indication

For treatment and relief of pain in attacks of acute gouty arthritis.

pharmacology

Colchicine is a highly poisonous alkaloid, originally extracted from plants of the genus Colchicum (Autumn crocus, also known as the "Meadow saffron"). Originally used to treat rheumatic complaints and especially gout, it was also prescribed for its cathartic and emetic effects. Its present medicinal use is mainly in the treatment of gout; as well, it is being investigated for its potential use as an anti-cancer drug. It can also be used as initial treatment for pericarditis and preventing recurrences of the condition.

mechanism of action

The precise mechanism of action has not been completely established. In patients with gout, colchicine apparently interrupts the cycle of monosodium urate crystal deposition in joint tissues and the resultant inflammatory response that initiates and sustains an acute attack. Colchicine decreases leukocyte chemotaxis and phagocytosis and inhibits the formation and release of a chemotactic glycoprotein that is produced during phagocytosis of urate crystals. Colchicine also inhibits urate crystal deposition, which is enhanced by a low pH in the tissues, probably by inhibiting oxidation of glucose and subsequent lactic acid production in leukocytes. Colchicine has no analgesic or antihyperuricemic activity. Colchicine inhibits microtubule assembly in various cells, including leukocytes, probably by binding to and interfering with polymerization of the microtubule subunit tubulin. Although some studies have found that this action probably does not contribute significantly to colchicine's antigout action, a recent in vitro study has shown that it may be at least partially involved.

toxicity

The onset of toxic effects is usually delayed for several hours or more after the ingestion of an acute overdose. Nausea, vomiting, abdominal pain, and diarrhea occur first. The diarrhea may be bloody due to hemorrhagic gastroenteritis. Burning sensations of the throat, stomach, and skin may be prominent symptoms. Extensive vascular damage may result in shock. Kidney damage, evidenced by hematuria and oliguria, may occur. Muscular weakness may be marked, and ascending paralysis of the central nervous system may develop; the patient usually remains conscious. Delirium and convulsions may occur. Death due to respiratory arrest may result. Although death from the ingestion of as little as 7 mg has been reported, much larger doses have been survived .

biotransformation

Probably hepatic. Although colchicine metabolites have not been identified in humans, metabolism by mammalian hepatic microsomes has been demonstrated in vitro.

absorption

Colchicine is rapidly absorbed after oral administration, probably from the jejunum and ileum. However, the rate and extent of absorption are variable, depending on the tablet dissolution rate; variability in gastric emptying, intestinal motility, and pH at the absorption site; and the extent to which colchicine is bound to microtubules in gastrointestinal mucosal cells.

half life

Elimination half-life is approximately 1 hour in healthy subjects, although a study with an extended sampling time reported mean terminal elimination half-life values of approximately 9 to 10.5 hours. Other studies have reported half-life values of approximately 2 hours in patients with alcoholic cirrhosis and approximately 2.5 hours in patients with familial Mediterranean fever.

route of elimination

In healthy volunteers (n=12) 40 – 65% of 1 mg orally administered colchicine was recovered unchanged in urine. Enterohepatic recirculation and biliary excretion are also postulated to play a role in colchicine elimination.

drug interactions

Atorvastatin: Increased risk of rhadbomyolysis with this combination.

Bicalutamide: CYP3A4 Inhibitors like bicalutamide may increase the serum concentration of colchicine. Increase monitoring for colchicine-related toxicity when using such combinations. Use extra caution in patients with impaired renal and/or hepatic function.

Cerivastatin: Increased risk of rhabdomyolysis with this combination

Clarithromycin: Severe colchicine toxicity can occur

Clotrimazole: CYP3A4 Inhibitors (Moderate) such as clotrimazole may increase the serum concentration of colchicine. Reduce colchicine dose (for gout flares: to 1.2 mg x 1 dose, with next dose no sooner than 3 days later; for Familial Mediterranean Fever: to no more than 1.2 mg/day) when using in combination with a moderate CYP3A4 inhibitor such as erythromycin or verapamil. Increase monitoring for colchicine-related toxicity when using such combinations. Use extra caution in patients with impaired renal and/or hepatic function.

Conivaptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Colchicine. In patients with normal renal and hepatic function, reduce colchicine dose (for gout flares: to 0.6 mg x 1 dose, followed by 0.3 mg 1 hour later, with next dose no sooner than 3 days later; for gout flare prophylaxis: if target dose would otherwise be 0.6 mg daily, change to 0.3 mg every other day, and if target dose would otherwise be 0.6 mg twice daily, change to 0.3 mg daily; for Familial Mediterranean Fever: to no more than 0.6 mg/day) when using in combination with a strong CYP3A4 inhibitor such as clarithromycin or ritonavir. Increase monitoring for colchicine-related toxicity when using such combinations. Colchicine use is contraindicated in patients with impaired renal and/or hepatic function who are also receiving a strong CYP3A4 inhibitor.

Cyclosporine: Increased toxicity of both drugs

Erythromycin: Severe colchicine toxicity can occur

Fluvastatin: Increased risk of rhabdomyolysis with this combination

Lovastatin: Increased risk of rhabdomyolysis with this combination

Pravastatin: Increased risk of rhabdomyolysis with this combination

Rosuvastatin: Increased risk of rhabdomyolysis with this combination

Simvastatin: Increased risk of rhabdomyolysis with this combination

Telithromycin: Telithromycin may reduce clearance of Colchicine. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Colchicine if Telithromycin is initiated, discontinued or dose changed.

Troleandomycin: Severe colchicine toxicity can occur

Verapamil: Verapamil may increase the serum concentration of Colchicine. This likely occurs via Verapamil-mediated inhibition of CYP3A4 and p-glycoprotein-mediated transport. Monitor for changes in the therapeutic/adverse effects of Colchicine if Verapamil is initiated, discontinued or dose changed.

Voriconazole: Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of colchicine by decreasing its metabolism. A dose reduction of colchicine is recommended along with increased monitoring for colchicine toxicity. Concomitant therapy is contraindicated in patients with renal and/or hepatic impairment.