Mitotane (Tablets) Instructions for Use

Marketing Authorization Holder

Pharmalab, LLC (Russia)

Manufactured By

Nanopharma Development, LLC (Russia)

Packaging and Quality Control Release

NANOFARMA DEVELOPMENT, LLC (Russia)

Primary Packaging

IZVARINO PHARMA, LLC (Russia)

ATC Code

L01XX23 (Mitotane)

Active Substance

Mitotane (Rec.INN registered by WHO)

Dosage Form

Mitotane

Tablets 500 mg: 10, 20, 30, 40, 50 or 100 pcs.

Dosage Form, Packaging, and Composition

Tablets are white or almost white, oblong, biconvex, with a score line.

Excipients: microcrystalline cellulose – 242 mg, colloidal silicon dioxide – 10 mg, sodium carboxymethyl starch – 40 mg, magnesium stearate – 8 mg.

10 pcs. – contour cell packaging (1) – cardboard packs.
10 pcs. – contour cell packaging (2) – cardboard packs.
10 pcs. – contour cell packaging (3) – cardboard packs.
10 pcs. – contour cell packaging (4) – cardboard packs.
10 pcs. – contour cell packaging (5) – cardboard packs.
10 pcs. – contour cell packaging (10) – cardboard packs.
10 pcs. – polymer jars (1) – cardboard packs.
20 pcs. – polymer jars (1) – cardboard packs.
30 pcs. – polymer jars (1) – cardboard packs.
40 pcs. – polymer jars (1) – cardboard packs.
50 pcs. – polymer jars (1) – cardboard packs.
100 pcs. – polymer jars (1) – cardboard packs.

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agents; other antineoplastic agents

Pharmacological Action

Antineoplastic agent. Mitotane has a cytotoxic effect on adrenal cells, and it also appears to be able to suppress adrenal cortex function without destroying cells.

The exact biochemical mechanism of its action is unknown. Existing data suggest that Mitotane alters the peripheral metabolism of steroids and also directly suppresses adrenal cortex function.

Mitotane intake changes the adrenal metabolism of cortisol in humans, leading to a decrease in the concentration of 17-hydroxycorticosteroids even in the absence of a decrease in plasma corticosteroid levels.

Apparently, Mitotane causes an increase in the formation of 6-beta-hydroxy-cholesterol. The efficacy of mitotane was noted in patients whose plasma mitotane level exceeded 14 mg/L.

A decrease in adrenal function is accompanied by a reduction/disappearance of the severity of Cushing’s syndrome manifestations in patients with secreting adrenal carcinoma and, in some cases, necessitates replacement hormone therapy.

Pharmacokinetics

When mitotane was prescribed at a dose of 2-3 g/day, a highly significant correlation was found between the dose and its plasma concentration.

The target plasma concentration of mitotane (14 mg/L) is achieved in patients after 3-5 months, the total dose of mitotane is in the range of 283-387 g (mean value – 363 g).

The threshold value of 20 mg/L was reached after taking a total mitotane dose of about 500 g.

There is evidence that Mitotane is found in most body tissues. The main depot is adipose tissue.

Studies have shown that 1,1-(o,p-dichlorodiphenyl) acetic acid (o,p’-DDA) is the main circulating metabolite, and there is also a small amount of 1,1-(o,p-dichlorodiphenyl)-2,2 dichloroethane (o,p-DDE) – an analogue of mitotane.

Unchanged Mitotane was not detected in saliva or urine, o,p’-DDA predominates, as well as some of its hydroxylated metabolites.

After IV administration, 25% of the dose is excreted with metabolites within 24 hours. After discontinuation of Mitotane, it is slowly released from fat depots, T_1/2 in the terminal phase ranges from 18 to 159 days.

Indications

Symptomatic treatment of progressive (inoperable, metastatic, or recurrent) adrenal cortex cancer.

ICD codes

Dosage Regimen

Determine the dosage individually based on disease stage, therapeutic regimen, plasma mitotane concentration, and clinical tolerance.

Initiate therapy in a specialized hospital setting under the supervision of a physician experienced in cytostatic chemotherapy.

Start with a low daily dose and escalate gradually to the maximum tolerated dose, typically ranging from 2 to 6 grams per day.

Divide the total daily dose into three or four separate administrations.

Administer tablets with a high-fat meal to enhance absorption and improve gastrointestinal tolerance.

Continue treatment with the maximum tolerated dose for as long as a clinical response is observed.

Achieve and maintain a target plasma concentration of 14 to 20 mg/L for optimal efficacy.

Monitor plasma mitotane levels regularly, especially during dose escalation and in overweight patients, due to drug accumulation in adipose tissue.

Adjust the dosage based on plasma level monitoring and the occurrence of adverse reactions.

Discontinue treatment immediately in the event of shock, severe trauma, or infection due to the risk of adrenal insufficiency.

For pediatric patients (over 3 years of age), calculate the dose individually based on body surface area.

Exercise caution in elderly patients and those with mild to moderate hepatic or renal impairment, requiring more frequent plasma level monitoring.

Adverse Reactions

From the hematopoietic system: very often – leukopenia, prolonged bleeding time; often – anemia, thrombocytopenia.

From the nervous system: very often – ataxia, paresthesia, vertigo, drowsiness, confusion; often – decreased mental activity, polyneuropathy, movement disorders, dizziness, headache; frequency unknown – balance disorder.

From the organ of vision frequency unknown – maculopathy, toxic retinal damage, double vision, lens opacity, blurred vision.

From the digestive system: very often – mucositis, vomiting, diarrhea, nausea, epigastric pain; frequency unknown – hypersalivation, dysgeusia, dyspepsia.

From the liver and biliary tract: often – autoimmune hepatitis; frequency unknown – liver damage (hepatocellular/cholestatic/mixed).

From the urinary system: frequency unknown – hemorrhagic cystitis, hematuria, proteinuria.

From the endocrine system: very often – adrenal cortex hypofunction; frequency unknown – thyroid dysfunction.

From metabolism: very often – anorexia, hypercholesterolemia, hypertriglyceridemia; frequency unknown – hyperuricemia.

From the reproductive system: very often – gynecomastia; frequency unknown – ovarian macrocysts.

From laboratory parameters very often – increased activity of “liver” enzymes; frequency unknown – decreased blood levels of androstenedione and testosterone (in women), increased level of sex hormone-binding globulin, decreased blood level of unbound testosterone (in men).

Other very often – skin rash, asthenia, myasthenia; frequency unknown – hyperpyrexia, generalized pain sensations.

Contraindications

Hypersensitivity to mitotane; pregnancy, breastfeeding period; children under 3 years of age; severe renal and/or hepatic insufficiency; simultaneous use of spironolactone.

With caution obesity, adrenal cortex hypofunction; mild to moderate renal and/or hepatic insufficiency; simultaneous use with anticonvulsants, rifabutin, rifampicin, griseofulvin, St. John’s wort, sunitinib, midazolam.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Available limited data on the use of mitotane during pregnancy indicate the possibility of fetal adrenal abnormalities. Animal studies have revealed reproductive toxicity.

Women of childbearing age should use effective methods of contraception during treatment, and also directly after discontinuation of treatment, as long as Mitotane is detected in plasma. The slow elimination of mitotane from the body after discontinuation of its use must be taken into account.

Due to the lipophilic nature of mitotane, there is a high probability of its excretion in breast milk during lactation. Breastfeeding is contraindicated during mitotane intake, as well as after discontinuation of treatment, as long as Mitotane is detected in plasma.

Use in Hepatic Impairment

Contraindicated for use in severe hepatic insufficiency. Patients with mild or moderate hepatic insufficiency are advised to exercise caution and more carefully monitor the plasma level of mitotane.

Use in Renal Impairment

Contraindicated for use in severe renal insufficiency. Patients with mild or moderate renal insufficiency are advised to exercise caution and more carefully monitor the plasma level of mitotane.

Pediatric Use

Use in children under 3 years of age is contraindicated. Doses for children are determined individually, based on body surface area, based on monitoring of plasma mitotane content and clinical tolerance.

Geriatric Use

Elderly patients should be prescribed with caution. It is necessary to regularly check the concentration of mitotane in the blood plasma in this category of patients.

Special Precautions

Mitotane should be used by physicians experienced in cytostatic chemotherapy. Dose selection and initial therapy should be carried out in a specialized hospital setting. It should be taken into account that continuous treatment with mitotane is more effective than the use of intermittent courses.

Large metastases should be surgically removed as early as possible before starting mitotane to minimize the risk of tumor necrosis and bleeding (due to the rapid cytotoxic effect of mitotane).

Adipose tissue, which serves as a kind of depot-reservoir for mitotane, contributes to the prolongation of the half-life and accumulation of mitotane. In this regard, even while taking an unchanged dose of mitotane, its concentration may increase. It is strongly recommended to exercise caution and carefully monitor the plasma level of mitotane in overweight patients.

All patients with non-hormone-producing tumors and 75% of patients with hormone-producing tumors develop signs of adrenal cortex insufficiency. Such patients may require replacement steroid therapy. Since Mitotane increases the level of steroid-binding proteins in plasma, it is necessary to measure the level of free cortisol and corticotropin for the optimal selection of the steroid replacement regimen.

The effect of mitotane on non-hormone-producing adrenal cortex cancer has not been established.

Mitotane intake should be stopped immediately after the occurrence of shock conditions, severe trauma, or infection, since its primary action is to suppress adrenal cortex function. Moreover, the need for exogenous steroids may arise, since the adrenal glands with suppressed function will not be able to immediately start producing steroids. Due to the increased risk of developing acute adrenocortical insufficiency, patients should immediately consult their doctor in case of injury, development of various infections, or occurrence of other concomitant diseases.

It is necessary to monitor the plasma content of mitotane to assess the need for correction of its dosage regimen, especially if it is necessary to prescribe a high initial dose. Dose adjustment may be necessary to achieve the target therapeutic level in the range of 14-20 mg/L and to prevent the development of specific adverse reactions.

Hepatotoxicity has been observed in patients taking Mitotane. Cases of liver damage (manifestations of hepatocellular, cholestatic and mixed hepatitis), as well as autoimmune hepatitis, have been reported. Periodic monitoring of liver function (activity of “liver” transaminases, bilirubin level) should be carried out, especially during the first months of treatment or if it is necessary to increase the dose.

Prolonged continuous use of high doses of mitotane can lead to reversible brain damage. It is necessary to monitor behavioral and neurological symptoms at regular intervals, especially if the plasma level of mitotane exceeds 20 mg/L.

Mitotane intake can affect all blood cells. Cases of leukopenia (including neutropenia), anemia and thrombocytopenia are often reported. When taking mitotane, it is necessary to monitor the number of red blood cells, white blood cells and platelets.

Increased bleeding time has been noted in patients taking Mitotane. This fact must be taken into account when considering the need for surgical intervention.

When mitotane is taken by patients while taking coumarin-like anticoagulants, blood clotting should be carefully monitored for timely detection of signs of excessive hypocoagulation and appropriate adjustment of the anticoagulant dosage regimen.

Mitotane is a stimulator of liver enzymes, caution should be exercised when using it concomitantly with drugs that affect the activity of liver enzymes.

Women of childbearing age should use effective contraception while taking mitotane.

The development of ovarian macrocysts is often observed in premenopausal women. In some cases, complications such as torsion and hemorrhagic rupture of cysts have been reported. Improvement was observed after discontinuation of mitotane. Women should immediately consult a doctor if gynecological symptoms appear, for example, bleeding and/or pelvic pain.

Use in pediatrics

Neuropsychiatric inhibition may be observed in children and adolescents when taking mitotane. In such cases, it is necessary to assess thyroid function to identify possible thyroid damage associated with mitotane intake.

Effect on ability to drive vehicles and operate machinery

During the treatment period, patients should avoid driving vehicles and other activities requiring high concentration and speed of psychomotor reactions.

Drug Interactions

Mitotane is contraindicated to be taken simultaneously with spironolactone, as it may block the action of mitotane.

Mitotane accelerates the metabolism of warfarin due to the induction of liver microsomal enzymes, which leads to an increase in the required dose of warfarin. Thus, patients should be carefully monitored for changes in the required dose of anticoagulants when mitotane is taken by patients simultaneously taking coumarin-like anticoagulants.

Mitotane has an inducing effect on the cytochrome P450(3A4) system enzymes, which is why the plasma concentration of substances metabolized under the action of cytochrome P450 may change.

In the absence of information on specific P450 isoenzymes, caution should be exercised when co-administering drugs metabolized with the participation of this enzyme system, including anticonvulsants, rifabutin, rifampicin, griseofulvin and St. John’s wort, sunitinib and midazolam.

Mitotane in high concentrations can have an undesirable effect on the CNS. The potential for specific pharmacodynamic interaction should be kept in mind when co-administering mitotane with drugs that have a depressant effect on the CNS.

Food rich in fats enhances the absorption of mitotane.

It has been shown that Mitotane increases the level of hormone-binding proteins in plasma (for example, sex hormone-binding globulin and corticosteroid-binding globulin), which must be taken into account when interpreting hormone test results. In addition, this may lead to gynecomastia.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.