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Logo CLIMARA-50
CLIMARA-75
CLIMARA-100

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

CLIMARA-50
CLIMARA-75
CLIMARA-100
Estradiol transdermal systems

COMPOSITION
Climara-50: 12,5 cm² patch containing 3,9 mg of estradiol hemihydrate (corresponding to estradiol 3,8 mg).
Climara-75: 18,75 cm² patch containing 5,9 mg of estradiol hemihydrate (corresponding to estradiol 5,7 mg).
Climara-100: 25,0 cm² patch containing 7,8 mg of estradiol hemihydrate (corresponding to estradiol 7,6 mg).

PHARMACOLOGICAL CLASSIFICATION
A. 21.8.1 Estrogens.

PHARMACOLOGICAL ACTION
Estrogens are largely responsible for development and maintenance of the female reproductive and secondary sexual characteristics. Estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites estrone and estriol at receptor level. Circulating estrogens modulate the pituitary secretion of gonadotrophins, luteinising hormone (LH) and follicle stimulating hormone (FSH) through a negative feedback mechanism.
After dermal application of Climara, estradiol is absorbed through the skin. Nominal average estradiol absorption rates of 50, 75 and 100 micrograms/day were calculated for Climara-50, Climara-75 and Climara-100, respectively.
During a once-a-week application regimen of Climara patches, smooth and consistent estradiol and estrone serum level profiles within the desired range are achieved. The estradiol serum level profile is directly proportional to the area of the patch. Mean steady state estradiol serum levels are approximately 35 pg/mL (12,5 cm² patch), 53 pg/mL (18,75 cm² patch) and 70 pg/mL (25 cm² patch).

INDICATIONS
Estrogen replacement therapy for patients with symptoms due to natural menopause or surgically induced menopause (only if due to noncarcinomatous diseases) eg vasomotor symptoms (hot flushes).
To reduce the risk of postmenopausal osteoporosis.

CONTRA-INDICATIONS
Pregnancy; lactation; suspected or existing tumour of the uterus, breast or ovaries; endometriosis; severe disturbances of liver function; previous or existing liver tumours; active deep venous thrombosis, thromboembolic disorders, or a documented history of these conditions; severe diabetes with vascular changes; sickle cell anaemia; disturbances of lipometabolism; a history of herpes of pregnancy; otosclerosis with deterioration during pregnancy; jaundice or persistent itching during a previous pregnancy.

WARNINGS
Before starting Climara patches, a thorough general medical and gynaecological examination (including the breasts and a Pap smear) should be carried out and pregnancy excluded. As a precaution, control examinations should be conducted at intervals of about 6 months during treatment.
Where applicable, contraception should be practised with non-hormonal methods (with the exception of the rhythm and temperature methods).
If irregular bleeding occurs repeatedly during the use of Climara patches or if the bleeding in the treatment-free weeks is unusually profuse, thorough differential-diagnostic clarification is essential.
If there are, repeatedly, persistent skin irritations (eg persistent erythema or pruritus) at the application site even if the application site is changed according to the directions, one should consider cessation of transdermal treatment.
Epidemiological studies have suggested that hormone replacement therapy may be associated with an increased relative risk of developing venous thromboembolism, ie deep venous thrombosis or pulmonary embolism. Risk/benefit should therefore be carefully weighted in consultation with the patient when prescribing hormone replacement therapy to women with a risk factor for venous thromboembolism.
Generally recognised risk factors for venous thromboembolism include a personal history, a family history (the occurrence of venous thromboembolism in a direct relative at a relatively early age may indicate genetic disposition) and severe obesity. The risk of venous thromboembolism also increases with age. There is no consensus about the possible role of varicose veins in venous thromboembolism.
The risk of venous thromboembolism may be temporarily increased with prolonged immobilisation, major elective or post-traumatic surgery, or major trauma. Depending on the nature of the event and the duration of the immobilisation, consideration should be given to a temporary discontinuation of hormone replacement therapy.
Close medical supervision is necessary in patients with diabetes, hypertension, varicose veins, otosclerosis, multiple sclerosis, epilepsy, porphyria, tetany, chorea minor, heart failure, disturbances of kidney or liver function, migraine. Patients with fibrocystic disease of the breasts and patients with first degree relatives who have had breast cancer also require close supervision. The same applies to patients with benign tumours of the uterine smooth muscles, since the size of such tumours can increase under estrogen therapy.
A meta-analysis from 51 epidemiological studies reported that there is a modest increase in the risk of having breast cancer diagnosed in women who have used hormone replacement therapy for more than five years. The findings may be due to an earlier diagnosis, the biological effects of hormone replacement therapy, or a combination of both. The relative risk increases with duration of treatment (by 2,3% per year of use). This is comparable to the increased risk of breast cancer observed in women with every year of delay of natural menopause. The increased risk gradually disappears during the course of the first five years after cessation of hormone replacement therapy. Breast cancers found in women using hormone replacement therapy are more likely to be localised to the breast than those found in non-users.
Regular breast examinations and, where appropriate, mammography should be carried out in women on hormone replacement therapy. Breast status should also be closely monitored in women with a history of, or known breast nodules or fibrocystic breast disease.
In rare cases benign and malignant liver tumours may lead to life-threatening intraabdominal haemorrhage after the use of sex steroid containing preparations. If severe upper abdominal complaints, liver enlargement or signs of intraabdominal haemorrhage occur, a liver tumour should be included in the differential-diagnostic considerations.
Reasons for immediate discontinuation
Occurrence for the first time of migrainous headaches or more frequent occurrence of unusually severe headaches, sudden perceptual disorders (eg disturbances of vision or hearing), first signs of thrombophlebitis or thromboembolic symptoms (for example, unusual pains in or swelling of the legs, stabbing pains on breathing or coughing for no apparent reason), a feeling of pain and tightness in the chest, pending operations (six weeks beforehand), immobilisation (for instance, following accidents), onset of jaundice, onset of hepatitis, itching of the whole body, increase in epileptic seizures, significant rise in blood pressure, pregnancy.

DOSAGE AND DIRECTIONS FOR USE
Treatment is usually initiated with Climara-50, applied to the skin on the lower trunk once weekly. If it is considered necessary, a higher dose should be used.
Once treatment has been initiated, the lowest effective dose necessary for the relief of symptoms should be established.
The treatment can be given without interruption or it can be interrupted for 1 week after every 3 weeks.
For risk reduction of osteoporosis: Treatment with Climara patches to reduce the risk of postmenopausal bone loss should be initiated as soon as possible after the menopause. Treatment should be based on individual considerations.
Unopposed estrogen therapy should not be used unless the patient has had a hysterectomy. In all other cases the appropriate dose of a progestogen should normally be administered for 10 to 12 days in every month to avoid endometrial hyperplasia and the consequent increased risk of endometrial carcinoma.
If a continuous treatment regimen has been chosen, the administration of a progestogen may be initiated at an arbitrarily selected time (eg at the beginning or at the end of a month) and should be repeated at regular intervals of about 4 weeks.
If a cyclical (3 week) treatment regimen has been chosen, the progestogen should be administered during the last 10 to 12 days of the cycle.
A menstruation-like bleeding normally occurs 2 to 3 days after the end of the period of progestogen administration.
Following removal of the protective liner the adhesive side of Climara patches should be placed on a clean, dry area of the skin of the trunk. Climara patches should not be applied to the breasts. The sites of application should be rotated, with an interval of at least one week between applications to a particular site. The area selected should not be oily, damaged, or irritated. The waistline should be avoided since tight clothing may rub the patch off. The patch should be applied immediately after opening the pouch and removing the protective liner. The patch should be pressed firmly in place with the palm of the hand for about 10 seconds, making sure there is good contact, especially around the edges.
The patch should be changed once weekly.
If the patch is applied correctly, the patient can bath or shower as usual. The patch might, however, become detached from the skin in very hot bath water or in the sauna.
In the event that a patch falls off, a new patch should be applied for the remainder of the 7 day dosing interval.

SIDE EFFECTS AND SPECIAL PRECAUTIONS
The most commonly reported side effect was skin irritation at the application site.
The following additional side effects are possible
Genitourinary system - changes in uterine bleeding pattern, breakthrough bleeding and spotting, increase in size of uterine leiomyomata, alterations in the amount of cervical secretion.
Breasts - tenderness, enlargement.
Gastrointestinal - nausea, abdominal pain, bloating, cholestatic jaundice.
Skin - chloasma or melasma which may be persistent. In individual cases an allergic contact dermatitis, a post-inflammatory pruritus and a generalised exanthema may occur.
Central nervous system - headache, migraine, dizziness.
Miscellaneous - alteration in body weight, worsening of porphyria, oedema, changes in libido.
The requirement for oral antidiabetics or insulin can change.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
Overdosage is unlikely with this type of application. Overdosage may cause nausea and vomiting and withdrawal bleeding may occur in some women. There is no specific antidote. Treatment should be symptomatic and the patch(es) should be removed.

IDENTIFICATION
A protective pouch containing an oval Climara-50 patch (approximately 4,5 x 3,3 cm) with a surface area of 12,5 cm², an oval Climara-75 patch (approximately 5,5 x 4,1 cm) with a surface area of 18,75 cm², or an oval Climara-100 patch (approximately 6,3 x 4,7 cm) with a surface area of 25 cm². The patches comprise two layers: an acrylate adhesive matrix containing estradiol on a translucent (see-through) polyethylene film. A clear protective liner of release-coated polyester film is attached to the adhesive surface and must be removed prior to use. The protective pouch contains a desiccant.

PRESENTATION
Packs containing 4 patches.
Packs containing 12 patches.

STORAGE INSTRUCTIONS
Store below 30°C. For shelf-life, refer to imprint on the pack. Keep out of reach of children.
Do not store unpouched. Apply immediately upon removal from the protective pouch.

REGISTRATION NUMBER
Climara-50:         29/21.8.1/0610
Climara-75:         35/21.8.1/0032
Climara-100:         29/21.8.1/0611

NAME AND BUSINESS ADDRESS OF THE APPLICANT
Schering (Pty) Ltd
(Reg No: 1964/009072/07)
106 Sixteenth Road
Randjespark
Midrand        1685
P O Box 5278
Halfway House        1685

DATE OF PUBLICATION OF THIS PACKAGE INSERT
12 February 2002

SCHERING (PTY) LTD
(Reg No: 1964/009072/07)
Subsidiary of Schering AG, Germany

Updated on this site: April 2003
Current: January 2005
Source: Pharmaceutical Industry

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