Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

LYSODREN (NDA-016885)

(MITOTANE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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10/28/2024 (SUPPL-33)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

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:

…

Respiratory, thoracic and mediastinal disorders: Dyspnea
Cardiac: QT prolongation

01/09/2024 (SUPPL-32)

Approved Drug Label (PDF)

Boxed Warning

Additions and/or revisions underlined:

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)].

5 Warnings and Precautions

5.1 Adrenal Insufficiency and Adrenal Crisis

Additions and/or revisions underlined:

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

Additions and/or revisions underlined:

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

Additions and/or revisions underlined:

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

Newly added subsection:

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

Newly added subsection:

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

Newly added subsection:

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

Newly added subsection:

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

Additions and/or revisions underlined:

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

Addition and/or revisions underlined:

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)]

6.1 Clinical Trials Experience

Newly added subsection title

Additions and/or revisions underlined:

Reported adverse reactions include:

Metabolism and nutrition disorders: Anorexia
Gastrointestinal disorders: Epigastric discomfort, nausea, vomiting, diarrhea, mucosal inflammation, dyspepsia
Nervous system disorders: Depression, 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

7 Drug Interactions

7.1 Effects of Other Drugs on LYSODREN

Newly added subsection:

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

Additions and/or revisions underlined:

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

8.3 Females and Males of Reproductive Potential

Additions and/or revisions underlined:

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

Additions and/or revisions underlined:

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.

8.6 Hepatic Impairment

Additions and/or revisions underlined:

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

Newly added subsection:

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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Adrenal Insufficiency and Adrenal Crisis

Advise patients of the risk of adrenal suppression that may require steroid treatment and interruption or discontinuation of LYSODREN [see Warnings and Precautions (5.1)].
Advise patients to discontinue LYSODREN in the case of shock, severe trauma or infection and contact their healthcare provider immediately [see Warnings and Precautions (5.1)].
Advise patients to inform their healthcare provider of any planned surgeries [see Warnings and Precautions (5.1)].

Central Nervous System Toxicity

Advise patients to contact their healthcare provider if they experience new or worsening symptoms of central nervous system (CNS) toxicity including sedation, lethargy and vertigo [see Warnings and Precautions (5.2)].

Instruct patients not to drive or operate hazardous machinery if they are experiencing CNS adverse reactions [see Warnings and Precautions (5.2)].

Ovarian Macrocysts in Premenopausal Women

Advise premenopausal women that their healthcare provider will monitor them with routine imaging and to contact their healthcare provider if they experience gynecological symptoms such as vaginal bleeding and/or pelvic pain [see Warnings and Precautions (5.3)].

Hepatotoxicity

Advise patients that their healthcare provider will monitor them with laboratory tests to monitor liver function and to immediately contact their healthcare provider to report signs and symptoms of hepatotoxicity [see Warnings and Precautions (5.4)].

Hematologic Toxicity

Advise patients to immediately contact their healthcare provider for fever, other signs of infection, unusual bruising, bleeding, tiredness or pallor [see Warnings and Precautions (5.5)].

Prolonged Bleeding Time

Advise patients of the possibility of prolonged bleeding time while taking LYSODREN and of the need to withhold LYSODREN if surgery or dental procedures are needed [see Warnings and Precautions (5.6)].
Advise patients to inform their healthcare provider of any planned surgeries or dental procedures [see Warnings and Precautions (5.6)].

Advise patients to contact their healthcare provider for bruising or bleeding [see Warnings and Precautions (5.6)].

…

Females of Reproductive Potential

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 (8.3)].

…

Drug Interactions

Advise patients and their caregivers to inform their healthcare providers of all concomitant medications, herbal and dietary supplements [see Drug Interactions (7.1, 7.2)].

MEDICATION GUIDE

Newly added information; please refer to label for complete information

06/15/2021 (SUPPL-29)

Approved Drug Label (PDF)

6 Adverse Reactions

Additions and/or revisions underlined:

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

7 Drug Interactions

Additions and/or revisions underlined:

7.1 Certain CYP3A Substrates

Mitotane is a strong CYP3A inducer. Concomitant use of LYSODREN may decrease the concentrations of CYP3A substrates, which may reduce the efficacy of these substrates. Avoid the concomitant use of LYSODREN with certain CYP3A4 substrates where minimal concentration changes may lead to therapeutic failure. If concomitant use cannot be avoided, increase the CYP3A substrate dosage in accordance with approved product labeling.

05/09/2017 (SUPPL-27)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 Ovarian Macrocysts in Premenopausal Women

(Newly added subsection)

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.

6 Adverse Reactions

(Additions and/or revisions are underlined)

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

Ovarian macrocysts

Common adverse reactions occurring with LYSODREN treatment include:

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

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Ovarian Macrocysts

Advise premenopausal women to seek medical care if they experience gynecological symptoms such as vaginal bleeding and/or pelvic pain.