LYSODRENR (mitotane tablets, USP) is an oral chemotherapeutic agent. It is best known by its trivial name, o,p'-DDD, and is chemically, 1,1-dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl) ethane. The chemical structure is shown below:

LYSODREN is a white granular solid composed of clear colorless crystals. It is tasteless and has a slight pleasant aromatic odor. It is soluble in ethanol, isooctane and carbon tetrachloride. It has a molecular weight of 320.05.

Inactive ingredients in LYSODREN tablets are: avicel, Polyethylene Glycol 3350, silicon dioxide, and starch.

LYSODREN is available as 500 mg scored tablets for oral administration.

LYSODREN is indicated in the treatment of inoperable adrenal cortical carcinoma of both functional and nonfunctional types.

The recommended treatment schedule is to start the patient at 2 to 6 g of LYSODREN per day in divided doses, either three or four times a day. Doses are usually increased incrementally to 9 to 10 g per day. If severe side effects appear, the dose should be reduced until the maximum tolerated dose is achieved. If the patient can tolerate higher doses and improved clinical response appears possible, the dose should be increased until adverse reactions interfere. Experience has shown that the maximum tolerated dose (MTD) will vary from 2 to 16 g per day, but has usually been 9 to 10 g per day. The highest doses used in the studies to date were 18 to 19 g per day.

Treatment should be instituted in the hospital until a stable dosage regimen is achieved.

Treatment should be continued as long as clinical benefits are observed. Maintenance of clinical status or slowing of growth of metastatic lesions can be considered clinical benefits if they can clearly be shown to have occurred.

If no clinical benefits are observed after 3 months at the maximum tolerated dose, the case would generally be considered a clinical failure. However, 10% of the patients who showed a measurable response required more than 3 months at the MTD. Early diagnosis and prompt institution of treatment improve the probability of a positive clinical response. Clinical effectiveness can be shown by reduction in tumor mass; reduction in pain, weakness or anorexia; and reduction of symptoms and signs due to excessive steroid production.

A number of patients have been treated intermittently with treatment being restarted when severe symptoms have reappeared. Patients often do not respond after the third or fourth such course. Experience accumulated to date suggests that continuous treatment with the maximum possible dosage of LYSODREN is the best approach.

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.^1-8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

To minimize the risk of dermal exposure, always wear impervious gloves when handling bottles containing LYSODREN Tablets. This includes all handling activities in clinical settings, pharmacies, storerooms, and home healthcare settings, including during unpacking and inspection, transport within a facility, and dose preparation and administration.

LYSODREN® (mitotane tablets, USP)

NDC 0015-3080-60-500 mg Tablets, bottle of 100

Storage

Store at 25° C (77° F); excursions permitted to 15° C-30° C (59° F-86° F) [see USP Controlled Room Temperature].

REFERENCES

1.ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for Practice. Pittsburgh, PA: Oncology Nursing Society; 1999:32-41.

2. Recommendations for the safe handling of parenteral antineoplastic drugs. Washington, DC: Division of Safety, Clinical Center Pharmacy Department and Cancer Nursing Services, National Institutes of Health; 1992. US Dept of Health and Human Services, Public Health Service Publication NIH 92-2621.

3. AMA Council on Scientific Affairs. Guidelines for handling parenteral antineoplastics.JAMA. 1985;253:1590-1592.

4. National Study Commission on Cytotoxic Exposure. Recommendations for handling cytotoxic agents. 1987. Available from Louis P. Jeffrey, ScD, Chairman, National Study Commission on Cytotoxic Exposure. Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, MA 02115.

5. Clinical Oncological Society of Australia. Guidelines and recommendations for safe handling of antineoplastic agents. Med J Aust. 1983;1:426-428.

6. Jones RB, Frank R, Mass T. Safe handling of chemotherapeutic agents: a report from The Mount Sinai Medical Center. CA Cancer J Clin. 1983; 33:258-263.

7. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm. 1990;47:1033-1049.

8. Controlling occupational exposure to hazardous drugs. (OSHA Work-Practice Guidelines.) Am J Health-Syst Pharm. 1996;53:1669-1685.

Bristol-Myers Squibb Company, Princeton, New Jersey 08543, USA. Made in Italy. Revised August 2006. FDA Rev date: 7/10/2003

A very high percentage of patients treated with LYSODREN have shown at least one type of side effect. The main types of adverse reactions consist of the following:

1. Gastrointestinal disturbances, which consist of anorexia, nausea or vomiting, and in some cases diarrhea, occur in about 80% of the patients.
2. Central nervous system side effects occur in 40% of the patients. These consist primarily of depression as manifested by lethargy and somnolence (25%), and dizziness or vertigo (15%).
3. Skin toxicity has been observed in about 15% of the cases. These skin changes consist primarily of transient skin rashes which do not seem to be dose related. In some instances, this side effect subsided while the patients were maintained on the drug without a change of dose. Infrequently occurring side effects involve the eye (visual blurring, diplopia, lens opacity, toxic retinopathy); the genitourinary system (hematuria, hemorrhagic cystitis, and albuminuria); cardiovascular system (hypertension, orthostatic hypotension, and flushing); and some miscellaneous effects including generalized aching, hyperpyrexia, and lowered protein bound iodine (PBI).

LYSODREN has been reported to accelerate the metabolism of warfarin by the mechanism of hepatic microsomal enzyme induction, leading to an increase in dosage requirements for warfarin. Therefore, physicians should closely monitor patients for a change in anticoagulant dosage requirements when administering LYSODREN to patients on coumarin-type anticoagulants. In addition, LYSODREN should be given with caution to patients receiving other drugs susceptible to the influence of hepatic enzyme induction.

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

LYSODREN should be administered with care to patients with liver disease other than metastatic lesions from the adrenal cortex, since the metabolism of LYSODREN may be interfered with and the drug may accumulate.

All possible tumor tissues should be surgically removed from large metastatic masses before LYSODREN administration is instituted. This is necessary to minimize the possibility of infarction and hemorrhage in the tumor due to a rapid cytotoxic effect of the drug.

Long-term continuous administration of high doses of LYSODREN may lead to brain damage and impairment of function. Behavioral and neurological assessments should be made at regular intervals when continuous LYSODREN treatment exceeds 2 years.

A substantial percentage of the patients treated show signs of adrenal insufficiency. It therefore appears necessary to watch for and institute steroid replacement in those patients. However, some investigators have recommended that steroid replacement therapy be administered concomitantly with LYSODREN. It has been shown that the metabolism of exogenous steroids is modified and consequently somewhat higher doses than normal replacement therapy may be required.

General

Adrenal insufficiency may develop in patients treated with LYSODREN, and adrenal steroid replacement should be considered for these patients.

Since sedation, lethargy, vertigo, and other CNS side effects can occur, ambulatory patients should be cautioned about driving, operating machinery, and other hazardous pursuits requiring mental and physical alertness.

Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenic and mutagenic potentials of LYSODREN (mitotane tablets, USP) are unknown. However, the mechanism of action of this compound suggests that it probably has less carcinogenic potential than other cytotoxic chemotherapeutic drugs.

Pregnancy

Pregnancy Category C

Animal reproduction studies have not been conducted with LYSODREN. It is also not known whether LYSODREN can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. LYSODREN should be given to a pregnant woman only if clearly needed.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from mitotane, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of LYSODREN did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

No proven antidotes have been established for LYSODREN overdosage.

LYSODREN (mitotane tablets, USP) should not be given to individuals who have demonstrated a previous hypersensitivity to it.

LYSODREN can best be described as an adrenal cytotoxic agent, although it can cause adrenal inhibition, apparently without cellular destruction. Its biochemical mechanism of action is unknown. Data are available to suggest that the drug modifies the peripheral metabolism of steroids as well as directly suppressing the adrenal cortex. The administration of LYSODREN alters the extra-adrenal metabolism of cortisol in man; leading to a reduction in measurable 17-hydroxy corticosteroids, even though plasma levels of corticosteroids do not fall. The drug apparently causes increased formation of 6-β-hydroxycortisol.

Data in adrenal carcinoma patients indicate that about 40% of oral LYSODREN is absorbed and approximately 10% of administered dose is recovered in the urine as a water-soluble metabolite. A variable amount of metabolite (1 to 17%) is excreted in the bile and the balance is apparently stored in the tissues.

Following discontinuation of LYSODREN, the plasma terminal half-life has ranged from 18 to 159 days. In most patients blood levels become undetectable after 6 to 9 weeks. Autopsy data have provided evidence that LYSODREN is found in most tissues of the body; however, fat tissues are the primary site of storage. LYSODREN is converted to a water-soluble metabolite.

No unchanged LYSODREN has been found in urine or bile.

No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

MITOTANE - ORAL

(MY-toe-tain)

COMMON BRAND NAME(S): Lysodren

WARNING: Mitotane causes your body to decrease its ability to quickly respond to stress (shock, severe injury, or infection). Mitotane may need to be stopped if you experience an injury, infection, or other stress. Your doctor may also prescribe another medication (corticosteroid).

Tell your doctor if you experience unusual weakness, tiredness, dizziness, fainting, loss of appetite, nausea, vomiting, diarrhea, or signs of an infection (e.g., persistent sore throat, fever).

USES: Mitotane is used to treat cancer of the adrenal glands. The adrenal glands produce hormones, which are needed by the body to deal with stress, fight infection, and maintain normal functions such as blood pressure. Certain cancers cause the adrenal glands to produce too much cortisol and other hormones, causing a certain serious condition (Cushing's syndrome). Too much of these hormones can cause many problems such as blood pressure changes, weight changes, muscle/bone weakness, thinning skin, and diabetes. Mitotane works by killing or slowing the growth of adrenal gland cells and also reverses the side effects caused by too much hormone production.

OTHER USES: This section contains uses of this drug that are not listed in the approved professional labeling for the drug but that may be prescribed by your health care professional. Use this drug for a condition that is listed in this section only if it has been so prescribed by your health care professional.

This drug may also be used alone or with other medications to treat other forms of Cushing's syndrome not caused by adrenal cancer (e.g., non-pituitary tumor).

HOW TO USE: Take this medication by mouth with or without food, usually 3 or 4 times daily or as directed by your doctor. This medication is often started in the hospital, where your doctor can follow you closely as your dose is adjusted to the best dose for you. Dosage is based on your medical condition and response to therapy (e.g., cortisol levels).

Usually, you will need to take replacement corticosteroids (e.g., hydrocortisone) every day while you are taking this drug and for some time after stopping mitotane.

Use this medication regularly to get the most benefit from it. To help you remember, take it at the same times each day. Do not increase your dose or take this medication more often than prescribed. Your condition will not improve any faster, and the risk of serious side effects may be increased.

It may take up to several months to receive the full benefit from this drug. Inform your doctor if your condition persists or worsens.

Since this drug can be absorbed through the skin and lungs, women who are pregnant or who may become pregnant should not handle this medication or breathe the dust from the tablets. Learn proper technique for safe handling and disposal of this medicine and its container. Consult your pharmacist.

SIDE EFFECTS: Dizziness, drowsiness, nausea, diarrhea, loss of appetite, headache, or unusual weakness may occur. If these effects persist or worsen, notify your doctor promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: severe dizziness, flushing, fast/pounding heartbeat, shakiness (tremors), unusual/rapid weight loss, change in skin color/thickness.

Tell your doctor immediately if any of these rare but very serious side effects occur: easy bleeding/bruising, breast tenderness/enlargement (males), unwanted facial/body hair (females), mental/mood changes (e.g., depression, irritability, difficulty concentrating, confusion), speech problems, numbness/tingling of hands/feet, unsteadiness, pink urine, vision problems.

This medication can lower the body's ability to fight an infection. Notify your doctor promptly if you develop any signs of an infection such as fever, chills, or persistent sore throat.

Mitotane can commonly cause a rash that usually goes away. However, you may not be able to tell it apart from a rash that could be a sign of a severe reaction. Therefore, seek immediate medical attention if you develop a rash.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking mitotane, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: current infection (especially viral infections such as chickenpox, herpes), blood pressure problems, liver disease.

This drug may make you dizzy or drowsy. Use caution while driving, using machinery, or doing any activity that requires alertness. Limit alcoholic beverages.

This medication can make it difficult to control your blood pressure. To minimize dizziness and lightheadedness, get up slowly when rising from a sitting or lying position.

If you have been using this product, your body may not produce enough natural steroids. You may need to start taking additional corticosteroids (e.g., hydrocortisone), especially if your body is stressed due to a major infection, surgery or injury. Tell your doctor immediately if a stress situation (e.g., trauma, surgery, serious infection) is occurring or any of the following side effects occur: unusual weakness, sudden weight loss, dizziness. This advice applies during and up to 8 months after stopping mitotane treatment. Carry an emergency card or bracelet with this information. Consult your doctor or pharmacist for more details.

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

It is not known if this drug passes into breast milk and could have undesirable effects on a nursing infant. Therefore, breast-feeding is not recommended while using this drug. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: "blood thinners" (e.g., warfarin), corticosteroids (e.g., dexamethasone, prednisone), "water pills"/diuretics (e.g., furosemide, spironolactone), drugs removed from your body by certain liver enzymes (such as barbiturates, phenytoin).

Tell your doctor or pharmacist if you also take drugs that cause drowsiness such as: certain antihistamines (e.g., diphenhydramine), anti-seizure drugs (e.g., carbamazepine), medicine for sleep or anxiety (e.g., alprazolam, diazepam, zolpidem), muscle relaxants, narcotic pain relievers (e.g., codeine), psychiatric medicines (e.g., chlorpromazine, risperidone, amitriptyline, trazodone).

Check the labels on all your medicines (e.g., cough-and-cold products) because they may contain drowsiness-causing ingredients. Ask your pharmacist about using those products safely.

This product can affect the results of certain lab tests (including thyroid function tests), possibly causing false test results. Make sure laboratory personnel and all your doctors know you use this drug.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (e.g., complete blood count, blood pressure, cortisol, electrolytes, liver tests) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature between 59-86 degrees F (15-30 degrees C) away from light and moisture. Keep all medications away from children and pets

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For information about enrolling in MedicAlert, call 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.