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colchicine (Colcrys, Lodoco)

Alkaloid isolated from Colchicum autumale. Antimitotic agent used in the study of cell division. Indications: 1) gout & pseudogout a) treatment of acute gouty arthritis b) prevention of attacks of acute gouty arthritis - colchicine may also diminish cardiovascular risk [27] 2) management of familial Mediterranean fever 3) primary biliary cirrhosis 4) inflammatory dermatoses [10] a) psoriasis b) Behcet syndrome 5) pericarditis: primary treatment & prevention of recurrence - may be used in combination with NSAID or glucocorticoid [13,22,23,25] 6) 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] 7) may reduce recurrent stroke & cardiovascular events in patients with coronary artery disease [35] Contraindications: 1) use with caution in elderly 2) use with caution in patients with hepatic, renal, GI or heart disease 3) avoid use when creatinine clearance < 10 mL/min [11] 4) hypersensitivity 5) blood dyscrasias 6) 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] 7) 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] 8) Covid-19: colchicine does not reduce mechanical ventilation or 28-day mortality in patients hospitalized with COVID-19 pneumonia [32] Dosage: (Gout): 1) acute attack a) 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] b) 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or nausea, vomiting or diarrhea occur - generally 4-8 mg needed to control acute attack c) 2 mg IV over 2-5 min [3] (withdrawn from market) 2) maintenance: a) 0.6 mg PO QD [3]. b) starting dose: 0.6 mg PO QD [4] c) 0.5-1.8 mg PO QD [6] 3) familial Mediterranean fever 0.6 mg PO BID 4) 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0.5 mg/day for coronary artery disease & after myocardial infarction [29,30,31,33] Tabs 0.5, 0.6, 1 mg Injection: withdrawn 2008, safety concerns, unapproved status [15] Colcrys: single ingredient* colchicine for treatment of acute flairs of gout & familial Mediterranean fever [16]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] Pharmacokinetics: 1) rapidly absorbed & deacetylated by the liver 2) protein binding 10-31% 3) time to peak concentration after oral dose 30-120 minutes 4) distribution: [10] a) kidney, liver, spleen & intestine contain large amounts b) colchicine excluded from skeletal muscle, heart, brain 5) metabolism by cyt P450 3A4 6) pumped out of cells by P-glycoprotein 7) hepatobiliary (80-90%) & renal (10-20%) excretion 8) 1/2life 12-30 minutes [8] a) second delayed increased in plasma levels due to enterohepatic circulation [8] b) detectable in leukocytes & urine 9 days after IV dose Dosage adjustment in renal failure: 1) decrease dose by 50% for creatinine clearance < 30-50 mL/min 2) avoid use when creatinine clearance < 10 mL/min [11] Adverse effects: 1) common (> 10%) a) nausea/vomiting b) diarrhea c) abdominal pain 2) less common (1-10%) - anorexia, alopecia 3) uncommon (< 1%) - myopathy*, peripheral neuritis, rash, agranulocytosis, aplastic anemia, hepatotoxicity, azoospermia, bone marrow suppression, malabsorption of vit B12 4) 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] 1) hemorrhagic gastroenteritis - nausea, vomiting, abdominal pain, inflammatory diarrhea 2) cardiovascular injury: ST segment elevation 3) acute respiratory distress syndome 4) nephrotoxicity leading to renal failure 5) disseminated intravascular coagulation 6) muscle weakness 7) ascending paralysis involving CNS 8) delirium, convulsions, shock 9) deaths associated with use of compounded injectable colchicine [14] Drug interactions: 1) colchicine increases sympathomimetic toxicity 2) colchicine increases effects of CNS depressants 3) drugs that inhibit cyt P450 3A4 & P-glycoprotein can increase toxicity of colchicine [12,16] a) erythromycin, clarithromycin (potentially fatal) [22,28] b) diltiazem, nicardipine, verapamil c) itraconazole, ketoconazole d) indinavir, ritonavir 4) cyclosporine [19] Test interactions: - may cause false positive urine tests for erythrocytes or hemoglobin Mechanism of action: 1) inhibits microtubule formation 2) supresses release of fibroblast growth factors, fibronectin & alveolar macrophage-derived growth factor 3) inhibits fibroblast proliferation & total collagen synthesis 4) inhibits leukocyte migration 5) diminished production of lactic acid 6) diminished deposition of uric acid crystals 7) reduces inflammatory response to & phagocytosis of crystals Structure: C22 H23 N O6

General

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

Properties

SIZE: MW = 399.44 G/M MISC-INFO: elimination route LIVER MELTING_POINT 157-124 C protein-binding 10-31% 1/2life 12-30 MINUTES pregnancy-category D safety in lactation ?

Database Correlations

PUBCHEM correlations

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: 2023222
  12. Prescriber's Letter 12(9): 2005 Fatal Interaction Between Clarithromycin and Colchicine Detail-Document#: 211004 (subscription needed) http://www.prescribersletter.com
  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: 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: 17667033
  14. FDA Medwatch: Colchicine Compounded Injectable Products http://www.fda.gov/medwatch/safety/2007/safety07.htm#Colchicine
  15. Prescriber's Letter 16(2): 2009 New Drugs Approved by the FDA in 2008 Detail-Document#: 250213 (subscription needed) http://www.prescribersletter.com
  16. 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
  17. Prescriber's Letter 16(9): 2009 New Safety Information for Colchicine and the Approval of Colcrys Detail-Document#: 250902 (subscription needed) http://www.prescribersletter.com
  18. 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. Prescriber's Letter 18(12): 2011 Colchicine Dosing and Drug Interactions Detail-Document#: 271208 (subscription needed) http://www.prescribersletter.com
  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: 20131255
  21. Prescriber's Letter 19(12): 2012 CHART: Comparison of Gout Therapies CHART: Colchicine Dosing and Drug Interactions Detail-Document#: 281224 (subscription needed) http://www.prescribersletter.com
  22. Medical Knowledge Self Assessment Program (MKSAP) 16, 18 American College of Physicians, Philadelphia 2012, 2018.
  23. Imazio M et al. for the ICAP Investigators. A randomized trial of colchicine for acute pericarditis. N Engl J Med 2013 Sep 1 PMID: 23992557 http://www.nejm.org/doi/full/10.1056/NEJMoa1208536
  24. Yang LP. Oral colchicine (Colcrys): in the treatment and prophylaxis of gout. Drugs. 2010 Aug 20;70(12):1603-13 PMID: 20687623
  25. 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: 24694983 - Cacoub PP. Colchicine for treatment of acute or recurrent pericarditis. Lancet 2014 Mar 30 PMID: 24694984
  26. 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: 21480191
  27. 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: 26582823
  28. 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: 16007523
  29. Tardif JC et al. Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med 2019 Nov 16; PMID: 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: 31733139 https://www.nejm.org/doi/10.1056/NEJMe1914378
  30. Nidorf SM, Fiolet ATL, Mosterd A Colchicine in Patients with Chronic Coronary Disease. N Engl J Med. Aug 31, 2020 PMID: 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: 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: 32862667 https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.120.050771
  31. 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: 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: 34446157 https://www.jacc.org/doi/10.1016/j.jacc.2021.07.002
  32. 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-19. A Randomized Clinical Trial. JAMA Netw Open. 2021;4(12):e2141328 PMID: 34964849 Free article https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2787585
  33. Hughes S FDA OKs Low-Dose Colchicine for Broad CV Indication. Medscape. June 20, 2023 https://www.medscape.com/viewarticle/993433
  34. NEJM Knowledge+ Complex Medical Care
  35. Hughes S Colchicine a New Tool for Ischemic Stroke, CVD Event Recurrence? Medscape. May 29, 2024 https://www.medscape.com/viewarticle/colchicine-new-tool-ischemic-stroke-cvd-event-recurrence-2024a1000a2p

Component-of

colchicine/probenecid (ColBENEMID)