PMS data not yet available

"Data not yet available for gemifloxacin.

"Data not yet available for gemifloxacin.

It is of note that temafloxacin, tosufloxacin, and trovafloxacin are the only compounds developed that have the 1(2,4)-difluorophenyl substituent. Their nuclear and sidechain structure is otherwise dissimilar.

Subsequently, the two fluoroquinolone class effects most frequently causing comment, sometimes associated with specific instructions from registration authorities to include special cautions and warnings in the data sheet, have been CNS effects, phototoxicity, and tendinitis, as well as QTc prolongation and associated ventricular tachyarrhythmias [99,107]

CNS effects—particularly headaches, insomnia, and dizziness—occur more commonly with ofloxacin and lomefloxacin than with other fluoroquinolones (FDA Antiinfective Advisory Committee, Open Meeting, 23 September 1993). Major psychiatric disturbances were also more common, and, in the case of lomefloxacin, convulsions have occurred significantly more frequently than with other fluoroquinolones, often with no past history or predisposing factors. However, all quinolones are contraindicated in patients with a history of convulsions.

Quinolone phototoxicity is predictably more common and potentially severe with plurally fluorinated (e.g., lomefloxacin, fleroxacin, and sparfloxacin) and, most notably 8-chloro compounds (e.g., clinafloxacin and sitafloxacin) [3,100]. It results from absorption of light by quinolones or their metabolites in tissue, following which transfer of photo energy releases oxygen radicals, allowing damage to lipids in cell membranes [102]. Differences between fluoroquinolones are dramatic: clinafloxacin and Bay 3118 were withdrawn and sparfloxacin incurred special labeling to warn of this effect, while the 8-methoxyquinolones moxifloxacin and gatifloxacin have minimal phototoxic potential [100,101, 103,104].

Skeletal problems remain a theoretical possibility in children, but tendinitis and tendon rupture have occurred in a small number of adults [105]. The effect may be more common with pefloxacin but occurs with all agents, most frequently affects the Achilles tendon, is often associated with prior corticosteroid therapy, and, although resolving spontaneously in the majority, may persist for several months in around 10% of patients.

A new effect, dose-related prolongation of the QT interval, was noted during investigation of sparfloxacin, and subsequent close surveillance of exposed populations revealed a number of ventricular arrhythmias possibly associated with therapy [106]. It has been responsible for the withdrawal of grepafloxacin, which was recognized to cause QT prolongation and subsequently reported to cause torsade de pointes (a malignant ventricular tachyrhythmia associated with QT prolongation) and seven possibly related cardiac deaths [107]. QT prolongation is a quinolone class effect and, as others, varies in degree between agents. However, all quinolones that have been tested cause QT prolongation in animals and, in sufficient quantity (far higher than human dosage), may precipitate ventricular arrhythmias, usually torsade de pointes. Very rare reports have associated sparfloxacin, grepafloxacin, and levofloxacin with ventricular arrhythmias in man, but so far no other agents have been implicated. Prolongation of the corrected (QTc) interval may be caused by other drugs, notably macrolides, antiarrhythmics, terfenadine, and cisapride, and is associated with various risk factors. These include female gender, aging, ischemic and other cardiac disease, and electrolyte disturbance. Risk factors may combine to precipitate arrhythmias [107]. All new quinolones are now labeled as causing QTc prolongation and having potential for cardiac rhythm disturbances.

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