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medroxyprogesterone
medroxyprogesterone
SYNONYM(S): methylacetoxyprogesterone; metipregnone; MPA
COMMON TRADE NAME(S): Provera® (multiple brands available)
Medroxyprogesterone is a long acting progestogen derived from soybeans. The mode of anticancer action of the progestins includes an indirect action on the hypothalamic-pituitary axis consisting of inhibition of gonadotrophin releasing hormone release as well as a direct action on estrogen receptors resulting in the inhibition of cellular proliferation. The growth inhibitory effects of progestins are not cell cycle phase-specific, but may be maximal in the G1 phase of dividing cells.
| Bioavailability |
oral: Rapid, subject to first-pass metabolism in the liver |
| Peak plasma levels | Tmax: 2-4 hours (oral) |
Not elucidated, detectable in breast milk.
| Cross blood brain barrier? | Yes |
| Volume of distribution | No information found. |
| PPB | 90 % |
Promptly metabolized in liver, first pass effect.
| Active metabolites | No |
| Inactive metabolites | Yes |
Urine (20-40%) and feces (5-13%)
| Urine | 20-42% |
| Half-life | Apparent t ½ : 30 hours |
- Hormone dependent, recurrent metastatic breast cancer (in post-menopausal women)
- Recurrent and/or metastatic endometrial cancer
- Refer to the Product monograph for non-cancer indications
Emetogenic Potential:
Extravasation Potential: Not applicable
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Arrhythmia (rare) | E | |||
| Arterial thromboembolism (1%) | E D | ||||
| Hypertension (less common) | E | ||||
| Tachycardia (rare) | E | ||||
| Venous thromboembolism (1%) | E D | ||||
| Dermatological | Alopecia (rare) | E | |||
| Hirsutism (1%) | D | ||||
| Other (chloasma) | D | ||||
| Rash (1%) (acne- rare) | E | ||||
| Gastrointestinal | Abdominal pain (common) | E | |||
| Bloating (common) | E | ||||
| Constipation | E | ||||
| Diarrhea (1%) | E | ||||
| Nausea, vomiting (4%) | I | ||||
| Weight changes (less common) | E | ||||
| General | Fatigue (5%) | E | |||
| Fluid retention (including effusions) | E | ||||
| Hematological | Leukocytosis / thrombocytosis | E D | |||
| Myelosuppression (rare) | E | ||||
| Sickle cell crisis (rare) | E | ||||
| Hepatobiliary | Cholecystitis | D | |||
| ↑ LFTs | E | ||||
| Hypersensitivity | Hypersensitivity (rare) | I | |||
| Infection | Infection (not related to myelosuppression; rare) | E | |||
| Injection site | Injection site reaction | I | |||
| Metabolic / Endocrine | Adrenal insufficiency (less common) | E | |||
| Glucose intolerance | E | ||||
| Hyperlipidemia (abnormal lipids) | E | ||||
| Other corticosteroid effects | E D | ||||
| Musculoskeletal | Musculoskeletal pain | E | |||
| Osteoporosis (premenopausal) | D | ||||
| Neoplastic | Secondary malignancy | D | |||
| Nervous System | Dizziness (6%) | E | |||
| Headache (17%) | E | ||||
| Mood changes (2%) | E | ||||
| Neuropathy (1%) | E | ||||
| Somnolence / insomnia | E | ||||
| Ophthalmic | Visual disorders (visual changes) | E | |||
| Reproductive and breast disorders | Estrogen deprivation symptoms (or androgen deprivation symptoms; less common) | E | |||
| Gynecomastia / breast pain (less common) | E | ||||
| Vaginal bleeding | E | ||||
| Respiratory | Dyspnea (1%) | E | |||
| Urinary | Urinary symptoms (less common) | E D | |||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
Dose-limiting side effects are underlined.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
The most common side effects for medroxyprogesterone are abdominal pain, bloating, headache and anxiety.
Medroxyprogesterone can cause mild fluid retention and body weight gain, which is usually not clinically significant. The effect on body weight gain has been used therapeutically.
Medroxyprogesterone should be discontinued at the first sign of thromboembolic disorders or sudden onset of ocular problems (e.g., loss of vision, proptosis, and double vision). Patients with a history of migraine may be at increased risk of stroke.
May cause acute hypercalcemia in breast cancer patients with bone metastases during the first 2 weeks of therapy.
Exposure to medroxyprogesterone or other progestogens (in combination with estrogen) may increase the risk of breast, ovarian and cervical cancer, and is associated with an increased risk of stroke, myocardial infarction, dementia and thromboembolic disorders. The risk vs. benefit should be assessed before treatment.
Consider calcium and vitamin D supplementation in view of the risk of osteoporosis. For more information about bone health via dietary and lifestyle measures, see pamphlet, "Bone Health in Post Menopausal Women".
Refer to protocol by which patient is being treated.
Oral:
- Endometrial cancer: 200 to 400mg/day PO
- Breast Cancer: 400mg/day given in divided doses
Intramuscular injections:
- Renal and endometrial cancer: 400-1000mg / week intramuscularly (decrease to 400mg / month when stable)
- Breast cancer: 500mg/day intramuscularly for 28 days then 500mg intramuscularly twice per week
|
Toxicity
|
Dose
|
|
Myelosuppression
|
Continue treatment
|
|
Vaginal bleeding
|
Hold and investigate
|
|
Ophthalmic vascular disease |
Discontinue
|
|
Arterial or vascular thromboembolism |
Discontinue
|
|
↑ LFTs
|
Hold until ≤ ULN; discontinue if no recovery
|
Do not use in patients with abnormal LFTs.
No information found
No adjustment required. There is an increased risk of arterial thromboembolism and breast cancer in patients ≥ 75 years.
No data available. There are no pediatric indications.
- Oral self-administration; drug available by retail prescription.
- Depot formulation for intramuscular injections available.
- Medroxyprogesterone is not for i.v. use.
- patients with active or past history of significant arterial or venous thromboembolic disease, cerebrovascular disorders
- known or suspected pregnancy
- undiagnosed vaginal and/or urinary tract bleeding
- progestin dependent neoplasia, undiagnosed breast pathology
- liver dysfunction or disease
- preexisting ophthalmic vascular disease
- known hypersensitivity to medroxyprogesterone or any of its other ingredients
- use with caution in patients with migraines,
- epilepsy,
- depression,
- severe cardiovascular disorders or diabetes,
- patients with galactose/lactose intolerance/malabsorption
-
Embryotoxicity:
Yes
May be carcinogenic. Medroxyprogesterone is not recommended for use in pregnancy. Adequate contraception should be used by both sexes during treatment, and for at least 6 months after the last dose.
-
Excretion into breast milk:
Documented in humans
Breastfeeding is not recommended. Effects on the nursing infant is not significant but the long term effects of exposure on the infant are unknown.
Medroxyprogesterone is metabolized primarily by CYP3A4. The clinical significance of drug interactions with CYP3A4 inhibitors and inducers has not been studied.
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| Amino-glutethimide | ↓ medroxyprogesterone concentration and/or efficacy | Aminoglutethimide increases hepatic metabolism of medroxyprogesterone | Caution and monitor; clinical significance not known |
| CYP3A4 inducers (i.e. phenytoin, rifampin, dexamethasone, carbamazepine, phenobarbital, St. John’s Wort, etc) | ↓ medroxyprogesterone concentration and/or efficacy | ↑ hepatic metabolism of medroxyprogesterone | Caution and monitor |
| CYP3A4 inhibitors (i.e. ketoconazole, clarithromycin, ritonavir, fruit or juice from grapefruit, Seville oranges or starfruit) | ↑ medroxyprogesterone concentration and/or toxicity | ↓ metabolism of medroxyprogesterone | Caution and monitor for toxicity |
| Thyroid function tests | ↑ total T4 (thyroxine) | ↑ thyroxine binding globulin | thyroid function unlikely to be affected |
| Monitor Type | Monitor Frequency |
|---|---|
Breast examination (including mammography and self-examination) |
Baseline and routine |
| Pelvic examination (including Papanocolaou smear) | Baseline and routine |
| Complete physical examination | Baseline and routine |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version and monitor for thromboembolism, hot flashes, disease flare.
| Monitor Type | Monitor Frequency |
|---|---|
Blood glucose in diabetes |
Baseline and regular |
| Liver function tests | Baseline and regular |
| Cholesterol and triglycerides | Baseline and as indicated |
| Electrolytes (calcium) | Baseline and as indicated |
Blood pressure |
Baseline and as indicated |
Cancer Drug Manual (the Manual), 1994, British Columbia Cancer Agency (BCCA).
Compendium of Pharmaceuticals and Specialities. Accessed 2007. Provera®. Canadian Pharmacists Association.
Compendium of Pharmaceuticals and Specialities. Accessed 2007. Depo-Provera®. Canadian Pharmacists Association.
Product Monograph: Provera ® (medroxyprogesterone acetate tablet). Pfizer Canada Inc, September 2014.
October 2017 updated adverse effects, special precautions and interactions sections
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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