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medroxyprogesterone 2.5 mg tab generic provera

In stock Manufacturer TEVA USA 00555087202
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Uses

Prevention of Endometrial Changes Associated with Estrogens

Medroxyprogesterone acetate is used orally to reduce the incidence of endometrial hyperplasia and the attendant risk of endometrial carcinoma in postmenopausal women receiving estrogen replacement therapy. When estrogens are used in combination with progestins, such therapy usually is referred to as hormone replacement therapy (HRT) or postmenopausal replacement therapy. Evidence from the Women's Health Initiative (WHI) study indicates that combined estrogen (conjugated estrogens 0.625 mg daily) and medroxyprogesterone acetate (2.5 mg daily) therapy in postmenopausal women is associated with increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep-vein thrombosis. The risks identified in this study should be assumed to be similar with other hormonal regimens, including different dosages of these drugs as well as other estrogen/progestin combinations not studied in WHI, in the absence of comparable data to the contrary. If HRT is used, it should be prescribed in the lowest effective dosage and for the shortest duration consistent with treatment goals and risks for the individual women.

While there appears to be no increased risk of endometrial carcinoma in postmenopausal women receiving estrogen therapy for less than 1 year, prolonged estrogen therapy may be associated with an increased risk of such carcinoma. The risk of endometrial cancer reportedly is increased 2- to 12-fold in postmenopausal women receiving unopposed estrogen therapy compared with those not receiving estrogens; such increased risk may depend on dosage and duration of estrogen therapy and may be increased 15- to 24-fold in women receiving long-term (5 years or more) estrogen therapy. Limited data indicate that a substantial increased risk of endometrial carcinoma may persist for up to 15 years following discontinuance of estrogen therapy. Results of several studies indicate that addition of a progestin (e.g., medroxyprogesterone acetate) to estrogen replacement therapy reduces the incidence of endometrial hyperplasia and risk of endometrial carcinoma in women with an intact uterus. In a randomized, double-blind, controlled, multicenter study in postmenopausal women, endometrial hyperplasia occurred in 20 or 1% or less of women receiving conjugated estrogens alone or in conjunction with medroxyprogesterone acetate, respectively. Although estrogen-associated risk of endometrial carcinoma is substantially reduced when estrogens are administered concomitantly with progestins, a risk still exists. Therefore, clinical evaluation of all menopausal women receiving estrogen therapy in conjunction with a progestin is essential. Existing data do not support addition of a progestin in women who have undergone hysterectomy and are receiving estrogen replacement therapy.

Clinical studies indicate that use of a progestin in conjunction with estrogen replacement therapy does not interfere with the efficacy of the estrogen in the management of vasomotor symptoms associated with menopause, treatment of vulvar and vaginal atrophy, or prevention of osteoporosis. However, addition of a progestin to estrogen therapy may adversely affect some metabolic effects associated with long-term estrogen therapy and potential risks of concomitant therapy may include adverse effects on lipid metabolism and glucose tolerance. Results of several clinical studies in postmenopausal women indicate that replacement therapy with unopposed conjugated estrogens may reduce LDL-cholesterol and increase HDL-cholesterol by about 8-15%; concomitant progestin therapy may blunt some of the favorable effects of estrogens on the lipid profile of menopausal women. Data from several studies suggest that administration of a progestin concomitantly with estrogen therapy is associated with an increased risk of breast cancer beyond that associated with estrogen alone.

Contraception in Females

Medroxyprogesterone acetate (alone or in fixed combination with estradiol cypionate) is used parenterally as a long-acting contraceptive in women.

Medroxyprogesterone acetate (e.g., Depo-Provera Contraceptive, depo-subQ provera 104) is used parenterally for the prevention of conception. However, long-term use of parenteral medroxyprogesterone is associated with loss in bone mineral density (BMD). The loss of BMD in women of all ages and the possible impact on peak bone mass in adolescents should be considered when assessing the risks versus benefits of this contraceptive method. Parenteral medroxyprogesterone should be used as a long-term contraceptive method (e.g., longer than 2 years) only if other contraceptive methods are inadequate and the benefits are expected to outweigh the risks. (See Cautions: Precautions and Contraindications). Contraceptive measures other than parenteral medroxyprogesterone should be considered in women at risk for osteoporosis. When used according to the prescribed regimen (once every 3 months), parenteral medroxyprogesterone used alone provides almost completely effective contraception. The pregnancy rate in women using the drug alone generally is reported as less than 1 pregnancy per 100 women-years of use (as calculated via the Pearl index method) or as ranging from 0-0.7% during the first year of use (as calculated via life-table analysis). Compared with common contraceptive methods (e.g., estrogen-progestin combinations, condoms) other than intrauterine devices, implants, and sterilization, for which efficacy depends in large part on the reliability of appropriate use (patient compliance), contraceptive efficacy of parenteral medroxyprogesterone monotherapy depends on substantially less frequent patient-initiated actions (i.e., compliance with receipt of the injection only once every 3 months).

Medroxyprogesterone has been used extensively and effectively worldwide for many years as a contraceptive and has been recommended for this use by the World Health Organization (WHO) and the International Planned Parenthood Federation (IPPF); contraceptive use of medroxyprogesterone was added to the labeling approved by the US Food and Drug Administration (FDA) in the early 1990s. FDA's delay of approval of medroxyprogesterone for use as a contraceptive was based on questions of safety raised by studies in beagles in which the drug was associated with an increased incidence of mammary tumors; the availability of safer alternate methods for contraception and the lack of clear evidence that a substantial patient population in need of the drug exists in the US; the possibility that increased drug-induced bleeding disturbances may necessitate concomitant administration of an estrogen, imposing an additional risk and decreasing the benefits of progestin-only contraception; the possibility that exposure (possibly prolonged) of the fetus to the drug, if contraception fails, poses a risk of congenital malformation; and concerns that postmarketing surveillance for breast and cervical carcinoma might not provide meaningful data. Subsequently, the WHO Toxicology Review Panel, the IPPF, and several scientific advisory panels concluded that available evidence does not indicate a risk of adverse effects associated with parenteral medroxyprogesterone that would preclude its use as a contraceptive. These conclusions generally have been confirmed by various epidemiologic studies, including those conducted by WHO regarding the risk of various neoplasms and contraceptive steroid use. (See Cautions: Mutagenicity and Carcinogenicity and also see Pregnancy, Fertility, and Lactation.)

Medroxyprogesterone in a fixed combination with estradiol is used parenterally for the prevention of conception. In clinical trials with the fixed combination containing medroxyprogesterone acetate and estradiol cypionate (Lunelle), the 12-month pregnancy rate reportedly was less than 0.2%. Because of limitations of the available data (e.g., loss to follow-up, lack of pregnancy testing, use of barrier contraceptives, concomitant drug therapy), it is not possible to estimate precisely the contraceptive failure rate, but the failure rate is likely to range from 0.1-1%. As with other estrogen-progestin contraceptives, the efficacy of medroxyprogesterone acetate in fixed combination with estradiol cypionate depends largely on adherence to the recommended dosage schedule. To ensure that the fixed combination of medroxyprogesterone acetate and estradiol cypionate is not inadvertently administered to a pregnant woman, the first injection should be given during the first 5 days of a normal menstrual period.(See Pregnancy, Fertility, and Lactation: Pregnancy, in Cautions.)

Endometriosis

Medroxyprogesterone acetate (depo-subQ provera 104) is used parenterally in the management of pain associated with endometriosis. In controlled clinical studies, medroxyprogesterone acetate (104 mg administered subcutaneously every 3 months for 6 months) was effective in relieving clinical symptoms (e.g., dysmenorrhea, dyspareunia, pelvic pain) and signs (e.g., pelvic tenderness, pelvic induration) of endometriosis. Long-term use of parenteral medroxyprogesterone is associated with loss in bone mineral density (BMD). The loss of BMD in women of all ages and the possible impact on peak bone mass in adolescents should be considered when assessing the risks versus benefits of therapy with medroxyprogesterone. (See Cautions: Precautions and Contraindications).

Amenorrhea and Uterine Bleeding

Medroxyprogesterone acetate is used orally for the treatment of secondary amenorrhea and for the treatment of abnormal uterine bleeding caused by hormonal imbalance in patients without underlying organic pathology such as fibroids or uterine cancer.

Endometrial or Renal Carcinoma

Medroxyprogesterone acetate is used parenterally as adjunctive and palliative therapy for the treatment of inoperable, recurrent, and metastatic endometrial carcinoma. The initial treatment of the early stages (I and II) of endometrial carcinoma is surgery, sometimes combined with radiation therapy. In advanced endometrial carcinoma that is no longer amenable to surgery or radiation, hormonal therapy with progestins or chemotherapy should be considered.

Although medroxyprogesterone has been used in the treatment of metastatic renal cell carcinoma, other agents are considered more effective for the systemic treatment of this cancer. and

Paraphilia in Males

Medroxyprogesterone acetate has been used parenterally (e.g., 100-500 mg IM weekly) for the management of paraphilia (e.g., homosexual, heterosexual, or bisexual pedophilia; heterosexual voyeurism, sexual sadism, or exhibitionism; transvestism) in males. The drug has been shown to decrease the frequency of erotic imagery and the intensity of erotic cravings in most of these males. Sexual deviance generally returns following discontinuance of the drug.

Other Uses

Medroxyprogesterone acetate has been used for the management of both GnRH-dependent (central) and -independent (peripheral) forms of precocious puberty and was the most widely used drug for the management of various forms of precocity. However, use of medroxyprogesterone in the management of central (true) precocious puberty generally has been supplanted by GnRH analogs (e.g., leuprolide) because of the improved pharmacologic specificity and adverse effect profile of these latter drugs; occasionally, medroxyprogesterone continues to be used for central precocity in patients who do not tolerate GnRH analog therapy. The optimum therapeutic regimen for the management of familial male precocious puberty (testotoxicosis) or for McCune-Albright syndrome, both GnRH-independent forms of precocity, remains to be established, and medroxyprogesterone is one of several therapeutic regimens (e.g., medroxyprogesterone, testolactone/spironolactone, testolactone/flutamide, or ketoconazole for familial male precocity; medroxyprogesterone or testolactone for McCune-Albright syndrome) currently being employed. While comparative safety and efficacy have not been established by controlled studies, medroxyprogesterone may be less likely than other regimens to favorably affect growth rate and skeletal maturation and more likely to adversely affect adrenocortical function.

Medroxyprogesterone acetate also has been used in the management of postmenopausal symptoms in females, obesity-hypoventilation syndrome (Pickwickian syndrome), obstructive sleep apnea syndrome and hypersomnolence in adults, hirsutism and homozygous sickle-cell disease.

Dosage and Administration

Administration

Medroxyprogesterone acetate (alone or in fixed combination with estrogens [i.e., conjugated estrogens, estradiol cypionate]) is administered orally, subcutaneously, or IM. When used as a contraceptive in females, medroxyprogesterone acetate is administered subcutaneously or IM; the drug is administered subcutaneously for the management of pain associated with endometriosis. Medroxyprogesterone acetate is administered IM in the treatment of cancer or male sexual deviance (paraphilia). Because of the prolonged action, parenteral administration of the drug is not recommended for the treatment of secondary amenorrhea or abnormal uterine bleeding.

Medroxyprogesterone acetate injectable suspension (containing medroxyprogesterone acetate alone or in fixed combination with estradiol cypionate) must be vigorously shaken immediately before each use to ensure complete suspension of the drug(s). IM injection of medroxyprogesterone acetate alone (Depo-Provera Contraceptive, Depo-Provera, Medroxyprogesterone Acetate Contraceptive) or in combination with estradiol cypionate (Lunelle Monthly Contraceptive) should be made deep into the gluteal, deltoid, or anterior thigh muscle. Subcutaneous injection of medroxyprogesterone acetate (depo-subQ provera 104) is made into the anterior thigh or abdomen; the preparation for subcutaneous administration should not be administered IM.

Oral dosage preparations containing medroxyprogesterone acetate in combination with conjugated estrogens as monophasic or biphasic regimens are commercially available in a mnemonic dispensing package that is designed to aid the user in complying with the prescribed dosage schedule. The monophasic combination (Prempro) is available in a 28-day dosage preparation that contains 28 tablets of conjugated estrogens (0.625 mg) in fixed combination with medroxyprogesterone acetate (2.5 or 5 mg). The monophasic combination (Prempro) also is available in a 28-day dosage preparation that contains 28 tablets of conjugated estrogens USP (0.3 or 0.45 mg) in fixed combination with medroxyprogesterone acetate (1.5 mg). The biphasic combination (Premphase) also is available in a 28-day dosage preparation that contains 14 tablets of conjugated estrogens (0.625 mg) and 14 tablets of conjugated estrogens (0.625 mg) in fixed combination with medroxyprogesterone acetate (5 mg).

Dosage

Prevention of Endometrial Changes Associated with Estrogens

When medroxyprogesterone acetate is used in conjunction with estrogen replacement therapy, medroxyprogesterone may be administered in a monophasic (Prempro) or biphasic (Premphase) manner. In the monophasic regimen, oral conjugated estrogens is administered in a daily dosage of 0.3 mg in conjunction with oral medroxyprogesterone acetate in a daily dosage of 1.5 mg. Alternatively, conjugated estrogens is administered in a daily dosage of 0.45 mg in conjunction with medroxyprogesterone acetate in a daily dosage of 1.5 mg, or conjugated estrogens is administered in a daily dosage of 0.625 mg in conjunction with medroxyprogesterone acetate in a daily dosage of 2.5 or 5 mg. In the biphasic regimen (Premphase) oral conjugated estrogens is administered in a daily dosage of 0.625 mg, while oral medroxyprogesterone acetate is administered in a dosage of 5 mg daily on days 15-28 of the cycle.

Contraception in Females

When medroxyprogesterone acetate injectable suspension (Depo-Provera Contraceptive, Medroxyprogesterone Acetate Contraceptive) is used for the prevention of conception in women, the recommended dosage of medroxyprogesterone acetate is 150 mg IM every 3 months. The possibility of pregnancy should be excluded prior to administering the first dose of medroxyprogesterone and whenever more than 13 weeks has elapsed since the previous dose. To avoid inadvertent administration of the contraceptive to a pregnant woman, the initial injection should be given during the first 5 days of a normal menstrual cycle, within 5 days postpartum in those who do not breast-feed, or during the sixth postpartum week in women who breast-feed.(See Pregnancy, Fertility, and Lactation: Pregnancy, in Cautions.) Parenteral medroxyprogesterone should be used as a long-term contraceptive method (e.g., longer than 2 years) only if other contraceptive methods are inadequate and the benefits are expected to outweigh the risks. (See Cautions: Precautions and Contraindications.)

When medroxyprogesterone acetate injectable suspension (depo-subQ provera 104) is used for the prevention of conception in women, the recommended dosage of medroxyprogesterone acetate is 104 mg administered subcutaneously every 3 months (12-14 weeks). The possibility of pregnancy should be excluded prior to administering the first dose of medroxyprogesterone and whenever more than 14 weeks has elapsed since the previous dose. To avoid inadvertent administration of the contraceptive to a pregnant woman, the initial injection should be given during the first 5 days of a normal menstrual cycle. In addition, the initial injection should be given no earlier than 6 weeks postpartum in women who breast-feed.(See Pregnancy, Fertility, and Lactation: Pregnancy, in Cautions.) When switching from other contraceptive methods, the manufacturer recommends that therapy with medroxyprogesterone acetate (depo-subQ provera 104) be initiated in a manner that ensures continuous contraceptive coverage based on the mechanism of action of both methods (e.g., patients switching from combined estrogen-progestin contraceptives should be given an initial injection within 7 days after taking the last hormonally active tablet or removal of a transdermal patch or vaginal ring; patients switching from IM injections of medroxyprogesterone acetate [Depo-Provera Contraceptive] to depo-subQ provera 104 should be given an initial injection of depo-subQ provera 104 within the dosing period recommended for the IM contraceptive preparation). Parenteral medroxyprogesterone should be used as a long-term contraceptive method (e.g., longer than 2 years) only if other contraceptive methods are inadequate and the benefits are expected to outweigh the risks. (See Cautions: Precautions and Contraindications.)

When Lunelle is used for the prevention of conception in women, the usual dosage of medroxyprogesterone acetate is 25 mg (in fixed combination with 5 mg of estradiol cypionate per 0.5 mL) IM monthly. To avoid inadvertent administration of the contraceptive to a pregnant woman, the initial injection should be given during the first 5 days of a normal menstrual cycle or within 5 days of a complete first-trimester abortion. In addition, the initial injection should be given no earlier than 6 weeks postpartum in women who breast-feed and no earlier than 4 weeks postpartum in those who do not breast-feed. Subsequent injections should be given monthly (every 28-30 days, but no more than 33 days after the previous injection); the dosage schedule should be determined by the number of days between injections and not by bleeding episodes. If the patient has not adhered to the prescribed administration schedule (i.e., if more than 33 days have elapsed since the previous injection), an alternative (i.e., barrier) method of contraception should be instituted, and pregnancy ruled out, prior to continuation of Lunelle (medroxyprogesterone acetate-estradiol cypionate) therapy. It should be noted that shortening of the injection interval may result in a change in menstrual pattern. When switching from other contraceptive methods, the manufacturer recommends that therapy with the fixed combination of medroxyprogesterone acetate and estradiol cypionate be initiated in a manner that ensures continuous contraceptive coverage based on the mechanism of action of both methods (e.g., patients switching from oral contraceptives should be given an initial injection within 7 days after taking the last hormonally active tablet).

Endometriosis

When medroxyprogesterone acetate injectable suspension (depo-subQ provera 104) is used for the management of pain associated with endometriosis, the recommended dosage of medroxyprogesterone acetate is 104 mg administered subcutaneously every 3 months (12-14 weeks). The possibility of pregnancy should be excluded prior to administering the first dose of medroxyprogesterone and whenever more than 14 weeks has elapsed since the previous dose. To avoid inadvertent administration of the drug to a pregnant woman, the initial injection should be given during the first 5 days of a normal menstrual cycle. In addition, the initial injection should be given no earlier than 6 weeks postpartum in women who breast-feed. Efficacy of medroxyprogesterone acetate (depo-subQ provera 104) for the management of pain associated with endometriosis was established in studies of 6 months' duration; data establishing continued efficacy with use beyond 6 months are lacking. Therapy with the drug for longer than 2 years is not recommended because of concerns about the potential long-term effects on bone density. If retreatment is considered following recurrence of endometriosis, bone density should be assessed. (See Effects on Bone under Cautions: Adverse Effects in Women.)

Amenorrhea and Uterine Bleeding

For the treatment of secondary amenorrhea, the usual oral dosage of medroxyprogesterone acetate is 5-10 mg daily for 5-10 days; although one manufacturer states that therapy may be initiated at any time, the drug is usually started during the assumed latter half (e.g., 16th to 21st day) of the menstrual cycle. In patients with a poorly developed endometrium, conventional estrogen therapy may be used in conjunction with medroxyprogesterone acetate. To induce optimum secretory transformation of an endometrium that has been adequately primed with endogenous or exogenous estrogen, one manufacturer recommends an oral dosage of 10 mg daily for 10 days. Progestin-induced withdrawal bleeding usually occurs within 3-7 days after discontinuing therapy with the drug.

For the treatment of abnormal uterine bleeding, 5-10 mg of medroxyprogesterone acetate may be given orally for 5-10 days beginning on the assumed or calculated 16th or 21st day of the menstrual cycle. When bleeding is caused by a deficiency of estrogen and progestin, as indicated by a poorly proliferative endometrium, estrogens should be used in conjunction with medroxyprogesterone acetate; if bleeding is controlled satisfactorily, 2 subsequent cycles of combined therapy should be given. To induce optimum secretory transformation of an endometrium that has been adequately primed with endogenous or exogenous estrogen, one manufacturer recommends that 10 mg of the drug may be given orally for 10 days beginning on the calculated 16th day of the cycle. Progestin-induced withdrawal bleeding usually occurs within 3-7 days after discontinuing therapy with the drug. Patients with a history of recurrent episodes of abnormal uterine bleeding may benefit from planned menstrual cycling with medroxyprogesterone acetate.

Endometrial or Renal Carcinoma

For the adjunctive and palliative treatment of advanced, inoperable endometrial or renal carcinoma, an initial IM medroxyprogesterone acetate dosage of 400-1000 mg/week has been recommended. If improvement is noted within a few weeks or months and the disease appears to have stabilized, it may be possible to maintain response with as little as 400 mg/month. Medroxyprogesterone acetate is not recommended as primary therapy, but as adjunctive and palliative therapy in advanced inoperable cases including those with recurrent or metastatic disease.

Paraphilia in Males

For the management of paraphilia in males, initial IM dosages of 200 mg 2 or 3 times daily or 500 mg weekly have been used. Dosage is generally adjusted according to patient response and tolerance and/or plasma testosterone concentration. Generally, the dose and/or frequency of administration is decreased to an effective maintenance level. In one study, maintenance dosages ranged from 100 mg once weekly to once monthly. Published protocols should be consulted for more specific dosage information in these males.

Cautions

Adverse Effects in Women

Genitourinary Effects

In women receiving parenteral medroxyprogesterone for contraception (alone or in fixed combination with estradiol cypionate) or the management of pain associated with endometriosis, the most common adverse effects are menstrual abnormalities. Irregular and unpredictable menstrual bleeding pattern, including spotting, occurs frequently during the first months of therapy with the drug. In women receiving IM medroxyprogesterone acetate in fixed combination with estradiol cypionate, about 59% experienced alterations in menstrual bleeding pattern (e.g., amenorrhea; frequent, irregular, prolonged, or infrequent bleeding) after 1 year of use; the incidence of irregular bleeding remained relatively constant at approximately 30% throughout the first year of use. If abnormal bleeding persists or is severe, appropriate steps to investigate the possibility of organic pathology should be undertaken, and appropriate therapy instituted as necessary.

Amenorrhea also occurs frequently in women receiving the drug for contraception or the management of pain associated with endometriosis, and as the duration of therapy increases the likelihood of intermenstrual bleeding decreases and that of amenorrhea increases; up to about 60 and 70% of women reportedly have amenorrhea after 1 and 2 years, respectively, of contraceptive therapy with medroxyprogesterone.

Although concomitant use of low doses of estrogens has been suggested to treat medroxyprogesterone-induced menstrual disturbances, the evidence for efficacy of this therapy is equivocal. Contraceptive use of the drug should be discontinued in women who do not tolerate irregular and unpredictable bleeding or amenorrhea.

Heavy or continuous vaginal bleeding may occur in some women receiving medroxyprogesterone, but rarely requires estrogen therapy. Impaired fertility persists long after discontinuance of the drug. (See Cautions: Pregnancy, Fertility, and Lactation.)

Effects on Bone

Use of parenteral medroxyprogesterone acetate (e.g., Depo-Provera Contraceptive, depo-subQ provera 104) reduces serum estrogen concentrations and is associated with loss of bone mineral density (BMD) as bone metabolism adjusts to lower serum estrogen concentrations. Bone loss is greater with increasing duration of medroxyprogesterone therapy and may not be completely reversible following discontinuance. In one clinical study, adult women receiving parenteral medroxyprogesterone (Depo-Provera Contraceptive) for up to 5 years experienced a 5-6% loss in BMD of lumbar spine, total hip, and femoral neck; clinically important changes in BMD were not observed in a control group of women not receiving a hormonal contraceptive. The decline in BMD was more pronounced during the first 2 years of use of medroxyprogesterone; smaller declines were observed in subsequent years. Bone loss during the first 2 years of therapy with depo-subQ provera 104 is similar to that observed during the first 2 years of therapy with Depo-Provera Contraceptive. In one comparative study, women receiving depo-subQ provera 104 for the management of endometriosis experienced a loss in BMD of lumbar spine and total hip of 0.03-1.2% over 6 months of therapy compared with a loss in BMD of 1.8-4.1% in women receiving leuprolide for the same period of time.

Evaluation of BMD 2 years after discontinuance of medroxyprogesterone indicates that BMD increases toward baseline values over this time period. However, longer duration of medroxyprogesterone therapy is associated with less complete recovery of BMD over the 2-year period after discontinuance of the drug. In an ongoing, open-label, self-selected, non-randomized study in adolescent females 12-18 years of age, use of parenteral medroxyprogesterone (Depo-Provera Contraceptive) was associated with decreased bone density at the lumbar spine, total hip, and femoral neck; adolescents usually increase BMD during growth following menarche. Limited data indicate that BMD increases following discontinuance of medroxyprogesterone in these females. However, loss of BMD is of particular concern during adolescence and early adulthood.

It remains to be determined whether use of parenteral medroxyprogesterone in younger women will reduce peak bone mass and increase the risk of fractures secondary to osteoporosis later in life. Osteoporosis, including osteoporotic fractures, rarely has been reported during postmarketing surveillance of patients receiving IM medroxyprogesterone for contraception. (For information on women at risk for osteoporosis, see Cautions: Precautions and Contraindications.) The effect of BMD changes in women receiving medroxyprogesterone acetate in fixed combination with estradiol cypionate remains to be determined.

Effects on Body Weight

Weight changes (e.g., gain) also occur commonly during use of parenteral medroxyprogesterone (Depo Provera Contraceptive, depo-subQ provera 104). From an initial body weight averaging 61.8 kg, average weight gains of 2.45, 3.68, 6.27, and 7.5 kg occur after completion of 1, 2, 4, and 6 years of contraceptive use, respectively. In several large studies, 2-6% of women discontinued therapy with medroxyprogesterone alone or in fixed combination with estradiol cypionate because of excessive weight gain.

Other Adverse Effects

Medroxyprogesterone, like other progestins, may cause cholestatic jaundice, melasma or chloasma, and mental depression. Breast tenderness or galactorrhea has occasionally occurred. Alopecia, acne, and hirsutism have been reported rarely. Adverse CNS effects including nervousness, insomnia, somnolence, fatigue, and dizziness have occasionally occurred. Rarely, headache, hyperpyrexia, nausea, or jaundice, including neonatal jaundice, has been reported. Hypersensitivity reactions including urticaria, pruritus, angioedema, generalized rash (with or without pruritus), and anaphylactoid reactions and anaphylaxis have occasionally occurred in patients receiving the drug. Adverse local effects at the site of injection include residual lump, skin discoloration, and sterile abscess.

Other adverse effects reported during contraceptive use of medroxyprogesterone alone or in fixed combination with estradiol cypionate include abdominal pain or discomfort (e.g., bloating, enlarged abdomen), changes in mood or libido, emotional lability, anorgasmia, asthenia (weakness or fatigue), hot flushes (flashes), edema, absent hair growth, leukorrhea, vaginitis (e.g., candidiasis), vulvovaginal disorder, pelvic pain, breast pain, leg cramps, and backache. Infrequent (in less than 1% of patients) adverse effects associated with contraceptive use of medroxyprogesterone include seizures, appetite changes, GI disturbances, genitourinary infections, vaginal cysts, dyspareunia, paresthesia, chest pain, pulmonary embolus, anemia, and drowsiness. Other infrequent adverse effects associated with such use include syncope, dyspnea and asthma, tachycardia, fever, excessive sweating or body odor, dry skin, chills, increased or decreased libido, excessive thirst, hoarseness, pain at the 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, accidental pregnancy, uterine hyperplasia, cervical cancer, thrombophlebitis, deep vein thrombosis, varicose veins, dysmenorrhea, paralysis, scleroderma, and osteoporosis.

Other adverse effects reported with noncontraceptive use of estrogen-progestin combination preparations include increased blood pressure in susceptible individuals, premenstrual-like syndrome, changes in libido or appetite, cystitis-like syndrome, backache, loss of scalp hair, erythema multiforme or nodosum, hemorrhagic skin eruption, and itching.

Allergic reactions reported with the injectable fixed combination of medroxyprogesterone acetate and estradiol cypionate (Lunelle) have been principally dermatologic rather than respiratory in nature. If an anaphylactic reaction occurs, appropriate measures should be instituted; serious anaphylactic reactions require emergency medical treatment.

Cholecystitis and cholelithiasis have been reported in women receiving the fixed combination of medroxyprogesterone acetate and estradiol cypionate for up to 15 months. Other adverse effects reported with IM medroxyprogesterone acetate in fixed combination with estradiol cypionate generally are similar to those reported with estrogen-progestin oral contraceptives.

Thromboembolic disorders including thrombophlebitis and pulmonary embolism have occurred in patients receiving medroxyprogesterone. An association between thrombophlebitis, pulmonary embolism, and cerebral thrombosis and embolism and use of estrogen-progestin combination preparations has been shown. The possibility that thromboembolic disorders may occur in patients receiving medroxyprogesterone should be considered and patients should be carefully observed for these effects during therapy with the drug.

Although available evidence suggests that an association exists between neuro-ocular lesions such as optic neuritis or retinal thrombosis and use of estrogen-progestin combination preparations, such a relationship has been neither confirmed nor refuted.

Use of estrogen-progestin combinations has also been associated with increased levels of coagulation factors VII, VIII, IX, and X. The possibility that these effects may occur in patients receiving medroxyprogesterone should be considered and patients should be carefully observed for these effects during therapy with the drug.

Adverse Effects in Males

In males receiving parenteral medroxyprogesterone for the management of paraphilia, fatigue and weight gain occur commonly. Plasma testosterone concentrations decrease in most patients receiving the drug, and the decrease is generally associated with a diminution in the frequency and quality of erection and ejaculation; in one study, impotence generally occurred when plasma testosterone concentration decreased to one-fourth the pretreatment concentration. The drug is reportedly nonfeminizing in these males. Other adverse effects reported in these males include hot and cold flashes, headache, insomnia, nausea, and phlebitis.

Precautions and Contraindications

Medroxyprogesterone acetate shares the toxic potentials of progestins, and the usual precautions of progestin therapy should be observed. Because oral contraceptive combinations contain progestins, the precautions associated with oral contraceptives should generally be considered in patients receiving progestins. In addition, when medroxyprogesterone is used in conjunction with estrogens (i.e., conjugated estrogens, estradiol cypionate), the cautions, precautions, and contraindications associated with estrogens must be considered in addition to those associated with medroxyprogesterone.

Prior to initiation of therapy with medroxyprogesterone-containing preparations in women and annually thereafter during continued use (e.g., as a contraceptive, for the management of endometriosis, in conjunction with estrogen replacement therapy), a history should be obtained and physical examination performed, including special attention to the breasts and pelvic organs and a Papanicolaou test (Pap smear). Women receiving medroxyprogesterone-containing preparations should be given a copy of the patient labeling for the drug. In addition, women receiving the drug alone or in fixed combination with estradiol cypionate for contraceptive purposes or for management of endometriosis should be advised of anticipated effects on menstruation (e.g., initial irregular and unpredictable bleeding pattern), with the eventual development of amenorrhea in a large proportion of such women as use of the drug continues, and of the likelihood of weight gain during such use. (See Cautions: Adverse Effects Associated with Contraceptive Use in Women.) Women receiving parenteral medroxyprogesterone acetate alone or in fixed combination with estradiol cypionate for contraceptive purposes also should be advised that the contraceptive efficacy of such therapy depends on adherence to the recommended dosage schedule. Women with a family history of breast cancer or who have breast nodules should be monitored with particular care, and appropriate diagnostic measures to rule out malignancy should be employed if abnormal vaginal bleeding persists or recurs during therapy with the drug. In addition, women also should be advised that the contraceptive effect of parenteral medroxyprogesterone is prolonged, persisting long after the last dose of the drug. (See Pregnancy, Fertility, and Lactation: Fertility, in Cautions.) When medroxyprogesterone is to be used in conjunction with estrogen replacement therapy, potential risks may include adverse effects on lipid metabolism and glucose tolerance; addition of a progestin may adversely affect some beneficial metabolic effects associated with long-term estrogen therapy. Addition of medroxyprogesterone to estrogen replacement therapy appears to increase the risk of breast cancer beyond that associated with estrogen alone. In addition, it should be considered that although estrogen-associated risk of endometrial carcinoma is substantially reduced when estrogens are administered concomitantly with progestins, such risk still exists, therefore, clinical evaluation of all menopausal women receiving estrogen therapy in conjunction with a progestin is essential. Diagnostic tests, including endometrial sampling when indicated, should be performed in all women who have undiagnosed, persistent, or abnormal vaginal bleeding.

Long-term use of parenteral medroxyprogesterone is associated with loss of bone mineral density (BMD). Parenteral medroxyprogesterone should be used as a long-term contraceptive method (e.g., longer than 2 years) only if other contraceptive methods are inadequate and the benefits are expected to outweigh the risks. Use of medroxyprogesterone (depo-subQ provera 104) for the management of endometriosis for longer than 2 years is not recommended. BMD should be evaluated periodically when medroxyprogesterone is used long term; the patient's age (adult or adolescent) and skeletal maturity should be considered when evaluating BMD results. If retreatment with medroxyprogesterone is considered following recurrence of endometriosis, bone density should be assessed.Therapies other than parenteral medroxyprogesterone should be considered in women with preexisting risk factors for osteoporosis; use of medroxyprogesterone may be an additional risk in women at risk for osteoporosis. Risk factors for osteoporosis include metabolic bone disease, drinking excessive amounts of alcohol, cigarette smoking, anorexia nervosa, a family history of osteoporosis, and long-term use of drugs that can reduce BMD (e.g., anticonvulsants, corticosteroids). Whether supplemental calcium and vitamin D can reduce BMD loss that occurs in women using long-term medroxyprogesterone remains to be determined; all women should have adequate intake of calcium and vitamin D.

If medroxyprogesterone is to be used for the treatment of cancer, patients should be referred to physicians who are actively engaged in investigation of the disease and are therefore familiar with the latest and most advantageous forms of therapy.

Medroxyprogesterone should be used with caution, and only with careful monitoring, in patients with conditions that might be aggravated by fluid retention (e.g., asthma, seizure disorders, migraine, or cardiac or renal dysfunction). The drug should also be used with caution in patients with a history of mental depression; medroxyprogesterone should be discontinued if depression recurs to a serious degree during therapy with the drug. While a causal relationship to the drug and the possible contribution of a preexisting condition remain unclear, the possibility of seizures during medroxyprogesterone use should be considered.

When breakthrough bleeding or irregular vaginal bleeding occurs during medroxyprogesterone therapy, nonfunctional causes should be considered. Adequate diagnostic procedures should be performed in patients with undiagnosed vaginal bleeding.

The manufacturers caution that the effect of long-term medroxyprogesterone therapy on pituitary, ovarian, adrenal, hepatic, or uterine function has not been determined. Diabetic patients should be carefully monitored during medroxyprogesterone therapy, since decreased glucose tolerance has been observed in women receiving estrogen-progestin combinations. Medroxyprogesterone may mask the onset of climacteric in women.

The clinician and the patient using medroxyprogesterone should be alert to the earliest signs and symptoms of thromboembolic and thrombotic disorders (e.g., thrombophlebitis, pulmonary embolism, cerebrovascular insufficiency, coronary occlusion, retinal thrombosis, mesenteric thrombosis). The drug should be discontinued immediately when any of these disorders occurs or is suspected. The clinician and patient also should be alert to the earliest manifestations of hepatic dysfunction (e.g., jaundice) during use of the drug. The drug should be discontinued and the patient's status reevaluated if such manifestations occur or are suspected. The manufacturer states that medroxyprogesterone acetate in fixed combination with estradiol cypionate (Lunelle) should not be readministered to women in whom thromboembolic or thrombotic disorders have occurred or are suspected.

If unexplained, sudden or gradual, partial or complete loss of vision; proptosis or diplopia; papilledema; retinal vascular lesions; or migraine occur during therapy with medroxyprogesterone, the drug should be discontinued and appropriate diagnostic and therapeutic measures instituted. If ocular examination reveals evidence of papilledema or retinal vascular lesions, medroxyprogesterone therapy should not be reinitiated.

The onset or exacerbation of migraine or development of headache with a new pattern that is recurrent, persistent, or severe requires evaluation of the cause before further administration of medroxyprogesterone acetate in fixed combination with estradiol cypionate for contraceptive purposes.

Medroxyprogesterone is contraindicated in patients with active thrombophlebitis or a current or past history of thromboembolic disorders or of cerebral vascular disease or apoplexy. The drug is also contraindicated in patients with undiagnosed vaginal bleeding, missed abortion, liver dysfunction or disease or with known or suspected malignancy of the genital organs, known sensitivity to the drug or any ingredient in the formulation, or known or suspected pregnancy or carcinoma of the breast, or for use as a pregnancy test. The manufacturer states that use of medroxyprogesterone acetate in combination with estradiol cypionate for contraceptive purposes also is contraindicated in patients with carcinoma of the endometrium, severe hypertension, diabetes mellitus with vascular involvement, headaches with focal neurologic symptoms, valvular heart disease with complications, and those 35 years of age or older who smoke 15 cigarettes or more daily. Women receiving medroxyprogesterone acetate in fixed combination with estradiol cypionate should be strongly advised not to smoke.

Mutagenicity and Carcinogenicity

Administration of medroxyprogesterone to beagles has been associated with the development of mammary nodules, some of which were malignant. Although nodules occasionally occurred in control beagles, they were intermittent in nature; nodules in drug-treated beagles were larger, more numerous, persistent, and occasionally malignant with metastases. The clinical relevance of these findings to humans has not been established. In addition, there is evidence of species differences in the response of beagles and humans to medroxyprogesterone; because of these species differences, some experts state that it is not possible to draw conclusions from the observations in beagles. In long-term (10 years) toxicology studies in monkeys, 2 of the animals developed undifferentiated carcinoma of the uterus following administration of 150 mg/kg every 90 days. The relevance of this finding has been questioned since progestins are thought to protect against the development of endometrial cancer and because of the unusual nature of the cancer in these monkeys; additional study is needed to determine the relevance to humans. Transient mammary nodules occurred in control monkeys and those receiving 3 or 30 mg/kg every 90 days, but not in those receiving 150 mg/kg. At sacrifice, nodules still existed in 3 monkeys; histopathologic examination showed the nodules to be hyperplastic. No evidence of uterine or breast abnormalities was revealed in rats.

Analysis of worldwide epidemiologic evidence on the relationship between the risk of breast cancer and postmenopausal hormone replacement therapy and results of most, but not all, studies indicate that prolonged use of postmenopausal hormone replacement therapy is associated with an increased risk of breast cancer in current or recent recipients. In the Women's Health Initiative (WHI) study evaluating estrogen/progestin therapy, there was a small increase in the risk of breast cancer in postmenopausal women receiving hormone replacement therapy (i.e., conjugated estrogens 0.625 mg in conjunction with medroxyprogesterone acetate 2.5 mg daily) compared with those receiving placebo. The increase in breast cancer risk was apparent after 4 years of estrogen/progestin therapy, and the risk appeared to be cumulative. Results of a large (involving more than 100,000 women) prospective cohort study (the Nurses' Health Study) in postmenopausal women who received conjugated estrogens indicated that while there appears to be no increased risk of breast cancer in postmenopausal women with prior or relatively short-term use of estrogens, long-term (exceeding 5 years) estrogen therapy may be associated with an increased risk of such carcinoma, especially in women 55 years and older. Addition of progestins to estrogen replacement therapy appears to increase the risk of breast cancer beyond that associated with estrogen alone.

In one retrospective study in black women who received sterile medroxyprogesterone acetate suspension for contraception, there was no evidence of an increased risk of developing cancer of the breast, uterine corpus, or ovary. Although the study indicated that there was no strong association between medroxyprogesterone and these cancers, limitations of the study included inability to detect a weak carcinogenic effect of the drug or a carcinogenic effect that would become evident only after a long latent period.

Long-term case-controlled studies conducted by the World Health Organization (WHO) in other users of medroxyprogesterone contraception have revealed slight or no evidence of increased overall risk of breast cancer and no evidence of increased overall risk of ovarian or cervical cancer. While there also was no evidence of an increased overall risk of liver cancer among users in populations in which hepatitis B infection was endemic, the relevance of these findings to populations in which this infection is not endemic currently is not known since relative risks of live cancer associated with use of oral estrogen-progestin combinations have been estimated to be lower among populations in which this infection is endemic compared with nonendemic populations. In the case-control study assessing the risk of breast cancer, there was evidence of an increased risk of breast cancer within the first 4 years of initial exposure to medroxyprogesterone, principally among those younger than 35 years of age. The relative risk estimated for users whose first exposure to the drug was within the previous 4 years was 2.19 times that in nonusers; this would represent an increase in the annual risk of breast cancer from 26.7 cases per 100,000 women among nonusers to 58.5 cases per 100,000 women among medroxyprogesterone users. Thus, the attributable annual risk for breast cancer among users in the US is 3.18 per 10,000 women. In the case-control study assessing the risk of cervical cancer, while there was no evidence of an increased overall risk of this cancer among medroxyprogesterone users (even after more than 12 years since initial use), there was a statistically insignificant increase in the relative risk (to 1.22-1.28) of invasive squamous cell carcinoma among users who were first exposed to the drug before age 35; however, no trends in risk with duration of use or times since initial or most recent use were observed.

There also is evidence from a long-term case-control study conducted by WHO in users of medroxyprogesterone contraception of a prolonged (e.g., for at least 8 years after discontinuance of the drug) protective effect manifested as a reduced risk of endometrial cancer among users; however, this possible protective effect of medroxyprogesterone may be reduced by concomitant estrogen use.

Pregnancy, Fertility, and Lactation

Pregnancy

Although progestins have been used beginning in the first trimester of pregnancy to prevent habitual abortion or to treat threatened abortion, there is no adequate evidence from well-controlled studies to substantiate the efficacy of progestins for these uses; however, there is evidence of potential adverse effects on the fetus when these drugs are administered within the first 4 months of pregnancy. In addition, in most women, the cause of abortion is a defective ovum, which progestins could not be expected to influence. Because of their uterine-relaxant effects, progestins may delay spontaneous abortion of fertilized defective ova. Masculinization of the female fetus has reportedly occurred when progestins were used during pregnancy. Clitoral hypertrophy and fusion of the labia have been reported in a few female neonates born to women who had received medroxyprogesterone during pregnancy; hypospadias in male neonates born to women receiving progestational agents occurs at approximately twice the rate of occurrence in male neonates born to women not receiving the drugs. Postpartum bleeding, postabortal bleeding, and missed abortion have been reported in women who received the drug during pregnancy. An association between intrauterine exposure to female sex hormones and congenital anomalies, including cardiovascular and limb defects, has been suggested. Use of progestins, including medroxyprogesterone, is not recommended during the first 4 months of pregnancy. If a woman becomes pregnant while receiving medroxyprogesterone or is inadvertently exposed to the drug during the first 4 months of pregnancy, she should be advised of the potential risks to the fetus. To increase ensurance that the drug is not administered inadvertently to a pregnant woman, it is important that use of the drug be initiated only during the first 5 days after onset of normal menses, within 5 days postpartum if the woman is not lactating, or at the sixth postpartum week if she is. If more than 13-14 weeks has elapsed since the last dose of medroxyprogesterone, appropriate assessment should be performed to ensure that the woman is not pregnant prior to administering a dose.

When medroxyprogesterone is used as a contraceptive, unintended pregnancies that occur within 1-2 months after IM injection of the drug may be characterized by impaired fetal growth as evidenced by low birthweights, which theoretically could result in an increased risk of neonatal death. However, the attributable risk of this adverse effect is low because such pregnancies are unlikely. The risk of low birthweight was particularly evident when conception was estimated to occur within 4 weeks of medroxyprogesterone injection. While an increase in polysyndactyly, particularly among offspring of women younger than 30 years of age, and chromosomal anomalies also have been observed in neonates born to women who received IM medroxyprogesterone contraception, the unrelated nature of these effects, the lack of confirmation from other studies, the prolonged period of time between use of the drug and conception in many cases, and chance effects resulting from the multiple statistical comparisons applied make an association between these effects and the drug unlikely.

The possibility of ectopic pregnancy should be considered in any women using medroxyprogesterone contraception if pregnancy occurs or the woman develops complaints of severe abdominal pain.

Medroxyprogesterone should not be used to induce withdrawal bleeding as a test for pregnancy.

Fertility

Impairment of fertility persists for prolonged periods after the last dose of parenteral medroxyprogesterone in women receiving the drug for contraception or the management of endometriosis. Life-table analysis of data from one study in which follow-up was available in 61% of participants who received IM medroxyprogesterone indicated that, in women who intend to become pregnant following discontinuance of the drug, 68, 83, and 93% of women who successfully conceive are likely to do so within 12, 15, and 18 months, respectively, after the last dose. The median time to conception for those who do conceive is 10 months (range: 4-31 months) after the last dose and is unrelated to the duration of contraceptive medroxyprogesterone use. However, pregnancy (e.g., unintended) can occur rarely within 4 weeks after a dose of the drug. The median time to ovulation in women who received several doses of depo-subQ provera 104 was 10 months after the last injection; 80% of women ovulated within 1 year after the last injection. Ovulation may occur as early as 14 weeks after a single dose of depo-subQ provera 104.

Lactation

Progestins reportedly are distributed into milk, and detectable amounts of medroxyprogesterone have been identified in milk of lactating women receiving the drug IM. Milk composition, quality, and volume are not affected adversely by medroxyprogesterone use. While the manufacturers warn that the possible effects of progestins in milk on nursing infants have not been determined, study of infants exposed to the drug via breast milk has revealed no evidence of adverse developmental or behavioral effects through puberty.

The effects of combined medroxyprogesterone acetate and estradiol cypionate therapy on lactation and nursing infants have not been established. However, because adverse effects such as jaundice and breast enlargement have been reported in nursing infants of women receiving estrogen-progestin combination oral contraceptives, the usual cautions and precautions associated with estrogens must be considered in lactating women receiving IM medroxyprogesterone acetate in fixed combination with estradiol cypionate. The manufacturer states that use of estrogen-progestin combination contraceptives should be deferred until 6 weeks postpartum. For additional information,

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