Bayer Limited

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.