Medroxyprogesterone

Medroxyprogesterone acetate is a synthetic progestogen, structurally related to progesterone. It has anti-oestrogenic, anti-androgenic and anti-gonadotrophic effects and has shown activity against hormone-dependent tumours, including hormone-dependent breast carcinoma. In women with adequate endogenous oestrogen, recommended doses turn a proliferative endometrium into a secretory one, which is the basis of the gynaecological use of the tablets.

Mechanism of Action

• Endometrium: it opposes the proliferative effect of oestrogen. In laboratory studies it reduces nuclear oestrogen receptors and DNA synthesis in endometrial epithelial cells and, in some cancer cell lines, induces p53-dependent apoptosis.
• Pituitary and hormone levels: it inhibits the pituitary gonadotrophins (FSH and LH) and lowers blood levels of ACTH, cortisol, testosterone and oestrogens. The fall in oestrogen follows both FSH inhibition and induction of a hepatic reductase, which raises testosterone clearance and reduces the conversion of androgens to oestrogens.
• Other actions: androgenic and anabolic effects have been observed, but it has no significant oestrogenic activity.

Pharmacokinetics

• Absorption: oral medroxyprogesterone acetate is absorbed rapidly and peaks after 2–4 hours. Food increases bioavailability: a 10 mg dose taken just before or just after a meal raised mean peak concentration by 51% and 77% and mean AUC by 18% and 33%, with no change in half-life. After intramuscular injection of a depot formulation absorption is slow, with peak levels after about 5 days and a mean elimination half-life of about 24 days (DrugBank values for the intramuscular route; the SmPC of the 500 mg suspension should be consulted for its own data).
• Distribution: about 90% bound to plasma proteins, mainly albumin, and not to sex hormone-binding globulin. The unbound fraction modulates the pharmacological response.
• Metabolism: after an oral dose it is metabolised mostly in the liver, by hydroxylation of the A ring and/or the side chain followed by conjugation; at least 16 metabolites have been identified. CYP3A4 is the main enzyme involved.
• Elimination: most metabolites are excreted in urine as glucuronide conjugates and a minority as sulphates. The elimination half-life of the oral form is 12–17 hours.
• Special populations: no clinical studies have assessed liver or kidney disease. Because elimination is almost entirely by hepatic metabolism, steroid metabolism may be reduced in severe hepatic impairment; no dose adjustment is expected to be needed in renal impairment.

Medroxyprogesterone acetate is authorised nationally in the EU as separate products with different indications.

• Depo Prodasone 500 mg suspension for injection (France): hormonal treatment of certain hormone-dependent cancers.
  • Metastatic breast cancer, after failure of selective oestrogen receptor modulators (SERMs), aromatase inhibitors and/or fulvestrant.
  • Recurrent or metastatic endometrioid endometrial cancer.
• Progevera 5 mg and 10 mg tablets (Spain): gynaecological disorders.
  • Adjunct to oestrogen therapy in menopausal women who have not had a hysterectomy.
  • Secondary amenorrhoea, once pregnancy has been excluded.
  • Dysfunctional uterine bleeding (menometrorrhagia).
  • Infertility where poor corpus luteum function is the cause.
  • Premenstrual syndrome.
  • Dysmenorrhoea.
  • Mild to moderate endometriosis.

Depo Prodasone injection

• Hypersensitivity to the active substance or to any excipient.
• Current or past venous thromboembolism (phlebitis, pulmonary embolism).
• Current or past arterial thromboembolic events, in particular myocardial infarction and stroke.
• Severe liver disease or severe abnormalities of liver tests.
• Genital bleeding of undiagnosed cause.
• Concomitant use of St John’s wort.

Progevera tablets

• Hypersensitivity to the active substance or to any excipient.
• Pregnancy or suspected pregnancy.
• Breast cancer, past or suspected.
• Abnormal uterine bleeding until a definitive diagnosis has been made and malignancy of the genital tract excluded.
• Current or previous idiopathic venous thromboembolism (deep vein thrombosis, pulmonary embolism).
• Acute liver disease, or a history of liver disease until liver function tests have returned to normal.
• Missed miscarriage.
• Severe arterial hypertension.
• Porphyria.

The SmPCs of the two products list different reactions, so they are given separately.

Depo Prodasone injection

Very common (≥1/10): none listed.

Common (≥1/100 to <1/10): weight fluctuation, increased appetite, insomnia, headache, dizziness, tremor, vomiting, constipation, nausea, hyperhidrosis, erectile dysfunction, injection-site reactions, oedema, fluid retention, fatigue.

Uncommon (≥1/1,000 to <1/100): corticoid-like (Cushing-type) effects, worsening of diabetes mellitus, depression, change in libido, congestive heart failure, thrombophlebitis, pulmonary embolism, diarrhoea, dry mouth, acne, hirsutism, angioedema, breast pain, injection-site pain or tenderness, muscle spasms.

Rare (≥1/10,000 to <1/1,000): drug hypersensitivity, nervousness, cerebral infarction, somnolence, myocardial infarction, embolism and thrombosis, cholestatic jaundice, alopecia, rash, malaise, fever, osteoporosis and osteoporotic fractures, decreased glucose tolerance, raised blood pressure.

Not known: anaphylactic and anaphylactoid reactions, prolonged anovulation, confusion, loss of concentration, adrenergic-type effects, retinal thrombosis and embolism, worsened vision, diabetic cataract, tachycardia, palpitations, worsening of the symptoms of leg venous insufficiency, bronchospasm, liver disorders, acquired lipodystrophy, urticaria, pruritus, chloasma, glycosuria, amenorrhoea, cervical erosion, galactorrhoea, menstrual cycle disorders, altered cervical secretions, persistent injection-site atrophy or nodule, abnormal liver function tests, lower blood ACTH and cortisol, lower plasma and urinary steroids, gonadotrophins and sex hormone-binding proteins, meningioma.

Progevera tablets

Very common: headache, nausea, dysfunctional uterine bleeding (irregular, heavier, lighter or between periods).

Common: drug hypersensitivity, depression, insomnia, nervousness, dizziness, alopecia, acne, urticaria, pruritus, cervical discharge, breast pain and tenderness, raised temperature, fatigue, weight increase.

Uncommon: somnolence, hirsutism, galactorrhoea, oedema, fluid retention.

Rare: anaphylactic and anaphylactoid reactions, angioedema, embolism and thrombosis, rash, decreased glucose tolerance.

Not known: prolonged anovulation, jaundice and cholestatic jaundice, amenorrhoea, cervical erosion, weight decrease.

Thromboembolic events (including cerebral infarction, myocardial infarction and pulmonary embolism), anaphylactic reactions, cholestatic jaundice and visual disturbances need urgent medical attention. Meningioma, osteoporosis and osteoporotic fractures, and injection-site reactions, were identified after marketing.

Medroxyprogesterone acetate is metabolised mainly by CYP3A4, and substances that induce liver enzymes can lower its levels.

• St John’s wort (Hypericum perforatum): a contraindicated combination with the injection. It lowers medroxyprogesterone acetate levels by enzyme induction, with a risk of reduced or lost effect. The tablet SmPC gives the same warning for herbal preparations containing it.
• Enzyme-inducing medicines (not recommended with the injection): anticonvulsants (phenobarbital, phenytoin, fosphenytoin, primidone, carbamazepine, oxcarbazepine, eslicarbazepine), rifabutin, rifampicin, nevirapine, efavirenz, dabrafenib and enzalutamide reduce efficacy by increasing hepatic metabolism.
• Nelfinavir and ritonavir: not recommended. Although strong CYP3A4 inhibitors, they behave as inducers with steroid hormones and may reduce efficacy.
• Bosentan: precaution needed, as it may reduce efficacy. Clinical monitoring is advised, with adjustment of the hormone dose if necessary during and after bosentan.
• Aminoglutethimide: with high oral doses of medroxyprogesterone acetate it can lower serum levels significantly and reduce efficacy.
• Glucose-lowering medicines: reduced glucose tolerance may call for a higher dose of oral hypoglycaemic agents.
• Anticoagulants: progestogens can affect clotting factors, so the effect of anticoagulants may be lost.
• Food: tablets taken with food are better absorbed (see Pharmacokinetics).
• The injection SmPC lists further combinations that need precautions; check it before prescribing.

The 500 mg suspension is given by deep intramuscular injection only; the tablets are taken by mouth. According to the French SmPC the dose of the injection varies with the type and stage of the tumour.

Depo Prodasone Injection (Cancer)

• Metastatic breast cancer: 500 mg daily for 4 weeks as initial treatment, then 500 mg twice a week as maintenance.
• Endometrial cancer: 500 to 1,000 mg per week.
• Method: never inject intravenously. Shake the vial well before use and observe strict asepsis.

Progevera Tablets (Gynaecology)

• Menopause: 5–10 mg daily for the last 10–14 days of oestrogen therapy. Combined oestrogen–progestogen treatment should use the lowest effective dose for the shortest possible time and be reviewed regularly.
• Secondary amenorrhoea: 2.5–10 mg daily for 5–10 days, starting on day 16 or 21 of the cycle. With endometrial atrophy, 10 mg daily for 10 days together with oestrogen. Bleeding usually follows within 3 days of stopping; repeat for three consecutive cycles to restore the normal cycle.
• Dysfunctional uterine bleeding: 2.5–10 mg daily for 5–10 days from day 16 or 21, for two consecutive cycles; once bleeding is controlled, repeat for two further cycles.
• Infertility: 2.5–10 mg daily from the second half of the cycle (day 14).
• Premenstrual syndrome: 2.5–10 mg daily for 5–7 days before the end of the cycle.
• Dysmenorrhoea: 2.5–10 mg daily from day 5 to day 25 of the cycle.
• Mild to moderate endometriosis: 10 mg three times daily from the first day of the cycle for 90 consecutive days. Light, self-limiting bleeding may occur and needs no extra hormone therapy.
• Periodic check-ups are recommended. Unless endometriosis has been diagnosed, adding a progestogen is not recommended in women without a uterus. The scored tablet can be divided into equal doses.

Special Populations

• Hepatic impairment: not studied. Metabolism may be reduced in severe impairment, and severe liver disease is a contraindication for the injection.
• Renal impairment: not studied; no dose adjustment is expected to be needed.
• Adolescents: use of the injection is not recommended because of the risk of reduced bone mineral density.

Thromboembolic Events

Past or present venous or arterial thromboembolism rules out the injection, and it must be stopped if such an event occurs. The tablets have not been causally linked to thrombotic disorders, but they are not recommended in anyone with previous venous thromboembolism and should be stopped if it develops.

Visual Disturbance

Stop treatment, and do not restart until an examination has been done, if there is sudden partial or complete loss of vision, sudden protrusion of the eye, double vision or migraine. If the examination shows papilloedema or retinal vascular lesions, do not give the medicine again.

Genital Bleeding and Examination

Genital bleeding of unknown cause must be investigated before treatment, and again if bleeding appears unexpectedly during treatment. The injection should be started only after a complete gynaecological examination. Regular medical examination is advised during prolonged progestogen treatment, with closer follow-up of patients with cardiovascular disease, smokers, and those with renal dysfunction, epilepsy, migraine, diabetes or hypertension. Before the tablets, the doctor reviews personal and family history and examines the patient, including blood pressure, breast and pelvic examination and cervical cytology, to exclude genital or breast neoplasia. Patients should contact their doctor about severe headache, visual changes or vaginal bleeding.

Meningioma

Single and multiple meningiomas have been reported with prolonged use (several years). Patients should be watched for signs and symptoms of meningioma according to clinical practice. If a meningioma is diagnosed, the need to continue treatment must be reviewed case by case, weighing individual benefits and risks; in some cases the meningioma regressed after treatment was stopped.

Bone Mineral Density

The injection lowers serum oestrogen and is associated with a significant decrease in bone mineral density in premenopausal women. Loss may be greater with longer use and may not be fully reversible. Use is not recommended in adolescents, or in women with risk factors for osteoporosis (metabolic bone disease, chronic alcohol or tobacco use, anorexia nervosa, a maternal history of osteoporotic fracture, or long-term use of medicines that reduce bone mass such as anticonvulsants or corticosteroids). Other endometrial treatments should be considered for them.

Other Precautions

• Fluid retention: take care in conditions that fluid retention could worsen.
• Diabetes: glucose tolerance may fall, so diabetic patients need close monitoring.
• Depression: patients with a history of depression should be watched closely.
• Endocrine effects: with the injection, Cushing-like symptoms, adrenal suppression (lower blood ACTH and cortisol) and prolonged anovulation with amenorrhoea may occur. Some laboratory markers of endocrine activity can fall, so the pathologist should be told when endocervical or endometrial tissue is examined.
• Chloasma: women prone to it should avoid sun exposure during treatment.

Excipients

The injection contains methyl and propyl parahydroxybenzoates (E218, E216), which can cause allergic reactions that may be delayed, and polysorbate 80, which can cause hypersensitivity reactions. It contains less than 1 mmol (23 mg) of sodium per 3.3 mL vial. The tablets contain lactose and sucrose (amounts under Composition); the SmPC gives the related warnings.

Pregnancy, Breastfeeding and Fertility

• Tablets in pregnancy: contraindicated, and pregnancy must be excluded before treatment starts. Doses of up to 30 mg a day may not suppress ovulation, so patients who could become pregnant should be advised on appropriate precautions. Exposure to progestogens in the womb during the first trimester has, in some circumstances, been associated with genital anomalies in foetuses, and a woman who becomes pregnant should be told of the potential risk to the foetus.
• Injection in pregnancy: there is no indication for use in pregnancy. Most recent epidemiological studies find no link between exposure at the doses used in gynaecology and malformations, so finding a pregnancy during treatment does not justify ending the pregnancy.
• Breastfeeding: the substance passes into milk. For the injection at cancer doses there are no clinical data, and breastfeeding is not advised as a precaution. The tablet SmPC advises against giving it earlier than six weeks after delivery.
• Fertility: animal studies showed adverse effects on fertility, and prolonged anovulation with amenorrhoea may follow the injection.

Effect on Driving

The effect on the ability to drive or use machines has not been systematically evaluated. Dizziness, somnolence and visual disturbances are listed as side effects, so patients who experience them should not drive.

Depo Prodasone suspension: store at a temperature not exceeding 25 °C. Progevera tablets need no special storage conditions. Neither product needs cold-chain handling. Keep out of the sight and reach of children.

5 years for both the injection and the tablets. Once an injection vial is opened, the suspension should be used immediately.

Prescription only (Rx). The 500 mg injection is given by deep intramuscular injection, so it is supplied to the hospital or clinic that administers it. The 5 mg and 10 mg tablets are taken at home and are supplied to the patient or the treating clinic on prescription.