![[U.S. Food and Drug Administration]](https://webarchive.library.unt.edu/eot2008/20081028093215im_/http://www.fda.gov/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 2½ 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.
Labeling includes the following Plasma-Lyte products:
Plasma-Lyte 56 (electrolyte sodium) in Plastic Container, Plasma-Lyte M in 5% Dextrose in Plastic
Container, Plasma-Lyte 56 in 5% Dextrose in Plastic container, Plasma-Lyte
148 in Water in plastic Container, (includes Plasma-Lyte A), Plasma-Lyte R Injection
in Plastic Container, Plasma-Lyte in 5% Dextrose in Plastic Container.
DESCRIPTION:
2 nd Paragraph, 3 rd & 4 th sentences:
Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period, e.g., di-2-ethylhexyl phthalate (DEHP), up to 5 parts per million. However, the safety of the plastic has been confirmed in tests in
animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies.
The sentences were replaced with:
Solutions in contact with the plastic container may leach out certain chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the plastic container materials.
PRECAUTIONS:
"Clinical studies of Plasma-Lyte 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, 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 start in at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy.
PRECAUTIONS:
Geriatric Use:
New subsection:
The safety and effectiveness of Protropin 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.
New boxed warning text added to the
Medguide section of the product label, as follows:
You and your partner must not become pregnant while either of you are being treated with Rebetron Combination Therapy containing INTRON A and Rebetol (ribavirin, USP) Capsules or for 6 months after stopping therapy. Do not use Rebetron Combination Therapy
if you or your partner are pregnant. If you or your partner become pregnant during treatment or within 6 months of stopping treatment, call your doctor right away. You or your doctor should also call (800) 727-7064.
Inclusion of additional text at the end of the first bulleted point in the "What should I avoid while taking combination REBETOL/INTRON A therapy section, as follows:
Schering has established the (800) number to collect patient and/or partner pregnancy information for entry into a pregnancy registry database. This database is used to monitor the outcome of fetal exposure to assess the known risks of death and serious birth defects expected based on animal
studies. You and/or your physician will be requested to provide follow-up information on the outcome of the pregnancy.
PRECAUTIONS:
Information for Patients -
Phenylketonurics -
New subsection -
Phenylketonuric patients should be informed that Remeron SolTab contains phenlyalanine 2.6 mg per 15 mg tablet, 5.2 mg per 30 mg tablet, and 7.8 mg per 45 mg tablet.
Labeling provides for the use of Sonata capsules for up to 5 weeks (35-nights) of treatment in a controlled trial setting.
Contact the company for a copy of the new labeling/package insert or go to the following under February 22:
http://www.fda.gov/cder/ogd/rld/rld_labeling_approved_february_2001.html
New labeling provides for the new use of Toprol-XL
for the treatment of congestive heart failure and for a 25 mg dosage strength scored tablet. Contact the company for a copy of the new labeling/ package insert or go to the following link under February 15:
http://www.fda.gov/cder/ogd/rld/rld_labeling_approved_february_2001.html
CLINICAL PHARMACOLOGY:
Microbiology--The bactericidal action of vancomycin results primarily from inhibition of cell-wall biosynthesis. In addition, vancomycin alters bacterial-cell-membrane permeability and RNA synthesis. There is no cross-resistance between vancomycin and other antibiotics.
["Vancomycin is active against C. difficile (eg, toxigenic strains implicated in pseudomembranous enterocolitis). It is also active against staphylococci, including Staphylococcus aureus. For further information, see prescribing information for Vancocin HCl, IntraVenous. Vancomycin is not active in vitro against gram-negative bacilli, mycobacteria, or fungi.
Disk Susceptibility Tests --The standardized disk and/or dilution methods described by the National Committee for Clinical Laboratory Standards have been recommended to test susceptibility to vancomycin." deleted]
Replaced with the following text -
NOTE: The oral form of vancomycin is effective only for the infections noted in the INDICATIONS AND USAGE section. The oral form is not effective for any other type of infection. Vancomycin has been shown to be active against most strains of the following microorganisms in clinical infections the following microorganisms in clinical infections as described in the INDICATIONS AND USAGE section.
Aerobic gram-positive microorganisms
Staphylococcus aureus (gram-positive microorganisms including methicillin-resistant strains) associated with enterocolitis
Anaerobic gram-positive microorganisms
Clostridium difficile antibiotic-associated pseudomembranous colitis
Previous section -
Pulvules Vancocin HCl may be administered orally for treatment of staphylococcal enterocolitis and antibiotic-associated pseudomembranous colitis caused by C. difficile . Parenteral administration of Vancocin HCl is not effective for the above indications; therefore, Vancocin HCl must be given orally for these indications. Orally administered Vancocin HCl is not effective for other types of infection.
Revised to read as follows:
Vancocin HCl Pulvules may be administered orally for treatment of enterocolitis caused by Staphylococcus aureus (including methicillin-resistant strains) and antibiotic-associated pseudomembranous colitis caused by C. difficile. Parenteral administration of Vancocin
HCl is not effective for the above indications; therefore, Vancocin HCl must be given orally for these indications.
Orally administered Vancocin HCl is not effective for other types of infection.
PRECAUTIONS:
Nursing Mothers -
"Blood concentrations achieved with oral administration are very low ( see CLINICAL PHARMACOLOGY )."
Revised and replaced with -
"However, systemic absorption of vancomycin is very low
following oral administration of Vancocin HCl Pulvules (see CLINICAL PHARMACOLOGY)."
CLINICAL PHARMACOLOGY:
Clinical Pharmacology in Pediatric Patients -
New subsection added -
A multiple dose pharmacokinetic study was conducted in 40 hypertensive male and female pediatric patients aged 2 months to <16 years following daily oral administration of 0.07 to 0.14 mg/kg enalapril maleate. At steady state, the mean effective half-life for accumulation of enalaprilat was 14 hours and the mean urinary recovery of total enalapril and enalaprilat in 24 hours was 68%of the administered dose. Conversion of enalapril to enalaprilat was in the range of 63-76%.The overall results of this study indicate that the pharmacokinetics of enalapril in hypertensive children aged 2 months to <16 years are consistent across the studied age groups and consistent with pharmacokinetic historic data in healthy adults.
In a clinical study involving 110 hypertensive pediatric patients 6 to 16 years of age, patients who weighed <50 kg received either 0.625, 2.5 or 20 mg of enalapril daily and patients who weighed kg received either 1.25, 5, or 40 mg of enalapril daily. Enalapril administration once daily lowered trough blood pressure in a dose-dependent manner. The dose-dependent antihypertensive efficacy of enalapril was consistent across all subgroups (age, Tanner stage, gender, race). However, the lowest doses studied, 0.625 mg and 1.25 mg, corresponding to an average of 0.02 mg/kg once daily, did not appear to offer consistent antihypertensive efficacy. In this study, VASOTEC was generally well tolerated. In the above pediatric studies, enalapril maleate was given as tablets of VASOTEC and for those children and infants who were unable to swallow tablets or who required a lower dose than is available in tablet form, enalapril was administered in a suspension formulation (see Preparation of Suspension under DOSAGE AND ADMINISTRATION).
ADVERSE EVENTS:
Pediatric Patients
New subsection -
The adverse experience profile for pediatric patients appear to be similar to that seen in adult patients.
DOSAGE AND ADMINISTRATION
Pediatric Hypertensive Patients
New subsection -
The usual recommended starting dose is 0.08 mg/kg (up to 5 mg) once daily. Dosage should be adjusted according to blood pressure response. Doses above 0.58 mg/kg (or in excess of 40 mg) have not been studied in pediatric patients.
See CLINICAL PHARMACOLOGY,Clinical Pharmacology in Pediatric Patients.
VASOTEC is not recommended in neonates and in pediatric patients with glomerular filtration rate <30 mL/min/1.73 m 2 ,as
no data are available.
Preparation of Suspension (for 200 mL of a 1.0 mg/mL suspension)
New subsection -
Add 50 mL of Bicitra to a polyethylene terephthalate (PET) bottle containing ten 20 mg tablets of VASOTEC and shake for
at least 2 minutes. Let concentrate stand for 60 minutes. Following the 60-minute hold time, shake the concentrate for
an additional minute. Add 150 mL of Ora-Sweet SF to the concentrate in the PET bottle and shake the suspension to disperse the ingredients. The suspension should be refrigerated at 2-8 °C (36-46 °F) and can be stored for up to 30 days. Shake the suspension before each use.
The complete label may be viewed at the link below under Feb 13:
http://www.fda.gov/cder/ogd/rld/rld_labeling_approved_february_2001.html
DOSAGE AND ADMINISTRATION:
Next to last paragraph added -
Other intravenous substances, additives, or medications should not be added to ZITHROMAX (azithromycin for injection), or infused simultaneously through the same intravenous line.
[Other changes not found in 2001 PDR: http://www.fda.gov/medwatch/safety/2000/nov00.htm#zoloft ]
PRECAUTIONS:
Weak Uricosuric Effect –ZOLOFT (sertraline hydrochloride)is associated with a mean decrease in serum uric acid of approximately 7%.The clinical significance of this weak uricosuric effect is unknown. ["and there have been no reports of acute renal failure with Zoloft" deleted]
Information for Patients -
New text in bolded italics -
Physicians are advised to discuss the following issues with patients for whom they prescribe ZOLOFT:
Patients should be told that although ZOLOFT has not been shown to impair the ability of normal subjects to perform tasks requiring complex motor and mental skills in laboratory experiments, drugs that act upon the central nervous system may affect some individuals adversely. Therefore, patients should be told that until they learn how they respond to ZOLOFT they should be careful doing activities when they need to be alert, such as driving a car or operating machinery.
Text in the previous Geriatric use subsection deleted and replaced with the following:
Geriatric Use – U.S. geriatric clinical studies of ZOLOFT in depression included 663 ZOLOFT- treated subjects =65 years of age, of those,180 were =75 years of age.1 No overall differences in the pattern of adverse reactions were observed in the geriatric clinical trial subjects relative to
those reported in younger subjects 1,2 (see ADVERSE REACTIONS), and other reported experience has not identified differences in safety patterns between the elderly and younger subjects.3,4 As with all medications, greater sensitivity of some older individuals cannot be ruled out. There were 947 subjects in placebo-controlled geriatric clinical studies of ZOLOFT in depression. No overall differences in the pattern of efficacy were observed in the geriatric clinical trial subjects relative to those reported in younger subjects.
Other Adverse Events in Geriatric Patients. In 354 geriatric subjects treated with ZOLOFT in placebo-controlled trials, the overall profile of adverse events was generally similar to that shown in Tables 1 and 2. Urinary tract infection was the only adverse event not appearing in Tables 1
and 2 and reported at an incidence of at least 2%and at a rate greater than placebo in placebo-controlled trials.
As with other SSRIs, ZOLOFT has been associated with cases of clinically significant hyponatremia in elderly patients (see Hyponatremia under PRECAUTIONS).
PATIENT SUMMARY OF INFORMATION ABOUT
This summary contains important information about ZOLOFT.It is not meant to take the
place of your doctor ’s instructions. Read this information carefully before you start taking
ZOLOFT Ask your doctor or pharmacist if you do not understand any of this information or
if you want to know more about ZOLOFT.
What Conditions Does ZOLOFT Treat?
ZOLOFT is a prescription medicine used to treat depression, panic disorder, obsessive-
compulsive disorder (also called OCD) and Posttraumatic Stress Disorder (also called PTSD)
in adults. ZOLOFT is also used to treat OCD in children (ages 6-12)and adolescents (ages
12-17).
Depression
Symptoms of depression vary from person to person. You may have depression if you have
five or more of the following symptoms and you have these symptoms almost all of the
time during the same two-week period or longer. At least one of the symptoms must be a
("sad" feeling that will not go away or a loss of interest or pleasure in most activities. Other
symptoms are:
• changes in sleeping patterns • trouble concentrating
• restlessness or slowed movements or making decisions
• fatigue or lack of energy • repeated thoughts of death
• changes in appetite or weight or suicide
• feeling worthless or guilty
for no real reason
In depression,these symptoms interfere with your day-to-day activities.
Panic Disorder
People with panic disorder have repeated unexpected panic attacks. A panic attack is an
unexpected attack of fear, anxiety or discomfort with at least four or more of the following
symptoms that develop suddenly and usually reach a peak within 10 minutes:
• fast heart rate or pounding heart • nausea or upset stomach
• chest pain or discomfort • dizziness or feeling faint
• sweating • numbness or tingling
• trembling or shaking • chills or hot flashes
• shortness of breath or • feeling out of touch with reality
a feeling of smothering • fear of losing control
• choking feeling • fear of dying
In panic disorder, the panic attack(s )are followed by one month or longer of concern
about having more attacks, or concern about what effect the panic attack(s )may have, or
having a change in behavior.
Obsessive-Compulsive Disorder (OCD)
In OCD, a person may have two types of symptoms called obsessions or compulsions.
Obsessions: These are unwanted thoughts that stay in a person ’s mind. Even though the
person knows these thoughts do not make sense, they cannot get rid of them. These
thoughts can be frightening and embarrassing.
Compulsions: These are actions or thoughts that a person does over and over again to get rid
of their unwanted thoughts. They believe this will help prevent something terrible from
happening. These repeated actions may take hours to perform and can interfere with daily life.
Posttraumatic Stress Disorder (PTSD)
People with PTSD suffer from symptoms because they suffered, witnessed or learned of a
life-threatening event or other serious event and felt intense fear, helplessness or horror
because of the event.
A person with PTSD must have one or more symptoms from each of the following
categories for at least a month and these symptoms must seriously interfere with being able
to lead a normal life.
• Reliving the event through upsetting thoughts, nightmares or flashbacks, or having
very strong mental and physical reactions if something reminds the person of the
event.
• Avoiding activities, thoughts, feelings or conversations that remind the person of the
event; feeling numb to one ’s surroundings; or being unable to remember details of
the event. Having a loss of interest in important activities, feeling all alone, being
unable to have normal emotions or feeling that there is nothing to look forward to
in the future may also be experienced.
• Feeling that one can never relax and must be on guard all the time to protect
oneself, trouble sleeping, feeling irritable, overreacting when startled, angry
outbursts or trouble concentrating.
ZOLOFT is approved to treat PTSD in both men and women. More women than men
experience PTSD. There were three times more women than men in ZOLOFT PTSD
clinical studies, and in these studies women responded better to ZOLOFT than men. What
this means to the treatment of a patient is unknown. Only a doctor can determine if
ZOLOFT is right for a patient
How ZOLOFT Works
Everyone has a normal substance in the brain called serotonin. It is thought that not having
enough serotonin may contribute to depression, panic disorder, OCD and PTSD. How
ZOLOFT works for all of these conditions is not known. What is known is that ZOLOFT
may help correct the chemical imbalance of serotonin in the brain. This helps relieve your
symptoms. It may take several weeks for your symptoms to get better.
ZOLOFT Is Not For Everyone
While you are taking ZOLOFT, you should never take a monoamine oxidase inhibitor
(MAOI) medicine. MAOI medicines are used to treat depression and other conditions. If you
have been taking an MAOI, you must stop the MAO I at least 14 days before you start taking
ZOLOFT. In addition, you must wait at least 14 days after stopping ZOLOFT before you can
safely start taking an MAO1 medicine. A very serious reaction or even death could occur if
ZOLOFT is taken at the same time as an MAOI medicine. Be sure to ask your doctor or
pharmacist if any medicine you are taking is an MAOI.
The liquid form of ZOLOFT contains alcohol and should not be taken if you are taking Antabuse
(disulfiram).
What To Tell Your Doctor
Before You Start ZOLOFT
Only your doctor can decide if ZOLOFT is right for you. Before you start ZOLOFT be sure to
tell your doctor if you:
• are taking or have taken any prescription medicines within the past 14 days
•are taking or have taken any over-the-counter medicines you can buy without a
prescription, including natural/herbal remedies, within the past 14 days
•have had any liver problems
•have ever had a seizure
•are pregnant, plan to become pregnant, think you might be pregnant or are breast-
feeding
•are allergic to any medicines or latex
•have ever had an allergic reaction to sertraline or any of the other ingredients of
ZOLOFT tablets or Oral Concentrate. Ask your doctor or pharmacist for a list of these
ingredients if you have any questions.
ZOLOFT And Other Medicines
Some medicines can affect how ZOLOFT works. Check with your doctor or pharmacist before
starting any new prescription or non-prescription medicines, including natural/herbal
remedies. Do not stop any of your other medicines while you are on ZOLOFT without
checking with your doctor.
How To Take ZOLOFT
ZOLOFT comes in three different strengths of tablets (25 mg,50 mg,100 mg) as well as a
liquid (20 mg/mL). Your doctor will tell you how much to take, and may decide to adjust
your dose over time.
If you were prescribed ZOLOFT Oral Concentrate, you must mix it with another liquid
before taking it.
• Pour 4 oz.(1 / cup) of any of the following liquids into a drinking glass: water, ginger
ale, lemon/lime soda, lemonade or orange juice. Do not use any other liquids besides
these.
• Draw up the proper amount of ZOLOFT Oral Concentrate into the special dropper
that comes with the medicine.
• Squeeze the ZOLOFT Oral Concentrate out of the dropper into the drinking glass. Stir
well. It is normal if a slight haze appears after mixing.
• Drink all the liquid as soon as you have mixed it. Do not mix it in advance.
Since the dropper bulb for the liquid form of ZOLOFT is made from dry natural rubber,
make sure to let your doctor know if you have had allergic reactions to latex.
Take ZOLOFT once a day in the morning or evening. You can take ZOLOFT with or without
food. Try to take ZOLOFT at the same time every day.
Do not take an extra dose if you are having a bad day. ZOLOFT does not work right away.
Do not stop taking ZOLOFT without talking to your doctor first .
Do not run out of ZOLOFT. Make sure you have your refill for ZOLOFT at home before you
need it. Continue to take ZOLOFT even when you feel better for as long as your doctor says.
It may take several weeks before you start to feel better. Do not get discouraged. Keep taking
ZOLOFT every day for as long as your doctor tells you to take it.
Possible Side Effects
Like all medicines, ZOLOFT may cause side effects in some people. In clinical studies, few
people had to stop taking ZOLOFT because of side effects. The most common ones are:
• dry mouth • feeling unusually tired or sleepy • tremor
• diarrhea/loose stools • feeling agitated
• upset stomach • trouble sleeping • indigestion
• decreased appetite • sexual problems in men and women • increased sweating
Children who take ZOLOFT may also have other side effects such as excessive movement or
twitching, fever, not "feeling well ", trouble concentrating, not thinking normally, nosebleeds,
weight loss, easy bruising, manic or excited behavior, or rapid mood swings.
Until you learn how you are going to respond to ZOLOFT ,be careful doing activities when
you need to be alert, such as driving a car or operating machinery. Drinking alcohol is not
advised while you are being treated with ZOLOFT.
ZOLOFT may cause other less common side effects besides those listed here. For a list of all
side effects that have been reported, ask your doctor or pharmacist for the ZOLOFT
What To Do For An Overdose
In case of an overdose, call your doctor or poison control center right away or go to the
nearest emergency room.
How To Store ZOLOFT
Keep ZOLOFT and all medicines out of the reach of children. Store ZOLOFT tablets and
Oral Concentrate at room temperature (59 °86 °F or 15 °30 °C).
For More Information About ZOLOFT
This sheet is only a summary. If you have any questions or want more information about
ZOLOFT talk with your doctor or pharmacist. You can also visit the Pfizer Internet site at
www.pfizer.com.
CLINICAL PHARMACOLOGY:
Use In Patients With Chronic Obstructive Pulmonary Disease (COPD): ZYBAN was evaluated in a randomized, double-blind, comparative study of 404 patients with mild-to-moderate COPD, defined as FEV1 >35%, FEV1/FVC<70% and a diagnosis of chronic bronchitis, emphysema and/or small airways disease. Patients aged 36 to 76 years were randomized to ZYBAN 300 mg/day (n = 204) or placebo (n = 200) and treated for 12 weeks. Treatment with ZYBAN was initiated at 150 mg/day for 3 days while the patient was still smoking and increased to 150 mg twice daily for the remaining treatment period. Abstinence from smoking was determined by patient daily diaries and verified by carbon monoxide levels in expired air. Quitters are defined as subjects who were abstinent during the last 4 weeks of treatment. Table 3 shows quit rates in the COPD Trial.
Table 3: COPD Trial: Quit Rates by Treatment Group
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Treatment Groups |
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| 4-week Abstinence Period |
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Weeks 9 through 12 |
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ADVERSE REACTIONS:
Adverse Events Occurring at an Incidence of 1% or More Among Patients Treated with ZYBAN subsection:
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ZYBAN was well tolerated in the long-term maintenance trial, that evaluated chronic administration of ZYBAN for up to 1 year
and in the COPD trial that evaluated patients with mild-to-moderate COPD for a 12-week period .
INFORMATION for the PATIENT:
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3. Can I take ZYBAN if I have mild-to-moderate chronic bronchitis and/or emphysema (also called chronic obstructive pulmonary disease or COPD)?
Yes, ZYBAN combined with a behavior modification program has been shown to help people with COPD quit smoking. It is important to participate in the behavior program, counseling, or other support program your health care professional recommends.
WARNINGS:
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Myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) has been reported in patients receiving linezolid. In cases where the outcome is known, when linezolid was discontinued, the affected hematologic parameters have risen toward
pretreatment levels. Complete blood counts should be monitored weekly in patients who receive linezolid, particularly in those who receive linezolid for longer than two weeks, those with pre-existing myelosuppression, those receiving concomitant drugs that produce bone marrow suppression, or those with a chronic infection who have received previous or concomitant antibiotic therapy. Discontinuation of therapy with linezolid should be considered in patients who develop or have worsening myelosuppression.
PRECAUTIONS:
Subsection describing Thrombocytopenia has been deleted.
ADVERSE REACTIONS:
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Postmarketing Experience
Myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) has been reported during post-marketing use of ZYVOX (see WARNINGS). The events have been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection to
ZYVOX, or a combination of these factors. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made and causal relationship can not be precisely established.
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