Lysodren 500 mg tablets

Please note that Lysodren Product Information has been updated : further to a signal detection (ovarian macrocyst), the PRAC recommended to updated the PI, and the variation submitted.

 

Changes are as follow :

-          To update sections 4.4 and 4.8 of the SmPC to implement the PRAC signal recommendations on ‘Sex hormone disturbances and development of ovarian macrocysts     AND    To align the Product information with the latest QRD template (version 10

Section 2
For the full list of excipients, see section 6.1

Section 4.1
Symptomatic treatment of advanced (unresectable, metastatic or relapsed) adrenal cortical carcinoma (ACC).

Section 4.2
Posology
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

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.

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.

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).

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

Section 4.3
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

Section 4.4
Monitoring of plasma levels: Mitotane plasma levels should be monitored in order to adjust the mitotane dose, particularly if high starting doses are considered necessary. Dose adjustments may be necessary to achieve the desired therapeutic levels in the window between 14 - 20 mg/l and avoid specific adverse reactions (see section 4.2

Warfarin and coumarin-like anticoagulants: When administering mitotane to patients on coumarin-like anticoagulants, patients should be closely monitored for a change in anticoagulant dose requirements (see section 4.5).

Substances metabolised through cytochrome P450: Mitotane is a hepatic enzyme inducer and it should be used with caution in case of concomitant use of medicinal products influenced by hepatic metabolism (see section 4.5).

Section 4.5
Warfarin and coumarin-like anticoagulants: Mitotane has been reported to accelerate the metabolism of warfarin through hepatic microsomal enzyme induction, leading to an increase in dose requirements for warfarin. Therefore, patients should be closely monitored for a change in anticoagulant dose requirements when mitotane is administered to patients on coumarin like anticoagulants

Section 4.6
Fertility, pregnancy and lactation

Breast-feeding
Due to the lipophilic nature of mitotane, it is likely to be excreted in breast milk. Breast feeding is contraindicated while taking mitotane (see section 4.3) and after treatment discontinuation as long as mitotane plasma levels are detectable.


Section 4.8

Nervous system disorders

Ataxia Paresthesia Vertigo Sleepiness

Mental impairment Polyneuropathy Movement disorder Dizziness Headache

Balance disorders

Gastrointestinal disorders

Mucositis Vomiting Diarrhoea Nausea Epigastric discomfort

Salivary hypersecretion Dysgeusia Dyspepsia

Description of selected adverse reactions

Paediatric patients
Neuro-psychological retardation may be observed during mitotane treatment. In such cases, thyroid function should be investigated in order to identify a possible thyroid impairment linked to mitotane treatment. Hypothyroidism and growth retardation may be also observed. One case of encephalopathy has been observed in a paediatric patient five months after initiation of the treatment; this case was considered to be related to an increased mitotane plasma level of 34.5 mg/l. After six months mitotane plasma levels were undetectable and the patient recovered clinically.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Section 5.1

Mitotane plasma levels and the possible relationship with its efficacy were studied in the FIRM ACT trial, a randomized, prospective, controlled, open–label, multicenter, parallel-group study to compare the efficacy of etoposide, doxorubicin and cisplatin plus mitotane (EDP/M) to that of streptozotocin plus mitotane (Sz/M) as first-line treatment in 304 patients. The analysis of patients who achieved mitotane levels ≥ 14 mg/l at least once in 6 six months versus patients who mitotane levels were < 14 mg/l could suggest that patients with mitotane plasma levels ≥ 14 mg/l could have an improvement in disease control rate (62.9% versus 33.5%; p< 0. 0001). However, this result should be cautiously taken since the examination of the mitotane effects was not the primary endpoint of the study.


Biotransformation
Metabolism studies in man have identified the corresponding acid, 1,1-(o,p'-dichlorodiphenyl) acetic acid (o,p’-DDA), as the major circulating metabolite, together with smaller quantities of the 1,1-(o,p'-dichlorodiphenyl)-2,2 dichloroethene (o,p’-DDE) analogue of mitotane. No unchanged mitotane has been found in bile or in urine, where o,p’-DDA predominates, together with several of its hydroxylated metabolites. For induction with cytochrome P450, see section 4.5.

Elimination
After intravenous administration, 25% of the dose was excreted as metabolites within 24 hours. Following discontinuation of mitotane treatment, it is slowly released from storage sites in fat, leading to reported terminal plasma half-lives ranging from 18 to 159 days.

Section 6.4
Store in the original packaging

Section 10
Date of revision : 30 May 2013

The following text has been added to section 4.4 Special warnings and precautions for use

Blood and lymphatic system disorders: All blood cells can be affected with mitotane treatment. Leucopenia (including neutropenia), anemia and thrombocytopenia have been reported frequently during mitotane treatment (see section 4.8). Red blood cell, white blood cell and platelet counts should be monitored during mitotane treatment.

Section 10 - Date of Revision of the text : 13/01/2012

None provided