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

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

† Patients with renal or hepatic impairment should not be given LODOCO in conjunction with strong CYP3A4 or P-gp inhibitors [see Contraindications (4)].

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 colchicineexposed
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)].

14. CLINICAL STUDIES

The evidence for the efficacy of colchicine in patients with cardiovascular events is derived from published literature (LoDoCo2) along with other supportive studies.
The LoDoCo2 trial was an investigator-initiated, randomized, placebo controlled, double-blind, event-driven trial conducted to assess the efficacy of colchicine 0.5mg once daily orally in patients with stable coronary artery disease. The study included 5522 patients, in which 2762 were assigned to the colchicine group and 2760 to placebo. The baseline characteristics of the patients were balanced between the trial groups. Patients were treated for chronic coronary disease, with 99.7% taking an antiplatelet agent or an anticoagulant, 96.6% a lipid-lowering agent, 97.3% of which were statins, 62.1% a beta-blocker, and 71.7% an inhibitor of the renin–angiotensin system.
LoDoCo2 assessed the efficacy of colchicine 0.5 mg once daily in patients with stable coronary artery disease. Patients between 35-85 years were eligible for participation in the LoDoCo2 trial if they had proven coronary artery disease, were clinically stable for at least 6 months, without comorbidities that would preclude follow-up, or contraindication to colchicine use. The mean (±SD) age of the patients was 66±8.6 years, and 846 (15.3%) were female. The median time on study medication was 28.6 months. The primary end point of LoDoCo2 trial was a composite of cardiovascular death, spontaneous (nonprocedural) myocardial infarction, ischemic stroke, or ischemia-driven coronary revascularization.

In the LoDoCo2 trial, 0.5 mg of colchicine once daily resulted in a 31% lower relative risk (RRR) of the primary composite endpoint events compared to placebo (HR, 0.69; 95% [CI] 0.57 to 0.83; p<0.001) and the number needed to treat (NNT) was 36.

Figure 1: Cumulative Incidence of Primary End point in LoDoCo2 trial

The results of the primary endpoint are summarized in Table 4.

Table 4: Summary of efficacy results of LoDoCo2 trial

Myocardial infarction refers to spontaneous (non-procedural) myocardial infarction.

PATIENT INFORMATION

This Patient Information has been approved by the U.S. Food and Drug Administration. Issued: 06/2023