Drug Interaction Report

MONITOR: The use of fumaric acid esters in combination with medications that can cause nephrotoxicity (e.g., aminoglycosides, diuretics, nonsteroidal anti-inflammatory drugs, cyclosporine, lithium, methotrexate) may increase the potential for adverse renal reactions. In clinical trials in patients with multiple sclerosis treated with dimethyl fumarate, a fumaric acid ester that is converted to the active metabolite monomethyl fumarate, adverse events of proteinuria were reported at slightly higher frequencies than in patients receiving placebo. The clinical significance of these observations is unknown. Cases of Fanconi syndrome have been reported for a medicinal product containing dimethyl fumarate in combination with other fumaric acid esters. Renal toxicity, including tubular changes and/or interstitial fibrosis, has been observed in animal studies with dimethyl fumarate and diroximel fumarate.

MANAGEMENT: The use of fumaric acid esters in patients who receive concomitant treatment with potentially nephrotoxic agents, particularly for longer durations, has not been evaluated and should be approached with caution. Assessment of renal function (e.g., serum creatinine, blood urea nitrogen, urinalysis) is recommended prior to initiating treatment with fumaric acid esters and as clinically indicated during treatment.

GENERALLY AVOID: Theoretically, grapefruit and grapefruit juice may increase the plasma concentrations of hydroxychloroquine or chloroquine and the risk of toxicities such as QT interval prolongation and ventricular arrhythmias. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall induced by certain compounds present in grapefruit. Following coadministration with cimetidine, a weak to moderate CYP450 3A4 inhibitor, a 2-fold increase in chloroquine exposure occurred. Since chloroquine and hydroxychloroquine have similar structures and metabolic elimination pathways, a similar interaction may be observed with hydroxychloroquine. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict.

ADJUST DOSING INTERVAL: Administration with food or milk may reduce the incidence of hydroxychloroquine-related gastrointestinal adverse effects.

MANAGEMENT: Although clinical data are lacking, it may be advisable to avoid the consumption of grapefruit, grapefruit juice, and any supplement containing grapefruit extract during hydroxychloroquine or chloroquine therapy. Hydroxychloroquine should be administered with food or milk to reduce the occurrence of gastrointestinal upset.