NONCLINICAL TOXICOLOGY SECTION.


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

NURSING MOTHERS SECTION.


8.3Nursing Mothers. Detectable amounts of drug have been identified in the milk of mothers receiving Depo-Provera CI. [See Warnings and Precautions (5.13) .].

ADVERSE REACTIONS SECTION.


6ADVERSE REACTIONS. The following important adverse reactions observed with the use of Depo-Provera CI are discussed in greater detail in the Warnings and Precautions section (5):Loss of Bone Mineral Density [see Warnings and Precautions (5.1)] Thromboembolic disease [see Warnings and Precautions (5.2)] Breast Cancer [see Warnings and Precautions (5.3)] Anaphylaxis and Anaphylactoid Reactions [see Warnings and Precautions (5.5)] Bleeding Irregularities[see Warnings and Precautions (5.10)] Weight Gain [see Warnings and Precautions (5.11)] Loss of Bone Mineral Density [see Warnings and Precautions (5.1)] Thromboembolic disease [see Warnings and Precautions (5.2)] Breast Cancer [see Warnings and Precautions (5.3)] Anaphylaxis and Anaphylactoid Reactions [see Warnings and Precautions (5.5)] Bleeding Irregularities[see Warnings and Precautions (5.10)] Weight Gain [see Warnings and Precautions (5.11)] Most common adverse reactions (incidence >5%) are: menstrual irregularities (bleeding or spotting) 57% at 12 months, 32% at 24 months, abdominal pain/discomfort 11%, weight gain >10 lbs at 24 months 38%, dizziness 6%, headache 17%, nervousness 11%, decreased libido 6%. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.In the two clinical trials with Depo-Provera CI, over 3,900 women, who were treated for up to years, reported the following adverse reactions, which may or may not be related to the use of Depo-Provera CI. The population studied ranges in age from 15 to 51 years, of which 46% were White, 50% Non-White, and 4.9% Unknown race. The patients received 150 mg Depo-Provera CI every 3-months (90 days). The median study duration was 13 months with range of 1-84 months. Fifty eight percent of patients remained in the study after 13 months and 34% after 24 months.Table Adverse Reactions that Were Reported by More than 5% of SubjectsBody SystemBody System represented from COSTART medical dictionary. Adverse Reactions [Incidence (%)]Body as WholeHeadache (16.5%)Abdominal pain/discomfort (11.2%)Metabolic/NutritionalIncreased weight> 10lbs at 24 months (37.7%)NervousNervousness (10.8%)Dizziness (5.6%)Libido decreased (5.5%)UrogenitalMenstrual irregularities:(bleeding (57.3% at 12 months, 32.1% at 24 months) amenorrhea (55% at 12 months, 68% at 24 months)Table Adverse Reactions that Were Reported by between and 5% of Subjects Body SystemBody System represented from COSTART medical dictionary. Adverse Reactions [Incidence (%)]Body as WholeAsthenia/fatigue (4.2%)Backache (2.2%) Dysmenorrhea (1.7%)Hot flashes (1.0%)DigestiveNausea (3.3%)Bloating (2.3%)Metabolic/NutritionalEdema (2.2%)MusculoskeletalLeg cramps (3.7%)Arthralgia (1.0%)NervousDepression (1.5%)Insomnia (1.0%)Skin and AppendagesAcne (1.2%)No hair growth/alopecia (1.1%)Rash (1.1%)UrogenitalLeukorrhea (2.9%)Breast pain (2.8%)Vaginitis (1.2%)Adverse reactions leading to study discontinuation in >=2% of subjects: bleeding (8.2%), amenorrhea (2.1%), weight gain (2.0%). 6.2Post-Marketing Experience. The following adverse reactions have been identified during post approval use of Depo-Provera CI. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.There have been cases of osteoporosis including osteoporotic fractures reported post-marketing in patients taking Depo-Provera CI.Table Adverse Reactions Reported during Post-Marketing Experience Body SystemBody System represented from COSTART medical dictionary. Adverse ReactionsBody as WholeChest pain, Allergic reactions including angioedema, Fever, Injection site abscessInjection site abscess and injection site infections have been reported; therefore strict aseptic injection technique should be followed when administering Depo Provera CI in order to avoid injection site infections [see Dosage and Administration (2.1)]. Injection site infection, Injection site nodule/lump, Injection site pain/tenderness, Injection site persistent atrophy/indentation/dimpling, Injection-site reaction, Lipodystrophy acquired, Chills, Axillary swellingCardiovascular Syncope, Tachycardia, Thrombophlebitis, Deep vein thrombosis, Pulmonary embolus, Varicose veinsDigestiveChanges in appetite, Gastrointestinal disturbances, Jaundice, Excessive thirst, Rectal bleedingHematologic and LymphaticAnemia, Blood dyscrasiaMusculoskeletalOsteoporosisNeoplasmsCervical cancer, Breast cancerNervousParalysis, Facial palsy, Paresthesia, DrowsinessRespiratoryDyspnea and asthma, HoarsenessSkin and AppendagesHirsutism, Excessive sweating and body odor, Dry skin, SclerodermaUrogenitalLack of return to fertility, Unexpected pregnancy, Prevention of lactation, Changes in breast size, Breast lumps or nipple bleeding, Galactorrhea, Melasma, Chloasma, Increased libido, Uterine hyperplasia, Genitourinary infections, Vaginal cysts, Dyspareunia.

BOXED WARNING SECTION.


WARNING: LOSS OF BONE MINERAL DENSITY. Women who use Depo-Provera Contraceptive Injection (Depo-Provera CI) may lose significant bone mineral density. Bone loss is greater with increasing duration of use and may not be completely reversible [see Warnings and Precautions (5.1)].It is unknown if use of Depo-Provera CI during adolescence or early adulthood, critical period of bone accretion, will reduce peak bone mass and increase the risk for osteoporotic fracture in later life [see Warnings and Precautions (5.1)].Depo-Provera CI is not recommended as long-term (i.e., longer than years) birth control method unless other options are considered inadequate [see Indications and Usage (1) and Warnings and Precautions (5.1)].. WARNING: LOSS OF BONE MINERAL DENSITYSee full prescribing information for complete boxed warning.Women who use Depo-Provera Contraceptive Injection (Depo-Provera CI) may lose significant bone mineral density. Bone loss is greater with increasing duration of use and may not be completely reversible. (5.1)It is unknown if use of Depo-Provera CI during adolescence or early adulthood, critical period of bone accretion, will reduce peak bone mass and increase the risk for osteoporotic fracture in later life. (5.1)Depo-Provera CI is not recommended as long-term (i.e., longer than years) birth control method unless other options are considered inadequate. (1, 5.1). Women who use Depo-Provera Contraceptive Injection (Depo-Provera CI) may lose significant bone mineral density. Bone loss is greater with increasing duration of use and may not be completely reversible. (5.1). It is unknown if use of Depo-Provera CI during adolescence or early adulthood, critical period of bone accretion, will reduce peak bone mass and increase the risk for osteoporotic fracture in later life. (5.1). Depo-Provera CI is not recommended as long-term (i.e., longer than years) birth control method unless other options are considered inadequate. (1, 5.1).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


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

CLINICAL PHARMACOLOGY SECTION.


12CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Depo-Provera CI (medroxyprogesterone acetate [MPA]) inhibits the secretion of gonadotropins which primarily prevents follicular maturation and ovulation and causes thickening of cervical mucus. These actions contribute to its contraceptive effect.. 12.2 Pharmacodynamics. No specific pharmacodynamic studies were conducted with Depo-Provera CI.. 12.3 Pharmacokinetics. AbsorptionFollowing single 150 mg IM dose of Depo-Provera CI in eight women between the ages of 28 and 36 years old, medroxyprogesterone acetate concentrations, measured by an extracted radioimmunoassay procedure, increase for approximately weeks to reach peak plasma concentrations of to ng/mL.. DistributionPlasma protein binding of MPA averages 86%. MPA binding occurs primarily to serum albumin. No binding of MPA occurs with sex-hormone-binding globulin (SHBG).. MetabolismMPA is extensively metabolized in the liver by P450 enzymes. Its metabolism primarily involves ring and/or side-chain reduction, loss of the acetyl group, hydroxylation in the 2-, 6-, and 21-positions or combination of these positions, resulting in more than 10 metabolites.. ExcretionThe concentrations of medroxyprogesterone acetate decrease exponentially until they become undetectable (<100 pg/mL) between 120 to 200 days following injection. Using an unextracted radioimmunoassay procedure for the assay of medroxyprogesterone acetate in serum, the apparent half-life for medroxyprogesterone acetate following IM administration of Depo-Provera CI is approximately 50 days. Most medroxyprogesterone acetate metabolites are excreted in the urine as glucuronide conjugates with only minor amounts excreted as sulfates.. Specific PopulationsThe effect of hepatic and/or renal impairment on the pharmacokinetics of Depo-Provera CI is unknown.

CLINICAL STUDIES SECTION.


14CLINICAL STUDIES. 14.1 Contraception. In five clinical studies using Depo-Provera CI, the 12-month failure rate for the group of women treated with Depo-Provera CI was zero (no pregnancies reported) to 0.7 by Life-Table method. The effectiveness of Depo-Provera CI is dependent on the patient returning every months (13 weeks) for reinjection.. 14.2 Bone Mineral Density Changes in Women Treated with Depo-Provera CI. In controlled, clinical study, adult women using Depo-Provera CI (150mg) for up to years showed spine and hip bone mineral density (BMD) mean decreases of 5-6%, compared to no significant change in BMD in the control group. The decline in BMD was more pronounced during the first two years of use, with smaller declines in subsequent years. Mean changes in lumbar spine BMD of -2.86%, -4.11%, -4.89%, -4.93% and -5.38% after 1, 2, 3, 4, and years, respectively, were observed. Mean decreases in BMD of the total hip and femoral neck were similar.After stopping use of Depo-Provera CI, there was partial recovery of BMD toward baseline values during the 2-year post-therapy period. Longer duration of treatment was associated with less complete recovery during this 2-year period following the last injection. Table shows the change in BMD in women after years of treatment with Depo-Provera CI and in women in control group, as well as the extent of recovery of BMD for the subset of the women for whom 2-year post treatment data were available.Table 4. Mean Percent Change from Baseline in BMD in Adults by Skeletal Site and Cohort (5 Years of Treatment and Years of Follow-Up)Time in StudySpineTotal HipFemoral NeckDepo-ProveraThe treatment group consisted of women who received Depo-Provera CI for years and were then followed for years post-use (total time in study of years). ControlThe control group consisted of women who did not use hormonal contraception and were followed for years. Depo-Provera Control Depo-Provera Control years-5.38%n=330.43%n=105-5.16%n=210.19%n=65-6.12%n=34-0.27%n=1067 years-3.13%n=120.53%n=60-1.34%n=70.94%n=39-5.38%n=13-0.11%n=63. 14.3 Bone Mineral Density Changes in Adolescent Females (12 to 18 Years of Age) Treated with Depo-Provera CI. The impact of Depo-Provera CI (150 mg) use for up to 240 weeks (4.6 years) was evaluated in an open-label non-randomized clinical study in 389 adolescent females (12 to 18 years of age). Use of Depo-Provera CI was associated with significant decline from baseline in BMD.Partway through the trial, drug administration was stopped (at 120 weeks). The mean number of injections per Depo-Provera CI user was 9.3. Table summarizes the study findings. The decline in BMD at total hip and femoral neck was greater with longer duration of use. The mean decrease in BMD at 240 weeks was more pronounced at total hip (-6.4%) and femoral neck (-5.4%) compared to lumbar spine (-2.1%).Adolescents in the untreated cohort had an increase in BMD during the period of growth following menarche. However, the two cohorts were not matched at baseline for age, gynecologic age, race, BMD and other factors that influence the rate of acquisition of BMD.Table 5. BMD Mean Percent Change from Baseline in Adolescents Receiving >=4 Injections per 60-week Period, by Skeletal Site and CohortDuration of TreatmentDepo-Provera CI(150 mg IM)Unmatched, Untreated CohortNMean ChangeNMean ChangeTotal Hip BMDWeek 60 (1.2 years)113-2.751661.22Week 120 (2.3 years)73-5.401092.19Week 240 (4.6 years)28-6.40841.71Femoral Neck BMD Week 60113-2.961661.75 Week 12073-5.301082.83 Week 24028-5.40841.94Lumbar Spine BMD Week 60114-2.471673.39 Week 12073-2.741095.28 Week 24027-2.11846.40. BMD Recovery Post-Treatment in AdolescentsLonger duration of treatment and smoking were associated with less recovery of BMD following the last injection of Depo-Provera CI. Table shows the extent of recovery of BMD up to 60 months post-treatment for adolescents who received Depo-Provera CI for two years or less compared to more than two years. Post-treatment follow-up showed that, in women treated for more than two years, only lumbar spine BMD recovered to baseline levels after treatment was discontinued. Adolescents treated with Depo-Provera CI for more than two years did not recover to their baseline BMD level at femoral neck and total hip even up to 60 months post-treatment. Adolescents in the untreated cohort gained BMD throughout the trial period (data not shown) [see Warnings and Precautions (5.1)].Table 6: BMD Recovery (Months Post-Treatment) in Adolescents by Years of Depo Provera CI Use (2 Years or Less vs. More than Years)Duration of Treatment2 years or lessMore than yearsNMean Change from baselineNMean Change from baselineTotal Hip BMD End of Treatment49-1.5%49-6.2%12 post-treatment33-1.4%24-4.6%24 post-treatment180.3%17-3.6%36 post-treatment122.1%11-4.6%48 post-treatment101.3%9-2.5%60 post-treatment30.2%2-1.0%Femoral Neck BMD End of Treatment49-1.6%49-5.8%12 post-treatment33-1.4%24-4.3%24 post-treatment180.5%17-3.8%36 post-treatment121.2%11-3.8%48 post-treatment102.0%9-1.7%60 post-treatment31.0%2-1.9%Lumbar Spine BMD End of Treatment49-0.9%49-3.5%12 post-treatment330.4%23-1.1%24 post-treatment182.6%171.9%36 post-treatment122.4%110.6%48 post-treatment106.5%93.5%60 post-treatment36.2%25.7%. 14.4Bone Fracture Incidence in Women Treated with Depo-Provera CI. retrospective cohort study to assess the association between Depo-Provera CI injection and the incidence of bone fractures was conducted in 312,395 female contraceptive users in the UK. The incidence rates of fracture were compared between Depo-Provera CI users and contraceptive users who had no recorded use of Depo-Provera CI. The Incident Rate Ratio (IRR) for any fracture during the follow-up period (mean=5.5 years) was 1.41 (95% CI 1.35, 1.47). It is not known if this is due to Depo-Provera CI use or to other related lifestyle factors that have bearing on fracture rate.In the study, when cumulative exposure to Depo-Provera CI was calculated, the fracture rate in users who received fewer than injections was higher than that in women who received or more injections. However, it is not clear that cumulative exposure, which may include periods of intermittent use separated by periods of non-use, is useful measure of risk, as compared to exposure measures based on continuous use.There were very few osteoporotic fractures (fracture sites known to be related to low BMD) in the study overall, and the incidence of osteoporotic fractures was not found to be higher in Depo-Provera CI users compared to non-users. Importantly, this study could not determine whether use of Depo-Provera CI has an effect on fracture rate later in life.

CONTRAINDICATIONS SECTION.


4CONTRAINDICATIONS. The use of Depo-Provera CI is contraindicated in the following conditions:Known or suspected pregnancy or as diagnostic test for pregnancy.Active thrombophlebitis, or current or past history of thromboembolic disorders, or cerebral vascular disease [see Warnings and Precautions (5.2)].Known or suspected malignancy of breast [see Warnings and Precautions (5.3)].Known hypersensitivity to Depo-Provera CI (medroxyprogesterone acetate) or any of its other ingredients [see Warnings and Precautions (5.5)].Significant liver disease [see Warnings and Precautions (5.7)].Undiagnosed vaginal bleeding [see Warnings and Precautions (5.10)].. Known or suspected pregnancy or as diagnostic test for pregnancy.. Active thrombophlebitis, or current or past history of thromboembolic disorders, or cerebral vascular disease [see Warnings and Precautions (5.2)].. Known or suspected malignancy of breast [see Warnings and Precautions (5.3)].. Known hypersensitivity to Depo-Provera CI (medroxyprogesterone acetate) or any of its other ingredients [see Warnings and Precautions (5.5)].. Significant liver disease [see Warnings and Precautions (5.7)].. Undiagnosed vaginal bleeding [see Warnings and Precautions (5.10)].. Known or suspected pregnancy or as diagnostic test for pregnancy. (4)Active thrombophlebitis, or current or past history of thromboembolic disorders, or cerebral vascular disease. (4)Known or suspected malignancy of breast. (4) Known hypersensitivity to Depo-Provera CI (medroxyprogesterone acetate or any of its other ingredients). (4)Significant liver disease. (4)Undiagnosed vaginal bleeding. (4). Known or suspected pregnancy or as diagnostic test for pregnancy. (4). Active thrombophlebitis, or current or past history of thromboembolic disorders, or cerebral vascular disease. (4). Known or suspected malignancy of breast. (4). Known hypersensitivity to Depo-Provera CI (medroxyprogesterone acetate or any of its other ingredients). (4). Significant liver disease. (4). Undiagnosed vaginal bleeding. (4).

DESCRIPTION SECTION.


11DESCRIPTION. Depo-Provera CI contains medroxyprogesterone acetate, derivative of progesterone, as its active ingredient. Medroxyprogesterone acetate is active by the parenteral and oral routes of administration. It is white to off-white; odorless crystalline powder that is stable in air and that melts between 200C and 210C. It is freely soluble in chloroform, soluble in acetone and dioxane, sparingly soluble in alcohol and methanol, slightly soluble in ether, and insoluble in water.The chemical name for medroxyprogesterone acetate is pregn-4-ene-3, 20-dione, 17-(acetyloxy)-6-methyl-, (6-).The structural formula is as follows:Depo-Provera CI for IM injection is available in vials and prefilled syringes, each containing mL of medroxyprogesterone acetate sterile aqueous suspension 150 mg/mL.For Depo-Provera CI vials, each mL of sterile aqueous suspension contains:Medroxyprogesterone acetate150 mgPolyethylene glycol 335028.9 mgPolysorbate 802.41 mgSodium chloride8.68 mgMethylparaben1.37 mgPropylparaben0.150 mgWater for injectionquantity sufficientWhen necessary, pH is adjusted with sodium hydroxide or hydrochloric acid, or both.For Depo-Provera CI prefilled syringes, each mL of sterile aqueous suspension contains:Medroxyprogesterone acetate150 mgPolyethylene glycol 335028.5 mgPolysorbate 802.37 mgSodium chloride8.56 mgMethylparaben1.35 mgPropylparaben0.147 mgWater for injectionquantity sufficientWhen necessary, pH is adjusted with sodium hydroxide or hydrochloric acid, or both.. Chemical Structure.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PRINCIPAL DISPLAY PANEL 150 mg/mL Vial Label. NDC 0009-0746-30 Rx only Depo-Provera(R) ContraceptiveInjectionmedroxyPROGESTERone acetateinjectable suspension, USP150 mg/mL. PRINCIPAL DISPLAY PANEL 150 mg/mL Vial Label.

DOSAGE & ADMINISTRATION SECTION.


2DOSAGE AND ADMINISTRATION. The recommended dose is 150 mg of Depo-Provera CI every months (13 weeks) administered by deep, intramuscular (IM) injection in the gluteal or deltoid muscle. (2.1). The recommended dose is 150 mg of Depo-Provera CI every months (13 weeks) administered by deep, intramuscular (IM) injection in the gluteal or deltoid muscle. (2.1). 2.1Prevention of Pregnancy. Both the mL vial and the mL prefilled syringe of Depo-Provera CI should be vigorously shaken just before use to ensure that the dose being administered represents uniform suspension.The recommended dose is 150 mg of Depo-Provera CI every months (13 weeks) administered by deep intramuscular (IM) injection using strict aseptic technique in the gluteal or deltoid muscle, rotating the sites with every injection. As with any IM injection, to avoid an inadvertent subcutaneous injection, body habitus should be assessed prior to each injection to determine if longer needle is necessary particularly for gluteal IM injection.Use for longer than years is not recommended (unless other birth control methods are considered inadequate) due to the impact of long-term Depo-Provera CI treatment on bone mineral density (BMD) [see Warnings and Precautions (5.1)]. Dosage does not need to be adjusted for body weight [see Clinical Studies (14.1)].To ensure the patient is not pregnant at the time of the first injection, the first injection should be given ONLY during the first days of normal menstrual period; ONLY within the first 5-days postpartum if not breast-feeding; and if exclusively breast-feeding, ONLY at the sixth postpartum week. If the time interval between injections is greater than 13 weeks, the physician should determine that the patient is not pregnant before administering the drug. The efficacy of Depo-Provera CI depends on adherence to the dosage schedule of administration.. 2.2 Switching From Other Methods of Contraception. When switching from other contraceptive methods, Depo-Provera CI should be given in manner that ensures continuous contraceptive coverage based upon the mechanism of action of both methods, (e.g., patients switching from oral contraceptives should have their first injection of Depo-Provera CI on the day after the last active tablet or at the latest, on the day following the final inactive tablet).

DOSAGE FORMS & STRENGTHS SECTION.


3DOSAGE FORMS AND STRENGTHS. Sterile Aqueous suspension: 150mg/mlPrefilled syringes are available packaged with 22-gauge 1 1/2 inch Terumo(R) SurGuard(TM) Needles.. Vials containing sterile aqueous suspension: 150 mg per mL (3)Prefilled syringes: prefilled syringes are available packaged with 22-gauge 1 1/2 inch Terumo(R) SurGuard(TM) Needles. (3). Vials containing sterile aqueous suspension: 150 mg per mL (3). Prefilled syringes: prefilled syringes are available packaged with 22-gauge 1 1/2 inch Terumo(R) SurGuard(TM) Needles. (3).

DRUG INTERACTIONS SECTION.


7DRUG INTERACTIONS. Drugs or herbal products that induce certain enzymes, including CYP3A4, may decrease the effectiveness of contraceptive drug products. Counsel patients to use back-up method or alternative method of contraception when enzyme inducers are used with Depo-Provera CI. (7.1). 7.1 Changes in Contraceptive Effectiveness Associated With Co-Administration of Other Products. If woman on hormonal contraceptives takes drug or herbal product that induces enzymes, including CYP3A4, that metabolize contraceptive hormones, counsel her to use additional contraception or different method of contraception. Drugs or herbal products that induce such enzymes may decrease the plasma concentrations of contraceptive hormones, and may decrease the effectiveness of hormonal contraceptives. Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include:barbituratesbosentancarbamazepinefelbamategriseofulvinoxcarbazepinephenytoinrifampinSt. Johns worttopiramate. barbiturates. bosentan. carbamazepine. felbamate. griseofulvin. oxcarbazepine. phenytoin. rifampin. St. Johns 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.. 7.2Laboratory 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 Depo-Provera CI:(a) Plasma and urinary steroid levels are decreased (e.g., progesterone, estradiol, pregnanediol, testosterone, cortisol).(b)Gonadotropin levels are decreased.(c)Sex-hormone-binding-globulin concentrations are decreased.(d)Protein-bound iodine and butanol extractable protein-bound iodine may increase.T3-uptake values may decrease.(e)Coagulation test values for prothrombin (Factor II), and Factors VII, VIII, IX, and may increase.(f)Sulfobromophthalein and other liver function test values may be increased.(g)The effects of medroxyprogesterone acetate on lipid metabolism are inconsistent. Both increases and decreases in total cholesterol, triglycerides, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol have been observed in studies.. (a) Plasma and urinary steroid levels are decreased (e.g., progesterone, estradiol, pregnanediol, testosterone, cortisol).. (b)Gonadotropin levels are decreased.. (c)Sex-hormone-binding-globulin concentrations are decreased.. (d)Protein-bound iodine and butanol extractable protein-bound iodine may increase.T3-uptake values may decrease.. (e)Coagulation test values for prothrombin (Factor II), and Factors VII, VIII, IX, and may increase.. (f)Sulfobromophthalein and other liver function test values may be increased.. (g)The effects of medroxyprogesterone acetate on lipid metabolism are inconsistent. Both increases and decreases in total cholesterol, triglycerides, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol have been observed in studies.

GERIATRIC USE SECTION.


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

HOW SUPPLIED SECTION.


16HOW SUPPLIED/STORAGE AND HANDLING. Depo-Provera CI is supplied in the following strengths and package configurations:Package ConfigurationStrengthNDC Depo-Provera CI (medroxyprogesterone acetate sterile aqueous suspension 150 mg/mL)1 mL vial150 mg/mLNDC 0009-0746-3025 1 mL vials150 mg/mLNDC 0009-0746-35 Depo-Provera CI prefilled syringes packaged with 22 gauge 1 1/2 inch Terumo(R) SurGuard(TM) Needles1 mL prefilled syringe150 mg/mLNDC 0009-7376-11. Vials MUST be stored upright at controlled room temperature 20 to 25C (68 to 77F) [see USP].

INDICATIONS & USAGE SECTION.


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

INFORMATION FOR PATIENTS SECTION.


17PATIENT COUNSELING INFORMATION. See FDA-approved patient labeling (Patient Information).Advise patients at the beginning of treatment that their menstrual cycle may be disrupted and that irregular and unpredictable bleeding or spotting results, and that this usually decreases to the point of amenorrhea as treatment with Depo-Provera CI continues, without other therapy being required.Counsel patients about the possible increased risk of breast cancer in women who use Depo-Provera CI [see Warnings and Precautions (5.3)]. Counsel patients that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.Counsel patients on Warnings and Precautions associated with use of Depo-Provera CI.Counsel patients to use back-up method or alternative method of contraception when enzyme inducers are used with Depo-Provera CI.This products labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com.. Advise patients at the beginning of treatment that their menstrual cycle may be disrupted and that irregular and unpredictable bleeding or spotting results, and that this usually decreases to the point of amenorrhea as treatment with Depo-Provera CI continues, without other therapy being required.. Counsel patients about the possible increased risk of breast cancer in women who use Depo-Provera CI [see Warnings and Precautions (5.3)]. Counsel patients that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.. Counsel patients on Warnings and Precautions associated with use of Depo-Provera CI.. Counsel patients to use back-up method or alternative method of contraception when enzyme inducers are used with Depo-Provera CI.

MECHANISM OF ACTION SECTION.


12.1 Mechanism of Action. Depo-Provera CI (medroxyprogesterone acetate [MPA]) 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.

PEDIATRIC USE SECTION.


8.4Pediatric Use. Depo-Provera CI is not indicated before menarche. Use of Depo-Provera CI is associated with significant loss of BMD. This loss of BMD is of particular concern during adolescence and early adulthood, critical period of bone accretion. In adolescents, interpretation of BMD results should take into account patient age and skeletal maturity. It is unknown if use of Depo-Provera CI by younger women will reduce peak bone mass and increase the risk of osteoporotic fractures in later life. Other than concerns about loss of BMD, the safety and effectiveness are expected to be the same for postmenarchal adolescents and adult women.

PHARMACODYNAMICS SECTION.


12.2 Pharmacodynamics. No specific pharmacodynamic studies were conducted with Depo-Provera CI.

PHARMACOKINETICS SECTION.


12.3 Pharmacokinetics. AbsorptionFollowing single 150 mg IM dose of Depo-Provera CI in eight women between the ages of 28 and 36 years old, medroxyprogesterone acetate concentrations, measured by an extracted radioimmunoassay procedure, increase for approximately weeks to reach peak plasma concentrations of to ng/mL.. DistributionPlasma protein binding of MPA averages 86%. MPA binding occurs primarily to serum albumin. No binding of MPA occurs with sex-hormone-binding globulin (SHBG).. MetabolismMPA is extensively metabolized in the liver by P450 enzymes. Its metabolism primarily involves ring and/or side-chain reduction, loss of the acetyl group, hydroxylation in the 2-, 6-, and 21-positions or combination of these positions, resulting in more than 10 metabolites.. ExcretionThe concentrations of medroxyprogesterone acetate decrease exponentially until they become undetectable (<100 pg/mL) between 120 to 200 days following injection. Using an unextracted radioimmunoassay procedure for the assay of medroxyprogesterone acetate in serum, the apparent half-life for medroxyprogesterone acetate following IM administration of Depo-Provera CI is approximately 50 days. Most medroxyprogesterone acetate metabolites are excreted in the urine as glucuronide conjugates with only minor amounts excreted as sulfates.. Specific PopulationsThe effect of hepatic and/or renal impairment on the pharmacokinetics of Depo-Provera CI is unknown.

PREGNANCY SECTION.


8.1Pregnancy. Depo-Provera CI should not be administered during pregnancy. [See Contraindications and Warnings and Precautions (5.17).].

RECENT MAJOR CHANGES SECTION.


Indications and Usage (1)12/2020.

REFERENCES SECTION.


15 REFERENCES. Li CI, Beaber EF, Tang, MCT et al. Effect of Depo-Medroxyprogesterone Acetate on Breast Cancer Risk among Women 20 to 44 years of Age. Cancer Research 2012;72:2028-2035.Paul C, Skegg DCG, Spears GFS. Depot medroxyprogesterone (Depo-Provera) and risk of breast cancer. Br Med 1989; 299:759-62.. Li CI, Beaber EF, Tang, MCT et al. Effect of Depo-Medroxyprogesterone Acetate on Breast Cancer Risk among Women 20 to 44 years of Age. Cancer Research 2012;72:2028-2035.. Paul C, Skegg DCG, Spears GFS. Depot medroxyprogesterone (Depo-Provera) and risk of breast cancer. Br Med 1989; 299:759-62.

SPL PATIENT PACKAGE INSERT SECTION.


Patient Information. Depo-Provera(R) (DEP-po pro-VAIR-ah) CI (medroxyprogesterone acetate injectable suspension) Contraceptive InjectionRead this Patient Information carefully before you decide if Depo-Provera CI is right for you. This information does not take the place of talking with your gynecologist or other healthcare provider who specializes in womens health. If you have any questions about Depo-Provera CI, ask your healthcare provider. You should also learn about other birth control methods to choose the one that is best for you.What is the most important information should know about Depo-Provera CIDepo-Provera CI can cause serious side effects, including:Use of Depo-Provera CI may cause you to lose calcium stored in your bone and decrease your bone mass. The longer you use Depo-Provera CI, the greater your loss of calcium from your bones. Your bones may not recover completely when you stop using Depo-Provera CI. If you use Depo-Provera CI continuously for long time (for more than years), it may increase the risk of weak, porous bones (osteoporosis) that could increase the risk of broken bones, especially after menopause. You should not use Depo-Provera CI for more than two years unless you cannot use other birth control methods.It is not known if your risk of developing osteoporosis is greater if you are teenager or young adult when you start to use Depo-Provera CI (see What are the possible side effects of Depo-Provera CI).Depo-Provera CI is intended to prevent pregnancy. Depo-Provera CI does not protect against HIV infection (AIDS) and other sexually transmitted diseases (STDs).What is Depo-Provera CIDepo-Provera CI is progestin hormone birth control method that is given by injection (a shot) to prevent pregnancy.How well does Depo-Provera CI workYour chance of getting pregnant depends on how well you follow the directions for taking your Depo-Provera CI. The more carefully you follow the directions (such as returning every months for your next injection), the less chance you have of getting pregnant.In clinical studies, about out of 100 women got pregnant during the first year that they used Depo-Provera CI.The following chart shows the chance of getting pregnant for women who use different methods of birth control. Each box on the chart contains list of birth control methods that are similar in effectiveness. The most effective methods are at the top of the chart. The box on the bottom of the chart shows the chance of getting pregnant for women who do not use birth control and are trying to get pregnant.How should take Depo-Provera CIDepo-Provera CI is given by your healthcare provider as shot into your muscle (intramuscular injection). The shot is given in your buttock or upper arm time every months. At the end of the months, you will need to return to your healthcare provider for your next injection in order to continue your protection against pregnancy. To make sure that you are not pregnant before you take Depo-Provera CI, the first injection should be given only:during the first days of normal menstrual period, orwithin the first days after giving birth, if you are not breastfeeding, orat the 6th week after giving birth, if you are feeding your baby only breastmilk. Depo-Provera CI may be given at other times than those listed above, but you will likely need to have pregnancy test first to show that you are not pregnant.During treatment with Depo-Provera CI, you should see your healthcare provider every year for blood pressure check and other healthcare needs.Who Should Not Use Depo-Provera CIDo not use Depo-Provera CI if you:are pregnant or think you might be pregnanthave bleeding from your vagina that has not been explainedhave breast cancer now or in the past, or think you have breast cancerhave had strokeever had blood clots in your arms, legs or lungshave problems with your liver or liver diseaseare allergic to medroxyprogesterone acetate or any of the other ingredients in Depo-Provera CI. See the end of this leaflet for complete list of ingredients in Depo-Provera CI.What should tell my healthcare provider before taking Depo-Provera CIBefore taking Depo-Provera CI, tell your healthcare provider if you have:risk factors for weak bones (osteoporosis) such as bone disease, use alcohol or smoke regularly, anorexia nervosa, or strong family history of osteoporosisirregular or lighter than usual menstrual periodsbreast cancer now or in the past, or think you have breast cancera family history of breast canceran abnormal mammogram (breast X-ray), lumps in your breasts, or bleeding from your nippleskidney problemshigh blood pressurehad strokehad blood clots in your arms, legs or lungsmigraine headachesasthmaepilepsy (convulsions or seizures)diabetesdepression or history of depressionany other medical conditionsIf you are breastfeeding or plan to breastfeed, Depo-Provera CI can pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take Depo-Provera CI.Tell your healthcare provider about all of the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements.Depo-Provera CI and certain other medicines may affect each other, causing serious side effects. Sometimes the doses of other medicines may need to be changed while you are taking Depo-Provera CI.Some medicines may make Depo-Provera CI less effective at preventing pregnancy, including those listed below.Especially tell your healthcare provider if you take:medicine to help you sleepbosentanmedicine for seizuresgriseofulvinan antibioticmedicine for HIV (AIDS)St. Johns wortKnow the medicines you take. Keep list of your medicines with you to show your healthcare provider or pharmacist before you first start taking Depo-Provera CI or when you get new medicine.Follow your healthcare providers instructions about using back-up method of birth control if you are taking medicines that may make Depo-Provera CI less effective.What are the possible side effects of Depo-Provera CIDepo-Provera CI can cause serious side effects, including: Effect on the bones: See What is the most important information should know about Depo-Provera CI.Teenage years are the most important years to gain bone strength. The decrease in calcium in your bones is of most concern if you are teenager or have the following problems:bone diseasean eating disorder (anorexia nervosa)a strong family history of osteoporosisyou take drug that can lower the amount of calcium in your bones (drugs for epilepsy or steroid drugs)you drink lot of alcohol (more than drinks day)you smoke If you need birth control method for more than years, your healthcare provider may switch you to another birth control method instead of using Depo-Provera CI. If you continue using Depo-Provera CI, your healthcare provider may ask you to have bone test, especially if you have other risks for weak bones. When Depo-Provera CI is stopped, your bones may start to regain calcium. However, in study of teenage girls who used Depo-Provera CI for more than years, their hip bones did not completely recover by years after they stopped using Depo-Provera CI. Taking calcium and Vitamin and exercising daily may lessen the loss of calcium from your bones. possible increased risk of breast cancer. Women who use Depo-Provera CI may have slightly increased risk of breast cancer compared to non-users.blood clots in your arms, legs, lungs, and eyes stroke pregnancy outside of your uterus (ectopic pregnancy). Ectopic pregnancy is medical emergency that often requires surgery. Ectopic pregnancy can cause internal bleeding, infertility, and even death.allergic reactions. Severe allergic reactions have been reported in some women using Depo-Provera CI.loss of vision or other eye problemsmigraine headachesdepressionconvulsions or seizuresliver problemsCall your healthcare provider right away if you have:sharp chest pain, coughing up blood, or sudden shortness of breath (indicating possible clot in the lung)sudden severe headache or vomiting, dizziness or fainting, problems with your eyesight or speech, weakness, or numbness in an arm or leg (indicating possible stroke)severe pain or swelling in the calf (indicating possible clot in the leg)sudden blindness, partial or complete (indicating possible clot in the blood vessels of the eye)unusually heavy vaginal bleedingsevere pain or tenderness in the lower abdominal areapersistent pain, pus, or bleeding at the injection siteyellowing of the eyes or skinhivesdifficulty breathingswelling of the face, mouth, tongue or neckThe most common side effects of Depo-Provera CI include:irregular vaginal bleeding, such as lighter or heavier menstrual bleeding, or continued spottingweight gain. You may experience weight gain while you are using Depo-Provera CI. About two-thirds of the women who used Depo-Provera CI in the clinical trials reported weight gain of about pounds during the first year of use. You may continue to gain weight after the first year. Women who used Depo-Provera CI for years gained an average of pounds over those years.abdominal painheadacheweaknesstirednessnervousnessdizzinessTell your healthcare provider if you have any side effect that bothers you or does not go away.These are not all the possible side effects of Depo-Provera CI. For more information, ask your healthcare provider or pharmacist.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1- 800-FDA-1088.What other information should know before choosing Depo-Provera CIPregnancy. When you take Depo-Provera CI every months, your chance of getting pregnant is very low. You could miss period or have light period and not be pregnant. If you miss or periods and think you might be pregnant, see your healthcare provider as soon as possible. You should not use Depo-Provera CI if you are pregnant. However, Depo-Provera CI taken by accident during pregnancy does not seem to cause birth defects.Nursing Mothers. Although Depo-Provera CI can be passed to the nursing baby in the breast milk, no harmful effects on babies have been found. Depo-Provera CI does not stop the breasts from producing milk, so it can be used by nursing mothers. However, to minimize the amount of Depo-Provera CI that is passed to the baby in the first weeks after birth, you should wait until your baby is weeks old before you start using Depo-Provera CI for birth control.How will Depo-Provera CI change my periods Change in normal menstrual cycle. The side effect reported most frequently by women who use Depo-Provera CI for birth controls is change in their normal menstrual cycle. During the first year of using Depo-Provera CI, you might have one or more of the following changes:irregular or unpredictable bleeding or spottingan increase or decrease in menstrual bleedingno bleeding at all. In clinical studies of Depo-Provera CI, 55% of women reported no menstrual bleeding (amenorrhea) after one year of use and 68% of women reported no menstrual bleeding after two years of use.Missed period. During the time you are using Depo-Provera CI for birth controls, you may skip period, or your periods may stop completely. If you have been receiving your shot of Depo-Provera CI regularly every months, then you are probably not pregnant. However, if you think that you may be pregnant, see your healthcare provider.Unusually heavy or continuous bleeding is not usual effect of Depo-Provera CI and if this happens you should see your healthcare provider right away.With continued use of Depo-Provera CI, bleeding usually decreases and many women stop having periods completely. When you stop using Depo-Provera CI your menstrual period will usually, in time, return to its normal cycle.What if want to become pregnant Because Depo-Provera CI is long-acting birth control method, it takes some time after your last shot for its effect to wear off. Most women who try to get pregnant after using Depo-Provera CI get pregnant within 18 months after their last shot. The length of time you use Depo-Provera CI has no effect on how long it takes you to become pregnant after you stop using it.General Information about Depo-Provera CIMedicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. This leaflet summarizes the most important information about Depo-Provera CI. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider for information about Depo-Provera CI that is written for healthcare providers.What are the ingredients in Depo-Provera CI Active ingredient: medroxyprogesterone acetateInactive ingredients: polyethylene glycol 3350, polysorbate 80, sodium chloride, methylparaben, propylparaben, and water for injection. When necessary, pH is adjusted with sodium hydroxide or hydrochloric acid, or both.This Patient Information has been approved by the U.S. Food and Drug Administration.This products labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com.LAB-0148-13.0Revised December 2020. Use of Depo-Provera CI may cause you to lose calcium stored in your bone and decrease your bone mass. The longer you use Depo-Provera CI, the greater your loss of calcium from your bones. Your bones may not recover completely when you stop using Depo-Provera CI. If you use Depo-Provera CI continuously for long time (for more than years), it may increase the risk of weak, porous bones (osteoporosis) that could increase the risk of broken bones, especially after menopause. You should not use Depo-Provera CI for more than two years unless you cannot use other birth control methods.. It is not known if your risk of developing osteoporosis is greater if you are teenager or young adult when you start to use Depo-Provera CI (see What are the possible side effects of Depo-Provera CI).. Depo-Provera CI is given by your healthcare provider as shot into your muscle (intramuscular injection). The shot is given in your buttock or upper arm time every months. At the end of the months, you will need to return to your healthcare provider for your next injection in order to continue your protection against pregnancy. To make sure that you are not pregnant before you take Depo-Provera CI, the first injection should be given only:during the first days of normal menstrual period, orwithin the first days after giving birth, if you are not breastfeeding, orat the 6th week after giving birth, if you are feeding your baby only breastmilk. during the first days of normal menstrual period, or. within the first days after giving birth, if you are not breastfeeding, or. at the 6th week after giving birth, if you are feeding your baby only breastmilk. Depo-Provera CI may be given at other times than those listed above, but you will likely need to have pregnancy test first to show that you are not pregnant.. During treatment with Depo-Provera CI, you should see your healthcare provider every year for blood pressure check and other healthcare needs.. are pregnant or think you might be pregnant. have bleeding from your vagina that has not been explained. have breast cancer now or in the past, or think you have breast cancer. have had stroke. ever had blood clots in your arms, legs or lungs. have problems with your liver or liver disease. are allergic to medroxyprogesterone acetate or any of the other ingredients in Depo-Provera CI. See the end of this leaflet for complete list of ingredients in Depo-Provera CI.. risk factors for weak bones (osteoporosis) such as bone disease, use alcohol or smoke regularly, anorexia nervosa, or strong family history of osteoporosis. irregular or lighter than usual menstrual periods. breast cancer now or in the past, or think you have breast cancer. family history of breast cancer. an abnormal mammogram (breast X-ray), lumps in your breasts, or bleeding from your nipples. kidney problems. high blood pressure. had stroke. had blood clots in your arms, legs or lungs. migraine headaches. asthma. epilepsy (convulsions or seizures). diabetes. depression or history of depression. any other medical conditions. medicine to help you sleep. bosentan. medicine for seizures. griseofulvin. an antibiotic. medicine for HIV (AIDS). St. Johns wort. Effect on the bones: See What is the most important information should know about Depo-Provera CI.Teenage years are the most important years to gain bone strength. The decrease in calcium in your bones is of most concern if you are teenager or have the following problems:bone diseasean eating disorder (anorexia nervosa)a strong family history of osteoporosisyou take drug that can lower the amount of calcium in your bones (drugs for epilepsy or steroid drugs)you drink lot of alcohol (more than drinks day)you smoke If you need birth control method for more than years, your healthcare provider may switch you to another birth control method instead of using Depo-Provera CI. If you continue using Depo-Provera CI, your healthcare provider may ask you to have bone test, especially if you have other risks for weak bones. When Depo-Provera CI is stopped, your bones may start to regain calcium. However, in study of teenage girls who used Depo-Provera CI for more than years, their hip bones did not completely recover by years after they stopped using Depo-Provera CI. Taking calcium and Vitamin and exercising daily may lessen the loss of calcium from your bones. bone disease. an eating disorder (anorexia nervosa). strong family history of osteoporosis. you take drug that can lower the amount of calcium in your bones (drugs for epilepsy or steroid drugs). you drink lot of alcohol (more than drinks day). you smoke. possible increased risk of breast cancer. Women who use Depo-Provera CI may have slightly increased risk of breast cancer compared to non-users.. blood clots in your arms, legs, lungs, and eyes stroke a pregnancy outside of your uterus (ectopic pregnancy). Ectopic pregnancy is medical emergency that often requires surgery. Ectopic pregnancy can cause internal bleeding, infertility, and even death.. allergic reactions. Severe allergic reactions have been reported in some women using Depo-Provera CI.. loss of vision or other eye problems. migraine headaches. depression. convulsions or seizures. liver problems. sharp chest pain, coughing up blood, or sudden shortness of breath (indicating possible clot in the lung). sudden severe headache or vomiting, dizziness or fainting, problems with your eyesight or speech, weakness, or numbness in an arm or leg (indicating possible stroke). severe pain or swelling in the calf (indicating possible clot in the leg). sudden blindness, partial or complete (indicating possible clot in the blood vessels of the eye). unusually heavy vaginal bleeding. severe pain or tenderness in the lower abdominal area. persistent pain, pus, or bleeding at the injection site. yellowing of the eyes or skin. hives. difficulty breathing. swelling of the face, mouth, tongue or neck. irregular vaginal bleeding, such as lighter or heavier menstrual bleeding, or continued spotting. weight gain. You may experience weight gain while you are using Depo-Provera CI. About two-thirds of the women who used Depo-Provera CI in the clinical trials reported weight gain of about pounds during the first year of use. You may continue to gain weight after the first year. Women who used Depo-Provera CI for years gained an average of pounds over those years.. abdominal pain. headache. weakness. tiredness. nervousness. dizziness. Pregnancy. When you take Depo-Provera CI every months, your chance of getting pregnant is very low. You could miss period or have light period and not be pregnant. If you miss or periods and think you might be pregnant, see your healthcare provider as soon as possible. You should not use Depo-Provera CI if you are pregnant. However, Depo-Provera CI taken by accident during pregnancy does not seem to cause birth defects.. Nursing Mothers. Although Depo-Provera CI can be passed to the nursing baby in the breast milk, no harmful effects on babies have been found. Depo-Provera CI does not stop the breasts from producing milk, so it can be used by nursing mothers. However, to minimize the amount of Depo-Provera CI that is passed to the baby in the first weeks after birth, you should wait until your baby is weeks old before you start using Depo-Provera CI for birth control.. Change in normal menstrual cycle. The side effect reported most frequently by women who use Depo-Provera CI for birth controls is change in their normal menstrual cycle. During the first year of using Depo-Provera CI, you might have one or more of the following changes:irregular or unpredictable bleeding or spottingan increase or decrease in menstrual bleedingno bleeding at all. In clinical studies of Depo-Provera CI, 55% of women reported no menstrual bleeding (amenorrhea) after one year of use and 68% of women reported no menstrual bleeding after two years of use.. irregular or unpredictable bleeding or spotting. an increase or decrease in menstrual bleeding. no bleeding at all. In clinical studies of Depo-Provera CI, 55% of women reported no menstrual bleeding (amenorrhea) after one year of use and 68% of women reported no menstrual bleeding after two years of use.. Missed period. During the time you are using Depo-Provera CI for birth controls, you may skip period, or your periods may stop completely. If you have been receiving your shot of Depo-Provera CI regularly every months, then you are probably not pregnant. However, if you think that you may be pregnant, see your healthcare provider.. Chart. Logo.

SPL UNCLASSIFIED SECTION.


Limitations of Use:The use of Depo-Provera CI is not recommended as long-term (i.e., longer than years) birth control method unless other options are considered inadequate [see Dosage and Administration (2.1) and Warnings and Precautions (5.1)].

STORAGE AND HANDLING SECTION.


Vials MUST be stored upright at controlled room temperature 20 to 25C (68 to 77F) [see USP].

USE IN SPECIFIC POPULATIONS SECTION.


8USE IN SPECIFIC POPULATIONS. Nursing Mothers: Detectable amounts of drug have been identified in the milk of mothers receiving Depo-Provera CI. (8.3)Pediatric Patients: Depo-Provera CI is not indicated before menarche. (8.4). Nursing Mothers: Detectable amounts of drug have been identified in the milk of mothers receiving Depo-Provera CI. (8.3). Pediatric Patients: Depo-Provera CI is not indicated before menarche. (8.4). 8.1Pregnancy. Depo-Provera CI should not be administered during pregnancy. [See Contraindications and Warnings and Precautions (5.17).] 8.3Nursing Mothers. Detectable amounts of drug have been identified in the milk of mothers receiving Depo-Provera CI. [See Warnings and Precautions (5.13) .] 8.4Pediatric Use. Depo-Provera CI is not indicated before menarche. Use of Depo-Provera CI is associated with significant loss of BMD. This loss of BMD is of particular concern during adolescence and early adulthood, critical period of bone accretion. In adolescents, interpretation of BMD results should take into account patient age and skeletal maturity. It is unknown if use of Depo-Provera CI by younger women will reduce peak bone mass and increase the risk of osteoporotic fractures in later life. Other than concerns about loss of BMD, the safety and effectiveness are expected to be the same for postmenarchal adolescents and adult women.. 8.5Geriatric Use. This product has not been studied in post-menopausal women and is not indicated in this population.. 8.6 Renal Impairment. The effect of renal impairment on Depo-Provera CI pharmacokinetics has not been studied.. 8.7 Hepatic Impairment. The effect of hepatic impairment on Depo-Provera CI pharmacokinetics has not been studied. Depo-Provera CI should not be used by women with significant liver disease and should be discontinued if jaundice or disturbances of liver function occur. [See Contraindications (4) and Warnings and Precautions (5.7) .].

WARNINGS AND PRECAUTIONS SECTION.


5WARNINGS AND PRECAUTIONS. Thromboembolic Disorders: Discontinue Depo-Provera CI in patients who develop thrombosis. (5.2)Cancer Risks: Monitor women with strong family history of breast cancer carefully. (5.3)Ectopic Pregnancy: Consider ectopic pregnancy if woman using Depo-Provera CI becomes pregnant or complains of severe abdominal pain. (5.4)Anaphylaxis and Anaphylactoid Reactions: Provide emergency medical treatment. (5.5)Liver Function: Discontinue Depo-Provera CI if jaundice or disturbances of liver function develop. (5.7)Carbohydrate Metabolism: Monitor diabetic patients carefully. (5.12). Thromboembolic Disorders: Discontinue Depo-Provera CI in patients who develop thrombosis. (5.2). Cancer Risks: Monitor women with strong family history of breast cancer carefully. (5.3). Ectopic Pregnancy: Consider ectopic pregnancy if woman using Depo-Provera CI becomes pregnant or complains of severe abdominal pain. (5.4). Anaphylaxis and Anaphylactoid Reactions: Provide emergency medical treatment. (5.5). Liver Function: Discontinue Depo-Provera CI if jaundice or disturbances of liver function develop. (5.7). Carbohydrate Metabolism: Monitor diabetic patients carefully. (5.12). 5.1Loss of Bone Mineral Density. Use of Depo-Provera CI reduces serum estrogen levels and is associated with significant loss of bone mineral density (BMD). This loss of BMD is of particular concern during adolescence and early adulthood, critical period of bone accretion. It is unknown if use of Depo-Provera CI 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 Depo-Provera CI. After discontinuing Depo-Provera CI in these adolescents, mean BMD loss at the total hip and femoral neck did not fully recover by years (60 months) post-treatment in the sub-group of adolescents who were treated for more than years see Clinical Studies (14.3)]. Similarly, in adults, there was only partial recovery of mean BMD at the total hip, femoral neck, and lumbar spine towards baseline by years post-treatment [see Clinical Studies (14.2)]. The use of Depo-Provera CI is not recommended as long-term (i.e., longer than years) birth control method unless other options are considered inadequate. BMD should be evaluated when woman needs to continue to use Depo-Provera CI 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 Depo-Provera CI in women with osteoporosis risk factors. Depo-Provera CI 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 Depo-Provera CI (150 mg). However, Depo-Provera CI has not been causally associated with the induction of thrombotic or thromboembolic disorders. Any patient who develops thrombosis while undergoing therapy with Depo-Provera CI should discontinue treatment unless she has no other acceptable options for birth control.Do not re-administer Depo-Provera CI pending examination if there is sudden partial or complete loss of vision or if there is sudden onset of proptosis, diplopia, or migraine. Do not re-administer if examination reveals papilledema or retinal vascular lesions.. 5.3 Cancer Risks. Breast CancerWomen who have or have had history of breast cancer should not use hormonal contraceptives, including Depo-Provera CI, because breast cancer may be hormonally sensitive [see Contraindications (4)]. Women with strong family history of breast cancer should be monitored with particular care.The results of five large case-control studies assessing the association between depo-medroxyprogesterone acetate (DMPA) use and the risk of breast cancer are summarized in Figure 1. Three of the studies suggest slightly increased risk of breast cancer in the overall population of users; these increased risks were statistically significant in one study. One recent US study1 evaluated the recency and duration of use and found statistically significantly increased risk of breast cancer in recent users (defined as last use within the past five years) who used DMPA for 12 months or longer; this is consistent with results of previous study2.Figure Risk estimates for breast cancer in DMPA usersOdds 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, doubling of risk would increase the incidence of breast cancer in women who use Depo-Provera CI from about 72 to about 144 cases per 100,000 women.. Figure 1. Cervical CancerA statistically nonsignificant increase in RR estimates of invasive squamous-cell cervical cancer has been associated with the use of Depo-Provera CI 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 Depo-Provera CI 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 CancersLong-term case-controlled surveillance of users of Depo-Provera CI 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 Depo-Provera CI 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 Depo-Provera CI. Institute emergency medical treatment if an anaphylactic reaction occurs.. 5.6Injection Site Reactions. Injection site reactions have been reported with use of Depo-Provera CI [see Adverse Reactions (6.2)]. Persistent injection site reactions may occur after administration of Depo-Provera CI 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 Depo-Provera CI 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 Depo-Provera CI causation has been excluded.. 5.8 Convulsions. There have been few reported cases of convulsions in patients who were treated with Depo-Provera CI. Association with drug use or pre-existing conditions is not clear.. 5.9 Depression. Monitor patients who have history of depression and do not re-administer Depo-Provera CI if depression recurs.. 5.10 Bleeding Irregularities. Most women using Depo-Provera CI 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 Depo-Provera CI, fewer experience irregular bleeding and more experience amenorrhea. In clinical studies of Depo-Provera CI, by month 12 amenorrhea was reported by 55% of women, and by month 24, amenorrhea was reported by 68% of women using Depo-Provera CI.. 5.11Weight Gain. Women tend to gain weight while on therapy with Depo-Provera CI. From an initial average body weight of 136 lb, women who completed year of therapy with Depo-Provera CI gained an average of 5.4 lb. Women who completed years of therapy gained an average of 8.1 lb. Women who completed years gained an average of 13.8 lb. Women who completed years gained an average of 16.5 lb. Two percent of women withdrew from large-scale clinical trial because of excessive weight gain.. 5.12Carbohydrate Metabolism. decrease in glucose tolerance has been observed in some patients on Depo-Provera CI treatment. Monitor diabetic patients carefully while receiving Depo-Provera CI.. 5.13Lactation. Detectable amounts of drug have been identified in the milk of mothers receiving Depo-Provera CI. In nursing mothers treated with Depo-Provera CI, 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.. 5.14Fluid Retention. Because progestational drugs including Depo-Provera CI 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.. 5.15Return of Fertility. Return to ovulation and fertility is likely to be delayed after stopping Depo-Provera CI. In large US study of women who discontinued use of Depo-Provera CI to become pregnant, data are available for 61% of them. Of the 188 women who discontinued the study to become pregnant, 114 became pregnant. Based on Life-Table analysis of these data, it is expected that 68% of women who do become pregnant may conceive within 12 months, 83% may conceive within 15 months, and 93% may conceive within 18 months from the last injection. The median time to conception for those who do conceive is 10 months following the last injection with range of to 31 months, and is unrelated to the duration of use. No data are available for 39% of the patients who discontinued Depo-Provera CI to become pregnant and who were lost to follow-up or changed their mind.. 5.16Sexually Transmitted Diseases. Patients should be counseled that Depo-Provera CI does not protect against HIV infection (AIDS) and other sexually transmitted diseases.. 5.17Pregnancy. Although Depo-Provera CI 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.. 5.18Monitoring A woman who is taking hormonal contraceptive should have yearly visit with her healthcare provider for blood pressure check and for other indicated healthcare.. 5.19Interference With Laboratory Tests. The use of Depo-Provera CI may change the results of some laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins. [See Drug Interactions (7.2).].