Colchicine
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Prophylaxis of gout flares | Adults (Colcrys, Mitigare, Gloperba) | Monotherapy or adjunctive to urate-lowering therapy | FDA Approved |
| Acute gout flare treatment | Adults (Colcrys) | Monotherapy at first sign of flare | FDA Approved |
| Familial Mediterranean fever (FMF) | Adults and children ≥4 years (Colcrys) | Long-term monotherapy | FDA Approved |
| ASCVD risk reduction | Adults with established ASCVD or multiple CV risk factors (Lodoco) | Adjunctive to standard CV therapy | FDA Approved |
Colchicine is one of the oldest medications still in clinical use, with origins tracing back thousands of years. It holds a unique position as a drug spanning rheumatology and cardiology, having gained its most recent FDA approval in June 2023 for atherosclerotic cardiovascular disease risk reduction based on the landmark COLCOT and LoDoCo2 trials. Its role in gout remains foundational, recommended as first-line therapy for acute flares by the American College of Rheumatology (2020).
Recurrent pericarditis — Well-established adjunctive role; supported by the COPE, CORP, and CORP-2 trials. Evidence quality: High.
Acute pericarditis — First-line adjunctive therapy per ESC 2015 guidelines (COPE trial). Evidence quality: High.
Calcium pyrophosphate deposition disease (pseudogout) — Used for prophylaxis and acute flares. Evidence quality: Moderate.
Behçet’s disease — Oral and genital ulcers, joint involvement. Evidence quality: Moderate.
Post-pericardiotomy syndrome / atrial fibrillation prophylaxis after cardiac surgery — Supported by the COPPS and COPPS-2 trials. Evidence quality: Moderate.
Primary biliary cholangitis / hepatic cirrhosis — Limited evidence. Evidence quality: Low.
Dosing
Adult Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Acute gout flare — first sign of symptoms | 1.2 mg (2 tabs) then 0.6 mg 1 h later | N/A (single course) | 1.8 mg per course | Must be taken at flare onset; efficacy decreases with delay Repeat course no earlier than 3 days later |
| Gout flare prophylaxis — during urate-lowering therapy initiation | 0.6 mg once daily | 0.6 mg once or twice daily | 1.2 mg/day | Continue for at least 3–6 months of ULT Without regard to meals |
| FMF — adult maintenance | 1.2 mg/day | 1.2–2.4 mg/day in 1–2 divided doses | 2.4 mg/day | Titrate in 0.3 mg increments based on response and tolerability |
| ASCVD risk reduction — established disease or high risk | 0.5 mg once daily | 0.5 mg once daily | 0.5 mg/day | Lodoco formulation; adjunctive to statin and antiplatelet therapy No loading dose required |
| Recurrent pericarditis — adjunctive (off-label) | 0.5 mg BID (≥70 kg) or 0.5 mg daily (<70 kg) | Same as starting | 1 mg/day | Given with NSAID or aspirin; taper colchicine last Typical duration 6–12 months |
| Acute pericarditis — adjunctive (off-label) | 0.5 mg BID (≥70 kg) or 0.5 mg daily (<70 kg) | Same as starting | 1 mg/day | Per ESC 2015 guidelines; 3-month course |
Pediatric Dosing (FMF Only)
| Age Group | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| 4–6 years | 0.3 mg/day | 0.3–1.8 mg/day | 1.8 mg/day | Titrate in 0.3 mg increments; single or divided doses |
| 6–12 years | 0.9 mg/day | 0.9–1.8 mg/day | 1.8 mg/day | Adjust based on disease control and GI tolerability |
| >12 years | 1.2 mg/day | 1.2–2.4 mg/day | 2.4 mg/day | Same as adult dosing |
Renal Impairment Adjustments
| Renal Function | Gout Prophylaxis | Acute Gout Flare | FMF | Notes |
|---|---|---|---|---|
| Mild–moderate (CrCl 30–80 mL/min) | No adjustment | No adjustment | Monitor closely; reduce if needed | Close monitoring for toxicity |
| Severe (CrCl <30 mL/min) | 0.3 mg/day | Standard dose; repeat no more than q2wk | Start 0.3 mg/day | Contraindicated with P-gp/CYP3A4 inhibitors |
| Dialysis (CrCl <15 mL/min) | 0.3 mg twice weekly | 0.6 mg x 1 dose; repeat no more than q2wk | Start 0.3 mg/day | Not removed by hemodialysis |
The older high-dose regimen (4.8 mg over 6 hours) is no longer recommended. A pivotal RCT demonstrated that the low-dose regimen (1.8 mg over 1 hour) provides equivalent efficacy with significantly fewer gastrointestinal adverse effects — GI events occurred in 26% with low-dose versus 77% with high-dose versus 20% with placebo (FDA PI).
Pharmacology
Mechanism of Action
Colchicine is a tricyclic lipid-soluble alkaloid derived from Colchicum autumnale (autumn crocus). Its primary anti-inflammatory action centres on the inhibition of β-tubulin polymerisation into microtubules, which disrupts multiple neutrophil functions including migration, adhesion, degranulation, and chemotaxis. By preventing microtubule assembly, colchicine interferes with the intracellular transport machinery that inflammatory cells require to mount an effective response at sites of crystal deposition or vascular injury.
Beyond microtubule disruption, colchicine inhibits the NLRP3 inflammasome complex in neutrophils and monocytes, thereby reducing interleukin-1β (IL-1β) release — a key driver of both gouty inflammation and atherosclerotic plaque instability. It also attenuates the NF-κB signalling pathway and suppresses superoxide production by neutrophils. These combined mechanisms explain its clinical utility across gout, autoinflammatory syndromes, pericarditis, and atherosclerotic cardiovascular disease.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Oral bioavailability ~45%; Tmax 1–1.4 h; food reduces extent by ~15% without clinical significance | Rapid onset; may be taken without regard to meals |
| Distribution | Vd 5–8 L/kg; protein binding 39 ± 5% (albumin); crosses placenta; enters breast milk | Large Vd reflects extensive tissue binding to intracellular tubulin; not dialyzable |
| Metabolism | Hepatic via CYP3A4 to 2-O-demethylcolchicine and 3-O-demethylcolchicine; P-gp substrate | Critical pathway for drug interactions; dual CYP3A4/P-gp inhibitors can cause fatal toxicity |
| Elimination | t½ 26.6–31.2 h (young adults); 10–20% excreted unchanged renally; primarily hepatobiliary | Long half-life supports once-daily dosing; accumulation risk in renal/hepatic impairment |
Side Effects
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Diarrhoea | 23% (acute gout, low-dose); up to 20% (FMF); ~10% (CV dose 0.5 mg) | Dose-dependent; early sign of toxicity if severe; reduce dose or stop if persistent |
| Nausea | 4–17% (dose-dependent); up to 20% (FMF) | More common at higher doses and with FMF regimens; usually transient |
| Abdominal pain / cramping | Up to 20% (FMF) | May herald more significant GI toxicity; dose-limiting |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Vomiting | Up to 17% (high-dose); 0% (recommended low-dose gout) | Essentially absent with current low-dose gout regimen; more common in FMF dosing |
| Pharyngolaryngeal pain | 3% | Reported in the acute gout flare trial (FDA PI) |
| Headache | 1–10% | Reported in PK studies at ~10%; lower in clinical trials |
| Fatigue | 1–4% | Generally mild and transient |
| Myalgia | ~21% (CV trials, colchicine) vs 19% (placebo) | From LoDoCo2 Netherlands cohort; distinguish from neuromuscular toxicity |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Myelosuppression (pancytopenia, aplastic anaemia) | Rare | Weeks to months of chronic use | Hold colchicine; obtain urgent CBC; haematology referral |
| Neuromuscular toxicity / rhabdomyolysis | Rare; higher risk with CYP3A4/P-gp inhibitors or statins | Weeks to months; cumulative | Discontinue colchicine; check CK and renal function; resolves within 1 week to months |
| Disseminated intravascular coagulation (DIC) | Very rare; usually in overdose | 24–72 h post-overdose (phase 2) | Emergency supportive care; ICU admission |
| Multi-organ failure (overdose) | Dose ≥0.5 mg/kg usually fatal | 24–72 h post-ingestion | No specific antidote; aggressive supportive care; not dialyzable |
| Sensorimotor neuropathy | Rare; cumulative toxicity | Months of chronic therapy | Discontinue; monitor for resolution; nerve conduction studies |
| Pneumonia (CV indication) | ~0.9% vs 0.4% placebo (COLCOT) | Variable | Standard infectious disease workup and treatment |
| Reason for Discontinuation | Incidence | Context |
|---|---|---|
| Diarrhoea | Most common reason across all indications | Dose-dependent; GI effects are the primary driver of treatment cessation |
| Nausea / vomiting | Second most common | Predominantly seen at FMF doses (1.2–2.4 mg/day) and the obsolete high-dose gout regimen |
| Myalgia / muscle weakness | Uncommon but may prompt cessation | Warrants CK check to exclude rhabdomyolysis, especially with concurrent statin use |
Gastrointestinal symptoms are the most frequent adverse effects and should be treated as dose-limiting signals. If diarrhoea becomes persistent or severe, reduce the dose or temporarily hold colchicine. Severe GI symptoms may herald the onset of more dangerous systemic toxicity, particularly in patients with concomitant CYP3A4/P-gp inhibitor use or renal impairment. Reassuringly, the low-dose cardiovascular regimen (0.5 mg daily) shows GI event rates that are barely distinguishable from placebo.
Drug Interactions
Colchicine is a substrate of both CYP3A4 and P-glycoprotein (P-gp). Inhibition of either pathway raises colchicine plasma levels; dual inhibition of both CYP3A4 and P-gp has resulted in fatal colchicine toxicity at standard therapeutic doses. All potential interacting medications must be reviewed before initiating colchicine.
Monitoring
-
CBC with Differential
Baseline, then every 3–6 months for chronic use
Routine Monitor for myelosuppression, leukopenia, thrombocytopenia, or pancytopenia. More frequent monitoring if co-administered with interacting drugs. -
Renal Function
Baseline, then at least annually
Routine Serum creatinine and estimated CrCl. Colchicine accumulates in renal impairment; dose adjustment required if CrCl falls below 30 mL/min. -
Hepatic Function
Baseline, then as clinically indicated
Routine LFTs before initiation. Clearance is significantly reduced in hepatic impairment, prolonging half-life and increasing toxicity risk. -
Creatine Kinase (CK)
If muscle symptoms develop
Trigger-based Check CK and renal function if patient reports new muscle pain, weakness, or tenderness, particularly with concurrent statin or fibrate therapy. -
GI Symptoms
Every visit; ongoing self-monitoring
Routine Diarrhoea, nausea, vomiting, and abdominal pain are dose-limiting and may signal early toxicity. Severe GI symptoms warrant dose reduction or interruption. -
Drug Interaction Review
At initiation and every prescription change
Trigger-based Screen for new CYP3A4 inhibitors, P-gp inhibitors, and myotoxic agents. Particular vigilance with antibiotics (macrolides, azole antifungals) and immunosuppressants.
Contraindications & Cautions
Absolute Contraindications
- Concurrent use of strong CYP3A4 inhibitors or P-gp inhibitors in patients with renal or hepatic impairment — fatal toxicity has been reported at therapeutic doses in this combination.
- Severe hepatic impairment (for the Lodoco ASCVD indication) — contraindicated per Lodoco PI.
- Renal failure (CrCl <15 mL/min) (for the Lodoco ASCVD indication) — contraindicated per Lodoco PI.
- Combined renal and hepatic impairment — patients with both organ impairments should not receive colchicine.
- Preexisting blood dyscrasias (for the Lodoco ASCVD indication).
Relative Contraindications (Specialist Input Recommended)
- Severe renal impairment (CrCl <30 mL/min) without concurrent CYP3A4/P-gp inhibitors — dose reduction and close monitoring required; specialist co-management advisable.
- Moderate-to-severe hepatic impairment — reduced clearance and prolonged half-life increase toxicity risk; dose reduction and close monitoring.
- Concurrent use of multiple myotoxic agents (statins + fibrates + colchicine) — document risk-benefit discussion.
- Elderly patients — at increased risk of neuromuscular toxicity even with normal renal and hepatic function; lower starting doses preferred.
Use with Caution
- Mild-to-moderate renal impairment (CrCl 30–80 mL/min) — standard dosing acceptable but monitor closely for toxicity.
- Mild hepatic impairment — no dose adjustment required; monitor LFTs.
- Pregnancy — use only if potential benefit justifies the risk; crosses the placenta.
- Lactation — present in breast milk at <10% of the maternal weight-adjusted dose; observe infant for GI symptoms.
- Fertility — colchicine may transiently impair fertility (reversible upon discontinuation).
Fatal overdoses, both accidental and intentional, have been reported in adults and children who have ingested colchicine. Colchicine should be kept out of the reach of children. Life-threatening and fatal drug interactions have been reported when colchicine was co-administered with P-gp and/or strong CYP3A4 inhibitors, including clarithromycin and cyclosporine, particularly in patients with renal or hepatic impairment. Acute overdose exceeding 0.5 mg/kg (approximately 35 mg in a 70 kg adult) is usually fatal.
Patient Counselling
Purpose of Therapy
Colchicine works by reducing inflammation in the body. Depending on the reason it was prescribed, it may be used to treat or prevent gout attacks, to control familial Mediterranean fever symptoms, to reduce the risk of heart attacks and strokes in people with established heart disease, or to treat inflammation around the heart (pericarditis). It is not a painkiller and should not be used for general pain relief.
How to Take
Take colchicine exactly as prescribed. It may be taken with or without food. For an acute gout flare, take two tablets (1.2 mg) at the very first sign of a flare and then one tablet (0.6 mg) one hour later. Do not take more than this amount. For preventive use or heart disease, take the prescribed dose at the same time each day. If a dose is missed, take it as soon as remembered but do not double the next dose.
Sources
- Colcrys (colchicine) Prescribing Information. Takeda Pharmaceuticals America, Inc. Revised October 2022. DailyMed Primary FDA-approved PI for gout and FMF indications; source for dosing, adverse reactions, and drug interaction data.
- Lodoco (colchicine 0.5 mg) Prescribing Information. Agepha Pharma USA, LLC. 2023. FDA FDA-approved PI for the cardiovascular disease indication; source for ASCVD dosing and contraindications.
- FDA Safety Communication: Colchicine (marketed as Colcrys) Information. FDA, 2009. FDA.gov Documents the transition from unapproved to approved colchicine products and highlights fatal drug interactions.
- Tardif J-C, Kouz S, Waters DD, et al. Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med. 2019;381(26):2497–2505. doi:10.1056/NEJMoa1912388 The COLCOT trial: demonstrated 23% relative risk reduction in MACE with 0.5 mg colchicine daily post-MI.
- Nidorf SM, Fiolet ATL, Mosterd A, et al. Colchicine in patients with chronic coronary disease. N Engl J Med. 2020;383(19):1838–1847. doi:10.1056/NEJMoa2021372 The LoDoCo2 trial: demonstrated 31% relative risk reduction in MACE with 0.5 mg colchicine daily in chronic coronary disease.
- Terkeltaub RA, Furst DE, Bennett K, et al. High versus low dosing of oral colchicine for early acute gout flare. Arthritis Rheum. 2010;62(4):1060–1068. doi:10.1002/art.27327 AGREE trial: established that low-dose colchicine (1.8 mg total) is equally effective to high-dose (4.8 mg) with significantly fewer GI adverse effects.
- Imazio M, Brucato A, Cemin R, et al. A randomized trial of colchicine for acute pericarditis. N Engl J Med. 2013;369(16):1522–1528. doi:10.1056/NEJMoa1208536 ICAP trial: demonstrated that colchicine as adjunct to conventional therapy reduces pericarditis recurrence (16.7% vs 37.5% placebo); established weight-based dosing for pericarditis.
- FitzGerald JD, Dalbeth N, Mikuls T, et al. 2020 American College of Rheumatology guideline for management of gout. Arthritis Care Res. 2020;72(6):744–760. doi:10.1002/acr.24180 Current ACR guideline recommending colchicine as first-line therapy for acute gout flares and prophylaxis during ULT initiation.
- Virani SS, Newby LK, Arnold SV, et al. 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the Management of Patients With Chronic Coronary Disease. J Am Coll Cardiol. 2023;82(9):833–955. doi:10.1016/j.jacc.2023.04.003 AHA/ACC guideline incorporating low-dose colchicine as a consideration for residual inflammatory risk reduction in chronic coronary disease.
- Leung YY, Yao Hui LL, Kraus VB. Colchicine — update on mechanisms of action and therapeutic uses. Semin Arthritis Rheum. 2015;45(3):341–350. doi:10.1016/j.semarthrit.2015.06.013 Comprehensive review of colchicine’s mechanisms including microtubule inhibition, inflammasome suppression, and NF-κB pathway effects.
- Deftereos SG, Beber S, Giannopoulos G, et al. Colchicine pharmacokinetics and mechanism of action. Curr Pharm Des. 2018;24(6):659–663. doi:10.2174/1381612824666180123110042 Concise review covering PK parameters, CYP3A4/P-gp dependence, and primary anti-inflammatory mechanisms.
- Ferron GM, Rochdi M, Jusko WJ, Scherrmann JM. Oral absorption characteristics and pharmacokinetics of colchicine in healthy volunteers after single and multiple doses. J Clin Pharmacol. 1996;36(10):874–883. doi:10.1002/j.1552-4604.1996.tb04753.x Established key PK parameters including bioavailability (~45%), Vss (419 L), and terminal half-life (57.8 h IV).
- Rochdi M, Sabouraud A, Girre C, Venet R, Scherrmann JM. Pharmacokinetics and absolute bioavailability of colchicine after i.v. and oral administration in healthy human volunteers and elderly subjects. Eur J Clin Pharmacol. 1994;46(4):351–354. doi:10.1007/BF00194404 Demonstrated similar bioavailability (44–45%) in elderly versus young adults, but higher peak levels and AUC in elderly patients with reduced renal function.
- Ben-Chetrit E, Levy M. Colchicine: 1998 update. Semin Arthritis Rheum. 1998;28(1):48–59. doi:10.1016/S0049-0172(98)80028-0 Foundational review of colchicine’s PK and clinical pharmacology including Vd, protein binding, and hepatobiliary excretion pathway.