Colchicine

From Anvita Health Wiki

Contents 1 Introduction 2 Structure 3 Indications 4 Contraindications 5 Dosage 6 Dosage-adjustment-in-renal-failure 7 Pharmacokinetics 8 Adverse-effects 9 Drug-interactions 10 Test-interactions 11 Mechanism-of-action 12 More General Terms 13 Internet Database 14 References

Introduction

• Alkaloid isolated from Colchicum autumale. Antimitotic agent used in the study of cell division.

Structure

• C22 H23 N O6

Indications

• gout & pseudogout

• treatment of acute gouty arthritis
• prevention of attacks of acute gouty arthritis

• management of familial Mediterranean fever
• primary biliary cirrhosis
• inflammatory dermatoses [10]

• psoriasis
• Behcet syndrome

• prevention of recurrence of pericarditis [13]

Contraindications

• use with caution in elderly
• use with caution in patients with hepatic, renal, GI or heart disease
• avoid use when creatinine clearance < 10 mL/min [11]
• hypersensitivity
• blood dyscrasias
  

• pregnancy category = d
• safety in lactation = ?

Dosage

• (Gout):
• acute attack

• Colcrys: 1.2 mg (2 tabs) followed by 0.6 mg (1 tab) in 1 hour (total 1.8mg) [19,20]

• see dosage adjustment in renal failure
• use 1/2 dose in combination with cyclosporine or strong CYP3A4 inhibitors ( clarithromycin ...) [19]

• older dosing (prior to FDA-approval of Colcrys)

• 0.5-1.0 mg every 1-2 hours until pain subsides or nausea, vomiting or diarrhea occur
• generally 4-8 mg needed to control acute attack

• 2 mg IV over 2-5 min [3] (withdrawn from market)

• maintenance:

• 0.6 mg PO QD [3].
• starting dose: 0.6 mg PO QD [4]
• 0.5-1.8 mg PO QD [6] Tabs 0.5, 0.6, 1 mg

• Injection: withdrawn 2008, safety concerns, unapproved status [15] Colcrys: single ingredient* colchicine for treatment of acute flairs of gout & familial Mediterranean fever [16]
• * lower doses work as well as higher doses with fewer interactions & toxicity [16]

Dosage-adjustment-in-renal-failure

• decrease dose by 50% for creatinine clearance < 50 mL/min
• avoid use when creatinine clearance < 10 mL/min [11]

Pharmacokinetics

• rapidly absorbed & deacetylated by the liver
• protein binding 10-31%
• time to peak concentration after oral dose 30-120 minutes
• distribution: [10]

• kidney, liver, spleen & intestine contain large amounts
• colchicine excluded from skeletal muscle, heart, brain

• metabolism by cyt P450 3A4
• pumped out of cells by P-glycoprotein
• hepatobiliary (80-90%) & renal (10-20%) excretion
• 1/2life 12-30 minutes [8]

• second delayed increased in plasma levels due to enterohepatic circulation [8]
• detectable in leukocytes & urine 9 days after IV dose
  

• elimination via liver
• protein binding = 10-31 %
• 1/2life = 12-30 minutes

Adverse-effects

• common (> 10%)

• nausea/vomiting
• diarrhea
• abdominal pain

• less common (1-10%)

• anorexia, alopecia

• uncommon (< 1%)

• myopathy*, peripheral neuritis, rash, agranulocytosis, aplastic anemia, hepatotoxicity, azoospermia, bone marrow suppression, malabsorption of vit B12

• other [10]

• transient leukopenia replaced by leukocytosis ( basophilia)

• * muscle weakness, proximal > distal [7] serum creatine kinase may be elevated
• Toxicity: (acute) [12]

• hemorrhagic gastroenteritis
• nausea, vomiting, abdominal pain, inflammatory diarrhea
• cardiovascular injury: ST segment elevation
• acute respiratory distress syndome
• nephrotoxicity leading to renal failure
• disseminated intravascular coagulation
• muscle weakness
• ascending paralysis involving CNS
• delirium, convulsions, shock
• deaths associated with use of compounded injectable colchicine [14]

Drug-interactions

• colchicine increases sympathomimetic toxicity
• colchicine increases effects of CNS depressants
• drugs that inhibit cyt P450 3A4 & P-glycoprotein can increase toxicity of colchicine [12,16]

• erythromycin, clarithromycin (potentially fatal)
• diltiazem, nicardipine, verapamil
• itraconazole, ketoconazole
• indinavir, ritonavir

• cyclosporine [19]

Test-interactions

• may cause false positive urine tests for erythrocytes or hemoglobin

Mechanism-of-action

• inhibits microtubule formation
• supresses release of fibroblast growth factors, fibronectin & alveolar macrophage-derived growth factor
• inhibits fibroblast proliferation & total collagen synthesis
• inhibits leukocyte migration
• diminished production of lactic acid
• diminished deposition of uric acid crystals
• reduces inflammatory response to & phagocytosis of crystals

More General Terms

• alkaloid
• ketone
• cycloheptane
• anti-inflammatory agent
• metabolic agent (metabolic modifier)

Internet Database

PubChem: 6167
PubChem: 2833

References

1. Merck Index 11th ed #2470
2. Research Biochemicals International 1993-94 catalog
3. The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
4. Kaiser Permanente Northern California Regional Drug Formulary, 1998
5. Ryu et al, Mayo Clinic Proc 73:1085-1101, 1998
6. Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
7. Geriatrics Review Syllabus, American Geriatrics Society, 5th edition, 2002-2004
8. Geriatric Dosage Handbook, 6th edition, Selma et al eds, Lexi-Comp, Cleveland, 2001
9. Department of Veterans Affairs, VA National Formulary
10. The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996 pg 647-649
11. Wallace SL et al, J Rheumatol 18:1942, 1991 PMID: [1]
12. Prescriber's Letter 12(9): 2005 Fatal Interaction Between Clarithromycin and Colchicine Detail-Document#: [2] (subscription needed) [3]
13. Imazio M, Bobbio M, Cecchi E, Demarie D, Pomari F, Moratti M, Ghisio A, Belli R, Trinchero R. Colchicine as first-choice therapy for recurrent pericarditis: results of the CORE (COlchicine for REcurrent pericarditis) trial. Arch Intern Med. 2005 Sep 26;165(17):1987-91. PMID: [4]
14. FDA Medwatch: Colchicine Compounded Injectable Products [5]
15. Prescriber's Letter 16(2): 2009 New Drugs Approved by the FDA in 2008 Detail-Document#: [6] (subscription needed) [7]
16. FDA MedWatch 07/30/2009 Colchicine (marketed as Colcrys) [8]
    - Information for Healthcare Professionals: New Safety Information for Colchicine (marketed as Colcrys) [9]
17. Prescriber's Letter 16(9): 2009 New Safety Information for Colchicine and the Approval of Colcrys Detail-Document#: [10] (subscription needed) [11]
18. Kesselheim AS and Solomon DH Incentives for Drug Development - The Curious Case of Colchicine N Engl J Med 2010, 362:2045-2047 [12]
19. Prescriber's Letter 18(12): 2011 Colchicine Dosing and Drug Interactions Detail-Document#: [13] (subscription needed) [14]
20. Terkeltaub RA, Furst DE, Bennett K, et al. High versus low dosing of oral colchicine for early acute gout flare: Twenty-four-hour outcome of the first multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-comparison colchicine study. Arthritis Rheum 2010; 62(4):1060-1068. PMID: [15]

colchicine (Colcrys)