The SmPC has been updated to implement the Art.31 Referral procedure (EMEA/H/A-31/1488) outcome on the risk of meningioma of cyproterone containing medicinal

products. The text update was published by the PRAC and endorsed by the CMDh on 26th March 2020.

Change to section 4.1, Therapeutic Indications:

[….]

• Reduction of drive in sexual deviations in men, cyproterone acetate 100 mg can be used when other interventions are considered inappropriate

[….]

Change to section 4.2, Posology and Method of administration:

[….]

Reduction of drive in sexual deviation:

Generally, treatment is started with 50 mg twice daily. It may be necessary to increase the dose to 100 mg twice daily, or even 100 mg three times daily for a short period of time. The duration of cyproterone acetate treatment should be defined on an individual basis. When a satisfactory result has been achieved, the therapeutic effect should be maintained with the lowest possible dose, one should try to maintain the therapeutic effect with the lowest possible dose. Quite often 25 mg twice daily is sufficient. When establishing

the maintenance dose, when changing the dose or when discontinuing cyproterone acetatethe preparation, one should not adjust the dosage abruptly, this should be done but gradually. To this end, the daily dose should be reduced by 50 mg or, better, 25 mg at intervals of several weeks.

To stabilise the therapeutic effect, it is necessary to take Androcur 100 over a protracted period of time, if possible with the simultaneous use of psychotherapeutic measures.

[….]

Change to section 4.4, Special Warning and Precautions for Use:

[….]

[….]

Meningioma

The occurrence of (single and multiple) meningiomas (single and multiple) has been reported in association with longer term use (years) of cyproterone acetate primarily at doses of 25 mg/day and above. The risk of meningioma increases with increasing cumulative doses of cyproterone acetate (see section 5.1). High

cumulative doses can be reached with prolonged use (several years) or shorter duration with high daily doses. Patients should be monitored for meningiomas in accordance with clinical practice. If a patient treated with Androcur 100 mg tablets is diagnosed with meningioma, treatment with Androcur 100 mg tablets and other cyproterone-containing products must be permanently stopped (see section 4.3 Contra-indications).

There is some evidence that the meningioma risk may decrease after treatment discontinuation of cyproterone.

[….]

Change to section 4.8, Undesirable effects:

[….]

Undesirable Effects

<Medra category: Neoplasms benign, malignant and unspecified, Meningioma frequency: not known rare>

<Medra category: Respiratory, thoracisc and mediastinal disorders >

[….]

The occurrence of meningiomas (single and multiple) has been reported in association with use of cyproterone acetate (see section 4.4).Meningiomas have been reported in association with longer term use (several years) of cyproterone acetate at doses of 25 mg/day and above (see sections 4.3 Contra-indications and 4.4 Special warnings and precautions for use).

[….]

Change to section 4.8,Reporting of Side effect details:

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: HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. website: www.hpra.ie.; E-mail: medsafety@hpra.ie.

Ireland

HPRA Pharmacovigilance

Website: www.hpra.ie

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

Change to section 5.1, Pharmacodynamic properties:

[….]

<New statement added>

Meningioma
Based on results from a French epidemiological cohort study, a cumulative dose-dependent association between cyproterone acetate and meningioma has been observed. This study was based on data from the French Health insurance (CNAM) and included a population of 253,777 women using 50 - 100 mg cyproterone tablets. The incidence of meningioma treated with surgery or radiotherapy was compared between women exposed to high-dose cyproterone acetate (cumulative dose ≥3 g) and women who were slightly exposed to cyproterone acetate (cumulative dose <3 g). A cumulative dose-response relationship was demonstrated.

^a Adjusted based on age as a time-dependent variable and oestrogen at inclusion

 A cumulative dose of 12g for example can correspond with one year of treatment with 50 mg/day for 20 days each month.

[….]

Change to section 10, Date of Revision of the Text:

January 2015 June 2020

The PIL has been updated to implement the Art.31 Referral procedure (EMEA/H/A-31/1488) outcome on the risk of meningioma of cyproterone containing medicinal products. The text update was published by the PRAC and endorsed by the CMDh on 26th March 2020.

Change to section 1, What is Androcur 100mg used for:

[….]

• Androcur 100mg is also used to control sexual desire in men who have a sexual deviation. You should only take Androcur 100 mg, if your doctor considers that other interventions are inappropriate.

[….]

Change to section 2, Before you take Androcur:

[….]

Take special care with Androcur:

Several blood tests or checks may be required while you are taking this medicine:

• meningioma (a generally benign tumour of the tissue layer between the brain and the skull) has been reported with longer term use (years) of Androcur at doses of 25mg or above. Use of Androcur has been linked to the development of meningioma. The risk increases especially when you use it for longer duration (several years) or for a shorter duration with high doses (25 mg per day and above). If you are diagnosed with meningioma, your doctor will stop your treatment with cyproterone acetate (see section ‘Do not take Androcur’). If you notice any symptoms such as changes in vision (e.g. seeing double or blurriness), hearing loss or ringing in the ears, loss of smell, headaches that worsen with time, memory loss, seizures, weakness in your arms or legs, you must tell your doctor straightaway.

[……]

Change to section 4, Possible side effects:

[….]

Rare –

up to 1 in every 1000 people may get these

• meningiomas (a generally benign tumour of the tissue layer between the brain and the skull)
• allergic reaction

[…..]

Other changes that have been reported include (incidence not

known):

• meningiomas (a generally benign tumour of the tissue layer between the brain and the skull)

[…..]

Change to section 4, Reporting of side effect details:

[…..]

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via: HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. website: www.hpra.ie; E-mail: medsafety@hpra.ie.

Ireland

HPRA Pharmacovigilance.

Website: www.hpra.ie

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

By reporting side effects you can help provide more information on the safety of this medicine.

 […..]

Change to section 6, Date of revision:

[…..]

This leaflet was last approved in September 2016 June 2020

[…..]

In section 2. Qualitative and Quantitative Composition, two sentences were expanded upon adding: “see section 4.4 ‘Special warnings and precautions for use’” and “ ‘List of excipients’”

In section 3. Pharmaceutical Form the reason for a score line has been added “The tablet can be divided into equal halves.”

In section 4.1 Therapeutic Indications, the indication was changed to “Antiandrogen treatment in inoperable carcinoma of the prostate”

Scetion 4.2 Posology and Method of Administration has largely changed to add information on special populations

The following sencence was added to section 4.3:
   " •Androcur 100 must not be used in patients with meningioma or a history of meningioma."

In section 4.4 the following paragraph was added:
" The occurrence of (multiple) meningiomas has been reported in association with longer term use (years) of cyproterone acetate at doses of 25 mg/day and above. If a patient treated with Androcur 100 is diagnosed with meningioma, treatment with Androcur 100 must be stopped (see section 4.3)" as well as information on anemia, diabetes mellitus, shortness of breath, adrenocortical function and lactose.

In section 4.5 Interaction with other Medicinal products and other forms of Interaction the following paragraphs were added:

“Although clinical interaction studies have not been performed, since this drug is metabolized by CYP3A4, it is expected that ketoconazole, itraconazole, clotrimazole, ritonavir and other strong inhibitors of CYP3A4 inhibit the metabolism of cyproterone acetate. On the other hand, inducers of CYP3A4 such as e.g. rifampicin, phenytoin and products containing St. John’s wort may reduce the levels of cyproterone acetate.” And

“In the indication “reduction of drive in sexual deviations”, the drive-reducing effect of Androcur can be diminished under the disinhibitory influence of alcohol.”

Section 4.6 Pregnancy and Lactation has changed to “Treatment with Androcur 100 (for use in men) is not indicated in women”

Section 4.7 Effects on Ability to Drive and Use Machines has been updated to say “Androcur 100 mg can lead to tiredness and diminished vitality and can impair the ability to concentrate. Patients receiving the drug should not drive or operate machinery unless it has been shown not to effect physical or mental ability.”

Section 4.8 Undesirable Effects has been updated to read:

The most frequently observed adverse drug reactions (ADRs) in patients receiving Androcur are decreased libido, erectile dysfunction and reversible inhibition of spermatogenesis.

The most serious adverse drug reactions (ADRs) in patients receiving Androcur are hepatic toxicity, benign and malignant liver tumors which may lead to intra-abdominal hemorrhage, and thromboembolic events.

The frequencies of ADRs reported with Androcur are summarized in the table below. Frequencies are defined as very common (³ 1/10), common (³ 1/100 and < 1/10), uncommon (³ 1/1,000 and < 1/100), rare (³ 1/10,000 and < 1/1,000) and very rare (< 1/10,000). The ADRs identified only during postmarketing surveillance, and for which a frequency could not be estimated are listed under “not known”.

*⁾ For further information see section ‘Special warnings and precautions for use’.

**⁾ A causal relationship with Androcur has not been established.

The occurrence of (multiple) meningiomas has been reported in association with longer term use (years) of cyproterone acetate at doses of 25 mg/day and above.

Under treatment with Androcur, sexual drive and potency are reduced and gonadal function is inhibited. These changes are reversible after discontinuation of therapy.

Over the course of several weeks, Androcur inhibits spermatogenesis as a result of the antiandrogenic and antigonadotropic actions. Spermatogenesis recovers gradually within a few months of discontinuing the therapy.

Androcur may lead to gynaecomastia (sometimes combined with tenderness to touch of the mammillae) which usually regresses after withdrawal of the preparation.

As with other antiandrogenic treatments, long-term androgen deprivation with Androcur may lead to osteoporosis.

The most appropriate MedDRA term (version 8.0) to describe a certain adverse reaction is listed. Synonyms or related conditions are not listed, but should be taken into account as well.

In section 5.1 Pharmacodynamic Properties “Pharmacotherapeutic group: Antiandrogens, plain” and “ATC code: G03HA01” were added

Section 5.2 Pharmacokinetic Properties was updated to include:

“Cyproterone acetate is almost exclusively bound to plasma albumin. About 3.5 - 4 % of total drug levels are present unbound. Because protein binding is non-specific, changes in SHBG (sex hormone binding globulin) levels do not affect the pharmacokinetics of cyproterone acetate.

According to the long half-life of the terminal disposition phase from plasma (serum) and the daily intake, an accumulation of cyproterone acetate by a factor of about 3 can be expected in the serum during repeated daily administration. 2

In section 5.3 Preclinical Safety Data there was a deletion of text.

Section 10 Date of Revision of the Text was updated to February 2010

Main Changes to the SPC

Section 2 Qualitative and Quantitative Composition

Addition of information regarding lactose content of the tablets.

Section 4.4 Special Warnings and Precautions for Use

Addition of the following:

“This medicinal product contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medication.”

Section 6.4 Special Precautions for Storage

Inclusion of the standard statement:

This medicinal product does not require any special storage conditions.

Section 6.6 Instructions for Use and Handling

Inclusion of the standard statement:

No special requirements.