Drug Interactions between colchicine and letrozole / ribociclib

ADJUST DOSE: 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: Caution is advised if colchicine is prescribed in combination with moderate CYP450 3A4 inhibitors. In patients with normal renal and hepatic function, the dosage of colchicine should be reduced when used with moderate CYP450 3A4 inhibitors or within 14 days of using them. For the treatment of acute gout flares, the adjusted dosage recommended is 1.2 mg for one dose. Administration should not be repeated for at least three days. For the prophylaxis of gout flares, the adjusted dosage should be 0.3 mg twice a day (or 0.6 mg once a day) if the original regimen was 0.6 mg twice a day, and 0.3 mg once a day if the original regimen was 0.6 once a day. For the treatment of familial Mediterranean fever, the maximum dosage of colchicine is 1.2 mg/day (may be given as 0.6 mg twice a day) when used in the presence of moderate CYP450 3A4 inhibitors. Other significant inhibitors of CYP450 3A4 include amiodarone, dronedarone, imatinib, posaconazole, and quinupristin-dalfopristin, although the extent to which they may interact with colchicine is unknown. A similar dosage adjustment may be required. 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.

MONITOR: Coadministration with ribociclib may increase the plasma concentrations and pharmacologic effects of drugs that are substrates of CYP450 3A4. The proposed mechanism is decreased clearance due to ribociclib-mediated inhibition of CYP450 3A4 metabolism. In healthy study subjects, administration of midazolam, a sensitive CYP450 3A4 substrate, with multiple 400 mg daily doses of ribociclib increased the midazolam peak plasma concentration (Cmax) and systemic exposure (AUC) by 2.1-fold and 3.8-fold, respectively, compared to midazolam administered alone. When given at a clinically relevant dose of 600 mg daily, ribociclib is predicted to increase midazolam Cmax and AUC by 2.4-fold and 5.2-fold, respectively.

MANAGEMENT: Caution is advised when ribociclib is used concomitantly with drugs that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ribociclib is added to or withdrawn from therapy.