DEPO-SUBQ PROVERA

Depo-subQ provera 104 contains medroxyprogesterone acetate (MPA), a derivative of progesterone, as its active ingredient. MPA is a white to off-white, odorless crystalline powder that is stable in air and that melts between 205°C and 209°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 MPA is 17-hydroxy-6α-methylpregn-4-ene-3,20-dione 17-acetate. The structural formula is as follows: Depo-subQ provera 104 for subcutaneous use is available in pre-filled syringes, each containing 0.65 mL (104 mg) of sterile medroxyprogesterone acetate injectable suspension. Each 0.65 mL contains the following inactive ingredients: Methylparaben 1.040 mg Propylparaben 0.098 mg Sodium Chloride 5.200 mg Polyethylene Glycol 18.688 mg Polysorbate 80 1.950 mg Monobasic Sodium Phosphate H 2 O 0.451 mg Dibasic Sodium Phosphate 12H 2 O 0.382 mg Methionine 0.975 mg Povidone 3.250 mg Water for Injection qs When necessary, the pH is adjusted with sodium hydroxide or hydrochloric acid, or both. Chemical Structure

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) ].

• 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

The use of depo-subQ provera 104 is contraindicated in the following conditions: • Active thrombophlebitis, or current or history of thromboembolic disorders, or cerebral vascular disease [see Warnings and Precautions (5.2) ] . • Known, suspected, or past malignancy of the breast [see Warnings and Precautions (5.3) ] . • Significant liver disease [see Warnings and Precautions (5.14) ] . • Known hypersensitivity to medroxyprogesterone acetate or any of the ingredients in depo-subQ provera 104 [see Warnings and Precautions (5.6) ] . • Undiagnosed vaginal bleeding [see Warnings and Precautions (5.12) ] . • Active thrombophlebitis, or current or history of thromboembolic disorders, or cerebral vascular disease. ( 4 ) • Known, suspected, or past malignancy of the breast. ( 4 ) • Significant liver disease. ( 4 ) • Known hypersensitivity to medroxyprogesterone acetate or any of the ingredients of depo-subQ provera 104. ( 4 ) • Undiagnosed vaginal bleeding. ( 4 )

The following important adverse reactions are described in more detail in other sections of the prescribing information: • Loss of bone mineral density [see Warnings and Precautions (5.1) ] • Arterial and venous thromboembolic disorders [see Warnings and Precautions (5.2) ] • Anaphylaxis [see Warnings and Precautions (5.6) ] • Fluid retention [see Warnings and Precautions (5.7) ] • Delayed return of ovulation or fertility [see Warnings and Precautions (5.9) ] • Depression [see Warnings and Precautions (5.10) ] • Injection site reactions [see Warnings and Precautions (5.11) ] • Bleeding irregularities [see Warnings and Precautions (5.12) ] Most common adverse reactions (incidence >5%) are dysfunctional uterine bleeding, headache, increased weight, amenorrhea, and injection site reactions. ( 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 Clinical trials are conducted under widely varying conditions, therefore adverse reaction rates observed in the clinical trials 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. The data described below reflect exposure to depo-subQ provera 104 in five clinical trials involving 2325 women including 2043 women who received treatment for contraception (1780 treated up to 1 year and 263 treated for up to 2 years) and 282 women for endometriosis for up to 6 months. In these pooled trials, 9% of women discontinued treatment due to an adverse reaction and the most common reason for discontinuation was dysfunctional uterine bleeding (3%). Adverse Reactions in the Contraception Adult Studies Table 1 presents frequently reported adverse reactions (>1%) in the contraception pooled studies. In these studies, the most frequently reported adverse reactions (>5%) were dysfunctional uterine bleeding (e.g., irregular, increased, decreased, or spotting), headache, increased weight, amenorrhea, and injection site reactions (e.g., pain/tenderness, nodule/lump, persistent atrophy/indentation/dimpling or lipodystrophy). The frequency reported is based on the all-causality incidence in the pooled results of the three contraception studies. Closely related "Adverse Reaction" terms were grouped but individual patients reporting two or more grouped events were only counted once. Table 1. Frequently Reported Adverse Reactions in the Contraception Studies (>1%) Adverse Reaction Frequency Dysfunctional uterine bleeding (irregular, increase, decrease, spotting) 18% Headache 9% Increased weight (see below) 7% Amenorrhea 6% Injection site reactions (such as pain/tenderness, nodule/lump, persistent atrophy/indentation/dimpling, lipodystrophy, discoloration) 6% Vaginitis, including candidiasis and bacterial 5% Abdominal pain 4% Urinary tract infections 4% Acne 4% Depression 3% Decreased libido 3% Nausea 3% Back pain 3% Breast pain/tenderness 2% Fatigue 2% Anxiety 1% Irritability 1% Dizziness 1% Dysfunctional Uterine Bleeding The extent of bleeding and spotting in the three contraception trials is presented in Figure N; data from the endometriosis trials are presented in Figure O [see Warnings and Precautions (5.1) ]. Figure N. Mean Number of Bleeding or Spotting Days in the Subgroup of Women with Bleeding or Spotting Among Women Treated with depo-subQ provera 104 in Contraception Studies N=Number of subjects with bleeding or spotting during indicated month. Figure O. Mean Number of Bleeding or Spotting Days in the Subgroup of Women with Bleeding or Spotting Among Women Treated with depo-subQ provera 104 in Endometriosis Studies N=Number of subjects with bleeding or spotting during indicated month. Figure N Figure O Weight Gain In three large clinical trials, the mean weight gain in depo-subQ provera 104 treated patients was 3.5 lb (1.6 kg) in the first year of use. Half (50%) of women remained within 4.9 lb (2.2 kg) of their initial body weight; 12% of women lost more than 4.9 lb (2.2 kg), and 38% of women gained more than 5.1 lb (2.3 kg). In a small, 2-year study comparing depo-subQ provera 104 to DMPA-IM, the mean weight gain observed for women using depo-subQ provera 104 [7.5 lb (3.4 kg)] was similar to the mean weight gain for women using DMPA-IM [7.7 lb (3.5 kg)]. Other Adverse Reactions Observed in Contraception Clinical Trials with depo-subQ provera 104 Other adverse reactions occurring at an incidence of <1% in women who received depo-subQ provera 104 were as follows: • Neoplasms benign, malignant and unspecified (including cysts and polyps): breast lump • Blood and lymphatic system disorders: anemia • Immune system disorders: drug hypersensitivity • Metabolism and nutrition disorders: weight decreased, fluid retention • Nervous system disorders: facial palsy, syncope, paresthesia, somnolence • Cardiac disorders: tachycardia • Vascular disorders: hot flushes • Respiratory, thoracic and mediastinal disorders: asthma, dyspnea • Gastrointestinal disorders: diarrhea, abdominal distension • Skin and subcutaneous tissue disorders: urticaria, pruritus, dry skin • Reproductive system and breast disorders: dysmenorrhea, galactorrhea, dyspareunia • General disorders and administration site conditions: chest pain Adverse Reactions in the Endometriosis Adult Studies The safety profile of depo-subQ provera 104 in endometriosis clinical trials was similar to the safety profile of depo-subQ provera 104 in the contraception studies with the exception of the following adverse reactions which were more frequently reported in patients with endometriosis: abdominal pain, diarrhea, nausea, and back pain. In endometriosis studies, subjects recorded daily the occurrence and severity of hot flushes. Of the depo-subQ provera 104 users, 29% reported experiencing moderate or severe hot flushes at baseline, 36% at Month 3, and 27% at Month 6. Of the leuprolide users, 33% reported experiencing moderate or severe hot flushes at baseline, 74% at Month 3, and 69% at Month 6. Adverse Reactions in the Adolescent Contraception Study Depo-sub-Q provera 104 and DMPA-IM clinical trials reported similar safety profiles in adult study populations (see Table 1 above). Accordingly, a similar safety profile is expected for adolescents receiving depo-subQ provera 104 as for adolescents receiving DMPA-IM. The safety profile of DMPA-IM for prevention of pregnancy in adolescents was observed to be generally similar to the safety profile of adult women using DMPA-IM for prevention of pregnancy, with the exception of the following adverse reactions which were reported more frequently by adolescents: abdominal pain, diarrhea, back pain, weight increased, depression, headache, and dysmenorrhea. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of DMPA-IM. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure: • Immune system disorders: anaphylactic reaction, anaphylactoid reaction, angioedema • Vascular disorders: pulmonary embolism, deep vein thrombosis, thrombophlebitis • Musculoskeletal and connective tissue disorders: osteoporosis (including osteoporotic fractures) • Reproductive system and breast disorders: prolonged anovulation, unexpected pregnancy, uterine hyperplasia • Respiratory, thoracic and mediastinal disorders: hoarseness • Skin and subcutaneous tissue disorders: increased body odor • Gastrointestinal disorders: gastrointestinal disturbances • General disorders and administration site conditions: axillary swelling, chills, thirst

Strong CYP3A inhibitors and inducers: Avoid concomitant use. ( 7 ) 7.1 Effect of Other Drugs on depo-SubQ provera 104 Moderate or Strong CYP3A Inducers Concomitant use with moderate or strong CYP3A inducers may decrease concentrations of medroxyprogesterone acetate which may reduce depo-subQ provera 104 efficacy. This effect is based upon the primary metabolism of medroxyprogesterone acetate by CYP3A and was not confirmed by a clinical study. Avoid coadministration of depo-subQ provera 104 with moderate or strong CYP3A inducers. Some examples of moderate CYP3A inducers are bosentan, efavirenz, etravirine, and modafinil. Some examples of strong CYP3A inducers are rifampin, carbamazepine, phenytoin, phenobarbital, mitotane, and St. John's wort (the CYP3A4 induction effect of St. John's wort varies widely and is preparation dependent). These examples are a guide and do not represent a comprehensive list of all possible drugs that may fit these categories. The use of CYP3A inducers may require using a back-up or alternate contraceptive method.

16.2 Storage Store at controlled room temperature 20° C to 25° C (68° F to 77°F) [see USP]. Do not refrigerate.