Drug Interaction Report

MONITOR: Coadministration with vadadustat may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4, CYP450 2C8 and CYP450 2C9 isoenzymes as well as substrates of the organic anion transporter 3 (OAT3). Vadadustat is an inhibitor of CYP450 3A4 and CYP450 2C8 in vitro and an inhibitor of CYP450 2C9 and OAT3 in vivo. A drug interaction study evaluating the effect of vadadustat (600 mg) on the pharmacokinetics of celecoxib, a CYP450 2C9 substrate, showed an increase in peak plasma concentration (Cmax) and systemic exposure (AUC) by 60% and 11%, respectively. In another drug interaction study evaluating the effect of repeat doses of vadadustat (600 mg once daily) on the pharmacokinetics of furosemide, an OAT1/OAT3 substrate, a 2-fold increase in furosemide systemic exposure (AUC) was observed. However, clinical data are not available for vadadustat with CYP450 3A4 or CYP450 2C8 substrates.

MONITOR: Coadministration of vadadustat with drugs that are known to increase the risk of gastrointestinal erosion may increase the risk of gastric or esophageal erosions. Serious erosions, including gastrointestinal bleeding and the need for red blood cell transfusions, were reported during vadadustat clinical trials. Patients with a history of gastrointestinal erosion, peptic ulcer disease, and current tobacco smokers and alcohol drinkers may be at higher risk of gastrointestinal injury.

MANAGEMENT: Caution is advised if vadadustat is coadministered with drugs that are substrates of CYP450 3A4, CYP450 2C8, CYP450 2C9 and/or OAT3 and that also carry a known risk of gastrointestinal erosion including certain NSAIDs (e.g., naproxen, ibuprofen, diclofenac), corticosteroids (e.g., methylprednisolone, prednisolone, prednisone), and certain chemotherapeutic agents (e.g., kinase inhibitors, paclitaxel, docetaxel). Patients should be advised to contact their physician if they develop potential signs and symptoms of gastrointestinal injury such as abdominal pain, hematemesis, trouble swallowing, chest or throat pain, and/or black, tarry stools. Monitoring for other signs and symptoms of increased exposure to the affected substrate should be considered whenever vadadustat is added to or withdrawn from therapy. The prescribing information for concomitant medications may be consulted to assess the benefits versus risks of coadministration, as well as any dosage adjustments that may be required during coadministration and/or following the discontinuation of a CYP450 3A4, CYP450 2C8, CYP450 2C9 and/or OAT3 inhibitor.

ADJUST DOSING INTERVAL: Food may alter the oral bioavailability of cabozantinib. When healthy subjects were given a single 140 mg oral dose with a high-fat meal, cabozantinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 41% and 57%, respectively, relative to administration under fasting conditions. In clinical studies, patients were administered cabozantinib without food.

GENERALLY AVOID: Coadministration with grapefruit juice is likely to increase the plasma concentrations of cabozantinib, 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.

MANAGEMENT: Cabozantinib should be administered at least one hour before or two hours after a meal. The consumption of grapefruit, grapefruit juice, and supplements that contain grapefruit extract should be avoided.

MONITOR: Smoking and alcohol consumption during therapy with vadadustat may increase the risk of gastrointestinal erosions. Serious erosions, including gastrointestinal bleeding and the need for red blood cell transfusions, have been reported during vadadustat clinical trials. Patients with a history of gastrointestinal erosion, peptic ulcer disease, and current tobacco smokers and alcohol drinkers may be at higher risk of gastrointestinal injury.

MANAGEMENT: Caution is advised if vadadustat is prescribed to current tobacco smokers or alcohol drinkers. Patients should be advised to contact their physician if they develop potential signs and symptoms of gastrointestinal injury such as abdominal pain, hematemesis, trouble swallowing, chest or throat pain, and/or black, tarry stools.