Colchicine is an antigout and antimitotic agent.
Colchicine is used to relieve acute gout flares (acute attacks of gouty arthritis).123, 124, 125, 126, 127, 142, 143, 152 Nonsteroidal anti-inflammatory agents (NSAIAs) (e.g., indomethacin, ibuprofen, naproxen, sulindac, piroxicam, ketoprofen) are as effective as, and better tolerated than, usual dosages of colchicine for short-term use in relieving acute attacks of gouty arthritis.124, 125, 128, 129 (See Indomethacin 28:08.04.24.) Corticosteroids also are used to relieve acute attacks of gouty arthritis.142, 143 Colchicine is considered a second-line agent;142, 143 colchicine may be used for the treatment of acute gouty arthritis in patients who have not responded to or who cannot tolerate recommended therapies (i.e., NSAIAs, corticosteroids).142
Colchicine should be initiated at the first sign of an acute gout flare.152 When colchicine is administered orally within 12 hours of the onset of an acute gout flare, 38% of patients receiving the drug in the currently recommended dosage have a favorable response.152
Colchicine also is used in the prophylactic treatment of recurrent gout flares.152 Colchicine has no effect on plasma concentrations or urinary excretion of uric acid; therefore, concomitant administration of allopurinol or a uricosuric agent (e.g., febuxostat, probenecid, sulfinpyrazone) is necessary to decrease serum urate concentrations.123, 124, 129, 130, 143, 146 Prophylactic doses of colchicine should be administered before the initiation of allopurinol or uricosuric therapy because sudden changes in serum urate concentrations may precipitate acute gout attacks.124, 125, 127, 129 After the serum urate concentration has been reduced to the desired level and acute gout attacks have not occurred for 3-6 months (some clinicians suggest 1-12 months), colchicine may be discontinued and the patient may be treated with urate-lowering agents alone.124, 126, 143 Colchicine is frequently used in combination with probenecid to facilitate prophylactic therapy in patients with chronic gouty arthritis. The usefulness of the commercially available fixed-dosage preparation is limited, however, because the colchicine present exceeds the amount required by most patients.
Colchicine is used in the management of familial Mediterranean fever.100, 103, 104, 105, 106, 107, 108, 109, 110, 111, 149, 152 The drug has been used effectively for chronic prophylactic therapy to reduce the frequency and severity of the episodic attacks of painful serositis in patients with familial Mediterranean fever.100, 103, 104, 105, 106, 107, 108, 109, 149, 150, 152 Chronic prophylactic therapy reportedly is associated with marked amelioration of attacks (both frequency and severity) or remission100, 103, 104, 105, 106, 107, 108, 109, 149, 150 in about 90% of patients with this condition,100 but therapy with the drug is not curative and manifestations of this condition return to pretreatment levels following discontinuance of colchicine.100, 104, 107, 108, 109 Chronic prophylactic therapy also appears to prevent amyloidosis, manifested by nephropathy, in patients with familial Mediterranean fever who lack evidence of amyloidosis when therapy is initiated.100 Colchicine appears to be effective in preventing amyloidosis regardless of whether patients continue to experience episodic attacks of serositis during chronic prophylactic therapy with the drug.149, 150 Colchicine may prevent deterioration in patients in the proteinuric phase of the disease when amyloid involvement is minimal.100 The drug generally appears to be of limited value in altering the effects of amyloid deposits when clinical amyloidosis is evident, particularly when proteinuria has progressed to nephrosis,100 although a beneficial effect (e.g., restoration of serum albumin concentrations toward normal, slight improvement in renal function) may be evident in some patients.105
Regulatory Actions Affecting Colchicine
Colchicine injection became available in the US in the 1950s and has been used for the treatment of acute attacks of gout.144, 145 Colchicine injection preparations that have been commercially available have not been approved by the US Food and Drug Administration (FDA).144, 145 Serious adverse events, some fatal, have been reported in patients receiving colchicine injection.144, 145 (See Cautions: Adverse Effects.) Because of the potentially serious health risks associated with unapproved colchicine injection, FDA announced on February 8, 2008, that it would take enforcement action (e.g., seizure, injunction, other judicial proceeding) against all firms, including compounding pharmacies, attempting to manufacture, ship, or deliver colchicine injection.144, 145
Although commercially available, single-entity, oral preparations of colchicine also lacked FDA approval, FDA did not take action against colchicine tablets in February 2008; risks associated with use of the tablets are believed to be lower than those associated with use of the injection.144, 145, 153 In July 2009, FDA approved a single-ingredient oral colchicine preparation.152, 153 During the review process, FDA identified 2 safety concerns associated with use of colchicine.153 Reports suggested that drug interactions play an important role in the development of colchicine toxicity.153 There also was evidence that the dosage of colchicine previously used for treatment of acute gout flares could be reduced without reducing the drug's efficacy.153 The labeling now includes extensive information on drug interactions and a new (lower) dosage for acute gout flare.152, 153 Colchicine in fixed combination with probenecid is approved by the FDA for the management of recurrent gouty arthritis.144, 145, 146
Colchicine is administered orally without regard to meals.152 Colchicine has been administered by IV injection; however, IV preparations of colchicine have been withdrawn from the US market because of safety concerns.144, 145 (See Uses: Regulatory Actions Affecting Colchicine and see Cautions.)
Patients receiving colchicine should be instructed on how to resume therapy in the event of a missed dose.152 Patients with gout who are receiving colchicine for treatment of an acute flare but not for prophylaxis of recurrent flares should be instructed to take the missed dose as soon as possible.152 Those receiving the drug to treat an acute gout flare during colchicine prophylaxis should be instructed to take the missed dose immediately and then wait 12 hours before resuming the previous dosing schedule.152 Patients receiving colchicine for treatment of familial Mediterranean fever or for prophylaxis of recurrent gout flares (without treatment for an acute gout flare) should be instructed to take the missed dose as soon as possible and then resume their usual dosing schedule, but not to take a double dose to make up for the missed dose.152
Dosage of colchicine depends on the patient's age, renal and hepatic function, and whether the drug is administered concomitantly with or within 14 days following therapy with drugs that affect hepatic metabolism or the P-glycoprotein transport system.152
The recommended oral dosage of colchicine for relief of an acute gout flare in patients who are not receiving concomitant therapy with a moderate or potent inhibitor of cytochrome P-450 (CYP) isoenzyme 3A4 or an inhibitor of the P-glycoprotein transport system, and who have not received such therapy during the prior 14 days, is 1.2 mg given at the first sign of flare followed by 0.6 mg one hour later.152 The maximum recommended dosage for treatment of acute gout flare is 1.8 mg administered over a one-hour period.152 Higher dosages of colchicine have not been shown to be more effective in relieving acute gout flares.152 Additional courses of colchicine therapy for treatment of an acute gout flare should not be repeated until 3 days have elapsed.152 Patients receiving colchicine for prevention of gout flares who are not receiving a CYP3A4 inhibitor also may receive colchicine (1.2 mg initially followed by 0.6 mg 1 hour later) to relieve an acute gout flare; following the 2-dose treatment course, 12 hours should elapse before prophylactic doses of the drug are resumed.152
In patients receiving concomitant therapy with a potent inhibitor of CYP3A4, such as atazanavir, boceprevir, clarithromycin, darunavir with low-dose ritonavir ( ritonavir-boosted darunavir), ritonavir-boosted fosamprenavir, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telaprevir, telithromycin, ritonavir-boosted tipranavir, the fixed combination of lopinavir and ritonavir (lopinavir/ritonavir), or the fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir, and those who have received such therapy during the prior 14 days, the recommended oral dosage of colchicine for relief of an acute gout flare is 0.6 mg given at the first sign of flare followed by 0.3 mg 1 hour later.152, 154, 155, 163, 164 Additional courses of colchicine therapy for treatment of an acute gout flare should not be repeated until 3 days have elapsed.152, 154 Use of colchicine for the treatment of acute gout flares is not recommended in individuals receiving the drug for prevention of gout flares who also are receiving therapy with a CYP3A4 inhibitor.152
In patients receiving concomitant therapy with a moderate inhibitor of CYP3A4, such as aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir (without ritonavir), grapefruit juice, or verapamil, and those who have received such therapy during the prior 14 days, the recommended oral dosage of colchicine for relief of an acute gout flare is a single 1.2-mg dose given at the first sign of flare.152, 154 Additional courses of colchicine therapy for treatment of an acute gout flare should not be repeated until 3 days have elapsed.152, 154 Use of colchicine for the treatment of acute gout flare is not recommended in individuals receiving the drug for prevention of gout flares who also are receiving therapy with a CYP3A4 inhibitor.152
In patients receiving concomitant therapy with a drug that inhibits the P-glycoprotein transport system, such as cyclosporine or ranolazine, and those who have received such therapy during the prior 14 days, the recommended oral dosage of colchicine for relief of an acute gout flare is a single 0.6-mg dose given at the first sign of flare.152 Additional courses of colchicine therapy for treatment of an acute gout flare should not be repeated until 3 days have elapsed.152
The safety and efficacy of repeat courses of colchicine for treatment of acute gout flare have not been evaluated.152
Prophylactic Treatment of Recurrent Gout Flare
The recommended oral dosage of colchicine for prophylaxis of recurrent gout flares in adults and adolescents older than 16 years of age who are not receiving concomitant therapy with a moderate or potent inhibitor of CYP3A4 or an inhibitor of the P-glycoprotein transport system, and who have not received such therapy during the prior 14 days, is 0.6 mg once or twice daily.152 The maximum recommended dosage is 1.2 mg daily.152
In patients receiving concomitant therapy with a potent inhibitor of CYP3A4, such as atazanavir, boceprevir, clarithromycin, ritonavir-boosted darunavir, ritonavir-boosted fosamprenavir, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telaprevir, telithromycin, ritonavir-boosted tipranavir, lopinavir/ritonavir, or the fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir, and those who have received such therapy during the prior 14 days, the recommended oral dosage of colchicine for prophylaxis of recurrent gout flares is 0.3 mg daily or every other day.152, 154, 155, 163, 164
In patients receiving concomitant therapy with a moderate inhibitor of CYP3A4, such as aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir (without ritonavir), grapefruit juice, or verapamil, and those who have received such therapy during the prior 14 days, the recommended oral dosage of colchicine for prophylaxis of recurrent gout flares is 0.3 mg twice daily, 0.6 mg once daily, or 0.3 mg once daily.152, 154
In patients receiving concomitant therapy with a drug that inhibits the P-glycoprotein transport system, such as cyclosporine or ranolazine, and those who have received such therapy during the prior 14 days, the recommended oral dosage of colchicine for prophylaxis of recurrent gout flares is 0.3 mg once daily or every other day.152
For management of familial Mediterranean fever in patients who are not receiving concomitant therapy with a moderate or potent inhibitor of CYP3A4 or an inhibitor of the P-glycoprotein transport system, and who have not received such therapy during the prior 14 days, colchicine may be given in a dosage of 1.2-2.4 mg daily in adults and adolescents older than 12 years of age, a dosage of 0.9-1.8 mg daily in children 6-12 years of age, and a dosage of 0.3-1.8 mg daily in children 4-6 years of age.152 The daily dosage may be given once daily or in 2 divided doses.152 Dosage of the drug may be increased in increments of 0.3 mg daily to the maximum recommended dosage.152 Alternatively, in patients experiencing intolerable adverse effects, dosage may be decreased in increments of 0.3 mg daily.152
In adults and adolescents receiving concomitant therapy with a potent inhibitor of CYP3A4, such as atazanavir, boceprevir, clarithromycin, ritonavir-boosted darunavir, ritonavir-boosted fosamprenavir, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telaprevir, telithromycin, ritonavir-boosted tipranavir, lopinavir/ritonavir, or the fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir, and those who have received such therapy during the prior 14 days, the maximum recommended dosage of colchicine for the management of familial Mediterranean fever is 0.6 mg daily; the daily dosage may be given as 0.3 mg twice daily.152, 154, 155, 163, 164
In adults and adolescents receiving concomitant therapy with a moderate inhibitor of CYP3A4, such as aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir (without ritonavir), grapefruit juice, or verapamil, and those who have received such therapy during the prior 14 days, the maximum recommended dosage of colchicine for the management of familial Mediterranean fever is 1.2 mg daily; the daily dosage may be given as 0.6 mg twice daily.152, 154
In adults and adolescents receiving concomitant therapy with a drug that inhibits the P-glycoprotein transport system, such as cyclosporine or ranolazine, and those who have received such therapy during the prior 14 days, the maximum recommended dosage of colchicine for the management of familial Mediterranean fever is 0.6 mg daily; the daily dosage may be given as 0.3 mg twice daily.152
These maximum recommended dosages for patients with familial Mediterranean fever who are receiving CYP3A4 or P-glycoprotein inhibitors are intended for individuals for whom a dosage range of 1.2-2.4 mg daily would be appropriate in the absence of interacting drugs (i.e., adults and adolescents older than 12 years of age).152 The manufacturer currently makes no specific recommendations regarding maximum colchicine dosage in children 4-12 years of age who are receiving CYP3A4 or P-glycoprotein inhibitors.152
Dosage in Renal and Hepatic Impairment
Use of colchicine in combination with a potent CYP3A4 inhibitor, such as atazanavir, boceprevir, clarithromycin, ritonavir-boosted darunavir, ritonavir-boosted fosamprenavir, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telaprevir, telithromycin, ritonavir-boosted tipranavir, lopinavir/ritonavir, or the fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir, or with a P-glycoprotein inhibitor, such as cyclosporine or ranolazine, in patients with renal impairment is contraindicated.152, 154, 155, 163, 164
Use of colchicine for the treatment of an acute gout flare is not recommended in patients with renal impairment who are receiving the drug for prevention of gout flares.152
Colchicine dosage adjustment is not needed in patients with mild (creatinine clearance 50-80 mL/minute) to moderate (creatinine clearance 30-50 mL/minute) renal impairment who are receiving the drug for treatment of an acute gout flare or for prophylaxis of recurrent gout flares; however, such patients should be monitored for adverse effects.152
In patients with severe renal impairment, the recommended initial dosage of colchicine for prophylaxis of recurrent gout flares is 0.3 mg daily; close monitoring is needed if the dosage is increased.152 When colchicine is used for the treatment of an acute gout flare in patients with severe renal impairment, dosage adjustment is not needed, but additional courses of colchicine therapy for acute gout flares should not be repeated until 2 weeks have elapsed.152 Alternative therapy should be considered for patients with severe renal impairment requiring repeat courses of therapy.152
In patients who are undergoing dialysis, the recommended dosage of colchicine for prophylaxis of recurrent gout flares is 0.3 mg twice weekly; close monitoring is advised.152 When colchicine is used for the treatment of an acute gout flare in patients who are undergoing dialysis, the recommended dosage of colchicine is 0.6 mg at the first sign of flare.152 Additional courses of colchicine therapy for acute gout flares should not be repeated until 2 weeks have elapsed.152
Patients with mild (creatinine clearance 50-80 mL/minute) to moderate (creatinine clearance 30-50 mL/minute) renal impairment who are receiving colchicine for management of familial Mediterranean fever should be monitored for adverse effects.152 Dosage adjustment may be needed.152
In patients with severe (creatinine clearance less than 30 mL/minute) renal impairment or undergoing dialysis, the recommended initial dosage of colchicine for management of familial Mediterranean fever is 0.3 mg daily.152 Dosage can be increased with careful monitoring.152
Use of colchicine in combination with a potent CYP3A4 inhibitor, such as atazanavir, boceprevir, clarithromycin, ritonavir-boosted darunavir, ritonavir-boosted fosamprenavir, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telaprevir, telithromycin, ritonavir-boosted tipranavir, lopinavir/ritonavir, the fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir, or with a P-glycoprotein inhibitor, such as cyclosporine or ranolazine, in patients with hepatic impairment is contraindicated.152, 154, 155, 163, 164
Colchicine dosage adjustment is not needed in patients with mild to moderate hepatic impairment who are receiving the drug for treatment of an acute gout flare or for prophylaxis of recurrent gout flares; however, such patients should be monitored for adverse effects.152
Dosage reduction should be considered in patients with severe hepatic impairment who are receiving colchicine for prophylaxis of recurrent gout flares.152 When colchicine is used for the treatment of an acute gout flare in patients with severe hepatic impairment, dosage adjustment is not needed, but additional courses of colchicine therapy for acute gout flares should not be repeated until 2 weeks have elapsed.152 Alternative therapy should be considered for patients with severe hepatic impairment requiring repeat courses of therapy.152
Patients with mild to moderate hepatic impairment who are receiving colchicine for management of familial Mediterranean fever should be monitored for adverse effects.152
Dosage adjustment should be considered for patients with severe hepatic impairment who are receiving colchicine for management of familial Mediterranean fever.152
The most common adverse effects of oral colchicine therapy are nausea, abdominal discomfort, vomiting, and diarrhea. Pharyngolaryngeal pain has been reported.152
Bladder spasm, paralytic ileus, stomatitis, hypothyroidism, nonthrombocytopenic purpura, and prostration have also been reported with colchicine therapy.
Myelosuppression, disseminated intravascular coagulation, and renal, hepatic, circulatory, and CNS cellular injury have been reported in patients receiving colchicine, generally in those receiving excessive dosages of the drug.152 Leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, and aplastic anemia have been reported.152 Death has occurred in one patient with normal renal and hepatic function who developed pancytopenia and bone marrow aplasia following IV administration of 10 mg of colchicine (IV preparations are no longer commercially available in the US) over a 5-day period.
Neuromuscular toxicity and rhabdomyolysis have been reported in patients receiving long-term colchicine therapy.152 Patients with renal dysfunction and geriatric patients, including those with normal renal and hepatic function, are at increased risk.152 Concomitant therapy with an HMG-CoA reductase inhibitor (statin), fibric acid derivative, or cyclosporine also may increase the risk for development of myopathy.152, 156, 157 Following discontinuance of colchicine, symptoms generally resolve within one week to several months.152
Loss of body and scalp hair, rash, vesicular dermatitis, peripheral neuritis or neuropathy, myopathy, rhabdomyolysis, anuria, renal damage, hematuria, and one case of purpura have been reported with prolonged administration of colchicine. Colchicine may also cause increased serum concentrations of alkaline phosphatase, aminotransferases (AST, ALT),152 and creatine kinase (CK, creatine phosphokinase, CPK).152 Other reported adverse effects include sensory motor neuropathy, maculopapular rash, abdominal pain or cramping, lactose intolerance, myotonia, muscle weakness or pain, azoospermia, and oligospermia.152
Serious adverse events have been reported in patients receiving IV colchicine.144, 145, 148 Many of these adverse effects were the result of colchicine toxicity.144, 145 As of June 2007, the US Food and Drug Administration (FDA) was aware of 50 reports of adverse effects associated with use of IV colchicine; 23 of these events were fatal.144, 145 Reported adverse effects included neutropenia, acute renal failure, thrombocytopenia, congestive heart failure, and pancytopenia.144, 145 Three deaths were associated with use of compounded IV colchicine.144, 145, 148 Tests of vials from the same lot used to treat these 3 patients indicated that the concentration of colchicine was 4 mg/mL; labeling on the vial indicated that the concentration of colchicine was 0.5 mg/mL.148 Because of the potentially serious health risks associated with colchicine injection, FDA announced on February 8, 2008, that it would take enforcement action against all firms, including compounding pharmacies, attempting to manufacture, ship, or deliver colchicine injection.144, 145
Oral preparations containing colchicine remain on the market; risks associated with use of the tablets are believed to be lower than those associated with use of the injection.144, 145
Precautions and Contraindications
Concomitant use of colchicine with certain drugs is contraindicated or requires particular caution.152 (See Drug Interactions and also see Dosage and Administration: Dosage.)
Colchicine is contraindicated in patients with renal or hepatic impairment who are receiving a drug that inhibits the P-glycoprotein transport system or is a potent CYP3A4 inhibitor (see Dosage and Administration: Dosage in Renal and Hepatic Impairment); fatal or life-threatening colchicine toxicity has occurred in such patients following therapeutic doses of colchicine.152
Safety and efficacy of colchicine for treatment of gout in children have not been established.152
Safety and efficacy of colchicine for management of familial Mediterranean fever in children have been evaluated in uncontrolled studies.152 Long-term use of colchicine did not appear to affect growth in children with familial Mediterranean fever.152
Clinical studies of colchicine for treatment of acute gout flares, prophylactic treatment of recurrent gout flares, or management of familial Mediterranean fever did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients.152 Drug dosage generally should be titrated carefully in geriatric patients with gout; the greater frequency of decreased renal function and of concomitant disease and drug therapy observed in geriatric patients also should be considered.152
Pregnancy, Fertility, and Lactation
Chromosomal aberrations have been reported in a limited number of patients receiving prolonged colchicine therapy. Colchicine crosses the placenta in humans and has been shown in animal reproduction and development studies to cause embryofetal toxicity, teratogenic effects, and altered postnatal development at exposure levels within or above the therapeutic range.152 Although there are no adequate and controlled studies to date in humans,152 results of one study suggest that patients receiving prolonged colchicine therapy may have a greater risk of producing trisomic offspring if conception occurs during therapy with the drug. Other clinicians, however, contend that this study is inconclusive and at most merely suggestive of a probable increased risk to the offspring. Data from a limited number of published studies indicate that use of colchicine for the treatment of familial Mediterranean fever in pregnant women was not associated with increased risk of miscarriage, stillbirth, or teratogenic effects.152 Colchicine should be used during pregnancy only if the potential benefits outweigh the risks.152
The effect of colchicine on labor and delivery is not known.152
Colchicine has adversely affected spermatogenesis in humans and animals.147 Reversible azoospermia has been reported in a 36-year-old man who received 0.6 mg of colchicine twice daily for several months.
Colchicine is distributed into milk.139, 152 (See Pharmacokinetics: Distribution.) Limited information suggests that exclusively breast-fed infants receive less than 10% of the maternal weight-adjusted dose.152 Although the drug can affect GI cell renewal and permeability,152 some experts state that the actual amounts of the drug distributed into breast milk are not high enough to warrant cessation of nursing.139, 141 No adverse effects have been reported to date in breast-fed infants of women receiving colchicine therapy who were observed over periods of up to 10 months.139, 141 The American Academy of Pediatrics (AAP) states that the drug usually is compatible with breast-feeding.139, 140 Some clinicians have suggested that exposure of the infant to the drug could be minimized by waiting 8-12 hours after a dose to breast-feed the infant.139 The manufacturer states that caution is advised; the infant should be observed for adverse effects.152
Drugs Affecting Hepatic Microsomal Enzymes
Colchicine is metabolized by cytochrome P-450 (CYP) isoenzyme 3A4.152 In vitro studies indicate that colchicine does not inhibit or induce CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4.152
Concomitant use of colchicine with potent CYP3A4 inhibitors, such as atazanavir, boceprevir, clarithromycin, ritonavir-boosted darunavir, ritonavir-boosted fosamprenavir, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telaprevir, telithromycin, ritonavir-boosted tipranavir, lopinavir/ritonavir, or the fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir, or with moderate CYP3A4 inhibitors, such as aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir (without ritonavir), grapefruit juice, or verapamil, may result in substantially increased plasma concentrations of colchicine.152, 154, 155, 163, 164 If concomitant therapy is required, the dosage of colchicine must be reduced or treatment with colchicine may need to be interrupted.152 (See Dosage and Administration: Dosage.) Use of colchicine in combination with a potent CYP3A4 inhibitor in patients with renal or hepatic impairment is contraindicated.152
An increase in plasma colchicine concentrations (227% increase in peak plasma concentration, 281% increase in area under the plasma concentration-time curve [AUC]) was observed when a single 0.6-mg dose of colchicine was administered concomitantly with clarithromycin (250 mg twice daily for 7 days).152 Severe or fatal colchicine toxicity has been reported with concomitant clarithromycin and colchicine therapy.152, 158, 160
An increase in plasma colchicine concentrations (102% increase in peak plasma concentration, 212% increase in AUC) was observed when a single 0.6-mg dose of colchicine was administered concomitantly with ketoconazole (200 mg twice daily for 5 days).152
An increase in plasma colchicine concentrations (184% increase in peak plasma concentration, 296% increase in AUC) was observed when a single 0.6-mg dose of colchicine was administered concomitantly with ritonavir (100 mg twice daily for 5 days).152
An increase in plasma colchicine concentrations (40% increase in peak plasma concentration, 103% increase in AUC) was observed when a single 0.6-mg dose of colchicine was administered concomitantly with verapamil (240 mg daily for 5 days).152 Neuromuscular toxicity has been reported with concomitant verapamil and colchicine therapy.152
An increase in plasma colchicine concentrations (44% increase in peak plasma concentration, 93% increase in AUC) was observed when a single 0.6-mg dose of colchicine was administered concomitantly with diltiazem (240 mg daily for 7 days).152 Neuromuscular toxicity has been reported with concomitant diltiazem and colchicine therapy.152
No substantial change in plasma concentrations of colchicine was observed when a single 0.6-mg dose of colchicine was administered concomitantly with grapefruit juice (240 mL twice daily for 4 days).152 However, when colchicine was given concomitantly with other moderate CYP3A4 inhibitors (e.g., diltiazem, verapamil), substantial increases in plasma colchicine concentrations were reported.152 The manufacturer states that patients receiving colchicine should be advised not to consume grapefruit or grapefruit juice.152 If a moderate CYP3A4 inhibitor (including grapefruit juice) is given concomitantly with colchicine, the manufacturer recommends adjustment of colchicine dosage (see Dosage and Administration: Dosage).152
Drugs Affecting the P-glycoprotein Transport System
Concomitant use of colchicine with drugs that inhibit the P-glycoprotein transport system, such as cyclosporine or ranolazine, results in substantially increased plasma concentrations of colchicine.152 If use of a P-glycoprotein inhibitor is required, the dosage of colchicine must be reduced or treatment with colchicine may need to be interrupted.152 (See Dosage and Administration: Dosage.) Use of colchicine in combination with a P-glycoprotein inhibitor in patients with renal or hepatic impairment is contraindicated.152
Administration of a single 100-mg dose of cyclosporine, a P-glycoprotein inhibitor, concomitantly with a single 0.6-mg dose of colchicine resulted in increases in plasma colchicine concentrations (270% increase in peak plasma concentration, 259% increase in AUC).152 Fatal colchicine toxicity has been reported with concomitant cyclosporine and colchicine therapy.152 Concomitant use of cyclosporine and colchicine also may result in increased cyclosporine concentrations and additive nephrotoxic effects;159, 161, 162 therefore, renal function and blood concentrations of cyclosporine should be monitored and cyclosporine dosage should be adjusted accordingly if colchicine is initiated or discontinued or the colchicine dosage is altered in patients receiving cyclosporine.159, 161, 162
Addition of an HMG-CoA reductase inhibitor (statin) or other lipid-lowering agents (e.g., fibric acid derivatives) to long-term therapy with colchicine or addition of colchicine to long-term therapy with these antilipemic agents has resulted in myopathy and rhabdomyolysis; death has been reported.152, 156, 157 Potential benefits and risks of such concomitant therapy should be weighed.120 Patients should be monitored for muscle pain, tenderness, and weakness, especially during the initial phase of such concomitant therapy.152
An increase in plasma colchicine concentrations (22% increase in peak plasma concentration, 57% increase in AUC) was observed when a single 0.6-mg dose of colchicine was administered concomitantly with azithromycin (500 mg initially, followed by 250 mg daily for 4 days).152
Digoxin is a P-glycoprotein transport system substrate.152 Rhabdomyolysis has been reported in an individual receiving colchicine and digoxin concomitantly.152 Potential benefits and risks of concomitant therapy with colchicine and digoxin should be weighed.152 Patients should be monitored for muscle pain, tenderness, and weakness, especially during the initial phase of such concomitant therapy.152
Administration of an oral contraceptive (ethinyl estradiol 35 mcg with norethindrone 1 mg) concomitantly with colchicine (0.6 mg twice daily for 14 days) in healthy women did not alter the plasma concentrations of either the estrogen or the progestin.152
No change in plasma concentrations of theophylline was observed when theophylline was administered concomitantly with colchicine (0.6 mg twice daily for 14 days) in healthy individuals.152
Colchicine has been reported to interfere with urinary determinations of 17-hydroxycorticosteroids using the Reddy, Jenkins, and Thorn procedure. Colchicine may cause false-positive results in urine tests for erythrocytes or hemoglobin.
Poisoning may occur from repeated administration of large doses or from a single toxic dose of colchicine. Death has occurred following ingestion of as little as 7 mg of colchicine, although individuals have survived larger doses. The lethal dose in humans has been estimated to be 65 mg. In individuals receiving IV colchicine, death has occurred following cumulative doses as low as 5.5 mg.148 The median IV lethal dose in rats is 1.7 mg/kg.122 There is usually a delay of a few hours between ingestion of the toxic dose of colchicine and the appearance of the first toxic symptoms, regardless of the route of administration.
The first stage of acute colchicine toxicity typically begins within 24 hours of ingestion and includes adverse GI effects resulting in fluid loss and volume depletion; peripheral leukocytosis also may occur.152 Life-threatening complications occur during the second stage, which occurs 24-72 hours after administration, and result from multiorgan failure.152
The first symptoms of acute colchicine toxicity involve the GI tract and include nausea, anorexia, abdominal pain, vomiting, paralytic ileus, and diarrhea which may be severe and bloody due to hemorrhagic gastroenteritis. Stomatitis, arthralgia, malaise, hypocalcemia, fever, and rashes including scarlatiniform rash may also occur. Dehydration may occur resulting in oliguria. Renal damage as evidenced by hematuria and oliguria has been reported. Hepatomegaly and liver tenderness with elevated serum concentrations of AST (SGOT) and alkaline phosphatase may occur. Extreme vascular damage may result in shock and cardiovascular collapse. Leukopenia may occur and may persist for several days followed by leukocytosis with numerous metamyelocytes and myelocytes. Other hematologic manifestations of colchicine toxicity include bone marrow depression, thrombocytopenia, granulocytopenia, immature leukocytes, pancytopenia, anemia with anisocytosis, polychromasia, and basophilic stippling. Muscular weakness is marked and an ascending paralysis of the CNS may develop, although the patient usually remains conscious. Mental confusion, delirium, and seizures may occur. There may be a loss of deep tendon and Achilles tendon reflexes, and Babinski's reflex may be elicited. Death usually occurs as a result of respiratory depression or cardiovascular collapse.
There is no specific antidote for colchicine poisoning. Gastric lavage should be performed initially and measures initiated to prevent shock.152 Other treatment is symptomatic and supportive.152 Colchicine is not removed by dialysis.152
Colchicine possesses antigout activity. The drug also has weak anti-inflammatory activity but has no analgesic activity. The drug has no effect on urinary excretion of uric acid or on serum urate concentration, solubility, or binding to serum proteins. Although the mechanism of the antigout effect of colchicine is not completely known, the drug appears to disrupt cytoskeletal functions through inhibition of β-tubulin polymerization into microtubules, thus preventing activation, degranulation, and migration of neutrophils believed to mediate some gout symptoms.152
The mechanism of colchicine's beneficial effects in familial Mediterranean fever has not been fully elucidated.152 Colchicine may interfere with intracellular assembly of the inflammasome complex in neutrophils and monocytes that mediates activation of interleukin-1β.152
Following oral administration, colchicine is absorbed from the GI tract and is partially metabolized in the liver. The drug and its metabolites re-enter the intestinal tract via biliary secretions and the unchanged drug may be reabsorbed from the intestine. Following oral administration of colchicine 1.8 mg over 1 hour under fasting conditions, peak plasma concentrations of 6.2 ng/mL were reached in 1.8 hours.152 Following oral administration of 0.6 mg twice daily for 10 days, a mean peak plasma concentration of 3.6 ng/mL was reached at 1.3 hours after a dose.152 Administration of colchicine with food did not affect rate of absorption but decreased the extent of absorption by 15%.152 Absolute bioavailability is reported to be approximately 45%.152
The presence of a secondary peak in colchicine concentrations, ranging from 39-155% of the height of the initial peak concentration, has been reported in some individuals 3-36 hours after oral administration and has been attributed to intestinal secretion and reabsorption and/or biliary circulation.152
Colchicine is about 39% bound to serum proteins, mainly albumin.152
Colchicine crosses the placenta.152 Fetal plasma concentrations of the drug are reported to be approximately 15% of the maternal concentration.152
Colchicine is distributed into milk.139, 152 In a limited number of nursing women receiving long-term colchicine therapy at dosages of 1-1.5 mg daily, peak concentrations of the drug in milk were similar to serum concentrations and ranged from 1.9-8.6 ng/mL.139, 141 Higher concentrations of the drug in milk (31, 24-27, or 10 ng/mL at 2, 4, or 7 hours, respectively, after a dose) have been reported in the absence of concurrent serum concentration data in a nursing woman receiving colchicine 1 mg daily.139
Following IV administration of a single therapeutic dose (IV preparations are no longer commercially available in the US), colchicine is rapidly removed from the plasma; plasma half-life is about 20 minutes. The drug has a half-life of about 60 hours in leukocytes.
Colchicine is demethylated in the liver by cytochrome P-450 (CYP) isoenzyme 3A4.152 In healthy individuals, 40-65% of an orally administered 1-mg dose of the drug is excreted unchanged in urine.152 Enterohepatic circulation and biliary excretion may occur.152 A half-life of 26.6-31.2 hours has been reported in healthy young adults receiving colchicine 0.6 mg orally twice daily.152 Colchicine is a substrate of the P-glycoprotein transport system.152 Colchicine is not removed by hemodialysis.152
Clearance of colchicine is decreased in patients with renal impairment.152 In one study, patients with severe renal disease eliminated little or no colchicine or its metabolites in the urine, resulting in a prolonged plasma half-life. Total body clearance of colchicine was reduced by 75% in patients with end-stage renal disease requiring dialysis.152
In patients with hepatic impairment, substantial interpatient variability in colchicine pharmacokinetics has been observed.152 In some patients with mild to moderate cirrhosis, clearance of colchicine was decreased substantially and plasma half-life was prolonged compared with healthy individuals; however, no consistent trends were observed in patients with primary biliary cirrhosis.152
Colchicine, a phenanthrene derivative, is an antigout drug obtained from species of Colchicum. Colchicine occurs as pale yellow, amorphous scales or powder and is soluble in water and freely soluble in alcohol.
Colchicine darkens on exposure to light and should be stored in tight, light-resistant containers.
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets | 500 mg Probenecid and Colchicine 0.5 mg* | Probenecid and Colchicine Tablets |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
AHFS® Drug Information. © Copyright, 1959-2025, Selected Revisions April 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
Only references cited for selected revisions after 1984 are available electronically.
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