DEPO-PROVERA® CI

Limitations of Use:

The use of Depo-Provera CI 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)].

2.1 Prevention of Pregnancy

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 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 a longer needle is necessary particularly for gluteal IM injection.

Use for longer than 2 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 5 days of a normal menstrual period or within the first 5-days post‑partum. In post‑partum mothers who exclusively breastfeed, administer Depo‑Provera CI during or after the sixth post‑partum 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 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 Depo-Provera CI on the day after the last active tablet or at the latest, on the day following the final inactive tablet).

5.1 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). 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.

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 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 Depo-Provera CI 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 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 a sudden partial or complete loss of vision or if there is a sudden onset of proptosis, diplopia, or migraine. Do not re-administer if examination reveals papilledema or retinal vascular lesions.

5.3 Cancer Risks

Breast Cancer

Women who have or have had a history of breast cancer should not use hormonal contraceptives, including Depo-Provera CI, 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 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 study1 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 study2.

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 Depo-Provera CI from about 72 to about 144 cases per 100,000 women.

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.

5.6 Injection 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 a 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 a 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.

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

5.12 Carbohydrate Metabolism

A decrease in glucose tolerance has been observed in some patients on Depo-Provera CI treatment. Monitor diabetic patients carefully while receiving Depo-Provera CI.

5.13 Fluid 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.

5.14 Return of Fertility

Return to ovulation and fertility is likely to be delayed after stopping Depo-Provera CI. In a 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 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 Depo-Provera CI to become pregnant and who were lost to follow-up or changed their mind.

5.15 Sexually Transmitted Infections

Patients should be counseled that Depo-Provera CI does not protect against HIV infection (AIDS) and other sexually transmitted infections.

5.16 Monitoring

A woman who is taking hormonal contraceptive should have a yearly visit with her healthcare professional for a blood pressure check and for other indicated healthcare.

5.17 Interference 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)].

6.1 Clinical Trials Experience

Clinical trials are conducted under widely varying conditions, therefore, 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 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 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 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 represented from COSTART medical dictionary.

 

Table 2. Adverse Reactions that Were Reported by between 1 and 5% of Subjects

 

* 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%).

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of Depo-Provera CI. 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 Depo-Provera CI.

 

Table 3. Adverse Reactions Reported during Post-Marketing Experience

 

* 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 Depo‑Provera CI in order to avoid injection site infections [see Dosage andAdministration (2.1)].

7.1 Changes in Contraceptive Effectiveness Associated with Co-Administration of Other Products

If a woman on hormonal contraceptives takes a drug or herbal product that induces enzymes, including CYP3A4, that metabolize contraceptive hormones, counsel her to use additional contraception or a different method of contraception. Drugs or herbal products that induce such enzymes may decrease the plasma concentrations of contraceptive hormones, and may decrease the effectiveness of hormonal contraceptives. Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include:

•

barbiturates

•

bosentan

•

carbamazepine

•

felbamate

•

griseofulvin

•

oxcarbazepine

•

phenytoin

•

rifampin

•

St. John's wort

•

topiramate

7.2 Laboratory Test Interactions

The pathologist should be advised of progestin therapy when relevant specimens are submitted.

The following laboratory tests may be affected by progestins including 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 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.

8.1 Pregnancy

Risk Summary

There is no use for contraception in pregnancy; therefore, Depo-Provera CI should be discontinued during pregnancy.

Epidemiologic studies and meta‑analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to progestins before conception or during early pregnancy.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

8.2 Lactation

Risk Summary

Although medroxyprogesterone acetate is detectable in the milk of mothers receiving Depo-Provera CI, milk composition, quality, and amount do not appear to be adversely affected. Effects on milk production and lactation initiation/duration remain unclear when administered before 6 weeks after delivery, therefore, in mothers who exclusively breastfeed, initiate Depo-Provera CI during or after the sixth post-partum week [see Dosage and Administration (2.1)].

No adverse effects in breastfed infants would be expected with maternal use of progestins. Neonates and infants exposed to medroxyprogesterone acetate from breast milk have been studied and no adverse effects have been noted.

The developmental and health benefits of breast-feeding should be considered along with the mother’s clinical need for Depo-Provera CI and any potential adverse effects on the breastfed child from Depo-Provera CI or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential

Depo-Provera CI is indicated for the prevention of pregnancy and would therefore be expected to impair female fertility until cessation of treatment. Women may experience a delay in return to ovulation and fertility (conception) following discontinuation of Depo-Provera CI [see Warnings and Precautions (5.14)].

8.4 Pediatric 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, 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 postmenarchal adolescents and adult women.

8.5 Geriatric Use

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

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

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

[see Warnings and Precautions (5.3, 5.14) and Use in Specific Populations (8.3)].

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 3 months (13 weeks) for reinjection.

14.2 Bone Mineral Density Changes in Women Treated with DepoProvera CI

In a controlled, clinical study, adult women using Depo-Provera CI (150mg) for up to 5 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 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, 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 Depo-Provera CI 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.

14.3 Bone Mineral Density Changes in Adolescent Females (12 to 18 Years of Age) Treated with DepoProvera 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 a 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 5 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.

14.4 Bone Fracture Incidence in Women Treated with DepoProvera CI

A 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 a 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 8 injections was higher than that in women who received 8 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 a 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.

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