AMARYL (glimepiride)	AMIDATE (etomidate)	ARTHROTEC (diclofenac Na/ misoprostol)	ASTELIN (azelastine HCl)
AZACTAM (aztreonam)	AZMACORT (triamcinolone acetonide)	BRETHINE (terbutaline sulfate)	CEDAX (ceftibuten)
CEREZYME (imiglucerase)	CHLOROMYCETIN IV (chloramphenicol Na succinate)	CHLOROMYCETIN (chloramphenicol)	DIFLUCAN (fluconazole)
DOBUTAMINE	FURADANTIN (nitrofurantoin)	IMDUR (isosorbide mononitrate)	LUPRON (leuprolide acetate)
NASALIDE (flunisolide)	NITRO-DUR (nitroglycerin)	PRILOSEC (omeprazole)	PRIMAXIN IM (imipenem/ cilastatin)
PRIMAXIN IV (imipenem/ cilastatin)	PRINIVIL (lisinopril)	PRINZIDE (lisinopril/ hydrochlorothiazide)	RHINOCORT (budesonide)
SINGULAIR (montelukast Na)	TECZEM (enalapril maleate/ diltiazem maleate)	TRANSDERM-NITRO (nitroglycerin)	TUBOCURARINE CHLORIDE
VANCERIL (beclomethasone dipropionate)	VASERETIC (enalapril maleate/ hydrochlorothiazide)	VASOTEC (enalapril maleate)	VASOTEC IV (enalaprilat)
VERSED (midazolam HCl)	ZOFRAN (ondansetron HCl)	ZYBAN (bupropion HCl)

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CLINICAL PHARMACOLOGY:

Third paragraph, text added as new third sentence -

"However, clinical data indicates that etomidate administration in geriatric patients, particularly those with hypertension, may result in decreases in heart rate, cardiac index, and mean arterial blood pressure."

Text added as new sixth paragraph -

"In clinical studies, elderly patients demonstrated decreased initial distribution volumes and total clearance of etomidate. Protein binding of etomidate to serum albumin was also significantly decreased in these individuals."

PRECAUTIONS:

Geriatric Use (new subsection): "Clinical data indicates that etomidate may induce cardiac depression in elderly patients, particularly those with hypertension (see CLINICAL PHARMACOLOGY and OTHER ADVERSE OBSERVATIONS, Circulatory System).

"Elderly patients may require lower doses of etomidate than younger patients. Age-related differences in pharmacokinetic parameters have been observed in clinical studies (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

"This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function."

OTHER ADVERSE OBSERVATIONS:

Circulatory System: Text added as new second paragraph -

"Geriatric patients, particularly those with hypertension, may be at increased risk for the development of cardiac depression following etomidate administration (see CLINICAL PHARMACOLOGY).

DOSAGE AND ADMINISTRATION:

Text added at end of first paragraph -

"Geriatric patients may require reduced doses of etomidate."

PRECAUTIONS:

Geriatric Use: Existing text -

"Approximately 1800 patients treated with diclofenac in U.S. trials and 500 patients treated with ARTHROTEC in multinational trials were older than 65 years of age. No overall differences were observed between efficacy, adverse events or pharmacokinetic profiles of older and younger patients. However, as with any NSAID, the elderly are likely to tolerate adverse events less well than younger patients."

Deleted and replaced with -

"Of the more than 2100 subjects in clinical studies with Arthrotec, 25% were 65 and over, while 6% were 75 and over. In studies with diclofenac, 31% of subjects were 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older patients cannot be ruled out. As with any NSAID, the elderly are likely to tolerate adverse events less well than younger patients.

"Diclofenac is known to be substantially excreted by the kidney, and the risk of toxic reactions to Arthrotec may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (See PRECAUTIONS - Renal Effects).

"Based on studies in the elderly, no adjustment of the dose of Arthrotec is necessary in the elderly for pharmacokinetic reasons (See Pharmacokinetics of Arthrotec - Special populations), although many elderly may need to receive a reduced dose because of low body weight or disorders associated with aging."

ADVERSE REACTIONS:

Text added as new last paragraph -

"In addition, the following spontaneous adverse events have been reported during the marketing of Astelin Nasal Spray and may have no causal relationship with the drug: anaphylactoid reaction, application site reaction, chest pain, condition aggravated, confusion, diarrhea, dyspnea, facial edema, involuntary muscle contractions, paresthesia, parosmia, pruritis, rash, tolerance, urinary retention, vision abnormal, and xerophthalmia."

CLINICAL PHARMACOLOGY:

Microbiology: First paragraph, text added as new fourth sentence -

"It is active against many strains that are multiply-resistant to other antibiotics, such as certain cephalosporins, penicillin, and aminoglycosides."

First paragraph, last sentence that reads -

"Aztreonam is active in vitro and is effective in laboratory animal models and clinical infections against most strains of the following organisms, including many that are multiply-resistant to other antibiotics (i.e., certain cephalosporins, penicillin, and aminoglycosides):"

deleted and replaced with new second paragraph -

"Aztreonam has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section."

The title "Aerobic gram-negative microorganisms" added before first list of microorganisms. List of microorganisms reorganized into alphabetical order.

The following organisms had revisions (new text in italics) -

Citrobacter species, including C. freundii
Enterobacter species, including E. cloacae
["Serratia marcescens" deleted]
Serratia species, including S. marcescens

Third paragraph that reads -

"While in vitrostudies have demonstrated the susceptibility to aztreonam of most strains of the following organisms, clinical efficacy for infections other than those included in the INDICATIONS AND USAGE section has not been documented:"

deleted and replaced with -

"The following in vitro data are available, but their clinical significance is unknown.

"Aztreonam exhibits in vitro minimal inhibitory concentrations (MIC's) of 8 ug/mL or less against most (> or = 90%) strains of the following microorganisms; however, the safety and effectiveness of aztreonam in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials."

The title "Aerobic gram-negative microorganisms" added before second list of microorganisms. List of microorganisms reorganized into alphabetical order.

Text revised (new text in italics) -

Aeromonas hydophilia
Morganella morganii ["(formerly Proteus morganii)" deleted]
Neisseria gonorrhoeae (including penicillinase-producing strains)
["Neisseria meningitidis" deleted]
["Shigella species" deleted]
["Pseudomonas species" deleted]
Pasteurella multocida
Proteus vulgaris
Providencia ["species, including P. stuartii and P. rettgeri (formerly Proteus rettgeri)" deleted]
Providencia staurtii
Providencia rettgeri
Yersinia enterocolitica

Susceptibility Tests ["Testing" deleted]

Labeling for this subsection extensively revised. Contact the company for a copy of the new labeling/package insert.

DESCRIPTION:

Text added as new fourth sentence -

"The canister must be primed prior to the first use."

New fifth sentence, former fourth sentence revised (new text in italics) -

"After an initial priming of 2 actuations, each actuation delivers 200 mcg triamcinolone acetonide from the valve and 100 mcg from the spacer-mouthpiece under defined in vitro test conditions."

Text added as new sixth and seventh sentences -

"The canister will remain primed for 3 days. If the canister is not used for more than 3 days, then it should be reprimed with 2 actuations."

INFORMATION FOR THE PATIENT Sheet

STEP 5 revised (new text in italics): First paragraph - Remove the mouthpiece cap.

"To prepare your Azmacort Inhalation Aerosol for use, the inhaler must be primed prior to the first use. To prime, hold the inhaler upright, with the mouthpiece facing away from you. Shake the inhaler gently, then press the canister firmly and quickly. Repeat this procedure again so a total of 2 puffs are released. Your Azmacort Inhalation Aerosol is now ready for use.

"Repriming is only necessary when your inhaler has not been used for more than 3 days. To reprime, shake the inhaler and release one puff. Repeat this procedure again so a total of two puffs are released."

IMPORTANT TIPS FOR USING YOUR AZMACORT INHALATION AEROSOL INHALER

New third bullet -

"Remember, repriming is only necesary when the inhaler has not been used for more than 3 days. To reprime, shake the inhaler gently and release one puff. Repeat this procedure again so that a total of two puffs have been released. Do not reprime between more frequent usage."

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ADVERSE EVENTS:

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

"[In addition to the events reported during clinical trials with ceftibuten" deleted] The following adverse experiences have been reported during worldwide post-marketing surveillance: ["Cedax Capsules" deleted] aphasia, jaundice, melena, psychosis, serum sickness-like reactions, stridor and toxic epidermal necrolysis. ["Cedax Oral Suspension: Melena" deleted]"

WARNINGS:

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

Approximately 15% of ["85" deleted] patients treated and tested to date have developed IgG antibody to Cerezyme (imiglucerase for injection) during the first year of therapy."

ADVERSE REACTIONS:

Section revised (new text in italics) -

"Experience in ["over 200" deleted] patients treated with Cerezyme (imiglucerase for injection) ["to date" deleted] has revealed ["a small number of adverse events" deleted] that approximately 8.5% of patients experienced adverse events which were judged to be related to Cerezyme administration and which occurred with an increase in frequency. Some of the adverse events were related to the route of administration. These include: discomfort, pruritis, burning, swelling or sterile abscess at the site of venipuncture. Each of these events were found to occur in < 1% of the total patient population.

"Symptoms suggestive of hypersensitivity have been noted in ["a limited number" deleted] approximately 4% of patients. Onset of such symptoms has occurred during or shortly after infusions; these symptoms include: pruritis, flushing, urticaria/angioedema ["(a small number of patients have had upper airway involvement)" deleted], chest discomfort, ["and" deleted] respiratory symptoms, and hypotension. ["has been reported to occur during a few of these events" deleted] (See WARNINGS). Pretreatment with antihistamines and reduced rate of infusion has allowed continued use of Cerezyme in most patients. Each of these events were found to occur in <1% of the total patient population.

"Additional adverse reactions that have been reported in ["a limited number" deleted] approximately 4.5% of patients treated with Cerezyme include: nausea, abdominal pain, ["cramping" deleted] diarrhea, rash, fatigue, headache, fever, ["and" deleted] dizziness, chills, backache and tachycardia. Each of these events were found to occur in < 1% of the total patient population.

"In addition to the adverse reactions that have been observed in patients treated with Cerezyme, the following adverse reactions have been reported for this therapeutic class of drug: ["backache and" deleted] transient peripheral edema [", chills, abdominal discomfort, or" deleted] and vomiting. ["None of these events were judged to be serious." deleted]"

OVERDOSE:

Section revised (new text in italics) -

"["Effects of dosages exceeding 120 U/kg per four weeks have not been studied and therefore dosages above 120 U/kg are not recommended." deleted] Experience with doses up to 240 U/kg every two weeks have been reported. At that dose there have been no reports of obvious toxicity. "

DOSAGE AND ADMINISTRATION:

First paragraph revised (new text in italics) -

"Cerezyme (imiglucerase for injection) is administered by intravenous infusion over 1-2 hours. Dosage should be individualized to each patient. ["Initial dosage may be as little as 2.5 units/kg of body weight 3 times a week up to as much as 60 U/kg administered as frequently as once a week or as infrequently as every 4 weeks." deleted] Initial dosages range from 2.5 U/kg of body weight 3 times a week to 60 U/kg once every 2 weeks. 60 units/kg every 2 weeks is the dosage for which the most data are available. Disease severity may dictate that the treatment be initiated at a relatively high dose or relatively frequent administration. ["After patient response is well established, a reduction in dosage may be attempted for maintenance therapy. Progressive reductions can be made at intervals of 3-6 months while carefully monitoring response parameters" deleted] Dosage adjustments should be made on an individual basis, and may increase or decrease, based on achievement of therapeutic goals as assessed by routine comprehensive evaluations of the patient's clinical manifestations."

Fourth paragraph revised (new text in italics) -

"A nominal 5.0 ml volume is then withdrawn from each vial. The appropriate amount of Cerezyme for each patient is diluted with 0.9% Sodium Chloride Injection, USP, to a final volume of 100 to 200 mL. Cerezyme is administered by intravenous infusion over 1 to 2 hours. ["Alternately, the appropriate dose of Cerezyme may be administered such that a rate of no greater than 1 unit per kg body weight per minute is infused." deleted] or at a rate between 0.5-1.0 unit per kg body weight per minute. Aseptic techniques should be used when diluting the dose. Since Cerezyme does not contain any preservative, after reconstitution, vials should be promptly diluted and not stored for subsequent use. Cerezyme, after reconstitution, has been shown to be stable for up to 12 hours when stored at room temperature (25^o C) and at 2-8^oC. Cerezyme, when diluted ["to 50 mL" deleted] has been shown to be stable for up to 24 hours when stored at 2-8^oC ["(36-46^oF)" deleted]."

CLINICAL PHARMACOLOGY:

Drug Interaction Studies:

Rifabutin (new subsection): "There have been published reports that an interaction exists when fluconazole is administered concomitantly with rifabutin, leading to increased serum levels of rifabutin. (See PRECAUTIONS.)"

Tacrolimus (new subsection): "There have been published reports that an interaction exists when fluconazole is administered concomitantly with tacrolimus, leading to increased serum levels of tacrolimus. (see PRECAUTIONS.)"

Cisapride (new subsection): "A preliminary report from a placebo-controlled, randomized multiple-dose study in subjects given fluconazole 200 mg daily and cisapride 20 mg four times daily starting after 7 days of fluconazole dosing found that fluconazole significantly increased the AUC and Cmax of cisapride both after single (AUC 102% and Cmax 92% increases) and multiple (AUC 192% and Cmax 153% increases) dosing of cisapride. Fluconazole significantly increased the QTc interval in subjects receiving cisapride 20 mg four times daily for 5 days. (See CONTRAINDICATIONS and PRECAUTIONS.)"

CONTRAINDICATIONS:

Last sentence revised (new text in italics) -

"Coadministration of cisapride is contraindicated in patients receiving Diflucan (fluconazole). (See CLINICAL PHARMACOLOGY: Drug Interaction Studies and PRECAUTIONS.)"

PRECAUTIONS:

Drug Interactions:

Cisapride and Astemizole: Subsection revised and split into two new subsections (new text in italics-

"Cisapride: "There have been reports of cardiac events, including torsade de pointes in patients to whom fluconazole and cisapride were coadministered. The combined use of fluconazole with cisapride is contraindicated. (See CONTRAINDICATIONS and CLINICAL PHARMACOLOGY: Drug Interaction Studies.)

"Astemizole: The use of fluconazole in patients concurrently taking ["cisapride," deleted] astemizole or other drugs metabolized by the cytochrome P450 system may be associated with elevations in serum levels of these drugs. In the absence of definitive information, caution should be used when coadministering fluconazole. Patients should be carefully monitored."

Rifabutin (new subsection): "There have been reports of uveitis in patients to whom fluconazole and rifabutin were coadministered. Patients receiving rifabutin and fluconazole concomitantly should be carefully monitored. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.)"

Tacrolimus (new subsection): "There have been reports of nephrotoxicity in patients to whom fluconazole and tacrolimus were coadministered. Patients receiving tacrolimus and fluconazole concomitantly should be carefully monitored. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.)"

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ADVERSE REACTIONS:

Neurologic: Second paragraph revised (new text in italics)

[Note: this change appears in the 1999 PDR.]

"Asthenia, vertigo, ["and" deleted] nystagmus, dizziness, headache, and drowsiness have also been reported with the use of nitrofurantoin."

Allergic: Text added as new last sentence -

"Hypersensitivity reactions present the most frequent spontaneously-reported adverse events in worldwide postmarketing experience with nitrofurantoin formulations."

Miscellaneous: Text added as new last sentence -

"There are sporadic reports of Clostridium difficile superinfections, or pseudomembranous colitis with the use of nitrofurantoin."

Laboratory Events: Last two sentences in subsection deleted -

"Hypersensitivity reactions present the most frequent spontaneously-reported adverse events in worldwide postmarketing with nitrofurantoin formulations. In almost all cases the events are reversible after discontinuation of the drug."

DOSAGE AND ADMISTRATION:

The word "children" replaced with "pediatric patients" throughout section.

WARNINGS:

Text added as new first paragraph -

"Amplification of the vasodilatory effects of Imdur/Nitro-Dur patch by sildenafil can result in severe hypotension. The time course and dose dependence of this interaction have not been studied. Appropriate supportive care has not been studied, but it seems reasonable to treat this as a nitrate overdose, with elevation of the extremities and with central volume expansion."

CLINICAL PHARMACOLOGY:

Pharmacokinetics: Metabolism: Text added as new second paragraph -

"In a pharmacokinetic/pharmacodynamic study of endometriosis patients, intramuscular 11.25 mg Lupron Depot (n=19) every 12 weeks or intramuscular 3.75 mg Lupron Depot (n=15) every 4 weeks was administered for 24 weeks. There was no statistically significant difference between the 2 treatment groups in trough plasma concentrations of leuprolide or M-I collected from weeks 4 through 24. No accumulation of plasma leuprolide or M-I concentrations was observed with multiple dosing of either treatment group. There was also no statistically significant difference in changes of serum estradiol concentrations from baseline between the 2 treatment groups."

CLINICAL STUDIES:

Endometriosis: First paragraph, text added as new last sentence -

"Suppression is defined as no new menses for at least 60 consecutive days."

Uterine Leiomyomata (Fibroids): Fourth paragraph, text added as new second sentence -

"The pretreatment mean fibroid diameter was 6.3 cm and decreased to 5.6 cm at the end of treatment."

Fifth paragraph, text added as new third sentence -

"The pretreatment mean fibroid diameter was 5.6 cm and decreased to 4.7 cm at the end of treatment."

PRECAUTIONS:

6. First word changed from "Retreatment" to "Treatment"

ADVERSE REACTIONS:

Fifth paragraph, text added as new last sentence -

"In general the safety profiles of the two formulations were comparable in this study."

Table 3 - deleted

CHANGES IN LABORATORY VALUES DURING TREATMENT:

Chemistry (new subsection) -

"Slight to moderate mean increases were noted for glucose, uric acid, BUN, creatinine, total protein, albumin, bilirubin, alkaline phosphatase, LDH, calcium, and phosphorous."

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ADVERSE REACTIONS:

Body As A Whole: "Allergic reactions, including, rarely, anaphylaxis (see also Skin below)" added to beginning of subsection.

Skin: "purpura and/or petechiae (some with rechallenge)" added to list of reactions.

CLINICAL PHARMACOLOGY:

Microbiology: Subsection revised -

"Imipenem has been shown to be active in vitro against the following microorganisms; however, the clinical significance of these data is unknown." deleted and replaced with -

"Imipenem exibits in vitro minimal inhibitory concentrations (MICs) of 4 ug/mL or less against most ( > or = to 90%) strains of the following microorganisms: however, the safety and effectiveness of imipenem in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials."

Following this portion of the microbiology section , there have been extensive changes to the bacterial species listed in the 1999 PDR. Contact the company for a copy of the new labeling/package insert.

WARNINGS:

Fourth paragraph, third sentence revised (new text in italics) -

"In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation and treatment with an antibacterial drug clinically effective against C. difficile colitis."

CLINICAL PHARMACOLOGY:

Microbiology: Subsection revised -

"The following in vitro data are available, but their clinical significance is unknown. Imipenem exibits in vitro minimum inhibitory concentrations (MICs) of 4 ug/ml or less against most (greater than or equal to 90%) strains of the following microorganisms: however, the safety and effectiveness of imipenem in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials."

There have been extensive changes to the bacterial species listed in the 1999 PDR. Contact the company for a copy of the new labeling/package insert.

CONTRAINDICATIONS:

Section revised (new text in italics): -

"Prinivil is contraindicated in patients who are hypersensitive to this product and in patients with a history of angioedema related to previous treatment with an angiotensin converting enzyme inhibitor and in patients with hereditary or idiopathic angioedema."

PRECAUTIONS:

General: Aortic Stenosis/Hypertrophic Cardiomyopathy (new subsection): "As with all vasodilators, lisinopril should be given with caution to patients with obstruction in the outflow tract of the left ventricle."

Drug Interactions: Non-steroidal Anti-inflammatory Agents: (new subsection): "In some patients with compromised renal function who are being treated with non-steroidal anti-inflammatory drugs, the coadministration of lisinopril may result in a further deterioration of renal function. These effects are usually reversible."

The information formerly in the subsection "Indomethacin" now follows the above two sentences. The "Indomethacin" subheading has been deleted.

ADVERSE REACTIONS:

Respiratory System: "eosinophilic pneumonitis" added.

Special Senses: "taste disturbances" added.

OVERDOSAGE:

Second paragraph revised (new text in italics) -

"Lisinopril can be removed by hemodialysis. (See WARNINGS, Anaphylactoid reactions during membrane exposure.)"

CONTRAINDICATIONS:

First sentence revised (new text in italics) -

"Prinzide is contraindicated in patients who are hypersensitive to any component of this product and in patients with a history of angioedema related to previous treatment with an angiotensin converting enzyme inhibitor and in patients with hereditary or idiopathic angioedema."

PRECAUTIONS:

General: Lisinopril: Aortic Stenosis/Hypertrophic Cardiomyopathy (new subsection): "As with all vasodilators, lisinopril should be given with caution to patients with obstruction in the outflow tract of the left ventricle."

Drug Interactions: Lisinopril: Non-steroidal Anti-inflammatory Agents (new subsection): "In some patients with compromised renal function who are being treated with non-steroidal anti-inflammatory drugs, the coadministration of lisinopril may result in a further deterioration of renal function. These effects are usually reversible."

The information formerly in the subsection "Indomethacin" now follows the above two sentences. The "Indomethacin" subheading has been deleted.

ADVERSE REACTIONS:

Lisinopril:

Respiratory System- "eosinophilic pneumonitis" added

Special Senses- "taste disturbances" added

OVERDOSAGE:

Lisinopril:

Second paragraph revised (new text in italics) -

"Lisinopril can be removed by hemodialysis. (See WARNINGS, Anaphylactoid reactions during membrane exposure.)"

[NOTE: These changes appear in 1999 PDR]

ADVERSE REACTIONS:

Subsections "Incidence Less than 1% Causal Relationship Probable" and Incidence Less than 1% Causal Relationship Unknown" -

deleted and replaced with -

"Incidence Less than 1% (Based on control clinical trials):
Respiratory: dyspnea, moniliasis, hoarseness, wheezing, nasal pain.
Special Senses: reduced sense of smell, bad taste.
Digestive: nausea.
Skin and Appendages: facial edema, rash, pruritus, herpes simplex.
Nervous System: nervousness.
Musculoskeletal: myalgia, arthralgia.

"Adverse Event Reports from Other Sources: Rare adverse events reported in the published literature or from marketing experience include: immediate and delayed hypersensitivity reactions including rash, contact dermatitis, urticaria, angioedema, and bronchospasm; nasal septal disorders including atrophy, necrosis and/or perforation; symptoms of hypocorticism and hypercorticism; alopecia; psychiatric symptoms including depression, aggressive reactions, irritability, anxiety and psychosis."

PRECAUTIONS:

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

"No evidence of tumorigenicity was seen in either a 2-year carcinogenicity study in Sprague Dawley rats, at oral (gavage) doses up to 200 mg/kg/day ["(approximately 160 times the maximum recommended daily dose in adults and 190 times the maximum recommended daily oral dose in children , on a mg/m² basis)" deleted] (estimated exposure was approximately 120 times the area under the plasma concentration versus time curve (AUC) for adults and children at the maximum recommended daily oral dose) or in a 92-week carcinogenicity study in mice at oral (gavage) doses up to 100 mg/kg/day ["(approximately 40 times the maximum recommended daily oral dose in adults and 50 times the maximum recommended daily oral dose in children, on a mg/m² basis.)" deleted] (estimated exposure was approximately 45 times the AUC for adults and children at the maximum recommended daily oral dose).

Pregnancy, Teratogenic Effects: Pregnancy Category B: First paragraph, first two sentences revised (new text in italics) -

"No teratogenicity was observed in rats at oral doses up to 400 mg/kg/day ["(approximately 320 times the maximum recommended daily dose in adults, on a mg/m² basis.)" deleted] (estimated exposure was approximately 100 times the AUC for adults at the maximum recommended daily oral dose) and in rabbits at oral doses up to 300mg/kg/day ["(approximately 490 times the maximum recommended daily dose in adults, on a mg/m² basis.)" deleted] (estimated exposure was approximately 110 times the AUC for adults at the maximum recommended daily oral dose).

New paragraph added - "Merck & Co., Inc. maintains a registry to monitor the pregnancy outcomes of women exposed to Singulair while pregnant. Healthcare providers are encouraged to report any prenatal exposure to Singulair by calling the Pregnancy Registry at (800) 986-8999."

OVERDOSAGE:

First paragraph revised (new text in italics) -

"No mortality occurred following single oral doses of montelukast up to 5000 mg/kg in mice ["(approximately 2000 times the maximum recommended daily oral dose in adults and 2400 times the maximum recommended daily oral dose in children, on a mg/m² basis)" deleted] estimated exposure was approximately 340 times the AUC for adults and children at the maximum recommended daily oral dose) and rats ["(approximately 4100 times the maximum recommended daily oral dose in adults and 4800 times the maximum recommended daily oral dose in children, on a mg/m² basis)." deleted] (estimated exposure was approximately 230 times the AUC for adults and children at the maximum recommended daily oral dose)."

CONTRAINDICATIONS:

Second sentence revised (new text in italics)-

"Due to the enalapril component, Teczem is contraindicated in patients with a history of angioedema related to previous treatment with an angiotensin converting enzyme inhibitor and in patients with hereditary or idiopathic angioedema.

WARNINGS:

General: Enalapril Maleate: Neutropenia/Agranulocytosis: Third sentence revised -

"Marketing experience has revealed ["several" deleted] cases of neutropenia or agranolocytosis in which a causal relationship to enalapril cannot be excluded."

PRECAUTIONS:

General: Enalapril Maleate: Aortic Stenosis/Hypertrophic Cardiomyopathy (new subsection): -

"As with all vasodilators, enalapril should be given with caution to patients with obstruction in the outflow tract of the left ventricle."

Drug Interactions: Enalapril Maleate : Non-steroidal Anti-inflammatory Agents (new subsection): -

"In some patients with compromised renal function who are being treated with non-steroidal anti-inflammatory drugs, the coadministration of enalapril may result in a further deterioration of renal function. These effects are usually reversible."

ADVERSE REACTIONS:

Enalapril Maleate: Respiratory: "eosinophilic pneumonitis" added.

OVERDOSAGE:

Enalapril Maleate: Text added as new last sentence -

"(See WARNINGS, Anaphylactoid reactions during membrane exposure.)"

CONTRAINDICATIONS:

Text added as new first paragraph -

"Use of Transderm-Nitro (nitroglycerin) transdermal system is contraindicated in patients using Viagra (sildenafil) because sildenafil may amplify the vasodilatory effects of Transderm-Nitro resulting in severe hypotension."

CLINICAL PHARMACOLOGY:

Pharmacokinetics: New paragraph between first and second paragraph -

"Clinical data suggests that geriatric patients receiving tubocurarine chloride have a lower total body clearance, lower volume of distribution, and longer elimination half-life than younger patients."

PRECAUTIONS:

Geriatric Use (new subsection): "Clinical studies of Tubocurarine Chloride Injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosage range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Clinical data indicate the presence of age-related differences in pharmacokinetic parameters. (See CLINICAL PHARMACOLOGY, Pharmacokinetics and DOSAGE AND ADMINISTRATION, Adult and Geriatric Dosage.)

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. (See CLINICAL PHARMACOLOGY, Pharmacokinetics.)"

DOSAGE AND ADMINISTRATION:

Adult and Geriatric Dosage: First sentence, second paragraph revised (new text in italics) -

["Preliminary clinical data indicate that both dosage requirements and recovery times may be increased in elderly patients." deleted] "Due to the marked patient variability in response to tubocurarine, monitoring of neuromuscular function may be useful in geriatric patients. Clinical data indicate that recovery times may be increasd in these patients."

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CONTRAINDICATIONS:

First sentence revised (new text in italics)-

"Vaseretic is contraindicated in patients who are hypersensitive to any component of this product and in patients with a history of angioedema related to previous treatment with an angiotensin converting enzyme inhibitor and in patients with hereditary or idiopathic angioedema."

WARNINGS:

General: Enalapril Maleate: Neutropenia/Agranulocytosis: Third sentence revised -

"Marketing experience has revealed ["several" deleted] cases of neutropenia or agranolocytosis in which a causal relationship to enalapril cannot be excluded."

PRECAUTIONS:

General: Enalapril Maleate: Aortic Stenosis/Hypertrophic Cardiomyopathy (new subsection): -

"As with all vasodilators, enalapril should be given with caution to patients with obstruction in the outflow tract of the left ventricle."

Drug Interactions: Enalapril Maleate : Non-steroidal Anti-inflammatory Agents (new subsection): -

"In some patients with compromised renal function who are being treated with non-steroidal anti-inflammatory drugs, the coadministration of enalapril may result in a further deterioration of renal function. These effects are usually reversible."

ADVERSE REACTIONS:

Enalapril Maleate: Respiratory: "eosinophilic pneumonitis" added.

OVERDOSAGE:

Enalapril Maleate: Text added as new last sentence -

"(See WARNINGS, Anaphylactoid reactions during membrane exposure.)"

CONTRAINDICATIONS:

Section revised (new text in italics)-

"VASOTEC is contraindicated in patients who are hypersensitive to this product and in patients with a history of angioedema related to previous treatment with an angiotensin converting enzyme inhibitor and in patients with hereditary or idiopathic angioedema.

WARNINGS:

Neutropenia/Agranulocytosis:Third sentence revised -

"Marketing experience has revealed ["several" deleted] cases of neutropenia or agranolocytosis in which a causal relationship to enalapril cannot be excluded."

PRECAUTIONS:

General: Aortic Stenosis/Hypertrophic Cardiomyopathy (new subsection) -

"As with all vasodilators, enalapril should be given with caution to patients with obstruction in the outflow tract of the left ventricle."

Drug Interactions: Non-steroidal Anti-inflammatory Agents (new subsection): -

"In some patients with compromised renal function who are being treated with non-steroidal anti-inflammatory drugs, the co-administration of enalapril may result in a further deterioration of renal function. These effects are usually reversible."

ADVERSE REACTIONS:

Respiratory: "eosinophilic pneumonitis" added.

OVERDOSAGE:

Fourth paragraph, text added as new last sentence -

"(See WARNINGS, Anaphylactoid reactions during membrane exposure.)"

CONTRAINDICATIONS:

Section revised (new text in italics)-

"VASOTEC I.V. is contraindicated in patients who are hypersensitive to any component of this product and in patients with a history of angioedema related to previous treatment with an angiotensin converting enzyme inhibitor and in patients with hereditary or idiopathic angioedema.

WARNINGS:

Neutropenia/Agranulocytosis:Third sentence revised -

"Marketing experience has revealed ["several" deleted] cases of neutropenia or agranolocytosis in which a causal relationship to enalapril cannot be excluded."

PRECAUTIONS:

General: Aortic Stenosis/Hypertrophic Cardiomyopathy (new subsection) -

"As with all vasodilators, enalapril should be given with caution to patients with obstruction in the outflow tract of the left ventricle."

Drug Interactions: Non-steroidal Anti-inflammatory Agents (new subsection): -

"In some patients with compromised renal function who are being treated with non-steroidal anti-inflammatory drugs, the co-administration of enalapril may result in a further deterioration of renal function. These effects are usually reversible."

ADVERSE REACTIONS:

Respiratory: "eosinophilic pneumonitis" added.

OVERDOSAGE:

Fourth paragraph, text added as new last sentence -

"(See WARNINGS, Anaphylactoid reactions during membrane exposure.)"

PRECAUTIONS:

Geriatric Use (new subsection):

"Because geriatric patients may have altered drug distribution and diminished hepatic and/or renal function, reduced doses of Versed are recommended. Intravenous and intramuscular doses of Versed should be decreased for elderly and for debilitated patients (see WARNINGS and DOSAGE AND ADMINISTRATION) and subjects over 70 years of age may be particularly sensitive. These patients will also probably take longer to recover completely after Versed administration for the induction of anesthesia. Administration of IM and IV Versed to elderly and/or high risk surgical patients has been associated with rare reports of death under circumstances compatible with cardiorespiratory depression. In most of these cases, the patients also received other central nervous system depressants capable of depressing respiration, especially narcotics (see DOSAGE AND ADMINISTRATION).

"Specific dosing and monitoring guidelines for geriatric patients are provided in the DOSAGE AND ADMINISTRATION section for premedicated patients for sedation/anxiolysis/amnesia following IV and IM administration, for induction of anesthesia following IV administration and for continous infusion."

ADVERSE REACTIONS:

The list of adverse events reported "during controlled clinical trials or in the routine management of patients" split into the following two subsections and revised (new text in italics) -

"The following have been reported during controlled clinical trials:
Cardiovascular: Rare cases of angina (chest pain), electrocardiographic alterations, and tachycardia have been reported. In many cases, the relationship to Zofran Injection was unclear.
Gastrointestinal: Constipation has been reported in 11% of chemotherapy patients receiving multiday ondansetron.
Hepatic: In comparative trials in cisplatin chemotherapy patients with normal baseline values of aspartate transaminase (AST) and alanine transaminase (ALT), these enzymes have been reported to exceed twice the upper limit of normal in approximately 5% of patients. The increases were transient and did not appear to be related to dose or duration of therapy. On repeat exposure, similar transient elevations in transaminase values occurred in some courses, but symptomatic hepatic disease did not occur.
Integumentary: Rash has occurred in approximately 1% or patients receiving ondansetron.
Neurological: There have been rare reports consistent with, but not diagnostic of, extrapyramidal reaction in patients receiving Zofran Injection, and rare cases of grand mal seizure. The relationship to Zofran was unclear.
Other:Bronchospasm and rare cases of hypokalemia have been reported. The relationship to Zofran Injection was unclear."

and

"Observed During Clinical Practice: In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of intravenous formulations of Zofran. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. The events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to Zofran.
Cardiovascular: Arrhythmias (including ventricular and supraventricular tachycardia, premature ventricular contractions, and atrial fibrillation), electrocardiographic alterations (including second degree heart block), palpitations, and syncope.
General: Rare cases of hypersensitivity reactions, sometimes severe (e.g., anaphylaxis, bronchospasm, shortness of breath, hypotension, shock, angioedema, urticaria) have also been reported.
Hepatic: Liver failure and death have been reported in patients with cancer receiving concurrent medications including potentially hepatotoxic cytotoxic chemotherapy and antibiotics. The etiology of the liver failure is unclear.
Local reactions: Pain, redness, and burning at site of injection.
Neurological: Oculogyric crisis, appearing alone, as well as with other dystonic reactions.
Special Senses: Transient blurred vision, in some cases associated with abnormalities of accommodation."

CLINICAL PHARMACOLOGY:

Population Subgroups: Age: Subsection revised (new text in italics) -

"The effects of age on the pharmacokinetics of bupropion and its metabolites have not been fully characterized, but an exploration of steady-state bupropion concentrations from several depression efficacy studies involving patients dosed in a range of 300 to 750 mg/day, on a three times a day schedule, revealed no relationship between age (18 to 83 years) and plasma concentration of bupropion. A single-dose pharmacokinetic study demonstrated that the disposition of bupropion and its metabolites in elderly subjects was similar to that of younger subjects. These data suggest there is no prominent effect of age on bupropion concentrations; however, another pharmacokinetic study, single and multiple dose, has suggested that the elderly are at increased risk for accumulation of bupropion and its metabolites. (see PRECAUTIONS: ["Use in Elderly" deleted] Geriatric Use)."

PRECAUTIONS:

Pregnancy: Teratogenic Effects: Pregnancy Category B: Text added as new last paragraph - [Note: This change does appear in the 1999 PDR.]

"To monitor fetal outcomes of pregnant women exposed to Zyban, Glaxo Wellcome Inc. maintains a Bupropion Pregnancy Registry. Health care providers are encouraged to register patients by calling (800) 722-9292, ext. 39441."

Geriatric Use (title changed from "Use in the Elderly"): Subsection revised (new text in italics) -

"["In general, older patients are known to metabolize drugs more slowly and to be more sensitive to the side effects of drugs." deleted] Of the approximately ["5,600" deleted] 6,000 patients who participated in clinical trials with bupropion sustained-release tablets (depression and smoking cessation studies), ["303" deleted] 275 were ["60 to 69 years old and 88 were 70 years of age or older" deleted] 65 and over and 47 were 75 and over. ["The experience with patients 60 years of age or older was similar to that in younger patients." deleted] In addition, several hundred patients 65 and over participated in clinical trials using the immediate-release formulation of bupropion (depression studies). (No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.)

"A single-dose pharmacokinetic study demonstrated that the disposition of bupropion and its metabolites in elderly subjects was similar to that of younger subjects; however, another pharmacokinetic study, single and multiple dose, has suggested that the elderly are at increased risk for accumulation of bupropion and its metabolites. (see CLINICAL PHARMACOLOGY).

"Bupropion hydrochloride and its metabolites are almost completely excreted through the kidney and metabolites are likely to undergo conjugation in the liver prior to urinary excretion. The risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see Use in Patients with Systemic Illness).