LODOCO

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 ).

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 ).

4. CONTRAINDICATIONS 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. 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 ).

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 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 ).

6. ADVERSE REACTIONS 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.

8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk summary Available human data from published literature on colchicine use in pregnancy over several decades have not identified any drug associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data) . Colchicine crosses the human placenta. Although animal reproduction and developmental studies were not conducted with LODOCO (colchicine), published animal reproduction and development studies indicate that colchicine causes embryofetal toxicity and altered postnatal development at exposures within or above the clinical therapeutic range. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Human Data Available data from published observational studies, case series, and case reports over several decades do not suggest an increased risk for major birth defects or miscarriage in pregnant women with rheumatic diseases (such as rheumatoid arthritis, Behcet’s disease, or Familial Mediterranean fever (FMF)) treated with colchicine at therapeutic doses during pregnancy. Limitations of these data include the lack of randomization and inability to control for confounders such as underlying maternal disease and maternal use of concomitant medications. 8.2 Lactation Risk summary Colchicine is present in human milk (see Data) . Adverse events in breastfed infants have not been reported in the published literature after administration of colchicine to lactating women. There are no data on the effects of colchicine on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for LODOCO and any potential adverse effects on the breastfed infant from LODOCO or from the underlying maternal condition. Data Limited published data from case reports and a small lactation study demonstrate colchicine is present in breastmilk. A systematic review of literature reported no adverse effects in 149 breastfed children and advised to reconsider breastfeeding if the infant has diarrhea. In a prospective observational cohort study, no gastrointestinal or other symptoms were reported in 38 colchicine-exposed breastfed infants. 8.3 Females and Males of Reproductive Potential Infertility Case reports and epidemiology studies in human male subjects on colchicine therapy indicated that infertility from colchicine is rare and may be reversible. 8.4 Pediatric Use Safety and effectiveness have not been established in pediatric patients. 8.5 Geriatric Use The total number of subjects included in the LoDoCo2 study who were 65 and over and 75 and over were 3098 (56.1%). No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. This drug is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function. 8.6 Renal Impairment Colchicine is known to be excreted renally. In renally impaired patients, the total clearance of colchicine is significantly reduced. In patients, with renal impairment, elevated plasma concentrations of colchicine were observed, and may lead to the development of colchicine toxicity and adverse reactions like myeloneuropathy characterized by proximal weakness and elevated serum creatinine, and possibly rhabdomyolysis [see Warnings and Precautions (5)]. LODOCO is contraindicated in patients with renal failure (Creatinine clearance less than 15 mL/minute). Patients with renal impairment should be monitored closely for adverse effects of colchicine [see Contraindications (4)] . Avoid use in patients with moderate renal impairment receiving moderate CYP3A4 inhibitors [see Contraindications (4), Warnings and Precautions (5) and Clinical Pharmacology (12.3)] . 8.7 Hepatic Impairment Colchicine is primarily metabolized in liver. The clearance of colchicine may be significantly reduced, and plasma half-life prolonged in patients with chronic hepatic impairment, compared to healthy subjects [see Clinical Pharmacology (12.3)] . In patients with hepatic impairment, monitor closely for adverse reactions with LODOCO. LODOCO use in severe hepatic impairment is contraindicated. Avoid use in patients with any degree of hepatic impairment and receiving strong P-gp inhibitors or strong or moderate CYP3A4 inhibitors [see Contraindications (4) and Clinical Pharmacology (12.3)]. • Females and Males of Reproductive Potential: Advise males that LODOCO may rarely and transiently impair fertility ( 8.3 ). • Patients with renal or hepatic impairment should be monitored closely for adverse effects of colchicine ( 8.6 , 8.7 ).