LODOCO

Clinical summary

Indications and usage 1. INDICATION AND USAGE LODOCO is indicated to reduce the risk of myocardial infarction (MI), stroke, coronary revascularization, and cardiovascular death in adult patients with established atherosclerotic disease or with multiple risk factors for cardiovascular disease. LODOCO is an alkaloid indicated: • to reduce the risk of myocardial infarction (MI), stroke, coronary revascularization, and cardiovascular death in adult patients with established atherosclerotic disease or with multiple risk factors for cardiovascular disease ( 1 ). Dosage and administration 2. DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage The recommended dosage is 0.5 mg orally once daily. If a dose of LODOCO is missed, the missed dose should be taken as soon as possible, and the patient should then return to the normal dosing schedule. If a dose is skipped, the patient should not double the next dose. The recommended dosage is 0.5 mg orally once daily ( 2.1 ). Warnings and cautions 5. WARNINGS AND PRECAUTIONS 5.1 Blood Dyscrasias LODOCO can cause myelosuppression, leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, and aplastic anemia, which can be life-threatening or fatal [see Adverse Reactions (6)] . Gastrointestinal symptoms often are the first sign of colchicine toxicity, so new symptoms should prompt an evaluation for toxicity. Concomitant use of drugs that reduce the metabolism of colchicine or the presence of hepatic or renal impairment increases the risk of developing blood dyscrasias. Use of LODOCO in patients with pre-existing blood dyscrasias, renal failure (Creatinine clearance less than 15 mL/minute), or severe hepatic dysfunction, and concomitant use of strong CYP3A4 inhibitors or P-glycoprotein inhibitors is contraindicated [see Contraindications (4)] . Concomitant use of moderate CYP3A4 inhibitors with LODOCO should be avoided in patients with risk factors for increased systemic exposure of colchicine. Monitor patients with any degree of renal impairment and hepatic impairment for colchicine toxicity [see Use in Specific Populations (8.6, 8.7)] . 5.2 Neuromuscular Toxicity LODOCO can cause neuromuscular toxicity and rhabdomyolysis. Concomitant use of drugs that reduce the metabolism of colchicine or the presence of hepatic or renal impairment increases the risk of developing neuromuscular toxicity. Gastrointestinal symptoms often are the first sign of colchicine toxicity, so new symptoms should prompt evaluation for toxicity. Use of LODOCO in patients with renal failure (Creatinine clearance less than 15 mL/minute), or severe hepatic dysfunction, and concomitant use of strong CYP3A4 inhibitors or P-glycoprotein inhibitors is contraindicated [see Contraindications (4)] . Concomitant use of moderate CYP3A4 inhibitors with LODOCO should be avoided in patients with risk factors for increased systemic exposure of colchicine [see Use in Specific Populations (8.6, 8.7) and Drug Interactions (7)] . If a patient develops signs of neuromuscular toxicity, discontinue LODOCO, investigate other causes, and treat appropriately. Concomitant use of LODOCO and HMG CoA reductase inhibitors, gemfibrozil, and fenofibric acid or cyclosporine may potentiate the development of myopathy [see Drug interactions (7)] . Monitor patients with any degree of renal and hepatic impairment for adverse effects of LODOCO. • Blood dyscrasias : myelosuppression, leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, and aplastic anemia have been reported ( 5.1 ). • Neuromuscular toxicity : Myotoxicity including rhabdomyolysis may occur, especially in combination with other drugs known to cause this effect. Consider temporary interruption or discontinuation of LODOCO ( 5.2 ). Drug interactions 7. DRUG INTERACTIONS Colchicine is a substrate for the efflux transporter P-glycoprotein (P-gp). CYP3A4 is the primary enzyme involved in the metabolism of colchicine. If LODOCO is administered with drugs that inhibit P-gp, most of which also inhibit CYP3A4, increased concentrations of colchicine are likely (Table 1). Table 1: Drug Interactions Drug class Outcome/effect Clinical comment Strong CYP3A4 Inhibitors † atazanavir clarithromycin darunavir/ritonavir indinavir itraconazole ketoconazole lopinavir/ritonavir nefazodone nelfinavir ritonavir saquinavir telithromycin tipranavir/ritonavir Significant increases in colchicine plasma levels [see Clinical Pharmacology (12.3)] . Concomitant use of LODOCO with strong CYP3A4 inhibitors is contraindicated [see Contraindications (4)] . Moderate CYP3A4 Inhibitors amprenavir aprepitant diltiazem erythromycin fluconazole, fosamprenavir (prodrug of amprenavir) verapamil Significant increase in colchicine plasma concentration is anticipated. Monitor patients receiving moderate CYP3A4 inhibitors for signs of colchicine toxicity. Avoid use in patients with existing renal or hepatic impairment [see Warnings and Precautions (5)] . Grapefruit grapefruit juice Grapefruit juice increases exposu