18 prevent toxicity. (See Table 1. Treatment and Tapering of Initial Therapies for Acute and Recurrent Pericarditis.) Furthermore, colchicine is metabolized by CYP3A4 and is also a substrate of P-glycoprotein, which consequently increases the risk for significant drug-drug interactions. Concomitant use of colchicine with strong CYP3A4 or P-glycoprotein inhibitors should be avoided, and close monitoring for colchicine toxicity is warranted with concomitant use of moderate CYP3A4 inhibitors. (See Table 2.)50 Particular caution should be exercised in patients receiving drugs that affect both CYP3A4 and P-glycoprotein. The most common adverse reactions of colchicine are gastrointestinal effects. Colchicine commonly causes diarrhea, and occasionally nausea and vomiting.51 If patients experience diarrhea that is likely to be attributable to colchicine, given the benefits, the dose should be halved in the first instance, rather than discontinued. Colchicine can also cause an acquired lactose intolerance that may contribute to diarrhea. Therefore, in addition to reducing the colchicine dose, a lactose-free diet should be attempted.52 Consider signposting patients to information about lactosefree diets.53 Proton pump inhibitors can also occasionally contribute to diarrhea. If these are used, consider the need for these and/or switch to a histamine type-2 receptor (H2)- antagonist. Side effects of colchicine that are less common but serious, and thus require close monitoring and possible dose reduction or discontinuation of the drug, include bone marrow suppression, renal or hepatic impairment, and neuromuscular toxicity. Extra caution is necessary in the elderly, who are at increased risk for neuromuscular toxicity and rhabdomyolysis.54 Colchicine is contraindicated in end-stage renal failure (creatinine clearance <15 mL/min), severe hepatic impairment and blood dyscrasias. Although there are varying recommendations based on different product package inserts and indications, the use of colchicine in patients with severe renal impairment is not well-studied. Patients with chronic kidney disease who are also receiving colchicine should be closely monitored for adverse effects. Colchicine is generally avoided in dialysis because it is not removed by dialysis. Avoidance with strong P-glycoprotein inhibitors or CYP3A4 inhibitors should also be strongly considered. Although colchicine crosses the placenta and is generally avoided during pregnancy, it has not been associated with increased fetal malformations when used for familial Mediterranean fever.55,56,57 Muscle toxicity and rhabdomyolysis with colchicine and HMG-CoA reductase inhibitors Both colchicine and HMG-CoA reductase inhibitors (statins) can cause myotoxicity through unique mechanisms.66 In addition to colchicine being a substrate for both CYP3A4 and P-gp, select statins are also metabolized by CYP3A4 or eliminated through P-gp, which lends to more multiple interactions between CYP3A4/P-gp inhibitors. Consequently, their coadministration poses an even greater risk for rhabdomyolysis, and data suggests this may become life-threatening. If there is an indication for concomitant statin therapy, hydrophilic statins such as pravastatin or rosuvastatin should be used to mitigate this risk. Other risk factors for myopathies should be assessed (e.g., renal/ hepatic impairment, CYP3A4/P-gp inhibitors). Consider lowering the statin dose and monitoring creatine kinase after two weeks of concomitant colchicine therapy. Visit https://www.ahajournals.org/doi/10.1161/ ATVBAHA.124.319851 for more information.46,65,66,67,68 Table 3. Inducers of CYP3A4 and P-glycoprotein CYP3A4 inducer P-gp inducer barbiturates X bosentan X carbamazepine X X phenytoin X rifabutin X rifampin X X rifapentine X Concomitant therapy with colchicine may increase rate of colchicine metabolism and decrease plasma concentrations. Avoid if possible. Corticosteroids For most patients, glucocorticoids should be avoided, if possible, as a first-line therapy for acute pericarditis. Although initially they can provide quick relief of symptoms, they may reduce the efficacy of colchicine, and they have been associated with increased rates of recurrent pericarditis. However, glucocorticoids are considered second-line treatment if a patient does not respond to effective doses of NSAIDs, and they are
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