Pharmacokinetics

The pharmacokinetics of MPA were determined in 20 postmenopausal women following a single-dose administration of eight medroxyprogesterone acetate 2.5 mg tablets or a single administration of two medroxyprogesterone acetate 10 mg tablets under fasting conditions. In another study, the steady-state pharmacokinetics of MPA were determined under fasting conditions in 30 postmenopausal women following daily administration of one medroxyprogesterone acetate 10 mg tablet for 7 days. In both studies, MPA was quantified in serum using a validated gas chromatography-mass spectrometry (GC-MS) method. Estimates of the pharmacokinetic parameters of MPA after single and multiple doses of medroxyprogesterone acetate tablets were highly variable and are summarized in Table 1.

*Following Day 7 dose

Effects on the Endometrium

In a 3-year, double-blind, placebo-controlled study of 356 nonhysterectomized, postmenopausal women between 45 and 64 years of age randomized to receive placebo (n=119), 0.625 mg conjugated estrogen only (n=119), or 0.625 mg conjugated estrogen plus cyclic medroxyprogesterone acetate (n=118), results showed a reduced risk of endometrial hyperplasia in the treatment group receiving 10 mg medroxyprogesterone acetate plus 0.625 mg conjugated estrogens compared to the group receiving 0.625 mg conjugated estrogens only. See Table 2.

In a second 1-year study, 832 postmenopausal women between 45 and 65 years of age were treated with daily 0.625 mg conjugated estrogen (days 1 to 28), plus either 5 mg cyclic medroxyprogesterone acetate or 10 mg cyclic medroxyprogesterone acetate (days 15 to 28), or daily 0.625 mg conjugated estrogen only. The treatment groups receiving 5 or 10 mg cyclic medroxyprogesterone acetate (days 15 to 28) plus daily conjugated estrogens showed a significantly lower rate of hyperplasia as compared to the conjugated estrogens only group. See Table 3.

Women’s Health Initiative Studies

The WHI enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of daily oral CE (0.625 mg)-alone or in combination with MPA (2.5 mg) compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (defined as nonfatal MI, silent MI and CHD death), with invasive breast cancer as the primary adverse outcome. A “global index” included the earliest occurrence of CHD, invasive breast cancer, stroke, PE, endometrial cancer (only in the CE plus MPA substudy), colorectal cancer, hip fracture, or death due to other cause. These substudies did not evaluate the effects of CE-alone or CE plus MPA on menopausal symptoms.

WHI Estrogen Plus Progestin Substudy

The WHI estrogen plus progestin substudy was stopped early. According to the predefined stopping rule, after an average follow-up of 5.6 years of treatment, the increased risk of invasive breast cancer and cardiovascular events exceeded the specified benefits included in the “global index.” The absolute excess risk of events included in the “global index” was 19 per 10,000 women-years.

For those outcomes included in the WHI “global index” that reached statistical significance after 5.6 years of follow-up, the absolute excess risks per 10,000 women-years in the group treated with CE plus MPA were 7 more CHD events, 8 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reduction per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures.

Results of the CE plus MPA substudy which included 16,608 women (average 63 years of age, range 50 to 79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other) are presented in Table 4. These results reflect centrally adjudicated data after an average follow-up of 5.6 years.

Timing of the initiation of estrogen plus progestin therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen plus progestin substudy stratified by age showed in women 50 to 59 years of age a nonsignificant trend toward reduced risk in overall mortality [hazard ration (HR) 0.69 (95 percent CI, 0.44 to 1.07)].

Women's Health Initiative Memory Study

The WHIMS estrogen plus progestin ancillary study of WHI enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 percent were aged 65 to 69 years of age, 35 percent were 70 to 74 years of age, and 18 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia (primary outcome) compared to placebo.

After an average follow-up of 4 years, the relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21 to 3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 33 per 10,000 women-years. Probable dementia as defined in this study included Alzheimer’s disease (AD), vascular dementia (VaD) and mixed type (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women. (See WARNINGS,Probable Dementia and PRECAUTIONS, Geriatric Use).

1. Cardiovascular Disorders.

An increased risk of PE, DVT, stroke, and MI has been reported with estrogen plus progestin therapy. Should any of these events occur or be suspected, estrogen plus progestin therapy should be discontinued immediately.

Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (for example, personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately.

2. Malignant Neoplasms

3. Probable Dementia

In the WHIMS estrogen plus progestin ancillary study of WHI, a population of 4,532 postmenopausal women aged 65 to 79 years was randomized to daily CE (0.625 mg) plus MPA (2.5 mg) or placebo.

After an average follow-up of 4 years, 40 women in the CE plus MPA group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21 to 3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years. It is unknown whether these findings apply to younger postmenopausal women. (See CLINICAL STUDIES and PRECAUTIONS, Geriatric Use.)

4. Visual Abnormalities

Discontinue estrogen plus progestin therapy pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia or migraine. If examination reveals papilledema or retinal vascular lesions, estrogen plus progestin therapy should be permanently discontinued.

A. General

1. Addition of a progestin when a woman has not had a hysterectomy
2. Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer.
3. There are, however, possible risks that may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include an increased risk of breast cancer.
4. Unexpected abnormal vaginal bleeding
5. In cases of unexpected abnormal vaginal bleeding, adequate diagnostic measures are indicated.
6. Elevated blood pressure
   
   
7. Blood pressure should be monitored at regular intervals with estrogen plus progestin therapy.
8. Hypertriglyceridemia
   
   
9. In women with pre-existing hypertriglyceridemia, estrogen plus progestin therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of treatment if pancreatitis occurs.
10. Hepatic Impairment and/or past history of cholestatic jaundice
    
    
11. Estrogens plus progestins may be poorly metabolized in women with impaired liver function. For women with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised, and in the case of recurrence, medication should be discontinued.
12. Fluid Retention
    
    
13. Progestins may cause some degree of fluid retention. Women who have conditions which might be influenced by this factor, such as cardiac or renal impairment, warrant careful observation when estrogen plus progestin are prescribed.
14. Hypocalcemia
    
    
15. Estrogen plus progestin therapy should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur.
16. Exacerbation of other conditions
    
    
17. Estrogen plus progestin therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions.

B. Patient Information

Physicians are advised to discuss the Patient Information leaflet with women for whom they prescribe medroxyprogesterone acetate.

There may be an increased risk of minor birth defects in children whose mothers are exposed to progestins during the first trimester of pregnancy. The possible risk to the male baby is hypospadias, a condition in which the opening of the penis is on the underside rather than the tip of the penis. This condition occurs naturally in approximately 5 to 8 per 1000 male births. The risk may be increased with exposure to medroxyprogesterone acetate. Enlargement of the clitoris and fusion of the labia may occur in female babies. However, a clear association between hypospadias, clitoral enlargement and labial fusion with use of medroxyprogesterone acetate has not been established.

Inform the patient of the importance of reporting exposure to medroxyprogesterone acetate in early pregnancy.

C. Drug-Laboratory Test Interactions

The following laboratory results may be altered by the use of estrogen plus progestin therapy:

1. Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of anti-factor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.
2. Increased thyroid-binding globulin (TBG) levels leading to increased circulating total thyroid hormone levels as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels by radioimmunoassay, T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Women on thyroid replacement therapy may require higher doses of thyroid hormone.
3. Other binding proteins may be elevated in serum for example, corticosteroid binding globulin (CBG), sex hormone binding globulin (SHBG) leading to increased circulating corticosteroid and sex steroids, respectively. Free hormone concentrations, such as testosterone and estradiol, may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).
4. Increased plasma high-density lipoprotein (HDL) and HDL2 cholesterol subfraction concentrations, reduced low-density lipoprotein (LDL) cholesterol concentration, increased triglycerides levels.
5. Impaired glucose tolerance.

D. Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity: Long-term intramuscular administration of medroxyprogesterone acetate has been shown to produce mammary tumors in beagle dogs. There was no evidence of a carcinogenic effect associated with the oral administration of medroxyprogesterone acetate to rats and mice.

Long-term continuous administration of estrogen plus progestin therapy has shown an increased risk of breast cancer and ovarian cancer. (See WARNINGS and PRECAUTIONS.)

Genotoxicity: Medroxyprogesterone acetate was not mutagenic in a battery of in vitro or in vivo genetic toxicity assays.

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

E. Pregnancy

F. Nursing Mothers

Medroxyprogesterone acetate should not be used during lactation. Detectable amounts of progestin have been identified in the breast milk of nursing mothers receiving progestins.

G. Pediatric Use

Medroxyprogesterone acetate tablets are not indicated in children. Clinical studies have not been conducted in the pediatric population.

H. Geriatric Use

There have not been sufficient numbers of geriatric women involved in clinical studies utilizing medroxyprogesterone acetate alone to determine whether those over 65 years of age differ from younger subjects in their response to medroxyprogesterone acetate alone.

The Women’s Health Initiative Studies

In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age. (See CLINICAL STUDIES.)

The Women’s Health Initiative Memory Study

In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen- alone or estrogen plus progestin when compared to placebo. (See WARNINGS, Probable Dementia.)

Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women. (See WARNINGS, Probable Dementia.)

Secondary Amenorrhea

Medroxyprogesterone acetate tablets may be given in dosages of 5 or 10 mg daily for 5 to 10 days. A dose for inducing an optimum secretory transformation of an endometrium that has been adequately primed with either endogenous or exogenous estrogen is 10 mg of medroxyprogesterone acetate daily for 10 days. In cases of secondary amenorrhea, therapy may be started at any time. Progestin withdrawal bleeding usually occurs within three to seven days after discontinuing medroxyprogesterone acetate therapy.

Abnormal Uterine Bleeding Due to Hormonal Imbalance in the Absence of Organic Pathology

Beginning on the calculated 16th or 21st day of the menstrual cycle, 5 or 10 mg of medroxyprogesterone acetate may be given daily for 5 to 10 days. To produce an optimum secretory transformation of an endometrium that has been adequately primed with either endogenous or exogenous estrogen, 10 mg of medroxyprogesterone acetate daily for 10 days beginning on the 16th day of the cycle is suggested. Progestin withdrawal bleeding usually occurs within three to seven days after discontinuing therapy with medroxyprogesterone acetate. Patients with a past history of recurrent episodes of abnormal uterine bleeding may benefit from planned menstrual cycling with medroxyprogesterone acetate.

Reduction of Endometrial Hyperplasia in Postmenopausal Women Receiving Daily 0.625 mg Conjugated Estrogens

When estrogen is prescribed for a postmenopausal woman with a uterus, a progestin should also be initiated to reduce the risk of endometrial cancer. A woman without a uterus does not need progestin. Use of estrogen, alone or in combination with a progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Patients should be re-evaluated periodically as clinically appropriate (for example, 3 to 6 month intervals) to determine if treatment is still necessary (see WARNINGS). For women who have a uterus, adequate diagnostic measures, such as endometrial sampling, when indicated, should be undertaken to rule out malignancy in cases of undiagnosed persistent or recurring abnormal vaginal bleeding.

Medroxyprogesterone acetate tablets may be given in dosages of 5 or 10 mg daily for 12 to 14 consecutive days per month, in postmenopausal women receiving daily 0.625 mg conjugated estrogens, either beginning on the 1st day of the cycle or the 16th day of the cycle.

Patients should be started at the lowest dose.

The lowest effective dose of medroxyprogesterone acetate has not been determined.

What is medroxyprogesterone acetate?

Medroxyprogesterone acetate is a medicine that contains medroxyprogesterone acetate, a progestin hormone.

What is medroxyprogesterone acetate used for?

Medroxyprogesterone acetate is used to:

• Treat menstrual periods that have stopped or to treat abnormal uterine bleeding. Women with a uterus who are not pregnant, who stop having regular menstrual periods or who begin to have irregular menstrual periods may have a drop in their progesterone level. Talk with your healthcare provider about whether medroxyprogesterone acetate is right for you.
• Reduce your chances of getting cancer of the uterus (womb). In postmenopausal women with a uterus who use estrogens, taking progestin in combination with estrogen will reduce your chance of getting cancer of the uterus (womb).

Who should not take medroxyprogesterone acetate?

Do not start taking medroxyprogesterone acetate if you:

• have unusual vaginal bleeding
• currently have or have had certain cancers
  
  
  
  Estrogen plus progestin may increase your chance of getting certain types of cancers, including cancer of the breast. If you have or have had cancer, talk with your healthcare provider about whether you should use medroxyprogesterone acetate.
• had a stroke or heart attack
• currently have or have had blood clots
• currently have or have had liver problems
• are allergic to medroxyprogesterone acetate tablets or any of its ingredients
  
  
  
  See the list of ingredients inmedroxyprogesterone acetate tablets at the end of this leaflet.
• think you may be pregnant
  
  
  
  Medroxyprogesterone acetate is not for pregnant women. If you think you may be pregnant, you should have a pregnancy test and know the results. Do not use medroxyprogesterone acetate if the test is positive and talk to your healthcare provider. There may be an increased risk of minor birth defects in children whose mothers take medroxyprogesterone acetate during the first 4 months of pregnancy.

  Medroxyprogesterone acetate should not be used as a test for pregnancy.

What should I tell my healthcare provider before taking medroxyprogesterone acetate? Before you take medroxyprogesterone acetate, tell your healthcare provider if you:

• have any other medical problems
  
  Your healthcare provider may need to check you more carefully if you have certain conditions such as asthma (wheezing), epilepsy (seizures), diabetes, migraine, endometriosis (severe pelvic pain), lupus, or problems with your heart, liver, thyroid, kidneys, or have high calcium in your blood.
• are going to have surgery or will be on bed rest
  
  Your healthcare provider will let you know if you need to stop taking medroxyprogesterone acetate.
• are breast feeding
  
  The hormone in medroxyprogesterone acetate can pass into your breast milk.

Tell your healthcare provider about all the medicines you take including prescription and nonprescription medicines, vitamins, and herbal supplements. Some medicines may affect how medroxyprogesterone acetate works. Medroxyprogesterone acetate may also affect how other medicines work.

How should I take medroxyprogesterone acetate?

Start at the lowest dose and talk to your healthcare provider about how well that dose is working for you. The lowest effective dose of medroxyprogesterone acetate has not been determined. You and your healthcare provider should talk regularly (every 3 to 6 months) about the dose you are taking and whether you still need treatment with medroxyprogesterone acetate.

1. Absence of menstrual period: Medroxyprogesterone acetate may be given in doses ranging from 5 to 10 mg daily for 5 to 10 days.
2. Abnormal Uterine Bleeding: Medroxyprogesterone acetate may be given in doses ranging from 5 to 10 mg daily for 5 to 10 days.
3. Overgrowth of the lining of the uterus: When used in combination with oral conjugated estrogens in postmenopausal women with a uterus, medroxyprogesterone acetate may be given in doses ranging from 5 or 10 mg daily for 12 to 14 straight days per month.

What are the possible side effects of medroxyprogesterone acetate?

The following side effects have been reported with the use of medroxyprogesterone acetate alone:

• breast tenderness
• breast milk secretion
• breakthrough bleeding
• spotting (minor vaginal bleeding)
• irregular periods
• amenorrhea (absence of menstrual periods)
• vaginal secretions
• headaches
• nervousness
• dizziness
• depression
• insomnia, sleepiness, fatigue
• premenstrual syndrome-like symptoms
• thrombophlebitis (inflamed veins)
• blood clot
• itching, hives, skin rash
• acne
• hair loss, hair growth
• abdominal discomfort
• nausea
• bloating
• fever
• increase in weight
• swelling
• changes in vision and sensitivity to contact lenses

Call your healthcare provider right away if you get hives, problems breathing, swelling of the face, mouth, tongue or neck.

The following side effects have been reported with the use of medroxyprogesterone acetate with an estrogen.

Side effects are grouped by how serious they are and how often they happen when you are treated.

Serious, but less common side effects include:

• heart attack
• stroke
• blood clots
• dementia
• breast cancer
• cancer of the uterus
• cancer of the ovary
• high blood pressure
• high blood sugar
• gallbladder disease
• liver problems
• changes in your thyroid hormone levels
• enlargements of benign tumors (“fibroids”)

Call your healthcare provider right away if you get any of the following warning signs or any other unusual symptoms that concern you:

• new breast lumps
• unusual vaginal bleeding
• changes in vision and speech
• sudden new severe headaches
• severe pains in your chest or legs with or without shortness of breath, weakness and fatigue
• memory loss or confusion

Less serious but common side effects include:

• headache
• breast pain
• irregular vaginal bleeding or spotting
• stomach or abdominal cramps, bloating
• nausea and vomiting
• hair loss
• fluid retention
• vaginal yeast infection

These are not all the possible side effects of medroxyprogesterone acetate with or without estrogen. For more information, ask your healthcare provider or pharmacist for advice about side effects. Tell your healthcare provider if you have side effect that bothers you or does not go away. You may report side effects to Teva at 1-866-832-8537 or FDA at 1-800-FDA-1088.

What can I do to lower my chances of a serious side effect with medroxyprogesterone acetate?

• Talk with your healthcare provider regularly about whether you should continue taking medroxyprogesterone acetate. The addition of a progestin is generally recommended for women with a uterus to reduce the chance of getting cancer of the uterus (womb).
• See your healthcare provider right away if you get vaginal bleeding while taking medroxyprogesterone acetate.
• Have a pelvic exam, breast exam and mammogram (breast X-ray) every year unless your healthcare provider tells you something else. If members of your family have had breast cancer or if you have ever had breast lumps or an abnormal mammogram, you may need to have breast exams more often.
• If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or if you use tobacco, you may have a higher chance of getting heart disease. Ask your healthcare provider for ways to lower your chance of getting heart disease.

General information about safe and effective use of medroxyprogesterone acetate

• Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets.
• Do not take medroxyprogesterone acetate for conditions for which it was not prescribed.
• Do not give medroxyprogesterone acetate to other people, even if they have the same symptoms you have. It may harm them.

Keep medroxyprogesterone acetate out of the reach of children.

This leaflet provides a summary of the most important information about medroxyprogesterone acetate. If you would like more information, talk with your health care provider or pharmacist. You can ask for information about medroxyprogesterone acetate that is written for health professionals. You can get more information by calling the toll-free number, 1-888-838-2872.

What are the ingredients in medroxyprogesterone acetate?

Each medroxyprogesterone acetate tablet for oral administration contains 2.5 mg, 5 mg or 10 mg of medroxyprogesterone acetate.

Inactive ingredients: crospovidone, lactose monohydrate, magnesium stearate, methylcellulose, pregelatinized corn starch, and sodium lauryl sulfate.

TEVA PHARMACEUTICALS USA, INC.

North Wales, PA 19454

Rev. A 5/2015