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Depo-SubQ Provera 104™
(medroxyprogesterone acetate) Injectable Suspension 104 mg/0.65 mL

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

DESCRIPTION

depo-subQ provera 104 contains medroxyprogesterone acetate (MPA), 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 205°and 209°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 17-hydroxy-6α-methylpregn-4ene-3,20-dione 17-acetate. The structural formula is as follows:

depo-subQ provera (medroxyprogesterone acetate) 104 for subcutaneous (SC) injection is available in pre-filled syringes (160 mg/mL), each containing 0.65 mL (104 mg) of medroxyprogesterone acetate sterile aqueous suspension.

Each 0.65 mL contains:

When necessary, the pH is adjusted with sodium hydroxide or hydrochloric acid, or both.

INDICATIONS

depo-subQ provera 104 is indicated for the prevention of pregnancy in women of child bearing potential.

depo-subQ provera 104 also is indicated for management of endometriosis-associated pain.

In considering use for either indication, 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-subQ provera 104 longterm (see WARNINGS, section 1).

Contraception Studies

In three clinical studies, no pregnancies were detected among 2,042 women using deposubQ provera 104 for up to 1 year. The Pearl Index pregnancy rate in women who were less than 36 years old at baseline, based on cycles in which they used no other contraceptive methods, was 0 pregnancies per 100 women-years of use (upper 95% confidence interval = 0.25).

Pregnancy rates for various contraceptive methods are typically reported for only the first year of use and are shown in Table 2.

Table 2: Percentage of Women Experiencing an Unintended Pregnancy During the First Year of Typical Use and the First Year of Perfect Use of Contraception and the Percentage Continuing Use at the End of the First Year: United States

Endometriosis Studies

The efficacy of depo-subQ provera 104 in the reduction of endometriosis-associated pain in women with the signs and symptoms of endometriosis was demonstrated in two active comparator-controlled studies. Each study assessed reduction in endometriosis-associated pain over 6 months of treatment and recurrence of symptoms for 12-months post treatment. Subjects treated with depo-subQ provera 104 for 6 months received a 104 mg dose every 3 months (2 injections), while women treated with leuprolide microspheres for 6 months received a dose of 11.25 mg every 3 months (2 injections) or 3.75 mg every month (6 injections). Study 268 was conducted in the U.S. and Canada and enrolled 274 subjects (136 on depo-subQ provera 104 and 138 on leuprolide). Study 270 was conducted in South America, Europe and Asia, and enrolled 299 subjects (153 on deposubQ provera 104 and 146 on leuprolide).

Reduction in pain was evaluated using a modified Biberoglu and Behrman scale that consisted of three patient-reported symptoms (dysmenorrhea, dyspareunia, and pelvic pain not related to menses) and two signs assessed during pelvic examination (pelvic tenderness and induration). For each category, a favorable response was defined as improvement of at least 1 unit (severity was assessed on a scale of 0 to 3) relative to baseline score (Figure 2).

Figure 2: Percentages of Responders at End of Treatment (Month 6 or Last Assessment if Earlier) in Studies 268 & 270

Favorable Response = reduction in severity of symptom or sign of > 1 point on a scale of 0 to 3, as compared to baseline

Additionally, scores from each of the five categories were combined, with the total (composite score) considered a global measurement of overall disease improvement. For subjects with baseline scores for each of the 5 categories, a mean decrease of 4 points relative to baseline was considered a clinically meaningful improvement. Across both studies, for both treatment groups, the mean changes in the composite score met the protocol-defined criterion for improvement.

In the clinical trials, treatment with depo-subQ provera 104 was limited to six months. Data on the persistence of benefit with longer treatment are not available.

Subjects recorded daily the occurrence and severity of hot flushes. Of the depo-subQ provera 104 users, 28.6% reported experiencing moderate or severe hot flushes at baseline, 36.2% at month 3, and 26.7% at month 6. Of the leuprolide users, 32.8% reported experiencing moderate or severe hot flushes at baseline, 74.2% at month 3, and 68.5% at month 6.

REFERENCES

i Trussell J. Contraceptive efficacy. In Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Kowel D, Guest F, Contraceptive Technology: 17th Revised Edition. New York, NY: Irvington Publishers, 1998.

DOSAGE AND ADMINISTRATION

Contraception And Endometriosis Indications

Route Of Administration

depo-subQ provera 104 must be given by subcutaneous injection into the anterior thigh or abdomen, once every 3 months (12 to 14 weeks), rotating the sites with every injection. depo-subQ provera 104 is not formulated for intramuscular injection. Dosage does not need to be adjusted for body weight. The pre-filled syringe of depo-subQ provera 104 must be vigorously shaken just before use to create a uniform suspension.

First Injection

Ensure that the patient is not pregnant at the time of the first injection. For women who are sexually active and having regular menses, the first injection should be given only during the first 5 days of a normal menstrual period. Women who are breast-feeding may have their first injection during or after their sixth postpartum week.

Second And Subsequent Injections

Dosing is every 12 to 14 weeks. If more than 14 weeks elapse between injections, pregnancy should be ruled out before the next injection.

If Using For Contraception And Switching From Another Method

When switching from other contraceptive methods, depo-subQ provera 104 should be given in a manner that ensures continuous contraceptive coverage. For example, patients switching from combined (estrogen plus progestin) contraceptives should have their first injection of depo-subQ provera 104 within 7 days after the last day of using that method (7 days after taking the last active pill, removing the patch or ring). Similarly, contraceptive coverage will be maintained in switching from Depo-Provera CI (150 mg) to depo-subQ provera 104, provided the next injection is given within the prescribed dosing period for Depo-Provera CI (150 mg).

If Using For Treatment Of Endometriosis

Treatment for longer than two years is not recommended, due to the impact of long-term depo-subQ provera 104 on bone mineral density. If symptoms return after discontinuation of treatment, bone mineral density should be evaluated prior to retreatment.

Instructions For Use Of Depo-SubQ Provera 104

FOR SUBCUTANEOUS ADMINISTRATION ONLY

Please read these instructions carefully. It is very important that the entire dose of deposubQ provera 104 is given.

Getting Ready

Do not refrigerate. Ensure that the medication is at room temperature prior to injection (to ensure appropriate viscosity of the suspension). Make sure the following components are available.

depo-subQ provera 104, as with other parenteral drug products, should be inspected visually for particulate matter and discoloration prior to administration.

Step 1: Choosing & preparing the injection Area

Choose the injection area.

• Avoid boney areas and the umbilicus
• The upper thigh or abdomen are preferred injection sites. See shaded areas in diagram. Sites should be rotated with every injection.

Use an alcohol pad to wipe the skin in the injection area you have chosen.

• Allow the skin to dry

Preferred injection areas:

Upper thigh or abdomen

Step 2: Syringe preparation

Carefully remove the needle and syringe from the packaging.

Hold the syringe firmly by the barrel, with the barrel pointing upward.

• Shake it vigorously for at least 1 minute to thoroughly mix the medication

Hold the syringe barrel firmly.

• Remove the protective cap from the tip of the syringe barrel

Shake vigorously for 1 minute

Hold the syringe barrel firmly.

• Attach the needle to the barrel of the syringe firmly by pushing the plastic needle cover down fully with a slight twisting movement.

• Move the safety shield away from the needle and toward the syringe barrel. The safety shield will remain in an open 45 to 90 degree position

• While holding the syringe barrel firmly, remove the plastic needle cover from the needle without twisting, ensuring the needle is still firmly attached to the syringe

• While holding the syringe with the needle pointing upward, gently push in the plunger until the medicine is up to the top of the syringe. There should be no air within the barrel

Step 3: Injecting the dose

Gently grasp and squeeze a large area of skin in the chosen injection area between the thumb and forefinger, pulling it away from the body.

Insert the needle at a 45 degree angle so that most of the needle is in the fatty tissue.

• The plastic hub of the needle should be nearly or almost touching the skin

Inject the medication slowly until the syringe is empty.

• This should take about 5–7 seconds
• It is important that the entire dose of deposubQ provera 104 is given

Inject slowly (5-7 seconds)

Step 4: Disposing the needle and syringe

After completing the injection, remove the needle from the skin and activate the safety shield.

Position shield about 40°- 45°. With a firm quick motion, press down against a flat surface until a click is heard or felt.

If uncertain that the safety shield is fully engaged, repeat this step.

Use a clean cotton pad to press lightly on the injection area for a few seconds.

• Do NOT rub the area

Following the administration of each dose, the used syringe should be discarded in a safe and proper manner.

Keep away from children.

HOW SUPPLIED

depo-subQ provera 104 for subcutaneous use (medroxyprogesterone acetate injectable suspension 104 mg/0.65 mL) is available as a pre-filled syringe, packaged with a 26- gauge x 3/8 inch Terumo® Surguard™ needle in the following presentation:

NDC 0009-4709-13 0.65 mL single-use, disposable syringe

Store at controlled room temperature 20° to 25° C (68° to 77°F) [see USP].

This product’s label may have been updated. For current full prescribing information, please visit www.pfizer.com

Distributed by: Pharmacia & Upjohn Co., Division of Pfizer inc, NY, NY 10017. Revised : Dec 2016

SIDE EFFECTS

In five clinical studies of depo-subQ provera 104 involving 2,325 women (282 treated for up to 6 months, 1,780 treated for up to 1 year and 263 treated for up to 2 years), 9% of women discontinued treatment for adverse reactions. Among these 212 women, the most common reasons for discontinuation were:

• Uterine bleeding irregularities (35%, n=75)
• Increased weight (18%, n=39)
• Decreased libido (11%, n=23)
• Acne (10%, n=21)
• Injection site reactions (6%, n=12)

Adverse reactions reported by 5% or more of all women in these clinical trials included:

• Headache (9%)
• Intermenstrual bleeding (7%)
• Increased weight (6%)
• Amenorrhea (6%)
• Injection site reactions (5%)

Adverse reactions reported by 1% to <5% of all women in these clinical trials included:

General disorders: fatigue, injection site pain

Gastrointestinal disorders: abdominal distention, abdominal pain, diarrhea, nausea

Infections: bronchitis, influenza, nasopharyngitis, pharyngitis, sinusitis, upper respiratory tract infection, urinary tract infection, vaginal candidiasis, vaginitis, vaginitis bacterial

Investigations: abnormal cervix smear

Musculoskeletal, connective tissue, and bone disorders: arthralgia, back pain, limb pain

Nervous system disorders: dizziness, insomnia

Psychiatric disorders: anxiety, depression, irritability, decreased libido

Reproductive system and breast disorders: breast pain, breast tenderness, dysmenorrhea, menometrorrhagia, menorrhagia, menstruation irregular, uterine hemorrhage, vaginal hemorrhage

Skin disorders: acne

Vascular disorders: hot flushes

Postmarketing Experience

Anaphylactic reaction, anaphylactoid reaction, angioedema, and drug hypersensitivity have been reported with depo-subQ provera 104. There have been rare cases of osteoporosis including osteoporotic fractures reported postmarketing in patients taking DEPO-PROVERA Contraceptive Injection.

The following additional reactions have been reported with Depo-Provera Contraceptive Injection and may occur with use of depo-subQ provera 104:

General disorders: asthenia, axillary swelling, chills, chest pain, fever, excessive thirst, injection site nodule/lump, injection site pain/tenderness, injection site persistent atrophy/indentation/dimpling, injection site reactions

Blood and lymphatic system disorders: anemia, blood dyscrasia

Cardiac disorders: tachycardia

Gastrointestinal disorders: gastrointestinal disturbances, rectal bleeding

Hepato-biliary disorders: jaundice

Infections: genitourinary infections

Investigations: decreased glucose tolerance

Musculoskeletal, connective tissue, and bone disorders: loss of bone mineral density, scleroderma

Neoplasms: breast cancer, cervical cancer

Nervous system disorders: convulsions, facial palsy, fainting, paralysis, paresthesia, somnolence

Psychiatric disorders: increased libido, nervousness

Reproductive system and breast disorders: breast lumps, galactorrhea, nipple discharge or bleeding, oligomenorrhea, prevention of lactation, prolonged anovulation, unexpected pregnancy, uterine hyperplasia, vaginal cyst

Respiratory disorders: asthma, dyspnea, hoarseness

Skin disorders: dry skin, increased body odor, melasma, pruritus, urticaria

Vascular disorders: deep vein thrombosis, pulmonary embolus, thrombophlebitis

DRUG INTERACTIONS

No drug-drug interaction studies have been conducted with depo-subQ provera 104. Aminoglutethimide administered concomitantly with depo-subQ provera 104 may significantly decrease the serum concentrations of MPA.

WARNINGS

Loss Of Bone Mineral Density

Use of depo-subQ provera 104 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-subQ provera 104 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 (150 mg medroxyprogesterone acetate IM, DMPA). After discontinuing Depo-Provera CI in adolescents, mean BMD loss at total hip and femoral neck did not fully recover by 60 months (240 weeks) post-treatment. 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.

depo-subQ provera 104 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 depo-subQ provera 104 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-subQ provera 104 in women with osteoporosis risk factors. depo-subQ provera 104 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 lessen BMD loss in women using deposubQ provera 104, all patients should have adequate calcium and Vitamin D intake.

BMD Changes In Adult Women After Long-Term Treatment For Contraception

A study comparing changes in BMD in women using depo-subQ provera 104 with women using Depo-Provera Contraceptive Injection (Depo-Provera CI, 150 mg) showed no significant differences in BMD loss between the two groups after two years of treatment. Mean percent changes in BMD in the depo-subQ provera 104 group are listed in Table 3.

Table 3: Mean Percent Change from Baseline in BMD in Women Using depo-subQ provera 104

In another controlled clinical study, adult women using Depo-Provera CI (150 mg) 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 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.

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)

Bone Mineral Density Changes In Adolescent Females (12–18 Years Of Age)

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 (12-18 years). 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. 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

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 Depo-Provera CI. Table 6 shows the extent of recovery of BMD up to 60 months post-treatment for adolescent women who received Depo- Provera CI 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 Depo-Provera 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 Depo Provera CI Use (2 Years or Less vs. More than 2 Years)

BMD Changes In Adult Women After Six Months Of Treatment For Endometriosis

In two clinical studies of 573 adult women with endometriosis, the BMD effects of 6 months of depo-subQ provera 104 treatment were compared to 6 months of leuprolide treatment. Subjects were then observed, off therapy, for an additional 12 months (Table 7).

Table 7: Mean Percent Change from Baseline in BMD after 6 Months on Therapy with depo-subQ provera 104 or Leuprolide and 6 and 12 Months after Stopping Therapy (Studies 268 and 270 Combined)

Bleeding Irregularities

Most women using depo-subQ provera 104 experienced changes in menstrual bleeding patterns, such as amenorrhea, irregular spotting or bleeding, prolonged spotting or bleeding, and heavy bleeding. As women continued using depo-subQ provera 104, fewer experienced irregular bleeding and more experienced amenorrhea. If abnormal bleeding is persistent or severe, appropriate investigation and treatment should be instituted.

In three contraception trials, 39.0 % of women experienced amenorrhea during month six, and 56.5% experienced amenorrhea during month 12. The changes in menstrual bleeding patterns from the three contraception trials are presented in Figures 3 and 4.

Figure 3: Percentages of depo-subQ provera 104 Treated Women with Amenorrhea per 30-Day Month in Contraception Studies (ITT Population, N=2053)

N = Number of subjects in analysis for indicated month

Figure 4: Mean (25th, 75th Percentiles) Number of Bleeding and/or Spotting Days in the Subgroup of Women with Bleeding and/or Spotting by Month for Women Treated with depo-subQ provera 104 in Contraception Studies

N = Number of subjects with bleeding and/or spotting during indicated month

The changes in menstrual patterns in the two endometriosis trials are presented in Figures 5 and 6.

Figure 5: Percentages of depo-subQ provera 104 Treated Women with Amenorrhea per 30-Day Month in Endometriosis Studies (Combined ITT Population, N=289)

N = Number of subjects in analysis for indicated month

Figure 6: Mean (25th, 75th Percentiles) Number of Bleeding and/or Spotting Days in the Subgroup of Women with Bleeding and/or Spotting by Month for Women Treated with depo-subQ provera 104 in Endometriosis Studies Combined

N = Number of subjects with bleeding and/or spotting during indicated month

Cancer Risks

Women who have or have had breast cancer should not use hormonal contraceptives, including depo sub-Q provera 104, because breast cancer may be hormonally sensitive [see CONTRAINDICATIONS]. Women with a strong family history of breast cancer should be monitored with particular care. The results of five large case-control studies ii iii iv v vi assessing the association between depo-medroxyprogesterone acetate (DMPA) use and the risk of breast cancer are summarized in Figure 7. 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 studyii evaluated the recency and duration of use and found a statistically significant 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 studyv.

Figure 7: Risk estimates of 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 49vii 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.

The relative rate of invasive squamous-cell cervical cancer in women who ever used Depo-Provera CI (150 mg) 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.

Thromboembolic Disorders

Although MPA has not been causally associated with the induction of thrombotic or thromboembolic disorders, there have been rare reports of serious thrombotic events in women using Depo-Provera CI (150 mg). Any patient who develops thrombosis while undergoing therapy with depo-subQ provera 104 should discontinue treatment unless she has no other acceptable options for birth control (see CONTRAINDICATIONS).

Ocular Disorders

Medication should not be re-administered 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 re-administered.

Ectopic Pregnancy

Healthcare providers should be alert to the possibility of an ectopic pregnancy among women using depo-subQ provera 104 who become pregnant or complain of severe abdominal pain.

Anaphylaxis And Anaphylactoid Reaction

Serious anaphylactic reactions have been reported in women using depo-subQ provera 104. If an anaphylactic reaction occurs, appropriate emergency medical treatment should be instituted.

PRECAUTIONS

Physical Examination

It is good medical practice for all women to have annual history and physical examinations, including women using depo-subQ provera 104. The physical examination, however, may be deferred until after initiation of depo-subQ provera 104 if requested by the woman and judged appropriate by the clinician. The physical examination should include special reference to blood pressure, breasts, abdomen and pelvic organs, including cervical cytology and relevant laboratory tests. In case of undiagnosed, persistent or recurrent abnormal vaginal bleeding, appropriate measures should be conducted to rule out malignancy. Women with a strong family history of breast cancer should be monitored with particular care.

Fluid Retention

Because progestational drugs may cause some degree of fluid retention, conditions that might be influenced by this condition, such as epilepsy, migraine, asthma, and cardiac or renal dysfunction, require careful observation.

Weight Gain

Weight gain is a common occurrence in women using depo-subQ provera 104. In three large clinical trials using depo-subQ provera 104, the mean weight gain was 3.5 lb in the first year of use. In a small, two-year study comparing depo-subQ provera 104 to Depo- Provera CI (150 mg), the mean weight gain observed for women using depo-subQ provera 104 (7.5 lb) was similar to the mean weight gain for women using Depo-Provera CI, 150 mg (7.6 lb).

Although there are no data related to weight gain beyond 2 years for depo-subQ provera 104, the data on Depo-Provera CI (150 mg) may be relevant. In a clinical study, after five years, 41 women using Depo-Provera CI (150 mg) had a mean weight gain of 11.2 lb, while 114 women using non-hormonal contraception had a mean weight gain of 6.4 lb.

Return To Ovulation And Fertility

Return to ovulation is likely to be delayed after stopping therapy. Among 15 women who received multiple doses of depo-subQ provera 104:

• Median time to ovulation was 10 months after the last injection
• Earliest return to ovulation was 6 months after the last injection
• 12 women (80%) ovulated within 1 year of the last injection

However, ovulation has occurred as early as 14 weeks after a single dose of depo-subQ provera 104, and therefore it is important to follow the recommended dosing schedule.

Return to fertility also is likely to be delayed after stopping therapy. Among 28 women using depo-subQ provera 104 for contraception who stopped treatment to become pregnant, 1 became pregnant within 1 year of her last injection. A second woman became pregnant 443 days after her last injection. Seven women were lost to follow-up.

Depression

Patients with a history of treatment for clinical depression should be carefully monitored while receiving depo-subQ provera 104.

Injection Site Reactions

In 5 clinical studies of depo-subQ provera 104 involving 2,325 women (282 treated for up to 6 months, 1,780 treated for up to 1 year and 263 women treated for up to 2 years), 5% of women reported injection site reactions, and 1% had persistent skin changes, typically described as small areas of induration or atrophy.

In post-marketing experience, injection site reactions such as persistent atrophy of the injection site, dimpling/indentation and injection site lump/nodule have been reported.

Carbohydrate/Metabolism

Some patients receiving progestins may exhibit a decrease in glucose tolerance. Diabetic patients should be carefully observed while receiving such therapy.

Liver Function

If jaundice or any other liver abnormality develops in any woman receiving depo-subQ provera 104, treatment should be stopped while the cause is determined. Treatment may be resumed when liver function is acceptable and when the healthcare provider has determined that depo-subQ provera 104 did not cause the abnormality.

Laboratory Tests

The pathologist should be advised of progestin therapy when relevant specimens are submitted. The physician should be informed that certain endocrine and liver function tests, and blood components may be affected by progestin therapy:

1. Plasma and urinary steroid levels are decreased (e.g., progesterone, estradiol, pregnanediol, testosterone, cortisol).
2. Plasma and urinary gonadotropin levels are decreased (e.g., LH, FSH).
3. SHBG concentrations are decreased.
4. T3-uptake values may decrease.
5. There may be small changes in coagulation factors.
6. Sulfobromophthalein and other liver function test values may be increased slightly.
7. There may be small changes in lipid profiles.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

See WARNINGS, and PRECAUTIONS

Pregnancy

Although depo-subQ provera 104 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.

Nursing Mothers

Although the drug is detectable in the milk of mothers receiving Depo-Provera CI (150 mg), milk composition, quality, and amount are not adversely affected. Neonates and infants exposed to medroxyprogesterone acetate from breast milk have been studied for developmental and behavioral effects through puberty, and no adverse effects have been noted.

Pediatric Use

depo-subQ provera 104 is not indicated before menarche. Use of depo-subQ provera 104 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. In adolescents, interpretation of BMD results should take into account patient age and skeletal maturity. It is unknown if use of depo-subQ provera 104 by younger women will reduce peak bone mass and increase the risk for 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

depo-subQ provera 104 is intended for use in women with childbearing potential. Studies with depo-subQ provera 104 in geriatric women have not been conducted.

REFERENCES

ii Li CI, Beaber EF, Tang MCT et al. Effect of Depo-Medroxyprogesterone Acetate on Breast Cancer Risk among Women 20 to 44 years of Age. Cancer Research 2012; 72:2028-2035.

iii Shapiro S, Rosenberg L, Hoffman M et al. Risk of Breast Cancer in Relation to the Use of Injectable Progestogen Contraceptives and Combined Estrogen/Progestogen Contraceptives. Am J Epidemiol 2000: Vol.151, No. 4, 396-403.

iv WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Breast cancer and depotmedroxyprogesterone acetate: a multinational study. Lancet 1991; 338:833-38.

v Paul C, Skegg DCG, Spears GFS. Depot medroxyprogesterone (Depo-Provera) and risk of breast cancer. Br Med J 1989; 299:759-62.

vi Lee NC, Rosero-Bixby L, Oberle MW et al. A Case-Control Study of Breast Cancer and Hormonal Contraception in Costa Rica. JNCI 1987; 79:1247-1254.

vii http://seer.cancer.gov/faststats/index.php (Accessed on August 14, 2014).

OVERDOSE

No Information provided

CONTRAINDICATIONS

1. Known or suspected pregnancy.
2. Undiagnosed vaginal bleeding.
3. Known or suspected malignancy of the breast.
4. Active thrombophlebitis, or current or past history of thromboembolic disorders, or cerebral vascular disease.
5. Significant liver disease.
6. Known hypersensitivity to medroxyprogesterone acetate or any of its other ingredients.

CLINICAL PHARMACOLOGY

depo-subQ provera 104 (medroxyprogesterone acetate injectable suspension), when administered at 104 mg/0.65 mL to women every 3 months (12 to 14 weeks), inhibits the secretion of gonadotropins, which prevents follicular maturation and ovulation and causes endometrial thinning. These actions produce its contraceptive effect.

Supression of serum estradiol concentrations and a possible direct action of depo-subQ provera 104 on the lesions of endometriosis are likely to be responsible for the therapeutic effect on endometriosis-associated pain.

Pharmacokinetics

The pharmacokinetic parameters of medroxyprogesterone acetate (MPA) following a single SC injection of depo-subQ provera 104 are shown in Table 1 and Figure 1.

Table 1: Pharmacokinetic Parameters of MPA after a Single SC Injection of depo-subQ provera 104 in Healthy Women (n = 42)

Absorption

Following a single SC injection of depo-subQ provera 104, serum MPA concentrations reach ≥ 0.2 ng/mL within 24 hours. The mean Tmax is attained approximately 1 week after injection.

Figure 1: Mean (SD) Serum Concentration-Time Profile of MPA after a Single Injection of depo-subQ provera 104 to Healthy Women

In a study to assess accumulation and the achievement of steady state following multiple SC administrations, trough concentrations of MPA were determined after 6, 12, and 24 months, and in a subset of 8 subjects, bi-weekly concentrations were determined within one dosing interval in the second year of administration. The mean (SD) MPA trough concentrations were 0.67 (0.36) ng/mL (n=157), 0.79 (0.36) ng/mL (n=144), and 0.87 (0.33) ng/mL (n=106) at 6, 12 and 24 months, respectively.

Effect Of Injection Site

depo-subQ provera 104 was administered into the anterior thigh or the abdomen to evaluate effects on the MPA concentration-time profile. MPA trough concentrations (Cmin; Day 91) were similar for the two injection locations.

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

Residual MPA concentrations at the end of the first dosing interval (12 to 14 weeks) of depo-subQ provera 104 are generally below 0.5 ng/mL, consistent with its apparent terminal half-life of ~40 days after SC administration. Most MPA metabolites are excreted in the urine as glucuronide conjugates with only small amounts excreted as sulfates.

Linearity/Non-Linearity

Following a single SC administration of doses ranging from 50 to 150 mg, the AUC and Cmin (Day 91) increased with higher doses of depo-subQ provera 104, but there was considerable overlap across dose levels. Serum MPA concentrations at Day 91 increased in a dose proportional manner but Cmax did not appear to increase proportionally with increasing dose. The AUC data were suggestive of dose linearity.

Special Populations

Race

There were no significant differences in the pharmacokinetics and/or pharmacodynamics of MPA after SC administration of depo-subQ provera 104 in African-American and Caucasian women. The pharmacokinetics/pharmacodynamics of depo-subQ provera 104 were evaluated in Asian women in a separate study and also found to be similar to African-American and Caucasian women.

Effect Of Body Weight

Although total MPA exposure was lower in obese women, no dosage adjustment of depo-subQ provera 104 is necessary based on body weight. The effect of body weight on the pharmacokinetics of MPA following a single dose was assessed in a subset of women (n = 42, body mass index [BMI] ranged from 18.2 to 46.7 kg/m²). The AUC0–91 values for MPA were 71.6, 67.9, and 46.3 ng·day/mL in women with BMI categories of ≤ 28 kg/m², >28–38 kg/m², and >38 kg/m², respectively. The mean MPA Cmax was 1.74 ng/mL in women with BMI ≤ 28 kg/m², 1.53 ng/mL in women with BMI >28–38 kg/m², and 1.02 ng/mL in women with BMI > 38 kg/m², respectively. The MPA trough (Cmin) concentrations had a tendency to be lower in women with BMI >38 kg/m².

Hepatic Insufficiency

No clinical studies have evaluated the effect of hepatic disease on the disposition of depo-subQ provera 104. However, steroid hormones may be poorly metabolized in patients with severe liver dysfunction (see CONTRAINDICATIONS).

Renal Insufficiency

No clinical studies have evaluated the effect of renal disease on the pharmacokinetics of depo-subQ provera 104.

Drug-Drug Interactions

See PRECAUTIONS, section 9

PATIENT INFORMATION

No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.