Schedule H

Oral

• Tablets: 60 mg, 90 mg

INDICATIONS + DOSING — FOR CLINICIAN USE ONLY

Primary Indications (Approved / Standard in India)

1. Acute Coronary Syndrome (ACS) — Unstable Angina, NSTEMI, STEMI (with or without PCI)

Adults — In Combination with Low-Dose Aspirin:

Parameter Recommendation

Starting dose 180 mg loading dose (two 90 mg tablets) as single dose

Titration Not applicable

Usual maintenance dose 90 mg orally twice daily

Maximum dose 180 mg/day (90 mg twice daily)

Duration Up to 12 months from index event

Clinical Notes:

• Always administer with low-dose aspirin (75–100 mg once daily)

• Do NOT use aspirin doses >100 mg/day — may reduce ticagrelor efficacy

• Loading dose given as early as possible at presentation

• No need for CYP2C19 genotyping (unlike clopidogrel)

• Contraindicated in patients with history of intracranial haemorrhage

1. Secondary Prevention of Atherothrombotic Events — High-Risk Patients with History of MI (≥12 Months Post-MI)

Adults — Long-Term Secondary Prevention:

Parameter Recommendation

Starting dose 60 mg orally twice daily

Titration Not applicable

Usual maintenance dose 60 mg twice daily

Maximum dose 120 mg/day (60 mg twice daily)

Duration Up to 3 years from index MI

Clinical Notes:

• Initiate after completion of initial 12-month therapy with 90 mg twice daily

• Continue low-dose aspirin (75–100 mg once daily) concomitantly

• Indicated for patients with high-risk features (diabetes, multivessel CAD, recurrent MI, age ≥65, CKD)

• Reassess bleeding risk periodically during extended therapy

Pre-Operative Management

Clinical Scenario Recommendation

Elective surgery requiring discontinuation Stop ticagrelor at least 5 days before surgery

Urgent CABG Avoid ticagrelor initiation if urgent CABG planned; discontinue at least 3–5 days prior if already on therapy

Minor procedures (dental, skin) May continue with caution; assess bleeding risk

Secondary Indications – Adults Only (Off-label)

Indication Dose Duration Supervision Evidence Basis

Minor Ischaemic Stroke or High-Risk TIA (in CYP2C19 loss-of-function carriers) — OFF-LABEL Loading: 180 mg; Maintenance: 90 mg BD 21–30 days in combination with aspirin Specialist only (Neurology) CHANCE-2 trial; not standard practice in India; requires genotyping

Post-Transcatheter Aortic Valve Implantation (TAVI) — OFF-LABEL 90 mg BD with low-dose aspirin 3–6 months Specialist only (Interventional Cardiology) Limited RCT data; not superior to clopidogrel in some trials

PAEDIATRIC DOSING (Specialist Only)

Primary Indications

Regulatory Status: NOT approved for paediatric use in India.

Age Restriction: Not recommended below 18 years of age.

Secondary Indications – Paediatric (Off-label)

• NOT AVAILABLE in India — no paediatric dosing established in Indian guidelines

• International studies in congenital heart disease exist but not adopted in Indian practice

• LMWH or aspirin remain preferred antiplatelet/anticoagulant options in paediatric cardiac conditions

• Use only in exceptional circumstances under specialist paediatric cardiology/haematology supervision

Minimum Age Statement:

Not recommended below 18 years of age except in highly specialised settings with paediatric cardiology supervision.

Note: Ticagrelor may transiently increase serum creatinine (reversible, not indicative of nephrotoxicity).

• Active pathological bleeding (e.g., GI haemorrhage, intracranial bleeding)

• History of intracranial haemorrhage (ICH) — regardless of cause or timing

• Severe hepatic impairment (Child-Pugh C)

• Known hypersensitivity to ticagrelor or any excipient

• Concomitant use with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin)

• Concomitant use with strong CYP3A4 inducers (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital)

• Bradyarrhythmias — sinus node dysfunction, second or third degree AV block (without permanent pacemaker); risk of ventricular pauses

• Asthma or COPD — dyspnoea is common adverse effect; may exacerbate respiratory symptoms

• History of hyperuricaemia or gout — ticagrelor increases uric acid levels

• Moderate hepatic impairment (Child-Pugh B) — increased drug exposure

• Bleeding diathesis or recent significant bleeding

• Concomitant use with anticoagulants — markedly increased bleeding risk

• Recent major surgery or trauma

• Planned surgery or invasive procedure — discontinue at least 5 days prior

• Elderly (>75 years) — increased bleeding risk

• Low body weight (<60 kg) — potentially increased exposure

• Concomitant use with moderate CYP3A4 inhibitors (diltiazem, verapamil)

• Concomitant use with drugs that increase bleeding risk (NSAIDs, SSRIs)

Parameter Details

Risk category Not formally assigned in India; animal studies show embryo-fetal toxicity at supratherapeutic doses

Preferred alternatives Low-dose aspirin (if antiplatelet indicated); clopidogrel has more established (though limited) safety data

When may be used Only if no suitable alternative and potential benefit clearly justifies risk; specialist decision (cardiology + obstetrics)

Monitoring Maternal bleeding risk; fetal growth monitoring; plan delivery with haematology/cardiology input

Parameter Details

Compatibility Not recommended — unknown if excreted in human breast milk; excreted in animal milk

Drug levels in milk Unknown in humans; expected to be low based on protein binding

Preferred alternatives Clopidogrel (more established safety) or low-dose aspirin if antiplatelet required

Infant monitoring If exposure occurs: monitor for bleeding, bruising, feeding difficulties

Parameter Recommendation

Starting dose Same as younger adults — 180 mg loading, then 90 mg twice daily for ACS

Titration Not applicable

Special risks Increased bleeding risk (particularly GI and intracranial); falls risk; polypharmacy with interacting drugs; assess renal and hepatic function

Monitoring Close monitoring for bleeding; regular haemoglobin checks; assess for dyspnoea and bradycardia

Note: Age alone is not a contraindication; benefit in reducing cardiovascular events generally outweighs bleeding risk in appropriately selected elderly patients.

Drug/Class Mechanism/Effect Recommendation

Strong CYP3A4 inhibitors (ketoconazole, itraconazole, voriconazole, ritonavir, nelfinavir, clarithromycin) Marked increase in ticagrelor exposure → high bleeding risk Contraindicated — avoid concomitant use

Strong CYP3A4 inducers (rifampicin, phenytoin, carbamazepine, phenobarbital, St. John's Wort) Significant reduction (~60%) in ticagrelor levels → loss of efficacy Contraindicated — avoid concomitant use

Anticoagulants (warfarin, rivaroxaban, apixaban, dabigatran, LMWH) Additive bleeding risk Avoid unless specifically indicated (e.g., AF with ACS) — specialist supervision mandatory

Digoxin Ticagrelor inhibits P-glycoprotein → increased digoxin levels (up to 75%) Monitor digoxin levels; consider dose reduction; watch for toxicity

Aspirin doses >100 mg/day Reduced ticagrelor efficacy demonstrated in PLATO trial Avoid — use only low-dose aspirin (75–100 mg/day)

Drug/Class Effect Recommendation

Moderate CYP3A4 inhibitors (diltiazem, verapamil, fluconazole, erythromycin) Modest increase in ticagrelor levels Use with caution; monitor for bleeding and dyspnoea

Simvastatin, lovastatin Ticagrelor increases statin levels via CYP3A4 inhibition Limit simvastatin to ≤40 mg/day; consider atorvastatin or rosuvastatin (less interaction)

Cyclosporine Increased ticagrelor exposure via P-gp and CYP3A4 inhibition Monitor closely; avoid if possible

NSAIDs (diclofenac, ibuprofen, naproxen) Additive GI bleeding risk Avoid chronic use; use short courses with gastroprotection

SSRIs/SNRIs (fluoxetine, sertraline, venlafaxine) Increased bleeding tendency Monitor for bleeding; counsel patient

Proton pump inhibitors No significant interaction (unlike clopidogrel) Can be used together for gastroprotection

Other P2Y12 inhibitors (clopidogrel, prasugrel) Overlapping mechanism; no additive benefit; bleeding risk Avoid combination

• Dyspnoea (up to 14%) — usually mild, transient; rarely requires discontinuation

• Bleeding — minor (bruising, epistaxis, gingival bleeding, haematuria)

• Elevated serum creatinine (reversible; not true nephrotoxicity)

• Hyperuricaemia (usually asymptomatic)

• Headache

• Dizziness

• Nausea

• Diarrhoea

• Back pain

Adverse Effect Clinical Action

Major bleeding (GI haemorrhage, intracranial haemorrhage, retroperitoneal bleeding) Immediate discontinuation; supportive care; platelet transfusion may have limited efficacy (reversible inhibitor); hospitalisation

Ventricular pauses (>3 seconds) Usually occur in first week; typically asymptomatic; monitor ECG in high-risk patients (elderly, sinus node dysfunction); generally resolve with continued therapy

Bradyarrhythmias (symptomatic — syncope, presyncope) Evaluate for pacemaker requirement; consider alternative antiplatelet

Severe hypersensitivity / Angioedema Discontinue immediately; emergency management

Gout flare Treat acute gout; consider alternative antiplatelet if recurrent

Thrombotic Thrombocytopenic Purpura (TTP) Very rare; discontinue immediately; urgent haematology referral

Note: Unlike thienopyridines (clopidogrel, prasugrel), ticagrelor is a reversible inhibitor — platelet function recovers within 3–5 days of discontinuation.

Baseline:

• Complete blood count (haemoglobin, platelet count)

• Renal function (serum creatinine, eGFR)

• Liver function tests

• Serum uric acid

• ECG (assess baseline rhythm, PR interval)

• Bleeding risk assessment

After Initiation:

• Clinical assessment for dyspnoea and bradycardia in first week

• Monitor for bleeding at 2–4 weeks

• Repeat haemoglobin if bleeding symptoms or unexplained fatigue

• Serum creatinine at 1 month (expect mild increase; usually not clinically significant)

Long-term Monitoring:

• Complete blood count every 3–6 months

• Renal function every 6 months

• Serum uric acid if history of gout or symptoms

• Clinical assessment for bleeding at each visit

• Reassess indication and bleeding risk annually

Pre-Operative:

• Document when last dose taken

• Ensure ≥5 days discontinuation before elective major surgery

• Liaise with surgical team regarding timing of resumption

Originator:

• Brilinta (AstraZeneca)

Generic/Licensed Brands:

• Ticavag (Intas)

• Ticabid (Zydus Cadila)

• Ticari (Lupin)

• Tigrelor (Torrent)

• Ticamet (Sun Pharma)

• Axcer (Mankind)

• Brilor (Cipla)

Fixed-Dose Combinations:

• Not currently under NPPA price control

• Not included in NLEM 2022

• Significant price variation between originator and generic brands

• Generic options substantially more affordable

• May be available through government hospital procurement for ACS management in tertiary centres

1. Superior to clopidogrel in ACS — PLATO trial demonstrated significant reduction in cardiovascular death, MI, and stroke compared to clopidogrel; preferred P2Y12 inhibitor for most ACS patients in Indian cardiology practice

1. Aspirin dose matters — use ONLY low-dose aspirin (75–100 mg/day); higher doses reduce ticagrelor efficacy (post-hoc PLATO analysis); common prescribing error to avoid

1. Dyspnoea is expected and usually manageable — occurs in ~14% of patients; typically mild, transient, and self-limiting; does not require discontinuation in most cases; counsel patients proactively

1. No CYP2C19 dependency — unlike clopidogrel, ticagrelor does not require hepatic activation; more predictable antiplatelet effect; useful when clopidogrel resistance suspected or confirmed

1. Reversible inhibition — platelet function recovers faster (3–5 days) compared to thienopyridines; advantageous if urgent surgery needed, but daily compliance critical due to shorter duration of effect

1. Switching protocols — when switching FROM clopidogrel to ticagrelor: give ticagrelor loading dose without clopidogrel loading; when switching FROM ticagrelor to clopidogrel: give clopidogrel 600 mg loading dose 24 hours after last ticagrelor dose

1. Ventricular pauses — usually occur in first week; generally asymptomatic and benign; avoid in patients with sick sinus syndrome or high-grade AV block without pacemaker

antiplatelet; P2Y12-inhibitor; ACS; STEMI; NSTEMI; PCI; secondary-prevention; dyspnoea; reversible; CYP3A4-substrate; Schedule H; pregnancy-avoid

RxIndia v1.0 — 05 Jun 2025

• CDSCO approved product inserts

• Indian Pharmacopoeia

• API Textbook of Medicine

• AIIMS Cardiology Treatment Protocols

• Cardiological Society of India — ACS Management Guidelines

• ICMR Guidelines on STEMI and ACS Management

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

• Harrison's Principles of Internal Medicine (supportive)

• PLATO trial (primary efficacy data)

• PEGASUS-TIMI 54 trial (extended secondary prevention)

• CHANCE-2 trial (for stroke off-label context only)