medroxyprogesterone acetate 400 MG/ML Injectable Suspension

INDICATIONS AND USAGE Depo-subQ provera 104 is indicated in females of reproductive age for: • Prevention of pregnancy and • Management of endometriosis-associated pain. Depo-subQ provera 104 is a progestin that is indicated in females of reproductive age for: • Prevention of pregnancy. ( 1 ) • Management of endometriosis-associated pain. ( 1 ) Limitations of Use : Use of depo-subQ provera 104 is not recommended as a long-term (i.e., longer than 2 years) birth control method or medical therapy for endometriosis-associated pain unless other options are considered inadequate. ( 1 , 5.1 ) Limitations of Use : The use of depo-subQ provera 104 is not recommended as a long-term (i.e., longer than 2 years) birth control method or medical therapy for endometriosis-associated pain unless other options are considered inadequate [see Dosage and Administration (2.1) and Warnings and Precautions (5.1) ].

DOSAGE AND ADMINISTRATION • Only for healthcare professional administration. ( 2.1 ) • Prior to first injection, confirm the patient is not pregnant. ( 2.1 ) • Administer 104 mg of depo-subQ provera 104 by subcutaneous injection into the anterior thigh or abdomen, once every 12 to 14 weeks. ( 2.1 ) • See Full Prescribing Information for recommendations on switching from another contraceptive method to depo-subQ provera 104. ( 2.2 ) • See Full Prescribing Information for important preparation and administration instructions. ( 2.3 ) 2.1 Important Dosage and Administration Instructions Depo-subQ provera 104 is only for subcutaneous administration and is only to be administered by a healthcare professional. Use for longer than 2 years is not recommended (unless other birth control methods or medical therapies for endometriosis-associated pain are considered inadequate) due to the impact of long-term depo-subQ provera 104 treatment on bone mineral density (BMD) [see Warnings and Precautions (5.1) ] . Prior to the first injection confirm that the patient is not pregnant. For women who are sexually active and who have regular menses, administer the first injection only during the first 5 days of a normal menstrual period. For women who are breast-feeding, administer the first injection during or after the sixth post-partum week. The recommended dosage of depo-subQ provera 104 is 104 mg given subcutaneously every 12 to 14 weeks. If more than 14 weeks elapse between injections, confirm that the patient is not pregnant before the next injection. Instruct the patient that if they are unable to receive an injection within 12–14 weeks, another contraceptive method should be used until the next depo-subQ provera 104 injection. The dosage does not need to be adjusted for body weight. Inject the entire contents of the pre-filled syringe using strict aseptic technique into the upper anterior thigh or abdomen, rotating the sites with every injection [see Dosage and Administration (2.3) ] . 2.2 Switching from Another Method of Contraception When switching from another contraceptive method to depo-subQ provera 104, administer depo-subQ provera 104 in a manner that ensures continuous contraceptive coverage. Follow the respective recommendations when switching from the contraceptive methods listed below: • Combined hormonal contraceptives : administer the first injection of depo-subQ provera 104 within 7 days after the last day of using the combined hormonal contraceptive method (i.e., within 7 days after taking the last active pill). • An implant : administer the first injection of depo-subQ provera 104 on the day of implant removal. • A contraceptive vaginal ring or transdermal system : administer the first injection of depo-subQ provera 104 on the day the patient would have inserted the next ring or applied the next transdermal system. • An Intrauterine Device (IUD) or Intrauterine System (IUS) : administer the first injection of depo-subQ provera 104 on the day of IUD/IUS removal. If the IUD/IUS is not removed on the first day of the patient's menstrual cycle, instruct patients to use a non-hormonal back-up method of birth control for the first 7 days after administration of depo-subQ provera 104. • Depot medroxyprogesterone acetate injectable suspension for intramuscular use (DMPA-IM) : inject depo-subQ provera 104 12 to 14 weeks after the last dose of DMPA-IM. 2.3 Preparation and Administration Instructions Prior to injection: • Ensure all the components in Figure A are available and that depo-subQ provera 104 is at room temperature . • Shake the pre-filled syringe vigorously prior to injection to ensure appropriate viscosity of the suspension. • Inspect depo-subQ provera 104 visually for particulate matter and discoloration. Figure A. Components in the Package Step 1: Select & Prepare the Injection Area • Select a preferred injection area, i.e., the left or right upper thigh or the abdomen (see shaded areas , Figure B ). • Avoid selection of bony areas and the umbilicus. • Clean the skin in the injection area you have chosen with a clean cotton pad or clean paper tissue. • Rotate the injection site by injecting into a different puncture site than used for the previous injection. Figure B. Preferred injection areas: Left or right upper thigh or abdomen Step 2: Prepare Syringe • Carefully remove the needle and syringe from the packaging. • Hold the syringe firmly by the barrel, with the barrel pointing upward. • Shake the syringe vigorously for at least 1 minute to mix thoroughly ( Figure C ). Figure C. Shake vigorously for 1 minute • While holding the syringe barrel firmly, remove the protective cap from the tip of the syringe barrel by unscrewing it ( Figure D ). Figure D. • While holding the syringe barrel firmly, attach the needle to the barrel of the syringe firmly by pushing the plastic needle cover down fully and firmly with a slight twisting movement ( Figure E ). Figure E. • Move the safety shield away from the needle and toward the syringe barrel. The safety shield will remain in an open 45- to 90-degree position ( Figure F ). Figure F. • While holding the syringe barrel firmly, remove the plastic needle cover from the needle without twisting, ensuring the needle is still firmly attached to the syringe ( Figure G ). Figure G. • While holding the syringe with the needle pointing upward, gently push in the plunger until the liquid is up to the top of the syringe ( Figure H ). There should be no air within the barrel. Figure H. Step 3: Injecting depo-Sub Q provera 104 • Gently grasp and squeeze a large area of skin in the chosen injection area between the thumb and forefinger, pulling it away from the body ( Figure I ). • Insert the needle at a 45-degree angle so that most of the needle is in the fatty tissue. • The plastic hub of the needle should be nearly or almost touching the skin. Figure I. Inject slowly until the syringe is empty ( Figure J ). • This should take about 5 to 7 seconds. • It is important that the entire dose is given. Figure J. Inject slowly (5–7 seconds) Step 4: Remove the Needle and Activate the Safety Shield • After completing the injection, remove the needle from the skin and activate the safety shield as follows: o While positioning the shield about 40°– 45°, and with a firm quick motion, press down against a flat surface until a click is heard or felt ( Figure K ). o If uncertain that the safety shield is fully engaged, repeat this step. Figure K. • Use a clean cotton pad to press lightly on the injection area for a few seconds ( Figure L ). • Do not rub the area. Figure L. Figure A Figure B Figure C Figure D Figure E Figure F Figure G Figure H Figure I Figure J Figure K Figure L

WARNINGS AND PRECAUTIONS Thromboembolic Disorders: Discontinue medroxyprogesterone acetate injectable suspension in patients who develop thrombosis. ( 5.2 ) Cancer Risks: Monitor women with a strong family history of breast cancer carefully. ( 5.3 ) Ectopic Pregnancy: Consider ectopic pregnancy if a 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. ( 5.1 2) 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, a 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. A 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 5 years (60 months) post-treatment in the sub-group of adolescents who were treated for more than 2 years [see Clinical Studies (14.3)]. Similarly, in adults, there was only partial recovery of mean BMD at the total hip, femoral neck, and lumbar spine towards baseline by 2 years post-treatment [See Clinical Studies (14.2)]. The use of medroxyprogesterone acetate injectable suspension is not recommended as a long-term (i.e., longer than 2 years) birth control method unless other options are considered inadequate. BMD should be evaluated when a woman needs to continue to use medroxyprogesterone acetate 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 a sudden partial or complete loss of vision or if there is a sudden onset of proptosis, diplopia, or migraine. Do not re-administer if examination reveals papilledema or retinal vascular lesions. 5.3 Cancer Risks Breast Cancer Women who have or have had a history of breast cancer should not use hormonal contraceptives, including medroxyprogesterone acetate injectable suspension, because breast cancer may be hormonally sensitive [see Contraindications ( 4 )]. Women with a strong family history of breast cancer should be monitored with particular care. The results of five large case-control studies 1, 2 assessing the association between depo-­medroxyprogesterone acetate (DMPA) use and the risk of breast cancer are summarized in Figure 1. Three of the studies suggest a slightly increased risk of breast cancer in the overall population of users; these increased risks were statistically significant in one study. One recent US study 1 evaluated the recency and duration of use and found a 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 a 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, a 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 A 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 a 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 a 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 disr

CONTRAINDICATIONS The use of medroxyprogesterone acetate 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 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 )

CLINICAL PHARMACOLOGY Medroxyprogesterone acetate (MPA) administered orally or parenterally in the recommended doses to women with adequate endogenous estrogen, transforms proliferative into secretory endometrium. Androgenic and anabolic effects have been noted, but the drug is apparently devoid of significant estrogenic activity. While parenterally administered MPA inhibits gonadotropin production, which in turn prevents follicular maturation and ovulation, available data indicate that this does not occur when the usually recommended oral dosage is given as single daily doses. Pharmacokinetics The pharmacokinetics of MPA were determined in 20 postmenopausal women following a single-dose administration of eight medroxyprogesterone acetate 2.5 mg tablets or a single administration of two medroxyprogesterone acetate 10 mg tablets under fasting conditions. In another study, the steady-state pharmacokinetics of MPA were determined under fasting conditions in 30 postmenopausal women following daily administration of one medroxyprogesterone acetate 10 mg tablet for 7 days. In both studies, MPA was quantified in serum using a validated gas chromatography-mass spectrometry (GC-MS) method. Estimates of the pharmacokinetic parameters of MPA after single and multiple doses of medroxyprogesterone acetate tablets were highly variable and are summarized in Table 1. Table 1. Mean (SD) Pharmacokinetic Parameters for Medroxyprogesterone Acetate (MPA) Tablet Strength C max (ng/mL) T max (h) Auc 0-(∞) (ng·h/mL) t 1/2 (h) Vd/f (L) CL/f (mL/min) Single Dose 2 x 10 mg 1.01 (0.599) 2.65 (1.41) 6.95 (3.39) 12.1 (3.49) 78024 (47220) 64110 (42662) 8 x 2.5 mg 0.805 (0.413) 2.22 (1.39) 5.62 (2.79) 11.6 (2.81) 62748 (40146) 74123 (35126) Multiple Dose 10 mg * 0.71 (0.35) 2.83 (1.83) 6.01 (3.16) 16.6 (15.0) 40564 (38256) 41963 (38402) *Following Day 7 dose A. Absorption: No specific investigation on the absolute bioavailability of MPA in humans has been conducted. MPA is rapidly absorbed from the gastrointestinal tract, and maximum MPA concentrations are obtained between 2 to 4 hours after oral administration. Administration of medroxyprogesterone acetate tablets with food increases the bioavailability of MPA. A 10 mg dose of medroxyprogesterone acetate tablets, taken immediately before or after a meal, increased MPA C max (50 to 70%) and AUC (18 to 33%). The half-life of MPA was not changed with food. B. Distribution: MPA is approximately 90% protein bound, primarily to albumin; no MPA binding occurs with sex hormone binding globulin. C. Metabolism: Following oral dosing, MPA is extensively metabolized in the liver via hydroxylation, with subsequent conjugation and elimination in the urine. D. Excretion: Most MPA metabolites are excreted in the urine as glucuronide conjugates with only minor amounts excreted as sulfates. E. Specific Populations Hepatic Insufficiency MPA is almost exclusively eliminated via hepatic metabolism. In 14 patients with advanced liver disease, MPA disposition was significantly altered (reduced elimination). In patients with fatty liver, the mean percent dose excreted in the 24-hour urine as intact MPA after a 10 mg or 100 mg dose was 7.3% and 6.4%, respectively. Renal Insufficiency The effect of renal impairment on the pharmacokinetics of medroxyprogesterone acetate has not been studied. F. Drug Interactions Medroxyprogesterone acetate (MPA) is metabolized in-vitro primarily by hydroxylation via the CYP3A4. Specific drug-drug interaction studies evaluating the clinical effects with CYP3A4 inducers or inhibitors on MPA have not been conducted. Inducers and/or inhibitors of CYP3A4 may affect the metabolism of MPA.