* Grouped because of similarity of labeling. 

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The following additional adverse reactions have been reported in post-marketing experience: Bleeding: Intracranial bleeding, retroperitoneal bleeding, hemopericardium and pulmonary (alveolar) hemorrhage. Fatal bleedings have been reported rarely; Body as a Whole: Acute and/or severe decreases in platelet counts which may be associated with chills, low-grade fever, or bleeding complications (see Laboratory Findings above); Hypersensitivity: Rash and/or hives.

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PRECAUTIONS:

New subsection- 

Of the 955 patients in clinical studies who were treated with nizatidine, 337 (35.3%) were 65 and older. No overall differences in safety or effectiveness were observed between these and younger subjects. 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. 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 (see Dosage and Administration)"

[Other labeling information not appearing in 2001 PDR:  http://www.fda.gov/medwatch/safety/2000/nov00.htm#baycol ]

CLINICAL PHARMACOLOGY:

Metabolism:

The following paragraph has been added:

In Vitro studies show that the hepatic cytochrome P450 (CYP) enzyme system catalyzes the cerivastatin biotransformation reactions. Specifically, two P450 enzyme sub-classes are involved. The first is CYP 2C8, which leads predominately to the major active metabolite, M23, and to a lesser extent, the other active metabolite, M1. The second is CYP 3A4, which primarily contributes to the formation of the less abundant metabolite, M1. The CYP 3A4 enzyme sub-class is also involved in the metabolism of a significant number of common drugs. The potential importance of the dual pathway hepatic metabolism of cerivastatin as a protective mechanism is shown in clinical studies examining the effect of the known potent CYP 3A4 inhibitors, erythromycin and itraconazole. In these interaction studies, specific inhibition of the CYP 3A4 enzyme sub-class resulted in a minimal 1.4- to 1.5-fold mean increase in cerivastatin plasma levels following co-treatment with erythromycin or itraconazole, possibly because of effective metabolism via the alternate CYP 2C8 pathway.

PRECAUTIONS:

Drug Interactions:

The following statements have been added:

OMEPRAZOLE: There were no changes in the pharmacokinetic parameters of either cerivastatin or its major active metabolites, or in omeprazole in healthy young males given single 0.3 mg oral doses of cerivastatin alone or on the fifth day of a five-day omeprazole 20 mg daily pre-treatment.

CYCLOSPORINE: The single dose pharmacokinetics of 0.2 mg of cerivastatin in healthy subjects was compared to single and multiple doses in renal transplant patients who were at steady-state with respect to cyclosporine. Cyclosporine levels were unaffected by cerivastatin. Plasma concentration of cerivastatin and its metabolites increased 3- to 5-fold with no change in its elimination. No cerivastatin accumulation occurred with multiple dosing.

WARNINGS: 

Drug interactions - 

The following paragraph was added:

Particular caution should be used when prescribing sildenafil in patients receiving indinavir. Coadministration of Crixivan with sildenafil is expected to substantially increase sildenafil plasma concentrations and may result in an increase in sildenafil-associated adverse events, including

hypotension, visual changes, and priapism (see PRECAUTIONS, Drug Interactions and Information for Patients, and the manufacturer’s complete prescribing information for sildenafil).

The following paragraphs were added:

Information for patients - 

Patients receiving sildenafil should be advised that they may be at an increased risk of sildenafil-associated adverse events including hypotension, visual changes, and priapism, and should promptly report any symptoms to their doctors.

Particular caution should be used when prescribing sildenafil for patients receiving indinavir. The results of one published study in six HIV-infected subjects indicated that coadministration of indinavir (800 mg every 8 hours chronically) and sildenafil (25 mg as a single dose) resulted in increased indinavir

and sildenafil concentrations. In two of the six subjects, prolonged clinical effects of sildenafil were noted for 72 hours after a single dose of sildenafil in combination with indinavir. Based on the results of this study, the dose of sildenafil should not exceed 25 mg in a 48-hour period. Patients receiving sildenafil

should be advised that they are at an increased risk of sildenafil-associated adverse events including hypotension, visual changes, and priapism, and should promptly report any symptoms to their health care provider (see CLINICAL PHARMACOLOGY, Drug Interactions and WARNINGS).

Subsection added - 

Geriatric Use:

Clinical studies of Crixivan did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

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cortical necrosis, and central retinal artery and vein obstructions) have been rarely reported in patients. receiving  tranexamic acid for

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New sentence added to section:

ELAVIL should not be given with Cisapride due to the potential for increased QT interval and increased risk for arrhythmia.

Information regarding discontinued marketing of Propulsid:

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[Other labeling information not appearing in 2001 PDR: http://www.fda.gov/medwatch/SAFETY/2001/jan01.htm#epivir ]

CLINICAL PHARMACOLOGY:

New information on HBV infected patients. See the following link and look for March 6:

http://www.fda.gov/cder/ogd/rld/RLD_LABELING_APPROVED_MARCH_2001.HTML

Previous paragraph deleted -

Patients With HIV and Hepatitis B Virus Coinfection:   In clinical trials and postmarketing experience, some patients with HIV infection who have chronic liver disease due to hepatitis B virus infection experienced clinical or laboratory evidence of recurrent hepatitis upon discontinuation of lamivudine. Consequences may be more severe in patients with decompensated liver disease.

Replaced with the following:

Patients with HIV and Hepatitis B Virus Coinfection: Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in patients dually infected with HIV and HBV. In non-HIV-infected patients treated with lamivudine for chronic hepatitis B, emergence of lamivudine-resistant HBV has been detected and has been associated with diminished treatment response (see EPIVIR-HBV package insert for additional information). Emergence of hepatitis B virus variants associated with resistance to lamivudine has also been reported in HIV-infected

patients who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus.

Information for Patients:

New second paragraph added - 

Patients should be advised that EPIVIR Tablets and Oral Solution contain a higher dose of the same active ingredient (lamivudine) as EPIVIR-HBV Tablets and Oral Solution. If a decision is made to include lamivudine in the HIV treatment regimen of a patient dually infected with HIV and

HBV, the formulation and dosage of lamivudine in EPIVIR (not EPIVIR-HBV) should be used.

Third sentence revised (new text in bolded, underlined italics) -

However, lamivudine showed no evidence of in vivo genotoxic activity in the rat at oral doses of up to 2000 mg/kg producing plasma levels of 35 to 45 times those in humans at the recommended dose for HIV infection ["(approximately 65 times the recommended human dose based on body surface area comparisons)" deleted]. In a study of reproductive performance, lamivudine administered to rats at doses up to 4000 mg/kg per day, producing plasma levels 47 to 70 times those in humans ["administered to rats at doses up to 130 times the usual adult dose based on body surface area comparisons" deleted], revealed no evidence of impaired fertility and no effect on the survival, growth, and development to weaning of the offspring.

First two sentences revised - 

Pregnancy:   Pregnancy Category C. Reproduction studies have been performed in rats and rabbits at orally administered doses up to approximately 130 and 60 times, respectively, the usual adult dose and have revealed no evidence of harm to the fetus due to lamivudine. Some evidence of early embryolethality was seen in the rabbit at doses similar to those produced by the usual adult dose and higher, but there was no indication of this effect in the rat at orally administered doses up to 130 times the usual adult dose.

Revisions incorporated in the following text:

Pregnancy: Pregnancy Category C. Reproduction studies have been performed in rats and rabbits at orally administered doses up to 4000 mg/kg per day and 1000 mg/kg per day respectively, producing plasma levels up to approximately 35 times that for the adult HIV dose. No

evidence of teratogenicity due to lamivudine was observed. Evidence of early embryolethality was seen in the rabbit at exposure levels similar to those observed in humans, but there was no indication of this effect in the rat at exposure levels up to 35 times that in humans. 

Pediatric Use:HIV:

New sentence and paragraph added to subsection:

The effect of renal impairment on lamivudine pharmacokinetics in pediatric patients is not known.

HBV: See the complete prescribing information for EPIVIR-HBV Tablets and Oral Solution for additional information on the pharmacokinetics of lamivudine in HBV-infected children. 

New subsection added -  

Geriatric Use: Clinical studies of EPIVIR did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased

hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. In particular, because lamivudine is substantially excreted by the kidney and elderly patients are more likely to have decreased renal function, renal function should be monitored and dosage adjustments

should be made accordingly (see PRECAUTIONS: Patients with Impaired Renal Function and DOSAGE AND ADMINISTRATION).

Drug Resistance:   Penciclovir-resistant mutants of HSV and VZV can result from complete loss of viral thymidine kinase activity (TK negative), reduced TK activity (TK altered) or DNA polymerase mutations. The most commonly encountered acyclovir-resistant mutants that are TK negative are also resistant to penciclovir. The possibility of viral resistance to penciclovir should be considered in patients who fail to respond or experience recurrent viral infections during therapy.

Revised with revisions incorporated below:

Drug Resistance: Resistance of HSV and VZV to antiviral nucleoside analogs can result from mutations in the viral thymidine kinase (TK) and DNA polymerase genes. Mutations in the viral TK gene may lead to complete loss of viral TK activity (TK negative), reduced levels of TK activity (TK partial) or alteration in the ability of viral TK to phosphorylate the drug without an equivalent loss in the ability to phosphorylate thymidine (TK altered). The most commonly encountered acyclovir-resistant mutants are TK negative and they are also resistant to penciclovir. The possibility of viral resistance to penciclovir should be considered in patients who fail to respond or experience recurrent viral infections during therapy.

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PRECAUTIONS:

Geriatric Use:

Subsection revised with revisions incorporated below:

Safety data have been collected on 280 patients (Flovent Diskus n = 83, Flovent Rotodisk n = 197) 65 years of age or older and 33 patients (Flovent Diskus n = 14, Flovent Rotodisk n = 19) 75 years of age or older who have been treated with fluticasone propionate inhalation powder in US and non-US clinical trials. There were no differences in adverse reactions compared to those reported by younger patients. In addition, there were no apparent differences in efficacy between patients 65 years of age or older and younger patients. Fifteen patients 65 years of age or older and 1 patient 75 years of age or older were included in the efficacy evaluation of US clinical studies.

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[Other information not appearing in 2001 PDR: http://www.fda.gov/medwatch/SAFETY/2001/jan01.htm#kaletr ]

 The new labeling provides for changes in the oral volumes listed in the pediatric dose recommendation table contained in the DOSAGE AND ADMINISTRATION section of the Package Insert. The changes are intended to make the oral volumes closer to the recommended

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[Letter from Novartis, July 7, 2000,  regarding other safety information about Mellaril:  http://www.fda.gov/medwatch/safety/2000/mellar.htm ]

[Letter from Norvartis, September 22, 2000 regarding other safety information about Serentil:  http://www.fda.gov/medwatch/safety/2000/serent.htm ]

 specifically modification of labeling text to more clearly state that these agents are indicated for the treatment of schizophrenia.

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PRECAUTIONS:

New first paragraph -

A statement to patients and health care providers is included on the product ’s bottle label: ALERT: Find out about medicines

that should NOT be taken with NORVIR. A Patient Package Insert (PPI) for Norvir is available for patient information.

For a copy of the label containing the Patient Package Insert, go to the following link and look for March 6:

http://www.fda.gov/cder/ogd/rld/RLD_LABELING_APPROVED_MARCH_2001.HTML

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[Other information regarding these labeling changes: http://www.fda.gov/medwatch/safety/2001/safety01.htm#orlaam

Boxed WARNING

The following paragraphs added:

Due to its potential for serious and possibly life-threatening, proarrhythmic effects, LAAM should be reserved for use in the treatment of opiate-addicted patients who fail to show an acceptable response to other adequate treatments for opiate addiction, either because of insufficient effectiveness or the inability to achieve effective dose due to intolerable adverse effects from those drugs (see Warnings, and Contraindications).

Cases of QT prolongation and serious arrhythmia (torsade de pointes) have been observed during post-marketing treatment with Orlaam. Based on these reports, all patients should undergo a 12-lead ECG prior to administration of Orlaam to determine if a prolonged QT interval (QTc greater than 430 [male] or 450 [female] ms) is present. If there is a prolonged QT interval, Orlaam should NOT be administered. For patients in whom the potential benefit of Orlaam treatment is felt to outweigh the risks of potentially serious arrhythmias, an ECG should be performed prior to treatment, 12-14 days after initiating treatment, and periodically thereafter, to rule out any alterations in the QT interval.

Orlaam should be administered with extreme caution to patients who may be at risk for development of prolonged QT syndrome (e.g. congestive heart failure, bradycardia, use of a diuretic, cardiac hypertrophy, hypokalemia or hypomagnesemia).

Orlaam is metabolized to active metabolites by the cytochrome P450 isoform, CYP3A4. Therefore, the addition of drugs that induce this enzyme (such as rifampin, phenobarbital, and phenytoin) or inhibit this enzyme (such as ketoconazole, erythromycin, and saquinavir) could increase the levels of parent drug or its active metabolites an a patient that was previously at steady-state, and this could potentially precipitate serious arrhythmias, including torsade de pointes (see PRECAUTIONS, Drug Interactions).

CLINICAL PHARMACOLOGY:

Metabolism and Elimination:

First sentence revised -

Orlaam is metabolized by the cytochrome P450 isoform, CYP3A4.

Replaced by -

The cytochrome P450 isoform, CYP3A4, plays a major role in the metabolism of Orlaam.

INDICATIONS:

Previous paragraph deleted -

Orlaam is indicated for the management of opiate dependence

Replaced with -

Orlaam is indicated for the management of opiate dependence. Orlaam should be reserved for the use in treatment of opiate-addicted patients who fail to show an acceptable response to other adequate treatments for opiate addiction, either because of insufficient effectiveness or the inability to achieve effective dose due to intolerable adverse effects from those drugs (see Black Box Warning).

CONTRANDICATIONS:

[Labeling changes not appearing in 2000 PDR] 

Revisions for 2001 PDR in bolded, underlined italics -

ORLAAM is contraindicated in patients with known or suspected QT prolongation (QTc interval greater than 430 [male] or 450 [female] ms) ["440 or 450 ms)" deleted]. This would include patients with congenital long QT syndrome, or conditions which may lead to QT prolongation (see WARNINGS, Effects on Cardiac Conduction) such as: 1) clinically significant bradycardia (less than 50 bpm), 2) any clinically significant cardiac disease, 3) treatment with Class I and Class III antiarrhythmics, 4) treatment with monoamine oxidase inhibitors (MAOI’s), 5) concomitant treatment with other drug products known to prolong the QT interval (see PRECAUTIONS, Drug Interactions), and 6) electrolyte imbalance, in particular hypokalemia and hypomagnesemia

WARNINGS:
Effects on Cardiac Conduction:

First two sentences revised (new text in bolded, underlined italics)-

Orlaam has been shown to prolong the ST segment of the electrocardiogram in beagle dogs dosed five days a week and to inhibit the rapidly-activating delayed rectifier current IKr in isolated myocytes in vitro. Serial EKGs performed in a human pharmacokinetics study showed a prolongation of the QTc interval in some patients which was not associated with dose.

 Second paragraph, last sentence revised (new text in bolded, underlined italics) - 

For patients in whom the potential benefit of Orlaam treatment is felt to outweigh the risks of potentially serious arrhythmias, an ECG should be performed prior to treatment, 12-14 days after initiating treatment, and periodically thereafter, to rule out any alterations in the QT interval.

Fourth paragraph revised with revisions incorporated below: 

 ORLAAM is metabolized to active metabolites by the cytochrome P450 isoform. Therefore the addition of drugs that induce this enzyme (such as rifampin, phenobarbital and phenytoin) or inhibit this enzyme (such as ketaconazole, erthromycin, and saquinavir) could increase the levels of parent drug or its active metabolites in a patient that was previously at steady-state, and this could potentially precipitate severe arrhythmias, including torsade de pointes (see PRECAUTIONS, Drug Interactions).

Cases of QT prolongation and serious arrhythmia (torsade de pointes) have been observed during post-marketing treatment with Orlaam. If a patient taking Orlaam experiences symptoms suggestive of an arrhythmia (such as palpitations, dizziness, lightheadedness, syncope, or seizures), that patient should seek medical attention immediately.

PRECAUTIONS:

Drug Interactions:

[Labeling not found in 2000 PDR]

No interaction studies have been performed in humans. ORLAAM is metabolized by the cytochrome P450 isoform, CYP3A4. The addition of drugs that induce this enzyme could increase the levels of active metabolites in a patient that was previously at steady-state.

Potentially Arrhythmogenic Agents - Any drug known to have the potential to prolong the QT interval should not be used together with ORLAAM. Possible pharmacodynamic interactions can occur between ORLAAM and potentially arrhythmogenic agents such as class I or III antiarrhythmics, antihistamines that prolong the QT interval, antimalarials, calcium channel blockers, neuroleptics that prolong the QT interval, and antidepressants

Caution should be used when prescribing concomitant drugs known to induce hypokalemia or hypomagnesemia as they may precipitate QT prolongation and interact with ORLAAM. These would include diuretics, laxatives and supraphysiological use of steroid hormones with mineralocorticoid potential.

ADVERSE EVENTS:

Text revision in brackets -

These reactions were reported with low frequency in controlled and uncontrolled studies of LAAM, are not known to be causally related to the administration of the drug, and are provided as alerting information for physicians.

Cardiovascular - Hypertension ["prolongation of the QT interval, non-specific ST-T wave changes" deleted from the 2001 PDR]

Hepatic -            Hepatitis and abnormal liver function tests.

Urogenital -        Amenorrhea, pyuria.

[Labeling not found in 2000 PDR] -

The following adverse reactions have been reported in the post-marketing setting (all reactions in less than 1% of patients).

Body as a Whole -Altered hormone level, chest pain.

Cardiovascular -    QT interval prolongation, torsade de pointes,

                             cardiac arrest, ST segment elevation,

                             ventricular tachycardia, myocardial

                             infarction, angina pectoris, syncope,

                             migraine.

Nervous System - Convulsions, confusion, hallucination,

                             incoordination, amnesia.

Respiratory -         Apnea, dyspnea.

Urogenital -           Breast enlargement.

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[Other information not appearing in the 2001 PDR: http://www.fda.gov/medwatch/SAFETY/2001/feb01.htm#rebetr ]

WARNINGS:

New subsection added - 

INTRON A therapy suppresses bone marrow function and may result in severe cytopenias including very rare events of aplastic anemia. It is advised that complete blood counts (CBC) be obtained pre-treatment and monitored routinely during therapy (see PRECAUTIONS:

Laboratory Tests). INTRON A therapy should be discontinued in patients who develop severe decreases in neutrophil (<0.5 x 10 9 /L) or platelet counts (<25 x 10 9 /L) (see DOSAGE AND ADMINISTRATION: Guidelines for Dose Modifications).

PRECAUTIONS:

New subsection added -

Geriatric Use: Clinical studies of REBETRON Combination Therapy did not include sufficient numbers of subjects aged 65 and over to determine if they respond differently from younger subjects. In clinical trials, elderly subjects had a higher frequency of anemia (67%) than did younger patients (28%) (see WARNINGS).

In general, REBETOL (ribavirin) should be administered to elderly patients cautiously, starting at the lower end of the dosing range, reflecting the greater frequency of decreased renal, hepatic and/or cardiac function, and of  concomitant disease or other drug therapy.

REBETOL (ribavirin) is known to be substantially excreted by the kidney, and the risk of adverse reactions to ribavirin may be greater in patients with impaired renal function. Because elderly patients often have decreased renal function, care should be taken in dose selection. Renal function should be monitored and dosage adjustments of ribavirin should be made accordingly (see DOSAGE AND ADMINISTRATION: Guidelines for Dose

Modifications). REBETOL (ribavirin) should be used in elderly patients with creatinine clearance <50 mL/min only if the potential benefit outweighs the risk, and should not be administered to patients with creatinine clearance <30 mL/min (see WARNINGS).

REBETRON Combination Therapy should be used very cautiously in elderly patients with a history of psychiatric disorders (see WARNINGS).

ADVERSE REACTIONS:

Third sentence revised (revised text in bolded, underlined italics) -

In addition, hearing disorders (tinnitus and hearing loss) and vertigo have occurred in patients treated with combination REBETOL/INTRON A therapy ["the following spontaneous adverse events have been reported during the marketing surveillance of REBETOL/INTRON A therapy: hearing disorder and vertigo." deleted].

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[Other information not appearing in 2001 PDR: http://www.fda.gov/medwatch/SAFETY/2001/jan01.htm#serzon ]

Postintroduction Clinical Experience

New text in bolded, underlined italics -

Postmarketing experience with SERZONE has shown an adverse experience profile similar to that seen during the premarketing evaluation of nefazodone. Voluntary reports of adverse events temporally associated with SERZONE have been received since market introduction that are not listed above and for which a causal relationship has not been established. These include: Anaphylactic reactions; angioedema; convulsions (including grand mal seizures); galactorrhea; gynecomastia (male); hyponatremia; liver necrosis and liver failure, in some cases leading to liver transplantation and/or

death; priapism (see PRECAUTIONS ); prolactin increased; rhabdomyolysis involving patients receiving the combination of SERZONE and lovastatin or simvastatin (see PRECAUTIONS ); serotonin syndrome; and Stevens-Johnson syndrome; and thrombocytopenia.

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DOSAGE AND ADMINISTRATION:

[Not found in 2000 PDR]

New text in bolded, underlined italics - 

Damaged tablets or tablets without a release portal should not be consumed.

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VISTARIL (hydroxyzine HCl) Injection

ATARAX (hydroxyzine HCl) Tablets & Syrup

VISTARIL (hydroxyzine pamoate) Capsules & Oral Suspension
[March 21, 2001: Pfizer]

New subsection added -

Geriatric Use:

A determination has not been made whether controlled clinical studies of VISTARIL included sufficient numbers of subjects aged 65 and over to define a difference in response 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 dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

The extent of renal excretion of VISTARIL has not been determined. Because elderly patients are more likely to have decreased renal function, care should be taken is dose selections.

Sedating drugs may cause confusion and over sedation in the elderly; elderly patients generally should be started on low doses of VISTARIL and observed closely.

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