2.5 mg, 5 mg, 10 mg
For the use of a Registered Medical Practitioner or a Hospital or a Institution only.
MIPROX (Medroxyprogesterone acetate) is progestogen structurally related to progesterone, with actions and uses similar to those of the progestogens. Chemically, Medroxyprogesterone acetate is 17-Hydroxy-6∝-methylpregn-4-ene-3,20-dione acetate. The molecular formula is C24H34O4 and molecular weight is 386.53.
STRUCTURAL FORMULA :
Its structural formula is :
MIPROX-5 tablets are white in colour, round, beveled, scored and debosed with PRP on one side.
MIPROX-10 tablets are white in colour, round, beveled, scored and debosed with PRP on one side.
Each uncoated tablet contains :
Medroxyprogesterone Acetate USP 5 mg
Each uncoated tablet contains :
Medroxyprogesterone Acetate USP 10 mg
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 the drug 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 specific investigation on the absolute bioavailability of medroxyprogesterone acetate in humans has been conducted. Medroxyprogesterone acetate is rapidly absorbed from the gastrointestinal tract, and maximum medroxyprogesterone acetate concentrations are obtained between 2 to 4 hours after oral administration. Administration of medroxyprogesterone acetate with food increases the bioavailability of medroxyprogesterone acetate. A 10 mg dose of medroxyprogesterone acetate, taken immediately before or after a meal, increased medroxyprogesterone acetate Cmax (50 to 70 %) and AUC (18 to 33 %). The half-life of medroxyprogesterone acetate was not changed with food.
Medroxyprogesterone acetate is approximately 90 % protein bound, primarily to albumin; no medroxyprogesterone acetate binding occurs with sex hormone binding globulin.
Following oral dosing, medroxyprogesterone acetate is extensively metabolized in the liver via hydroxylation, with subsequent conjugation and elimination in the urine.
Most medroxyprogesterone acetate metabolites are excreted in the urine as glucuronide conjugates with only minor amounts excreted as sulfates.
Special Populations :
Renal Insufficiency :
The pharmacokinetics of medroxyprogesterone acetate in patients with varying degrees of renal insufficiency have not been investigated.
Hepatic Insufficiency :
Medroxyprogesterone acetate is almost exclusively eliminated via hepatic metabolism.
MIPROX contains a progestin indicated for the treatment of secondary amenorrhoea and abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology, such as fibroids or uterine cancer. Medroxyprogesterone acetate is also indicated to reduce the incidence of endometrial hyperplasia in nonhysterectomized postmenopausal women receiving daily oral conjugated oestrogens 0.625 mg tablets.
For oral use.
Secondary Amenorrhoea :
MIPROX may be given in dosages of 5 or 10 mg daily for 5 to 10 days. A dose for inducing an optimum secretory transformation of an endometrium that has been adequately primed with either endogenous or exogenous oestrogen is 10 mg of medroxyprogesterone acetate daily for 10 days. In cases of secondary amenorrhoea, therapy may be started at any time. Progestin withdrawal bleeding usually occurs within three to seven days after discontinuing medroxyprogesterone acetate therapy.
Abnormal Uterine Bleeding Due to Hormonal Imbalance in the Absence of Organic Pathology :
Beginning on the calculated 16th or 21st day of the menstrual cycle, 5 or 10 mg of medroxyprogesterone acetate may be given daily for 5 to 10 days. To produce an optimum secretory transformation of an endometrium that has been adequately primed with either endogenous or exogenous oestrogen, 10 mg of medroxyprogesterone acetate daily for 10 days beginning on the 16th day of the cycle is suggested. Progestin withdrawal bleeding usually occurs within three to seven days after discontinuing therapy with medroxyprogesterone acetate. Patients with a past history of recurrent episodes of abnormal uterine bleeding may benefit from planned menstrual cycling with medroxyprogesterone acetate.
Reduction of Endometrial Hyperplasia in Postmenopausal Women Receiving Daily 0.625 mg Conjugated Oestrogens :
When oestrogen is prescribed for a postmenopausal woman with a uterus, a progestin should also be initiated to reduce the risk of endometrial cancer. A woman without a uterus does not need progestin. Use of oestrogen, alone or in combination with a progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Patients should be re-evaluated periodically as clinically appropriate (for example, 3-month to 6-month intervals) to determine if treatment is still necessary. For women who have a uterus, adequate diagnostic measures, such as endometrial sampling, when indicated, should be undertaken to rule out malignancy in cases of undiagnosed persistent or recurring abnormal vaginal bleeding.
MIPROX may be given in dosages of 5 or 10 mg daily for 12 to 14 consecutive days per month, in postmenopausal women receiving daily 0.625 mg conjugated oestrogens, either beginning on the 1st day of the cycle or the 16th day of the cycle. Patients should be started at the lowest dose. The lowest effective dose of medroxyprogesterone acetate has not been determined.
Medroxyprogesterone acetate should not be used in women with any of the following
1. Undiagnosed abnormal genital bleeding.
2. Known, suspected, or history of cancer of the breast.
3. Known or suspected oestrogen- or progesterone-dependent neoplasia.
4. Active deep vein thrombosis, pulmonary embolism or a history of these conditions.
5. Active or recent (within the past year) arterial thromboembolic disease (for example, stroke and myocardial infarction).
6. Known liver dysfunction or disease.
7. Missed abortion.
8. As a diagnostic test for pregnancy.
9. Known hypersensitivity to the ingredients in medroxyprogesterone acetate tablets.
10. Known or suspected pregnancy.
See BOXED WARNINGS.
1. Cardiovascular Disorders :
An increased risk of stroke, deep vein thrombosis (DVT), pulmonary embolism and myocardial infarction has been reported with oestrogen plus progestin therapy. Should any of these events occur or be suspected, oestrogen plus progestin therapy should be discontinued immediately. Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia and obesity) and/or venous thromboembolism (for example, personal history or family history of venous thromboembolism [VTE]), obesity and systemic lupus erythematosus should be managed appropriately.
a. Stroke :
In the oestrogen plus progestin substudy of the Women’s Health Initiative (WHI) a statistically significant increased risk of stroke was reported in women receiving daily conjugated oestrogens (CE 0.625 mg) plus medroxyprogesterone acetate (MPA 2.5 mg) compared to women receiving placebo (31 versus 24 per 10,000 women-years). The increase in risk was demonstrated after the first year and persisted.
b. Coronary heart disease :
In the oestrogen plus progestin substudy of WHI, no statistically significant increase of CHD events (defined as non-fatal myocardial infarction [MI], silent MI or CHD death was reported in women receiving CE/MPA compared to women receiving placebo (39 versus 33 per 10,000 women-years). An increase in relative risk was demonstrated in year one, and a trend toward decreasing relative risk was reported in years 2 through 5. In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years), in a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Oestrogen/Progestin Replacement Study [HERS]), treatment with daily CE 0.625 mg/MPA 2.5 mg per day demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE/MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the CE/MPA-treated group than in the placebo group in year 1, but not during the subsequent years. Two thousand three hundred and twenty one (2,321) women from the original HERS trial agreed to participate an open label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the CE/MPA group and the placebo group in HERS, HERS II and overall.
c. Venous thromboembolism (VTE) :
In the oestrogen plus progestin substudy of WHI, a statistically significant two-fold greater rate of VTE, (DVT and pulmonary embolism [PE]), was reported in women receiving daily CE/MPA compared to women receiving placebo (35 versus 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 versus 13 per 10,000 women-years) and PE (18 versus 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was observed during the first year and persisted.
2. Malignant Neoplasms :
a. Breast cancer :
The use of oestrogens and progestins by postmenopausal women has been reported to increase the risk of breast cancer in some studies. Observational studies have also reported an increased risk of breast cancer for oestrogen plus progestin therapy, and a smaller increased risk for oestrogen alone therapy, after several years of use. The risk increased with duration of use and appeared to return to baseline in about 5 years after stopping treatment (only the observational studies have substantial data on risk after stopping). Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with oestrogen plus progestin therapy as compared to oestrogen alone therapy. However, these studies have not found significant variation in the risk of breast cancer among different oestrogens or among different oestrogen plus progestin combinations, doses, or routes of administration. The most important randomized clinical trial providing information about this issue is the Women’s Health Initiative (WHI) substudy of daily conjugated oestrogens (CE 0.625 mg) plus medroxyprogesterone acetate (MPA 2.5 mg).
In the oestrogen plus progestin substudy of WHI, after a mean follow-up of 5.6 years, the WHI substudy reported an increased risk of breast cancer in women who took daily CE/MPA. In this substudy, prior use of oestrogen alone or oestrogen plus progestin therapy was reported by 26 percent of the women. The relative risk of invasive breast cancer was 1.24 (95 percent nominal confidence interval [nCI], 1.01-1.54), and the absolute risk was 41 versus 33 cases per 10,000 women-years, for oestrogen plus progestin compared with placebo, respectively. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 versus 25 cases per 10,000 women-years, for CE/MPA compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 versus 36 cases per 10,000 women-years, for oestrogen plus progestin compared with placebo. In the same substudy, invasive breast cancers were larger and diagnosed at a more advanced stage in the CE/MPA group compared with the placebo group. Metastatic disease was rare with no apparent difference between the two groups. Other prognostic factors such as histologic subtype, grade, and hormone receptor status did not differ between the groups.
The use of oestrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation. All women should receive yearly breast examinations by a health care provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.
b. Endometrial cancer :
An increased risk of endometrial cancer has been reported with the use of unopposed oestrogen therapy in women with a uterus. The reported endometrial cancer risk among unopposed oestrogen users is about 2- to 12 times greater than in nonusers, and appears dependent on duration of treatment and on oestrogen dose. Most studies show no significant increased risk associated with the use of oestrogens for less than 1 year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for 5 to 10 years or more. This risk has been shown to persist for at least 8 to 15 years after oestrogen therapy is discontinued. Clinical surveillance of all women using oestrogen plus progestin therapy is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of natural oestrogens results in a different endometrial risk profile than synthetic oestrogens of equivalent oestrogen dose. Adding a progestin to oestrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.
c. Ovarian cancer :
The oestrogen plus progestin substudy of WHI reported that daily CE/MPA increased the risk of ovarian cancer. After an average follow- up of 5.6 years, the relative risk for ovarian cancer for CE/MPA versus placebo was 1.58 (95 percent nCI, 0.77-3.24) but was not statistically significant. The absolute risk for CE/MPA was 4.2 versus 2.7 cases per 10,000 women-years.
3. Dementia :
In the oestrogen plus progestin Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, a population of 4,532 postmenopausal women aged 65 to 79 years was randomized to daily conjugated oestrogens (CE 0.625 mg) plus medroxyprogesterone acetate (MPA 2.5 mg) or placebo. After an average follow-up of 4 years, 40 women in the CE/MPA group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE/MPA versus placebo was 2.05 (95 percent CI, 1.21-3.48). The absolute risk of probable dementia for CE/MPA versus placebo was 45 versus 22 cases per 10,000 women-years. It is unknown whether these findings apply to younger postmenopausal women.
4. Visual Abnormalities :
Discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia or migraine. If examination reveals papilloedema or retinal vascular lesions, medication should be permanently discontinued.
1. Addition of a progestin when a woman has not had a hysterectomy :
Studies of the addition of a progestin for 10 or more days of a cycle of oestrogen administration, or daily with oestrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by oestrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer. There are, however, possible risks that may be associated with the use of progestins with oestrogens compared to oestrogen-alone regimens. These include a possible increased risk of breast cancer, adverse effects on lipoprotein metabolism (lowering HDL, raising LDL) and impairment of glucose tolerance.
2. Undiagnosed abnormal vaginal bleeding :
In cases of undiagnosed abnormal vaginal bleeding, adequate diagnostic measures are indicated.
3. Elevated blood pressure :
Blood pressure should be monitored at regular intervals with oestrogen plus progestin therapy.
4. Hypertriglyceridaemia :
In patients with pre-existing hypertriglyceridaemia, oestrogen plus progestin therapy may be associated with elevations of plasma triglycerides leading to pancreatitis and other complications.
5. Impaired liver function and past history of cholestatic jaundice :
Oestrogens plus progestins may be poorly metabolized in patients with impaired liver function. For patients with a history of cholestatic jaundice associated with past oestrogen use or with pregnancy, caution should be exercised, and in the case of recurrence, medication should be discontinued.
6. Fluid Retention :
Progestins may cause some degree of fluid retention. Patients who have conditions which might be influenced by this factor, such as cardiac or renal dysfunction, warrant careful observation when oestrogen plus progestin are prescribed.
7. Hypocalcaemia :
Oestrogen plus progestin therapy should be used with caution in individuals with severe hypocalcaemia.
8. Exacerbation of other conditions :
Oestrogen plus progestin therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus and hepatic haemangiomas and should be used with caution in women with these conditions.
Pregnancy : Category X
Medroxyprogesterone acetate should not be used during pregnancy. (See CONTRAINDICATIONS.) There may be increased risks for hypospadias, clitoral enlargement and labial fusion in children whose mothers are exposed to medroxyprogesterone acetate during the first trimester of pregnancy. However, a clear association between these conditions with use of medroxyprogesterone acetate has not been established.
Nursing mothers :
Medroxyprogesterone acetate should not be used during lactation. Detectable amounts of progestin have been identified in the milk of nursing mothers receiving progestins.
Paediatric Use :
Medroxyprogesterone acetate is not intended for paediatric use and no clinical data has been collected in children.
Geriatric Use :
Of the total number of subjects in the oestrogen plus progestin substudy of the Women’s Health Initiative (WHI), 44 percent (n = 7,320) were 65 years and older, while 6.6 percent (n = 1,095) were 75 years and older. In women 75 and older compared to women less than 75 years of age, there was a higher relative risk of non-fatal stroke and invasive breast cancer in the oestrogen plus progestin group versus placebo. In women greater than 75 years of age, the increased risk of non-fatal stroke and invasive breast cancer observed in the oestrogen plus progestin group compared to placebo was 75 versus 24 per 10,000 women-years and 52 versus 12 per 10,000 women-years, respectively.
In the oestrogen plus progestin Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, a population of 4,532 postmenopausal women, aged 65 to 70 years, was randomized to receive daily CE 0.625 mg/MPA 2.5 mg or placebo. In the oestrogen plus progestin group, after an average follow-up of 4 years, the relative risk (CE/MPA versus placebo) of probable dementia was 2.05 (95 percent CI, 1.21-3.48). The absolute risk of developing probable dementia with CE/MPA was 45 versus 22 cases per 10,000 women-years compared with placebo. Eighty-two percent of the cases of probable dementia occurred in women that were older than 70 in the CE/MPA group. The most common classification of probable dementia in the oestrogen plus progestin and placebo groups was Alzheimer’s disease. When data from the oestrogen alone and oestrogen plus progestin WHIMS substudies were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent CI, 1.19-2.60). Since both substudies were conducted in women aged 65 to 79 years, it is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNINGS and WARNINGS, Dementia.)
DRUG/LABORATORY TEST INTERACTIONS :
1. Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of anti- factor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity ; increased plasminogen antigen and activity.
2. Increased thyroid binding globulin (TBG) levels leading to increased circulating total thyroid hormone levels as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay), or T3 levels by radioimmunoassay . T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Patients on thyroid replacement therapy may require higher doses of thyroid hormone.
3. Other binding proteins may be elevated in serum, i.e., corticosteroid binding globulin (CBG), sex hormone binding globulin (SHBG), leading to increased total circulating corticosteroids and sex steroids, respectively. Free hormone concentrations may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).
4. Increased plasma HDL and HDL2 cholesterol subfraction concentrations, reduced LDL cholesterol concentration, increased triglyceride levels.
5. Impaired glucose tolerance.
6. Reduced response to metyrapone test.
7. Aminoglutethimide administered concomitantly with medroxyprogesterone acetate may significantly depress the bioavailability of medroxyprogesterone acetate.
SIDE EFFECTS :
See BOXED WARNINGS, WARNINGS and PRECAUTIONS.
The following adverse reactions have been reported in women taking progestins, including medroxyprogesterone acetate tablets, without concomitant oestrogens treatment :
1. Genitourinary System :
Abnormal uterine bleeding (irregular, increase, decrease), change in menstrual flow, breakthrough bleeding, spotting, amenorrhoea, changes in cervical erosion and cervical secretions.
2. Breasts :
Breast tenderness, mastodynia or galactorrhoea has been reported.
3. Cardiovascular :
Thromboembolic disorders including thrombophlebitis and pulmonary embolism have been reported.
4. Gastrointestinal :
Nausea, cholestatic jaundice.
5. Skin :
Sensitivity reactions consisting of urticaria, pruritus, oedema and generalized rash have occurred. Acne, alopecia and hirsutism have been reported.
6. Eyes :
Neuro-ocular lesions, for example, retinal thrombosis, and optic neuritis.
7. Central Nervous System :
Mental depression, insomnia, somnolence, dizziness, headache, nervousness.
8. Miscellaneous :
Hypersensitivity reactions (for example, anaphylaxis and anaphylactoid reactions, angiooedema), rash (allergic) with and without pruritus, change in weight (increase or decrease), pyrexia, oedema/fluid retention, fatigue, decreased glucose tolerance.
The following additional adverse reactions have been reported with oestrogen and/or progestin therapy :
1. Genitourinary System :
Abnormal uterine bleeding/spotting, or flow; breakthrough bleeding; spotting; dysmenorrhoeal/pelvic pain; increase in size of uterine leiomyomata; vaginitis, including vaginal candidiasis; change in amount of cervical secretion; changes in cervical ectropion; ovarian cancer; endometrial hyperplasia; endometrial cancer.
2. Breasts :
Tenderness, enlargement, pain, nipple discharge, galactorrhoea; fibrocystic breast changes; breast cancer.
3. Cardiovascular :
Deep and superficial venous thrombosis; pulmonary embolism; thrombophlebitis; myocardial infarction; stroke; increase in blood pressure.
4. Gastrointestinal :
Nausea, vomiting; abdominal cramps, bloating; cholestatic jaundice; increased incidence of gallbladder disease; pancreatitis; enlargement of hepatic haemangiomas.
5. Skin :
Chloasma or melasma that may persist when drug is discontinued; erythema multiforme; erythema nodosum; haemorrhagic eruption; loss of scalp hair; hirsutism; pruritus, rash.
6. Eyes :
Retinal vascular thrombosis, intolerance to contact lenses.
7. Central Nervous System :
Headache; migraine; dizziness; mental depression; chorea; nervousness; mood disturbances; irritability; exacerbation of epilepsy, dementia.
8. Miscellaneous :
Increase or decrease in weight; reduced carbohydrate tolerance; aggravation of porphyria; oedema; arthralgias; leg cramps; changes in libido; urticaria, angiooedema, anaphylactoid/anaplylactic reactions; hypocalcaemia; exacerbation of asthma; increased triglycerides.
INFORMATION FOR PATIENTS :
Physicians are advised to discuss the Patient Information leaflet with patients for whom they prescribe medroxyprogesterone acetate. There may be an increased risk of minor birth defects in children whose mothers are exposed to progestins during the first trimester of pregnancy. The possible risk to the male baby is hypospadias, a condition in which the opening of the penis is on the underside rather than the tip of the penis. This condition occurs naturally in approximately 5 to 8 per 1,000 male births. The risk may be increased with exposure to medroxyprogesterone acetate. Enlargement of the clitoris and fusion of the labia may occur in female babies. However, a clear association between hypospadias, clitoral enlargement and labial fusion with use of medroxyprogesterone acetate has not been established. Inform the patient of the importance of reporting exposure to medroxyprogesterone acetate in early pregnancy.
Overdosage of oestrogen plus progestin therapy may cause nausea and vomiting, breast tenderness, dizziness, abdominal pain, drowsiness/fatigue and withdrawal bleeding may occur in women.
TREATMENT OF OVERDOSAGE :
Treatment of overdose consists of discontinuation of CE/MPA together with institution of appropriate symptomatic care.
Store in a cool dry place below 30oC protected from moisture and light.
SHELF LIFE :
36 months from the date of manufacture.
MIPROX contains Medroxyprogesterone Acetate USP 5 mg/10 mg.
1 blister of 10 Tablets per Box.
Disclaimer : For the use of a Registered Medical Practitioner or a Hospital or a Institution only. Also it is not intended to be used by healthcare professionals or patients for the purpose of prescribing or administering these products. Questions regarding the complete and current content of product labeling / specification / presentation should be directed to SGPharma.