Colchicine: uses, appearance and warnings

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 ).

Tablets: 0.5 mg - White to slightly yellow, round, biconvex tablets, debossed with ‘L1’ on one side and plain on the other side. Tablets: 0.5 mg ( 3 ).

16.1 How Supplied LODOCO (colchicine) tablets 0.5 mg are white to slightly yellow, round, and biconvex and debossed with ‘L1’ on one side and plain on the other side and they are available as a single Aluminum/PVC blister pack of 30 tablets, which is secondary packaged in a carton: NDC 82867-001-01. 16.2 Storage Store LODOCO at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F), [See USP Controlled Room Temperature]. Store LODOCO tablets in the original package in order to protect from light.

Concurrent use of strong CYP3A4 inhibitors or P-glycoprotein inhibitors with LODOCO is contraindicated, because life-threatening and fatal colchicine toxicity has been reported in these patients with colchicine taken in therapeutic doses [see Drug interactions (7)] . LODOCO use is contraindicated in patients with renal failure (Creatinine clearance less than 15 mL/minute) and severe hepatic impairment. LODOCO is contraindicated in patients with pre-existing blood dyscrasias and in patients hypersensitive to this drug or any inactive ingredient of LODOCO [see Description (11)] . • Concurrent use of strong CYP3A4 inhibitors or P-gp inhibitors with LODOCO is contraindicated, including in patients with hepatic or renal impairment ( 4 ). • LODOCO is contraindicated in patients with pre-existing blood dyscrasias, renal failure, and severe hepatic impairment ( 4 ).

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 ).

6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice. In the LoDoCo2 trial, myalgia was reported for 21.2% of individuals randomized to colchicine and 18.5% of individuals randomized to matching placebo (hazard ratio 1.15, 95%CI 1.01-1.31). 6.2 Postmarketing Experience The following adverse reactions have been identified with colchicine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or establish a causal relationship to drug exposure. …

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)] . …