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CLINICAL PHARMACOLOGY:

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Data from second study is included and repositioned in table format21 - 

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Special Populations: Children: Following administration of a 20 mg dose of zafirlukast to 20 boys and girls between 7 and 11 years of age, and in a second study, to 29 boys and girls between 5 and 6 years of age, the following pharmacokinetics parameters were obtained:

"Carcinogenesis, Mutagenesis, Impairment of fertility" and "Pregnancy Category B" subsections to include corresponding exposure factors for the pediatric population. Contact the company for copy of the labeling which includes these subsections.

Pediatric Use: Age range revised from "7 –11 years of age" to "5 – 11 years of age" throughout the labeling.

DOSAGE AND ADMINISTRATION:

 ACCUPRIL (quinapril HCl) Tablets

Subsection has been added as follows:

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

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.

Elderly patients exhibited increased area under the plasma concentration time curve and peak levels for quinaprilat compared to values observed in younger patients; this appeared to relate to decreased renal function rather than to age itself.

Other: amblyopia, edema, arthralgia, pharyngitis, agranulocytosis, hepatitis, thrombocytopenia.

 AVELOX (moxifloxacin HCl) Tablets

Labeling provides for the indication  for the treatment of uncomplicated skin and skin structure infections. Contact the company for a copy of the new labeling/package insert.

Information for Patients: That moxifloxacin may be associated with hypersensitivity reactions, including anaphylactic reactions, even following a single dose, and to discontinue the drug at the first sign of a skin rash or other signs of an allergic reaction..

 AZELEX (azelaic acid) Cream

 The product will also be distributed by Berlex Laboratories under the Brand name Finevin (azelaic acid ) cream 20%.

 CLIMARA (estradiol) Transdermal 

 Extensive changes to the Package Insert and the Patient’s Package Insert (Revised Black Box WARNING, CLINICAL PHARMACOLOGY, INDICATIONS AND USAGE, CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, ADVERSE REACTIONS, AND DOSAGE AND ADMINISTRATION SECTIONS). Contact the company for a copy of the new label/package insert.

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In two controlled studies (Studies 1 and 2), symptoms of ADHD were evaluated by laboratory school teachers using the SKAMP* laboratory school rating scale. The combined results from these two studies demonstrated significant improvements in attention and behavior in patients treated with Concerta  versus placebo that were maintained through 12 hours after dosing. Figure 3 presents the laboratory school teacher SKAMP ratings for Concerta qd and placebo.

*Swanson, Kotkin, Agler, M-Flynn and Pelham

CORVERT (ibutilide fumarate) Injection

Geriatric Use: 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.

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Teratogenic Effects. Pregnancy Category C:

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It is not know whether cysteamine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Teratology studies have been performed in rats at oral doses in a range of 37.5 to 150 mg/kg/day (about 0.2 to 0.7 times the recommended human maintenance dose on a body surface basis) and have revealed cysteamine bitartrate to be teratogenic and fetotoxic. Observed teratogenic findings were cleft palate, Kyphosis, heart ventricular septal defects, microcephaly and exencephaly. There are no adequate and well-controlled studies in pregnant women. Cystagon® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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 INDICATION AND USAGE, PRECAUTIONS: Nursing Mothers, OVERDOSAGE: Management of Overdosage, and DOSAGE AND ADMINISTRATION sections extensively revised.  Contact the company for a copy of the new labeling/package insert.

Revisions incorporated in the following text:

The most consistent effects of dopamine in 57 publications (between the years 1966 through 1997) were increases in systolic and mean arterial pressure. Renal function was variably affected, except that in a single publication renal function was preserved in the face of treatment with indomethacin. No consistent effect on heart rate was described. Because of the variability of clearance, especially in the neonate and newborn, low doses of dobutamine and slow deliberate titration should be employed (see DOSAGE and ADMINISTRATION).

DOSAGE and ADMINSTRATION:

A new Pediatric Dosing and Administration subsection has been added to read as follows:

Pediatric Dosing and Administration In publications, the most common starting doses were 1-5 micrograms/kilograms/minute. Particularly in neonates, such low doses require considerable dilution of this product; careful consideration should be given to the use of this product in such circumstances. Dosing increments that were reported ranged from 2.5 to 5.0 micrograms/kilogram/minute.

Pharmacokinetics subsection, 7 th paragraph:

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Fentanyl is metabolized primarily in the liver. In humans the drug appears to be metabolized primarily by N-dealkylation to norfentanyl and other inactive metabolites that do not contribute materially to the observed activity of the drug. Fentanyl is metabolized primarily via human cytochrome P450 3A4 isoenzyme system. In humans the drug appears to be metabolized primarily by oxidative N-dealkylation to norfentanyl and other inactive metabolites that do not contribute materially to the observed activity of the drug."

PRECAUTIONS: 

Cardiac Disease:

Intravenous Fentanyl may produce bradycardia. Fentanyl should be administered with caution to patients with bradyarrhythmias.

CYP3A4 Inhibitors: Since the metabolism of fentanyl is mediated by the CYP3A4 isozyme, coadministration of drugs that inhibit CYP3A4 activity may cause decreased clearance of fentanyl. The expected clinical results would be increased or prolonged opioid effects. Thus patients coadministered with inhibitors of CYP3A4 such as macrolide antibiotics (e.g., erythromycin), azole antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritanovir) while receiving Duragesic should be carefully monitored and dosage adjustment made if warranted.

CYP3A4 Inducers: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and as such may cause increased clearance of fentanyl. Caution is advised when administering Duragesic to patients receiving these medications and if necessary dose adjustments should be considered.

ADVERSE REACTIONS:

Pre-marketing Clinical Trial Experience:

Added: "Cardiovascular: bradycardia"

Post-Marketing Experience:

 The following adverse reactions reported to have been observed in association with the use of Duragesic and not reported in the pre-marketing adverse reaction section above include:

Body as a whole: edema

Cardiovascular: tachycardia

Metabolic and Nutritional: weight loss

Special Senses: blurred vision

Added: " Opioid withdrawal symptoms (such as nausea, vomiting, diarrhea, anxiety, and shivering) are possible in some patients after conversion or dose adjustment."

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ADVERSE REACTIONS:

  Approximately 200 patients over the age of 64 were evaluated for safety in controlled clinical trials with Flumadine . (rimantadine hydrochloride). Geriatric subjects who received either 200 mg or 400 mg of rimantadine daily for 1 to 50 days experienced considerably more central nervous system and gastrointestinal adverse events than comparable geriatric subjects receiving placebo. Central nervous system events included dizziness, headache, anxiety, asthenia, and fatigue, occurred up to two times more often in subjects treated with rimantadine than those treated with placebo. Gastrointestinal symptoms, particularly nausea, vomiting, and abdominal pain occurred at least twice as frequently in subjects receiving rimantadine than in those receiving placebo. The gastrointestinal symptoms appeared to be dose related. In patients over 64, the recommended dose is 100 mg, daily. (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

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GLUCOPHAGE_ XR (metformin HCL extended-release) Tablets

Patients randomized to the combination arm started therapy with GLUCOPHAGE 500 mg and glyburide 20 mg. At the end of each week of the first four weeks of the trial, these patients had their dosages of GLUCOPHAGE increased by 500 mg if they had failed to reach target fasting plasma glucose. After week four, such dosage adjustments were made based on glycemic control monthly, although no patient was allowed to exceed GLUCOPHAGE 2500 mg. Patients in the GLUCOPHAGE only arm (metformin plus placebo) followed the same titration schedule. At the end of the trial, approximately 70% of the patients in the combination group were taking GLUCOPHAGE 2000 mg/glyburide 20 mg or GLUCOPHAGE 2500 mg/glyburide 20 mg.

In a clinical trial of patients with type 2 diabetes and prior failure on glyburide, patients started on GLUCOPHAGE 500 mg and glyburide 20 mg were titrated to 1000/20 mg, 1500/20 mg, 2000/20 mg or 2500/20 mg of GLUCOPHAGE and glyburide, respectively, to reach the goal of glycemic control as measured by FPG, HbA1c and plasma glucose response (see CLINICAL PHARMACOLOGY:Clinical Studies).

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LAMISIL  is not recommended for patients with chronic or active liver disease. Before prescribing LAMISIL  Tablets, pre-existing liver disease should be assessed. Hepatotoxicity may occur in patients with and without pre-existing liver disease. Pretreatment serum transaminase (ALT and AST) tests are advised for all patients before taking LAMISIL Tablets. Patients prescribed LAMISIL (terbinafine HCl) Tablets should be warned to report immediately to their physician any symptoms of persistent nausea, anorexia, fatigue, vomiting, right upper abdominal pain or jaundice, dark urine or pale stools (see WARNINGS). Patients with these symptoms should discontinue taking oral terbinafine, and the patient’s liver function should be immediately evaluated.

In patients with either pre-existing liver disease or renal impairment (creatinine clearance less than or equal to 50 mL/min), the use of Lamisil has not been adequately studied, and therefore, is not recommended (see CLINICAL PHARMACOLOGY,Pharmacokinetics).

In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism of tolbutamide, ethinylestradiol, ethoxycoumarin, and cyclosporine. In vitro studies have also shown that terbinafine inhibits CYP2D6-mediated metabolism. This may be of clinical relevance for compounds predominantly metabolized by this enzyme, such as tricyclic antidepressants, ß-blockers, selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAO-Is) Type B, if they have a narrow therapeutic window.

In vivo drug-drug interaction studies conducted in normal volunteer subjects showed that terbinafine does not affect the clearance of antipyrine, or digoxin, and the antihistamine terfenadine. Terbinafine decreases the clearance of intravenously administered caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%.

Terbinafine clearance is increased 100% by rifampin, a CyP450 enzyme inducer, and decreased 33% by cimetidine, a CyP450 enzyme inhibitor. Terbinafine exposure (AUC) is increased 16% by terfenadine. Terbinafine clearance is unaffected by cyclosporine.

In a 28-month oral carcinogenicity study in rats, an marginal increase in the incidence of liver tumors was observed in males at the highest dose level tested, 69 mg/kg/day [3.6x 2 x the Maximum Recommended Human Dose (MRHD) based on body surface area (BSA) AUC comparisons of the parent terbinafine].; however, even though dose-limiting toxicity was not achieved at the highest tested dose, higher doses were not tested. There was no dose-related trend and the mid-dose male rats (20 mg/kg/day; 1.0x the MRHD based on BSA) did not have any tumors. No increased incidence in liver tumors was noted in female rats at dose levels up to 97 mg/kg/day (4.5x the MRHD based on BSA) or in male or female mice treated orally for 23 months at doses up to 156 mg/kg/day (3.9x the MRHD based on BSA).

A wide range of in vivo studies in mice, rats, dogs, and monkeys, and in vitro studies using rat, monkey, and human hepatocytes suggest that the development of liver tumors in the high-dose male rats may be associated with peroxisome proliferation, and support the conclusion that this is a rat-specific finding. In vivo investigations included evaluations of the effects of Lamisil on liver weight, morphology, and ultrastructure; hepatic cytochrome P450; and peroxisome proliferation assessed morphologically and biochemically (peroxisomal enzymes) in mice, rats, dogs, and monkeys. The effects of Lamisil  and two known metabolites on hepatic morphology and peroxisomal and P450 enzyme activities were also evaluated in vivo in male rats and in vitro in primary hepatocyte cultures from male rats and humans and from monkeys. The results of the in vivo investigations indicated that oral administration of Lamisil  (500 mg/kg/day) resulted in peroxisome proliferation in rats, and that these effects did not occur in mice, dogs, or monkeys. Further, in vitro studies indicated that peroxisome proliferation occurred in rat hepatocytes, but not in monkey or human hepatocytes.

The results of a variety of in vitro (mutations in E. coli and S. typhimurium, DNA repair in rat hepatocytes, mutagenicity in Chinese hamster fibroblasts, chromosome aberration and sister chromatid exchanges in Chinese hamster lung cells), and in vivo (chromosome aberration in Chinese hamsters, micronucleus test in mice) genotoxicity tests gave no evidence of a mutagenic or clastogenic potential. and demonstrated the absence of tumor-initiating or cell-proliferating activity. Oral reproduction studies in rats at doses up to 300 mg/kg/day (approximately 12x the MRHD based on body surface area comparisons, BSA) did not reveal any specific effects on fertility or other reproductive parameters. Intravaginal application of terbinafine hydrochloride at 150 mg/day in pregnant rabbits did not increase the incidence of abortions or premature deliveries nor affect fetal parameters.

Pregnancy Category B: Oral reproduction studies have been performed in rabbits and rats at doses up to 300 mg/kg/day (9x 12x to 12x 23x the MRHD, in rabbits and rats, respectively, based on BSA) and have revealed no evidence of impaired fertility or harm to the fetus due to terbinafine. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, and because treatment of onychomycosis can be postponed until after pregnancy is completed, it is recommended that Lamisil not be initiated during pregnancy or in women attempting to become pregnant.

 Rare adverse events, base don worldwide experience with Lamisil (terbinafine hydrochloride tablets) Tablets use, include: idiosyncratic and symptomatic idiosyncratic hepatobilliary dysfunction hepatic injury and more rarely, cases of liver failure, some leading to death or liver transplant (see WARNINGS and PRECAUTIONS). (including cholestatic hepatitis and very rarely liver failure) (see WARNINGS AND PRECAUTIONS)  serious skin reactions see WARNINGS), severe neutropenia (see PRECAUTIONS), , thrombocytopenia and allergic reactions (including anaphylaxis). Uncommonly, Lamisil may cause taste disturbance (including taste loss) which usually recovers within several weeks after discontinuation of the drug. There have been isolated reports of prolonged (greater than one year) taste disturbance. Rarely, taste disturbances associated with oral terbinafine have been reported to be severe enough to result in decreased food intake leading to significant and unwanted weight loss.

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CLINICAL PHARMACOLOGY:

Pharmacokinetics subsection

The following paragraph has been added:

In a study including 16 elderly patients between 70-78 years of age who received MEVACOR 80 mg/day, the mean plasma level of HMG-CoA reductase inhibitory activity was increased approximately 45% compared with 18 patients between 18-30 years of age. (see PRECAUTIONS, Geriatric Use).

WARNINGS:

Skeletal Muscle -

The following information has been added:

Although the data are insufficient for lovastatin, the risk of myopathy appears to be increased when verapamil is used concomitantly with a closely related HMG-CoA reductase inhibitor.

PRECAUTIONS

Drug Interactions

The following information has been added:

Although the data are insufficient for lovastatin, the risk of myopathy appears to be increased when verapamil is used concomitantly with a closely related HMG-CoA reductase inhibitor.

Geriatric Use:

New subsection - 

A pharmacokinetic study with lovastatin showed the mean plasma level of HMG-CoA reductase inhibitory activity to be approximately 45% higher in elderly patients between 70-78 years of age compared with patients between 18-30 years of age; however, clinical study experience in the elderly indicates that dosage adjustment based on this age-related pharmacokinetic difference is not needed. In the two large clinical studies conducted with lovastatin (EXCEL and AFCAPS/TexCAPS), 21% (3094/14850) of patients were = 65 years of age. Lipid-lowering efficacy with lovastatin was at least as great in elderly patients compared with younger patients, and there were no overall differences in safety over the 20 to 80 mg/day dosage range (see CLINICAL PHARMACOLOGY).

ADVERSE REACTIONS: 

Hypersensitivity Reactions:

Added:

"dermatomyositis"

CLINICAL PHARMACOLGY:

Paragraphs added:

In healthy elderly volunteers (65-75 years of age with normal renal function for their age), norfloxacin is eliminated more slowly because of their slightly decreased renal function. Following a single 400 mg dose of norfloxacin, the mean (± SD) AUC and Cmax of 9.8 (2.83) µg·hr/mL and 2.02 (0.77) µg/mL respectively, were observed in healthy elderly volunteers. The extent of systemic exposure was slightly higher than that seen in younger adults (AUC 6.4 µg·hr/mL and Cmax 1.5 µg/mL. Drug absorption appears unaffected. However, the effective half-life of norfloxacin in these elderly subjects is 4 hours.

There is no information on accumulation of norfloxacin with repeated administration in elderly patients. However, no dosage adjustment is required based on age alone. In elderly patients with reduced renal function, the dosage should be adjusted as for other patients with renal impairment (see DOSAGE AND ADMINISTRATION, Renal Impairment).

In elderly subjects (average creatinine clearance was 91 mL/min/1.73m² .) approximately 22% of the administered dose was recovered in urine and renal clearance averaged 154 mL/min.

Fifth paragraph added:

Quinolones, including norfloxacin, may exacerbate the signs of myasthenia gravis and lead to life threatening weakness of the respiratory muscles. Caution should be exercised when using quinolones, including Noroxin, in patients with myasthenia gravis (see ADVERSE REACTIONS).

Information for Patients:

Revised to add information concerning Videx :

Multivitamins or other products containing iron or zinc, antacids or Videx (Didanosine), chewable/buffered tablets or the pediatric powder for oral solution, should not be taken within the two-hour period before or within the two-hour period after taking norfloxacin. (See PRECAUTIONS, Drug Interactions.)

Information for Patients:

Sentence added to the end of this subsection to include information concerning convulsions :

Convulsions have been reported in patients taking quinolones, including norfloxacin, and to notify their physician before taking this drug if there is a history of this condition.

Drug Interactions: 

Revised to add information concerning Videx :

Videx (Didanosine) chewable/buffered tablets or the pediatric powder for oral solution should not be administered concomitantly with, or within 2 hours of, the administration of norfloxacin, because these products may interfere with absorption resulting in lower serum and urine levels of norfloxacin.

Subsection added:

Of the 340 subjects in one large clinical study of NOROXIN for treatment of urinary tract infections, 103 patients were 65 and older, 77 of whom were 70 and older; no overall differences in safety and effectiveness were evident between these subjects and younger subjects. In clinical practice, no difference in the type of reported adverse experiences have been observed between the elderly and younger patients; however, increased risk for adverse experiences in some older individuals cannot be ruled out (see ADVERSE REACTIONS).

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).

A pharmacokinetic study of NOROXIN in elderly volunteers (65 to 75 years of age with normal renal function for their age) was carried out (see CLINICAL PHARMOCOLOGY).

"CNS effects characterized as generalized seizures, myoclonus and tremors have been reported with NOROXIN (see WARNINGS). Visual disturbances have been reported with drugs in this class."

A causal relationship to Noroxin has not been established

Tendinitis, tendon rupture; possible exacerbation of myasthenia gravis (see PRECAUTIONS).

Transient hearing loss (rare), tinnitus, diplopia, dysgeusia.

Multivitamins, other products containing iron or zinc, antacids containing magnesium and aluminum, sucralfate, or Videx (Didanosine), chewable/buffered tablets or the pediatric powder for oral solution, should not be taken within 2 hours of administration of norfloxacin.