Compiled by:
Neil W. Hitchcock, PharmD candidate
McWhorter School of Pharmacy
Samford University
Birmingham, AL

ARIMIDEX (anastrozole)	ASTELIN (azelastine HCl)	ATIVAN (lorazepam)	BIAXIN (clarithromycin)	BiCNU (carmustine)
CARDIZEM (diltiazem HCl)	CEFTIN (cefuroxime axetil)	CIPRO (ciprofloxacin)	CLOZARIL (clozapine)	CRIXIVAN (indinavir SO4)
DEMADEX (torsemide)	FAMVIR (famciclovir)	LUPRON DEPOT (leuprolide acetate)	LYSODREN (mitotane)	MEGACE (megestrol acetate)
NASACORT AQ (triamcinolone acetonide)	NOVANTRONE (mitoxantrone)	PROVENTIL REPETABS (albuterol SO4)	STATROL (neomycin/polymyxin B sulfates)	TRASYLOL (aprotinin)
VALTREX (valacyclovir HCl)	VIRACEPT (nelfinavir mesylate)

ADVERSE REACTIONS:

Urogenital: New paragraph added - "Vaginal bleeding has been reported infrequently, mainly in patients during the first few weeks after changing from existing hormonal therapy to treatment with Arimidex. If bleeding persists, further evaluation should be considered."

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PRECAUTIONS:

Information for Patients: First paragraph, fifth sentence added - "In case of accidental ingestion by a young child, seek professional assistance or contact a poison control center immediately."

OVERDOSAGE:

Second and third sentences revised (new text in italics) -

"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."

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CLINICAL PHARMACOLOGY:

Pharmacokinetics: New last paragraph added - "For information on lansoprazole or amoxicillin, refer to the CLINICAL PHARMACOLOGY section of their package inserts."

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.

INDICATIONS AND USAGE:

Adults: New seventh paragraph added and eighth and ninth paragraphs revised (new text in italics) -

"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."

CONTRAINDICATIONS:

New last paragraph added - "For information on lansoprazole or amoxicillin, refer to the CONTRAINDICATIONS section of their package inserts."

WARNINGS:

New last paragraph added - "For information on lansoprazole or amoxicillin, refer to the WARNINGS section of their package inserts."

PRECAUTIONS:

General: New last paragraph added - "For information on lansoprazole or amoxicillin, refer to the PRECAUTIONS section of their package inserts."

DOSAGE AND ADMINISTRATION:

H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence (new subsection): "Triple therapy: Biaxin/lansoprazole/amoxicillin: The recommended adult oral dose is 500 mg Biaxin, 30 mg lansoprazole, and 1 gram amoxicillin, all given twice daily (q12h) for 14 days. (See INDICATIONS AND USAGE.)

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]"

CLINICAL STUDIES:

Mycobacterial Infections: Treatment: New text added to end of section -

"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.

H. pylori Eradication Rates-Triple Therapy
Percent of Patients Cured
[95% Confidence Interval]
(number of patients)

Study	Triple Therapy (Evaluable Analysis)*	Triple Therapy (Intent-to-Treat Analysis)**
Study 131	92† [80.0 – 97.7] (n = 48)	86† [73.3 – 93.5] (n = 55)
Study 392	86‡ [75.7 – 93.6] (n = 66)	83‡ [72.0 – 90.8] (n = 70)

* Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H. pylori infection as baseline defined as at least two of three positive endoscopic tests from Clotest (Delta West LTD., Bentley, Australia), histology, and/or culture. Patients were included in the analysis if they completed the study. Additionally, if patients were dropped out of the study due to an adverse event related to the study drug, they were included as failures of therapy.
** Patients were included in the analysis if they had documented H. pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year). All dropouts were included as failures of therapy.
^† (p<0.05) versus Biaxin/lansoprazole and lansoprazole/amoxicillin dual therapy.
^‡ (p<0.05) versus Biaxin/amoxicillin dual therapy.

"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."

REFERENCES:

First, second, and fourth references revised (new text in italics) -

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]

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BOXED WARNINGS

Last paragraph revised (new text in italics) - "Delayed pulmonary toxicity can occur years after treatment, and can result in death, particularly in patients treated in childhood (see "ADVERSE REACTIONS" and "PRECAUTIONS: Pediatric Use").

WARNINGS:

Third paragraph, third sentence revised (new text in italics) - "Additionally delayed onset pulmonary fibrosis occurring up to 17 ["15" deleted] years after treatment, has been reported in patients who received BiCNU in childhood and early adolescence (see "ADVERSE REACTIONS")."

PRECAUTIONS:

Nursing Mothers: Last sentence deleted -

"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")"

ADVERSE REACTIONS:

Hematologic Toxicity: First sentence revised (new text in italics) - "A ["The most" deleted] frequent and ["most" deleted] serious toxicity of BiCNU is delayed myelosuppression."

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."

REFERENCES:

Previous Reference 7 deleted and replaced with -

"7. Controlling occupational exposure to hazardous drugs. (OSHA WORK PRACTICE GUIDELINES). Am J Health-Syst Pharm 1996; 53:1669-1685."

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DOSAGE AND ADMINISTRATION:

Continuous Intravenous Infusion: Dilution: Addition of new third and fourth sentences -

"Keep diluted Cardizem Injectable refrigerated until use. Diluted Cardizem Lyo-Ject may be stored at room temperature 15-30^oC (59-86^oF)." ["Keep refrigerated until use." deleted]

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WARNINGS:

Second revised (new text in italics) - "[Convulsions have been reported in patients receiving ciprofloxacin." deleted] Convulsions, increased intracranial pressure, and toxic psychosis have been reported in patients receiving ["drugs in this class" deleted] quinolones, including ciprofloxacin. ["Quinolones" deleted] Ciprofloxacin may also cause central nervous system (CNS) ["stimulation, which may lead to" deleted] events including: dizziness, confusion, tremors,["restlessness, lightheadedness" deleted] hallucinations, depression, and, rarely, suicidal thoughts or acts. These reactions may occur following the first dose. If these reactions occur in patients receiving ciprofloxacin, the drug should be discontinued and appropriate measures instituted. As with all quinolones, ciprofloxacin should be used with caution in patients with known or suspected CNS disorders ["such as severe cerebral arteriosclerosis, epilepsy, and other factors" deleted] that may predispose to seizures or lower the seizure threshold (e.g. severe cerebral arteriosclerosis, epilepsy), or in the presence of other risk factors that may predispose to seizures or lower the seizure threshold (e.g., certain drug therapy, renal dysfunction). (See PRECAUTIONS: General, Information for Patients, Drug Interactions and ADVERSE REACTIONS.)"

PRECAUTIONS:

General: New second paragraph added - "Quinolones, including ciprofloxacin, may also cause central nervous system (CNS) events, including: nervousness, agitation, insomnia, anxiety, nightmares or paranoia. (See WARNINGS, Information for Patients, and Drug Interactions.)"

ADVERSE REACTIONS:

New last paragraph added in the oral ciprofloxacin labeling - "In randomized, double-blind controlled clinical trials comparing ciprofloxacin tablets (500 mg BID) to cefuroxime axetil (250 mg - 500 mg BID) and to clarithromycin (500 mg BID) in patients with respiratory tract infections, ciprofloxacin demonstrated a CNS adverse event profile comparable to the control drugs."

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."

Labeling for Cipro Tablets and Solution formulations have also been revised to incorporate new information pertaining to the use of Cipro in cystic fibrosis patients.
Contact the company for a copy of the labeling/package insert.

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PRECAUTIONS:

Hyperglycemia (new subsection): "Severe hyperglycemia, sometimes leading to ketoacidosis, has been reported during Clozaril (clozapine) treatment in patients with no prior history of hyperglycemia. While a causal relationship to Clozaril use has not been definitively established, glucose levels normalized in most patients after discontinuation of Clozaril (clozapine), and a rechallenge in one patient produced a recurrence of hyperglycemia. The effect of Clozaril (clozapine) on glucose metabolism in patients with diabetes mellitus has not been studied. The possibility of impaired glucose tolerance should be considered in patients receiving Clozaril (clozapine) who develop symptoms of hyperglycemia, such as polydipsia, polyuria, polyphagia, and weakness. In patients with significant treatment-emergent hyperglycemia, the discontinuation of Clozaril (clozapine) should be considered."

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WARNINGS:

Section revised (new text in italics) - "Nephrolithiasis: Nephrolithiasis ["may occur" deleted] has occurred with Crixivan. In some cases, nephrolithiasis has been associated with renal insufficiency or acute renal failure. If signs and symptoms of nephrolithiasis, including flank pain with or without hematuria (including microscopic hematuria), occur, temporary interruption of therapy (e.g., 1-3 days) during the acute episode of nephrolithiasis or discontinuation of therapy may be considered. Adequate hydration is recommended in all patients treated with Crixivan. (See ADVERSE REACTIONS, Post-Marketing Experience and DOSAGE AND ADMINISTRATION, Nephrolithiasis.)

"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."

PRECAUTIONS:

Other: Third paragraph revised (new text in italics) -

"["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."

ADVERSE REACTIONS:

Post-Marketing Experience: Subsection revised (new text in italics) -
"The following additional adverse experiences have been reported in post-marketing experience:

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."

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[Other changes within past 12 months: Jan97, Jul97]

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ADVERSE REACTIONS:

"Table 2: Adverse Events Reported to be Causally Related to Drug in > or = 5% of Patients" has been revised to correct errors found in the approved label. Contact the company for a copy of the labeling/package insert.

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.

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PRECAUTIONS:

Pediatric Use: (new subsection added) - "Safety and effectiveness in pediatric patients have not been established."

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CONTRAINDICATIONS:

Section revised (new text in italics) -

"History of hypersensitivity to megestrol acetate or any component of the formulation. As a diagnostic test for pregnancy.

WARNINGS:

New fourth paragraph added - "Although the glucocorticoid activity of Megace tablets has not been fully evaluated, laboratory evidence of adrenal suppression has been observed. Clinical cases of new onset diabetes, exacerbation of pre-existing diabetes, and Cushing's syndrome have been reported in association with the use of Megace. Rare cases of clinically apparent adrenal insufficiency have also been reported in association with Megace. The possibility of adrenal suppression should be considered in any patient taking or withdrawing from chronic Megace therapy who presents with symptoms of adrenal insufficiency such as hypotension, nausea, vomiting, dizziness, or weakness. Laboratory evaluation for adrenal insufficiency and replacement stress doses of a rapidly acting glucocorticoid may be indicated for such patients."

PRECAUTIONS:

General: Section revised (new text in italics) - "Close surveillance is indicated for any patient treated for recurrent or metastatic cancer. Use with caution in patients with a history of ["thrombophlebitis" deleted] thromboembolic disease. [Patients should be observed for clinical evidence of adrenal cortical insufficiency when Megace is abruptly withdrawn." deleted]"

Use in Diabetics (new subsection): "Exacerbation of pre-existing diabetes with increased insulin requirements has been reported in association with the use of Megace."

ADVERSE REACTIONS:

Thromboembolic Phenomena: Sentence revised (new text in italics) - "Thromboembolic phenomena including thrombophlebitis and pulmonary embolism (in some cases fatal) have been ["rarely" deleted] reported."

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."

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PRECAUTIONS:

Nursing Mothers: Section revised (new text in italics) -

"[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."

DOSAGE AND ADMINISTRATION:

Preparation and Administration Precautions: Fifth paragraph, following sentences deleted - "Spills on equipment and environmental surfaces may be cleaned using an aqueous solution of calcium hypochlorite (5.5 parts calcium hypochlorite in 13 parts by weight of water for each 1 part Novantrone). Absorb the solution with gauze or towels and dispose of these in a safe manner. Appropriate safety equipment such as goggles and gloves should be worn while working with calcium hypochlorite."

REFERENCES:

New first reference added -
"1. Azuno Y, et al. Mitoxantrone and Etoposide in Breast Milk. Am J Hematol. 1995;48: 131-132.

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PRECAUTIONS:

Pediatric Use (new subsection): "Safety and effectiveness in pediatric patients below the age of 2 years have not been established."

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PRECAUTIONS:

Pediatric Use: Section revised (new text in italics) - "Safety and effectiveness in ["children" deleted] pediatric patient(s) have not been established."

ADVERSE REACTIONS:

First paragraph, third and fourth sentences deleted and replaced - "Adverse events reported, up to time of discharge from the hospital, from placebo-controlled studies conducted in the United States involving 2002 aprotinin patients are listed in the following tables. The tables list those events which occurred in patients treated with Trasylol without regard to causal relationship."

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."

INCIDENCE RATES OF ADVERSE EVENTS (> = 2%)
BY BODY SYSTEM AND TREATMENT
FOR ALL PATIENTS FROM US PLACEBO-CONTROLLED CLINICAL TRIALS

Adverse Event	Aprotinin (n = 2002) values in %	Placebo (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	Percentage of patients treated with Trasylol N = 2002	Percentage of patients 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."

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[Other changes within past 12 months: Oct96, Apr97]

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