colchicine (Colcrys, Lodoco)
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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
- colchicine may also diminish cardiovascular risk[27]
- management of familial Mediterranean fever
- primary biliary cirrhosis
- inflammatory dermatoses[10]
- pericarditis: primary treatment & prevention of recurrence
- cardiovascular risk reduction for myocardial infarction, ischemic stroke, coronary revascularization, & cardiovascular death in adult patients with established atherosclerotic disease or multiple cardiovascular risk factors[33]
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
- acute coronary syndrome
- may reduce risk of adverse cardiovascular events after myocardial infarction (RR=0.77)[29] but associated with increased all-cause mortality[30]
- coronary artery disease
- may reduce cardiovascular events but increase all-cause mortality[30]
- reduces cardiovascular mortality, myocardial infarction, ischemic stroke regardless of prior acute coronary syndrome[31]
- Covid-19: colchicine does not reduce mechanical ventilation or 28-day mortality in patients hospitalized with COVID-19 pneumonia[32]
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)
- 2 mg IV over 2-5 min[3] (withdrawn from market)
- Colcrys: 1.2 mg (2 tabs) followed by 0.6 mg (1 tab) in 1 hour (total 1.8mg)[19][20]
- maintenance:
- familial Mediterranean fever 0.6 mg PO BID
- Lococo: 0.5 mg/day for coronary artery disease & after myocardial infarction[29][30][31][33] 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Injection: withdrawn 2008, safety concerns, unapproved status[15] Colcrys: single ingredient* colchicine for treatment of acute flairs of gout & familial Mediterranean fever[16]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 < 30-50 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%)
- less common (1-10%)
- uncommon (< 1%)
- other[10]
- transient leukopenia replaced by leukocytosis (basophilia)
* muscle weakness, proximal > distal[7]
- serum creatine kinase may be elevated
- muscle biopsy shows intracytoplasmic vacuoles of lysosomal origin[34]
Toxicity: (acute)[12]
- hemorrhagic gastroenteritis
- 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)[22][28]
- 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
Component of
References
- ↑ Merck Index 11th ed #2470
- ↑ Research Biochemicals International 1993-94 catalog
- ↑ 3.0 3.1 3.2 The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
- ↑ 4.0 4.1 Kaiser Permanente Northern California Regional Drug Formulary, 1998
- ↑ Ryu et al, Mayo Clinic Proc 73:1085-1101, 1998
- ↑ 6.0 6.1 Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
- ↑ 7.0 7.1 Geriatrics Review Syllabus, American Geriatrics Society, 5th edition, 2002-2004
- ↑ 8.0 8.1 8.2 Geriatric Dosage Handbook, 6th edition, Selma et al eds, Lexi-Comp, Cleveland, 2001
- ↑ Department of Veterans Affairs, VA National Formulary
- ↑ 10.0 10.1 10.2 10.3 The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996 pg 647-649
- ↑ 11.0 11.1 11.2 Wallace SL et al, J Rheumatol 18:1942, 1991 PMID: https://www.ncbi.nlm.nih.gov/pubmed/2023222
- ↑ 12.0 12.1 12.2 Prescriber's Letter 12(9): 2005 Fatal Interaction Between Clarithromycin and Colchicine Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=211004&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 13.0 13.1 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: https://www.ncbi.nlm.nih.gov/pubmed/16186468
Imazio M, Cecchi E, Ierna S et al Investigation on Colchicine for Acute Pericarditis: a multicenter randomized placebo-controlled trial evaluating the clinical benefits of colchicine as adjunct to conventional therapy in the treatment and prevention of pericarditis; study design amd rationale. J Cardiovasc Med (Hagerstown). 2007 Aug;8(8):613-7. PMID: https://www.ncbi.nlm.nih.gov/pubmed/17667033 - ↑ 14.0 14.1 FDA Medwatch: Colchicine Compounded Injectable Products http://www.fda.gov/medwatch/safety/2007/safety07.htm#Colchicine
- ↑ 15.0 15.1 Prescriber's Letter 16(2): 2009 New Drugs Approved by the FDA in 2008 Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=250213&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 16.0 16.1 16.2 16.3 FDA MedWatch 07/30/2009 Colchicine (marketed as Colcrys) http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm174596.htm
Information for Healthcare Professionals: New Safety Information for Colchicine (marketed as Colcrys) http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm174315.htm - ↑ Prescriber's Letter 16(9): 2009 New Safety Information for Colchicine and the Approval of Colcrys Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=250902&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ Kesselheim AS and Solomon DH Incentives for Drug Development - The Curious Case of Colchicine N Engl J Med 2010, 362:2045-2047 http://content.nejm.org/cgi/content/extract/362/22/2045
- ↑ 19.0 19.1 19.2 19.3 Prescriber's Letter 18(12): 2011 Colchicine Dosing and Drug Interactions Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=271208&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 20.0 20.1 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: https://www.ncbi.nlm.nih.gov/pubmed/20131255
- ↑ Prescriber's Letter 19(12): 2012 CHART: Comparison of Gout Therapies CHART: Colchicine Dosing and Drug Interactions Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=281224&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 22.0 22.1 22.2 Medical Knowledge Self Assessment Program (MKSAP) 16, 18 American College of Physicians, Philadelphia 2012, 2018.
- ↑ 23.0 23.1 Imazio M et al. for the ICAP Investigators. A randomized trial of colchicine for acute pericarditis. N Engl J Med 2013 Sep 1 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/23992557 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMoa1208536
- ↑ Yang LP. Oral colchicine (Colcrys): in the treatment and prophylaxis of gout. Drugs. 2010 Aug 20;70(12):1603-13 PMID: https://www.ncbi.nlm.nih.gov/pubmed/20687623
- ↑ 25.0 25.1 Meyer BJ Mounting Evidence Supports Colchicine for Pericarditis. NEJM Journal Watch. May 19, 2014 Massachusetts Medical Society (subscription needed) http://www.jwatch.org
Imazio M et al. Efficacy and safety of colchicine for treatment of multiple recurrences of pericarditis (CORP-2): A multicentre, double- blind, placebo-controlled, randomised trial. Lancet 2014 Mar 30; PMID: https://www.ncbi.nlm.nih.gov/pubmed/24694983
Cacoub PP. Colchicine for treatment of acute or recurrent pericarditis. Lancet 2014 Mar 30 PMID: https://www.ncbi.nlm.nih.gov/pubmed/24694984 - ↑ Terkeltaub RA, Furst DE, Digiacinto JL, Kook KA, Davis MW. Novel evidence-based colchicine dose-reduction algorithm to predict and prevent colchicine toxicity in the presence of cytochrome P450 3A4/P-glycoprotein inhibitors. Arthritis Rheum. 2011 Aug;63(8):2226-37 PMID: https://www.ncbi.nlm.nih.gov/pubmed/21480191
- ↑ 27.0 27.1 Solomon DH, Liu CC, Kuo IH, Zak A, Kim SC. Effects of colchicine on risk of cardiovascular events and mortality among patients with gout: A cohort study using electronic medical records linked with Medicare claims. Ann Rheum Dis. 2016 Sep;75(9):1674-9 PMID: https://www.ncbi.nlm.nih.gov/pubmed/26582823
- ↑ 28.0 28.1 Hung IF, Wu AK, Cheng VC et al Fatal interaction between clarithromycin and colchicine in patients with renal insufficiency: a retrospective study. Clin Infect Dis. 2005 Aug 1;41(3):291-300. Epub 2005 Jun 23. PMID: https://www.ncbi.nlm.nih.gov/pubmed/16007523
- ↑ 29.0 29.1 29.2 Tardif JC et al. Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med 2019 Nov 16; PMID: https://www.ncbi.nlm.nih.gov/pubmed/31733140 https://www.nejm.org/doi/10.1056/NEJMoa1912388
Newby LK. Inflammation as a treatment target after acute myocardial infarction. N Engl J Med 2019 Nov 16 PMID: https://www.ncbi.nlm.nih.gov/pubmed/31733139 https://www.nejm.org/doi/10.1056/NEJMe1914378 - ↑ 30.0 30.1 30.2 30.3 Nidorf SM, Fiolet ATL, Mosterd A Colchicine in Patients with Chronic Coronary Disease. N Engl J Med. Aug 31, 2020 PMID: https://www.ncbi.nlm.nih.gov/pubmed/32865380 https://www.nejm.org/doi/full/10.1056/NEJMoa2021372
Opstal TSJ et al. Colchicine attenuates inflammation beyond the inflammasome in chronic coronary artery disease: A LoDoCo2 proteomic substudy. Circulation 2020 Aug 31; [e-pub]. PMID: https://www.ncbi.nlm.nih.gov/pubmed/32864998 https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.120.050560
Tong DC et al. Colchicine in patients with acute coronary syndrome: The Australian COPS randomized clinical trial. Circulation 2020 Aug 29; [e-pub] PMID: https://www.ncbi.nlm.nih.gov/pubmed/32862667 https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.120.050771 - ↑ 31.0 31.1 31.2 Wendling P Colchicine Effective Regardless of ACS History, Timing: LoDoCo2 Medscape - Aug 23, 2021. https://www.medscape.com/viewarticle/957078
Opstal TSJ, Fiolet ATL, van Broekhoven A et al Colchicine in Patients With Chronic Coronary Disease in Relation to Prior Acute Coronary Syndrome. J Am Coll Cardiol. 2021 Aug, 78 (9) 859-866 PMID: https://www.ncbi.nlm.nih.gov/pubmed/34446156 https://www.jacc.org/doi/10.1016/j.jacc.2021.06.037
Tardif JC, Marquis-Gravel G Low-Dose Colchicine for the Management of Coronary Artery Disease J Am Coll Cardiol. 2021 Aug, 78 (9) 867-869 PMID: https://www.ncbi.nlm.nih.gov/pubmed/34446157 https://www.jacc.org/doi/10.1016/j.jacc.2021.07.002 - ↑ 32.0 32.1 Diaz R, Orlandini A, Castellana N et al Effect of Colchicine vs Usual Care Alone on Intubation and 28-Day Mortality in Patients Hospitalized With COVID-19A Randomized Clinical Trial. JAMA Netw Open. 2021;4(12):e2141328 PMID: https://www.ncbi.nlm.nih.gov/pubmed/34964849 Free article https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2787585
- ↑ 33.0 33.1 33.2 Hughes S FDA OKs Low-Dose Colchicine for Broad CV Indication. Medscape. June 20, 2023 https://www.medscape.com/viewarticle/993433
- ↑ 34.0 34.1 NEJM Knowledge+ Complex Medical Care