Mitotane

12.1 Mechanism of Action Mitotane is an adrenal cytotoxic agent with an unknown mechanism of action. Mitotane modifies the peripheral metabolism of steroids and directly suppresses the adrenal cortex. A reduction in 17-hydroxycorticosteroids in the absence of decreased corticosteroid levels and increased formation of 6-β-hydroxycortisol have been reported.

1 INDICATIONS AND USAGE LYSODREN is indicated for the treatment of patients with inoperable, functional or nonfunctional, adrenocortical carcinoma (ACC). LYSODREN is an adrenal cytotoxic agent indicated for the treatment of patients with inoperable, functional or nonfunctional, adrenocortical carcinoma (ACC). ( 1 )

2 DOSAGE AND ADMINISTRATION The recommended initial dose of LYSODREN is 2000 mg to 6000 mg orally, in three or four divided doses per day with food. ( 2.3 ) Titrate LYSODREN dose to achieve a plasma level of 14 to 20 mg/L. ( 2.3 ) LYSODREN is lipophilic and accumulates in adipose tissue. ( 2.3 ) 2.1 Recommended Evaluation and Testing Before Initiating LYSODREN Before initiating LYSODREN, evaluate pelvic ultrasound in premenopausal women, liver functions tests and complete blood count [see Warnings and Precautions (5.3 , 5.4 , 5.5) ]. 2.2 General Precautions LYSODREN is a hazardous drug. Advise caregivers to wear disposable gloves when handling LYSODREN tablets [see References (15) and Storage and Handling (16) ]. 2.3 Recommended Dosage and Administration Recommended Dosage The recommended initial dose of LYSODREN is 2000 mg to 6000 mg orally, in three or four divided doses per day. Monitor mitotane plasma levels and increase the dose based on patient tolerance and clinical response incrementally to achieve a mitotane plasma level of 14 to 20 mg/L, or as tolerated. Consider monitoring mitotane plasma levels every 2 weeks after starting treatment and after each dose adjustment. The target plasma level is usually reached within a period of 3 to 5 months. Monitor mitotane plasma levels periodically (e.g., monthly). Severe neurotoxicity may occur with levels > 20 mg/L. Dose Adjustments, Monitoring and Discontinuation In case of mitotane plasma levels above 20 mg/L without toxicities, consider reducing the dose by 50 to 75%. Monitor mitotane plasma levels regularly (e.g., every two months) after discontinuation of treatment. Due to the prolonged half-life, significant levels may persist for weeks after cessation of therapy. LYSODREN is lipophilic and accumulates in adipose tissue. Despite maintaining a constant dose, mitotane levels may suddenly increase. Monitor mitotane plasma levels even when LYSODREN has been withheld as adipose tissue may continue to release mitotane [see Clinical Pharmacology (12.3) ] . Due to adipose tissue accumulation of mitotane, close monitoring of mitotane plasma levels is recommended in overweight patients and patients with recent weight loss. Administration Swallow LYSODREN tablets whole; do not crush, chew or split. Take LYSODREN with food. Timing of the dose relative to meals must be consistent. Administration with high fat food enhances absorption [See Clinical Pharmacology Section (12.3) ]. Do not take tablets showing signs of deterioration. Caregivers should wear disposable gloves when handling the tablets. Avoid exposure to crushed and/or broken tablets. If contact with crushed/broken tablets occurs, wash the contaminated skin immediately and thoroughly. If a patient misses a dose, instruct the patient to take the next dose as scheduled. If a patient vomits after taking a dose, instruct the patient to take the next dose as scheduled. 2.4 Dosage Modifications for Adverse Reactions The recommended dosage reduction for adverse reactions is to decrease the usual daily dose by 500 – 1000 mg. Table 1 describes the dosage modifications for specific adverse reactions. Table 1: Recommended Dosage Modifications for LYSODREN for Adverse Reactions Adverse Reaction Severity Severity defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. Dosage Modification Adrenal Crisis and Adrenal Insufficiency [see Warnings and Precautions (5.1) ] All Grades Withhold LYSODREN during shock, trauma, infection or adrenal insufficiency until recovery to Grade ≤1 or baseline. Resume LYSODREN at a reduced dose or permanently discontinue based on severity. Central Nervous System (CNS) Toxicity [see Warnings and Precautions (5.2) ] Grade 2 Measure mitotane plasma level and modify the dosage according to the following recommendations: Mitotane plasma level less than 14 mg/L: reduce the daily dose by 1000 mg. Mitotane plasma level in the therapeutic window (14 to 20 mg/L): reduce the daily dose by 1500 mg. Mitotane plasma level above 20 mg/L: withhold LYSODREN until recovery to grade ≤1 or baseline. Seven to ten (7-10) days after symptoms resolve, resume LYSODREN at reduced dose. Grade 3 or 4 Measure mitotane plasma level and modify the dosage according to the following recommendations: Withhold LYSODREN until recovery to grade ≤ 1 or baseline. Seven to ten (7-10) days after symptoms resolve, resume LYSODREN at a reduced dose or permanently discontinue based on severity. Gastrointestinal (GI) toxicity Grade 3 or 4 Measure mitotane plasma level and modify the dosage according to the following recommendations: Mitotane plasma level less than 14 mg/L: reduce the daily dose by 1000 mg. Mitotane plasma level in the therapeutic window (14 to 20 mg/L): reduce the daily dose by 1500 mg. Mitotane plasma level above 20 mg/L: withhold LYSODREN until recovery to grade ≤1 or baseline. After symptoms resolve, resume LYSODREN at a reduced dose or permanently discontinue base

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Adrenal Insufficiency and Adrenal Crisis [see Warnings and Precautions (5.1)] • Central Nervous System Toxicity [see Warnings and Precautions (5.2)] • Ovarian Macrocysts in Premenopausal Women [see Warnings and Precautions (5.3)] • Hepatotoxicity [see Warnings and Precautions (5.4)] • Hematologic Toxicity [see Warnings and Precautions (5.5)] • Prolonged Bleeding Time [see Warnings and Precautions (5.6)] • Hormone Binding Protein [see Warnings and Precautions (5.7)] • Embryo-Fetal Toxicity [see Warnings and Precautions (5.8)] Most common adverse reactions include: anorexia, epigastric discomfort, nausea, vomiting, diarrhea, dizziness, vertigo, rash, hypercholesterolemia, hypertriglyceridemia, hypothyroidism, and decreased blood free testosterone in males. (6) To report SUSPECTED ADVERSE REACTIONS, contact Direct Success Inc.at 1-844-597-6373 or FDA at 1-800-FDA-1088 or www.FDA.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Reported adverse reactions include: Metabolism and nutrition disorders: Anorexia Gastrointestinal disorders: Epigastric discomfort, nausea, vomiting, diarrhea, mucosal inflammation, dyspepsia Nervous system disorders: Dizziness, vertigo, confusion, headache, ataxia, mental impairment, weakness, dysarthria, paresthesia, polyneuropathy, movement disorder, balance disorder, dysgeusia Skin and subcutaneous tissue disorders: Rash, pruritus, hypersensitivity reactions Blood and lymphatic system disorders: Leukopenia, anemia, thrombocytopenia, prolonged bleeding time, hematuria, hemorrhagic cystitis Endocrine: Growth retardation, hypothyroidism Eye disorders: Maculopathy, visual blurring, diplopia, lens opacity, retinopathy Hepatobiliary disorders: Hepatitis, elevation of liver enzymes, liver injury (hepatocellular/cholestatic/mixed) Reproductive system and breast disorders: Gynecomastia, hypogonadism (in males) Investigations: Hypercholesterolemia, hypertriglyceridemia, decreased plasma androstenedione, decreased plasma testosterone in females, increased sex hormone binding globulin in females and males, decreased blood free testosterone in males, hypouricemia Musculoskeletal disorders: Muscular weakness, generalized aching General disorders: Fever Renal and urinary disorders: Albuminuria/proteinuria Vascular disorders: Hypertension, orthostatic hypotension, flushing Infections: Opportunistic infection Respiratory, thoracic and mediastinal disorders: Dyspnoea

7 DRUG INTERACTIONS Spironolactone: Avoid concomitant use with LYSODREN. ( 7.1 ) Certain CYP3A Substrates: Avoid concomitant use with LYSODREN. ( 7.2 ) Hormonal contraceptives: Avoid concomitant use with LYSODREN. ( 7.2 ) Warfarin: Avoid concomitant use with LYSODREN. ( 7.2 ) 7.1 Effects of Other Drugs on LYSODREN Spironolactone Spironolactone may block the action of mitotane. Avoid concomitant use of mitotane with spironolactone [see Clinical Pharmacology (12.3) ]. 7.2 Effects of LYSODREN on Other Drugs Certain CYP3A substrates Mitotane is a strong CYP3A inducer. Concomitant use of LYSODREN may decrease the levels of CYP3A substrates, which may reduce the activity of these substrates [see Clinical Pharmacology (12.3) ]. Avoid concomitant use of LYSODREN with other CYP3A substrates, where minimal level changes may lead to serious therapeutic failures. If concomitant use cannot be avoided, modify the dosage of the CYP3A substrate in accordance with the approved product labeling. Hormonal Contraceptives Avoid concomitant use of LYSODREN with hormonal contraceptives [see Warnings and Precautions (5.8) , Use in Specific Populations (8.3) ]. Warfarin Mitotane may induce the metabolism of warfarin, which may reduce its level and its efficacy [see Clinical Pharmacology (12.3) ] . Avoid concomitant use of LYSODREN with warfarin. If concomitant use cannot be avoided, monitor INR more frequently and adjust warfarin dose as recommended in accordance with the recommendations in the warfarin Prescribing Information.