Colchicineinteractions

Colchicine is a substrate of the efflux transporter P-glycoprotein (P-gp). Of the cytochrome P450 enzymes tested, CYP3A4 was mainly involved in the metabolism of colchicine. If colchicine tablets are administered with drugs that inhibit P-gp, most of which also inhibit CYP3A4, increased concentrations of colchicine are likely. Fatal drug interactions have been reported. Physicians should ensure that patients are suitable candidates for treatment with colchicine tablets and remain alert for signs and symptoms of toxicities related to increased colchicine exposure as a result of a drug interaction. Signs and symptoms of colchicine tablets toxicity should be evaluated promptly and, if toxicity is suspected, colchicine tablets should be discontinued immediately. Table 4 provides recommendations as a result of other potentially significant drug interactions. Table 1 provides recommendations for strong and moderate CYP3A4 inhibitors and P-gp inhibitors. Table 4. Other Potentially Significant Drug Interactions Concomitant Drug Class or Food Noted or Anticipated Outcome Clinical Comment HMG-CoA Reductase Inhibitors: atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin Pharmacokinetic and/or pharmacodynamic interaction: the addition of one drug to a stable long-term regimen of the other has resulted in myopathy and rhabdomyolysis (including a fatality) Weigh the potential benefits and risks and carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy; monitoring CPK (creatine phosphokinase) will not necessarily prevent the occurrence of severe myopathy.

Other Lipid-Lowering Drugs: fibrates, gemfibrozil Digitalis Glycosides: digoxin P-gp substrate; rhabdomyolysis has been reported Coadministration of P-gp and/or CYP3A4 inhibitors (e.g., clarithromycin or cyclosporine) have been demonstrated to alter the concentration of colchicine. The potential for drug-drug interactions must be considered prior to and during therapy. See FPI for a complete list of reported and potential interactions ( Error! Hyperlink reference not valid., Error! Hyperlink reference not valid., Error! Hyperlink reference not valid. ).

Drug Interactions In Vitro Drug Interactions In vitro studies in human liver microsomes have shown that colchicine is not an inhibitor or inducer of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4 activity. In Vivo Drug Interactions The effects of coadministration of other drugs with colchicine tablets on C max, AUC and C min are summarized in Table 6 (effect of other drugs on colchicine) and Table 7 (effect of colchicine on other drugs). For information regarding clinical recommendations, see Table 1 in Dose Modification for Coadministration of Interacting Drugs. Table 6.

Drug Interactions: Pharmacokinetic Parameters for Colchicine Tablets in the Presence of the Coadministered Drug Coadministered Drug Dose of Coadministered Drug (mg) Dose of Colchicine Tablets (mg) N % Change in Colchicine Concentrations from Baseline (Range: Min – Max) C max AUC 0-t Cyclosporine 100 mg single dose 0.6 mg single dose 23 270.0 (62.0 to 606.9) 259.0 (75.8 to 511.9) Clarithromycin 250 mg twice daily, 7 days 0.6 mg single dose 23 227.2 (65.7 to 591.1) 281.5 (88.7 to 851.6) Ketoconazole 200 mg twice daily, 5 days 0.6 mg single dose 24 101.7 (19.6 to 219.0) 212.2 (76.7 to 419.6) Ritonavir 100 mg twice daily, 5 days 0.6 mg single dose 18 184.4 (79.2 to 447.4) 296.0 (53.8 to 924.4) Verapamil 240 mg daily, 5 days 0.6 mg single dose 24 40.1 (-47.1 to 149.5) 103.3 (-9.8 to 217.2) Diltiazem 240 mg daily, 7 days 0.6 mg single dose 20 44.2 (-46.0 to 318.3) 93.4 (-30.2 to 338.6) Azithromycin 500 mg x 1 day, then 250 mg x 4 days 0.6 mg single dose 21 21.6 (-41.7 to 222.0) 57.1 (-24.3 to 241.1) Grapefruit juice 240 mL twice daily, 4 days 0.6 mg single dose 21 -2.55 (-53.4 to 55.0) -2.36 (-46.4 to 62.2) Estrogen-containing oral contraceptives: In healthy female volunteers given ethinyl estradiol and norethindrone (Ortho-Novum ® 1/35) coadministered with colchicine tablets (0.6 mg twice daily × 14 days), hormone concentrations are not affected. In healthy volunteers given theophylline coadministered with colchicine tablets (0.6 mg twice daily × 14 days), theophylline concentrations were not affected. Table 7.

Drug Interactions: Pharmacokinetic Parameters for Coadministration of Drug in the Presence of Colchicine Tablets Coadministered Drug Dose of Coadministered Drug (mg) Dose of Colchicine Tablets (mg) N % Change in Coadministered Drug Concentrations from Baseline (Range: Min – Max) C max AUC 0-t Theophylline 300 mg (elixir) single dose 0.6 mg twice daily x 14 days 27 1.6 (-30.4 to 23.1) 1.6 (-28.5 to 27.1) Ethinyl Estradiol (Ortho-Novum ® 1/35) 21-day cycle (active treatment) + 7-day placebo 0.6 mg twice daily x 14 days 27 Conducted in healthy adult females -6.7 (-40.3 to 44.7) -3.0 AUC Ʈ (-25.3 to 24.9) Norethindrone (Ortho-Novum ® 1/35) 0.94 (-37.3 to 59.4) -1.6 (-32.0 to 33.7)