SUMMARY OF SAFETY-RELATED DRUG LABELING CHANGES APPROVED BY FDA
DECEMBER 2000

(Posted: 3/30/01)

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 2000 Physicians' Desk Reference (PDR), if drug's labeling included in the PDR.

Quick Reference:

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

AGENERASE (amprenavir) Capsules & Oral Solution
[December 19, 2000: Glaxo Wellcome]

WARNINGS:

New paragraph:

Concomitant use of AGENERASE and St. John's wort (hypericum perforatum) or products

containing St. John's wort is not recommended. Coadministration of protease inhibitors,

including AGENERASE, with St. John's wort is expected to substantially decrease protease

inhibitor concentrations and may result in suboptimal levels of amprenavir and lead to loss of

virologic response and possible resistance to AGENERASE or to the class of protease inhibitors.

PRECAUTIONS: Information for Patients - 

New text in bolded italics:

AGENERASE may interact with some drugs; [" Some drugs should not be used with

AGENERASE" deleted]. Therefore, patients should be advised to report to their doctor the

use of any other prescription, or nonprescription medication, or herbal products, particularly St.

John's wort.

Patient Package Insert 

New bulleted text: 

Taking AGENERASE with St. John’s Wort (hypericum perforatum, a nonprescription herbal

product) or products containing St. John’s Wort is not recommended. Talk with your doctor.35

if you are taking or are planning to take St. John’s Wort because St. John's Wort may reduce

the effect of AGENERASE.

ANTIZOL (fomepizole) Injection

[December 8, 2000: Orphan Medical, Inc.]

This supplemental new drug application provides for the use of Antizol for suspected or confirmed

methanol poisoning, either used alone or in combination with hemodialysis. Contact the company for a copy of the label/package insert.

CELEBREX (celecoxib) Capsules
[December 1, 2000: Searle]

PRECAUTIONS:

Pregnancy:

Previous text revised -

Teratogenic effects:   Pregnancy Category C. Celecoxib was not teratogenic in rabbits up to an oral dose of 60 mg/kg/day (equal to human exposure at 200 mg BID as measured by AUC _0-24 ); however, at oral doses greater than or equal to150 mg/kg/day (approximately 2-fold human exposure at 200 mg BID as measured by AUC _0-24 ), an increased incidence of fetal alterations, such as ribs fused, sternebrae fused and sternebrae misshapen, was observed. A dose-dependent increase in diaphragmatic hernias was observed in one of two rat studies at oral doses greater than or eaual to 30 mg/kg/day (approximately 6-fold human exposure based on the AUC _0-24 at 200 mg BID). There are no studies in pregnant women. CELEBREX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Revised text in bolded italics - 

Teratogenic effects: Pregnancy Category C. Celecoxib at oral doses greater than or equal to 150 mg/kg/day

(approximately 2-fold human exposure at 200 mg BID as measured by AUC _0–24 ), caused an increased incidence of ventricularseptal defects, a rare event, and fetal alterations, such as ribs fused, sternebrae fused and sternebrae misshapen, when rabbits were treated throughout organogenesis. A dose-dependent increase in diaphragmatic hernias was observed when rats were given celecoxib at oral doses greater than or equal to 30 mg/kg/day (approximately 6 - fold human exposure based on the AUC _0–24 at 200 mg BID) throughout organogenesis. There are no studies in pregnant women. CELEBREX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

CellCept  (mycophenolate mofetil) Capsules, Tablets & Oral Solution 
[December 20, 2000: Syntex ]

These supplemental new drug applications provide for the use of CellCept  (mycophenolate mofetil)

Capsules, Tablets, and Oral Solution for the prevention of acute rejection in pediatric renal transplant

patients. Contact the company for a copy of the new labeling/package insert or go to the following link:

http://www.fda.gov/cder/ogd/rld/rld_labeling_approved_december_2000.html

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CLARITIN (loratadine) Syrup
[December 4, 2000: Schering]

This supplemental new drug application provides for the use of Claritin  for the relief

of nasal and non-nasal symptoms of seasonal allergic rhinitis and for the treatment of chronic idiopathic

urticaria in patients 2 years of age and older. Contact the company for a copy of the new labeling/package insert or go to the following link:

http://www.fda.gov/cder/ogd/rld/rld_labeling_approved_december_2000.html

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CYTOVENE  (ganciclovir & ganciclovir sodium) Capsules &  Injection

 [December 1, 2000: Hoffman-LaRoche]

New text in bolded italics - 

The pharmacokinetic profiles of CYTOVENE-IV and CYTOVENE in elderly patients have not been established. Since elderly individuals frequently have a reduced glomerular filtration rate, particular attention should be paid to assessing renal function before and during administration of CYTOVENE-IV or CYTOVENE (see DOSAGE AND ADMINISTRATION).

Clinical studies of CYTOVENE-IV and CYTOVENE 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." Deleted] In general, dose selection for an elderly patient should be cautious, ["usually starting at the low end of the dosing range," deleted] reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. CYTOVENE-IV and CYTOVENE are 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. In addition, renal function should be monitored and dosage adjustments should be made accordingly (see Use in Patients With Renal Impairment and DOSAGE AND ADMINISTRATION).

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GLUCOPHAGE (metformin HCl )
[December 15, 2000: Bristol-Myers Squibb]

This supplemental new drug application provides for the use of Glucophage for the treatment of type 2

diabetes in pediatric patients (ages 10-16 years) Contact the company for a copy of the new labeling/package insert.

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The Geriatric Use subsection of Precautions formerly read:

[2000 PDR]

Use in the Elderly: Although the pharmacokinetic disposition of the drug in elderly is

similar to that seen in younger adults, there is no information about the safety and

effectiveness of sumatriptan in this population because patients over age 65 were

excluded from the controlled clinical trials.

And now reads:

[2001 PDR]

Geriatric Use:The use of sumatriptan in elderly patients is not recommended because elderly patients are

more likely to have decreased hepatic function,they are at higher risk for CAD,and blood pressure

increases may be more pronounced in the elderly (see WARNINGS).

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LESCOL (fluvastatin sodium) Capsules
[December 18, 2000: Novartis]

This supplemental new drug application provides for the addition of data on the HDL-raising effects of

Lescol (fluvastatin sodium) at daily doses of 20 mg, 40 mg, and 80 mg (40 mg twice a day) to be

included under the Clinical Studies subsection of the CLINICAL PHARMACOLOGY section of the

package insert. Contact the company for a copy of the new labeling/package insert or go to the following link:

http://http://www.fda.gov/cder/ogd/rld/rld_labeling_approved_december_2000.html

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MAXALT & MAXALT MLT (rizatriptan) Tablets
[December 11, 2000: Merck]

WARNINGS:

New text in bolded italics:

Cardiac Events and Fatalities Associated with 5-HT1 Agonists: Serious adverse cardiac events, including acute myocardial infarction, have been reported within a few hours following the administration of rizatriptan. Life-threatening disturbances of cardiac rhythm and death have been reported within a few hours following the administration of other 5-HT1 agonists. Considering the extent of use of 5-HT1 agonists in patients with migraine, the incidence of these events is extremely low. MAXALT can cause coronary vasospasm. Because of the close proximity of the events to MAXALT use, a causal relationship cannot be excluded. In the cases where there has been known underlying coronary artery disease, the relationship is uncertain.

Postmarketing experience with rizatriptan: Serious cardiovascular events have been reported in association with the use of MAXALT. The uncontrolled nature of postmarketing surveillance, however, makes it impossible to determine definitively the proportion of the reported cases that were actually caused by rizatriptan or to reliably assess causation in individual cases.

PRECAUTIONS:

New text in bolded italics:

In a general reproductive study in rats, birth weights and pre- and post-weaning weight gain were reduced in the offspring of females treated prior to and during mating and throughout gestation and lactation with doses of 10 and 100 mg/kg/day. Maternal drug exposures (AUC) at these doses were approximately 15 and 225 times, respectively, the exposure in humans receiving the maximum recommended daily dose (MRDD) of 30 mg. In a pre- and post-natal developmental toxicity study in rats, an increase in mortality of the offspring at birth and for the first three days after birth, a decrease in pre-and post-weaning weight gain, and decreased performance in a passive avoidance test (which indicates a decrease in learning capacity of the offspring) were observed at doses of 100 and 250 mg/kg/day. The no-effect dose for all of these effects was 5 mg/kg/day, approximately 7.5 times the exposure in humans receiving the MRDD. With doses of 100 and 250 mg/kg/day, the decreases in average weight of both the male and female offspring persisted into adulthood. All of these effects on the offspring in both reproductive toxicity studies occurred in the absence of any apparent maternal toxicity.

Pediatric Use:

This paragraph replaces the previous subsection - 

The efficacy of MAXALT Tablets (5 mg) in patients aged 12 to 17 years was not established in arandomized placebo-controlled trial of 291 adolescent migraineurs (see Clinical Studies). Adverse events observed were similar in nature to those reported in clinical trials in adults. Postmarketing experience with other triptans includes a limited number of reports that describe pediatric patients who have experienced clinically serious adverse events that are similar in nature to those reported rarely in adults. The long-term safety of rizatriptan in pediatric patients has not been studied.

ADVERSE REACTIONS:

Previous subsection replaced with the following text:

The following section enumerates potentially important adverse events that have occurred in clinical practice and which have been reported spontaneously to various surveillance systems. The events enumerated represent reports arising from both domestic and non-domestic use of rizatriptan. The events enumerated include all except those already listed in the ADVERSE REACTIONS section above or those too general to be informative. Because the reports cite events reported spontaneously from worldwide postmarketing experience, frequency of events and the role of rizatriptan in their causation cannot be reliably determined.

Cardiovascular: Myocardial ischemia, Myocardial infarction (see WARNINGS).

Cerebrovascular: Stroke.

Skin and Skin Appendage: Toxic epidermal necrolysis.

Special Senses: Dysgeusia.

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NASONEX (mometasone furoate) Nasal Spray
[December 1, 2000: Schering]

ADVERSE REACTIONS:

New text in bolded italics - 

In postmarketing surveillance of this product, cases of nasal burning and irritation, anaphylaxis and angioedema and rare cases of nasal septal perforation have been reported.

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PROGRAF (tacrolimus) Capsules & Injection
[December 1, 2000: Fujisawa]

CLINICAL PHARMACOLOGY:

Pharmacokinetics:

Special Populations:

New text in bolded italics - 

Hepatic Insufficiency:

Tacrolimus pharmacokinetics have been determined in six patients with mild hepatic dysfunction (mean Pugh score: 6.2) following single IV and oral administrations. The mean clearance of tacrolimus in patients with mild hepatic dysfunction was not substantially different from that in normal volunteers (see previous table). Tacrolimus pharmacokinetics were studied in 6 patients with severe hepatic dysfunction (mean Pugh score:>10). The mean clearance was substantially lower in patients with severe hepatic dysfunction, irrespective of the route of administration.

PRECAUTIONS:

Drugs that May Alter Tacrolimus Concentrations:

New text in bolded italics - 

Since tacrolimus is metabolized mainly by the CYP3A enzyme systems, substances known to inhibit these enzymes may decrease the metabolism or increase bioavailability of tacrolimus with resultant increases in as indicated by increased whole blood or plasma concentrations. Drugs known to induce these enzyme systems may result in an increased metabolism of tacrolimus and or decreased bioavailability as indicated by decreased whole blood or plasma concentrations. Monitoring of blood concentrations and appropriate dosage adjustments are essential when such drugs are used concomitantly.

In a study of 6 normal volunteers, a significant increase in tacrolimus oral bioavailability (14±5% vs. 30±8%) was observed with concomitant ketoconazole administration (200 mg). The apparent oral clearance of tacrolimus during ketoconazole administration was significantly decreased compared to tacrolimus alone (0.430±0.129 L/hr/kg vs. 0.148±0.043 L/hr/kg). Overall, IV clearance of tacrolimus was not significantly changed by ketoconazole co-administration, although it was highly variable between patients.

In a study of 6 normal volunteers, a significant decrease in tacrolimus oral bioavailability (14±6% vs. 7±3%) was observed with concomitant rifampin administration (600 mg). In addition, there was a significant increase in tacrolimus clearance (0.036±0.008 L/hr/kg vs. 0.053±0.010 L/hr/kg) with concomitant rifampin administration. Interaction studies with drugs used in HIV therapy have not been conducted. However, care should be exercised when drugs that are nephrotoxic (e.g., ganciclovir) or that are metabolized by CYP3A (e.g., ritonavir) are administered concomitantly with tacrolimus. Tacrolimus may affect the pharmacokinetics of other drugs (e.g., phenytoin) and increase their concentration. Grapefruit juice affects CYP3A-mediated metabolism and should be avoided (See DOSAGE AND ADMINISTRATION).

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PROVENTIL (albuterol) Inhalation Aerosol
[December 4, 2000: Schering]

DESCRIPTION:

The following text added to the section:

Proventil Inhalation Aerosol should be primed by actuating into the air, away from the eyes and face, four times before using for the first time and two times when the aerosol has not been used for a period of at least four days.

DOSAGE AND ADMINISTRATION:

Fifth paragraph deleted

It is recommended to "test spray" PROVENTIL Inhalation Aerosol into the air before using for the first time and in cases where the aerosol has not been used for a prolonged period of time.

Replaced with - 

As with all other inhalation aerosol medications, patients should make sure that the canister is firmly seated in the plastic mouthpiece adapter before each use and the product is primed at specific times. Patients should prime Proventil Inhalation Aerosol by actuating into the air, away from the eyes and face, four times before using for the first time and two times when the aerosol has not been used for a period of at least four days.

Patient’s Instruction for Use:

Instruction 2. deleted - 

2. As with all aerosol medications, it is recommended to "test spray" into the air before using for the first time and in cases where the aerosol has not been used for a prolonged period of time.

Replaced with - 

2. As with all other inhalation aerosol medications, patients should make sure that the canister is firmly seated in the plastic mouthpiece adapter before each use and the product is primed at specific times. Patients should prime Proventil Inhalation Aerosol by actuating into the air, away from the eyes and face, four times before using for the first time and two times when the aerosol has not been used for a period of at least four days.

REBETRON (ribavirin & interferon alpha-2b)  Capsules & Injection
[December 18, 2000: Schering]

[Not in 2000 PDR]

The Following Deleted - 

SEVERE PSYCHIATRIC ADVERSE EVENTS, INCLUDING DEPRESSION AND SUICIDAL BEHAVIOR (SUICIDAL IDEATION, SUICIDAL ATTEMPTS, AND SUICIDES) HAVE OCCURRED DURING COMBINATION REBETOL/INTRON A THERAPY AND WITH INTERFERON ALPHA MONOTHERAPY (including INTRON A therapy), BOTH IN PATIENTS WITH AND WITHOUT A PREVIOUS PSYCHIATRIC ILLNESS. REBETOL/INTRON A therapy should be used with extreme caution in patients with a history of pre-existing psychiatric disorders who report a history of severe depression, and physicians should monitor all patients for evidence of depression. In severe cases, therapy should be stopped and psychiatric intervention sought. In general, the adverse events resolve on cessation of therapy; however, adjunctive psychiatric medications may be required. (See ADVERSE REACTIONS.)

Replaced with - 

Severe psychiatric adverse events, including depression, psychoses, aggressive behavior, hallucinations, violent behavior (suicidal ideation, suicidal attempts, suicides) and rare instances of homicidal ideation have occurred during combination Rebetol/Intron A therapy, both in patients with and without a previous psychiatric disorder.  Rebetol/Intron A therapy should be used with extreme caution in patients with a history of pre-existing psychiatric disorders, and all patients should be carefully monitored for evidence of depression and other psychiatric symptoms. Suspension of Rebetol/Intron A therapy should be considered if psychiatric intervention and/or dose reduction is unsuccessful in controlling psychiatric symptoms. In severe cases, therapy should be stopped immediately and psychiatric intervention sought. (See ADVERSE REACTIONS.)

Other -

[Not in 2000 PDR]

 New second bullet added - 

Fatal and non-fatal pancreatitis has been observed in patients treated with REBETOL/INTRON A therapy.

REBETOL/INTRON A therapy should be suspended in patients with signs and symptoms of pancreatitis

and discontinued in patients with confirmed pancreatitis.

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SYMMETREL (amantadine HCl) Tablets & Syrup
[December 6, 2000:  Endo Pharmaceuticals]

New text in bolded italics - 

Deaths: Deaths have been reported from overdose with SYMMETREL. The lowest reported acute lethal dose was 1 gram ["2 grams" deleted]. Acute toxicity may be attributable to the anticholinergic effects of amantadine. Drug overdose has resulted in cardiac, respiratory, renal or central nervous system toxicity. Cardiac dysfunction includes arrhythmia, tachycardia and hypertension (see OVERDOSAGE).

PRECAUTIONS:

New text in bolded italics - 

Other: The dose of SYMMETREL may need careful adjustment in patients with congestive heart failure, peripheral edema, or orthostatic hypotension. Care should be exercised when administering SYMMETREL to patients with a history of recurrent eczematoid rash, or to patients with psychosis or severe psychoneurosis not controlled by chemotherapeutic agents.

Serious bacterial infections may begin with influenza-like symptoms or may coexist with or occur as complications during the course of influenza. SYMMETREL has not been shown to prevent such complications.

OVERDOSAGE:

New text in bolded italics -

  Deaths: Deaths have been reported from overdose with SYMMETREL. The lowest reported acute lethal dose was 1 gram ["2 grams" deleted].

XALATAN (latanoprost) Ophthalmic Solution
[December 26, 2000: Pharmacia & Upjohn]

ADVERSE REACTIONS:

New text in bolded italics - 

Clinical Practice:

The following events have been identified during postmarketing use of XALATAN in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. The events, which have been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection to XALATAN, or a combination of these factors, include: asthma and exacerbation of asthma; corneal edema and erosions; dyspnea; eyelash changes (increased length, thickness, pigmentation, and number of lashes); eyelid skin darkening; herpes keratitis; intraocular inflammation (iritis/uveitis); keratitis; macular edema, including cystoid macular edema; and toxic epidermal necrolysis

ZIAGEN (abacavir sulfate) Tablets & Oral Solution
[December 15, 2000: Glaxo Wellcome]

Data for the Study CNAAB3005 can be found in the section of the labeling titled "Description of Clinical Studies".

The link to the labeling containing this study data is given below:

http://www.fda.gov/cder/ogd/rld/rld_labeling_approved_december_2000.html

Safety related changes are given below:

PRECAUTIONS:

Drug Interactions:

New last paragraph - 

The addition of methadone has no clinically significant effect on the pharmacokinetic properties of

abacavir. In a study of 11 HIV-infected subjects receiving methadone-maintenance therapy (40 mg and 90 mg daily), with 600 mg of ZIAGEN twice daily (twice the current recommended dose), oral methadone clearance increased 22% (90% CI 6% to 42%) This alteration will not result in a methadone dose.modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients.

ADVERSE REACTIONS:

Therapy-Naive Adults:

Table 3. added - 

Table 3: Selected Clinical Adverse Events Grades 1-4 ( greater than or equal to 5% Frequency)

Five subjects in the abacavir arm of study CNAAB3005 experienced worsening of pre-existing depression compared to none in the indinavir arm. The background rates of pre-existing depression were similar in the 2 treatment arms.

The following subsections revised to include CNAAB3005 information:

Laboratory Abnormalities: Laboratory abnormalities (anemia, neutropenia, liver function test abnormalities, and CPK elevations) were observed with similar frequencies in the 2 treatment groups in studies CNAAB3003 and CNAA3006. Mild elevations of blood glucose were more frequent in subjects receiving abacavir. In study CNAAB3003, triglyceride elevations (all grades) were more common on the abacavir arm (25%) than on the placebo arm (11%). In study CNAAB3005, hyperglycemia and disorders of lipid metabolism occurred with similar frequency in the abacavir and indinavir treatment arms.

Other Adverse Events: In addition to adverse events in Tables 2, 3, and 4, other adverse events observed in the expanded access program were pancreatitis and increased GGT.

ZOFRAN (ondansetron HCl) Tablets, Solution & Injection
[December 13, 2000: Glaxo Wellcome]

[For Zofran Tablets & Solution]

CLINICAL PHARMACOLOGY:

New text in bolded italics - 

Ondansetron is extensively metabolized in humans, with approximately 5% of a radiolabeled dose recovered from the urine as the parent compound. The primary metabolic pathway is hydroxylation on the indole ring followed by subsequent glucuronide or sulfate conjugation. Although some nonconjugated metabolites have pharmacologic activity, these are not found in plasma at concentrations likely to significantly contribute to the biological activity of ondansetron.

In vitro metabolism studies have shown that ondansetron is a substrate for human hepatic cytochrome P-450 enzymes, including CYP1A2, CYP2D6, and CYP3A4. In terms of overall ondansetron turnover, CYP3A4 played the predominant role. Because of the multiplicity of metabolic enzymes capable of metabolizing ondansetron, it is likely that inhibition or loss of one enzyme (e.g., CYP2D6 genetic deficiency) will be compensated by others and may result in little change in overall rates of ondansetron elimination. Ondansetron elimination may be affected by cytochrome P-450 inducers. In a pharmacokinetic study of 16 epileptic patients maintained chronically on carbamazepine or phenytoin, reduction in AUC, Cmax and T½ of ondansetron was observed. This resulted in a significant increase in clearance. However, on the basis of available data, no dosage adjustment is recommended (see PRECAUTIONS: Drug Interactions).

Ondansetron is ["passively and completely" deleted] well absorbed from the gastrointestinal tract and undergoes some first-pass metabolism. Mean bioavailability in healthy subjects, following administration of a single 8-mg tablet, ["has ranged from 48% to 75%" deleted] is approximately 56%.

Gender differences were shown in the disposition of ondansetron given as a single dose. The extent and rate of ondansetron's absorption is greater in women than men. Slower clearance in women, a smaller apparent volume of distribution (adjusted for weight), and higher absolute bioavailability resulted in higher plasma ondansetron levels. These higher plasma levels may in part be explained by differences in body weight between men and women. It is not known whether these gender-related differences were clinically important. More detailed pharmacokinetic information is contained in Tables 1 and 2 taken from two studies.

A reduction in clearance and increase in elimination half-life are seen in patients over 75 years of age. In clinical trials with cancer patients, safety and efficacy was similar in patients over 65 years of age and those under 65 years of age; there was an insufficient number of patients over 75 years of age to permit conclusions in that age-group. No dosage adjustment is recommended in the elderly.

The following paragraph deleted (text underlined) -

In patients with mild-to-moderate hepatic impairment, clearance is reduced twofold and mean half-life is increased to 11.6 hours compared to 5.7 hours in normals. In patients with severe hepatic impairment (Child-Pugh 1 score of 10 or greater), clearance is reduced twofold to threefold and apparent volume of distribution is increased with a resultant increase in half-life to 20 hours ["and bioavailability approaching 100%" deleted]. In ["such" deleted] patients with severe hepatic impairment, a total daily dose of 8 mg should not be exceeded.

Due to the very small contribution (5%) of renal clearance to the overall clearance, renal impairment was not expected to significantly influence the total clearance of ondansetron. However, ondansetron oral mean plasma clearance was reduced by about 50% ["(95% CI 22% to 68%)" deleted] in patients with severe renal impairment (creatinine clearance <30 mL/min). This reduction in clearance is variable and was not consistent with an increase in half-life. No reduction in dose or dosing frequency in these patients is warranted.

Plasma protein binding of ondansetron as measured in vitro was 70% to 76% over the concentration range of 10 to 500 ng/mL. Circulating drug also distributes into erythrocytes.

Four- and 8-mg doses of either ZOFRAN Oral Solution or ZOFRAN ODT Orally Disintegrating Tablets are bioequivalent to corresponding doses of ZOFRAN Tablets and may be used interchangeably. One 24-mg ZOFRAN Tablet is bioequivalent to and interchangeable with three 8-mg ZOFRAN Tablets.

New text in bolded italics -

["Ondansetron has no effect on the pharmacokinetics of high dose methotrexate," deleted] In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate.

Previous Geriatric Use subsection deleted and replaced with -

Geriatric Use: Of the total number of subjects enrolled in cancer chemotherapy-induced and postoperative nausea and vomiting in US- and foreign-controlled clinical trials, for which there were subgroup analyses, 938 were 65 years of age 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 individuals cannot be ruled out. Dosage adjustment is not needed in patients over the age of 65 (see CLINICAL PHARMACOLOGY).

[For Zofran Injection; not in 2000 PDR]

New text in bolded italics  -

Cardiovascular: Arrhythmias (including ventricular and supraventricular tachycardia, premature ventricular contractions, and atrial fibrillation), bradycardia, electrocardiographic alterations (including second-degree heart block and ST segment depression), palpitations, and syncope.

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