INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
SYNAPAUSE-E3® 2 mg (tablets)

        RU M 1720.061.013

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

SYNAPAUSE-E3^® 2 mg (tablets)

COMPOSITION
Each tablet contains 2 mg estriol

PHARMACOLOGICAL CLASSIFICATION
A/21.8/Female sex hormones

PHARMACOLOGICAL ACTION
Synapause-E3 2-mg tablets contain the natural female hormone estriol. Estriol induces the normalization of the vaginal epithelium and thus helps to restore the normal microflora and the physiological pH in the vagina. As a result, it increases the resistance of the vaginal epithelial cells to infection and inflammation.
Estriol is short acting since it has only a short retention time in the nuclei of endometrial cells. Therefore, the risk for endometrial proliferation is low when the total recommended daily dose is taken at one time.
Pharmacokinetics
After oral administration estriol is rapidly and almost completely absorbed from the gastrointestinal tract. Peak plasma levels of unconjugated estriol are reached within 1 hour of administration. Nearly all (90%) estriol is bound to albumin in the plasma and estriol is hardly bound to sex hormone-binding globulin. The metabolism of estriol consists mainly of conjugation and deconjugation during enterohepatic circulation. Estriol, a metabolic end product, is mainly excreted via the urine in the conjugated form. Only a small fraction (± 2%) is excreted via the faeces, mainly as unconjugated estriol.

INDICATIONS

-	Atrophy of the lower urogenital tract related to estrogen deficiency.
-	Pre- and postoperative therapy in postmenopausal women undergoing vaginal surgery.
-	Climacteric complaints such as hot flushes and night sweating.
-	diagnostic aid in case of a doubtful atrophic cervical smear.
-	Infertility due to cervical hostility.

CONTRA-INDICATIONS

-	Pregnancy
-	Thrombosis
-	Known or suspected estrogen-dependant tumours
-	Undiagnosed vaginal bleeding/
-	A history of a manifestation or deterioration of otosclerosis during pregnancy or previous use of steroids.

Use during pregnancy and breast feeding:
This medicine is contra- indicated during pregnancy. There are insufficient data on the use of this medicine during breast-feeding to assess potential harm to the infant. It is known, however, that estriol is excreted in breast milk and may decrease milk production.

DOSAGE AND DIRECTIONS FOR USE
Atrophy of the lower urogenital tract related to estrogen deficiency:
4-8 mg per day for the first weeks, followed by a gradual reduction, based on relief of symptoms, until a maintenance dosage (e.g. 1- 2 mg per day) is reached. In certain cases of urinary incontinence a higher maintenance dosage will be required.
Pre- and postoperative therapy in postmenopausal women undergoing vaginal surgery:
4-8 mg per day in the 2 weeks before surgery; 1- 2 mg per day in the 2 weeks after surgery.
Climacteric complaints such as hot flushes and night sweating:
4-8 mg per day during the first weeks, followed by a gradual reduction. For maintenance therapy the lowest effective dosage should be used.
A diagnostic aid in case of a doubtful atrophic cervical smear:
2-4 mg per day for 7 days before taking the next smear.
Infertility due to cervical hostility:
In general 1-2 mg per day on days 6-15 of the menstrual cycle. However, for some patients dosages as low as 0,25 mg per day are sufficient, whereas others may need up to 8 mg per day. Therefore, the dosage should be increased each month until an optimal effect on the cervical mucus is obtained.
Synapause E3 tablets should be taken orally, preferably with some fluid. It is important that the total daily dose is taken at one time.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Breast tension or pain, nausea, spotting, fluid retention and cervical hypersecretion may occasionally occur and be indicative of too high a dosage. Headache, hypertension, leg cramps and vision disturbances are observed occasionally. In general, most of these adverse reactions disappear after the first treatment weeks.
In order to prevent endometrial stimulation, the daily dose should not exceed 8 mg nor should this maximum dose be used for longer than several weeks.
During prolonged treatment with estrogens, periodic medical examinations are advisable.
With vaginal infections, a concomitant specific treatment is recommended.
There are reports indicating an association between the use of estrogen-containing preparations and the occurrence of cholelithiasis. However, it is at present not known whether this association exists for estriol.
Patients with any of the following conditions (or a history of these conditions) should be monitored: a history of thromboembolic disorders, latent or overt cardiac failure, fluid retention due to renal dysfunction, hypertension, epilepsy or migraine, severe liver disorders, endometriosis, fibrocystic mastopathy, porphyria, hyperlipoproteinaemia, a history during pregnancy or previous use of steroids of severe pruritus, cholestatic jaundice or herpes gestationis.
Interactions
There are strong indications that estrogens, estriol included, can increase the pharmacologic effects of certain corticosteroids. If necessary, the dosage of the corticosteroids should be reduced.
There are also some indications, mainly obtained with other estrogens or oral contraceptives, that concurrent use of estriol with activated charcoal, barbiturates (primidone included), hydantoins and rifampicin may possibly decrease the effectiveness of estriol. Conversely, estriol may possibly increase the effectiveness of beta-adrenergic blockers and change the effectiveness of insulins.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
The acute toxicity of estriol in animals is very low. Symptoms that may occur in the case of an acute overdosage are nausea, vomiting, and possibly withdrawal bleeding in females. No specific antidote is known. If necessary a symptomatic treatment should be instituted.

IDENTIFICATION
White, round, flat tablets with bevelled edges and a diameter of 6 mm, coded DG above 8 and below a breakline on one side and ORGANON and a star on the reverse.

PRESENTATION
Synapause-E3 2-mg tablets are packed in 30's in push-through strips of PVC film, backed by aluminium foil. The strips are packed in cartons.

STORAGE INSTRUCTIONS
Keep at 2 - 30°C. Protect from light and moisture.
Keep out of reach of children.
REGISTRATION NUMBER
30/21.8/ 0152

NAME AND BUSINESS ADDRESS OF THE APPLICANT
Donmed Pharmaceuticals (Pty) Limited
Donmed House
Cambridge Place
cnr Kirkby & Oxford Roads
Bedfordview - 2007

DATE OF NOTIFICATION OF APPROVAL OF THIS PACKAGE INSERT
1 July 1996

Under license of NV Organon, The Netherlands

RU M 1720.061.013

Updated on this site: March 2004
Source: Pharmaceutical Industry
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