Depo-Provera

6 ADVERSE REACTIONS The following important adverse reactions observed with the use of Depo-Provera CI 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 Pfizer Inc. at 1-800-438-1985 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 Depo-Provera CI, 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 Depo-Provera CI. 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 Depo-Provera CI 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> 10lbs 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) 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%) 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 Depo-Provera CI. 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 Depo-Provera CI. 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 injection technique should be followed when administering Depo Provera CI in order to avoid injection site infections [see Dosage and Administration (2.1) ]. , 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

4 CONTRAINDICATIONS The use of Depo-Provera CI 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 Depo-Provera CI (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 Depo-Provera CI (medroxyprogesterone acetate or any of its other ingredients). ( 4 ) Significant liver disease. ( 4 ) Undiagnosed vaginal bleeding. ( 4 )

11 DESCRIPTION Depo-Provera CI 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: Depo-Provera CI for IM injection is available in vials and prefilled syringes, each containing 1 mL of medroxyprogesterone acetate sterile aqueous suspension 150 mg/mL. For Depo-Provera CI vials, 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. For Depo-Provera CI prefilled syringes, each mL of sterile aqueous suspension contains: Medroxyprogesterone acetate 150 mg Polyethylene glycol 3350 28.5 mg Polysorbate 80 2.37 mg Sodium chloride 8.56 mg Methylparaben 1.35 mg Propylparaben 0.147 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 Depo-Provera CI 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 Depo-Provera CI 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 Depo-Provera CI 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 Depo-Provera CI 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 Depo-Provera CI depends on adherence to the dosage schedule of administration. 2.2 Switching From Other Methods of Contraception When switching from other contraceptive methods, Depo-Provera CI 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 Depo-Provera CI on the day after the last active tablet or at the latest, on the day following the final inactive tablet).

1 INDICATIONS AND USAGE Depo-Provera CI is indicated for use by females of reproductive potential to prevent pregnancy. Depo-Provera CI is a progestin indicated for use by females of reproductive potential to prevent pregnancy. ( 1 ) Limitations of Use: The use of Depo-Provera CI 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 ) Limitations of Use : The use of Depo-Provera CI 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) ].

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 Depo-Provera CI. ( 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 Depo-Provera CI: (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.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Depo-Provera CI (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 Depo-Provera CI. 12.3 Pharmacokinetics Absorption Following a single 150 mg IM dose of Depo-Provera CI 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 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 Depo-Provera CI 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 Depo-Provera CI is unknown.

12.1 Mechanism of Action Depo-Provera CI (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 Depo-Provera CI.

12.3 Pharmacokinetics Absorption Following a single 150 mg IM dose of Depo-Provera CI 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 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 Depo-Provera CI 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 Depo-Provera CI is unknown.

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

Depo-Provera medroxyprogesterone acetate MEDROXYPROGESTERONE ACETATE MEDROXYPROGESTERONE POLYETHYLENE GLYCOL 3350 POLYSORBATE 80 SODIUM CHLORIDE METHYLPARABEN PROPYLPARABEN WATER SODIUM HYDROXIDE HYDROCHLORIC ACID Depo-Provera 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) . ]

NDA020246

Depo-Provera

medroxyprogesterone acetate

0009-7376

HUMAN PRESCRIPTION DRUG

INTRAMUSCULAR

PRINCIPAL DISPLAY PANEL - 150 mg/mL Vial Label NDC 0009-0746-30 Rx only Depo-Provera ® Contraceptive Injection medroxy PROGESTER one acetate injectable suspension, USP 150 mg/mL PRINCIPAL DISPLAY PANEL - 150 mg/mL Vial Label

Indications and Usage ( 1 ) 12/2020

LAB-0149-20.0 Logo

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 Depo-Provera CI continues, without other therapy being required. Counsel patients about the possible increased risk of breast cancer in women who use Depo-Provera CI [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 Depo-Provera CI. Counsel patients to use a back-up method or alternative method of contraception when enzyme inducers are used with Depo-Provera CI. This product's labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com .

14 CLINICAL STUDIES 14.1 Contraception In five clinical studies using Depo-Provera CI, the 12-month failure rate for the group of women treated with Depo-Provera CI was zero (no pregnancies reported) to 0.7 by Life-Table method. The effectiveness of Depo-Provera CI is dependent on the patient returning every 3 months (13 weeks) for reinjection. 14.2 Bone Mineral Density Changes in Women Treated with Depo-Provera CI In a controlled, clinical study, adult women using Depo-Provera CI (150mg) for up to 5 years showed spine and hip bone mineral density (BMD) mean decreases of 5–6%, 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 Depo-Provera CI, 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 Depo-Provera CI 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 Depo-Provera The treatment group consisted of women who received Depo-Provera CI for 5 years and were then followed for 2 years post-use (total time in study of 7 years). Control The control group consisted of women who did not use hormonal contraception and were followed for 7 years. Depo-Provera Control Depo-Provera 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 14.3 Bone Mineral Density Changes in Adolescent Females (12 to 18 Years of Age) Treated with Depo-Provera CI The impact of Depo-Provera CI (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 Depo-Provera CI 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 Depo-Provera CI 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 Depo-Provera CI (150 mg IM) Unmatched, Untreated Cohort N Mean % Change N Mean % Change Total Hip BMD Week 60 (1.2 years) 113 -2.75 166 1.22 Week 120 (2.3 years) 73 -5.40 109 2.19 Week 240 (4.6 years) 28 -6.40 84 1.71 Femoral Neck BMD Week 60 113 -2.96 166 1.75 Week 120 73 -5.30 108 2.83 Week 240 28 -5.40 84 1.94 Lumbar Spine BMD Week 60 114 -2.47 167 3.39 Week 120 73 -2.74 109 5.28 Week 240 27 -2.11 84 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 Depo-Provera CI. Table 6 shows the extent of recovery of BMD up to 60 months post-treatment for adolescents who received Depo-Provera CI 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 Depo-Provera CI 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 Depo Provera CI 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 Depo-Provera CI A retrospective cohort study to assess the association between Depo-Provera CI injection 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 Depo-Provera CI users and contraceptive users who had no recorded use of Depo-Provera CI. 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 Depo-Provera CI use or to other related lifestyle factors that have a bearing on fracture rate. In the study, when cumulative exposure to Depo-Provera CI 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 Depo-Provera CI users compared to non-users. Importantly, this study could not determine whether use of Depo-Provera CI has an effect on fracture rate later in life.

15 REFERENCES 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. 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 Depo-Provera CI. [ See Warnings and Precautions (5.13) .]

8.4 Pediatric Use Depo-Provera CI is not indicated before menarche. Use of Depo-Provera CI 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 Depo-Provera CI 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 Depo-Provera CI 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 Depo-Provera CI. ( 8.3 ) Pediatric Patients : Depo-Provera CI is not indicated before menarche. ( 8.4 ) 8.1 Pregnancy Depo-Provera CI 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 Depo-Provera CI. [ See Warnings and Precautions (5.13) .] 8.4 Pediatric Use Depo-Provera CI is not indicated before menarche. Use of Depo-Provera CI 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 Depo-Provera CI 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 Depo-Provera CI pharmacokinetics has not been studied. 8.7 Hepatic Impairment The effect of hepatic impairment on Depo-Provera CI pharmacokinetics has not been studied. Depo-Provera CI 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 Depo-Provera CI is supplied in the following strengths and package configurations: Package Configuration Strength NDC Depo-Provera CI (medroxyprogesterone acetate sterile aqueous suspension 150 mg/mL) 1 mL vial 150 mg/mL NDC 0009-0746-30 25 × 1 mL vials 150 mg/mL NDC 0009-0746-35 Depo-Provera CI prefilled syringes packaged with 22 gauge × 1 1/2 inch Terumo® SurGuard™ Needles 1 mL prefilled syringe 150 mg/mL NDC 0009-7376-11 Vials MUST be stored upright at controlled room temperature 20° to 25°C (68° to 77°F) [see USP].

Vials MUST be stored upright at controlled room temperature 20° to 25°C (68° to 77°F) [see USP].

WARNING: LOSS OF BONE MINERAL DENSITY Women who use Depo-Provera Contraceptive Injection (Depo-Provera CI) 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 Depo-Provera CI 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) ] . Depo-Provera CI 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 Depo-Provera Contraceptive Injection (Depo-Provera CI) 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 Depo-Provera CI 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 ) Depo-Provera CI 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 )