Detailed View: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER)
General Disorders and Administration Site Condition: (addition to this section)
- injection site reaction, injection site pain/tenderness, injection site persistent atrophy/indentation/dimpling, lipodystrophy acquired, injection site nodule/lump. In a few instances there have been undesirable sequelae at the site of injection, such as residual lump, change in color of skin, or sterile abscess.
- …euphoria, corticoid-like effects (e.g., Cushingoid syndrome), malaise, erectile dysfunction and hypercalcemia…
- Medroxyprogesterone acetate is metabolized primarily by hydroxylation via the CYP3A4. Though no formal drug interaction trials have been conducted, concomitant administration of strong CYP3A inhibitors is expected to increase concentrations of medroxyprogesterone acetate, whereas the concomitant administration of strong CYP3A inducers is expected to decrease medroxyprogesterone acetate concentrations. Therefore, coadministration with strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) or strong CYP3A inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. John’s Wort) should be avoided.
Carcinogenesis, Mutagenesis, Impairment of Fertility
- Long-term intramuscular administration of Medroxyprogesterone acetate (MPA) has been shown to produce mammary tumors in beagle dogs. There is no evidence of a carcinogenic effect associated with the oral administration of MPA to rats and mice.
- Medroxyprogesterone acetate was not mutagenic in a battery of in vitro or in vivo genetic toxicity assays.
- Medroxyprogesterone acetate at high doses is an anti-fertility drug and return to ovulation and fertility may be delayed after stopping treatment.
- Women who have or have had a history of breast cancer should be advised against the use of DEPO-PROVERA, as breast cancer may be hormonally sensitive. Women with a strong family history of breast cancer should be monitored with particular care.
- Monitor patients for hepatic dysfunction periodically and temporarily interrupt DEPOPROVERA Sterile Aqueous Suspension use if the patient develops hepatic dysfunction. Do not resume use until markers of liver function return to normal.
Decrease in Bone Mineral Density
- Medroxyprogesterone acetate given as 150 mg intramuscularly every three months reduces serum estrogen levels and is associated with loss of bone mineral density (BMD). This loss of BMD is of particular concern during adolescence and early adulthood, a critical period of bone accretion. It is unknown if use of Depo-Provera by younger women will reduce peak bone mass and increase the risk for osteoporotic fracture in later life. An evaluation of BMD may be appropriate in some patients who use higher doses of medroxyprogesterone acetate for long-term treatment of endometrial or renal carcinoma.
Effects on the Hypothalmic-Pituitary-Adrenal Axis
- Some patients receiving medroxyprogesterone acetate may exhibit suppressed adrenal function. Medroxyprogesterone acetate may have cortisol-like glucocorticoid activity and provide negative feedback to the hypothalamus or pituitary. This may result in decreased plasma cortisol levels, decreased cortisol secretion, and low plasma ACTH levels. The use of DEPO-PROVERA Sterile Aqueous Suspension may, due to its cortisol-like glucocorticoid activity, also produce Cushingoid symptoms such as weight gain, edema/fluid retention, and facial swelling.
- Safety and efficacy of DEPO-PROVERA for endometrial and renal carcinoma have not been established in pediatric patients.
Interference with Laboratory Tests
- The use of DEPO-PROVERA Sterile Aqueous Suspension may change the results of some laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins.
WARNINGS AND PRECAUTIONS
Loss of Bone Mineral Density
- After discontinuing Depo-Provera CI in adolescents, mean BMD loss at total hip and femoral neck did not fully recover by 60 months (240 weeks) post-treatment. Similarly, in adults, there was only partial recovery of mean BMD at total hip, femoral neck and lumbar spine towards baseline by 24 months post-treatment.
- Women who currently have or have had breast cancer should not use hormone contraceptives, including Depo-Provera CI, because breast cancer may be hormonally sensitive. Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care.