T
In some subjects, secondary colchicine peaks are seen, occurring between 3 and 36 hours post-dose 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 COLCRYS with food has no effect on the rate of colchicine absorption, but did decrease the extent of colchicine by approximately 15%. This is without clinical significance.
Distribution
The mean apparent volume of distribution in healthy young volunteers was 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 Pregnancy (8.1) and Nursing Mothers (8.3)
].
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 – 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: Pharmacokinetics of colchicine has not been determined in elderly patients. 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 – 93), mean weight was 47 kg (38 – 61 kg) and mean creatinine clearance was 46 mL/min (range 25 – 75 mL/min). Mean peak plasma levels and AUC of colchicine were two times higher in elderly subjects compared to young healthy males. However, it is possible that the higher exposure in the elderly subjects was due to decreased renal function.
Renal impairment: Pharmacokinetics of colchicine in patients with mild and moderate renal impairment is not known. A published report described the disposition of colchicine (1 mg) in young adult men and women with FMF who had normal renal function or end-stage renal disease requiring dialysis. Patients with end-stage renal disease had 75% lower colchicine clearance (0.17 vs 0.73 L/hr/kg) and prolonged plasma elimination half-life (18.8 hrs vs 4.4 hrs) as compared to subjects with FMF and normal renal function [see Dose Modification in Renal Impairment (2.5) and Renal Impairment (8.6)
].
Hepatic impairment: Published reports on the pharmacokinetics of IV colchicine in patients with severe chronic liver disease, as well as those with alcoholic or primary biliary cirrhosis, and normal renal function suggest wide inter-patient variability. In some subjects with mild to moderate cirrhosis, the clearance of colchicine is significantly reduced and plasma half-life prolonged compared to healthy subjects. In subjects with primary biliary cirrhosis, no consistent trends were noted [see Dose Modification in Hepatic Impairment (2.6) and Hepatic Impairment (8.7)
]. No pharmacokinetic data are available for patients with severe hepatic impairment (Child-Pugh C).
Drug interactions:
In vitro
drug interactions:
In vitro studies in human liver microsomes have shown that colchicine is not an inhibitor or inducer of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4 activity.
In vivo
drug interactions:
The effects of co-administration of other drugs with COLCRYS on Cmax, AUC, and Cmin are summarized in Table 6 (effect of other drugs on colchicine) and Table 7 (effect of colchicine on other drugs). For information regarding clinical recommendations, see Table 1 in Dose Modification for Co-administration of Interacting Drugs [see Dose Modification for Co-administration of Interacting Drugs (2.4)
].
Table 6 Drug Interactions: Pharmacokinetic Parameters for COLCRYS (colchicine, USP) tablets in the Presence of the Co-Administered Drug
Co-administered Drug |
Dose of Co-administered Drug (mg) |
Dose of COLCRYS (mg) |
N |
% Change in Colchicine Concentrations from Baseline (Range: Min - Max) |
|
|
|
|
Cmax
|
AUC0-t
|
Cyclosporine |
100 mg single-dose |
0.6 mg single-dose |
23 |
270.0 (62.0 to 606.9) |
259.0 (75.8 to 511.9) |
Clarithromycin |
250 mg BID, 7 days |
0.6 mg single-dose |
23 |
227.2 (65.7 to 591.1) |
281.5 (88.7 to 851.6) |
Ketoconazole |
200 mg BID, 5 days |
0.6 mg single-dose |
24 |
101.7 (19.6 to 219.0) |
212.2 (76.7 to 419.6) |
Ritonavir |
100 mg BID, 5 days |
0.6 mg single-dose |
18 |
184.4 (79.2 to 447.4) |
296.0 (53.8 to 924.4) |
Verapamil |
240 mg daily, 5 days |
0.6 mg single-dose |
24 |
40.1 (-47.1 to 149.5) |
103.3 (-9.8 to 217.2) |
Diltiazem |
240 mg daily, 7 days |
0.6 mg single-dose |
20 |
44.2 (-46.0 to 318.3) |
93.4 (-30.2 to 338.6) |
Azithromycin |
500 mg × 1 day, then 250 mg × 4 days |
0.6 mg single-dose |
21 |
21.6 (-41.7 to 222.0) |
57.1 (-24.3 to 241.1) |
Grapefruit Juice |
240 mL BID, 4 days |
0.6 mg single-dose |
21 |
-2.55 (-53.4 to 55.0) |
-2.36 (-46.4 to 62.2) |
Estrogen-containing oral contraceptives: In healthy female volunteers given ethinyl estradiol and norethindrone (Ortho-Novum® 1/35) co-administered with COLCRYS (0.6 mg b.i.d. × 14 days), hormone concentrations are not affected.
In healthy volunteers given theophylline co-administered with COLCRYS (0.6 mg b.i.d. × 14 days), theophylline concentrations were not affected.
Table 7 Drug Interactions: Pharmacokinetic Parameters for Co-Administration of Drug in the Presence of COLCRYS (colchicine, USP) tablets
Co-administered Drug |
Dose of Co-administered Drug (mg) |
Dose of COLCRYS (mg) |
N |
% Change in Co-Administered Drug Concentrations from Baseline (Range: Min - Max) |
|
|
|
|
Cmax
|
AUC0-t
|
Theophylline |
300 mg (elixir) single-dose |
0.6 mg BID × 14 days |
27 |
1.6 (-30.4 to 23.1) |
1.6 (-28.5 to 27.1) |
Ethinyl Estradiol (Ortho-Novum® 1/35) |
21-Day Cycle (Active Treatment) + 7-Day Placebo |
0.6 mg BID × 14 days |
27 *
|
-6.7 (-40.3 to 44.7) |
-3.0 †
(-25.3 to 24.9) |
Norethindrone (Ortho-Novum® 1/35) |
0.94 (-37.3 to 59.4) |
-1.6
(-32.0 to 33.7) |
Conducted in healthy adult females
NONCLINICAL TOXICOLOGY
Carcinogenesis
Carcinogenicity studies of colchicine have not been conducted. Due to the potential for colchicine to produce aneuploid cells (cells with an unequal number of chromosomes), there is theoretically an increased risk of malignancy.
Mutagenesis
Colchicine was negative for mutagenicity in the bacterial reverse mutation assay. In a chromosomal aberration assay in cultured human white blood cells, colchicine treatment resulted in the formation of micronuclei. Since published studies demonstrated that colchicine induces aneuploidy from the process of mitotic nondisjunction without structural DNA changes, colchicine is not considered clastogenic, although micronuclei are formed.
Impairment of Fertility
No studies of colchicine effects on fertility were conducted with COLCRYS. However, published nonclinical studies demonstrated that colchicine-induced disruption of microtubule formation affects meiosis and mitosis. Reproductive studies also reported abnormal sperm morphology and reduced sperm counts in males, and interference with sperm penetration, second meiotic division, and normal cleavage in females when exposed to colchicine. Colchicine administered to pregnant animals resulted in fetal death and teratogenicity. These effects were dose dependent, with the timing of exposure critical for the effects on embryofetal development. The nonclinical doses evaluated were generally higher than an equivalent human therapeutic dose, but safety margins for reproductive and developmental toxicity could not be determined.
Case reports and epidemiology studies in human male subjects on colchicine therapy indicated that infertility from colchicine is rare. A case report indicated that azoospermia was reversed when therapy was stopped. Case reports and epidemiology studies in female subjects on colchicine therapy have not established a clear relationship between colchicine use and female infertility. However, since the progression of FMF without treatment may result in infertility, the use of colchicine needs to be weighed against the potential risks.