Drug Interaction Report

MONITOR: Concomitant use of immunosuppressive or myelosuppressive agents with denosumab may increase the risk of serious infections. Denosumab binds to and inhibits the receptor activator of nuclear factor kappa-B ligand (RANKL), which is expressed on activated T and B lymphocytes and in lymph nodes. Thus, denosumab alone may increase the risk of infections. In a clinical trial of over 7800 women with postmenopausal osteoporosis, the incidence of nonfatal serious infections was 3.3% in the placebo group and 4.0% in the denosumab group. Specifically, hospitalizations due to skin infections including erysipelas and cellulitis (<0.1% placebo vs. 0.4% denosumab) and serious infections in the abdomen (0.7% placebo vs. 0.9% denosumab), urinary tract (0.5% placebo vs. 0.7% denosumab), and ear (0.0% placebo vs. 0.1% denosumab) were reported. Endocarditis was reported in no placebo patients and 3 denosumab-treated patients. There was no difference in the incidence of opportunistic infections or infections resulting in death between the placebo and denosumab groups. The overall incidence of infections was also similar between the two groups.

MANAGEMENT: Caution is advised if denosumab must be used in combination with immuno- or myelosuppressive agents. Patients should be advised to contact their physician if they develop signs and symptoms of infection such as fever, chills, diarrhea, sore throat, muscle aches, shortness of breath, blood in phlegm, weight loss, red or inflamed skin, body sores, and pain or burning during urination. The need for continued denosumab therapy should be assessed when serious infections occur during treatment.

Although they are often combined in clinical practice, the concomitant use of beta-2 adrenergic agonists and corticosteroids may result in additive hypokalemic effects. Since beta-2 agonists can sometimes cause QT interval prolongation, the development of hypokalemia may potentiate the risk of ventricular arrhythmias including torsade de pointes. However, clinical data are limited, and the potential significance is unknown. Patients who are receiving systemic or nebulized formulations of beta-2 agonists, high dosages of inhaled beta-2 agonists, or systemic corticosteroid therapy may be at a greater risk of developing hypokalemia.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations and systemic effects of orally administered budesonide. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. According to the manufacturer, the systemic exposure of oral budesonide approximately doubles after extensive intake of grapefruit juice.

MANAGEMENT: Patients receiving budesonide should avoid the regular consumption of grapefruits and grapefruit juice to prevent undue increases in plasma budesonide levels and systemic effects.

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.