Medroxyprogesterone Acetate

1 INDICATIONS AND USAGE Medroxyprogesterone acetate injectable suspension is indicated for use by females of reproductive potential to prevent pregnancy. Limitations of Use: The use of medroxyprogesterone acetate injectable suspension is not recommended as a long-term (i.e., longer than 2 years) birth control method unless other options are considered inadequate [see Dosage and Administration (2.1) and Warnings and Precautions (5.1) ]. Medroxyprogesterone acetate injectable suspension is a progestin indicated for use by females of reproductive potential to prevent pregnancy. ( 1 ) Limitations of Use: The use of medroxyprogesterone acetate injectable suspension is not recommended as a long-term (i.e., longer than 2 years) birth control method unless other options are considered inadequate. ( 1 , 5.1 )

2 DOSAGE AND ADMINISTRATION The recommended dose is 150 mg of medroxyprogesterone acetate injectable suspension every 3 months (13 weeks) administered by deep, intramuscular (IM) injection in the gluteal or deltoid muscle. ( 2.1 ) 2.1 Prevention of Pregnancy 1 mL vial of medroxyprogesterone acetate injectable suspension should be vigorously shaken just before use to ensure that the dose being administered represents a uniform suspension. The recommended dose is 150 mg of medroxyprogesterone acetate injectable suspension every 3 months (13 weeks) administered by deep intramuscular (IM) injection using strict aseptic technique in the gluteal or deltoid muscle, rotating the sites with every injection. As with any IM injection, to avoid an inadvertent subcutaneous injection, body habitus should be assessed prior to each injection to determine if a longer needle is necessary particularly for gluteal IM injection. Use for longer than 2 years is not recommended (unless other birth control methods are considered inadequate) due to the impact of long-term medroxyprogesterone acetate injectable suspension treatment on bone mineral density (BMD) [see Warnings and Precautions (5.1) ] . Dosage does not need to be adjusted for body weight [see Clinical Studies (14.1) ] . To ensure the patient is not pregnant at the time of the first injection, the first injection should be given ONLY during the first 5 days of a normal menstrual period or within the first 5-days post-partum. In post-partum mothers who exclusively breastfeed, administer medroxyprogesterone acetate injectable during or after the sixth post-partum week. If the time interval between injections is greater than 13 weeks, the physician should determine that the patient is not pregnant before administering the drug. The efficacy of medroxyprogesterone acetate injectable suspension depends on adherence to the dosage schedule of administration. 2.2 Switching from Other Methods of Contraception When switching from other contraceptive methods, medroxyprogesterone acetate injectable suspension should be given in a manner that ensures continuous contraceptive coverage based upon the mechanism of action of both methods, (e.g., patients switching from oral contraceptives should have their first injection of medroxyprogesterone acetate injectable suspension on the day after the last active tablet or at the latest, on the day following the final inactive tablet).

5 WARNINGS AND PRECAUTIONS Thromboembolic Disorders: Discontinue medroxyprogesterone acetate in patients who develop thrombosis. ( 5.2 ) Cancer Risks: Monitor women with a strong family history of breast cancer carefully. ( 5.3 ) Meningioma: Discontinue medroxyprogesterone acetate if meningioma is diagnosed. Monitor patients for signs and symptoms of meningioma. ( 5.4 ) Ectopic Pregnancy: Consider ectopic pregnancy if a woman using medroxyprogesterone acetate becomes pregnant or complains of severe abdominal pain. ( 5.5 ) Anaphylaxis and Anaphylactoid Reactions: Provide emergency medical treatment. ( 5.6 ) Liver Function: Discontinue medroxyprogesterone acetate if jaundice or disturbances of liver function develop. ( 5.8 ) Carbohydrate Metabolism: Monitor diabetic patients carefully. ( 5.13 ) 5.1 Loss of Bone Mineral Density Use of medroxyprogesterone acetate reduces serum estrogen levels and is associated with significant 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 medroxyprogesterone acetate by younger women will reduce peak bone mass and increase the risk for osteoporotic fracture in later life. A study to assess the reversibility of loss of BMD in adolescents was conducted with medroxyprogesterone acetate. After discontinuing medroxyprogesterone acetate in these adolescents, mean BMD loss at the total hip and femoral neck did not fully recover by 5 years (60 months) post-treatment in the sub-group of adolescents who were treated for more than 2 years [see Clinical Studies (14.3) ]. Similarly, in adults, there was only partial recovery of mean BMD at the total hip, femoral neck, and lumbar spine towards baseline by 2 years post-treatment [see Clinical Studies (14.2) ]. The use of medroxyprogesterone acetate is not recommended as a long-term (i.e., longer than 2 years) birth control method unless other options are considered inadequate. BMD should be evaluated when a woman needs to continue to use medroxyprogesterone acetate long-term. In adolescents, interpretation of BMD results should take into account patient age and skeletal maturity. Other birth control methods should be considered in the risk/benefit analysis for the use of medroxyprogesterone acetate in women with osteoporosis risk factors. Medroxyprogesterone acetate can pose an additional risk in patients with risk factors for osteoporosis (e.g., metabolic bone disease, chronic alcohol and/or tobacco use, anorexia nervosa, strong family history of osteoporosis or chronic use of drugs that can reduce bone mass such as anticonvulsants or corticosteroids). 5.2 Thromboembolic Disorders There have been reports of serious thrombotic events in women using medroxyprogesterone acetate (150 mg). However, medroxyprogesterone acetate has not been causally associated with the induction of thrombotic or thromboembolic disorders. Any patient who develops thrombosis while undergoing therapy with medroxyprogesterone acetate should discontinue treatment unless she has no other acceptable options for birth control. Do not re-administer medroxyprogesterone acetate 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. Do not re-administer if examination reveals papilledema or retinal vascular lesions. 5.3 Cancer Risks Breast Cancer Women who have or have had a history of breast cancer should not use hormonal contraceptives, including medroxyprogesterone acetate, because breast cancer may be hormonally sensitive [see Contraindications (4) ]. Women with a strong family history of breast cancer should be monitored with particular care. The results of five large case-control studies assessing the association between depo-medroxyprogesterone acetate (DMPA) use and the risk of breast cancer are summarized in Figure 1. Three of the studies suggest a slightly increased risk…

4 CONTRAINDICATIONS The use of medroxyprogesterone acetate is contraindicated in the following conditions: Active thrombophlebitis, or current or history of thromboembolic disorders, or cerebral vascular disease [see Warnings and Precautions (5.2) ] . Known or suspected malignancy of breast [see Warnings and Precautions (5.3) ] . Known hypersensitivity to medroxyprogesterone acetate injectable suspension or any of its other ingredients [see Warnings and Precautions (5.6) ] . Significant liver disease [see Warnings and Precautions (5.8) ] . Undiagnosed vaginal bleeding [see Warnings and Precautions (5.11) ] . Active thrombophlebitis, or current or past history of thromboembolic disorders, or cerebral vascular disease. ( 4 ) Known or suspected malignancy of breast. ( 4 ) Known hypersensitivity to medroxyprogesterone acetate injectable suspension (medroxyprogesterone acetate or any of its other ingredients). ( 4 ) Significant liver disease. ( 4 ) Undiagnosed vaginal bleeding. ( 4 )

7 DRUG INTERACTIONS Drugs or herbal products that induce certain enzymes, including CYP3A4, may decrease the effectiveness of contraceptive drug products. Counsel patients to use a back-up method or alternative method of contraception when enzyme inducers are used with medroxyprogesterone acetate. ( 7.1 ) 7.1 Changes in Contraceptive Effectiveness Associated with Co-Administration of Other Products If a woman on hormonal contraceptives takes a drug or herbal product that induces enzymes, including CYP3A4, that metabolize contraceptive hormones, counsel her to use additional contraception or a different method of contraception. Drugs or herbal products that induce such enzymes may decrease the plasma concentrations of contraceptive hormones, and may decrease the effectiveness of hormonal contraceptives. Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include: barbiturates bosentan carbamazepine felbamate griseofulvin oxcarbazepine phenytoin rifampin St. John’s wort topiramate HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors : Significant changes (increase or decrease) in the plasma levels of progestin have been noted in some cases of co-administration of HIV protease inhibitors. Significant changes (increase or decrease) in the plasma levels of the progestin have been noted in some cases of co-administration with non-nucleoside reverse transcriptase inhibitors. Antibiotics : There have been reports of pregnancy while taking hormonal contraceptives and antibiotics, but clinical pharmacokinetic studies have not shown consistent effects of antibiotics on plasma concentrations of synthetic steroids. Consult the labeling of all concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations. 7.2 Laboratory Test Interactions The pathologist should be advised of progestin therapy when relevant specimens are submitted. The following laboratory tests may be affected by progestins including medroxyprogesterone acetate: (a) Plasma and urinary steroid levels are decreased (e.g., progesterone, estradiol, pregnanediol, testosterone, cortisol). (b) Gonadotropin levels are decreased. (c) Sex-hormone-binding-globulin concentrations are decreased. (d) Protein-bound iodine and butanol extractable protein-bound iodine may increase. T 3 -uptake values may decrease. (e) Coagulation test values for prothrombin (Factor II), and Factors VII, VIII, IX, and X may increase. (f) Sulfobromophthalein and other liver function test values may be increased. (g) The effects of medroxyprogesterone acetate on lipid metabolism are inconsistent. Both increases and decreases in total cholesterol, triglycerides, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol have been observed in studies.

8.1 Pregnancy Risk Summary There is no use for contraception in pregnancy; therefore, medroxyprogesterone acetate should be discontinued during pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to progestins before conception or during early pregnancy. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

6 ADVERSE REACTIONS The following important adverse reactions observed with the use of medroxyprogesterone acetate are discussed in greater detail in the Warnings and Precautions section ( 5 ): Loss of Bone Mineral Density [see Warnings and Precautions (5.1) ] Thromboembolic disease [see Warnings and Precautions (5.2) ] Breast Cancer [see Warnings and Precautions (5.3) ] Anaphylaxis and Anaphylactoid Reactions [see Warnings and Precautions (5.6) ] Bleeding Irregularities [see Warnings and Precautions (5.11) ] Weight Gain [see Warnings and Precautions (5.12) ] Most common adverse reactions (incidence >5%): menstrual irregularities (bleeding or spotting) 57% at 12 months, 32% at 24 months, abdominal pain/discomfort 11%, weight gain >10 lb at 24 months 38%, dizziness 6%, headache 17%, nervousness 11%, decreased libido 6%. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Xiromed, LLC at 844-XIROMED (844-947-6633) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Clinical trials are conducted under widely varying conditions, therefore, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In the two clinical trials with medroxyprogesterone acetate, over 3,900 women, who were treated for up to 7 years, reported the following adverse reactions, which may or may not be related to the use of medroxyprogesterone acetate. The population studied ranges in age from 15 to 51 years, of which 46% were White, 50% Non-White, and 4.9% Unknown race. The patients received 150 mg medroxyprogesterone acetate every 3-months (90 days). The median study duration was 13 months with a range of 1 to 84 months. Fifty-eight percent of patients remained in the study after 13 months and 34% after 24 months. Table 1. Adverse Reactions that Were Reported by More than 5% of Subjects Body System* Adverse Reactions [Incidence (%)] Body as a Whole Headache (16.5%) Abdominal pain/discomfort (11.2%) Metabolic/Nutritional Increased weight >10 lb at 24 months (37.7%) Nervous Nervousness (10.8%) Dizziness (5.6%) Libido decreased (5.5%) Reproductive (Urogenital*) Menstrual irregularities: bleeding (57.3% at 12 months, 32.1% at 24 months) amenorrhea (55% at 12 months, 68% at 24 months) * Body System represented from COSTART medical dictionary. Table 2. Adverse Reactions that Were Reported by between 1 and 5% of Subjects Body System* Adverse Reactions [Incidence (%)] Body as a Whole Asthenia/fatigue (4.2%) Backache (2.2%) Dysmenorrhea (1.7%) Hot flashes (1.0%) Digestive Nausea (3.3%) Bloating (2.3%) Metabolic/Nutritional Edema (2.2%) Musculoskeletal Leg cramps (3.7%) Arthralgia (1.0%) Nervous Depression (1.5%) Insomnia (1.0%) Skin and Appendages Acne (1.2%) No hair growth/alopecia (1.1%) Rash (1.1%) Reproductive (Urogenital*) Leukorrhea (2.9%) Breast pain (2.8%) Vaginitis (1.2%) * Body System represented from COSTART medical dictionary. Adverse reactions leading to study discontinuation in ≥2% of subjects: bleeding (8.2%), amenorrhea (2.1%), weight gain (2.0%). 6.2 Post-Marketing Experience The following adverse reactions have been identified during post approval use of medroxyprogesterone acetate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. There have been cases of osteoporosis including osteoporotic fractures reported post-marketing in patients taking medroxyprogesterone acetate. Table 3. Adverse Reactions Reported during Post-Marketing Experience Body System* Adverse Reactions Body as a Whole Chest pain, Allergic reactions including angioedema, Fever, Injection site abscess † , Injection site infection † , Injection site nodule/lump, Injection site pain/tenderness, Injection site persistent atrophy/indentation/dimpling, Injection-site reacti…