MEDROXYPROGESTERONE: 8,405 Adverse Event Reports & Safety Profile

Medroxyprogesterone Acetate Injectable Suspension, USP contains medroxyprogesterone acetate , a derivative of progesterone, as its active ingredient. Medroxyprogesterone acetate is active by the parenteral and oral routes of administration. It is a white to off-white; odorless crystalline powder that is stable in air and that melts between 200°C and 210°C. It is freely soluble in chloroform, soluble in acetone and dioxane, sparingly soluble in alcohol and methanol, slightly soluble in ether, and insoluble in water. The chemical name for medroxyprogesterone acetate is pregn-4-ene-3, 20-dione, 17-(acetyloxy)-6-methyl-, (6α-). The structural formula is as follows: MPA Injectable Suspension, USP for IM injection is available in vials and prefilled syringes, each containing 1 mL of medroxyprogesterone acetate sterile aqueous suspension 150 mg/mL. For MPA Injectable Suspension, USP vials, each mL of sterile aqueous suspension contains: Medroxyprogesterone acetate 150 mg Polyethylene glycol 3350 28.9 mg Polysorbate 80 2.41 mg Sodium chloride 8.68 mg Methylparaben 1.37 mg Propylparaben 0.150 mg Water for injection quantity sufficient When necessary, pH is adjusted with sodium hydroxide or hydrochloric acid, or both. For MPA Injectable Suspension, USP prefilled syringes, each mL of sterile aqueous suspension contains: Medroxyprogesterone acetate 150 mg Polyethylene glycol 3350 28.5 mg Polysorbate 80 2.37 mg Sodium chloride 8.56 mg Methylparaben 1.35 mg Propylparaben 0.147 mg Water for injection quantity sufficient When necessary, pH is adjusted with sodium hydroxide or hydrochloric acid, or both.

Chemical

Structure

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) ].

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) <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span> . 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> .

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 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 )

REACTIONS 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

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. ( 5.12 )

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, 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 <span class="opacity-50 text-xs">[see Clinical Studies (14.3) ]</span>. 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 <span class="opacity-50 text-xs">[see Clinical Studies (14.2) ]</span>. 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 (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 <span class="opacity-50 text-xs">[see Contraindications (4) ]</span>. 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 2 .

Figure

1 Risk estimates for breast cancer in DMPA 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. Based on the published SEER-18 2011 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 medroxyprogesterone acetate injectable suspension from about 72 to about 144 cases per 100,000 women.

Figure

1 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.

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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) ]</span> . 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.1) ]</span>.

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 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 1 year of therapy with medroxyprogesterone acetate injectable suspension gained an average of 5.4 lb. Women who completed 2 years of therapy gained an average of 8.1 lb. Women who completed 4 years gained an average of 13.8 lb. Women who completed 6 years gained an average of 16.5 lb. Two percent of women withdrew from a large-scale clinical trial because of excessive weight gain.

5.12 Carbohydrate Metabolism A 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.

5.13 Lactation 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 a large US 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 a range of 4 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 A woman who is taking hormonal contraceptive should have a yearly visit with her healthcare provider for a 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) .]

PRECAUTIONS A. General

• Addition of a progestin when a woman has not had a hysterectomy Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer. There are, however, possible risks that may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include an increased risk of breast cancer.
• Unexpected abnormal vaginal bleeding In cases of unexpected abnormal vaginal bleeding, adequate diagnostic measures are indicated.
• Elevated blood pressure Blood pressure should be monitored at regular intervals with estrogen plus progestin therapy.
• Hypertriglyceridemia In women with pre-existing hypertriglyceridemia, estrogen plus progestin therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of treatment if pancreatitis occurs.
• Hepatic Impairment and/or past history of cholestatic jaundice Estrogens plus progestins may be poorly metabolized in women with impaired liver function. For women with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised, and in the case of recurrence, medication should be discontinued.
• Fluid Retention Progestins may cause some degree of fluid retention. Women who have conditions which might be influenced by this factor, such as cardiac or renal impairment, warrant careful observation when estrogen plus progestin are prescribed.
• Hypocalcemia Estrogen plus progestin therapy should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur.
• Exacerbation of other conditions Estrogen plus progestin therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions. B.

Patient Information

Physicians are advised to discuss the Patient Information leaflet with women for whom they prescribe medroxyprogesterone acetate. There may be an increased risk of minor birth defects in children whose mothers are exposed to progestins during the first trimester of pregnancy. The possible risk to the male baby is hypospadias, a condition in which the opening of the penis is on the underside rather than the tip of the penis. This condition occurs naturally in approximately 5 to 8 per 1000 male births. The risk may be increased with exposure to medroxyprogesterone acetate. Enlargement of the clitoris and fusion of the labia may occur in female babies. However, a clear association between hypospadias, clitoral enlargement and labial fusion with use of medroxyprogesterone acetate has not been established. Inform the patient of the importance of reporting exposure to medroxyprogesterone acetate in early pregnancy. C. Drug-Laboratory Test Interactions The following laboratory results may be altered by the use of estrogen plus progestin therapy:

• Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of anti-factor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.
• Increased thyroid-binding globulin (TBG) levels leading to increased circulating total thyroid hormone levels as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels by radioimmunoassay, T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Women on thyroid replacement therapy may require higher doses of thyroid hormone.
• Other binding proteins may be elevated in serum for example, corticosteroid binding globulin (CBG), sex hormone binding globulin (SHBG) leading to increased circulating corticosteroid and sex steroids, respectively. Free hormone concentrations, such as testosterone and estradiol, may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).
• Increased plasma high-density lipoprotein (HDL) and HDL2 cholesterol subfraction concentrations, reduced low-density lipoprotein (LDL) cholesterol concentration, increased triglycerides levels.
• Impaired glucose tolerance. D. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity: Long-term intramuscular administration of medroxyprogesterone acetate has been shown to produce mammary tumors in beagle dogs. There was no evidence of a carcinogenic effect associated with the oral administration of medroxyprogesterone acetate to rats and mice. Long-term continuous administration of estrogen plus progestin therapy has shown an increased risk of breast cancer and ovarian cancer. ( See WARNINGS and PRECAUTIONS . ) Genotoxicity: Medroxyprogesterone acetate was not mutagenic in a battery of in vitro or in vivo genetic toxicity assays. Fertility: Medroxyprogesterone acetate at high doses is an antifertility drug and high doses would be expected to impair fertility until the cessation of treatment. E.

Pregnancy Teratogenic Effects Pregnancy

Category X Medroxyprogesterone acetate should not be used during pregnancy. ( See CONTRAINDICATIONS . ) There may be increased risks for hypospadias, clitoral enlargement and labial fusion in children whose mothers are exposed to medroxyprogesterone acetate during the first trimester of pregnancy. However, a clear association between these conditions with use of medroxyprogesterone acetate has not been established. F.

Nursing Mothers

Medroxyprogesterone acetate should not be used during lactation. Detectable amounts of progestin have been identified in the breast milk of nursing mothers receiving progestins. G.

Pediatric Use

Medroxyprogesterone acetate tablets are not indicated in children. Clinical studies have not been conducted in the pediatric population. H.

Geriatric Use

There have not been sufficient numbers of geriatric women involved in clinical studies utilizing medroxyprogesterone acetate alone to determine whether those over 65 years of age differ from younger subjects in their response to medroxyprogesterone acetate alone.

The

Women’s Health Initiative Studies In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age. (See CLINICAL STUDIES . )

The

Women’s Health Initiative Memory Study In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen- alone or estrogen plus progestin when compared to placebo. (See WARNINGS , Probable Dementia . ) Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women. (See WARNINGS , Probable Dementia . )

INTERACTIONS Drugs or herbal products that induce certain enzymes, including CYP3A4, may decrease the effectiveness of contraceptive drug products. Counsel patients to use a back-up method or alternative method of contraception when enzyme inducers are used with medroxyprogesterone acetate injectable suspension. ( 7.1 )

7.1 Changes in Contraceptive Effectiveness Associated with Co-Administration of Other Products If a woman on hormonal contraceptives takes a drug or herbal product that induces enzymes, including CYP3A4, that metabolize contraceptive hormones, counsel her to use additional contraception or a different method of contraception. Drugs or herbal products that induce such enzymes may decrease the plasma concentrations of contraceptive hormones, and may decrease the effectiveness of hormonal contraceptives. Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include: barbiturates bosentan carbamazepine felbamate griseofulvin oxcarbazepine phenytoin rifampin St. John’s wort topiramate HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors : Significant changes (increase or decrease) in the plasma levels of progestin have been noted in some cases of co-administration of HIV protease inhibitors. Significant changes (increase or decrease) in the plasma levels of the progestin have been noted in some cases of co-administration with non-nucleoside reverse transcriptase inhibitors. Antibiotics : There have been reports of pregnancy while taking hormonal contraceptives and antibiotics, but clinical pharmacokinetic studies have not shown consistent effects of antibiotics on plasma concentrations of synthetic steroids. Consult the labeling of all concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations.

7.2 Laboratory Test Interactions The pathologist should be advised of progestin therapy when relevant specimens are submitted. The following laboratory tests may be affected by progestins including 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. T 3 -uptake values may decrease. (e) Coagulation test values for prothrombin (Factor II), and Factors VII, VIII, IX, and X may increase. (f) Sulfobromophthalein and other liver function test values may be increased. (g) The effects of medroxyprogesterone acetate on lipid metabolism are inconsistent. Both increases and decreases in total cholesterol, triglycerides, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol have been observed in studies.