Provera Medroxyprogesterone Acetate

WARNING

Women who use Depo-Provera Contraceptive Injection may lose significant bone mineral density. Bone loss is greater with increasing duration of use and may not be completely reversible.

It is unknown if use of Depo-Provera Contraceptive Injection during adolescence or early adulthood, a critical period of bone accretion, will reduce peak bone mass and increase the risk for osteoporotic fracture in later life.

Depo-Provera Contraceptive Injection should be used as a long-term birth control method (e.g. longer than 2 years) only if other birth control methods are inadequate.  (See WARNINGS.)



  Patient Information from TFL
  • • Provera is sometimes used to treat endometriosis. Find additional health information on endometriosis including other treatment options at TFL.com.


DESCRIPTION

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

Medroxyprogesterone acetate is a derivative of progesterone and is active by the parenteral and oral routes of administration. It is a white to off-white, odorless crystalline powder, stable in air, melting between 200 and 210C. It is freely soluble in chloroform, soluble in acetone and in dioxane, sparingly soluble in alcohol and in 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-,(6a)-.  The structural formula is as follows:

Contraceptive Injection: Depo-Provera contraceptive injection for intramuscular (IM) injection is available in vials and prefilled syringes, each containing 1 ml medroxyprogesterone acetate sterile aqueous suspension 150 mg/ml.

Each ml contains:

Medroxyprogesterone Acetate: 150 mg

Polyethylene Glycol 3350: 28.9 mg

Polysorbate 80: 2.41 mg

Sodium Chloride: 8.68 mg

Methylparaben: 1.37 mg

Propylparaben: 0.150 mg

Water for Injection: qs

When necessary, pH is adjusted with sodium hydroxide and/or hydrochloric acid.

INDICATIONS

Contraceptive Injection

Medroxyprogesterone acetate contraceptive injection is indicated only for the prevention of pregnancy. To ensure that medroxyprogesterone acetate contraceptive injection 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. The efficacy of medroxyprogesterone acetate contraceptive injection depends on adherence to the recommended dosage schedule (see

DOSAGE AND ADMINISTRATION

). 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 medroxyprogesterone acetate contraceptive injection, the 12-month failure rate for the group of women treated with medroxyprogesterone acetate contraceptive injection 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 medroxyprogesterone acetate contraceptive injection, the efficacy of these contraceptive measures depends in party on the reliability of use. The effectiveness of medroxyprogesterone acetate contraceptive injection is dependent upon the patient returning every 3 months (13 weeks) for reinjection.

TABLE 1 Lowest Expected and Typical Failure Rates* Expressed as Percent of Women Experiencing an Accidental Pregnancy in the First Year of Continuous Use
Method Lowest Expected Typical
 Injectable progestogen
   medroxyprogesterone acetate contraceptive injection 0.3 0.3
 Implants
   Norplant (6 capsules) 0.2 0.2
 Female Sterilization 0.2 0.4
 Male Sterilization 0.1 0.15
 Pill   3
   Combined 0.1  
   Progestogen only 0.5  
 IUD   3
   Progestasert 2  
   Copper T 380A 0.8  
 Condom 2 12
 Diaphragm 6 18
 Cap 6 18
 Spermicides

3

21

 Sponge
   Parous women 9 28
   Nulliparous women 6 18
 Periodic abstinence 1-9 20
 Withdrawal 4 18
 No method 85 85
Source: Trussell et al.5
* Lowest expectedwhen used exactly as directed. Typicalincludes those not following directions exactly.
from Norplant package insert.


DOSAGE AND ADMINISTRATION

Contraceptive Injection

Both the 1 ml vial and the 1 ml prefilled syringe of medroxyprogesterone acetate contraceptive injection 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 contraceptive injection 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 medroxyprogesterone acetate contracptive injection depends on adherence to the dosage schedule of administration.

HOW SUPPLIED

DEPO- PROVERA  Contraceptive Injection (medroxyprogesterone acetate sterile aqueous suspension 150 mg/mL) is available as:
NDC 0009-0746-30                        1 mL vial
NDC 0009-0746-35                        25 1 mL vials
NDC 0009-7376-01                        1 mL prefilled syringe
NDC 0009-7376-02                        6 1 mL prefilled syringes
NDC 0009-7376-03                        24 1 mL prefilled syringes

DEPO- PROVERA  Contraceptive Injection prefilled syringes are available packaged with 22-gauge 1 1/2 inch BD SafetyGlide Needles in the following presentations:
NDC 0009-7376-04                        1 mL prefilled syringe
NDC 0009-7376-05                        6 1 mL prefilled syringes
NDC 0009-7376-06                        24 1 mL prefilled syringes

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

REFERENCES

Oral Tablets

1. Royal College of General Practitioners: Oral contraception and thromboembolic disease. J Coll Gen Pract 13:267-279, 1967.

2. Inman WHW, Vessey MP: Investigation of deaths from pulmonary, coronary, and cerebral thrombosis and embolism in women of child-bearing age. Br Med J 2:193-199, 1968.

3. Vessey MP, Doll R: Investigation of relation between use of oral contraceptives and thromboembolic disease. A further report. Br Med J 2:651-657, 1969.

4. Sartwell PE, Masi AT, Arthes FG, et al: Thromboembolism and oral contraceptives: An epidemiological case-control study. Am J Epidemiol 90:365-380, 1969.

5. Trussell J, Hatcher RA, Cates W Jr, Stewart FH, Kost K: A guide to interpreting contraceptive efficacy studies. Obstet Gynecol. 1990; 76:558-567.

6. Schwallie PC, Assenzo JR. Contraceptive use-efficacy study utilizing medroxyprogesterone acetate administered as an intramuscular injection once every 90 days.Fertil Steril. 1973: 24:331-339.

7. WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Breast cancer and depot-medroxyprogesterone acetate: a multi-national study. Lancet 1991; 338:833-838.

8. WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Depot-medroxyprogesterone acetate (DPMA): and risk of epithelial ovarian cancer. Int J Cancer. 1991; 49:191-195.

9. WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Depot-medroxyprogesterone acetate (DPMA) and risk of liver cancer. Int J Cancer. 1991;49:182-185.

10. WHO Collaborative Study of Neoplasia and Steroid Contraceptives Depot-medroxyprogesterone acetate (DPMA) and risk of invasive squamous-cell cervical cancer. Contraception. 1992;45:299-312.

11. WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Depot-medroxyprogesterone acetate (DMPA) and risk of endometrial cancer. Int J Cancer. 1991; 49:186-190.

12. Surveillance, Epidemiology, and End Results: Incidence and Mortality Data, 1973-77, National Cancer Institute Monograph, 57: June 1981. (NIH publication No. 81-2330).

13. Gray RH, Pardthaisong T:In Utero exposure to steroid contraceptives and survival during infancy. Am J Epidemiol 1991; 134:804-811.

14. Pardthaisong T, Gray RH. In Utero exposure to steroid contraceptives and outcome of pregnancy. Am J Epidemiol. 1991;134:795-803.

15. Pardthaisong T. Gray RH, McDaniel EB, Chandacham A: Steroid contraceptive use and pregnancy outcome.Teratology. 1988; 38:51-58.

16. Van Deijk WA, Biljham GH, Mellink WAM, Meulenberg PMM. Influence of aminoglutethimide on plasma levels of medroxyprogesterone acetate: its correlation with serum cortisol. Cancer Treatment Reports 1985; 69:1, 85-90.

17. Paul C, Skegg DCG, Spears GFS. Depot medroxyprogesterone (Depo-Provera) and risk of breast cancer. Br Med J. 1989; 299:759-762.

18. Skegg DCG, Noonan EA, Paul C, Spears GFS, Meirik O, Thomas DB. Depot Medroxyprogesterone Acetate and Breast Cancer: A Pooled Analysis from the World Health Organization and New Zealand Studies. JAMA. 1995; 273(10):799-804.

PATIENT INFORMATION

Contraceptive Injection

This product is intended to prevent pregnancy. It does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

Introduction: Every woman who considers using Depo-Provera contraceptive injection needs to understand the benefits and risks of this form of birth control and to discuss them with he health-care provider. This leaflet is intended to give you much of the information you will need in order to decide if Depo-Provera is the right choice for you. Your health-care provider will help you to compare Depo-Provera contraceptive injection with other contraceptive methods and will answer any questions you have after you have read this information.

Depo-Provera contraceptive injection is given as an intramuscular injection (a shot) in the buttock or upper arm once every 3 months (13 weeks). Promptly at the end of the 3-month interval, you will need to return to your health-care provider for your next injection in order to continue your contraceptive protection.

Depo-Provera contraceptive injection contains medroxyprogesterone acetate, a chemical similar to (but not the same as) the natural hormone progesterone that is produced by your ovaries during the second half of your menstrual cycle. Depo-Provera contraceptive injection acts by preventing your egg cells from ripening. If an egg is not released from the ovaries during your menstrual cycle, it cannot become fertilized by sperm and result in pregnancy. Depo-Provera contraceptive injection also causes changes in the lining of your uterus that makes it less likely for pregnancy to occur.

Effectiveness of Depo-Provera Contraceptive Injection: To ensure that Depo-Provera contraceptive injection is not administered inadvertantly to a pregnant woman, the first injection must be given ONLY during the first 5 days of a normal menstrual period; ONLY within in the first 5-days postpartum if not breast-feeding, and if exclusively breast-feeding, ONLY at the sixth postpartum week (see Administration of Depo-Provera Contraceptive Injection). The efficacy of Depo-Provera contraceptive injection depends upon adherence to the recommended dosage schedule.

Depo-Provera contraceptive injection is over 99% effective, making it one of the most reliable methods of birth control available. This means that the average annual pregnancy rate is less than one for every 100 women who use Depo-Provera contraceptive injection. The effectiveness of most contraceptive methods depends, in part, on how reliably each woman uses the method. The effectiveness of Depo-Provera contraceptive injection depends only on the patient returning every three (3) months for her next injection.

TABLE 1 shows the percent of women who become pregnant while using different kinds of contraceptive methods. It gives both the lowest expected rate of pregnancy (the rate expected in women who use each method exactly as it should be used) and the typical rate of pregnancy (which includes women who became pregnant because they forgot to use their birth control or because they did not follow the directions exactly).

Who Should Not Use Depo-Provera Contraceptive Injection: Certain women should not use Depo-Provera contraceptive injection. You should not use Depo-Provera contraceptive injection if you have any of the following conditions:

  • If you think you might be pregnant.
  • If you have any vaginal bleeding without a known reason.
  • If you have had cancer of the breast.
  • If you have had a stroke.
  • If you have or have had blood clots (phlebitis) in your legs.
  • If you have problems with your liver or liver disease.
  • If you are allergic to Depo-Provera contraceptive injection (medroxyprogesterone acetate or any of its other ingredients).

Other Things to Consider Before Choosing Depo-Provera Contraceptive Injection: Before your doctor prescribes Depo-Provera contraceptive injection, you will have a physical examination. It is important to tell your doctor or health-care provider if you have any of the following:

  • A family history of cancer of the breast.
  • An abnormal mammogram (breast x-ray), fibrocystic breast disease, breast nodules or lumps, or bleeding from your nipples.
  • Kidney disease.
  • Irregular or scanty menstrual periods.
  • High blood pressure.
  • Migraine headaches.
  • Asthma.
  • Epilepsy (convulsions or seizures).
  • Diabetes or a family history of diabetes.
  • A history of depression.
  • If you are taking any prescription or over-the-counter medications.

This product is intended to prevent pregnancy. It does not protect against transmission of HIV (AIDS) and other sexually transmitted diseases such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis.

Return of Fertility: Because Depo-Provera contraceptive injection is a long-acting birth control method, it takes some time after your last injection for its effect to wear off. Based on results from a large study done in the United States, of those women who stop using Depo-Provera contraceptive injection in order to become pregnant about half of those who become pregnant do so in about 10 months after their last injection; about two-thirds of those who become pregnant do so in about 12 months, about 83% of those who become pregnant do so in about 15 months, and about 93% of those who become pregnant do so in about 18 months after their last injection. The length of time you use Depo-Provera contraceptive injection has no effect on how long it takes you to become pregnant after you stop using it.

Risks of Using Depo-Provera Contraceptive Injection

1. Irregular Menstrual Bleeding: The side effect reported most frequently by women who use Depo-Provera contraceptive injection for contraception is a change in their normal menstrual cycle. During the first year of using Depo-Provera contraceptive injection, you might have one or more of the following changes:

Irregular or unpredictable bleeding or spotting.

An increase or decrease in menstrual bleeding, or

No bleeding at all.

Unusually heavy or continuous bleeding, however, is not a usual effect of Depo-Provera contraceptive injection and if this happens you should see your health-care provider right away.

With continued use of Depo-Provera contraceptive injection, bleeding usually decreases and many women stop having periods completely. In clinical studies of Depo-Provera contraceptive injection, 55% of the women studied reported no menstrual bleeding (amenorrhea) after 1 year of use and 68% of the women studied reported no menstrual bleeding after 2 years of use.

The reason that your periods stop is because Depo-Provera contraceptive injection causes a resting state in your ovaries. When your ovaries do not release an egg monthly, the regular monthly growth of the lining of your uterus does not occur and, therefore, the bleeding that comes with your normal menstruation does not take place. When you stop using Depo-Provera contraceptive injection your menstrual period will usually, in time, return to its normal cycle.

2. Bone Mineral Changes: Use of Depo-Provera contraceptive injection may be associated with a decrease in the amount of mineral stored in your bones. This could increase your risk of developing bone fractures. The rate of bone mineral loss is greatest in the early years of Depo-Provera contraceptive injection use but, after that, it begins to resemble the normal rate of age-related bone mineral loss.

3. Cancer: Studies of women who have used different forms of contraception found that women who used Depo-Provera contraceptive injection for contraception had no increased overall risk of developing cancer of the breast, ovary, uterus, cervix, or liver. However, women under 35 years of age whose first exposure to Depo-Provera contraceptive injection was within the previous 4 years may have a slightly increased risk of developing breast cancer similar to that seen with oral contraceptives. You should discuss this with your health-care provider.

4. Accidental Pregnancy: Because Depo-Provera contraceptive injection is such an effective contraceptive method, the risk of accidental pregnancy for women who get their shots regularly (every 3 months [13 weeks]) is very low. While there have been reports of an increased risk of low birth weight and neonatal infant death or other health problems in infants conceived close to the time of injection, such pregnancies are uncommon. If you think that you may have become pregnant while using Depo-Provera contraceptive injection for contraception, see your health-care provider as soon as possible.

5. Allergic Reactions: Severe allergic reactions known as anaphylaxis and anaphylactoid reactions have also been reported in some women using Depo-Provera contraceptive injection.

6. Other Risks: Women who use hormone-based contraceptives may have an increased risk of blood clots or stroke. Also, if a contraceptive method fails, there is a possibility that the fertilized egg will begin to develop outside of the uterus (ectopic pregnancy). While these events are rare, you should tell your health-care provider if you have any of the Warning Signals listed in the next section.

Warning Signals: If any of these problems occur following an injection of Depo-Provera contraceptive injection, call your health-care provider immediately:

  • Sharp chest pain, coughing up of blood, or sudden shortness of breath (indicating a possible clot in the lung).
  • Sudden severe headache or vomiting, dizziness or fainting, problems with your eyesight or speech, weakness, or numbness in an arm or leg (indicating a possible stroke).
  • Severe pain or swelling in the calf (indicating a possible clot in the leg).
  • Unusually heavy vaginal bleeding.
  • Severe pain or tenderness in the lower abdominal area.
  • Persistent pain, pus, or bleeding at the injection site.

Side Effects of Depo-Provera Contraceptive Injection

1. Weight Gain: You may experience a weight gain while you are using Depo-Provera contraceptive injection. About two-thirds of the women who used Depo-Provera contraceptive injection in the clinical trials reported a weight gain of about 5 pounds during the first year of use. You may continue to gain weight after the first year. Women in one large study who used Depo-Provera contraceptive injection for 2 years gained an average total of 8.1 pounds over those 2 years, or approximately 4 pounds per year. Women who continued for 4 years gained an average of 13.8 pounds over those 4 years, or approximately 3.5 pounds per year. Women who continued for 6 years gained an average total of 16.5 pounds over those 6 years, or approximately 2.75 pounds per year.

2. Other Side Effects: In a clinical study of over 3900 women who used Depo-Provera contraceptive injection for up to 7 years, some women reported the following effects that may or may not have been related to their use of Depo-Provera contraceptive injection:

    Irregular menstrual bleeding.
    Amenorrhea.
    Headache.
    Nervousness.
    Abdominal cramps.
    Dizziness.
    Weakness or fatigue.
    Decreased sexual desire.
    Leg cramps.
    Nausea.
    Vaginal discharge or irritation.
    Breast swelling and tenderness.
    Bloating.
    Swelling of the hands or feet.
    Backache.
    Depression.
    Insomnia.
    Acne.
    Pelvic pain.
    No hair growth or excessive hair loss.
    Rash.
    Hot flashes.
    Joint pain.

Other problems were reported by very few of the women in the clinical trials, but some of these could be serious. These include: convulsions, jaundice, urinary tract infections, allergic reactions, fainting, paralysis, osteoporosis, lack of return to fertility, deep vein thrombosis, pulmonary embolus, breast cancer, or cervical cancer. If these or any other problems occur during your use of Depo-Provera contraceptive injection, discuss them with your health-care provider.

General Precautions

1. Missed Periods: During the time you are using Depo-Provera contraceptive injection for contraception, you may skip a period, or your periods may stop completely. If you have been receiving your Depo-Provera injections regularly every 3 months (13 weeks), then you are probably not pregnant. However, if you think that you may be pregnant, see your health-care provider.

2. Laboratory Test Interactions: If you are scheduled for any laboratory tests, tell your health-care provider that you are using Depo-Provera contraceptive injection for contraception. Certain blood tests are effected by hormones such as Depo-Provera contraceptive injection.

3. Drug Interactions: Cytadren (aminoglutethimide) is an anticancer drug that may significantly decrease the effectiveness of Depo-Provera contraceptive injection if the two drugs are given during the same time.

4. Nursing Mothers: Although Depo-Provera contraceptive injection can be passed to the nursing infant in the breast milk, no harmful effects have been found in these children. Depo-Provera contraceptive injection does not prevent the breasts from producing milk, so it can be used by nursing mothers. However, to minimize the amount of Depo-Provera that is passed to the infant in the first weeks after birth, you should wait until 6 weeks after childbirth before you start using Depo-Provera contraceptive injection for contraception.

Administration of Depo-Provera Contraceptive Injection: The recommended dose of Depo-Provera contraceptive injection is 150 mg every 3 months (13 weeks) given in a single intramuscular injection in the buttock or upper arm. To ensure that you are not pregnant at the time of the first injection, it is essential that the injection be given ONLY during the first 5 days of a normal menstrual period. If used following the delivery of a child, the first Depo-Provera injection should be given within 5 days after childbirth if you are not breast-feeding, or if you are exclusively breast-feeding, the injection MUST be given 6 weeks after childbirth. If you wait longer than 3 months (13 weeks) between injections, or longer than 6 weeks after delivery, your health-care provider should determine that you are not pregnant before giving you your Depo-Provera contraceptive injection.

CLINICAL PHARMACOLOGY

Contraceptive Injection: Medroxyprogesterone acetate contraceptive injection, 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 medroxyprogesterone acetate contraceptive injection, 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 medroxyprogesterone acetate contraceptive injection is approximately 50 days.

Women with lower body weights conceive sooner than women with higher body weights after discontinuing medroxyprogesterone acetate contraceptive injection.

The effect of hepatic and/or renal disease on the pharmacokinetics of medroxyprogesterone acetate contraceptive injection is unknown.

SIDE EFFECTS

Oral Tablets

Pregnancy: See BOXED WARNING for possible adverse effects on the fetus.

Breast: Breast tenderness or galactorrhea has been reported rarely.

Skin: Sensitivity reactions consisting of urticaria, pruritus, edema and generalized rash have occurred in an occasional patient. Acne, alopecia and hirsutism have been reported in a few cases.

Thromboembolic Phenomena: Thromboembolic phenomena including thrombophlebitis and pulmonary embolism have been reported.

The following adverse reactions have been observed in women taking progestins including medroxyprogesterone acetate tablets: breakthrough bleeding, spotting, change in menstrual flow, amenorrhea, edema, change in weight (increase or decrease), changes in cervical erosion and cervical secretions, cholestatic jaundice, anaphylactoid reactions and anaphylaxis, rash (allergic) with and without pruritus, mental depression, pyrexia, insomnia, nausea, somnolence.

A statistically significant association has been demonstrated between use of estrogen-progestin combination drugs and the following serious adverse reactions: thrombophlebitis; pulmonary embolism and cerebral thrombosis and embolism. For this reason patients on progestin therapy should be carefully observed.

Although available evidence is suggestive of an association, such a relationship has been neither confirmed nor refuted for the following serious adverse reactions: neuro-ocular lesions, e.g., retinal thrombosis and optic neuritis.

Sterile Aqueous Suspension

See WARNINGS for possible adverse effects on the fetus.

  • Breakthrough bleeding.
  • Spotting.
  • Change in menstrual flow.
  • Amenorrhea.
  • Headache.
  • Nervousness.
  • Dizziness.
  • Edema.
  • Change in weight (increase or decrease).
  • Changes in cervial erosion and cervial secretions.
  • Cholestatic jaundice, including neonatal jaundice.
  • Breast tenderness and galactorrhea.
  • Skin sensitivity reactions consisting of urticaria, pruritus, edema and generalized rash.
  • Acne, alopecia and hirsutism.
  • Rash (allergic) with and without pruritis.
  • Anaphylactoid reactions and anaphylaxis.
  • Mental depression.
  • Pyrexia.
  • Fatigue.
  • Insomnia.
  • Nausea.
  • Somnolence.

In a few instances there have been undesirable sequelae at the first site of injection, such as residual lump, change in color of skin, or sterile abscess.

A statistically significant association has been demonstrated between use of estrogen-progestin combination durgs and pulmonary embolism and cerebral thrombosis and embolism. For this reason patients on progestin therapy should be carefully observed. There is also evidence suggestive of an associatin with neuro-ocular lesions, e.g., retinal thrombosis and optic neuritis.

Oral Tablets and Sterile Aqueous Suspension

The following adverse reactions have been observed in patients receiving estrogen progestin combination drugs: rise in blood pressure in susceptible individuals; premenstrual-like syndrome; changes in libido; changes in appetite; cystitis-like syndrome; headache; nervousness; fatigue; backache; hirsutism; loss of scalp hair; erythema multiforme; erythema nodosum; hemorrhagic eruption; itching; dizziness.

In view of these observations, patients on progestin therapy should be carefully observed.

The following laboratory results may be altered by the use of estrogen-progestin combination drugs:

Increased sulfobromophthalein retention and other hepatic function tests.

Coagulation tests: increase in prothrombin factors VII, VIII, IX and X

Metyrapone test.

Pregnanediol determination.

Thyroid function: increase in PBI, and butanol extractable protein bound iodine and decrease in T3 uptake values.

Contraceptive Injection

In the largest clinical trial with medroxyprogesterone acetate contraceptive injection, over 3900 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 contraceptive injection.

The Following Adverse Reactions Reported By More Than 5% of Subjects:

    Menstrual irregularities (bleeding or amenorrhea, or both).
    Abdominal pain or discomfort.
    Weight changes.
    Dizziness.
    Headache.
    Asthenia (weakness or fatigue).
    Nervousness.

Adverse Reactions Reported By 1% To 5% of Subjects:

    Decreased libido or anorgasmia.
    Pelvic Pain.
    Backache.
    Breast Pain.
    Leg Cramps.
    No hair growth or alopecia.
    Depression.
    Bloating.
    Nausea.
    Rash.
    Insomnia.
    Edema.
    Leukorrhea.
    Hot flashes.
    Acne.
    Arthralgia.
    Vaginitis.

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.

In addition, voluntary reports have been received of anaphylaxis and anaphylactoid reaction with use of medroxyprogesterone acetate contraceptive injection.

DRUG INTERACTIONS

Sterile Aqueous Suspension and Contraceptive Injection: Aminoglutethimide administered concomitantly with the medroxyprogesterone acetate sterile aqueous suspension or contraceptive injection may significantly depress the serum concentrations of medroxyprogesterone acetate.16 Users of medroxyprogesterone acetate should be warned of the possibility of decreased efficacy with the use of this or any related drugs.

WARNINGS

Contraceptive Injection

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.

Table 2. Mean Percent Change from Baseline in BMD in Adults by Skeletal Site
and Cohort

*The treatment group consisted of women who received Depo-Provera Contraceptive Injection for 5 years and were then followed for 2 years post-use.
**The control group consisted of women who did not use hormonal contraception and were followed for 7 years.

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.

Table 3. Mean Percent Change from Baseline in BMD in Adolescents by Skeletal
Site and Cohort

2. Bleeding Irregularities: Most women using medroxyprogesterone acetate contraceptive injection 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 medroxyprogesterone acetate contraceptive injection, fewer experience irregular bleeding and more experience amenorrhea. By month 12 amenorrheas was reported by 55% of women, and by month 24 amenorrhea was reported by 68% of women using medroxyprogesterone acetate contraceptive injection.5

3. Cancer Risks: Long-term case-controlled surveillance of users of medroxyprogesterone acetate contraceptive injection found slight or no increased overall risk of breast cancer7 and no overall increased risk of ovarian,8 liver,9 or cervical10 cancer and a prolonged, protective effect of reducing the risk of endometrial11 cancer in the population of users.

A pooled analysis18 from two case-control studies, the World Health Organization Study7 and the New Zealand Study,17 reported the relative risk (RR) of breast cancer for women who had ever used medroxyprogesterone acetate contraceptive injection as 1.1 (95% confidence interval [CI] 0.97 to 1.4). Overall, there was no increase in risk with increasing duration of use of medroxyprogesterone acetate contraceptive injection. The RR of breast cancer for women of all ages who had initiated use of medroxyprogesterone acetate contraceptive injection within the previous 5 years was estimated to be 2.0 (95% CI 1.5 to 2.8).

The World Health Organization Study,7 a component of the pooled analysis18 described above, showed an increased RR of 2.19 (95%) CI 1.23 to 3.89) of breast cancer associated with use of medroxyprogesterone acetate contraceptive injection in women whose first exposure to drug was within the previous 4 years and who were under 35 years of age. However the overall RR for ever-users of medroxyprogesterone acetate contraceptive injection 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% C.I. 1.23- to 3.89-fold) increased risk of breast cancer relative to nonusers. The National Cancer Institute12 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 medroxyprogesterone acetate contraceptive injection 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 medroxyprogesterone acetate contraceptive injection 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 medroxyprogesterone acetate contraceptive injection 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 medroxyprogesterone acetate contraceptive injection 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.13, 14

A significant increase in incidence of polysyndactyly and chromosomal anomalies was observed among infants of users of medroxyprogesterone acetate contraceptive injection, 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 medroxyprogesterone acetate contraceptive injection, and the chance effects due to multiple statistical comparisons, make a causal association unlikely.15

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 hypospadia (5 to 8 per 1000 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 hypospadia in the male fetus, it is prudent to avoid use of these drugs during the first trimester of pregnancy.

To ensure that medroxyprogesterone acetate contraceptive injection 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 medroxyprogesterone acetate contraceptive injection who become pregnant or complain of severe abdominal pain.

8. Lactation: Detectable amounts of drug have been identified in the milk of mothers receiving medroxyprogesterone acetatecontraceptive injection. In nursing mothers treated with medroxyprogesterone acetate contraceptive injection, 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 medroxyprogesterone acetate contraceptive injection. If an anaphylactic reaction occurs appropriate therapy should be instituted. Serious anaphylactic reactions require emergency medical treatment.

PRECAUTIONS

Oral Tablets

1. The pretreatment physical examination should include special reference to breast and pelvic organs, as well as Papanicolaou smear.

2. Because progestogens may cause some degree of fluid retention, conditions which might be influenced by this factor, such as epilepsy, migraine, asthma, cardiac or renal dysfunction, require careful observation.

3. In cases of breakthrough bleeding, as in all cases of irregular bleeding per vaginum, nonfunctional causes should be borne in mind. In cases of undiagnosed vaginal bleeding, adequate diagnostic measures are indicated.

4. Patients who have a history of psychic depression should be carefully observed and the drug discontinued if the depression recurs to a serious degree.

5. Any possible influence of prolonged progestin therapy on pituitary, ovarian, adrenal, hepatic or uterine functions awaits further study.

6. A decrease in glucose tolerance has been observed in a small percentage of patients on estrogen-progestin combination drugs. The mechanism of this decrease is obscure. For this reason, diabetic patients should be carefully observed while receiving progestin therapy.

7. The age of the patient constitutes no absolute limiting factor although treatment with progestins may mask the onset of the climacteric.

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

9. Because of the occasional occurrence of thrombotic disorders, (thrombophlebitis, pulmonary embolism, retinal thrombosis, and cerebrovascular disorders) in patients taking estrogen-progestin combinations and since the mechanism is obscure, the physician should be alert to the earliest manifestation of these disorders.

10. Studies of the addition of a progestin product to an estrogen replacement regimen for seven or more days of a cycle of estrogen administration have reported a lowered incidence of endometrial hyperplasia. Morphological and biochemical studies of endometrium suggest that 10-13 days of a progestin are needed to provide maximal maturation of the endometrium and to eliminate any hyperplastic changes. Whether this will provide protection from endometrial carcinoma has not been clearly established. There are possible additional risks which may be associated with the inclusion of progestin in estrogen replacement regimen. The potential risks include adverse effects on carbohydrate and lipid metabolism. The dosage used may be important in minimizing these adverse effects.

11. Aminoglutethimide administered concomitantly with medroxyprogesterone acetate tablets may significantly depress the bioavailability of medroxyprogesterone acetate.

12. Safety and effectiveness in pediatric patients below the age of 12 years have not been established.

Carcinogenesis, Mutagenesis, and Impairment of Fertility: Long-term intramuscular administration of medroxyprogesterone acetate has been shown to produce mammary tumors in beagle dogs (see

WARNINGS

). There was no evidence of a carcinogenic effect associated with the oral administration of medroxyprogesterone acetate to rats and mice. Medroxyprogesterone acetate was not mutagenic in a battery of in vitro or in vivo genetic toxicity assays.

Medroxyprogesterone acetate at high doses is an antifertility drug and high doses would be expected to impair fertility until the cessation of treatment.

Information for the Patient: See PATIENT PACKAGE INSERT.

Sterile Aqueous Suspension

1. Physical Examination: It is good medical practice for all women to have annual history and physical examinations, including women using medroxyprogesterone acetate contraceptive injection. The physical examination, however, may be deferred until after initation of medroxyprogesterone acetate sterile aqueous suspension 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 cervial 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 or who have breast nodules should be monitored with particular care.

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

3. Vaginal Bleeding: In cases of breakthrough bleeding, as in all cases of irregular bleeding per vaginum, nonfunctional causes should be borne in mind and adequate diagnostic measures undertaken.

4. Depression: Patients who have a history of psychic depression should be carefully observed and the drug discontinued if the depression recurs to a serious degree.

5. Masking of Climacteric: The age of the patient constitutes no absolute limiting factor although treatment with progestin may mask the onset of the climacteric.

6. Use with Estrogen: Studies of the addition of a progestin product to an estrogen replacement regimen for seven or more days of a cycle of estrogen administration have reported a lowered incidence of endometrial hyperplasia. Morphological and biochemical studies of endometria suggest that 10-13 days of a progestin are needed to provide maximal maturation of the endometrium and to eliminate any hyperplastic changes. Whether this will provide protection from endometrial carcinoma has not been clearly established. There are possible risks which may be associated with the inclusion of progestin in estrogen replacement regimen, including adverse effects on carbohydrate and lipid metabolism. The dosage used may be important in minimizing these adverse effects. A decrease in glucose tolerance has been observed in a small percentage of patients on estrogen-progestin combination treatment. The mechanism of this decreas is obscure. For this reason, diabetic patients should be carefully observed while receiving such therapy.

7. Prolonged Use: The effect of prolonged use of medroxyprogesterone acetate sterile aqueous suspension at the recommended doses on pituitary, ovarian, adrenal, hepatic, and uterine function is not known.

8. Multi-Dose Use: When multi-dose vials are used, special care to prevent contamination of the contents is essential. There is some evidence that benzalkonium chloride is not an adequate antiseptic for sterilizing medroxyprogesterone acetate sterile aqueous suspension multi-dose vials. A povidone-iodine solution or similar product is recommended to cleanse the vial top prior to aspiration of contents. (See

WARNINGS

Contraceptive Injection

1. Physical Examination: It is good medical practice for all women to have annual history and physical examination, including women using medroxygrogesterone acetate congtraceptive injection. The physical examination, however, may be deferred until after initiation of medroxygrogesterone acetate contraceptive injection 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, inlcuding 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 or who have breast nodules should be monitored with particular care.

2. 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.

3. Weight Changes: There is a tendency for women to gain weight while on therapy with medroxyprogesterone acetate contraceptive injection. From an initial average body weight of 136 lb, women who completed 1 year of therapy with medroxyprogesterone acetate contraceptive injection 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.

4. Return of Fertility: Medroxyprogesterone acetate contraceptive injection has a prolonged contraceptive effect. In a large U.S. study of women who discontinued use of medroxyprogesterone acetate contraceptive injection to become pregnant, data are available for 61% of them. 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 contraceptive injection to become pregnant and who were lost to follow-up or changed their mind.

5. CNS Disorders and Convulsions: Patients who have a history of psychic depression should be carefully observed and the drug not be readministered if the depression recurs.

There have been a few reported cases of convulsions in patients who were treated with medroxyprogesterone acetate contraceptive injection. Association with drug use or pre-existing conditions is not clear.

6. Carbohydrate Metabolism: A decrease in glucose tolerance has been observed in some patients on medroxyprogesterone acetate contraceptive injection treatment. The mechanism of this decrease is obscure. For this reason, diabetic patients should be carefully observed while receiving such therapy.

7. Liver Function: If jaundice develops, consideration should be given to not readministering the drug.

8. Protection Against Sexually Transmitted Diseases: Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

Carcinogenesis: See WARNINGS, Cancer.

Pregnancy Category X See WARNINGS, Lactation.

Nursing Mothers: See WARNINGS, Lactation.

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.

Information for the Patient: Patient labeling is included with each single-dose vial and prefilled syringe of medroxyprogesterone acetate contraceptive injection to help describe its characteristics to the patient (see PATIENT PACKAGE INSERT). It is recommended that prospective users be given this labeling and be informed about the risks and benefits associated with the use of medroxyprogesterone acetate contraceptive injection, 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 medroxyprogesterone acetate contraceptive injection continues, without other therapy being required.

Laboratory Test Interactions

Sterile Aqueous Suspension and Contraceptive Injection

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.

OVERDOSE

No information provided.

CONTRAINDICATIONS

1. Known or suspected pregnancy or as a diagnostic test for 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. Liver dysfunction or disease.

6. Known sensitivity to medroxyprogesterone acetate or any of the inactive ingredients.