4. Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens, which may result in clinically significant drug-drug interactions. Drug-drug interactions considered clinically relevant for oral fluoroquinolones are summarized in Table 5. Only those drug-drug interactions classified as contraindicated or those considered life-threatening which have not yet been classified will be reviewed.

Table 5. Oral Fluoroquinolone Drug-Drug Interactions¹

Target Drug	Interacting Drug	Interaction	Recommendation	Clinical Significance Level#
ciprofloxacin	drugs metabolized by CYP1A2 (e.g., alosetron, caffeine, clozapine, duloxetine, mexiletine, ropinirole, tizanidine)	concurrent administration ciprofloxacin, a known CYP1A2 inhibitor, with drugs metabolized by CYP1A2 may result in increased serum levels of drugs metabolized by CYP1A2 and potentially increased pharmacologic/adverse effects	if combination necessary, monitor for increased adverse effects; alternative FQ that does not affect CYP1A2 enzymes may be considered	contraindicated,  major, moderate (DrugReax) 2-major, 3-moderate (CP)
ciprofloxacin	drugs metabolized by CYP3A4 (flibanserin, lomitapide, lonafarnib	concurrent administration ciprofloxacin, a known CYP3A4 inhibitor, with drugs metabolized by CYP3A4 may result in increased serum levels of drugs metabolized by CYP3A4 and potentially increased pharmacologic/adverse effects	if combination necessary, monitor for increased adverse effects; alternative FQ that does not affect CYP3A4 enzymes may be considered	contraindicated
ciprofloxacin	methotrexate	co-administration may result in reduced methotrexate renal tubular transport and potential for increased methotrexate levels and increased pharmacologic/adverse effects	measure methotrexate concentrations and observe patients for increased adverse effects	moderate (DrugReax) 3-moderate (CP)
ciprofloxacin	mycophenolate	concurrent administration may decrease mycophenolic acid concentrations	monitor response to therapy when ciprofloxacin is started or stopped	moderate (DrugReax) 3-moderate (CP)
ciprofloxacin	phenytoin	concurrent use may result in increased or decreased phenytoin concentrations ; mechanism unknown	measure phenytoin concentrations and observe patients for increased or decreased pharmacologic  effects	moderate (DrugReax) 3-moderate (CP)
ciprofloxacin	phosphodiesterase type 5 (PDE5) inhibitors	concurrent administration may increase PDE5 inhibitor plasma levels and risk of adverse reactions	during coadministration, consider lower dose of PDE5 inhibitor or withholding PDE5 inhibitor in patients at high risk of developing PDE5 inhibitor adverse reactions	moderate (DrugReax)
ciprofloxacin	probenecid	co-administration may result in increased serum ciprofloxacin levels due to probenecid inhibition of renal tubular secretion	monitor patients for increased ciprofloxacin adverse effects	moderate (DrugReax) 4-minor (CP)
ciprofloxacin	theophyllines	adjuvant administration may result in decreased theophylline clearance and potential for increased serum theophylline levels and enhanced pharmacologic/toxic effects as ciprofloxacin interferes with theophylline clearance	if adjunctive therapy necessary, closely monitor theophylline levels and observe for increased adverse effects; may consider alternative FQ that does not interfere with theophylline clearance	major (DrugReax) 3-moderate (CP)
ciprofloxacin	tizanidine (Ziaflex®)	combined administration may result in enhanced tizanidine pharmacologic effects and/or adverse effects (e.g., sedation, hypotension) due to ciprofloxacin inhibition of CYP1A2-mediated tizanidine metabolism	avoid concurrent administration; use alternative spasticity medication	contraindicated  (DrugReax) 1-severe (CP)
fluoroquinolones (FQ)	antacids	simultaneous administration may result in reduced absorption/bioavailability and clinical effectiveness of the FQ due to chelation of the antacid cations with the quinolone molecule	avoid concurrent administration; give FQ 2 hours before or 6 hours after giving antacids; may consider H2 receptor antagonist as alternative to antacids (e.g., ranitidine) in some clinical situations	moderate (DrugReax) 2-major (CP)
FQ	antidiabetic agents	adjunctive administration may result in altered blood glucose levels and increased risk for hypo- or hyperglycemia	monitor serum glucose levels closely with concurrent administration	major (DrugReax) 3-moderate (CP)
FQ	corticosteroids	concurrent therapy may increase risk for tendon rupture, especially in patients over 60 years of age	discontinue FQ therapy with any signs of tendon inflammation or pain	moderate (DrugReax) 3-moderate (CP)
FQ	didanosine (Videx®) oral solution	didanosine buffers consist of magnesium-aluminum cations; concomitant administration with FQ may result in reduced FQ absorption/ bioavailability and clinical effectiveness due to chelation of the antacid cations with the quinolone molecule	avoid concurrent administration; give FQ 2 hours before or 6 hours after giving didanosine	moderate (DrugReax) 2-major (CP)
FQ	iron salts (including iron in multivitamins)	iron salts may bind FQ in GI tract forming insoluble, unabsorbable complexes with resultant reduced FQ serum concentrations/pharmacologic effects	avoid concurrent administration; give FQ 2 hours before or 6 hours after giving drugs containing iron	moderate (DrugReax) 2-major (CP)
FQ	nonsteroidal anti-inflammatory drugs (NSAIDs)	concurrent administration may increase risk of central nervous system (CNS) stimulation and convulsive seizures	administer cautiously together and monitor patients closely for increased CNS adverse effects	moderate (DrugReax) 3-moderate (CP)
FQ	QTc interval-prolonging medications (e.g., class IA, III anti-arrhythmics, tricyclic antidepressants, clozapine, cyclobenzaprine, macrolide antibiotics, cisapride, ziprasidone)	concurrent administration may increase risk of significant cardiotoxicity (e.g., life-threatening arrhythmias, cardiac arrest) as FQ may cause QTc interval prolongation and, rarely, torsades de pointes	adjunctive administration should be avoided	contraindicated, major (DrugReax) 1-severe, 2-major (CP)
FQ	sevelamer (Renagel®)	concurrent administration may cause decreased FQ bioavailability and potential for reduced pharmacologic effects	avoid concurrent administration; administer FQ 1 hour before or 3 hours after sevelamer	moderate (DrugReax) 2-major (CP)
FQ	sucralfate	concurrent administration may result in decreased FQ efficacy due to FQ chelation by sucralfate in GI tract	avoid concurrent administration; give FQ 2 hours before or 6 hours after giving sucralfate	moderate (DrugReax) 2-major (CP)
FQ	warfarin	concomitant administration may result in enhanced hypoprothrombinemic effects and increased bleeding risk;  mechanism of this interaction not identified; changes in PT/INR may occur 2-16 days after addition of FQ to warfarin therapy	if combination cannot be avoided, monitor PT/INR closely and observe for increased adverse effects	major (DrugReax) 2-major (CP)
FQ	zinc salts, calcium	zinc salts or calcium may bind FQ in GI tract forming insoluble, unabsorbable complexes with resultant reduced FQ serum concentrations/ pharmacologic effects	avoid concurrent administration; give FQ 2 hours before or 6 hours after giving drugs containing zinc	moderate (DrugReax)
select FQ (ciprofloxacin, levofloxacin)	cyclosporine	adjunctive administration has resulted in transiently increased serum creatinine levels and/or increased cyclosporine levels	monitor serum creatinine and cyclosporine levels; observe patients for cyclosporine adverse effects	moderate (DrugReax)