Mitotane (Systemic)


VA CLASSIFICATION
Primary: AN900
Secondary: HS900

Commonly used brand name(s): Lysodren.

Another commonly used name is
o,p´-DDD .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antineoplastic—

antiadrenal—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Carcinoma, adrenocortical (treatment)—Mitotane is indicated in the treatment of inoperable functional and nonfunctional adrenocortical carcinoma {01}.

[Cushing's syndrome (treatment)]1—Mitotane is used in the treatment of Cushing's syndrome.

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    320.05

Mechanism of action/Effect:

Mitotane apparently suppresses the activity of the adrenal cortex. Mechanism of cytotoxic action is unknown, but may be related to adrenal suppression.

Absorption:

Approximately 35 to 40% absorbed from the gastrointestinal tract.

Distribution:

To all body tissues; stored in fat; small amount (as metabolite) crosses blood-brain barrier.

Biotransformation:

Hepatic and renal, to water-soluble metabolite.

Half-life:

18 to 159 days {01}.

Onset of action:

Reduced concentrations of 17-hydroxycorticosteroid usually occur within 2 or 3 days after initiation of therapy; tumor response may occur within 6 weeks.

Time to peak plasma concentration

3 to 5 hours.

Elimination:
    Renal, 10 to 25% (as metabolite); bile, 1 to 17% (as metabolite). Measurable plasma concentrations persist for 6 to 9 weeks after withdrawal of mitotane. {01}


Precautions to Consider

Carcinogenicity/Mutagenicity

Studies have not been done {01}.

Pregnancy/Reproduction

Pregnancy—
Studies have not been done in either animals or humans. Problems in humans have not been documented. However, caution is recommended, especially during the first trimester.

FDA Pregnancy Category C {01}.

Breast-feeding

It is not known whether mitotane is distributed into breast milk. However, problems in humans have not been documented.

Pediatrics

Appropriate studies with mitotane have not been performed in the pediatric population. However, pediatrics-specific problems that would limit the usefulness of this medication in children are not expected.


Geriatrics


No geriatrics-specific information is available on the use of mitotane in geriatric patients.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Central nervous system (CNS) depression–producing medications (see Appendix II )    (concurrent use may produce additive CNS depressant effects)


Corticosteroids, glucocorticoid and mineralocorticoid    (higher dosage may be required to treat adrenal insufficiency since mitotane alters metabolism of these steroids)


Corticotropin (ACTH)    (mitotane may inhibit the adrenal response to ACTH; this may interfere with the therapeutic response to ACTH)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Plasma cortisol concentrations and
Urinary 17-hydroxycorticosteroid concentrations    (may be decreased as a result of adrenocortical inhibition)


Protein-bound iodine (PBI) concentrations    (may be decreased as a result of mitotane binding to thyroid-binding globulin)


Serum uric acid concentrations    (may be decreased)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Hepatic function impairment other than metastatic lesion of the adrenal cortex    (reduced metabolism and possible accumulation; reduction in dosage may be required)


» Infection
Sensitivity to mitotane

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Neurological assessments    (recommended at periodic intervals in patients receiving mitotane for longer than 2 years)


» 8 a.m. plasma cortisol concentrations or
» 24-hour urinary 17-hydroxycorticosteroid concentrations    (recommended at periodic intervals to aid in assessing clinical response and to determine if steroid supplement therapy is necessary)




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
—40 to 80%    
Adrenocortical insufficiency (darkening of skin; diarrhea; dizziness; drowsiness; loss of appetite; mental depression; nausea and vomiting; skin rash; unusual tiredness)

Incidence less frequent
    
Double vision
    
hemorrhagic cystitis (blood in urine)
    
lens opacity or toxic retinopathy (blurred vision)

Incidence rare
    
Allergic reaction (shortness of breath; wheezing)



Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent
    
Aching muscles
    
fever
    
flushing or redness of skin
    
muscle twitching
    
orthostatic hypotension (dizziness or lightheadedness when getting up from a lying or sitting position)





Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Mitotane (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
  Conditions affecting use, especially:
Sensitivity to mitotane

Pregnancy—Caution is recommended, especially during the first trimester
Other medications, especially CNS depressants
Other medical problems, especially hepatic function impairment other than metastatic lesion of the adrenal cortex or infection

Proper use of this medication
» Importance of not taking more or less medication than the amount prescribed

» Checking with physician before discontinuing medication because of risk of adrenal suppression

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses; checking with physician

» Proper storage

Precautions while using this medication
» Importance of close monitoring by the physician

Carrying medical identification card

» Caution in taking alcohol or other CNS depressants

» Caution if dizziness or drowsiness occurs, especially if driving, using machines, or doing other things that require alertness

» Checking with physician immediately if injury, infection, or other illness occurs, because of the risk of adrenal insufficiency; physician may prescribe steroid supplement


Side/adverse effects
Signs of potential side effects, especially adrenocortical insufficiency, double vision, hemorrhagic cystitis, lens opacity, toxic retinopathy, and allergic reaction


General Dosing Information
Patients receiving mitotane should be under supervision of a physician experienced in cancer chemotherapy.

Initial treatment often occurs in the hospital until dosage is stabilized.

Dosage must be adjusted to the maximum dose tolerated to meet the individual requirements of each patient, based on appearance of adverse reactions and improvement in clinical response.

Glucocorticoid therapy is usually required in patients being treated with mitotane; mineralocorticoid therapy may also be required, especially with prolonged therapy. Because metabolism of exogenous corticosteroids may be altered in patients receiving mitotane, higher than normal replacement doses may be required {01}. Steroid therapy may have to be continued after mitotane is withdrawn, until adrenocortical function returns to normal.

Continuous treatment with the maximum tolerated dosage of mitotane appears to be more effective than intermittent courses.

Duration of treatment depends on clinical response. Only 10% of patients showing no response after 3 months of treatment at the maximum tolerated dosage will show a response to continued therapy.

It is recommended that mitotane be temporarily withdrawn immediately following shock or severe trauma and that steroids be administered, because adrenal suppression may prevent the normal response to stress.


Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

MITOTANE TABLETS USP

Usual adult dose
Carcinoma, adrenocortical
Initial: Oral, 2 to 6 grams per day in three or four divided doses; the dosage may be increased until adverse reactions occur.

Note: The maximum tolerated dosage may vary from 2 to 16 grams per day, with an average dosage of 9 to 10 grams per day.


[Cushing's syndrome]1
Initial: Oral, 3 to 6 grams per day in three or four divided doses.

Maintenance: Oral, 500 mcg (0.5 mg) two times a week to 2 grams per day.


Usual pediatric dose
Carcinoma, adrenocortical
Oral, 100 to 500 mcg (0.1 to 0.5 mg) per kg of body weight; or initially, 1 to 2 grams per day in divided doses, the dosage being gradually increased to 5 to 7 grams per day.


Strength(s) usually available
U.S.—


500 mg (Rx) [Lysodren (scored)]

Canada—


500 mg (Rx) [Lysodren (scored)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by the manufacturer. Store in a tight, light-resistant container.

Auxiliary labeling:
   • May cause drowsiness.



Revised: 07/08/1998



References

Note: References used in the development and subsequent revisions of this monograph have not been incorporated into the database and therefore are not listed below.

  1. Lysodren package insert (Bristol—US), Rev 5/87.
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