ADVERSE REACTIONS SECTION.


6 ADVERSE REACTIONS. The following important adverse reactions observed with the use of medroxyprogesterone acetate injectable suspension 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) . 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 NorthStar RxLLC at 1-800-206-7821 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 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 injectable suspension, over 3,900 women, who were treated for up to years, reported the following adverse reactions, which may or may not be related to the use of medroxyprogesterone acetate injectable suspension. 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 injectable suspension every 3-months (90 days). The median study duration was 13 months with range of to 84 months. Fifty eight percent of patients remained in the study after 13 months and 34% after 24 months. Table Adverse Reactions that Were Reported by More than 5% of Subjects Body SystemBody System represented from COSTART medical dictionary. Adverse Reactions [Incidence (%)] Body as 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 Adverse Reactions that Were Reported by between and 5% of Subjects Body System Adverse Reactions [Incidence (%)] Body as 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 Postmarketing Experience. The following adverse reactions have been identified during post approval use of medroxyprogesterone acetate injectable suspension. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. There have been cases of osteoporosis including osteoporotic fractures reported post-marketing in patients taking medroxyprogesterone acetate injectable suspension.Table Adverse Reactions Reported during Post-Marketing Experience Body SystemBody System represented from COSTART medical dictionary. Adverse Reactions Body as Whole Chest pain, Allergic reactions including angioedema, Fever, Injection site abscessInjection site abscess and injection site infections have been reported; therefore strict aseptic injection technique should be followed when administering medroxyprogesterone acetate injectable suspension 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.

BOXED WARNING SECTION.


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, 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 long-term (i.e., longer than years) birth control method unless other options are considered inadequate [see Indications and Usage (1) and Warnings and Precautions (5.1)].. 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, 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 long-term (i.e., longer than years) birth control method unless other options are considered inadequate [see Indications and Usage (1) and Warnings and Precautions (5.1)].. 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, 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 long-term (i.e., longer than years) birth control method unless other options are considered inadequate. (1, 5.1) 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, 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 long-term (i.e., longer than years) birth control method unless other options are considered inadequate. (1, 5.1).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


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

CLINICAL PHARMACOLOGY SECTION.


12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Medroxyprogesterone acetate (MPA) injectable suspension, 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 injectable suspension. 12.3 Pharmacokinetics. Absorption Following single 150 mg IM dose of medroxyprogesterone acetate injectable suspension in eight women between the ages of 28 and 36 years old, medroxyprogesterone acetate concentrations, measured by an extracted radioimmunoassay procedure, increase for approximately weeks to reach peak plasma concentrations of to 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 and/or side-chain reduction, loss of the acetyl group, hydroxylation in the 2-, 6-, and 21- positions or 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 injectable suspension 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 injectable suspension is unknown.

CLINICAL STUDIES SECTION.


14 CLINICAL STUDIES. 14.1 Contraception. In five clinical studies using medroxyprogesterone acetate injectable suspension, the 12-month failure rate for the group of women treated with medroxyprogesterone acetate injectable suspension was zero (no pregnancies reported) to 0.7 by Life-Table method. The effectiveness of medroxyprogesterone acetate injectable suspension is dependent on the patient returning every months (13 weeks) for reinjection. 14.2 Bone Mineral Density Changes in Adult Women Treated with Medroxyprogesterone Acetate Injectable Suspension. In controlled, clinical study, adult women using medroxyprogesterone acetate injectable suspension (150 mg) for up to years showed spine and hip bone mineral density (BMD) mean decreases of 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 years, respectively, were observed. Mean decreases in BMD of the total hip and femoral neck were similar. After stopping use of medroxyprogesterone acetate injectable suspension, 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 shows the change in BMD in women after years of treatment with medroxyprogesterone acetate injectable suspension and in women in 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 Years of Follow-Up) Time in Study Spine Total Hip Femoral Neck Medroxyprogesterone acetate injectable suspensionThe treatment group consisted of women who received medroxyprogesterone acetate injectable suspension for years and were then followed for years post-use (total time in study of years). ControlThe control group consisted of women who did not use hormonal contraception and were followed for years. Medroxyprogesterone acetate injectable suspension Control Medroxyprogesterone acetate injectable suspension Control 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 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 Medroxyprogesterone Acetate Injectable Suspension. The impact of medroxyprogesterone acetate injectable suspension (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 injectable suspension was associated with 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 injectable suspension user was 9.3. Table 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 Injectable Suspension (150 mg IM)Unmatched, Untreated Cohort NMean ChangeNMean ChangeTotal Hip BMD Week 60 (1.2 years) Week 120 (2.3 years) Week 240 (4.6 years) 1137328 -2.75-5.40-6.40 166 10984 1.222.191.71 Femoral Neck BMD Week 60 Week 120 Week 240 1137328 -2.96-5.30-5.40 166 10884 1.752.831.94 Lumbar Spine BMD Week 60 Week 120 Week 240 11473 27 -2.47-2.74-2.11 167 109 84 3.395.286.40 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 injectable suspension. Table shows the extent of recovery of BMD up to 60 months post-treatment for adolescents who received medroxyprogesterone acetate injectable suspension 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 injectable suspension 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 Injectable Suspension Use (2 Years or Less vs. More than Years) Duration of Treatment years or lessMore than years NMean Change from baselineNMean Change from baselineTotal Hip BMDEnd of Treatment 49 -1.5% 49 -6.2% 12 post-treatment 33 -1.4% 24 -4.6% 24 post-treatment 18 0.3% 17 -3.6% 36 post-treatment 12 2.1% 11 -4.6% 48 post-treatment 10 1.3% -2.5% 60 post-treatment 0.2% -1.0% Femoral Neck BMDEnd of Treatment 49 -1.6% 49 -5.8% 12 post-treatment 33 -1.4% 24 -4.3% 24 post-treatment 18 0.5% 17 -3.8% 36 post-treatment 12 1.2% 11 -3.8% 48 post-treatment 10 2.0% -1.7% 60 post-treatment 1.0% -1.9% Lumbar Spine BMDEnd of Treatment 49 -0.9% 49 -3.5% 12 post-treatment 33 0.4% 23 -1.1% 24 post-treatment 18 2.6% 17 1.9% 36 post-treatment 12 2.4% 11 0.6% 48 post-treatment 10 6.5% 3.5% 60 post-treatme 6.2% 5.7% 14.4 Bone Fracture Incidence in Women Treated with Medroxyprogesterone Acetate Injectable Suspension. retrospective cohort study to assess the association between medroxyprogesterone acetate injectable suspension and the incidence of bone fractures was conducted in 312,395 female contraceptive users in the U.K. The incidence rates of fracture were compared between medroxyprogesterone acetate injectable suspension users and contraceptive users who had no recorded use of medroxyprogesterone acetate injectable suspension. 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 injectable suspension use or to other related lifestyle factors that have bearing on fracture rate. In the study, when cumulative exposure to medroxyprogesterone acetate injectable suspension was calculated, the fracture rate in users who received fewer than injections was higher than that in women who received 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 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 injectable suspension users compared to non-users. Importantly, this study could not determine whether use of medroxyprogesterone acetate injectable suspension has an effect on fracture rate later in life.

CONTRAINDICATIONS SECTION.


4 CONTRAINDICATIONS. The use of medroxyprogesterone acetate injectable suspension is contraindicated in the following conditions: Known or suspected pregnancy or as 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 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 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 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 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 or any of its other ingredients. (4) Significant liver disease. (4) Undiagnosed vaginal bleeding. (4). Known or suspected pregnancy or as 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 or any of its other ingredients. (4) Significant liver disease. (4) Undiagnosed vaginal bleeding. (4).

DESCRIPTION SECTION.


11 DESCRIPTION. Medroxyprogesterone acetate injectable suspension, USP, contraceptive injection, contains medroxyprogesterone acetate, USP derivative of progesterone, as its active ingredient. Medroxyprogesterone acetate is active by the parenteral and oral routes of administration. It is white or almost white, crystalline powder that is stable in air and that melts between 205C and 209C. 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-, (6-).The structural formula is as follows: Medroxyprogesterone acetate injectable suspension, USP for IM injection is available in vials containing mL of medroxyprogesterone acetate sterile aqueous suspension 150 mg/mL. For Medroxyprogesterone acetate injectable suspension vials, each mL of sterile aqueous suspension contains: Medroxyprogesterone acetate 150 mgPolyethylene glycol 3350 28.90 mgPolysorbate 80 2.41 mgSodium chloride 8.68 mgMethylparaben 1.37 mgPropylparaben 0.15 mgWater for injection quantity sufficientWhen necessary, pH is adjusted with sodium hydroxide or hydrochloric acid, or both.. spl-medroxy-structure.

DOSAGE & ADMINISTRATION SECTION.


2 DOSAGE AND ADMINISTRATION. The recommended dose is 150 mg of medroxyprogesterone acetate injectable suspension every months (13 weeks) administered by deep, intramuscular (IM) injection in the gluteal or deltoid muscle. (2.1) 2.1 Prevention of Pregnancy. The mL vial of medroxyprogesterone acetate injectable suspension should be vigorously shaken just before use to ensure that the dose being administered represents uniform suspension.The recommended dose is 150 mg of medroxyprogesterone acetate injectable suspension every 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 longer needle is necessary particularly for gluteal IM injection. Use for longer than 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 days of 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 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).

DOSAGE FORMS & STRENGTHS SECTION.


3 DOSAGE FORMS AND STRENGTHS. Sterile Aqueous suspension: 150 mg/mL. Vials containing sterile aqueous suspension: 150 mg per mL (3) Vials containing sterile aqueous suspension: 150 mg per mL (3).

PHARMACOKINETICS SECTION.


12.3 Pharmacokinetics. Absorption Following single 150 mg IM dose of medroxyprogesterone acetate injectable suspension in eight women between the ages of 28 and 36 years old, medroxyprogesterone acetate concentrations, measured by an extracted radioimmunoassay procedure, increase for approximately weeks to reach peak plasma concentrations of to 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 and/or side-chain reduction, loss of the acetyl group, hydroxylation in the 2-, 6-, and 21- positions or 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 injectable suspension 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 injectable suspension is unknown.

DRUG INTERACTIONS SECTION.


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 back-up method or alternative method of contraception when enzyme inducers are used with medroxyprogesterone acetate injectable suspension. (7.1) 7.1 Changes in Contraceptive Effectiveness Associated With Co-Administration of Other Products. If woman on hormonal contraceptives takes drug or herbal product that induces enzymes, including CYP3A4, that metabolize contraceptive hormones, counsel her to use additional contraception or 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 carbamazepinefelbamate griseofulvin oxcarbazepine phenytoin rifampin St. Johns wort topiramateHIV 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 coadministration 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. barbiturates bosentan carbamazepine. felbamate griseofulvin oxcarbazepine phenytoin rifampin St. Johns wort topiramate. 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 injectable suspension: (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 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.

GERIATRIC USE SECTION.


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

HOW SUPPLIED SECTION.


16 HOW SUPPLIED/STORAGE AND HANDLING. Medroxyprogesterone acetate injectable suspension, USP is supplied as follows:Package Configuration Strength NDC Medroxyprogesterone acetate injectable suspension, USP, 150 mg/mL, mL vial mL vial 150 mg/mL NDC 16714-981-01 25 1 mL vials 150 mg/mL NDC 16714-981-02 Vial MUST be stored upright at 20 to 25C (68 to 77F); excursions permitted to 15 to 30C (59 to 86F) [see USP Controlled Room Temperature].

INDICATIONS & USAGE SECTION.


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

INFORMATION FOR PATIENTS SECTION.


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 injectable suspension continues, without other therapy being required. Counsel patients about the possible increased risk of breast cancer in women who use medroxyprogesterone acetate injectable suspension [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 injectable suspension.Counsel patients to use back-up method or alternative method of contraception when enzyme inducers are used with medroxyprogesterone acetate injectable suspension.Manufactured for:Northstar Rx LLCMemphis, TN 38141.Manufactured by:Sun Pharmaceutical Industries LimitedHalol-Baroda Highway,Halol-389 350, Gujarat, India.. 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 injectable suspension continues, without other therapy being required. Counsel patients about the possible increased risk of breast cancer in women who use medroxyprogesterone acetate injectable suspension [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 injectable suspension.. Counsel patients to use back-up method or alternative method of contraception when enzyme inducers are used with medroxyprogesterone acetate injectable suspension.

MECHANISM OF ACTION SECTION.


12.1 Mechanism of Action. Medroxyprogesterone acetate (MPA) injectable suspension, 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.

NONCLINICAL TOXICOLOGY SECTION.


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

NURSING MOTHERS SECTION.


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

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PACKAGE LABEL.PRINCIPAL DISPLAY PANEL-Vial Label. Rx only NDC 16714-981-01 medroxyPROGESTERrone Acetate Injectable Suspension, USP 150 mg/mL For intramuscular use only Store upright at 20 to 25C (68 to 77F) [see USP]. mL Single-dose vial Northstar Rx spl-medroxy-label.

PEDIATRIC USE SECTION.


8.4 Pediatric Use. Medroxyprogesterone acetate injectable suspension is not indicated before menarche. Use of medroxyprogesterone acetate injectable suspension is associated with significant loss of BMD. This loss of BMD is of particular concern during adolescence and early adulthood, 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 injectable suspension 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.

PHARMACODYNAMICS SECTION.


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

PREGNANCY SECTION.


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

RECENT MAJOR CHANGES SECTION.


Indications and Usage (1) 12/2020.

REFERENCES SECTION.


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 1989; 299:759-62.. 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 1989; 299:759-62.

SPL UNCLASSIFIED SECTION.


2.1 Prevention of Pregnancy. The mL vial of medroxyprogesterone acetate injectable suspension should be vigorously shaken just before use to ensure that the dose being administered represents uniform suspension.The recommended dose is 150 mg of medroxyprogesterone acetate injectable suspension every 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 longer needle is necessary particularly for gluteal IM injection. Use for longer than 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 days of 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.

USE IN SPECIFIC POPULATIONS SECTION.


8 USE IN SPECIFIC POPULATIONS. Nursing Mothers: Detectable amounts of drug have been identified in the milk of mothers receiving medroxyprogesterone acetate injectable suspension. (8.3) Pediatric Patients: Medroxyprogesterone acetate injectable suspension is not indicated before menarche. (8.4) Nursing Mothers: Detectable amounts of drug have been identified in the milk of mothers receiving medroxyprogesterone acetate injectable suspension. (8.3) Pediatric Patients: Medroxyprogesterone acetate injectable suspension is not indicated before menarche. (8.4) 8.1 Pregnancy. Medroxyprogesterone acetate injectable suspension 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 injectable suspension. [See Warnings and Precautions (5.13) .] 8.4 Pediatric Use. Medroxyprogesterone acetate injectable suspension is not indicated before menarche. Use of medroxyprogesterone acetate injectable suspension is associated with significant loss of BMD. This loss of BMD is of particular concern during adolescence and early adulthood, 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 injectable suspension 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 injectable suspension pharmacokinetics has not been studied. 8.7 Hepatic Impairment. The effect of hepatic impairment on medroxyprogesterone acetate injectable suspension pharmacokinetics has not been studied. Medroxyprogesterone acetate injectable suspension 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) .].

WARNINGS AND PRECAUTIONS SECTION.


5 WARNINGS AND PRECAUTIONS. Thromboembolic Disorders: Discontinue medroxyprogesterone acetate injectable suspension in patients who develop thrombosis. (5.2)Cancer Risks: Monitor women with strong family history of breast cancer carefully. (5.3)Ectopic Pregnancy: Consider ectopic pregnancy if woman using medroxyprogesterone acetate injectable suspension becomes pregnant or complains of severe abdominal pain. (5.4)Anaphylaxis and Anaphylactoid Reactions: Provide emergency medical treatment. (5.5) Liver Function: Discontinue medroxyprogesterone acetate injectable suspension if jaundice or disturbances of liver function develop. (5.7) Carbohydrate Metabolism: Monitor diabetic patients carefully. (5.12) Thromboembolic Disorders: Discontinue medroxyprogesterone acetate injectable suspension in patients who develop thrombosis. (5.2). Cancer Risks: Monitor women with strong family history of breast cancer carefully. (5.3). Ectopic Pregnancy: Consider ectopic pregnancy if woman using medroxyprogesterone acetate injectable suspension becomes pregnant or complains of severe abdominal pain. (5.4). Anaphylaxis and Anaphylactoid Reactions: Provide emergency medical treatment. (5.5) Liver Function: Discontinue medroxyprogesterone acetate injectable suspension if jaundice or disturbances of liver function develop. (5.7) Carbohydrate Metabolism: Monitor diabetic patients carefully. (5.12) 5.1 Loss of Bone Mineral Density. Use of medroxyprogesterone acetate injectable suspension 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, critical period of bone accretion. It is unknown if use of medroxyprogesterone acetate injectable suspension by younger women will reduce peak bone mass and increase the risk for osteoporotic fracture in later life. study to assess the reversibility of loss of BMD in adolescents was conducted with medroxyprogesterone acetate injectable suspension. After discontinuing medroxyprogesterone acetate injectable suspension in these adolescents, mean BMD loss at the total hip and femoral neck did not fully recover by years (60 months) post-treatment in the sub-group of adolescents who were treated for more than 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 years post-treatment. [See Clinical Studies (14.2).] The use of medroxyprogesterone acetate injectable suspension is not recommended as long-term (i.e., longer than years) birth control method unless other options are considered inadequate. BMD should be evaluated when woman needs to continue to use medroxyprogesterone acetate injectable suspension 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 injectable suspension in women with osteoporosis risk factors. Medroxyprogesterone acetate injectable suspension 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 injectable suspension (150 mg). However, medroxyprogesterone acetate injectable suspension has not been causally associated with the induction of thrombotic or thromboembolic disorders. Any patient who develops thrombosis while undergoing therapy with medroxyprogesterone acetate injectable suspension should discontinue treatment unless she has no other acceptable options for birth control. Do not re-administer medroxyprogesterone acetate injectable suspension pending examination if there is sudden partial or complete loss of vision or if there is 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 history of breast cancer should not use hormonal contraceptives, including medroxyprogesterone acetate injectable suspension, because breast cancer may be hormonally sensitive [see Contraindications (4)]. Women with strong family history of breast cancer should be monitored with particular care. The results of five large case-control studies1, 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 slightly increased risk of breast cancer in the overall population of users; these increased risks were statistically significant in one study. One recent US study1 evaluated the recency and duration of use and found statistically significantly increased risk of breast cancer in recent users (defined as last use within the past five years) who used DMPA for 12 months or longer; this is consistent with results of previous study. Odds ratio estimates were adjusted for the following covariates:Lee et al. (1987): age, parity, and socioeconomic status. Paul et al. (1989): age, parity, ethnic group, and year of interview. WHO (1991): age, center, and age at first live birth. Shapiro et al. (2000): age, ethnic group, socioeconomic status, and any combined estrogen/progestogen oral contraceptive use. Li et al. (2012): age, year, BMI, duration of OC use, number of full-term pregnancies, family history of breast cancer, and history of screening mammography. Based on the published SEER-18 2011 incidence rate (age-adjusted to the 2000 U.S. Standard Population) of breast cancer for U.S. women, all races, age 20 to 49 years, doubling of risk would increase the incidence of breast cancer in women who use medroxyprogesterone acetate injectable suspension from about 72 to about 144 cases per 100,000 women.Cervical Cancer statistically nonsignificant increase in RR estimates of invasive squamous-cell cervical cancer has been associated with the use of medroxyprogesterone acetate injectable suspension in women who were first exposed before the age of 35 years (RR 1.22 to 1.28 and 95% CI 0.93 to 1.70). The overall, nonsignificant relative rate of invasive squamous-cell cervical cancer in women who ever used medroxyprogesterone acetate injectable suspension was estimated to be 1.11 (95% CI 0.96 to 1.29). No trends in risk with duration of use or times since initial or most recent exposure were observed. Other Cancers Long-term case-controlled surveillance of users of medroxyprogesterone acetate injectable suspension found no overall increased risk of ovarian or liver cancer. spl-medroxy-fig1. 5.4 Ectopic Pregnancy. Be alert to the possibility of an ectopic pregnancy among women using medroxyprogesterone acetate injectable suspension who become pregnant or complain of severe abdominal pain. 5.5 Anaphylaxis and Anaphylactoid Reaction. Anaphylaxis and anaphylactoid reaction have been reported with the use of medroxyprogesterone acetate injectable suspension. Institute emergency medical treatment if an anaphylactic reaction occurs. 5.6 Injection Site Reactions. Injection site reactions have been reported with use of medroxyprogesterone acetate injectable suspension [see Adverse Reactions (6.2)]. Persistent injection site reactions may occur after administration of medroxyprogesterone acetate injectable suspension due to inadvertent subcutaneous administration or release of the drug into the subcutaneous space while removing the needle [see Dosage and Administration (2.1)]. 5.7 Liver Function. Discontinue medroxyprogesterone acetate injectable suspension use if jaundice or acute or chronic disturbances of liver function develop. Do not resume use until markers of liver function return to normal and medroxyprogesterone acetate injectable suspension causation has been excluded. 5.8 Convulsions. There have been few reported cases of convulsions in patients who were treated with medroxyprogesterone acetate injectable suspension. Association with drug use or pre-existing conditions is not clear. 5.9 Depression. Monitor patients who have history of depression and do not re-administer medroxyprogesterone acetate injectable suspension if depression recurs. 5.10 Bleeding Irregularities. Most women using medroxyprogesterone acetate injectable suspension experience disruption of menstrual bleeding patterns. Altered menstrual bleeding patterns include amenorrhea, irregular or unpredictable bleeding or spotting, prolonged spotting or bleeding, and heavy bleeding. Rule out the possibility of organic pathology if abnormal bleeding persists or is severe, and institute appropriate treatment. As women continue using medroxyprogesterone acetate injectable suspension, fewer experience irregular bleeding and more experience amenorrhea. In clinical studies of medroxyprogesterone acetate injectable suspension, by month 12 amenorrhea was reported by 55% of women, and by month 24, amenorrhea was reported by 68% of women using medroxyprogesterone acetate injectable suspension.. 5.11 Weight Gain. Women tend to gain weight while on therapy with medroxyprogesterone acetate injectable suspension. From an initial average body weight of 136 lb, women who completed year of therapy with medroxyprogesterone acetate injectable suspension gained an average of 5.4 lb. Women who completed years of therapy gained an average of 8.1 lb. Women who completed years gained an average of 13.8 lb. Women who completed years gained an average of 16.5 lb. Two percent of women withdrew from large-scale clinical trial because of excessive weight gain. 5.12 Carbohydrate Metabolism. decrease in glucose tolerance has been observed in some patients on medroxyprogesterone acetate injectable suspension treatment. Monitor diabetic patients carefully while receiving medroxyprogesterone acetate injectable suspension. 5.13Lactation. Detectable amounts of drug have been identified in the milk of mothers receiving medroxyprogesterone acetate injectable suspension. In nursing mothers treated with medroxyprogesterone acetate injectable suspension, milk composition, quality, and amount are not adversely affected. Neonates and infants exposed to medroxyprogesterone from breast milk have been studied for developmental and behavioral effects through puberty. No adverse effects have been noted. 5.14 Fluid Retention. Because progestational drugs including medroxyprogesterone acetate injectable suspension may cause some degree of fluid retention, monitor patients with conditions that might be influenced by this condition, such as epilepsy, migraine, asthma, and cardiac or renal dysfunction. 5.15 Return of Fertility. Return to ovulation and fertility is likely to be delayed after stopping medroxyprogesterone acetate injectable suspension. In large U.S. study of women who discontinued use of medroxyprogesterone acetate injectable suspension to become pregnant, data are available for 61% of them. Of the 188 women who discontinued the study to become pregnant, 114 became pregnant. Based on Life-Table analysis of these data, it is expected that 68% of women who do become pregnant may conceive within 12 months, 83% may conceive within 15 months, and 93% may conceive within 18 months from the last injection. The median time to conception for those who do conceive is 10 months following the last injection with range of to 31 months, and is unrelated to the duration of use. No data are available for 39% of the patients who discontinued medroxyprogesterone acetate injectable suspension to become pregnant and who were lost to follow-up or changed their mind. 5.16 Sexually Transmitted Diseases. Patients should be counseled that medroxyprogesterone acetate injectable suspension does not protect against HIV infection (AIDS) and other sexually transmitted diseases. 5.17 Pregnancy. Although medroxyprogesterone acetate injectable suspension should not be used during pregnancy, there appears to be little or no increased risk of birth defects in women who have inadvertently been exposed to medroxyprogesterone acetate injections in early pregnancy. Neonates exposed to medroxyprogesterone acetate in-utero and followed to adolescence showed no evidence of any adverse effects on their health including their physical, intellectual, sexual or social development. 5.18 Monitoring. woman who is taking hormonal contraceptive should have yearly visit with her healthcare provider for blood pressure check and for other indicated healthcare.. 5.19 Interference With Laboratory Tests. The use of medroxyprogesterone acetate injectable suspension may change the results of some laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins. [See Drug Interactions (7.2).].