Schedule H

Oral

• Tablets: 2.5 mg, 5 mg

INDICATIONS + DOSING — FOR CLINICIAN USE ONLY

Primary Indications (Approved / Standard in India)

1. Non-Valvular Atrial Fibrillation (NVAF) — Prevention of Stroke and Systemic Embolism

Standard Dosing (Adults):

Parameter Recommendation

Starting dose 5 mg orally twice daily

Titration Not applicable

Usual maintenance dose 5 mg twice daily

Maximum dose 10 mg/day (5 mg twice daily)

Reduced Dose Criteria — Use 2.5 mg twice daily if patient has ≥2 of the following:

• Age ≥80 years

• Body weight ≤60 kg

• Serum creatinine ≥1.5 mg/dL

Parameter Recommendation

Starting dose 2.5 mg orally twice daily

Titration Not applicable

Usual maintenance dose 2.5 mg twice daily

Maximum dose 5 mg/day (2.5 mg twice daily)

Clinical Notes:

• May be taken with or without food

• Contraindicated in valvular AF (mechanical prosthetic valves, moderate-to-severe mitral stenosis)

• If only one dose-reduction criterion present, use standard 5 mg twice daily dose

1. Treatment of Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE)

Acute Treatment Phase (Days 1–7):

Parameter Recommendation

Starting dose 10 mg orally twice daily

Titration Not applicable during loading phase

Duration 7 days

Maximum dose 20 mg/day

Maintenance Phase (Day 8 onwards):

Parameter Recommendation

Starting dose 5 mg orally twice daily (from Day 8)

Titration Not applicable

Usual maintenance dose 5 mg twice daily

Maximum dose 10 mg/day

Clinical Notes:

• Minimum treatment duration: 3 months

• Provoked VTE with reversible risk factor: 3 months usually sufficient

• Unprovoked or recurrent VTE: consider extended therapy

• Reassess bleeding risk periodically during long-term treatment

1. Prevention of Recurrent DVT and PE (Extended Secondary Prevention)

Adults — After Completion of Initial 6 Months of Anticoagulation:

Parameter Recommendation

Starting dose 2.5 mg orally twice daily

Titration Not applicable

Usual maintenance dose 2.5 mg twice daily

Maximum dose 5 mg/day

Clinical Notes:

• Initiate after completing at least 6 months of standard therapeutic anticoagulation

• Periodically reassess need for continued therapy versus bleeding risk

• May be taken with or without food

1. Prophylaxis of Venous Thromboembolism (VTE) after Elective Hip or Knee Replacement Surgery

Adults:

Parameter Recommendation

Starting dose 2.5 mg orally twice daily

Timing of first dose 12–24 hours post-surgery, after haemostasis established

Titration Not applicable

Usual maintenance dose 2.5 mg twice daily

Maximum dose 5 mg/day

Duration:

• Knee replacement: 10–14 days

• Hip replacement: 32–38 days

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)

Treatment of VTE in Children — OFF-LABEL

• NOT RECOMMENDED for routine paediatric use in India

• Paediatric dosing formulations NOT AVAILABLE in India

• International weight-band based dosing exists but not established in Indian protocols

• Use only in exceptional circumstances under specialist paediatric haematology supervision

• LMWH (enoxaparin) remains preferred anticoagulant for paediatric VTE in India

Minimum Age Statement:

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

Apixaban has dual elimination (approximately 27% renal, 73% hepatic) — less affected by renal impairment compared to other DOACs:

Renal Function NVAF Indication VTE Treatment/Prophylaxis

End-Stage Renal Disease on Haemodialysis May be used with caution at 5 mg BD (or 2.5 mg BD if dose-reduction criteria met); limited data Limited data; use with caution

Notes:

• Serum creatinine ≥1.5 mg/dL is one of the three dose-reduction criteria for NVAF (when ≥2 criteria present)

• Monitor renal function every 6–12 months in stable patients

• More frequent monitoring during acute illness or if receiving nephrotoxic drugs

Hepatic disease with coagulopathy Contraindicated regardless of Child-Pugh class

• Active clinically significant bleeding (including GI, intracranial, or any site)

• Hepatic disease associated with coagulopathy and clinically relevant bleeding risk

• Known hypersensitivity to apixaban or any excipient

• Lesions at high risk of clinically significant bleeding (e.g., active peptic ulcer, recent brain/spinal surgery, intracranial neoplasm, arteriovenous malformation)

• Valvular atrial fibrillation:

• Mechanical prosthetic heart valves (any position)

• Moderate-to-severe mitral stenosis (usually rheumatic)

• Concomitant treatment with any other anticoagulant (except during transition periods)

• Concomitant use with strong dual CYP3A4 and P-glycoprotein inhibitors (e.g., ketoconazole, itraconazole, ritonavir)

• Concomitant use with strong dual CYP3A4 and P-glycoprotein inducers (e.g., rifampicin, phenytoin, carbamazepine)

• Moderate renal impairment (eGFR 15–29 mL/min) — limited data; use with caution

• Elderly patients (≥75 years) — increased bleeding risk

• Low body weight (<60 kg) — potential for increased drug exposure; consider dose reduction in NVAF

• Concomitant use of antiplatelet agents (aspirin, clopidogrel, prasugrel, ticagrelor) — additive bleeding risk

• Chronic NSAID use — increased GI bleeding risk

• Recent major surgery or trauma

• History of GI bleeding, peptic ulcer disease, or GI malignancy

• Active malignancy with high bleeding risk

• Uncontrolled severe hypertension

• Neuraxial anaesthesia or spinal puncture — risk of epidural/spinal haematoma:

• Delay apixaban for at least 20–30 hours after catheter removal

• Remove catheter at least 20–30 hours after last apixaban dose

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

• Patients with antiphospholipid syndrome (especially triple-positive) — warfarin preferred

• Extremes of body weight (>120 kg) — limited pharmacokinetic data

• Prosthetic heart valves (bioprosthetic) — limited data; specialist decision

Parameter Details

Risk category Not recommended — crosses placenta; potential for fetal bleeding; embryotoxicity in animal studies

Preferred alternatives Low Molecular Weight Heparin (LMWH) — enoxaparin is anticoagulant of choice during pregnancy in India

When may be used Only in exceptional circumstances if LMWH absolutely contraindicated and no alternative exists; requires specialist decision (haematology/obstetrics)

Monitoring If inadvertent exposure: maternal bleeding assessment; fetal ultrasound for anomalies; plan delivery with haematology input

Parameter Details

Compatibility Not recommended — insufficient human data on excretion in breast milk

Drug levels in milk Unknown; expected to be low due to high protein binding (~87%)

Preferred alternatives LMWH (enoxaparin) — not excreted in breast milk; warfarin — compatible with breastfeeding

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

Parameter Recommendation

Starting dose 5 mg twice daily (standard); use 2.5 mg twice daily if ≥2 dose-reduction criteria present (age ≥80 + weight ≤60 kg or creatinine ≥1.5 mg/dL)

Titration Not applicable — fixed dosing

Special risks Increased bleeding risk (particularly GI and intracranial); higher prevalence of renal impairment; falls risk; polypharmacy with interacting drugs; cognitive impairment affecting adherence

Monitoring Renal function at baseline and every 6 months; more frequently during acute illness; regular clinical assessment for bleeding

Note: Age ≥80 years alone is not sufficient for dose reduction in NVAF; requires at least one additional criterion (weight ≤60 kg OR serum creatinine ≥1.5 mg/dL).

Drug/Class Mechanism/Effect Recommendation

Strong CYP3A4 + P-gp inhibitors (ketoconazole, itraconazole, voriconazole, posaconazole, ritonavir, lopinavir) Marked increase in apixaban exposure → high bleeding risk Contraindicated — avoid concomitant use

Strong CYP3A4 + P-gp inducers (rifampicin, rifabutin, carbamazepine, phenytoin, phenobarbital, St. John's Wort) Significant reduction (~50%) in apixaban levels → loss of efficacy Contraindicated — avoid concomitant use

Other anticoagulants (warfarin, LMWH, UFH, fondaparinux, rivaroxaban, dabigatran) Additive anticoagulant effect → major bleeding risk Avoid — exception: brief overlap during transition (specialist supervision)

Thrombolytics (alteplase, tenecteplase, streptokinase) Markedly increased bleeding risk Avoid concomitant use; hold apixaban during thrombolysis

Dual antiplatelet therapy (DAPT — aspirin + P2Y12 inhibitor) Significantly increased bleeding risk Use with extreme caution; triple therapy duration should be minimised; specialist decision

Drug/Class Effect Recommendation

Moderate CYP3A4 and/or P-gp inhibitors (erythromycin, clarithromycin, diltiazem, verapamil, amiodarone, dronedarone, fluconazole) Modest increase in apixaban levels (~1.5–2 fold) Use with caution; no routine dose adjustment but monitor for bleeding; consider 2.5 mg BD in high-risk patients

Single antiplatelet (aspirin ≤100 mg, clopidogrel) Increased bleeding risk Use only when clinically indicated; monitor for bleeding

NSAIDs (diclofenac, ibuprofen, naproxen) Increased GI and overall bleeding risk Avoid chronic use; if short-term use required, consider gastroprotection

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

Naproxen Increased GI bleeding risk; modest increase in apixaban exposure Avoid if possible; use short courses only

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

• Anaemia (may indicate occult blood loss)

• Nausea

• Contusion / ecchymosis

• Elevated transaminases (usually mild and transient)

• Fatigue

Adverse Effect Clinical Action

Major bleeding (GI haemorrhage, intracranial haemorrhage, retroperitoneal bleeding) Immediate discontinuation; supportive care; consider reversal agent (andexanet alfa if available) or Prothrombin Complex Concentrate (PCC); hospitalisation

Spinal/Epidural haematoma (with neuraxial procedures) Emergency — can cause permanent paralysis; urgent neurosurgical consultation

Severe hypersensitivity/Anaphylaxis Discontinue immediately; emergency management

Hepatotoxicity (rare) Discontinue if significant transaminase elevation (>3× ULN with symptoms)

Thrombocytopenia (rare) Monitor; may need to discontinue

Reversal in Major Bleeding:

• Andexanet alfa — specific reversal agent (limited availability in India)

• Prothrombin Complex Concentrate (PCC) — 4-factor PCC 25–50 units/kg

• Tranexamic acid — adjunctive

• Activated charcoal — if ingestion within 2–3 hours

• No role for FFP, vitamin K, or protamine

Baseline:

• Complete blood count (haemoglobin, platelet count)

• Renal function (serum creatinine, calculated CrCl or eGFR)

• Liver function tests (transaminases, bilirubin)

• Coagulation screen (PT/INR, aPTT) — for baseline documentation only, not for monitoring efficacy

• Weight and age assessment for dose-reduction criteria in NVAF

• Bleeding risk assessment (HAS-BLED score for AF patients)

After Initiation / Dose Change:

• Clinical assessment for bleeding at 1 month

• Haemoglobin if bleeding suspected

• Renal function at 1–3 months (especially in elderly, CKD, acute illness)

Long-term Monitoring:

• Renal function: Every 6–12 months in stable patients; more frequently if eGFR <60 or at-risk (elderly, diabetes, heart failure, dehydration, nephrotoxic drugs)

• Haemoglobin: Annually or if bleeding symptoms

• Liver function: Annually or if symptoms suggestive of hepatotoxicity

• Clinical bleeding assessment at every visit

• Reassess indication and bleeding risk annually

• Reassess dose-reduction criteria in NVAF if clinical status changes

Note: Routine coagulation monitoring (PT/INR, aPTT) not required and not reliable for assessing apixaban effect. Anti-Xa chromogenic assay (apixaban-calibrated) may be used in special situations (overdose, emergency surgery, extremes of body weight).

Originator:

• Eliquis (Pfizer/BMS)

Generic/Licensed Brands:

• Apigat (Lupin)

• Apiblitz (Glenmark)

• Apixaban (Cipla)

• Apixano (Dr. Reddy's)

• Apixamed (Medley)

• Apiban (Sun Pharma)

• Apixa (Torrent)

• Xareliq (Alkem)

• Not currently under NPPA price control

• Not included in NLEM 2022

• Significant price variation between originator and generic brands

• Generic options substantially more affordable

• Government supply mostly limited to tertiary care centres

1. Lower GI bleeding risk than rivaroxaban — apixaban often preferred in patients with GI bleeding history or elderly patients due to lower GI bleeding rates in clinical trials

1. Preferred DOAC in renal impairment — dual hepatic/renal elimination makes apixaban safest choice among DOACs when eGFR 15–30 mL/min

1. Dose reduction requires ≥2 criteria in NVAF — common error is reducing dose with only one criterion present (e.g., age ≥80 alone); this leads to under-dosing and increased stroke risk

1. No food requirement — unlike rivaroxaban, apixaban bioavailability is unaffected by food; can be taken with or without meals

1. Twice daily dosing — remember BD dosing schedule; missed dose can be taken if remembered within 6 hours, otherwise skip and continue usual schedule

1. Not for valvular AF — contraindicated in mechanical prosthetic valves and moderate-to-severe rheumatic mitral stenosis; use warfarin for these patients

1. Reversal agent limited in India — andexanet alfa not widely available; PCC is the practical option for major bleeding requiring reversal

anticoagulant; DOAC; factor-Xa-inhibitor; apixaban; atrial-fibrillation; DVT; PE; VTE-prophylaxis; renal-preferred; lower-GI-bleeding; pregnancy-contraindicated; elderly-safe; Schedule H

RxIndia v1.0 — 05 Jun 2025

• CDSCO approved product inserts

• Indian Pharmacopoeia

• National Formulary of India

• API Textbook of Medicine

• AIIMS Anticoagulation Protocols

• Cardiological Society of India — AF and VTE management recommendations

• Harrison's Principles of Internal Medicine (supportive)

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

• ARISTOTLE, AMPLIFY, ADVANCE trials (for indication context)

• CARAVAGGIO trial (for cancer-associated VTE off-label context)