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Colchicine is useful for the prevention and treatment of gout and a variety of other disorders. It is a substrate for CYP3A4 and P-glycoprotein (P-gp), and concomitant administration with CYP3A4/P-gp inhibitors can cause life-threatening drug–drug interactions (DDIs) such as pancytopenia, multiorgan failure, and cardiac arrhythmias. Colchicine can also cause myotoxicity, and coadministration with other myotoxic drugs may increase the risk of myopathy and rhabdomyolysis. Many sources of DDI information including journal publications, product labels, and online sources have errors or misleading statements regarding which drugs interact with colchicine, as well as suboptimal recommendations for managing the DDIs to minimize patient harm. Furthermore, assessment of the clinical importance of specific colchicine DDIs can vary dramatically from one source to another. In this paper we provide an evidence-based evaluation of which drugs can be expected to interact with colchicine, and which drugs have been stated to interact with colchicine but are unlikely to do so. Based on these evaluations we suggest management options for reducing the risk of potentially severe adverse outcomes from colchicine DDIs. The common recommendation to reduce the dose of colchicine when given with CYP3A4/P-gp inhibitors is likely to result in colchicine toxicity in some patients and therapeutic failure in others. A comprehensive evaluation of the almost 100 reported cases of colchicine DDIs is included in table form in the electronic supplementary material. Colchicine is a valuable drug, but improvements in the information about colchicine DDIs are needed in order to minimize the risk of serious adverse outcomes. [ABSTRACT FROM AUTHOR]

Colchicine is increasingly used as the number of potential indications expands. However, it also has a narrow therapeutic index that is associated with bothersome to severe side effects. When concomitantly use with medications inhibiting its metabolism, higher plasma levels will result and increase likelihood of colchicine toxicity. We conducted a cohort study using electronic health records comparing encounters with colchicine plus a macrolide and colchicine with an antibiotic non-macrolide. We assessed the relationship between the two groups using adjusted multivariate logistic regression models and the risk of rhabdomyolysis, pancytopenia, muscular weakness, heart failure, acute hepatic failure and death. 12670 patients on colchicine plus an antibiotic non-macrolide were compared to 2199 patients exposed to colchicine plus a macrolide. Patients exposed to colchicine and a macrolide were majority men (n = 1329, 60.4%) and white (n = 1485, 67.5%) in their late sixties (mean age in years 68.4, SD 15.6). Heart failure was more frequent in the colchicine plus a macrolide cohort (n = 402, 18.3%) vs the colchicine non-macrolide one (n = 1153, 9.1%) (p < 0.0001) and also had a higher mortality rate [(85 (3.87%) vs 289 (2.28%), p < 0.0001 macrolides vs non-macrolides cohorts, respectively]. When the sample was limited to individuals exposed to either clarithromycin or erythromycin and colchicine, the adjusted OR for acute hepatic failure was 2.47 (95% CI 1.04–5.91) and 2.06 for death (95% CI 1.07–3.97). There is a significant increase in the risk of hepatic failure and mortality when colchicine is concomitantly administered with a macrolide. Colchicine should not be used concomitantly with these antibiotics or should be temporarily discontinued to avoid toxic levels of colchicine. [ABSTRACT FROM AUTHOR]

Introduction: Tizanidine is primarily metabolized via cytochrome P450 (CYP) 1A2 and therefore medications that inhibit the enzyme will affect the clearance of tizanidine, leading to increased plasma concentrations of tizanidine and potentially serious adverse events.Objectives: Our aim was to study the occurrence of adverse events reported in the FDA Adverse Event Reporting System (FAERS) involving the combination of tizanidine and drugs that inhibit the metabolic activity of CYP1A2.Methods: A disproportionality analysis of FAERS reports from 2004 quarter 1 through 2020 quarter 3 was conducted to calculate the reporting odds ratio (ROR) of reports mentioning tizanidine in a suspect or interacting role or having any role, a CYP1A2 inhibitor, and the following adverse events: hypotension, bradycardia, syncope, shock, cardiorespiratory arrest, and fall or fracture.Results: A total of 89 reports were identified mentioning tizanidine, at least one CYP1A2 inhibitor, and one of the adverse events of interest. More than half of the reports identified tizanidine as having a suspect or interacting role (n = 59, 66.3%), and the reports more frequently involved women (n = 58, 65.1%). The median age was 56.1 years (standard deviation 17.1). Some of the important safety signals included interactions between tizanidine in a suspect or interacting role and ciprofloxacin (ROR for hypotension 28.1, 95% confidence interval [CI] 19.2-41.2) or fluvoxamine (ROR for hypotension 36.9, 95% CI 13.1-103.4), and also when reported in "any role" with ciprofloxacin (ROR for hypotension 6.3, 95% CI 4.7-8.5), fluvoxamine (ROR for hypotension 11.4, 95% CI 4.5-28.8), and zafirlukast (ROR for falls 16.0, 95% CI 6.1-42.1).Conclusions: Reports involving tizanidine and a CYP1A2 inhibitor have higher odds of reporting hypotension. This study suggests that concurrent use of tizanidine with CYP1A2 inhibitors may lead to serious health consequences associated with low blood pressure such as falls and fractures. [ABSTRACT FROM AUTHOR]

9276413 8 Norén GN, Sundberg R, Bate A. A statistical methodology for drug-drug interaction surveillance. Dear Editor, Thank you for the opportunity to respond to the comment by Dr. Yoshiro Noguchi [[1]] concerning our paper entitled " I A Disproportionality Analysis of Drug-Drug Interactions of Tizanidine and CYP1A2 Inhibitors from the FDA Adverse Event Reporting System (FAERS i )" [[2]]. 10.1007/s40264-022-01240-w. 36223038 2 Villa-Zapata L, Gómez-Lumbreras A, Horn J. A Disproportionality analysis of drug-drug interactions of tizanidine and CYP1A2 inhibitors from the fda adverse event reporting system (FAERS). [Extracted from the article]