Depo-Provera Special Precautions

General: Unexpected vaginal bleeding during therapy with MPA should be investigated.
MPA may cause some degree of fluid retention, therefore, caution should be exercised in treating any patient with a pre-existing medical condition that might be adversely affected by fluid retention.
Patients with a history of treatment for clinical depression should be carefully monitored while receiving MPA therapy.
Some patients receiving MPA may exhibit a decreased glucose tolerance. Diabetic patients should be carefully observed while receiving such therapy.
The pathologist (laboratory) should be informed of the patient's use of MPA if endometrial or endocervical tissue is submitted for examination.
The physician/laboratory should be informed that use of MPA may decrease the levels of the following endocrine biomarkers: Plasma/urinary steroids (e.g., cortisol, estrogen, pregnanediol, progesterone, testosterone); Plasma/urinary gonadotropins [e.g., luteinizing hormone (LH) and follicle-stimulating hormone (FSH)]; Sex hormone-binding-globulin.
Medication should not be readministered, pending examination, if there is a sudden partial or complete loss of vision or if there is a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilloedema or retinal vascular lesions, medication should not be readministered.
MPA has not been causally associated with the induction of thrombotic or thromboembolic disorders, however, MPA is not recommended in any patient with a history of venous thromboembolism (VTE). Discontinuation of MPA is recommended in patients who develop VTE while undergoing therapy with MPA.
Meningiomas have been reported following long-term administration of progestins, including MPA. MPA should be discontinued if a meningioma is diagnosed. Caution is advised when recommending medroxyprogesterone to patients with a history of meningioma.
Additional Warnings and Precautions for Specific Use or Formulation: Contraception/Endometriosis - Injectable Formulations: Loss of Bone Mineral Density (BMD): Use of DMPA injection reduces serum estrogen levels in pre-menopausal women and is associated with a statistically significant loss of BMD as bone metabolism accommodates to a lower estrogen level. Bone loss may be greater with increasing duration of use and may not be completely reversible in some women. It is unknown if use of DMPA injection during adolescence and early adulthood, a critical period of bone accretion, will reduce peak bone mass. In both adult and adolescent females, the decrease in BMD during treatment appears to be substantially reversible after DMPA injection is discontinued and ovarian estrogen production increases (see Pharmacology: Pharmacodynamics: Clinical Studies: BMD Studies under Actions). After discontinuing Depo-Provera injection in adolescents, full recovery of mean BMD required 1.2 years at the lumbar spine, 4.6 years at the total hip and 4.6 years at the femoral neck (see Pharmacology: Pharmacodynamics: Clinical Studies: BMD Studies: BMD Recovery Post-treatment in Adolescents under Actions).
In adults, BMD was observed for a period of 2 years after DMPA injection was discontinued and partial recovery of mean BMD towards baseline was observed at total hip, femoral neck and lumbar spine (see Pharmacology: Pharmacodynamics: Clinical Studies: BMD Studies: BMD Changes in Adult Women under Actions). A large observational study of female contraceptive users showed that use of Depo-Provera injection has no effect on a woman's risk for osteoporotic or non-osteoporotic fractures (see Pharmacology: Pharmacodynamics: Clinical Studies: BMD Studies: Relationship of fracture incidence to use of DMPA injectable (150 mg IM) or non-use by women of reproductive age under Actions).
Other birth control methods or endometrial treatments should be considered in the risk/benefit analysis for the use of DMPA injection in women with osteoporotic risk factors such as: Chronic alcohol and/or tobacco use; Chronic use of drugs that can reduce bone mass, e.g., anticonvulsants or corticosteroids; Low body mass index (BMI) or eating disorder, e.g., anorexia nervosa or bulimia; Metabolic bone disease; Strong family history of osteoporosis.
It is recommended that all patients have adequate calcium and Vitamin D intake.
Contraception: Most women using DMPA injectable suspension experience disruption of menstrual bleeding patterns (e.g., irregular or unpredictable bleeding/spotting, rarely, heavy or continuous bleeding). As women continue using DMPA injectable suspension, fewer experience irregular bleeding and more experience amenorrhoea.
Long-term case-controlled surveillance of users of DMPA injectable suspension 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.
DMPA IM injectable suspension has a prolonged contraceptive effect. The median time to contraception following the last injection, for those who do conceive, is 10 months, with a range of 4 to 31 months, and is unrelated to the duration of use.
There was a tendency for women to gain weight while on therapy with DMPA.
If jaundice develops, consideration should be given to not readminister the drug.
Sexually Transmitted Infections: Women should be counseled that DMPA injectable suspension does not protect against sexually transmitted infections (STIs) including HIV infection (AIDS) but equally, DMPA is a sterile injection and, used as directed, will not expose them to sexually transmitted infections. Safer sex practices including correct and consistent use of condoms reduce the transmission of STIs through sexual contact, including HIV.
Breast Cancer: See as follows.
Gynecology: Treatment of Menopausal Vasomotor Symptoms/Opposition of Endometrial Effects of Estrogen in Menopausal Women Being Treated with Estrogen (Menopausal Hormone Therapy): Other doses of oral conjugated estrogens with medroxyprogesterone acetate, and other combinations and dosage forms of Menopausal Hormone Therapy (MHT) were not studied in the Women's Health Initiative (WHI) trial (see Pharmacology: Pharmacodynamics: Clinical Studies: Women's Health Initiative Study under Actions) and, in the absence of comparable data, these risks should be assumed to be similar.
Breast Cancer: The use of combined oral estrogen-progestin by post-menopausal women has been reported to increase the risk of breast cancer. Results from a randomized placebo-controlled trial, the WHI trial, and epidemiological studies (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions) have reported an increased risk of breast cancer in women taking estrogen-progestin combinations for MHT for several years. In the WHI conjugated equine estrogens (CEE) plus MPA trial and observational studies, the excess risk increased with duration of use (see Dosage & Administration). The use of estrogen plus progestin has also been reported to result in an increase in abnormal mammograms requiring further evaluation.
A large meta-analysis of observational studies reported that when estrogen 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 estrogen-progestin for MHT becomes apparent after about1-4 years.
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 only a few 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.
Cardiovascular Disorders: Estrogens with or without progestins should not be used for the prevention of cardiovascular disease. Several randomized, prospective trials on the long-term effects (see Dosage & Administration) of a combined estrogen-progestin regimen in post-menopausal women have reported an increased risk of cardiovascular events, such as myocardial infarction, coronary heart disease, stroke, and venous thromboembolism.
Coronary Artery Disease: There is no evidence from randomized controlled trials of cardiovascular benefit with continuous combined conjugated estrogen and medroxyprogesterone acetate (MPA). Two large clinical trials [WHI CEE/MPA and Heart and Estrogen-progestin Replacement Study (HERS) (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions)] showed a possible increased risk of cardiovascular morbidity in the first year of use and no overall benefit.
In the WHI CEE/MPA trial, an increased risk of coronary heart disease (CHD) events (defined as non-fatal myocardial infarction and CHD death) was observed in women receiving CEE/MPA compared to women receiving placebo (37 vs. 30 per 10,000 person-years). The increase in VTE risk was observed in year one and persisted over the observation period (see Dosage & Administration).
Stroke: In the WHI CEE/MPA trial, an increased risk of stroke was observed in women receiving CEE/MPA compared to women receiving placebo (29 vs. 21 per 10,000 person-years). The increase in risk was observed in year one and persisted over the observation period (see Dosage & Administration).
Venous thromboembolism/Pulmonary embolism: HT is associated with a higher relative risk of developing venous thromboembolism (VTE), i.e., deep vein thrombosis or pulmonary embolism. In the WHI CEE/MPA trial, a 2-fold greater rate of VTE, including deep venous thrombosis and pulmonary embolism was observed in women receiving CEE/MPA compared to women receiving placebo. The increase in risk was observed in year one and persisted over the observation period (see Precautions).
Dementia: The Women's Health Initiative Memory Study (WHIMS) (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions), an ancillary study of WHI CEE/MPA reported an increased risk of developing probable dementia in post-menopausal women 65 years of age or older. In addition, CEE/MPA therapy did not prevent mild cognitive impairment (MCI) in these women. Use of menopausal hormone therapy (MHT) to prevent dementia or MCI in women 65 years or older is not recommended.
Ovarian Cancer: Current use of estrogen-alone or estrogen plus progestin products in post-menopausal women for five or more years has been associated with an increased risk of ovarian cancer in some epidemiological studies. Past users of estrogen-alone or estrogen plus progestin products were at no increased risk for ovarian cancer. Other studies did not show a significant association. The WHI CEE/MPA trial reported that estrogen plus progestin increased the risk of ovarian cancer, but this risk was not statistically significant. In one study, women who use MHT are at increased risk of fatal ovarian cancer.
History and Physical Exam Recommendation: A complete medical and family history should be taken before the initiation of any hormone therapy. Pretreatment and periodic physical examinations should include special reference to blood pressure, breasts, abdomen, and pelvic organs, including cervical cytology.
Gynecology-Injectable Formulations: Prolonged anovulation with amenorrhoea and/or erratic menstrual patterns may follow the administration of either a single or multiple injectable doses of DMPA.
Oncology: MPA may produce Cushingoid symptoms.
Some patients receiving MPA may exhibit suppressed adrenal function. MPA may decrease ACTH and hydrocortisone blood levels.
The physician/laboratory should be informed that in addition to the endocrine biomarkers listed in Precautions, the use of MPA 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.
Oncology-injectable Formulations: Prolonged anovulation with amenorrhoea and/or erratic menstrual patterns may follow the administration of either a single or multiple injectable doses of DMPA.
High Dose Parenteral Formulations (e.g., oncology use in pre-menopausal women): Decrease in Bone Mineral Density: There are no studies on the bone mineral density (BMD) effects of high doses of parenteral DMPA (e.g., for oncology use). An evaluation of BMD may be appropriate in some patients who use MPA long-term, (see previously mentioned - Loss of Bone Mineral Density).
Effects on Ability to Drive and Use Machines: The effect of medroxyprogesterone acetate on the ability to drive and use machinery has not been systematically evaluated.