Drug Interactions between avacopan and chlorpheniramine / dihydrocodeine / phenylephrine

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

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ADJUST DOSING INTERVAL: Food significantly enhances the oral bioavailability of avacopan. When a 30 mg capsule of avacopan was administered with a high-fat, high-calorie meal, avacopan peak plasma concentration (Cmax) and systemic exposure (AUC) increased by approximately 8% and 72%, respectively, while the time to reach peak concentration (Tmax) was delayed by approximately 4 hours (from 2.0 hours to 6.0 hours).

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of avacopan. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit juice, but has been reported for itraconazole, a potent CYP450 3A4 inhibitor. When avacopan was administered with itraconazole (200 mg once daily for 4 days), avacopan peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 1.9-fold and 2.2-fold, respectively. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict. Increased exposure to avacopan may increase the risk and/or severity of serious adverse reactions such as hepatotoxicity and infections.

MANAGEMENT: To ensure maximal oral absorption, avacopan should be administered with food. Patients should preferably avoid or limit consumption of grapefruit, grapefruit juice, or any supplement containing grapefruit extract during avacopan therapy.

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MONITOR: Coadministration of two or more sympathomimetic agents may increase the risk of adverse effects such as nervousness, irritability, and increased heart rate. Central nervous system (CNS) stimulants, particularly amphetamines, can potentiate the adrenergic response to vasopressors and other sympathomimetic agents. Additive increases in blood pressure and heart rate may occur due to enhanced peripheral sympathetic activity.

MANAGEMENT: Caution is advised if two or more sympathomimetic agents are coadministered. Pulse and blood pressure should be closely monitored.

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