COLCHICINE (LODOCO®)

• ACRONYMS AND DEFINITIONS

• ACS - Acute coronary syndrome
• CAC - Coronary artery calcium
• CAD - Coronary artery disease
• CPK - Creatine phosphokinase
• CTA - CT angiography
• CrCl - Creatinine clearance
• CVD - Cardiovascular disease
• MI - Myocardial infarction
• NYHA - New York Heart Association heart failure classification
• RCT - Randomized controlled trial
• ULN - Upper limit of normal

• DRUGS IN CLASS

• Colchicine is an antiinflammatory agent used for many years to treat and prevent gout flares (see colchicine for gout)
• In 2023, colchicine (Lodoco®) received FDA approval for cardiovascular disease prevention after several large trials showed that it lowered the risk of CVD events

• MECHANISM OF ACTION

• Colchicine's mechanism of action in the prevention of major cardiovascular events is not understood. However, it is known that colchicine disrupts cytoskeletal functions through inhibition of β-tubulin polymerization into microtubules and consequently prevents the activation, degranulation, and migration of neutrophils. Colchicine may also interfere with the intracellular assembly of the inflammasome complex in neutrophils and monocytes that mediates activation of interleukin-1β. These anti-inflammatory effects are consistent with clinical data demonstrating that colchicine reduces high sensitivity C- reactive protein (hs-CRP).

• FDA-APPROVED INDICATIONS

• Lodoco is indicated to reduce the risk of myocardial infarction (MI), stroke, coronary revascularization, and cardiovascular death in adult patients with established atherosclerotic disease or with multiple risk factors for cardiovascular disease.

• CARDIOVASCULAR DISEASE

• Overview
• The effects of colchicine on the secondary prevention of CVD events were evaluated in the two trials detailed below

• Summary
• In the two studies above, colchicine lowered the risk of cardiovascular events by 2 - 3% over two years in patients with a history of CVD. It had no significant effect on overall mortality, and in the LoDoCo2 trial, noncardiovascular deaths were more common in the colchicine group (HR 1.51 95%CI [0.99 - 2.31]); the reason for this is unclear, as there were no clear trends in the individual causes of death. Colchicine side effects, including diarrhea, were similar to placebo in both trials, and an increased risk of myopathy from combining colchicine with statins was not observed.
• A study published in 2021 found that high-dose colchicine at the time of PCI for ST-segment-elevation myocardial infarction did not limit infarct size. [PMID 34420373]

• SIDE EFFECTS

• General
• In the two large trials detailed above, side effects with colchicine were mostly similar to placebo. In the LoDoCo2 trial, myalgias were slightly more common in the colchicine group (21.2% vs 18.5%, HR 1.15 95%CI [1.01 - 1.31]).

• Blood dyscrasias
• Blood dyscrasias, including leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, and aplastic anemia, have been reported in patients receiving colchicine. The risk is greater in patients with conditions that increase colchicine exposure, including kidney disease, liver disease, and concomitant CYP3A4 and/or P-glycoprotein inhibitors. Use caution in at-risk patients and monitor for gastrointestinal symptoms, which are often the first signs of toxicity. In the LoDoCo2 and COLCOT trials, where patients with significant renal and hepatic disease were excluded, colchicine therapy did not increase the risk of blood dyscrasias.

• Neuromuscular toxicity
• Neuromuscular toxicity, including rhabdomyolysis, has been reported in patients receiving colchicine. The risk is greater in patients with conditions that increase colchicine exposure, including kidney disease, liver disease, and concomitant CYP3A4 and/or P-glycoprotein inhibitors. Combined use with other myopathy-inducing drugs (e.g. statins, fibrates) may also increase the risk. Use caution in at-risk patients and monitor for gastrointestinal symptoms, which are often the first signs of toxicity. In the LoDoCo2 and COLCOT trials, where patients with significant renal and hepatic disease were excluded, colchicine therapy did not increase the risk of muscle toxicity, even in patients receiving statins.

• CONTRAINDICATIONS

• Concomitant strong CYP3A4 inhibitors
• Concomitant P-glycoprotein inhibitors
• CrCl < 15 ml/min
• Child-Pugh C liver disease
• Pre-existing blood dyscrasia

• PRECAUTIONS

• Kidney disease
• CrCl 15 - 59 ml/min with moderate CYP3A4 inhibitor: DO NOT USE
• CrCl < 15 ml/min: DO NOT USE

• Liver disease
• Child-Pugh A or B with strong P-glycoprotein inhibitor or strong or moderate CYP3A4 inhibitor: DO NOT USE
• Child-Pugh C: DO NOT USE

• DRUG INTERACTIONS

• NOTE: The drug interactions presented here are NOT all-inclusive. Other interactions may exist. Drug interaction checkers provide the most efficient and practical way to check for interactions among multiple medications. A free interaction checker is available from Drugs.com (see Drugs.com interactions checker).

• Colchicine (Lodoco®)
• CYP3A4 inhibitors - colchicine is a sensitive CYP3A4 substrate, and CYP3A4 inhibitors may increase its exposure. Colchicine is contraindicated with strong CYP3A4 inhibitors. Patients receiving colchicine with moderate CYP3A4 inhibitors should be monitored for gastrointestinal side effects, often the first signs of toxicity. Patients with renal or hepatic impairment should not take colchicine with a moderate CYP3A4 inhibitor.
• Digoxin - digoxin is a P-glycoprotein substrate, and it may increase colchicine exposure. Monitor for signs of muscle toxicity when combining.
• Fibrates - the risk of myopathy may be increased when colchicine is taken with fibrates. Consider alternative therapy and monitor for signs of muscle toxicity.
• Grapefruit juice - grapefruit juice is a strong CYP3A4 inhibitor and may increase colchicine exposure. Patients should not eat grapefruit or drink grapefruit juice while taking colchicine.
• Oral contraceptives - colchicine may interact with oral contraceptives like norethindrone and ethinyl estradiol and increase the risk of adverse events, including diarrhea, nausea, and upper abdominal pain. In a pharmacokinetic study, colchicine 0.6 mg twice daily for 14 days did not affect ethinyl estradiol and norethindrone levels.
• P-glycoprotein inhibitors - colchicine is a sensitive P-glycoprotein substrate, and P-glycoprotein inhibitors may increase its exposure. Colchicine is contraindicated with strong P-glycoprotein inhibitors. Patients with renal or hepatic impairment should not take colchicine with any P-glycoprotein inhibitor.
• Statins - the risk of myopathy may be increased when colchicine is taken with statins. Consider alternative therapy and monitor for signs of muscle toxicity. In the LoDoCo2 trial and COLCOT trial, the incidence of myopathy was not increased in patients receiving concomitant statins.

• Metabolism and clearance
• CYP3A4 - sensitive substrate

• DOSING

• Dosage form
• 0.5 mg tablet

• Dosing
• Dosing: 0.5 mg once daily
• Missed dose: take missed dose as soon as possible. Do not double the next dose to make up for skipped doses.


• Kidney disease
• CrCl 15 - 59 ml/min with moderate CYP3A4 inhibitor: DO NOT USE
• CrCl < 15 ml/min: DO NOT USE


• Liver disease
• Child-Pugh A or B with strong P-glycoprotein inhibitor or strong or moderate CYP3A4 inhibitor: DO NOT USE
• Child-Pugh C: DO NOT USE

• LONG-TERM SAFETY

• Colchicine has been used for many decades to treat gout. It has been proven safe when prescribed appropriately.

• BIBLIOGRAPHY

• 1 - Lodoco PI