Drug Interaction Report

MONITOR: Thalidomide can cause peripheral neuropathy, and concurrent use of other agents that are also associated with this adverse effect can potentiate the risk and/or severity of nerve damage. Peripheral neuropathy is a common, potentially severe side effect of thalidomide that may be irreversible. The condition generally occurs following chronic use over a period of months, although there have also been reported cases following relatively short-term use. The median time to first neuropathy event was 42.3 weeks in one phase 3 study. Occasionally, symptoms may occur some time after thalidomide treatment has been discontinued. The incidence of neuropathy requiring thalidomide discontinuation, dosage reduction, or interruption increases with cumulative dose and duration of therapy.

MANAGEMENT: Caution is advised if thalidomide is used in combination with other neurotoxic agents. All patients treated with thalidomide should be examined at monthly intervals for the first three months of therapy and periodically thereafter to detect early signs of neuropathy such as burning, tingling, pain, or numbness in the hands and feet. Electrophysiological testing may be performed at baseline and every six months during therapy to detect asymptomatic neuropathy. Consideration should be given to immediate discontinuation of thalidomide in patients who develop peripheral neuropathy to limit further damage. Symptoms may improve or return to baseline in some patients upon discontinuation of thalidomide, although the complete time course of this toxicity has not been fully characterized. If necessary, therapy should generally be reinstituted only after neuropathy returns to baseline status. A dosage reduction of thalidomide may be required as clinically indicated.

GENERALLY AVOID: Coadministration with grapefruit juice may increase the serum concentrations of colchicine. Clinical toxicity including myopathy, neuropathy, multiorgan failure, and pancytopenia may occur. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism and P-glycoprotein efflux in the gut wall by certain compounds present in grapefruits. A published case report describes an eight-year-old patient with familial Mediterranean fever who developed acute clinical colchicine intoxication after ingesting approximately one liter of grapefruit juice per day for two months prior to hospital admission while being treated with colchicine 2 mg/day. Her condition progressed to circulatory shock and multiorgan failure, but she recovered with supportive therapy after 24 days in the hospital. In a study of 21 healthy volunteers, administration of 240 mL grapefruit juice twice a day for 4 days was found to have no significant effect on the pharmacokinetics of a single 0.6 mg dose of colchicine. However, significant interactions have been reported with other CYP450 3A4 inhibitors such as clarithromycin, diltiazem, erythromycin, ketoconazole, ritonavir, and verapamil.

MANAGEMENT: Patients treated with colchicine should be advised to avoid the consumption of grapefruit and grapefruit juice, and to contact their physician if they experience symptoms of colchicine toxicity such as abdominal pain, nausea, vomiting, diarrhea, fatigue, myalgia, asthenia, hyporeflexia, paresthesia, and numbness.

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.