Medroxyprogesterone acetate injectable suspension is indicated for use by females of reproductive potential to prevent pregnancy. Limitations of Use: 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 [see Dosage and Administration (2.1) and Warnings and Precautions (5.1) ]. Medroxyprogesterone acetate injectable suspension is a progestin indicated for use by females of reproductive potential to prevent pregnancy.
( 1 ) Limitations of Use: 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. ( 1 , 5.1 )
Contraindicaciones
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 )
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Thromboembolic Disorders: Discontinue medroxyprogesterone acetate 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 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 if jaundice or disturbances of liver function develop. ( 5.7 )
of medroxyprogesterone acetate 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 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.
After discontinuing medroxyprogesterone acetate in these adolescents, mean BMD loss at the total hip and femoral neck did not fully recover by 5 years (60 months) post-treatment in the sub-group of adolescents who were treated for more than 2 years [see Clinical Studies (14.3) ]. Similarly, in adults, there was only partial recovery of mean BMD at the total hip, femoral neck, and lumbar spine towards baseline by 2 years post-treatment [see Clinical Studies (14.2) ].
The use of medroxyprogesterone acetate 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 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 in women with osteoporosis risk factors.
Medroxyprogesterone acetate 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).
5.2Thromboembolic Disorders
There have been reports of serious thrombotic events in women using medroxyprogesterone acetate (150 mg). However, medroxyprogesterone acetate has not been causally associated with the induction of thrombotic or thromboembolic disorders. Any patient who develops thrombosis while undergoing therapy with medroxyprogesterone acetate should discontinue treatment unless she has no other acceptable options for birth control.
Do not re-administer medroxyprogesterone acetate 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.
5.3Cancer Risks Breast Cancer
Women who have or have had a history of breast cancer should not use hormonal contraceptives, including medroxyprogesterone acetate, because breast cancer may be hormonally sensitive [see Contraindications (4) ]. Women with a strong family history of breast cancer should be monitored with particular care. The results of five large case-control studies 1 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.
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 from about 72 to about 144 cases per 100,000 women.
Cervical Cancer A statistically nonsignificant increase in RR estimates of invasive squamous-cell cervical cancer has been associated with the use of medroxyprogesterone acetate 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 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 found no overall increased risk of ovarian or liver cancer. Logarithmic scale.JPG
5.4Ectopic Pregnancy
Be alert to the possibility of an ectopic pregnancy among women using medroxyprogesterone acetate who become pregnant or complain of severe abdominal pain.
5.5Anaphylaxis and Anaphylactoid Reaction Anaphylaxis
and anaphylactoid reaction have been reported with the use of medroxyprogesterone acetate. Institute emergency medical treatment if an anaphylactic reaction occurs.
5.6Injection Site Reactions
Injection site reactions have been reported with use of medroxyprogesterone acetate [see Adverse Reactions (6.2) ] . Persistent injection site reactions may occur after administration of medroxyprogesterone acetate due to inadvertent subcutaneous administration or release of the drug into the subcutaneous space while removing the needle [see Dosage and Administration (2.1) ] .
5.7Liver Function
Discontinue medroxyprogesterone acetate 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 causation has been excluded.
5.8Convulsions
There have been a few reported cases of convulsions in patients who were treated with medroxyprogesterone acetate. Association with drug use or pre-existing conditions is not clear.
5.9Depression
Monitor patients who have a history of depression and do not re-administer medroxyprogesterone acetate if depression recurs.
5.10Bleeding Irregularities
Most women using medroxyprogesterone acetate 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, fewer experience irregular bleeding and more experience amenorrhea.
In clinical studies of medroxyprogesterone acetate, by month 12 amenorrhea was reported by 55% of women, and by month 24, a
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Interacciones
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. ( 7.1 )
7.1Changes 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.
7.2Laboratory 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 medroxyprogesterone acetate: (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 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.
Embarazo y lactancia
8.1Pregnancy
Medroxyprogesterone acetate should not be administered during pregnancy. [ See Contraindications and Warnings and Precautions (5.17) .]
Reacciones adversas
The following important adverse reactions observed with the use of medroxyprogesterone acetate 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) ] 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 Mylan at 1-877-446-3679 (1-877-INFO-RX) 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 a 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 medroxyprogesterone acetate, over 3,900 women, who were treated for up to 7 years, reported the following adverse reactions, which may or may not be related to the use of medroxyprogesterone acetate.
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 medroxyprogesterone acetate every 3-months (90 days). The median study duration was 13 months with a range of 1 to 84 months. Fifty eight percent of patients remained in the study after 13 months and 34% after 24 months. Table 1 Adverse Reactions that Were Reported by More than 5% of Subjects Body System* Adverse Reactions [Incidence (%)] Body as a Whole Headache (16.5%) Abdominal pain/discomfort (11.2%) Metabolic/Nutritional Increased weight > 10lbs at 24 months (37.7%) Nervous Nervousness (10.8%) Dizziness (5.6%) Libido decreased (5.5%) Urogenital Menstrual irregularities: (bleeding (57.3% at 12 months, 32.1% at 24 months) amenorrhea (55% at 12 months, 68% at 24 months) *Body System represented from COSTART medical dictionary.
Table 2 Adverse Reactions that Were Reported by between 1 and 5% of Subjects Body System* Adverse Reactions [Incidence (%)] Body as a Whole Asthenia/fatigue (4.2%) Backache (2.2%) Dysmenorrhea (1.7%) Hot flashes (1.0%) Digestive Nausea (3.3%) Bloating (2.3%) Metabolic/Nutritional Edema (2.2%) Musculoskeletal Leg cramps (3.7%) Arthralgia (1.0%) Nervous Depression (1.5%) Insomnia (1.0%) Skin and Appendages Acne (1.2%) No hair growth/alopecia (1.1%) Rash (1.1%) Urogenital Leukorrhea (2.9%) Breast pain (2.8%) Vaginitis (1.2%) * Body System represented from COSTART medical dictionary.
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 medroxyprogesterone acetate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. There have been cases of osteoporosis including osteoporotic fractures reported post-marketing in patients taking medroxyprogesterone acetate.
Table 3 Adverse Reactions Reported during Post-Marketing Experience Body System* Adverse Reactions Body as a Whole Chest pain, Allergic reactions including angioedema, Fever, Injection site abscess † , Injection site infection † , Injection site nodule/lump, Injection site pain/tenderness, Injection site persistent atrophy/indentation/dimpling, Injection-site reaction, Lipodystrophy acquired, Chills, Axillary swelling Cardiovascular Syncope, Tachycardia, Thrombophlebitis, Deep vein thrombosis, Pulmonary embolus, Varicose veins Digestive Changes in appetite, Gastrointestinal disturbances, Jaundice, Excessive thirst, Rectal bleeding Hematologic and Lymphatic Anemia, Blood dyscrasia Musculoskeletal Osteoporosis Neoplasms Cervical cancer, Breast cancer Nervous Paralysis, Facial palsy, Paresthesia, Drowsiness Respiratory Dyspnea and asthma, Hoarseness Skin and Appendages Hirsutism, Excessive sweating and body odor, Dry skin, Scleroderma Urogenital Lack 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 * Body System represented from COSTART medical dictionary. † Injection site abscess and injection site infections have been reported; therefore strict aseptic injection technique should be followed when administering medroxyprogesterone acetate in order to avoid injection site infections [see Dosage and Administration (2.1) ].
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