Schedule H

Intravenous infusion

Formulation Strength

Solution for IV infusion (single-use vial) 300 mg/15 mL

INDICATIONS + DOSING — FOR CLINICIAN USE ONLY

Primary Indications (Approved / Standard in India):

1. Relapsing Forms of Multiple Sclerosis (RMS)

Includes relapsing-remitting MS (RRMS) and active secondary progressive MS with relapses.

Parameter Recommendation

Starting dose 300 mg IV infusion over 1 hour, once every 4 weeks

Titration Not applicable

Usual maintenance dose 300 mg IV every 4 weeks

Maximum dose 300 mg per infusion (do not exceed)

Clinical Notes:

• Reserved for patients with inadequate response to, or inability to tolerate, first-line disease-modifying therapies (interferon-beta, glatiramer acetate)

• Also indicated as first-line in rapidly evolving severe RRMS

• JC virus (JCV) antibody testing mandatory before initiation and periodically thereafter

• Administer only in settings equipped to manage anaphylaxis

• Observe patient during infusion and for 1 hour post-infusion

• Do not use concurrently with other immunosuppressants or biologics

Secondary Indications – Adults (Off-label):

Indication Dose Duration Notes

Moderate-to-severe Crohn's disease (refractory) 300 mg IV every 4 weeks Assess response by 12 weeks; discontinue if no benefit OFF-LABEL in India; Specialist gastroenterologist only; Evidence: ENACT-1, ENACT-2, ENCORE trials

PAEDIATRIC DOSING (Specialist Only)

Primary Indications:

Relapsing Multiple Sclerosis in Adolescents — OFF-LABEL

≥12 years >40 kg 300 mg IV Every 4 weeks

≥12 years ≤40 kg Weight-based dosing not established Specialist discretion

Clinical Notes:

• Not approved by CDSCO for paediatric use; use based on international data and specialist judgement

• Use only under paediatric neurologist supervision

• Same monitoring as adults required

Safety Monitoring:

• Baseline and periodic: JCV antibody status, MRI brain, CBC, LFTs

• Monitor for infusion reactions

• Annual MRI brain surveillance for PML detection

Age Restrictions:

• Not recommended in children <12 years except in clinical trial settings under specialist supervision

Secondary Indications – Paediatrics (Off-label):

Not applicable. No established paediatric off-label indications beyond MS in India.

• Known hypersensitivity to natalizumab or any excipient

• History of progressive multifocal leukoencephalopathy (PML)

• Current serious active infection (acute or chronic)

• Concurrent use with other immunosuppressants (azathioprine, methotrexate, ciclosporin, mycophenolate)

• Concurrent use with other biologic immunomodulators (e.g., rituximab, ocrelizumab, alemtuzumab)

• Known active malignancy (except treated basal cell carcinoma)

• Immunocompromised states (including HIV infection with low CD4 counts)

• JCV antibody-positive status — significantly elevated PML risk, especially with:

• Prior immunosuppressant use

• Treatment duration >2 years

• High JCV antibody index (>1.5)

• Prior immunosuppressant therapy — allow adequate washout before initiation

• History of recurrent infections

• Hepatic dysfunction — monitor LFTs; discontinue if significant elevation

• Elderly patients — increased susceptibility to infections

• Patients with history of malignancy

• Women of childbearing potential — counsel on contraception

Parameter Recommendation

Overall safety Limited human data; animal studies show reproductive toxicity at high doses

Risk category Avoid unless benefit clearly outweighs risk

Preferred alternatives Glatiramer acetate, Interferon-beta (in specific cases with specialist input)

When may be used Severe/aggressive MS with no alternatives; after multidisciplinary discussion

Maternal monitoring LFTs, CBC, clinical status

Fetal monitoring Growth surveillance; neonatal haematological assessment at birth

Special note Third trimester exposure associated with transient neonatal anaemia and thrombocytopenia

Parameter Recommendation

Compatibility Not recommended during breastfeeding

Milk excretion Present in breast milk (IgG antibody); levels likely low but clinical significance unknown

Preferred alternatives Glatiramer acetate, Interferon-beta

Infant monitoring If breastfeeding unavoidable: monitor for feeding difficulties, infections, haematological abnormalities

Parameter Recommendation

Starting dose 300 mg IV every 4 weeks (same as younger adults)

Titration Not applicable

Special considerations Limited clinical experience in patients >65 years

Key risks Increased susceptibility to infections; higher PML risk with advanced age; hepatic function decline

Monitoring More frequent clinical assessment; baseline cognitive evaluation; closer infection surveillance

Interacting Drug/Class Effect & Recommendation

Immunosuppressants (azathioprine, methotrexate, ciclosporin, mycophenolate) Additive immunosuppression; significantly increased PML risk — Avoid concurrent use

Other biologic immunomodulators (rituximab, ocrelizumab, alemtuzumab, fingolimod) Synergistic immunosuppression — Avoid concurrent use; ensure adequate washout period before switching

Live attenuated vaccines Risk of vaccine-induced infection — Avoid during treatment and for at least 3 months post-discontinuation

Anti-CD20 therapies Profound B-cell depletion — Allow 6-month washout before initiating natalizumab

Interacting Drug/Class Effect & Recommendation

Systemic corticosteroids Additive immunosuppression — short-term use for relapses acceptable; avoid prolonged concurrent use

Inactivated vaccines May have reduced immunogenicity — assess serological response if clinically indicated

Hepatotoxic drugs (e.g., anti-TB drugs, statins, antiepileptics) Monitor LFTs closely when co-administered

Interferons (prior use) No direct interaction; standard washout before switching adequate

Note: Natalizumab is not metabolised via cytochrome P450 pathways; no significant CYP-mediated interactions expected.

• Headache

• Fatigue

• Arthralgia

• Urinary tract infection

• Nasopharyngitis and upper respiratory infections

• Infusion-related reactions (flushing, nausea, rigors, pruritus)

• Dizziness

• Nausea

• Depression

• Peripheral oedema

Adverse Effect Clinical Action

Progressive multifocal leukoencephalopathy (PML) High mortality/morbidity; permanent discontinuation required; urgent MRI and CSF JCV PCR; supportive care; consider plasmapheresis to accelerate drug clearance

Immune reconstitution inflammatory syndrome (IRIS) May occur after PML diagnosis/drug discontinuation; corticosteroids may be required

Severe hypersensitivity/anaphylaxis Discontinue infusion immediately; standard anaphylaxis management

Opportunistic infections (herpes encephalitis, cryptococcal meningitis) Discontinue; initiate appropriate antimicrobial therapy

Hepatotoxicity Discontinue if significant transaminase elevation (>5× ULN) with symptoms

Neonatal haematological abnormalities Transient anaemia, thrombocytopenia reported with third-trimester exposure

Each infusion visit Clinical assessment for new neurological symptoms; vital signs during and post-infusion; observation for infusion reactions (minimum 1 hour post-infusion)

Every 3–6 months CBC with differential; LFTs

Every 6 months (if JCV-negative) Repeat JCV antibody testing

Annually JCV antibody status (with index); MRI brain surveillance for subclinical PML (especially if JCV-positive or treatment >2 years)

If new neurological symptoms Urgent MRI brain and lumbar puncture for CSF JCV PCR

Brand Name Manufacturer Pack Size

Tysabri Biogen (imported) 300 mg/15 mL vial

Note: Limited availability; typically accessed through tertiary care centres or specialty import channels.

• Not included in NLEM 2022

• Not under NPPA price control

• Availability limited to select tertiary care centres and specialty neurology hospitals

• Patient assistance programmes may be available through manufacturer

• JCV antibody stratification is essential — PML risk increases substantially with positive JCV antibody status (especially index >1.5), prior immunosuppressant use, and treatment duration >2 years

• PML vigilance is non-negotiable — any new neurological symptom (cognitive changes, visual disturbances, motor weakness, speech abnormalities) warrants immediate MRI brain and CSF analysis

• Avoid concurrent or recent immunosuppression — allow adequate washout (typically 3–6 months depending on prior agent) before initiating natalizumab

• Do not stop abruptly without a plan — discontinuation without transition to another DMT may lead to severe rebound MS activity within 3–6 months

• Infusion reactions are usually manageable — premedication with antihistamines/paracetamol may reduce mild reactions; true anaphylaxis requires permanent discontinuation

• Extended interval dosing (EID) — some international centres use 6-week intervals in stable, JCV-positive patients to reduce PML risk; not yet standard in India but may be considered by specialists

natalizumab; multiple sclerosis; RRMS; monoclonal antibody; anti-integrin; PML risk; JCV monitoring; IV infusion; immunomodulator; specialist-only; NLEM-excluded

RxIndia v1.0 — 21 May 2025

• CDSCO approved product information (Tysabri)

• API Textbook of Medicine, 12th Edition

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

• Goodman & Gilman's The Pharmacological Basis of Therapeutics, 14th Edition

• AIIMS Neurology MS Treatment Protocols

• Tysabri product insert (imported pack, India)

• AFFIRM Trial (Polman et al., NEJM 2006) — efficacy data

• SENTINEL Trial — combination therapy data

• ENACT-1, ENACT-2, ENCORE trials — off-label Crohn's disease evidence only