Depo-Provera (Medroxyprogesterone Acetate)

DEPO-PROVERA®

Pharmacia & Upjohn

Medroxyprogesterone Acetate

Progestogen

Action And Clinical Pharmacology: Medroxyprogesterone acetate is a long-acting progestational steroid (progestogen) derived from a natural source (soybeans). Its long duration of action is a result of slow absorption from the injection site. Depo-Provera does not contain estrogen.

For conception control, medroxyprogesterone inhibits the secretion of gonadotropins which, in turn, prevents follicular maturation and ovulation, and results in endometrial thinning. Additional progestational effects that may contribute to the contraceptive effectiveness of medroxyprogesterone include the transformation and maintenance of an endometrium hostile to implantation, and thickening of cervical mucus making sperm penetration of the cervix more difficult.

Medroxyprogesterone administered parenterally to women with adequate endogenous estrogen transforms proliferative endometrium into secretory endometrium.

The anticancer activity of medroxyprogesterone at pharmacologic doses may be dependent on its effect on the hypopituitary/gonadal axis, estrogen receptors and the metabolism of steroids at the tissue level.

Following a single 150 mg i.m. dose of Depo-Provera, medroxyprogesterone acetate (MPA) concentrations, measured by an extracted radioimmunoassay procedure, increase for approximately 3 weeks to reach peak plasma concentrations of 1 to 7 ng/mL.

The principal metabolite of medroxyprogesterone acetate that has been identified is a 6a-methyl-6b, 17a, 21-trihydroxy-4-pregnene-3, 20-dione-17-acetate, which is excreted in the urine.

Medroxyprogesterone is approximately 90 to 95% protein bound. It crosses the blood-brain barrier and is secreted in breast milk.

The effect of hepatic and/or renal disease on the pharmacokinetics of medroxyprogesterone is unknown.

Indications And Clinical Uses: Conception control (prevention of pregnancy). Treatment of endometriosis. Adjunctive and/or palliative treatment of recurrent and/or metastatic endometrial or renal cell carcinoma (hypernephroid carcinomas). Adjunctive or palliative treatment of hormonally-dependent, recurrent inoperable, or metastatic carcinoma of the breast in postmenopausal women.

Contra-Indications: Not for i.v. use.

Medroxyprogesterone is contraindicated in women with: Known or suspected pregnancy or as a diagnostic test for pregnancy. Undiagnosed vaginal and/or urinary tract bleeding. Undiagnosed breast pathology. Thrombophlebitis, thromboembolic disorders, cerebral apoplexy or women with a past history of these conditions. Liver dysfunction or disease. Known hypersensitivity to medroxyprogesterone or any of its other ingredients.

Manufacturers’ Warnings In Clinical States: Irregular Menstrual Patterns: Disruption of menstrual patterns is common following the administration of medroxyprogesterone. This includes irregular or unpredictable bleeding or spotting, or rarely heavy or continuous bleeding. If undiagnosed vaginal bleeding occurs, or if abnormal bleeding persists or is severe, appropriate investigation should be instituted to rule out the possibility of organic pathology, and appropriate treatment instituted if necessary.

As women continue to use medroxyprogesterone, fewer experience irregular bleeding patterns and more experience amenorrhea. By month 12, amenorrhea was reported by 55% of women, and by month 24 amenorrhea was reported by 68% of women using medroxyprogesterone.

Because of the prolonged effect following i.m. injection of medroxyprogesterone, re-establishment of menstruation may be delayed and difficult to predict. For this reason, medroxyprogesterone is not recommended for treatment of secondary amenorrhea or functional uterine bleeding. For these conditions, oral progestogen therapy is recommended.

Bone Mineral Density Changes: Medroxyprogesterone may be a risk factor for osteoporosis, similar to race, family history, low weight/height ratio, sedentary lifestyle and smoking. Until further information is available, risk factors for osteoporosis should be reviewed, and bone density measurements should be obtained for women with multiple risk factors, especially if the drug is being considered for long-term use. It may be advisable to consider alternate methods for women with bone density measurements in the lower normal range.

Physiologically, although medroxyprogesterone slows the loss of bone density in postmenopausal women due to its anabolic effects, in premenopausal women, it suppresses estrogen production which may lead to a loss of bone density. One study conducted in New Zealand showed a relative decrease in bone density in long-term users of medroxyprogesterone. The level of bone density decrease did not meet the criteria for diagnosis of osteoporosis (>2.5 standard deviations below the mean) and no fractures were reported. The effect appeared to be reversible upon discontinuation. Further prospective study, which is ongoing, is needed to clarify this issue.

Risk of Malignancy: Long-term case-controlled surveillance of users of medroxyprogesterone found slight or no increased overall risk of breast cancer and no overall increased risk of ovarian, liver, or cervical cancer and a prolonged, protective effect of reducing the risk of endometrial cancer in the population of users.

The World Health Organization Study, a component of a pooled analysis, showed an increased RR of 2.19 (95% CI 1.23 to 3.89) of breast cancer associated with use of medroxyprogesterone in women whose first exposure to drug was within the previous 4 years and who were under 35 years of age. However, the overall RR for women who have ever used medroxyprogesterone was only 1.2 (95% CI 0.96 to 1.52).

[Note: An RR of 1.0 indicates neither an increased nor a decreased risk of cancer associated with the use of the drug, relative to no use of the drug. In the case of the subpopulation with a RR of 2.19, the 95% CI is fairly wide and does not include the value of 1.0, thus inferring an increased risk of breast cancer in the defined subgroup relative to nonusers. The value of 2.19 means that women whose first exposure to drug was within the previous 4 years and who are under 35 years of age have a 2.19-fold (95% CI 1.23 to 3.89-fold) increased risk of breast cancer relative to nonusers. The National Cancer Institute reports an average annual incidence rate for breast cancer for U.S. women, all races, age 30 to 34 years of 26.7/100 000. An RR of 2.19, thus, increases the possible risk from 26.7 to 58.5 cases/100 000 women. The attributable risk, thus, is 31.8 per 100 000 women/year.]

A statistically insignificant increase in RR estimates of invasive squamous-cell cervical cancer has been associated with the use of medroxyprogesterone in women who were first exposed before the age of 35 years (RR 1.22 to 1.28 and 95% CI 0.93 to 1.70). The overall, nonsignificant relative rate of invasive squamous-cell cervical cancer in women who ever used medroxyprogesterone contraceptive injection was estimated to be 1.11 (95% CI 0.96 to 1.29). No trends in risk with duration of use or times since initial or most recent exposure were observed.

Thromboembolic Disorders: Before prescribing medroxyprogesterone, 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 or be suspected, the drug should be discontinued immediately.

Ocular Disorders: 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 papilledema or retinal vascular lesions, medication should be withdrawn.

Return of Fertility: There is no evidence that medroxyprogesterone causes infertility. A large study of return of fertility, shows that women conceived 9 months on average after the last injection, or 5.5 months after discontinuing (discontinuance is assumed to be 15 weeks after the last injection). In addition, the number of users who had conceived within 2 years of discontinuing their method of contraception (92% of medroxyprogesterone users had conceived within 2 years after discontinuing compared with 93% for users of the IUD and 95% for users of oral contraceptives) were comparable. Discuss this information with women who intend to conceive in the next 1 to 2 years.

In some cases women have not become pregnant after stopping injections of medroxyprogesterone. It is not known whether medroxyprogesterone or other factors resulted in a change in the ability to conceive. Many reasons exist for such changes, including increased age and the onset of menopause. The infertility rate in the normal population is 7%.

Pregnancy: To increase assurance that the woman is not pregnant at the time of the first administration, it is recommended that the first injection be given only within the first 5 days of the onset of a normal menstrual period or, only within the first 5 days postpartum if not breast-feeding. If the woman has chosen to breast-feed, discuss the risk of pregnancy and possible risks of medroxyprogesterone to determine the most appropriate course of action of the individual woman (see Lactation and Dosage).

Infants from unexpected pregnancies that occurred 1 to 2 months after injection of medroxyprogesterone 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 such pregnancies are uncommon.

A significant increase incidence of polysyndactyly and chromosomal anomalies was observed among infants of users of medroxyprogesterone, the former being most pronounced in women under 30 years of age. The unrelated nature of these defects, the lack of confirmation from other studies, the distant preconceptual exposure to medroxyprogesterone and the chance effects due to multiple statistical comparisons, make a causal association unlikely.

Children exposed to medroxyprogesterone in utero and followed to adolescence, showed no evidence of any adverse effects on their health including their physical, intellectual, sexual, or social development.

Several reports suggest an association between intra-uterine exposure to progestational drugs in the first trimester of pregnancy and genital abnormalities in male and female fetuses. The risk of hypospadias (5 to 8/1 000 male births in the general population) may be approximately doubled with exposure to these drugs. Although there are insufficient data to quantify the risk to exposed female fetuses, some of these drugs induce mild virilization of the external genitalia of the female fetus. Because of these changes, it is prudent to avoid the use of progestogens during the first trimester of pregnancy.

Lactation: Detectable amounts of progestogen have been identified in the milk of mothers receiving medroxyprogesterone. Two studies have indicated that the maximum amount of medroxyprogesterone which might be ingested by a breast-feeding infant whose mother is receiving medroxyprogesterone for contraception would be 1.0 to 1.5 µg/day (or 0.0015 mg/day, 0.045 mg/month, 0.27 mg over 6 months which is about 0.05 mg/kg over 6 months for a 5.5 kg baby). If absorption properties between adult and infant are comparable, this amount would be too low to suppress pituitary function in the infant. No adverse effects related to lactation itself or infant growth were reported in studies where medroxyprogesterone was started 1 to 4 days, 7 days or within 6 weeks postpartum.

In nursing mothers treated with medroxyprogesterone, milk composition, quality and amount are not adversely affected.

To date, no adverse effects have been observed in children whose mothers were using medroxyprogesterone while lactating. A study of children exposed to MPA with median observation periods of 14 to 16 years, indicated no incidence of adverse effects on physical growth, mental growth and development of general health status. However, the long-term effects on the child are not fully understood. The physician and woman should discuss the risks of pregnancy versus the risks to the child, if medroxyprogesterone is used during lactation, to determine the most appropriate course of action for the individual woman.

Ectopic Pregnancy: Physicians should investigate the possibility of an ectopic pregnancy among women using medroxyprogesterone who complain of severe abdominal pain.

Anaphylactic Reactions: Anaphylactic and anaphylactoid reactions have occasionally been reported in women treated with medroxyprogesterone. If an anaphylactic reaction occurs, appropriate therapy should be instituted. Serious anaphylactic reactions require emergency medical treatment.

Adrenocortical Function: Clinical suppression of adrenocortical functions has not been observed at low dose levels used for contraception (ovulation suppression). However, at very high doses (500 mg daily or more) used in the treatment of certain cancers, corticoid-like activity has been reported.

Cushingoid Symptoms: The high doses of medroxyprogesterone used in the treatment of cancer may, in some cases, produce Cushingoid symptoms, e.g., moon faces and blood pressure elevation.

Precautions: General: Pretreatment Examination: Before using medroxyprogesterone, a thorough history and physical examination – including breasts, liver, pelvic organs, blood pressure determination, and Papanicolaou smear – should be performed. Periodic follow-up examinations should be conducted and include all procedures done at the initial visit.

Hepatic Function: Liver function tests should be performed periodically in women who are suspected of, or who are at risk of, having hepatic disease. The physician should be alert to the earliest manifestations of impaired liver function. Should this occur or be suspected, the treatment should not be continued. The woman’s status should be re-evaluated at appropriate intervals. If jaundice develops, consideration should be given to discontinue the drug.

Carbohydrate Metabolism: A decrease in glucose tolerance has been observed in some women receiving medroxyprogesterone. The mechanisms of this decrease is obscure. For this reason, diabetic women should be carefully observed while receiving medroxyprogesterone.

Cardiovascular Function: Medroxyprogesterone has not been shown to affect coagulation and has been associated only rarely with cardiovascular incidents (e.g., medullary infarction in a heavy smoker).

Fluid Retention: Since progestogens may cause some degree of fluid retention, conditions that might be influenced by this factor, such as epilepsy, migraine, asthma, or cardiac or renal dysfunction, require careful observation.

CNS Disorders and Convulsions: Women who have a history of mental depression should be carefully observed and this drug discontinued if serious depression reoccurs. Some women may complain of premenstrual-like depression while on medroxyprogesterone therapy. There have been few reported cases of convulsions in patients who were treated with medroxyprogesterone. Association with medroxyprogesterone use or pre-existing conditions is not clear.

Weight Changes: Weight gain may be associated with the use of medroxyprogesterone (see Adverse Effects).

Age: The age of the woman constitutes no absolute limiting factor although treatment with a progestogen may mask the onset of the climacteric.

Laboratory Tests: Certain endocrine and possibly liver function tests may be affected by treatment with medroxyprogesterone. Therefore, if such tests are abnormal in a woman taking medroxyprogesterone, it is recommended that they be repeated 6 to 12 months after the drug has been withdrawn.

The clinical chemist or pathologist should be advised of progestogen therapy when a woman’s blood or tissue specimens are submitted for laboratory diagnosis or biochemical analysis.

The following laboratory tests may be affected by the use of medroxyprogesterone: (a) Gonadotropin levels: inhibition of the midcycle LH surge. (b) Plasma progesterone levels: inhibition of ovulation and thus the postovulatory rise of progesterone. (c) Plasma estrogen levels: do not exceed early-to-mid-proliferative phase levels. (d) Plasma cortisol levels: not significantly affected by the dose used for contraception. (e) Glucose tolerance test: occasionally some degree of glucose intolerance may develop. (f) Metyrapone test: modest depression of response to metyrapone test. (g) Plasma lipid concentrations: decrease in high density lipoprotein cholesterol (HDL-C) in some studies. The clinical relevance of this has yet to be determined. (h) Urinary pregnanediol levels. (Note: Medroxyprogesterone does not interfere with the assay of human chorionic gonadotropin (HCG) either chemically or pharmacologically.)

Drug Interactions: Aminoglutethimide: Aminoglutethimide administered concomitantly with medroxyprogesterone may significantly depress the serum concentration of medroxyprogesterone. Users of medroxyprogesterone should be warned of the possibility of decreased efficacy with the use of this or any related drugs.

Rifampin: Rifampin can increase the metabolism of exogenously administered progestational agents. Norethindrone has specifically been affected; a reduction of plasma concentrations has occurred. The extent to which rifampin may alter the metabolism of other progestogens remains to be determined; the possibility of an interaction should be considered.

Conception Control: Counselling: It is very important that adequate explanations of the long-term nature of medroxyprogesterone as a contraceptive be given to each woman prior to her first injection. The possible side effects including changes in menstrual cycle and the relatively slow return of fertility should be emphasized. Every effort should be made to ensure that each woman receives such counselling as to enable her to understand fully these explanations and the possible consequences. A detailed supplementary information booklet that describes the actions, benefits, risks and adverse effects of this contraceptive should be made available to each woman before she makes the decision to use medroxyprogesterone for conception control.

Sexually Transmitted Diseases: Women should be counselled that this product offers no protection from the acquisition of sexually transmitted infections, including HIV and that latex or polyurethane condoms are recommended for this purpose.

Followup Examination: The first followup examination should be made within 6 months after medroxyprogesterone is prescribed and thereafter at least once a year. At each annual visit, the examination should include all procedures done at the initial visit.

The woman must return every 10 to 13 weeks for a repeat injection to maintain contraceptive effectiveness (see Dosage). If an injection is not given within 13 weeks, a pregnancy test should be done before any further treatment with medroxyprogesterone.

Weight Changes: The majority of studies report a mean weight gain of 2.5 kg at the end of 1 year, but only 2% of women discontinued treatment due to excessive weight gain. Many studies indicate that weight gain occurs mainly in the first year of use, however, others do report a slow and continuing increase which may reach a mean of 3.6 kg by the end of 2 years. Some 20 to 40% of medroxyprogesterone users actually lose weight during treatment.

Adverse Reactions: The following adverse reactions have been associated with the use of medroxyprogesterone: Irregular Menstrual Patterns: The most common adverse reactions associated with the use of medroxyprogesterone for contraception is the disruption of menstrual patterns. This includes irregular or unpredictable bleeding or spotting, or rarely heavy or continuous bleeding.

In U.S. studies of 3 905 women receiving medroxyprogesterone every 3 months, unpredictable bleeding or spotting were commonly reported during the first few menstrual cycles with frequency, duration and amount of bleeding diminishing gradually. By month 12, amenorrhea was reported by 55% of the women, and by month 24 amenorrhea was reported by 68% of the women using medroxyprogesterone. Bleeding or spotting persisted for more than 10 days of the month in about 12% of the users. And abnormally heavy or prolonged bleeding occurs in about 1 to 2% of users.

Nonmenstrual Adverse Reactions: Other than menstrual changes, weight gain, headache and abdominal discomfort are the most common side effects.

The U.S. studies of 3 905 women receiving medroxyprogesterone every 3 months report a mean weight gain of 2.5 kg at the end of 1 year, but only 2% of women discontinued treatment due to excessive weight gain. Many studies indicate that weight gain occurs mainly in the first year of use, however, others report a slow and continuing increase which may reach a mean of 3.6 kg by the end of 2 years. However, some 20 to 40% of medroxyprogesterone users actually lose weight during treatment.

In a few instances there have been undesirable sequelae at the site of injection, such as a residual lump, change in color of the skin or a sterile abscess.

Anaphylactic and anaphylactoid reactions have been reported on rare occasions.

The occurrence rates for nonmenstrual adverse reactions reported in U.S. studies of 3 905 women receiving medroxyprogesterone every 3 months are listed below; 2 253 women were in the study for 12 months or more; 827 women were in the study for 36 months or more. The total number of patient-months of experience was 82 384. A total of 2 117 of the 3 905 women (54%) reported no side effects.

Allergic: allergic reactions, hives (0.2 to 1.0%).

Cardiovascular: chest pain, tachycardia (0.2 to 1.0%).

CNS: headache (17%), nervousness (12%), dizziness (6%), depression (2%), insomnia, pain, somnolence or drowsiness (0.2 to 1.0%).

Dermatologic: acne, alopecia, rash (1%).

Endocrine: decreased libido (6%), breast swelling/tenderness (3%), hot flashes (1%), galactorrhea, chloasma, hirsutism (0.2 to 1.0%).

Gastrointestinal: abdominal distress (12%), nausea (4%), bloating (2%), anorexia, increased appetite, diarrhea, heartburn, abdominal swelling, vomiting, constipation (0.2 to 1.0%).

Gynecologic/Urologic: vaginal discharge (3%), dysmenorrhea (2%), pruritus vulvae (1%), genitourinary infection, dysuria, bleeding requiring D&C, dyspareunia, urinary frequency (0.2 to 1.0%).

Hepatic: liver disorders with no other symptoms, altered liver function (0.2 to 1.0%).

Metabolic: peripheral edema (2%).

Musculoskeletal: backache (2%).

Neurologic: asthenia (5%), limb pain (4%), pruritus, paresthesia or sensory disturbances (0.2 to 1.0%).

Respiratory: dyspnea (0.2 to 1.0%).

Special Senses: eye discomfort (0.2 to 1.0%).

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Overdosage may result in a period of amenorrhea of a variable length and may be followed by irregular menses for several cycles. There is no known therapy for overdosage.

Dosage And Administration: Medroxyprogesterone is intended for i.m. administration only. Immediately before use, the sterile aqueous suspension should be vigorously shaken to assure that the dose being administered represents a uniform suspension.

Conception Control (Contraception): The recommended dose for contraception is 150 mg every 3 months, administered by deep i.m. injection. To increase assurance that the woman is not pregnant at the time of the first administration, it is recommended that this injection be given only within the first 5 days of the onset of a normal menstrual period or, only within the first 5 days postpartum if not breast-feeding. If the woman has chosen to breast-feed, discuss the risks of pregnancy and possible risks of medroxyprogesterone to determine the most appropriate course of action for the individual woman (see Warnings).

If administered within the first 5 days after the onset of a normal menstrual period, medroxyprogesterone is effective from the day of injection. When medroxyprogesterone is given later in the menstrual cycle it may not be effective for the first 3 to 4 weeks after the injection and another method of contraception (nonhormonal) should be used during this time.

After miscarriage or first trimester therapeutic abortion, the injection is normally given within 5 days of the procedure and no extra precautions are required. After a late (second trimester) abortion, some further delay is recommended to reduce the risk of heavy and prolonged bleeding, therefore, the first injection should not be given until 4 weeks after the procedure.

Intervals between injections must not exceed 13 weeks (3 months).

Endometriosis: The recommended dose is 50 mg weekly or 100 mg every 2 weeks i.m. for at least 6 months. It should be noted that return of ovulation may be delayed following this therapy due to the depot properties of the drug (see Warnings).

Endometrial and Renal Carcinoma: Doses of 400 mg to 1 000 mg i.m./week are recommended initially. If improvement is noted within a few weeks or months and the disease appears stabilized, it may be possible to maintain improvement with as little as 400 mg/month. Medroxyprogesterone is not recommended as a primary therapy, but as adjunctive and palliative treatment in advanced, inoperable cases including those with recurrent or metastatic disease.

Breast Cancer: The recommended dosage schedule is 500 mg/day i.m. for 28 days. The woman should then be placed on a maintenance schedule of 500 mg twice weekly as long as she is responding to treatment. A response may not be evident until 8 to 10 weeks of therapy. If a rapid progression of disease occurs at any time during therapy, medroxyprogesterone should be terminated.

Availability And Storage: 50 mg/mL: Each mL contains: medroxyprogesterone acetate 50 mg. Nonmedicinal ingredients: methylparaben, polyethylene glycol 3350, polysorbate 80, propylparaben, sodium chloride and water for injection. Vials of 5 mL, boxes of 1.

150 mg/mL: Each mL contains: medroxyprogesterone acetate 150 mg. Nonmedicinal ingredients: methylparaben, polyethylene glycol 3350, polysorbate 80, propylparaben, sodium chloride and water for injection. Vials of 1 mL, boxes of 1 and 5.

Protect from freezing. Store at controlled room temperature 15 to 30°C. Shake well before using.

DEPO-PROVERA® Pharmacia & Upjohn Medroxyprogesterone Acetate Progestogen

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