Provera 100 Mg/500 Mg Tablets

PROVERA is indicated in the palliative treatment of:

• Recurrent and/or metastatic endometrial cancer
• Recurrent and/or metastatic renal cancer
• Recurrent and/or metastatic breast cancer in post-menopausal women

Posology
PROVERA is not recommended as primary therapy, but as adjunctive and palliative treatment in advanced, inoperable cases including those with recurrent or metastatic disease. For the treatment of endometrial and renal cancer a dosage of 200 mg to 600 mg PROVERA per day is recommended. For the treatment of breast cancer in post-menopausal women, a dosage of 400 mg to 1 200 mg PROVERA per day is recommended.

Method of administration
For oral use.

PROVERA is contraindicated in patients with the following conditions:

• Known hypersensitivity to medroxyprogesterone acetate or any of the excipients of PROVERA
• Known or suspected pregnancy
• Undiagnosed vaginal bleeding
• Severe liver dysfunction

General
Before using PROVERA, the status of the patient should be carefully evaluated. Unexpected vaginal bleeding during therapy with PROVERA should be investigated. PROVERA may cause weight gain and fluid retention. Therefore, caution should be exercised in treating any patient with a pre-existing medical condition that may be adversely affected by weight gain or fluid retention. Depressed mood and depression are well-known undesirable effects of hormonal contraceptive use and preparations containing oestrogen and/or progesterone/progestogen (see section 4.8).

Depression can be serious and is a well-known risk factor for suicidal behaviour and suicide. Women should be advised to contact their medical practitioner in case of mood changes and depressive symptoms, including shortly after initiating the treatment. Patients with a history of treatment for depression should be carefully monitored while receiving PROVERA therapy. Some patients may complain of premenstrual-like depression while on PROVERA therapy.

Patients receiving PROVERA may exhibit a decreased glucose tolerance. The mechanism for this is not known. This fact should be borne in mind when treating all patients and especially known diabetics. Diabetic patients should be carefully observed while receiving PROVERA.

The pathologist (laboratory) should be informed of the patient's use of PROVERA if endometrial or endocervical tissue is submitted for examination. The medical practitioner/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., luteinising hormone (LH) and follicle-stimulating hormone (FSH))
• Sex hormone-binding-globulin

The following laboratory tests may be affected by the use of PROVERA:

• Glucose tolerance test
• Metyrapone test

If there is a sudden partial or complete loss of vision or if there is a sudden onset of proptosis, diplopia, or migraine PROVERA should not be used, pending examination. If examination reveals papilloedema or retinal vascular lesions, PROVERA should not be used again.

PROVERA has not been causally associated with the induction of thromboembolic disorders. However, PROVERA is not recommended in any patient with a history of venous thromboembolism (VTE). Discontinuation of PROVERA is recommended in patients who develop VTE while undergoing therapy with PROVERA.

Decrease in bone mineral density
Long-term use of PROVERA causes loss of bone mineral density.

Oncology
The high doses of PROVERA used in the treatment of cancer patients may produce cushingoid symptoms, e.g. moon faces, fluid retention, glucose intolerance and blood pressure elevations. Patients receiving PROVERA may exhibit suppressed adrenal function. PROVERA may decrease ACTH and hydrocortisone blood levels. The medical practitioner/laboratory should be informed that in addition to the endocrine biomarkers listed above, the use of PROVERA in oncology indications may also cause partial adrenal insufficiency (decrease in pituitary-adrenal axis response) during metyrapone testing. Thus, the ability of adrenal cortex to respond to ACTH should be demonstrated before metyrapone is administered.

Breast cancer
The use of combined oral oestrogen/progestin by postmenopausal women has been reported to increase the risk of breast cancer. Results from a randomised placebo-controlled trial, the Womenu2019s Health Initiative (WHI) trial, and epidemiological studies have reported an increased risk of breast cancer in women taking oestrogen/progestin combinations for hormone therapy (HT) for several years. In the WHI conjugated equine oestrogens (CEE) plus medroxyprogesterone acetate trial and observational studies, the excess risk increased with duration of use. The use of oestrogen plus progestin has also been reported to result in an increase in abnormal mammograms requiring further evaluation.

In several epidemiologic studies no overall increased risk for breast cancer was found among users of injectable depot progestogens in comparison to non-users. However, an increased relative risk (e.g., 2,0 in one study) was found for women who currently used injectable depot progestogens or had used them up to five years before. It is not possible to infer from these data whether this increased rate of breast cancer diagnosis among current users is due to increased surveillance among current users, the biological effects of injectable progestogens, or a combination of reasons.

Mortality can be increased in those who are diagnosed with incident breast cancers. The possible effect of menopausal hormone therapy (MHT) on mammographic density and on the sensitivity and specificity of breast cancer screening should also be considered. Combination MHT 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.

A large meta-analysis of observational studies reported that when oestrogen-plus-progestin therapy was taken for more than 5 years, the increased risk of breast cancer may persist for 10 years or more after discontinuation of treatment. The reported risk at 10 years or more after discontinuation of treatment was not increased when therapy was taken for less than 5 years. In current users the increased risk of breast cancer in women taking combined oestrogen-progestin for MHT becomes apparent after about 1-4 years.

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

PROVERA is metabolised in vitro primarily by hydroxylation via CYP3A4. Specific interaction studies evaluating the clinical effects with CYP3A4 inducers or inhibitors on PROVERA have not been conducted and therefore the clinical effects of CYP3A4 inducers or inhibitors are unknown.

Pregnancy
PROVERA is contraindicated in women who are pregnant (see section 4.3). Reports suggest an association between intra-uterine exposure to progestational medicines in the first trimester of pregnancy and genital abnormalities in foetuses. If the patient becomes pregnant while using PROVERA, the patient should be apprised of the potential hazard to the foetus.

Breastfeeding
PROVERA and its metabolites are excreted in breast milk. Mothers on PROVERA therapy should not breastfeed their infants.

The effect of PROVERA on the ability to drive and use machinery has not been systematically evaluated. Side effects of PROVERA that may affect driving and use of machinery are e.g., dizziness, tremors, loss of concentration, retinal embolism and euphoria (see section 4.8). Patients should determine how they are affected before engaging in such activities.

The table below provides a listing of adverse medicine reactions with frequencies based on all-causality data from 1 337 patients who received PROVERA in 4 pivotal studies that evaluated efficacy and safety of PROVERA for oncology indications. Frequencies are defined as: Very common ( u2265 1/10), common ( u2265 1/100 to < 1/10), uncommon ( u2265 1/1 000 to <1/100), rare ( u2265 1/10 000 to < 1/1 000), very rare (< 1/10 000).

System organ class Frequency Side effect

Neoplasms benign, malignant and unspecified Not known Meningioma

Immune system disorders Uncommon Angioedema
Rare Medicine hypersensitivity
Not known Anaphylactic reaction, anaphylactoid reaction

Endocrine disorders Uncommon Corticoid-like effects
Not known Prolonged anovulation

Metabolism and nutrition disorders Common Increased weight, increased appetite
Uncommon Exacerbated diabetes mellitus, hypercalcaemia

Psychiatric disorders Common Insomnia
Uncommon Depression, euphoria, decreased libido
Rare Nervousness
Not known Confusion

Nervous system disorders Common Headache, dizziness, tremors
Rare Cerebral infarction, somnolence
Not known Loss of concentration, adrenergic-like effects

Eye disorders Not known Retinal embolism and thrombosis, diabetic cataract, visual impairment

Cardiac disorders Uncommon Congestive cardiac failure
Rare Myocardial infarction
Not known Tachycardia, palpitations

Vascular disorders Uncommon Thrombophlebitis
Rare Venous thromboembolism

Respiratory, thoracic and mediastinal disorders Uncommon Pulmonary embolism

Gastrointestinal disorders Common Vomiting, constipation, nausea
Uncommon Diarrhoea, dry mouth

Hepato-biliary disorders Rare Jaundice

Skin and subcutaneous tissue disorders Common Hyperhidrosis
Uncommon Acne, hirsutism
Rare Alopecia, rash
Not known Urticaria, pruritus

Musculoskeletal and connective tissue disorders Uncommon Muscle spasms

Renal and urinary disorders Not known Glycosuria

Reproductive system and breast disorders Common Erectile dysfunction
Uncommon Dysfunctional uterine bleeding (irregular, increased, decreased, spotting), breast pain
Not known Amenorrhoea, uterine cervical erosions, cervical discharge, galactorrhoea

General disorders and administration site conditions Common Oedema/fluid retention, fatigue
Rare Malaise, pyrexia

Investigations Rare Decreased glucose tolerance, increased blood pressure
Not known Abnormal liver function test, increased white blood cell count, increased platelet count

The side effects below were reported during post-marketing experience

System organ class Side effect

Metabolism and nutrition disorders Moon faces

Psychiatric disorders Severe depression with a higher risk of suicidal thoughts/behaviour and suicide

Skin and subcutaneous tissue disorders Acquired lipodystrophy

Reproductive system and breast disorders Breast tenderness

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are requested to report any suspected adverse reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website. Report any suspected adverse drug reactions associated with the use of the medicine directly to Pfizer via [email protected].

Patients receiving pharmacological doses of PROVERA for the treatment of neoplasms (400 mg/day or greater) may exhibit effects resembling those of corticoid excess. Observation only is recommended for management, although it may be necessary to consider dose reduction. No symptoms of acute overdosage have been observed. Overdose treatment is symptomatic and supportive.