Colchicine

Mechanism

Amiodarone blocks CYP3A4 and the P-glycoprotein transporter – two colchicine clearance routes. Colchicine plasma levels rise; myopathy and neuropathy risk grows.

Symptoms

The first signs of colchicine toxicity are nausea, vomiting, abdominal pain and diarrhoea (colchicine SmPC). Muscle weakness and pain, peripheral neuropathy with numbness and tingling in the feet and hands, and rhabdomyolysis may follow; with prolonged use, bone marrow suppression with falling white cells and platelets, up to aplastic anaemia (colchicine SmPC).

Management

The combination is contraindicated: the Spanish colchicine SmPC forbids colchicine during use of CYP3A4 or P-glycoprotein inhibitors and for 14 days afterwards (colchicine SmPC), and amiodarone inhibits both pathways (amiodarone SmPC). The US label of colchicine 0.5 mg for cardiovascular prevention, approved by the US Food and Drug Administration (FDA), also contraindicates it with P-glycoprotein inhibitors (colchicine label, FDA). Amiodarone interactions can persist for several months after it is stopped (amiodarone SmPC). Other colchicine manufacturers require a lower maximum colchicine dose and close monitoring with a P-glycoprotein inhibitor, and avoid the combination whenever possible in renal or hepatic impairment (colchicine SmPC). At the first sign of nausea, vomiting, abdominal pain or diarrhoea, colchicine is stopped and the patient needs urgent care (colchicine SmPC).

Mechanism

Cyclosporine inhibits both CYP3A4 and P-glycoprotein – the clearance routes of colchicine. Fatal myopathy, neuropathy, and pancytopenia have been reported in transplant patients on both drugs.

Symptoms

Profuse diarrhoea, vomiting, abdominal pain – first signs of toxicity. Pancytopenia (drop in leukocytes, erythrocytes, platelets), muscle weakness, peripheral neuropathy, hepatic and renal injury follow. Fatal cases have been reported.

Management

In Spain the colchicine SmPC contraindicates it during use of CYP3A4 or P-glycoprotein inhibitors and for 14 days afterwards, and cyclosporine blocks both routes. So a patient taking cyclosporine is not given colchicine. An acute gout flare after transplantation is treated with a glucocorticoid, intra-articular or as a short oral course. The FDA label contraindicates the pair in renal or hepatic impairment. With normal renal and hepatic function the FDA allows colchicine at a reduced dose, for example 0.3 mg once daily instead of 0.6 mg twice daily for flare prophylaxis.

Mechanism

Colchicine is cleared through the CYP3A4 enzyme and the P-glycoprotein transporter and has a narrow therapeutic margin (colchicine SmPC). Ciprofloxacin's own labels describe it as a CYP1A2 inhibitor, while the US Food and Drug Administration (FDA) also lists it as a moderate CYP3A4 inhibitor. CYP3A4 inhibition can raise colchicine blood levels and, with them, the risk of toxicity.

Symptoms

Nausea, vomiting, diarrhoea, muscle weakness, paraesthesias. With severe toxicity: myopathy, neuropathy, bone marrow suppression.

Management

The combination is contraindicated by the Spanish colchicine SmPC, which forbids colchicine during use of CYP3A4 or P-glycoprotein inhibitors and for 14 days afterwards (colchicine SmPC). The US Food and Drug Administration (FDA) classifies ciprofloxacin as a moderate CYP3A4 inhibitor (FDA list), so colchicine is not given during a ciprofloxacin course or for 14 days after it. Other colchicine manufacturers require a lower maximum colchicine dose and close monitoring with a moderate CYP3A4 inhibitor (colchicine SmPC), and the US label of colchicine for cardiovascular prevention advises avoiding such drugs in renal or hepatic impairment (colchicine label, FDA). Colchicine itself is contraindicated in severe renal or hepatic impairment (colchicine SmPC). At the first sign of nausea, vomiting, abdominal pain or diarrhoea, colchicine is stopped and the patient needs urgent care (colchicine SmPC).

Mechanism

Colchicine is cleared via hepatic CYP3A4 and the P-glycoprotein transporter. Clarithromycin inhibits both. Colchicine plasma levels rise several-fold. The narrow therapeutic window makes any increase clinically dangerous. FDA Colcrys carries a boxed warning for fatal toxicity.

Symptoms

Profuse diarrhoea, vomiting, abdominal pain – first signs of toxicity. Pancytopenia (drop in leukocytes, erythrocytes, platelets), muscle weakness, peripheral neuropathy, hepatic and renal injury follow. Fatal cases have been reported.

Management

For patients with renal impairment (creatinine clearance below 60 mL/min) or hepatic impairment, the combination is not prescribed. With preserved renal and hepatic function, use colchicine 0.3 mg every other day, no more than 5 days. Alternative antibiotic: azithromycin (minimal interaction).

Mechanism

Diltiazem is a moderate CYP3A4 inhibitor and a weak P-glycoprotein inhibitor (diltiazem SmPC). Colchicine is cleared through both pathways and has a narrow therapeutic margin (colchicine SmPC). Diltiazem 240 mg/day raised colchicine exposure (area under the curve, AUC) by 93%, almost twofold (colchicine label, US Food and Drug Administration, FDA). Higher levels bring a higher risk of bone marrow suppression and nerve and muscle toxicity.

Symptoms

Profuse diarrhoea, vomiting, abdominal pain. With prolonged combination: muscle weakness, peripheral neuropathy, falling leukocytes and platelets.

Management

The combination is contraindicated: the Spanish colchicine SmPC forbids colchicine during use of CYP3A4 or P-glycoprotein inhibitors and for 14 days afterwards, and names diltiazem in its interactions section (colchicine SmPC). The diltiazem SmPC does not recommend combining it with colchicine (diltiazem SmPC). US labels allow it only if there is no alternative and only with a reduced colchicine dose: for gout flare prophylaxis 0.3 mg twice daily or 0.6 mg once daily instead of 0.6 mg twice daily, for a flare 1.2 mg as a single dose, repeated no earlier than 3 days later (colchicine label, US Food and Drug Administration, FDA). In renal or hepatic impairment the combination is avoided, and neuromuscular toxicity has been reported with diltiazem (colchicine label, FDA). At the first sign of nausea, vomiting, abdominal pain or diarrhoea, colchicine is stopped and the patient needs urgent care (colchicine SmPC).

Mechanism

Dronedarone is a moderate CYP3A4 inhibitor and a potent P-glycoprotein inhibitor (dronedarone SmPC). Colchicine is cleared through both pathways and has a narrow therapeutic margin (colchicine SmPC), so its blood levels rise, and with them the risk of myopathy, neuropathy and bone marrow suppression.

Symptoms

Profuse diarrhoea, vomiting, abdominal pain. With prolonged combination: muscle weakness, peripheral neuropathy, falling leukocytes and platelets.

Management

The combination is contraindicated: the Spanish colchicine SmPC forbids colchicine during use of CYP3A4 or P-glycoprotein inhibitors and for 14 days afterwards (colchicine SmPC), and dronedarone inhibits both pathways (dronedarone SmPC). The US label of colchicine 0.5 mg for cardiovascular prevention, approved by the US Food and Drug Administration (FDA), also contraindicates it with P-glycoprotein inhibitors (colchicine label, FDA). Other colchicine manufacturers require a lower maximum colchicine dose and close monitoring with a P-glycoprotein inhibitor, and avoid the combination whenever possible in renal or hepatic impairment (colchicine SmPC). At the first sign of nausea, vomiting, abdominal pain or diarrhoea, colchicine is stopped and the patient needs urgent care (colchicine SmPC).

Mechanism

Fluconazole is a moderate CYP3A4 inhibitor (fluconazole SmPC), and colchicine is cleared through CYP3A4 and the P-glycoprotein transporter and has a narrow therapeutic margin (colchicine SmPC). In a study, fluconazole 200 mg/day raised colchicine exposure (area under the curve, AUC) by 40% (colchicine label, US Food and Drug Administration, FDA). With long-term colchicine use the risk of nerve and muscle toxicity grows, up to rhabdomyolysis (colchicine SmPC).

Symptoms

Profuse diarrhoea, vomiting, abdominal pain. With prolonged combination: muscle weakness, peripheral neuropathy, falling leukocytes and platelets.

Management

The combination is contraindicated: the Spanish colchicine SmPC forbids colchicine during use of CYP3A4 or P-glycoprotein inhibitors and for 14 days afterwards (colchicine SmPC), and fluconazole is a moderate CYP3A4 inhibitor (fluconazole SmPC). US labels are less strict: if there is no alternative, the colchicine dose is reduced with a moderate CYP3A4 inhibitor – for gout flare prophylaxis 0.3 mg twice daily or 0.6 mg once daily instead of 0.6 mg twice daily, for a flare 1.2 mg as a single dose, repeated no earlier than 3 days later (colchicine label, US Food and Drug Administration, FDA). In renal or hepatic impairment the combination is avoided (colchicine label, FDA). The fluconazole SmPC requires monitoring of patients who also take narrow therapeutic margin drugs metabolised by CYP3A4 (fluconazole SmPC). At the first sign of nausea, vomiting, abdominal pain or diarrhoea, colchicine is stopped and the patient needs urgent care (colchicine SmPC).

Mechanism

Colchicine is cleared via CYP3A4 and P-glycoprotein. Ketoconazole strongly inhibits both. Colchicine plasma levels rise several-fold. FDA Colcrys carries a boxed warning for fatal toxicity.

Symptoms

Profuse diarrhoea, vomiting, abdominal pain – first signs of toxicity. Pancytopenia (drop in leukocytes, erythrocytes, platelets), muscle weakness, peripheral neuropathy, hepatic and renal injury follow. Fatal cases have been reported.

Management

For patients with renal or hepatic impairment, the combination is not prescribed. With preserved function, use colchicine 0.3 mg every other day, no more than 5 days. Alternative antifungals: terbinafine or echinocandins.

Mechanism

Colchicine is a CYP3A4 and P-glycoprotein substrate with narrow therapeutic window. Ritonavir is the strongest CYP3A4 inhibitor and a notable P-glycoprotein inhibitor. Colchicine levels rise 4-fold or more. FDA carries a boxed warning.

Symptoms

Profuse diarrhoea, vomiting, abdominal pain – first signs of toxicity. Pancytopenia (drop in leukocytes, erythrocytes, platelets), muscle weakness, peripheral neuropathy, hepatic and renal injury follow. Fatal cases have been reported.

Management

The combination is not prescribed. For acute gout in a patient on ritonavir, use glucocorticoids (intra-articular or short systemic) or NSAIDs. For long-term prophylaxis, allopurinol.

Mechanism

Verapamil inhibits the CYP3A4 enzyme and the P-glycoprotein transporter (verapamil SmPC), the two colchicine clearance pathways. With verapamil, colchicine exposure (area under the curve, AUC) doubles and peak concentration rises 1.3-fold (verapamil SmPC). The risk of myopathy, neuropathy and bone marrow suppression grows; one case of tetraparesis has been reported with this combination (verapamil SmPC).

Symptoms

Profuse diarrhoea, vomiting, abdominal pain. With prolonged combination: muscle weakness, peripheral neuropathy, falling leukocytes and platelets.

Management

The combination is contraindicated: the Spanish colchicine SmPC forbids colchicine during use of CYP3A4 or P-glycoprotein inhibitors and for 14 days afterwards, and names verapamil in its interactions section (colchicine SmPC). The verapamil SmPC requires a lower colchicine dose (verapamil SmPC). US labels allow the combination only if there is no alternative and only with a reduced colchicine dose: for gout flare prophylaxis 0.3 mg twice daily or 0.6 mg once daily instead of 0.6 mg twice daily, for a flare 1.2 mg as a single dose, repeated no earlier than 3 days later (colchicine label, US Food and Drug Administration, FDA). In renal or hepatic impairment the combination is avoided (colchicine SmPC). At the first sign of nausea, vomiting, abdominal pain or diarrhoea, colchicine is stopped and the patient needs urgent care (colchicine SmPC).

Mechanism

Additive myopathy and rhabdomyolysis risk. Atorvastatin injures muscle fibre by suppressing ubiquinone synthesis; colchicine disrupts microtubule function in myocytes. Particularly dangerous in older patients and chronic kidney disease.

Symptoms

Pain and weakness in large muscle groups (thighs, shoulders, calves), dark urine, elevated creatine kinase. Severe cases progress to rhabdomyolysis with acute kidney injury. Symptoms appear within 1–4 weeks of co-administration.

Management

Avoid prolonged combination. For acute gout, a short colchicine course (3–5 days) at 0.3 mg every other day is acceptable with muscle symptom and creatine kinase monitoring. Alternative for gout: intra-articular or short systemic glucocorticoid.

Mechanism

Colchicine is cleared with the help of the P-glycoprotein transporter and the CYP3A4 enzyme (colchicine SmPC). Azithromycin inhibits P-glycoprotein and increases colchicine exposure: the area under the curve (AUC) rises by 57% and the peak concentration by 22% (azithromycin SmPC). Colchicine has a narrow therapeutic index and azithromycin has a long half-life, so its effect persists after the course ends (azithromycin SmPC).

Symptoms

Profuse diarrhoea, vomiting, abdominal pain as first signs. With prolonged combination, muscle weakness, peripheral neuropathy, and pancytopenia follow.

Management

Monitor the patient clinically during the azithromycin course and after it ends (azithromycin SmPC) and, where possible, check colchicine blood concentrations (colchicine SmPC). Azithromycin inhibits P-glycoprotein, and in renal or hepatic impairment colchicine should not be combined with such drugs whenever possible; if colchicine is continued, reduce its dose substantially and monitor the patient closely (colchicine SmPC). Colchicine itself is contraindicated in severe renal or hepatic impairment (colchicine SmPC). In older patients and in renal impairment, the total colchicine dose over a 4-day gout attack should not exceed 3 mg (colchicine SmPC). At the first sign of nausea, vomiting, abdominal pain or diarrhoea, stop colchicine; the patient needs urgent care (colchicine SmPC).

Mechanism

Carvedilol is a moderate P-glycoprotein inhibitor; colchicine is a P-glycoprotein substrate with a narrow therapeutic window. Colchicine plasma levels rise; myelosuppression and neuromyopathy risk.

Symptoms

Profuse diarrhoea, vomiting, abdominal pain. With prolonged combination: muscle weakness, peripheral neuropathy, falling leukocytes and platelets.

Management

In chronic kidney disease or hepatic impairment, the combination is not prescribed. With preserved function, colchicine 0.3 mg every other day for no more than 5 days. Alternative for gout: intra-articular glucocorticoid.

Mechanism

Additive myopathy and rhabdomyolysis risk. Rosuvastatin suppresses muscle ubiquinone synthesis; colchicine disrupts microtubule function in myocytes. Severe muscle toxicity has been reported, especially in older patients and chronic kidney disease.

Symptoms

Pain and weakness in large muscle groups (thighs, shoulders, calves), dark urine, elevated creatine kinase. Severe cases progress to rhabdomyolysis with acute kidney injury. Symptoms appear within 1–4 weeks of co-administration.

Management

Avoid prolonged combination. For acute gout, a short colchicine course (3–5 days) at 0.3 mg every other day is acceptable with muscle symptom and creatine kinase monitoring. Alternative: intra-articular or short systemic glucocorticoid.

Mechanism

Tacrolimus and colchicine are both P-glycoprotein substrates. Competition at this transporter raises colchicine levels, especially in transplant patients with borderline renal function.

Symptoms

Profuse diarrhoea, vomiting, abdominal pain. With prolonged combination: muscle weakness, peripheral neuropathy, falling leukocytes and platelets. In transplant patients: accelerated graft decline.

Management

For acute gout in transplant patients, a short colchicine course (3–5 days) at 0.3 mg every other day with muscle symptom and blood count monitoring. For chronic gout, allopurinol. For acute attacks, intra-articular glucocorticoid.

Mechanism

In a gout flare both are used, but along routes whose adverse effects overlap: colchicine damages intestinal mucosa while etoricoxib inhibits COX-2 with renal and blood pressure impact. The colchicine label warns that macrolides, CYP3A4 inhibitors, ciclosporin, protease inhibitors, calcium antagonists and statins raise its levels and can cause toxicity; etoricoxib is not on that list, so the risk here is additive rather than metabolic.

Symptoms

Diarrhoea, nausea and abdominal pain come first and are the classic warning of excess colchicine. Etoricoxib adds oedema, rising blood pressure and reduced urine output. Muscle weakness with dark urine points to colchicine myopathy, especially with statins or low renal filtration.

Management

In a flare use the short low-dose colchicine regimen and keep etoricoxib as brief as possible, watching blood pressure and oedema. Diarrhoea marks the colchicine ceiling: once it appears, reduce or stop. With low renal filtration or statins, review the colchicine dose before starting.

Mechanism

Both drugs can damage muscle on their own: simvastatin causes myopathy and rhabdomyolysis (simvastatin SmPC), and colchicine taken long term at therapeutic doses causes neuromuscular toxicity and rhabdomyolysis (colchicine SmPC). Together the risk of myopathy rises: adding one drug to a stable long-term regimen of the other has resulted in myopathy and rhabdomyolysis, including a fatal case (US colchicine label, FDA). The interaction may be pharmacokinetic, pharmacodynamic or both (US colchicine label). Such cases with this combination have also been reported in patients with renal impairment (simvastatin SmPC).

Symptoms

Pain and weakness in large muscle groups (thighs, shoulders, calves), dark urine, elevated creatine kinase. Severe cases progress to rhabdomyolysis with acute kidney injury. The risk is higher in older patients and in renal impairment.

Management

Before combining, weigh the benefit against the increased risk of myopathy and rhabdomyolysis (US simvastatin and colchicine labels, FDA). If it is used, monitor for muscle pain, tenderness and weakness, especially at the start of treatment and when the dose of either drug is increased (US simvastatin label); creatine kinase monitoring will not necessarily prevent severe myopathy (US colchicine label). Monitor patients with renal impairment closely (simvastatin SmPC). Adjust the colchicine dose to age and renal function: in older patients and in renal impairment the total dose over a 4-day gout attack should not exceed 3 mg, in moderate renal impairment the dose may need to be halved, and in severe renal impairment colchicine is contraindicated (colchicine SmPC). If muscle toxicity appears, interrupt or stop colchicine (US colchicine label); symptoms usually resolve within one week to several months after stopping (colchicine SmPC).

Mechanism

Spironolactone is a weak P-glycoprotein inhibitor and may slightly raise colchicine levels. Clinically significant toxicity is described in chronic kidney disease and on long-term combination.

Symptoms

Nausea, vomiting, diarrhoea, muscle weakness, paraesthesias. With severe toxicity: myopathy, neuropathy, bone marrow suppression.

Management

With normal renal function, no dose adjustment needed. With creatinine clearance below 50 mL/min, halve the colchicine dose. Check creatinine, CK, and CBC every 3 months. In gout flares, a short colchicine course (0.5 mg 2–3 times daily for 1–3 days) is better tolerated than long-term use.