TABLE 1

MAY 2002

DRUGS WITH BLACK BOX WARNINGS

The package insert for prescription products remains one of the primary sources for certain information about a marketed drug in the United States. It essentially provides the template and guidelines for safe and rational use of a drug and reflects data collected in premarketing trials. Within the last decade, certain data (mostly safety data) collected in post-marketing surveillance has also been added to the package insert. One of the most important part of the package insert is the Black Box. This is a section of the package insert that alerts clinicians to particularly important information as designated by the FDA. Typically but not always, black box data pertains to safety information, including, adverse events, drug interactions, and restrictions for use. Not all new safety warnings or changes to package inserts are black box warnings. Not all package inserts contain black boxes. Notification of black box warning additions and other safety information is posted by the FDA on the MedWatch website (http://www.fda.gov/medwatch/).

A recent article in JAMA [2002; 287(17) May 1:2215-20] examined past issues of the PDR for the frequency and timing of new black box warnings or drug withdrawals for 548 new chemical entities approved by the FDA between 1975 and 1999. Of these new chemicals, approximately 10% acquired a new black box warning (45) or were withdrawn from the market (16). The authors estimated that the probability of a drug acquiring a black box warning or being withdrawn from the market was 20%. Half of the black box additions occurred within the first seven years after a drug was marketed and half of the drug withdrawals occurred within the first two years after a drug was marketed.

It is important for health care professionals to be familiar with black box data as these drugs may be associated with significant risk or require specific monitoring to optimize efficacy and/or safety. Although black box data is included in several tertiary resources which summarize or present product package insert information (e.g., PDR, Drug Facts and Comparisons), a listing of drugs with black box warnings is not currently available. Such a list would be helpful in creating awareness of drugs with specific safety data or requirements. The following table represents the black box data found in selected anti-infectives. A more comprehensive list of drugs with black box warnings is being developed by the Drug Information Center. Drugs with Black Box warnings will be specified within the new KUH formulary on the web

(http://www.formularyproductions.com/kumc)

TABLE 1. BLACK BOX DATA FOR SELECTED ANTI-INFECTIVES
GENERIC NAME	BLACK BOX SYNOPSIS¹	ORGAN SYSTEM/ OTHER	MONITORING RECOMMENDATIONS RELATED TO BLACK BOX DATA²
*Aminoglycosides*
Tobramycin Gentamicin Kanamycin Amikacin	Neurotoxicity: manifests as both auditory and vestibular ototoxicity, and primarily occurs in patients with pre-existing renal damage or in normal renal function with prolonged therapy. Partial or total irreversible deafness may continue to develop after drug is stopped. Other features of neurotoxicity include paresthesias, twitching, and seizures. Nephrotoxicity: usually reversible (see monitoring) Premature infants & neonates: use with caution Avoid concurrent use of nephrotoxic agents: Avoid concurrent use of diuretics: increase risk of ototoxicity. Teratogenic in pregnancy	Neurotoxicity Nephrotoxicity Concurrent drugs Population Teratogenic	· Renal and eighth nerve function closely monitored in patients with suspected renal dysfunction. Monitor peak and trough concentrations during therapy to ensure appropriate levels. · Dosage adjustments required in renal impairment
*Anitfungals*
Amphotericin	Use primarily for treatment of patients with progressive and potentially fatal fungal infections. Do not use to treat noninavsive forms of fungal diseases in patients with normal neutrophil counts.	Indications
Flucytosine	Use with extreme caution in patients with renal impairment	Toxicity	· Frequent monitoring of hematological, renal and hepatic status of all patients
Ketoconazole (oral)	Hepatotoxicity: including fatalities Drug Interactions: Severe cardiovascular events when coadministered with cisapride	Hepatotoxicity	· LFTs and bilirubin at baseline and frequent intervals during therapy
Itraconazole (oral)	CHF: not be administered to treat onychomycosis patients with evidence of ventricular dysfunction (e.g., CHF) or history of CHF. Drug Interactions: Itraconazole is potent inhibitor of CYP450 3A4. Coadministration with cisapride, pimozide, quinidine, or dofetilide can cause serious cardiovascular events, including QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest, and/or sudden death.	Cardiotoxicity Drug Interactions	· Monitor for signs and symptoms of CHF · obtain nail specimens for laboratory testing prior to prescribing the medications for onychomycosis to confirm the diagnosis
Terbinafine (oral)	Hepatotoxicity: Rare cases of severe and fatal liver failure. Not recommended for patients with chronic or active liver disease. May occur in patients without pre-existing liver disease	Hepatotoxicity	· Baseline ALT and AST prior to treatment · obtain nail specimens for laboratory testing prior to prescribing the medications for onychomycosis to confirm the diagnosis
*Antituberculins*
Isoniazid	Hepatitis: Severe and sometime fatal hepatitis may occur during and many months after treatment. Risk is related to age and increased with daily alcohol consumption. Patients should be instructed about signs and symptoms of hepatitis. If reinitiated, start in small and gradual doses. Not for use in patient with active liver disease	Hepatotoxicity	· Careful monitoring and monthly interviews · Discontinue abruptly if symptoms appear
Streptomycin	Neurotoxicity: Risk of severe reactions increased in patients with impaired renal dysfunction Nephrotoxicity: Avoid concurrent use of nephrotoxic/neurotoxic drugs	Neurotoxicity Nephrotoxicity	· Renal function should be monitored carefully and patients with reduced function should have reduced doses. · Peak serum concentrations in patients with renal dysfunction: < 20 to 25 mcg/mL
*Antivirals*
Abacavir	Fatal Hypersensitivity Reactions: associated with therapy. Drug should not be restarted after suspected reaction. Severe of fatal reaction may occur within hrs after reintroduction of drug in patients with unrecognized symptoms of hypersensitivity. Lactic Acidosis & Hepatomegaly:: reported with steatosis (including fatal cases) reported with the use of nucleoside analogues alone or in combination.	Hypersensitivity Hepatotoxicity Lactic acidosis	· Patients developing signs or symptoms of hypersensitivity should stop drug immediately. If hypersensitivity reaction can not be ruled out, the drug should be permanently discontinued to prevent life-threatening reaction. Drug should not be restarted after suspected reaction.
Amprenavir	Propylene Gylcol Excipient: Risk of toxicity from large amount of excipient contraindicates use in children < 4 yrs and in certain other populations and used with caution in others. Consult complete prescribing information.	Propylene Glycol toxicity
Cidofovir	Nephrotoxicity: Major toxicity. Cases of acute renal failure resulting in dialysis and/or contributing to death with as few as one or two doses. Reduce possible nephrotoxicity with intravenous prehydration (normal saline) and administration of probenecid. Renal monitoring (see monitoring recommendations). Contraindicated in patients receiving other nephrotoxic agents. Neutropenia: observed during therapy. Monitor. Indications: Only for treatment of CMV retinitis in patients with AIDS. Animal Data: Carcinogenic, teratogenic	Nephrotoxicity Hematological Indications Carcinogenic Teratogenic	· Serum creatinine and urine protein monitored within 48 hrs prior to each dose. Dose adjustment required for changes in renal function. · Neutrophils counts should be monitored during therapy
Delaviridine	Resistance: Resistant viruses emerge during monotherapy. Administer with combination therapy	Resistance	·
Didanosine	Pancreatitis: Fatal and nonfatal cases have occurred with monotherapy or in combination. Hepatotoxicity: with steatosis (including fatal cases) have been reported with nucleoside analogues alone or in combination. Lactic Acidosis: Reported in pregnant women who have received didanosine and stavudine with other antiretroviral agents. Use the combination with caution in pregnant women.	Hepatotoxicity Lactic acidosis Pancreatitis	· Patients with prodromal symptoms of hepatitis should seek medical attention immediately and promptly discontinue drug.
Foscarnet	Nephrotoxicity: Major toxicity Seizures related to levels of minerals and electrolytes. May require supplementation. Indications: For use only in immunosuppressed patients with CMV retinitis and mucocutaneous acyclovir resistant HSV infections.	Nephrotoxicity Seizures	· Frequent serum creatinine monitoring with dose adjustments for changes in renal function and adequate hydration is essential · Monitor plasma electrolytes and minerals
Ganciclovir	Hematological: Granulocytopenia, anemia and thrombocytopenia Animal Data: Aspermatogenensis, carcinogenic, teratogenic Indications: IV and oral products have specific indications (see package insert) Oral Capsules: associated with risk of rapid rate of CMV retinitis progression and should be used as maintenance therapy only in patients who benefit from avoiding daily intravenous infusions.	Hematological Animal Data Indications	· Frequent complete blood counts and platelet counts performed, especially in patients with previous hematological reactions with this drug or other nucleoside analogues.
Lamivudine	Lactic Acidosis & Hepatomegaly:: reported with steatosis (including fatal cases) reported with the use of nucleoside analogues alone or in combination. Dosing Formulation: Epivir tablets and oral solution are used to treat HIV infection and contain higher dose of lamivudine than either Epivir-HBV, which is used to treat chronic hepatitis B infection. HIV patients should receive only Epivir formulations.	Hepatotoxicity Lactic Acidosis Dosing Formulations	· Patients with prodromal symptoms of hepatitis should seek medical attention immediately and promptly discontinue drug.
Nevirapine	Hepatotoxicity: Severe, life threatening and in some cases fatal cases, including fulminant and cholestatic hepatitis, necrosis and failure. Dermal Reactions: Severe, life-threatening skin reactions (sometimes fatal) have occurred during therapy. Cases include Stevens-Johnson syndrome, TEN, and hypersensitivity reactions. Patient Monitoring: Close monitoring for first 12 wks to detect signs & symptoms of skin/hepatic reactions Dosing: 14 day initiation period (200 mg daily) must be strictly followed Resistance: Resistance proven with monotherapy. Nevirapine should always be administered in combination therapy with other antiretrovirals.	Hepatotoxicity Dermal Reactions Patient Monitoring Initial Dosing Resistance	· Patients should be closely monitored at baseline and for first 12 wks for signs of potentially life-threatening liver or skin reactions. Optimal frequency of monitoring not defined. · Patients with prodromal symptoms of hepatitis should seek medical attention immediately and promptly discontinue drug. · Patients developing signs or symptoms of severe skin reactions or hypersensitivity reactions should discontinue drug immediately
Ribavirin	Respiratory function: Sudden deterioration has occurred with initiation of aerosolized therapy. Monitor carefully. (See monitoring) Population: Not for use in adults Mechanical Ventilation: Ventilator assistance only undertaken by physician familiar with specific ventilator Animal Data: Tetratogenic and carcinogenic	Respiratory Population Mechanical ventilation Animal data	· Respiratory function should be carefully monitored during therapy. If sudden deterioration occurs, stop drug and restart only with extreme caution. Continue monitoring and consider concurrent therapy with bronchodilators.
Ritonavir	Drug Interactions : with certain drugs (e.g. some nonsedating antihistamines, sedative hypnotics, antiarrhythmics, or ergot alkaloids) may result in serious/life threatening adverse events.	Drug Interactions
Saquinivar	Brand products Invirase (capsules) and Fortovase (soft gelatin capsules) are not bioequivalent and are not interchangeable.	Bioequivalency
Stavudine	Pancreatitis: Fatal and nonfatal cases have occurred with monotherapy or in combination with didanosine with or without hydroxyurea. Hepatotoxicity: with steatosis (including fatal cases) have been reported with nucleoside analogues alone or in combination. Lactic Acidosis: Reported in pregnant women who have received didanosine and stavudine with other antiretroviral agents. Use the combination with caution in pregnant women.	Pancreatitis Hepatotoxicity Lactic Acidosis	· Patients with prodromal symptoms of hepatitis should seek medical attention immediately and promptly discontinue drug.
Valganciclovir	Valganciclovir is metabolized to ganciclovir. See Ganciclovir for hematological and Animal Data	Hematological Animal Data	· Frequent complete blood counts and platelet counts performed, especially in patients with previous hematological reactions with this drug or other nucleoside analogues.
Zalcitabine	Neuropathy: Severe peripheral neuropathy, use with extreme caution in patients with pre-existing neuropathy. Pancreatitis: Rarely occur. Monitor Lactic Acidosis & Hepatomegaly:: reported with steatosis (including fatal cases) reported with the use of nucleoside analogues alone or in combination.	Neuropathy Pancreatitis Hepatic Lactic Acidosis	· Patients with symptoms of hepatitis or pancreatitis should seek medical attention immediately and promptly discontinue
Zidovudine	Hematological: Neutropenia and severe anemia, particularly in patients with advanced HIV disease. Myopathy: associated with prolonged use Lactic Acidosis & Hepatomegaly:: reported with steatosis (including fatal cases) reported with the use of nucleoside analogues alone or in combination.	Hematological Hepatic Lactic Acidosis Myopathy	· Frequent blood counts strongly recommended during therapy in patients with advanced HIV disease. Periodic blood counts recommended for HIV infected individuals who are asymptomatic or have early HIV disease. · Patients with prodromal symptoms of hepatitis should seek medical attention immediately and promptly discontinue drug.
*Miscellaneous*
Bacitracin	Nephrotoxicity: Tubular and glomerular necrosis associated with parenteral (IM) use. Restrict use to infants with staphylococcal pneumonia or empyema due to susceptible organisms. Use with adequate facilities and supervision. Avoid concurrent nephrotoxic drugs	Nephrotoxicity	· Monitor renal function at baseline and daily during therapy · Do not exceed recommended daily dose · Maintain fluid intake and urinary output at proper levels.
Chloramphenicol	Hematological: Serious and fatal blood dyscrasias have occurred including, aplastic anemia, hypoplastic anemia, thrombocytopenia & granulocytopenia. Use only in serious infections	Hematological	·