Drug Interaction Report

CONTRAINDICATED: Coadministration with potent inhibitors of CYP450 3A4 or dual CYP450 3A4 and P-glycoprotein (P-gp) inhibitors may significantly increase the plasma concentrations of colchicine in patients with renal or hepatic impairment. The proposed mechanism is inhibition of CYP450 3A4, the isoenzyme responsible for the metabolic clearance of colchicine, as well as reduced excretion of colchicine due to inhibition of the P-gp efflux transporter in the intestine, renal proximal tubule, and liver. Clinical toxicities associated with the interaction have included neuromyopathy, rhabdomyolysis, hepato- and nephrotoxicity, cardiotoxicity, bone marrow suppression, multiorgan failure, and fatality.

ADJUST DOSE: Coadministration with potent inhibitors of CYP450 3A4 or dual inhibitors of CYP450 3A4 and P-glycoprotein (P-gp) may significantly increase the serum concentrations of colchicine in patients with normal hepatic and renal function. In one case report, a patient with familial Mediterranean fever and amyloidosis involving the kidney, liver, and gastrointestinal tract was admitted to the hospital with life-threatening colchicine toxicity after a two-week course of erythromycin, a moderate CYP450 3A4 inhibitor. During the year prior to admission, the patient had developed recurrent diarrhea and abdominal pain and demonstrated toxic levels of colchicine on two occasions. It is likely the patient had acute colchicine toxicity brought on by the addition of erythromycin and superimposed on chronic colchicine intoxication secondary to renal and hepatic impairment. The patient improved with supportive therapy and intensive hemodialysis and was discharged on day 70 of hospitalization. Another report describes two fatal cases of agranulocytosis due to presumed interaction between colchicine and clarithromycin, a potent CYP450 3A4 inhibitor. Risk factors include mild liver function test abnormalities in one patient and end-stage renal failure in the other. Several other cases of suspected interaction with clarithromycin have also been reported in which patients developed rhabdomyolysis, pancytopenia, or neuromyopathy during treatment with colchicine. In most cases, concomitant risk factors such as preexisting renal and/or hepatic impairment were present. In a retrospective study of 116 patients who were prescribed clarithromycin and colchicine during the same hospital admission, 9 out of 88 patients (10.2%) who received the two drugs concomitantly died, compared to only 1 of 28 patients (3.6%) who received the drugs sequentially. The rate of pancytopenia was 10.2% in the concomitant group versus 0% in the sequential group. Multivariate analysis of the patients who received concomitant therapy found that longer overlapped therapy, the presence of baseline renal impairment, and the development of pancytopenia were independently associated with death. Overall, the risk of death was increased 25-fold in patients who received concomitant therapy and who developed pancytopenia.

MANAGEMENT: Please consult the product labeling for the specific brand of colchicine being used for complete dosing information.
For the Lodoco brand, the use of colchicine and potent CYP450 3A4 inhibitors is considered contraindicated in all patients.
For the Colcrys brand, the use of colchicine and potent CYP450 3A4 inhibitors in patients with renal or hepatic impairment is considered contraindicated. In patients with normal renal and hepatic function, the dosage of colchicine should be reduced when used with potent CYP450 3A4 inhibitors or within 14 days of using them. For the prophylaxis of gout flares, if the original dose was 0.6 mg twice a day the adjusted dosage recommended is 0.3 mg once a day. If the original dose was 0.6 mg once a day the adjusted dosage recommended is 0.3 mg once every other day. For the treatment of gout flares, the adjusted dosage recommended is 0.6 mg for one dose, followed by 0.3 mg one hour later. Administration should not be repeated for at least three days. For the treatment of familial Mediterranean fever, the maximum recommended daily dosage of colchicine is 0.6 mg/day (may be given as 0.3 mg twice a day).
For the brands Gloperba and Mitigare, the use of colchicine and dual inhibitors of CYP450 3A4 and P-gp in patients with renal or hepatic impairment is considered contraindicated. In patients with normal renal and hepatic function, the use of colchicine and potent CYP450 3A4 or combined CYP450 3A4 and P-gp inhibitors should be generally avoided. If coadministration is required, the dose of colchicine should be adjusted by reducing the dose or reducing the dose frequency and the patient should be closely monitored for signs of colchicine toxicity.
The product labeling for itraconazole states that concomitant use with colchicine is contraindicated in patients with renal or hepatic impairment during and for 2 weeks after treatment with itraconazole; in all other patients concomitant treatment is not recommended during and for 2 weeks after treatment with itraconazole. Patients should be advised to contact their physician if they experience symptoms of toxicity such as abdominal pain, nausea, vomiting, diarrhea, fatigue, myalgia, asthenia, hyporeflexia, paraesthesia, and numbness.

GENERALLY AVOID: Coadministration with grapefruit juice may increase the serum concentrations of colchicine. Clinical toxicity including myopathy, neuropathy, multiorgan failure, and pancytopenia may occur. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism and P-glycoprotein efflux in the gut wall by certain compounds present in grapefruits. A published case report describes an eight-year-old patient with familial Mediterranean fever who developed acute clinical colchicine intoxication after ingesting approximately one liter of grapefruit juice per day for two months prior to hospital admission while being treated with colchicine 2 mg/day. Her condition progressed to circulatory shock and multiorgan failure, but she recovered with supportive therapy after 24 days in the hospital. In a study of 21 healthy volunteers, administration of 240 mL grapefruit juice twice a day for 4 days was found to have no significant effect on the pharmacokinetics of a single 0.6 mg dose of colchicine. However, significant interactions have been reported with other CYP450 3A4 inhibitors such as clarithromycin, diltiazem, erythromycin, ketoconazole, ritonavir, and verapamil.

MANAGEMENT: Patients treated with colchicine should be advised to avoid the consumption of grapefruit and grapefruit juice, and to contact their physician if they experience symptoms of colchicine toxicity such as abdominal pain, nausea, vomiting, diarrhea, fatigue, myalgia, asthenia, hyporeflexia, paresthesia, and numbness.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of lonafarnib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit juice, but has been reported for other CYP450 3A4 inhibitors. When a single 50 mg oral dose of lonafarnib was administered following pretreatment with the potent CYP450 3A4 inhibitor ketoconazole (200 mg once daily for 5 days) in healthy study subjects, lonafarnib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 270% and 425%, respectively, compared to lonafarnib administered alone. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Increased exposure to lonafarnib may increase the risk and/or severity of adverse effects such as nausea, vomiting, diarrhea, anorexia, electrolyte disturbances, liver enzyme elevations, myelosuppression, infection, and hypertension.

ADJUST DOSING INTERVAL: Food does not have clinically relevant effects on the oral bioavailability of lonafarnib. When a single 75 mg oral dose of lonafarnib was administered with a high-fat meal (952 calories; approximately 43% from fat) in healthy subjects, lonafarnib Cmax and AUC decreased by 55% and 29%, respectively, compared to administration under fasted conditions. When administered with a low-fat meal (421 calories; approximately 12% from fat), lonafarnib Cmax decreased by 25% and AUC decreased by 21% relative to fasting. However, administration with food may help improve gastrointestinal tolerance to lonafarnib, which may commonly cause nausea, vomiting, diarrhea, and abdominal pain.

MANAGEMENT: Lonafarnib should be administered with the morning and evening meals and an adequate amount of water. Patients should avoid consumption of grapefruit or grapefruit juice and Seville oranges (also known as bitter or sour oranges).during treatment with lonafarnib.