Lysodren

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 based on severity. Hepatotoxicity [see Warnings and Precautions (5.4) ] 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. Resume at a reduced dose or permanently discontinue based on severity. Hematologic Toxicity [see Warnings and Precautions (5.5) ] Grade 2 Measure mitotane plasma level and modify the dosage according to the following recommendations: Withhold LYSODREN until recovery to Grade ≤1 or baseline. Resume at the same 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. Resume at a reduced dose or permanently discontinue based on severity. Other Adverse Reactions [see Adverse Reactions (6.1) ] Grade 2 Measure mitotane plasma level and modify the dosage according to the following recommendations: Withhold LYSODREN until recovery to Grade ≤1 or baseline. Resume at the same 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. Resume at a reduced dose or permanently discontinue based on severity.

4 CONTRAINDICATIONS None. None. ( 4 )

5 WARNINGS AND PRECAUTIONS Adrenal Insufficiency and Adrenal Crisis: Temporarily withhold LYSODREN during shock, trauma, infection or adrenal insufficiency. Steroid replacement may be necessary. (5.1) Central Nervous System (CNS) Toxicity : Monitor behavioral and neurologic assessments and mitotane plasma levels at regular intervals. Mitotane plasma levels exceeding 20 mg/L are associated with a greater incidence of toxicity. Advise patients not to drive or operate hazardous machinery if experiencing CNS adverse reactions. (5.2) Ovarian Macrocysts in Premenopausal Women : Monitor pelvic ultrasound at baseline and at regular intervals. Withhold, reduce the dose, or permanently discontinue LYSODREN based on severity. (5.3) Hepatotoxicity : Monitor liver functions tests prior to starting LYSODREN, during dose titration and as clinically indicated. Withhold, reduce the dose or permanently discontinue based on severity. (5.4) Hematologic Toxicity: Monitor complete blood counts prior to starting LYSODREN, during dose titration and as clinically indicated. Withhold, reduce the dose or permanently discontinue based on severity. (5.5) Prolonged Bleeding Time : Prolonged bleeding time has occurred in patients treated with mitotane and this should be taken into account when surgery is considered. (5.6) Embryo-Fetal Toxicity : Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective, nonhormonal contraception. (5.8) 5.1 Adrenal Insufficiency and Adrenal Crisis Adrenal Insufficiency LYSODREN can cause adrenal insufficiency or worsen existing adrenal insufficiency in patients with adrenocortical carcinoma. Monitor for both glucocorticoid and mineralocorticoid insufficiency and replace systemic corticosteroids accordingly. Due to increased steroid clearance and increase of steroid-binding protein, high-dose replacement therapy may be required and free cortisol and corticotropin (ACTH) should be monitored to adapt the systemic corticosteroids. Withhold, reduce the dose, or permanently discontinue LYSODREN based on severity [see Dosage and Administration (2.4) ]. Adrenal Crisis in the Setting of Shock, Severe Trauma or Infection LYSODREN can cause adrenal suppression and adrenal crisis in the setting of shock, severe trauma or infection. Advise patients of the signs and symptoms of adrenal suppression and to contact their healthcare provider immediately if shock, trauma, infection, or adrenal suppression occurs. Withhold LYSODREN before planned surgeries. Temporarily withhold LYSODREN during shock, trauma, infection or adrenal suppression [see Dosage and Administration (2.4) ]. Provide supportive care and administer systemic corticosteroids until recovery. 5.2 Central Nervous System Toxicity LYSODREN can cause central nervous system toxicity, including sedation, lethargy, and vertigo [see Adverse Reactions (6.1) ]. Monitor behavioral and neurologic assessments and mitotane plasma levels at regular intervals. Mitotane plasma levels exceeding 20 mg/L are associated with a greater incidence of toxicity. In cases of cognitive dysfunction, thyroid function should be evaluated as mitotane may induce hypothyroidism. LYSODREN can impair the ability to drive and operate machinery. Advise patients not to drive or operate hazardous machinery if they are experiencing CNS adverse reactions. Withhold, reduce the dose, or permanently discontinue LYSODREN based on severity [see Dosage and Administration (2.4) ]. 5.3 Ovarian Macrocysts in Premenopausal Women LYSODREN can cause non-malignant, multiple and bilateral ovarian macrocysts in premenopausal women. Ovarian macrocysts can be symptomatic (e.g., pelvic pain or discomfort, or menstrual irregularities) or asymptomatic. Complications from these cysts, including adnexal torsion and hemorrhagic cyst rupture, have occurred. Advise female patients to contact their healthcare provider immediately for gynecological symptoms such as vaginal bleeding and/or pelvic pain [see Adverse Reactions (6.1) ]. Monitor pelvic imaging in premenopausal females at baseline and in regular intervals during treatment with LYSODREN. Withhold, reduce the dose, or permanently discontinue LYSODREN based on severity [see Dosage and Administration (2.4) ]. 5.4 Hepatotoxicity LYSODREN can cause hepatoxicity, including liver injury or failure. Monitor liver function tests prior to starting treatment with LYSODREN, during dose titration, and periodically during treatment as clinically indicated. Isolated gamma-glutamyl transferase (GGT) elevation may occur. Withhold, reduce the dose, or permanently discontinue LYSODREN based on severity of hepatoxicity [see Dosage and Administration (2.4) ]. 5.5 Hematologic toxicity LYSODREN can cause leukopenia, anemia and thrombocytopenia [ see Adverse Reactions (6) ] . Monitor complete blood counts including neutrophil count prior to starting treatment with LYSODREN, during dose titration, and periodically during treatment as clinically indicated. Withhold, reduce the dose, or permanently discontinue LYSODREN based on severity of cytopenia [see Dosage and Administration (2.4) ] . 5.6 Prolonged Bleeding Time LYSODREN can cause platelet function disorders due to abnormal adenosine diphosphate (ADP)-induced platelet aggregation. Some patients may have a prolonged bleeding time, while others may have a normal bleeding time. Routine in vitro bleeding time is not suitable to detect this platelet defect and to assess bleeding risk. Perform ADP-inducted platelet aggregometry testing prior to surgery or dental procedures to determine mitotane-induced bleeding risk. For patients with prolonged bleeding time, withhold or reduce the dose of LYSODREN as clinically indicated. 5.7 Hormone binding protein Mitotane has been shown to increase plasma levels of hormone binding proteins (e.g., sex hormone-binding globulin (SHBG) and corticosteroid-binding globulin (CBG)). This should be taken into account when interpreting the results of hormonal assays and may result in gynecomastia. 5.8 Embryo-Fetal Toxicity LYSODREN can cause fetal harm when administered to a pregnant woman. Abnormal pregnancy outcomes, such as preterm births and early pregnancy loss, can occur in patients exposed to mitotane during pregnancy. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective nonhormonal contraception, during treatment with LYSODREN and after discontinuation of treatment for as long as mitotane plasma levels are detectable, since LYSODREN can render some hormonal contraceptives ineffective [see Drug Interactions (7.2) , Use in Specific Populations (8.1 , 8.3) ].

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.

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

8.1 Pregnancy Risk Summary LYSODREN can cause fetal harm. Limited postmarketing cases report preterm births and early pregnancy loss in women treated with LYSODREN during pregnancy. Animal reproduction studies have not been conducted with mitotane. Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.