Colchicine (Page 5 of 8)

9 DRUG ABUSE AND DEPENDENCE

Tolerance, abuse or dependence with colchicine has not been reported.

10 OVERDOSAGE


The exact dose of colchicine that produces significant toxicity is unknown. Fatalities have occurred after ingestion of a dose as low as 7 mg over a four day period, while other patients have survived after ingesting more than 60 mg. A review of 150 patients who overdosed on colchicine found that those who ingested less than 0.5 mg/kg survived and tended to have milder toxicities such as gastrointestinal symptoms, whereas those who took 0.5 to 0.8 mg/kg had more severe reactions such as myelosuppression. There was 100% mortality in those who ingested more than 0.8 mg/kg. The first stage of acute colchicine toxicity typically begins within 24 hours of ingestion and includes gastrointestinal symptoms such as abdominal pain, nausea, vomiting, diarrhea and significant fluid loss, leading to volume depletion. Peripheral leukocytosis may also be seen. Life-threatening complications occur during the second stage, which occurs 24 to 72 hours after drug administration, attributed to multiorgan failure and its consequences. Death is usually a result of respiratory depression and cardiovascular collapse. If the patient survives, recovery of multiorgan injury may be accompanied by rebound leukocytosis and alopecia starting about one week after the initial ingestion.

Treatment of colchicine poisoning should begin with gastric lavage and measures to prevent shock. Otherwise, treatment is symptomatic and supportive. No specific antidote is known. Colchicine is not effectively removed by dialysis [see Clinical Pharmacology (12.3)].

11 DESCRIPTION

Colchicine is an alkaloid chemically described as Acetamide, N-(5,6,7,9-tetrahydro-1,2,3,10-tetramethoxy-9-oxobenzo[a]heptalen-7-yl)-,(S) with a molecular formula of C 22 H 25 NO 6 and a molecular weight of 399.44. The structural formula of colchicine is given below.

structure
(click image for full-size original)

Colchicine USP occurs as pale yellow to pale greenish-yellow crystalline powder. Is odorless or nearly so, and darkens on exposure to light. Colchicine is freely soluble in alcohol, in chloroform and soluble in water.
Colchicine tablets, USP are supplied for oral administration as purple, film-coated, capsule-shaped, bevel edged, biconvex tablets, debossed with “H” on one side and scored with “C2” on the other side; where ‘C’ and ‘2’ are separated by a score line, containing 0.6 mg of the active ingredient colchicine USP. Inactive ingredients: carnauba wax, FD&C blue #2/indigo carmine AL, FD&C red #40/allura red AC aluminum lake, hypromellose, lactose monohydrate, macrogol, magnesium stearate, microcrystalline cellulose, polydextrose, pregelatinized starch, sodium starch glycolate, titanium dioxide and triacetin.
The botanical source of pregelatinized starch is corn starch. FDA approved dissolution test specifications differ from USP

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The mechanism by which colchicine 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.

12.3 Pharmacokinetics

Absorption
In healthy adults, colchicine is absorbed when given orally, reaching a mean C max 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 ng/mL), occurring 1.3 to 1.4 hours postdose (range 0.5 to 3 hours). Mean pharmacokinetic parameter values in healthy adults are shown in Table 5.

Table 5. Mean (%CV) Pharmacokinetic Parameters in Healthy Adults Given Colchicine
C max (Co lchicine ng/mL) T max* (h ) Vd/F (L ) CL /F (L /hr) t 1 /2 (h )
Colchicine 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)
Colchicine 0.6 mg Twice Daily × 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)

* T max mean (range)
CL = Dose/AUC 0 — t (calculated from mean values)
Vd = CL/Ke (calculated from mean values)
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 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.

A pharmacokinetic study using a single oral dose of one 0.6 mg colchicine tablet was conducted in young healthy subjects (n=20) between the ages of 18 and 30 years and elderly subjects (n=18) between the ages of 60 and 70 years. Elderly subjects in this study had a median age of 62 years and a mean (±SD) age of 62.83 ± 2.83 years. A statistically significant difference in creatinine clearance (mean ± SD) was found between the two age groups (132.56 ± 23.16 mL/min for young vs 87.02 ± 17.92 mL/min for elderly subjects, respectively). The following pharmacokinetic parameter values (mean ± SD) were observed for colchicine in the young and elderly subjects, respectively: AUC 0 to inf (ng/hr/mL) 22.39 ± 6.95 and 25.01 ± 6.92; C max (ng/mL) 2.61 ± 0.71 and 2.56 ± 0.97; T max (hr) 1.38 ± 0.42 and 1.25 ± 0.43; apparent elimination half-life (hr) 24.92 ± 5.34 and 30.06 ± 10.78; and clearance (mL/min) 0.0321 ± 0.0091 and 0.0292 ± 0.0071.
Clinical studies with colchicine for prophylaxis and treatment of gout flares and for treatment of FMF did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently than younger patients. In general, dose selection for an elderly patient with gout should be cautious, reflecting the greater frequency of decreased renal function, concomitant disease or other drug therapy [see Dosage and Administration (2.4), Use in Specific Populations (8.5)].
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 vs 4.4 hours) as compared to subjects with FMF and normal renal function [see Dosage and Administration (2.5),Use in Specific Populations (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 interpatient 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 Dosage and Administration (2.6),Use in Specific Populations (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 coadministration of other drugs with colchicine on C max , AUC and C min 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 Coadministration of Interacting Drugs [see Dosage and Administration (2.4)].

Table 6. Drug Interactions: Pharmacokinetic Parameters for Colchicine Tablets in the Presence of the Coadministered Drug
C oad ministered Drug Dose of Coadministered Drug (mg) Dose of Colchicine (mg) N % Change in Colchicine Concentrations from Baseline (Range: Min Max)
C max AUC 0-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 twice daily, 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 twice daily, 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 twice daily, 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 x 1 day, then 250 mg x 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 twice daily, 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) coadministered with colchicine (0.6 mg twice daily x 14 days), hormone concentrations are not affected. In healthy volunteers given theophylline coadministered with colchicine (0.6 mg twice daily x 14 days), theophylline concentrations were not affected.

Table 7. D rug Interactions: Pharmacokinetic Parameters for Coadministration of Drug in the Presence of Colchicine Tablets
Coadministered Drug Dose of Coadministered Drug (mg) Dose of Colchicine (mg) N % Change in Coadministered Drug Concentrations from Baseline (Range: Min Max)
C max AUC 0-t
Theophylline 300 mg (elixir) single dose 0.6 mg twice daily x 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 twice daily x 14 days 27* -6.7 (-40.3 to 44.7) -3 (-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 AUC τ

All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.

This site is provided for educational and informational purposes only, in accordance with our Terms of Use, and is not intended as a substitute for the advice of a medical doctor, nurse, nurse practitioner or other qualified health professional.

Privacy Policy | Copyright © 2024. All Rights Reserved.