A Guide To Drug-Drug Interactions In Podiatry

Robert G. Smith, DPM, MSc, RPh, CPed

   If alternative agents are not appropriate, then one should monitor the patient for evidence of myopathy (muscle pain or weakness) and myoglobinuria (dark urine). Temporarily stopping simvastatin/lovastatin during the short-term itraconazole therapy is a reasonable alternative as long as patients keep their primary care providers informed of the drug regimen. Alternative statin agents like fluvastatin (Lescol, Novartis), rosuvastatin (Crestor, AstraZeneca) or even pravastatin (Pravachol, Bristol-Myers Squibb) may prove beneficial in patients who need long-term therapy of itraconazole.

   All “azoles” inhibit the CYP3A4 isoenzyme.16 Yu and colleagues reported the potential fluconazole drug interactions were very frequent among hospitalized patients on systemic azole antifungal therapy, but they had few apparent clinical consequences.17 The authors reported that among the 4,185 admissions who took azole agents (fluconazole, itraconazole or ketoconazole), 2,941 (70.3 percent) admissions experienced potential azole–drug interactions. This included 2,716 (92.3 percent) patients who experienced fluconazole interactions.

   The most frequent interactions with potential moderate to major severity were co-administration of fluconazole with prednisone (25.3 percent), midazolam (Dormicum, Roche) (17.5 percent), warfarin (14.7 percent), methylprednisolone (Medrol, Pfizer) (14.1 percent), cyclosporine (Gengraf, Abbott Laboratories) (10.7 percent) and nifedipine (Adalat, Bayer HealthCare) (10.1 percent).17 Fluconazole causes an increase of phenobarbital (Solfoton) and phenytoin (Dilantin, Pfizer) levels in the blood when patients take it concurrently with these anti-seizure agents.18

   Itraconazole appears to increase the bioavailability of digoxin (Lanoxin, GlaxoSmithKline) and/or reduce the renal and non-renal clearance of digoxin by inhibiting P-glycoprotein (PGP). Digoxin toxicity may occur when one uses it in combination with itraconazole.19 P-glycoprotein is an efflux transporter found in the small intestine, kidney, liver and brain. To manage this interaction, the preferred management strategy is to use an alternative antifungal that does not inhibit P-glycoprotein.

   Digoxin toxicity may occur when one uses it in combination with clarithromycin (Biaxin, Abbott Laboratories). Clarithromycin, a macrolide, enhances the absorption of digoxin and/or reduces its elimination by inhibiting PGP transport of digoxin.20 To manage this interaction, the preferred management strategy is to use an alternative antibiotic, preferably an anti-infective that does not inhibit PGP.

   Warfarin is an anticoagulant racemic mixture of S- and R-warfarin enantiomers. The metabolism of these enantiomers is by different CYPs. S-warfarin is primarily metabolized by CYP2C9 and R-warfarin is metabolized by CYP1A2, CYP2C19 and CYP3A4. Fluconazole causes a dose-related inhibition of the metabolism by CYP2C9 and increases warfarin concentration and bleeding risk.21

   Monitor carefully for an altered warfarin response if the patient starts on an interacting “azole antifungal,” stops taking it or changes dosage. Inhibition of warfarin metabolism by CYPC9 and resulting bleeding risk can occur with sulfamethoxazole/trimethoprim (Bactrim, Roche) and metronidazole (Flagyl, Pfizer).21 Researchers have reported that quinolones and macrolides increase the anticoagulant effects of warfarin.21 Oral penicillin, amoxicillin (Amoxil, GlaxoSmithKline), ampicillin, oral cephalosporins and penicillins have not been shown to interact with warfarin. These agents are considered preferred alternatives. In those cases when alternatives are not appropriate, carefully monitor the international normalized ratio (INR) and check for signs of bleeding.

NSAIDs And Drug Interactions: What You Should Know

All NSAIDs, with the possible exception of nabumetone (Relafen, GlaxoSmithKline), affect platelet aggregation and can increase bleeding, thereby affecting anticoagulant therapy. The interaction between warfarin and NSAIDs is considered pharmacodynamic in nature with an additive risk of bleeding related to the antiplatelet effects and gastrointestinal erosion associated with NSAIDs and the anticoagulant effect of warfarin.

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