Author: druginteractionchecker_lgaiz4

WARNINGS

See BOXED .

The use of unopposed estrogens in women who have a uterus is associated with an increased risk of endometrial cancer.

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.

(See CLINICAL PHARMACOLOGY, Clinical Studies ).

In the CE/MPA substudy of WHI an increased risk of coronary heart disease (CHD) events (defined as non-fatal myocardial infarction and CHD death) was observed in women receiving CE/MPA compared to women receiving placebo (37 vs 30 per 10,000 women-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 non-fatal 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 (see CLINICAL PHARMACOLOGY, Clinical Studies ).

In the CE/MPA substudy of WHI, a 2-fold 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 women-years in the CE/MPA group compared to 16 per 10,000 women-years 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 the use of estrogens for less than 1 year.

The greatest risk appears to be associated with prolonged use with increased risks of 15- to 24-fold for five to ten years or more, and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.

Clinical surveillance of all women taking estrogen/progestin combinations 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 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 vs 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 vs placebo was 45 vs 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 Administration of estrogen 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 A bnormalities 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.

WARNINGS

Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use.

This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age.

Women who use oral contraceptives should be strongly advised not to smoke .

The use of oral contraceptives is associated with increased risks of several serious conditions including myocardial infarction, thromboembolism, stroke, hepatic neoplasia, and gallbladder disease, although the risk of serious morbidity or mortality is very small in healthy women without underlying risk factors.

The risk of morbidity and mortality increases significantly in the presence of other underlying risk factors such as hypertension, hyperlipidemias, obesity, and diabetes.

Practitioners prescribing oral contraceptives should be familiar with the following information relating to these risks.

The information contained in this package insert is principally based on studies carried out in patients who used oral contraceptives with higher formulations of estrogens and progestogens than those in common use today.

The effect of long-term use of the oral contraceptives with lower formulations of both estrogens and progestogens remains to be determined.

Throughout this labeling, epidemiological studies reported are of two types: retrospective or case control studies and prospective or cohort studies.

Case control studies provide a measure of the relative risk of a disease, namely, a ratio of the incidence of a disease among oral contraceptive users to that among non-users.

The relative risk does not provide information on the actual clinical occurrence of a disease.

Cohort studies provide a measure of attributable risk, which is the difference in the incidence of disease between oral contraceptive users and nonusers.

The attributable risk does provide information about the actual occurrence of a disease in the population (adapted from References 8 and 9 with the author’s permission).

For further information, the reader is referred to a text on epidemiological methods.

1.

Thromboembolic Disorders and Other Vascular Problems a.

Myocardial infarction An increased risk of myocardial infarction has been attributed to oral contraceptive use.

This risk is primarily in smokers or women with other underlying risk factors for coronary artery disease such as hypertension, hypercholesterolemia, morbid obesity, and diabetes.

The relative risk of heart attack for current oral contraceptive users has been estimated to be two to six.

The risk is very low under the age of 30.

Smoking in combination with oral contraceptive use has been shown to contribute substantially to the incidence of myocardial infarctions in women in their mid-thirties or older with smoking accounting for the majority of excess cases.

Mortality rates associated with circulatory disease have been shown to increase substantially in smokers over the age of 35 and non-smokers over the age of 40 (Figure 3) among women who use oral contraceptives.

Oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age and obesity.

In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism.

Oral contraceptives have been shown to increase blood pressure among users (see section 9 in ).

Similar effects on risk factors have been associated with an increased risk of heart disease.

Oral contraceptives must be used with caution in women with cardiovascular disease risk factors.

Mortality Rates b.

Thromboembolism An increased risk of thromboembolic and thrombotic disease associated with the use of oral contraceptives is well established.

Case control studies have found the relative risk of users compared to nonusers to be 3 for the first episode of superficial venous thrombosis, 4 to 11 for deep vein thrombosis or pulmonary embolism, and 1.5 to 6 for women with predisposing conditions for venous thromboembolic disease.

Cohort studies have shown the relative risk to be somewhat lower, about 3 for new cases and about 4.5 for new cases requiring hospitalization.

The risk of thromboembolic disease due to oral contraceptives is not related to length of use and disappears after pill use is stopped.

A two- to four-fold increase in relative risk of postoperative thromboembolic complications has been reported with the use of oral contraceptives.

The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions.

If feasible, oral contraceptives should be discontinued at least 4 weeks prior to and for 2 weeks after elective surgery of a type associated with an increase in risk of thromboembolism and during and following prolonged immobilization.

Since the immediate postpartum period is also associated with an increased risk of thromboembolism, oral contraceptives should be started no earlier than 4 to 6 weeks after delivery in women who elect not to breast feed.

c.

Cerebrovascular disease Oral contraceptives have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older (>35 years) hypertensive women who also smoke.

Hypertension was found to be a risk factor for both users and nonusers, for both types of strokes, while smoking interacted to increase the risk for hemorrhagic strokes.

In a large study, the relative risk of thrombotic strokes has been shown to range from 3 for normotensive users to 14 for users with severe hypertension.

The relative risk of hemorrhagic stroke is reported to be 1.2 for non-smokers who used oral contraceptives, 2.6 for smokers who did not use oral contraceptives, 7.6 for smokers who used oral contraceptives, 1.8 for normotensive users, and 25.7 for users with severe hypertension.

The attributable risk is also greater in older women.

d.

Dose-related risk of vascular disease from oral contraceptives A positive association has been observed between the amount of estrogen and progestogen in oral contraceptives and the risk of vascular disease.

A decline in serum high-density lipoproteins (HDL) has been reported with many progestational agents.

A decline in serum high-density lipoproteins has been associated with an increased incidence of ischemic heart disease.

Because estrogens increase HDL cholesterol, the net effect of an oral contraceptive depends on a balance achieved between doses of estrogen and progestin and the nature of the progestin used in the contraceptives.

The amount and activity of both hormones should be considered in the choice of an oral contraceptive.

Minimizing exposure to estrogen and progestogen is in keeping with good principles of therapeutics.

For any particular oral contraceptive, the dosage regimen prescribed should be one which contains the least amount of estrogen and progestogen that is compatible with the needs of the individual patient.

New acceptors of oral contraceptive agents should be started on preparations containing the lowest dose of estrogen which produces satisfactory results for the patient.

e.

Persistence of risk of vascular disease There are two studies which have shown persistence of risk of vascular disease for ever-users of oral contraceptives.

In a study in the United States, the risk of developing myocardial infarction after discontinuing oral contraceptives persists for at least 9 years for women 40-49 years who had used oral contraceptives for 5 or more years, but this increased risk was not demonstrated in other age groups.

In another study in Great Britain, the risk of developing cerebrovascular disease persisted for at least 6 years after discontinuation of oral contraceptives, although excess risk was very small.

However, both studies were performed with oral contraceptive formulations containing 50 mcg or higher of estrogens.

2.

Estimates of Mortality from Contraceptive Use One study gathered data from a variety of sources which have estimated the mortality rate associated with different methods of contraception at different ages (Table 4).

These estimates include the combined risk of death associated with contraceptive methods plus the risk attributable to pregnancy in the event of method failure.

Each method of contraception has its specific benefits and risks.

The study concluded that with the exception of oral contraceptive users 35 and older who smoke and 40 and older who do not smoke, mortality associated with all methods of birth control is low and below that associated with childbirth.

The observation of a possible increase in risk of mortality with age for oral contraceptive users is based on data gathered in the 1970’s but not reported until 1983.

However, current clinical practice involves the use of lower estrogen dose formulations combined with careful restriction of oral contraceptive use to women who do not have the various risk factors listed in this labeling.

Because of these changes in practice and, also, because of some limited new data which suggest that the risk of cardiovascular disease with the use of oral contraceptives may now be less than previously observed (Porter JB, Hunter J, Jick H, et al.

Oral contraceptives and nonfatal vascular disease.

Obstet Gynecol 1985;66:1-4; and Porter JB, Hershel J, Walker AM.

Mortality among oral contraceptive users.

Obstet Gynecol 1987;70:29-32), the Fertility and Maternal Health Drugs Advisory Committee was asked to review the topic in 1989.

The Committee concluded that although cardiovascular disease risks may be increased with oral contraceptive use after age 40 in healthy nonsmoking women (even with the newer low-dose formulations), there are greater potential health risks associated with pregnancy in older women and with the alternative surgical and medical procedures which may be necessary if such women do not have access to effective and acceptable means of contraception.

Therefore, the Committee recommended that the benefits of oral contraceptive use by healthy nonsmoking women over 40 may outweigh the possible risks.

Of course, older women, as all women who take oral contraceptives, should take the lowest possible dose formulation that is effective.

Table 4.

Annual Number of Birth-Related or Method-Related Deaths Associated with Control of Fertility Per 100,000 Nonsterile Women by Fertility Control Method According to Age Method of control and outcome 15-19 20-24 25-29 30-34 35-39 40-44 No fertility control methods * 7.0 7.4 9.1 14.8 25.7 28.2 Oral contraceptives non-smoker ** 0.3 0.5 0.9 1.9 13.8 31.6 Oral contraceptives smoker ** 2.2 3.4 6.6 13.5 51.1 117.2 IUD ** 0.8 0.8 1.0 1.0 1.4 1.4 Condom * 1.1 1.6 0.7 0.2 0.3 0.4 Diaphragm/spermicide * 1.9 1.2 1.2 1.3 2.2 2.8 Periodic abstinence * 2.5 1.6 1.6 1.7 2.9 3.6 * Deaths are birth related.

** Deaths are method related.

Adapted from H.W.

Ory 3.

Carcinoma of the Reproductive Organs and Breasts Epidemiologic studies have been conducted examining the relationship between combination oral contraceptives and breast cancer.

Norethindrone acetate and ethinyl estradiol tablets were not included in these studies, and the majority of the combination oral contraceptives used by women in these studies have higher doses of estrogen than norethindrone acetate and ethinyl estradiol tablets.

These studies suggest that the risk of having breast cancer diagnosed may be slightly increased among current and recent users of combination oral contraceptives; however, these studies do not provide evidence for causation.

The observed pattern of increased risk of breast cancer diagnosis may be due to earlier detection of breast cancer in combination oral contraceptive users, the biological effects of combination oral contraceptives, or a combination of reasons.

The risk appears to decrease over time after combination oral contraceptive discontinuation, and by 10 years after cessation of combination oral contraceptive use, the additional risk disappears.

The risk does not appear to increase with duration of use and no consistent relationships have been found with age at first use or doses studied or type of steroid.

Most studies show a similar pattern of risk with combination oral contraceptive use regardless of a woman’s reproductive history or her family breast cancer history.

Breast cancers diagnosed in current or previous combination oral contraceptive users tend to be less clinically advanced than in nonusers.

Women who currently have or have had breast cancer should not use oral contraceptives because breast cancer is a hormonally-sensitive tumor.

Some studies suggest that oral contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia in some populations of women.

However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors.

4.

Hepatic Neoplasia Benign hepatic adenomas are associated with oral contraceptive use, although the incidence of benign tumors is rare in the United States.

Indirect calculations have estimated the attributable risk to be in the range of 3.3 cases/100,000 for users, a risk that increases after 4 or more years of use.

Rupture of rare, benign, hepatic adenomas may cause death through intra-abdominal hemorrhage.

Studies from Britain have shown an increased risk of developing hepatocellular carcinoma in long-term (>8 years) oral contraceptive users.

However, these cancers are extremely rare in the US, and the attributable risk (the excess incidence) of liver cancers in oral contraceptive users approaches less than one per million users.

5.

Ocular Lesions There have been clinical case reports of retinal thrombosis associated with the use of oral contraceptives.

Oral contraceptives should be discontinued if there is unexplained partial or complete loss of vision; onset of proptosis or diplopia; papilledema; or retinal vascular lesions.

Appropriate diagnostic and therapeutic measures should be undertaken immediately.

6.

Oral Contraceptive Use Before and During Early Pregnancy Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy.

Studies also do not suggest a teratogenic effect, particularly insofar as cardiac anomalies and limb reduction defects are concerned, when taken inadvertently during early pregnancy The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy.

Oral contraceptives should not be used during pregnancy to treat threatened or habitual abortion.

It is recommended that for any patient who has missed two consecutive periods, pregnancy should be ruled out before continuing oral contraceptive use.

If the patient has not adhered to the prescribed schedule, the possibility of pregnancy should be considered at the time of the first missed period.

Oral contraceptive use should be discontinued if pregnancy is confirmed.

7.

Gallbladder Disease Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogens.

More recent studies, however, have shown that the relative risk of developing gallbladder disease among oral contraceptive users may be minimal.

The recent findings of minimal risk may be related to the use of oral contraceptive formulations containing lower hormonal doses of estrogens and progestogens.

8.

Carbohydrate and Lipid Metabolic Effects Oral contraceptives have been shown to cause glucose intolerance in a significant percentage of users.

Oral contraceptives containing greater than 75 mcg of estrogens cause hyperinsulinism, while lower doses of estrogen cause less glucose intolerance.

Progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents.

However, in the non-diabetic woman, oral contraceptives appear to have no effect on fasting blood glucose.

Because of these demonstrated effects, prediabetic and diabetic women should be carefully observed while taking oral contraceptives.

A small proportion of women will have persistent hypertriglyceridemia while on the pill.

As discussed earlier (see , 1a .

and 1d .), changes in serum triglycerides and lipoprotein levels have been reported in oral contraceptive users.

9.

Elevated Blood Pressure An increase in blood pressure has been reported in women taking oral contraceptives and this increase is more likely in older oral contraceptive users and with continued use.

Data from the Royal College of General Practitioners and subsequent randomized trials have shown that the incidence of hypertension increases with increasing concentrations of progestogens.

Women with a history of hypertension or hypertension-related diseases or renal disease should be encouraged to use another method of contraception.

If women elect to use oral contraceptives, they should be monitored closely, and if significant elevation of blood pressure occurs, oral contraceptives should be discontinued.

For most women, elevated blood pressure will return to normal after stopping oral contraceptives, and there is no difference in the occurrence of hypertension among ever and never users.

10.

Headache The onset or exacerbation of migraine or development of headache with a new pattern which is recurrent, persistent, or severe requires discontinuation of oral contraceptives and evaluation of the cause.

11.

Bleeding Irregularities Breakthrough bleeding and spotting are sometimes encountered in patients on oral contraceptives, especially during the first three months of use.

Non-hormonal causes should be considered, and adequate diagnostic measures taken to rule out malignancy or pregnancy in the event of prolonged breakthrough bleeding, as in the case of any abnormal vaginal bleeding.

If pathology has been excluded, time or a change to another formulation may solve the problem.

In the event of amenorrhea, pregnancy should be ruled out.

Some women may encounter post-pill amenorrhea or oligomenorrhea, especially when such a condition was pre-existent.

WARNINGS

Warnings Reye’s syndrome Children and teenagers who have or are recovering from chicken pox or flu-like symptoms should not use this product.

When using this product, if changes in behavior with nausea and vomiting occur, consult a doctor because these symptoms could be an early sign of Reye’s syndrome, a rare but serious illness.

Allergy alert Aspirin may cause a severe allergic reaction which may include: hives facial swelling asthma (wheezing) shock Stomach bleeding warning This product contains an NSAID, which may cause severe stomach bleeding.

The chance is higher if you are age 60 or older have had stomach ulcers or bleeding problems take a blood thinning (anticoagulant) or steroid drug take other drugs containing prescription or nonprescription NSAIDs (aspirin, ibuprofen, naproxen, or others) have 3 or more alcoholic drinks every day while using this product take more or for a longer time than directed Do not use if you are allergic to aspirin or any other pain reliever/fever reducer Ask a doctor before use if stomach bleeding warning applies to you you have a history of stomach problems, such as heartburn you have high blood pressure, heart disease, liver cirrhosis, or kidney disease you are taking a diuretic you have asthma Ask a doctor or pharmacist before use if you are taking a prescription drug for gout diabetes arthritis Stop use and ask a doctor if an allergic reaction occurs.

Seek medical right away.

you experience any of the following signs of stomach bleeding: feel faint vomit blood have bloody or black stools have stomach pain that does not get better pain gets worse or lasts more than 10 days redness or swelling is present new symptoms occur ringing in the ears or a loss of hearing occurs If pregnant or breast-feeding, ask a health professional before use.

It is especially important not to use aspirin during the last 3 months of pregnancy unless definitely directed to do so by a doctor because it may cause problems in the unborn child or complications during delivery.

Keep out of reach of children.

In case of overdose, get medical help or contact a Poison Control Center right away.

WARNINGS

Warnings For external use only.

Avoid getting into eyes or on mucous membranes.

If the conditions worsens, or if the symptoms persists for more than 7 days or clears up and occurs again within a few days, discontinue use of this product and consult a doctor.

Do not apply to wounds or damaged skin.

Do not bandage tightly.

OTC – Keep Out of Reach of Children Section Keep out of reach of children.

Other Warnings Use only as directed.

Do not use if pregnant or breastfeeding.

If swallowed, get medical help or contact a poison Control center right away.

WARNINGS

Warnings For external use only Do not use on children under 2 years of age unless directed by a doctor When using this product avoid contact with eyes Stop use and ask a doctor if irritation occurs or if there is no improvement within 4 weeks (for athlete’s foot and ringworm) irritation occurs or if there is no improvement within 2 weeks (for jock itch) Keep this and all drugs out of the reach of children.

In case of accidental ingestion, seek professional assistance or contact a Poison Control Center immediately.

WARNINGS

Cardiac Failure In general, beta-blocking agents should be avoided in patients with overt congestive failure.

However, in some patients with compensated cardiac failure, it may be necessary to utilize these agents.

In such situations, they must be used cautiously.

Patients Without a History of Cardiac Failure Continued depression of the myocardium with beta-blockers can, in some patients, precipitate cardiac failure.

At the first signs or symptoms of heart failure, discontinuation of ZIAC should be considered.

In some cases ZIAC therapy can be continued while heart failure is treated with other drugs.

Abrupt Cessation of Therapy Exacerbations of angina pectoris and, in some instances, myocardial infarction or ventricular arrhythmia, have been observed in patients with coronary artery disease following abrupt cessation of therapy with beta-blockers.

Such patients should, therefore, be cautioned against interruption or discontinuation of therapy without the physician’s advice.

Even in patients without overt coronary artery disease, it may be advisable to taper therapy with ZIAC (bisoprolol fumarate and hydrochlorothiazide) over approximately 1 week with the patient under careful observation.

If withdrawal symptoms occur, beta-blocking agent therapy should be reinstituted, at least temporarily.

Peripheral Vascular Disease Beta-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease.

Caution should be exercised in such individuals.

Bronchospastic Disease PATIENTS WITH BRONCHOSPASTIC PULMONARY DISEASE SHOULD, IN GENERAL, NOT RECEIVE BETA-BLOCKERS.

Because of the relative beta 1 -selectivity of bisoprolol fumarate, ZIAC may be used with caution in patients with bronchospastic disease who do not respond to, or who cannot tolerate other antihypertensive treatment.

Since beta 1 -selectivity is not absolute, the lowest possible dose of ZIAC should be used.

A beta 2 agonist (bronchodilator) should be made available.

Major Surgery Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.

Hypoglycemia Beta-blockers may prevent early warning signs of hypoglycemia, such as tachycardia, and increase the risk for severe or prolonged hypoglycemia at any time during treatment, especially in patients with diabetes mellitus or children and patients who are fasting (i.e., surgery, not eating regularly, or are vomiting).

If severe hypoglycemia occurs, patients should be instructed to seek emergency treatment.

Also, latent diabetes mellitus may become manifest and diabetic patients given thiazides may require adjustment of their insulin dose.

Thyrotoxicosis Beta-adrenergic blockade may mask clinical signs of hyperthyroidism, such as tachycardia.

Abrupt withdrawal of beta-blockade may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate thyroid storm.

Renal Disease Cumulative effects of the thiazides may develop in patients with impaired renal function.

In such patients, thiazides may precipitate azotemia.

In subjects with creatinine clearance less than 40 mL/min, the plasma half-life of bisoprolol fumarate is increased up to threefold, as compared to healthy subjects.

If progressive renal impairment becomes apparent, ZIAC should be discontinued (See Pharmacokinetics and Metabolism ).

Hepatic Disease ZIAC should be used with caution in patients with impaired hepatic function or progressive liver disease.

Thiazides may alter fluid and electrolyte balance, which may precipitate hepatic coma.

Also, elimination of bisoprolol fumarate is significantly slower in patients with cirrhosis than in healthy subjects (See Pharmacokinetics and Metabolism ).

Acute Angle-Closure Glaucoma with or without Acute Myopia and Choroidal Effusions Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute angle-closure glaucoma and elevated intraocular pressure with or without a noticeable acute myopic shift and/or choroidal effusions.

Symptoms may include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation.

Untreated, the acute angle-closure glaucoma may result in permanent visual field loss.

The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible.

Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled.

Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

WARNINGS

Warnings Do not use if taking a prescription monoamine oxidase inhibitor (MAOI) (certain drugs for depression, psychiatric, or emotional conditions, or Parkinson’s disease), or for 2 weeks after stopping the MAOI drug.

If you do not know if your prescription drug contains an MAOI, ask a doctor or pharmacist before taking this product.

Ask a doctor before use if you have chronic cough that lasts or occurs with smoking, asthma, chronic bronchitis or emphysema cough that occurs with too much phlegm (mucus) Stop use and ask a doctor if cough lasts more than 7 days, comes back, or occurs with fever, rash or headache that lasts.

These could be signs of a serious condition.

If pregnant or breast-feeding, ask a health professional before use.

Keep out of reach of children.

In case of overdose, get medical help or contact a Poison Control Center right away.

WARNINGS

Warnings Do not use in a child who is taking a prescription monoamine oxidase inhibitor (MAOI) (certain drugs for depression, psychiatric or emotional conditions, or Parkinson’s disease), or for 2 weeks after stopping the MAOI drug.

If you do not know if your child’s prescription drug contains an MAOI, ask a doctor or pharmacist before giving this product.

Ask a doctor before use if the child has heart disease high blood pressure thyroid disease diabetes persistent or chronic cough such as occurs with asthma cough that occurs with too much phlegm (mucus) a sodium-restricted diet When using this product do not exceed recommended dose Stop use and ask a doctor if nervousness, dizziness, or sleeplessness occur symptoms do not improve within 7 days or occur with a fever cough gets worse or lasts for more than 7 days cough tends to come back or occurs with fever, rash or headache that lasts These could be signs of a serious condition.

Keep out of reach of children.

In case of overdose, get medical help or contact a Poison Control Center right away.

(1-800-222-1222)

WARNINGS

Hypersensitivity Reactions Before therapy with ceftriaxone for injection is instituted, careful inquiry should be made to determine whether the patient has had previous hypersensitivity reactions to cephalosporins, penicillins and other beta-lactam agents or other drugs.

This product should be given cautiously to penicillin and other beta-lactam agent-sensitive patients.

Antibacterial drugs should be administered with caution to any patient who has demonstrated some form of allergy, particularly to drugs.

Serious acute hypersensitivity reactions may require the use of subcutaneous epinephrine and other emergency measures.

As with all beta-lactam antibacterial agents, serious and occasionally fatal hypersensitivity reactions (i.e., anaphylaxis) have been reported.

In case of severe hypersensitivity reactions, treatment with ceftriaxone must be discontinued immediately and adequate emergency measures must be initiated.

Interaction with Calcium-Containing Products Do not use diluents containing calcium, such as Ringer’s solution or Hartmann’s solution, to reconstitute ceftriaxone vials or to further dilute a reconstituted vial for IV administration because a precipitate can form.

Precipitation of ceftriaxone-calcium can also occur when ceftriaxone is mixed with calcium-containing solutions in the same IV administration line.

Ceftriaxone must not be administered simultaneously with calcium-containing IV solutions, including continuous calcium-containing infusions such as parenteral nutrition via a Y-site.

However, in patients other than neonates, ceftriaxone and calcium-containing solutions may be administered sequentially of one another if the infusion lines are thoroughly flushed between infusions with a compatible fluid.

In vitro studies using adult and neonatal plasma from umbilical cord blood demonstrated that neonates have an increased risk of precipitation of ceftriaxone-calcium (see CLINICAL PHARMACOLOGY , CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION ).

Neurological Adverse Reactions Serious neurological adverse reactions have been reported during postmarketing surveillance with ceftriaxone use.

These reactions include encephalopathy (disturbance of consciousness including somnolence, lethargy, and confusion), seizures, myoclonus, and non-convulsive status epilepticus (see ADVERSE REACTIONS ).

Some cases occurred in patients with severe renal impairment who did not receive appropriate dosage adjustment.

However, in other cases, neurological adverse reactions occurred in patients receiving an appropriate dosage adjustment.

The neurological adverse reactions were reversible and resolved after discontinuation.

If neurological adverse reactions associated with ceftriaxone for injection therapy occur, discontinue ceftriaxone for injection and institute appropriate supportive measures.

Make appropriate dosage adjustments in patients with severe renal impairment (see DOSAGE AND ADMINISTRATION ).

Clostridium difficile -Associated Diarrhea Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including ceftriaxone, and may range in severity from mild diarrhea to fatal colitis.

Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C.

difficile .

C.

difficile produces toxins A and B which contribute to the development of CDAD.

Hypertoxin producing strains of C.

difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy.

CDAD must be considered in all patients who present with diarrhea following antibiotic use.

Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C.

difficile may need to be discontinued.

Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C.

difficile , and surgical evaluation should be instituted as clinically indicated.

Hemolytic Anemia An immune mediated hemolytic anemia has been observed in patients receiving cephalosporin class antibacterials including ceftriaxone.

Severe cases of hemolytic anemia, including fatalities, have been reported during treatment in both adults and children.

If a patient develops anemia while on ceftriaxone, the diagnosis of a cephalosporin associated anemia should be considered and ceftriaxone stopped until the etiology is determined.