Medroxyprogesterone acetate

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 (5.5) ] Bleeding Irregularities [see Warnings and Precautions (5.10) ] Weight Gain [see Warnings and Precautions (5.11) ] 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 Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, 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 lbs at 24 months (37.7%) Nervous Nervousness (10.8%) Dizziness (5.6%) Libido decreased (5.5%) 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%) 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 reaction, Lipodystrophy acquired, Chills, Axillary swelling Cardiovascular Syncope, Tachycardia, Thrombophlebitis, Deep vein thrombosis, Pulmonary embolus, Varicose veins Digestive Changes in appetite, Gastrointestinal disturbances, Jaundice, Excessive thirst, Rectal bleeding Hematologic and Lymphatic Anemia, Blood dyscrasia Musculoskeletal Osteoporosis Neoplasms Cervical cancer, Breast cancer Nervous Paralysis, Facial palsy, Paresthesia, Drowsiness Respiratory Dyspnea and asthma, Hoarseness Skin and Appendages Hirsutism, Excessive sweating and body odor, Dry skin, Scleroderma Urogenital Lack of return to fertility, Unexpected pregnancy, Prevention of lactation, Changes in breast size, Breast lumps or nipple bleeding, Galactorrhea, Melasma, Chloasma, Increased libido, Uterine hyperplasia, Genitourinary infections, Vaginal cysts, Dyspareunia * Body System represented from COSTART medical dictionary. † Injection site abscess and injection site infections have been reported; therefore strict aseptic injection technique should be followed when administering medroxyprogesterone acetate in order to avoid injection site infections [see Dosage and Administration (2.1) ].

4 CONTRAINDICATIONS The use of medroxyprogesterone acetate injectable suspension is contraindicated in the following conditions: Known or suspected pregnancy or as a diagnostic test for pregnancy. 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 injectable suspension (medroxyprogesterone acetate) or any of its other ingredients [see Warnings and Precautions (5.5) ] . Significant liver disease [see Warnings and Precautions (5.7) ] . Undiagnosed vaginal bleeding [see Warnings and Precautions (5.10) ] . Known or suspected pregnancy or as a diagnostic test for pregnancy. (4) 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)

11 DESCRIPTION Medroxyprogesterone Acetate Injectable Suspension, USP contains medroxyprogesterone acetate, USP, a derivative of progesterone, as its active ingredient. Medroxyprogesterone acetate, USP is active by the parenteral and oral routes of administration. It is a white to almost white; microcrystalline powder that is stable in air and that melts between 205°C and 209°C. It is freely soluble in chloroform and methylene chloride, 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, USP is pregn-4-ene-3,20-dione,17-(acetyloxy)-6-methyl-, (6α)-17-hydroxy-6α-methylpregn-4-ene-3,20-dione acetate. The structural formula is as follows: Medroxyprogesterone acetate injectable suspension, USP, for intramuscular (IM) injection is available in vials and prefilled syringes, each containing 1 mL of medroxyprogesterone acetate sterile aqueous suspension 150 mg/mL. Medroxyprogesterone acetate injectable suspension, USP vials and prefilled syringes: Each mL of sterile aqueous suspension contains: Medroxyprogesterone acetate, USP 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

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 Both the 1 mL vial and the 1 mL prefilled syringe 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; ONLY within the first 5-days postpartum if not breast-feeding; and if exclusively breast-feeding, ONLY at the sixth postpartum 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).

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)

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. T3-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.

12 CLINICAL PHARMACOLOGY 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. 12.2 Pharmacodynamics No specific pharmacodynamic studies were conducted with medroxyprogesterone acetate. 12.3 Pharmacokinetics Absorption Following a single 150 mg IM dose of medroxyprogesterone acetate in eight women between the ages of 28 and 36 years old, medroxyprogesterone acetate concentrations, measured by an extracted radioimmunoassay procedure, increase for approximately 3 weeks to reach peak plasma concentrations of 1 ng/mL to 7 ng/mL. Distribution Plasma protein binding of MPA averages 86%. MPA binding occurs primarily to serum albumin. No binding of MPA occurs with sex-hormone-binding globulin (SHBG). Metabolism MPA is extensively metabolized in the liver by P450 enzymes. Its metabolism primarily involves ring A and/or side-chain reduction, loss of the acetyl group, hydroxylation in the 2-, 6-, and 21-positions or a combination of these positions, resulting in more than 10 metabolites. Excretion The concentrations of medroxyprogesterone acetate decrease exponentially until they become undetectable (< 100 pg/mL) between 120 to 200 days following injection. Using an unextracted radioimmunoassay procedure for the assay of medroxyprogesterone acetate in serum, the apparent half-life for medroxyprogesterone acetate following IM administration of medroxyprogesterone acetate is approximately 50 days. Most medroxyprogesterone acetate metabolites are excreted in the urine as glucuronide conjugates with only minor amounts excreted as sulfates. Specific Populations The effect of hepatic and/or renal impairment on the pharmacokinetics of medroxyprogesterone acetate is unknown.

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.

12.2 Pharmacodynamics No specific pharmacodynamic studies were conducted with medroxyprogesterone acetate.

12.3 Pharmacokinetics Absorption Following a single 150 mg IM dose of medroxyprogesterone acetate in eight women between the ages of 28 and 36 years old, medroxyprogesterone acetate concentrations, measured by an extracted radioimmunoassay procedure, increase for approximately 3 weeks to reach peak plasma concentrations of 1 ng/mL to 7 ng/mL. Distribution Plasma protein binding of MPA averages 86%. MPA binding occurs primarily to serum albumin. No binding of MPA occurs with sex-hormone-binding globulin (SHBG). Metabolism MPA is extensively metabolized in the liver by P450 enzymes. Its metabolism primarily involves ring A and/or side-chain reduction, loss of the acetyl group, hydroxylation in the 2-, 6-, and 21-positions or a combination of these positions, resulting in more than 10 metabolites. Excretion The concentrations of medroxyprogesterone acetate decrease exponentially until they become undetectable (< 100 pg/mL) between 120 to 200 days following injection. Using an unextracted radioimmunoassay procedure for the assay of medroxyprogesterone acetate in serum, the apparent half-life for medroxyprogesterone acetate following IM administration of medroxyprogesterone acetate is approximately 50 days. Most medroxyprogesterone acetate metabolites are excreted in the urine as glucuronide conjugates with only minor amounts excreted as sulfates. Specific Populations The effect of hepatic and/or renal impairment on the pharmacokinetics of medroxyprogesterone acetate is unknown.

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3 DOSAGE FORMS AND STRENGTHS Sterile Aqueous suspension: 150 mg/mL Prefilled syringes are available packaged with 22-gauge x 1 1/2 inch Needles. Vials containing sterile aqueous suspension: 150 mg per mL (3) Prefilled syringes: prefilled syringes are available packaged with 22-gauge x 1 1/2 inch needles. (3)

medroxyprogesterone acetate medroxyprogesterone acetate MEDROXYPROGESTERONE ACETATE MEDROXYPROGESTERONE POLYETHYLENE GLYCOL 3350 POLYSORBATE 80 SODIUM CHLORIDE METHYLPARABEN PROPYLPARABEN WATER SODIUM HYDROXIDE HYDROCHLORIC ACID medroxyprogesterone acetate medroxyprogesterone acetate MEDROXYPROGESTERONE ACETATE MEDROXYPROGESTERONE POLYETHYLENE GLYCOL 3350 POLYSORBATE 80 SODIUM CHLORIDE METHYLPARABEN PROPYLPARABEN WATER SODIUM HYDROXIDE HYDROCHLORIC ACID

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility [See Warnings and Precautions, (5.3 , 5.15 and 5.17) ].

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility [See Warnings and Precautions, (5.3 , 5.15 and 5.17) ].

ANDA215397

Medroxyprogesterone acetate

medroxyprogesterone acetate

70121-1467

HUMAN PRESCRIPTION DRUG

INTRAMUSCULAR

PRINCIPAL DISPLAY PANEL NDC 70121-1467-2 Medroxyprogesterone Acetate Injectable Suspension, USP 150 mg/mL (1 mL) Rx only (1 Single-Dose Vial in a Carton) Amneal Pharmaceuticals LLC NDC 70121-1467-5 Medroxyprogesterone Acetate Injectable Suspension, USP 150 mg/mL (1 mL) Rx only (25 x 1 mL Single-Dose Vials in a Carton) Amneal Pharmaceuticals LLC NDC 70121-1480-1 Medroxyprogesterone Acetate Injectable Suspension, USP 150 mg/mL (1 mL) Rx only (1 Prefilled Single-Dose Syringe in a Carton) Amneal Pharmaceuticals LLC 1 1 1 1 1

17 PATIENT COUNSELING INFORMATION “See FDA-approved patient labeling (Patient Information).” Advise patients at the beginning of treatment that their menstrual cycle may be disrupted and that irregular and unpredictable bleeding or spotting results, and that this usually decreases to the point of amenorrhea as treatment with medroxyprogesterone acetate continues, without other therapy being required. Counsel patients about the possible increased risk of breast cancer in women who use medroxyprogesterone acetate [see Warnings and Precautions (5.3) ]. Counsel patients that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases. Counsel patients on Warnings and Precautions associated with use of medroxyprogesterone acetate. Counsel patients to use a back-up method or alternative method of contraception when enzyme inducers are used with medroxyprogesterone acetate. This product’s labeling may have been updated. For the most recent prescribing information, please visit www.amneal.com. Manufactured by: Laboratories Farmalan S.A. (Chemo) Calle La Vallina, (Pol. Ind. Navatejera) S/N - EDIF. 2, Villaquilambre, 24193 Spain (ESP) Distributed by: Amneal Pharmaceuticals LLC Bridgewater, NJ 08807 Rev. 10-2022-00

14 CLINICAL STUDIES 14.1 Contraception In five clinical studies using medroxyprogesterone acetate, the 12-month failure rate for the group of women treated with medroxyprogesterone acetate was zero (no pregnancies reported) to 0.7 by Life-Table method. The effectiveness of medroxyprogesterone acetate is dependent on the patient returning every 3 months (13 weeks) for reinjection. 14.2 Bone Mineral Density Changes in Adult Women Treated with Medroxyprogesterone Acetate In a controlled, clinical study, adult women using medroxyprogesterone acetate (150 mg) for up to 5 years showed spine and hip bone mineral density (BMD) mean decreases of 5% to 6%, compared to no significant change in BMD in the control group. The decline in BMD was more pronounced during the first two years of use, with smaller declines in subsequent years. Mean changes in lumbar spine BMD of -2.86%, -4.11%, -4.89%, -4.93% and -5.38% after 1, 2, 3, 4, and 5 years, respectively, were observed. Mean decreases in BMD of the total hip and femoral neck were similar. After stopping use of medroxyprogesterone acetate, there was partial recovery of BMD toward baseline values during the 2-year post-therapy period. Longer duration of treatment was associated with less complete recovery during this 2-year period following the last injection. Table 4 shows the change in BMD in women after 5 years of treatment with medroxyprogesterone acetate and in women in a control group, as well as the extent of recovery of BMD for the subset of the women for whom 2-year post treatment data were available. Table 4: Mean Percent Change from Baseline in BMD in Adults by Skeletal Site and Cohort (5 Years of Treatment and 2 Years of Follow-Up) Time in Study Spine Total Hip Femoral Neck Medroxyprogesterone acetate* Control** Medroxyprogesterone acetate* Control** Medroxyprogesterone acetate* Control** 5 years -5.38% n=33 0.43% n=105 -5.16% n=21 0.19% n=65 -6.12% n=34 -0.27% n=106 7 years -3.13% n=12 0.53% n=60 -1.34% n=7 0.94% n=39 -5.38% n=13 -0.11% n=63 *The treatment group consisted of women who received medroxyprogesterone acetate for 5 years and were then followed for 2 years post-use (total time in study of 7 years). **The control group consisted of women who did not use hormonal contraception and were followed for 7 years. 14.3 Bone Mineral Density Changes in Adolescent Females (12 to 18 Years of Age) Treated with Medroxyprogesterone Acetate The impact of medroxyprogesterone acetate (150 mg) use for up to 240 weeks (4.6 years) was evaluated in an open-label non-randomized clinical study in 389 adolescent females (12 to 18 years of age). Use of medroxyprogesterone acetate was associated with a significant decline from baseline in BMD. Partway through the trial, drug administration was stopped (at 120 weeks). The mean number of injections per medroxyprogesterone acetate user was 9.3. Table 5 summarizes the study findings. The decline in BMD at total hip and femoral neck was greater with longer duration of use. The mean decrease in BMD at 240 weeks was more pronounced at total hip (-6.4%) and femoral neck (-5.4%) compared to lumbar spine (-2.1%). Adolescents in the untreated cohort had an increase in BMD during the period of growth following menarche. However, the two cohorts were not matched at baseline for age, gynecologic age, race, BMD and other factors that influence the rate of acquisition of BMD. Table 5: BMD Mean Percent Change from Baseline in Adolescents Receiving ≥ 4 Injections per 60-week Period, by Skeletal Site and Cohort Duration of Treatment Medroxyprogesterone acetate (150 mg IM) Unmatched, Untreated Cohort N Mean % Change N Mean % Change Total Hip BMD Week 60 (1.2 years) Week 120 (2.3 years) Week 240 (4.6 years) 113 73 28 -2.75 -5.40 -6.40 166 109 84 1.22 2.19 1.71 Femoral Neck BMD Week 60 Week 120 Week 240 113 73 28 -2.96 -5.30 -5.40 166 108 84 1.75 2.83 1.94 Lumbar Spine BMD Week 60 Week 120 Week 240 114 73 27 -2.47 -2.74 -2.11 167 109 84 3.39 5.28 6.40 BMD Recovery Post-Treatment in Adolescents Longer duration of treatment and smoking were associated with less recovery of BMD following the last injection of medroxyprogesterone acetate. Table 6 shows the extent of recovery of BMD up to 60 months post-treatment for adolescents who received medroxyprogesterone acetate for two years or less compared to more than two years. Post-treatment follow-up showed that, in women treated for more than two years, only lumbar spine BMD recovered to baseline levels after treatment was discontinued. Adolescents treated with medroxyprogesterone acetate for more than two years did not recover to their baseline BMD level at femoral neck and total hip even up to 60 months post-treatment. Adolescents in the untreated cohort gained BMD throughout the trial period (data not shown) [see Warnings and Precautions (5.1) ] . Table 6: BMD Recovery (Months Post-Treatment) in Adolescents by Years of Medroxyprogesterone acetate Use (2 Years or Less vs. More than 2 Years) Duration of Treatment 2 years or less More than 2 years N Mean % Change from baseline N Mean % Change from baseline Total Hip BMD End of Treatment 49 -1.5% 49 -6.2% 12 M post-treatment 33 -1.4% 24 -4.6% 24 M post-treatment 18 0.3% 17 -3.6% 36 M post-treatment 12 2.1% 11 -4.6% 48 M post-treatment 10 1.3% 9 -2.5% 60 M post-treatment 3 0.2% 2 -1.0% Femoral Neck BMD End of Treatment 49 -1.6% 49 -5.8% 12 M post-treatment 33 -1.4% 24 -4.3% 24 M post-treatment 18 0.5% 17 -3.8% 36 M post-treatment 12 1.2% 11 -3.8% 48 M post-treatment 10 2.0% 9 -1.7% 60 M post-treatment 3 1.0% 2 -1.9% Lumbar Spine BMD End of Treatment 49 -0.9% 49 -3.5% 12 M post-treatment 33 0.4% 23 -1.1% 24 M post-treatment 18 2.6% 17 1.9% 36 M post-treatment 12 2.4% 11 0.6% 48 M post-treatment 10 6.5% 9 3.5% 60 M post-treatment 3 6.2% 2 5.7% 14.4 Bone Fracture Incidence in Women Treated with Medroxyprogesterone Acetate A retrospective cohort study to assess the association between medroxyprogesterone acetate and the incidence of bone fractures was conducted in 312,395 female contraceptive users in the UK. The incidence rates of fracture were compared between medroxyprogesterone acetate users and contraceptive users who had no recorded use of medroxyprogesterone acetate. The Incident Rate Ratio (IRR) for any fracture during the follow-up period (mean = 5.5 years) was 1.41 (95% CI 1.35, 1.47). It is not known if this is due to medroxyprogesterone acetate use or to other related lifestyle factors that have a bearing on fracture rate. In the study, when cumulative exposure to medroxyprogesterone acetate was calculated, the fracture rate in users who received fewer than 8 injections was higher than that in women who received 8 or more injections. However, it is not clear that cumulative exposure, which may include periods of intermittent use separated by periods of non-use, is a useful measure of risk, as compared to exposure measures based on continuous use. There were very few osteoporotic fractures (fracture sites known to be related to low BMD) in the study overall, and the incidence of osteoporotic fractures was not found to be higher in medroxyprogesterone acetate users compared to non-users. Importantly, this study could not determine whether use of medroxyprogesterone acetate has an effect on fracture rate later in life.

15 REFERENCES 1. Li CI, Beaber EF, Tang, MCT et al. Effect of Depo-Medroxyprogesterone Acetate on Breast Cancer Risk among Women 20 to 44 years of Age. Cancer Research 2012;72:2028-2035. 2. Paul C, Skegg DCG, Spears GFS. Depot medroxyprogesterone (Depo-Provera) and risk of breast cancer. Br Med J 1989; 299:759-62.

8.5 Geriatric Use This product has not been studied in post-menopausal women and is not indicated in this population.

8.3 Nursing Mothers Detectable amounts of drug have been identified in the milk of mothers receiving medroxyprogesterone acetate [see Warnings and Precautions (5.13) ] .

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.

8.1 Pregnancy Medroxyprogesterone acetate should not be administered during pregnancy [see Contraindications and Warnings and Precautions (5.17) ].

8 USE IN SPECIFIC POPULATIONS Nursing Mothers: Detectable amounts of drug have been identified in the milk of mothers receiving medroxyprogesterone acetate. (8.3) Pediatric Patients: Medroxyprogesterone acetate is not indicated before menarche. (8.4) 8.1 Pregnancy Medroxyprogesterone acetate should not be administered during pregnancy [see Contraindications and Warnings and Precautions (5.17) ]. 8.3 Nursing Mothers Detectable amounts of drug have been identified in the milk of mothers receiving medroxyprogesterone acetate [see Warnings and Precautions (5.13) ] . 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. 8.6 Renal Impairment The effect of renal impairment on medroxyprogesterone acetate pharmacokinetics has not been studied. 8.7 Hepatic Impairment The effect of hepatic impairment on medroxyprogesterone acetate pharmacokinetics has not been studied. Medroxyprogesterone acetate should not be used by women with significant liver disease and should be discontinued if jaundice or disturbances of liver function occur [see Contraindications (4) and Warnings and Precautions (5.7) ] .

16 HOW SUPPLIED/STORAGE AND HANDLING Medroxyprogesterone Acetate Injectable Suspension, USP is supplied in the following strengths and package configurations: Package Configuration Strength NDC Medroxyprogesterone acetate sterile aqueous suspension 150 mg/mL 1 mL single-dose vial in 1 carton 150 mg/mL NDC 70121-1467-2 25 x 1 mL single-dose vials in 1 carton 150 mg/mL NDC 70121-1467-5 Medroxyprogesterone acetate prefilled syringes packaged with 22 gauge x 1 1/2 inch Needles 1 mL single-dose prefilled syringe 150 mg/mL NDC 70121-1480-1 Vials: Vials MUST be stored upright at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Shake vigorously immediately before use. Prefilled Syringes: Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Shake vigorously before use with protective cap in place.

WARNING: LOSS OF BONE MINERAL DENSITY Women who use medroxyprogesterone acetate injectable suspension may lose significant bone mineral density. Bone loss is greater with increasing duration of use and may not be completely reversible [see Warnings and Precautions (5.1) ] . It is unknown if use of medroxyprogesterone acetate injectable suspension during adolescence or early adulthood, a critical period of bone accretion, will reduce peak bone mass and increase the risk for osteoporotic fracture in later life [see Warnings and Precautions (5.1) ] . 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 Indications and Usage (1) and Warnings and Precautions (5.1) ] . WARNING: LOSS OF BONE MINERAL DENSITY See full prescribing information for complete boxed warning . Women who use medroxyprogesterone acetate injectable suspension may lose significant bone mineral density. Bone loss is greater with increasing duration of use and may not be completely reversible. (5.1) It is unknown if use of medroxyprogesterone acetate injectable suspension during adolescence or early adulthood, a critical period of bone accretion, will reduce peak bone mass and increase the risk for osteoporotic fracture in later life. (5.1) 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)