Schedule H

Oral

• Tablets: 1 mg, 2 mg

• Oral solution: 1 mg/mL

INDICATIONS + DOSING — FOR CLINICIAN USE ONLY

Primary Indications (Approved / Standard in India)

1. Renal Transplant — Prophylaxis of Organ Rejection

(In low- to moderate-immunologic risk patients; used with cyclosporine and corticosteroids)

Parameter With Concurrent Cyclosporine After Cyclosporine Withdrawal

Starting dose 6 mg oral loading dose on Day 1 Not applicable (continuation phase)

Titration Adjust based on trough levels every 5–7 days Adjust to achieve higher target trough

Usual maintenance dose 2 mg orally once daily 2–5 mg orally once daily

Maximum dose Guided by trough levels (target 4–12 ng/mL) Guided by trough levels (target 12–20 ng/mL)

Clinical Notes:

• Do not initiate earlier than 24 hours post-transplant surgery

• Dose must be individualized using whole-blood sirolimus trough levels (LC-MS/MS preferred)

• Cyclosporine withdrawal typically considered 2–4 months post-transplant in stable patients

• Contraindicated in liver transplant recipients due to increased risk of hepatic artery thrombosis

• Contraindicated in lung transplant recipients due to increased risk of bronchial anastomotic dehiscence

1. Lymphangioleiomyomatosis (LAM)

(For patients with advanced disease or declining pulmonary function)

Parameter Recommendation

Starting dose 2 mg orally once daily

Titration Adjust every 7–14 days based on trough levels and tolerability

Usual maintenance dose 1–5 mg orally once daily (individualized)

Maximum dose Guided by trough levels (target 5–15 ng/mL)

Clinical Notes:

• Clinical improvement typically observed within 3–6 months

• Continue therapy as long as clinical benefit maintained

• Specialist supervision mandatory

Secondary Indications — Adults (Off-label)

Indication Dose Duration Notes

Tuberous Sclerosis Complex — Renal Angiomyolipoma Starting: 1–2 mg/day orally; Titrate to trough 5–15 ng/mL Long-term; reassess periodically OFF-LABEL. Specialist only. Evidence: EXIST-2 trial, Indian tertiary centre experience

Cardiac Allograft Vasculopathy (post heart transplant) Starting: 1 mg/day; Titrate to trough 6–12 ng/mL Indefinite with monitoring OFF-LABEL. Specialist only. Used in select centres as CNI-sparing strategy

Note: Sirolimus-eluting coronary stents deliver drug locally; systemic dosing not applicable.

PAEDIATRIC DOSING (Specialist Only)

Primary Indications (Approved / Standard in India)

1. Renal Transplant — Prophylaxis of Organ Rejection

(Age ≥13 years; specialist supervision mandatory)

Parameter Recommendation

Starting dose Loading dose: 3 mg/m² orally once on Day 1

Titration Adjust every 5–7 days based on trough levels

Usual maintenance dose 1 mg/m² orally once daily

Maximum dose Guided by trough levels

Target Trough Levels:

• With concurrent cyclosporine: 4–12 ng/mL

• After cyclosporine withdrawal: 12–20 ng/mL

Safety Monitoring:

• Sirolimus trough levels every 5–7 days after dose changes until stable

• Complete blood count weekly initially, then monthly

• Lipid profile at baseline, 1 month, then every 3 months

• Growth velocity monitoring (particularly with concurrent corticosteroids)

• Renal function every 2–4 weeks initially

Minimum Age: Safety and efficacy not established below 13 years in India. Use in younger children only under paediatric transplant specialist supervision with careful benefit-risk assessment.

Secondary Indications — Paediatrics (Off-label)

Indication Dose Duration Notes

Tuberous Sclerosis Complex — Renal Angiomyolipoma or SEGA 1 mg/m²/day orally; Titrate to trough 5–15 ng/mL Long-term; reassess periodically OFF-LABEL. Specialist only. Evidence: EXIST-1/EXIST-2 trials, limited paediatric data

Not recommended below 13 years except under specialist supervision in tertiary centres.

• No dose adjustment required for renal impairment

• Sirolimus is not significantly removed by haemodialysis or peritoneal dialysis

• Continue therapeutic drug monitoring as usual

Note: Loading dose generally does not require adjustment, but close monitoring essential.

• Known hypersensitivity to sirolimus, its derivatives, or any excipient

• Known hypersensitivity to macrolide antibiotics (structural similarity)

• Liver transplant recipients (increased risk of hepatic artery thrombosis and graft failure)

• Lung transplant recipients (increased risk of bronchial anastomotic dehiscence)

• Concurrent use with strong CYP3A4 inhibitors without appropriate dose adjustment and monitoring

• Recent major surgery or wounds: Sirolimus impairs wound healing; delay initiation until adequate healing achieved

• Hyperlipidaemia: May significantly elevate cholesterol and triglycerides; pre-existing dyslipidaemia requires careful monitoring

• Concurrent use with calcineurin inhibitors: Increased nephrotoxicity risk; consider cyclosporine withdrawal protocols

• Pulmonary symptoms: Monitor for interstitial lung disease; any unexplained cough or dyspnoea warrants investigation

• Infection risk: Increased susceptibility to opportunistic infections; avoid live vaccines

• Concurrent use with CYP3A4 inducers or inhibitors: Significant effect on sirolimus levels

• Proteinuria: May worsen existing proteinuria

• Skin malignancies: Increased risk with sun exposure; advise sun protection

Aspect Recommendation

Risk category Contraindicated unless no suitable alternatives available

Overall safety Animal studies show embryo-foetal toxicity; human data limited

Preferred alternatives Azathioprine (better safety profile in pregnancy); Tacrolimus under specialist guidance

When it may be used Only if maternal benefit clearly outweighs foetal risk and no alternatives; specialist supervision mandatory

Contraception Effective contraception required during treatment and for at least 12 weeks after discontinuation

Monitoring If exposed: Detailed fetal anatomical ultrasound, growth monitoring, maternal-foetal medicine referral

Aspect Recommendation

Compatibility Not compatible with breastfeeding

Expected levels in milk Unknown but likely present; drug is lipophilic

Recommendation Avoid breastfeeding during treatment and for at least 2 months after last dose

Preferred alternatives Tacrolimus (more data available, considered relatively safer)

Infant monitoring (if inadvertent exposure) Weight gain, feeding difficulties, signs of immunosuppression, oral mucosal changes

• Starting dose: Same as adults; consider starting at lower end of dosing range

• Titration: Slower titration recommended; allow longer intervals between dose adjustments

• Special considerations:

• Higher susceptibility to infections due to age-related immunosenescence

• Increased risk of impaired wound healing

• More frequent monitoring for cytopenias

• Baseline and periodic assessment of renal function (age-related decline)

• Monitor closely for pulmonary symptoms

• Higher incidence of hyperlipidaemia requiring lipid-lowering therapy

Drug/Class Mechanism Clinical Effect Recommendation

Strong CYP3A4 inhibitors (Ketoconazole, Itraconazole, Clarithromycin, Ritonavir) Inhibits sirolimus metabolism Marked increase in sirolimus levels; toxicity risk Avoid combination; if unavoidable, reduce sirolimus dose significantly and monitor trough levels closely

Strong CYP3A4 inducers (Rifampicin, Rifabutin, Phenytoin, Carbamazepine, Phenobarbital) Induces sirolimus metabolism Marked decrease in sirolimus levels; therapeutic failure risk Avoid combination if possible; if unavoidable, increase sirolimus dose substantially and monitor trough levels closely

Cyclosporine Inhibits CYP3A4 and P-glycoprotein Increases sirolimus exposure Administer sirolimus 4 hours after cyclosporine; monitor both drug levels

Grapefruit juice Inhibits intestinal CYP3A4 Increased sirolimus absorption and levels Avoid consumption during treatment

Live vaccines Immunosuppression Risk of disseminated infection Contraindicated during treatment and for period after discontinuation

Drug/Class Mechanism Clinical Effect Recommendation

Statins (particularly Simvastatin, Atorvastatin) Additive myotoxicity; possible CYP interaction Increased risk of rhabdomyolysis Use with caution; monitor CPK; consider Pravastatin (less interaction potential)

Fluconazole Moderate CYP3A4 inhibition Increased sirolimus levels Monitor sirolimus trough levels; may need dose reduction

ACE inhibitors, ARBs Unknown; possibly pharmacodynamic Increased risk of angioedema; potential for renal function deterioration Use with caution; monitor for angioedema and renal function

Diltiazem, Verapamil Moderate CYP3A4 inhibition Increased sirolimus levels Monitor trough levels; consider dose reduction

Tacrolimus Both are immunosuppressants; overlapping toxicity Increased nephrotoxicity and immunosuppression Combination used cautiously in specific protocols; close monitoring required

• Hyperlipidaemia (elevated total cholesterol, LDL, triglycerides) — very common

• Peripheral oedema

• Oral ulcers/stomatitis

• Anaemia

• Thrombocytopenia

• Leukopenia

• Diarrhoea, nausea

• Acneiform rash

• Arthralgia

• Headache

• Hypertension

• Interstitial lung disease/pneumonitis: May present with cough, dyspnoea, fever; requires immediate evaluation and possible discontinuation

• Hepatic artery thrombosis: Reported in liver transplant recipients — sirolimus is contraindicated in this population

• Bronchial anastomotic dehiscence: Reported in lung transplant recipients — sirolimus is contraindicated in this population

• Thrombotic microangiopathy (including HUS/TTP): Especially when combined with calcineurin inhibitors

• Angioedema: Risk increased with concurrent ACE inhibitor use

• Severe infections: Including opportunistic infections (PCP, CMV reactivation, fungal infections)

• Lymphocele: Common post-renal transplant; may require intervention

• Delayed wound healing/wound dehiscence: Consider in peri-operative period

• Posterior reversible encephalopathy syndrome (PRES): Rare

• Lymphoproliferative disorders: Long-term risk with all immunosuppressants

After initiation/dose change Sirolimus whole-blood trough level (Day 5–7 post dose change; repeat until stable); CBC weekly for first month; Lipid profile at 2–4 weeks

Long-term Sirolimus trough levels monthly (stable patients) or as clinically indicated; CBC every 1–2 months; Lipid profile every 3 months; Renal function every 3 months; Liver function every 3–6 months; Urinalysis for proteinuria every 3–6 months; Dermatological screening annually (skin malignancies); Clinical assessment for pulmonary symptoms at each visit

• Rapacan® (Biocon)

• Siromus® (Zydus Cadila)

• Siroboon® (Intas)

• Sirolim® (Cipla)

• Rapamune® (Pfizer) — limited availability

NLEM Status: Not included in NLEM 2022

Note: Prices vary significantly between brands; government supply availability limited.

• Therapeutic drug monitoring is mandatory — sirolimus has narrow therapeutic index and significant inter-patient variability in pharmacokinetics; use LC-MS/MS assay for accurate trough measurement.

• Always stagger with cyclosporine — administer sirolimus 4 hours after cyclosporine to minimize drug interaction effect on sirolimus absorption.

• Delay initiation post-surgery — wait until adequate wound healing (typically 4–6 weeks post-transplant in elective settings) due to significant impairment of wound healing.

• Proactive lipid management — hyperlipidaemia is expected; initiate statin therapy early, but prefer pravastatin over simvastatin to minimize interaction risk.

• Vigilance for pulmonary toxicity — counsel patients about symptoms of cough and dyspnoea; low threshold for chest imaging if symptoms develop.

• Oral ulcers are common and dose-related — may respond to dose reduction; symptomatic management with topical agents helpful.

sirolimus; mTOR inhibitor; immunosuppressant; renal transplant; LAM; lymphangioleiomyomatosis; tuberous sclerosis; nephrology; therapeutic drug monitoring; CYP3A4 substrate

RxIndia v1.0 — 12 Apr 2025

• CDSCO product inserts

• Indian Pharmacopoeia

• AIIMS Transplant Immunosuppression Protocols

• API Textbook of Medicine

• Goodman & Gilman's The Pharmacological Basis of Therapeutics

• Harrison's Principles of Internal Medicine

• EXIST-1 and EXIST-2 trials (for tuberous sclerosis off-label use)

• Indian paediatric nephrology specialist centre protocols