LYSODREN- mitotane tablet
HRA Pharma Rare Diseases
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HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use LYSODREN safely and effectively. See full prescribing information for LYSODREN.
LYSODREN® (mitotane) tablets, for oral use Initial U.S. Approval: 1970 WARNING: ADRENAL CRISIS IN THE SETTING OF SHOCK, SEVERE TRAUMA OR INFECTIONSee 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). RECENT MAJOR CHANGES
INDICATIONS AND USAGELYSODREN is an adrenal cytotoxic agent indicated for the treatment of patients with inoperable, functional or nonfunctional, adrenocortical carcinoma (ACC). (1) DOSAGE AND ADMINISTRATIONDOSAGE FORMS AND STRENGTHSTablets: 500 mg, scored. (3) CONTRAINDICATIONSNone. (4) WARNINGS AND PRECAUTIONS
ADVERSE REACTIONSMost common adverse reactions include: anorexia, epigastric discomfort, nausea, vomiting, diarrhea, depression, 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. DRUG INTERACTIONSUSE IN SPECIFIC POPULATIONS
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 1/2024 |
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)].
LYSODREN is indicated for the treatment of patients with inoperable, functional or nonfunctional, adrenocortical carcinoma (ACC).
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)].
LYSODREN is a hazardous drug. Advise caregivers to wear disposable gloves when handling LYSODREN tablets [see References (15) and Storage and Handling (16)].
Recommended Dosage
Dose Adjustments, Monitoring and Discontinuation
Administration
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.
Adverse Reaction | Severity* | Dosage Modification |
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Adrenal Crisis and Adrenal Insufficiency [see Warnings and Precautions (5.1)] | All Grades |
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Central Nervous System (CNS) Toxicity [see Warnings and Precautions (5.2)] | Grade 2 |
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Grade 3 or 4 |
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Gastrointestinal (GI) toxicity | Grade 3 or 4 |
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Hepatotoxicity [see Warnings and Precautions (5.4)] | Grade 3 or 4 |
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Hematologic Toxicity [see Warnings and Precautions (5.5)] | Grade 2 |
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Grade 3 or 4 |
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Other Adverse Reactions [see Adverse Reactions (6.1)] | Grade 2 |
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Grade 3 or 4 |
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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.
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)].
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)].
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)].
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)].
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.
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.
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:
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:
Spironolactone
Spironolactone may block the action of mitotane. Avoid concomitant use of mitotane with spironolactone [see Clinical Pharmacology (12.3)].
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.
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.
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.
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)].
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.
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.
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)].
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.
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.
LYSODREN (mitotane) is an oral adrenal cytotoxic agent. The chemical name is (±)-1,1-dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl) ethane (also known as o,p'-DDD). The chemical structure is:
Mitotane is a white granular solid composed of clear colorless crystals. It is tasteless and has a slight pleasant aromatic odor. It is soluble in ethanol and has a molecular weight of 320.05.
Inactive ingredients in LYSODREN are: microcrystalline cellulose, polyethylene glycol 3350, silicon dioxide, and starch.
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.
Mitotane exposure-response relationships and the time course of pharmacodynamic response have not been fully characterized.
Distribution
Mitotane is found in most tissues of the body; however, fat is the primary site of distribution.
Elimination
Following discontinuation of mitotane, the plasma terminal half-life ranges from 18 to 159 days (median 53 days).
LYSODREN tablets are supplied as 500 mg white, round, biconvex, scored tablets, bisected on one side and impressed with "BL" over "L1" on the other side.
Store bottles at 25°C (77°F); excursions permitted between 15°C and 30°C (59°F-86°F).
Mitotane is a hazardous drug. Follow applicable special handling and disposal procedures [see References (15)].
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Adrenal Insufficiency and Adrenal Crisis
Central Nervous System Toxicity
Ovarian Macrocysts in Premenopausal Women
Hepatotoxicity
Hematologic Toxicity
Prolonged Bleeding Time
Embryo-Fetal Toxicity
Females of Reproductive Potential
Lactation
Drug Interactions
Address medical inquiries to:
Direct Success Inc.
1710 Hwy 34
Farmingdale, NJ 07727
1-844-597-6373
Fax: 1-855-674-6767
Manufactured by:
Latina Pharma S.p.A.
Via Murillo, 7
04013 Sermoneta (Latina)
Italy
For: HRA Pharma Rare Diseases
MEDICATION GUIDE LYSODREN® (LY-SO-DREN) (mitotane) tablets, for oral use |
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This Medication Guide has been approved by the U.S. Food and Drug Administration. | Issued: 01/2024 | |||||
What is the most important information I should know about LYSODREN? | ||||||
LYSODREN can cause serious side effects including: | ||||||
Adrenal Insufficiency and Adrenal Crisis.
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Your healthcare provider will check your levels of corticosteroid hormones during treatment and may give you corticosteroid medicine if you develop adrenal gland problems. Tell your healthcare provider right away if you develop any signs or symptoms of adrenal gland problems, including: | ||||||
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See "What are the possible side effects of LYSODREN?" for more information about side effects. | ||||||
What is LYSODREN? | ||||||
LYSODREN is a prescription medicine used to treat people with cancer of the adrenal glands (adrenocortical carcinoma) that is functional (when the adrenal glands make more corticosteroid hormone than normal) or nonfunctional (when the adrenal glands make less corticosteroid hormone than normal) and the cancer cannot be removed by surgery. | ||||||
Effectiveness in pediatric patients has not been established. | ||||||
Before taking LYSODREN, tell your healthcare provider about all of your medical conditions, including if you:
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Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking LYSODREN with certain other medicines may affect the way LYSODREN and the other medicines work and may increase your risk of side effects. | ||||||
Especially tell your healthcare provider if you take: | ||||||
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Ask your healthcare provider about any other medicine that may not be listed above. | ||||||
Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. | ||||||
How should I take LYSODREN?
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What should I avoid while taking LYSODREN? | ||||||
Do not drive or operate machinery until you know how LYSODREN affects you. LYSODREN may cause sleepiness, decreased energy, and dizziness, which may affect your ability to drive and operate machinery. | ||||||
What are the possible side effects of LYSODREN? | ||||||
LYSODREN can cause serious side effects including: | ||||||
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Your healthcare provider may test your blood to make sure your thyroid is producing enough thyroid hormone and to check the mitotane level if you develop any of these signs and symptoms during treatment. | ||||||
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Your healthcare provider will do blood tests before you start treatment with LYSODREN, during your treatment, and after you stop treatment with LYSODREN to check mitotane levels in your body and to check for side effects. | ||||||
Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with LYSODREN if you develop certain side effects. | ||||||
The most common side effects of LYSODREN include: | ||||||
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These are not all of the possible side effects of LYSODREN. | ||||||
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. | ||||||
You may also report side effects to Direct Success Inc. at 1-844-597-6373. | ||||||
How should I store LYSODREN? | ||||||
Store LYSODREN at 77°F (25°C). | ||||||
Keep LYSODREN and all medicines out of the reach of children. | ||||||
General information about the safe and effective use of LYSODREN. | ||||||
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use LYSODREN for a condition for which it was not prescribed. Do not give LYSODREN to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about LYSODREN that is written for health professionals. | ||||||
What are the ingredients in LYSODREN? | ||||||
Active ingredient: mitotane | ||||||
Inactive ingredients: microcrystalline cellulose, polyethylene glycol 3350, silicon dioxide, and starch. | ||||||
Manufactured by: Latina Pharma S.p.A., Via Murillo, 7, 04013 Sermoneta (Latina), Italy; Manufactured for HRA Pharma Rare Diseases. | ||||||
For more information, go to www.lysodren.com or call 1-844-597-6373. | ||||||
LYSODREN
mitotane tablet |
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Labeler - HRA Pharma Rare Diseases (571682231) |
Establishment | |||
Name | Address | ID/FEI | Business Operations |
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Latina Pharma S.p.A. | 339062883 | MANUFACTURE(76336-080) , ANALYSIS(76336-080) , LABEL(76336-080) , PACK(76336-080) |
Establishment | |||
Name | Address | ID/FEI | Business Operations |
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ISP Chemicals LLC | 078413681 | API MANUFACTURE(76336-080) |