LYSODREN- mitotane tablet

Lysodren by

Drug Labeling and Warnings

Lysodren by is a Prescription medication manufactured, distributed, or labeled by HRA Pharma Rare Diseases, Corden Pharma Latina S.p.A., ISP Chemicals LLC. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

  • BOXED WARNING (What is this?)

    WARNING: ADRENAL CRISIS IN THE SETTING OF SHOCK OR SEVERE TRAUMA

    In patients taking LYSODREN, adrenal crisis occurs in the setting of shock or severe trauma and response to shock is impaired. Administer hydrocortisone, monitor for escalating signs of shock and discontinue LYSODREN until recovery [see Dosage and Administration (2.2) and Warnings and Precautions (5.1)].

  • 1 INDICATIONS AND USAGE

    LYSODREN is indicated for the treatment of patients with inoperable, functional or nonfunctional, adrenal cortical carcinoma.

  • 2 DOSAGE AND ADMINISTRATION

    2.1 Recommended Dose

    The recommended initial dose of LYSODREN is 2 g to 6 g orally, in three or four divided doses per day. Increase doses incrementally to achieve a blood concentration of 14 to 20 mg/L, or as tolerated.

    LYSODREN is a cytotoxic drug. Follow applicable special handling and disposal procedures.

    2.2 Dose Modifications

    Adrenal Crisis in the Setting of Shock or Severe Trauma

    Discontinue LYSODREN until recovery [see Warnings and Precautions (5.1)].

    Central Nervous System (CNS) Toxicity

    Discontinue LYSODREN until symptoms resolve. Seven to 10 days after symptoms resolve, restart at a lower dose (for example, decrease by 500-1000 mg) [see Warnings and Precautions (5.2)].

  • 3 DOSAGE FORMS AND STRENGTHS

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

  • 4 CONTRAINDICATIONS

    None.

  • 5 WARNINGS AND PRECAUTIONS

    5.1 Adrenal Crisis in the Setting of Shock or Severe Trauma

    In patients taking LYSODREN, adrenal crisis occurs in the setting of shock or severe trauma and response to shock is impaired. Administer hydrocortisone, monitor for escalating signs of shock, and discontinue LYSODREN until recovery [see Dosage and Administration (2.2)].

    5.2 CNS Toxicity

    CNS toxicity, including sedation, lethargy, and vertigo, occurs with LYSODREN treatment. Mitotane plasma concentrations exceeding 20 mcg/mL are associated with a greater incidence of toxicity.

    5.3 Adrenal Insufficiency

    Treatment with LYSODREN can cause adrenal insufficiency. Institute steroid replacement as clinically indicated. Measure free cortisol and corticotropin (ACTH) levels to achieve optimal steroid replacement.

    5.4 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 contraception during treatment with LYSODREN and after discontinuation of treatment for as long as mitotane plasma levels are detectable [see Use in Specific Populations (8.1, 8.3)].

    5.5 Ovarian Macrocysts in Premenopausal Women

    Ovarian macrocysts, often bilateral and multiple, have been reported in premenopausal patients receiving LYSODREN. Complications from these cysts, including adnexal torsion and hemorrhagic cyst rupture, have been reported. In some cases, improvement after mitotane discontinuation has been described. Advise female patients to seek medical care if they experience gynecological symptoms such as vaginal bleeding and/or pelvic pain [seeAdverse Reactions (6)].

  • 6 ADVERSE REACTIONS

    The following adverse reactions are discussed in greater detail in other sections of the label:

      Adrenal Crisis in the Setting of Shock or Severe Trauma [see Warnings and Precautions (5.1)]

       CNS Toxicity [seeWarnings and Precautions (5.2)]

       Adrenal Insufficiency [seeWarnings and Precautions (5.3)]
       Ovarian macrocysts [seeWarnings and Precautions (5.5)]

    The following adverse reactions associated with the use of LYSODREN were identified in clinical trials or postmarketing reports. Because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or to establish a causal relationship to drug exposure.

    Common adverse reactions occurring with LYSODREN treatment include:

    Anorexia, nausea, vomiting, and diarrhea (80%)

    Depression, dizziness, or vertigo (15%-40%)

    Rash (15%)NeutropeniaGrowth retardation, hypothyroidism

    Confusion, headache, ataxia, mental impairment, weakness, dysarthria

    MaculopathyHepatitis, elevation of liver enzymesGynecomastia

       Hypercholesterolemia, hypertriglyceridemia

    Decreased blood androstenedione and decreased blood testosterone in females, increased sex hormone binding globulin in females      and males, decreased blood free testosterone in males.

    Less common adverse reactions include: visual blurring, diplopia, lens opacity, retinopathy, prolonged bleeding time, hematuria, hemorrhagic cystitis, albuminuria, hypertension, orthostatic hypotension, flushing, generalized aching, and fever.

  • 7 DRUG INTERACTIONS

    7.1 CYP3A4 Substrates

    Mitotane is a strong inducer of cytochrome P450 3A4 (CYP3A4). Monitor patients for a change in dosage requirements for the concomitant drug when administering LYSODREN to patients receiving drugs that are substrates of CYP3A4.

    7.2 Warfarin

    When administering coumarin-type anticoagulants to patients receiving LYSODREN, monitor coagulation tests and adjust the anticoagulant dose as needed.

  • 8 USE IN SPECIFIC POPULATIONS

    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. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

    8.2 Lactation

    Risk Summary

    Mitotane is excreted in human milk; however, the effect of LYSODREN on the breastfed infant, or effect on milk production is unknown. Because of the potential for serious adverse reactions in the breastfed infant, advise nursing women that breastfeeding is not recommended 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

    Contraception

    Females

    LYSODREN can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise female patients of reproductive potential to use effective contraception during treatment with LYSODREN and after discontinuation of therapy for as long as mitotane plasma levels are detectable [see Clinical Pharmacology (12.3)].

    8.4 Pediatric Use

    Safety and effectiveness in pediatric patients have not been established.

    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 elderly and younger patients. In general, dose selection for an elderly 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

    Hepatic impairment may interfere with the metabolism of mitotane and the drug may accumulate. Administer LYSODREN with caution to patients with hepatic impairment.

  • 11 DESCRIPTION

    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:

    Image Mitotane Chemical Structure

    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.

  • 12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    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 concentrations and increased formation of 6-β-hydroxycortisol have been reported.

    12.2 Pharmacodynamics

    The pharmacodynamics of mitotane are unknown.

    12.3 Pharmacokinetics

    Absorption

    Following oral administration of LYSODREN, 40% of the dose is absorbed.

    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).

    Metabolism

    Mitotane is converted to a water-soluble metabolite.

    Excretion

    No unchanged mitotane is found in urine or bile. Approximately 10% of the administered dose is recovered in the urine as a water-soluble metabolite. A variable amount of metabolite (1%-17%) is excreted in the bile.

  • 13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

    The carcinogenicity and mutagenicity of mitotane are unknown.

  • REFERENCES

    15 REFERENCES

    1.OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    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.

    100 tablets per bottle: NDC: 76336-080-60

    Store bottles at 25°C (77°F); excursions permitted between 15°C and 30°C (59°F-86°F).

    Mitotane is a cytotoxic drug. Follow applicable special handling and disposal procedures [see References (15)].

  • 17 PATIENT COUNSELING INFORMATION

    Adrenal Crisis

    • Advise patients to discontinue LYSODREN in the case of shock or severe trauma and contact their healthcare provider immediately.
    • Advise patients to tell their healthcare provider of any planned surgeries.

    Ovarian Macrocysts

    Advise premenopausal women to seek medical care if they experience gynecological symptoms such as vaginal bleeding and/or pelvic pain [see Warnings and Precautions(5.5)].

    Embryo-Fetal Toxicity

    Lactation

  • SPL UNCLASSIFIED SECTION

    Address medical inquiries to:
    Direct Success Inc.
    1710 Hwy 34
    Farmingdale, NJ 07727
    844-597-6373
    844 Lysodren
    Fax: (855) 674-6767

    Manufactured by:
    Corden Pharma Latina S.p.A.
    Via del Murillo Km. 2.800
    04013 Sermoneta (Latina)
    Italy

    For : HRA Pharma Rare Diseases, France

  • PRINCIPAL DISPLAY PANEL - 100 Tablet Bottle Carton

    NDC: 76336-080-60

    LYSODREN
    (mitotane) tablets, for oral use

    EACH TABLET CONTAINS
    500 mg

    100 Tablets
    Rx only

    HRA Pharma Rare Diseases

    PRINCIPAL DISPLAY PANEL - 100 Tablet Bottle Carton
  • INGREDIENTS AND APPEARANCE
    LYSODREN 
    mitotane tablet
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 76336-080
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    mitotane (UNII: 78E4J5IB5J) (mitotane - UNII:78E4J5IB5J) mitotane500 mg
    Inactive Ingredients
    Ingredient NameStrength
    MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)  
    polyethylene glycol 3350 (UNII: G2M7P15E5P)  
    silicon dioxide (UNII: ETJ7Z6XBU4)  
    Product Characteristics
    ColorWHITEScore2 pieces
    ShapeROUNDSize13mm
    FlavorImprint Code BL;L1
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 76336-080-601 in 1 CARTON01/06/2009
    1100 in 1 BOTTLE; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    NDANDA01688501/06/2009
    Labeler - HRA Pharma Rare Diseases (571682231)
    Establishment
    NameAddressID/FEIBusiness Operations
    Corden Pharma Latina S.p.A.339062883MANUFACTURE(76336-080) , ANALYSIS(76336-080) , LABEL(76336-080) , PACK(76336-080)
    Establishment
    NameAddressID/FEIBusiness Operations
    ISP Chemicals LLC078413681API MANUFACTURE(76336-080)

    • Trademark Results [Lysodren]

    Mark Image

    Registration | Serial
    Company
    Trademark
    Application Date
    LYSODREN
    LYSODREN
    73358100 1243390 Live/Registered
    Bristol-Myers Company
    1982-04-05
    LYSODREN
    LYSODREN
    73156066 1099245 Live/Registered
    CALBIOCHEM-BEHRING CORP.
    1978-01-23
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