Drug Interactions between amoxicillin / clarithromycin / vonoprazan 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 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. No data are available for other, less potent CYP450 3A4 inhibitors. Theoretically, 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: Caution is advised when selumetinib is coadministered with CYP450 3A4 inhibitors. Dosage adjustments may be required based on clinical response and tolerance. Please refer to the product labeling for specific guidelines on dosing adjustments.

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.