Boxed Warning
Adrenal crisis:
In patients taking mitotane, 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 mitotane until recovery occurs.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Lysodren: 500 mg
Lysodren: 500 mg [scored]
Pharmacology
Mechanism of Action
Mitotane is an adrenolytic agent that suppresses (directly) the adrenal cortex and alters the peripheral metabolism of steroids
Pharmacokinetics/Pharmacodynamics
Absorption
Oral: ~40%
Distribution
Stored primarily in fat tissue but is found in all body tissues
Metabolism
Hepatic and other tissues; converted to a water soluble metabolite
Excretion
Urine (~10%, as metabolites); feces (1% to 17%, as metabolites)
Onset of Action
Antitumor response: Achieved at serum concentrations ≥14 mcg/mL; Pediatric patients: In experience with treatment of adenocarcinoma reported 1.5 to 12.5 months to reach 10 mcg/mL with subsequent rapid escalation of serum concentration, clinical response may be observed earlier (Rodriguez-Galindo 2005; Zancanella 2006).
Duration of Action
Measurable serum levels may persist for months after discontinuation (Veytsman 2009).
Half-Life Elimination
18 to 159 days (median: 53 days)
Use in Specific Populations
Special Populations: Hepatic Function Impairment
Hepatic impairment may interfere with mitotane metabolism and may result in accumulation.
Use: Labeled Indications
Adrenocortical carcinoma: Treatment of inoperable (functional or nonfunctional) adrenocortical carcinoma
Use: Off Label
Cushing syndromeayes
Data from a small prospective study in patients with pituitary ACTH-dependent adrenocortical hyperfunction (ie, Cushing disease) suggests that mitotane may be beneficial for the treatment of Cushing syndrome (Schteingart 1980). In a consensus statement on the treatment of Cushing syndrome, mitotane may be used especially for long term suppression of hypercortisolism; however, the onset of action is slow and monitoring for side effects (eg, digestive and neurological) is necessary Biller 2008.
Based on the Endocrine Society’s Clinical Practice Guidelines for Treatment of Cushing's Syndrome, mitotane is effective and recommended adjunctive therapy as a first-line or second-line therapy (after unsuccessful transsphenoidal selective adenomectomy) while awaiting the effects of pituitary radiation therapy or when surgery is not possible.
Contraindications
There are no contraindications listed in the manufacturer's US labeling.
Canadian labeling: Hypersensitivity to mitotane or any component of the formulation
Dosage and Administration
Dosing: Adult
Note: Mitotane is associated with a moderate emetic potential; antiemetics may be needed to prevent nausea and vomiting.
Adrenocortical carcinoma: Oral: Initial: 2 to 6 g per day in 3 to 4 divided doses, then increase incrementally to achieve a blood concentration of 14 to 20 mcg/mL or as tolerated.
Off-label dosing: Initial 1 to 2 g per day; increase by 1 to 2 g per day at 1- to 2-week intervals as tolerated; usual dose 4 to 6 g per day; maximum of 6 to 10 g per day (Veytsman 2009)
Cushing syndrome (off-label use): Oral: Initial: 500 mg 3 times daily (Biller 2008); may increase dose rapidly during the first 4 to 6 weeks up to a maximum of 4,000 mg to 8,000 mg per day in 3 divided doses, with the largest dose given in the evening to minimize discomfort (Baudry 2012; ES [Neiman 2015]; Schteingart 1980); after achieving control of cortisol secretion, gradually taper to the minimal dose required to maintain remission (Baudry 2012)
Dosing: Geriatric
Refer to adult dosing.
Dosing: Pediatric
Adrenocortical carcinoma (stage III or IV): Limited data available; efficacy results variable; optimal dose not established: Children and Adolescents: Oral: Initial: 0.5 to 1 g/day in 3 divided doses, titrate dose to target serum concentration range of 14 to 20 mcg/mL (see Reference Range)
Mitotane has been used in combination with CED regimen (cisplatin, etoposide, and doxorubicin). An initial dose of 0.5 to 1 g/day divided 3 times a day, increased weekly to a target dose of 4 g/m2/day (divided 3 times a day) was used in an open-label, prospective study (n=11; age range: 2 to 15 years); however, the reported range to initially achieve a serum concentration of 14 ± 2 mcg/mL was 1.6 to 7.3 g/m2/day; and then further reductions to 1 to 5.3 g/m2/day were required to maintain therapeutic concentrations (Zancanella 2006)
Dosing adjustment for toxicity: The presented dosing adjustments are based on experience in adult patients; specific recommendations for pediatric patients are limited. Refer to specific protocol for management in pediatric patients if available.
Adult:
Adrenal crisis in the setting of shock or severe trauma: Discontinue mitotane until recovery occurs.
CNS toxicity: Discontinue mitotane until symptoms resolve; 7 to 10 days after symptoms resolve, restart at a lower dose (eg, decrease dose by 0.5 to 1 g).
Significant neuropsychiatric adverse effects: Withhold treatment for at least 1 week and restart at a lower dose (Allolio 2006)
Dosing: Adjustment for Toxicity
Adrenal crisis in the setting of shock or severe trauma: Discontinue mitotane until recovery occurs.
CNS toxicity: Discontinue mitotane until symptoms resolve; 7 to 10 days after symptoms resolve, restart at a lower dose (eg, decrease dose by 500 to 1,000 mg).
Significant neuropsychiatric adverse effects: Withhold treatment for at least 1 week and restart at a lower dose (Allolio 2006).
Administration
Note: Mitotane is associated with a moderate emetic potential; antiemetics may be needed to prevent nausea and vomiting.
Administer in 3 to 4 divided doses/day.
Storage
Store at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).
Drug Interactions
Abemaciclib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Abemaciclib. Avoid combination
Abiraterone Acetate: CYP3A4 Inducers (Strong) may decrease the serum concentration of Abiraterone Acetate. Management: Avoid whenever possible. If such a combination cannot be avoided, increase abiraterone acetate dosing frequency from once daily to twice daily during concomitant use. Consider therapy modification
Acalabrutinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Acalabrutinib. Management: Avoid co-administration of strong CYP3A inducers in patients taking acalabrutinib. If strong CYP3A inducers cannot be avoided, increase the dose of acalabrutinib to 200 mg twice daily. Consider therapy modification
Alpelisib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Alpelisib. Avoid combination
Antihepaciviral Combination Products: CYP3A4 Inducers (Strong) may decrease the serum concentration of Antihepaciviral Combination Products. Avoid combination
Apalutamide: CYP3A4 Inducers (Strong) may decrease the serum concentration of Apalutamide. Monitor therapy
Apixaban: CYP3A4 Inducers (Strong) may decrease the serum concentration of Apixaban. Management: Avoid concurrent use of apixaban with strong CYP3A4 inducers whenever possible. Use of a strong CYP3A4 inducer with apixaban should be strictly avoided in any patient who is using an agent (either the CYP3A4 inducer or a third drug) that induces P-gp. Consider therapy modification
Apremilast: CYP3A4 Inducers (Strong) may decrease the serum concentration of Apremilast. Avoid combination
Aprepitant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Aprepitant. Avoid combination
ARIPiprazole: CYP3A4 Inducers (Strong) may decrease the serum concentration of ARIPiprazole. Management: Double the oral aripiprazole dose and closely monitor. Reduce oral aripiprazole dose to 10-15 mg/day (for adults) if the inducer is discontinued. Avoid use of strong CYP3A4 inducers for more than 14 days with extended-release injectable aripiprazole. Consider therapy modification
ARIPiprazole Lauroxil: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of ARIPiprazole Lauroxil. Management: Patients taking the 441 mg dose of aripiprazole lauroxil increase their dose to 662 mg if used with a strong CYP3A4 inducer for more than 14 days. No dose adjustment is necessary for patients using the higher doses of aripiprazole lauroxil. Consider therapy modification
Artemether: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Artemether. Specifically, dihydroartemisinin concentrations may be reduced. CYP3A4 Inducers (Strong) may decrease the serum concentration of Artemether. Avoid combination
Asunaprevir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Asunaprevir. Avoid combination
Avapritinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Avapritinib. Avoid combination
Axitinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Axitinib. Avoid combination
Bedaquiline: CYP3A4 Inducers (Strong) may decrease the serum concentration of Bedaquiline. Avoid combination
Benperidol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Benperidol. Monitor therapy
Bictegravir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Bictegravir. Management: Rifampin is specifically contraindicated, and the use of carbamazepine, phenytoin, or phenobarbital is not recommended when alternatives are acceptable Monitor therapy
Bortezomib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Bortezomib. Avoid combination
Bosutinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Bosutinib. Avoid combination
Brentuximab Vedotin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be decreased. Monitor therapy
Brexpiprazole: CYP3A4 Inducers (Strong) may decrease the serum concentration of Brexpiprazole. Management: If brexpiprazole is used together with a strong CYP3A4 inducer, the brexpiprazole dose should gradually be doubled over the course of 1 to 2 weeks. Consider therapy modification
Brigatinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Brigatinib. Avoid combination
BusPIRone: CYP3A4 Inducers (Strong) may decrease the serum concentration of BusPIRone. Management: Consider alternatives to this combination. If coadministration of these agents is deemed necessary, monitor patients for reduced buspirone effects and increase buspirone doses as needed. Consider therapy modification
Cabozantinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Cabozantinib. Management: Avoid use of strong CYP3A4 inducers with cabozantinib if possible. If combined, cabozantinib dose adjustments are recommended and vary based on the cabozantinib product used and the indication for use. See monograph for details. Consider therapy modification
Calcifediol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Calcifediol. Monitor therapy
Cannabidiol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Cannabidiol. Monitor therapy
Cannabis: CYP3A4 Inducers (Strong) may decrease the serum concentration of Cannabis. More specifically, tetrahydrocannabinol and cannabidiol serum concentrations may be decreased. Monitor therapy
Cariprazine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Cariprazine. Avoid combination
Ceritinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ceritinib. Avoid combination
ChlorproPAMIDE: CYP3A4 Inducers (Strong) may decrease the serum concentration of ChlorproPAMIDE. Monitor therapy
Clarithromycin: CYP3A4 Inducers (Strong) may increase serum concentrations of the active metabolite(s) of Clarithromycin. Clarithromycin may increase the serum concentration of CYP3A4 Inducers (Strong). CYP3A4 Inducers (Strong) may decrease the serum concentration of Clarithromycin. Management: Consider alternative antimicrobial therapy for patients receiving a CYP3A inducer. Drugs that enhance the metabolism of clarithromycin into 14-hydroxyclarithromycin may alter the clinical activity of clarithromycin and may impair clarithromycin efficacy. Consider therapy modification
Clindamycin (Systemic): CYP3A4 Inducers (Strong) may decrease the serum concentration of Clindamycin (Systemic). Refer to the specific clindamycin (systemic) - rifampin drug interaction monograph for information concerning that combination. Monitor therapy
CloZAPine: CYP3A4 Inducers (Strong) may decrease the serum concentration of CloZAPine. Avoid combination
Cobimetinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Cobimetinib. Avoid combination
Codeine: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Codeine. Monitor therapy
Copanlisib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Copanlisib. Avoid combination
Corticosteroids (Systemic): Mitotane may decrease the serum concentration of Corticosteroids (Systemic). Consider therapy modification
Crizotinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Crizotinib. Avoid combination
CYP3A4 Substrates (High risk with Inducers): Mitotane may decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification
Dabrafenib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Dabrafenib. Monitor therapy
Daclatasvir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Daclatasvir. Avoid combination
Dasabuvir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Dasabuvir. Avoid combination
Dasatinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Dasatinib. Management: Avoid when possible. If such a combination cannot be avoided, consider increasing dasatinib dose and monitor clinical response and toxicity closely. Consider therapy modification
Deflazacort: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Deflazacort. Avoid combination
Delamanid: CYP3A4 Inducers (Strong) may decrease the serum concentration of Delamanid. Avoid combination
DexAMETHasone (Systemic): CYP3A4 Inducers (Strong) may decrease the serum concentration of DexAMETHasone (Systemic). Management: Consider dexamethasone dose increases in patients receiving strong CYP3A4 inducers and monitor closely for reduced dexamethasone efficacy. Consider avoiding this combination when treating life threatening conditions (ie, multiple myeloma). Consider therapy modification
Dienogest: CYP3A4 Inducers (Strong) may decrease the serum concentration of Dienogest. Management: Avoid use of dienogest for contraception when using medications that induce CYP3A4 and for at least 28 days after discontinuation of a CYP3A4 inducer. An alternative form of contraception should be used during this time. Avoid combination
Diethylstilbestrol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Diethylstilbestrol. Monitor therapy
Doravirine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Doravirine. Avoid combination
Doxercalciferol: CYP3A4 Inducers (Strong) may increase serum concentrations of the active metabolite(s) of Doxercalciferol. Monitor therapy
DOXOrubicin (Conventional): CYP3A4 Inducers (Strong) may decrease the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to strong CYP3A4 inducers in patients treated with doxorubicin. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification
Dronabinol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Dronabinol. Monitor therapy
Dronedarone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Dronedarone. Avoid combination
Duvelisib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Duvelisib. Avoid combination
Elagolix: CYP3A4 Inducers (Strong) may decrease the serum concentration of Elagolix. Monitor therapy
Elbasvir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Elbasvir. Avoid combination
Elexacaftor, Tezacaftor, and Ivacaftor: CYP3A4 Inducers (Strong) may decrease the serum concentration of Elexacaftor, Tezacaftor, and Ivacaftor. Avoid combination
Eliglustat: CYP3A4 Inducers (Strong) may decrease the serum concentration of Eliglustat. Avoid combination
Encorafenib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Encorafenib. Avoid combination
Enfortumab Vedotin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Enfortumab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be decreased. Monitor therapy
Entrectinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Entrectinib. Avoid combination
Enzalutamide: CYP3A4 Inducers (Strong) may decrease the serum concentration of Enzalutamide. Management: Consider using an alternative agent that has no or minimal CYP3A4 induction potential when possible. If this combination cannot be avoided, increase the dose of enzalutamide from 160 mg daily to 240 mg daily. Consider therapy modification
Eravacycline: CYP3A4 Inducers (Strong) may decrease the serum concentration of Eravacycline. Management: Increase the eravacycline dose to 1.5 mg/kg every 12 hours when combined with strong CYP3A4 inducers. Consider therapy modification
Erdafitinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Erdafitinib. Avoid combination
Erlotinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Erlotinib. Management: Avoid combination if possible. If combination must be used, increase erlotinib dose by 50 mg increments every 2 weeks as tolerated, to a maximum of 450 mg/day. Consider therapy modification
Estriol (Systemic): CYP3A4 Inducers (Strong) may decrease the serum concentration of Estriol (Systemic). Monitor therapy
Estriol (Topical): CYP3A4 Inducers (Strong) may decrease the serum concentration of Estriol (Topical). Monitor therapy
Etoposide: CYP3A4 Inducers (Strong) may decrease the serum concentration of Etoposide. Management: When possible, seek alternatives to strong CYP3A4-inducing medications in patients receiving etoposide. If combined, monitor patients closely for diminished etoposide response and need for etoposide dose increases. Consider therapy modification
Etoposide Phosphate: CYP3A4 Inducers (Strong) may decrease the serum concentration of Etoposide Phosphate. Management: When possible, seek alternatives to strong CYP3A4-inducing medications in patients receiving etoposide phosphate. If these combinations cannot be avoided, monitor patients closely for diminished etoposide phosphate response. Consider therapy modification
Etravirine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Etravirine. Avoid combination
Everolimus: CYP3A4 Inducers (Strong) may decrease the serum concentration of Everolimus. Management: Avoid concurrent use of strong CYP3A4 inducers if possible. If coadministration cannot be avoided, double the daily dose of everolimus using increments of 5 mg or less. Monitor everolimus serum concentrations closely when indicated. Consider therapy modification
Evogliptin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Evogliptin. Monitor therapy
Exemestane: CYP3A4 Inducers (Strong) may decrease the serum concentration of Exemestane. Management: Exemestane U.S. product labeling recommends using an increased dose (50 mg/day) in patients receiving concurrent strong CYP3A4 inducers. The Canadian product labeling does not recommend a dose adjustment with concurrent use of strong CYP3A4 inducers. Consider therapy modification
Fedratinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Fedratinib. Avoid combination
FentaNYL: CYP3A4 Inducers (Strong) may decrease the serum concentration of FentaNYL. Monitor therapy
Flibanserin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Flibanserin. Avoid combination
Fosaprepitant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Fosaprepitant. Specifically, CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite aprepitant. Avoid combination
Fosnetupitant: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Fosnetupitant. Avoid combination
Fostamatinib: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Fostamatinib. Avoid combination
Gefitinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Gefitinib. Management: In the absence of severe adverse reactions, increase gefitinib dose to 500 mg daily in patients receiving strong CYP3A4 inducers; resume 250 mg dose 7 days after discontinuation of the strong inducer. Carefully monitor clinical response. Consider therapy modification
Gemigliptin: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Gemigliptin. CYP3A4 Inducers (Strong) may decrease the serum concentration of Gemigliptin. Avoid combination
Glasdegib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Glasdegib. Avoid combination
Glecaprevir and Pibrentasvir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Glecaprevir and Pibrentasvir. Monitor therapy
Grazoprevir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Grazoprevir. Avoid combination
GuanFACINE: CYP3A4 Inducers (Strong) may decrease the serum concentration of GuanFACINE. Management: Increase the guanfacine dose by up to double when initiating guanfacine in a patient taking a strong CYP3A4 inducer. Increase guanfacine dose gradually over 1 to 2 weeks if initiating strong CYP3A4 inducer therapy in a patient already taking guanfacine. Consider therapy modification
Ibrutinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ibrutinib. Avoid combination
Idelalisib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Idelalisib. Avoid combination
Ifosfamide: CYP3A4 Inducers (Strong) may increase serum concentrations of the active metabolite(s) of Ifosfamide. CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Ifosfamide. Monitor therapy
Imatinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Imatinib. Management: Avoid concurrent use of imatinib with strong CYP3A4 inducers when possible. If such a combination must be used, increase imatinib dose by at least 50% and monitor the patient's clinical response closely. Consider therapy modification
Irinotecan Products: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, serum concentrations of SN-38 may be reduced. CYP3A4 Inducers (Strong) may decrease the serum concentration of Irinotecan Products. Avoid combination
Isavuconazonium Sulfate: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Isavuconazonium Sulfate. Specifically, CYP3A4 Inducers (Strong) may decrease isavuconazole serum concentrations. Avoid combination
Istradefylline: CYP3A4 Inducers (Strong) may decrease the serum concentration of Istradefylline. Avoid combination
Itraconazole: CYP3A4 Inducers (Strong) may decrease the serum concentration of Itraconazole. Avoid combination
Ivabradine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ivabradine. Avoid combination
Ivacaftor: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ivacaftor. Avoid combination
Ivosidenib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ivosidenib. Avoid combination
Ixabepilone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ixabepilone. Management: Avoid this combination whenever possible. If this combination must be used, a gradual increase in ixabepilone dose from 40 mg/m2 to 60 mg/m2 (given as a 4-hour infusion), as tolerated, should be considered. Consider therapy modification
Ixazomib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ixazomib. Avoid combination
Lapatinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lapatinib. Management: If therapy overlap cannot be avoided, consider titrating lapatinib gradually from 1,250 mg/day up to 4,500 mg/day (HER2 positive metastatic breast cancer) or 1,500 mg/day up to 5,500 mg/day (hormone receptor/HER2 positive breast cancer) as tolerated. Avoid combination
Larotrectinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Larotrectinib. Management: Avoid use of strong CYP3A4 inducers with larotrectinib. If this combination cannot be avoided, double the larotrectinib dose. Reduced to previous dose after stopping the inducer after a period of 3 to 5 times the inducer half-life. Consider therapy modification
Lefamulin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lefamulin. Management: Avoid concomitant use of lefamulin with strong CYP3A4 inducers unless the benefits outweigh the risks. Consider therapy modification
Lefamulin (Intravenous): CYP3A4 Inducers (Strong) may decrease the serum concentration of Lefamulin (Intravenous). Management: Avoid concomitant use of lefamulin intravenous infusion with strong CYP3A4 inducers unless the benefits outweigh the risks. Consider therapy modification
Lemborexant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lemborexant. Avoid combination
LinaGLIPtin: CYP3A4 Inducers (Strong) may decrease the serum concentration of LinaGLIPtin. Management: Strongly consider using an alternative to any strong CYP3A4 inducer in patients who are being treated with linagliptin. If this combination is used, monitor patients closely for evidence of reduced linagliptin effectiveness. Consider therapy modification
Lorlatinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lorlatinib. Avoid combination
Lumacaftor and Ivacaftor: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lumacaftor and Ivacaftor. Specifically, the serum concentration of ivacaftor may be decreased. Avoid combination
Lumateperone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lumateperone. Avoid combination
Lumefantrine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lumefantrine. Avoid combination
Lurasidone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lurasidone. Avoid combination
Macimorelin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Macimorelin. Avoid combination
Macitentan: CYP3A4 Inducers (Strong) may decrease the serum concentration of Macitentan. Avoid combination
Manidipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Manidipine. Management: Consider avoiding concomitant use of manidipine and strong CYP3A4 inducers. If combined, monitor closely for decreased manidipine effects and loss of efficacy. Increased manidipine doses may be required. Consider therapy modification
Maraviroc: CYP3A4 Inducers (Strong) may decrease the serum concentration of Maraviroc. Management: Increase maraviroc adult dose to 600 mg twice daily when used with strong CYP3A4 inducers. This does not apply to patients also receiving strong CYP3A4 inhibitors. Do not use maraviroc with strong CYP3A4 inducers in patients with CrCl less than 30 mL/min. Consider therapy modification
Meperidine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Meperidine. Monitor therapy
MethylPREDNISolone: CYP3A4 Inducers (Strong) may decrease the serum concentration of MethylPREDNISolone. Management: Consider methylprednisolone dose increases in patients receiving strong CYP3A4 inducers and monitor closely for reduced steroid efficacy. Consider therapy modification
Midostaurin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Midostaurin. Avoid combination
MiFEPRIStone: CYP3A4 Inducers (Strong) may decrease the serum concentration of MiFEPRIStone. Avoid combination
Mirodenafil: CYP3A4 Inducers (Strong) may decrease the serum concentration of Mirodenafil. Management: Consider avoiding the concomitant use of mirodenafil and strong CYP3A4 inducers. If combined, monitor for decreased mirodenafil effects. Mirodenafil dose increases may be required to achieve desired effects. Consider therapy modification
Naldemedine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Naldemedine. Avoid combination
Naloxegol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Naloxegol. Avoid combination
Neratinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Neratinib. Avoid combination
Netupitant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Netupitant. Avoid combination
NIFEdipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of NIFEdipine. Avoid combination
Nilotinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Nilotinib. Avoid combination
NiMODipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of NiMODipine. Avoid combination
Nisoldipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Nisoldipine. Avoid combination
Olaparib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Olaparib. Avoid combination
Osimertinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Osimertinib. Consider therapy modification
OXcarbazepine: CYP3A4 Inducers (Strong) may decrease the serum concentration of OXcarbazepine. Specifically, the concentrations of the 10-monohydroxy active metabolite of oxcarbazepine may be decreased. Monitor therapy
Palbociclib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Palbociclib. Avoid combination
Panobinostat: CYP3A4 Inducers (Strong) may decrease the serum concentration of Panobinostat. Avoid combination
PAZOPanib: CYP3A4 Inducers (Strong) may decrease the serum concentration of PAZOPanib. Avoid combination
Perampanel: CYP3A4 Inducers (Strong) may decrease the serum concentration of Perampanel. Management: Increase the perampanel starting dose to 4 mg/day when perampanel is used concurrently with moderate and strong CYP3A4 inducers. Consider therapy modification
Pexidartinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Pexidartinib. Avoid combination
Pimavanserin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Pimavanserin. Avoid combination
Piperaquine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Piperaquine. Avoid combination
Pitolisant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Pitolisant. Management: For patients who are stable on pitolisant doses of 8.9 mg or 17.8 mg/day and who are also taking a strong CYP3A4 inducer, increase the pitolisant dose over 7 days to double the original dose (ie, to either 17.8 mg/day or 35.6 mg/day, respectively). Consider therapy modification
Polatuzumab Vedotin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Polatuzumab Vedotin. Exposure to unconjugated MMAE, the cytotoxic small molecule component of polatuzumab vedotin, may be decreased. Monitor therapy
PONATinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of PONATinib. Avoid combination
Praziquantel: CYP3A4 Inducers (Strong) may decrease the serum concentration of Praziquantel. Management: Use of praziquantel with strong CYP3A4 inducers is contraindicated. Discontinue rifampin 4 weeks prior to initiation of praziquantel therapy. Rifampin may be resumed the day following praziquantel completion. Avoid combination
Pretomanid: CYP3A4 Inducers (Strong) may decrease the serum concentration of Pretomanid. Avoid combination
Propafenone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Propafenone. Monitor therapy
QUEtiapine: CYP3A4 Inducers (Strong) may decrease the serum concentration of QUEtiapine. Management: An increase in quetiapine dose (as much as 5 times the regular dose) may be required to maintain therapeutic benefit. Reduce the quetiapine dose back to the previous/regular dose within 7-14 days of discontinuing the inducer. Consider therapy modification
Radotinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Radotinib. Management: Consider alternatives to this combination when possible as the risk of radotinib treatment failure may be increased. Consider therapy modification
Ramelteon: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ramelteon. Monitor therapy
Ranolazine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ranolazine. Avoid combination
Reboxetine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Reboxetine. Monitor therapy
Regorafenib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Regorafenib. Avoid combination
Ribociclib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ribociclib. Avoid combination
RisperiDONE: CYP3A4 Inducers (Strong) may decrease the serum concentration of RisperiDONE. Management: Consider increasing the dose of oral risperidone (to no more than double the original dose) if a strong CYP3A4 inducer is initiated. For patients on IM risperidone, consider an increased IM dose or supplemental doses of oral risperidone. Consider therapy modification
Rivaroxaban: CYP3A4 Inducers (Strong) may decrease the serum concentration of Rivaroxaban. Avoid combination
Roflumilast: CYP3A4 Inducers (Strong) may decrease the serum concentration of Roflumilast. Management: Roflumilast U.S. prescribing information recommends against combining strong CYP3A4 inducers with roflumilast. The Canadian product monograph makes no such recommendation but notes that such agents may reduce roflumilast therapeutic effects. Avoid combination
Rolapitant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Rolapitant. Management: Avoid rolapitant use in patients requiring chronic administration of strong CYP3A4 inducers. Monitor for reduced rolapitant response and the need for alternative or additional antiemetic therapy even with shorter-term use of such inducers. Consider therapy modification
RomiDEPsin: CYP3A4 Inducers (Strong) may decrease the serum concentration of RomiDEPsin. Avoid combination
Ruxolitinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ruxolitinib. Monitor therapy
SAXagliptin: CYP3A4 Inducers (Strong) may decrease the serum concentration of SAXagliptin. Monitor therapy
Sertraline: CYP3A4 Inducers (Strong) may decrease the serum concentration of Sertraline. Monitor therapy
Simeprevir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Simeprevir. Avoid combination
Sirolimus: CYP3A4 Inducers (Strong) may decrease the serum concentration of Sirolimus. Management: Avoid concomitant use of strong CYP3A4 inducers and sirolimus if possible. If combined, monitor for reduced serum sirolimus concentrations. Sirolimus dose increases will likely be necessary to prevent subtherapeutic sirolimus levels. Consider therapy modification
Sonidegib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Sonidegib. Avoid combination
SORAfenib: CYP3A4 Inducers (Strong) may decrease the serum concentration of SORAfenib. Avoid combination
Spironolactone: May diminish the therapeutic effect of Mitotane. Management: Consideration should be given to discontinuing spironolactone prior to initiating mitotane in order to eliminate the risk of therapeutic failure of the mitotane. Consider therapy modification
SUFentanil: CYP3A4 Inducers (Strong) may decrease the serum concentration of SUFentanil. Monitor therapy
SUNItinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of SUNItinib. Management: Avoid when possible. If such a combination cannot be avoided, sunitinib dose increases are recommended, and vary by indication. See full monograph for details. Consider therapy modification
Tadalafil: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tadalafil. Management: Erectile dysfunction: monitor for decreased effectiveness - no standard dose adjustments recommended. Avoid use of tadalafil for pulmonary arterial hypertension in patients receiving a strong CYP3A4 inducer. Consider therapy modification
Tamoxifen: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Tamoxifen. CYP3A4 Inducers (Strong) may decrease the serum concentration of Tamoxifen. Management: Consider alternatives to concomitant use of strong CYP3A4 inducers and tamoxifen. If the combination cannot be avoided, monitor for reduced therapeutic effects of tamoxifen. Consider therapy modification
Tasimelteon: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tasimelteon. Avoid combination
Tazemetostat: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tazemetostat. Avoid combination
Telithromycin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Telithromycin. Avoid combination
Temsirolimus: CYP3A4 Inducers (Strong) may decrease the serum concentration of Temsirolimus. Management: Consider increasing the dose of temsirolimus to 50 mg IV/week (from 25 mg IV/week) if a concomitant CYP3A4 strong inducer is necessary. Consider therapy modification
Tetrahydrocannabinol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tetrahydrocannabinol. Monitor therapy
Tetrahydrocannabinol and Cannabidiol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tetrahydrocannabinol and Cannabidiol. Monitor therapy
Tezacaftor and Ivacaftor: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tezacaftor and Ivacaftor. Avoid combination
Thiotepa: CYP3A4 Inducers (Strong) may increase serum concentrations of the active metabolite(s) of Thiotepa. CYP3A4 Inducers (Strong) may decrease the serum concentration of Thiotepa. Management: Thiotepa prescribing information recommends avoiding concomitant use of thiotepa and strong CYP3A4 inducers. If concomitant use is unavoidable, monitor for adverse effects. Consider therapy modification
TiaGABine: CYP3A4 Inducers (Strong) may decrease the serum concentration of TiaGABine. Management: Approximately 2-fold higher tiagabine doses and a more rapid dose titration will likely be required in patients concomitantly taking a strong CYP3A4 inducer. Consider therapy modification
Ticagrelor: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Ticagrelor. CYP3A4 Inducers (Strong) may decrease the serum concentration of Ticagrelor. Avoid combination
Tofacitinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tofacitinib. Avoid combination
Tolvaptan: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tolvaptan. Management: If concurrent use is necessary, increased doses of tolvaptan (with close monitoring for toxicity and clinical response) may be needed. Avoid combination
Toremifene: CYP3A4 Inducers (Strong) may decrease the serum concentration of Toremifene. Avoid combination
Trabectedin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Trabectedin. Avoid combination
Tropisetron: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tropisetron. Monitor therapy
Ubrogepant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ubrogepant. Avoid combination
Udenafil: CYP3A4 Inducers (Strong) may decrease the serum concentration of Udenafil. Monitor therapy
Ulipristal: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ulipristal. Avoid combination
Upadacitinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Upadacitinib. Avoid combination
Valbenazine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Valbenazine. Avoid combination
Vandetanib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Vandetanib. Avoid combination
Velpatasvir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Velpatasvir. Avoid combination
Vemurafenib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Vemurafenib. Management: Avoid concurrent use of vemurafenib with a strong CYP3A4 inducer and replace with another agent when possible. If a strong CYP3A4 inducer is indicated and unavoidable, the dose of vemurafenib may be increased by 240 mg (1 tablet) as tolerated. Consider therapy modification
Venetoclax: CYP3A4 Inducers (Strong) may decrease the serum concentration of Venetoclax. Avoid combination
Vilazodone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Vilazodone. Management: Consider increasing vilazodone dose by as much as 2-fold (do not exceed 80 mg/day), based on response, in patients receiving strong CYP3A4 inducers for > 14 days. Reduce to the original vilazodone dose over 1-2 weeks after inducer discontinuation. Consider therapy modification
VinCRIStine (Liposomal): CYP3A4 Inducers (Strong) may decrease the serum concentration of VinCRIStine (Liposomal). Avoid combination
Vinflunine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Vinflunine. Avoid combination
Vorapaxar: CYP3A4 Inducers (Strong) may decrease the serum concentration of Vorapaxar. Avoid combination
Vortioxetine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Vortioxetine. Management: Consider increasing the vortioxetine dose to no more than 3 times the original dose when used with a strong drug metabolism inducer for more than 14 days. The vortioxetine dose should be returned to normal within 14 days of stopping the strong inducer. Consider therapy modification
Voxelotor: CYP3A4 Inducers (Strong) may decrease the serum concentration of Voxelotor. Management: Avoid concomitant use of voxelotor and strong CYP3A4 inducers. If concomitant use is unavoidable, increase the voxelotor dose to 2,500 mg once daily. Consider therapy modification
Voxilaprevir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Voxilaprevir. Avoid combination
Zaleplon: CYP3A4 Inducers (Strong) may decrease the serum concentration of Zaleplon. Management: Consider the use of an alternative hypnotic that is not metabolized by CYP3A4 in patients receiving strong CYP3A4 inducers. If zalephon is combined with a strong CYP3A4 inducer, monitor for decreased effectiveness of zaleplon. Consider therapy modification
Zanubrutinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Zanubrutinib. Avoid combination
Zuclopenthixol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Zuclopenthixol. Monitor therapy
Adverse Reactions
>10%:
Dermatologic: Skin rash (15%)
Gastrointestinal: Anorexia (≤80%), diarrhea (≤80%), nausea (≤80%), vomiting (≤80%)
Nervous system: Depression (≤40%), dizziness (≤40%), vertigo (≤40%)
Frequency not defined:
Cardiovascular: Flushing, hypertension, orthostatic hypotension
Endocrine & metabolic: Adrenocortical insufficiency, albuminuria, altered hormone level (decreased serum androstenedione), decreased plasma testosterone (males and females), growth retardation, gynecomastia, hypercholesterolemia, hypertriglyceridemia, hypothyroidism, increased sex hormone binding globulin, ovarian cyst (including bilateral, multiple)
Genitourinary: Hematuria, hemorrhagic cystitis
Hematologic & oncologic: Neutropenia, prolonged bleeding time
Hepatic: Hepatitis, increased liver enzymes
Nervous system: Ataxia, central nervous system toxicity, confusion, dysarthria, generalized ache or pain, headache, lethargy, mental deficiency, sedated state
Neuromuscular & skeletal: Asthenia
Ophthalmic: Blurred vision, cataract, diplopia, maculopathy, retinopathy
Miscellaneous: Fever
Postmarketing: Subacute cutaneous lupus erythematosus (Mayor-Ibarguren 2016)
Warnings/Precautions
Concerns related to adverse effects:
- Adrenal crisis: [US Boxed Warning]: Adrenal crisis occurs in the setting of shock or severe trauma and response to shock is impaired in patients taking mitotane. Administer hydrocortisone, monitor for escalating signs of shock, and discontinue mitotane until recovery occurs.
- Adrenal insufficiency: Patients treated with mitotane may develop adrenal insufficiency; steroid replacement therapy may be required. Monitor free cortisol and corticotropin (ACTH) levels to achieve optimal steroid replacement.
- CNS toxicity: CNS adverse effects, including lethargy, sedation, and vertigo may occur; mitotane plasma concentrations above 20 mcg/mL are associated with higher incidence of toxicity. Patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).
- Gastrointestinal toxicity: Mitotane is associated with a moderate emetic potential; antiemetics may be needed to prevent nausea and vomiting.
- Ovarian macrocysts: Ovarian macrocysts (often bilateral and multiple) have been reported in premenopausal females receiving mitotane. Complications due to the cysts have been reported (including adnexal torsion and hemorrhagic cyst rupture). Improvement following discontinuation of mitotane has occurred in some cases. Female patients should obtain medical care if they experience vaginal bleeding and/or pelvic pain.
- Prolonged bleeding time: Although uncommon, prolonged bleeding time may occur; consider bleeding possibility prior to any surgical intervention. If currently on anticoagulant therapy, monitor coagulation parameters and adjust anticoagulant dose as needed.
Disease-related concerns:
- Hepatic impairment: Use with caution in patients with hepatic impairment; hepatic impairment may interfere with mitotane metabolism and may result in accumulation.
Concurrent drug therapy issues:
- Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
Monitoring Parameters
Monitor for therapeutic mitotane levels; monitor free cortisol and corticotropin levels; monitor adrenal function; signs/symptoms of CNS toxicity, signs/symptoms of ovarian macrocysts (eg, vaginal bleeding and/or pelvic pain). Monitor adherence.
Mitotane level monitoring (gas chromatography-flame ionization assay): Adults: Every 4 to 8 weeks until target levels are attained, then monitor every 3 months; urinary free cortisol levels; TSH and free thyroxine every few months (Veytsman 2009).
Pediatrics (adrenocortical carcinoma): Monitor mitotane serum concentrations initially every 2 to 4 weeks until serum concentration of 10 mcg/mL is achieved, then monitor every 1 to 2 weeks (even after target concentration of 14 to 20 mcg/mL is reached) and use conservative dose adjustments due to drug accumulation and narrow therapeutic window (Zancanella 2006).
Pregnancy
Pregnancy Considerations
Mitotane crosses the placenta (Gerl 1992) and may cause fetal harm if administered during pregnancy. Although use in pregnancy is limited, preterm birth and early pregnancy loss have been reported (Baszko-Błaszyk 2011; Kojori 2011; Tripto-Shkolnik 2013).
Mitotane has a long elimination half-life. Women of reproductive potential should use effective contraception during treatment and after treatment until plasma levels are no longer detected. When used to treat Cushing disease, available guidelines recommend avoiding pregnancy for years after stopping mitotane therapy (Nieman 2015).
Patient Education
- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
- Patient may experience nausea, vomiting, dizziness, headache, diarrhea, lack of appetite, or loss of strength and energy. Have patient report immediately to prescriber signs of infection, signs of adrenal gland problems (severe nausea, vomiting, severe dizziness, passing out, muscle weakness, severe fatigue, mood changes, lack of appetite, or weight loss), signs of thyroid problems (change in weight without trying, anxiety, agitation, feeling very weak, hair thinning, depression, neck swelling, difficulty focusing, inability handling heat or cold, menstrual changes, tremors, or sweating), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin), vision changes, confusion, depression, change in balance, change in speech, enlarged breasts, abnormal vaginal bleeding, pelvic pain, or severe fatigue (HCAHPS).
- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.
