Fluoroquinolone Adverse Effects and Drug Interactions

Douglas N. Fish, PharmD

Disclosures

Pharmacotherapy. 2001;21(10s) 

In This Article

Drug-Drug Interactions

The potential for drug-drug interactions is an important aspect of overall drug safety. As with adverse effects, the fluoroquinolones cause both class-specific and agent-specific interactions ( Table 3 ).[119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175,176,177,178,179,180,181,182,183] Because few head-to-head comparative studies have been performed, the relative potential for certain drug interactions among fluoroquinolones is inferred from noncomparative studies against the same or similar nonfluoroquinolone comparators.

Antacids, Mineral Supplements, Sucralfate, and Food Effect

Without exception, all fluoroquinolones interact with multivalent cation-containing products, such as aluminum- or magnesium-containing antacids and products containing calcium, iron, or zinc. Concomitant use invariably results in marked reduction of oral absorption of the antimicrobial. The mechanism of this interaction is formation of insoluble chelation complexes in the gastrointestinal tract that inhibit drug absorption. Chelation of fluoroquinolones occurs to a greater degree with aluminum- and magnesium-containing products than with products containing calcium, iron, or zinc; however, the resulting decrease in fluoroquinolone absorption with all of these products is potentially significant and increases the possibility of therapeutic failure.[119]

Multivitamin preparations that contain minerals should be avoided. Similar adverse effects on fluoroquinolone absorption were observed with concomitant administration of ferrous sulfate, with decreases in bioavailability of the antibiotic of 19-66%.[27,29,38,120,121,122,123]

Although it is usually recommended that concomitant intake of calcium-rich foods (e.g., milk) be avoided because of the potential for chelation effects, the actual influence of dairy products on fluoroquinolone absorption varies.[17,123,124,125]

Sucralfate significantly interferes with oral absorption of fluoroquinolones. It decreased the bioavailability of these drugs by up to 98% when given within 2 hours of antibiotic administration.[27,126,127,128] The mechanism of this interaction has been attributed to both the aluminum content of the sucralfate salt and direct binding of the fluoroquinolone by the sucralfate itself.

Proper timing of drug administration may minimize these interactions in the gastrointestinal tract. Antacids and other multivalent cation-containing products as well as sucralfate should be taken at least 2 hours before or 4-6 hours after the fluoroquinolone dose.[27,29,38,120,129,130,131,132,133,134]

The degree to which fluoroquinolones are absorbed is not significantly affected by food. Studies involving ciprofloxacin, levofloxacin, gatifloxacin, and moxifloxacin consistently reported alterations in drug absorption rates without change in the extent of absorption.[23,134,135,136,137] When fluoroquinolones are administered with food, peak concentration times are usually slightly delayed, and maximum plasma concentrations (Cmax) are decreased 8-16%. The area under the plasma concentration versus time curve (AUC) is invariably unchanged; alterations in absorption rates are considered to be clinically insignificant.

Histamine2 Receptor Antagonists and Proton Pump Inhibitors. Concomitant administration of histamine2 (H2)-receptor antagonists and proton pump inhibitors (agents that modify gastric pH) have no clinically significant effects on the absorption of the fluoroquinolones.[27,29,38,133,138,139,140,141,142] Cimetidine can inhibit renal tubular secretion and therefore reduce systemic clearance of fluoroquinolones that are primarily excreted renally (levofloxacin, ciprofloxacin, lomefloxacin, sparfloxacin, gatifloxacin). The reduction in renal and total systemic clearance of fluoroquinolones, including moxifloxacin and gatifloxacin, caused by cimetidine or other H2-receptor antagonists is usually not clinically or statistically significant.[27,29,38,125,138,141,142,143]

Probenecid. Like cimetidine, probenecid can inhibit renal tubular secretion of fluoroquinolones that are primarily eliminated through renal excretion. Approximate reductions in renal and total systemic clearance caused by probenecid are 24% for levofloxacin,[143] 50% for ciprofloxacin,[14] and 42% for gatifloxacin.[29] Coadministration of moxifloxacin and probenecid did not alter the renal clearance of the fluoroquinolone.[38] Although the decrease in renal clearance and increase in serum concentrations of most fluoroquinolones are not likely to be clinically significant, patients receiving probenecid concomitantly with fluoroquinolones that are primarily excreted renally should be monitored for adverse effects. Fluoroquinolones that are primarily eliminated through hepatic metabolism, such as trovafloxacin, are not likely to be affected by concomitant administration of probenecid.

Theophylline and Caffeine. Fluoroquinolones can inhibit clearance of xanthine derivatives, including theophylline and caffeine. This is not a class effect; the relative inhibitory capacity depends on the specific affinity of each fluoroquinolone for the cytochrome P450 (CYP) isozyme 1A2.[144] Fluoroquinolones ranked in the approximate order in which they significantly interact with theophylline (based on published literature) are as follows: enoxacin > ciprofloxacin > norfloxacin > ofloxacin, levofloxacin, trovafloxacin, gatifloxacin, moxifloxacin.[23,133,144,145,146,147,148,149,150,151,152,153,154] Enoxacin causes significant alterations in theophylline metabolism and increased Cmax and AUC of theophylline by as much as 240%.[145] In numerous studies ciprofloxacin decreased theophylline clearance by 25-30%, and increased theophylline plasma concentrations by up to 308%.[147,148]

The effects of ciprofloxacin and enoxacin on caffeine metabolism are similar to effects on theophylline metabolism; hepatic clearance of caffeine was decreased by 33% and 78% when healthy volunteers received concurrent doses of ciprofloxacin and enoxacin, respectively.[148,149] Norfloxacin has moderate effects on theophylline elimination, reducing its hepatic clearance by 10-15%.[145] Because the actual degree of interaction between fluoroquinolones discussed above and methylxanthines vary considerably among individuals, all patients receiving fluoroquinolones must be monitored carefully for signs of theophylline-related and caffeine-related adverse effects. In addition, patients receiving theophylline plus enoxacin should have the theophylline dosage empirically reduced by 50% at start of fluoroquinolone therapy.[145] Theophylline concentrations should be measured frequently in patients receiving enoxacin or ciprofloxacin.

In contrast to the fluoroquinolones mentioned, pharmacokinetic studies of ofloxacin, lomefloxacin, levofloxacin, sparfloxacin, and trovafloxacin concluded that these agents do not significantly alter the metabolism of theophylline[23,147,150,151,152,153]; ofloxacin and trovafloxacin also have no significant effects on caffeine metabolism.[149,153] Among the newest drugs, moxifloxacin and gatifloxacin have no significant effects on theophylline metabolism.[133,154,155]

Warfarin. A number of anecdotal case reports describe possible interactions between fluoroquinolones and warfarin. Because certain fluoroquinolones inhibit hepatic CYP enzymes, it is conceivable that an interaction with warfarin could result in decreased warfarin metabolism and increased therapeutic response. However, prospective studies designed to elucidate fluoroquinolone- warfarin interactions generally failed to record pharmacokinetically or clinically significant interactions. Enoxacin reduced the clearance of warfarin's R-enantiomer by 32%; however, clearance of the S-enantiomer, which is more potent and is thought to cause most of warfarin's anticoagulant activity, was not affected.[157] Therefore, this interaction was not thought to be clinically significant. A similar 15-32% increase in serum concentrations of R-warfarin was observed after starting ciprofloxacin, but again the S-warfarin concentrations remained unchanged, and the interaction was not considered clinically significant.[148,158] No apparent effects on either R- or S-warfarin concentrations or prothrombin times were noted during concomitant dosing of levofloxacin, trovafloxacin, sparfloxacin, moxifloxacin, or gatifloxacin.[14,17,20,23,27,29,38,159,160,161] Although nonsignificant pharmacokinetic or pharmaco-dynamic interactions between fluoroquinolones and warfarin were documented in studies, published case reports that describe such interactions and the potential for significant morbidity compel clinicians to closely monitor anticoagulation of patients receiving concomitant therapy with the agents.

Nonsteroidal Antiinflammatory Drugs. Seizures were reported when enoxacin was given with fenbufen.[162] The mechanism of this potential interaction appears to be potentiation by the nonsteroidal antiinflammatory drug of the competitive inhibition of GABA receptors by fluoroquinolones.[138] Although this interaction between fenbufen and both enoxacin and ciprofloxacin produced convulsions in rats,[163,164] a study in humans failed to find evidence of a significant interaction between ciprofloxacin and fenbufen.[165] Furthermore, no case reports of such an interaction have been published. Thus it does not appear that any interaction between nonsteroidal antiinflammatory drugs and fluoroquinolones, particularly with newer agents, will be clinically significant.[164,166,167,168]

Antiviral Agents. Ciprofloxacin has been associated with an increased frequency of foscarnet-induced convulsions, which also arise through GABA-mediated mechanisms.[169] The significance of this interaction is unknown. Concomitant administration of levofloxacin and zidovudine was not associated with significant alterations in the pharmacokinetics of either agent.[170] The absorption of ciprofloxacin was also adversely effected (26-29% decrease in plasma Cmax and AUC) when ciprofloxacin was administered concomitantly with didanosine, an antiretroviral drug that is formulated with an aluminum carbonate and magnesium hydroxide buffer.[171] Other fluoroquinolones should be considered to interact with didanosine in this manner, and concomitant administration should be avoided.

Other Drugs. Ciprofloxacin caused an increase in serum phenytoin concentrations when administered with phenytoin. Clinical evidence of toxicity also was reported when the agents were administered concurrently.[148,172]

Both ciprofloxacin and norfloxacin decreased clearance and increased serum concentrations of cyclosporine.[148,173] Ciprofloxacin also enhanced cyclosporine-induced nephrotoxicity, possibly as a result of an increase in the concentration of cyclosporine[148]; ciprofloxacin also was associated with increased rejection rates in renal transplant recipients, the causes of which are unknown.[174] Administration of trovafloxacin did not signifi-cantly alter the pharmacokinetics of cyclosporine.[27] Whether a significant interaction truly exists between cyclosporine and ciprofloxacin or other fluoroquinolones is unknown.

Trovafloxacin bioavailability and Cmax were reduced by 36% and 46%, respectively, when the antibiotic was coadministered intravenously with morphine; the time to Cmax of trovafloxacin was also prolonged.[175] Whether this interaction results in decreased concentrations of other fluoroquinolones is unknown.

The fluoroquinolones are increasingly administered to treat mycobacterial infections. Reports suggest that significant interactions may exist between certain fluoroquinolones and some antimycobacterial drugs, specifically rifampin, pyrazinamide, and cycloserine. Rifampin, a well-known inducer of hepatic CYP enzymes, increased the metabolism of grepafloxacin, resulting in potentially subtherapeutic fluoroquinolone serum concentrations.[176] Pyrazinamide and cycloserine interacted with ofloxacin, with a resulting increase in CNS toxicities with cycloserine and poor tolerability with pyrazinamide.[177,178] Although the significance of these interactions is controversial, caution is advised when prescribing the drugs in combination.[179] Fluoroquinolones that are primarily excreted renally or that are associated with a low frequency of CNS adverse effects may be preferred for treatment of mycobacterial infections; however, in light of the controversial nature of interactions, the primary consideration in fluoroquinolone selection should still be clinical experience and proven efficacy for the indication.

Although fluoroquinolones were occasionally implicated in causing increased serum concen-trations of digoxin, studies of levofloxacin, trovafloxacin, and sparfloxacin all failed to find a significant alteration in digoxin pharmaco-kinetics.[27,156,180,181] No clinically significant interactions were observed after coadministration of digoxin and moxifloxacin.[38] However, concurrent digoxin and gatifloxacin led to modest increases in digoxin's Cmax and AUC values; significant increases in digoxin concentrations were observed for several patients.[156] Although the clinical significance of this interaction is unclear, patients receiving the drugs together should be closely monitored. In addition, ofloxacin was reported to cause decreases in plasma clearance and increases in AUC and Cmax of procainamide by 22-27%; the mechanism of these effects is presumably decreased renal tubular secretion of procainamide.[182]

The potential for a significant interaction between gatifloxacin and glyburide was evaluated in 34 patients with non-insulin-dependent diabetes mellitus.[183] No pharmacokinetic interactions and no adverse effects on patients' glucose tolerance or insulin concentrations were observed.

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