Cyproterone/ Estradiol-17-Valerate [Discontinued in SA Market]

Registered South African indications:

• Climacteric symptomatology in patients with intact uteri
• As an adjunct in preventing osteoporosis in postmenopausal women

Registered South African contraindications

• Pregnancy
• Lactation
• Severe disturbances of liver function
• Jaundice
• Persistent itching during a previous pregnancy
• Previous or existing tumours of the liver, uterus, ovaries, or breast, or a suspicion of such tumours
• Endometriosis
• Existing or previous thromboembolic processes
• Severe diabetes mellitus with vascular changes
• Sickle-cell anaemia
• Disturbances of lipometabolism
• A history of herpes of pregnancy
• Otosclerosis with deterioration during pregnancy

South African recommendations

• Renal impairment
• Mild to moderate hepatic impairment
• Elderly
• Diabetes mellitus without vascular changes
• Hypertension
• Varicose veins
• Phlebitis or a history therof
• Otosclerosis
• Multiple sclerosis
• Epilepsy
• Porphyria
• Tetany
• Chorea minor
• Repeated occurrence of intermenstrual bleeding in women undergoing replacement therapy must be clarified by diagnostic measures

Reasons for immediate discontinuation 

• Migrainous headaches or more frequent occurrence of unusually severe headaches
• Sudden perceptual disorders (e.g disturbances of vision or hearing)
• First signs of thrombophlebitis or thromboembolic symptoms
• Feeling of pain and tightness in the chest, pending operations (six weeks beforehand)
• Immobilisation
• Onset of jaundice
• Onset of hepatitis
• Itching of the whole body
• Increase in epileptic seizures
• Significant rise in blood pressure
• Pregnancy

Forms avail. in SA and covered in this monograph: tab

South African registered indications and dosages

Climacteric symptomatology in patients with intact uteri
As an adjunct in preventing osteoporosis in postmenopausal women

Estradiol-17-Valerate 2mg (11 tab), Estradiol-17-Valerate 2mg/ Cyproterone Acetate 1mg (10 tab), Non-hormonal tablets (7 tab)

• Oral (tab): 1 tab, daily starting from the blister marked 'Start' taken on day 5 of the cycle (1st day of menstruation = 1st day of cycle) and continued daily in the direction of the arrows until all 28 tablets have been taken

The tablets are to be swallowed whole with some liquid

After completing the 1st pack, the next pack of cyproterone/ estradiol-17-valerate should be started the following day

If no withdrawal bleeding happens during the intake of the 7 non-hormonal tablets at the end of the pack, do not start the new pack until ruling out pregnancy

Missed dose: If a tablet is not consumed at its regular time, it should be taken within 12 hours to avoid the possibility of intermenstrual bleeding

For general prescribing guidance see additional prescribing points

Not indicated for use in children

Pregnancy

South African recommendation

• Contraindicated
• Pregnancy is a contraindication for the use of cyproterone/ estradiol-17-valerate
• If there is a chance that pregnancy has occurred, tablet-taking must be interrupted until it has been ruled out

Breastfeeding

South African recommendation

• Contraindicated

South African recommendation

• Caution; no information available

South African recommendation

• Mild to moderate: Caution; no information available
• Severe: Contraindicated
  Cyproterone/ estradiol-17-valerate is contraindicated in severe disturbances of liver function

South African recommendation

• Caution; no information available

Central Nervous System Disorders

• Headache
• Depressive moods
• Seizures

Cardiovascular Disorders

• Thrombophlebitis or thromboembolic symptoms
• Hypertension
• Oedema
• Feeling pain and tightness in chest

Gastrointestinal Disorders

•  Gastric complaints
•  Nausea
• Intra-abdominal haemorrhage
• Severe upper abdominal complaints

Hepatobiliary Disorders

• Benign or malignant liver tumours
• Liver enlargement
• Hepatitis
• Jaundice

Genitourinary Disorders

• Feeling of tension in the breasts
• Intermenstrual bleeding
• Changes in libido

Endocrine and Metabolic Disorders

• Changes in body weight

Skin and Subcutaneous Tissue Disorders

• Itching of the whole body

Sensory Disorders

• Disturbances of vision and hearing

Reproductive Disorders

• Feminisation in male foetuses (following higher doses)

• Barbiturates
• Phenylbutazone
• Hydantoins
• Rifampicin
• Antibiotics
• Ampicillin
• Oral antidiabetics 
• Insulin

• Gynaecological exam
  - Including the breast and a cytological smear of the cervix and portio
• Pregnancy status
• General medical exam
  - Blood pressure
  - Urinalysis for sugar

Specific cases may require

• Hepatic function

General prescribing guidance for cyproterone/ estradiol-17-valerate

Prior to using cyproterone/ estradiol-17-valerate:

• Perform a thorough general medical examination, including; blood pressure measurement, urine analysis for sugar, special liver diagnostics, if applicable
• Conduct a gynaecological examination that includes; breast examination, cytological smear of the cervix and portio, ensure diseases requiring treatment or risk factors are identified and rule out pregnancy if applicable
• During the use of cyproterone/ estradiol-17-valerate, regular check-ups at intervals of about 6 months are recommended
• The pack contains seven self-adhesive strips marked with the days of the week. Each strip starts with a different day of the week. Stick the appropriate strip at the top of the memo-pack. This will indicate whether the tablet for a specific day has been taken
• Tablet-taking always begins from the blister marked "Start" and continues in the direction of the arrows until all 28 tablets are consumed
• Menstruation generally occurs while taking the 7 non-hormonal tablets, before starting the next pack
• Postmenopausal women and patients with amenorrhoea (after ruling out pregnancy) can start taking the tablets - 1 per day for 28 days - on any day of their choosing

Estradiol valerate and cyproterone acetate are completely absorbed after oral administration. During the absorption process and the first liver passage, estradiol valerate but not cyproterone acetate is extensively metabolised. Despite complete absorption and ester hydrolysis of estradiol valerate only 3% of the dose is bioavailable as estradiol after oral administration. Cyproterone acetate is completely bioavailable after oral administration. During the absorption process and the first liver passage estradiol valerate is rapidly hydrolysed to 17β-estradiol and valeric acid. Cyproterone acetate is mainly metabolised to 15β-OH cyproterone acetate, a pharmacologically active metabolite with similar high antiandrogenic but much lower progestogenic activity as compared to the parent drug.