PRECAUTIONS:

Pediatric Use (new subsection): "The safety and effectiveness have not been established. Its limited use in pediatric patients has been inadequate to fully define proper dosage and limitations for use."

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PRECAUTIONS:

Pediatric Use (new subsection): "The safety and effectiveness of Bacteriostatic Water for Injection have not been established in pediatric patients. Due to the potential for toxicity, solutions containing benzyl alcohol should not be used in neonates."

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ADVERSE REACTIONS:

Post-Marketing Experience: Subsection revised (new text in italics) -

"The following adverse reactions have been reported in post-marketing experience: Hypersensitivity: Angioedema (involving swelling of the face, lips , pharynx and/or tongue) has been reported rarely in patients treated with losartan.

"Hyperkalemia has been reported with losartan." (N.B. "with losartan" appears only in the labeling for Hyzaar

[Changes for other formulations not reflected in 1998 PDR: Jan97]

PRECAUTIONS:

6. Use with Estrogen: Entire subsection deleted and replaced with -

"6. Carbohydrate Metabolism: A decrease in glucose tolerance has been observed in some patients on Depo-Provera Sterile Aqueous Suspension treatment. The mechanism of this decrease is obscure. For this reason, diabetic patients should be carefully observed while receiving such therapy."

PRECAUTIONS:

Pediatric Use: Addition of text as first paragraph of subsection -

"There are no well-controlled clinical trials in pediatric patients. The information on oral dosing in pediatric patients, other than infants, is supported by evidence from empiric use in this age group."

Third paragraph revised (new text in italics) -

"Safety and effectiveness of oral and parenteral use in infants have not been established (see CONTRAINDICATIONS)."

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CLINICAL PHARMACOLOGY:

Third paragraph revised (new text in italics) -

"Corticosteroids are capable of producing a rise in intraocular pressure. In clinical studies ["on patients' eyes treated with both dexamethasone and fluorometholone 0.1% suspensions" deleted] of documented steroid-responders, flurometholone demonstrated a ["lower propensity" deleted] significantly longer average time to ["increase" deleted] produce a rise in intraocular pressure than ["did" deleted] dexamethasone phosphate; however, in a small percentage of individuals, a significant rise in intraocular pressure occurred within one week. The ultimate magnitude of the rise was equivalent for both drugs."

WARNINGS:

Third paragraph revised -

"Acute purulent ["untreated" deleted] infections of the eye may be masked or activity enhanced by the presence of corticosteroid medication."

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CONTRAINDICATIONS:

Addition of text as new #2 -

"2. Congestive heart failure requiring pharmacologic treatment."

Current #2, #3, & #4 renumbered as #3, #4, & #5.

WARNINGS:

Boxed Warning - Lactic Acidosis: Second paragraph revised (new text in italics) -

The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases/1,000 patient-years, with approximately 0.015 fatal cases/1,000 patient-years). Reported cases have occurred primarily in diabetic patients with significant renal insufficiency, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient's age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking Glucophage and by use of the minimum effective dose of Glucophage. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Glucophage treatment should not be initiated in patients > or = 80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis. In addition, Glucophage should be promptly withheld in the presence of any condition associated with hypoxemia, ["or" deleted] dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, Glucophage should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Patients should be cautioned against excessive alcohol intake, either acute or chronic, when taking Glucophage, since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In addition, Glucophage should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure (see also PRECAUTIONS)."

PRECAUTIONS:

General: Monitoring of renal function: First paragraph, addition of new last sentence -

"For patients > or = 80 years of age, see WARNINGS."

Geriatric Use: Last sentence revised (new text in italics) -

"Generally, elderly patients should not be titrated to the maximum dose of Glucophage (see also WARNINGS and DOSAGE AND ADMINISTRATION)."

DOSAGE AND ADMINISTRATION:

Specific Patient Populations: New text added as new second to last paragraph -

"Monitoring of renal function is necessary to aid in prevention of lactic acidosis, particularly in the elderly. (See WARNINGS.)"

PATIENT INFORMATION ABOUT GLUCOPHAGE (metformin hydrochloride tablets):

Question #10 revised (new text in italics) -

"Q10. Are there other risk factors for lactic acidosis?
Your risk of developing lactic acidosis from taking Glucophage is very low as long as your kidneys and liver are healthy. However, some factors can increase your risk because they can affect kidney and liver function. You should discuss your risk with your physician. You should not take Glucophage if:

• You have chronic kidney or liver problems.
• You have congestive heart failure which is treated with medications, e.g., digoxin (Lanoxin) or furosemide (Lasix)
• You drink alcohol excessively (all the time or short-term "binge" drinking)
• You are seriously dehydrated (have lost a large amount of body fluids))
• You are going to have certain x-ray procedures with injectable contrast agents
• You are going to have surgery
• You develop a serious condition such as a heart attack, severe infection, or a stroke
• You are > or = 80 years of age and have NOT had your kidney function tested."

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WARNINGS:

Diabetes and Hypoglycemia: Text deleted and replaced with -

"Beta-adrenergic blockade may prevent the appearance of certain premonitory signs and symptoms (pulse rate and pressure changes) of acute hypoglycemia in labile insulin-dependent diabetes. In these patients, it may be more difficult to adjust the dosage of insulin. Hypoglycemic attacks may be accompanied by a precipitous elevation of blood pressure in patients on propranolol.

"Propranolol therapy, particularly in infants and children, diabetic or not, has been associated with hypoglycemia especially during fasting as in preparation for surgery. Hypoglycemia also has been found after this type of drug therapy and prolonged physical exertion and has occurred in renal insufficiency, both during dialysis and sporadically, in patients on propranolol."

PRECAUTIONS:

General: Text added at end of subsection -

Risk of anaphylactic reaction. While taking beta blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction."

Carcinogenesis, Mutagenesis, Impairment of Fertility: Text deleted and replaced with -

"In dietary administration studies in which mice and rats were treaed with propranolol for up to 18 months at doses of up to 150 mg/kg/day, there was no evidence of drug-related tumorigenesis. In a study in which both male and female rats were exposed to propranolol in their diets at concentrations of up to 0.05%, from 60 days prior to mating and throughout pregnancy and lactation for two generations, there were no effects on fertility. Based on differing results from Ames Tests performed by different laboratories, there is equivocal evidence for a genotoxic effect of propranolol in bacteria (S. typhimurium strain TA 1538)."

Pregnancy: Pregnancy Category C: First paragraph deleted and replaced with -

"In a series of reproductive and developmental toxicology studies, propranolol was given to rats by gavage or in the diet throughout pregnancy and lactation. At doses of 150 mg/kg/day (> 10 times the maximum recommended human daily dose of propranolol on a body weight basis), but not at doses of 80 mg/kg/day, treatment was associated with embryotoxicity (reduced litter size and increased resorption sites) as well as neonatal toxicity (deaths). Propranolol also was administered (in the feed) to rabbits (throughout pregnancy and lactation) at doses as high as 150 mg/kg/day (> 15 times the maximum recommended daily human dose). No evidence of embryo or neonatal toxicity was noted."

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WARNINGS:

Diabetes and Hypoglycemia: Text deleted and replaced with -

"Beta-andrenergic blockade may prevent the appearance of certain premonitory signs and symptoms (pulse rate and pressure changes) of acute hypoglycemia in labile insulin-dependent diabetes. In these patients, it may be more difficult to adjust the dosage of insulin. Hypoglycemic attacks may be accompanied by a precipitous elevation of blood pressure in patients on propranolol.

"Propranolol therapy, particularly in infants and children, diabetic or not, has been associated with hypoglycemia especially during fasting as in preparation for surgery. Hypoglycemia also has been found after this type of drug therapy and prolonged physical exertion and has occurred in renal insufficiency, both during dialysis and sporadically, in patients on propranolol."

PRECAUTIONS:

General: Text added at end of subsection -

Risk of anaphylactic reaction. While taking beta blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction."

Carcinogenesis, Mutagenesis, Impairment of Fertility: Text deleted and replaced with -

"Combinations of propranolol and hydrochlorothiazide have not been evaluated for carcinogenic or mutagenic potential or for potential to adversely affect fertility.

"Propranolol hydrochloride (Inderal): In dietary administration studies in which mice and rats were treated with propranolol for up to 18 months at doses of up to 150 mg/kg/day, there was no evidence of drug-related tumorigenesis. In a study in which both male and female rats were exposed to propranolol in their diets at concentrations of up to 0.05%, from 60 days prior to mating and throughout pregnancy and lactation for two generations, there were no effects on fertility. Based on differing results from Ames Tests performed by different laboratories, there is equivocal evidence for a genotoxic effect of propranolol in bacteria (S. typhimurium strain TA 1538).

"Hydrochlorothiazide: Two year feeding studies in mice and rats conducted under the auspices of the National Toxicology Program (NTP) uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in female mice (at doses of up to approximately 600 mg/kg/day) or in male and female rats (at doses of up to approximately 100 mg/kg/day). The NTP, however, found equivocal evidence for hepatocarcinogenicity in male mice.

"Hydrochlorothiazide was not genotoxic in vitro in the Ames bacterial mutagen assay (S. typhimurium strains TA 98, TA 100, TA 1535, TA1537 and TA 1538) or in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations. Nor was it genotoxic in vivo in assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained in the in vitro CHO Sister Chromatid Exchange (clastogenicity), Mouse Lymphoma Cell (mutagenicity) and Aspergillus nidulans non-disjunction assays.

"Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diet, to doses of up to 100 mg/kg and 4 mg/kg, respectively, prior to mating and throughout gestation."

Pregnancy: Pregnancy Category C: Text deleted and replaced with -

"Combinations of propranolol and hydrochlorothiazide have not been evaluated for effects on pregnancy in animals. Nor are there adequate and well-controlled studies of propranolol, hydrochlorothiazide, or Inderide in pregnant women. Inderide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

"Propranolol hydrochloride (Inderal): In a series of reproduction and developmental toxicology studies, propranolol was given to rats by gavage or in the diet throughout pregnancy and lactation. At doses of 150 mg/kg/day (> 30 times the dose of propranolol contained in the maximum recommended human daily dose of Inderide), but not at doses of 80 mg/kg/day, treatment was associated with embryotoxicity (reduced litter size and increased resorption sites) as well as neonatal toxicity (deaths).

"Propranolol was also administered (in the feed) to rabbits (throughout pregnancy and lactation) at doses as high as 150 mg/kg/day (> 45 times the dose of propranolol contained in the maximum recommended daily human dose of Inderide). No evidence of embryo or neonatal toxicity was noted. Intrauterine growth retardation has been reported in human neonates whose mothers received propranolol during pregnancy. Neonates whose mothers are receiving propranolol at parturition have exhibited bradycardia, hypoglycemia and respiratory depression. Adequate facilities for monitoring these infants at birth should be available.

"Hydrochlorothiazide: Studies in which hydrochlorothiazide was orally administered to pregnancy mice and rats at doses of up to 3000 and 1000 mg/kg/day, respectively, provided no evidence of harm to the fetus.

"Thiazides cross the placental barrier and appear in cord blood. The use of thiazides in pregnant women requires that the anticipated benefit be weighed against possible hazards to the fetus. These hazards include fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in the adult."

DOSAGE AND ADMINISTRATION:

Second sentence revised (new text in italics) -

"Hydrochlorothiazide can be given at doses of ["25 to 100" deleted] 12.5 to 50 mg per day when used alone."

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PRECAUTIONS:

Carcinogenesis, Mutagenesis, Impairment of Fertility: Text deleted and replaced with -

"No significant change in tumor incidence or type was observed following two years of oral administration of apraclonidine HCl to rats at dosages of 1 and 0.6 mg/kg/day, up to 50 and 30 times, respectively, the maximum dose recommended for human topical ocular use.

"Apraclonidine HCl was not mutagenic in a series of in vitro mutagenicity assays, including the Ames test, a mouse lymphoma forward mutation assay, a chromosome aberration assay in cultured Chinese hamster ovary (CHO) cells, a sister chromatid exchange assay in CHO cells, and a cell transformation assay. An in vivo mouse micronucleous assay conducted with apraclonidine HCl also provided no evidence of mutagenicity. Reproduction and fertility studies in rats showed no adverse effect on male or female fertility at a dose of 0.5 mg/kg (25 times the maximum recommended human dose)."

Pregnancy: Pregnancy Category C: Text deleted and replaced with -

"Apraclonidine HCl has been shown to have an embryocidal effect in rabbits when given in an oral dose of 3 mg/kg (150 times the maximum recommended human dose). Dose related maternal toxicity was observed in pregnant rats at 0.3 mg/kg (15 times the maximum recommended human dose). There are no adequate and well controlled studies in pregnant women. Iopidine 1% Ophthalmic Solution should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus."

STORAGE:

First sentence revised (new text in italics) -

"Store at ["room temperature:" deleted] 2 to 25^o C (34 to 77^o F)."

CLINICAL PHARMACOLOGY:

Mechanism of Action: Text added to the end of the third paragraph -

"Although frequently found in association with low HDL-C, elevated plasma TG has not been established as an independent risk factor for coronary heart disease. The independent effect of raising HDL-C or lowering TG on the risk for coronary and cardiovascular morbidity and mortality has not been established."

ADVERSE REACTIONS:

Clinical Adverse Experiences: Sentence added prior to the list of reported adverse events by body system -

"The events in italics occurred in > or = 2% of patients and the events in plain type in < 2% of patients."

Body as a Whole: "Chest pain" added

Digestive System: "Nausea" added

Respiratory system: "Bronchitis, rhinitis" added

Nervous system: "Insomnia" and "depression, hypesthesia, hypertonia" added

Musculoskeletal System: "Arthritis" added

Skin and Appendages: "Pruritis" added

Urogenital System: "Urinary tract infection" added

Cardiovascular system: "angina pectoris, hypertension" added

Metabolic and Nutritional Disorders: "Peripheral edema" added

Postintroduction Reports (new subsection): "Adverse events associated with Lipitor that have been received since market introduction, that are not listed above, and that may have no causal relationship to drug include the following: angioneurotic edema."

DOSAGE AND ADMINISTRATION:

Second sentence revised (new text in italics) -

"Hydrochlorothiazide is usually given at a dosage of ["25 to 100" deleted] 12.5 to 50 mg per day."

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WARNINGS:

4. Carcinoma of the Breast and Reproductive Organs: New second paragraph added -

"A meta-analysis of 54 studies found a small increase in the frequency of having breast cancer diagnosed for women who were currently using combined oral contraceptives or had used them within the past ten years. This increase in the frequency of breast cancer diagnosis, within ten years of stopping use, was generally accounted for by cancers localized to the breast. There was no increase in the frequency of having breast cancer diagnosed ten or more years after cessation of use."

5. Hepatic Neoplasia: Second paragraph, first sentence revised -

"Studies ["from Britain and the U.S." deleted] have shown an increased risk of developing hepatocellular carcinoma in combined oral contraceptive users." [N.B. this change does appear in the 1998 PDR.]

DETAILED PATIENT LABELING:

Risks of Taking POPS: Cancer of the Reproductive Organs and Breasts: Text added to subsection -

"A meta-analysis of 54 studies found a small increase in the frequency of having breast cancer diagnosed for women who were currently using combined oral contraceptives or had used them within the past ten years. This increase in the frequency of breast cancer diagnosis, within ten years of stopping use, was generally accounted for by cancers localized to the breast. There was no increase in the frequency of having breast cancer diagnosed ten or more years after cessation of use."

INDICATIONS AND USAGE:

First paragraph revised (new text in italics)-

"Oral contraceptives are indicated for the prevention of pregnancy in women who elect to use this product as a method of contraception. Oral contraceptive products such as Ortho-Novum 1+50 28-Day and Ortho-Novum 1+50 21-Day, which contain 50 mcg of estrogen, should not be used unless medically indicated."

WARNINGS:

Thromboembolic Disorders and Other Vascular Problems: d. Dose-related risk of vascular disease from oral contraceptives: Sentence added to end of subsection -

"Products containing 50 mcg estrogen should be used only when medically indicated."

DETAILED PATIENT LABELING:

Introduction: New first sentence -

"You should not use Ortho-Novum 1+50 28-Day and Ortho-Novum 1+50 21-Day, which contains higher doses of estrogen than other oral contraceptives, unless specifically recommended by your health care provider."

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DOSAGE AND ADMINISTRATION:

Addition of "(see Stability, Pepcid Injection)" to each of the paragraphs describing the preparation of Pepcid intravenous solution and Pepcid Intravenous infusion solutions.

Stability: Pepcid Injection: Deletion of "Sodium Bicarbonate Injection, 5%" from the list of compatible diluents for Pepcid Injection.

Addition of new paragraph at end of subsection -

"When added to or diluted with Sodium Bicarbonate Injection, 5%, Pepcid Injection at a concentration of 0.2 mg/mL (the recommended concentration of Pepcid Intravenous infusion solution) is physically and chemically stable (i.e., maintains at least 90% of initial potency) for 7 days at room temperature - see HOW SUPPLIED, Storage. However, a precipitate may form at higher concentrations of Pepcid Injection (>0.2 mg/mL) in Sodium Bicarbonate Injection, 5%."

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PRECAUTIONS:

Pediatric Use: Text deleted - "Safety and effectiveness in pediatric patients have not been established"

and replaced with -

"The safety and effectiveness of Physiosol Irrigation pH 7.4 have not been established. Its limited use in pediatric patients has been inadequate to fully define proper dosage and limitations for use."

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[N.B. For the latest recommendations regarding potential liver toxicity not included in these November 19, 1997 labeling changes, see December 1, 1997 - ( Letter) - Parke-Davis, and ( Talk Paper) - FDA]

[Other changes not reflected in 1998 PDR: Aug97

WARNINGS: (new section)

"Hepatic: Rare cases of severe idiosyncratic hepatocellular injury have been reported during marketed use (See ADVERSE REACTIONS, Postintroduction Reports). The hepatic injury is usually reversible, but very rare cases of hepatic failure, including death, have been reported. Injury has occurred after both short- and long-term troglitazone treatment.

"During all clinical studies in North America, a total of 48 of 2510 (1.9%) Rezulin-treated patients and 3 of 475 (0.6%) placebo-treated patients had ALT levels greater than 3 times the upper limit of normal. Twenty of the Rezulin-treated and one of the placebo-treated patients were withdrawn from treatment. Two of the 20 Rezulin-treated patients developed reversible jaundice; one of these patients had a liver biopsy which was consistent with an idiosyncratic drug reaction. An additional Rezulin-treated patient had a liver biopsy which was also consistent with an idiosyncratic drug reaction. (See ADVERSE REACTIONS, Laboratory Abnormalities).

"It is recommended that serum transaminase levels be checked within the first one to two months and then every three months during the first year of troglitazone therapy, and periodically thereafter. Liver function tests also should be obtained for patients at the first symptoms suggestive of hepatic dysfunction, e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, dark urine. Rezulin should be discontinued if the patient has jaundice or laboratory measurements suggest liver injury (e.g., ALT > 3 times the upper limit of normal)."

PRECAUTIONS:

General: Paragraph on Hepatic moved to "WARNINGS, Hepatic" as second paragraph - see above.

Information for Patients: Addition of new third paragraph -

"Patients who develop nausea, vomiting, abdominal pain, fatigue, anorexia, dark urine or other symptoms suggestive of hepatic dysfunction or jaundice should immediately report these signs or symptoms to their physician."

ADVERSE REACTIONS:

Ending of first paragraph changed from "(see PRECAUTIONS, General)" to "(see WARNINGS)".

Laboratory Abnormalities: Serum Transaminase Levels: Sentence added to beginning of subsection -

"During all clinical studies in North America, a total of 48 of 2510 (1.9(%) Rezulin-treated patients and 3 of 475 (0.6%) placebo-treated patients had ALT levels greater than 3 times the upper limit of normal."

Ending of subsection changed from "(see PRECAUTIONS, General, Hepatic)" to "(see WARNINGS)".

Postintroduction Reports (new subsection): "Adverse events associated with Rezulin that have been reported since market introduction, that are not listed above, and for which causal relationship to drug has not been established include the following: jaundice, hepatitis, liver transplant, death. Also see WARNINGS."

PRECAUTIONS:

Risk of Anaphylactic Reaction (new subsection): "While taking beta-blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction."

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CLINICAL PHARMACOLOGY:

Pharmacology and Clinical Trials: Third paragraph revised (new text in italics) -

"["Beta-agonists and methylxanthines administered concurrently" deleted] Studies in laboratory animals (minipigs, rodents, and dogs) ["cause" deleted] have demonstrated the occurrence of cardiac arrhythmias and sudden death (with histologic evidence of myocardial necrosis) when beta-agonists and methylxanthines are administered concurrently. ["Whether" deleted] The clinical significance of these findings ["are relevant to humans" deleted] is ["not known" deleted] unknown."

INDICATIONS AND USAGE:

First paragraph revised (new text in italics) -

"Serevent Inhalation Aerosol is indicated for long-term, twice-daily (morning and evening) administration in the maintenance treatment of asthma and in the prevention of bronchospasm in patients 12 years of age and older with reversible obstructive airway disease, including patients with symptoms of nocturnal asthma, who require ["regular" deleted] daily treatment with inhaled short-acting beta₂-agonists. It should not be used in patients whose asthma can be managed by occasional use of short-acting, inhaled beta₂-agonists."

WARNINGS:

6. Paradoxical Bronchospasm: Subsection revised (new text in italics) -

["As with other inhaled asthma medications," deleted] Serevent Inhalation Aerosol can produce paradoxical bronchospasm, which ["can" deleted] may be life threatening ["has been reported following the use of Serevent Inhalation Aerosol" deleted]. If ["it" deleted] paradoxical bronchospasm occurs, ["treatment with" deleted] Serevent Inhalation Aerosol should be discontinued immediately and alternative therapy instituted. It should be recognized that paradoxical bronchospasm, when associated with inhaled formulations, frequently occurs with the first use of a new canister or vial."

8. Upper Airway Symptoms: Subsection revised (new text in italics) -

"Symptoms of laryngeal spasm, irritation, or swelling, such as stridor and choking have been reported rarely in patients receiving Serevent Inhalation Aerosol.

"Serevent Inhalation Aerosol, like all other beta-adrenergic agonists, can produce a clinically significant cardiovascular effect in some patients as measured by pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of Serevent Inhalation Aerosol at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiogram (ECG) changes, such as flattening of the T wave, prolongation of the QT_c interval, and ST segment depression. The clinical significance of these findings is unknown. Therefore, Serevent Inhalation Aerosol, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insuffiency, cardiac arrhythmias, and hypertension."

PRECAUTIONS:

General: 3. Metabolic Effects: First paragraph revised (new text in italics) -

Doses of the related beta₂-adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabets mellitus and ketoacidosis. No effects on glucose have been seen with Serevent Inhalation Aerosol at recommended doses. ["Administration of beta₂-adrenoceptor agonists" deleted] Beta-adrenergic agonist medications may ["cause a decrease in serum potassium" deleted] produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to ["increase the likelihood of arrhythmias" deleted] produce adverse cardiovascular effects. The decrease is usually transient, not requiring supplementation."

Information for Patients: #2: Revised (new text in italics) -

"The action of Serevent Inhalation Aerosol may last up to 12 hours or longer. The recommended dosage (two inhalations twice daily, morning and evening) should not be exceeded.

#6: Revised (new text in italics) -

"6. Patients should be cautioned regarding ["potential" deleted] common adverse cardiovascular effects, such as palpitations, ["or" deleted} chest pain, rapid heart rate, tremor, or nervousness ["related to the use of additional beta₂-agonist" deleted]."

#9 & #10: New points-

"9. If you are pregnant or nursing, contact your physician about use of Serevent Inhalation Aerosol.

"10. Effective and safe use of Serevent Inhalation Aerosol includes an understanding of the way that is should be administered."

Drug Interactions: Addition of two paragraphs at end of subsection -

"Beta-adrenergic receptor blocking agents not only block the pulmonary effect of beta-agonists, such as Serevent Inhalation Aerosol, but may produce severe bronchospasm in asthmatic patients. Therefore, patients with asthma should not normally be treated with beta-blockers. However, under certain circumstances, e.g., as prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-andrenergic blocking agents in patients with asthma. In this setting, cardioselective beta-blockers should be considered, although they should be administered with caution.

"The ECG changes and/or hypokalemia that may result from the administration of nonpotassium- sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of beta-agonists with nonpotassium-sparing diuretics."

Use in Labor and Delivery: Subsection revised (new text in italics) -

"There are no well-controlled human studies that have investigated effects of salmeterol on preterm labor or labor at term. Because of the potential for beta-agonist interference with uterine contractility, use of Serevent Inhalation Aerosol for relief of bronchospasm during labor should be restricted to those patients in whom the benefits clearly outweigh the risks."

OVERDOSAGE:

Section revised (new text in italics) -

"["Overdosage with salmeterol may be expected to result in exaggeration of the pharmacologic adverse effects associated with beta-adrenergic agonists, including tachycardia and/or arrhythmia, tremor, headache, and muscle cramps." deleted] The expected symptoms with overdosage are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the symptoms listed under ADVERSE REACTIONS, e.g. seizures, angina, hyperension or hypotension, tachycardia with rates up to 200 beats per minute, arrhythmias, nervousness, headache, tremor, muscle cramps, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, and insomia. Overdosage with salmeterol can lead to clinically significant prolongation of the QT_c interval, which can produce ventricular arrhythmias. Other signs of overdosage may include hypokalemia and hyperglycemia.

"[In these cases, therapy with Serevent Inhalation Aerosol and all beta-adrenergic stimulant drugs should be stopped, supportive therapy provided, and judicious use of a beta-adrenergic blocking agent should be considered, bearing in mind the possibility that such agents can produce bronchospasm. Cardiac monitoring is recommended in cases of overdosage." deleted]

"As with all sympathomimetic ["pressurized" deleted] aerosol medications, cardiac arrest and even death may be associated with abuse of Serevent Inhalation Aerosol. Treatment consists of discontinuation of Serevent Inhalation Aerosol together with appropriate symptomatic therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage of Serevent Inhalation Aerosol.

"Rats and dogs survived the maximum practicable inhalation doses of salmeterol of ["2.9" deleted] 17.4 and ["0.7 mg/kg" deleted] 14.0 mg/m², respectively. The maximum nonlethal oral doses in mice and rats were approximately ["150 mg/kg" deleted] 450 mg/m² and ["1,000 mg/kg" deleted] > 6,000 mg/m², respectively.

["Dialysis is not appropriate treatment for overdosage of Serevent Inhalation Aerosol." deleted]"

HOW SUPPLIED:

Third paragraph revised (new text in italics) -

"For use with Serevent Inhalation Aerosol actuator only. The actuator with Serevent Inhalation Aerosol should not be used with other aerosol medications, and actuators from other aerosol medications should not be used with a Serevent Inhalation Aerosol.

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PRECAUTIONS:

Pediatric Use (new subsection): "The safety and effectiveness of sodium lactate have not been established in pediatric patients. Its limited use has been inadequate to fully define proper dosage and limitations for use."

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PRECAUTIONS:

Pediatric Use (new subsection): "The safety and effectiveness of sodium phosphate has been established in pediatric patients (neonates, infants, children and adolescents)."

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PRECAUTIONS:

Pediatric Use (new subsection): "The safety and effectiveness of Sorbitol-Mannitol irrigation have not been established in pediatric patients. Its limited use in pediatric patients has been inadequate to fully define proper dosage and limitations for use."

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"Sulfite-free" added to name of the product throughout the labeling.

CONTRAINDICATIONS:

Subsection revised - " Travasol-sulfite-free (Amino Acid) in Dextrose Injections are contraindicated in patients having intracranial or intraspinal hemorrhage, in patients who are severely dehydrated, ["in patients who are anuric," deleted] in patients hypersensitive to one or more amino acids, and in patients with severe liver disease or hepatic coma."

WARNINGS:

New first paragraph added -

"Additives may be incompatible. Consult with pharmacist, if available. When introducing additives, use aseptic techniques. Mix thoroughly. Do not store. Because of the potential for life-threatening events, caution should be taken to ensure that precipitates have not formed in any parenteral nutrient admixture.

Paragraph (moved from the PRECAUTIONS section) added as fifth paragraph -

"Frequent clinical evaluation and laboratory determinations are necessary for proper monitoring during administrations. Studies should include blood sugar, serum proteins, kidney and liver function tests, electrolytes, complete blood count with differential, carbon dioxide combining power or content, serum osmolarities, blood cultures and blood ammonia levels."

Last sentence in section deleted -

"Administration by central venous catheter should be used only by those familiar with this technique and its complications."

PRECAUTIONS:

New paragraph two added -

"Use with caution when administered to patients with anuria or renal failure."

Paragraph deleted (moved to the WARNINGS section, see above) -

"Frequent clinical evaluation ..."

Pediatric Use (new subsection): "See Dosage and Administration."

DOSAGE AND ADMINISTRATION:

Peripheral Vein Administration: Addition of new fifth paragraph which was moved from the Pregnancy Category C subsection -

"Do not administer unless V seal is separated, other seals are intact and solution is clear and thoroughly mixed."

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CONTRAINDICATIONS:

Section revised (new text in italics) -

"Ventolin Inhalation Aerosol is contraindicated in patients with a history of hypersensitivity to albuterol or any of its components."

PRECAUTIONS:

General: First paragraph, new last sentence added -

"Clinically significant changes in systolic and diastolic blood pressure have been seen in individual patients and could be expected to occur in some patients after use of any beta-adrenergic bronchodilator."

Drug Interactions:First sentence revised (new text in italics) -

"Other short-acting sympathomimetic aerosol bronchodilators should not be used concomitantly with albuterol"

Carcinogenesis, Mutagenesis, Impairment of Fertility: First paragraph revised (new text in italics) -

"In a 2-year study in Sprague-Dawley rats, albuterol sulfate, caused a significant dose-related increase in the incidence of benign leiomyomas of the mesovarium at dietary doses of 2.0, 10, and 50 mg/kg ["per day" deleted] (approximately 15, ["75" deleted] 70 and ["370" deleted] 340 times, respectively, the maximum recommended daily inhalation dose for adults on a mg/m² basis ,or, approximately ["8, 44, and 220" deleted] 6, 30, and 160 times, respectively, the maximum recommended daily inhalation dose in children on a mg/m² basis). In another study this effect was blocked by the coadministration of propranolol, a non-selective beta-adrenergic antagonist. In an ["study of" deleted] 18-month study in ["the" deleted]CD-1 ["mouse" deleted] mice ["with" deleted] albuterol sulfate showed no evidence of tumorigenicity ["was seen" deleted] at dietary doses of ["50, 150, and" deleted] up to 500 mg/kg [", up to" deleted] ( approximately ["1100" deleted] 1700 times the maximum recommended daily ["oral" deleted] inhalation dose for adults ["and children" deleted] on a mg/m² basis, or, approximately 800 times the maximum recommended daily inhalation dose for children on a mg/m² basis). In a ["study of" deleted] 22-month study in the Golden Hamster ["with" deleted] albuterol sulfate showed no evidence of tumorigenicity ["was seen" deleted] at dietary doses of ["10 or" deleted] up to 50 mg/kg [", up to" deleted] (approximately ["140" deleted] 225 times the maximum recommended daily ["oral" deleted] inhalation dose for adults ["and children" deleted] on a mg/m² basis, or approximately 110 times the maximum recommended daily inhalation dose for children on a mg/m² basis)."

Last paragraph revised (new text in italics) -

"Reproduction studies in rats ["revealed" deleted] demonstrated no evidence of impaired fertility at oral doses up to 50 mg/kg (approximately ["370" deleted] 340 times the maximum recommended daily inhalation dose for adults ["and children" deleted] on a mg/m² basis).

Pregnancy: Teratogenic Effects: Pregnancy Category C: Subsection revised (new text in italics) -

"Albuterol sulfate has been shown to be teratogenic in mice. A study in CD-1 mice at subcutaneous (sc) doses of 0.025, 0.25, and 2.5 mg/kg (approximately ["0.09, 0.9 and 9.0" deleted] 2/25, 1.0, and 8.0 times, respectively, the maximum recommended daily inhalation dose for adults on a mg/m² basis), showed cleft palate formation in 5 of 111 (4.5%) fetuses at 0.25 mg/kg and in 10 of 108 (9.3%) fetuses at 2.5 mg/kg. The drug did not induce cleft palate formation at the lowest dose, 0.025mg/kg. Cleft palate also occurred in 22 of 72 (30.5%) fetuses from females treated with 2.5 mg/kg of isoproterenol (positive control) ["subcutaneously" deleted] sc (approximately ["eight" deleted] 8 times the maximum recommended daily inhalation dose for adults on a mg/m² basis).

"A reproduction study in Stride Dutch rabbits revealed cranioschisis in 7 of 19 fetuses (37%) when albuterol sulfate was administered orally at a 50 mg/kg dose ["between days 1 and 29 of gestation," deleted] (approximately ["750" deleted] 680 times the maximum recommended daily inhalation dose for adults on a mg/m² basis)."

OVERDOSAGE:

Third paragraph revised (new text in italics) -

"The oral median lethal dose of albuterol sulfate in mice is greater than 2000 mg/kg (approximately ["7500" deleted] 6800 times the maximum recommended daily inhalation dose for adults on a mg/m² basis, or, approximately ["4400" deleted] 3200 times the maximum recommended daily inhalation dose for children on a mg/m² basis). In mature rats the ["subcutaneous" deleted] sc median lethal dose is approximately 450 mg/kg (approximately ["3300" deleted] 3000 times the maximum recommended daily inhalation dose for adults on a mg/m² basis, or, approximately ["2000" deleted] 1400 times the maximum recommended daily inhalation dose for children on a mg/m² basis). In small young rats the ["subcutaneous" deleted] sc median lethal dose is approximately 2000 mg/kg (approximately ["15000" deleted] 14,000 times the maximum recommended daily ["oral" deleted] inhalation dose for adults on a mg/m² basis, or, approximately ["3800" deleted] 6400 times the maximum recommended daily inhalation dose for children on a mg/m² basis). The inhalational median lethal dose ["could" deleted] has not been determined in animals.

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CLINICAL PHARMACOLOGY:

First paragraph, last sentence revised (new text in italics) -

"The precise function of these [", however, is" deleted] receptors has not ["yet" deleted] been established. (See WARNINGS).

INDICATIONS AND USAGE:

Section revised (new text in italics) -

"Volmax Extended-Release Tablets are indicated for the relief of bronchospasm in ["patients" deleted] adults and children 6 years of age and older with reversible obstructive airway disease."

CONTRAINDICATIONS:

Section revised (new text in italics) -

"Volmax Extended-Release Tablets are contraindicated in patients with a history of hypersensitivity to albuterol or any of ["their" deleted] its components."

WARNINGS:

Cardiovascular Effects: First paragraph revised (new text in italics) -

"["Controlled clinical studies and other clinical experience have shown that albuterol" deleted] Volmax Extended-Release Tablets, like all other beta-adrenergic agonists, can produce a clinically significant cardiovascular effect in some patients, as measured by pulse rate, blood pressure, and/or ["electrocardiographic changes" deleted] symptoms. although such effects are uncommon after administration of Volmax Extended-Release Tablets at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiogram (ECG) changes, such as flattening of the T wave, prolongation of the QT_c, and ST segment depression. The clinical significance of these findings is unknown. Therefore, Volmax Extended-Release Tablets, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension."

Deletion of last paragraph in subsection -

"As with other beta agonists, cardiac arrhythmias and sudden death have been reported in patients receiving Volmax. Whether these adverse events are directly related to Volmax administration is unclear."

Addition of new last paragraph in WARNINGS -

"Rarely, erythema multiforme and Stevens-Johnson syndrome have been associated with the administration of oral albuterol in children."

PRECAUTIONS:

Drug Interactions: First paragraph revised (new text in italics) -

"The concomitant use of Volmax Extended-Release Tablets and other oral sympathomimetic agents is not recommended since such combined use may lead to deleterious cardiovascular effects. this recommendation does not preclude the judicious use of an aerosol bronchodilator of the adrenergic stimulant type in patients receiving Volmax Extended-Release Taablets. Such concomitant use, however, should be individualized and not given on a routine basis. If regular coadministration is required, then alternative therapy should be considered."

Carcinogenesis, Mutagenesis, Impairment of Fertility: First paragraph revised (new text in italics) -

"In a 2-year study in Sprague-Dawley rats, albuterol sulfate, caused a significant dose-related increase in the incidence of benign leiomyomas of the mesovarium at ["oral" deleted] dietary doses of 2.0, 10, and 50 mg/kg ["/day, corresponding to" deleted] (approximately ["1, 5, and 25" deleted] 1/2, 3, and 15 times , respectively, the maximum recommended daily oral dose for adults ["and children," deleted] on a mg/m² basis ,or, approximately 2/5, 2, and 10 times, respectively, the maximum recommended daily oral dose for children on a mg/m² basis). In another study this effect was blocked by the coadministration of propranolol, a non-selective beta-adrenergic antagonist. ["The relevance of these findings to humans is not known." deleted] In an 18-month study in CD-1 mice, albuterol sulfate showed no evidence of tumorigenicity at dietary doses of up to ["50, 150, and" deleted] 500 mg/kg ["/day, up to" deleted] ( approximately ["125" deleted] 65 times the maximum recommended daily oral dose for adults ["and children" deleted] on a mg/m² basis, or, approximately 50 times the maximum recommended daily oral dose for children on a mg/m² basis) ["no evidence of tumorigenicity was seen" deleted]. In a ["study of" deleted] 22-month study in the Golden Hamster, ["with" deleted] albuterol sulfate showed no evidence of tumorigenicity ["was seen" deleted] at dietary doses of ["10 or" deleted] up to 50 mg/kg [", up to" deleted] (approximately ["16" deleted] 7 times the maximum recommended daily oral dose for adults and children on a mg/m² basis).

Last paragraph revised (new text in italics) -

"Reproduction studies in rats ["revealed" deleted] demonstrated no evidence of impaired fertility at oral doses up to 50 mg/kg (approximately ["25" deleted] 15 times the maximum recommended daily oral dose for adults ["and children" deleted] on a mg/m² basis).

Pregnancy: Teratogenic Effects: Pregnancy Category C: Subsection revised (new text in italics) -

"Albuterol sulfate has been shown to be teratogenic in mice. A study in CD-1 mice at subcutaneous (SC) doses of 0.025, 0.25, ["or" deleted] and 2.5 mg/kg ( approximately ["0.006, 0.06 and 0.6" deleted] 3/1000, 3/100, and 3/10 times the maximum recommended daily oral dose for adults on a mg/m² basis), ["induced" deleted] showed cleft palate formation in 5 to 111 (4.5%) fetuses at 0.25 mg/kg ["as well as" deleted] and in 10 of 108 (9.3%) fetuses at ["the" deleted] 2.5 mg/kg ["dose" deleted]. The drug did not induce cleft palate formation at the lowest dose, 0.025mg/kg. Cleft palate also occurred ["Isoproterenol, the positive control, induced cleft palate" deleted] in 22 of 72 (30.5%) fetuses of females treated with ["when administered at a SC dose of" deleted] 2.5 mg/kg of isoproterenol (positive control) subcutaneously (approximately ["0.6" deleted] 3/10 times the maximum recommended daily oral dose for adults on a mg/m² basis). ["In a" deleted] A reproduction study in Stride Dutch rabbits [", albuterol sulfate caused" deleted] revealed cranioschisis in 7/19 fetuses (37%) when albuterol sulfate was administered orally at a ["dose of" deleted] 50 mg/kg dose (approximately ["100" deleted] 25 times the maximum recommended daily oral dose for adults on a mg/m² basis).

"There are no adequate ["or" deleted] and well-controlled studies in pregnant women. Albuterol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

"During worldwide marketing experience, various congenital anomalies, including cleft palate and limb defects, have been rarely reported in the offspring of patients being treated with albuterol. Some of the mothers were taking multiple medications during their pregnancies. No consistent pattern of defects can be discerned, and a relationship between albuterol use and congenital anomalies has not been established."

Labor and Delivery: Subsection revised (new text in italics) -

["Oral albuterol has been shown to delay preterm labor in some reports; there are no well controlled studies that demonstrate that it will stop preterm labor or prevent labor at term." deleted] Because of the potential for beta-agonist interference with uterine contractility, use of Volmax Extended-Release Tablets for relief of bronchospasm during labor should be restricted to those patients in whom the benefits clearly outweigh the risks."

Tocolysis: New subsection heading. Text revised (new text in italics) -

"Albuterol has not been approved for the management of pre-term labor. The benefit:risk ratio when albuterol is administered for tocolysis has not been established. Serious adverse reactions including pulmonary edema have been reported during or following treatment of premature labor with beta₂-agonists, ["administration of" deleted] including albuterol ["to women in labor" deleted]."

OVERDOSAGE:

Third paragraph revised (new text in italics) -

"The oral median lethal dose of albuterol sulfate in mice is greater than 2000 mg/kg ( approximately ["500" deleted] 250 times the maximum recommended daily oral dose for adults ["and children" deleted] on a mg/m² basis, or, approximately 200 times the maximum recommended daily oral dose for children on a mg/m² basis). In mature rats , ["(500 - 600 g, 4 -5 months old)," deleted] the ["oral" deleted] subcutaneous median lethal dose of albuterol sulfate is approximately 450 mg/kg (approximately ["225" deleted] 110 times the maximum recommended daily oral dose for adults ["and children" deleted] on a mg/m² basis, or, approximately 90 times the maximum recommended daily oral dose for children on a mg/m² basis). In small young rats, ["(150-200 g, 1-2 months old)." deleted] the ["oral" deleted] subcutaneous median lethal dose is approximately 2000 mg/kg (approximately ["1000" deleted] 500 times the maximum recommended daily oral dose for adults ["and children" deleted] on a mg/m² basis, or, approximately 400 times the maximum recommended daily oral dose for children on a mg/m² basis)."

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