Progesterone PROVERAŽ

Medroxyprogesterone acetate USP
2.5mg, 5mg and 10mg tablets

Presentation
PROVERA 2.5mg tablets are orange circular, biconvex, scored, and coded "U" on reverse. Diameter - 6.4mm, thickness 2.6mm.

PROVERA 5mg tablets are blue circular biconvex coded "U" on one side, and single scored on the reverse. Diameter - 6.4mm, thickness 2.7mm.

PROVERA 10mg tablets are white circular biconvex embossed with "Upjohn 50" on one side and single scored on the reverse. Diameter - 7.2mm.

Uses
Actions
Medroxyprogesterone acetate, administered orally or parenterally in the recommended doses to women with adequate endogenous oestrogen, transforms proliferative into secretory endometrium. Androgenic and anabolic effects have been noted, but medroxyprogesterone acetate is apparently devoid of significant oestrogenic activity.

While parenterally administered medroxyprogesterone acetate inhibits gonadotropin production, which in turn prevents follicular maturation and ovulation, available data indicate that this does not occur when the usually recommended oral dosage is given as single daily doses.

No information is available regarding onset and duration of pharmacodynamic effect.

PHARMACOKINETICS

Medroxyprogesterone acetate is rapidly absorbed from the gastrointestinal tract after oral administration of PROVERA tablets. Mean time to peak serum levels is approximately 2 to 6 hours.

Medroxyprogesterone acetate is 90 to 95% protein bound, with volume of distribution reported as 20+/- 3 litres. Medroxyprogesterone acetate crosses the blood - brain - barrier and is secreted in breast milk.

Numerous metabolites have been reported, however these have not been well quantified.

The terminal half life of orally administered Medroxyprogesterone acetate is approximately 30 to 60 hours, Medroxyprogesterone acetate is primarily excreted in the faeces, via biliary secretion, with approximately 44% of unchanged MPA excreted in the urine. Urinary metabolites are classified in four groups 1) non-conjugated neutrals, 2) glucuronide conjugated neutrals, 3) sulphate conjugated neutrals and 4) enzyme resistant acid fraction.

Indications
PROVERA is indicated in 1) for diagnostic use; primary and secondary amenorrhoea; 2) Dysfunctional (anovulatory) uterine bleeding; 3) To oppose the endometrial effects of oestrogen in menopausal women being treated with oestrogen; 4) the treatment of endometriosis.

Dosage and Administration
Primary and secondary amenorrhea - 2.5 to 10mg per day for 10 days. Progestin withdrawal bleeding should ensue within 3-7 days if the endometrium has been previously primed with adequate endogenous oestrogen.

Dysfunctional (anovulatory) uterine bleeding -initially 2.5 to 10mg per day for 10 days should gradually, during the course of treatment lead to a cessation of bleeding. Withdrawal progestin bleeding will then follow within 3 to 7 days after stopping PROVERA. 2.5-10mg of PROVERA for 10 days may then be repeated starting on the 16th cycle day for 2-3 cycles and then discontinued to see if the dysfunction has regressed.

To oppose the endometrial effects of oestrogen in oestrogen treated postmenopausal women - 10 to 20mg per day for at least 10 days of each cycle or 2.5 to 5mg per day continuously for 28 days of each cycle.

Endometriosis - 10mg PROVERA TID for 90 days beginning on cycle day 1. Breakthrough bleeding, which is self limited, may occur in 30-40% of patients treated. No additional hormonal therapy is recommended for the management of this break-through bleeding.

Contraindications
Known sensitivity to medroxyprogesterone acetate or tablet excipients.
Undiagnosed vaginal bleeding. Missed abortion. Thrombophlebitis, thromboembolic disorders, cerebral apoplexy or a past history of these conditions. Liver dysfunction or disease. Known or suspected malignancy of breast or genital organs.

Warnings and Precautions
High doses of PROVERA may, in some cases, produce Cushingoid symptoms, e.g. adiposity of the face, fluid retention, glucose intolerance, and blood pressure elevation.

Before using PROVERA, the status of the patient should be carefully evaluated. This evaluation should exclude the presence of pregnancy, or genital or breast neoplasia before considering the use of PROVERA.

Detectable amounts of progestin have been identified in the milk of mothers receiving medroxyprogesterone. The effect of this on the nursing infant has not been determined.
The risk of venous thromboembolism is increased with a positive family history, obesity (body mass index > 30kg/m2), prolonged immobilisation, surgery, trauma or severe varicose veins. If any signs of thromboembolic processes occur, treatment should be discontinued immediately.

PROVERA, especially in the high doses used for cancer therapy, may cause weight gain and fluid retention. With this in mind, caution should be exercised in treating any patient with a pre-existing medical condition that might be adversely affected by weight gain or fluid retention.

Patients with a history of treatment for mental depression should be carefully monitored while receiving PROVERA therapy. Some patients may complain of premenstrual like depression while on PROVERA therapy.

Some patients receiving low dose PROVERA may exhibit a decrease glucose tolerance. The mechanism for this is not known. This fact should be borne in mind when treating all patients and especially known diabetics.

Pathologists should be informed of the patients ingestion of PROVERA if endometrial or endocervical tissue is submitted for examination.

The following laboratory tests may be affected by the use of PROVERA.
a) Gonadotropin levels.
b) Plasma progesterone levels.
c) Urinary pregnanediol levels.
d) Plasma testosterone (in the male).
e) Plasma oestrogen levels (in the female).
f) Plasma cortisol levels.
g) Glucose tolerance test.
h) Metyrapone test.

Adverse Effects
The following events, listed in order of seriousness rather than frequency of occurrence, have been occasionally-to-rarely associated with the use of progestogens:
Anaphylaxis and anaphylactoid-like reactions.
Thromboembolic disease - cerebral thrombosis, thrombophlebitis and pulmonary embolism.
Central nervous system - nervousness, insomnia, somnolence, fatigue, depression, dizziness and headache.
Skin and mucous membranes - urticaria, pruritus, rash, acne, hirsutism and alopecia.
Gastrointestinal - nausea.
Breast - tenderness and galactorrhoea.
Miscellaneous - pyrexia, change in weight, moon facies, oedema, cholestatic jaundice and menstrual disorders.

Interactions
Aminoglutethimide administered concomitantly with PROVERA may significantly depress the bioavailability of PROVERA.

Overdosage
Nil

Pharmaceutical Precautions
Store below 30 degrees Celsius.

Medicine Classification
Prescription Medicine

Package Quantities
PROVERA 2.5mg tablets are available in blister packs of 30 tablets.
PROVERA 5mg tablets are available in blister packs of 100 tablets.
PROVERA 10mg tablets are available in blister packs of 30 tablets.

Further Information
PROVERA is a registered trademark.