Medroxyprogesterone acetate

Warnings and Precautions, Meningioma ( 5.4 ) 12/2025

1 INDICATIONS AND USAGE Medroxyprogesterone acetate is indicated for use by females of reproductive potential to prevent pregnancy. Limitations of Use: 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 [ see Dosage and Administration ( 2.1 ) and Warnings and Precautions ( 5.1 ) ]. Medroxyprogesterone acetate is a progestin indicated for use by females of reproductive potential to prevent pregnancy. ( 1 ) Limitations of Use: 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. ( 1 , 5.1 )

2 DOSAGE AND ADMINISTRATION The recommended dose is 150 mg of Medroxyprogesterone acetate every 3 months (13 weeks) administered by deep, intramuscular (IM) injection in the gluteal or deltoid muscle. ( 2.1 ) 2.1 Prevention of Pregnancy Both the 1 mL vial and the 1 mL prefilled syringe of Medroxyprogesterone acetate 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 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 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 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 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 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 on the day after the last active tablet or at the latest, on the day following the final inactive tablet).

3 DOSAGE FORMS AND STRENGTHS Sterile Aqueous suspension: 150 mg/mL Prefilled syringes are available packaged with a 22-gauge × 1 1/2 inch Needle Pro ® EDGETM Safety Device. Vials containing sterile aqueous suspension: 150 mg per mL ( 3 ) Prefilled syringes: prefilled syringes are available packaged with 22-gauge × 1 1/2 inch Needle-Pro ® EDGETM Safety Device. ( 3 )

4 CONTRAINDICATIONS The use of Medroxyprogesterone acetate is contraindicated in the following conditions: Active thrombophlebitis, or current or past 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 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 (medroxyprogesterone acetate or any of its other ingredients). ( 4 ) Significant liver disease. ( 4 ) Undiagnosed vaginal bleeding. ( 4 )

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%) are: menstrual irregularities (bleeding or spotting) 57% at 12 months, 32% at 24 months, abdominal pain/discomfort 11%, weight gain > 10 lbs at 24 months 38%, dizziness 6%, headache 17%, nervousness 11%, decreased libido 6%. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Amphastar Pharmaceuticals, Inc. at 1-800-423-4136 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 1–84 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 Body System represented from COSTART medical dictionary. Adverse Reactions [Incidence (%)] Body as a Whole Headache (16.5%) Abdominal pain/discomfort (11.2%) Metabolic/Nutritional Increased weight > 10 lbs 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) Table 2. Adverse Reactions that Were Reported by between 1 and 5% of Subjects Body System Body System represented from COSTART medical dictionary. 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%) 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 Body System represented from COSTART medical dictionary. Adverse Reactions Body as a Whole Chest pain, Allergic reactions including angioedema, Fever, Injection site abscess Injection site abscess and injection site infections have been reported; therefore, strict aseptic inj …

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 USE IN SPECIFIC POPULATIONS Pregnancy: Discontinue if pregnancy occurs. ( 8.1 ) Lactation: Detectable amounts of drug have been identified in the milk of mothers receiving Medroxyprogesterone acetate. ( 8.2 ) Pediatric Patients: Medroxyprogesterone acetate is not indicated before menarche. ( 8.4 ) 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. 8.2 Lactation Risk Summary Although medroxyprogesterone acetate is detectable in the milk of mothers receiving Medroxyprogesterone acetate, milk composition, quality, and amount do not appear to be adversely affected. Effects on milk production and lactation initiation/duration remain unclear when administered before 6 weeks after delivery, therefore, in mothers who exclusively breastfeed, initiate Medroxyprogesterone acetate during or after the sixth post-partum week [ see Dosage and Administration (2.1) ] . No adverse effects in breastfed infants would be expected with maternal use of progestins. Neonates and infants exposed to medroxyprogesterone acetate from breast milk have been studied and no adverse effects have been noted. The developmental and health benefits of breast-feeding should be considered along with the mother’s clinical need for Medroxyprogesterone acetate and any potential adverse effects on the breastfed child from Medroxyprogesterone acetate or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential Medroxyprogesterone acetate is indicated for the prevention of pregnancy and would therefore be expected to impair female fertility until cessation of treatment. Women may experience a delay in return to ovulation and fertility (conception) following discontinuation of Medroxyprogesterone acetate [ see Warnings and Precautions (5.15) ] . 8.4 Pediatric Use Medroxyprogesterone acetate is not indicated before menarche. Use of Medroxyprogesterone acetate is associated with significant loss of BMD. This loss of BMD is of particular concern during adolescence and early adulthood, a critical period of bone accretion. In adolescents, interpretation of BMD results should take into account patient age and skeletal maturity. It is unknown if use of Medroxyprogesterone acetate by younger women will reduce peak bone mass and increase the risk of osteoporotic fractures in later life. Other than concerns about loss of BMD, the safety and effectiveness are expected to be the same for postmenarchal adolescents and adult women. 8.5 Geriatric Use This product has not been studied in post-menopausal women and is not indicated in this population.

12.1 Mechanism of Action Medroxyprogesterone acetate (MPA) inhibits the secretion of gonadotropins which primarily prevents follicular maturation and ovulation and causes thickening of cervical mucus. These actions contribute to its contraceptive effect.

11 DESCRIPTION Medroxyprogesterone acetate contains medroxyprogesterone acetate, a derivative of progesterone, as its active ingredient. Medroxyprogesterone acetate is active by the parenteral and oral routes of administration. It is a white to off-white; odorless crystalline powder that is stable in air and that melts between 200°C and 210°C. It is freely soluble in chloroform, soluble in acetone and dioxane, sparingly soluble in alcohol and methanol, slightly soluble in ether, and insoluble in water. The chemical name for medroxyprogesterone acetate is pregn-4-ene-3, 20-dione, 17-(acetyloxy)-6-methyl-, (6α-). The structural formula is as follows: Medroxyprogesterone acetate for IM injection is available in vials and prefilled syringes, each containing 1 mL of medroxyprogesterone acetate sterile aqueous suspension 150 mg/mL. For Medroxyprogesterone acetate vials and prefilled syringes, each mL of sterile aqueous suspension contains: Medroxyprogesterone acetate 150 mg Polyethylene glycol 3350 28.9 mg Polysorbate 80 2.41 mg Sodium chloride 8.68 mg Methylparaben 1.37 mg Propylparaben 0.150 mg Water for injection quantity sufficient When necessary, pH is adjusted with sodium hydroxide or hydrochloric acid, or both. chemical-structure

16 HOW SUPPLIED/STORAGE AND HANDLING Medroxyprogesterone acetate injectable suspension, USP, 150 mg/mL is available as: NDC 0548-5400-00 1 mL single dose vial Stock No. 5400 The 1 mL dose vials are packaged in individual cartons. NDC 0548-5400-25 1 mL single dose vial Stock No. 5401 The 1 mL dose vials are packaged with 25 vials per carton. NDC 0548-5701-00 1 mL single dose syringe Stock No. 5701 The 1 mL dose syringes are packaged in individual cartons. Each syringe is packaged with a 22 gauge × 1 1/2 inch needle with the Needle-Pro ® EDGE TM Safety Device. Instructions for using the Needle: 1. WARNINGS for use with the Needle-Pro ® EDGETM Safety Device: 1.1 A needle stick with a contaminated needle may cause infectious diseases. 1.2 Intentional disengagement of the Needle-Pro ® EDGETM safety device may result in a needle stick with a contaminated needle. 1.3 Bent or damaged needles can result in breakage or damage to the tissue or accidental needle puncture. If the needle is bent or damaged, no attempt should be made to straighten the needle or engage the Needle-Pro ® EDGETM safety device. Immediately discard into a sharps container. The Needle-Pro ® EDGETM safety device may not properly contain a bent needle and/or the needle could puncture the needle protection device which may result in a needle stick with a contaminated needle. 1.4 Mishandling of this device, including excessive engagement force, may cause the needle to protrude from the needle protection device which may result in a contaminated needle stick. 1.5 Do not use free hand to press sheath over the needle. This may result in a needle stick with a contaminated needle. 2. CAUTIONS for use with the Needle-Pro ® EDGETM Safety Device: 2.1 Follow standard infection control procedures as specified by the Centers for Disease Control and Prevention (USA) or local equivalent. 2.2 Do Not Reuse: Medical devices require specific material characteristics to perform as intended. These characteristics have been verified for single use only. Any attempt to re-process the device for subsequent reuse may adversely affect the integrity of the device or lead to deterioration in performance. 3. I NSTRUCTIONS for use of the Prefilled Syringe with the Needle-Pro ® EDGETM Safety Device: 3.1 Remove syringe end cap exposing the luer fitting. Peel blister pouch for the Needle-Pro ® EDGETM safety device open half way. Grasp sheath using the plastic peel pouch. To prevent contamination, be careful not to touch the needle’s Luer connector. 3.2 Attach prefilled syringe to the Luer connection of the Needle-Pro ® EDGETM safety device. Insert plunger rod into open end of syringe until it contacts the stopper. Secure with 3 clockwise half turns. Shake vigorously with needle cap in place. 3.3 Pull needle cap (plastic component covering needle) straight away from the needle. Do not twist cap as Needle-Pro ® EDGETM safety device may be loosened from the prefilled syringe. 3.4 For user convenience, the needle is in the “bevel up” position when the safety sheath is located to the right as indicated by the “arrow” on the device. 3.5 Perform injection according to local standard practice using aseptic technique. 3.6 After procedure is completed, actuate needle protection by pressing the sheath against a flat surface using a one-handed technique. An audible click may be heard as an indication that the needle is engaged into the needle protection device. AS THE SHEATH IS PRESSED (FIGURE 1), THE NEEDLE IS FIRMLY ENGAGED INTO THE SHEATH (FIGURE 2). 3.7 Visually confirm that the needle is fully engaged into the needle protection sheath. 3.8 After use, place syringe and needle into a sharps container. Dispose of sharps container containing used syringe and needle in a safe manner according to Centers for Disease Control and Prevention, USA and Federal/State/Local regulations (EPA, OSHA) and health care facility guidelines or local equivalent. The Smiths Medical and Jelco design marks; Needle-Pro ® EDGE; and …