colchicine

Colgout / Lengout / Colcine, 500 mcg (0.5 mg) tabs

Dose: ii po STAT +/- I po 12 hours later, and then stop

Although NSAIDs are now first-line drugs for acute gout, colchicine, was the primary treatment for many years. Colchicine is more specific in gout but NSAIDs are often used in its stead, because of troublesome diarrhoea and risk of toxicity associated with colchicine therapy. Instead, colchicine is more often now used (at low doses) in the inter-critical period between attacks for prolonged prophylaxis. Colchicine, an alkaloid isolated from the autumn crocus, is also effective in preventing attacks of acute Mediterranean fever and may have a mild beneficial effect in sarcoid arthritis and in hepatic cirrhosis.¹

Contraindication:

• neutropenic patients
• renal failure: eGFR < 10 mL/min/1.73m².
• concurrent CYP3A4 and/or P-glycoprotein inhibitors in those with renal or hepatic impairment

Colchicine is absorbed readily after oral administration, reaches peak plasma levels within 2 hours, and is eliminated with a serum half-life of 9 hours.²

Adverse effects – look for these, in a patient with potential colchicine toxicity:

• nausea, vomiting, diarrhoea, abdominal pain
• bone marrow depression
• alopecia
• hepatocellular failure
• mental depression and seizures
• respiratory depression

The risk of colchicine toxicity is increased when taken concurrently with inhibitors of cytochrome P450 3A4 (CYP3A4) or P-glycoprotein (P-gp), e.g. some azole antifungals (e.g. fluconazole), calcium channel blockers (e.g. diltiazem, verapamil) and macrolide antibiotics (e.g. erythromycin). Where these medicines are required at the same time as colchicine, the dose of colchicine should be reduced and the patient monitored for symptoms and signs of colchicine toxicity. These combinations are contraindicated in patients with renal or hepatic impairment, as this increases the risk of toxicity.¹

Interactions: susceptible to inhibition of CYP3A4 metabolism and P-glycoprotein transport.

• Amiodarone: [NP] Decreased colchicine metabolism and transport.
• Amprenavir: [P] Decreased colchicine metabolism.
• Carbamazepine: [P] Increased metabolism of colchicine.
• Clarithromycin: [P] Decreased colchicine metabolism and transport.
• Cyclosporine: [P] Decreased colchicine metabolism and transport.
• Dronedarone: [NE] Decreased colchicine transport.
• Erythromycin: [P] Decreased colchicine metabolism and transport.
• Nefazodone: [NE] Decreased colchicine metabolism.
• Rifampin: [P] Increased colchicine metabolism.
• Ritonavir: [P] Decreased colchicine metabolism.
• Azole antifungals
• Calcium channel blockers¹

HP: Highly predictable. Interaction occurs in almost all patients receiving the interacting combination; P: Predictable. Interaction occurs in most patients receiving the combination; NP: Not predictable. Interaction occurs only in some patients receiving the combination; NE: Not established. Insufficient data available on which to base estimate
of predictability.¹

Historically, colchicine dose instructions included advice to continue dosing until the pain settled or gastrointestinal adverse effects occurred, and many patients in the community still rest on that understanding Since then, however, the standard dose instructions have been significantly revised to improve safety. Patients are now told to stop taking colchicine immediately if they experience abdominal pain, diarrhoea, nausea or vomiting, or a burning feeling in their throat, stomach or on their skin. Indeed, in the acute setting, most patients should take colchicine for no more than 24 hours, taking two tablets together, and one tablet 12 hours later, and then no more. Where eGFR is 10-50 mL/min/1.73m², reduce the initial dose by half (i.e. 500 micrograms); do not exceed 1.5 mg over three days. Do not repeat acute course within three days. Inter-critical dosing can be considered in reliable patients with good renal function, who can be instructed to take 500 mcg (1 tablet), twice daily, during the first three to six months of orate-lowering treatment with allopurinol (Progout).Reduce the dose to 500 mcg (1 tablet), once daily, or on alternate days, if not tolerated, e.g. diarrhoea develops, chronic kidney disease or concurrent use of CYP3A4/P-glycoprotein inhibitors (e.g. erythromycin, verapamil)..Avoid colchicine, or use with extreme caution, in frail patients, those who weigh < 50 kg, or patients with hepatic or renal impairment.²

Indications for urate-lowering treatment:

• frequency: 2 or more flares per year
• chronicity: tophi or erosions on X-ray
• complicating: urolithiasis (past or present)
• end-organ: renal impairment, eGFR < 60 mL/min/1.73 m²
• serum urate level: ≥ 0.54 mmol/L

Colchicine has a narrow therapeutic index: acute overdose exceeding 0.5 mg/kg is usually fatal, and doses as low as 0.18 mg/kg (about 15 mg for an average-sized adult) have resulted in deaths. Abdominal pain, diarrhoea, nausea and vomiting are usually the first symptoms of colchicine toxicity.These symptoms, particularly diarrhoea, can also occur with doses within the therapeutic range. Hepatic necrosis, acute renal failure, disseminated intravascular coagulation, and seizures have all been observed. Colchicine may rarely cause hair loss and bone marrow depression, as well as peripheral neuritis, myopathy, and a toxicity causing an ascending central nervous system depression that can be fatal (most commonly with an intravenous preparation that has now been discontinued), a toxicity heralded by burning throat pain, a bloody diarrhoea, shock, haematuria and oliguria.¹

All patients with known or suspected overdose of colchicine, or displaying symptoms of colchicine toxicity, should be immediately referred to hospital. Although colchicine is rapidly absorbed from the gastrointestinal tract, removal of even a small amount can improve the patient’s prognosis. Patients who do not present soon after ingestion, and those with pre-existing renal or hepatic impairment, have a less favourable prognosis.²

Summary Recommendations:

• Limit colchicine prescriptions to the anticipated number of tablets required for managing the acute attack of gout: this may be only a handful of tablets
• Prescribe monthly for prophylactic use and ensure colchicine is stopped after three to six months
• Be aware of significant medicine interactions with colchicine, especially in those with renal or hepatic impairment
• watch for early gastrointestinal toxicity and be on the look for evidence of ascending CNS depression

References

1. Safer prescribing of high-risk medicines: Colchicine – extremely toxic in overdose. Best Practice Journal 2014 (63). Available at https://bpac.org.nz/bpj/2014/september/safer-prescribing.aspx.
2. Katzung, Bertram G., Masters, Susan B. and Trevor, Anthony J. “Ch. 36: NSAIDs, Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout.” In Basic and Clinical Pharmacology. 12th Ed. McGraw-Hill, 2012: 651-2, 1156.