(Posted: October 31, 1997)
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.
NB: Comparison made to 1997 Physicians' Desk Reference (PDR), if drug's labeling included in the PDR.
Compiled by:
Neil W. Hitchcock, PharmD candidate
McWhorter School of Pharmacy
Samford University
Birmingham, AL
(anastrozole) |
(azelastine HCl) |
(lorazepam) |
(clarithromycin) |
(carmustine) |
(diltiazem HCl) |
(cefuroxime axetil) |
(ciprofloxacin) |
(clozapine) |
(indinavir SO4) |
(torsemide) |
(famciclovir) |
(leuprolide acetate) |
(mitotane) |
(megestrol acetate) |
(triamcinolone acetonide) |
(mitoxantrone) |
(albuterol SO4) |
(neomycin/polymyxin B sulfates) |
(aprotinin) |
(valacyclovir HCl) |
(nelfinavir mesylate) |
ARIMIDEX
[September 19, 1997: Zeneca]
ASTELIN
[September 29, 1997: Wallace]
"Acute overdosage by adults with this dosage form is unlikely to result in clinically significant adverse events, other than increased somnolence, since one bottle of Astelin Nasal Spray contains 17 mg of azelastine hydrochloride. Clinical studies in adults with single doses of the oral formulation of azelastine hydrochloride (up to 16 mg) have not resulted in increased incidence of serious adverse events."
New fifth, sixth, and seventh sentences added - "There is no known antidote to Astelin Nasal Spray. Oral ingestion of antihistamines has the potential to cause serious adverse effects in young children. Accordingly, Astelin Nasal Spray should be kept out of the reach of children."
ATIVAN
[September 5, 1997: Wyeth-Ayerst]
BIAXIN
[September 16, 1997: Abbott]
[Other changes within past 12 months: Dec96,
Aug97]
Microbiology: Paragraph prior to Helicobacter Subsection revised (new text in italics) - "Clarithromycin has been shown to be active against most strains of Helicobacter pylori in vitro and in clinical infections when combined with omeprazole, lansoprazole and amoxicillin, or ranitidine bismuth citrate as described in the INDICATIONS AND USAGE section."
Aerobic Gram-negative microorganisms: "Neisseria gonorrhoeae" deleted.
Other microorganisms: "Chlamydia trachomatis" deleted.
"Biaxin (clarithromycin) Filmtab tablets in combination with Prevacid (lansoprazole) Delayed-Release Capsules and amoxicillin, as triple therapy, are indicated for the treatment of patients with H. pylori infection and duodenal ulcer disease (active or one-year history of duodenal ulcer) to eradicate H. pylori.
"Biaxin ["(clarithromycin)" deleted] Filmtab tablets in combination with Prilosec (omeprazole) capsules or Tritec (ranitidine bismuth citrate) tablets are also ["is" deleted] indicated for the treatment of patients with an active duodenal ulcer associated with H. pylori infection. However, regimens which contain clarithromycin as the single antimicrobial agent are more likely to be associated with the development of clarithromycin resistance among patients who fail therapy. Clarithromycin-containing regimens should not be used in patients with known or suspected clarithromycin resistant isolates because the efficacy of treatment is reduced in this setting. ["The eradication of H. pylori has been demonstrated to reduce the risk of duodenal ulcer recurrence." deleted]
"In patients who fail therapy, susceptibility testing should be done if possible. If resistance to clarithromycin is demonstrated, ["alternative" deleted] a non-clarithromycin-containing therapy is recommended. (For information on development of resistance see Microbiology section.) The eradication of H. pylori has been demonstrated to reduce the risk of duodenal ulcer recurrence."
For information on lansoprazole or amoxicillin, refer to the DOSAGE AND ADMINISTRATION section of their package inserts."
Mycobacterial infections: Treatment:Second sentence revised (new text in italics) - "Clarithromycin should be used in combination with other antimycobacterial drugs that have shown in vitro activity against MAC or clinical benefit in MAC treatment. (See CLINICAL STUDIES) [", including ethambutol, clofazimine, and rifampin. Although no controlled clinical trial information is available for combination therapy with clarithromycin, the U.S. Public Health Service Task Force has provided recommendations for the treatment of MAC4." deleted]"
"Study 069 compared the safety and efficacy of clarithromycin in combination with ethambutol versus clarithromycin in combination with ethambutol and clofazimine for the treatment of disseminated MAC (dMAC) infection 4. This 24-week study enrolled 106 patients with AIDS and dMAC, with 55 patients randomized to receive clarithromycin and ethambutol, and 51 patients randomized to receive clarithromycin, ethambutol and clofazimine. Baseline characteristics between study arms were similar with the exception of median CFU counts being at least 1 log higher in the clarithromycin, ethambutol, and clofazimine arm.
"Compared to prior experience with clarithromycin monotherapy, the two-drug regimen of clarithromycin and ethambutol was well tolerated and extended the time to microbiologic relapse, largely through suppressing the emergence of clarithromycin resistant strains. However, the addition of clofazamine to the regimen added no additional microbiologic or clinical benefit. Tolerability of both multidrug regimens was comparable with the most common adverse events being gastrointestinal in nature. Patients receiving the clofazimine-containing regimen had reduced survival rates; however, their baseline mycobacterial colony counts were higher. The results of this trial support the addition of ethambutol to clarithromycin for the treatment of initial dMAC infections but do not support adding clofazimine as a third agent."
Duodenal Ulcer Associated with H. pylori Infection: Clarithromycin + Lansoprazole and Amoxicillin (new subsection):
"H. pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence: Two U.S. randomized, double-blind clinical studies in patients with H. pylori and duodenal ulcer disease (defined as an active ulcer or history of an active ulcer within one year) evaluated the efficacy of clarithromycin in combination with lansoprazole and amoxicillin capsules as triple 14-day therapy for eradication of H. pylori. Based on the results of these studies, the safety and efficacy of the following eradication regimen were established:
"Triple therapy: Biaxin 500 mg b.i.d. + lansoprazole 30 mg b.i.d. + amoxicillin 1 gm b.i.d.
"Treatment was for 14 days. H. pylori eradication was defined as two negative tests (culture and histology) at 4 to 6 weeks following the end of treatment.
"The combination of Biaxin plus lansoprazole and amoxicillin as triple therapy was effective in eradicating H. pylori. Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence.
Study |
(Evaluable Analysis)* |
(Intent-to-Treat Analysis)** |
Study 131 |
[80.0 – 97.7] (n = 48) |
[73.3 – 93.5] (n = 55) |
Study 392 |
[75.7 – 93.6] (n = 66) |
[72.0 – 90.8] (n = 70) |
"Safety: In clinical trials using combination therapy with Biaxin plus lansoprazole and amoxicillin, no adverse reactions peculiar to this drug combination have been observed. Adverse reactions that have occurred have been limited to those that have been previously reported with Biaxin, lansoprazole, or amoxicillin.
"Triple Therapy: Biaxin + lansoprazole + amoxicillin: The most frequently reported adverse events for patients who receive triple therapy were diarrhea (7%), headache (6%), and taste perversion (5%). No treatment-emergent adverse events were observed at significantly higher rates with triple therapy than with any dual therapy regimen."
1. National Committee for Clinical Laboratory Standards, Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically - ["Third" deleted] Fourth Edition. Approved Standard NCCLS Document ["M7-A3" deleted] M7-A4, Vol. ["13" deleted] 17, No. ["25" deleted] 2, NCCLS, Villanova, PA, ["December, 1993" deleted] January 1997.
2. National Committee for Clinical Laboratory Standards, Performance Standards for Antimicrobial Disk Susceptibility Tests - ["Fifth" deleted] dssSixth Edition. Approved Standard NCCLS Document ["M2-A5" deleted] M2-A6, Vol. ["13" deleted] 17, No. ["24" deleted] 1, NCCLS, Villanova, PA, ["December, 1993" deleted] January 1997.
4. Chaisson RE, et al. Clarithromycin and Ethambutol with or without Clofazimine for the Treatment of Bacteremic Mycobacterium avium Complex Disease in Patients with HIV Infection. AIDS. 1997;11:311-317. ["Public Health Service Task Force on Prophylaxis and Therapy for Disseminated Mycobacterium avium complex. Recommendations on Prophylaxis and Therapy for Mycobacterium avium Complex Disease in Patients Infected With The Human Immunodeficiency Virus. NEJM. 1993;329:898-904." deleted]
BiCNU
[September 10, 1997: Bristol-Myers Squibb]
"Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from BiCNU, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother."
and replaced with - "Because of the potential for serious adverse events in nursing infants, nursing should be discontinued while taking BiCNU."
Pediatric Use: New text added to end of subsection - "Delayed onset pulmonary fibrosis occurring up to 17 years after treatment, has been reported in a long term study of patients who received BiCNU in childhood and early adolescence (1-16 years). Eight out of the 17 patients (47%) who survived childhood brain tumors, including all of the five patients initially treated at less than five years of age, died of pulmonary fibrosis. Therefore, the risks and benefits of BiCNU therapy must be carefully considered, due to the extremely high risk of pulmonary toxicity. (See "ADVERSE REACTIONS: Pulmonary Toxicity")"
Pulmonary Toxicity: Second paragraph, first sentence revised (new text in italics) -
"Additionally, delayed onset pulmonary fibrosis occurring up to 17 ["15" deleted]
years after treatment has been reported in a long-term study with 17 patients who received
BiCNU in childhood and early adolescence (1-16 years) in cumulative doses ranging
from 770 to 1800
mg/m2 combined with cranial radiotherapy for intracranial
tumors."
Second paragraph, fifth sentence revised (new text in italics) - "There was ["appears to be" deleted] some late reduction of pulmonary function in all long-term survivors."
Second paragraph, last sentence revised (new text in italics) - "In this long-term study, 8 of 17 died of delayed pulmonary lung fibrosis, including all those initially treated (5 of 17) at less than 5 years of age."
Other Toxicities: Last paragraph revised (new text in italics) - "Neuroetinitis, chest pain, headache, allergic reaction, hypotension, and tachycardia ["has" deleted] have been reported as part of ongoing surveillance."
"7. Controlling occupational exposure to hazardous drugs. (OSHA WORK PRACTICE GUIDELINES). Am J Health-Syst Pharm 1996; 53:1669-1685."
CARDIZEM
[September 2, 1997: Hoechst Marion Roussel]
"Keep diluted Cardizem Injectable refrigerated until use. Diluted Cardizem Lyo-Ject may be stored at room temperature 15-30oC (59-86oF)." ["Keep refrigerated until use." deleted]
CEFTIN
[September 17, 1997: Glaxo Wellcome]
[Other changes within past 12 months:
Jun97]
CIPRO
[September 26, 1997: Bayer]
[Other changes within past 12 months: Nov96,
Aug97]
New last paragraph added in the IV ciprofloxacin labeling - "In randomized, double-blind controlled clinical trials comparing (I.V. and I.V. P.O. sequential) with intravenous beta-lactam control antibiotics, the CNS adverse event profile of ciprofloxacin was comparable to that of the control drugs."
CLOZARIL
[September 19, 1997: Novartis]
[Other changes within past 12 months: Apr97,
Jun97]
CRIXIVAN
[September 26, 1997: Merck]
[Other changes within past 12 months:
Mar97]
"Drug Interactions: Indinavir should not be administered concurrently with terfenadine, astemizole, cisapride, triazolam, and midazolam because competition for CYP3A4 by indinavir could result in inhibition of the metabolism of these drugs and create the potential for serious and/or life-threatening events (i.e., cardiac arrhythmias, prolonged sedation).
"Hemolytic Anemia: Acute hemolytic anemia has been reported which in some cases was severe and progressed rapidly. Once a diagnosis is apparent, appropriate measures for the treatment of hemolytic anemia should be instituted which may include discontinuation of Crixivan."
"Hepatitis: Hepatitis including cases of hepatic failure have been reported in patients treated with Crixivan. Because the majority of these patients had confounding medical conditions and/or were receiving concomitant therapy(ies), a causal relationship between Crixivan and these events has not been established."
"Hyperglycemia: New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus and hyperglycemia have been reported during post-marketing surveillance in HIV-infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established."
"["Other drugs that induce CYP3A4 less potently" deleted] Interactions between indinavir and less potent CYP3A4 inducers than rifampin, such as phenobarbital, phenytoin, carbamazepine, and dexamethasone ["should be used cautiously together with indinavir since they could also diminish plasma concentrations of indinavir." deleted] have not been studied. These agents should be used with caution if administered concomitantly with indinavir because decreased indinavir plasma concentrations may result."
Body As A Whole: redistribution/accumulation of body fat in areas such as the back of the neck, abdomen, and retroperitoneum.
Digestive System: liver function abnormalities; hepatitis including ["rare" deleted] reports of hepatic failure (see WARNINGS).
Hematologic: increased spontaneous bleeding in patients with hemophilia (see PRECAUTIONS); acute hemolytic anemia (see WARNINGS).
Endocrine/Metabolic: new onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, hyperglycemia (see WARNINGS).
Hypersensitivity: anaphylactoid reactions.
Skin and Skin Appendage: rash including erythema multiforme and Stevens-Johnson Syndrome; hyperpigmentation; alopecia.
Urogenital System: nephrolithiasis; in some cases ["nephrolithiasis has been associated with" deleted] resulting in renal insufficiency or acute renal failure (see WARNINGS); crystalluria; interstitial nephritis."
Laboratory Abnormalities (new subsection): "Increased serum triglycerides."
DEMADEX
[September 9, 1997: Boehringer Mannheim]
FAMVIR
[September 17, 1997: SmithKline Beecham]
[Other changes within past 12 months: Jan97, Jul97]
LUPRON DEPOT
[September 4, 1997: TAP]
[Changes to other formulations of Lupron within past 12 months:
Jan97,
May97]
Postmarketing: New fourth paragraph added - "Symptoms consistent with fibromyalgia (e.g., joint and muscle pain, headaches, sleep disorders, gastrointestinal distress, and shortness of breath) have been reported individually and collectively."
Cardiovascular System: "Pulmonary embolism" added.
LYSODREN
[September 4, 1997: Bristol-Myers Squibb]
MEGACE
[September 4, 1997: Bristol-Myers Squibb]
[Changes to other formulations within past 12 months:
Oct96,
Aug97]
"History of hypersensitivity to megestrol acetate or any component of the formulation. As a diagnostic test for pregnancy.
Use in Diabetics (new subsection): "Exacerbation of pre-existing diabetes with increased insulin requirements has been reported in association with the use of Megace."
Glucocorticoid Effects: Text deleted - "The glucocorticoid effects have not been fully evaluated. Laboratory evidence of pituitary-adrenal axis abnormalities have been observed. Although the significance of these laboratory findings has not been fully established, clinically apparent adrenal insufficiency has been reported to rarely occur in patients shortly after Megace treatment was discontinued."
and replaced with - "(See WARNINGS and PRECAUTIONS sections)."
Other Adverse Reactions: Section revised (new text in italics) - "Heart failure, nausea and vomiting, edema, breakthrough menstrual bleeding, dyspnea, tumor flare (with or without hypercalcemia), hyperglycemia, glucose intolerance, alopecia, hypertension, carpal tunnel syndrome, mood changes, hot flashes, and sweating, and rash."
NASACORT AQ
[September 26, 1997: Rhone-Poulenc Rorer]
NOVANTRONE
[September 19, 1997: Immunex]
"[It is not known whether" deleted] Novantrone is excreted in human milk and significant concentrations (180 mg/mL) have been reported for 28 days after the last administration.1 Because of the potential for serious adverse reactions in infants from Novantrone, breast feeding should be discontinued before starting treatment."
PROVENTIL REPETABS
[September 18, 1997: Schering]
STATROL
[September 9, 1997: Alcon]
TRASYLOL
[September 30, 1997: Bayer]
[Other changes within past 12 months:
Aug97]
The one table of adverse events has been revised into two tables and one list (See Below). The following adverse reactions have been deleted from the original table - "surgery" (including the footnote) and "respiratory disorder".
The following adverse reactions have been added to the new tables/or list - "chest pain, asthenia, constipation, anemia, musculoskeletal-any event, insomnia, atelectasis, hypoxia, skin and appendages-rash, urinary retention, thrombosis, shock, cerebrovascular accident, thrombophlebitis, deep thrombophlebitis, lung edema, pulmonary embolus, acute kidney failure, kidney tubular necrosis, death, multi-system organ failure, immune system disorder, hemoperitoneum, bradycardia, hemorrhage, bundle branch block, myocardial ischemia, heart block, pericardial effusion, ventricular arrhythmia, pulmonary hypertension, dyspepsia, gastrointestinal hemorrhage, jaundice, hepatic failure, occlusion, arterial thrombosis, pulmonary thrombosis, coronary occlusion, embolus, cerebral embolism, coagulation disorder (which includes disseminated intravascular coagulation), decreased prothrombin, hypokalemia, hypervolemia, acidosis, arthralgia, agitation, dizziness, anxiety, convulsion, increased cough, skin discoloration, and oliguria."
Adverse Event |
(n = 2002) values in % |
(n = 1084) values in % |
Any Event |
76 |
77 |
Body as a Whole |
||
Fever |
15 |
14 |
Infection |
6 |
7 |
Chest Pain |
2 |
2 |
Asthenia |
2 |
2 |
Cardiovascular |
||
Atrial Fibrillation |
21 |
23 |
Hypotension |
8 |
10 |
Myocardial Infarct |
6 |
6 |
Atrial Flutter |
6 |
5 |
Ventricular Extrasystoles |
6 |
4 |
Tachycardia |
6 |
7 |
Ventricular Tachycardia |
5 |
4 |
Heart Failure |
5 |
4 |
Pericarditis |
5 |
5 |
Peripheral Edema |
5 |
5 |
Hypertension |
4 |
5 |
Arrhythmia |
4 |
3 |
Supraventricular Tachycardia |
4 |
3 |
Atrial Arrhythmia |
3 |
3 |
Digestive |
||
Nausea |
11 |
9 |
Constipation |
4 |
5 |
Vomiting |
3 |
4 |
Diarrhea |
3 |
2 |
Liver Function Tests Abnormal |
3 |
2 |
Hemic and Lymphatic |
||
Anemia |
2 |
8 |
Metabolic & Nutritional |
||
Creatinine Phosphokinase Increased |
2 |
1 |
Musculoskeletal |
||
Any Event |
2 |
3 |
Nervous |
||
Confusion |
4 |
4 |
Insomnia |
3 |
4 |
Respiratory |
||
Lung Disorder |
8 |
8 |
Pleural Effusion |
7 |
9 |
Atelectasis |
5 |
6 |
Dyspnea |
4 |
4 |
Pneumothorax |
4 |
4 |
Asthma |
2 |
3 |
Hypoxia |
2 |
1 |
Skin and Appendages |
||
Rash |
2 |
2 |
Urogenital |
||
Kidney Function Abnormal |
3 |
2 |
Urinary Retention |
3 |
3 |
Urinary Tract Infection |
2 |
2 |
In comparison to the placebo group, no increase in mortality in patients treated with Trasylol was observed. Additional events of particular interest from controlled US trials with an incidence of less than 2%, are listed below:
EVENT |
treated with Trasylol N = 2002 |
Treated with Placebo N = 1084 |
Thrombosis |
1.0 |
0.6 |
Shock |
0.7 |
0.4 |
Cerebrovascular Accident |
0.7 |
2.1 |
Thrombophlebitis |
0.2 |
0.5 |
Deep Thrombophlebitis |
0.7 |
1.0 |
Lung Edema |
1.3 |
1.5 |
Pulmonary Embolus |
0.3 |
0.6 |
Kidney Failure |
1.0 |
0.6 |
Acute Kidney Failure |
0.5 |
0.6 |
Kidney Tubular Necrosis |
0.8 |
0.4 |
"Listed below are additional events, from controlled US trials with an incidence between 1 and 2%, and also from uncontrolled, compassionate use trials and spontaneous post-marketing reports. Estimates of frequency cannot be made for spontaneous post-marketing reports (italicized).
"Body as a Whole: Sepsis, death, multi-system organ failure, immune system disorder, hemoperitoneum.
"Cardiovascular: Ventricular fibrillation, heart arrest, bradycardia, congestive heart failure, hemorrhage, bundle branch block, myocardial ischemia, ventricular tachycardia, heart block, pericardial effusion, ventricular arrhythmia, shock, pulmonary hypertension.
""Digestive: Dyspepsia, gastrointestinal hemorrhage, jaundice, hepatic failure.
"Hematologic and Lymphatic: Although thrombosis was not reported more frequently in aprotinin versus placebo-treated patients in controlled trials, it has been reported in uncontrolled trials, compassionate use trials, and spontaneous post-marketing reporting. These reports of thrombosis encompass the following terms: thrombosis, occlusion, arterial thrombosis, pulmonary thrombosis, coronary occlusion, embolus, pulmonary embolus, thrombophlebitis, deep thrombophlebitis, cerebrovascular accident, cerebral embolism. Other hematologic events reported include leukocytosis, thrombocytopenia, coagulation disorder (which includes disseminated intravascular coagulation), decreased prothrombin.
"Metabolic and Nutritional: Hyperglycemia, hypokalemia, hypervolemia, acidosis.
"Musculoskeletal: Arthralgia.
"Nervous: Agitation, dizziness, anxiety, convulsion.
"Respiratory: Pneumonia, apnea increased cough, lung edema.
"Skin: Skin discoloration.
"Urogenital: Oliguria, kidney failure, acute kidney failure, kidney tubular necrosis."
VALTREX
[September 26, 1997: Glaxo Wellcome]
[Other changes within past 12 months: Oct96, Apr97]
VIRACEPT
[September 30, 1997: Agouron]