Schedule H

Oral

• Mitotane 500 mg tablet (imported; limited availability — may require special procurement through oncology centres)

INDICATIONS + DOSING — FOR CLINICIAN USE ONLY

Primary Indications (Approved / Standard in India)

1. Adrenocortical Carcinoma (Advanced, Inoperable, or Metastatic)

Specialist oncology initiation only — standard therapy at tertiary cancer centres (AIIMS, Tata Memorial, SGPGI)

Parameter Recommendation

Starting dose 2–3 g/day orally, divided into 2–3 doses with meals (high-fat meals enhance absorption)

Titration Increase by 0.5–1 g/day every 1–2 weeks based on tolerability and serum mitotane levels

Usual maintenance dose 4–6 g/day in divided doses

Maximum dose 6–8 g/day (only with serum level monitoring; specialist supervision mandatory)

Target Serum Concentration: 14–20 mg/L (therapeutic range)

• Serum levels <14 mg/L: Subtherapeutic; consider dose escalation

• Serum levels >20 mg/L: Increased CNS toxicity risk; consider dose reduction

Clinical Notes:

• Administer with meals, preferably high-fat content, to enhance absorption

• Adrenal insufficiency develops in nearly all patients — initiate glucocorticoid replacement (Hydrocortisone 30–50 mg/day or equivalent) at treatment start

• Mineralocorticoid replacement (Fludrocortisone 0.1 mg/day) often required

• Continue therapy as long as clinical benefit observed or until disease progression/unacceptable toxicity

• Prolonged half-life (18–159 days) — effects persist weeks after discontinuation

1. Adjuvant Therapy Post-Resection of Adrenocortical Carcinoma

High-risk patients with incomplete resection or high Ki-67 index — specialist oncology decision

Parameter Recommendation

Starting dose 2–3 g/day orally in divided doses

Titration Escalate by 0.5–1 g/day every 1–2 weeks to achieve target serum levels

Usual maintenance dose 4–6 g/day

Maximum dose 6–8 g/day (with serum monitoring)

Clinical Notes:

• Duration of adjuvant therapy: Typically 2–5 years based on risk stratification

• Mandatory concurrent glucocorticoid and mineralocorticoid replacement

• Regular imaging surveillance for recurrence

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

Indication Dose Notes

Cushing's syndrome due to adrenocortical carcinoma 2–6 g/day in divided doses OFF-LABEL; Specialist only; Used to control hypercortisolism in inoperable cases; Based on international oncology practice and Indian tertiary centre experience

PAEDIATRIC DOSING (Specialist Only)

Primary Indications (Approved / Standard in India)

Adrenocortical Carcinoma in Children

Paediatric oncology specialist supervision mandatory

Parameter Recommendation

Starting dose 1–2 g/m²/day orally in 2–3 divided doses

Titration Increase gradually based on serum levels and tolerability; adjust every 1–2 weeks

Usual maintenance dose 3–4 g/m²/day (targeting serum level 14–20 mg/L)

Maximum dose Do not exceed 6 g/day total regardless of BSA

Safety Monitoring:

• Serum mitotane levels weekly during titration, then monthly

• Daily assessment for signs of adrenal insufficiency

• Mandatory glucocorticoid replacement (Hydrocortisone 10–15 mg/m²/day in divided doses)

• Mineralocorticoid replacement as needed

• Monitor growth parameters, CNS function, and hepatic enzymes

Minimum Age: Not recommended below 4 years of age except under paediatric oncology supervision with documented risk-benefit assessment

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

Not applicable. No established off-label paediatric indications in Indian practice.

Mild to moderate impairment No dose adjustment required

Severe impairment (eGFR <30) Use with caution; altered protein binding may affect drug levels; monitor serum mitotane levels closely

Dialysis Not dialysable due to high lipophilicity and protein binding; no supplemental dosing required

Note: Mitotane is hepatically metabolised; accumulation and toxicity risk increases with hepatic dysfunction.

• Known hypersensitivity to Mitotane or any excipient

• Pregnancy (teratogenic and fetotoxic)

• Concurrent use with Spironolactone (may block adrenal suppression effect)

• Shock or severe trauma (impaired stress response due to adrenal suppression)

• Adrenal insufficiency: Occurs in nearly all patients; initiate steroid replacement before or at treatment start; patients must carry steroid emergency card

• CNS toxicity: Drug is highly lipophilic and crosses blood-brain barrier; risk increases when serum levels >20 mg/L

• Prolonged tissue accumulation: Very long half-life; drug effects persist for weeks to months after discontinuation

• Surgery or trauma: Patients may not mount adequate stress response; increase steroid dose during acute illness or surgery

• Occupational handling: Cytotoxic precautions required for healthcare workers handling the drug

• Hormonal contraceptives: Efficacy reduced; advise non-hormonal contraception

• Thyroid function: May affect thyroid hormone binding; monitor TFTs if clinically indicated

Parameter Details

Overall safety Contraindicated — Teratogenic and fetotoxic in animal studies; no controlled human data

Recommendation Avoid pregnancy during treatment and for at least 2 years after discontinuation (due to prolonged tissue accumulation)

Preferred alternatives No alternative antineoplastic for adrenocortical carcinoma during pregnancy — defer treatment if possible

If life-threatening situation May be considered only with documented informed consent; specialist multidisciplinary team input mandatory

Monitoring Fetal ultrasound for structural abnormalities; fetal growth surveillance; neonatal adrenal function assessment

Parameter Details

Compatibility Not compatible — Contraindicated during breastfeeding

Excretion in milk Unknown but expected due to high lipophilicity

Recommendation Complete cessation of breastfeeding required if Mitotane therapy is necessary

Preferred alternatives No safe alternatives for adrenocortical carcinoma during lactation

Infant monitoring Not applicable — breastfeeding must be discontinued

Parameter Recommendation

Starting dose 1.5–2 g/day (lower range); increase cautiously

Titration Slower titration (0.5 g/day every 2 weeks) based on tolerability and serum levels

Special considerations Higher susceptibility to CNS toxicity (confusion, ataxia, somnolence); monitor cognition closely

Additional risks Falls risk due to CNS effects; altered renal/hepatic reserve may delay drug clearance; prolonged adrenal suppression

Interacting Drug Effect Management

Spironolactone Blocks Mitotane's adrenal suppression effect Avoid combination — contraindicated

Warfarin ↓ Anticoagulant effect (Mitotane induces CYP enzymes metabolising warfarin) Monitor INR frequently; may require significant warfarin dose increase

Hormonal contraceptives ↓ Efficacy (CYP3A4 induction) Advise non-hormonal contraception

Glucocorticoids (Hydrocortisone, Prednisolone, Dexamethasone) ↑ Clearance of corticosteroids (CYP3A4 induction) Higher than usual replacement doses required; use Hydrocortisone at 1.5–2× standard replacement

CNS depressants (Opioids, Benzodiazepines) Additive CNS depression Use with caution; monitor for excessive sedation

Interacting Drug Effect Management

Phenytoin, Carbamazepine, Phenobarbital Mutual induction; altered levels of both drugs Monitor antiepileptic levels; monitor Mitotane serum levels

Rifampicin Enhanced CYP induction; may alter Mitotane metabolism Monitor Mitotane serum levels closely

CYP3A4 substrates (Antifungals, HAART, many chemotherapeutics) ↓ Levels of CYP3A4 substrates Monitor efficacy of concomitant medications; dose adjustment may be needed

Levothyroxine May affect thyroid hormone binding/metabolism Monitor TFTs; adjust levothyroxine dose if needed

Fludrocortisone ↑ Clearance May require higher mineralocorticoid replacement doses

• Nausea and vomiting (very common; often dose-limiting)

• Anorexia and weight loss

• Lethargy and fatigue

• Dizziness

• Diarrhoea

• Skin rash

• Elevated hepatic transaminases

• Gynecomastia (in males)

• Adrenal insufficiency symptoms (if replacement inadequate)

Adverse Effect Notes

Adrenal crisis Life-threatening; requires urgent parenteral glucocorticoid administration; patients must carry emergency steroid card

CNS toxicity Ataxia, confusion, dysarthria, somnolence, cognitive impairment; typically occurs when serum levels >20 mg/L; reversible on dose reduction

Hepatotoxicity Monitor LFTs; discontinue if severe elevation

Prolonged adrenal suppression May persist for months to years after drug discontinuation; lifelong steroid replacement may be needed

Cytopenias Rare; monitor CBC if symptoms suggest

Teratogenicity Documented in animal studies; pregnancy must be avoided

During titration (weekly) Serum Mitotane level (target: 14–20 mg/L); cortisol level; clinical assessment for adrenal insufficiency and CNS toxicity

After stabilisation (monthly) Serum Mitotane level; LFTs; electrolytes; cortisol; weight; CNS assessment

Long-term (every 3–6 months) Hormone levels (cortisol, aldosterone, DHEAS); LFTs; lipid profile; TFTs; imaging for disease response

Note: Serum Mitotane level monitoring is essential for both efficacy and toxicity assessment. Testing may require referral to specialised laboratories.

• Lysodren® (HRA Pharma / Bristol-Myers Squibb) — Imported; limited availability; often procured through hospital pharmacy or compassionate use programmes

• Generic Mitotane may be available through select oncology distributors on special order

Note: Availability is limited in India. Procurement typically through major tertiary cancer centres (Tata Memorial Hospital, AIIMS, SGPGI, Rajiv Gandhi Cancer Institute).

Note: Not listed under NLEM; prices not NPPA-controlled. Government tertiary centres and charitable trusts may provide subsidised access. Patient assistance programmes may be available through manufacturer.

1. Serum level monitoring is mandatory: Therapeutic effect and toxicity are not linearly related to dose — target serum level of 14–20 mg/L guides dosing; levels >20 mg/L increase CNS toxicity risk.

1. Steroid replacement is universal: Assume adrenal insufficiency in all patients; initiate Hydrocortisone (30–50 mg/day or higher due to increased clearance) ± Fludrocortisone at treatment start; patients must carry emergency steroid card.

1. High-fat meals enhance absorption: Always advise administration with fatty food to improve bioavailability.

1. Very prolonged half-life: Drug accumulates in adipose tissue with half-life of 18–159 days; effects persist for weeks to months after discontinuation; adrenal suppression may be permanent in some patients.

1. Contraception essential: Use non-hormonal contraception (hormonal methods have reduced efficacy due to CYP induction); avoid pregnancy for at least 2 years after stopping therapy.

1. Not for general use: Mitotane should only be initiated and managed by oncologists or endocrine specialists at tertiary centres with access to serum level monitoring.

mitotane; adrenocortical carcinoma; adrenal cancer; adrenal cytotoxic; Lysodren; oncology-specialist; pregnancy-contraindicated; adrenal insufficiency; CYP3A4 inducer; serum level monitoring; steroid replacement

RxIndia v1.0 — 01 Jun 2025

• CDSCO regulatory information

• Indian Pharmacopoeia

• API Textbook of Medicine

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

• Goodman & Gilman's Pharmacological Basis of Therapeutics

• AIIMS Oncology Protocols

• Tata Memorial Hospital treatment guidelines for adrenocortical carcinoma

• SGPGI Endocrine Oncology protocols

• ENSAT (European Network for the Study of Adrenal Tumors) guidelines — supportive reference for dosing