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(Posted: 3/03/2003)
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ACIPHEX (rabeprazole sodium) Delayed-Release Tablets
Labeling provides for the use of ACIPHEX (rabeprazole sodium) Delayed-Release Tablets for the eradication of Helicobacter pylori. Contact the company for a copy of the new labeling/package insert.
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ALLEGRA-D (fexofenadine HCl and pseudoephedrine HCl ) Extended-Release Tablets [November 1, 2002: Aventis Pharmaceuticals]
ADVERSE REACTIONS
Fexofenadine Hydrochloride
Second paragraph added -
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Hypersensitivity reactions (including angioedema and urticaria), vasomotor disturbances, flushing, tingling, nausea, vomiting, and cramps may occur.
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[Other safety related information: http://www.fda.gov/medwatch/SAFETY/2002/safety02.htm#bextra ]
Serious skin reactions, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported through postmarketing surveillance in patients receiving BEXTRA (see ADVERSE REACTIONS-Postmarketing Experience).
As these reactions can become life threatening, BEXTRA should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.
Postmarketing Experience
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[Other labeling information not found in 2002 PDR: http://www.fda.gov/medwatch/SAFETY/2002/sep02.htm#cancid]
Preparation of Cancidas for use: Do not mix or co-infuse CANCIDAS with other medications, as there are no data available on the compatibility of CANCIDAS with other intravenous substances, additives, or medications. DO NOT USE DILUENTS CONTAINING DEXTROSE a-D-GLUCOSE), as CANCIDAS is not stable in diluents containing dextrose. Preparation of the 70-mg Day 1 loading-dose infusion for Invasive Aspergillosis
1. Equilibrate the refrigerated vial of CANCIDAS to room temperature.
2. Aseptically add 10.5 mL of 0.9% Sodium Chloride Injection, Sterile Water for Injection, Bacteriostatic Water for Injection with methylparaben and propylparaben, or Bacteriostatic Water for Injection with 0.9% benzyl alcohol to the vial.a This reconstituted solution may be stored for up to one hour at £ 25°C £ 77°F).b
3. Aseptically transfer 10 mL c of reconstituted CANCIDAS to an IV bag (or bottle) containing 250 mL 0.9%, 0.45%, or 0.225% Sodium Chloride Injection, or Lactated Ringer’s Injection. This infusion solution must be used within 24 hours if stored at £ 25°C (£ 77°F) or within 48 hours if stored refrigerated at 2 to 8°C (36 to 46°F). (If a 70-mg vial is unavailable, see below: Alternative Infusion Preparation Methods, Preparation of 70-mg Day 1 loading dose from two 50-mg vials.)
1. Equilibrate the refrigerated vial of CANCIDAS to room temperature.
2. Aseptically add 10.5 mL of 0.9% Sodium Chloride Injection, Sterile Water for Injection, Bacteriostatic Water for Injection with methylparaben and propylparaben, or Bacteriostatic Water for Injection with 0.9% benzyl alcohol to the vial.a This reconstituted solution may be stored for up to one hour at £ 25°C (£ 77°F).b
3. Aseptically transfer 10 mL c of reconstituted CANCIDAS to an IV bag (or bottle)
containing 250 mL 0.9%, 0.45%, or 0.225% Sodium Chloride Injection, or Lactated Ringer’s Injection. This infusion solution must be used within 24 hours if stored at £ 25°C (£ 77°F) or within 48 hours if stored refrigerated at 2 to 8°C (36 to 46°F). (If a reduced infusion volume is medically necessary, see below: Alternative Infusion Preparation Methods, Preparation of 50-mg daily doses at reduced volume.)
Reconstitute two 50-mg vials with 10.5 mL of diluent each (see Preparation of the daily 50-mg infusion). Aseptically transfer a total of 14 mL of the reconstituted CANCIDAS from the two vials to 250 mL of 0.9%, 0.45%, or 0.225% Sodium Chloride Injection, or Lactated Ringer’s Injection.
Preparation of 50-mg daily doses at reduced volume
When medically necessary, the 50-mg daily doses can be prepared by adding 10 mL of reconstituted CANCIDAS to 100 mL of 0.9%, 0.45%, or 0.225% Sodium Chloride Injection, or Lactated Ringer’s Injection (see Preparation of the daily 50-mg infusion).
Aseptically transfer 7 mL of the reconstituted CANCIDAS from the vial to 250 mL or, if medically necessary, to 100 mL of 0.9%, 0.45%, or 0.225% Sodium Chloride Injection or Lactated Ringer’s Injection.
HOW SUPPLIED
The final patient infusion solution in the IV bag or bottle can be stored at £ 25°C (£ 77°F) for 24 hours or at 2 to 8°C (36 to 46°F) for 48 hours.
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Other Events Observed During the Non-US
Postmarketing Evaluation of Celexa (citalopram HBr):
It is estimated that approximately
8 over
30 million patients have been treated with
Celexa since market introduction. Although no causal relationship to Celexa
treatment has been found, the following adverse events have been reported to
be temporally associated with Celexa treatment in
at least 3 patients (unless otherwise noted),
and have not been described elsewhere in labeling: acute
renal failure, akathisia, allergic reaction, anaphylaxis,
angioedema, choreoathetosis, chest
pain, delerium, dyskinesia, ecchymosis,
epidermal necrolysis (3
cases) , erythema multiforme, gastrointestinal
hemorrhage, grand mal convulsions, hemolytic anemia,
hepatic necrosis (2
cases) , myoclonus, neuroleptic malignant
syndrome, nystagmus,
pancreatitis, priapism, prolactinemia,
prothrombin decreased, QT prolonged, rhabdomyolysis,
serotonin syndrome, spontaneous abortion, thrombocytopenia, thrombosis,
ventricular arrhythmia, Torsades de pointes, and withdrawal syndrome.
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Experience in patients treated with Cerezyme (imiglucerase
for injection) has revealed that approximately 9.8%
13.8%
of patients experienced adverse events which were judged to be related to Cerezyme
administration and which occurred with an increase in frequency. Some of
the adverse events were related to the route of administration. These include
discomfort, pruritus, burning, swelling or sterile abscess at the site of venipuncture.
Each of these events was found to occur in < 1% of the total patient population.
Symptoms suggestive of hypersensitivity have been
noted in approximately 4.4%
6.6%
of patients. Onset of such symptoms has occurred during or shortly after infusions;
these symptoms include pruritus, flushing, urticaria, angioedema, chest discomfort,
respiratory symptoms, cyanosis and hypotension. Anaphylactoid reaction has also
been reported (see WARNINGS). Each of these events was found to occur
in <
1% <
1.5% of the total patient population. Pre-treatment
with antihistamines and/or corticosteroids and reduced rate of infusion have
allowed continued use of Cerezyme in most patients.
Additional adverse reactions that have been reported
in approximately 5.4%
6.5%
of patients treated with Cerezyme include: nausea, abdominal pain, diarrhea,
rash, fatigue, headache, fever, dizziness, chills, backache, and tachycardia.
Each of these events was found to occur in <
1%
< 1.5%
of the total patient population.
Incidence rates cannot be calculated from the spontaneously reported adverse events in the post-marketing database. From this database, the most commonly reported adverse events in children (defined as ages 2-12 years) included dyspnea, fever, nausea, flushing, vomiting, and coughing, whereas in adolescents (>12 – 16 years) and in adults (>16 years) the most commonly reported events included headache, pruritus, and rash.
In addition to the adverse reactions that have been
observed in patients treated with Cerezyme, transient peripheral edema
and vomiting
has been reported for this therapeutic class of drug.
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CORTROSYN (cosyntropin) Injection
[November 5, 2002: Organon]
A suggested method for a rapid screening test of adrenal function has been described by Wood and associates (1). A control blood sample of 6 to 7 mL is collected in a heparinized tube. Reconstitute 0.25 mg of CORTROSYN with 1 mL of 0.9% Sodium Chloride Injection, USP and inject intramuscularly. The reconstituted drug product should be inspected visually for particulate matter and discoloration prior to injection. Reconstituted CORTROSYN should not be retained.
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PRECAUTIONS:
Care should be taken to avoid
circulatory overload, particularly in patients with cardiac insufficiency.
The administration of these solutions
can cause fluid and/or solute overloading resulting in dilution of serum electrolyte
concentrations, overhydration, congested states, or pulmonary edema. The risk
of dilutive states is inversely proportional to the electrolyte concentration
of the injections. The risk of solute overload causing congested states with
peripheral pulmonary edema is directly proportional to the electrolyte concentrations
of the injections.
Drug product contains no more than 25 µg/L of aluminum.
Clinical studies of Dextrose Injection, USP 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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[November 14, 2002: Wallace Laboratories]
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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[Other labeling information not in 2002 PDR: http://www.fda.gov/medwatch/SAFETY/2002/feb02.htm#etopop ]
Geriatric Use -
Clinical studies of etoposide for the treatment of refractory testicular tumors did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Of more than 600 patients in four clinical studies in the NDA databases who received ETOPOPHOS (etoposide phosphate) or etoposide in combination with other chemotherapeutic agents for the treatment of small cell lung cancer (SCLC), about one third were older than 65 years. When advanced age was determined to be a prognostic factor for response or survival in these studies, comparisons between treatment groups were performed for the elderly subset. In the one study (etoposide in combination with cyclophosphamide and vincristine compared with cyclophosphamide and vincristine or cyclophosphamide, vincristine and doxorubicin) where age was a significant prognostic factor for survival, a survival benefit for elderly patients was observed for the etoposide regimen compared with the control regimens. No differences in myelosuppression were seen between elderly and younger patients in these studies except for an increased frequency of WHO Grade III or IV leukopenia among elderly patients in a study of etoposide phosphate or etoposide in combination with cisplatin. Elderly patients in this study also had more anorexia, mucositis, dehydration, somnolence, and elevated BUN levels than younger patients.
In five single-agent studies of etoposide phosphate in patients with a variety of tumor types, 34% of patients were 65 years or more. WHO grade III or IV leukopenia, granulocytopenia, and asthenia were more frequent among elderly patients.
Postmarketing experience also suggests that elderly patients may be more sensitive to some of the known adverse effects of etoposide, including myelosuppression, gastrointestinal effects, infectious complications, and alopecia. Although some minor differences in pharmacokinetic parameters between elderly and nonelderly patients have been observed, these differences were not considered clinically significant. Etoposide and its metabolites are known to be substantially excreted by the kidney, and the risk of adverse reactions to ETOPOPHOS 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 PRECAIUTIONS, Renal Impairment for recommended dosing adjustments in patients with renal impairment).
DOSAGE AND ADMINISTRATION
Second paragraph -
Solutions of ETOPOPHOS should be prepared in an aseptic manner. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.
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Labeling provides for revisions to language in the package insert pertaining to hepatotoxins. Contact the company for a copy of the new label/package insert.
Renal Impairment: Felbamate's single dose monotherapy pharmacokinetic parameters were evaluated in 12 otherwise healthy individuals with renal impairment. There was a 40-50% reduction in total body clearance and 9-15 hours prolongation of half-life in renally impaired subjects compared to that in subjects with normal renal function. Reduced felbamate clearance and a longer half-life were associated with diminishing renal function.
New third sentence: In the renally-impaired, starting and maintenance doses should be reduced by one-half (see CLINICALPHARMACOLOGY/Pharmacokinetics and PRECAUTIONS).
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Added as first sentence to section-
Dosing must be individualized.
A patient whose blood pressure is not adequately controlled with losartan monotherapy (see above) or hydrochlorothiazide alone, may be switched to HYZAAR 50-12.5 (losartan 50 mg/hydrochlorothiazide 12.5 mg) once daily.
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[Other labeling information not found in 2002 PDR: http://www.fda.gov/medwatch/SAFETY/2002/jan02.htm#kaletr]
Labeling contains 48-week safety and efficacy data (updated from 24- week data) from Study M98-888 included in the original new drug application. This labeling supplement provides for the use of KALETRA Capsules and KALETRA Oral Solution in combination with other antiretroviral agents for the treatment of HIV-infection. This indication is based on analyses of plasma HIV RNA levels and CD4 cell counts in controlled studies of KALETRA of 48 weeks duration and in smaller uncontrolled dose-ranging studies of KALETRA of 72 weeks duration. Contact the company for a copy of the new labeling/package insert.
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KETALAR (ketamine HCl) Injection
[November 14, 2002: King Pharmaceuticals]
PRECAUTIONS:
Geriatric Use Clinical studies of ketamine hydrochloride 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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MIOSTAT (carbachol) Intraocular Ophthalmic Solution
Geriatric Use: No overall differences in safety or effectiveness have been observed between elderly and younger patients.
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This section was deleted.
Previous paragraph deleted and replaced with the following:
Pediatric Use: Safety and effectiveness of NAVELBINE in pediatric patients have not been established. Data from a single arm study in 46 patients with recurrent solid malignant tumors, including rhabdomyosarcoma/undifferentiated sarcoma, neuroblastoma, and CNS tumors, at doses similar to those used in adults showed no meaningful clinical activity. Toxicities were similar to those reported in adult patients.
DOSAGE AND ADMINISTRATION
Single-Agent NAVELBINE: The usual initial dose of single-agent NAVELBINE is 30 mg/m 2 administered weekly. The recommended method of administration is an intravenous injection over 6 to 10 minutes. In controlled trials, single-agent NAVELBINE was given weekly until progression or dose-limiting toxicity.
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Labeling incorporates the NSAID format and other revisions into the labeling. Contact the company for a copy of the new label/package insert.
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[Some editorial revision (alphabetizing effects in Manifestations and deletions in Treatment - retained text presented, deletions not included).]
In the event of overdosage, emergency treatment should be started immediately. Consultation with a poison control center should be considered.
Manifestations: Antihistamine overdosage effects may vary from central nervous system depression (apnea, arrhythmias, cardiovascular collapse, cyanosis, diminished mental alertness, sedation) to stimulation (convulsions, hallucinations, insomnia, or tremors) to death. Other signs and symptoms may be ataxia, blurred vision, dizziness, hypotension and tinnitus. Stimulation is particularly likely in children, as are atropine-like signs and symptoms (dry mouth; fixed, dilated pupils; flushing; gastrointestinal symptoms; and hyperthermia).
Treatment: Dialysis is of little value in antihistamine poisoning. Treatment of the signs and symptoms of overdosage is symptomatic and supportive. Consider standard measures to remove any unabsorbed drug. There is no specific antidote. Measures to enhance excretion (urinary acidification, hemodialysis) are not recommended.
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[November 14, 2002: Teva Pharmaceuticals]
CYP 3A changed to CYP 3A4 throughout labeling.
CONTRAINDICATIONS:
Item 3. - addition of the phrase, "or patients with known hypokalemia or hypomagnesemia (see also PRECAUTIONS-Drug Interactions)"
Because ORAP prolongs the QT interval of the electrocardiogram, an additive effect on QT interval would be anticipated if administered with other drugs, such as phenothiazines, tricyclic antidepressants or antiarrhythmic agents, which prolong the QT interval. Accordingly, pimozide should not be given with dofetilide, sotalol, quinidine, other Class Ia and III anti-arrhythmics, mesoridazine, thioridazine, chlorpromazine, droperidol, pimozide, sparfloxacin, gatifloxacin, moxifloxacin, halofantrine, mefloquine, pentamidine, arsenic trioxide, levomethadyl acetate, dolasetron mesylate, probucol, tacrolimus, ziprasidone, or other drugs that have demonstrated QT prolongation as one of their pharmacodynamic effects. Also, the use of macrolide antibiotics in patients with prolonged QT intervals has been rarely associated with ventricular arrhythmias. Such concomitant administration should not be undertaken (see CONTRAINDICATIONS).
Rare case reports have suggested possible additive effects of pimozide and fluoxetine leading to bradycardia.
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Serous Inflammation and Fibrosis --There have been rare reports of pleuritis, pleural effusion, pleural fibrosis, pericarditis, pericardial effusion, cardiac valvulopathy involving one or more valves, or retroperitoneal fibrosis in patients taking pergolide. In some cases, symptoms or manifestations of cardiac valvulopathy improved after discontinuation of pergolide. Pergolide should be used with caution in patients with a history of these conditions, particularly those patients who experienced the events while taking ergot derivatives. Patients with a history of such events should be carefully monitored clinically and with appropriate radiographic and laboratory studies while taking pergolide.
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PhosLo (calcium acetate) Tablets
[November 4, 2002: Braintree Laboratories]
PRECAUTIONS
Geriatric Use
Of the total number of subjects in clinical studies of PhosLo (n=91), 25 percent were 65 and over, while 7 percent were 75 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.
[This is identical to the statement in the PhosLo Gelcap label.]
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Added to the end of the first paragraph:
Elderly patients may be more susceptible to nephrotoxicity (see PRECAUTIONS: Geriatric Use).
Added to the end of the second paragraph:
Elderly patients may be more susceptible to peripheral neuropathy (see PRECAUTIONS: Geriatric Use).
PRECAUTIONS
Geriatric Use: Insufficient data are available from clinical trials of cisplatin in the treatment of metastatic testicular tumors or advanced bladder cancer to determine whether elderly patients respond differently than younger patients. In four clinical trials of combination chemotherapy for advanced ovarian carcinoma, 1484 patients received cisplatin either in combination with cyclophosphamide or paclitaxel. Of these, 426 (29%) were older than 65 years. In these trials, age was not found to be a prognostic factor for survival. However, in a later secondary analysis for one of these trials, elderly patients were found to have shorter survival compared with younger patients. In all four trials, elderly patients experienced more severe neutropenia than younger patients. Higher incidences of severe thrombocytopenia and leukopenia were also seen in elderly compared with younger patients, although not in all cisplatin-containing treatment arms. In the two trials where nonhematologic toxicity was evaluated according to age, elderly patients had a numerically higher incidence of peripheral neuropathy than younger patients. Other reported clinical experience suggests that elderly patients may be more susceptible to myelosuppression, infectious complications, and nephrotoxicity than younger patients.
Cisplatin is known to be substantially excreted by the kidney and is contraindicated in patients with preexisting renal impairment. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and renal function should be monitored.
ADVERSE REACTIONS
Nephrotoxicity
Elderly patients may be more susceptible to nephrotoxicity (see PRECAUTIONS: Geriatric Use).
Hematologic
Elderly patients may be more susceptible to myelosuppression (see PRECAUTIONS: Geriatric Use).
OTHER TOXICITIES
Neurotoxicity
Elderly patients may be more susceptible to peripheral neuropathy (see PRECAUTIONS: Geriatric Use).
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[Other safety related information: http://www.fda.gov/medwatch/SAFETY/2002/safety02.htm#premar ]
Labeling provides for revisions in the text of the direction circular to include recently published information from the Women’s Health Initiative (WHI) study and the American Cancer Society. Contact the company for a copy of the labeling/package insert.
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[Other safety related information: http://www.fda.gov/medwatch/SAFETY/2002/safety02.htm#premar]
Labeling provides for revisions in the text of the direction circular to include recently published information from the Women’s Health Initiative (WHI) study and the American Cancer Society. Contact the company for a copy of the labeling/package insert.
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PREVPAC (lansoprazole
30-mg capsules, amoxicillin 500-mg capsules,
& clarithromycin 500-mg tablets)
[November 22, 2002: TAP Pharmaceutical]
Multiple labeling changes delineated under "letter" and package insert/label under "label" found at the following link (see Prevpac): http://www.fda.gov/cder/ogd/rld/rld_labeling_approved_november_2002.htm
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PRECAUTIONS
Clinical studies of PRINZIDE 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. In a multiple dose pharmacokinetic study in elderly versus young hypertensive patients using the lisinopril/hydrochlorothiazide combination, area under the plasma concentration time curve (AUC) increased approximately 120% for lisinopril and approximately 80% for hydrochlorothiazide in older patients.
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. Evaluation of the hypertensive patient should always include assessment of renal function. (See DOSAGE AND ADMINISTRATION.)
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[Other labeling information not in 2002 PDR: http://www.fda.gov/medwatch/SAFETY/2002/sep02.htm#rebeto , http://www.fda.gov/medwatch/SAFETY/2002/feb02.htm#rebetr ]
Renal Dysfunction - REBETOL
is not recommended for patients with severe renal
Impairment, replaced with:
Patients with creatinine clearance < 50 mL/min
should not be treated with REBETOL.
WARNINGS
Pulmonary
(New section in the Rebetol label)
Pulmonary symptoms, including dyspnea, pulmonary
infiltrates, pneumonitis and pneumonia, have been reported during therapy with
REBETOL/INTRON A; occasional cases of fatal pneumonia have occurred. Pulmonary
symptoms, including dyspnea, pulmonary infiltrates, pneumonitis and pneumonia,
including fatality, have been reported during therapy with REBETOL/INTRON A.
In addition, sarcoidosis or the
exacerbation of sarcoidosis has been reported.
If there is evidence of pulmonary infiltrates or pulmonary function impairment,
the patient should be closely monitored, and if appropriate, combination REBETOL/INTRON
A treatment should be discontinued.
should be used with caution in patients with creatinine clearance
<50ml/min
replaced with: should not
be used in patients with creatinine clearance <50ml/min.
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).
Replaced with: REBETOL (ribavirin)
should not be used in elderly patients with creatinine clearance <50mL/min
(see WARNINGS).
•lung problems. REBETRON Combination Therapy can cause breathing problems or worsen breathing problems you already have.
Who should not take REBETOL Capsules?
• lung problems. REBETOL/interferon alfa-2b Therapy can cause breathing problems or worsen breathing problems you already have.
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Addition of hyperglycemia
Labeling provides for the use of SecreFlo (secretin) Injection for use in secretin stimulation testing for: Stimulation of pancreatic secretions to facilitate the identification of the ampulla of Vater and accessory papilla during endoscopic retrograde cholangio-pancreatography (ERCP). Contact the company for a copy of the new label/package insert.
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During postmarketing experience, rare cases of hypersensitivity reactions such as rash, itching and urticaria have been reported.
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Labeling provides for the use TAXOTERE in combination with cisplatin for the treatment of patients with unresectable, locally advanced or metastatic non-small cell lung cancer who have not previously received chemotherapy for this condition. Contact the company for a copy of the new label/package insert.
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In addition to the adverse experiences reported during
clinical testing of TOPAMAX, the following adverse experiences have been reported
worldwide
in patients receiving topiramate
post-approval marketed
TOPAMAX from worldwide use since approval.
These adverse experiences have not been listed above and data are insufficient
to support an estimate of their incidence or to establish causation. The listing
is alphabetized: hepatic failure (including
fatalities), hepatitis, pancreatitis, and
renal tubular acidosis.
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It should be administered with caution to patients
with: cardiovascular disease, including hypertension or ischemic disease; increased
intraocular pressure (see CONTRAINDICATIONS); diabetes mellitus; or in patients
receiving digitalis or
oral anticoagulants.
4. Patients should not take TRINALIN REPEATABS Tablets
if they are receiving a monoamine oxidase inhibitor or within 2 weeks of stopping
such a treatment, or
if they are receiving oral anticoagulants.
Geriatric Use: Clinical studies of TRINALIN REPEATABS Tablets 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 elderly and younger patients.
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PRECAUTIONS:
Geriatric Use
Clinical studies of VASERETIC 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. Evaluation of the hypertensive patient should always include assessment of renal function. (See DOSAGE AND ADMINISTRATION.)
DOSAGE AND ADMINISTRATION
The subsection Use in the Elderly has been deleted.
PRECAUTIONS:
Geriatric Use
Clinical studies of VASOTEC I.V. 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. Evaluation of the hypertensive patient should always include assessment of renal function. (See DOSAGE AND ADMINISTRATION.)
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After intravenous administration of 3 H-etoposide (70-290 mg/m 2 ), mean recoveries of radioactivity in the urine range from 42 to 67%, and fecal recoveries range from 0 to 16% of the dose. Less than 50% of an intravenous dose is excreted in the urine as etoposide with mean recoveries of 8 to 35% within 24 hours.
After intravenous administration of 14 C-etoposide (100-124 mg/m 2 ), mean recovery of radioactivity in the urine was 56% of the dose at 120 hours, 45% of which was excreted as etoposide: fecal recovery of radioactivity was 44% of the dose at 120 hours.
Biliary excretion appears to be a minor route of etoposide elimination. Only 6% or less of an intravenous dose is recovered in the bile as etoposide. Metabolism accounts for most of the nonrenal clearance of etoposide. The major urinary metabolite of etoposide in adults and children is the hydroxyacid [4’-demethylepipodophyllic acid-9- (4,6-0-(R)-ethylidene-β -D-glucopyranoside)], formed by opening of the lactone ring. It is also present in human plasma, presumably as the transisomer. Glucuronide and/or sulfate conjugates of etoposide are excretedin human urine and represent 5 to 22% of the dose. In addition, 0-demethylation of the dimethoxyphenol ring occurs through the
CYP450 3A4 isoenzyme pathway to produce the corresponding catechol.
Biliary excretion of unchanged drug and/or metabolites is an important route of etoposide elimination as fecal recovery of radioactivity is 44% of the intravenous dose. The hydroxy acid metabolite [4’-demethylepipodophyllic acid-9-(4,6-0-(R)-ethylidene-b -D-glucopyranoside)], formed by opening of the lactone ring, is found in the urine of adults and children. It is also present in human plasma, presumably as the trans isomer. Glucuronide and/or sulfate conjugates of etoposide are also excreted in human urine. Only 8% or less of an intravenous dose is excreted in the urine as radiolabeled metabolites of 14 C-etoposide. In addition, 0-demethylation of the dimethoxyphenol ring occurs through the CYP450 3A4 isoenzyme pathway to produce the corresponding catechol.
Geriatric Use: Clinical studies of VePesid (etoposide) for the treatment of refractory testicular tumors did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Of more than 600 patients in four clinical studies in the NDA databases who received VePesid or etoposide phosphate in combination with other chemotherapeutic agents for the treatment of small cell lung cancer (SCLC), about one third were older than 65 years. When advanced age was determined to be a prognostic factor for response or survival in these studies, comparisons between treatment groups were performed for the elderly subset. In the one study (etoposide in combination with cyclophosphamide and vincristine compared with cyclophosphamide and vincristine or cyclophosphamide, vincristine and doxorubicin) where age was a significant prognostic factor for survival, a survival benefit for elderly patients was observed for the etoposide regimen compared with the control regimens. No differences in myelosuppression were seen between elderly and younger patients in these studies except for an increased frequency of WHO grade III or IV leukopenia among elderly patients in a study of etoposide phosphate or etoposide in combination with cisplatin. Elderly patients in this study also had more anorexia, mucositis, dehydration, somnolence, and elevated BUN levels than younger patients.
In five single-agent studies of etoposide phosphate in patients with a variety of tumor types, 34% of patients were age 65 years or more. WHO Grade III or IV leukopenia, granulocytopenia, and asthenia were more frequent among elderly patients.
Postmarketing experience also suggests that elderly patients may be more sensitive to some of the known adverse effects of etoposide, including myelosuppression, gastrointestinal effects, infectious complications and alopecia.
Although some minor differences in pharmacokinetic parameters between elderly and nonelderly patients have been observed, these differences were not considered clinically significant. Etoposide and its metabolites are known to be substantially excreted by the kidney, and the risk of adverse 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 PRECAUTIONS, Renal Impairment for recommended dosing adjustments in patients with renal impairment.
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Zanaflex tablets and capsules are bioequivalent to each other under fasted conditions, but not under fed conditions.
A single dose of either two 4 mg tablets or two 4 mg capsules was administered under fed and fasting conditions in an open label, four period, randomized crossover study in 96 human volunteers, of whom 81 were eligible for the statistical analysis. Following oral administration of either the tablet or capsule (in the fasted state), tizanidine has peak plasma concentrations occurring 1.0 hours after dosing with a half-life of approximately 2 hours. When two 4 mg tablets are administered with food the mean maximal plasma concentration is increased by approximately 30%, and the median time to peak plasma concentration is increased by 25 minutes, to 1 hour and 25 minutes. In contrast, when two 4 mg capsules are administered with food the mean maximal plasma concentration is decreased by 20%, the median time to peak plasma concentration is increased by 2 hours to 3 hours. Consequently, the mean Cmax for the capsule when administered with food is approximately 2/3’s the Cmax for the tablet when administered with food. Food also increases the extent of absorption for both the tablets and capsules. The increase with the tablet (~30%) is significantly greater than with the capsule (~10%). Consequently when each is administered with food, the amount absorbed from the Jay, this area. What to do? capsule is about 80% of the amount absorbed from the tablet (See Figures 1 and 2). Administration of the capsule contents sprinkled on applesauce is not bioequivalent to administration of an intact capsule under fasting conditions. Administration of the capsule contents on applesauce results in a 15% - 20% increase in Cmax and AUC of tizanidine compared to administration of an intact capsule while fasting, and a 15 minute decrease in the median lag time and time to peak concentration.
Figure 1:Mean Tizanidine Concentration vs. Time Profiles For Zanaflex Tablets and Capsules (2 ´ 4 mg) Under Fasted and Fed Condition
[see company for copy of figure]
In safety studies, approximately 75 patients have been exposed to individual doses of 12 mg or more for at least one year or more and approximately 80 patients have been exposed to total daily doses of 30 to 36 mg/day for at least one year or more.
DISCONTINUING THERAPY If therapy needs to be discontinued, especially in patients who have been receiving high doses for long periods, the dose should be decreased slowly to minimize the risk of withdrawal and rebound hypertension, tachycardia, and hypertonia.
Patients should be advised of the change in the absorption profile of Zanaflex if taken with food and the potential changes in efficacy and adverse effect profiles that may result (see PHARMACOKINETICS).
Patients should be advised not to stop tizanidine suddenly as rebound hypertension and tachycardia may occur (see PRECAUTIONS: Discontinuing Therapy).
Rofecoxib
Rofecoxib may potentiate the adverse effects of tizanidine. Eight case reports of a potential rofecoxib-tizanidine drug interaction have been identified in postmarketing safety reports. Most of the adverse events reported involved the nervous system (e.g., hallucinations, psychosis, somnolence, hypotonia, etc.) and the cardiovascular system (e.g.. hypotension, tachycardia, bradycardia). In all cases, adverse events resolved following discontinuation of tizanidine, rofecoxib, or both. Rechallenges with both drugs were not performed. The possible mechanism and the potential for a drug interaction between tizanidine and rofecoxib remain unclear.
Tizanidine was administered to 1187
1385
patients in additional clinical studies where adverse event information was
available.
In the tabulations that follow, reported adverse
events were classified using a standard COSTART-based dictionary terminology.
The frequencies presented, therefore, represent the proportion of the 1187
1385 patients
exposed to tizanidine who experienced an event of the type cited on at least
one occasion while receiving tizanidine.
Tizanidine is closely related to clonidine, which is often abused in combination with narcotics and is known to cause symptoms of rebound upon abrupt withdrawal. Three cases of rebound symptoms on sudden withdrawal of tizanidine have been reported. The case reports suggest that these patients were also misusing narcotics. Withdrawal symptoms included hypertension, tachycardia, hypertonia, tremor, and anxiety. As with clonidine, withdrawal is expected to be more likely in cases where high doses are used, especially for prolonged periods.
A search of a safety surveillance database revealed a total of eighteen cases of tizanidine overdose. Of the fourteen intentional overdoses, five have resulted in fatality, and in at least three of these cases, other CNS depressants were involved. One fatality was secondary to pneumonia and sepsis, which were sequelae of the ingestion. The majority of cases involve depressed consciousness (somnolence, stupor, or coma), depressed cardiovascular function (bradycardia, hypotension), and depressed respiratory function (respiratory depression or failure).
Should overdose occur, basic steps to ensure the adequacy of an airway and the monitoring of cardiovascular and respiratory systems should be undertaken. In general, symptoms resolve within one to three days following discontinuation of tizanidine and administration of appropriate therapy. Due to the similar mechanism of action, symptoms and management of tizanidine overdose are similar to those following clonidine overdose. For the most recent information concerning the management of overdose, contact a poison control center.
Food has complex effects on tizanidine pharmacokinetics, which differ with the different formulations. These pharmacokinetic differences may result in clinically significant differences when [1] switching administration of the tablet between the fed or fasted state, [2] switching administration of the capsule between the fed or fasted state, [3] switching between the tablet and capsule in the fed state, or [4] switching between the intact capsule and sprinkling the contents of the capsule on applesauce. These changes may result in increased adverse events or delayed/more rapid onset of activity, depending upon the nature of the switch. For this reason, the prescriber should be thoroughly familiar with the changes in kinetics associated with these different conditions (see PHARMACOKINETICS).
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