Drug Interaction Report

MONITOR: Probiotic use during immunosuppressant or intense antineoplastic therapy may theoretically increase the risk of infections from the live microorganisms contained in probiotic products. Patients may be immunosuppressed if they have recently received or are receiving alkylating agents, antimetabolites, radiation, some antirheumatic agents, high dosages of corticosteroids or adrenocorticotropic agents, or long-term topical or inhaled corticosteroids. Although probiotics are generally considered safe, with minimal to low pathogenicity, infections such as bacteremia and endocarditis with various strains commonly found in probiotics (e.g., lactobacilli, bifidobacteria, Bacillus subtilis) have been rarely reported, primarily in critically ill patients or patients with significant underlying medical conditions such as malignancy, organ transplantation, AIDS, valvular heart disease, diabetes mellitus, recent surgery, or compromised immune system. Lactobacillus bacteremia has also been reported following endoscopy. In addition, cases of lactobacillus pneumonia and liver abscess, as well as Saccharomyces fungemia, pneumonia, liver abscess, peritonitis and vaginitis, have been described in the medical literature.

MANAGEMENT: Caution is advised when probiotics are used during immunosuppressant or intense antineoplastic therapy. It may be advisable to avoid using probiotics, particularly products containing saccharomyces boulardii, in patients who are significantly immunosuppressed unless benefits are anticipated to outweigh the potential risk of infection.

GENERALLY AVOID: Coadministration with grapefruit, grapefruit juice, or Seville oranges may significantly increase the plasma concentrations of ibrutinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Pharmacokinetic modeling suggests that other moderate CYP450 3A4 inhibitors such as diltiazem and erythromycin may increase ibrutinib systemic exposure (AUC) by 6- to 9-fold under fasting condition. The safety and efficacy of these exposures are unknown. The highest ibrutinib dose evaluated in clinical trials was 12.5 mg/kg (actual doses of 840 to 1400 mg) given for 28 days, which yielded single dose AUC values that were approximately 50% greater than steady-state exposures seen at the highest indicated dose of 560 mg.

ADJUST DOSING INTERVAL: Food increases the oral bioavailability of ibrutinib. The mechanism of interaction is unknown. According to the product labeling, administration with food increases ibrutinib exposure approximately 2-fold compared to administration after overnight fasting.

MANAGEMENT: Patients treated with ibrutinib should avoid consumption of Seville oranges, grapefruit, grapefruit juice, and any supplement containing grapefruit extract. Ibrutinib should be taken once daily at approximately the same time each day.

GENERALLY AVOID: Use of anticholinergic agents with alcohol may result in sufficient impairment of attention so as to render driving and operating machinery more hazardous. In addition, the potential for abuse may be increased with the combination. The mechanism of interaction is not established but may involve additive depressant effects on the central nervous system. No effect of oral propantheline or atropine on blood alcohol levels was observed in healthy volunteers when administered before ingestion of a standard ethanol load. However, one study found impairment of attention in subjects given atropine 0.5 mg or glycopyrrolate 1 mg in combination with alcohol.

MANAGEMENT: Alcohol should generally be avoided during therapy with anticholinergic agents. Patients should be counseled to avoid activities requiring mental alertness until they know how these agents affect them.