PROVERA tablets containing medroxyprogesterone acetate as the active ingredient are supplied as: 2.5 mg tablets: orange, circular, scored one side, marked U64 on the other. 5 mg tablets: blue, circular, scored one side and marked 286 twice, marked U on the other. 10 mg tablets: white, circular, scored marked UPJOHN 50. 100 mg tablets: white, scored, marked U467. 200 mg tablets: white, scored, marked U320.

Actions

Medroxyprogesterone acetate induces responses in laboratory animals comparable to those caused by progesterone. It is more potent than progesterone. Medroxyprogesterone acetate induces glandular maturation in the endometrium, maintains pregnancy, delays parturition, inhibits ovulation and suppresses oestrous cycles. It is devoid of androgenic and oestrogenic activity. In selected animal tests it has some adrenal corticoid-like activity and in dogs increases serum growth hormone levels.

PROVERA is a progestational agent. When administered in recommended doses to women with adequate endogenous oestrogen, it transforms proliferative into secretory endometrium. Medroxyprogesterone acetate may inhibit gonadotrophin production, which in turn prevents follicular maturation and ovulation. Like progesterone, medroxyprogesterone acetate is thermogenic. At the very high dosage levels used in the treatment of certain cancers (500 mg daily or more), corticoid-like activity may be manifest.

Pharmacokinetics

PROVERA is an orally active progestational steroid having an apparent half-life of about 30 hours. Medroxyprogesterone acetate is rapidly absorbed after oral administration. There is high interindividual variability in serum levels after standard doses given by either route of administration. Medroxyprogesterone acetate is metabolised and conjugated in the liver. Metabolic products are predominantly excreted in the urine both as conjugated and free forms.

INDICATIONS

PROVERA low dosage (2.5mg, 5mg and 10mg tablets) :

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.

PROVERA high dosage (100mg and 200mg tablets)

is indicated as adjunctive and/or palliative treatment of recurrent and/or metastatic endometrial or renal carcinoma and, in the treatment of hormonally-dependent, recurrent breast cancer in post-menopausal women.

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.

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:

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

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

Doses of 400-1500 mg per day are recommended. The patient should then be continued on therapy as long as she is responding to treatment. NOTE: Response to hormonal therapy for endometrial, renal or breast cancer may not be evident until after 8 - 10 weeks of therapy. In the event of a rapid progression of disease at any time during therapy, treatment with PROVERA should be terminated. PROVERA is not recommended as primary therapy, but as adjunctive and palliative treatment in advanced, inoperable cases including those with recurrent or metastatic disease.

CONTRAINDICATIONS

Thrombophlebitis, thrombotic or thromboembolic disorders, cerebral apoplexy or patients with a past history of these conditions. Markedly impaired liver function. Undiagnosed vaginal bleeding. Undiagnosed urinary tract bleeding. Undiagnosed breast pathology. Missed abortion. Known sensitivity to medroxyprogesterone acetate or to any of the excipients. Known or suspected pregnancy (see PRECAUTIONS).

Pregnancy: Category D The definition of Pregnancy Category D is drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human foetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Animal studies have shown that high doses of progestogens can cause masculinization of the female foetus. Several reports suggest an association between intrauterine exposure to progestational drugs in the first trimester of pregnancy and genital abnormalities in male and female foetuses. The risk of hypospadias may be approximately doubled with exposure to progesterones. Severe uncontrolled hypertension. Known or suspected malignancy of the breast (excluding use in oncology indications).

WARNINGS AND PRECAUTIONS

Warnings

The physician should be alert to the earliest manifestations of thrombotic disorders (thrombophlebitis, cerebrovascular disorders, pulmonary embolism, and retinal thrombosis). Should any of these occur, the drug should be discontinued immediately. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or if there is a sudden onset of proptosis, diplopia or migraine. If examination reveals papilloedema, or retinal vascular lesions, medication should be withdrawn. Clinical suppression of adrenocorticoid function has not been observed at low dose levels, however, at the high doses used in the treatment of cancer, corticoid-like activity has been reported. Medroxyprogesterone acetate may decrease adrenocorticotrophic hormone and hydrocortisone blood levels. Animal studies show that medroxyprogesterone possesses adrenocorticoid activity. The following laboratory tests may be affected by the use of PROVERA: Gonadotrophin levels Plasma progesterone levels Urinary pregnanediol levels Plasma testosterone levels (in the male) Plasma oestrogen levels (in the female) Sex-hormone-binding globulin Plasma cortisol levels Glucose tolerance test. Metyrapone test - the use of medroxyprogesterone acetate in oncology indications may cause partial adrenal insufficiency (decrease in pituitary-adrenal axis response) during metyrapone

testing. Thus the ability of the adrenal cortex to respond to adrenocorticotrophic hormone should be demonstrated before metyrapone is administered. Observational and 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. Mortality can be increased in those who are diagnosed with incident breast cancers. The possible effect of hormone replacement therapy (HRT) on mammographic density and on the sensitivity and specificity of breast cancer screening should also be considered. Combination HRT should not be used in hysterectomised women because it is not needed to prevent endometrial changes in these women and it may increase the risk of breast cancer. Current use of oestrogen only or oestrogen plus progestin products in post-menopausal women for five or more years has been associated with an increased risk of ovarian cancer. The benefits and risks of hormone replacement therapy (HRT) must always be carefully weighed, including consideration of the emergence of risks as therapy continues. Use of combined oestrogen/progestin therapy in postmenopausal women should be prescribed at the lowest effective doses and limited to the shortest duration consistent with treatment goals and risks for the individual women, and should be periodically evaluated. HRT in postmenopausal women is not generally appropriate for long term use and should not be prescribed for longer than 6 months without reexamining the patient.

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 FURTHER INFORMATION, Clinical Trial Data). 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.

Precautions

The pre-treatment physical examination should include special reference to breast and pelvic organs, as well as Papanicolaou smear. This evaluation should exclude the presence of genital or breast neoplasia unless the patient is to be treated with PROVERA for recurrent endometrial, breast or renal cancer. Because this drug may cause some degree of fluid retention, conditions which might be influenced by this factor, such as epilepsy, migraine, asthma, or cardiac or renal dysfunction, require careful observation.

Breakthrough bleeding is likely to occur in patients being treated for endometriosis. No other hormonal intervention is recommended for managing this bleeding. Non-functional causes should also be borne in mind and in cases of undiagnosed vaginal bleeding, adequate diagnostic measures are indicated. A decrease in glucose tolerance has been observed in some patients on progestogens. The mechanism of this decrease is obscure. This fact should be borne in mind when treating all patients and for this reason diabetic patients should be carefully observed while receiving progestogen therapy. Patients who have a history of mental depression should be carefully observed and the drug discontinued if the depression recurs to a serious degree. The age of the patient constitutes no absolute limiting factor although treatment with progestogens may mask the onset of the climacteric. The pathologist should be advised of progestogens therapy when relevant specimens are submitted. Weight gain may be associated with the use of PROVERA. Caution should therefore be exercised in treating any patient with a pre-existing condition that may be adversely affected by weight gain. The high doses of PROVERA used in the treatment of cancer patients may, in some cases, produce Cushingoid symptoms e.g., moon facies, fluid retention, glucose tolerance and blood pressure elevation.

PROVERA TABLETS ARE NOT TO BE USED AS A TEST FOR PREGNANCY OR WHERE PREGNANCY IS SUSPECTED.

If PROVERA is used during pregnancy, or if the patient becomes pregnant while using PROVERA, the patient should be apprised of the potential risk to the foetus. NOTE: In peri menopausal patients where the endometrium is still proliferative, persistence of the endometrial proliferation may occur during administration of hormone replacement therapy (HRT). An endometrial biopsy may be performed at the discretion of the attending physician. 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 in women on medroxyprogesterone acetate are uncommon. There is no definitive information for the other formulations of medroxyprogesterone acetate. 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.

A higher incidence of probable dementia in women aged 65 years and older has been reported during treatment with a HRT regimen of conjugated oestrogens and medroxyprogesterone acetate. Eighty-five percent of cases of probable dementia occurred in the subgroup of women (54%) that were older than 70 years of age. Use of hormone therapy to prevent dementia or mild cognitive impairment in women 65 years or older is not recommended.

ADVERSE EFFECTS

The following events listed in order of seriousness rather than frequency of occurrence, have been associated with the use of progestogens including medroxyprogesterone acetate: Allergy - hypersensitivity reactions (e.g., anaphylaxis, anaphylactoid-like reactions, angioedema). Cardiovascular - cerebral and myocardial infarction, congestive heart failure, increased blood pressure, palpitations, retinal thrombosis, tachycardia, thromboembolic disease, thrombophlebitis, pulmonary embolism. Central Nervous System - confusion, loss of concentration, euphoria, vision disorders, nervousness, insomnia, somnolence, fatigue, depression, dizziness, headache, and tremor. Some patients may complain of premenstrual-like depression while on PROVERA. Skin and Mucous Membranes - urticaria, pruritis, rash, acne, hirsutism, alopecia and sweating. Genitourinary - irregular uterine bleeding (increase, decrease), spotting, amenorrhoea, prolonged anovulation. Gastrointestinal/Hepatobiliary - nausea, vomiting, constipation, diarrhoea, dry mouth, disturbed liver function, jaundice. Metabolic and Nutritional - adrenergic-like effects (e.g., fine-hand tremors, cramps in calves at night), corticoid-like effects (e.g., Cushingoid syndrome), decreased glucose tolerance, diabetic cataract, exacerbation of diabetes mellitus, glycosuria. Breast - tenderness, galactorrhoea, mastodynia. The use of oestrogens and progestogens by post-menopausal women has been associated with an increased risk of breast cancer (refer WARNINGS). Cervix - cervical erosions, changes in excretions and secretions. Miscellaneous - Changes in appetite, changes in libido, oedema/fluid retention, hyperpyrexia, weight change, malaise, hypercalcaemia. Moderate elevation of blood pressure, transient elevations of alkaline phosphatase and/or serum transaminase activities, elevations of serum calcium and potassium levels, and increases in white cell and platelet counts.

Version: pfdprovt11013 Supersedes: pfdprovt10111

INTERACTIONS

Aminoglutethimide administered concomitantly with PROVERA may significantly depress the bioavailability of medroxyprogesterone acetate. Users of high-dose medroxyprogesterone acetate should be warned about the possibility of decreased efficacy with the use of aminoglutethimide. Medroxyprogesterone acetate (MPA) is metabolised in-vitro primarily by hydroxylation via the CYP3A4. While specific drug-drug interaction studies evaluating the clinical effect of CYP3A4 inhibitors or inducers of CYP3A4 on MPA have not been conducted or reported in the literature, physicians should consider that interactions could occur. Combined use of MPA with CYP3A4 inhibitors or inducers may result in compromised efficacy due to decreased systemic levels of MPA.

OVERDOSAGE

Oral doses up to 3 g per day have been well tolerated. Patients receiving pharmacological doses of medroxyprogesterone acetate for treatments of neoplasms (400 mg/day or greater) may occasionally exhibit effects resembling those of glucocorticoid excess. As with the management of any overdosage, the physician should carefully observe the patient for the potential side effects. Overdose treatment is symptomatic and supportive. Contact the Poisons Information Centre for advice on the management of an overdose.

PHARMACEUTICAL PRECAUTIONS

PROVERA 2.5 mg, 5 mg and 10 mg tablets: Store at or below 30degC. PROVERA 100 mg and 200 mg: Store at or below 25degC.

MEDICINE CLASSIFICATION

PACKAGE QUANTITIES

mg tablets: are supplied in blister packs of 100 tablets. 10 mg tablets: are supplied in blister packs of 30 tablets. 100 mg tablets: are supplied blister packs of 100 tablets. 200 mg tablets: are supplied in blister packs of 30 tablets.

FURTHER INFORMATION

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) 150 mg 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 150 mg 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.

The oral LD50 of medroxyprogesterone acetate was found to be >10,000 mg/kg in the mouse. The intraperitoneal LD50 in the mouse was 6985 mg/kg.

Medroxyprogesterone acetate administered orally to rats and mice (334 mg/kg/day) and dogs (167 mg/kg/day) for 30 days was found to be non-toxic. Medroxyprogesterone acetate was administered orally to dogs and rats at 3, 10 and 30 mg/kg/day for 6 months. The drug was considered to be non-toxic at these levels but with anticipated hormonal effects at the higher dose.

Medroxyprogesterone acetate given orally at 1, 10 and 50 mg/kg/day in pregnant beagle bitches produced clitoral hypertrophy in the female pups of the high dose animals. No abnormalities

were noted in any of the male pups. Subsequent evaluation of the reproductive potential of the bitches from the litters of treated females revealed no reduction in fertility potential.

Long-term toxicology studies in the monkey, dog and rat with parenteral medroxyprogesterone acetate have disclosed: Beagle dogs receiving 75 mg/kg and 3 mg/kg every 90 days for 7 years developed mammary nodules, as did some of the control animals. The nodules appearing in the control animals were intermittent in nature, whereas the nodules in the drug treated animals were larger, more numerous, persistent, and there were two high dose animals that developed breast malignancies. Two monkeys receiving 150 mg/kg every 90 days for 10 years developed undifferentiated carcinoma of the uterus. No uterine malignancies were found in monkeys receiving 30 mg/kg, 3 mg/kg, or placebo every 90 days for 10 years. Transient mammary nodules were found during the study in the control, 3 mg/kg and 30 mg/kg groups, but not in the 150 mg/kg group. At sacrifice (after 10 years), the only nodules extant were in three of the monkeys in the 30 mg/kg group. Upon histopathological examination these nodules were determined to be hyperplastic. No uterine or breast abnormalities were revealed in the rat after 2 years. The relevance of any of these findings with respect to humans has not been established.

Medroxyprogesterone acetate is a progestogen and a derivative of progesterone. It is a white to off-white, odourless crystalline powder, stable in air, melting between 200 and 210degC. It is freely soluble in chloroform, soluble in acetone and dioxane, sparingly soluble in ethanol and methanol, slightly soluble in ether and insoluble in water. Medroxyprogesterone acetate is -methyl-3,20-dioxopregn-4-en-17 -yl acetate, and its structural formula is as follows:

PROVERA 2.5 mg, 5 mg and 10 mg tablets contain excipients: calcium stearate, lactose, liquid paraffin, maize starch, purified talc, sucrose, and colouring agents sunset yellow FCF (2.5 mg tablets), indigo carmine (5 mg tablets).

PROVERA 100 mg and 200 mg tablets contain excipients: docusate sodium, gelatin, isopropyl alcohol, macrogol 400, magnesium stearate, maize starch, microcrystalline cellulose, sodium benzoate and sodium starch glycollate.

NAME AND ADDRESS

Pfizer New Zealand Ltd P O Box 3998 Auckland, New Zealand, 1140. Toll Free Number: 0800 736 363.

PROVERA(r)

Medroxyprogesterone acetate

mg, 5mg, 10mg, 100 mg and 200 mg Tablets

PRESENTATION

USES