Schedule H

Oral, Subcutaneous, Intramuscular, Intravenous, Intrathecal

• Tablets: 2.5 mg, 5 mg, 7.5 mg, 10 mg

• Injection (vial/ampoule): 15 mg/1.5 mL, 50 mg/2 mL, 1000 mg/10 mL

• Prefilled syringes (subcutaneous): 10 mg, 15 mg, 20 mg, 25 mg

INDICATIONS + DOSING — FOR CLINICIAN USE ONLY

Primary Indications (Approved / Standard in India)

1. Rheumatoid Arthritis (Moderate to Severe)

Parameter Recommendation

Starting dose 7.5–10 mg once weekly (oral or subcutaneous)

Titration Increase by 2.5–5 mg every 4–6 weeks based on response and tolerability

Usual maintenance dose 15–25 mg once weekly

Maximum dose 25–30 mg/week

Clinical Notes:

• Mandatory folic acid supplementation: 5 mg once weekly (day after methotrexate) OR 1 mg daily (excluding methotrexate day)

• Clinical response typically evident by 6–12 weeks

• Subcutaneous route preferred if inadequate oral response or GI intolerance

1. Psoriasis (Severe, Recalcitrant)

Parameter Recommendation

Test dose 5–10 mg single dose; check CBC after 7 days before continuing

Starting dose 10–15 mg once weekly (oral, IM, or SC)

Titration Increase by 2.5–5 mg every 2–4 weeks as needed

Usual maintenance dose 10–25 mg once weekly

Maximum dose 30 mg/week

Clinical Notes:

• Discontinue if no response after 8 weeks at optimal dosing

• Mandatory folic acid supplementation

• Alcohol abstinence essential (hepatotoxicity risk)

1. Acute Lymphoblastic Leukaemia (ALL) — Part of Chemotherapy Protocols

Regimen Type Dose Range Route Notes

Low-dose maintenance 15–20 mg/m²/week Oral Weekly, as per protocol

Intermediate dose 100–500 mg/m² IV With leucovorin rescue

High dose 1–5 g/m² every 2–3 weeks IV infusion Mandatory leucovorin rescue, hydration, urinary alkalinisation

Intrathecal (CNS prophylaxis) Age-based: 8–15 mg Intrathecal Protocol-specific

Clinical Notes:

• Haemato-oncology specialist use only

• Indian protocols: MCP841, ICiCLe, BFM-based

• High-dose therapy requires intensive monitoring and supportive care

1. Ectopic Pregnancy (Medical Management — Unruptured, Haemodynamically Stable)

Parameter Recommendation

Starting dose 50 mg/m² IM as single dose (Day 1)

Titration Not applicable

Usual maintenance dose Not applicable (single or two-dose regimen)

Maximum dose Second dose of 50 mg/m² if β-hCG decline <15% between Days 4–7

Clinical Notes:

• Confirm β-hCG on Days 1, 4, and 7

• Repeat dose if β-hCG plateau or rise

• Obstetrics/Gynaecology specialist supervision mandatory

• Ensure reliable contraception post-treatment

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

Indication Dose Duration Notes

Crohn's Disease (steroid-dependent/resistant) — OFF-LABEL Starting: 25 mg/week SC (induction); Maintenance: 15 mg/week Long-term; specialist discretion Specialist only; used in Indian IBD centres; evidence from international RCTs

Systemic Lupus Erythematosus (arthritis/skin involvement) — OFF-LABEL 10–15 mg/week orally Long-term Specialist only; used when hydroxychloroquine inadequate; Indian rheumatology practice

Dermatomyositis/Polymyositis — OFF-LABEL 15–25 mg/week orally or SC Long-term Specialist only; steroid-sparing agent

PAEDIATRIC DOSING (Specialist Only)

Primary Indications

1. Acute Lymphoblastic Leukaemia (ALL)

Phase Dose Route Frequency

Maintenance 15–20 mg/m² Oral Once weekly

Consolidation/Intensification 1–5 g/m² IV infusion Every 2–3 weeks (with leucovorin rescue)

CNS prophylaxis Age-based: 8 mg (<1 yr), 10 mg (1–2 yr), 12 mg (2–3 yr), 15 mg (>3 yr) Intrathecal Per protocol schedule

Clinical Notes:

• Paediatric haemato-oncology supervision mandatory

• Indian protocols: MCP841, ICiCLe

• Monitor: CBC, LFTs, renal function, neurotoxicity

1. Juvenile Idiopathic Arthritis (JIA)

Parameter Recommendation

Starting dose 10–15 mg/m²/week (oral or SC); maximum single dose 25 mg

Titration Assess response at 8–12 weeks; increase if inadequate

Usual maintenance dose 10–15 mg/m²/week

Maximum dose 25 mg/week

Clinical Notes:

• Folic acid supplementation: 5 mg weekly mandatory

• Clinical response typically by 3 months

• Monitor CBC, LFTs every 4–8 weeks

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

Indication Dose Duration Notes

Paediatric Psoriasis (severe/refractory) — OFF-LABEL 0.3–0.5 mg/kg once weekly (oral or SC); Max: 25 mg/week Long-term; specialist discretion Specialist only; folic acid 1–5 mg/week required; Indian dermatology practice

Localised Scleroderma (Morphea) — OFF-LABEL 0.3–0.5 mg/kg/week (max 25 mg) 12–24 months Specialist only; paediatric rheumatology/dermatology

Age Restriction: Not recommended in children <2 years except under specialist haematology/oncology supervision for malignancy protocols.

60 No dose adjustment required

30–59 Reduce dose by 50%; monitor closely for toxicity; avoid NSAIDs

<30 Contraindicated

Haemodialysis Not effectively dialysed; avoid use unless specialist recommendation

• Pregnancy (teratogenic — Category X equivalent)

• Breastfeeding

• Known hypersensitivity to methotrexate

• Severe renal impairment (eGFR <30 mL/min)

• Severe hepatic impairment or chronic liver disease (especially alcoholic)

• Pre-existing significant bone marrow suppression (leukopenia, thrombocytopenia, significant anaemia)

• Active serious infection (bacterial, viral, fungal, or tubercular)

• Immunodeficiency syndromes

• Concurrent live vaccine administration

• Latent tuberculosis — screen and treat before initiating immunosuppressive therapy

• Hepatitis B/C infection — screen before starting; risk of reactivation

• Diabetes mellitus or obesity (increased hepatotoxicity risk)

• Peptic ulcer disease or GI ulceration history

• Elderly patients (increased toxicity risk; reduced renal reserve)

• Concurrent NSAID use (increases methotrexate levels and toxicity)

• Pre-existing pulmonary disease (increased pneumonitis risk)

• Pleural effusion or ascites (acts as third-space reservoir; delayed clearance)

• Folate deficiency

• Dehydration

Parameter Details

Risk category Contraindicated (Category X equivalent); high teratogenicity

Teratogenic effects Neural tube defects, craniofacial abnormalities, limb defects

Contraception requirement Reliable contraception mandatory during treatment and for 3–6 months after cessation (both males and females)

Pre-treatment requirement Document negative pregnancy test before initiating in women of reproductive age

Exception Methotrexate may be used for ectopic pregnancy management under specialist supervision

Monitoring Not applicable (avoid in pregnancy)

Parameter Details

Breastfeeding compatibility Contraindicated

Drug levels in milk Present in breast milk; may cause immunosuppression and toxicity in infant

Preferred alternatives Sulfasalazine, hydroxychloroquine (for rheumatologic indications)

Infant monitoring Not applicable (complete cessation of breastfeeding required if methotrexate essential)

Parameter Recommendation

Starting dose Lower end of range (7.5–10 mg/week)

Titration Slower; increase by 2.5 mg every 6–8 weeks

Renal consideration Baseline and periodic creatinine/eGFR monitoring; adjust dose accordingly

Extra risks Myelosuppression, mucositis, hepatotoxicity, nephrotoxicity, infections

Special precautions Avoid in frail or dehydrated elderly; ensure adequate hydration

Drug/Class Interaction Management

Trimethoprim / Co-trimoxazole Additive antifolate effect; severe pancytopenia risk Avoid combination

NSAIDs (especially indomethacin, piroxicam, high-dose aspirin) Reduced renal clearance of methotrexate; enhanced toxicity Avoid or use with extreme caution; monitor closely

Penicillins (high-dose) Reduced methotrexate tubular secretion; increased toxicity Avoid concurrent high-dose penicillin

Leflunomide Additive hepatotoxicity and myelosuppression Avoid combination or use under strict specialist supervision

Live vaccines (BCG, MMR, OPV, yellow fever) Risk of disseminated infection due to immunosuppression Contraindicated during treatment

Probenecid Reduces renal elimination of methotrexate Avoid combination

Drug/Class Interaction Management

Proton-pump inhibitors (omeprazole, pantoprazole) May reduce methotrexate renal elimination Monitor for toxicity; use cautiously

Sulfasalazine Additive antifolate effect Ensure adequate folic acid supplementation; monitor CBC

Phenytoin Protein-binding competition; altered levels of both drugs Monitor phenytoin levels and methotrexate toxicity

Warfarin Methotrexate may enhance anticoagulant effect Monitor INR frequently

Ciprofloxacin Reduced methotrexate renal clearance Monitor for toxicity

Alcohol Increased hepatotoxicity risk Advise complete abstinence

Theophylline Methotrexate may reduce theophylline clearance Monitor theophylline levels

• Nausea, anorexia, vomiting

• Stomatitis, oral ulcers

• Fatigue, malaise

• Transaminase elevation (reversible)

• Mild hair thinning

• Photosensitivity

• Headache

• Dizziness

Adverse Effect Notes

Myelosuppression (pancytopenia, agranulocytosis, thrombocytopenia) May require hospitalisation; discontinue immediately

Hepatotoxicity (fibrosis, cirrhosis) Risk increases with cumulative dose >1.5 g; consider liver biopsy if persistent LFT elevation

Methotrexate-induced pneumonitis Non-infectious; presents with dry cough, dyspnoea, fever; discontinue immediately

Nephrotoxicity Especially with high-dose therapy; requires hydration and urinary alkalinisation

Severe mucocutaneous reactions (SJS/TEN) Rare; discontinue immediately

Opportunistic infections Including Pneumocystis jirovecii, reactivation of TB/Hepatitis B

Neurotoxicity With high-dose or intrathecal use; leukoencephalopathy

After initiation/dose change CBC, LFTs every 2–4 weeks for first 3 months

Stable long-term therapy CBC, LFTs, creatinine every 8–12 weeks

Cumulative dose monitoring Consider liver biopsy or FibroScan if cumulative dose exceeds 1.5 g (especially in psoriasis with risk factors)

Clinical monitoring Symptoms of pulmonary toxicity (cough, dyspnoea), mucositis, infection

• Folitrax® (IPCA)

• Methotrex® (Pfizer)

• Trexall® (Zydus)

• Neotrexate® (Neon)

• Biotrexate® (Biochem)

• Imutrex® (Samarth)

• Mexate® (Dabur Pharma)

• Multiple generic formulations available

Notes:

• Included in NLEM 2022 (oncology and rheumatology indications)

• NPPA ceiling prices applicable for scheduled formulations

• Government supply available at subsidised rates

1. Weekly dosing critical: Always specify "once weekly" clearly — accidental daily dosing has caused fatalities; educate patients and pharmacists.

1. Mandatory folic acid: Co-prescribe folic acid (5 mg weekly, day after methotrexate) to reduce mucosal, GI, and haematologic toxicity without compromising efficacy.

1. Subcutaneous advantage: SC route offers higher bioavailability than oral (especially at doses >15 mg/week) and is preferred for GI intolerance or inadequate oral response.

1. Toxicity rescue: In case of methotrexate toxicity or overdose, leucovorin (folinic acid) rescue is life-saving — administer within 24–48 hours of methotrexate exposure.

1. Alcohol restriction: Absolute alcohol abstinence advised, particularly in psoriasis patients, due to synergistic hepatotoxicity.

1. Pre-treatment screening: Screen for latent TB and Hepatitis B/C before initiation; reactivation can occur with immunosuppression.

DMARD; rheumatoid-arthritis; psoriasis; JIA; ALL; antimetabolite; folate-antagonist; hepatotoxicity; myelosuppression; pregnancy-contraindicated; NLEM-India; folic-acid-supplementation; Methotrexate

RxIndia v1.1 — 03 Apr 2025

• CDSCO approved product labelling

• Indian Pharmacopoeia / National Formulary of India 2021

• NLEM 2022

• API Textbook of Medicine (11th edition)

• AIIMS Rheumatology Treatment Protocols

• Indian Academy of Paediatrics (IAP) Guidelines

• ICMR Cancer Treatment Guidelines

• MCP841 and ICiCLe Protocols (Paediatric ALL)

• Harrison's Principles of Internal Medicine (21st edition)

• Indian Association of Dermatologists (IADVL) Guidelines on Psoriasis Management