Generic Name: medroxyprogesterone acetate
Dosage Form: injection
FULL PRESCRIBING INFORMATION
Women who use medroxyprogesterone acetate injectable suspension may lose significant bone mineral density. Bone loss is greater with increasing duration of use and may not be completely reversible.
It is unknown if use of medroxyprogesterone acetate injectable suspension during adolescence or early adulthood, a critical period of bone accretion, will reduce peak bone mass and increase the risk for osteoporotic fracture in later life.
Medroxyprogesterone acetate injectable suspension should not be used as a long-term birth control method (i.e., longer than 2 years) unless other birth control methods are considered inadequate [seeWarnings and Precautions (5.1)].
Indications and Usage for Medroxyprogesterone Injection
Medroxyprogesterone Acetate Injectable Suspension, USP is indicated only for the prevention of pregnancy. The loss of bone mineral density (BMD) in women of all ages and the impact on peak bone mass in adolescents should be considered, along with the decrease in BMD that occurs during pregnancy and/or lactation, in the risk/benefit assessment for women who use Medroxyprogesterone Acetate Injectable Suspension, USP long-term [seeWarnings and Precautions (5.1)].
Medroxyprogesterone Injection Dosage and Administration
Prevention of Pregnancy
Both the 1 mL vial and the 1 mL prefilled syringe of medroxyprogesterone acetate injectable suspension should be vigorously shaken just before use to ensure that the dose being administered represents a uniform suspension. The recommended dose is 150 mg of medroxyprogesterone acetate injectable suspension every 3 months (13 weeks) administered by deep IM injection in the gluteal or deltoid muscle. Medroxyprogesterone acetate injectable suspension should not be used as a long-term birth control method (i.e., longer than 2 years) unless other birth control methods are considered inadequate. Dosage does not need to be adjusted for body weight [seeClinical 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 5 days of a 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 medroxyprogesterone acetate injectable suspension depends on adherence to the dosage schedule of administration.
Switching from other Methods of Contraception
When switching from other contraceptive methods, medroxyprogesterone acetate injectable suspension should be given in a 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 medroxyprogesterone acetate injectable suspension on the day after the last active tablet or at the latest, on the day following the final inactive tablet).
Dosage Forms and Strengths
Sterile Aqueous suspension: 150mg/ml
Prefilled syringes are available packaged with 22-gauge x 1 1/2 inch BD SafetyGlideTM Needles.
Contraindications
The use of medroxyprogesterone acetate injectable suspension 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 (5.6)].
- Undiagnosed vaginal bleeding [see Warnings and Precautions (5.9)].
Warnings and Precautions
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.
After discontinuing medroxyprogesterone acetate injectable suspension in adolescents, mean BMD loss at total hip and femoral neck did not fully recover by 60 months (240 weeks) post-treatment [see Clinical Studies (14.3)]. Similarly, in adults, there was only partial recovery of mean BMD at total hip, femoral neck and lumbar spine towards baseline by 24 months post-treatment [see Clinical Studies (14.2)].
Medroxyprogesterone acetate injectable suspension should not be used as a long-term birth control method (i.e., longer than 2 years) unless other birth control methods 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). Although there are no studies addressing whether calcium and Vitamin D may lessen BMD loss in women using medroxyprogesterone acetate injectable suspension, all patients should have adequate calcium and Vitamin D intake.
Thromboembolic Disorders
There have been reports of serious thrombotic events in women using medroxyprogesterone acetate injectable suspension (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.
Cancer Risks
Breast Cancer
Women who currently have or have had breast cancer should not use hormone contraceptives, including medroxyprogesterone acetate injectable suspension, because breast cancer may be hormonally sensitive. Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care.
A pooled analysis from two case-control studies, the World Health Organization Study and the New Zealand Study, reported the relative risk (RR) of breast cancer for women who had ever used medroxyprogesterone acetate injectable suspension as 1.1 (95% confidence interval [CI] 0.97 to 1.4). Overall, there was no increase in risk with increasing duration of use of medroxyprogesterone acetate injectable suspension. The RR of breast cancer for women of all ages who had initiated use of medroxyprogesterone acetate injectable suspension within the previous 5 years was estimated to be 2.0 (95% CI 1.5 to 2.8).
The World Health Organization Study, a component of the pooled analysis described above, showed an increased RR of 2.19 (95% CI 1.23 to 3.89) of breast cancer associated with use of medroxyprogesterone acetate injectable suspension in women whose first exposure to drug was within the previous 4 years and who were under 35 years of age. However, the overall RR for ever-users of medroxyprogesterone acetate injectable suspension was 1.2 (95% CI 0.96 to 1.52).
The National Cancer Institute reports an average annual incidence rate for breast cancer for US women, all races, age 15 to 34 years, of 8.7 per 100,000. A RR of 2.19, thus, increases the possible risk from 8.7 to 19.0 cases per 100,000 women.
Cervical Cancer
A statistically non-significant 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, non-significant 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.
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.
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.
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.
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.
Depression
Monitor patients who have a history of depression and do not re-administer medroxyprogesterone acetate injectable suspension if depression recurs.
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.
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.
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.
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.
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.
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.
Sexually Transmitted Diseases
Patients should be counseled that medroxyprogesterone acetate injectable suspension does not protect against HIV infection (AIDS) and other sexually transmitted diseases.
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.
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.
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)].
Adverse Reactions
The following important adverse reactions observed with the use of medroxyprogesterone acetate injectable suspension 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 (5.9)]
- Weight Gain [see Warnings and Precautions (5.10)]
Clinical 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 injectable suspension, 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 injectable suspension. 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 injectable suspension every 3-months (90 days). The median study duration was 13 months with a range of 1-84 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 > 10 lbs 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%) |
| Digestive | Nausea (3.3%) Bloating (2.3%) |
| Metabolic/Nutritional | Edema (2.2%) |
| Musculoskeletal | Leg cramps (3.7%) Arthralgia (1%) |
| Nervous | Depression (1.5%) Insomnia (1%) |
| 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%)
Post-marketing Experience
The following adverse reactions have been identified during post approval use of medroxyprogesterone acetate injectable suspension. 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 injectable suspension.
Table 3. Adverse Reactions Reported during Post-Marketing Experience
| Body System | Adverse Reactions |
| Body as a Whole | Chest pain, Allergic reactions, Fever, Pain at injection site, 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 |
| Nervous | Paralysis, Facial palsy, Paresthesia, Drowsiness |
| Respiratory | Dyspnea and asthma, Hoarseness |
| Skin and Appendages | Hirsutism, Excessive sweating and body odor, Dry skin, Scleroderma |
| Urogenital | Cervical cancer, Breast cancer, 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.
Drug Interactions
Changes in Contraceptive Effectiveness Associated with Coadministration 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.
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.
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.
USE IN SPECIFIC POPULATIONS
Pregnancy
Medroxyprogesterone acetate injectable suspension should not be administered during pregnancy [see Contraindications (4) and Warnings and Precautions (5.16)].
Nursing Mothers
Detectable amounts of drug have been identified in the milk of mothers receiving medroxyprogesterone acetate injectable suspension [see Warnings and Precautions (5.12)]
Pediatric Use
Medroxyprogesterone acetate injectable suspension is not indicated before menarche. Use of medroxyprogesterone acetate injectable suspension is associated with significant loss of BMD. This loss of BMD is of particular concern during adolescence and early adulthood, a 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 medroxyprogesterone acetate injectable suspension 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.
Geriatric Use
This product has not been studied in post-menopausal women and is not indicated in this population.
Renal Impairment
The effect of renal impairment on medroxyprogesterone acetate injectable suspension pharmacokinetics has not been studied.
Hepatic Impairment
The effect of hepatic impairment on medroxyprogesterone acetate injectable suspension pharmacokinetics has not been studied. Medroxyprogesterone acetate injectable suspension 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 (5.6)].
Medroxyprogesterone Injection Description
Medroxyprogesterone Acetate Injectable Suspension, USP, a contraceptive injection, contains medroxyprogesterone acetate, a derivative of progesterone, as its active ingredient. Medroxyprogesterone Acetate Injectable Suspension, USP 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:
Medroxyprogesterone Acetate Injectable Suspension, USP for intramuscular (IM) injection is available in vials and prefilled syringes, each containing 1 mL of medroxyprogesterone acetate sterile aqueous suspension 150 mg/mL.
Each mL 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 . . . . . . . . . . . . . . . . . . . . . . . . . . . | qs |
When necessary, pH is adjusted with sodium hydroxide or hydrochloric acid, or both.
Medroxyprogesterone Injection - Clinical Pharmacology
Mechanism of Action
Medroxyprogesterone acetate injectable suspension, when administered at the recommended dose to women every 3 months, inhibits the secretion of gonadotropins which, in turn, prevents follicular maturation and ovulation and results in endometrial thinning. These actions produce its contraceptive effect.
Pharmacodynamics
No specific pharmacodynamic studies were conducted with medroxyprogesterone acetate injectable suspension.
Pharmacokinetics
Absorption
Following a single 150 mg IM dose of medroxyprogesterone acetate injectable suspension in eight women between the ages of 28 and 36 years old, medroxyprogesterone acetate concentrations, measured by an extracted radioimmunoassay procedure, increase for approximately 3 weeks to reach peak plasma concentrations of 1 to 7 ng/mL.
Distribution
Plasma protein binding of MPA averages 86%. MPA binding occurs primarily to serum albumin. No binding of MPA occurs with sex-hormone-binding globulin (SHBG).
Metabolism
MPA is extensively metabolized in the liver by P450 enzymes. Its metabolism primarily involves ring A and/or side-chain reduction, loss of the acetyl group, hydroxylation in the 2-, 6-, and 21-positions or a combination of these positions, resulting in more than 10 metabolites.
Excretion
The 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 medroxyprogesterone acetate injectable suspension is approximately 50 days. Most medroxyprogesterone acetate metabolites are excreted in the urine as glucuronide conjugates with only minor amounts excreted as sulfates.
Specific Populations
The effect of hepatic and/or renal impairment on the pharmacokinetics of medroxyprogesterone acetate injectable suspension is unknown.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
[See Warnings and Precautions, (5.3, 5.14, and 5.16)].
Clinical Studies
Contraception
In five clinical studies using medroxyprogesterone acetate injectable suspension, the 12-month failure rate for the group of women treated with medroxyprogesterone acetate injectable suspension was zero (no pregnancies reported) to 0.7 by Life-Table method. The effectiveness of medroxyprogesterone acetate injectable suspension is dependent on the patient returning every 3 months (13 weeks) for reinjection.
Bone Mineral Density (BMD) Changes in Adult Women
In a controlled, clinical study, adult women using medroxyprogesterone acetate injectable suspension for up to 5 years showed spine and hip BMD mean decreases of 5 to 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 5 years, respectively, were observed. Mean decreases in BMD of the total hip and femoral neck were similar.
After stopping use of medroxyprogesterone acetate injectable suspension (150 mg), 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 4 shows the change in BMD in women after 5 years of treatment with medroxyprogesterone acetate injectable suspension and in women in a 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 2 Years of Follow-Up)
| Time in Study | Spine | Total Hip | Femoral Neck | |||
| Medroxyprogesterone acetate injectable suspension* | Control** | Medroxyprogesterone acetate injectable suspension* | Control** | Medroxyprogesterone acetate injectable suspension* | Control** | |
| 5 years | -5.38% n = 33 | 0.43% n = 105 | -5.16% n = 21 | 0.19% n = 65 | -6.12% n = 34 | -0.27% n = 106 |
| 7 years | -3.13% n = 12 | 0.53% n = 60 | -1.34% n = 7 | 0.94% n = 39 | -5.38% n = 13 | -0.11% n = 63 |
*The treatment group consisted of women who received medroxyprogesterone acetate injectable suspension for 5 years and were then followed for 2 years post-use (total time in study of 7 years).
**The control group consisted of women who did not use hormonal contraception and were followed for 7 years.
Bone Mineral Density Changes in Adolescent Females (12 to 18 years of age)
The impact of medroxyprogesterone acetate injectable suspension (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 to18 years). Use of medroxyprogesterone acetate injectable suspension was associated with a significant decline from baseline in BMD.
Partway through the trial, drug administration was stopped (at 120 weeks). The mean number of injections per medroxyprogesterone acetate injectable suspension user was 9.3. The decline in BMD at total hip and femoral neck was greater with longer duration of use (see Table 5). 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%).
In general, adolescents increase bone density during the period of growth following menarche, as seen in the untreated cohort. 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 bone mineral density.
Table 5. Mean Percent Change from Baseline in BMD in Adolescents Receiving ≥ 4 Injections per 60-week Period, by Skeletal Site and Cohort
| Duration of Treatment | Medroxyprogesterone acetate injectable suspension (150 mg IM) | Unmatched, Untreated Cohort | ||
| N | N | Mean % Change | N | Mean % Change |
Total Hip BMD Week 60 (1.2 years) Week 120 (2.3 years) Week 240 (4.6 years) | 113 73 28 | -2.75 -5.40 -6.40 | 166 109 84 | 1.22 2.19 1.71 |
Femoral Neck BMD Week 60 Week 120 Week 240 | 113 73 28 | -2.96 -5.30 -5.40 | 166 108 84 | 1.75 2.83 1.94 |
Lumbar Spine BMD Week 60 Week 120 Week 240 | 114 73 27 | -2.47 -2.74 -2.11 | 167 109 84 | 3.39 5.28 6.40 |
BMD recovery post-treatment in adolescent women
Longer duration of treatment and smoking were associated with less recovery of BMD following the last injection of medroxyprogesterone acetate injectable suspension. Table 6 shows the extent of recovery of BMD up to 60 months post-treatment for adolescent women who received medroxyprogesterone acetate injectable suspension 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. Subjects treated with medroxyprogesterone acetate injectable suspension 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. Adolescent women in the untreated cohort gained BMD throughout the trial period (data not shown).
Table 6. Extent of BMD Recovery (Months Post-Treatment) in Adolescents by Years of Medroxyprogesterone Acetate Injectable Suspension Use (2 Years or Less vs. More than 2 Years)
Duration of Treatment | 2 years or less | More than 2 years | ||
| N | Mean % Change from baseline | N | Mean % Change from baseline | |
| Total Hip BMD | ||||
| End of Treatment | 49 | -1.5% | 49 | -6.2% |
| 12 M post-treatment | 33 | -1.4% | 24 | -4.6% |
| 24 M post-treatment | 18 | 0.3% | 17 | -3.6% |
| 36 M post-treatment | 12 | |||
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