Schedule H

Oral

• Tablets: 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg

• Tablets for oral suspension (transplant formulation): 0.25 mg, 0.5 mg, 0.75 mg

INDICATIONS + DOSING — FOR CLINICIAN USE ONLY

Primary Indications (Approved / Standard in India)

1. Advanced Renal Cell Carcinoma (after failure of VEGF-targeted therapy)

Parameter Recommendation

Starting dose 10 mg once daily

Titration Not routinely required

Usual maintenance dose 10 mg once daily

Maximum dose 10 mg once daily

Clinical notes Continue until disease progression or unacceptable toxicity; consider discontinuation if no clinical benefit after 8 weeks; take at same time daily with or without food consistently

Dose modification for toxicity:

• Grade 3 non-haematological toxicity: Hold until ≤Grade 1, then resume at 5 mg daily

• Grade 4 toxicity: Discontinue permanently

1. Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer (postmenopausal women, in combination with exemestane)

Parameter Recommendation

Starting dose 10 mg once daily (with exemestane 25 mg daily)

Titration Not applicable

Usual maintenance dose 10 mg once daily

Maximum dose 10 mg once daily

Clinical notes Continue combination until disease progression or unacceptable toxicity

Dose modification:

• Grade 2 stomatitis: Consider dose reduction to 5 mg daily

• Grade ≥3 adverse events: Reduce to 5 mg once daily after recovery

1. Subependymal Giant Cell Astrocytoma (SEGA) associated with Tuberous Sclerosis Complex (TSC)

When surgical resection not feasible

Parameter Recommendation

Starting dose 4.5 mg/m² once daily

Titration Adjust based on trough concentration every 2 weeks

Target trough level 5–15 ng/mL

Usual maintenance dose Individualized per therapeutic drug monitoring

Maximum dose As tolerated to achieve target trough

Clinical notes Therapeutic drug monitoring mandatory; assess tumour volume at 3 months

1. Renal Angiomyolipoma associated with Tuberous Sclerosis Complex (TSC)

Not requiring immediate surgery

Parameter Recommendation

Starting dose 10 mg once daily

Titration Adjust to achieve trough 5–15 ng/mL

Usual maintenance dose 10 mg once daily (adjusted per levels)

Maximum dose Per therapeutic drug monitoring

Clinical notes Evaluate response at 6 months; discontinue if no objective response; ensure effective contraception

1. Prophylaxis of Organ Rejection — Kidney Transplant

Used with calcineurin inhibitor and corticosteroids

Parameter Recommendation

Starting dose 0.75 mg twice daily

Titration Adjust to achieve trough 3–8 ng/mL (with standard-dose cyclosporine) or 6–10 ng/mL (with reduced cyclosporine)

Usual maintenance dose 0.75–1 mg twice daily

Maximum dose 1.5 mg twice daily

Clinical notes Initiate as soon as possible post-transplant; therapeutic drug monitoring essential; cyclosporine dose reduction required to minimize nephrotoxicity

1. Prophylaxis of Organ Rejection — Liver Transplant

Used with reduced-dose tacrolimus and corticosteroids

Parameter Recommendation

Starting dose 1 mg twice daily (initiate approximately 30 days post-transplant)

Titration Adjust to achieve trough 3–8 ng/mL

Usual maintenance dose 1 mg twice daily

Maximum dose Per trough levels and tolerability

Clinical notes Not for de novo use immediately post-transplant; requires specialist transplant hepatologist supervision; tacrolimus must be reduced concurrently

Secondary Indications — Adults (Off-label)

Indication Dose Duration Notes Evidence

Pancreatic Neuroendocrine Tumours (well-differentiated, progressive) 10 mg once daily Until progression or intolerance OFF-LABEL; Specialist oncologist only RADIANT-3 trial

Non-functional Neuroendocrine Tumours of Lung/GI origin (progressive) 10 mg once daily Until progression or intolerance OFF-LABEL; Specialist only; monitor for pneumonitis RADIANT-4 trial

PAEDIATRIC DOSING (Specialist Only)

Primary Indications

1. Subependymal Giant Cell Astrocytoma (SEGA) — TSC-associated

Age ≥1 year

BSA-based dosing Starting dose Target trough Monitoring

All paediatric patients 4.5 mg/m² once daily 5–15 ng/mL TDM at 2 weeks, then after each dose change

Dose adjustment:

• Increase by 1–2 mg if trough <5 ng/mL

• Decrease if trough >15 ng/mL or toxicity occurs

Safety monitoring:

• CBC, LFTs, lipids, glucose at baseline and periodically

• Monitor growth parameters

• Screen for infections

1. Renal Angiomyolipoma — TSC-associated

Age ≥1 year

Parameter Recommendation

Starting dose 4.5 mg/m² once daily

Titration Target trough 5–15 ng/mL

Monitoring Same as SEGA indication

Secondary Indications — Paediatrics (Off-label)

Indication Age Dose Notes Evidence

Kidney transplant rejection prophylaxis ≥2 years BSA-based; target trough 3–8 ng/mL OFF-LABEL; Specialist transplant centre only Institutional protocols, cohort data

Not recommended: Below 1 year of age except under specialist supervision at tertiary centres

Hepatic Impairment Oncology Indications (10 mg base dose) Transplant Indications

Mild (Child-Pugh A) Reduce to 7.5 mg once daily Reduce dose by ~33%; monitor trough levels

Moderate (Child-Pugh B) Reduce to 5 mg once daily Reduce dose by ~50%; monitor trough levels

Severe (Child-Pugh C) Use 2.5 mg once daily only if benefit outweighs risk; specialist supervision essential Avoid use; if essential, reduce dose significantly and monitor closely

• Hypersensitivity to everolimus, sirolimus, or other rapamycin derivatives

• Concurrent administration of live attenuated vaccines

• Severe uncontrolled infection

• Pregnancy (unless life-threatening indication with no alternative)

• History of non-infectious pneumonitis or interstitial lung disease

• Pre-existing pulmonary disease

• Active or latent tuberculosis (screen before initiation)

• Poorly controlled diabetes mellitus

• Dyslipidaemia

• Chronic wounds or planned surgery (impaired wound healing)

• Concurrent strong CYP3A4 inhibitors or inducers

• Hereditary galactose intolerance (tablets contain lactose)

• Elderly patients (increased sensitivity to adverse effects)

• Hepatitis B carriers (risk of reactivation)

Parameter Recommendation

Risk category Contraindicated (embryo-fetal toxicity in animal studies)

Use in pregnancy Only if life-threatening indication and no safer alternative

Preferred alternatives Discuss with transplant/oncology specialist; no established safe alternative for most indications

Contraception Effective contraception required during treatment and for 8 weeks after last dose

Monitoring if used Fetal growth monitoring; specialist obstetric oversight mandatory

Parameter Recommendation

Breastfeeding compatibility Not recommended

Expected milk levels Likely present (lipophilic compound)

Preferred alternatives Discontinue breastfeeding if treatment essential

Infant monitoring Not applicable — breastfeeding should be avoided

Parameter Recommendation

Starting dose Same as younger adults

Titration Consider slower titration if multiple comorbidities

Special considerations Higher risk of stomatitis, infections, pneumonitis, renal impairment, and fatigue

Monitoring More frequent renal function, glucose, and lipid monitoring; assess for drug interactions due to polypharmacy

Interacting Drug/Class Effect Recommendation

Strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin, ritonavir) Marked increase in everolimus levels Avoid concurrent use; if unavoidable, reduce everolimus to 2.5 mg daily and monitor levels

Strong CYP3A4 inducers (rifampicin, phenytoin, carbamazepine, phenobarbital) Significant reduction in everolimus levels Avoid concurrent use; if essential, double everolimus dose and monitor trough levels

Live attenuated vaccines Risk of disseminated infection Contraindicated during treatment

Cyclosporine Increases everolimus exposure Mandatory dose adjustment of both drugs; monitor levels closely

Tacrolimus (high doses) Increased nephrotoxicity risk Use reduced tacrolimus doses; monitor renal function and drug levels

Interacting Drug/Class Effect Recommendation

Moderate CYP3A4 inhibitors (erythromycin, fluconazole, verapamil, diltiazem) Increased everolimus levels Use with caution; consider 50% dose reduction

Grapefruit juice Inhibits CYP3A4 Avoid consumption during therapy

Statins (simvastatin, atorvastatin) Increased risk of myopathy/rhabdomyolysis Monitor CK levels; use lower statin doses

ACE inhibitors Increased risk of angioedema Monitor closely; use with caution

Antitubercular drugs (rifampicin, rifabutin) Reduced everolimus efficacy Prefer alternative anti-TB regimens if possible

P-glycoprotein inhibitors (amiodarone) Increased everolimus absorption Monitor trough levels

• Stomatitis and oral ulceration (very common; up to 40%)

• Rash and acneiform dermatitis

• Fatigue and asthenia

• Diarrhoea

• Nausea

• Peripheral oedema

• Hyperglycaemia

• Hypercholesterolaemia and hypertriglyceridaemia

• Decreased appetite

• Dysgeusia

• Headache

• Epistaxis

• Cough

Adverse Effect Action Required

Non-infectious pneumonitis / Interstitial lung disease Discontinue immediately; investigate; corticosteroids may be needed

Severe infections (opportunistic including CMV, PCP, TB) Hold therapy; treat infection; specialist input required

Renal failure (especially in transplant) Monitor closely; adjust calcineurin inhibitor doses

Hepatotoxicity Monitor LFTs; discontinue if severe

Severe myelosuppression (neutropenia, thrombocytopenia, anaemia) Hold until recovery; dose reduction on restart

Impaired wound healing Delay initiation peri-operatively; avoid if recent surgery

Angioedema (especially with concurrent ACE inhibitors) Discontinue; supportive care

Severe hypersensitivity / Anaphylaxis Discontinue permanently

Baseline:

• Complete blood count

• Renal function (serum creatinine, eGFR)

• Liver function tests

• Fasting lipid profile

• Fasting blood glucose / HbA1c

• Hepatitis B and C screening

• Tuberculosis screening (chest X-ray, Mantoux/IGRA)

• Pregnancy test (women of childbearing potential)

After initiation / dose change:

• Everolimus trough levels (transplant and TSC indications): at 2 weeks, then after each dose change

• CBC weekly for first month, then monthly

• Monitor for oral ulcers, respiratory symptoms, infections

Long-term:

• Renal function: every 1–3 months

• Liver function: every 1–3 months

• Fasting lipids: every 3–6 months

• Blood glucose / HbA1c: every 3 months

• Pulmonary assessment if symptomatic (cough, dyspnoea)

• Periodic dermatological evaluation

Brand Name Manufacturer Primary Use

Afinitor Novartis Oncology

Certican Novartis Transplant

Rolimus Cipla Oncology/Transplant

Evertor Biocon Oncology

Evermil Intas Oncology

Note: Afinitor and Certican are NOT interchangeable due to formulation differences

Strength Approximate Price (per tablet)

0.25 mg (transplant) ₹150–400

0.5 mg (transplant) ₹250–500

0.75 mg (transplant) ₹350–600

2.5 mg (oncology) ₹800–1500

5 mg (oncology) ₹1500–3500

10 mg (oncology) ₹2500–6500

• Not included in NLEM

• Not available under Jan Aushadhi

• Significant inter-brand price variation

• Patient assistance programmes available through some manufacturers

1. Stomatitis prevention: Prophylactic alcohol-free dexamethasone oral rinse (0.5 mg/5 mL, swish and spit four times daily) can reduce incidence and severity of oral mucositis

1. Therapeutic drug monitoring: Essential for transplant and TSC indications; oncology use typically does not require routine TDM

1. Peri-operative management: Hold everolimus for at least 1 week before elective surgery due to impaired wound healing; restart only after adequate wound healing

1. Metabolic effects: Proactive management of hyperglycaemia and dyslipidaemia is important; may require initiation of statins or glucose-lowering agents

1. Formulation awareness: Transplant formulations (Certican) and oncology formulations (Afinitor) are not interchangeable; ensure correct product is dispensed

1. Switching from sirolimus: Allow minimum 24-hour washout before initiating everolimus if switching between rapalogs

everolimus; mTOR inhibitor; renal cell carcinoma; breast cancer; tuberous sclerosis; transplant immunosuppression; SEGA; renal angiomyolipoma; therapeutic drug monitoring; pregnancy-contraindicated; Schedule H; NLEM-excluded

RxIndia v1.0 — 24 Apr 2025

• CDSCO approved prescribing information (Afinitor, Certican)

• Indian Pharmacopoeia

• National Formulary of India 2021

• AIIMS Transplant Unit Protocols

• AIIMS Oncology Treatment Guidelines

• API Textbook of Medicine

• Goodman & Gilman's The Pharmacological Basis of Therapeutics

• RADIANT-3 and RADIANT-4 trials (off-label NET indications)

• WHO Essential Medicines List 2023 (paediatric TSC use)