Drug Interaction Report

MONITOR: Coadministration with fostamatinib may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme and/or P-glycoprotein (P-gp) transporter. The proposed mechanism is decreased clearance in the intestine and/or liver due to inhibition of CYP450 3A4-mediated metabolism and P-gp-mediated efflux by fostamatinib. According to the product labeling, administration of a single 40 mg dose of the CYP450 3A4 substrate simvastatin with fostamatinib 100 mg twice daily increased simvastatin peak plasma concentration (Cmax) and systemic exposure (AUC) by 113% and 64%, respectively. In addition, simvastatin acid Cmax increased by 83% and AUC increased by 64%. When the P-gp substrate digoxin (0.25 mg once daily) was administered with fostamatinib (100 mg twice daily), digoxin Cmax and AUC increased by 70% and 37%, respectively.

MANAGEMENT: Caution is advised when fostamatinib is used concurrently with drugs that are known substrates of CYP450 3A4 and/or P-gp, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever fostamatinib is added to or withdrawn from therapy.

MONITOR: Coadministration with fostamatinib may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme and/or P-glycoprotein (P-gp) transporter. The proposed mechanism is decreased clearance in the intestine and/or liver due to inhibition of CYP450 3A4-mediated metabolism and P-gp-mediated efflux by fostamatinib. According to the product labeling, administration of a single 40 mg dose of the CYP450 3A4 substrate simvastatin with fostamatinib 100 mg twice daily increased simvastatin peak plasma concentration (Cmax) and systemic exposure (AUC) by 113% and 64%, respectively. In addition, simvastatin acid Cmax increased by 83% and AUC increased by 64%. When the P-gp substrate digoxin (0.25 mg once daily) was administered with fostamatinib (100 mg twice daily), digoxin Cmax and AUC increased by 70% and 37%, respectively.

MANAGEMENT: Caution is advised when fostamatinib is used concurrently with drugs that are known substrates of CYP450 3A4 and/or P-gp, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever fostamatinib is added to or withdrawn from therapy.

GENERALLY AVOID: Coadministration with grapefruit juice is likely to increase the plasma concentrations of tadalafil, which is primarily metabolized by CYP450 3A4. However, the interaction has not been studied. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit.

MONITOR: Additive hypotensive effects may occur when phosphodiesterase-5 (PDE5) inhibitors such as tadalafil are used with alcohol, as both are mild systemic vasodilators. In clinical pharmacology studies, more subjects administered alcohol at a dose of 0.7 g/kg (equivalent to approximately 6 ounces of 80-proof vodka in an 80-kg male; consumed within 10 minutes in study subjects, providing blood alcohol levels of 0.08%) in combination with tadalafil 10 or 20 mg single doses had clinically significant decreases in blood pressure than with alcohol alone. There were reports of postural dizziness, and orthostatic hypotension was observed in some. When tadalafil 20 mg was administered with alcohol at a lower dose of 0.6 g/kg (equivalent to approximately 4 ounces of 80-proof vodka in an 80-kg male), orthostatic hypotension was not observed, dizziness occurred with similar frequency relative to alcohol alone, and the hypotensive effects of alcohol were not potentiated. Neither tadalafil nor alcohol affected the plasma concentrations of the other.

MANAGEMENT: Caution is recommended with concurrent consumption of large amounts of alcohol in patients taking tadalafil as it may increase the potential for orthostatic signs and symptoms, such as increase in heart rate, decrease in standing blood pressure, dizziness, and headache. It may also be appropriate to avoid consuming large amounts of grapefruit juice.