Drug Interactions between itraconazole and Mitigare

GENERALLY AVOID: Coadministration with inhibitors of CYP450 3A4 may significantly increase the serum concentrations of colchicine, which is primarily metabolized by the isoenzyme. Clinical toxicity including myopathy, neuropathy, multiorgan failure, and pancytopenia may occur. In one case report, a patient with familial Mediterranean fever and amyloidosis involving the kidney, liver, and gastrointestinal tract was admitted to the hospital with life-threatening colchicine toxicity after a two-week course of erythromycin, a moderate CYP450 3A4 inhibitor. During the year prior to admission, the patient had developed recurrent diarrhea and abdominal pain and demonstrated toxic levels of colchicine on two occasions. It is likely the patient had acute colchicine toxicity brought on by the addition of erythromycin and superimposed on chronic colchicine intoxication secondary to renal and hepatic impairment. The patient improved with supportive therapy and intensive hemodialysis and was discharged on day 70 of hospitalization. Another report describes two fatal cases of agranulocytosis due to presumed interaction between colchicine and clarithromycin, a potent CYP450 3A4 inhibitor. Risk factors include mild liver function test abnormalities in one patient and end-stage renal failure in the other. Several other cases of suspected interaction with clarithromycin have also been reported in which patients developed rhabdomyolysis, pancytopenia, or neuromyopathy during treatment with colchicine. In most cases, concomitant risk factors such as preexisting renal and/or hepatic impairment were present. In a retrospective study of 116 patients who were prescribed clarithromycin and colchicine during the same hospital admission, 9 out of 88 patients (10.2%) who received the two drugs concomitantly died, compared to only 1 of 28 patients (3.6%) who received the drugs sequentially. The rate of pancytopenia was 10.2% in the concomitant group versus 0% in the sequential group. Multivariate analysis of the patients who received concomitant therapy found that longer overlapped therapy, the presence of baseline renal impairment, and the development of pancytopenia were independently associated with death. Overall, the risk of death was increased 25-fold in patients who received concomitant therapy and who developed pancytopenia.

MANAGEMENT: Due to the risk of life-threatening and fatal toxicity, concomitant use of colchicine with potent CYP450 3A4 inhibitors should generally be avoided if possible. Otherwise, caution is advised. In patients with normal renal and hepatic function, the dosage of colchicine should be reduced when used with potent CYP450 3A4 inhibitors or within 14 days of using them. Some authorities specify dose adjustment for gout (treatment and prophylaxis) and familial Mediterranean fever. For the treatment of acute gout flares, the recommended dose is 0.6 mg for one dose, followed by 0.3 mg one hour later. Administration should not be repeated for at least three days. For the prophylaxis of gout flares, the adjusted dosage should be 0.3 mg once a day if the original regimen was 0.6 mg twice a day, and 0.3 mg once every other day if the original regimen was 0.6 once a day. For the treatment of familial Mediterranean fever, the maximum dosage of colchicine is 0.6 mg/day (may be given as 0.3 mg twice a day) when used in the presence of potent CYP450 3A4 inhibitors. Patients should be advised to contact their physician if they experience symptoms of toxicity such as abdominal pain, nausea, vomiting, diarrhea, fatigue, myalgia, asthenia, hyporeflexia, paresthesia, and numbness. Coadministration of colchicine with potent CYP450 3A4 inhibitors in patients with renal or hepatic impairment is considered contraindicated. The product labeling for itraconazole states that concomitant use with colchicine is contraindicated in patients with moderate to severe renal or hepatic impairment during and for 2 weeks after treatment with itraconazole; in all other patient's concomitant treatment is not recommended during and 2 weeks after treatment with itraconazole.

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