Colchicine 0.6 mg · Tablets

The mechanism by which colchicine tablets exerts its beneficial effect in patients with FMF has not been fully elucidated; however, evidence suggests that colchicine may interfere with the intracellular assembly of the inflammasome complex present in neutrophils and monocytes that mediates activation of interleukin-1β. Additionally, colchicine disrupts cytoskeletal functions through inhibition of β-tubulin polymerization into microtubules and consequently prevents the activation, degranulation and migration of neutrophils.

Absorption — In healthy adults, colchicine is absorbed when given orally, reaching a mean Cmax of 2.5 ng/mL (range 1.1 to 4.4 ng/mL) in one to two hours (range 0.5 to 3 hours) after a single dose administered under fasting conditions.

Following oral administration of colchicine given as 1.8 mg colchicine over one hour to healthy, young adults under fasting conditions, colchicine appears to be readily absorbed, reaching mean maximum plasma concentrations of 6.2 ng/mL at a median 1.81 hours (range: 1.0 to 2.5 hours). Following administration of the nonrecommended high-dose regimen (4.8 mg over six hours), mean maximal plasma concentrations were 6.8 ng/mL, at a median 4.47 hours (range: 3.1 to 7.5 hours).

After ten days on a regimen of 0.6 mg twice daily, peak concentrations are 3.1 to 3.6 ng/mL (range 1.6 to 6.0 ng/mL), occurring 1.3 to 1.4 hours postdose (range 0.5 to 3.0 hours). Mean pharmacokinetic parameter values in healthy adults are shown in Table 5.

In some subjects, secondary colchicine peaks are seen, occurring between three and 36 hours postdose and ranging from 39 to 155% of the height of the initial peak. These observations are attributed to intestinal secretion and reabsorption and/or biliary recirculation.

Absolute bioavailability is reported to be approximately 45%.

Administration of colchicine tablets with food has no effect on the rate of colchicine absorption but does decrease the extent of colchicine by approximately 15%. This is without clinical significance.

Distribution — The mean apparent volume of distribution in healthy young volunteers is approximately 5 to 8 L/kg.

Colchicine binding to serum protein is low, 39 ± 5%, primarily to albumin regardless of concentration.

Colchicine crosses the placenta (plasma levels in the fetus are reported to be approximately 15% of the maternal concentration). Colchicine also distributes into breast milk at concentrations similar to those found in the maternal serum [see Use in Specific Populations (8.1, 8.2)].

Metabolism — Colchicine is demethylated to two primary metabolites, 2-O-demethylcolchicine and 3-O-demethylcolchicine (2-and 3-DMC, respectively) and one minor metabolite, 10-O-demethylcolchicine (also known as colchiceine). In vitro studies using human liver microsomes have shown that CYP3A4 is involved in the metabolism of colchicine to 2-and 3-DMC. Plasma levels of these metabolites are minimal (less than 5% of parent drug).

Elimination/Excretion — In healthy volunteers (n=12), 40 to 65% of 1 mg orally administered colchicine was recovered unchanged in urine. Enterohepatic recirculation and biliary excretion are also postulated to play a role in colchicine elimination. Following multiple oral doses (0.6 mg twice daily), the mean elimination half-lives in young healthy volunteers (mean age 25 to 28 years of age) is 26.6 to 31.2 hours. Colchicine is a substrate of P-gp.

Extracorporeal Elimination — Colchicine is not removed by hemodialysis.

Special Populations — There is no difference between men and women in the pharmacokinetic disposition of colchicine.

Pediatric Patients — Pharmacokinetics of colchicine was not evaluated in pediatric patients.

Elderly — A published report described the pharmacokinetics of 1 mg oral colchicine tablet in four elderly women compared to six young healthy males. The mean age of the four elderly women was 83 years (range 75 to 93), mean weight was 47 kg (38 to 61 kg) and mean creatinine clearance was 46 mL/min (range 25 to 75 mL/min). Mean peak plasma levels and AUC of colchicine were two times higher in elderly subjects compared to young healthy males.