Schedule H

Oral

• Tablet 10 mg

• Tablet 20 mg

INDICATIONS + DOSING — FOR CLINICIAN USE ONLY

Primary Indications (Approved / Standard in India):

1. Rheumatoid Arthritis (RA) — Adults

Parameter Details

Starting dose 100 mg once daily for 3 days (loading dose — optional; see clinical notes) OR 20 mg once daily without loading

Titration Not typically required; may reduce to 10 mg daily if tolerability issues occur

Usual maintenance dose 10–20 mg once daily

Maximum dose 20 mg once daily

Clinical Notes:

• Many Indian rheumatologists omit loading dose due to increased gastrointestinal adverse effects

• Therapeutic onset: 4–6 weeks; full clinical response may require 3–6 months

• Can be used as monotherapy or in combination with other DMARDs under specialist supervision

1. Psoriatic Arthritis (PsA) — Adults

Parameter Details

Starting dose 100 mg once daily for 3 days (optional loading) OR 10–20 mg once daily without loading

Titration Begin at 10 mg daily in patients at risk for intolerance; increase to 20 mg based on response and tolerability

Usual maintenance dose 20 mg once daily

Maximum dose 20 mg once daily

Clinical Notes:

• Efficacy comparable to methotrexate in certain studies

• Often used as second-line agent after methotrexate failure or intolerance

• Duration: Long-term therapy as per disease activity

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

1. Systemic Lupus Erythematosus (Non-renal, Mild-to-Moderate)

Parameter Details

Dose 10–20 mg once daily

Duration Long-term; as per disease activity and response

Status OFF-LABEL — Specialist only

Evidence Indian rheumatologist experience; international case series and cohort data

1. Sarcoidosis (Extrapulmonary Forms)

Parameter Details

Dose 10–20 mg once daily

Duration Variable; dependent on disease response and steroid-sparing requirements

Status OFF-LABEL — Specialist only

Evidence International cohort studies and case series

PAEDIATRIC DOSING (Specialist Only)

Primary Indications (Approved / Standard in India):

Not applicable — Leflunomide is NOT approved for paediatric use in India.

Secondary Indications — Paediatric Doses (Off-label, if any):

Juvenile Idiopathic Arthritis (JIA)

Status: OFF-LABEL — Use only under paediatric rheumatologist supervision in specialised centres

Age/Weight Eligibility: ≥3 years AND ≥10 kg body weight

Body Weight Dose Maximum Dose

10–20 kg 10 mg every alternate day 10 mg/day

20–40 kg 10 mg once daily 10 mg/day

40 kg 20 mg once daily 20 mg/day

Duration: Long-term; as per disease control

Evidence: WHO supportive sources; IAP consensus; international paediatric rheumatology experience

Safety Notes:

• Loading dose is NOT recommended in children

• Mandatory monitoring: LFTs and CBC at baseline, then every 2–4 weeks initially

• Not recommended below 3 years of age under any circumstances

• Should only be initiated after methotrexate failure or intolerance

• Known hypersensitivity to leflunomide or teriflunomide

• Severe hepatic impairment or pre-existing liver disease with ALT >2× ULN

• Pregnancy (teratogenic potential confirmed)

• Women of childbearing potential not using reliable contraception

• Breastfeeding mothers

• Severe immunodeficiency states (e.g., AIDS)

• Active serious infections including active tuberculosis

• Severe bone marrow suppression (pre-existing severe leukopenia, thrombocytopenia, or anaemia)

• Concurrent use with live vaccines

• Mild-to-moderate hepatic dysfunction — requires close LFT monitoring

• Moderate renal impairment — use with careful observation

• Latent tuberculosis — screen and treat before initiation; high prevalence in India

• History of interstitial lung disease — may exacerbate pulmonary fibrosis

• Alcohol consumption — advise complete abstinence due to compounded hepatotoxicity

• Pre-existing peripheral neuropathy — may worsen; can be dose-limiting

• Hypertension — blood pressure elevation possible; monitor regularly

• Planned surgery — consider drug washout if immunosuppression-related complications anticipated

• Concurrent methotrexate therapy — heightened hepatotoxicity risk

Parameter Details

Risk Category Contraindicated — confirmed teratogenicity in animal and human data

Preferred Alternatives Hydroxychloroquine, sulfasalazine (as per Indian obstetric rheumatology practice)

When It May Be Used Only after extensive washout and confirmed undetectable plasma metabolite levels

Monitoring Serum β-hCG at baseline mandatory; strict contraception throughout therapy

Important:

• Pregnancy must be excluded before initiating therapy

• If pregnancy occurs or is planned: Cholestyramine washout protocol (8 g three times daily for 11 days) to accelerate drug elimination

• Verify plasma teriflunomide level <0.02 mg/L on two occasions, 14 days apart

Parameter Details

Compatibility Not compatible with breastfeeding — avoid use

Drug Levels in Milk Active metabolite assumed to be excreted; quantitative data limited

Preferred Alternatives Hydroxychloroquine, sulfasalazine

Monitoring in Infant If inadvertent exposure: monitor for diarrhoea, poor feeding, and signs of immunosuppression

• Recommended starting dose: 10 mg once daily; skip loading dose

• Titration: Slower titration recommended due to reduced hepatic reserve

• Extra risks:

• Higher incidence of elevated transaminases

• Increased susceptibility to pancytopenia

• Greater risk of infections (especially if comorbid diabetes or renal impairment)

• Peripheral neuropathy more common

• Monitoring: More frequent LFTs and CBC; regular BP checks

Interacting Drug Effect & Mechanism Action

Methotrexate Additive hepatotoxicity risk Avoid combination or use with strict LFT monitoring every 2 weeks

Rifampicin Induces CYP enzymes → increased active metabolite (teriflunomide) levels; paradoxical toxicity Avoid combination; monitor if unavoidable

Cholestyramine / Activated charcoal Binds teriflunomide in GI tract → markedly reduced drug levels Used therapeutically for rapid drug elimination; avoid if therapeutic effect needed

Warfarin Unpredictable INR elevation; mechanism unclear Monitor INR closely; adjust warfarin dose as needed

Live vaccines Risk of vaccine-strain infection due to immunosuppression Contraindicated during therapy and for 6 months post-discontinuation

Interacting Drug Effect Recommendation

NSAIDs (diclofenac, ibuprofen) Slight increase in leflunomide exposure; additive GI and hepatic effects Monitor LFTs and GI symptoms

CYP2C8 inhibitors (gemfibrozil, clopidogrel) Increased teriflunomide levels Use with caution; monitor for toxicity

CYP1A2/CYP3A4 inducers (carbamazepine, phenytoin, phenobarbital) May reduce leflunomide efficacy Monitor clinical response

Teriflunomide Same active metabolite — avoid concurrent use Contraindicated

Hepatotoxic drugs (statins, azole antifungals, isoniazid) Additive liver injury risk Enhanced LFT monitoring

• Diarrhoea (most frequent — especially with loading dose)

• Nausea, dyspepsia, abdominal discomfort

• Elevated liver transaminases (ALT/AST)

• Hypertension

• Headache

• Alopecia (usually reversible upon dose reduction or discontinuation)

• Rash, pruritus

• Weight loss

• Respiratory tract infections

Adverse Effect Notes

Severe hepatotoxicity Can be fatal; immediate discontinuation and washout if ALT >3× ULN with symptoms

Pancytopenia / Agranulocytosis Stop drug; initiate supportive care

Severe infections Including opportunistic infections (TB reactivation, Pneumocystis)

Interstitial lung disease / Pulmonary fibrosis May be fatal; discontinue immediately if new respiratory symptoms

Peripheral neuropathy May be irreversible; consider dose reduction or discontinuation

Stevens-Johnson Syndrome / Toxic Epidermal Necrolysis Rare; immediate discontinuation and hospitalisation required

Severe hypertension Monitor BP; treat accordingly

First 6 months LFTs and CBC every 2–4 weeks

Long-term LFTs monthly for 6 months → then every 2–3 months; CBC every 3 months; BP at each visit

Ongoing Periodic assessment for peripheral neuropathy symptoms; annual TB screening if high-risk

Action Thresholds:

• ALT >3× ULN: Reduce dose or discontinue

• ALT >3× ULN with symptoms OR >5× ULN: Discontinue and initiate cholestyramine washout

• Arava (Sanofi)

• Lefra (Ipca)

• Lefno (Intas)

• Lefumide (Cipla)

• Flonida (Zydus)

• Leflox (Torrent)

• Lefide (Sun Pharma)

Notes:

• Not included in NLEM; not under NPPA price control

• Available through private retail pharmacies only

• No government supply under public health programmes

1. Skip the loading dose — This is standard practice among Indian rheumatologists to minimise early diarrhoea and GI intolerance

1. Screen for TB before initiation — Given high TB prevalence in India, exclude latent and active TB; treat latent TB before starting leflunomide

1. Cholestyramine washout is essential — If toxicity, serious infection, or planned pregnancy: 8 g cholestyramine three times daily for 11 days accelerates elimination

1. Alopecia is usually reversible — Reassure patients; often improves with dose reduction to 10 mg daily

1. Not interchangeable with teriflunomide — Although teriflunomide is the active metabolite, it is approved for multiple sclerosis, not rheumatic diseases; avoid confusion

1. Alcohol abstinence is mandatory — Emphasise this at every visit due to synergistic hepatotoxicity

rheumatoid arthritis; psoriatic arthritis; DMARD; leflunomide; immunosuppressant; hepatotoxicity; pregnancy-contraindicated; JIA off-label; pyrimidine inhibitor; Indian rheumatology

RxIndia v1.0 — 10 Jan 2025

• CDSCO approved product information

• Indian Pharmacopoeia

• API Textbook of Medicine

• AIIMS Rheumatology Protocols

• Indian Rheumatology Association Practice Recommendations

• NLEM (reviewed — drug not included)

• WHO Model Formulary (supportive reference for paediatric dosing)

• Goodman & Gilman's The Pharmacological Basis of Therapeutics

• Harrison's Principles of Internal Medicine