Medroxyprogesterone Acetate

• 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

5 WARNINGS AND PRECAUTIONS

• Thromboembolic disorders: Discontinue depo-subQ provera 104 in patients who develop arterial or venous thrombosis. ( 5.2 )
• Breast cancer risks: Monitor women with a family history of breast cancer or a significant risk of breast cancer carefully. ( 5.3 )
• Meningioma: Discontinue depo-subQ provera 104 if meningioma is diagnosed. Monitor patients for signs and symptoms of meningioma. ( 5.4 )
• Ectopic pregnancy: Consider ectopic pregnancy if a woman becomes pregnant or complains of severe abdominal pain. ( 5.5 )
• Anaphylaxis: Provide emergency medical treatment. ( 5.6 )
• Injection site reactions (e.g., persistent atrophy, dimpling/indentation, lump/nodule and discoloration) have been reported. ( 5.11 )
• Diabetics may be at greater risk of hyperglycemia. ( 5.13 )
• Jaundice and elevated transaminase: Discontinue depo-subQ provera 104 if jaundice or elevated transaminase levels develop. ( 5.14 )

5.1 Loss of Bone Mineral Density Use of depo-subQ provera 104 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 depo-subQ provera 104 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 DMPA-IM. After discontinuing DMPA-IM 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 (14.4) ] . 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 (14.3) ] . 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. BMD should be evaluated when a woman needs to continue to use depo-subQ provera 104 long-term. In adolescents, interpretation of BMD results should take into account patient age and skeletal maturity. Other birth control methods or therapies for endometriosis-associated pain should be considered in the risk/benefit analysis for the use of depo-subQ provera 104 in women with osteoporosis risk factors. Depo-subQ provera 104 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 Arterial and Venous Thromboembolic Disorders There have been reports of serious arterial and venous thrombotic events in women treated with DMPA-IM. Women with a history of thromboembolic disorders were not studied in clinical trials of depo-subQ provera 104. Although no causal relationship between the use of depo-subQ provera 104 and thrombotic events has been clearly established, patients who develop arterial or venous thrombosis while taking depo-subQ provera 104 should discontinue treatment. Do not re-administer depo-subQ provera 104 pending examination if there is a sudden onset of a suspected vascular ocular event (e.g., partial or complete loss of vision, proptosis, or diplopia) or migraine. Do not re-administer depo-subQ provera 104 if examination reveals papilledema or retinal vascular lesions.

5.3 Cancer Risks Breast Cancer The use of hormonal contraceptives, including depo sub-Q provera 104, is contraindicated in women who have or have had breast cancer because breast cancer may be sensitive to hormones [see Contraindications (4) ] . Women who have a family history of breast cancer or a significant risk of breast cancer should be monitored. The results of five large case-control studies assessing the association between DMPA-IM use and the risk of breast cancer are summarized in Figure M. 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 US study 1 evaluated the timing and duration of use and found a statistically significant increased risk of breast cancer in recent DMPA-IM users (defined as last use within the past five years) who used DMPA-IM for 12 months or longer; this is consistent with results of a previous study 2 . Figure M. Risk Estimates of Breast Cancer in DMPA-IM Users 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. Odds Ratio [95% confidence interval (CI)] displayed on logarithmic scale Based on the published SEER-18 2015 incidence rate (age-adjusted to the 2000 US Standard Population) of breast cancer for US women, all races, age 20 to 49 years, a doubling of risk would increase the incidence of breast cancer in women who use DMPA-IM from about 73 to about 146 cases per 100,000 women. Figure M Other Cancers The relative rate of invasive squamous-cell cervical cancer in women who ever used DMPA-IM 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. Long-term, case-controlled surveillance of users of DMPA-IM found no overall increased risk of ovarian or liver cancer.

5.4 Meningioma Cases of meningiomas have been reported following repeated administration of medroxyprogesterone acetate, primarily with long term use. Monitor patients on depo-subQ provera 104 for signs and symptoms of meningioma. Discontinue depo-subQ provera 104 if a meningioma is diagnosed.

5.5 Ectopic Pregnancy Healthcare professionals should be alert to the possibility of an ectopic pregnancy among women using depo-subQ provera 104 who become pregnant or complain of severe abdominal pain.

5.6 Anaphylaxis Serious anaphylactic reactions have been reported in women using depo-subQ provera 104. If an anaphylactic reaction occurs, appropriate emergency medical treatment should be administered.

5.7 Fluid Retention Because progestational drugs including depo-subQ provera 104 may cause fluid retention, monitor patients with conditions that might be affected by fluid retention.

5.8 Weight Gain Weight gain is a common occurrence in women using depo-subQ provera 104. In three large clinical trials using depo-subQ provera 104, the mean weight gain was 3.5 lb (1.6 kg) in the first year of use. In a small, two-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 [7.6 lb (3.5 kg)]. Although there are no data related to weight gain beyond 2 years for depo-subQ provera 104, the data on DMPA-IM may be relevant. In a clinical study, after five years, 41 women using Depo-Provera CI (150 mg) had a mean weight gain of 11.2 lb (5.1 kg), while 114 women using non-hormonal contraception had a mean weight gain of 6.4 lb (2.9 kg).

5.9 Delayed Return of Ovulation or Fertility Return to ovulation is likely to be delayed after stopping depo-subQ provera 104, as demonstrated in a study of 15 women who received multiple doses of depo-subQ provera 104:

• Median time to ovulation was 10 months after the last injection.
• Earliest return to ovulation was 6 months after the last injection.
• 12 women (80%) ovulated within 1 year of the last injection. However, ovulation has occurred as early as 14 weeks after a single dose of depo-subQ provera 104; therefore, administer the next depo-subQ provera 104 12 to 14 weeks after the last injection. Return to fertility also is likely to be delayed after stopping therapy. Among 28 women using depo-subQ provera 104 for contraception who stopped treatment to become pregnant, 7 women were lost to follow-up. One woman became pregnant within one year of her last injection and another woman became pregnant 443 days after her last injection. The remaining 19 women had not become pregnant; it is not known if these 19 women were still attempting to become pregnant or if they had started a new contraceptive method .

5.10 Depression Depression (3% of depo-subQ provera 104-treated patients) and other mood disorders have been reported in clinical trials of depo-subQ provera 104 [see Adverse Reactions (6.1) ] . Patients with a history of depression or who are on treatment for depression may be at increased risk for depression recurrence or exacerbation and for associated mood disorders while receiving depo-subQ provera 104. Therefore, patients should be monitored for symptoms of depression and mood changes.

5.11 Injection Site Reactions In five clinical studies of depo-subQ provera 104 involving 2325 women (282 treated for up to 6 months, 1780 treated for up to 1 year, and 263 women treated for up to 2 years), 5% of women reported injection site reactions (such as pain/tenderness, nodule/lump, lipodystrophy, discoloration), and 1% had persistent atrophy/indentation/dimpling [see Adverse Reactions (6.1) ] . These injection site reactions have also been reported in post-marketing experience.

5.12 Bleeding Irregularities Most women using depo-subQ provera 104 experienced changes in menstrual bleeding patterns, such as amenorrhea, irregular unpredictable spotting or bleeding, prolonged spotting or bleeding, or heavy bleeding [see Adverse Reactions (6.1) ] . Fewer women experienced irregular bleeding and more experienced amenorrhea with longer term use of depo‑subQ provera 104, consistent with expected endometrial thinning effects. In three contraception trials, 39% of 2053 depo-subQ provera 104-treated women experienced amenorrhea during Month 6, and 57% experienced amenorrhea during Month 12. In two endometriosis trials using depo-subQ provera 104, 24% of 289 women experienced amenorrhea during Month 6 [see Adverse Reactions (6.1) ] . If abnormal bleeding is persistent or severe, evaluate the patient for underlying pathology or pregnancy.

5.13 Risk of Hyperglycemia in Patients with Diabetes Some patients receiving progestins may exhibit a decrease in glucose tolerance; therefore, patients with diabetes may be at greater risk of hyperglycemia.

5.14 Jaundice and Elevated Transaminase Discontinue depo-subQ provera 104 if jaundice or elevated transaminase levels develop. Depo-subQ provera 104 may be resumed after both the jaundice and elevated transaminase levels resolve, and the healthcare professional determines that depo-subQ provera 104 did not cause the abnormalities.

5.15 Protection Against Sexually Transmitted Infections Patients should be counseled that this product does not protect against HIV infection (including AIDS) and other sexually transmitted infections.

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

12.1 Mechanism of Action Depo-subQ provera 104 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. Suppression of serum estradiol concentrations is likely to be responsible for the therapeutic effect on endometriosis-associated pain.

12.2 Pharmacodynamics The following laboratory tests are expected to be affected by progestins including depo-subQ provera 104:

• Plasma and urinary steroid levels are decreased (e.g., progesterone, estradiol, pregnanediol, testosterone, cortisol).
• Gonadotropin levels are decreased.
• Sex-hormone-binding-globulin concentrations are decreased.
• Histology specimens may demonstrate changes consistent with progestin effects. The following laboratory tests may be affected by depo-subQ provera 104, however the clinical significance is unknown:
• Protein-bound iodine and butanol extractable protein-bound iodine may increase.
• T 3 -uptake values may decrease.
• Coagulation test values for prothrombin (Factor II), and Factors VII, VIII, IX, and X may increase.
• Sulfobromophthalein and other liver function test values may be increased.
• 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.

12.3 Pharmacokinetics The pharmacokinetic parameters of MPA following a single subcutaneous injection of depo-subQ provera 104 in healthy women (n=42) are shown in Table 2 and Figure P. Table 2. Pharmacokinetic Parameters of MPA after a Single Subcutaneous Injection of depo-subQ provera 104 in Healthy Women C max (ng/mL) T max (day) C 91 (ng/mL) AUC 0–91 (ng∙day/mL) AUC 0–∞ (ng∙day/mL) t½ (day) Abbreviations: C max =peak serum concentration; T max =time when C max is observed; C 91 =serum concentration at 91 days; AUC 0–91 and AUC 0–∞ =area under the concentration-time curve over 91 days or infinity, respectively; t½=terminal half-life. Mean 1.56 8.8 0.402 66.98 92.84 43 Min 0.53 2.0 0.133 20.63 31.36 16 Max 3.08 80.0 0.733 139.79 162.29 114 Following subcutaneous administration of single depo-subQ provera 104 doses ranging from 50 to 150 mg (0.48 and 1.4 times the recommended dose, respectively), the AUC and C min (Day 91) increased with higher doses, but there was considerable overlap across dose levels. Serum MPA concentrations at Day 91 increased in a dose proportional manner but C max did not appear to increase proportionally with increasing dose. The AUC data were suggestive of dose linearity. Absorption Following a single subcutaneous injection of depo-subQ provera 104 in healthy women, serum MPA concentrations reached ≥0.2 ng/mL within 24 hours. The mean T max was attained approximately 1 week after injection. Figure P. Serum Concentration-Time Profile of MPA Mean (SD) after a Single Injection of depo-subQ provera 104 to Healthy Women In a study to assess accumulation and the achievement of steady state following multiple subcutaneous administrations, trough concentrations of MPA were determined after 6, 12, and 24 months, and in a subset of 8 subjects, bi-weekly concentrations were determined within one dosing interval in the second year of administration. The mean (SD) MPA trough concentrations were 0.67 (0.36) ng/mL (n=157), 0.79 (0.36) ng/mL (n=144), and 0.87 (0.33) ng/mL (n=106) at 6, 12, and 24 months, respectively. Depo-subQ provera 104 was administered subcutaneously into the anterior thigh or the abdomen to evaluate effects of injection site location on the MPA concentration-time profile. MPA trough concentrations (C min ; Day 91) were similar for the two injection site locations. Figure P 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). Elimination 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 Residual MPA concentrations at the end of the first dosing interval (12 to 14 weeks) of depo-subQ provera 104 were generally below 0.5 ng/mL, consistent with its apparent terminal half-life of ~40 days after subcutaneous administration. Most MPA metabolites were excreted in the urine as glucuronide conjugates with only small amounts excreted as sulfates. Specific Populations Racial Groups There were no significant differences in the pharmacokinetics and/or pharmacodynamics of MPA after subcutaneous administration of depo-subQ provera 104 in African-American, Caucasian, and Asian women. Effect of Body Weight Although total MPA exposure was lower in obese women, no dosage adjustment of depo-subQ provera 104 is necessary based on body weight. The effect of body weight on the pharmacokinetics of MPA following a single dose was assessed in a subset of women [n=42, body mass index (BMI) ranged from 18.2 to 46.7 kg/m 2 ]. The AUC 0–91 values for MPA were 71.6, 67.9, and 46.3 ng∙day/mL in women with BMI categories of ≤28 kg/m 2 , >28–38 kg/m 2 , and >38 kg/m 2 , respectively. The mean MPA C max was 1.74 ng/mL in women with BMI ≤28 kg/m 2 , 1.53 ng/mL in women with BMI >28–38 kg/m 2 , and 1.02 ng/mL in women with BMI >38 kg/m 2 , respectively. The MPA trough (C min ) concentrations had a tendency to be lower in women with BMI >38 kg/m 2 .