COLCHICINE Drug Interactions: What You Need to Know

INTERACTIONS 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 [see Error! Hyperlink reference not valid. ] .

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)

CONTRAINDICATIONS Hypersensitivity to this product or to probenecid or colchicine. Probenecid and colchicine tablets are contraindicated in children under 2 years of age. Not recommended in persons with known blood dyscrasias or uric acid kidney stones. Therapy with probenecid and colchicine should not be started until an acute gouty attack has subsided. Pregnancy: Probenecid crosses the placental barrier and appears in cord blood. Colchicine can arrest cell division in animals and plants. In certain species of animals under certain conditions, colchicine has produced teratogenic effects. The possibility of such effects in humans also has been reported. Because of the colchicine component, probenecid and colchicine is contraindicated in pregnant patients. The use of any drug in women of childbearing potential requires that the anticipated benefit be weighed against the possible hazards.

AND PRECAUTIONS

• Fatal overdoses have been reported with colchicine in adults and children. Keep colchicine tablets out of the reach of children ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. ).
• Blood dyscrasias: myelosuppression, leukopenia, granulocytopenia, thrombocytopenia and aplastic anemia have been reported ( Error! Hyperlink reference not valid. ).
• Monitor for toxicity and if present consider temporary interruption or discontinuation of colchicine ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. ).
• Drug interaction P-gp and/or CYP3A4 inhibitors: Coadministration of colchicine with P-gp and/or strong CYP3A4 inhibitors has resulted in life-threatening interactions and death ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. ).
• Neuromuscular toxicity: Myotoxicity including rhabdomyolysis may occur, especially in combination with other drugs known to cause this effect. Consider temporary interruption or discontinuation of colchicine tablets ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. ).

5.1 Fatal Overdose Fatal overdoses, both accidental and intentional, have been reported in adults and children who have ingested colchicine <span class="opacity-50 text-xs">[see Error! Hyperlink reference not valid. ]</span> . Colchicine tablets should be kept out of the reach of children.

5.2 Blood Dyscrasias Myelosuppression, leukopenia, granulocytopenia, thrombocytopenia, pancytopenia and aplastic anemia have been reported with colchicine used in therapeutic doses.

5.3 Drug Interactions Colchicine is a P-gp and CYP3A4 substrate. Life-threatening and fatal drug interactions have been reported in patients treated with colchicine given with P-gp and strong CYP3A4 inhibitors. If treatment with a P-gp or strong CYP3A4 inhibitor is required in patients with normal renal and hepatic function, the patient’s dose of colchicine may need to be reduced or interrupted <span class="opacity-50 text-xs">[see Error! Hyperlink reference not valid. ]</span> . Use of colchicine tablets in conjunction with P-gp or strong CYP3A4 inhibitors (this includes all protease inhibitors except fosamprenavir) is contraindicated in patients with renal or hepatic impairment <span class="opacity-50 text-xs">[see Error! Hyperlink reference not valid. ]</span>.

5.4 Neuromuscular Toxicity Colchicine-induced neuromuscular toxicity and rhabdomyolysis have been reported with chronic treatment in therapeutic doses. Patients with renal dysfunction and elderly patients, even those with normal renal and hepatic function, are at increased risk. Concomitant use of atorvastatin, simvastatin, pravastatin, fluvastatin, lovastatin, gemfibrozil, fenofibrate, fenofibric acid or benzafibrate (themselves associated with myotoxicity) or cyclosporine with colchicine tablets may potentiate the development of myopathy <span class="opacity-50 text-xs">[see Error! Hyperlink reference not valid. ]</span> . Once colchicine is stopped, the symptoms generally resolve within one week to several months.