Data Sheet

PROVERA^®

Medroxyprogesterone Acetate PhEur

2.5mg, 5mg and 10mg tablets

Presentations

PROVERA 2.5mg tablets are orange, circular, convex, one-side scored, and coded "U64" on the reverse.

PROVERA 5mg tablets are blue circular, convex coded "U" on one side, and single scored on the reverse with "286" marked on both sides of the scoreline.

PROVERA 10mg tablets are white, circular, convex embossed with "Upjohn 50" on one side and single scored on the reverse.

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

Absorption: 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.
Distribution: 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 the placental barrier, and is secreted in breast milk.

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

Excretion: 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.

Clinical Trials

BMD Changes

There are no studies on the bone mineral density (BMD) effects of PROVERA.

However, a clinical study of adult women of childbearing potential given medroxyprogesterone acetate (MPA) intra-muscular injection (IM) 150mg every 3 months, for contraception, demonstrated an average decrease of 5.4% in lumbar spine BMD over 5 years, with at least partial recovery of this bone loss during the first two years after treatment is discontinued. A similar clinical study of MPA 150mg IM injection every 3 months in adolescent females, for contraception, demonstrated similar decreases in BMD, which were also more pronounced during the first two years of treatment and which again were at least partially reversible when treatment was discontinued. Decreases in serum oestrogen due to PROVERA may result in a decrease in BMD in a pre-menopausal woman and may increase her risk for developing osteoporosis later in life.

See Warnings and Precautions

Indications

PROVERA is indicated for:

• diagnosis of primary and secondary amenorrhoea
• treatment of dysfunctional (anovulatory) uterine bleeding
• opposition of endometrial effects of oestrogen in menopausal women being treated with oestrogen (hormone replacement therapy [HRT])
• treatment of endometriosis

Dosage and Administration

Use of combined oestrogren/progestin therapy in postmenopausal women should be limited to the lowest effective dose and the shortest duration consistent with treatment goals and risks for the individual woman, and should be periodically evaluated (see Warnings and Precautions).

Unless there is a previous diagnosis of endometriosis, it is not recommended to add a progestin in a woman without an intact uterus.

Diagnosis of Primary and Secondary Amenorrhoea

2.5 to 10 mg per day for 5-10 days.

Dysfunctional (anovulatory) Uterine Bleeding

2.5 to 10 mg per day for 5 to 10 days for 2 to 3 cycles and then discontinued to see if the dysfunction has regressed. If bleeding occurs from a poorly proliferative endometrium, oestrogens should be used concomitantly with PROVERA therapy.

Opposition of Endometrial Effects of Oestrogen in Menopausal Women Being Treated with Oestrogen

For women taking 0.625 mg of conjugated oestrogen or an equivalent daily dose of another oestrogen, PROVERA can be given in one or two regimens:

• Continuous regimen of PROVERA: 2.5 to 5.0 mg daily.
  
• Sequential regimen of PROVERA: 5 to 10 mg daily for 10 to 14 consecutive days of a 28-day or monthly cycle.

Endometriosis

10 mg three times a day for 90 consecutive days, beginning on the first day of the menstrual cycle.

Contraindications

• Known hypersensitivity to medroxyprogesterone acetate or any component of the medicine.
• Undiagnosed vaginal bleeding.
• Severe liver dysfunction.
• Known or suspected malignancy of the breast.
• Known or suspected pregnancy.

Warnings and Precautions

• Unexpected vaginal bleeding during therapy with PROVERA should be investigated.
• PROVERA may cause some degree of fluid retention, therefore, caution should be exercised in treating any patient with a pre-existing medical condition that might be adversely affected by fluid retention.
• Patients with a history of treatment for clinical depression should be carefully monitored while receiving PROVERA therapy.
• Some patients receiving PROVERA may exhibit a decreased glucose tolerance. Diabetic patients should be carefully observed while receiving such therapy.
• The pathologist (laboratory) should be informed of the patient's use of PROVERA if endometrial or endocervical tissue is submitted for examination.
• The physician/laboratory should be informed that use of PROVERA may decrease the levels of the following endocrine biomarkers:
• Plasma/urinary steroids (e.g., cortisol, oestrogen, pregnanediol, progesterone, testosterone)
• Plasma/urinary gonadotrophins (e.g., LH and FSH)
• Sex-hormone-binding-globulin.
• Medication should not be readministered pending examination if there is a sudden partial or complete loss of vision or if there is a sudden onset of proptosis, diplopia, or migraine. If examinations reveals papilloedema or retinal vascular lesions, medication should not be readministered.
• Although PROVERA has not been causally associated with the induction of thrombotic or thromboembolic disorders, any patient with a history or who develops this kind of event while undergoing therapy with PROVERA should have their status and need for treatment carefully assessed before continuing therapy.
• Several randomised, prospective trials on the long-term effects of a combined oestrogen/progestin regimen in postmenopausal women have reported an increased risk of several disorders including cardiovascular diseases (e.g., coronary heart disease and stroke), breast cancer, and venous thromboembolism.

Decrease in Bone Mineral Density:

There are no studies on the bone mineral density (BMD) effects of PROVERA.

However, 2 clinical studies of adult women of childbearing potential and of adolescent females given medroxyprogesterone acetate 150 mg IM every 3 months, for contraception, demonstrated significant decreases in BMD (See Clinical Trials). Decreases in serum oestrogen due to PROVERA may result in a decrease in bone mineral density (BMD) in a pre-menopausal woman and may increase her risk for developing osteoporosis later in life.

An evaluation of BMD may be appropriate in some patients who use PROVERA long term.

It is recommended that all patients have adequate calcium and Vitamin D intake.

Breast Cancer

The use of combined oestrogen/progestin by postmenopausal women has been reported to increase the risk of breast cancer. Results from a randomised placebo-controlled trial, the WHI study, and epidemiological studies have reported an increased risk of breast cancer in women taking estrogen/progestin combinations for hormone replacement therapy (HRT) for several years. In the WHI conjugated equine oestrogens (CEO) plus MPA trial and observational studies, the excess risk increased with duration of use. The use of oestrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation.

Cardiovascular Disorders

Oestrogens with or without progestins should not be used for the prevention of cardiovascular disease. Several randomised, prospective trials on the long-term effects of a combined oestrogen/progestin regimen in postmenopausal women have reported an increased risk of cardiovascular events such as myocardial infarction, coronary heart disease, stroke, and venous thromboembolism.

Coronary Artery Disease: There is no evidence from randomised controlled trials of cardiovascular benefit with continuous combined conjugated oestrogen and medroxyprogesterone acetate (MPA). Two large clinical trials (WHI and HERS) showed a possible increased risk of cardiovascular morbidity in the first year of use and no overall benefit.

In the CEO/MPA substudy of WHI, an increased risk of coronary heart disease (CHD) events (defined as nonfatal myocardial infarction and CHD death) was observed in women receiving CEO/MPA compared to women receiving placebo (37 vs. 30 per 10,000 person years). The increase in VTE risk was observed in year one and persisted over the observation period.

Stroke: In the same substudy of WHI, an increased risk of stroke was observed in women receiving CEO/MPA compared to women receiving placebo (29 vs. 21 per 10,000 person-years). The increase in risk was observed in year one and persisted over the observation period.

Venous thromboembolism / Pulmonary embolism: HRT is associated with a higher relative risk of developing venous thromboembolism (VTE), i.e., deep vein thrombosis or pulmonary embolism. In the CEO/MPA substudy of WHI, a 2-fold greater rate of VTE, including deep venous thrombosis and pulmonary embolism was observed in women receiving CEO/MPA compared to women receiving placebo. The increase in risk was observed in year one and persisted over the observation period

Dementia

Pooling data from the Women's Health Initiative Memory Study (WHIMS) a substudy of WHI, for CEO-alone and CEO/MPA, reported an increased risk of developing probable dementia and mild cognitive impairment (MCI) in postmenopausal women 65 years of age or older. Use of HRT to prevent dementia or MCI in women is not recommended.

Ovarian Cancer

The CEO/MPA substudy of WHI reported that oestrogen plus progestin increased the risk of ovarian cancer, but this risk was not statistically significant.

History and Physical Examination Recommendation

A complete medical and family history should be taken before the initiation of any hormone therapy. Pre-treatment and periodic physical examinations should include special reference to blood pressure, breasts, abdomen, and pelvic organs, including cervical cytology.

Pregnancy and Lactation

PROVERA is contraindicated in women who are pregnant.

Some reports suggest an association between intrauterine exposure to progestational drugs in the first trimester of pregnancy and genital abnormalities in male and female foetuses.

Infants from unintentional pregnancies that occur 1 to 2 months after injection of medroxyprogesterone acetate injectable suspension may be at an increased risk of low birth weight, which, in turn, is associated with an increased risk of neonatal death. The attributable risk is low because pregnancies while on medroxyprogesterone acetate are uncommon. There is no definitive information for the other formulations of medroxyprogesterone acetate.

If PROVERA is used during pregnancy, or if the patient becomes pregnant while using this drug, the patient should be apprised of the potential hazard to the foetus.

Medroxprogesterone acetate and its metabolites are excreted in breast milk. There is no evidence to suggest that this presents any hazard to the nursing child.

Adverse Effects

Interactions

Aminoglutethimide administered concomitantly with high doses of medroxyprogesterone acetate may significantly depress the serum concentrations of medroxyprogesterone acetate. Users of high-dose PROVERA should be warned of the possibility of decreased efficacy with the use of aminoglutethimide.

Overdosage

Nil.

Pharmaceutical Precautions

Store below 30°C.

Medicine Classification

Prescription Medicine.

Package Quantities

PROVERA 2.5 mg tablets are available in blister packs of 30 tablets.

PROVERA 5 mg tablets are available in blister packs of 100 tablets

PROVERA 10 mg tablets are available in blister packs of 30 tablets.

Further Information

PROVERA is a registered trademark.

Name and Address

Pfizer New Zealand Ltd
PO Box 3998
Auckland, New Zealand
Toll Free Number: 0800 736 363

Date of Preparation

4 July 2005

(Ref: CDS 8/2/05)