Drug Interactions between amoxicillin / clarithromycin / lansoprazole and selumetinib

GENERALLY AVOID: Coadministration with potent or moderate inhibitors of CYP450 3A4 may increase the plasma concentrations of selumetinib, which is primarily metabolized by CYP450 3A4 and to a lesser extent by CYP450 2C19, 1A2, 2C9, 2E1, and 3A5. Selumetinib also undergoes glucuronidation by UGT1A1 and UGT1A3. When coadministered with itraconazole, a potent CYP450 3A4 inhibitor, selumetinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 19% and 49%, respectively. When coadministered with fluconazole, a potent CYP450 2C19 and moderate CYP450 3A4 inhibitor, selumetinib Cmax and AUC increased by 26% and 53%, respectively. Concomitant use of erythromycin, a moderate CYP450 3A4 inhibitor, is predicted to increase selumetinib Cmax and AUC by 23% and 41%, respectively. Although not studied, inhibition of CYP450 3A4 may also increase the plasma concentrations of N-desmethyl selumetinib, an active metabolite that is generated primarily by CYP450 2C19 and 1A2 and metabolized via the same routes as selumetinib. N-desmethyl selumetinib represents less than 10% of selumetinib levels in human plasma, but is approximately 3 to 5 times more potent than the parent compound and contributes about 21% to 35% of the overall pharmacologic activity. Increased exposures to selumetinib and N-desmethyl selumetinib may increase the risk and/or severity of serious adverse effects such as cardiomyopathy (decrease in left ventricular ejection fraction by 10% or more below baseline), ocular toxicity (blurred vision, photophobia, cataracts, ocular hypertension, retinal pigment epithelial detachment, retinal vein occlusion), gastrointestinal toxicity (diarrhea, colitis), skin toxicity (dermatitis acneiform, maculopapular rash, eczema), and musculoskeletal toxicity (creatine phosphokinase elevations, myalgia, rhabdomyolysis).

MANAGEMENT: Concomitant use of selumetinib with potent or moderate CYP450 3A4 inhibitors should generally be avoided. If coadministration is required, a reduction in the dosage of selumetinib is recommended. Patients receiving selumetinib 25 mg/m2 twice daily should have the dosage reduced to 20 mg/m2 twice daily, and those receiving 20 mg/m2 twice daily should have the dosage reduced to 15 mg/m2 twice daily. Further dosage adjustments should be made according to clinical response and tolerance. Please refer to the product labeling for more detailed information on dosing adjustments. After discontinuation of the strong or moderate CYP450 3A4 inhibitor for 3 elimination half-lives, the selumetinib dosage that was taken prior to initiating the inhibitor may be resumed.

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.

MONITOR: Coadministration with potent or moderate inhibitors of CYP450 2C19 may increase the plasma concentrations of selumetinib, which is primarily metabolized by CYP450 3A4 and to a lesser extent by CYP450 2C19, 1A2, 2C9, 2E1, and 3A5. Selumetinib's active metabolite, N-desmethyl selumetinib, is generated by CYP450 2C19 and 1A2 with additional contribution by CYP450 2C9 and 2A6, and metabolized through the same routes as selumetinib. N-desmethyl selumetinib represents less than 10% of selumetinib levels in human plasma, but is approximately 3 to 5 times more potent than the parent compound, contributing to about 21% to 35% of the overall pharmacologic activity. When coadministered with fluconazole, a potent CYP450 2C19 and moderate CYP450 3A4 inhibitor, selumetinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 26% and 53%, respectively. Concomitant use of fluoxetine, a potent CYP450 2C19 and 2D6 inhibitor, is predicted to increase selumetinib AUC by 30 to 40% and Cmax by 20%. Increased exposures to selumetinib may increase the risk and/or severity of serious adverse effects such as cardiomyopathy (decrease in left ventricular ejection fraction by 10% or more below baseline), ocular toxicity (blurred vision, photophobia, cataracts, ocular hypertension, retinal pigment epithelial detachment, retinal vein occlusion), gastrointestinal toxicity (diarrhea, colitis), skin toxicity (dermatitis acneiform, maculopapular rash, eczema), and musculoskeletal toxicity (creatine phosphokinase elevations, myalgia, rhabdomyolysis).

MANAGEMENT: Caution is advised when selumetinib is used with potent or moderate CYP450 2C19 inhibitors.

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.