Drug Interactions between amoxicillin / clarithromycin / omeprazole and colchicine

GENERALLY AVOID: Coadministration of colchicine with clarithromycin may significantly increase the serum concentrations of colchicine. The proposed mechanism is inhibition of the CYP450 3A4-mediated metabolism and P-glycoprotein (P-gp)-mediated transport of colchicine by clarithromycin. Clinical toxicity including myopathy, neuropathy, multiorgan failure, and pancytopenia may occur. A case report describes two fatal cases of agranulocytosis due to presumed interaction between colchicine and clarithromycin, one in a patient with mild liver function test abnormalities and the other in a patient with end-stage renal failure. 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 clarithromycin should generally be avoided if possible. Otherwise, caution is advised. Coadministration of colchicine with clarithromycin in patients with renal or hepatic impairment is considered contraindicated. 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. For the treatment of acute gout flares, the recommended dosage 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, paraesthesia, and numbness.

Although some in vitro data indicate synergism between macrolide antibiotics and penicillins, other in vitro data indicate antagonism. When these drugs are given together, neither has predictable therapeutic efficacy. Data are available for erythromycin, although theoretically this interaction could occur with any macrolide. Except for monitoring of the effectiveness of antibiotic therapy, no special precautions appear to be necessary.

Clarithromycin may increase and prolong the omeprazole plasma concentration. The mechanism may be related to clarithromycin inhibition of hepatic cytochrome P450 enzymes responsible for omeprazole metabolism. Coadministration of omeprazole may result in an increase in clarithromycin and 14-(R)-hydroxyclarithromycin plasma concentrations. These increases may be due to the effect of omeprazole on gastric pH.