Colchicine

5 WARNINGS AND PRECAUTIONS Fatal overdoses have been reported with colchicine in adults and children. Keep colchicine capsules out of the reach of children ( 5.1 , 10 ). Blood dyscrasias : Myelosuppression, leukopenia, granulocytopenia, thrombocytopenia, and aplastic anemia have been reported ( 5.2 ). Monitor for toxicity and if present consider temporary interruption or discontinuation of colchicine ( 5.2 , 5.3 , 5.4 , 6 , 10 ). Drug interaction with dual P-gp and CYP3A4 inhibitors : Co-administration of colchicine with dual P-gp and CYP3A4 inhibitors has resulted in life-threatening interactions and death ( 5.3 , 7 ). Neuromuscular toxicity : Myotoxicity including rhabdomyolysis may occur, especially in combination with other drugs known to cause this effect. Consider temporary interruption or discontinuation of colchicine capsules ( 5.4 , 7 ). 5.1 Fatal Overdose Fatal overdoses, both accidental and intentional, have been reported in adults and children who have ingested colchicine [see Overdosage (10) ] . Colchicine capsules should be kept out of the reach of children. 5.2 Blood Dyscrasias Myelosuppression, leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, and aplastic anemia have been reported with colchicine used in therapeutic doses. 5.3 Interactions with CYP3A4 and P-gp Inhibitors Because colchicine is a substrate for both the CYP3A4 metabolizing enzyme and the P-glycoprotein efflux transporter, inhibition of either of these pathways may lead to colchicine-related toxicity. Inhibition of both CYP3A4 and P-gp by dual inhibitors such as clarithromycin has been reported to produce life-threatening or fatal colchicine toxicity due to significant increases in systemic colchicine levels. Therefore, concomitant use of colchicine capsules and inhibitors of CYP3A4 or Pglycoprotein should be avoided [see Drug Interactions (7) ] . If avoidance is not possible, reduced daily dose should be considered and the patient should be monitored closely for colchicine toxicity. Use of colchicine capsules in conjunction with drugs that inhibit both P-gp and CYP3A4 is contraindicated in patients with renal or hepatic impairment [see Contraindications (4) ] . 5.4 Neuromuscular Toxicity Neuromuscular toxicity and rhabdomyolysis have been reported from chronic treatment with colchicine in therapeutic doses, especially in combination with other drugs known to cause this effect. Patients with impaired renal function and elderly patients (even those with normal renal and hepatic function) are at increased risk. Once colchicine treatment is ceased, the symptoms generally resolve within 1 week to several months.