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Logo EVOREL™ 50 Transdermal Therapeutic System (TTS)

SCHEDULING STATUS
Schedule 4.

PROPRIETARY NAME
(and dosage form)

EVOREL™ 50 Transdermal Therapeutic System (TTS)

COMPOSITION
Each 16 cm² patch contains 3,2 mg 17 ß-
estradiol micronised.

PHARMACOLOGICAL CLASSIFICATION
A 21.8.1 Estrogens.

PHARMACOLOGICAL ACTION
Transdermal Therapeutic Systems deliver the lowest effective dose of the hormone 17 ß-estradiol into the systemic circulation. EVOREL 50 provides a constant, controlled release of hormone for several days. The 17 ß-estradiol does not undergo first-pass liver metabolism.
Estrogens are derived by aromatization of the A-ring mainly in the follicle apparatus in the ovary. Estradiol is the main estrogen of the ovary.
The molecular mechanism of estradiol action in the target organ estrogen receptor sites follows the known mechanism of steroid-hormone action. Estradiol binds to the intracellular receptors. An estradiol-receptor complex is formed and various metabolic changes are induced, which leads to tissue differentiation and growth.
The estradiol/estrone ratio in the plasma of postmenopausal women is between 0,2 and 0,5 which increases after transdermal application of estradiol to approximately 1 (normal pre-menopausal levels. early follicular phase).
Pharmacokinetics:
Within 10 hours of the application of the 16 cm² adhesive patch, containing 3,2 mg of estradiol, on the skin, estradiol serum concentration increases from an average baseline of 2,3 pg/mL to an average level of 20,1 pg/mL. During the remainder of the application period (3 –4 days), the estradiol serum concentration is maintained at an average level 18,5 pg/mL. 24 hours after removal of the patch, estradiol serum concentration returns to the baseline.
Estradiol's most important metabolites are estriol/estrone and conjugates (glucuronide and sulphate) which are far less active than estradiol and undergo enterohepatic recirculation. Overall, 60 - 80% of the estrogens are excreted via the urine and 10% via the faeces.
The elimination half-life of the estradiol in the plasma is approximately 1 hour.

INDICATIONS
Treatment of symptoms associated with low serum levels of estrogens, and of estradiol in particular, either due to menopausal cessation of estrogen production and secretion or surgical removal of the ovaries. These comprise predominantly of vasomotor symptoms such as hot flushes and nocturnal sweating, atrophic vaginitis/vulvitis and/or atrophic urethritis.
Prevention of estrogen dependent post-menopausal osteoporosis.

CONTRA-INDICATIONS
Hypersensitivity to estrogen or any component of this product.
Known or suspected carcinoma of the breast, genital tract or other estrogen dependent neoplasia, severe hepatic, renal or cardiac disease, active or previous history of thrombosis or thrombo-embolic diseases; undiagnosed vaginal bleeding; endometriosis; pregnancy and porphyria.
Estrogens must not be used during pregnancy and lactation.
The risk benefits should be carefully weighed when the following medical problems exist: cardiac disease, renal or hepatic disorders, hypertension, epilepsy.

WARNINGS
Since prolonged estrogen monotherapy may increase the risk of endometrial hyperplasia and carcinoma in post-menopausal women with an intact uterus, it should be supplemented by sequential progestogen therapy. Sequential progestogen administration has been shown to confer protection to the endometrium.
At the present time, there is suggestive evidence of an overall increase in the relative risk of breast cancer in postmenopausal women receiving hormone replacement therapy. A careful appraisal of the risk/benefit ratio should be undertaken before treating for longer than 5 years.

DOSAGE AND DIRECTIONS FOR USE
In patients using oral estrogens, treatment with EVOREL 50 can be initiated one week after withdrawal.
EVOREL 50 should be applied twice weekly, ie. the patch should be changed every 3 to 4 days.
EVOREL 50 is administered in a cyclic manner, 3 weeks of treatment (6 applications) followed by an interval of one week without treatment. During this treatment free week, vaginal withdrawal bleeding can occur.
Continuous non-cyclic therapy maybe indicated in hysterectomised women and if climacteric symptoms occur during the treatment free week.
In cyclic estradiol treatment regimen, concomitant use of a progestogen is recommended during the last 10 –12 days of the 3 week treatment period. The 4th week of each treatment cycle remains without any hormone administration.
In the continuous estradiol treatment regimen concomitant use of a progestogen is recommended during the last 10-12 calendar, days of each month.
In both treatment regimens, discontinuation of progestogen is normally associated with withdrawal bleeding.
Administration instructions:
EVOREL 50 is to be placed on clean dry skin. No skin cream should have been applied to the selected area. The skin should be intact and free from irritation.
The patch is to be removed from the pouch and prepared for application as follows:
The two parts of the protecting foil are to be removed at the S-shaped incision in the middle of the protective foil. Touching the adhesive part of the patch with the fingers should be reduced to a minimum while applying the patch to the skin.
The patch is then placed with its adhesive side on the skin, preferably on the trunk below the waistline.
During the treatment period the patch should not be removed. It is possible to shower, bath or sauna while wearing the patch. Should the patch fall off, a new one should immediately be applied for the remaining days of the cycle. The patch which has fallen off should not be re-applied since it would be rendered inactive.
EVOREL 50 should not be applied to the breasts. The same area of the skin may not be used consecutively.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Skin reactions reported include transient erythema and irritation with or without pruritus at the site of patch application. Very rarely, contact dermatitis, reversible post-inflammatory pigmentation, generalised pruritus and exanthema did occur.
Breast tenderness, irregular vaginal bleeding, fluid retention with oedema, abdominal pain or bloating, headache or migraine, and dizziness have been reported. There may be nitrogen retention, weight gain, alterations in liver function, jaundice and depression. Dose related nausea and vomiting may occur. Other skin reactions due to estrogens include chloasma, rashes and urticaria.
Rarely reported adverse events in association with oral estrogen replacement therapy include among others: thromboembolic events, cholestasis, benign or malignant breast disease, uterine carcinoma, aggravation of epilepsy, liver adenoma and galactorrhoea. If such events occur, EVOREL 50 should be discontinued immediately.
Precautions:
Since estrogens may cause fluid retention they should be used with care in patients with asthma, epilepsy, heart or kidney disease. Estrogens may exacerbate diabetes mellitus. Estrogens have been reported to increase plasma concentrations of cortisol- and thyroxine binding globulin.
Appropriate monitoring is recommended in patients with mastopathy, a family history of breast cancer, or a history of cholestatic jaundice.
Regular gynaecological examinations (at least once a year) are recommended in patients on EVOREL 50 therapy. If climacteric disorders persist during therapy with EVOREL 50, a physician should be consulted.
Discontinuation should be considered prior to surgery.
Care should be taken in patients with headaches and migraine.
Interactions:
Medicines with a high potential for liver enzyme induction, eg. barbiturates, hydantoin, carbamazepine, meprobamate, phenylbutazone and rifampicin, may interfere with the actions of estrogens. Concurrent use of hepatotoxic medication, especially dantrolene, may increase the risk of hepatotoxicity.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
Treatment is symptomatic and supportive.

IDENTIFICATION
EVOREL 50 is an adhesive patch of 16 cm² with rounded corners.
The adhesive surface of the patch is covered with a protective foil with an S-shaped incision.

PRESENTATION
Cartons containing one or more EVOREL 50 patches. Each patch is sealed in a pouch.

STORAGE INSTRUCTIONS
Store below 25°C.
Do not freeze.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBER
Z/21.8.1/339

NAME AND BUSINESS ADDRESS OF THE APPLICANT
JANSSEN
PHARMACEUTICA
Janssen Pharmaceutica (Pty) Ltd
(Reg. No. 80/11122/07
15th Road
Halfway House
1685

© Janssen Pharmaceutica

DATE OF PUBLICATION OF THIS PACKAGE INSERT
12 April 1994

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