Lysodren 500 mg tablets

  • Name:

    Lysodren 500 mg tablets

  • Company:
    info
  • Active Ingredients:

    Mitotane

  • Legal Category:

    Product subject to medical prescription which may be renewed (B)

Patient Information Leaflet Patient Information Leaflet last updated on medicines.ie: 05/10/20

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Summary of Product Characteristics last updated on medicines.ie: 5/10/2020

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HRA Pharma UK and Ireland Limited

HRA Pharma UK and Ireland Limited

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Medicine Name Lysodren 500 mg tablets Active Ingredients Mitotane
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1 - 0 of 6 items.Total: Infinity pages

When a pharmaceutical company changes any document, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.

Updated on 5 October 2020 SmPC

Reasons for updating

  • Change to section 7 - Marketing authorisation holder
  • Change to section 8 - Marketing authorisation number(s)
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Updated on 5 October 2020 PIL

Reasons for updating

  • Change to section 6 - marketing authorisation holder
  • Change to section 6 - marketing authorisation number
  • Change to section 6 - date of revision

Updated on 24 April 2019 PIL

Reasons for updating

  • Change to section 6 - date of revision

Updated on 23 April 2019 SmPC

Reasons for updating

  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Updated on 9 May 2016 SmPC

Reasons for updating

  • New SmPC for new product

Legal category: Product subject to medical prescription which may be renewed (B)

Updated on 9 May 2016 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

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

Updated on 5 May 2016 PIL

Reasons for updating

  • New PIL for new product

Updated on 5 May 2016 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to side-effects
  • Change to date of revision

Updated on 13 April 2015 SmPC

Reasons for updating

  • Change to section 3 - Pharmaceutical form
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 6.5 - Nature and contents of container
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

Information updated following the PSUR submission and harmonisation of the text accordingly

Section 3 : addition of the following information : They are bisected on one side and impressed "BL" over "L1" on the other side.
Section 4.2 : For further information about the sample testing please contact the MAH or local representative
Section 4.4. Update of the section Hepatic or renal impairment
Section 4.5: Update of the section Substances metabolised through cytochrome P450
Section 6.5: information of container updated
Section 10: Date of revision of the text updated

Updated on 23 February 2015 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to drug interactions
  • Change to MA holder contact details

Updated on 4 July 2013 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.7 - Effects on ability to drive and use machines
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 6.4 - Special precautions for storage
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

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












Updated on 3 July 2013 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to side-effects
  • Change to date of revision
  • Improved electronic presentation
  • Removal/change of distributor

Updated on 29 March 2012 PIL

Reasons for updating

  • Change to MA holder contact details

Updated on 31 January 2012 PIL

Reasons for updating

  • Change of distributor details
  • Change to name of manufacturer

Updated on 20 January 2012 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

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

Updated on 22 February 2011 PIL

Reasons for updating

  • New PIL for medicines.ie

Updated on 11 February 2011 SmPC

Reasons for updating

  • New SPC for medicines.ie

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

None provided