Colchicine

Mechanism of Action

Colchicine demonstrates primarily anti-inflammatory effects; it disrupts cytoskeletal functions by inhibiting β-tubulin polymerization into microtubules, preventing activation, degranulation, and migration of neutrophils associated with mediating some gout symptoms. Colchicine does not inhibit phagocytosis of uric acid crystals, but it does seem to prevent the release of an inflammatory glycoprotein from phagocytes. Colchicine blocks metaphase through 2 separate anti-mitotic effects: disruption of mitotic spindle formation and disruption of the sol-gel formation. The toxic effects of colchicine are related to this anti-mitotic activity within proliferating tissue such as skin, hair, and bone marrow.[5][6]

The mechanism of action of colchicine as a treatment for familial Mediterranean fever is less well understood; it may interfere with the intracellular assembly of the inflammasome complex present in neutrophils and monocytes that mediate the activation or interleukin-1-β.

Pharmacokinetics

Absorption: Colchicine is readily absorbed within 3 hours when given orally to healthy adults. After a single dose of 0.6 mg administered under fasting conditions, this medication reaches a plasma concentration of 1.1 to 4.4 ng/mL. Oral colchicine has an absolute bioavailability of approximately 45%, and taking the drug with food reduces absorption by approximately 15%. However, this decrease does not appear to cause clinically significant differences.

Distribution: Colchicine has low protein binding, and its volume of distribution in healthy young adults ranges from 5 to 8 L/kg. The drug crosses the placenta and enters breast milk.

Metabolism: Colchicine is metabolized via CYP3A4 and demethylated into 2-O-demethylcolchicine and 3-O-demethylcolchicine in the liver and other tissues.

Elimination: The mean elimination half-life of colchicine in young, healthy adults is 26.6 to 31.2 hours. This drug is primarily eliminated unchanged in bile and urine.

Administration

Available Forms and Strengths

Colchicine is available as a tablet, capsule, and solution. In tablet form, it is available in 0.6 and 0.5 mg formulations. Capsules are available in 0.6 mg. There is a topical gel homeopathic formulation of Colchicum autumnale.

Colchicine is typically administered orally, and the use of the topical gel is rare. Due to toxicity, the injectable form is no longer available in the United States.

Adult Dosage

The long-term administration of colchicine is currently being evaluated as prophylaxis of gout flares and FMF. However, the efficacy and safety of repeated treatment for gout flares have not been studied. The dosing regimens for colchicine are different for each indication and must be individualized.

Prophylaxis of gout flares: Colchicine dosing is 0.6 mg once or twice a day in patients older than 16; the maximum dose is 1.2 mg daily. The initiation of uric acid-lowering therapies, such as allopurinol, pegloticase, and febuxostat, can lead to an increase in gout flares. This occurs because fluctuations in serum uric acid levels cause urate deposits in tissues to mobilize. To manage this, it is advisable to use colchicine as part of gout flare prophylaxis when starting these therapies. Prophylactic treatment is often recommended for a minimum of the first 6 months after beginning uric acid-lowering therapy.

Treatment of acute gout flare: Colchicine 1.2 mg is administered at the first sign of a gout flare, followed by 0.6 mg an hour later. The maximum allowed dose is 1.8 mg over 1 hour. If a patient uses colchicine for gout prophylaxis, this dose should not be administered until 12 hours later.

Familial Mediterranean fever: 1.2 mg to 2.4 mg for patients older than 12. The daily dose is administered in 1 or 2 doses and may be increased by 0.3 mg per day to control disease or reduced by 0.3 mg per day if adverse effects are intolerable. The maximum daily dose is 2.4 mg.

Specific Patient Populations

Hepatic impairment: The dose of colchicine might need to be adjusted depending on the degree of hepatic impairment, as discussed below.

Prophylaxis of gout flares

• Patients with mild to moderate hepatic function impairment are not required to adjust the dose but should be monitored closely for adverse effects.
• The initial dose should be reduced for patients with severe impairment, and any patients undergoing dose increases should be closely monitored. 

Treatment of gout flares

• The dose does not require adjustment for patients with mild to moderate hepatic function impairment, but the patient should be monitored closely for adverse effects.
• While the dose is the same for patients with severe impairment, a treatment course should not be repeated more than once every 2 weeks. If patients require repeated courses, consider alternate therapy.
• Treatment of gout flares with colchicine is not recommended for patients with hepatic impairment who are receiving colchicine for prophylaxis.

Familial Mediterranean fever

• Patients with mild to moderate hepatic function impairment are not required to adjust the dose but should be monitored closely for adverse effects.
• For patients with severe impairment, the initial dose should be reduced, and any increase in dose should be accompanied by close monitoring.

Renal impairment: The dose might need to be adjusted depending on the degree of renal impairment, as discussed below.

For prophylaxis of gout flares

• Patients with mild (CrCl of 50 to 80 mL/min) to moderate (CrCl of 30 to 50 mL/min) renal function impairment are not required to adjust the dose but should be monitored closely for adverse effects.
• For patients with severe impairment, the starting dose should be reduced to 0.3 mg daily, and any dose increases should be accompanied by close monitoring.
• For patients undergoing dialysis, the starting dose should be 0.3 mg, given twice a week with close monitoring.

Treatment of gout flares

• For patients with mild to moderate renal function impairment, there is no need to adjust the dose, but the patient should be monitored closely for adverse effects of colchicine.
• For patients with severe impairment, while the dose is the same, a treatment course should not be repeated more than once every 2 weeks. If patients require repeated courses, consider alternate therapy.
• For patients undergoing dialysis, the total recommended dose should be decreased, only a single 0.6 mg dose should be administered, and a treatment course should not be repeated more than once every 2 weeks.
• Treatment of gout flares with colchicine is not recommended for patients with renal impairment who are already receiving this drug for prophylaxis.

Familial Mediterranean fever

Caution is advised when administering colchicine to patients with moderate and severe renal impairment and those undergoing dialysis. The dosage should be reduced for these patients.

• Patients with mild to moderate renal impairment should be monitored closely for adverse effects, and a dose reduction may be necessary.
• Patients with severe renal impairment: initiate at 0.3 mg/day; if the dose must be increased, the patient should be monitored closely for adverse effects. 
• The recommended starting dose for patients undergoing dialysis is 0.3 mg daily. However, with adequate monitoring for colchicine's adverse effects, the dose may be increased. 

Pregnancy considerations: Colchicine is classified as a pregnancy category C drug. Colchicine therapy during pregnancy should only be initiated if the potential benefit to the mother justifies the possible risk to the fetus.

Breastfeeding considerations: Colchicine is excreted into human breast milk. Colchicine can alter gastrointestinal cell renewal and permeability; however, no adverse effects have been reported in breastfed infants. The American Academy of Pediatrics considers colchicine compatible with breastfeeding in most scenarios.

Pediatric patients:

Prophylaxis and treatment of gout flares: Colchicine is not recommended for prophylaxis or treatment of gout flares in pediatric patients.

Familial Mediterranean fever: The recommended colchicine dosage for FMF in pediatric patients 4 or older is based on the patient's age. The following daily doses can be administered either as a single dose or divided into 2 doses per day:

• Children aged 4 to 6: 0.3 mg to 1.8 mg daily
• Children aged 6 to 12: 0.9 mg to 1.8 mg daily
• Adolescents older than 12: 1.2 mg to 2.4 mg daily

Older patients: Older adults have an increased risk of neuromuscular toxicity and rhabdomyolysis when taking colchicine, regardless of renal and hepatic impairment. Caution is necessary, and a dose adjustment may be appropriate when prescribing colchicine to these patients.

Adverse Effects

The most common adverse reactions are related to the gastrointestinal tract. Diarrhea is the most commonly reported symptom (23%), followed by vomiting (17%) and nausea (4% to 17%). Central nervous system symptoms, such as fatigue and headache, and endocrine and metabolic conditions, such as gout and pharyngolaryngeal pain, have been reported.[7][8][9]

While less common, the following adverse reactions have been reported in patients receiving colchicine therapy and are thought to be reversible upon discontinuation of the medication or lowering the dose:

• Neurologic: sensorimotor neuropathy [10]
• Dermatologic: alopecia, maculopapular rash, purpura, rash [11]
• Gastrointestinal: abdominal cramping, abdominal pain, lactose intolerance
• Hematologic: leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, aplastic anemia
• Hepatobiliary: elevated AST, elevated ALT
• Musculoskeletal: myopathy, elevated CPK, myotonia, muscle weakness, muscle pain, rhabdomyolysis [12]
• Reproductive: azoospermia, oligospermia [13]

Drug-Drug Interactions

Colchicine is a substrate for the efflux transporter P-glycoprotein. Of the cytochrome P450 enzymes tested, CYP3A4 is the primary enzyme involved in the metabolism of colchicine. If administering colchicine with drugs that inhibit P-glycoprotein, most of which also inhibit CYP3A4, increased concentrations of colchicine are likely, and there are reports of fatal drug interactions. The colchicine dose should be adjusted when co-administered with drugs known to inhibit CYP3A4 or P-glycoprotein. These combinations should be avoided for patients with renal or hepatic impairment due to increased toxicity risk.[14]

The following medications should be used with caution when co-administered with colchicine:

Potent CYP3A4 inhibitors: 

These medications include atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin, darunavir/ritonavir, lopinavir/ritonavir, nefazodone, nelfinavir, and tipranavir/ritonavir. Avoid colchicine use with these drugs in patients with renal or hepatic impairment due to increased toxicity risk.

Prophylaxis of gout flares

• Standard dose: 0.6 mg once or twice daily
• Adjusted dose: Reduce to 0.3 mg once daily or every other day

Treatment of gout flares

• Standard dose: 1.2 mg initially, followed by 0.6 mg an hour later (repeat no earlier than 3 days)
• Adjusted dose: Reduce to 0.6 mg initially, followed by 0.3 mg an hour later (repeat no earlier than 3 days)

Familial Mediterranean fever

• Standard dose: Maximum daily dose of 1.2 to 2.4 mg
• Adjusted dose: Maximum daily dose reduced to 0.6 mg (may be given as 0.3 mg twice daily)

Moderate CYP3A4 inhibitors: 

The medications amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil can increase colchicine plasma levels, with risks of neuromuscular toxicity (notably with diltiazem and verapamil).

Prophylaxis of gout flares

• Standard: 0.6 mg twice daily → Adjusted: 0.3 mg twice daily or 0.6 mg once daily
• Standard: 0.6 mg once daily → Adjusted: 0.3 mg once daily

Treatment of gout flares

• Standard: 1.2 mg, followed by 0.6 mg an hour later →  Adjusted: Same initial dose but repeat dosing no earlier than 3 days

Familial Mediterranean fever

• Standard: Maximum daily dose of 1.2 to 2.4 mg → Adjusted: Reduce the maximum daily dose to 1.2 mg (eg, 0.6 mg twice daily)

P-glycoprotein inhibitors: 

This group includes the medications cyclosporine and ranolazine.

Prophylaxis of gout flares

• Standard dose: 0.6 mg twice daily
• Adjusted dose: 0.3 mg once daily

Treatment of gout flares

• Standard dose: 1.2 mg (2 tablets) initially, followed by 0.6 mg (1 tablet) 1 hour later
• Adjusted Dose: 0.6 mg (1 tablet) initially. Repeated doses should be administered no earlier than 3 days later.

Familial Mediterranean fever

• Standard dose: Maximum daily dose of 1.2 to 2.4 mg
• Adjusted Dose: Maximum daily dose reduced to 0.6 mg, which may be divided into 0.3 mg twice daily

Protease inhibitors: 

This group includes atazanavir (reyataz), darunavir (prezista), fosamprenavir (lexiva) and ritonavir, indinavir (crixivan), lopinavir/ritonavir (kaletra), nelfinavir (viracept), ritonavir (norvir), saquinavir (invirase), tipranavir (aptivus).

Prophylaxis of gout flares

• Standard dose: 0.6 mg twice daily → Adjust to 0.3 mg once daily
• Standard dose: 0.6 mg once daily → Adjust to 0.3 mg every other day

Treatment of gout flares

• Start with 0.6 mg, followed by 0.3 mg an hour later.
• Do not repeat within 3 days. Administering colchicine to treat gout flares is not recommended if the patient is already on prophylactic colchicine and CYP3A4 inhibitors.

Familial Mediterranean fever

• Maximum daily dose: 0.6 mg, divided into 2 doses of 0.3 mg each or taken as a single 0.6 mg dose

Drug-Food Interactions

Grapefruit juice may increase the serum concentration of colchicine. Therefore, the dose of colchicine may require adjustment when taking grapefruit juice. Patients should avoid grapefruit juice if they have hepatic or renal impairment and are taking colchicine.

Contraindications

Colchicine metabolism in the liver and other tissues depends on the P-glycoprotein transport and CYP 384 isoenzymes. This drug is eliminated unchanged in the urine and via metabolism. P-glycoprotein and CYP3A4 inhibitors can suppress the metabolism of colchicine and, therefore, increase plasma levels of colchicine. Impairment of renal and hepatic function can decrease the metabolism and clearance of colchicine and result in elevated concentrations. These elevated levels can cause adverse reactions, including death.[15][16][17]

• The concomitant use of a P-glycoprotein or CYP3A4 inhibitor and colchicine in the presence of renal or hepatic impairment is contraindicated.
• Dose adjustments or alternative therapies are considerations for patients with renal or hepatic impairment who are not taking a P-glycoprotein or CYP3A4 inhibitor.

Warning and Precautions 

Fatal overdoses have been reported in adults and children who have accidentally or intentionally ingested colchicine. This drug should be kept away from children's reach.

Biliary obstruction, renal impairment, hepatic disease, and renal disease

Dosage adjustments may be necessary for patients with normal renal and hepatic function, those taking interacting medications, and patients with renal or hepatic impairment. Patients with renal impairment or elevated plasma concentrations of colchicine due to renal disease can develop myeloneuropathy characterized by proximal weakness, elevated serum creatinine, and possibly rhabdomyolysis. Colchicine is eliminated through biliary pathways. Therefore, clinicians considering colchicine for patients with hepatic disease or hepatic biliary obstruction should consider alternative therapies.

Alcoholism and gastrointestinal disease

The risk for colchicine-induced gastrointestinal tissue damage may be elevated in patients with preexisting alcoholism or gastrointestinal disease. Clinicians should consider adjustments in dosing for these patients.

Bone marrow suppression

Prolonged colchicine therapy is associated with bone marrow suppression, so it should be used cautiously in patients with preexisting bone marrow suppression. Therapeutic doses of colchicine have reportedly been associated with myelosuppression, leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, and aplastic anemia. Colchicine may also worsen these types of blood dyscrasias.

Dialysis

Dialysis does not effectively remove colchicine; patients undergoing dialysis require a dosage reduction secondary to their impaired renal function.

Dental disease

Colchicine can cause myelosuppression, so it should be prescribed cautiously to patients with dental disease. Any significant dental procedures should be performed before initiating colchicine therapy or delayed until the patient's blood count returns to normal.

Neuromuscular toxicity

Colchicine-induced neuromuscular toxicity and rhabdomyolysis have been reported in patients receiving prolonged treatment. Patients with renal impairment and older patients, even those with normal renal and hepatic function, are at increased risk. Concomitant use of colchicine and atorvastatin, simvastatin, pravastatin, fluvastatin, gemfibrozil, and fenofibric acid or cyclosporine may potentiate the development of myopathy.[12]

Monitoring

Colchicine has a narrow therapeutic index; however, no blood test is available to determine its serum concentration. Colchicine accumulation is associated with severe and fatal adverse drug reactions, especially in patients with hepatic or renal impairment or those taking a P-glycoprotein or CYP3A4 inhibitor. Parameters that require monitoring include a complete blood count and renal and hepatic function tests. Patients should be advised to report signs and symptoms of colchicine toxicity, including nausea, vomiting, diarrhea, and abdominal pain.

Toxicity

The precise dose of colchicine that results in significant toxicity is unknown. Toxicity can occur after ingesting a dose as low as 7 mg over 4 days, while other patients have survived after taking doses exceeding 60 mg. In one review involving 150 patients who experienced a colchicine overdose, ingesting doses exceeding 0.8 mg/kg resulted in death.

Acute colchicine toxicity usually begins within 24 hours of ingestion and includes gastrointestinal symptoms, eventually leading to significant fluid loss and volume depletion. In this initial phase, peripheral leukocytosis may also be present. Life-threatening complications often occur 24 to 72 hours after administration and are usually attributed to multi-organ failure. Death is typically a result of respiratory depression and cardiovascular collapse.

Treatment of colchicine poisoning should start with gastric lavage and measures to prevent shock. Otherwise, treatment is symptomatic and supportive. There is no known specific antidote, and colchicine is not effectively removed by dialysis.

Enhancing Healthcare Team Outcomes

Before prescribing or administering colchicine to patients, providers must know the current dosing recommendations and any restrictions based on the patient's age and renal and liver function. At least 30% of all colchicine-related medication errors are related to incorrect dosing regimens. Also, it is important to know what else the patient is taking to prevent lethal drug interactions. Clinicians should ensure the patient knows how to take colchicine and that it is not an analgesic agent. Many errors have occurred with colchicine simply because patients did not know that the intended effects can take 24 to 36 hours to develop, and the patient should avoid taking repeated doses within this period. Further, patients should understand that they should discontinue colchicine if they develop gastrointestinal side effects or paresthesias. Finally, all patients must be educated on how to safely store colchicine in the home, away from the reach of children. Colchicine has a very high mortality rate should a high dose be ingested within a short time.[18][1]

Prescribers should work closely with the pharmacist and the nursing staff when initiating colchicine therapy. All providers need to provide patient counseling to emphasize the crucial points. The prescriber and pharmacist should review all patient parameters and ensure dose adjustments are unnecessary. Nurses should be familiar with signs of toxicity or adverse events to monitor the patient and inform the prescriber of any issues.