Lysodren Drug Information
Generic name: MITOTANE
Uses of Lysodren
LYSODREN is indicated for the treatment of patients with inoperable, functional or nonfunctional, adrenocortical carcinoma (ACC).
Dosage & Administration of Lysodren
Recommended Evaluation and Testing Before Initiating LYSODREN Before initiating LYSODREN, evaluate pelvic ultrasound in premenopausal women, liver functions tests and complete blood count.
General Precautions LYSODREN is a hazardous drug
Advise caregivers to wear disposable gloves when handling LYSODREN tablets.
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
| 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. |
Side Effects of Lysodren
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
Warnings & Cautions for Lysodren
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. 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. Provide supportive care and administer systemic corticosteroids until recovery.
Central Nervous System Toxicity LYSODREN can cause central nervous system toxicity, including sedation, lethargy, and vertigo. 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.
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. Monitor pelvic imaging in premenopausal females at baseline and in regular intervals during treatment with LYSODREN.
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.
Hematologic toxicity LYSODREN can cause leukopenia, anemia and thrombocytopenia. Monitor complete blood counts including neutrophil count prior to starting treatment with LYSODREN, during dose titration, and periodically during treatment as clinically indicated.
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.
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.
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.
Drug Interactions with Lysodren
Effects of Other Drugs on LYSODREN Spironolactone Spironolactone may block the action of mitotane. Avoid concomitant use of mitotane with spironolactone.
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. 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. Warfarin Mitotane may induce the metabolism of warfarin, which may reduce its level and its efficacy.
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.
Pregnancy Safety for Lysodren
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 respectively.
Pediatric Use of Lysodren
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.
Overdosage Information for Lysodren
LYSODREN overdosage (plasma levels are above 20 mg/L) can cause central nervous system toxicity, including sedation, lethargy, and vertigo, as well as muscular weakness and gait disturbance. Withhold LYSODREN as clinically indicated for signs or symptoms of toxicity. LYSODREN is lipophilic and has a prolonged half-life; therefore, it may take weeks for plasma levels to decrease.
LYSODREN is not likely to be dialyzable. Increase the frequency of mitotane plasma level monitoring, as clinically indicated.
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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