Estradiol

Dosage Form: tablet
Estradiol TABLETS, USP

EstradiolTABLETS USP

Rx  only

11001658

Iss. 3/2010

0899

0886

0887

ESTROGENS INCREASE THE RISK OF ENDOMETRIAL CANCER

Close clinical surveillance of all women taking estrogens is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of “natural” estrogens results in a different endometrial risk profile than “synthetic” estrogens at equivalent estrogen doses. (See WARNINGS, Malignant neoplasms, Endometrial cancer.)

CARDIOVASCULAR AND OTHER RISKS

Estrogens with or without progestins should not be used for the prevention of cardiovascular disease. (See WARNINGS, Cardiovascular disorders.)

The Women’s Health Initiative (WHI) study reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 years of age) during 5 years of treatment with oral conjugated estrogens (CE 0.625 mg) combined with medroxyprogesterone acetate (MPA 2.5 mg) relative to placebo. (See CLINICAL PHARMACOLOGY, Clinical Studies.)

The Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, reported increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with oral conjugated estrogens plus medroxyprogesterone acetate relative to placebo. It is unknown whether this finding applies to younger postmenopausal women or to women taking estrogen alone therapy. (See CLINICAL PHARMACOLOGY, Clinical Studies.)

Other doses of oral conjugated estrogens with medroxyprogesterone acetate, and other combinations and dosage forms of estrogens and progestins were not studied in the WHI clinical trials and, in the absence of comparable data, these risks should be assumed to be similar. Because of these risks, estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.

Estradiol Description

Estradiol Tablets USP for oral administration contains 0.5, 1 or 2 mg of micronized Estradiol per tablet. Estradiol (17β-Estradiol) is a white, crystalline solid, chemically described as estra-1,3,5,(10)-triene-3, 17β-diol. The structural formula is:

Inactive Ingredients: Colloidal silicon dioxide, corn starch, dibasic calcium phosphate, lactose monohydrate, magnesium stearate, and sodium starch glycolate. In addition, the 1 mg also contains FD&C blue no. 1 aluminum lake and D&C red no. 27 aluminum lake. The 2 mg also contains FD&C blue no. 1 aluminum lake and FD&C yellow no. 5 (tartrazine) aluminum lake.

Estradiol - Clinical Pharmacology

Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, Estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol at the receptor level.

The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of Estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women.

Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue.

Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH), through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.

Pharmacokinetics

Distribution

The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin.

Metabolism

Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women, a significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.

Excretion

Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates.

Special Populations

No pharmacokinetic studies were conducted in special populations, including patients with renal or hepatic impairment.

Drug Interactions

In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4 such as St. John’s Wort preparations (Hypericum perforatum), phenobarbital, carbamazepine, and rifampin may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may increase plasma concentrations of estrogens and may result in side effects.

Clinical Studies

Osteoporosis

Most prospective studies of efficacy for this indication have been carried out in white menopausal women, without stratification by other risk factors, and tend to show a universally salutary effect on bone.

The results of a two-year, randomized, placebo-controlled, double-blind, dose-ranging study have shown that treatment with 0.5 mg Estradiol daily for 23 days (of a 28 day cycle) prevents vertebral bone mass loss in postmenopausal women. When estrogen therapy is discontinued, bone mass declines at a rate comparable to the immediate postmenopausal period. There is no evidence that estrogen replacement therapy restores bone mass to premenopausal levels.

Women's Health Initiative Studies

The Women’s Health Initiative (WHI) enrolled a total of 27,000 predominantly healthy postmenopausal women to assess the risks and benefits of either the use of oral 0.625 mg conjugated estrogens (CE) per day alone or the use of oral 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate (MPA) per day compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome studied. A “global index” included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, or death due to other cause. The study did not evaluate the effects of CE or CE/MPA on menopausal symptoms.

The CE/MPA substudy was stopped early because, according to the predefined stopping rule, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the “global index.” Results of the CE/MPA substudy, which included 16,608 women (average age of 63 years, range 50 to 79; 83.9% White, 6.5% Black, 5.5% Hispanic), after an average follow-up of 5.2 years are presented in Table 1 below:

Table 1: RELATIVE AND ABSOLUTE RISK SEEN IN THE CE/MPA SUBSTUDY OF WHI*

* adapted from JAMA, 2002; 288:321-333 † a subset of the events was combined in a “global index”, defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes ‡ nominal confidence intervals unadjusted for multiple looks and multiple comparisons § includes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer ¶ not included in Global Index
Event †	Relative Risk CE/MPA vs placebo at 5.2 Years (95% CI‡)	Placebo n = 8102	CE/MPA n = 8506
		Absolute Risk per 10,000 Women-years
CHD events Non-fatal MI CHD death	1.29 (1.02 to 1.63) 1.32 (1.02 to 1.72) 1.18 (0.70 to 1.97)	30 23 6	37 30 7
Invasive breast cancer§	1.26 (1.00 to 1.59)	30	38
Stroke	1.41 (1.07 to 1.85)	21	29
Pulmonary embolism	2.13 (1.39 to 3.25)	8	16
Colorectal cancer	0.63 (0.43 to 0.92)	16	10
Endometrial cancer	0.83 (0.47 to 1.47)	6	5
Hip fracture	0.66 (0.45 to 0.98)	15	10
Death due to causes other than the events above	0.92 (0.74 to 1.14)	40	37
Global Index†	1.15 (1.03 to 1.28)	151	170
Deep vein thrombosis¶	2.07 (1.49 to 2.87)	13	26
Vertebral fractures¶	0.66 (0.44 to 0.98)	15	9
Other osteoporotic fractures¶	0.77 (0.69 to 0.86)	170	131

For those outcomes included in the “global index,” the absolute excess risks per 10,000 women-years in the group treated with CE/MPA were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the “global index” was 19 per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality. (See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.)

Women's Health Initiative Memory Study

The Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47% were age 65 to 69 years, 35% were 70 to 74 years, and 18% were 75 years of age and older) to evaluate the effects of CE/MPA (0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate) on the incidence of probable dementia (primary outcome) compared with placebo.

After an average follow-up of 4 years, 40 women in the estrogen/progestin group (45 per 10,000 women-years) and 21 in the placebo group (22 per 10,000 women-years) were diagnosed with probable dementia. The relative risk of probable dementia in the hormone therapy group was 2.05 (95% CI, 1.21 to 3.48) compared to placebo. Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNING and WARNINGS, Dementia.)

Indications and Usage for Estradiol

Estradiol Tablets USP are indicated in the:

1. Treatment of moderate to severe vasomotor symptoms associated with the menopause.


2. Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered.


3. Treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure.


4. Treatment of breast cancer (for palliation only) in appropriately selected women and men with metastatic disease.


5. Treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only).


6. Prevention of osteoporosis. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and for whom non-estrogen medications are not considered to be appropriate. (See CLINICAL PHARMACOLOGY, Clinical Studies.)
   

   The mainstays for decreasing the risk of postmenopausal osteoporosis are weight bearing exercise, adequate calcium and vitamin D intake, and when indicated, pharmacologic therapy. Postmenopausal women require an average of 500 mg/day of elemental calcium. Therefore, when not contraindicated, calcium supplementation may be helpful for women with suboptimal dietary intake. Vitamin D supplementation of 400-800 IU/day may also be required to ensure adequate daily intake in postmenopausal women.

   
   

Contraindications

Estrogens should not be used in individuals with any of the following conditions:

1. Undiagnosed abnormal genital bleeding.


2. Known, suspected or history of cancer of the breast except in appropriately selected patients being treated for metastatic disease.


3. Known or suspected estrogen-dependent neoplasia.


4. Active deep vein thrombosis, pulmonary embolism or history of these conditions.


5. Active or recent (e.g., within the past year) arterial thromboembolic disease (e.g., stroke, myocardial infarction.


6. Liver dysfunction or disease.


7. Estradiol Tablets USP should not be used in patients with known hypersensitivity to its ingredients. Estradiol Tablets, USP 2 mg, contain FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible individuals. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.


8. Known or suspected pregnancy. There is no indication for Estradiol tablets in pregnancy. There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins from oral contraceptives inadvertently during early pregnancy. (See PRECAUTIONS.)

Warnings

See BOXED WARNINGS.

1. Cardiovascular disorders.

Estrogen and estrogen/progestin therapy has been associated with an increased risk of cardiovascular events such as myocardial infarction and stroke, as well as venous thrombosis and pulmonary embolism (venous thromboembolism or VTE). Should any of these occur or be suspected estrogens should be discontinued immediately.

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

a. Coronary heart disease and stroke

In the Women’s Health Initiative (WHI) study, an increase in the number of myocardial infarctions and strokes has been observed in women receiving CE compared to placebo. These observations are preliminary, and the study is continuing. (See CLINICAL PHARMACOLOGY, Clinical Studies.)

In the CE/MPA substudy of WHI, an increased risk of coronary heart disease (CHD) events (defined as nonfatal myocardial infarction and CHD death) was observed in women receiving CE/MPA compared to women receiving placebo (37 vs 30 per 10,000 person years). The increase in risk was observed in year one and persisted.

In the same substudy of WHI, an increased risk of stroke was observed in women receiving CE/MPA compared to women receiving placebo (29 vs 21 per 10,000 women-years). The increase in risk was observed after the first year and persisted.

In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years) a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study; HERS) treatment with CE/MPA (0.625 mg/2.5 mg per day) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE/MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the CE/MPA-treated group than in the placebo group in year 1, but not during the subsequent years. Two thousand three hundred and twenty one women from the original HERS trial agreed to participate in an open label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the CE/MPA group and the placebo group in HERS, HERS II, and overall.

Large doses of estrogen (5 mg conjugated estrogens per day), comparable to those used to treat cancer of the prostate and breast, have been shown in a large prospective clinical trial in men to increase the risks of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis.

b.Venous thromboembolism (VTE)

In the Women’s Health Initiative (WHI) study, an increase in VTE has been observed in women receiving CE compared to placebo. These observations are preliminary, and the study is continuing. (See CLINICAL PHARMACOLOGY, Clinical Studies.)

In the CE/MPA substudy of WHI, a 2­fold greater rate of VTE, including deep venous thrombosis and pulmonary embolism, was observed in women receiving CE/MPA compared to women receiving placebo. The rate of VTE was 34 per 10,000 women­years in the CE/MPA group compared to 16 per 10,000 women­years in the placebo group. The increase in VTE risk was observed during the first year and persisted.

If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.

2. Malignant neoplasms

a. Endometrial cancer

The use of unopposed estrogens in women with intact uteri has been associated with an increased risk of endometrial cancer. The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12- fold greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than one year. The greatest risk appears associated with prolonged use—with increased risks of 15- to 24-fold for five to ten years or more—and this risk persists for 8 to over 15 years after estrogen therapy is discontinued.

Clinical surveillance of all women taking estrogen/progestin combinations is important (see PRECAUTIONS). Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.

b. Breast cancer

The use of estrogens and progestins by postmenopausal women has been reported to increase the risk of breast cancer. The most important randomized clinical trial providing information about this issue is the Women’s Health Initiative (WHI) substudy of CE/MPA (see CLINICAL PHARMACOLOGY, Clinical Studies). The results from observational studies are generally consistent with those of the WHI clinical trial and report no significant variation in the risk of breast cancer among different estrogens or progestins, doses, or routes of administration.

The CE/MPA substudy of WHI reported an increased risk of breast cancer in women who took CE/MPA for a mean follow-up of 5.6 years. Observational studies have also reported an increased risk for estrogen/progestin combination therapy, and a smaller increased risk for estrogen alone therapy, after several years of use. In the WHI trial and from observational studies, the excess risk increased with duration of use. From observational studies, the risk appeared to return to baseline in about five years after stopping treatment. In addition, observational studies suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen/progestin combination therapy as compared to estrogen alone therapy.

In the CE/MPA substudy, 26% of the women reported prior use of estrogen alone and/or estrogen/progestin combination hormone therapy. After a mean follow-up of 5.6 years during the clinical trial, the overall relative risk of invasive breast cancer was 1.24 (95% confidence interval 1.01-1.54), and the overall absolute risk was 41 vs 33 cases per 10,000 women-years, for CE/MPA compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 vs 25 cases per 10,000 women-years, for CE/MPA compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 vs 36 cases per 10,000 women-years for CE/MPA compared with placebo. In the same substudy, invasive breast cancers were larger and diagnosed at a more advanced stage in the CE/MPA group compared with the placebo group. Metastatic disease was rare with no apparent difference between the two groups. Other prognostic factors such as histologic subtype, grade and hormone receptor status did not differ between the groups.

The use of estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation. All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.

3. Dementia.

In the Women’s Health Initiative Memory Study (WHIMS), 4,532 generally healthy postmenopausal women 65 years of age and older were studied, of whom 35% were 70 to 74 years of age and 18% were 75 or older. After an average follow-up of 4 years, 40 women being treated with CE/MPA (1.8%, n = 2,229) and 21 women in the placebo group (0.9%, n = 2,303) received diagnoses of probable dementia. The relative risk for CE/MPA versus placebo was 2.05 (95% confidence interval 1.21 – 3.48), and was similar for women with and without histories of menopausal hormone use before WHIMS. The absolute risk of probable dementia for CE/MPA versus placebo was 45 versus 22 cases per 10,000 women-years, and the absolute excess risk for CE/MPA was 23 cases per 10,000 women-years. It is unknown whether these findings apply to younger postmenopausal women. (See CLINICAL PHARMACOLOGY, Clinical Studies and PRECAUTIONS, Geriatric Use.)

It is unknown whether these findings apply to estrogen alone therapy.

4. Gallbladder disease.

A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.

5. Hypercalcemia.

Estrogen administration may lead to severe hypercalcemia in patients with breast cancer and bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to reduce the serum calcium level.

6. Visual  abnormalities.

Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue medication 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, estrogens should be permanently discontinued.

Precautions

A. General

1. Addition of a progestin when a woman has not had a hysterectomy 

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.

There are, however, possible risks which may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include a possible increased risk of breast cancer.

2. Elevated blood pressure

In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogens on blood pressure was not seen. Blood pressure should be monitored at regular intervals with estrogen use.

3.  Hypertriglyceridemia

In patients with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis and other complications.

4.  Impaired liver function and past history of cholestatic jaundice

Estrogens may be poorly metabolized in patients with impaired liver function. For patients 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.

5.  Hypothyroidism

Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Patients with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Patients dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These patients should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.

6.  Fluid retention

Because estrogens may cause some degree of fluid retention, patients with conditions that might be influenced by this factor, such as asthma, epilepsy, migraine, and cardiac or renal dysfunction, warrant careful observation when estrogens are prescribed.

7.  Hypocalcemia

Estrogens should be used with caution in individuals with severe hypocalcemia.

8. Ovarian cancer

The CE/MPA substudy of WHI reported that estrogen plus progestin increased the risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE/MPA versus placebo was 1.58 (95% confidence interval 0.77 – 3.24) but was not statistically significant. The absolute risk for CE/MPA versus placebo was 4.2 versus 2.7 cases per 10,000 women-years. In some epidemiologic studies, the use of estrogen alone, in particular for ten or more years, has been associated with an increased risk of ovarian cancer. Other epidemiologic studies have not found these associations.

9. Exacerbation of endometriosis

Endometriosis may be exacerbated with administration of estrogens. A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen alone therapy. For patients known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered.

10.  Exacerbation of other conditions .

Estrogens may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine or porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions.

Estradiol Tablets, USP, 2 mg, contain FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible individuals. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.

B. Patient Information

Physicians are advised to discuss the PATIENT INFORMATION leaflet with patients for whom they prescribe Estradiol Tablets.

C. Laboratory Tests

Estrogen administration should be initiated at the lowest dose approved for the indication and then guided by clinical response rather than by serum hormone levels (e.g., Estradiol, FSH). (See DOSAGE AND ADMINISTRATION section.)

D. Drug/Laboratory Test Interactions

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) leading to increased circulating total thyroid hormone, 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. Patients on thyroid replacement therapy may require higher doses of thyroid hormone.


3. Other binding proteins may be elevated in serum, i.e., corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG), leading to increased circulating corticosteroids and sex steroids, respectively. Free hormone concentrations may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).


4. Increased plasma HDL and HDL2 subfraction concentrations, reduced LDL cholesterol concentration, increased triglycerides levels.


5. Impaired glucose tolerance.


6. Reduced response to metyrapone test.

E. Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term continuous administration of estrogen, with and without progestin, in women with and without a uterus, has shown an increased risk of endometrial cancer, breast cancer, and ovarian cancer. (See BOXED WARNINGS, WARNINGS and PRECAUTIONS.)

Long term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.

F. Pregnancy Category X

Estradiol Tablets should not be used during pregnancy. (See CONTRAINDICATIONS.)

G. Nursing Mothers

Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving this drug. Caution should be exercised when Estradiol is administered to a nursing woman.

H. Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Large and repeated doses of estrogen over an extended period of time have been shown to accelerate epiphyseal closure, resulting in short adult stature if treatment is initiated before the completion of physiologic puberty in normally developing children. In patients in whom bone growth is not complete, periodic monitoring of bone maturation and effects on epiphyseal centers is recommended.

Estrogen treatment of prepubertal children also induces premature breast development and vaginal cornification, and may potentially induce vaginal bleeding in girls. In boys, estrogen treatment may modify the normal pubertal process. All other physiological and adverse reactions shown to be associated with estrogen treatment of adults could potentially occur in the pediatric population, including thromboembolic disorders and growth stimulation of certain tumors. Therefore, estrogens should only be administered to pediatric patients when clearly indicated and the lowest effective dose should always be utilized.

I. Geriatric Use

The safety and efficacy of Estradiol tablets in geriatric patients has not been established. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greatest frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

In the Women’s Health Initiative Memory Study, including 4,532 women 65 years of age and older, followed for an average of 4 years, 82% (n = 3,729) were 65 to 74 while 18% (n = 803) were 75 and over. Most women (80%) had no prior hormone therapy use. Women treated with conjugated estrogens plus medroxyprogesterone acetate were reported to have a two-fold increase in the risk of developing probable dementia. Alzheimer’s disease was the most common classification of probable dementia in both the conjugated estrogens plus medroxyprogesterone acetate group and the placebo group. Ninety percent of the cases of probable dementia occurred in the 54% of women that were older than 70. (See WARNINGS, Dementia.)

It is unknown whether these findings apply to estrogen alone therapy.

Adverse Reactions

See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.

The following additional adverse reactions have been reported with estrogen and/or progestin therapy.

1. Genitourinary system

Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow; breakthrough bleeding, spotting, dysmenorrhea

Increase in size of uterine leiomyomata

Vaginitis, including vaginal candidiasis

Change in amount of cervical secretion

Changes in cervical ectropion

Ovarian cancer; endometrial hyperplasia; endometrial cancer

2. Breasts

Tenderness, enlargement, pain, nipple discharge, galactorrhea; fibrocystic breast changes; breast cancer

3. Cardiovascular

Deep and superficial venous thrombosis; pulmonary embolism; thrombophlebitis; myocardial infarction; stroke; increase in blood pressure

4. Gastrointestinal

Nausea, vomiting

Abdominal cramps, bloating

Cholestatic jaundice

Increased incidence of gallbladder disease

Pancreatitis

Enlargement of hepatic hemangiomas

5. Skin

Chloasma or melasma that may persist when drug is discontinued

Erythema multiforme

Erythema nodosum

Hemorrhagic eruption

Loss of scalp hair

Hirsutism

Pruritus, rash

6. Eyes

Retinal vascular thrombosis

Steepening of corneal curvature

Intolerance to contact lenses

7. Central Nervous System

Headache, migraine, dizziness

Mental depression

Chorea

Nervousness, mood disturbances, irritability

Exacerbation of epilepsy

Dementia

8. Miscellaneous

Increase or decrease in weight

Reduced carbohydrate tolerance

Aggravation of porphyria

Edema

Arthralgias; leg cramps

Changes in libido

Urticaria

Angioedema

Anaphylactoid/anaphylactic reactions

Hypocalcemia

Exacerbation of asthma

Increased triglycerides

Overdosage

Serious ill effects have not been reported following acute ingestion of large doses of estrogen-containing oral contraceptives by young children. Overdosage of estrogen may cause nausea and vomiting, and withdrawal bleeding may occur in females.

Dosage and Administration

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 reevaluated periodically as clinically appropriate (e.g., 3-month to 6-month intervals) to determine if treatment is still necessary (see BOXED WARNINGS and 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.

Patients should be started at the lowest dose for the indication.

1. For treatment of moderate to severe vasomotor symptoms, vulval and vaginal atrophy associated with the menopause, the lowest dose and regimen that will control symptoms should be chosen and medication should be discontinued as promptly as possible.

Attempts to discontinue or taper medication should be made at 3-month to 6-month intervals. The usual initial dosage range is 1 to 2 mg daily of Estradiol adjusted as necessary to control presenting symptoms. The minimal effective dose for maintenance therapy should be determined by titration. Administration should be cyclic (e.g., 3 weeks on and 1 week off).

2. For treatment of female hypoestrogenism due to hypogonadism, castration, or primary ovarian failure.

Treatment is usually initiated with a dose of 1 to 2 mg daily of Estradiol, adjusted as necessary to control presenting symptoms; the minimal effective dose for maintenance therapy should be determined by titration.

3. For treatment of breast cancer, for palliation only, in appropriately selected women and men with metastatic disease.

Suggested dosage is 10 mg three times daily for a period of at least three months.

4. For treatment of advanced androgen-dependent carcinoma of the prostate, for palliation only.

Suggested dosage is 1 to 2 mg three times daily. The effectiveness of therapy can be judged by phosphatase determinations as well as by symptomatic improvement of the patient.

5. For prevention of osteoporosis.

When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should be considered only for women at significant risk of osteoporosis and for whom non-estrogen medications are not considered to be appropriate.

The lowest effective dose of Estradiol has not been determined.

How Supplied:

Estradiol Tablets USP are available as:

0.5 mg:

White to off-white, oval, flat-faced, beveled-edge, scored tablet. Debossed with 899 / ½ on the scored side and stylized b on the other side, packaged in bottles of 100.

1 mg:

Light purple, oval, flat-faced, beveled-edge, scored tablet. Debossed with 886 / 1 on the scored side and stylized b on the other side, packaged in

Broncoten

Broncoten may be available in the countries listed below.

Ingredient matches for Broncoten

Ketotifen

Ketotifen fumarate (a derivative of Ketotifen) is reported as an ingredient of Broncoten in the following countries:

• Brazil

International Drug Name Search

Moxatag

Moxatag is a brand name of amoxicillin, approved by the FDA in the following formulation(s):

MOXATAG (amoxicillin - tablet, extended release; oral)

• 
  Manufacturer: SHIONOGI INC
  
  Approval date: January 23, 2008
  
  Strength(s): 775MG ^[RLD]

Has a generic version of Moxatag been approved?

No. There is currently no therapeutically equivalent version of Moxatag available.

Note: Fraudulent online pharmacies may attempt to sell an illegal generic version of Moxatag. These medications may be counterfeit and potentially unsafe. If you purchase medications online, be sure you are buying from a reputable and valid online pharmacy. Ask your health care provider for advice if you are unsure about the online purchase of any medication.

See also: About generic drugs.

Related Patents

Patents are granted by the U.S. Patent and Trademark Office at any time during a drug's development and may include a wide range of claims.

• 
  Antibiotic product, use and formulation thereof
  Patent 6,544,555
  Issued: April 8, 2003
  Inventor(s): Edward M.; Rudnic & James D.; Isbister & Donald J.; Treacy, Jr. & Sandra E.; Wassink
  Assignee(s): Advancis Pharmaceutical Corp.
  An antibiotic product is comprised of at least three dosages forms, each of which has a different release profile, with the Cmax for the antibiotic product being reached in less than about twelve hours. In one embodiment, there is an immediate release dosage form, as well as two or more delayed release dosage forms, with each of the dosage forms having a different release profile, wherein each reaches a Cmax at different times.
  
  Patent expiration dates:
  
  
  • October 13, 2020
    
    ✓ 
    Patent use: METHOD OF TREATING TONSILLITIS AND/OR PHARYNGITIS SECONDARY TO STREPTOCOCCUS PYOGENES IN A ONCE-A-DAY AMOXICILLIN PRODUCT
    ✓ 
    Drug substance
    ✓ 
    Drug product
  
  



• 
  Antibiotic product, use and formulation thereof
  Patent 6,669,948
  Issued: December 30, 2003
  Inventor(s): Edward M.; Rudnic & James D.; Isbister & Donald J.; Treacy, Jr. & Sandra E.; Wassink
  Assignee(s): Advancis Pharmaceutical Corp.
  An antibiotic product, in particular a betalactam such as cephalosporin (in particular cefuroxime and/or cefpodoxime) or a penicillin (in particular axmoxicillin or dicloxacillin) is comprised of at least three dosages forms, each of which has a different release profile, with the Cmax for the antibiotic product being reached in less than about twelve hours. In one embodiment, there is an immediate release dosage form, as well as two or more delayed release dosage forms, with each of the dosage forms having a different release profile, wherein each reaches a Cmax at different times.
  
  Patent expiration dates:
  
  
  • October 13, 2020
    
    ✓ 
    Patent use: METHOD OF TREATING TONSILLITIS AND/OR PHARYNGITIS SECONDARY TO STREPTOCOCCUS PYOGENES IN A ONCE-A-DAY AMOXICILLIN PRODUCT
    ✓ 
    Drug substance
    ✓ 
    Drug product
  
  



• 
  Antibiotic product, use and formulation thereof
  Patent 6,723,341
  Issued: April 20, 2004
  Inventor(s): Edward M.; Rudnic & James D.; Isbister & Donald J.; Treacy, Jr. & Sandra E.; Wassink
  Assignee(s): Advancis Pharmaceutical Corp.
  An antibiotic product is comprised of at least three dosages forms, each of which has a different release profile, with the Cmax for the antibiotic product being reached in less than about twelve hours. In one embodiment, there is an immediate release dosage form, as well as two or more delayed release dosage forms, with each of the dosage forms having a different release profile, wherein each reaches a Cmax at different times.
  
  Patent expiration dates:
  
  
  • October 13, 2020
    
    ✓ 
    Patent use: METHOD OF TREATING TONSILLITIS AND/OR PHARYNGITIS SECONDARY TO STREPTOCOCCUS PYOGENES IN A ONCE-A-DAY AMOXICILLIN PRODUCT
    ✓ 
    Drug substance
    ✓ 
    Drug product
  
  

See also...

• Moxatag Consumer Information (Drugs.com)
• Moxatag Extended-Release Tablets Consumer Information (Wolters Kluwer)
• Moxatag Consumer Information (Cerner Multum)
• Amoxicillin Consumer Information (Drugs.com)
• Amoxicillin Consumer Information (Wolters Kluwer)
• Amoxicillin Capsules Consumer Information (Wolters Kluwer)
• Amoxicillin Chewable Tablets Consumer Information (Wolters Kluwer)
• Amoxicillin Drops Consumer Information (Wolters Kluwer)
• Amoxicillin Extended-Release Tablets Consumer Information (Wolters Kluwer)
• Amoxicillin Suspension Consumer Information (Wolters Kluwer)
• Amoxicillin Consumer Information (Cerner Multum)
• Amoxicillin AHFS DI Monographs (ASHP)

Papaveryl

Papaveryl may be available in the countries listed below.

Ingredient matches for Papaveryl

Papaverine

Papaverine hydrochloride (a derivative of Papaverine) is reported as an ingredient of Papaveryl in the following countries:

• Venezuela

International Drug Name Search

Gemlipid

Gemlipid may be available in the countries listed below.

Ingredient matches for Gemlipid

Gemfibrozil

Gemfibrozil is reported as an ingredient of Gemlipid in the following countries:

• Italy

International Drug Name Search

Ceforan

Ceforan may be available in the countries listed below.

Ingredient matches for Ceforan

Cefadroxil

Cefadroxil is reported as an ingredient of Ceforan in the following countries:

• Romania

Cefotaxime

Cefotaxime is reported as an ingredient of Ceforan in the following countries:

• Ethiopia

Cefotaxime sodium salt (a derivative of Cefotaxime) is reported as an ingredient of Ceforan in the following countries:

• Vietnam

Ciprofloxacin

Ciprofloxacin is reported as an ingredient of Ceforan in the following countries:

• Bangladesh

International Drug Name Search

isradipine

is-RAD-i-peen

Commonly used brand name(s)

In the U.S.

• Dynacirc


• Dynacirc CR

Available Dosage Forms:

• Tablet


• Tablet, Extended Release


• Capsule

Therapeutic Class: Cardiovascular Agent

Pharmacologic Class: Calcium Channel Blocker

Chemical Class: Dihydropyridine

Uses For isradipine

Isradipine is used alone or together with other medicines (such as hydrochlorothiazide) to treat high blood pressure (hypertension). High blood pressure adds to the workload of the heart and arteries. If it continues for a long time, the heart and arteries may not function properly. This can damage the blood vessels of the brain, heart, and kidneys, resulting in a stroke, heart failure, or kidney failure. High blood pressure may also increase the risk of heart attacks. These problems may be less likely to occur if blood pressure is controlled .

Isradipine is a calcium channel blocker. It works by affecting the movement of calcium into the cells of the heart and blood vessels. As a result, isradipine relaxes blood vessels and increases the supply of blood and oxygen to the heart while reducing its workload .

isradipine is available only with your doctor's prescription .

Before Using isradipine

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For isradipine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to isradipine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of isradipine in the pediatric population. Safety and efficacy have not been established .

Geriatric

Appropriate studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of isradipine in the elderly. However, elderly patients are more likely to have liver or kidney problems which may require an adjustment of dose in patients receiving isradipine .

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	C	Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking isradipine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using isradipine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Bepridil


• Cisapride


• Levomethadyl


• Mefloquine


• Mesoridazine


• Pimozide


• Thioridazine


• Ziprasidone

Using isradipine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Acecainide


• Acetophenazine


• Ajmaline


• Amiodarone


• Amisulpride


• Amitriptyline


• Amoxapine


• Aprindine


• Arsenic Trioxide


• Astemizole


• Azimilide


• Bretylium


• Chloral Hydrate


• Chloroquine


• Chlorpromazine


• Clarithromycin


• Dantrolene


• Desipramine


• Dibenzepin


• Disopyramide


• Dofetilide


• Dolasetron


• Doxepin


• Droperidol


• Encainide


• Enflurane


• Erythromycin


• Ethopropazine


• Flecainide


• Fluconazole


• Fluoxetine


• Fluphenazine


• Foscarnet


• Gemifloxacin


• Halofantrine


• Haloperidol


• Halothane


• Hydroquinidine


• Ibutilide


• Imipramine


• Isoflurane


• Lidoflazine


• Lorcainide


• Methotrimeprazine


• Nortriptyline


• Octreotide


• Ondansetron


• Pentamidine


• Perphenazine


• Pipotiazine


• Pirmenol


• Prajmaline


• Probucol


• Procainamide


• Prochlorperazine


• Promazine


• Promethazine


• Propafenone


• Propiomazine


• Protriptyline


• Quetiapine


• Quinidine


• Risperidone


• Sematilide


• Sertindole


• Sotalol


• Spiramycin


• Sulfamethoxazole


• Sultopride


• Tedisamil


• Telithromycin


• Terfenadine


• Thiethylperazine


• Trifluoperazine


• Triflupromazine


• Trimeprazine


• Trimethoprim


• Trimipramine


• Vasopressin


• Zolmitriptan


• Zotepine

Using isradipine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Amprenavir


• Dalfopristin


• Indinavir


• Itraconazole


• Ketoconazole


• Magnesium


• Quinupristin


• Rifampin


• Rifapentine


• St John's Wort

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of isradipine. Make sure you tell your doctor if you have any other medical problems, especially:

• Bowel blockage or


• Congestive heart failure—Use with caution. May make these conditions worse .

• Kidney disease or


• Liver disease—Use with caution. The effects of isradipine may be increased because of the slower removal of the medicine from the body .

Proper Use of isradipine

In addition to the use of isradipine, treatment for your high blood pressure may include weight control and changes in the types of foods you eat, especially foods high in sodium. Your doctor will tell you which of these are most important for you. You should check with your doctor before changing your diet .

Many patients who have high blood pressure will not notice any signs of the problem. In fact, many may feel normal. It is very important that you take your medicine exactly as directed and that you keep your appointments with your doctor even if you feel well .

Remember that isradipine will not cure your high blood pressure, but it does help control it. You must continue to take it as directed if you expect to lower your blood pressure and keep it down. You may have to take high blood pressure medicine for the rest of your life. If high blood pressure is not treated, it can cause serious problems such as heart failure, blood vessel disease, stroke, or kidney disease .

Swallow the extended-release tablet whole with a full glass of water. Do not break, crush, or chew it .

If you are taking the extended-release tablets, part of the tablet may pass into your stools after your body has absorbed the medicine. This is normal and is nothing to worry about .

Dosing

The dose of isradipine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of isradipine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For high blood pressure:
  
  • For oral dosage form (capsules):
    
    • Adults—At first, 2.5 milligrams (mg) twice a day. Your doctor may increase your dose if needed.
    
    
    • Children—Use and dose must be determined by your doctor .
    
    
  
  
  • For oral dosage form (extended-release tablets):
    
    • Adults—At first, 5 milligrams (mg) once a day. Your doctor may increase your dose if needed.
    
    
    • Children—Use and dose must be determined by your doctor .
    
    
  
  

Missed Dose

If you miss a dose of isradipine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Precautions While Using isradipine

It is very important that your doctor check your progress at regular visits to make sure isradipine is working properly and to check for unwanted effects .

Low blood pressure (hypotension) may occur while taking isradipine. Check with your doctor right away if you have the following symptoms: blurred vision; confusion; severe dizziness, faintness, or lightheadedness when getting up from a lying or sitting position suddenly; sweating; or unusual tiredness or weakness .

isradipine may cause fluid retention (edema) in some patients. Tell your doctor right away if you have bloating or swelling of face, arms, hands, lower legs, or feet; tingling of hands or feet; or unusual weight gain or loss .

isradipine Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

More common

• Bloating or swelling of face, arms, hands, lower legs, or feet


• tingling of hands or feet


• unusual weight gain or loss

Less common

• Chest pain


• difficult or labored breathing


• dizziness


• fast, irregular, pounding, or racing heartbeat or pulse


• feeling of warmth


• full or bloated feeling


• nausea


• pressure in the stomach


• redness of the face, neck, arms and occasionally, upper chest


• shortness of breath


• swelling of abdominal or stomach area


• tightness in chest


• unusual tiredness or weakness


• vomiting


• wheezing

Get emergency help immediately if any of the following symptoms of overdose occur:

Symptoms of Overdose

• Blurred vision


• confusion


• dizziness, faintness, or lightheadedness when getting up from a lying or sitting position suddenly


• flushing


• sweating

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• Headache

Less common

• Diarrhea


• difficulty having a bowel movement (stool)


• rash


• stomach soreness or discomfort

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

See also: isradipine side effects (in more detail)

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

More isradipine resources

• Isradipine Side Effects (in more detail)
• Isradipine Use in Pregnancy & Breastfeeding
• Drug Images
• Isradipine Drug Interactions
• Isradipine Support Group
• 1 Review for Isradipine - Add your own review/rating

• isradipine Concise Consumer Information (Cerner Multum)


• Isradipine Prescribing Information (FDA)


• Isradipine MedFacts Consumer Leaflet (Wolters Kluwer)


• Isradipine Professional Patient Advice (Wolters Kluwer)


• Isradipine Monograph (AHFS DI)


• DynaCirc Prescribing Information (FDA)


• DynaCirc CR Extended-Release Tablets MedFacts Consumer Leaflet (Wolters Kluwer)


• DynaCirc CR Prescribing Information (FDA)

Compare isradipine with other medications

• Angina Pectoris Prophylaxis
• High Blood Pressure
• Raynaud's Syndrome

idursulfase

Generic Name: idursulfase (EYE dur SUL fase)

Brand Names: Elaprase

What is idursulfase?

Idursulfase is used to treat some of the symptoms of a genetic condition called Hunter's syndrome. Hunter syndrome is also called mucopolysaccharidosis (MYOO-koe-pol-ee-SAK-a-rye-DOE-sis).

Hunter syndrome is a metabolic disorder in which the body lacks the enzyme needed to break down certain sugars and proteins. These substances can build up in the body, causing enlarged organs, abnormal bone structure, changes in facial features, breathing problems, heart problems, vision loss, and changes in mental or physical abilities.

Idursulfase may improve walking ability in people with this condition. However, this medication is not a cure for Hunter syndrome.

Idursulfase may also be used for purposes not listed in this medication guide.

What is the most important information I should know about idursulfase?

Idursulfase may improve walking ability in people with Hunter syndrome. However, idursulfase is not a cure for this condition. Some people receiving an idursulfase injection have had a reaction to the infusion (when the medicine is injected into the vein). Tell your caregiver right away if you feel dizzy, light-headed, or have hives, seizure (convulsions), trouble breathing, or swelling of your face, lips, tongue, or throat.

It may still be possible for you to receive idursulfase even after you have had a reaction to it. There are other medications that can be given to you before your idursulfase infusion to help prevent any reaction symptoms.

You may be more likely to have a reaction to idursulfase if you have a breathing disorder. Tell your doctor if you have asthma or other lung disease.

Your name may need to be listed on a Hunter Outcome Survey while you are using this medication. The purpose of this registry is to track the progression of this disorder and the effects that idursulfase has on long-term treatment of Hunter syndrome.

What should I discuss with my health care provider before receiving idursulfase?

You should not receive this medication if you are allergic to idursulfase.

Before receiving idursulfase, tell your doctor if you are allergic to any drugs, or if you have asthma or other breathing disorder.

You may be more likely to have a reaction to idursulfase if you have a breathing disorder. You may need to receive other medications to prevent an symptoms of a reaction to idursulfase. Follow your doctor's instructions.

Your name may need to be listed on a Hunter Outcome Survey while you are using this medication. The purpose of this registry is to track the progression of this disorder and the effects that idursulfase has on long-term treatment of Hunter syndrome.

FDA pregnancy category C. This medication may be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment. It is not known whether idursulfase passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

How is idursulfase given?

Idursulfase is given as an injection through a needle placed into a vein. You will most likely receive this injection in a clinic or hospital setting. Idursulfase is usually given once per week.

The medicine must be given slowly through an IV infusion, and can take up to 3 hours to complete.

What happens if I miss a dose?

Call your doctor if you miss an appointment for your idursulfase injection.

What happens if I overdose?

Seek emergency medical attention if you think you have received too much of this medicine.

Symptoms of an idursulfase overdose are not known.

What should I avoid while receiving idursulfase?

Follow your doctor's instructions about any restrictions on food, beverages, or activity while you are receiving idursulfase.

Idursulfase side effects

Some people receiving a idursulfase injection have had a reaction to the infusion (when the medicine is injected into the vein). Tell your caregiver right away if you feel dizzy, light-headed, or have hives, seizure (convulsions), trouble breathing, or swelling of your face, lips, tongue, or throat.

It may still be possible for you to receive idursulfase even after you have had a reaction to it. There are other medications that can be given to you before your idursulfase infusion to help prevent any reaction symptoms.

Call your doctor at once if you have any of these serious side effects:

• 
  

  worsened asthma;

  
  


• 
  

  uneven heartbeats;

  
  


• 
  

  blue lips or fingernails;

  
  


• 
  

  fever;

  
  


• 
  

  vision problems; or

  
  


• 
  

  increased blood pressure (severe headache, blurred vision, trouble concentrating, chest pain, numbness, seizure).

  
  

Less serious side effects may include:

• 
  

  joint pain;

  
  


• 
  

  pain in your arms or legs;

  
  


• 
  

  headache;

  
  


• 
  

  itching, mild skin rash; or

  
  


• 
  

  weakness.

  
  

This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.

Idursulfase Dosing Information

Usual Adult Dose for Mucopolysaccharidosis Type II:

Recommended dose: 0.5 mg/kg of body weight every week administered as an intravenous infusion

Usual Pediatric Dose for Mucopolysaccharidosis Type II:

>= 5 years old
Recommended dose: 0.5 mg/kg of body weight every week administered as an intravenous infusion

What other drugs will affect idursulfase?

There may be other drugs that can interact with idursulfase. Tell your doctor about all your prescription and over-the-counter medications, vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start a new medication without telling your doctor.

More idursulfase resources

• Idursulfase Side Effects (in more detail)
• Idursulfase Dosage
• Idursulfase Use in Pregnancy & Breastfeeding
• Idursulfase Support Group
• 0 Reviews for Idursulfase - Add your own review/rating

• idursulfase Intravenous Advanced Consumer (Micromedex) - Includes Dosage Information


• Idursulfase Professional Patient Advice (Wolters Kluwer)


• Idursulfase MedFacts Consumer Leaflet (Wolters Kluwer)


• Idursulfase Monograph (AHFS DI)


• Elaprase Prescribing Information (FDA)


• Elaprase Consumer Overview

Compare idursulfase with other medications

• Mucopolysaccharidosis Type II

Where can I get more information?

• Your doctor or pharmacist can provide more information about idursulfase.

See also: idursulfase side effects (in more detail)

Ipramol Teva

Ipramol Teva may be available in the countries listed below.

Ingredient matches for Ipramol Teva

Ipratropium

Ipratropium Bromide monohydrate (a derivative of Ipratropium Bromide) is reported as an ingredient of Ipramol Teva in the following countries:

• Germany

Salbutamol

Salbutamol sulfate (a derivative of Salbutamol) is reported as an ingredient of Ipramol Teva in the following countries:

• Germany

International Drug Name Search

Chlorure de Potassium Biosedra

Chlorure de Potassium Biosedra may be available in the countries listed below.

Ingredient matches for Chlorure de Potassium Biosedra

Potassium Chloride

Potassium Chloride is reported as an ingredient of Chlorure de Potassium Biosedra in the following countries:

• France

International Drug Name Search

Adenosina Biol

Adenosina Biol may be available in the countries listed below.

Ingredient matches for Adenosina Biol

Adenosine

Adenosine is reported as an ingredient of Adenosina Biol in the following countries:

• Argentina

International Drug Name Search

Jutamox

Jutamox may be available in the countries listed below.

Ingredient matches for Jutamox

Amoxicillin

Amoxicillin trihydrate (a derivative of Amoxicillin) is reported as an ingredient of Jutamox in the following countries:

• Germany

International Drug Name Search

Cerivin

Cerivin may be available in the countries listed below.

Ingredient matches for Cerivin

Vinpocetine

Vinpocetine is reported as an ingredient of Cerivin in the following countries:

• Bangladesh

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Epoprostenol

FULL PRESCRIBING INFORMATION

Indications and Usage for Epoprostenol

Epoprostenol is indicated for:

• the long-term intravenous treatment of primary pulmonary hypertension


• and pulmonary hypertension associated with the scleroderma spectrum of disease in NYHA Class III and Class IV patients who do not respond adequately to conventional therapy


• [see CLINICAL STUDIES: Clinical Trials in Pulmonary Hypertension (14.1)].

Epoprostenol Dosage and Administration

Important Note: Epoprostenol for Injection must be reconstituted only as directed with Sterile Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP. Reconstituted solutions of Epoprostenol for Injection must not be diluted or administered with other parenteral solutions or medications [see WARNINGS AND PRECAUTIONS: General (5.1)].

Dosage

Continuous chronic infusion of Epoprostenol should be prepared as directed [see Reconstitution (2.4)], and administered through a central venous catheter. Temporary peripheral intravenous infusion may be used until central access is established. Chronic infusion of Epoprostenol should be initiated at 2 ng/kg/min and increased in increments of 2 ng/kg/min every 15 minutes or longer until dose-limiting pharmacologic effects are elicited or until a tolerance limit to the drug is established or further increases in the infusion rate are not clinically warranted [see Dosage Adjustments (2.2)]. If dose-limiting pharmacologic effects occur, then the infusion rate should be decreased to the point that the pharmacologic effects of Epoprostenol are tolerated. In clinical trials, the most common dose-limiting adverse events were nausea, vomiting, hypotension, sepsis, headache, abdominal pain, or respiratory disorder (most treatment-limiting adverse events were not serious). If the initial infusion rate of 2 ng/kg/min is not tolerated, use a lower dose.

In the controlled 12-week trial in PH/SSD, for example, the dose increased from a mean starting dose of 2.2 ng/kg/min. During the first 7 days of treatment, the dose was increased daily to a mean dose of 4.1 ng/kg/min on day 7 of treatment. At the end of week 12, the mean dose was 11.2 ng/kg/min. The mean incremental increase was 2 to 3 ng/kg/min every 3 weeks.

Dosage Adjustments

Changes in the chronic infusion rate should be based on persistence, recurrence, or worsening of the patient's symptoms of pulmonary hypertension and the occurrence of adverse events due to excessive doses of Epoprostenol. In general, increases in dose from the initial chronic dose should be expected.

Increments in dose should be considered if symptoms of pulmonary hypertension persist or recur after improving. The infusion should be increased by 1- to 2-ng/kg/min increments at intervals sufficient to allow assessment of clinical response; these intervals should be at least 15 minutes. In clinical trials, incremental increases in dose occurred at intervals of 24 to 48 hours or longer. Following establishment of a new chronic infusion rate, the patient should be observed, and standing and supine blood pressure and heart rate monitored for several hours to ensure that the new dose is tolerated.

During chronic infusion, the occurrence of dose-limiting pharmacological events may necessitate a decrease in infusion rate, but the adverse event may occasionally resolve without dosage adjustment. Dosage decreases should be made gradually in 2-ng/kg/min decrements every 15 minutes or longer until the dose-limiting effects resolve. Abrupt withdrawal of Epoprostenol or sudden large reductions in infusion rates should be avoided. Except in life-threatening situations (e.g., unconsciousness, collapse, etc.), infusion rates of Epoprostenol should be adjusted only under the direction of a physician.

In patients receiving lung transplants, doses of Epoprostenol were tapered after the initiation of cardiopulmonary bypass.

Administration

Epoprostenol for Injection, once prepared as directed [see Reconstitution (2.4)], is administered by continuous intravenous infusion via a central venous catheter using an ambulatory infusion pump. During initiation of treatment, Epoprostenol may be administered peripherally.

The ambulatory infusion pump used to administer Epoprostenol should: (1) be small and lightweight, (2) be able to adjust infusion rates in 2-ng/kg/min increments, (3) have occlusion, end-of-infusion, and low-battery alarms, (4) be accurate to ±6% of the programmed rate, and (5) be positive pressure-driven (continuous or pulsatile) with intervals between pulses not exceeding 3 minutes at infusion rates used to deliver Epoprostenol. The reservoir should be made of polyvinyl chloride, polypropylene, or glass. The infusion pump used in the most recent clinical trials was the CADD-1 HFX 5100 (SIMS Deltec). A 60-inch microbore non-DEHP extension set with proximal antisyphon valve, low priming volume (0.9 mL), and in-line 0.22 micron filter was used during clinical trials.

To avoid potential interruptions in drug delivery, the patient should have access to a backup infusion pump and intravenous infusion sets. A multi-lumen catheter should be considered if other intravenous therapies are routinely administered.

Reconstitution

Epoprostenol for Injection is stable only when reconstituted as directed using Sterile Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP. Epoprostenol for Injection must not be reconstituted or mixed with any other parenteral medications or solutions prior to or during administration.

Prior to use, Epoprostenol for Injection solutions reconstituted with 5 mL diluent must be protected from light and can be refrigerated at 2° to 8°C (36° to 46°F) for as long as 5 days or held at up to 25°C (77°F) for up to 48 hours prior to use. Do not freeze reconstituted solutions of Epoprostenol for Injection. Discard any reconstituted solution that has been frozen. Discard any reconstituted solution if it has been refrigerated for more than 5 days, or if held at room temperature for more than 48 hours.

During use, a single reservoir of diluted solution of Epoprostenol for Injection prepared as directed can be administered at room temperature for up to 24 hours. (If lower concentrations are chosen, pump reservoirs should be changed every 12 hours when administered at room temperature.) Do not expose this solution to direct sunlight.

A concentration for the solution of Epoprostenol should be selected that is compatible with the infusion pump being used with respect to minimum and maximum flow rates, reservoir capacity, and the infusion pump criteria listed above. Epoprostenol, when administered chronically, should be prepared in a drug delivery reservoir appropriate for the infusion pump. Outlined in Table 1 are directions for preparing different concentrations of Epoprostenol for up to a 24-hour period.

Table 1: Reconstitution and Dilution Instructions

To make 100 mL of solution with Final Concentration (ng/mL) of:	Directions:
* Higher concentrations may be prepared for patients who receive Epoprostenol long-term.
15,000 ng/mL*	Dissolve contents of one 1.5 mg vial with 5 mL of Sterile Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP. Withdraw entire vial contents and add to a sufficient volume of the identical diluent to make a total of 100 mL.
30,000 ng/mL*	Dissolve contents of two 1.5 mg vials each with 5 mL of Sterile Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP. Withdraw entire vial contents and add to a sufficient volume of the identical diluent to make a total of 100 mL.

Infusion rates may be calculated using the following formula:

Infusion Rate (mL/hr) =	[Dose (ng/kg/min) × Weight (kg) × 60 min/hr]
	Final Concentration (ng/mL)

Tables 2 and 3 provide infusion delivery rates for doses up to 16 ng/kg/min based upon patient weight, drug delivery rate, and concentration of the solution of Epoprostenol to be used. These tables may be used to select the most appropriate concentration of Epoprostenol that will result in an infusion rate between the minimum and maximum flow rates of the infusion pump and that will allow the desired duration of infusion from a given reservoir volume. For infusion/dose rates lower than those listed in Tables 2 and 3, it is recommended that the pump rate be set by a healthcare professional such that steady state is achieved in the patient, keeping in mind the half life of Epoprostenol is no more than six minutes. Higher infusion rates, and therefore, more concentrated solutions may be necessary with long-term administration of Epoprostenol. If lower concentrations are chosen, pump reservoirs should be changed every 12 hours when administered at room temperature.

Table 2: Infusion Rates for Epoprostenol at a Concentration of 15,000 ng/mL

	Dose or Drug Delivery Rate (ng/kg/min)
Patient weight (kg)	4	6	8	10	12	14	16
	Infusion Delivery Rate (mL/hr)
20	---	---	---	---	1.0	1.1	1.3
30	---	---	1.0	1.2	1.4	1.7	1.9
40	---	1.0	1.3	1.6	1.9	2.2	2.6
50	---	1.2	1.6	2.0	2.4	2.8	3.2
60	1.0	1.4	1.9	2.4	2.9	3.4	3.8
70	1.1	1.7	2.2	2.8	3.4	3.9	4.5
80	1.3	1.9	2.6	3.2	3.8	4.5	5.1
90	1.4	2.2	2.9	3.6	4.3	5.0	5.8
100	1.6	2.4	3.2	4.0	4.8	5.6	6.4

Table 3: Infusion Rates for Epoprostenol at a Concentration of 30,000 ng/mL

Dose or Drug Delivery Rate (ng/kg/min)
Patient weight (kg)	6	8	10	12	14	16
30	---	---	---	---	---	1.0
40	---	---	---	1.0	1.1	1.3
50	---	---	1.0	1.2	1.4	1.6
60	---	1.0	1.2	1.4	1.7	1.9
70	---	1.1	1.4	1.7	2.0	2.2
80	1.0	1.3	1.6	1.9	2.2	2.6
90	1.1	1.4	1.8	2.2	2.5	2.9
100	1.2	1.6	2.0	2.4	2.8	3.2

Dosage Forms and Strengths

Epoprostenol for Injection contains Epoprostenol sodium equivalent to 1.5 mg (1,500,000 ng) Epoprostenol and is supplied as a sterile lyophilized material in a 10 mL vial with a red flip-off seal.

Contraindications

A large study evaluating the effect of Epoprostenol on survival in NYHA Class III and IV patients with congestive heart failure due to severe left ventricular systolic dysfunction was terminated after an interim analysis of 471 patients revealed a higher mortality in patients receiving Epoprostenol plus conventional therapy than in those receiving conventional therapy alone. The chronic use of Epoprostenol in patients with congestive heart failure due to severe left ventricular systolic dysfunction is therefore contraindicated.

Some patients with pulmonary hypertension have developed pulmonary edema during dose initiation, which may be associated with pulmonary veno-occlusive disease. Epoprostenol should not be used chronically in patients who develop pulmonary edema during dose initiation.

Epoprostenol is also contraindicated in patients with known hypersensitivity to the drug or to structurally related compounds.

Warnings and Precautions

General

Epoprostenol for Injection must be reconstituted only as directed using Sterile Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP. Epoprostenol for Injection must not be reconstituted or mixed with any other parenteral medications or solutions prior to or during administration. [See Reconstitution (2.4)]

Epoprostenol should be used only by clinicians experienced in the diagnosis and treatment of pulmonary hypertension. The diagnosis of pulmonary hypertension should be carefully established.

Dose Initiation

Epoprostenol is a potent pulmonary and systemic vasodilator. Dose initiation with Epoprostenol must be performed in a setting with adequate personnel and equipment for physiologic monitoring and emergency care. Dose initiation in controlled PPH clinical trials was performed during right heart catheterization. In clinical trials, dose initiation was performed without cardiac catheterization. The risk of cardiac catheterization in patients with pulmonary hypertension should be carefully weighed against the potential benefits. During dose initiation, asymptomatic increases in pulmonary artery pressure coincident with increases in cardiac output occurred rarely. In such cases, dose reduction should be considered, but such an increase does not imply that chronic treatment is contraindicated.

Chronic Use and Dose Adjustment

During chronic use, Epoprostenol is delivered continuously on an ambulatory basis through a permanent indwelling central venous catheter. Unless contraindicated, anticoagulant therapy should be administered to PPH and PH/SSD patients receiving Epoprostenol to reduce the risk of pulmonary thromboembolism or systemic embolism through a patent foramen ovale. In order to reduce the risk of infection, aseptic technique must be used in the reconstitution and administration of Epoprostenol as well as in routine catheter care. Because Epoprostenol is metabolized rapidly, even brief interruptions in the delivery of Epoprostenol may result in symptoms associated with rebound pulmonary hypertension including dyspnea, dizziness, and asthenia. The decision to initiate therapy with Epoprostenol should be based upon the understanding that there is a high likelihood that intravenous therapy with Epoprostenol will be needed indefinitely, and the patient's ability to accept and care for a permanent intravenous catheter and infusion pump should be carefully considered.

Based on clinical trials, the acute hemodynamic response (reduction in pulmonary artery resistance) to Epoprostenol did not correlate well with improvement in exercise tolerance or survival during chronic use of Epoprostenol. Dosage of Epoprostenol during chronic use should be adjusted at the first sign of recurrence or worsening of symptoms attributable to pulmonary hypertension or the occurrence of adverse events associated with Epoprostenol [see DOSAGE AND ADMINISTRATION (2)]. Following dosage adjustments, standing and supine blood pressure and heart rate should be monitored closely for several hours.

Withdrawal Effects

Abrupt withdrawal (including interruptions in drug delivery) or sudden large reductions in dosage of Epoprostenol may result in symptoms associated with rebound pulmonary hypertension, including dyspnea, dizziness, and asthenia. In clinical trials, one Class III primary pulmonary hypertension patient's death was judged attributable to the interruption of Epoprostenol. Abrupt withdrawal should be avoided.

Sepsis

See ADVERSE REACTIONS, Adverse Events Attributable to the Drug Delivery System (6.1).

Adverse Reactions

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

During clinical trials, adverse events were classified as follows: (1) adverse events during dose initiation and escalation, (2) adverse events during chronic dosing, and (3) adverse events associated with the drug delivery system.

Adverse Events During Dose Initiation and Escalation

During early clinical trials, Epoprostenol was increased in 2-ng/kg/min increments until the patients developed symptomatic intolerance. The most common adverse events and the adverse events that limited further increases in dose were generally related to vasodilation, the major pharmacologic effect of Epoprostenol. The most common dose-limiting adverse events (occurring in ≥1% of patients) were nausea, vomiting, headache, hypotension, and flushing, but also include chest pain, anxiety, dizziness, bradycardia, dyspnea, abdominal pain, musculoskeletal pain, and tachycardia. Table 4 lists the adverse events reported during dose initiation and escalation in decreasing order of frequency.

Table 4: Adverse Events During Dose Initiation and Escalation

Adverse Events Occurring in ≥1% of Patients	Epoprostenol (n = 391)
Flushing	58%
Headache	49%
Nausea/vomiting	32%
Hypotension	16%
Anxiety, nervousness, agitation	11%
Chest pain	11%
Dizziness	8%
Bradycardia	5%
Abdominal pain	5%
Musculoskeletal pain	3%
Dyspnea	2%
Back pain	2%
Sweating	1%
Dyspepsia	1%
Hypesthesia/paresthesia	1%
Tachycardia	1%

Adverse Events During Chronic Administration for PPH

Interpretation of adverse events is complicated by the clinical features of PPH and PH/SSD, which are similar to some of the pharmacologic effects of Epoprostenol (e.g., dizziness, syncope). Adverse events probably related to the underlying disease include dyspnea, fatigue, chest pain, edema, hypoxia, right ventricular failure, and pallor. Several adverse events, on the other hand, can clearly be attributed to Epoprostenol. These include headache, jaw pain, flushing, diarrhea, nausea and vomiting, flu-like symptoms, and anxiety/nervousness.

In an effort to separate the adverse effects of the drug from the adverse effects of the underlying disease, Table 5 lists adverse events that occurred at a rate at least 10% different in the 2 groups in controlled trials for PPH.

Table 5: Adverse Events Regardless of Attributions Occurring in Patients With PPH With ≥ 10% Difference Between Epoprostenol and Conventional Therapy Alone

Adverse Event	Epoprostenol (n = 52)	Conventional Therapy (n = 54)
Occurrence More Common With Epoprostenol
General
Chills/fever/sepsis/flu-like symptoms	25%	11%
Cardiovascular
Tachycardia	35%	24%
Flushing	42%	2%
Gastrointestinal
Diarrhea	37%	6%
Nausea/vomiting	67%	48%
Musculoskeletal
Jaw pain	54%	0%
Myalgia	44%	31%
Nonspecific musculoskeletal pain	35%	15%
Neurological
Anxiety/nervousness/tremor	21%	9%
Dizziness	83%	70%
Headache	83%	33%
Hypesthesia, hyperesthesia, paresthesia	12%	2%
Occurrence More Common With Standard Therapy
Cardiovascular
Heart failure	31%	52%
Syncope	13%	24%
Shock	0%	13%
Respiratory
Hypoxia	25%	37%

Thrombocytopenia has been reported during uncontrolled clinical trials in patients receiving Epoprostenol.

Table 6 lists additional adverse events reported in PPH patients receiving Epoprostenol plus conventional therapy or conventional therapy alone during controlled clinical trials.

Table 6: Adverse Events Regardless of Attribution Occurring In Patients with PPH With <10% Difference between Epoprostenol and Conventional Therapy

Adverse Event	Epoprostenol (n = 52)	Conventional Therapy (n = 54)
General
Asthenia	87%	81%
Cardiovascular
Angina pectoris	19%	20%
Arrhythmia	27%	20%
Bradycardia	15%	9%
Supraventricular tachycardia	8%	0%
Pallor	21%	30%
Cyanosis	31%	39%
Palpitation	63%	61%
Cerebrovascular accident	4%	0%
Hemorrhage	19%	11%
Hypotension	27%	31%
Myocardial ischemia	2%	6%
Gastrointestinal
Abdominal Pain	27%	31%
Anorexia	25%	30%
Ascites	12%	17%
Constipation	6%	2%
Metabolic
Edema	60%	63%
Hypokalemia	6%	4%
Weight reduction	27%	24%
Weight gain	6%	4%
Musculoskeletal
Arthralgia	6%	0%
Bone pain	0%	4%
Chest pain	67%	65%
Neurological
Confusion	6%	11%
Convulsion	4%	0%
Depression	37%	44%
Insomnia	4%	4%
Respiratory
Cough increase	38%	46%
Dyspnea	90%	85%
Epistaxis	4%	2%
Pleural effusion	4%	2%
Skin and Appendages
Pruritus	4%	0%
Rash	10%	13%
Sweating	15%	20%
Special Senses
Amblyopia	8%	4%
Vision abnormality	4%	0%

Adverse Events During Chronic Administration for PH/SSD

In an effort to separate the adverse effects of the drug from the adverse effects of the underlying disease, Table 7 lists adverse events that occurred at a rate at least 10% different in the 2 groups in the controlled trial for patients with PH/SSD.

Table 7: Adverse Events Regardless of Attribution Occurring in Patients With PH/SSD With ≥10% Difference Between Epoprostenol and Conventional Therapy Alone

Adverse Event	Epoprostenol (n = 56)	Conventional Therapy (n = 55)
Occurrence More Common With Epoprostenol
Cardiovascular
Flushing	23%	0%
Hypotension	13%	0%
Gastrointestinal
Anorexia	66%	47%
Nausea/vomiting	41%	16%
Diarrhea	50%	5%
Musculoskeletal
Jaw pain	75%	0%
Pain/neck pain/arthralgia	84%	65%
Neurological
Headache	46%	5%
Skin and Appendages
Skin ulcer	39%	24%
Eczema/rash/urticaria	25%	4%
Occurrence More Common With Conventional Therapy
Cardiovascular
Cyanosis	54%	80%
Pallor	32%	53%
Syncope	7%	20%
Gastrointestinal
Ascites	23%	33%
Esophageal reflux/gastritis	61%	73%
Metabolic
Weight decrease	45%	56%
Neurological
Dizziness	59%	76%
Respiratory
Hypoxia	55%	65%

Table 8 lists additional adverse events reported in PH/SSD patients receiving Epoprostenol plus conventional therapy or conventional therapy alone during controlled clinical trials.

Table 8: Adverse Events Regardless of Attribution Occurring in Patients With PH/SSD With <10% Difference Between Epoprostenol and Conventional Therapy Alone

Adverse Event*	Epoprostenol (n = 56)	Conventional Therapy (n = 55)
* Adverse events that occurred in at least 2 patients in either treatment group.
General
Asthenia	100%	98%
Hemorrhage/hemorrhage injection site/hemorrhage rectal	11%	2%
Infection/rhinitis	21%	20%
Chills/fever/sepsis/flu-like symptoms	13%	11%
Blood and Lymphatic
Thrombocytopenia	4%	0%
Cardiovascular
Heart failure/heart failure right	11%	13%
Myocardial Infarction	4%	0%
Palpitation	63%	71%
Shock	5%	5%
Tachycardia	43%	42%
Vascular disorder peripheral	96%	100%
Vascular disorder	95%	89%
Gastrointestinal
Abdominal enlargement	4%	0%
Abdominal pain	14%	7%
Constipation	4%	2%
Flatulence	5%	4%
Metabolic
Edema/edema peripheral/edema genital	79%	87%
Hypercalcemia	48%	51%
Hyperkalemia	4%	0%
Thirst	0%	4%
Musculoskeletal
Arthritis	52%	45%
Back pain	13%	5%
Chest pain	52%	45%
Cramps leg