New Milestones Achieved in Fluoroquinolone Safety
New Milestones Achieved in Fluoroquinolone Safety
Within the last year there has been concern and discussion regarding the safety of fluoroquinolone antimicrobials. The considerable promise of new weapons to combat the growing problem of antimicrobial resistance among respiratory pathogens has been questioned due to drug withdrawals and restrictions. Some heartening and possibly reassuring data have surfaced, but queries remain unanswered about the new naphthyridones (gemifloxacin) and quinolones (sitafloxacin), which have not been extensively tested or approved.
In June 1999 the severe restriction of trovafloxacin secondary to severe hepatic reactions that led to six deaths raised further questions about the fluoroquinolones. The precise etiology of these events has not been elucidated; however, there appears to be an immunologic component, as evidenced by marked eosinophilia associated with the agent.
Subsequent to the trovafloxacin restriction was the global withdrawal of grepafloxacin by Glaxo Wellcome. This sudden, and largely unexpected, course of action resulted from seven deaths that were possibly due to cardiac events and included three cases of torsades de pointes in the 3.7 million grepafloxacin-treated patients. This drug was reported to induce a prolongation of the QTc interval by 10 milliseconds. However, as grepafloxacin is metabolized by the cytochrome P450 3A4 pathway, it may accumulate when given with drugs that block specific elements of this system. Nevertheless, this makes assessment of the relationship between drug and event difficult, as there may be confounding variables which can, individually or collectively, induce cardiac dysrhythmias.
Trovafloxacin and grepafloxacin ended a decade in which the development of several related class members was terminated due to severe adverse reactions (e.g., phototoxicity associated with Bay 3118). Other compounds elicited such severe events that their use has been markedly limited (e.g., phototoxicity with lomefloxacin, phototoxicity and cardiotoxicity with sparfloxacin). But perhaps the most notorious withdrawal was temafloxacin in June 1992 due to 95 cases of hemolytic uremic syndrome out of a patient base of 172,000. This situation was the first in which full evaluation was not available due to insufficient data being released. The precise etiology was thought to be immunologic, as many patients had a marked eosinophilic reaction. Curiously, there are some naphthyridones and fluoroquinolones that have not sought approval with either the Food and Drug Administration (FDA) or the European Medicines Evaluation Agency (e.g., tosufloxacin -- only available in Japan, or pefloxacin -- only extensively prescribed in France).
So where do we stand today, almost 1 year since two new true fluoroquinolones were approved by the FDA? Moxifloxacin was approved and launched in over 50 countries since September 1999, whereas gatifloxacin is available in only five nations. In the intervening period, moxifloxacin was prescribed in over 3 million patients and gatifloxacin in over a million. Both manufacturers have undertaken substantial postmarketing surveillance programs in accordance with regulatory authority requirements; these were instigated in light of trovafloxacin's restriction and grepafloxacin's withdrawal.
After phase I intravenous studies with moxifloxacin, there were some initial concerns regarding prolongation of the QTc interval. A substantial electrocardiogram analysis by Bayer prompted commendation by the FDA, yet despite the plethora of cardiac data, the FDA was still worried about potential ventricular tachycardias and other malignant arrhythmias. Thus moxifloxacin and gatifloxacin and previously approved levofloxacin received label warnings of potential interactions with type Ia and III antiarrhythmic agents such as cisapride or sotalol. None of them received "black-box" labeling.
Recently the results of large-scale, real-world safety analyses for both moxifloxacin and gatifloxacin were presented. These data are reassuring, with no major, unexpected adverse reactions, and only the usual reactions experienced with fluoroquinolones such as headache, dizziness, nausea, and diarrhea. Table 1 shows the more common adverse events that are considered drug related. The adverse event rates are similar to those seen with other classes of antimicrobials, such as cephalosporins or macrolides.
So where do we go now with this important new antimicrobial class? What have we learned from the unexpected problems seen with previous compounds? It is clear that any halogen atom at the C-8 position causes significant phototoxicity. The possession of a methyl or amino group at C-5 may cause more cardiac problems, as seen with grepafloxacin and sparfloxacin. Whereas a 2,4-difluorophenyl moiety at position C-1 may create some form of hapten (e.g., temafloxacin and trovafloxacin), alternatives are the naphthyridones, which possess a nitrogen atom at the 8 position of the pharmacore and could drive an eosinophilic response similar to that seen with trovafloxacin or tosufloxacin (hepatic and pulmonary eosinophilia, respectively).
Preliminary safety data from over 6000 gemifloxacin-treated patients look uneventful; however, several hundred thousand patients were required to recognize issues with temafloxacin and other compounds. The most well-known fluoroquinolones with very reliable safety profiles are ciprofloxacin and levofloxacin, which have been prescribed in over 280 million and 100 million patients worldwide, respectively. The newer agents, however, such as moxifloxacin -- prescribed in over 3 million patients with less than 1000 spontaneous events reported, -- appear to have comparable safety profiles and tolerabilities. We wait to see whether many or, indeed, any of the myriad of novelty compounds described by Bryskier in his recent excellent overview make it to the marketplace.
Since this manuscript was accepted for publication, gemifloxacin received a non-approvable letter from the FDA.
Within the last year there has been concern and discussion regarding the safety of fluoroquinolone antimicrobials. The considerable promise of new weapons to combat the growing problem of antimicrobial resistance among respiratory pathogens has been questioned due to drug withdrawals and restrictions. Some heartening and possibly reassuring data have surfaced, but queries remain unanswered about the new naphthyridones (gemifloxacin) and quinolones (sitafloxacin), which have not been extensively tested or approved.
In June 1999 the severe restriction of trovafloxacin secondary to severe hepatic reactions that led to six deaths raised further questions about the fluoroquinolones. The precise etiology of these events has not been elucidated; however, there appears to be an immunologic component, as evidenced by marked eosinophilia associated with the agent.
Subsequent to the trovafloxacin restriction was the global withdrawal of grepafloxacin by Glaxo Wellcome. This sudden, and largely unexpected, course of action resulted from seven deaths that were possibly due to cardiac events and included three cases of torsades de pointes in the 3.7 million grepafloxacin-treated patients. This drug was reported to induce a prolongation of the QTc interval by 10 milliseconds. However, as grepafloxacin is metabolized by the cytochrome P450 3A4 pathway, it may accumulate when given with drugs that block specific elements of this system. Nevertheless, this makes assessment of the relationship between drug and event difficult, as there may be confounding variables which can, individually or collectively, induce cardiac dysrhythmias.
Trovafloxacin and grepafloxacin ended a decade in which the development of several related class members was terminated due to severe adverse reactions (e.g., phototoxicity associated with Bay 3118). Other compounds elicited such severe events that their use has been markedly limited (e.g., phototoxicity with lomefloxacin, phototoxicity and cardiotoxicity with sparfloxacin). But perhaps the most notorious withdrawal was temafloxacin in June 1992 due to 95 cases of hemolytic uremic syndrome out of a patient base of 172,000. This situation was the first in which full evaluation was not available due to insufficient data being released. The precise etiology was thought to be immunologic, as many patients had a marked eosinophilic reaction. Curiously, there are some naphthyridones and fluoroquinolones that have not sought approval with either the Food and Drug Administration (FDA) or the European Medicines Evaluation Agency (e.g., tosufloxacin -- only available in Japan, or pefloxacin -- only extensively prescribed in France).
So where do we stand today, almost 1 year since two new true fluoroquinolones were approved by the FDA? Moxifloxacin was approved and launched in over 50 countries since September 1999, whereas gatifloxacin is available in only five nations. In the intervening period, moxifloxacin was prescribed in over 3 million patients and gatifloxacin in over a million. Both manufacturers have undertaken substantial postmarketing surveillance programs in accordance with regulatory authority requirements; these were instigated in light of trovafloxacin's restriction and grepafloxacin's withdrawal.
After phase I intravenous studies with moxifloxacin, there were some initial concerns regarding prolongation of the QTc interval. A substantial electrocardiogram analysis by Bayer prompted commendation by the FDA, yet despite the plethora of cardiac data, the FDA was still worried about potential ventricular tachycardias and other malignant arrhythmias. Thus moxifloxacin and gatifloxacin and previously approved levofloxacin received label warnings of potential interactions with type Ia and III antiarrhythmic agents such as cisapride or sotalol. None of them received "black-box" labeling.
Recently the results of large-scale, real-world safety analyses for both moxifloxacin and gatifloxacin were presented. These data are reassuring, with no major, unexpected adverse reactions, and only the usual reactions experienced with fluoroquinolones such as headache, dizziness, nausea, and diarrhea. Table 1 shows the more common adverse events that are considered drug related. The adverse event rates are similar to those seen with other classes of antimicrobials, such as cephalosporins or macrolides.
So where do we go now with this important new antimicrobial class? What have we learned from the unexpected problems seen with previous compounds? It is clear that any halogen atom at the C-8 position causes significant phototoxicity. The possession of a methyl or amino group at C-5 may cause more cardiac problems, as seen with grepafloxacin and sparfloxacin. Whereas a 2,4-difluorophenyl moiety at position C-1 may create some form of hapten (e.g., temafloxacin and trovafloxacin), alternatives are the naphthyridones, which possess a nitrogen atom at the 8 position of the pharmacore and could drive an eosinophilic response similar to that seen with trovafloxacin or tosufloxacin (hepatic and pulmonary eosinophilia, respectively).
Preliminary safety data from over 6000 gemifloxacin-treated patients look uneventful; however, several hundred thousand patients were required to recognize issues with temafloxacin and other compounds. The most well-known fluoroquinolones with very reliable safety profiles are ciprofloxacin and levofloxacin, which have been prescribed in over 280 million and 100 million patients worldwide, respectively. The newer agents, however, such as moxifloxacin -- prescribed in over 3 million patients with less than 1000 spontaneous events reported, -- appear to have comparable safety profiles and tolerabilities. We wait to see whether many or, indeed, any of the myriad of novelty compounds described by Bryskier in his recent excellent overview make it to the marketplace.
Since this manuscript was accepted for publication, gemifloxacin received a non-approvable letter from the FDA.
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