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Colcrys

"The U.S. Food and Drug Administration today took action against companies that manufacture, distribute, and/or market unapproved single-ingredient oral colchicine, a medication commonly used for the daily prevention of gout, to treat acute gout f"...

Colcrys

Colcrys

CLINICAL PHARMACOLOGY

Mechanism of Action

The mechanism by which COLCRYS 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 thought to mediate some gout symptoms.

Pharmacokinetics

Absorption

In healthy adults, COLCRYS is absorbed when given orally, reaching a mean Cmax of 2.5 ng/mL (range 1.1 to 4.4 ng/mL) in 1 to 2 hours (range 0.5 to 3 hours) after a single dose administered under fasting conditions.

Following oral administration of COLCRYS given as 1.8 mg colchicine over 1 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 non-recommended high-dose regimen (4.8 mg over 6 hours), mean maximal plasma concentrations were 6.8 ng/mL, at a median 4.47 hours (range: 3.1 to 7.5 hours).

After 10 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 post-dose (range 0.5 to 3.0 hours). Mean pharmacokinetic parameter values in healthy adults are shown in Table 5 below.

Table 5 : Mean (%CV) Pharmacokinetic Parameters in Healthy Adults Given COLCRYS

Cmax (colchicine ng/mL) Tmax1 (h) Vd/F (L) CL/F (L/hr) t½ (h)
COLCRYS 0.6 mg Single Dose (N=13)
2.5 (28.7) 1.5 (1.0 – 3.0) 341.5 (54.4) 54.1 (31.0) --
COLCRYS 0.6 mg b.i.d. x 10 days (N =13)
3.6 (23.7) 1.3 (0.5 – 3.0) 1150 (18.7) 30.3 (19.0) 26.6 (16.3)
1 Tmax mean (range)
CL= Dose/AUC0-t (Calculated from mean values)
Vd = CL/Ke (Calculated from mean values)

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 and Nursing Mothers].

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 and Renal Impairment].

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 and Hepatic Impairment]. 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].

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 271 -6.7 (-40.3 to 44.7) -3.02
(-25.3 to 24.9)
Norethindrone (Ortho-Novum® 1/35)       0.94
(-37.3 to 59.4)
-1.62
(-32.0 to 33.7)
1 Conducted in healthy adult females
2 AUCτ

Clinical Studies

The evidence for the efficacy of colchicine in patients with chronic gout is derived from the published literature. Two randomized clinical trials assessed the efficacy of colchicine 0.6 mg twice a day for the prophylaxis of gout flares in patients with gout initiating treatment with urate lowering therapy. In both trials, treatment with colchicine decreased the frequency of gout flares.

The efficacy of a low dosage regimen of oral colchicine (COLCRYS total dose 1.8 mg over 1 hour) for treatment of gout flares was assessed in a multicenter, randomized, double-blind, placebo-controlled, parallel group, 1 week, dose comparison study. Patients meeting American College of Rheumatology criteria for gout were randomly assigned to three groups: high-dose colchicine (1.2 mg, then 0.6 mg hourly 6 hours [4.8 mg total]); low-dose colchicine (1.2 mg, then 0.6 mg in 1 hour [1.8 mg total] followed by 5 placebo doses hourly); or placebo (2 capsules, then 1 capsule hourly 6 hours). Patients took the first dose within 12 hours of the onset of the flare and recorded pain intensity (11-point Likert scale) and adverse events over 72 hours. The efficacy of colchicine was measured based on response to treatment in the target joint, using patient self assessment of pain at 24 hours following the time of first dose as recorded in the diary. A responder was one who achieved at least a 50% reduction in pain score at the 24-hour post-dose assessment relative to the pre-treatment score and did not use rescue medication prior to the actual time of 24-hour post-dose assessment.

Rates of response were similar for the recommended low-dose treatment group (38%) and the non-recommended high-dose group (33%) but were higher as compared to the placebo group (16%) as shown in Table 8.

Table 8 : Number (%) of Responders Based on Target Joint Pain Score at 24 Hours Post First Dose

COLCRYS Dose Responders n (%) Placebo n (%)
(n=58)
% Differences in Proportion
Low-dose
(n=74)
High-dose
(n=52)
Low-dose vs Placebo (95% CI) High-dose vs Placebo (95% CI)
28 (38%) 17 (33%) 9 (16%) 22 (8, 37) 17 (1, 33)

Figure 1 below shows the percentage of patients achieving varying degrees of improvement in pain from baseline at 24 hours.

Figure 1 : Pain Relief on Low and High Doses of COLCRYS and Placebo (Cumulative)

Pain Relief on Low and High Doses of COLCRYS and Placebo - Illustration

The evidence for the efficacy of colchicine in patients with FMF is derived from the published literature. Three randomized, placebo-controlled studies were identified. The three placebo-controlled studies randomized a total of 48 adult patients diagnosed with FMF and reported similar efficacy endpoints as well as inclusion and exclusion criteria.

One of the studies randomized 15 patients with FMF to a 6-month crossover study during which 5 patients discontinued due to study non-compliance. The 10 patients completing the study experienced 5 attacks over the course of 90 days while treated with colchicine compared to 59 attacks over the course of 90 days while treated with placebo. Similarly, the second study randomized 22 patients with FMF to a 4-month crossover study during which 9 patients discontinued due to lack of efficacy while receiving placebo or study non-compliance. The 13 patients completing the study experienced 18 attacks over the course of 60 days while treated with colchicine compared to 68 attacks over the course of 60 days while treated with placebo. The third study was discontinued after an interim analysis of 6 of the 11 patients enrolled had completed the study; results could not be confirmed.

Open-label experience with colchicine in adults and children with FMF is consistent with the randomized, controlled trial experience, and was utilized to support information on the safety profile of colchicine and for dosing recommendations.

Last reviewed on RxList: 8/5/2011
This monograph has been modified to include the generic and brand name in many instances.

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