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Depo-Provera Contraceptive Injection (Pharmacia & Upjohn)
- Drugs index
Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.
DEPO-PROVERA Contraceptive Injection (CI) contains medroxyprogesterone acetate, a derivative of progesterone, as its active ingredient. Medroxyprogesterone acetate is active by the parenteral and oral routes of administration. It is a white to off-white, odorless crystalline powder that is stable in air and that melts between 200°C and 210°C. It is freely soluble in chloroform, soluble in acetone and dioxane, sparingly soluble in alcohol and methanol, slightly soluble in ether, and insoluble in water.
The chemical name for medroxyprogesterone acetate is pregn-4-ene-3,20-dione, 17-(acetyloxy)-6-methyl-, (6(alpha)-). The structural formula is as follows:
DEPO-PROVERA CI 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
Water for injection......................................qs
When necessary, pH is adjusted with sodium hydroxide or hydrochloric acid, or both.
DEPO-PROVERA CI (medroxyprogesterone acetate), 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.
Following a single 150 mg IM dose of DEPO-PROVERA Contraceptive Injection, 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. The levels then 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 Contraceptive Injection is approximately 50 days.
Women with lower body weights conceive sooner than women with higher body weights after discontinuing DEPO-PROVERA Contraceptive Injection.
The effect of hepatic and/or renal disease on the pharmacokinetics of DEPO-PROVERA Contraceptive Injection is unknown.
INDICATIONS AND USAGE
DEPO-PROVERA CI 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 Depo-Provera CI long-term (see WARNINGS .) It is a long-term injectable contraceptive in women when administered at 3-month (13-week) intervals. Dosage does not need to be adjusted for body weight.
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. Pregnancy rates with contraceptive measures are typically reported for only the first year of use as shown in Table 1. Except for intrauterine devices (IUD), implants, sterilization, and DEPO-PROVERA CI, the efficacy of these contraceptive measures depends in part on the reliability of use. The effectiveness of DEPO-PROVERA CI is dependent on the patient returning every 3 months (13 weeks) for reinjection.
1. Loss of Bone Mineral Density
Use of Depo-Provera CI reduces serum estrogen levels and is associated with significant loss of bone mineral density (BMD) as bone metabolism accommodates to a lower estrogen level. This loss of BMD is of particular concern during adolescence and early adulthood, a critical period of bone accretion. It is unknown if use of Depo-Provera CI by younger women will reduce peak bone mass and increase the risk for osteoporotic fracture in later life. In both adults and adolescents, the decrease in BMD appears to be at least partially reversible after Depo-Provera CI is discontinued and ovarian estrogen production increases. A study to assess the reversibility of loss of BMD in adolescents is ongoing.
Depo-Provera CI should be used as a long-term birth control method (e.g. longer than 2 years) only if other birth control methods are inadequate. BMD should be evaluated when a 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). Although there are no studies addressing whether calcium and Vitamin D may lessen BMD loss in women using Depo-Provera CI, all patients should have adequate calcium and Vitamin D intake.
BMD Changes in Adult Women
In a controlled, clinical study, adult women using Depo-Provera CI for up to 5 years showed spine and hip 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 5 years, respectively, were observed. Mean decreases in BMD of the total hip and femoral neck were similar.
After stopping use of Depo-Provera CI (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 2 shows the extent of recovery of BMD for women who completed 5 years of treatment.
BMD Changes in Adolescent Females (12-18 years of age)
Preliminary results from an ongoing, open-label, self-selected, non-randomized clinical study of adolescent females (12-18 years) also showed that Depo-Provera CI use was associated with a significant decline in BMD from baseline (Table 3). 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, with the result that they differed with respect to these demographic factors.
Preliminary data from the small number of adolescents participating in the 2-year post-use observation period demonstrated partial recovery of BMD.
2. Bleeding Irregularities
Most women using DEPO-PROVERA CI experience disruption of menstrual bleeding patterns. Altered menstrual bleeding patterns include irregular or unpredictable bleeding or spotting, or rarely, heavy or continuous bleeding. If abnormal bleeding persists or is severe, appropriate investigation should be instituted to rule out the possibility of organic pathology, and appropriate treatment should be instituted when necessary.
As women continue using DEPO-PROVERA CI, fewer experience irregular bleeding and more experience amenorrhea. 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. 2
3. Cancer Risks
Long-term case-controlled surveillance of users of DEPO-PROVERA CI found slight or no increased overall risk of breast cancer 3 and no overall increased risk of ovarian, 4 liver, 5 or cervical 6 cancer and a prolonged, protective effect of reducing the risk of endometrial 7 cancer in the population of users.
A pooled analysis 14 from two case-control studies, the World Health Organization Study 3 and the New Zealand Study 13 , reported the relative risk (RR) of breast cancer for women who had ever used DEPO-PROVERA CI 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 DEPO-PROVERA CI. The RR of breast cancer for women of all ages who had initiated use of DEPO-PROVERA CI within the previous 5 years was estimated to be 2.0 (95% CI 1.5 to 2.8).
The World Health Organization Study 3 , a component of the pooled analysis 14 described above, showed an increased RR of 2.19 (95% CI 1.23 to 3.89) of breast cancer associated with use of DEPO-PROVERA CI 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 DEPO-PROVERA CI was only 1.2 (95% CI 0.96 to 1.52).
[ NOTE: A RR of 1.0 indicates neither an increased nor a decreased risk of cancer associated with the use of the drug, relative to no use of the drug. In the case of the subpopulation with a RR of 2.19, the 95% CI is fairly wide and does not include the value of 1.0, thus inferring an increased risk of breast cancer in the defined subgroup relative to nonusers. The value of 2.19 means that women whose first exposure to drug was within the previous 4 years and who are under 35 years of age have a 2.19 fold (95% CI 1.23 to 3.89-fold) increased risk of breast cancer relative to nonusers. The National Cancer Institute 8 reports an average annual incidence rate for breast cancer for US women, all races, age 30 to 34 years of 26.7 per 100,000. A RR of 2.19, thus, increases the possible risk from 26.7 to 58.5 cases per 100,000 women. The attributable risk, thus, is 31.8 per 100,000 women per year.]
A statistically insignificant 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.
4. Thromboembolic Disorders
The physician should be alert to the earliest manifestations of thrombotic disorders (thrombophlebitis, pulmonary embolism, cerebrovascular disorders, and retinal thrombosis). Should any of these occur or be suspected, the drug should not be readministered.
5. Ocular Disorders
Medication should not be readministered 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. If examination reveals papilledema or retinal vascular lesions, medication should not be readministered.
6. Unexpected Pregnancies
To ensure that DEPO-PROVERA CI is not administered inadvertently to a pregnant woman, the first injection must 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 (see DOSAGE AND ADMINISTRATION ).
Neonates from unexpected pregnancies that occur 1 to 2 months after injection of DEPO-PROVERA CI may be at an increased risk of low birth weight, which, in turn, is associated with an increased risk of neonatal death. The attributable risk is low because such pregnancies are uncommon. 9,10
A significant increase in incidence of polysyndactyly and chromosomal anomalies was observed among infants of users of DEPO-PROVERA CI, the former being most pronounced in women under 30 years of age. The unrelated nature of these defects, the lack of confirmation from other studies, the distant preconceptual exposure to DEPO-PROVERA CI, and the chance effects due to mul-tiple statistical comparisons, make a causal association unlikely. 11
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.
Several reports suggest an association between intrauterine exposure to progestational drugs in the first trimester of pregnancy and genital abnormalities in male and female fetuses. The risk of hypospadias (five to eight per 1,000 male births in the general population) may be approximately doubled with exposure to these drugs. There are insufficient data to quantify the risk to exposed female fetuses, but because some of these drugs induce mild virilization of the external genitalia of the female fetus and because of the increased association of hypospadias in the male fetus, it is prudent to avoid the use of these drugs during the first trimester of pregnancy.
To ensure that DEPO-PROVERA CI is not administered inadvertently to a pregnant woman, it is important that the first injection be given only during the first 5 days after the onset of a normal menstrual period within 5 days postpartum if not breast-feeding and if breast-feeding, at the sixth week postpartum (see DOSAGE AND ADMINISTRATION ).
7. Ectopic Pregnancy
Health-care providers should be alert to the possibility of an ectopic pregnancy among women using DEPO-PROVERA CI who become pregnant or complain of severe abdominal pain.
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.
9. Anaphylaxis and Anaphylactoid Reaction
Anaphylaxis and anaphylactoid reaction have been reported with the use of DEPO-PROVERA CI. If an anaphylactic reaction occurs appropriate therapy should be instituted. Serious anaphylactic reactions require emergency medical treatment.
Aminoglutethimide administered concomitantly with the DEPO-PROVERA CI may significantly depress the serum concentrations of medroxyprogesterone acetate. 12 Users of DEPO-PROVERA CI should be warned of the possibility of decreased efficacy with the use of this or any related drugs.
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 DEPO-PROVERA CI:
See " WARNINGS " section 3 .
Pregnancy Category X. See " WARNINGS " section 6 .
See " WARNINGS " section 8 .
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, 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 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 postmen-archal adolescents and adult women.
INFORMATION FOR THE PATIENT
See Patient Labeling.
Patient labeling is included with each single-dose vial and prefilled syringe of DEPO-PROVERA CI to help describe its characteristics to the patient. It is recommended that prospective users be given this labeling and be informed about the risks and benefits associated with the use of DEPO-PROVERA CI, as compared with other forms of contraception or with no contraception at all. It is recommended that physicians or other health-care providers responsible for those patients advise them 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.
In the largest clinical trial with DEPO-PROVERA CI, 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 DEPO-PROVERA CI.
The following adverse reactions were reported by more than 5% of subjects:
Menstrual irregularities (bleeding or amenorrhea, or both)
Abdominal pain or discomfort
Asthenia (weakness or fatigue)
Adverse reactions reported by 1% to 5% of subjects using DEPO-PROVERA Contraceptive Injection were:
Decreased libido or anorgasmia
No hair growth or alopecia
Events reported by fewer than 1% of subjects included: galactorrhea, melasma, chloasma, convulsions, changes in appetite, gastrointestinal disturbances, jaundice, genitourinary infections, vaginal cysts, dyspareunia, paresthesia, chest pain, pulmonary embolus, allergic reactions, anemia, drowsiness, syncope, dyspnea and asthma, tachycardia, fever, excessive sweating and body odor, dry skin, chills, increased libido, excessive thirst, hoarseness, pain at injection site, blood dyscrasia, rectal bleeding, changes in breast size, breast lumps or nipple bleeding, axillary swelling, breast cancer, prevention of lactation, sensation of pregnancy, lack of return to fertility, paralysis, facial palsy, scleroderma, osteoporosis, uterine hyperplasia, cervical cancer, varicose veins, dysmenorrhea, hirsutism, unexpected pregnancy, thrombophlebitis, deep vein thrombosis.
There have been rare cases of osteoporosis including osteoporotic fractures reported postmarketing in patients taking Depo-Provera CI. In addition, there have been voluntary reports of anaphylaxis and anaphylactoid reaction associated with the use of Depo-Provera CI.
DOSAGE AND ADMINISTRATION
Both the 1 mL vial and the 1 mL prefilled syringe of DEPO-PROVERA CI 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 DEPO-PROVERA CI every 3 months (13 weeks) administered by deep, IM injection in the gluteal or deltoid muscle. To ensure the patient is not pregnant at the time of the first injection, the first injection MUST 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 DEPO-PROVERA CI depends on adherence to the dosage schedule of administration.
DEPO-PROVERA CI (medroxyprogesterone acetate sterile aqueous suspension 150 mg/mL) is available as:
NDC 0009-0746-301 mL vial
NDC 0009-0746-3525 × 1 mL vials
NDC 0009-7376-011 mL prefilled syringe
NDC 0009-7376-026 × 1 mL prefilled syringes
NDC 0009-7376-0324 × 1 mL prefilled syringes
DEPO-PROVERA CI prefilled syringes are available packaged with 22-gauge × 1 1/2 inch BD SafetyGlide Needles in the following presentations:
NDC 0009-7376-041 mL prefilled syringe
NDC 0009-7376-056 × 1 mL prefilled syringes
NDC 0009-7376-0624 × 1 mL prefilled syringes
Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP].
DEPO-PROVERA Contraceptive Injection 1 mL vials are manufactured by:
Pharmacia & Upjohn Company
Kalamazoo, MI 49001, USA
Division of Pfizer Inc, NY, NY 10017
DEPO-PROVERA Contraceptive Injection 1 mL prefilled syringes are manufactured by:
Pharmacia & Upjohn, N.V./S.A.
Division of Pfizer Inc, NY, NY 10017
LAB-0149-4.0 Revised November 2004