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(Posted: 4/7/2003)
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Statement
Labeling provides for revisions to the CLINICAL PHARMACOLOGY section, Clinical Studies subsection, PRECAUTIONS section and the ADVERSE REACTIONS. A copy of the new labeling can be found at the following link:
[ http://www.fda.gov/cder/ogd/rld/rld_labeling_approved_december_2002.htm ]
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[Other safety related information:
http://www.fda.gov/medwatch/SAFETY/2002/safety02.htm#thiazo
]
PRECAUTIONS
Weight Gain
In postmarketing experience, there have been rare reports of unusually rapid increases in weight and increases in excess of that generally observed in clinical trials. Patients who experience such increases should be assessed for fluid accumulation and volume-related events such as excessive edema and congestive heart failure.
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BECONASE (beclomethasone
dopropionate) Nasal Aerosol
[December 16, 2002: GlaxoSmithKline]
BECONASE AQ (beclomethasone dipropionate)
Nasal Spray [December 16 & 19, 2002: GlaxoSmithKline]
Nasal Spray and Nasal Aerosol labels - Labeling provides for revisions to the PRECAUTIONS, and ADVERSE REACTIONS sections of the package inserts to include information on the growth suppressive effects of inhaled corticosteroids. Contact the company for a copy of the labeling/package insert.
Nasal Spray label - Labeling provides for the addition of a Geriatric Use subsection to the PRECAUTIONS section of the package insert. Contact the company for a copy of the labeling/package insert.
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From: Current literature suggests that high busulfan area under the plasma concentration verses time curve (AUC) values (>1,500 m M/min) may be associated with an increased risk of developing hepatic veno-occlusive disease (HVOD). Patients who have received prior radiation therapy, greater than or equal to three cycles of chemotherapy, or a prior progenitor cell transplant may be at an increased risk of developing HVOD with the recommended BUSULFEX dose and regimen. Hepatic veno-occlusive disease developed in 8.2% (5/61) of patients treated with BUSULFEX in the setting of allogeneic transplantation and was fatal in 2/5 cases (40%). Jones’ criteria were used to diagnose VOD (hyperbilirubinemia, and two of the following three findings: painful hepatomegaly, weight gain > 5% or ascites) in this clinical trial. The incidence of HVOD reported in the literature from the randomized, controlled trials (see CLINICAL STUDIES) was 7.7% to 12%.
To:
Current literature suggests that high busulfan area under the plasma concentration verses time curve (AUC) values (>1,500mM/ min) may be associated with an increased risk of developing hepatic veno-occlusive disease (HVOD). Patients who have received prior radiation therapy, greater than or equal to three cycles of chemotherapy, or a prior progenitor cell transplant may be at an increased risk of developing HVOD with the recommended BUSULFEX dose and regimen. Based on clinical examination and laboratory findings, hepatic veno-occlusive disease was diagnosed in 8% (5/61) of patients treated with BUSULFEX in the setting of allogeneic transplantation, was fatal in 2/5 cases (40%),and yielded an overall mortality from HVOD in the entire study population of 2/61 (3%). Three of the five patients diagnosed with HVOD were retrospectively found to meet the Jones’ criteria. The incidence of HVOD reported in the literature from the randomized, controlled trials (see CLINICAL STUDIES) was 7.7%-2%.
From: Hepatic veno-occlusive disease (HVOD) is a recognized potential complication of conditioning therapy prior to transplant. Five of 61 (8%) patients treated in the allogeneic study developed HVOD and it was fatal in 2/5.
To:
Hepatic veno-occlusive disease (HVOD) is a recognized potential complication of conditioning therapy prior to transplant. Based on clinical examination and laboratory findings, hepatic veno-occlusive disease was diagnosed in 8% (5/61) of patients treated with BUSULFEX in the setting of allogeneic transplantation, was fatal in 2/5 cases (40%), and yielded an overall mortality from HVOD in the entire study population of 2/61 (3%). Three of the five patients diagnosed with HVOD were retrospectively found to meet the Jones’ criteria.
From:
Seventy-nine percent (79%) of patients exhibited some form of edema, hypervolemia, or weight increase; all events were reported as mild or moderate
To:
Patients receiving allogeneic transplant exhibited some form of edema (79%), hypervolemia, or documented weight increase (8%); all events were reported as mild or moderate.
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Geriatric Use: Clinical studies of CEFOBID (sterile cefoperazone sodium)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.
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Case series studies using enzyme replacement therapy have shown improvement in growth rate for those children and adolescents experiencing growth retardation related to Gaucher disease.
Ceredase (alglucerase injection) is indicated for use as long-term enzyme replacement therapy for children, adolescents and adult patients with a confirmed diagnosis of Type I Gaucher disease who exhibit signs and symptoms that are severe enough to result in one or more of the following conditions:
e) growth retardation related to Gaucher disease in children and adolescents.
The safety and effectiveness of Ceredase have been established in children and adolescents (from 2 up to 16 years of age). Use of Ceredasein these age groups is supported by evidence from well-controlled studies of Ceredase in adults and pediatric patients with additional data obtained from the literature and from long term follow-up information. There is limited data for pediatric patients under the age of two.
Relocated from first paragraph of the General subsection - As hCG has been detected in Ceredase, physicians should be alert for signs of early virilization in males under the age of ten. One case of precocious puberty has been reported to date, however due to the recent introduction of manufacturing steps designed to reduce the level of hCG in Ceredase, the likelihood of this occurrence is reduced.
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Geriatric Use:
Clinical studies of colistimethate sodium 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 response 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 likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
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1. Under PRECAUTIONS/Drug Interactions, the following new subsection has been added after the Immunosuppressives subsection :
HMG-CoA Reductase Inhibitors:
Simvastatin (CYP3A4 substrate) in combination with amiodarone has been associated with reports of myopathy/rhabdomyolysis.
2. Under ADVERSE REACTIONS/Postmarketing Reports, the term "rhabdomyolysis" has been added after "…toxic epidermal necrolysis, myopathy."
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Geriatric Use
Clinical studies of Cortisportin Cream 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 response 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.
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http://www.fda.gov/medwatch/SAFETY/2002/safety02.htm#depako ]
Labeling provides for additions to the CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, and ADVERSE REACTIONS sections of the package insert regarding hyperammonemic encephalopathy in patients receiving valproate therapy, particularly as it relates to patients with known urea cycle disorders (UCD).
Go to the link provided above for the full revised label.
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Elderly patients may suffer from asymptomatic renal and hepatic dysfunction. Care should be taken when administering this therapy to this patient population.
Replaced with:
Clinical studies of HELIDAC Therapy 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, the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in elderly patients should be considered when prescribing HELIDAC Therapy. As stated in the CONTRAINDICATIONS section, this therapy is contraindicated in patients with renal or hepatic impairment.
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WARNING: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum. Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.
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Labeling provides for a revision in the labeling to add statements in the Warnings, Information for Patients, and Adverse Reactions sections regarding the risk of secondary lung cancer in patients with Hodgkin’s disease who are treated with procarbazine in combination with other chemotherapy and/or radiation and the effects of tobacco on this risk. Contact the company for a copy of the new labeling/package insert.
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Replaces previous labeling for this subsection -
Geriatric Use: Clinical studies of Monurol 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.
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Clinical studies of clotrimazole 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.
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Last sentence added -
Differences in pharmacokinetics between NovoLog and regular human insulin are not associated with differences in overall glycemic control.
Last sentence added -
Differences in pharmacokinetics between NovoLog and regular human insulin are not associated with differences in overall glycemic control
Added to end of subsection -
However, clearance of NovoLog reduced by 28% in patients with BMI >32 compared to patients with BMI <23 when a single dose of 0.1 u/kg NovoLog was administered.
Third sentence added -
No apparent effect of creatinine clearance values on AUC and Cmax of NovoLog was found. However, only 2 patients with severe renal impairment were studied (<30 mL/min).
Increases in levels of anti-insulin antibodies that react with both human insulin and insulin aspart have been observed in patients treated with NovoLog. The number of patients treated with insulin aspart experiencing these increases is greater than the number among those treated with human regular insulin. Data from a 12-month controlled trial in patients with Type 1 diabetes suggest that the increase in these antibodies is transient. The differences in antibody levels between the human regular insulin and insulin aspart treatment groups observed at 3 and 6 months were no longer evident at 12 months. The clinical significance of these antibodies is not known. They do not appear to cause deterioration in HbA1c or to necessitate increases in insulin dose.
In a 12 month clinical trial, a
transient increase of cross-reactive insulin antibodies 6 months treatment return
to baseline level has been observed in some patients changes in HbA1c or increase
of insulin dose. The clinical significance of these has not been established.
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General: The use of PerioChip in an acutely abscessed periodontal pocket has not been studied and therefore is not recommended. Although rare, infectious events including abscesses and cellulitis, which have been reported after scaling and root planing alone, have also been reported with the adjunctive placement of the PerioChip post scaling and root planing. Management of patients with periodontal disease should include consideration of potentially contributing medical disorders, such as cancer, diabetes, and immunocompromised status.
Geriatric Use: Although subjects aged 65 years and over were included in clinical studies of PerioChip, there were not sufficient numbers of these subjects 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. Overall differences in safety or effectiveness have not been identified between the elderly and younger patients.
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Labeling extensively revised. Contact the company for a copy of the labeling/ package insert.
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WARNING: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum. Research indicates that patients with impaired kidney function, including premature neonates, who received parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.
Container label -
Contains no more than 200 micrograms/Liter of aluminum.
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PREVACID (lansoprazole)
Delayed-Release Capsules &
PREVACID (lansoprazole) for Delayed-Release Oral Suspension
[December 3, 2002: TAP Pharmaceutical Products]
[Other labeling information not found in 2002 PDR: http://www.fda.gov/medwatch/SAFETY/2002/jul02.htm#prevac]
PRECAUTIONS
Information for Patients
PREVACID Delayed-Release Capsules, PREVACID SoluTab Delayed-Release Orally Disintegrating Tablets and PREVACID for Delayed-Release Oral Suspension should be taken before eating. PREVACID products SHOULD NOT BE CRUSHED OR CHEWED.
Phenylketonurics: Contains Phenylalanine 2.5 mg per 15 mg Tablet and 5.1 mg per 30 mg Tablet.
Alternative Administration Options
For patients who have difficulty swallowing capsules, there are three options. 1. PREVACID Delayed-Release Capsules Sprinkle. PREVACID Delayed-Release Capsules can be opened, and the intact granules contained within can be sprinkled on one tablespoon of either applesauce, ENSURE pudding, cottage cheese, yogurt, or strained pears and swallowed immediately. Alternatively, PREVACID Delayed-Release Capsules may be emptied into a small volume of either apple juice, orange juice or tomato juice (60 mL – approximately 2 ounces), mixed briefly and swallowed immediately. 2. PREVACID SoluTab Delayed-Release Orally Disintegrating Tablets. PREVACID SoluTab Delayed-Release Orally Disintegrating Tablets are available in 15 mg and 30 mg strengths. PREVACID SoluTabs are not designed to be swallowed intact or chewed. The tablet typically disintegrates in less than 1 minute. Place the tablet on the tongue and allow it to disintegrate with or without water until the particles can be swallowed. 3. PREVACID for Delayed-Release Oral Suspension. PREVACID for Delayed-Release Oral Suspension is available in strengths of 15 mg and 30 mg. Directions for use: Empty packet contents into a container containing 2 tablespoons of WATER. DO NOT USE OTHER LIQUIDS OR FOODS. Stir well, and drink immediately. If any material remains after drinking, add more water, stir, and drink immediately.
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[Other labeling information not found in 2002 PDR:
http://www.fda.gov/medwatch/SAFETY/2002/feb02.htm#prilos,
http://www.fda.gov/medwatch/SAFETY/2002/jul02.htm#prilos]
CLINICAL PHARMACOLOGY
Microbiology
Susceptibility Test for Helicobacter pylori
MIC (m g/mL) value for Clarithromycin
from 0.015 to
0.016
And Amoxicillin from 0.015
to 0.016
And
Clarithromycin MIC (m g/mL) |
Interpretation |
£ 0.25 |
Susceptible (S) |
|
0.5 |
Intermediate (I) |
|
|
Resistant (R) |
DOSAGE AND ADMINISTRATION:
No dosage adjustment is necessary for patients with
renal impairment, hepatic
dysfunction or for the elderly.
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http://www.fda.gov/medwatch/SAFETY/2002/feb02.htm#retrov]
Observed During Clinical Practice Hemic and Lymphatic Hemic and Lymphatic: Aplastic anemia, hemolytic anemia, leukopenia, lymphadenopathy, pancytopenia with marrow hypoplasia, pure red cell aplasia.
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Third paragraph changed from -
There are two genetically determined patterns of propafenone metabolism. In over 90% of patients, the drug is rapidly and extensively metabolized with an elimination half-life from 2-10 hours. These patients metabolize propafenone into two active metabolites: 5 hydroxypropafenone and N-depropylpropafenone. In vitro preparations have shown these two metabolites to have antiarrhythmic activity comparable to propafenone but in man they both are usually present in concentrations less than 20% of propafenone. Nine additional metabolites have been identified, most only in trace amounts. It is the saturable hydroxylation pathway that is responsible for nonlinear pharmacokinetic disposition.
To the following two paragraphs:
There are two genetically determined patterns
of propafenone metabolism. In over 90% of patients, the drug is rapidly and
extensively metabolized with an elimination half-life from 2-10 hours. These
patients metabolize propafenone into two active metabolites: 5- hydroxypropafenone
which is formed by CYP2D6 and N-depropylpropafenone which is formed by both
CYP3A4 and CYP1A2.
There are two genetically determined patterns of propafenone metabolism. In over 90% of patients, the drug is rapidly and extensively metabolized with an elimination half-life from 2-10 hours. These patients metabolize propafenone into two active metabolites: 5- hydroxypropafenone which is formed by CYP2D6 and N-depropylpropafenone which is formed by both CYP3A4 and CYP1A2.
Last paragraph added -
In vitro and in vivo studies have shown that the R-isomer of propafenone is cleared faster than the S-isomer via the 5-hydroxylation pathway (CYP2D6). This results in a higher ratio of S-propafenone during steady state.
WARNINGS
In the National Heart, Lung and Blood Institute's Cardiac Arrhythmia Suppression Trial (CAST), a long-term, multi-center, randomized, double-blind study in patients with asymptomatic non-life-threatening ventricular arrhythmias who had a myocardial infarction more than six days but less than two years previously, an increased rate of death or reversed cardiac arrest rate (7.7%; 56/730) was seen in patients treated with encainide or flecainide (class 1C antiarrhythmics) compared with that seen in patients assigned to placebo (3.0%; 22/725).
RYTHMOL slows atrioventricular conduction and also causes first degree AV block. Average PR interval prolongation and increases in QRS duration are closely correlated with dosage increases and concomitant increases in propafenone plasma concentrations. The incidence of first degree, second degree, and third degree AV block observed in 2,127 ventricular arrhythmia patients was 2.5%, 0.6%, and 0.2%, respectively. Development of second or third degree AV block requires a reduction in dosage or discontinuation of RYTHMOL. Bundle branch block (1.2%) and intraventricular conduction delay (1.1%) have been reported in patients receiving propafenone. Bradycardia has also been reported (1.5%). Experience in patients with sick sinus node syndrome is limited and these patients should not be treated with propafenone.
Drugs that inhibit CYP2D6, CYP1A2 and CYP3A4 might lead to increased plasma levels of propafenone. When propafenone is administered with inhibitors of these enzymes, the patients should be closely monitored and the dose adjusted accordingly.
Animal Toxicology
subsection has been re-titled:
Renal changes have been observed in the rat following 6 months of oral administration of propafenone at doses of 180 and 360 mg/kg/day (12-24 times the maximum recommended human dose) but not 90 mg/kg/day. Both inflammatory and non-inflammatory changes in the renal tubules with accompanying interstitial nephritis were observed. These lesions were reversible, in that they were not found in rats treated at these dosage levels and allowed to recover for 6 weeks. Fatty degenerative changes of the liver were found in rats following chronic administration of propafenone at dose levels 19 times the maximum recommended human dose.
Renal changes have been observed in the rat following 6 months of oral administration of propafenone HCl at doses of 180 and 360 mg/kg/day (about 2 and 4 times, respectively, the maximum recommended human daily dose [MRHD] on a mg/m 2 basis). Both inflammatory and non-inflammatory changes in the renal tubules, with accompanying interstitial nephritis, were observed. These changes were reversible, as they were not found in rats allowed to recover for 6 weeks. Fatty degenerative changes of the liver were found in rats following longer durations of administration of propafenone HCl at a dose of 270 mg/kg/day (about 3 times the MRHD on a mg/m 2 basis.) There were no renal or hepatic changes at 90 mg/kg/day (equivalent to the MRHD on a mg/m 2 basis).
Lifetime maximally tolerated oral dose studies in mice (up to 360 mg/kg/day) and rats (up to 270 mg/kg/day) provided no evidence of a carcinogenic potential for propafenone. RYTHMOL was not mutagenic when assayed for genotoxicity in 1) mouse Dominant Lethal test, 2) rat bone marrow Chromosome Analysis, 3) Chinese hamster bone marrow and spermatogonia chromosome analysis, 4) Chinese hamster micronucleus test, and 5) Ames bacterial test. Propafenone administered intravenously to rabbits, dogs, and monkeys has been shown to decrease spermatogenesis. These effects were reversible, were not found following oral dosing of propafenone, were seen only at lethal or sublethal dose levels and were not seen in rats treated either orally or intravenously (see PRECAUTIONS, Impaired Spermatogenesis). Propafenone did not affect fertility rates when administered orally to male and female rats at doses of 270 mg/kg/day or when administered orally or intravenously to male rabbits at doses of 120 mg/kg/day or 3.5 mg/kg/day, respectively. On a body weight basis, the above noted oral doses in rat and rabbit are 18 times and 8 times, respectively, the maximum recommended daily human dose of 900 mg (based on a 60 kg human body weight).
Lifetime maximally tolerated oral dose studies in mice (up to 360 mg/kg/day, about twice the maximum recommended human oral daily dose [MRHD] on a mg/m 2 basis) and rats (up to 270 mg/kg/day, about 3 times the MRHD on a mg/m 2 basis) provided no evidence of a carcinogenic potential for propafenone HCl.
Propafenone HCl tested negative for mutagenicity in the Ames (salmonella) test and the mouse dominant lethal test, and tested negative for clastogenicity in the Chinese hamster micronucleus test, and other in vivo tests for chromosomal aberrations in rat bone marrow and Chinese hamster bone marrow and spermatogonia.
Propafenone HCl, administered intravenously to rabbits, dogs, and monkeys, has been shown to decrease spermatogenesis. These effects were reversible, were not found following oral dosing of propafenone HCl, were seen at lethal or near lethal dose levels and were not seen in rats treated either orally or intravenously (see PRECAUTIONS, Impaired Spermatogenesis). Treatment of male rabbits for 10 weeks prior to mating at an oral dose of 120 mg/kg/day (about 2.4 times the MRHD on a mg/m 2 basis) or an intravenous dose of 3.5 mg/kg/day (a spermatogenesis-impairing dose) did not result in evidence of impaired fertility. Nor was there evidence of impaired fertility when propafenone HCl was administered orally to male and female rats at dose levels up to 270 mg/kg/day (about 3 times the MRHD on a mg/m 2 basis).
Pregnancy-Teratogenic Effects/Pregnancy-Nonteratogenic Effects
Propafenone has been shown to be embryotoxic in rabbits and rats when given in doses 10 and 40 times, respectively, the maximum recommended human dose. No teratogenic potential was apparent in either species. There are no adequate and well-controlled studies in pregnant women. Propafenone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy-Nonteratogenic Effects:
In a perinatal and postnatal study in rats, propafenone, at dose levels of 6 or more times the maximum recommended human dose, produced dose dependent increases in maternal and neonatal mortality, decreased maternal and pup body weight gain and reduced neonatal physiological development.
Teratogenic Effects:
Propafenone HCl has been shown to be embryotoxic (decreased survival) in rabbits and rats when given in oral maternally toxic doses of 150 mg/kg/day (about 3 times the maximum recommended human dose [MRHD] on a mg/m 2 basis) and 600 mg/kg/day (about 6 times the MRHD on a mg/m 2 basis), respectively. Although maternally tolerated doses (up to 270 mg/kg/day, about 3 times the MRHD on a mg/m 2 basis) produced no evidence of embryotoxicity in rats, post-implantation loss was elevated in all rabbit treatment groups (doses as low as 15 mg/kg/day, about 1/3 the MRHD on a mg/m 2 basis). There are no adequate and well-controlled studies in pregnant women. Rythmol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Non-teratogenic Effects:
In a study in which female rats received daily oral doses of propafenone HCl from mid-gestation through weaning of their offspring, doses as low as 90 mg/kg/day (equivalent to the MRHD on a mg/m 2 basis) produced increases in maternal deaths. Doses of 360 or more mg/kg/day (4 or more times the MRHD on a mg/m 2 basis) resulted in reductions in neonatal survival, body weight gain and physiological development.
There do not appear to be any age related differences in adverse reaction rates in the most commonly reported adverse reactions. Because of the possible increased risk of impaired hepatic or renal function in this age group, RYTHMOL should be used with caution. The effective dose may be lower in these patients.
Clinical studies of RYTHMOL 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.
A number of patients with liver abnormalities associated
with propafenone therapy have been reported in foreign
post-marketing experience.
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STATICIN (erythromycin) Solution
[December 15, 2002: Bristol-Myers Squibb]
Geriatric Use: Clinical studies of erythromycin topical solution for the treatment of acne vulgaris did not include subjects 65 years of age and older. Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
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Hepatic Insufficiency: The multi-dose pharmacokinetics of nelfinavir have not been studied in HIV-positive patients with hepatic insufficiency.
Renal Insufficiency:
The pharmacokinetics of nelfinavir have not been studied in patients with hepatic
or renal insufficiency; however, less
than 2% of nelfinavir is excreted in the urine, so the impact of renal impairment
on nelfinavir elimination should be minimal.
VIRACEPT is contraindicated in patients with clinically significant hypersensitivity to any of its components.
VIRACEPT should not be administered
concurrently with cisapride, triazolam, midazolam, ergot derivatives, amiodarone
or quinidine because VIRACEPT may affect the hepatic metabolism of these drugs
and create the potential for serious and/or life-threatening events
Coadministration of VIRACEPT is
contraindicated with drugs that are highly dependent on CYP3A for clearance
and for which elevated plasma concentrations are associated with serious and/or
life-threatening adverse events.These drugs are listed in Table 4.
PRECAUTIONS:
Based on known metabolic profiles, clinically significant
drug interactions are not expected between VIRACEPT and dapsone, trimethoprim/sulfamethoxazole,
clarithromycin, azithromycin,
erythromycin, itraconazole or fluconazole.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies in animals have not yet been completed. Nelfinavir was not, however, mutagenic or clastogenic in a battery of in vitro and in vivo tests including microbial mutagenesis (Ames), mouse lymphoma, chromosome aberrations in human lymphocytes, and an in vivo rat micronucleus assay.
Long-term carcinogenicity studies in rats have been conducted with nelfinavir at doses of 0,100, 300, and 1000 mg/kg/day via oral gavage. Thyroid follicular cell adenomas and carcinomas were increased in male rats at 300 mg/kg/day and higher and in female rats at 1000 mg/kg/day. The systemic exposures (Cmax) at 300 and 1000 mg/kg/day were 1- to 3- fold, respectively, of those measured in humans at the recommended therapeutic dose (750 mg TID or 1250 mg BID). The mechanism of nelfinavir-induced tumorogenesis in rats is unknown. However, nelfinavir showed no evidence of mutagenic or clastogenic activity in a battery of in vitro and in vivo genetic toxicology assays. These studies included bacterial mutation assays in S. typhimurium and E. coli, a mouse lymphoma tyrosine kinase assay, a chromosomal aberration assay in human lymphocytes, and an in vivo mouse bone marrow micronucleus assay. Given the lack of genotoxic activity of nelfinavir, the relevance to humans of neoplasms in nelfinavir-treated rats is not known.
Pediatric Use
Nelfinavir was studied in one open-label, uncontrolled
trial in 38 pediatric patients ranging in age from 2 to 13 years. In order to
achieve plasma concentrations in pediatric patients which approximate those
observed in adults, the recommended pediatric dose is 20-30 mg/kg given three
times daily with a meal or
light snack, not to exceed 750 mg
three times a day (see DOSAGE AND ADMINISTRATION).
Adults: The recommended dose is 1250 mg (five
250 mg tablets) twice daily or 750 mg (three 250 mg tablets) three times daily.
VIRACEPT should be taken with a meal or
light snack.
If the mixture is not consumed immediately, it must be stored under refrigeration, but storage must not exceed 6 hours.
Pediatric Patients (2-13 years): The recommended
oral dose of VIRACEPT for pediatric patients 2 to 13 years of age is 20-30 mg/kg
per dose, three times daily with a meal or
a light snack.
If the mixture is not consumed immediately, it must be stored under refrigeration, but storage must not exceed 6 hours.
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VIRAMUNE (nevirapine) Tablets and Suspension
[December 31, 2002: Boehringer Ingleheim]
Labeling provides for the inclusion of information in the VIRAMUNE (nevirapine) labels regarding renal and hepatic insufficiency. Contact the company for a copy of the new labeling/package insert:
http://www.roxanetpi.com/BIPI/
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(see http://www.fda.gov/cder/ogd/rld/rld_labeling_approved_december_2002.htm)
Table 2. Drug Interactions: Changes in Pharmacokinetic Parameters for Co-administered Drug in the Presence of VIREAD 300 mg Once Daily
(see http://www.fda.gov/cder/ogd/rld/rld_labeling_approved_december_2002.htm)
Renal impairment, which may include hypophosphatemia, has been reported with the use of VIREAD (see Adverse Reactions). The majority of these cases occurred in patients with underlying systemic or renal disease, or in patients taking nephrotoxic agents.
VIREAD should be avoided with concurrent or recent use of a nephrotoxic agent. Patients at risk for, or with a history of, renal dysfunction and patients receiving concomitant nephrotoxic agents should be carefully monitored for changes in serum creatinine and phosphorus.
When administered with VIREAD, Cmax and AUC of didanosine, administered as either the buffered or enteric-coated formulations, increased significantly (see Table 2). The mechanism of this interaction is unknown. Increases in didanosine concentration of this magnitude could potentiate didanosine-associated adverse events, including pancreatitis and neuropathy. Co- administration of VIREAD and didanosine should be undertaken with caution and patients receiving this combination should be carefully monitored for didanosine-associated adverse events. In the absence of data to support specific didanosine and/or VIREAD dose modifications, didanosine should be discontinued in patients who develop didanosine- associated adverse events.
Clinical Monitoring for Bone and
Renal Toxicity
Although tenofovir-associated
renal toxicity has not been observed in pooled clinical studies for up to one
year, long term renal effects are unknown. Consideration should be given to
monitoring for changes in serum creatinine and serum phosphorus in patients
at risk or with a history of renal dysfunction.
Observed During Clinical Practice: In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of VIREAD. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting or potential causal connection to VIREAD. Body as a whole: Asthenia Gastrointestinal: Pancreatitis Metabolic and nutritional: Hypophosphatemia, lactic acidosis Nervous: Dizziness Respiratory: Dyspnea Skin: Rash Urogenital: Increased creatinine, renal insufficiency, kidney failure, Fanconi syndrome
Concomitant administration: Didanosine. When administered with didanosine VIREAD should be administered 2 hours before or one hour after administration of didanosine (See PRECAUTIONS, Drug Interactions).
PATIENT PACKAGE INSERT
· If
you are also taking didanosine you should take VIREAD two hours before or one
hour after didanosine.
· Marketing experience: Other side effects reported since VIREAD has been marketed include: weakness, inflammation of the pancreas, low blood phosphate, dizziness, shortness of breath, and rash.
· Some patients treated with VIREAD have had kidney problems. Your doctor may need to perform additional blood tests if you have had kidney problems in the past or need to take another drug that can also cause kidney problems.
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Adequate hydration may help reduce the risk of nephrotoxicity to renal tubular epithelium by decreasing renal and urinary concentration of the drug and its metabolites.
PRECAUTIONS
Injection-Site Reactions: ZANOSAR Sterile Powder is irritating to tissues.
Extravasation may cause severe tissue lesions and necrosis.
Drug Interactions: ZANOSAR may demonstrate additive toxicity when used in combination with other cytotoxic drugs. Streptozocin has been reported to prolong the elimination half-life of doxorubicin and may lead to severe bone marrow suppression; a reduction of the doxorubicin dosage should be considered in patients receiving ZANOSAR concurrently. The concurrent use of streptozocin and phenytoin has been reported in one case to result in reduced streptozocin cytotoxicity.
Information for Patients: Confusion, lethargy, and depression have been reported in a limited number of patients receiving continuous intravenous infusion of ZANOSAR for 5 days. Patients should be informed that there may be a potential risk in driving or using complex machinery.
Pregnancy Category C changed to Pregnancy Category D and moved to the WARNINGS section.
ZANOSAR Sterile Powder should be administered intravenously.
ZANOSAR Sterile Powder should be administered intravenously by rapid injection or short/prolonged infusion.
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Labeling provides for a Geriatric Use subsection and revisions to the ADVERSE REACTIONS section. In addition, all other sections of the label were updated. Contact the company for a copy of the new labeling/package insert.
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Effect of age: The pharmacokinetics of zileuton were investigated in healthy elderly volunteers (ages 65 to 81 years, 9 Males and 4 Females) and healthy young volunteers (ages 20 to 40 years, 5 Males and 4 Females) after single and multiple oral doses of 600 mg every 6 hours of zileuton. Zileuton pharmacokinetics were similar in healthy elderly subjects (³ 65 years) compared to healthy younger adults (18 to 40 years).
In a subset analyses, females over the age of 65 appeared to be at an increased risk for ALT elevations. Zileuton pharmacokinetics were similar in healthy elderly subjects (³ 65 years) compared to healthy younger adults (18 to 40 years) (see Clinical Pharmacology-Special Populations: Effect of age).
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Postmarketing Experience:
Neuropathy (peripheral, optic) has been reported in patients treated with ZYVOX. Although these reports have primarily been in patients treated for longer than the maximum recommended duration of 28 days, these events have also been reported in patients receiving shorter courses of therapy.
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