Mitotane

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 )

Tablets: 500 mg, scored. ( 3 ) Tablets: 500 mg white, round, biconvex, scored tablets, bisected on one side and impressed with "BL" over "L1" on the other side.

None. None. ( 4 )

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) ].

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 Esteve Pharmaceuticals, S.A. at 1-888-306-6259 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

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.

8 USE IN SPECIFIC POPULATIONS Lactation :Advise not to breastfeed. (8.2) Hepatic Impairment :LYSODREN is not recommended for patients with severe hepatic impairment. In patients with mild to moderate hepatic impairment, monitor mitotane plasma levels frequently and modify the dosage as needed. (8.6) Renal Impairment : LYSODREN is not recommended for patients with severe renal impairment. In patients with mild or moderate renal impairment, monitor mitotane plasma levels frequently and modify the dosage as needed. (8.7)

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.

8.2 Lactation Risk Summary Mitotane is excreted in human milk; however, the effect of LYSODREN on the breastfed child, or on milk production is unknown. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with LYSODREN and after discontinuation of treatment for as long as mitotane plasma levels are detectable.

8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating LYSODREN [see Use in Specific Populations (8.1) ] . Contraception LYSODREN can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ] . Females Advise females of reproductive potential to use effective nonhormonal contraception during treatment with LYSODREN and after discontinuation of therapy for as long as mitotane plasma levels are detectable [see Clinical Pharmacology (12.3) ] . LYSODREN can render hormonal contraceptives ineffective [see Drug Interaction (7.2) ] .

8.4 Pediatric Use Effectiveness in pediatric patients has not been established. Based on published case reports, mitotane may negatively impact neuro-psychological development (e.g., motor and speech delay, memory impairment) in children and adolescents. In cases of cognitive dysfunction, thyroid function should be evaluated as mitotane may induce hypothyroidism. Other effects of mitotane observed in pediatric patients that are cited in medical literature or in a pharmacovigilance database include growth delay and estrogenic-like effects such as uterine bleeding, breast development in females and gynecomastia in males.

8.5 Geriatric Use Clinical studies of LYSODREN did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between the older and younger patients. In general, dose selection for an older patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.6 Hepatic Impairment Mitotane is metabolized through the liver and mitotane plasma levels may increase if liver function is impaired. Because of the increased risk of adverse reactions in patients with mild or moderate hepatic impairment, monitor mitotane plasma levels more frequently and modify the dosage as needed [see Dosage and Administration (2.3) ]. LYSODREN is not recommended for use in patients with severe hepatic impairment [see Warnings and Precautions (5.4) ] .

8.7 Renal Impairment Mitotane is eliminated through the kidney and mitotane plasma levels may increase if renal function is impaired. Because of the increased risk of adverse reactions in patients with mild and moderate renal impairment, monitor mitotane plasma levels more frequently and modify the dosage as needed [see Dosage and Administration (2.4) ]. LYSODREN is not recommended for use in patients with severe renal impairment.

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.