![[U.S. Food and Drug Administration]](../../../icon/header.gif){kind=icon}
(Posted: MAY 17, 2001)
Note: The following summaries include only those safety-related sections that have been modified, and therefore do not contain all the information needed for safe and effective prescribing. Contact the manufacturer for the complete labeling/package insert.
|
(rosiglitazone maleate) |
(biclutamide) |
(cefuroxime axetil) |
(norfloxacin) |
|
(hydroxyurea) |
(metformin hydrochloride) |
(Glyburide/Metformin HCl) |
(somatropin) |
|
(hydroxyurea) |
(sumatriptan) |
(ketamine hydrochloride) |
(penbutolol sulfate) |
|
(fat emulsion) |
(sibutramine) |
(meropenem) |
(mivacurium chloride) |
|
(fosinopril Na/hydrochlorothiazide) |
(morphine sulfate controlled-release) |
(gemtuzumab ozogamicin) |
(cromolyn sodium) |
|
(paroxetine HCl) |
(famotidine) |
(promethazine HCl) |
|
|
(somatrem) |
(ribavirin/interferon alpha-2b) |
(mirtazapine) |
(zaleplon) |
|
(metoprolol succinate) |
(vancomycin HCl) |
(enalapril maleate) |
(sertraline HCl) |
|
(azithromycin) |
(bupropion hydrochloride) |
(linezolid) |
CLINICAL PHARMACOLOGY:
Clinical Studies -
Table 4. Glycemic Parameters in a 26-Week Combination Study
In the table - new text in bolded, underlined italics -
Difference from ["placebo" deleted] metformin alone (adjusted mean)
Table 5. Glycemic Parameters in Two 26-Week Combination Studies
In the table - new text in bolded, underlined italics -
Difference from ["placebo" deleted] sulfonylurea alone (adjusted mean)
For the complete view of Tables 4. and 5. click on the link below and find Avandia label under February 8 -
http://www.fda.gov/cder/ogd/rld/rld_labeling_approved_february_2001.html
WARNINGS:
New Section added -
Cardiac Failure and Other Cardiac Effects: Avandia, like other thiazolidinediones, alone or in combination with other antidiabetic agents, can cause fluid retention, which may exacerbate or lead to heart failure. Patients should be observed for signs and symptoms of heart failure. Avandia should be discontinued if any deterioration in cardiac status occurs.
Patients with New York Heart Association (NYHA) Class 3 and 4 cardiac status were not studied during the clinical trials. Avandia is not recommended in patients with NYHA Class 3 and 4 cardiac status.
In two 26-week U.S. trials involving 611 patients with type 2 diabetes, Avandia plus insulin therapy was compared with insulin therapy alone. These trials included patients with long-standing diabetes and a high prevalence of pre-existing medical conditions, including peripheral neuropathy (34%), retinopathy (19%), ischemic heart disease (14%), vascular disease (9%), and congestive heart failure (2.5%). In these clinical studies an
increased incidence of cardiac failure and other cardiovascular adverse events were seen in patients on Avandia and insulin combination therapy compared to insulin and placebo. Patients who experienced heart failure were on average older, had a longer duration of diabetes, and were mostly on the higher 8 mg daily dose of Avandia. In this population, however, it was not possible to determine specific risk factors that could be used to
identify all patients at risk of heart failure on combination therapy. Three of 10 patients who developed cardiac failure on combination therapy during the double blind part of the studies had no known prior evidence of congestive heart failure, or pre-existing cardiac condition. The use of Avandia in combination therapy with insulin is not indicated (see ADVERSE REACTIONS).
PRECAUTIONS:
General
Subsection revised, new text in bolded, underlined italics -
Due to its mechanism of action, Avandia is active only in the presence of endogenous insulin. Therefore, Avandia should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
Edema: Avandia should be used with caution in patients with edema. In a clinical study in healthy volunteers who received Avandia 8 mg once daily for 8 weeks, there was a [",there was a small," deleted] statistically significant increase in median plasma volume ["(1.8 mL/kg)" deleted] compared to placebo.
Since thiazolidinediones, including rosiglitazone, can cause fluid retention, which can exacerbate or lead to congestive heart failure, ["patients at risk for heart failure (particularly those on insulin) should be monitored for signs and symptoms of heart failure (See PRECAUTIONS, Use in Patients with Heart Failure) " deleted] Avandia should be used with caution in patients at risk for heart failure. Patients should be monitored for signs and symptoms of heart failure (see WARNINGS, Cardiac Failure and Other Cardiac Effects and PRECAUTIONS, Information for Patients).
In controlled clinical trials of patients with type 2 diabetes, mild to moderate edema was reported in patients treated with Avandia, and may be dose related. Patients with ongoing edema are more likely to have adverse events associated with edema if started on combination therapy with insulin and Avandia (see ADVERSE REACTIONS).
New Subsection and Table:
Weight Gain: Dose-related weight gain was seen with Avandia alone and in combination with other hypoglycemic agents (Table 6). The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation.
Table 6. Weight Changes (kg) from Baseline During Clinical Trials with Avandia
|
Control Group |
Avandia 4 mg
|
Avandia 8 mg |
|||
| Monotherapy | Duration |
Median (25 th , 75 th percentile) |
Median (25 th , 75 th percentile) |
Median (25 th , 75 th percentile) |
|
| 26 weeks | placebo | -0.9 (-2.8, 0.9) | 1.0 (-0.9, 3.6) | 3.1 (1.1, 5.8) | |
| 52 weeks | sulfonylurea | 2.0 (0, 4.0) | 2.0 (-0.6, 4.0) | 2.6 (0, 5.3) | |
|
Combination therapy |
|||||
| sulfonylurea | 26 weeks | sulfonylurea | 0 (-1.3, 1.2) | 1.8 (0, 3.1) | -- |
| metformin | 26 weeks | metformin | -1.4 (-3.2, 0.2) | 0.8 (-1.0, 2.6) | 2.1 (0, 4.3) |
| insulin | 26 weeks | insulin | 0.9 (-0.5, 2.7) | 4.1 (1.4, 6.3) | 5.4 (3.4, 7.3) |
Hematologic:
(New text to subsection in bolded, underlined italics) -
Across all controlled clinical studies, decreases in hemoglobin and hematocrit (mean decreases in individual studies <1.0 gram/dL and < 3.3%, respectively) were observed for Avandia alone and in combination with [" a sulfonylurea or metformin" deleted] other hypoglycemic agents. The changes occurred primarily during the first ["4 to 8 weeks of therapy and remained relatively constant thereafter" deleted] 3 months following initiation of Avandia therapy or following an increase in Avandia dose. White blood cell counts also decreased slightly in patients treated with Avandiaa. The observed changes may be related to the increased plasma volume observed with treatment with Avandia ["and have not been associated with any significant hematologic clinical effects" deleted] and may be dose related.
(see ADVERSE REACTIONS, Laboratory Abnormalities).
Hepatic Effects:
Previous fourth paragraph revised -
Although available clinical data show no evidence of Avandia -induced hepatotoxicity or ALT elevations, rosiglitazone is structurally related to troglitazone, which has been associated with idiosyncratic hepatotoxicity and rare cases of liver failure, liver transplants, and death. Pending the availability of the results of additional large, long-term controlled clinical trials and postmarketing safety data following wide clinical use of Avandia to more fully define its hepatic safety profile, it is recommended that patients treated with Avandia undergo periodic monitoring of liver enzymes.
Fourth paragraph with new text in bolded, underlined italics -
In postmarketing experience with Avandia, reports of hepatitis and of hepatic enzyme elevations to three or more times the upper limit of normal have been received. Very rarely, these reports have involved hepatic failure with and without fatal outcome,
although causality has not been established. Rosiglitazone is structurally related to troglitazone, a thiazolidinedione no longer marketed in the United States, which was associated with idiosyncratic hepatotoxicity and rare cases of liver failure, liver transplants, and death during clinical use. Pending the availability of the results of additional large, long-term controlled clinical trials and additional postmarketing safety data, it is recommended that patients treated with Avandia undergo periodic monitoring of liver enzymes.
Information for Patients -
New text in bolded, underlined italics -
Patients with unexplained symptoms of nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine should immediately report these symptoms to their physician. Patients who experience an unusually rapid increase in weight or edema or who develop shortness of breath or other symptoms of heart failure while on Avandia should immediately report these symptoms to their physician.
ADVERSE REACTIONS:
Trials of Avandia as Monotherapy and In Combination with Other Hypoglycemic Agents -
Two paragraphs added to end of subsection -
In 26-week double-blind studies, edema was reported with higher frequency in the Avandia plus insulin combination trials (insulin, 5.4%; and Avandia in combination with insulin, 14.7%). Reports of new onset or exacerbation of congestive heart failure occurred at rates of 1% for insulin alone, and 2% (4 mg) and 3% (8 mg) for insulin in combination with Avandia (see WARNINGS, Cardiac Failure and Other Cardiac Effects)
In postmarketing experience with Avandia, adverse events potentially related to volume expansion (e.g., congestive heart failure, pulmonary edema, and pleural effusions) have been reported.
Laboratory Abnormalities -
Serum Transaminase Levels:
Fourth paragraph, new text bolded, underlined and in italics -
In pre-approval clinical trials, there were no cases of idiosyncratic drug reactions leading to hepatic failure. In postmarketing experience with Avandia (rosiglitazone maleate), reports of hepatic enzyme elevations three or more times the upper limit of normal and
hepatitis have been received (see PRECAUTIONS, Hepatic Effects).
WARNINGS:
Hepatitis:
New section added:
Rare cases of death or hospitalization due to severe liver injury have been reported post-marketing in association with the use of CASODEX. Hepatotoxicity in these reports generally occurred within the first three to four months of treatment. Hepatitis or marked increases in liver enzymes leading to drug discontinuation occurred in approximately 1% of CASODEX patients in controlled clinical trials. Serum transaminase levels should be measured prior to starting treatment with CASODEX, at regular intervals for the first four months of treatment, and periodically thereafter. If clinical symptoms or signs suggestive of liver dysfunction occur, (e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, "flu-like" symptoms, dark urine, jaundice, or upper right quadrant tenderness), the serum transaminases, in particular the serum ALT, should be measured immediately. If at any time a patient has jaundice, or their ALT rises above two times the upper limit of normal, CASODEX should be should be discontinued with close follow-up of liver function.
CONTRAINDICATIONS:
The following statement in the second paragraph regarding use in women has been revised (revisions in bolded, underlined italics) -
CASODEX [" is not indicated in women. Further, CASODEX is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy," deleted] has no indication for women, and should not be used in this population, particularly for non-serious or non-life threatening conditions. Further, CASODEX should not be used by women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. CASODEX may cause fetal harm when administered to pregnant women.
ADVERSE REACTIONS:
Postmarketing Experience:
The following subsection added:
Rare cases of interstitial pneumonitis and pulmonary fibrosis have been reported with CASODEX.
PRECAUTIONS:
The following paragraph in the section deleted (revised and moved to WARNINGS section) -
4. Since transaminase abnormalities and, rarely, jaundice have been reported with the use of CASODEX, periodic liver function tests should be considered. If clinically indicated, e.g., when the patient has jaundice or laboratory evidence of liver injury in the absence of liver metastases,
CASODEX therapy should be discontinued. If transaminases increase over 2 times the upper limit of normal, treatment should be discontinued. Abnormalities are usually reversible upon discontinuation.
[Not in 2000 PDR]
PRECAUTIONS:
Pediatric Use:
Addition of the following sentences:
The safety and effectiveness of CEFTIN have been established for pediatric patients aged 3 months to 12 years for acute bacterial maxillary sinusitis based upon its approval in adults. Use of CEFTIN in pediatric patients is supported by pharmacokinetic and safety data in
adults and pediatric patients, and by clinical and microbiological data from adequate and well-controlled studies of the treatment of acute bacterial maxillary sinusitis in adults and of acute otitis media with effusion in pediatric patients. It is also supported by post-marketing
adverse events surveillance. (See CLINICAL PHARMACOLOGY, INDICATIONS AND USAGE, ADVERSE REACTIONS, DOSAGE AND ADMINISTRATION, and CLINICAL STUDIES).
DOSAGE AND ADMINISTRATION
addition of dosing information for pediatric patients (who can swallow tablets whole) as follows:
"Acute bacterial maxillary sinusitis, 250 mg b.i.d., 10 days"
ADVERSE REACTIONS:
New text in bolded, underlined italics -
In clinical trials, the most frequently reported drug-related adverse reaction was local burning or discomfort. Other drug-related adverse reactions were conjunctival hyperemia, chemosis, corneal deposits, photophobia and a bitter taste following instillation.
[Other labeling changes not appearing in 2001 PDR: http://www.fda.gov/medwatch/safety/2000/dec00.htm#glucop ] The complete label can be viewed by going to the link below.
New labeling provides for a revised patient
package insert and package insert necessitated by the approval of Glucophage XR Tablets, 500 mg.
Glucophage and Glucophage XR share common labeling. Contact the company for a copy of the new labeling or go to the following link (see February 8)
http://www.fda.gov/cder/ogd/rld/rld_labeling_approved_february_2001.html
Return to Quick Reference
WARNINGS:
Special Warning on Increased Risk Of Cardiovascular Mortality -
New subsection -
SPECIAL WARNING ON INCREASED RISK OF CARDIOVASCULAR MORTALITY
The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. The study involved 823 patients who were randomly assigned to one of four treatment groups (Diabetes 19 (Suppl. 2):747-830, 1970).
UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 g per day) had a rate of cardiovascular mortality approximately 2˝ times that of patients treated with diet alone. A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in overall mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and benefits of glyburide and of alternative modes of therapy.
Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure.
PRECAUTIONS:
Geriatric Use:
New subsection -
The safety and effectiveness of Humatrope in patients aged 65 and over has not been evaluated in clinical studies. Elderly patients may be more sensitive to the action of Protropin and may be more prone to develop adverse reactions.
WARNINGS:
New third paragraph -
Fatal and nonfatal pancreatitis have occurred in HIV-infected patients during therapy with hydroxyurea and didanosine, with or without stavudine. Hepatotoxicity and hepatic failure resulting in death have been reported during post-marketing surveillance in HIV-infected
patients treated with hydroxyurea and other antiretroviral agents. Fatal hepatic events were reported most often in patients treated with the combination of hydoxyurea, didanosine, and stavudine. Peripheral neuropathy, which was severe in some cases, has been reported in HIV-infected patients receiving hydroxyurea in combination with antiretroviral agents, including didanosine, with or without stavudine.
PRECAUTIONS:
New second paragraph -
Hydroxyurea is not indicated for the treatment of HIV infection; however ,if HIV-infected patients are treated with hydroxyurea, and in particular, in combination with didanosine and/or stavudine, close monitoring for signs and symptoms of pancreatitis and hepatotoxicity is
recommended. Patients who develop signs and symptoms of pancreatitis or hepatotoxicity should permanently discontinue therapy with hydroxyurea. (See WARNINGS and ADVERSE REACTIONS sections .)
ADVERSE REACTIONS:
New last paragraph -
Fatal and nonfatal pancreatitis and hepatotoxicity, and severe peripheral neuropathy have been reported in HIV-infected patients who received hydroxyurea in combination with antiretroviral agents, in particular, didanosine plus stavudine. Patients treated with hydroxyurea in combination
with didanosine, stavudine,and indinavir in study ACTG 5025 showed a median decline in CD4 cells of approximately 100/mm 3 .(See WARNINGS and PRECAUTIONS .)
Information added to the Patient Information labeling for DROXIA -
What should I know if I am HIV-positive?
Because of serious, life-threatening side effects associated with DROXIA used in combination with certain medications for HIV, your doctor should closely monitor your pancreas and liver function with frequent physical examinations and laboratory blood tests. Some studies have shown a
decrease in the number of CD4 (T-cells) for HIV-positive patients taking DROXIA. Although DROXIA is approved by the U.S .Food and Drug Administration for treating sickle cell anemia, it is not approved for treating HIV infection.
PRECAUTIONS:
Geriatric Use:
The following paragraph replaces the previous subsection [Not found in 2000 PDR] -
The use of sumatriptan in elderly patients is not recommended because elderly patients are more likely to have decreased hepatic function, they are at higher risk for CAD,and blood pressure increases may be more pronounced in the elderly (see WARNINGS).
ADVERSE REACTIONS: The following changes were made in the subsection (new text in bolded, underlined italics) -
"General: Anaphylaxis. Local pain and exanthema….."
DRUG ABUSE AND DEPENDENCE: This section was added.
"Ketamine has been reported being used as a drug of abuse. Reports suggest that ketamine produces a variety of symptoms including, but not limited to anxiety, dysphoria, disorientation, insomnia, flashbacks, hallucinations, and psychotic episodes. Ketamine dependence and tolerance are possible following prolonged administration. A withdrawal syndrome with psychotic features has been described following discontinuation of long-term ketamine use. Therefore, ketamine should be prescribed and administered with caution."
PRECAUTIONS:
Geriatric Use:
Clinical studies of Levatol 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.
"With the exception of heparin at 1 to 2 units/mL of fat emulsion, additives to the Liposyn II bottle are contraindicated."
"Partly used containers must not be stored for later use. Filters of less than 1.2 micron porosity must not be used with Liposyn II. Do not use any bottle in which there appears to be an oiling out of the emulsion."
The following statement has been deleted from the WARNINGS section and has been
included in the DOSAGE AND ADMINISTRATION section of the package insert:
"Studies have documented the stability of Liposyn II 10% and 20% with necessary Abbott electrolytes, Abbott trace metals, and Abbottt 10% through 70% Dextrose Injection, USP in a TPN admixture container (See Note) with the following Abbott amino acid solutions…."
The PRECAUTIONS section has been revised to include the following subsection:
"Nursing Mothers. It is not known whether the drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Liposyn II is administered to a nursing woman. Frequent (some advise daily) platelet counts should be done in neonatal patients
receiving parental nutrition with Liposyn II."
New paragraphs and table added:
Maintenance of weight loss with sibutramine was examined in a 2-year, double-blind, placebo-controlled trial. After a 6-month run-in phase in which all patients received sibutramine 10 mg (mean weight loss, 26 lbs.), patients were randomized to sibutramine (10 to 20 mg, 352 patients) or placebo (115 patients). The mean weight loss from initial body weight to endpoint was 21 lbs. and 12 lbs. for sibutramine and placebo patients, respectively. A statistically significantly (p<0.001) greater proportion of sibutramine treated patients, 75%, 62%, and 43%, maintained at least 80% of their initial weight loss at 12, 18, and 24 months, respectively, compared with the placebo group (38%, 23%, and 16%). Also 67%, 37%, 17%, and 9% of sibutramine treated patients compared with 49%, 19%, 5%, and 3% of placebo patients lost =5%, =10%, =15%, and =20%, respectively, of their
initial body weight at endpoint.2 From endpoint to the post-study follow-up visit (about 1 month), weight regain was approximately 4 lbs for the sibutramine patients and approximately 2 lbs for the placebo patients
The effect of sibutramine 15 mg once daily on measures of 24-hour blood pressure was evaluated in a 12-week placebo-controlled study. Twenty-six male and female, primarily Caucasian individuals with an average BMI of 34 kg/m 2 and an average age of 39 years underwent 24-hour ambulatory blood pressure monitoring (ABPM). The mean changes from baseline to Week 12 in various measures of ABPM are shown in the following table.
Normal diurnal variation of blood pressure was maintained
DOSAGE AND ADMINISTRATION:
New text in bolded, underlined italics -
The safety and effectiveness of MERIDIA, as demonstrated in double-blind, placebo-controlled trials, have not been determined beyond ["1 year" deleted] 2 years at this time.
PRECAUTIONS:
Drug Interactions:
"Other than probenecid, no specific drug interaction studies were conducted"
deleted and replaced with the following paragraph:
"There is evidence that meropenem may reduce serum levels of valproic acid to subtherapeutic levels (therapeutic range considered to be 50 to 100 mcgm/mL total valproate)."
ADVERSE REACTIONS:
Adult Patients -
"During the initial clinical investigations, 2038 immunocompetent adult patients were treated for infections outside the CNS with MERREM I.V. (500 mg or 1000 mg q 8 hours). Deaths in 3 patients were assessed as possibly related to meropenem; 28 (1.4%) patients had meropenem discontinued because of adverse events."
Revised and replaced with the following text:
"During clinical investigations, 2904 immunocompetent adult patients were treated for infections outside the CNS with MERREM I.V. (500 mg or 1000 mg q 8 hours). Deaths in 5 patients were assessed as possibly related to meropenem; 36 (1.2%) patients had meropenem discontinued because of adverse events."
Local Adverse Reactions -
New text in bolded, underlined italics -
Inflammation at the injection site 2.4% ["3.0%" deleted]
Phlebitis/thrombophlebitis 0.8% ["1.2% deleted]
Injection site reaction 0.9% ["1.1%" deleted]
Systemic Adverse Reactions -
New text in bolded, underlined italics -
Systemic adverse clinical reactions that were reported irrespective of the relationship to MERREM I.V. occurring in greater than 1.0% of the patients were diarrhea 4.8% ["(5.0%)" deleted], nausea/vomiting 3.6% ["(3.9%)" deleted], headache 2.3% ["(2.8%)" deleted], rash 1.9% ["(1.7%)" deleted], pruritus 1.2% ["(1.6%)" deleted], apnea 1.3% ["(1.2%)" deleted], constipation 1.4% ["(1.2%)" deleted] Sepsis 1.6% and Shock 1.2%.
Second paragraph, new text in bolded, underlined italics-
Additional adverse systemic clinical reactions that were reported irrespective of relationship to therapy with MERREM I.V. and occurring in less than or equal to 1.0% [" less than 1.0%" deleted] but greater than 0.1% of the patients are listed below within each body system in order of decreasing frequency:
Third paragraph revised -
"Bleeding events [gastrointestinal hemorrhage, melena, epistaxis, and hemoperitoneum] occurred in 0.7% of meropenem patients."
Deleted and replaced with -
"Bleeding events were seen as follows: gastrointestinal hemorrhage (0.5%), melena (0.3%), epistaxis (0.2%), hemoperitoneum (0.2%), summing to 1.2%."
Body as a Whole
New text in bolded, underlined italics -
Body as a Whole: pain, abdominal pain, chest pain, ["sepsis, shock" moved to subsection above], fever, abdominal enlargement, back pain, ["hepatic failure" moved to Digestive System] chills and pelvic pain
Digestive System: oral moniliasis, anorexia, cholestatic jaundice/jaundice, flatulence, ileus, hepatic failure (moved here from the Body as a Whole listing), dyspepsia and intestinal obstruction
Hemic/Lymphatic: anemia, hypochromic anemia and hypervolemia
Nervous System: insomnia, agitation/delirium, confusion, dizziness, seizure (see PRECAUTIONS) nervousness, paresthesia, hallucinations, somnolence, anxiety, depression, asthenia
Respiratory: respiratory disorder, dyspnea, pleural effusion, asthma, cough increased, and lung edema
Skin and Appendages: urticaria, sweating, skin ulcer
Urogenital System: dysuria, kidney failure, vaginal moniliasis and urinary incontinence
Adverse Laboratory Changes
Hematologic: increased platelets, increased eosinophils, prolonged prothrombin time, prolonged partial thromboplastin time, decreased platelets, ["positive direct or indirect Coombs test" deleted], decreased hemoglobin, decreased hematocrit, decreased WBC, [" shortened prothrombin time and shortened partial thromboplastin time" deleted] leukocytosis and hypokalemia.
Renal: increased creatinine and increased BUN
"NOTE: It is not known if the safety profile of MERREM I.V. is changed in patients with varying degrees of renal impairment."
Deleted and replaced with the following :
"NOTE: For patients with varying degrees of renal impairment, the incidence of heart failure, kidney failure, seizure and shock, irrespective of relationship to MERREM I.V., increased in patients with moderately severe renal impairment (creatinine clearance > 10 to 26 mL/min)."
New text in bolded, underlined italics -
MERREM I.V. was studied in 515 ["417" deleted] pediatric patients (> 3 months to <13 years of age) with serious bacterial infections at dosages of 10 to 20 mg/kg every 8 hours. The types of clinical adverse events seen in these patients are similar to the adults, with the most common adverse events reported as possibly, probably or definitely related to MERREM I.V. and their rates of occurrence as follows:
Diarrhea 3.5% [" 4.3% deleted]
Rash 1.6% ["1.4% deleted]
Nausea and Vomiting 0.8% ["1.0%" deleted]
MERREM I.V. was studied in 321 ["198" deleted] pediatric patients (> 3 months to <17 years of age) with meningitis at a dosage of 40 mg/kg every 8 hours. The types of clinical adverse events seen in these patients are similar to the adults, with the most common adverse events reported as possibly, probably, or definitely related to MERREM I.V. and their rates of occurrence as follows:
Rash (mostly diaper area moniliasis) 3.1% ["3.5%" deleted]
Diarrhea 4.7% ["3.5%" deleted]
Oral Moniliasis 1.9% ["2.0%" deleted]
Glossitis 1.0%
Post-Marketing Experience
Previous first paragraph -
"No post-marketing experience is available."
Deleted and replaced by the following:
"Worldwide post-marketing adverse events not previously listed in the product label and reported as possibly, probably, or definitely drug related
are listed within each body system in order of decreasing severity. Hematologic – agranulocytosis, neutropenia, and leukopenia. Skin – toxic
epidermal necrolysis, Stevens-Johnson Syndrome angioedema, and erythema multiform."
CLINICAL PHARMACOLOGY:
Pharmacokinetics:
Special Populations: Geriatric Patients ( > 60 years):
First paragraph, last sentence with revisions incorporated -
Two pharmacodynamic studies in which patients received infusions for a shorter duration (2 to 3 hours) have shown that the infusion rate requirements were lower (by 38%) in elderly patients (64 to 86 years of age) than in younger patients (18 to 41 years of age).
Last paragraph, last sentence with revisions incorporated -
However, the time to onset may be slower, the duration may be slightly longer, the rate of recovery may be slightly slower, therefore
MIVACRON requirements may be lower in geriatric patients.
PRECAUTIONS:
Geriatric Use:
Revisions included in the following text -
MIVACRON was safely
administered during clinical trials to 64 geriatric
["elderly" deleted] ( > 65 years) patients, including 31 patients
with significant cardiovascular disease (see PRECAUTIONS: General subsection). In general, the clearances of MIVACRON are most likely lower, the duration may be longer, the rate of recovery may be slower, therefore, MIVACRON requirements may be lower in geriatric patients (see CLINICAL PHARMACOLOGY: Special Populations: Geriatric Patients).
ADVERSE REACTIONS:
Addition of post-marketing information:
From post marketing surveillance, MIVACRON has been associated with reports of anaphylactic/anaphylactoid reactions. In some of these reports, sensitivity toMIVACRON was confirmed using skin test procedures.
PRECAUTIONS:
Geriatric Use:
New subsection:
Clinical studies of fosinopril sodium/hydrochlorothiazide 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. 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.
PRECAUTIONS:
Geriatric Use:
New subsection:
Clinical studies of MS CONTIN 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
greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
BOXED WARNING:
New text in bolded, underlined italics -
Mylotarg should be administered under the supervision of physicians experienced in the treatment of acute leukemia and in facilities equipped to monitor and treat leukemia patients.
Severe myelosuppression occurs when Mylotarg is used at recommended doses.
New paragraphs added:
HYPERSENSITIVITY REACTIONS INCLUDING ANAPHYLAXIS, INFUSION
REACTIONS, PULMONARY EVENTS -
Mylotarg administration can result in severe hypersensitivity reactions (including anaphylaxis), and other infusion-related reactions which may include severe pulmonary events. Infrequently, hypersensitivity reactions and pulmonary events have been fatal. In most cases, infusion-related
symptoms occurred during the infusion or within 24 hours of administration of Mylotarg and resolved. Mylotarg infusion should be interrupted for patients experiencing dyspnea or clinically significant hypotension. Patients should be monitored until signs and symptoms completely resolve.
Discontinuation of Mylotarg treatment should be strongly considered for patients who develop anaphylaxis, pulmonary edema, or acute respiratory distress syndrome. Since patients with high peripheral blast counts may be at greater risk for pulmonary events and tumor lysis syndrome,
physicians should consider leukoreduction with hydroxyurea or leukapheresis to reduce the peripheral white count to below 30,000 µL prior to administration of Mylotarg. (See WARNINGS.)
HEPATOTOXICITY:
Hepatotoxicity, including hepatic veno-occlusive disease (VOD), has been reported in association with the use of Mylotarg. (See WARNINGS.) Patients who receive Mylotarg either before or after hematopoietic stem-cell transplant may be at increased risk for developing severe VOD. Death from liver failure has been reported in patients who received Mylotarg.
INDICATIONS AND USAGE:
"other" was inserted into the main indication sentence to now read:
Mylotarg is indicated for the treatment of patients with CD33 positive acute myeloid leukemia in first relapse who are 60 years of age or older and who are not considered candidates for other cytotoxic chemotherapy.
WARNINGS:
New paragraphs added -
Hypersensitivity Reactions Including Anaphylaxis, Infusion Reactions, Pulmonary Events:
Mylotarg administration can result in severe hypersensitivity reactions (including anaphylaxis), and other infusion-related reactions, which may include severe pulmonary events. Infrequently, hypersensitivity reactions and pulmonary events have been fatal. In most cases, infusion-related
symptoms occurred during the infusion or within 24 hours of administration of Mylotarg and resolved. Mylotarg infusion should be interrupted for patients experiencing dyspnea or clinically significant hypotension. Patients should be monitored until signs and symptoms completely resolve.
Discontinuation of further Mylotarg treatment should be strongly considered for patients who develop anaphylaxis, pulmonary edema, or acute respiratory distress syndrome. Since patients with high peripheral blast counts may be at greater risk for such reactions, physicians should consider
leukoreduction with hydroxyurea or leukapheresis to reduce the peripheral white count to below 30,000 µL prior to administration of Mylotarg.
Infusion Reactions:
(previously titled Allergic Reactions)
Revisions to second paragraph (new text in bolded italics) -
"Anaphylaxis was not reported in the three phase II clinical studies (see CLINICAL STUDIES section). However, Mylotarg contains a humanized anti-CD33 antibody. As with any protein product, the possibility of anaphylaxis cannot be excluded." has been deleted.
In clinical studies, these symptoms generally occurred after the end of the 2-hour intravenous infusion and resolved after 2 to 4 hours with a supportive therapy of acetaminophen, diphenhydramine, and IV fluids. Fewer infusion-related events were observed after the second dose.
New subsections added -
Pulmonary Events: Severe pulmonary events leading to death have been reported infrequently with the use of Mylotarg in the postmarketing setting. Signs, symptoms and clinical findings include dyspnea, pulmonary infiltrates, pleural effusions, non-cardiogenic pulmonary edema, pulmonary
insufficiency and hypoxia, and acute respiratory distress syndrome. These events occur as sequelae of infusion reactions; patients with WBC counts > 30,000/µL may be at increased risk. (See Infusion Reactions section of WARNINGS.) Physicians should consider leukoreduction with hydroxyurea or
leukapheresis to reduce the peripheral white blood count to below 30,000 µL prior to administration of Mylotarg. Patients with symptomatic intrinsic lung disease may also be at greater risk of severe pulmonary reactions.
Hepatotoxicity: Hepatotoxicity, including VOD, has been reported in association with the use of Mylotarg. Patients who receive Mylotarg either before or after hematopoietic stem-cell transplant may be at increased risk for developing severe VOD. Death from liver failure has been reported in patients who received Mylotarg.
Subsection moved from PRECAUTIONS (new text in bolded italics) -
Tumor Lysis Syndrome (TLS): TLS may be a consequence of leukemia treatment with any chemotherapeutic agent including Mylotarg. Renal failure secondary to TLS has been reported in association with the use of Mylotarg. Appropriate measures, (e.g. hydration and allopurinol), must be taken to prevent hyperuricemia. Physicians should consider leukoreduction with hydroxyurea or leukapheresis to reduce the peripheral white blood count to < 30,000/L prior to administration of Mylotarg (see CLINICAL STUDIES section).
ADVERSE REACTIONS:
Hepatotoxicity:
Subsection revised (new text in bolded italics) -
Among 27 patients who received hematopoietic stem cell transplantation following Mylotarg,["four" deleted] three (["three" deleted]2
NRs and 1 CR) died of hepatic veno-occlusive disease (VOD) 22 to["392" deleted] 35 days following transplantation.
New subsection -
OTHER CLINICAL EXPERIENCE:
In postmarketing experience and other clinical trials, additional cases of VOD have been reported, some with a history of prior transplant. Renal failure secondary to TLS, hypersensitivity reactions, anaphylaxis, and pulmonary events, have also been reported in association with the use of Mylotarg.
(See WARNINGS section).
DOSAGE AND ADMINISTRATION:
First paragraph, new second and third sentences added -
Physicians should consider leukoreduction with hydroxyurea or leukapheresis to reduce the peripheral white blood count to below 30,000 microliters prior to administration of Mylotarg. Appropriate measures (e.g. hydration and allopurinol) must be taken to prevent hyperuricemia.
Geriatric Use:
New subsection:
No overall differences in safety or effectiveness have been observed between elderly and younger patients.
[New labeling my be viewed at the following link under Feb 15: http://www.fda.gov/cder/ogd/rld/rld_labeling_approved_february_2001.html
CONTRAINDICATIONS:
New text in bolded, underlined italics -
Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) OR thioridazine is contraindicated
(see WARNINGS and PRECAUTIONS).
WARNINGS:
New subsection added -
Potential Interaction with Thioridazine
Thioridazine administration alone produces prolongation of the QTc interval, which is associated with serious ventricular arrhythmias, such as torsade de pointes-type arrhythmias, and sudden death. This effect appears to be dose-related.
An in vivo study suggests that drugs which inhibit P450llD6, such as paroxetine, will elevate plasma levels of thioridazine. Therefore, it is recommended that paroxetine not be used in combination with thioridazine (see CONTRAINDICATIONS and PRECAUTIONS).
PRECAUTIONS:
Subsection header added -
Thioridazine: See CONTRAINDICATIONS and WARNINGS
PRECAUTIONS:
Geriatric Use:
Previous subsection deleted and replaced with the following:
Of the 4,966 subjects in clinical studies who were treated with famotidine, 488 subjects (9.8%) were 65 and older, and 88 subjects (1.7%) were greater than 75 years of age. 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. No dosage adjustment is required based on age (see CLINICAL PHARMACOLOGY IN ADULTS, Pharmacokinetics). 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. Dosage adjustment in the case of severe renal impairment is necessary (see
PRECAUTIONS, Patients with Severe Renal Insufficiency and DOSAGE AND ADMINISTRATION, Dosage Adjustment for Patients with Severe Renal Insufficiency).
[The following labeling change from March 23, 2001 Medwatch safety alert http://www.fda.gov/medwatch/safety/2001/safety01.htm#pepcid ]
New text in bolded, underlined italics -
CLINICAL PHARMACOLOGY: In adults
Pharmacokinetics
There is a close relationship between creatinine clearance values and the elimination half-life of PEPCID. In patients with severe renal insufficiency, i.e., creatinine clearance less than 10 mL/min, the elimination half-life of PEPCID may exceed 20 hours and adjustment of dose or dosing intervals in moderate and severe renal insufficiency may be necessary (see PRECAUTIONS, DOSAGE AND ADMINISTRATION).
In elderly patients, there are no clinically significant age-related changes in the pharmacokinetics of PEPCID. However, in elderly patients with decreased renal function, the clearance of the drug may be decreased (see PRECAUTIONS, Geriatric Use).
PRECAUTIONS:
General:
Symptomatic response to therapy with PEPCID does not preclude the presence of gastric
malignancy.
Patients with Moderate or Severe Renal Insufficiency
Since CNS adverse effects have been reported in patients with moderate and severe renal insufficiency, longer intervals between doses or lower doses may need to be used in patients with moderate (creatinine clearance <50 mL/min) or severe (creatinine clearance <10 mL/min) renal insufficiency to adjust for the longer elimination half-life of famotidine (see CLINICAL PHARMACOLOGY IN ADULTS and DOSAGE AND ADMINISTRATION).
PHENERGAN/Codeine (promethazine HCl & codeine phosphate) Syrup
PHENERGAN VC (promethazine HCl, phenylephrine HCl & codeine phosphate) Syrup
Geriatric Use:
Subsection revised to read as follows:
Clinical studies of Phenergan formulations 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.
Sedating drugs may cause confusion and over-sedation in the elderly; elderly patients generally should be started on low doses of (Phenergan with Dextromethorphan Syrup, Phenergan with Codeine Syrup, or Phenergan VC Syrup) and observed closely.