[U.S. Food and Drug Administration]

MedWatch

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SUMMARY OF SAFETY-RELATED DRUG LABELING CHANGES APPROVED BY FDA
July 1998

(Posted: 8/25/98)

Note: The following summaries include only those safety-related sections that have been modified, and therefore do not contain all the information needed for safe and effective prescribing. Contact the manufacturer for the complete labeling/package insert.

NB: Comparison made to 1998 Physicians' Desk Reference (PDR), if drug's labeling included in the PDR.

Compiled with the help of:
Sharon Wilkerson, Pharm.D. Candidate
McWhorter School of Pharmacy
Samford University
Birmingham, AL

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Quick Reference:

(Click on name of the product to go directly to the summary.)

AMOXIL
(amoxicillin)
AVAPRO HCT
(irbesartan/
hydrochlorothiazide)
BIAXIN
(clarithromycin)
CARDIOQUIN
(quinidine
polygalacturonante)
COGNEX
(tacrine
HCl)
COREG
(carvedilol)
DOBUTREX
(dobutamine
HCl)
DYNABAC
(dirithromycin)
FASTIN
(phentermine
HCl)
GENOTROPIN
(somatropin
rDNA origin)
LANOXIN & LANOXICAPS
(digoxin)
LEXXEL
(enalapril maleate/
felodipine)
LIPITOR
(atorvastatin
Ca)
LOTENSIN
(benazepril
HCl)
LOTENSIN HCT
(benazepril HCl/
hydrochlorothiazide)
ORTHO-NOVUM
(norethindrone/
mestranol)
PLENDIL
(felodipine)
PREVACID
(lansoprazole)
PROPULSID
(cisapride)
QUINAGLUTE DURA-TABS
(quinidine
gluconate)
REZULIN
(troglitazone)
TEGRETOL
(carbamazepine)
TICLID
(ticlopidine
HCl)
VENTOLIN
(albuterol &
albuterol
sulfate)
VERELAN
(verapamil
HCl)
ZOCOR
(simvastatin)
ZOLADEX
(goserelin acetate)

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AMOXIL (amoxicillin) Capsules, Tablets, Chewable Tablets, & Powder for Oral Suspension
[July 10, 1998: SmithKline Beecham]

[Other labeling changes not appearing in the 1998 PDR: Feb98]

Labeling revised to incorporate information on a change in the dosing from thrice daily to twice daily in adults and to provide for the use of new swallow tablet formulations. Contact the company for a copy of the new labeling/package insert.

In addition, the following specific change is noted -

DOSAGE AND ADMINISTRATION:
Dosing recommendations for adults with impaired renal function (new subsection):

"Patients with impaired renal function do not generally require a reduction in dose unless the impairment is severe. Severely impaired patients with a glomerular filtration rate of < 30 mL/minute should not receive the 875-mg tablet. Patients with a glomerular filtration rate of 10 to 30 mL/minute should receive 500 mg or 250 mg every 12 hours, depending on the severity of the infection. Patients with a less than 10 mL/minute glomerular filtration rate should receive 500 mg or 250 mg every 24 hours, depending on severity of the infection.

"Hemodialysis patients should receive 500 mg or 250 mg every 24 hours, depending on severity of the infection. They should receive an additional dose of both during and at the end of dialysis.

"There are currently no dosing recommendations for pediatric patients with impaired renal function."

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AVAPRO HCT (irbesartan/hydrochlorothiazide) Tablets
[July 14, 1998: Bristol-Myers Squibb]

WARNINGS:
Fetal/Neonatal Morbidity and Mortality: Text added as new last paragraph in subsection:

"Thiazides cross the placental barrier and appear in cord blood. There is a risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults."

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BIAXIN (clarithromycin) Filmtabs
[July 21, 1998: Abbott]

[Other labeling changes not appearing in the 1998 PDR: Sep97]

PRECAUTIONS:
Drug Interactions: Text added as new indented fourth paragraph following the paragraph "The following drug interactions, other than increased serum concentrations of carbamazepine..." -

"As with other macrolides, clarithromycin has been reported to increase concentrations of HMG-CoA reductase inhibitors (e.g., lovastatin and simvastatin), through inhibition of cytochrome P450 metabolism of these drugs. Rare reports of rhabdomyolysis have been reported in patients taking these drugs concomitantly."

ADVERSE REACTIONS:
Post-Marketing Experience: First paragraph, second sentence revised (new text in italics) -

"Other spontaneously reported adverse events include glossitis, stomatitis, oral moniliasis, vomiting, tongue discoloration, thrombocytopenia, leukopenia, neutropenia, and dizziness."

Last sentence of first paragraph revised (new text in italics) -

"Reports of alterations of the sense of smell, usually in conjunction with taste perversion or taste loss have also been reported."

Second paragraph beginning "Transient CNS events including..." -

"manic behavior" and "tremor" added to list in alphabetical order.

Sentence added as fourth paragraph -

"There have been rare reports of hypoglycemia, some of which have occurred in patients taking oral hypoglycemic agents or insulin."

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CARDIOQUIN (quinidine polygalacturonate) Tablets
[July 1, 1998: Purdue Frederick]

PRECAUTIONS:
Drug Interactions: Altered pharmacokinetics of quinidine: -

Sentence added to end of sixth paragraph -

"Diltiazem significantly decreases the clearance and increases the t1/2 of quinidine, but quinidine does not alter the kinetics of diltiazem."

Drug Interactions: Non-interaction of quinidine with other drugs: -

Second paragraph, first sentence revised -

"Conversely, the pharmacokinetics of quinidine are not significantly affected by caffeine, ciprofloxacin, digoxin, ["diltiazem" deleted], felodipine, omeprazole, or quinine."

OVERDOSAGE:
Accelerated Removal: Fourth paragraph revised (new text in italics) -

"Following quinidine overdose, drugs that delay elimination of quinidine (cimetidine, carbonic-anhydrase inhibitors, diltiazem, thiazide diuretics) should be withdrawn unless absolutely required."

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COGNEX (tacrine HCl) Capsules
[July 2, 1998: Parke-Davis]

[Other labeling changes not appearing in 1998 PDR: Oct97]

PRECAUTIONS:
Drug-Drug Interactions: Fluvoxamine (new subsection):

"In a study of 13 healthy, male volunteers, a single 40 mg dose of tacrine added to fluvoxamine 100 mg/day administered at steady-state was associated with five- and eight-fold increases in tacrine Cmax and AUC, respectively, compared to the administration of tacrine alone. Five subjects experienced nausea, vomiting, sweating, and diarrhea following coadministration, consistent with the cholinergic effects of tacrine."

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COREG (carvedilol) Tablets
[July 28, 1998: SmithKline Beecham]

ADVERSE REACTIONS:
Incidence > 1% to < 2%: Postmarketing Experience (new subsection):

"The following adverse reaction has been reported in postmarketing experience: reports of aplastic anemia have been rare and received only when carvedilol was administered concomitantly with other medications associated with the event."

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DOBUTREX (dobutamine HCl) Injection
[July 29, 1998: Lilly]

CLINICAL PHARMACOLOGY:
Paragraph added at end of section -

"The effective infusion rate of dobutamine varies widely from patient to patient, and titration is always necessary (see Dosage and Administration). At least in pediatric patients, dobutamine-induced increases in cardiac output and systemic pressure are generally seen, in any given patients, at lower infusion rates than those that cause substantial tachycardia (see Pediatric Use under Precautions).

INDICATIONS AND USAGE:
Section revised (new text in italics) -

"Dobutrex Solution is indicated when parenteral therapy is necessary for inotropic support in the short-term treatment of ["adults" deleted] patients with cardiac decompensation due to decreased contractility resulting either from organic heart disease or from cardiac surgical procedures. Experience with intravenous dobutamine in controlled trials does not extend beyond 48 hours of repeated boluses and/or continuous infusions.

"Whether given orally, continuously intravenously, or intermittently intravenously, neither dobutamine nor any other cyclic-AMP-dependent inotrope has been shown in controlled trials to be safe or effective in the long-term treatment of congestive heart failure. In controlled trials of chronic oral therapy with various such agents, symptoms were not consistently alleviated, and the cyclic-AMP-dependent inotropes were consistently associated with increased risks of hospitalization and death. Patients with NYHA Class IV symptoms appeared to be at particular risk.

["In patients who have atrial fibrillation with rapid ventricular response, a digitalis preparation should be used prior to institution of therapy with Dobutrex Solution." deleted and moved to WARNINGS (see below)]"

WARNINGS:
1. Increase in Heart Rate or Blood Pressure: Text added as new second to last sentence in subsection -

"In patients who have atrial fibrillation with rapid ventricular response, a digitalis preparation should be used prior to institution of therapy with Dobutrex Solution."

PRECAUTIONS:
Pediatric Use: Subsection revised (new text in italics) -

"["The safety and effectiveness of Dobutrex Solution for use in children have not been studied." deleted]

"Dobutamine has been shown to increase cardiac output and systemic pressure in pediatric patients of every age group. In premature neonates, however, dobutamine is less effective than dopamine in raising systemic blood pressure without causing undo tachycardia, and dobutamine has not been shown to provide any added benefit when given to such infants already receiving optimal infusions of dopamine."

ADVERSE REACTIONS:
Miscellaneous Uncommon Effects: "adult" added prior to the word "patients" in the first sentence.

Longer-Term Safety: Subsection deleted.

DOSAGE AND ADMINISTRATION:
Recommended Dosage: Subsection revised (new text in italics) -

["The rate of infusion needed to increase cardiac output usually ranged from 2.5 to 15 ug/kg/min (see Table 1). On rare occasions, infusion rates up to 40 ug/kg/min have been required to obtain the desired effect. [See table above]" deleted]

"Infusion of dobutamine should be started at a low rate (0.5-1.0 ug/kg/min) and titrated at intervals of a few minutes, guided by the patient's response, including systemic blood pressure, urine flow, frequency of ectopic activity, heart rate, and (whever possible) measurements of cardiac output, central venous pressure, and/or pulmonary capillary wedge pressure. In reported trials, the optimal infusion rates have varied from patient to patient, usually 2-20 ug/kg/min but sometimes slightly outside of this range. On rare occasions, infusion rates up to 40 ug/kg/min have been required to obtain the desired effect. Rates of infusion ["in" deleted] (mL/h) for Dobutrex Solution concentrations of 500 ug/mL, 1,000 ug/mL, and 2,000 ug/mL necessary to attain various delivery rates of dobutamine (ug/kg/for patients of different weights are given in Table ("2" deleted] 1."

Table 1. Dobutrex Solution Infusion Rate (mL/kg/min) for Concentrations of 250, 500, and 1,000 ug/mL - Table deleted.

Table 2. Dobutrex Solution Infusion Rate (mL/h) for 500 ug/mL concentration - renumbered as Table 1, expanded and revised - See new labeling/package insert.

Third to last paragraph in subsection deleted -

"The rate of administration and the duration of therapy should be adjusted according to the patient's response as determined by heart rate, presence of ectopic activity, blood pressure, urine flow, and, whenever possible, measurement of central venous or pulmonary wedge pressure and cardiac output."

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DYNABAC (dirithromycin) Tablets
[July 22, 1998: Lilly]

[Other labeling changes not appearing in the 1998 PDR: Dec97]

WARNINGS:
The first two paragraphs of this section have been deleted.

PRECAUTIONS:
Drug Interactions: Terfenadine: "See WARNINGS" has been deleted and replaced with the following text -

"In a prospective study involving 6-healthy-male volunteers, dirithromycin did not affect the metabolism of terfenadine. These six volunteers received terfenadine alone (60 mg twice daily) for 8 days, followed by terfenadine in combination with dirithromycin (500 mg once daily) for 10 days. (Both drugs were thus dosed to steady state.) The pharmacokinetics of terfenadine and its acid metabolite and the electrocardiograph QTc interval were measured during both periods: with terfenadine alone, and with terfenadine plus dirithromycin. In five men, terfenadine levels were undetectable (<5ng/mL) throughout the study; in one man, the Cmax of terfenadine was 8.1 ng/mL with terfenadine alone and 7.2 ng/mL with terfenadine plus dirithromycin. The mean Cmax, Tmax, and AUC of the acid metabolite of terfenadine were not significantly changed. The mean QTc interval (msec) was 369 with terfenadine alone and 367 with terfenadine plus dirithromycin.

"Also, in vitro experiments demonstrated a lack of interaction between dirithromycin and terfenadine. Thus, the interaction observed between erythromycin and terfenadine is not expected for dirithromycin.

"Serious cardiac dysrhythmias, some resulting in death, have occurred in patients receiving terfenadine concomitantly with other macrolide antibiotics. In addition, most macrolides are contraindicated in patients receiving terfenadine therapy who have pre-existing cardiac abnormalities (arrhythmia, bradycardia, QTc interval prolongation, ischemic heart disease, congestive heart failure, etc.) or electrolyte disturbances. (See terfenadine package insert.)"

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FASTIN (phentermine HCl) Capsules
[July 16, 1998: SmithKline Beecham]

[Other labeling changes not appearing in the 1998 PDR: Oct97, Jan98]

WARNINGS:
Valvular Heart Disease:

Text added at end of first paragraph -

"The possibility of an association between valvular heart disease and the use of phentermine alone cannot be ruled out; there have been rare cases of valvular heart disease in patients who reportedly have taken phentermine alone."

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GENOTROPIN (somatropin [rDNA origin]) Injection
[July 30, 1998: Pharmacia & Upjohn]

[Other labeling changes not appearing in the 1998 PDR: Oct97]

Instructions for use of the Pen 5 & 12 delivery devices are now available. Contact the company for a copy.

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LANOXIN (digoxin) Injection & Pediatric Injection
and
LANOXICAPS (digoxin) Capsules
[July 15, 1998: Glaxo Wellcome]

Labeling revised to be consistent with the package insert for Lanoxin Tablets. Contact the company for a copy of the new labeling/package insert.

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LEXXEL (enalapril maleate/felodipine) Tablets
[July 22, 1998: Astra]

[Other labeling changes not appearing in the 1998 PDR: Mar98]

ADVERSE REACTIONS:
Felodipine as an Extended-Release Formulation: Endocrine (new subsection): "Gynecomastia."

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LIPITOR (atorvastatin Ca) Tablets
[July 10, 1998: Parke-Davis]

[Other labeling changes not appearing in the 1998 PDR: Oct97, Nov97, Feb98, Jun98]

Labeling revised to incorporate information on new indications - use as adjunctive therapy to diet for the treatment of patients with elevated serum triglyceride levels (Frederickson Type IV) and use for the treatment of patients with primary dysbetalipoproteinemia (Frederickson Type III) who do not respond adequately to diet. Contact the company for a copy of the new labeling/package insert.

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LOTENSIN (benazepril HCl) Tablets
[July 29, 1998: Novartis]

ADVERSE REACTIONS:
Other adverse experiences reported in controlled clinical trials (in less than 1% of benazepril patients) ...

New paragraph added at end of subsection -

"Another potentially important adverse experience, eosinophilic pneumonitis, has been attributed to other ACE inhibitors."

Dermatologic: Subsection revised (new text in italics) -

"Stevens-Johnson syndrome, pemphigus, apparent hypersensitivity reactions (manifested by dermatitis, pruritus, or rash), photosensitivity, and flushing. ["There have been rare reports of pemphigus in patients receiving ACE inhibitors." deleted] "

Hematologic: Subsection revised (new text in italics) -

"Thrombocytopenia and hemolytic anemia. ["There have been rare reports of hemolytic anemia in patients receiving ACE inhibitors." deleted]"

Other: "Alopecia" added to alphabetical list.

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LOTENSIN HCT (benazepril HCl/hydrochlorothiazide) Tablets
[July 29, 1998: Novartis]

ADVERSE REACTIONS:
Other adverse experiences reported in 0.3% or more Lotensin HCT patients... ...

Last paragraph in subsection revised (new text in italics) -

"Monotherapy with benazepril has been evaluated for safety in over 6000 patients. In clinical trials, the observed adverse reactions to benazepril were similar to those seen in trials of Lotensin HCT. In post-marketing experience with benazepril, there have been rare reports of Stevens-Johnson syndrome, pancreatitis, hemolytic anemia, pemphigus, and thrombocytopenia. Another potentially important adverse experience, eosinophilic pneumonitis, has been attributed to other ACE inhibitors."

Dermatologic: Subsection revised -

"Photosensitivity and pruritus. ["There have been rare reports of pemphigus in patients receiving ACE inhibitors." deleted] "

Gastrointestinal: Subsection revised -

"Gastroenteritis, flatulence, and tooth disorder. ["There have been rare reports of pancreatitis in patients receiving ACE inhibitors." deleted] "

Hematologic: Subsection deleted.

Other: Subsection revised (new text in italics) -

"Conjunctivitis, arthritis, urinary tract infection, alopecia, and urinary frequency."

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ORTHO-NOVUM 1+50 (norethindrone/mestranol) Tablets
[July 10, 1998: Ortho-McNeil]

WARNINGS:
Carcinoma of the Breast and Reproductive Organs: Text added as new second paragraph

"A meta-analysis of 54 studies reports that women who are currently using combined oral contraceptives or have used them in the past 10 years are at a slightly increased risk of having breast cancer diagnosed although the additional cancers tend to be localized to the breast. There is no evidence of an increased risk of having breast cancer diagnosed 10 or more years after cessation of use." [NOTE: This change does appear in the 1998 PDR.]

Third paragraph, first sentence revised -

"Some studies suggest that oral contraceptive use has been associated with an increase in the risk of cervical ["intraepithelial" deleted] neoplasia in some populations of women." [NOTE: This change does appear in the 1998 PDR.]

Hepatic Neoplasia: Second paragraph revised (new text in italics) -

"Studies ["from Britain" deleted] have shown an increased risk of developing hepatocellular carcinoma in ["long-term (>8 years)" deleted] oral contraceptive users. However, these cancers are rare in the U.S. ["and the attributable risk (the excess incidence) of liver cancers in oral contraceptive users approaches less than one per million users" deleted].

[NOTE: This change does appear in the 1998 PDR.]

[NOTE: The above changes to the "Carcinoma of the Breast and Reproductive Organs" subsection have also been incorporated into the Detailed Patient Labeling. The "Hepatic Neoplasia" changes have been incorporated into both the Detailed Patient Labeling and the Brief Patient Summary]

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PLENDIL (felodipine) Extended-Release Tablets
[July 14, 1998: Astra Merck]

[Other labeling changes not appearing in the 1998 PDR: Jan98]

PRECAUTIONS:
Pediatric Use: Subsection revised (new text in italics) -

"Safety and effectiveness in ["children" deleted] pediatric patients have not been established."

ADVERSE REACTIONS:
Endocrine (new subsection): "Gynecomastia."

OVERDOSAGE:
Text added at end of subsection -

"To obtain up-to-date information about the treatment of overdose, consult your Regional Poison-Control Center. Telephone numbers of certified poison-control centers are listed in the Physicians Desk Reference (PDR). In managing overdose, consider the possibilities of multiple-drug overdoses, drug-drug interactions, and unusual drug kinetics in your patient."

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PREVACID (lansoprazole) Delayed-Release Capsules
[July 20, 1998: TAP]

[Other labeling changes not appearing in the 1998 PDR: Jun97, Mar98, Jun98]

Labeling revised to incorporate information on a new 10-day dosing regimen for triple therapy, Prevacid in combination with clarithromycin and amoxicillin, for the eradication of Helicobacter pylori in patients with duodenal ulcer disease. Contact the company for a copy of the new labeling/package insert.

In addition, the following changes have been made -

PRECAUTIONS:
Information for Patients: Second paragraph, text added as last sentence -

"The granules have also been shown in vitro to remain intact when exposed to apple, cranberry, grape, orange, pineapple, prune, tomato, and V-8 vegetable juice and stored for up to 30 minutes."

DOSAGE AND ADMINISTRATION:
Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome: Third paragraph, text added as last sentence -

"The granules have also been shown in vitro to remain intact when exposed to apple, cranberry, grape, orange, pineapple, prune, tomato, and V-8 vegetable juice and stored for up to 30 minutes."

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PROPULSID (cisapride) Tablets, Suspension & Quicksolv Rapidly-Disintegrating Tablets
[July 31, 1998: Janssen]

[Other information regarding these changes: June 26, 1998 (Letter) - Janssen]

A Medication Guide, joined by a perforation to the package insert to be implemented with unit of use packaging. Contact the company for a copy of the new guide.

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QUINAGLUTE DURA-TABS (quinidine gluconate) Extended-Release Tablets
[July 1, 1998: Berlex]

PRECAUTIONS:
Drug Interactions: Altered pharmacokinetics quinidine: Text added as new first sentence -

"Diltiazem significantly decreases the clearance and increases the t1/2 of quinidine, but quinidine does not alter the kinetics of diltiazem."

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REZULIN (troglitazone) Tablets
[July 22, 1998: Parke-Davis]

[Other information regarding these changes: July 28, 1998 (Letter) - Parke-Davis]

[Other labeling changes not appearing in the 1998 PDR: Aug97, Nov97, Dec97]

CLINICAL PHARMACOLOGY:
Special Populations: Hepatic Insufficiency: Last sentence revised (new text I italics) -

"However, Rezulin therapy should not be initiated if the patient exhibits clinical ["or laboratory" deleted] evidence of active liver disease or increased serum transaminase levels ("e.g., ALT>3" deleted] ALT>1.5 times the upper limit of normal); see WARNINGS."

BOXED WARNING:

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

"["It is recommended that" deleted] Serum transaminase levels should be checked at the start of therapy, monthly for the first ["six" deleted] eight months of therapy, every two months for the remainder of the first year of ["troglitazone" deleted] Rezulin therapy, and periodically thereafter."

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

"Rezulin therapy should not be initiated if the patient exhibits clinical ["or laboratory" deleted] evidence of active liver disease or increased serum transaminase levels (["e.g., ALT>3" deleted] ALT>1.5 times the upper limit of normal) ["and should be discontinued if the patient has jaundice or laboratory measurements suggest liver injury (e.g., ALT>3 times the upper limit of normal)" deleted]. 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. If serum transaminase levels are moderately increased (ALT>1.5 to 2 times the upper limit of normal), liver function tests should be repeated within a week and then weekly until the levels return to normal. If at any time a patient has jaundice or ALT rises above 3 times the upper limit of normal, Rezulin should be discontinued."

PRECAUTIONS:
Information for Patients: Text added to third paragraph -

"Patients should be informed that blood will be drawn to check liver function at the start of therapy, monthly for the first eight months of therapy, every two months for the remainder of the first year of Rezulin therapy, and periodically thereafter."

DOSAGE AND ADMINISTRATON:
Monotherapy: Second and third sentences revised (new text in italics) -

"For patients not responding to 400 mg once daily, the Rezulin dose should be increased to 600 mg after ["6-8 weeks" deleted] one month. For patients not responding adequately to 600 mg after ["6-8 weeks" deleted] one month, Rezulin should be discontinued and alternative therapeutic options should be pursued."

Patients with Hepatic Insufficiency: First sentence revised (new text in italics) -

"Rezulin therapy should not be initiated if the patient exhibits clinical evidence of active liver disease or increased serum transaminase levels (ALT>1.5 ["to 2" deleted] times the upper limit of normal)."

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TEGRETOL (carbamazepine) Tablets, Chewable Tablets, & Suspension
and TEGRETOL-XR (carbamazepine) Tablets
[July 15, 1998: Novartis]

[Other information regarding these changes: March 1998 (Letter) - Novartis]

WARNINGS:
Usage in Pregnancy (new subsection): "Carbamazepine can cause fetal harm when administered to a pregnant woman.

"Epidemiological data suggest that there may be an association between the use of carbamazepine during pregnancy and congenital malformations, including spina bifida. In treating or counseling women of childbearing potential, the prescribing physician will wish to weigh the benefits of therapy against the risks. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

"Retrospective case reviews suggest that, compared with monotherapy, there may be a higher prevalence of teratogenic effects associated with the use of anticonvulsants in combination therapy. Therefore, if therapy is to be continued, monotherapy may be preferable for pregnant women.

"In humans, transplacental passage of carbamazepine is rapid (30-60 minutes), and the drug is accumulated in the fetal tissues, with higher levels found in liver and kidney than in brain and lung.

"Carbamazepine has been shown to have adverse effects in reproduction studies in rats when given orally in dosages 10-25 times the maximum human daily dosage (MHDD) of 1200 mg on a mg/kg basis or 1.5-4 times the MHDD on a mg/m2 basis. In rat teratology studies, 2 of 135 offspring showed kinked ribs at 250 mg/kg and 4 of 119 offspring at 650 mg/kg showed other anomalies (cleft palate, 1; talipes, 1; anophthalmos, 2). In reproduction studies in rats, nursing offspring demonstrated a lack of weight gain and an unkempt appearance at a maternal dosage level of 200 mg/kg.

"Antiepileptic drugs should not be discontinued abruptly in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In individual cases where the severity and frequency of the seizure disorder are such that removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy, although it cannot be said with any confidence that even minor seizures do not pose some hazard to the developing embryo or fetus.

"Tests to detect defects using currently accepted procedures should be considered a part of routine prenatal care in childbearing women receiving carbamazepine.

"There have been a few cases of neonatal seizures and/or respiratory depression associated with maternal Tegretol and other concomitant anticonvulsant drug use. A few cases of neonatal vomiting, diarrhea, and/or decreased feeding have also been reported in association with maternal Tegretol use. These symptoms may represent a neonatal withdrawal syndrome."

PRECAUTIONS:
Drug Interactions: Text added as new first paragraph -

"There has been a report of a patient who passed an orange rubbery precipitate in his stool the day after ingesting Tegretol suspension immediately followed by Thorazine solution. Subsequent testing has shown that mixing Tegretol suspension and chlorpromazine solution (both generic and brand name) as well as Tegretol suspension and liquid Mellaril resulted in the occurrence of this precipitate. Because the extent to which this occurs with other liquid medications is not known, Tegretol suspension should not be administered simultaneously with other liquid medicinal agents or diluents. (See Dosage and Administration)."

Pregnancy Category C: Subsection deleted and replaced with -

"Usage in Pregnancy: Pregnancy Category D (See Warnings)."

ADVERSE REACTIONS:
Pancreatic (new subsection): "Pancreatitis."

OVERDOSAGE:
Acute Toxicity: First paragraph deleted and replaced with -

"Lowest known lethal dose: adults, 3.2 g (a 24-year-old woman died of a cardiac arrest and a 24-year-old man died of pneumonia and hypoxic encephalopathy); children, 4 g (a 14-year-old girl died of cardiac arrest), 1.6 g (a 3-year-old girl died of aspiration pneumonia)."

DOSAGE AND ADMINISTRATION:
Text added as new first paragraph -

"Tegretol suspension in combination with liquid chlorpromazine or thioridazine results in precipitate formation, and, in the case of chlorpromazine, there has been a report of a patient passing an orange rubbery precipitate in the stool following coadministration of the two drugs. (See Drug Interactions). Because the extent to which this occurs with other liquid medications is not known. Tegretol suspension should not be administered simultaneously with other liquid medications or diluents."

Sentence added at end of fifth paragraph -

"Tegretol-XR tablet coating is not absorbed and is excreted in the feces; these coatings may be noticeable in the stool." [NOTE: This change does appear in the 1998 PDR.]

HOW SUPPLIED:
XR Tablets 400mg: Last sentence deleted -

"Samples, when available, are identified by the word SAMPLE appearing on each tablet."

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TICLID (ticlopidine) Tablets
[July 15, 1998: Roche]

[Other information regarding these changes: August 1998 (Letter) - Roche]

BOXED WARNING (new section):
"WARNING: Ticlid can cause life-threatening hematological adverse reactions, including neutropenia/agranulocytosis and thrombotic thrombocytopenic purpura (TTP).

"Neutropenia/Agranulocytosis: Among 2048 patients in clinical trials, there were 50 cases (2.4%) of neutropenia (less than 1200 neutrophils/mm3), and the neutrophil count was below 450/mm3 in 17 of these patients (0.8% of the total population).

"TTP: Thrombotic thrombocytopenic purpura was not seen during clinical trials, but US physicians reported about 100 cases between 1992 and 1997. Based on an estimated patient exposure of 2 million to 4 million, and assuming an event reporting rate of 10% (the true rate is not known), the incidence of ticlopidine-associated TTP may be as high as one case in every 2000 to 4000 patients exposed.

"Monitoring of Clinical and Hematologic Status: Severe hematological adverse reactions may occur within a few days of the start of therapy. The incidence of TTP peaks after about 3 to 4 weeks of therapy and neutropenia peaks at approximately 4 to 6 weeks with both declining thereafter. Only a few cases have arisen after more than 3 months of treatment.

"Hematological adverse reactions cannot be reliably predicted by any identified demographic or clinical characteristics. During the first 3 months of treatment, patients receiving Ticlid must, therefore, be hematologically and clinically monitored for evidence of neutropenia or TTP. If any such evidence is seen, Ticlid should be immediately discontinued.

"The detection and treatment of ticlopidine-associated hematological adverse reactions are further described under Warnings.

INDICATIONS AND USAGE:
Second paragraph revised (new text in italics) -

"Because Ticlid is associated with a risk of life-threatening blood dyscrasias including thrombotic thrombocytopenic purpura (TTP) and neutropenia/agranulocytosis ["which may be life-threatening" deleted] (see BOXED WARNING and WARNINGS), Ticlid should be reserved for patients who are intolerant or allergic to aspirin therapy ["where indicated to prevent stroke" deleted] or who have failed aspirin therapy."

CONTRAINDICATIONS:
Second bullet after "The use of Ticlid is contraindicated in the following conditions:" revised (new text in italics)-

"Presence of hematopoietic disorders such as neutropenia and thrombocytopenia or a past history of TTP"

WARNINGS:
The existing box warning has been deleted and the following text has been added -

"Hematological Adverse Reactions: Neutropenia: Neutropenia may occur suddenly. Bone-marrow examination typically shows a reduction in myeloid precursors. After withdrawal of ticlopidine, the neutrophil count usually rises to >1200/mm3 within 1 to 3 weeks.

"Thrombocytopenia: Rarely, thrombocytopenia may occur in isolation or together with neutropenia.

"Thrombotic Thrombocytopenic Purpura (TTP): TTP is characterized by thrombocytopenia, microangiopathic hemolytic anemia (schistocytes [fragmented RBCs] seen on peripheral smear), neurological findings, renal dysfunction, and fever. The signs and symptoms can occur in any order; in particular, clinical symptoms may precede laboratory findings by hours or days. With prompt treatment (often including plasmapheresis), 70% to 80% of patients will survive with minimal or no sequelae. Because platelet transfusions may accelerate thrombosis in patients with TTP on ticlopidine, they should, if possible, be avoided.

"Monitoring for Hematologic Adverse Reactions: Starting just before initiating treatment and continuing through the third month of therapy, patients receiving Ticlid must be monitored every 2 weeks. Because of ticlopidine's long plasma half-life, patients who discontinue ticlopidine during this 3-month period should continue to be monitored for 2 weeks after discontinuation. More frequent monitoring, and monitoring after the first 3 months of therapy, is necessary only in patients with clinical signs (e.g., signs or symptoms suggestive of infection) or laboratory signs (eg, neutrophil count less than 70% of the baseline count, decrease in hematocrit or platelet count) that suggest incipient hematological adverse reactions.

"Clinically, fever might suggest either neutropenia or TTP; TTP might also be suggested by weakness, pallor, petechiae or purpura, dark urine (due to blood, bile pigments, or hemoglobin) or jaundice, or neurological changes. Patients should be told to discontinue Ticlid and to contact the physician immediately upon the occurrence of any of these findings.

"Laboratory monitoring should include a complete blood count, with special attention to the absolute neutrophil count (WBC x % neutrophils), platelet count, and the appearance of the peripheral smear. Ticlopidine is occasionally associated with thrombocytopenia unrelated to TTP. Any acute, unexplained reduction in hemoglobin or platelet count should prompt further investigation for a diagnosis of TTP, and the appearance of schistocytes (fragmented RBCs) on the smear should be treated as presumptive evidence of TTP. If there are laboratory signs of TTP, or if the neutrophil count is confirmed to be <1200/mm3, then the drug should be discontinued."

PRECAUTIONS:
Information for the Patient (see PPI): Text added to end of first paragraph -

"Thrombocytopenia may be part of a syndrome called TTP. symptoms and signs of TTP, such as fever, weakness, difficulty speaking, seizures, yellowing of skin or eyes, dark or bloody urine, pallor or petechiae (pinpoint hemorrhagic spots on the skin), should be reported immediately."

ADVERSE REACTIONS:
Hematological: Subsection revised (new text in italics) -

"Neutropenia/thrombocytopenia, TTP (see BOXED WARNING and WARNINGS), agranulocytosis, eosinophilia, pancytopenia, thrombocytosis and bone-marrow depression have been reported."

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VENTOLIN (albuterol sulfate) Rotacaps
and
VENTOLIN (albuterol) Inhalation Aerosol
[July 30, 1998: Glaxo Wellcome]

[Other labeling changes not appearing in the 1998 PDR: Oct97, Nov97]

ADVERSE REACTIONS:
Second to last paragraph in section -

deleted and replaced with -

"Cases of urticaria, angioedema, rash, bronchospasm, hoarseness, oropharyngeal edema, and arrhythmias (including atrial fibrillation, supraventricular tachycardia, extrasystoles) have been reported after the use of Ventolin Rotacaps for Inhalation/Ventolin Inhalation Aerosol."

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VERELAN (verapamil HCl) Sustained-Release Pellet Filled Capsules
[July 14, 1998: Lederle]

[Other labeling changes not appearing in the 1998 PDR: Jul97]

PRECAUTIONS:
Drug Interactions: Other: Aspirin: (new subsection) -

"In a few reported cases, coadministration of verapamil with aspirin has led to increased bleeding times greater than observed with aspirin alone."

OVERDOSAGE:
"Treatment of overdosage should be supportive. Beta-adrenergic stimulation or parenteral administration of calcium solutions may increase calcium ion flux across the slow channel, and have been used effectively in treatment of deliberate overdosage with verapamil. Verapamil cannot be removed by hemodialysis. Clinically significant hypotensive reactions or high degree AV block should be treated with vasopressor agents or cardiac pacing, respectively. Asystole should be handled by the usual measures including cardiopulmonary resuscitation."

deleted and replaced with -

"There is no specific antidote for verapamil overdosage; treatment should be supportive. Delayed pharmacodynamic consequences may occur with sustained-release formulations, and patients should be observed for at least 48 hours, preferably under continuous hospital care. Reported effects include hypotension, bradycardia, cardiac conduction defects, arrhythmias, hyperglycemia, and decreased mental status. In addition, there have been literature reports of noncardiogenic pulmonary edema in patients taking large overdoses of verapamil (up to approximately 9g).

"In acute overdosage, gastrointestinal decontamination with cathartics and whole bowel irrigation should be considered. Calcium, inotropes (i.e., isoproterenol, dopamine, and glucagon), atropine, vasopressors (i.e., norepinephrine, and epinephrine), and cardiac pacing have been used with variable results to reverse hypotension and myocardial depression. In a few reported cases, overdose with calcium channel blockers that was initially refractory to atropine became more responsive to this treatment when the patients received large doses (close to 1 gram/hour for more than 24 hours) of calcium chloride. Calcium chloride is preferred to calcium gluconate since it provides 3 times more calcium per volume. Asystole should be handled by the usual measures including cardiopulmonary resuscitation. Verapamil cannot be removed by hemodialysis."

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ZOCOR (simvastatin) Tablets
[July 10, 1998: Merck]

[Other labeling changes not appearing in the 1998 PDR: May97, Aug97, Oct97, Mar98, Jun98]

Labeling changed to provide for the use of a new dosage strength (80 mg) and dosing regimen (80 mg per day) and to incorporate information on a new indication - treatment of patients with homozygous familial hypercholesterolemia. Contact the company for a copy of the new labeling/package insert.

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ZOLADEX (goserelin acetate) Pellet, Implant
[July 27, 1998: Zeneca]

[Other labeling changes not appearing in the 1998 PDR: Jun97, Apr98]

Labeling changed to incorporate information on a new use - in combination with flutamide for the management of locally confined Stage T2b-T4 (Stage B2-C) carcinoma of the prostate. Contact the company for a copy of the new labeling/package insert.

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