LYSODREN Tablet Ref.[9129] Active ingredients: Mitotane

Treatment should be initiated and followed by a suitably experienced specialist.

Posology

Treatment in adults should be started with 2-3 g mitotane per day and increased progressively (e.g. at two-week intervals) until mitotane plasma levels reach the therapeutic window 14–20 mg/L.

If it is urgent to control Cushing’s symptoms in highly symptomatic patients, higher starting doses between 4-6 g per day could be necessary and daily dose increased more rapidly (e.g. every week). A starting dose higher than 6 g/day is generally not recommended.

Dose adjustments, monitoring and discontinuation

Dose adjustment is aimed to reach a therapeutic window (mitotane plasma levels 14-20 mg/L) which ensures optimal use of Lysodren with acceptable safety. Indeed, neurologic toxicity has been associated with levels above 20 mg/L and therefore this threshold should not be reached. There are some data suggesting that mitotane plasma above 14 mg/L may result in enhanced efficacy (see section 5.1). Mitotane plasma levels higher than 20 mg/L may be associated with severe undesirable effects and offer no further benefit in terms of efficacy. Mitotane plasma levels should therefore be monitored in order to adjust the Lysodren dose and to avoid reaching toxic levels. For further information on the sample testing please contact the Marketing Authorisation Holder or its local representative (see section 7).

Dosing should be individually adjusted based on mitotane plasma levels monitoring and clinical tolerance until mitotane plasma levels reach the therapeutic window 14-20 mg/L. The target plasma concentration is usually reached within a period of 3 to 5 months.

Mitotane plasma levels should be assessed after each dose adjustment and at frequent intervals (e.g. every two weeks), until the optimal maintenance dose is reached. Monitoring should be more frequent (e.g. every week) when a high starting dose has been used. It should be taken into account that dose adjustments do not produce immediate changes in plasma levels of mitotane (see section 4.4). In addition, because of tissue accumulation, mitotane plasma levels should be monitored regularly (e.g. monthly) once the maintenance dose has been reached.

Regular monitoring (e.g. every two months) of mitotane plasma levels is also necessary after interruption of treatment. Treatment can be resumed when mitotane plasma levels will be ranged between 14-20 mg/L. Due to the prolonged half-life, significant serum concentrations may persist for weeks after cessation of therapy.

If serious adverse reactions occur, such as neurotoxicity, treatment with mitotane may need to be temporarily interrupted. In case of mild toxicity, the dose should be reduced until the maximum tolerated dose is attained.

Treatment with Lysodren should be continued as long as clinical benefits are observed. If no clinical benefits are observed after 3 months at optimal dose, treatment should be permanently discontinued.

Special populations

Paediatric population

The experience in children is limited.

The paediatric posology of mitotane has not been well characterised but appears equivalent to that of adults after correction for body surface.

Treatment should be initiated at 1.5 to 3.5 g/m²/day in children and adolescents with the objective of reaching 4 g/m²/day. Mitotane plasma levels should be monitored as for adults, with particular attention when plasma levels reach 10 mg/L as a quick increase in plasma levels may be observed. Dose may be reduced after 2 or 3 months according to the mitotane plasma levels or in case of serious toxicity.

Hepatic impairment

There is no experience in the use of mitotane in patients with hepatic impairment, so data are insufficient to give a dose recommendation in this group. Since mitotane is mainly metabolised through the liver, mitotane plasma levels are expected to increase if liver function is impaired. The use of mitotane in patients with severe hepatic impairment is not recommended. In patients with mild to moderate hepatic impairment, caution should be exercised and monitoring of liver function should be performed. Monitoring of mitotane plasma levels is specially recommended in these patients (see section 4.4).

Renal impairment

There is no experience in the use of mitotane in patients with renal impairment, so data are insufficient to give a dose recommendation in this group. The use of mitotane in patients with severe renal impairment is not recommended and, in cases of mild to moderate renal impairment, caution should be exercised. Monitoring of mitotane plasma levels is specially recommended in these patients (see section 4.4).

Older patients (≥65 years old)

There is no experience on the use of mitotane in older patients, so data are insufficient to give a dose recommendation in this group. Caution should be exercised and frequent monitoring of mitotane plasma levels is especially recommended in these patients.

Method of administration

The total daily dose may be divided in two or three doses according to patient’s convenience. Tablets should be taken with a glass of water during meals containing fat-rich food (see section 4.5). Patients should be advised not to use any tablets showing signs of deterioration, and caregivers to wear disposable gloves when handling the tablets.

Mitotane overdose may lead to central nervous system impairment especially if mitotane plasma levels are above 20 mg/L. No proven antidotes have been established for mitotane overdose. The patient should be followed closely, taking into account that impairment is reversible, but given the long half-life and the lipophilic nature of mitotane, it may take weeks to return to normal. Other effects should be treated symptomatically. Because of its lipophilic nature, mitotane is not likely to be dialysable.

It is recommended to increase frequency of mitotane plasma level monitoring (e.g. every two weeks) in patients at risk of overdose (e.g. in case of renal or hepatic impairment, obese patients or patients with a recent weight loss).

Shelf life: 3 years.

After opening: 1 year.

Store in the original packaging.

Square opaque white HDPE bottle having a thread on the mouth containing 100 tablets.

Pack size of 1 bottle.

This medicinal product should not be handled by persons other than the patient and his/her caregivers, and especially not by pregnant women. Caregivers should wear disposable gloves when handling the tablets.

Any unused product or waste material should be disposed of in accordance with local requirements for cytotoxic medicinal products.