Lysodren

WARNING: ADRENAL CRISIS IN THE SETTING OF SHOCK, SEVERE TRAUMA OR INFECTION Patients treated with LYSODREN are at increased risk for developing adrenal crisis in the setting of shock, severe trauma or infection that may lead to death. If shock, severe trauma or infection occurs or develops, temporarily discontinue LYSODREN and administer exogenous steroids. Monitor patients closely for infections and instruct patients to contact their physician immediately if injury, infection, or any other concomitant illness occurs [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)]. WARNING: ADRENAL CRISIS IN THE SETTING OF SHOCK, SEVERE TRAUMA OR INFECTION See full prescribing information for complete boxed warning. Patients treated with LYSODREN are at increased risk for developing adrenal crisis in the setting of shock, severe trauma or infection that may lead to death. If shock, severe trauma or infection occurs or develops, temporarily discontinue LYSODREN and administer exogenous steroids. Monitor patients closely for infections and instruct patients to contact their physician immediately if injury, infection, or any other concomitant illness occurs ( 2.3 , 5.1 ).

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) ].

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 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