Drug Interactions between amoxicillin / clarithromycin / lansoprazole and hydroxychloroquine

GENERALLY AVOID: Coadministration with strong CYP450 3A4 or 2D6 inhibitors may significantly increase the plasma concentration and effects of hydroxychloroquine (HCQ), which is partially metabolized by the isoenzymes. Following coadministration with cimetidine, a weak to moderate CYP450 3A4 inhibitor and weak CYP450 2D6 inhibitor, a 2-fold increase in chloroquine exposure occurred. Because chloroquine and hydroxychloroquine have similar structures and metabolic elimination pathways, a similar interaction could be observed for hydroxychloroquine. The risk of QT prolongation may be further increased with concomitant use of strong CYP450 3A4 inhibitors (e.g., ceritinib, clarithromycin, mifepristone, saquinavir, telithromycin, some azole antifungals) or strong CYP450 2D6 inhibitors (e.g., fluoxetine) that are also known to prolong the QT interval. No data are available for more potent CYP450 3A4 or 2D6 inhibitors that also prolong the QT interval.

MANAGEMENT: Coadministration of hydroxychloroquine with strong CYP450 3A4 or CYP450 2D6 inhibitors that can prolong the QT interval should generally be avoided, particularly in patients with baseline QT prolongation (e.g., QTc greater than or equal to 500 msec) or congenital long QT syndrome. If concomitant use is required and benefits are anticipated to outweigh the risks, close monitoring of the QTc interval, electrolyte levels, and renal and hepatic function is recommended, and the dose adjusted as necessary whenever strong CYP450 3A4 or 2D6 inhibitor is added to or withdrawn from therapy. Electrolyte abnormalities should be corrected prior to initiating treatment with hydroxychloroquine. Patients should be advised to seek immediate medical attention if they experience symptoms of torsades de pointes (e.g., dizziness, fainting, palpitations, irregular heart rhythm, or syncope) or symptoms of other serious hydroxychloroquine-related adverse effects such as severe cutaneous adverse drug reactions (SCARs), renal or liver toxicity, hematologic toxicities, myopathy or neuropathy, retinopathy, neuropsychiatric symptoms, gastrointestinal distress, hypoglycemia, or heart failure. Because hydroxychloroquine is eliminated slowly from the body (terminal half-life: 40-50 days), potential drug interactions may persist for several weeks to months after its discontinuation.

MONITOR: Coadministration with clarithromycin may increase the plasma concentrations of lansoprazole. The proposed mechanism is clarithromycin inhibition of intestinal (first-pass) and hepatic metabolism of lansoprazole via CYP450 3A4. Although lansoprazole is primarily metabolized by CYP450 2C19 in the liver, 3A4-mediated metabolism is the predominant pathway in individuals who are 2C19-deficient (approximately 3% to 5% of the Caucasian and 17% to 20% of the Asian population). Additionally, inhibition of P-glycoprotein intestinal efflux transporter by clarithromycin may also contribute to the interaction, resulting in increased bioavailability of lansoprazole. In 18 healthy volunteers--six each of homozygous extensive metabolizers (EMs), heterozygous EMs, and poor metabolizers (PMs) of CYP450 2C19--clarithromycin (400 mg orally twice a day for 6 days) increased the peak plasma concentration (Cmax) of a single 60 mg oral dose of lansoprazole by 1.47, 1.71- and 1.52-fold, respectively, and area under the concentration-time curve (AUC) by 1.55-, 1.74- and 1.80-fold, respectively, in each of these groups compared to placebo. The AUC ratio of lansoprazole to lansoprazole sulphone, which is considered an index of CYP450 3A4 activity, was significantly increased by clarithromycin in all three groups. However, elimination half-life of lansoprazole was prolonged by 1.54-fold only in PMs. Mild diarrhea was reported in two subjects and mild abdominal disturbance in six subjects during clarithromycin coadministration. These side effects continued until day 6 and ameliorated the day after discontinuation of clarithromycin, whereas no adverse events were reported during placebo administration or after lansoprazole plus placebo. In another study, clarithromycin induced dose-dependent increases in the plasma concentration of lansoprazole in a group of 20 patients receiving treatment for H. pylori eradication. Mean 3-hour plasma lansoprazole concentration was 385 ng/mL for the control subjects who received lansoprazole 30 mg and amoxicillin 750 mg twice a day for 7 days; 696 ng/mL for patients coadministered clarithromycin 200 mg twice a day; and 947 ng/mL for patients coadministered clarithromycin 400 mg twice a day.

MANAGEMENT: Although lansoprazole is generally well tolerated, caution may be advised during coadministration with clarithromycin, particularly if higher dosages of one or both drugs are used. Dosage adjustment may be necessary in patients who experience excessive adverse effects of lansoprazole.

Although some in vitro data indicate synergism between macrolide antibiotics and penicillins, other in vitro data indicate antagonism. When these drugs are given together, neither has predictable therapeutic efficacy. Data are available for erythromycin, although theoretically this interaction could occur with any macrolide. Except for monitoring of the effectiveness of antibiotic therapy, no special precautions appear to be necessary.