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Mitotane

Pronunciation

(MYE toe tane)

Index Terms

  • Chloditan
  • Chlodithane
  • Khloditan
  • Mytotan
  • o,p′ - DDD
  • Ortho,para - DDD

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Lysodren: 500 mg [scored]

Brand Names: U.S.

  • Lysodren

Pharmacologic Category

  • Antineoplastic Agent, Miscellaneous

Pharmacology

Adrenolytic agent which causes adrenal cortical atrophy; affects mitochondria in adrenal cortical cells and decreases production of cortisol; also alters the peripheral metabolism of steroids

Absorption

Oral: ~40%

Distribution

Stored mainly in fat tissue but is found in all body tissues

Metabolism

Hepatic and other tissues

Excretion

Urine (~10%, as metabolites); feces (1% to 17%, as metabolites)

Time to Peak

Serum: 3-5 hours

Duration of Action

Blood levels undetectable in most patients after 6-9 weeks.

Half-Life Elimination

18-159 days

Special Populations: Hepatic Function Impairment

Administer with care in patients with liver disease other than metastatic lesions of the adrenal cortex. Interference with metabolism may occur, causing drug accumulation.

Use: Labeled Indications

Adrenocortical carcinoma: Treatment of inoperable adrenocortical carcinoma (both functional and non-functional types)

Use: Unlabeled

Treatment of Cushing syndrome

Contraindications

Hypersensitivity to mitotane or any component of the formulation

Dosage

Note: Mitotane is associated with a moderate emetic potential; antiemetics may be needed to prevent nausea and vomiting.

Adrenocortical carcinoma: Adults: Oral: Initial: 2 to 6 g daily in 3 to 4 divided doses, then increase incrementally to 9 to 10 g daily in 3 to 4 divided doses (maximum tolerated range: 2 to 16 g daily, usually 9 to 10 g daily; maximum dose studied: 18 to 19 g daily); continue as long as clinical benefit is demonstrated

Off-label dosing: Initial 1 to 2 g daily; increase by 1 to 2 g daily at 1 to 2 week intervals as tolerated to a maximum of 6 to 10 g daily; usual dose 4 to 5 g daily (Veytsman, 2009)

Cushing syndrome (off-label use): Adults: Oral: Initial dose: 500 mg 3 times daily; maximum dose: 3 g 3 times daily (Biller, 2008)

Dosage adjustment for toxicity:

Severe side effects: Reduce dose until a maximum tolerated dose is achieved

Significant neuropsychiatric adverse effects: Withhold treatment for at least 1 week and restart at a lower dose (Allolio, 2006)

Dosage adjustment in renal impairment: No dosage adjustment provided in manufacturer’s labeling.

Dosage adjustment in hepatic impairment: No dosage adjustment provided in manufacturer’s labeling. However, drug accumulation may occur in patients with liver disease; use with caution.

Administration

Note: Mitotane is associated with a moderate emetic potential; antiemetics may be needed to prevent nausea and vomiting.

Oral: Administer in 3 to 4 divided doses/day. Do not crush tablets. Mitotane is associated with a moderate emetic potential; antiemetics may be needed to prevent nausea and vomiting.

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]). Wear impervious gloves when handling; avoid exposure to crushed or broken tablets.

Storage

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

Drug Interactions

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. Avoid combination

Antihepaciviral Combination Products: CYP3A4 Inducers (Strong) may decrease the serum concentration of Antihepaciviral Combination Products. Avoid combination

Apixaban: CYP3A4 Inducers (Strong) may decrease the serum concentration of Apixaban. Avoid combination

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 may decrease the serum concentration of ARIPiprazole. Management: Double the oral aripiprazole dose and closely monitor response. Reduce oral aripiprazole dose to 10-15 mg/day (for adults) if the inducer is discontinued. Avoid use of 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 662 mg or 882 mg 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

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

Boceprevir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Boceprevir. Avoid combination

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

Cabozantinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Cabozantinib. Avoid combination

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

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

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

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: Mitotane may decrease the serum concentration of CYP3A4 Substrates. 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. Avoid combination

Daclatasvir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Daclatasvir. 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

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 steroid efficacy. 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

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

Eliglustat: CYP3A4 Inducers (Strong) may decrease the serum concentration of Eliglustat. 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. 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

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 these combinations cannot be avoided, monitor patients closely for diminished etoposide response. 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

Everolimus: CYP3A4 Inducers (Strong) may decrease the serum concentration of Everolimus. Management: Avoid concurrent use of strong CYP3A4 inducers, but if strong CYP3A4 inducers cannot be avoided, consider gradually (in 5 mg increments) increasing the everolimus dose from 10 mg/day to 20 mg/day (adult doses). Avoid combination

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

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

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

GuanFACINE: CYP3A4 Inducers (Strong) may decrease the serum concentration of GuanFACINE. Management: Consider increasing the guanfacine dose by 2-fold when adding a strong CYP3A4 inducer. Titrate the guanfacine dose up to a max of 8 mg/day when starting guanfacine in a patient who is taking a strong CYP3A4 inhibitor. 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

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

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

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

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

Macitentan: CYP3A4 Inducers (Strong) may decrease the serum concentration of Macitentan. Avoid combination

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

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

Mifepristone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Mifepristone. Avoid combination

Naloxegol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Naloxegol. 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. Avoid combination

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: Avoid use of perampanel with strong CYP3A inducers other than enzyme-inducing antiepileptic drugs (EIAEDs). Increase perampanel starting dose to 4 mg/day when used with EIAEDs such as phenytoin, carbamazepine, or oxcarbazepine. Avoid combination

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: Avoid concomitant use of praziquantel with strong CYP3A4 inducers. Discontinue rifampin 4 weeks prior to initiation of praziquantel therapy. Rifampin may be resumed the day following praziquantel completion. 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: Quetiapine dose increases to 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

Ranolazine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ranolazine. Avoid combination

Regorafenib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Regorafenib. Avoid combination

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

Saxagliptin: CYP3A4 Inducers may decrease the serum concentration of Saxagliptin. Monitor therapy

Simeprevir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Simeprevir. Avoid combination

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

SUNItinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of SUNItinib. Management: Avoid when possible. If such a combination cannot be avoided, consider increasing sunitinib dose and monitor clinical response and toxicity closely. Consider therapy modification

Suvorexant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Suvorexant. Avoid combination

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

Tasimelteon: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tasimelteon. Avoid combination

Telaprevir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Telaprevir. Avoid combination

Tetrahydrocannabinol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tetrahydrocannabinol. Monitor therapy

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

Ulipristal: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ulipristal. Avoid combination

Vandetanib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Vandetanib. Avoid combination

Vemurafenib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Vemurafenib. 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

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

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

Zuclopenthixol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Zuclopenthixol. Monitor therapy

Adverse Reactions

The majority of adverse events are dose-dependent.

>10%:

Central nervous system: Central nervous system depression (32%), lethargy/drowsiness (25%), dizziness/vertigo (15%)

Dermatologic: Skin rash (15%)

Gastrointestinal: Anorexia (24%), nausea (39%), vomiting (37%), diarrhea (13%)

Neuromuscular & skeletal: Weakness (12%)

1% to 10%:

Central nervous system: Headache (5%), confusion (3%)

Neuromuscular & skeletal: Tremor (3%)

<1% (Limited to important or life-threatening): Abnormal thyroid function test, adrenocortical insufficiency, albuminuria, anemia, autoimmune hepatitis, blurred vision, brain damage (may be reversible), cataract, decreased protein-bound iodine, diplopia, generalized aches, growth suppression, gynecomastia, hematuria, hemorrhagic cystitis, hepatitis, hypercholesterolemia, hyperpyrexia, hypertension, hypertriglyceridemia, hypogonadism (primary), hypouricemia, increased gamma-glutamyl transferase, increased liver enzymes, increased serum transaminases, increased serum triglycerides, increased sex hormone binding globulin, leukopenia, macular edema, maculopathy, memory impairment, mental deficiency, mucositis, myalgia, neuropathy, neutropenia, orthostatic hypotension, prolonged bleeding time, psychological disturbances (neuro), retinopathy (toxic), thrombocytopenia

ALERT: U.S. Boxed Warning

Experienced physician:

Mitotane should be administered under the supervision of a qualified health care provider experienced in the uses of cancer chemotherapeutic agents.

Adrenal insufficiency:

Mitotane should be temporarily discontinued immediately following shock or severe trauma because adrenal suppression is its prime action. Exogenous steroids should be administered in such circumstances because the depressed adrenal may not immediately start to secrete steroids.

Warnings/Precautions

Concerns related to adverse effects:

• Adrenal insufficiency: [U.S. Boxed Warning]: Because the primary action of mitotane is through adrenal suppression, discontinue mitotane temporarily with onset of shock or severe trauma; administer appropriate steroid coverage. Patients treated with mitotane may develop adrenal insufficiency; steroid replacement therapy may be required.

• CNS effects: CNS adverse effects, including lethargy, sedation, and vertigo may occur; 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.

• Neurotoxicity: Long-term (>2 years) use may lead to brain damage or functional impairment; observe patients for neurotoxicity (behavioral and neurological) at regular intervals. Plasma concentrations >20 mcg/mL are associated with an increased incidence of higher-grade neurotoxicity. Neurologic impairment may reverse upon discontinuation.

• Prolonged bleeding time: Prolonged bleeding time may occur; consider bleeding possibility prior to any surgical intervention.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with hepatic impairment (other than metastatic lesions from adrenal cortex); metabolism may be decreased.

• Metastatic masses: Surgically remove tumor tissues from metastatic masses prior to initiation of treatment; rapid cytotoxic effect may cause tumor hemorrhage.

Concurrent drug therapy issues:

• Corticosteroid replacement therapy: Steroid replacement with glucocorticoid, and sometimes mineralocorticoid, is necessary. It has been recommended that steroid replacement therapy be initiated at the start of therapy, rather than waiting for evidence of adrenal insufficiency. Because mitotane can increase the metabolism of exogenous steroids, higher than usual replacement steroid doses may be required. Mitotane increases hormone binding proteins; monitor free cortisol and corticotropin levels for optimal replacement.

• 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.

• Sedatives: CNS effects may be potentiated when used with other sedative drugs or ethanol.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Other warnings/precautions:

• Appropriate use: The manufacturer recommends initiating treatment within a hospital environment until a stabilized dose is achieved. Continue treatment as long as clinical benefit (clinical status maintenance or slowed growth of metastatic lesion) is observed. Clinical benefit is usually observed within 3 months at maximum tolerated dose, although 10% of patients may require more than 3 months for benefit. Continuous treatment at the maximum tolerated dose is generally the best approach. Some patients have been treated intermittently, restarting when severe symptoms reappear, although often response is no longer observed after 3 or 4 courses of intermittent treatment.

• Experienced physician: [U.S. Boxed Warning] Should be administered under the supervision of an experienced cancer chemotherapy physician.

Monitoring Parameters

Adrenal function; neurologic assessments (including behavioral) at regular intervals with chronic (>2 years) use.

Monitor mitotane levels (gas chromatography-flame ionization assay) every 4-8 weeks until levels at 10-14 mg/L are attained, then monitor every 3 months; urinary free cortisol levels; TSH and free thyroxine every few months (Veytsman, 2009)

Pregnancy Risk Factor

D

Pregnancy Considerations

Animal reproduction studies have not been conducted. May cause fetal harm if administered during pregnancy; adverse outcomes have been reported. Women of reproductive potential should use effective contraception during treatment and after treatment until plasma levels are no longer detected.

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, diarrhea, lack of appetite, or asthenia. Have patient report immediately to prescriber vision changes, hematuria, ecchymosis, hemorrhaging, severe headache, illogical thinking, considerable dizziness, syncope, or significant 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 healthcare 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.

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