2.1 Prevention of Pregnancy

Both the 1 mL vial and the 1 mL prefilled syringe of Medroxyprogesterone acetate 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 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.

Medroxyprogesterone acetate 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 [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; 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 depends on adherence to the dosage schedule of administration.

2.2 Switching from other Methods of Contraception

When switching from other contraceptive methods, Medroxyprogesterone acetate 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 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 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.

After discontinuing Medroxyprogesterone acetate 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 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 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). Although there are no studies addressing whether calcium and Vitamin D may lessen BMD loss in women using Medroxyprogesterone acetate, all patients should have adequate calcium and Vitamin D intake.

5.2 Thromboembolic 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 readminister 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 readminister if examination reveals papilledema or retinal vascular lesions.

5.3 Cancer Risks

5.4 Ectopic Pregnancy

Be alert to the possibility of an ectopic pregnancy among women using Medroxyprogesterone acetate who become pregnant or complain of severe abdominal pain.

5.5 Anaphylaxis 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.

5.6 Injection 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)].

5.7 Liver 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.

5.8 Convulsions

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.

5.9 Depression

Monitor patients who have a history of depression and do not readminister Medroxyprogesterone acetate if depression recurs.

5.10 Bleeding 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, amenorrhea was reported by 68% of women using Medroxyprogesterone acetate.

5.11 Weight Gain

Women tend to gain weight while on therapy with Medroxyprogesterone acetate. From an initial average body weight of 136 lb, women who completed 1 year of therapy with Medroxyprogesterone acetate 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 Medroxyprogesterone acetate treatment. Monitor diabetic patients carefully while receiving Medroxyprogesterone acetate.

5.13 Lactation

Detectable amounts of drug have been identified in the milk of mothers receiving Medroxyprogesterone acetate. In nursing mothers treated with Medroxyprogesterone acetate, milk composition, quality, and amount are not adversely affected. Neonates and infants exposed to medroxyprogesterone from breast milk have been studied for developmental and behavioral effects through puberty. No adverse effects have been noted.

5.14 Fluid Retention

Because progestational drugs including Medroxyprogesterone acetate 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.

5.15 Return of Fertility

Return to ovulation and fertility is likely to be delayed after stopping Medroxyprogesterone acetate. In a large US study of women who discontinued use of Medroxyprogesterone acetate 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 to become pregnant and who were lost to follow-up or changed their mind.

5.16 Sexually Transmitted Diseases

Patients should be counseled that Medroxyprogesterone acetate does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

5.17 Pregnancy

Although Medroxyprogesterone acetate should not be used during pregnancy, there appears to be little or no increased risk of birth defects in women who have inadvertently been exposed to medroxyprogesterone acetate injections in early pregnancy. Neonates exposed to medroxyprogesterone acetate in-utero and followed to adolescence showed no evidence of any adverse effects on their health including their physical, intellectual, sexual or social development.

5.18 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.

5.19 Interference with Laboratory Tests

The use of Medroxyprogesterone acetate 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

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 1–84 months. Fifty eight percent of patients remained in the study after 13 months and 34% after 24 months.

Adverse reactions leading to study discontinuation in ≥ 2% of subjects: bleeding (8.2%), amenorrhea (2.1%), weight gain (2.0%)

6.2 Post-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.

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 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.

8.1 Pregnancy

Medroxyprogesterone acetate should not be administered during pregnancy. [See Contraindications and Warnings and Precautions (5.17).]

8.3 Nursing Mothers

Detectable amounts of drug have been identified in the milk of mothers receiving Medroxyprogesterone acetate. [See Warnings and Precautions (5.13).]

8.4 Pediatric Use

Medroxyprogesterone acetate is not indicated before menarche. Use of Medroxyprogesterone acetate 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 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.

8.6 Renal Impairment

The effect of renal impairment on Medroxyprogesterone acetate pharmacokinetics has not been studied.

8.7 Hepatic Impairment

The effect of hepatic impairment on Medroxyprogesterone acetate pharmacokinetics has not been studied. Medroxyprogesterone acetate should not be used by women with significant liver disease and should be discontinued if jaundice or disturbances of liver function occur. [See Contraindications (4) and Warnings and Precautions (5.7).]

12.1 Mechanism of Action

Medroxyprogesterone acetate (MPA), 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.

12.2 Pharmacodynamics

No specific pharmacodynamic studies were conducted with Medroxyprogesterone acetate.

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

[See Warnings and Precautions, (5.3, 5.14, and 5.16).]

14.1 Contraception

In five clinical studies using Medroxyprogesterone acetate, the 12-month failure rate for the group of women treated with Medroxyprogesterone acetate was zero (no pregnancies reported) to 0.7 by Life-Table method. The effectiveness of Medroxyprogesterone acetate is dependent on the patient returning every 3 months (13 weeks) for reinjection.

14.2 Bone Mineral Density (BMD) Changes in Adult Women

In a controlled, clinical study, adult women using Medroxyprogesterone acetate 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 Medroxyprogesterone acetate (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 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 (12–18 years of age)

The impact of Medroxyprogesterone acetate (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 (12–18 years). Use of Medroxyprogesterone acetate 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 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.

14.4 Relationship of fracture incidence to use of DMPA 150 mg IM or non-use by women of reproductive age

A retrospective cohort study to assess the association between DMPA 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 DMPA users and contraceptive users who had no recorded use of DMPA. 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 DMPA use or to other related lifestyle factors that have a bearing on fracture rate.

In the study, when cumulative exposure to DMPA 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 DMPA users compared to non-users. Importantly, this study could not determine whether use of DMPA has an effect on fracture rate later in life.

Instructions for using the Needle:

1. WARNINGS for use with the Needle-Pro® EDGE™ Safety Device:

1.1   A needle stick with a contaminated needle may cause infectious diseases.

1.2   Intentional disengagement of the Needle-Pro® EDGE™ safety device may result in a needle stick with a contaminated needle.

1.3   Bent or damaged needles can result in breakage or damage to the tissue or accidental needle puncture. If the needle is bent or damaged, no attempt should be made to straighten the needle or engage the Needle-Pro® EDGE™ safety device. Immediately discard into a sharps container. The Needle-Pro® EDGE™ safety device may not properly contain a bent needle and/or the needle could puncture the needle protection device which may result in a needle stick with a contaminated needle.

1.4   Mishandling of this device, including excessive engagement force, may cause the needle to protrude from the needle protection device which may result in a contaminated needle stick.

1.5   Do not use free hand to press sheath over the needle. This may result in a needle stick with a contaminated needle.

2.   CAUTIONS for use with the Needle-Pro® EDGE™ Safety Device:

2.1   Follow standard infection control procedures as specified by the Centers for Disease Control and Prevention

(USA) or local equivalent.

2.2   Do Not Reuse: Medical devices require specific material characteristics to perform as intended. These characteristics have been verified for single use only. Any attempt to re-process the device for subsequent reuse may adversely affect the integrity of the device or lead to deterioration in performance.

3.   INSTRUCTIONS for use of the Prefilled Syringe with the Needle-Pro® EDGE™ Safety Device:

3.1   Remove syringe end cap exposing the luer fitting. Peel blister pouch for the Needle-Pro® EDGE™ safety device open half way. Grasp sheath using the plastic peel pouch. To prevent contamination, be careful not to touch the needle’s Luer connector.

3.2   Attach prefilled syringe to the Luer connection of the Needle-Pro® EDGE™ safety device. Insert plunger rod into open end of syringe until it contacts the stopper. Secure with 3 clockwise half turns. Shake vigorously with needle cap in place.

3.3   Pull needle cap (plastic component covering needle) straight away from the needle. Do not twist cap as Needle-Pro® EDGE™ safety device may be loosened from the prefilled syringe.

3.4   For user convenience, the needle is in the “bevel up” position when the safety sheath is located to the right as indicated by the “arrow” on the device.

3.5   Perform injection according to local standard practice using aseptic technique.

3.6   After procedure is completed, actuate needle protection by pressing the sheath against a flat surface using a one-handed technique. An audible click may be heard as an indication that the needle is engaged into the needle protection device. AS THE SHEATH IS PRESSED (FIGURE 1), THE NEEDLE IS FIRMLY ENGAGED INTO THE SHEATH (FIGURE 2).

3.7   Visually confirm that the needle is fully engaged into the needle protection sheath.3.8   After use, place syringe and needle into a sharps container. Dispose of sharps container containing used syringe and needle in a safe manner according to Centers for Disease Control and Prevention, USA and Federal/State/Local regulations (EPA, OSHA) and health care facility guidelines or local equivalent.

The Smiths Medical and Jelco design marks; Needle-Pro®EDGE; and the color orange applied to the needle protection device are trademarks of the Smiths Medical family of companies. The symbol ® indicates the trademark is registered in the U.S. Patent and Trademark Office and certain other countries.

The products described are covered by one or more of the following: U.S. Patent No. RE37, 110; counterpart

foreign patent(s); and other U.S. and/or foreign pending patents.

Syringe must be stored in carton at controlled room temperature 20° to 25°C (68° to 77°F) [see USP] until ready for use. Vials MUST be stored upright at controlled room temperature 20° to 25°C (68° to 77°F) [see USP].