter Recommendation

Starting dose 10–20 mg orally three times daily

Titration Increase gradually to target dose as tolerated

Usual maintenance dose 20–40 mg three times daily (usually combined with hydralazine)

Maximum dose 120 mg/day in divided doses

Clinical notes Used in patients intolerant to ACE inhibitors/ARBs or as add-on in persistent symptoms; limited use in Indian practice — specialist initiation recommended; maintain nitrate-free interval

Secondary Indications – Adults (Off-label)

1. Pulmonary Hypertension (WHO Group II/III) — OFF-LABEL

• Dose:

• Starting dose: 10 mg orally twice daily

• Titration: Increase to 20 mg two to three times daily as tolerated

• Usual maintenance dose: 20 mg two to three times daily

• Maximum dose: 60 mg/day

• Duration: Chronic use for symptom relief

• Specialist only: Yes — Pulmonologist/Cardiologist supervision required

• Evidence basis: Small observational studies; used occasionally with hydralazine for afterload reduction; not first-line therapy

PAEDIATRIC DOSING (Specialist Only)

Primary Indications

Not applicable. Isosorbide dinitrate is NOT a standard therapy in paediatric age group.

Secondary Indications – Paediatrics (Off-label)

1. Congestive Cardiac Failure — OFF-LABEL

• Dose:

• Starting dose: 0.2 mg/kg/dose orally

• Titration: Increase cautiously to 0.5 mg/kg/dose based on response and BP tolerance

• Usual maintenance dose: 0.2–0.5 mg/kg/dose every 6–8 hours

• Maximum dose: 10 mg per single dose

• Duration: As directed by specialist

• Specialist only: Yes — Paediatric cardiologist supervision mandatory

• Evidence basis: Limited paediatric data; extrapolated from adult practice and small case series

Safety monitoring:

• Blood pressure (supine and standing in older children)

• Heart rate

• Signs of hypotension (pallor, lethargy, poor perfusion)

⚠️ Age Restriction Statement:

Not recommended below 12 years of age except under direct supervision of paediatric cardiologist due to limited safety data and significant hypotension risk.

Mild to moderate impairment Standard dosing; monitor for hypotension

Severe impairment (eGFR <30) Use with caution; may accumulate active metabolites; monitor BP closely

Haemodialysis No supplemental dose required; not significantly dialysed

• Known hypersensitivity to organic nitrates

• Concurrent use of phosphodiesterase-5 (PDE-5) inhibitors (sildenafil, tadalafil, vardenafil, avanafil) — risk of severe, potentially fatal hypotension

• Concurrent use of riociguat (soluble guanylate cyclase stimulator)

• Acute circulatory failure (shock, circulatory collapse)

• Severe hypotension (systolic BP <90 mmHg)

• Acute myocardial infarction with low filling pressures

• Increased intracranial pressure (head trauma, cerebral haemorrhage)

• Severe anaemia

• Constrictive pericarditis or pericardial tamponade

• Hypertrophic obstructive cardiomyopathy with significant outflow obstruction

• Volume depletion or dehydration — correct before initiating therapy

• Hypotension-prone patients — start with lowest dose

• Concurrent alcohol use — potentiates hypotensive effect

• Closed-angle glaucoma — theoretical risk of increased intraocular pressure

• Elderly patients — increased sensitivity to hypotensive effects

• Aortic or mitral stenosis — use with caution

• Hypothyroidism or malnutrition — altered drug response possible

• Continuous or frequent dosing — tolerance develops rapidly; ensure nitrate-free interval

• Recent use of PDE-5 inhibitors — confirm minimum 24-hour (sildenafil/vardenafil) or 48-hour (tadalafil) washout period

Parameter Information

Risk category Limited human data; animal studies show no teratogenicity; likely low risk

Preferred alternatives Beta-blockers (metoprolol, labetalol) preferred for angina in pregnancy

When may be used Only when clearly indicated and benefit outweighs risk; obstetrician input recommended

What to monitor Maternal blood pressure (hypotension risk); fetal growth monitoring with long-term use

Parameter Information

Compatible with breastfeeding Likely compatible; very low expected transfer to milk

Preferred alternatives Short-acting nitrates or beta-blockers if alternatives needed

Expected drug levels in milk Low (based on pharmacokinetic properties)

What to monitor in infant Excessive sleepiness, poor feeding, lethargy (unlikely)

Parameter Recommendation

Starting dose 5 mg twice daily (use lowest effective dose)

Titration Slow titration over 1–2 weeks; assess tolerance before each increase

Extra risks Postural hypotension, dizziness, syncope, falls; increased sensitivity to vasodilatory effects

Monitoring Blood pressure (supine and standing); symptoms of orthostatic intolerance

Clinical notes Advise rising slowly from sitting/lying position; ensure adequate hydration

Interacting Drug Mechanism/Effect Recommendation

PDE-5 inhibitors (sildenafil, tadalafil, vardenafil, avanafil) Synergistic vasodilation via cGMP pathway CONTRAINDICATED — risk of severe, potentially fatal hypotension; minimum washout: 24 hours for sildenafil/vardenafil, 48 hours for tadalafil

Riociguat Additive cGMP-mediated vasodilation CONTRAINDICATED — avoid concurrent use

Ergot alkaloids (ergotamine, dihydroergotamine) Ergots cause coronary vasoconstriction; may counteract nitrate effect Avoid combination — risk of coronary vasospasm and reduced antianginal efficacy

Interacting Drug Effect Recommendation

Antihypertensives (beta-blockers, CCBs, ACE inhibitors, ARBs) Additive blood pressure lowering Monitor BP closely; may need dose adjustment of either agent

Alcohol Enhanced hypotensive effect Advise patients to limit alcohol consumption

Tricyclic antidepressants Increased orthostatic hypotension Monitor for postural symptoms; start with low nitrate dose

Antipsychotics (phenothiazines) Additive hypotensive effect Monitor BP; use lower starting doses

Diuretics Volume depletion potentiates hypotension Ensure adequate hydration before initiating nitrate

Heparin Nitrates may reduce heparin effect (unclear mechanism) Monitor aPTT if using concurrently

• Headache (most common; often dose-limiting; usually decreases with continued use)

• Dizziness and light-headedness

• Flushing

• Postural hypotension

• Tachycardia (reflex)

• Nausea

• Weakness and fatigue

Adverse Effect Clinical Features Action

Severe hypotension Syncope, shock, especially with first dose or in volume-depleted patients Discontinue; IV fluids; place patient supine with legs elevated

Rebound angina Worsening chest pain with abrupt discontinuation Taper gradually rather than abrupt withdrawal

Methaemoglobinaemia Cyanosis, dyspnoea, altered consciousness (very rare; overdose or prolonged high-dose use) Discontinue immediately; methylene blue therapy; supportive care

Paradoxical bradycardia Rare; vasovagal-type response Discontinue; supportive management

Phase Parameters

Baseline Blood pressure (supine and standing), heart rate, ECG, assessment of volume status

After initiation/dose change Blood pressure and heart rate within 24–48 hours; anginal symptom frequency

Long-term Periodic assessment for tolerance development; ensure nitrate-free interval is maintained; angina diary review; BP monitoring

Special situations In heart failure: monitor weight, oedema, dyspnoea

Single-ingredient formulations:

• Sorbitrate (Sun Pharma)

• Isordil (Wyeth/Pfizer)

• Isolan

• Cedocard

• Angiflux

• Cardiovas

• Nitrosorb

Extended-release formulations:

• Sorbitrate CR

• Isordil Tembids

Fixed-dose combinations (limited availability):

Not currently under NPPA price control. Available through government supply under NCD programmes and public hospital formularies.

1. Nitrate-free interval is essential: Schedule dosing to provide 10–14 hour nitrate-free period daily (typically overnight) to prevent tolerance development; avoid round-the-clock dosing

1. Headache management: Nitrate headaches are common but usually diminish after 1–2 weeks of continued therapy; starting with low doses and gradual titration helps reduce severity; paracetamol may be used for symptomatic relief

1. Sublingual technique: Advise patients to sit during sublingual use to prevent syncope; tablet should be placed under tongue and allowed to dissolve — not swallowed

1. PDE-5 inhibitor contraindication: Always ask about recent use of sildenafil/tadalafil before prescribing; this interaction is potentially fatal

1. Switching to isosorbide mononitrate: For patients requiring simplified once-daily regimen or experiencing tolerance, consider switching to isosorbide mononitrate extended-release formulation

1. Never stop abruptly: In patients on chronic nitrate therapy, gradual tapering is recommended to avoid rebound angina

Isosorbide dinitrate; ISDN; nitrate; antianginal; vasodilator; angina; heart failure; sublingual; PDE5-contraindicated; headache; NLEM-India; elderly-caution

RxIndia v1.0 — 20 Apr 2025

• CDSCO Product Information Database

• Indian Pharmacopoeia 2022

• NLEM 2022

• API Textbook of Medicine, 11th Edition

• Harrison's Principles of Internal Medicine, 21st Edition

• Goodman & Gilman's The Pharmacological Basis of Therapeutics

• AIIMS Cardiology Treatment Protocols

• AIIMS Drug Formulary