LODOCO

LODOCO contains colchicine, which is an alkaloid chemically described as (S)-N-(5,6,7,9-tetrahydro-1,2,3,10-tetramethoxy-9-oxobenzo[a]heptalen-7-yl)acetamide with a molecular formula of C 22 H 25 NO 6 and a molecular weight of 399.4 g/mol. The structural formula of colchicine is given below. Colchicine occurs as white to pale yellow powder, very soluble in water. LODOCO (colchicine) tablets are supplied for oral administration as white to slightly yellow, round, biconvex tablets debossed with ‘L1’ on one side and plain on the other side containing 0.5 mg of colchicine USP as the active ingredient and the following inactive ingredients: gelatin, lactose monohydrate, magnesium stearate, potato starch, and talc. Colchi-structure

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 ).

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 ).

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 ).

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. These most often occur with excessive accumulation or overdosage [see Overdosage (10)] . Neuromuscular : myotoxicity, weakness, numbness, paresthesia, rhabdomyolysis. Gastrointestinal : diarrhea, vomiting, abdominal cramping, abdominal pain. Renal : acute renal impairment Dermatology : rashes and alopecia Hematological : thrombocytopenia, leukopenia, pancytopenia The common side-effects reported in published clinical studies and literature with the use of colchicine are gastrointestinal symptoms (diarrhea; vomiting; abdominal cramping) and myalgia ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact AGEPHA Pharma FZ LLC at 1 (800) 963-0353 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 exposure to colchicine. Advise patients to avoid grapefruit or grapefruit juice when taking LODOCO. P- glycoprotein Inhibitors † cyclosporine ranolazine Significant increase in colchicine plasma levels is anticipated with P-gp inhibitors. Concomitant use of LODOCO with strong P-gp inhibitors is contraindicated [see Contraindications (4)] . HMG-Co A Reductase Inhibitors Pharmacokinetic and/or pharmacodynamic interaction: the addition of one drug to a stable long term regimen of the other has resulted in myopathy and rhabdomyolysis (including fatality). Monitor patients for signs or symptoms of muscle pain toxicity. Other Lipid Lowering drugs fibrates gemfibrozil Digitalis Glycosides digoxin P-gp substrate; rhabdomyolysis has been reported. Oral contraceptives Ethinyl estradiol and norethindrone (Ortho-Novum 1/35) In healthy female volunteers given coadministered with 0.6 mg colchicine twice daily, hormone concentrations are not affected [see Clinical Pharmacology (12.3)] . Colchicine can interact with oral contraceptives like norethindrone/ethinyl estradiol and can cause adverse events like diarrhea, nausea, upper abdominal pain, cold sweat etc. Females using oral contraceptives should be prescribed LODOCO with caution and observed for adverse events. † Patients with renal or hepatic impairment should not be given LODOCO in conjunction with strong CYP3A4 or P-gp inhibitors [see Contraindications (4)] . Coadministration of P-gp and/or CYP3A4 inhibitors (e.g., cyclosporine or clarithromycin) have been demonstrated to alter the concentration of colchicine. The potential for drug-drug interactions must be considered prior to and during therapy. See FPI for a complete list of reported and potential interactions ( 7 ).