FormalPara Key Points

Colchicine is a valuable drug for many indications, but it has a number of potentially serious drug interactions.

Most current sources of colchicine drug interaction information have errors of omission or commission regarding which drugs interact clinically with colchicine.

Adverse colchicine drug interactions can almost always be prevented through proper management and patient education.

1 Introduction

Colchicine has been a valuable drug in the prevention and treatment of gout for many centuries, and it is also approved for use in familial Mediterranean fever. Colchicine has a variety of off-label uses, including pericarditis, various dermatologic disorders, Behçet’s disease, and more recently it has been used to reduce cardiovascular events in patients with coronary artery disease [1,2,3,4]. Colchicine has also been tested in patients with COVID-19 in numerous clinical trials, but the results to date have been disappointing [5, 6]. Colchicine is still under investigation for treatment of long COVID [7], and it can be used to treat the pericarditis that can occur in COVID patients [8]. As the indications for colchicine increase beyond gout, it is logical to expect to see more adverse drug–drug interactions (DDIs) because more people will receive colchicine, and the prescribers may have little previous experience using the drug. In clinical trials of low-dose colchicine (0.5 mg/day) following myocardial infarction, few DDIs have been observed [2]. This lack of DDIs in low-dose colchicine trials is consistent with the case reports detailed in the electronic supplementary material (ESM), in which the vast majority of adverse colchicine DDIs involved colchicine doses > 0.5 mg. Nonetheless, it is likely that the risk of colchicine DDIs is lower in these clinical trials as opposed to the general clinical setting in which patients may receive higher colchicine doses and where patients are not as carefully screened for risk factors, concomitant therapy, and may not be carefully monitored for adverse outcomes [9]. Given that colchicine DDIs can result in serious or fatal outcomes, it is important that health care professionals (i) know which drugs can interact with colchicine, and (ii) understand how to manage such DDIs to minimize the risk of patient harm. The purpose of this paper is to provide that information, based on the evidence provided in the literature and the general principles of drug interaction management.

2 Colchicine Toxicity

Colchicine has a narrow therapeutic index and must be dosed carefully to minimize the risk of toxicity. Toxicity tends to occur when the serum colchicine concentration exceeds 3.0 μg/L [10]. While colchicine has been used safely in many patients for many centuries, colchicine toxicity can occur when patients develop excessive serum concentrations, often resulting from some combination of excessive dosing, drug interactions, and impaired renal or hepatic function [11]. Once serious colchicine toxicity occurs it can be very difficult to treat, especially if the toxicity damages the kidneys and liver, which further impairs the ability of the person to eliminate colchicine. Even when the patient survives, elevated colchicine concentrations may persist for weeks after it is discontinued [12,13,14] resulting in continuing damage to tissues and organs. Colchicine is not dialysable, so dialysis does not shorten the process. Indeed, patients on maintenance hemodialysis appear to be at greater risk from colchicine DDIs [15,16,17]. Colchicine toxicity usually manifests as gastrointestinal, musculoskeletal, hematologic, and—with severe toxicity—cardiovascular. These are summarized in Table 1. Over 100 DDI cases of colchicine-related toxicity, many of them life-threatening or fatal, have been published in case reports, case series, and adverse reaction reporting systems [18, 19]. A detailed analysis of colchicine DDI cases published in the medical literature is provided in the online Supplemental Table (see ESM).

Table 1 Clinical findings of colchicine toxicity
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3 Colchicine Pharmacokinetics

Despite colchicine being used for many centuries, its pharmacokinetics have only been studied in the past few decades after suitable assay techniques were developed. Research is still being conducted, particularly on the effect of transporters on colchicine disposition.

3.1 Absorption

Colchicine is a lipid-soluble alkaloid and undergoes extensive first-pass metabolism resulting in an absolute bioavailability of approximately 30–50% [11, 20, 21]. Bioavailability can vary substantially from one patient to another, probably due to the numerous enzymes and transporters involved during absorption. In one study of healthy subjects, mean bioavailability was 45%, but it varied among subjects from 28 to 88% [22]. Colchicine is a substrate for CYP3A4 and P-gp in the intestine, and P-gp appears to transport colchicine back into the intestinal lumen. It has been proposed that colchicine may be a substrate for transporters such as MRP2 and OATP2B1 [23, 24] but their role remains to be established.

3.2 Distribution

Colchicine is rapidly distributed, and the apparent volume of distribution of colchicine is large; it is usually about 5–10 L/kg but can range from 2 to 12 L/kg. The wide distribution and low (nanogram per milliliter) concentrations in the plasma are consistent with the failure of dialysis to effectively treat colchicine toxicity. Binding to serum protein is about 40%, again with high variability. Colchicine crosses the placenta and is distributed into breast milk [11, 21]. There are no reported DDIs based on changes in colchicine distribution.

3.3 Metabolism

Colchicine metabolism takes place primarily through demethylation by CYP3A4 in the intestine and liver. Other CYP isozymes and phase II metabolism do not appear to play a significant role in colchicine metabolism.

3.4 Elimination

The kidneys are important in the elimination of colchicine, but estimates of the percentage of total colchicine clearance by the kidneys have varied [21]. In 12 healthy subjects given colchicine 1 mg, 40–65% was recovered unchanged in the urine [25], but others have found lower percentages for renal elimination [21]. Biliary excretion also appears to be an important pathway of colchicine elimination, and P-gp appears to be involved in both the renal tubular secretion and the biliary excretion of colchicine [21, 26]. The half-life in healthy subjects is generally about 15–30 h [21, 22]. In one small study, total body clearance was about twice as high and area under the concentration–time curve (AUC) was about four times smaller for healthy subjects compared with elderly patients [22].

4 Mechanisms of Colchicine Drug Interactions

Colchicine can interact with other drugs by a variety of different mechanisms (see Table 2). For some colchicine DDIs, more than one mechanism is involved. For example, several drugs that cause myopathy also inhibit CYP3A4 and/or P-gp (e.g., amiodarone, cyclosporine, statins). Colchicine is rarely the perpetrator in DDIs with other drugs, and in this paper we address only colchicine as the victim drug in DDIs.

Table 2 Sites of potential interaction with colchicine
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4.1 Inhibition of CYP3A4 and/or P-gp

Colchicine is a substrate for CYP3A4 in the intestine and liver, and undergoes considerable first-pass metabolism resulting in bioavailability of 30–50% [11, 21]. It is also a substrate for P-gp in the small intestine, liver, and kidneys [11, 23]. Colchicine undergoes enterohepatic circulation as parent drug and metabolites. Many drugs that produce combined CYP3A4/P-gp inhibition have been shown to increase colchicine serum concentrations and cause colchicine toxicity as we describe elsewhere in this paper.

Because it is well documented that combined CYP3A4/P-gp inhibitors increase colchicine AUC, drugs that inhibit either CYP3A4 or P-gp alone are also often assumed to be capable of increasing colchicine AUC. The vast majority of drugs that inhibit CYP3A4 also inhibit P-gp, so this is not an issue for most colchicine DDIs. It is not established, however, that inhibition of either CYP3A4 or P-gp alone is enough to cause clinically significant DDIs with colchicine. In fact, the available evidence, although limited, suggests otherwise. Drugs that primarily inhibit one or the other—such as voriconazole (CYP3A4 inhibitor) or propafenone (P-gp inhibitor)—have not had much effect on colchicine pharmacokinetics.

Voriconazole is classified by the US FDA as a ‘strong’ CYP3A4 inhibitor, and it can substantially increase the AUC of CYP3A4 substrates [27, 28]. Voriconazole may not inhibit P-gp, however, suggested by a lack of voriconazole on digoxin pharmacokinetics in healthy subjects [29]. A pharmaceutical company applying to the US Food and Drug Administration (FDA) for approval of their colchicine product performed a non-randomized, open-label, crossover study in 12 healthy subjects given colchicine 0.6 mg before and after voriconazole 200 mg twice daily for 5 days. Voriconazole did not affect colchicine pharmacokinetics [30].

On the other hand, propafenone inhibits P-gp but is not known to inhibit CYP3A4. A pharmaceutical company applying to the US FDA for approval of their colchicine product conducted a non-randomized, open label, crossover study in nine healthy male subjects who were given a single dose of colchicine 0.6 mg before and after propafenone 225 mg twice daily for 5 days. Propafenone did not appear to affect colchicine pharmacokinetics [30]. However, one cannot rule out that a larger daily dose of propafenone given for a longer period might interact with colchicine. It is also possible that P-gp inhibition without CYP3A4 inhibition has little effect on colchicine pharmacokinetics. A tentative conclusion from the studies of voriconazole and propafenone is that inhibition of both CYP3A4 and P-gp is needed in order to manifest clinically important effects on colchicine pharmacokinetics. Nonetheless, one cannot rule out that inhibition of either CYP3A4 or P-gp alone may be sufficient to interact with colchicine, especially in patients predisposed to colchicine toxicity such as those with renal or hepatic toxicity, or those with reduced activity of P-gp or CYP3A4 due to genetics.

4.2 Enzyme Inducers

Enzyme inducers such as rifampin, barbiturates, carbamazepine, efavirenz, lumacaftor, phenytoin, primidone, and St. John’s wort increase CYP3A4/P-gp activity, and would be expected to reduce colchicine AUC. Case reports suggest that both rifampin and carbamazepine can substantially reduce colchicine concentrations [31, 32]. (See case report details in the online Supplemental Table in the ESM). Lesinurad appears to be a modest CYP3A4 inducer, and it produced modest reductions in colchicine AUC in healthy subjects [33]. Although the evidence for the effect of CYP3A43 inducers on colchicine is limited, it seems very likely that patients on enzyme inducers are at increased risk of subtherapeutic colchicine concentrations.

4.3 Additive Myotoxic Effects

Colchicine therapy alone has been associated with myopathy and rhabdomyolysis [34,35,36,37,38,39,40], and it is possible that additive myotoxic effects with other drugs can occur. Myotoxicity has been reported in numerous patients receiving colchicine along with drugs that can independently lead to myotoxicity such as certain statins and cyclosporine. (See case report details in the online Supplemental Table, ESM.) Although it is thought that these reactions are due to additive myotoxic effects, it cannot yet be ruled out that pharmacokinetic DDIs may also occur, involving CYP3A4, P-gp, OATP [24] or MRP2 [23, 41]. Evidence to date suggests that not all statins pose the same risk when combined with colchicine, as discussed in Table 3. The signs and symptoms of myotoxicity in these cases often included muscle weakness and/or muscle pain, and sometimes darkened urine; myopathy is also often accompanied by nonspecific symptoms such as fatigue and malaise, and shortness of breath.

Table 3 Management options for colchicine drug interactions
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5 Risk Factors for Colchicine DDIs

The risk of adverse outcomes from colchicine DDIs can be influenced substantially by the dose and duration of colchicine therapy as well as kidney and liver function

5.1 Colchicine Dose and Duration

Epidemiological studies using low-dose colchicine have generally found little evidence of adverse consequences with colchicine and interacting medications [1,2,3,4]. This is consistent with the case reports described in the online Supplemental Table in which the majority of adverse DDIs reported involved colchicine doses >0.5 mg/day (see ESM). Nonetheless, the epidemiological studies were not designed to detect adverse DDIs and we cannot rule out that some at-risk patients had DDIs. At colchicine doses > 0.5 mg/day, as one would expect, the risk of colchicine adverse DDIs appears to increase as the colchicine dose is increased. The duration of colchicine use is also important. It is unusual to see significant colchicine toxicity until at least 3 or 4 days of concurrent use of colchicine and the interacting drug, although in rare cases it can occur after only a day or two of concurrent therapy [18]. The case reports in the online Supplemental Table also provide onset of adverse reaction information. A more typical onset of adverse effects from the colchicine DDI would be after 5 or 10 days of concurrent therapy, and in some cases (especially DDIs causing myopathy) it may take weeks or even months.

5.2 Renal Disease/Age

Renal impairment predisposes to colchicine toxicity [42]. In 21 patients with varying levels of kidney impairment, the three patients with low estimated glomerular filtration rate (eGFR) (mean eGFR = 25) had 51% higher colchicine AUC compared with six patients with normal GFR (mean eGFR = 110). In patients on hemodialysis three times a week with eGFR = 0, colchicine AUC was more than 5-fold higher than those with normal GFR [16]. Another study found a colchicine half-life to be four times higher in patients with renal insufficiency compared with those with normal kidney function [26]. A study of colchicine pharmacokinetics found total body clearance of colchicine about twice as high in younger subjects as in elderly patients with a mean creatinine clearance (CrCl) of 46 mL/min [22]. Elderly patients may also be at higher risk of colchicine toxicity due to polypharmacy. Renal impairment may also increase the risk of colchicine DDIs by increasing the serum concentration of the drug interacting with colchicine. For example, fluconazole displays dose-dependent inhibition of CYP3A4, and undergoes renal elimination, so patients with severe renal dysfunction would tend to have higher concentrations of fluconazole [43]. This would lead to increased CYP3A4 inhibition, as well as compromised renal elimination of colchicine, a combination that may have led to colchicine toxicity [44].

In many case reports of colchicine toxicity due to DDIs described in the online Supplemental Table (see ESM), renal impairment appeared to be a predisposing factor. It is not possible to precisely determine the degree of increased risk of colchicine DDIs at given levels of renal impairment, but a consensus statement on the use of colchicine used an eGFR of < 30 mL/min as the point where colchicine concentrations can start to increase substantially [10]. Based on the available data, we might estimate that the renal elimination of colchicine starts to be compromised somewhere around an eGFR of 60 mL/min and becomes a serious problem as one approaches an eGFR of 30 mL/min.

5.3 Liver Disease

As with many drugs, the effect of liver disease on colchicine elimination is not well characterized. There are many types of liver disease with different etiologies, and varying effects on drug metabolism and elimination. Moreover, there is no agreed upon measurement of liver function, unlike eGFR for kidney function, to quantify the likely reduction in colchicine elimination in patients with liver disease. One consensus statement on the use of colchicine in liver disease used a Child-Pugh score of C as the point where the half-life of colchicine starts to increase substantially [10], and, in the absence of definitive data, reduction in colchicine dose at this level of hepatic impairment appears to be a reasonable guideline. Nonetheless, patients with lesser degrees of hepatic malfunction may have some reduction in colchicine clearance, thus increasing the risk of colchicine DDIs to some degree.

5.4 Transporter Polymorphisms

Given that colchicine is a substrate for P-gp, it would be expected that those with polymorphisms resulting in low P-gp activity may be at increased risk for adverse colchicine DDIs. For example, drugs that primarily inhibit CYP3A4 and appear to have little effect on colchicine (e.g., voriconazole) might have a greater effect in patients with low P-gp activity due to genomics or other drugs. Little is currently known regarding the effect of transporters other than P-gp on colchicine pharmacokinetics, so it may be useful to study the effect of polymorphisms in MRP2 or OATPs on colchicine disposition.

5.5 Dose/Duration of Perpetrator Drug

The magnitude of perpetrator drug inhibition or induction on drug metabolizing enzymes and transporters can be affected by the dose of the drug and the duration of perpetrator drug therapy.

6 Management Options

Given the potentially life-threatening outcomes of colchicine drug interactions and the difficulty of treating severe colchicine toxicity once it occurs, it is imperative to avoid putting patients at risk. There are essentially three ways to reduce the risk of adverse outcomes from colchicine DDIs: (i) avoid using the interacting drug while the patient is on colchicine, (ii) avoid using colchicine during administration of the interacting drug, or (iii) give colchicine and the interacting drug, but reduce the colchicine dose. We now consider these three approaches.

6.1 Avoid Using the Interacting Drug

If the patient on colchicine has severe renal or hepatic impairment, it is particularly important to avoid the use of CYP3A4/P-gp inhibitors. But even when the patient does not have significant renal or hepatic disease, avoiding the interacting drug is likely to be the preferred option when it is feasible. For example, it is difficult to imagine a scenario in which it would be necessary to give clarithromycin to a patient on colchicine, a combination that has produced numerous fatalities [18]. If another antibiotic is suitable, it would almost always be preferable to use it in place of the clarithromycin (most antibiotics do not inhibit CYP3A4 and P-gp). A similar argument could be made for calcium channel blockers, where diltiazem and verapamil inhibit CYP3A4 and P-gp, but most of the other calcium-channel blockers do not. Other calcium-channel blockers may or may not be appropriate to use in place of diltiazem or verapamil in any given patient, but if they are, an interaction with colchicine could be easily avoided. Table 3 presents non-interacting alternatives for many of the drugs that can interact with colchicine.

6.2 Stopping Colchicine During Use of the Interacting Drug

If the interacting drug is clinically necessary, stopping colchicine during the use of the interacting drug may be appropriate, especially if the interacting drug is used for a limited time (such as an antibiotic). Whether this is a viable option would also depend on the indication for colchicine. If colchicine is being used for gout, short-term alternatives to colchicine may be available. If colchicine is used for familial Mediterranean fever or for cardiovascular disorders such as pericarditis or post-myocardial infarction, stopping colchicine may or may not be the best option.

6.3 Reduce Colchicine Dose When Precipitant Drug is Started

If concurrent use of colchicine with the interacting drug cannot be avoided—which should rarely be the case—one could consider prophylactic colchicine dosage reductions. Theoretically, reducing the colchicine dose when the precipitant drug is added would offset the pharmacokinetic interaction and maintain colchicine serum concentrations in the therapeutic range, as has been recommended in the labeling for some colchicine products [25] and in published articles [45, 46]. In practice, however, because the magnitude of these DDIs is so variable from one person to another, a ‘one size fits all’ a priori colchicine dosage reduction is likely to be excessive for some people (resulting in subtherapeutic colchicine concentrations) and insufficient for others (leading to colchicine toxicity). Accordingly, colchicine dosage reduction is best considered a last resort, and only when both colchicine and the interacting drug must be used together. Consider the interaction with ritonavir, where the mean increase in colchicine AUC following ritonavir was 296%, but the range was 54–924% as shown in Fig. 1 [25, 45]. Despite this marked variability, the colchicine labeling for Colcrys states that if colchicine and ritonavir are used together, the colchicine dose should be reduced by 50% [25]. (One possible source of ritonavir’s highly variable effect on colchicine is that ritonavir affects transporters in addition to P-gp, and affects CYP isozymes in addition to CYP3A4, but this hypothesis requires confirmation.)

Fig. 1
figure 1

The high variability of changes in colchicine AUC in 18–24 healthy subjects given a single dose of colchicine 0.6 mg with and without pretreatment with various drugs. The bars represent the subject with the smallest increase and the subject with the largest increase for each interacting drug. Adapted from data presented in references [25, 45, 47]

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The marked variability seen in healthy subjects is likely to be even greater in patients, who may be taking various other medications, may have varying degrees of renal or hepatic impairment, and may have other disorders that affect colchicine pharmacokinetics. Moreover, the much larger numbers in the patient population will virtually guarantee that some patients will have pharmacogenomic differences that will predispose them to colchicine toxicity (e.g., low P-gp activity). Finally, the pharmacokinetic studies conducted in healthy subjects (shown in Fig. 1) involved single, small doses of colchicine, unlike what is usually the case for patients receiving colchicine therapeutically. In patients who develop serious colchicine toxicity from a DDI, multiorgan failure can occur with marked reduction in kidney function; this in turn can worsen the colchicine toxicity. None of these problems would occur with single-dose studies in healthy subjects. For all of these reasons, one cannot use the single-dose studies in healthy subjects to predict whether a small or marked increase in colchicine plasma concentrations will occur in any given patient.

Figure 2 represents a hypothetical estimate of what might be expected to happen if we follow the rule of thumb recommendations for avoiding colchicine toxicity when patients receive CYP3A4/P-gp inhibitors with colchicine. These are hypothetical scenarios but they are entirely plausible given the evidence of high intersubject variability in the magnitude of colchicine DDIs as shown in Fig. 1. In Fig. 2, ‘a’ represents the starting conditions in a group of patients, and to simplify the discussion let us assume that they all have therapeutic colchicine serum concentrations. Next is ‘b’, which represents what may happen if a CYP3A4/PGP inhibitor is added, but the DDI is ignored; here some patients are likely to develop colchicine toxicity and some may die. Next is ‘c’, in which we adopt the colchicine dosage reduction recommendations, but—due to the large variability—some patients become subtherapeutic, and others develop colchicine toxicity. Finally, ‘d’ represents what may happen if we lowered the colchicine dose sufficiently to avoid all colchicine toxicity, resulting in an unacceptable number of patients with subtherapeutic colchicine levels.

Fig. 2
figure 2

Hypothetical predicted outcomes for various ways of managing the addition of CYP3A4/P-gp inhibitors to colchicine. a Before interacting drug added, b interacting drug added with no change in colchicine dose, c colchicine dosage reduction method, d reducing colchicine dosage enough to avoid all colchicine toxicity

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Whether or not it is appropriate to prophylactically adjust the dose of an object drug when starting a precipitant drug depends on the drugs involved in the interaction. For some drugs, such as warfarin, if one adjusts the warfarin dose when adding a CYP2C9-inhibiting drug, at least one can monitor the INR to determine if the warfarin dosage adjustment was too large or too small. For colchicine, however, serum concentrations are not routinely available at this time, and life-threatening colchicine toxicity (e.g., pancytopenia, multi-organ failure, rhabdomyolysis) can begin after only a few days of administration of the interacting drug (see case reports in the online Supplemental Table, ESM). There is no specific remedy, and once the kidney and liver start to fail, colchicine may persist for weeks until the patient dies or (usually very slowly) recovers [48,49,50]. Dialysis is not effective in colchicine poisoning, but in one case the patient was successfully treated with kidney replacement therapy and plasmapheresis [51]. It is not known if giving an enzyme inducer such as rifampin would help eliminate colchicine, but it is an intriguing possibility given that rifampin probably increases colchicine elimination [31]. Rifampin has been used in poisonings with other drugs to increase elimination [52], but the efficacy and safety of using rifampin for colchicine toxicity is not established. The use of activated charcoal (and possibly other binding agents) may be worth trying, since colchicine undergoes enterohepatic circulation, although this has not been studied [11].

A summary of suggested management options for colchicine DDIs with CYP3A4/P-gp inhibtors is presented in Fig. 3.

Fig. 3
figure 3

Management option algorithm for minimizing the risk of colchicine drug–drug interactions

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6.4 Patient Education

If concomitant use of colchicine with interacting drugs is necessary, it is crucial to advise the patient to be alert for evidence of colchicine toxicity. There are three primary types of toxicity for which the patient should be vigilant:

  • Gastrointestinal toxicity: severe diarrhea (often with some combination of nausea, vomiting, or abdominal pain)

  • Neuromuscular toxicity: muscle weakness, myalgia, dark or brown urine

  • Hematologic toxicity (pancytopenia): fever, other signs of infection, excessive or unusual bleeding

Mild to moderate diarrhea is common when colchicine serum concentrations are elevated, but if the diarrhea is severe or prolonged, the patient should contact their prescriber. Regarding signs and symptoms of myopathy, some have proposed a ‘classic triad’ of myalgia, muscle weakness, and ‘tea-colored urine’ [53]. However, muscle weakness often occurs without myalgia, and sometimes the reverse is true (see cases in the online Supplemental Table, ESM). Darkened urine from myoglobinuria is usually a late sign of myotoxicity, and often occurs after the muscle weakness and/or myalgia has become so severe that the patient has already sought medical care. Moreover, using the term ‘tea-colored urine’ is problematic given that tea can have many different colors from dark brown to very light, so it would be better to say ‘dark’ or ‘brown’ urine. Darkened urine is a particularly ominous sign, because the excessive myoglobinuria may lead to acute kidney injury, thus prolonging the colchicine toxicity.

Colchicine toxicity can produce many other signs and symptoms, but they are either relatively nonspecific (fatigue, lethargy, malaise, insomnia), or they occur relatively infrequently (shortness of breath, cough, cardiac arrhythmias), or they tend to occur late in the course of colchicine toxicity (alopecia). Accordingly, it is probably best to concentrate the patient education on the more specific and common signs and symptoms as described above.

7 Drugs That May Interact with Colchicine

Colchicine DDIs have been extensively studied, and include pharmacokinetic studies, case reports, and case series. See Table 3 for a summary of these DDIs as well as management recommendations. Details of all case reports mentioned in Table 3, including supporting references, can be found in the online Supplemental Table (see ESM).

8 Misleading Colchicine Drug Interaction Information

Colchicine DDI information for health professionals is available from a variety of sources. The medical literature provides numerous pharmacokinetic studies, case reports, epidemiological studies, and reviews on colchicine DDIs, resulting in many conflicting recommendations. There are also numerous inconsistencies in the prescribing information for the various colchicine products, as well as in online DDI checking software and in clinical decision support systems [3, 10, 25, 30, 45, 46, 54,55,56,57]. The result is a jumble of confusion, with errors of omission, errors of commission, conflicting statements, and vague pronouncements as summarized in Table 4.

Table 4 Misleading statements in published literature, product information, online sources [3, 10, 25, 30, 45, 46, 54,55,56,57]
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A striking example is the variability in recommendations for using concurrent colchicine and statins. Some have claimed that combining colchicine and statins does not cause adverse DDIs [46, 54] while others urge that the combinations be avoided [55]. A thorough assessment of the data by Wiggins et al. fell between these extremes and provided nuanced and useful guidelines [58], and a systematic review of the colchicine-statin DDI thoroughly assessed the data and concluded that the DDIs can be serious, and mitigation strategies are necessary to avoid patient harm [59]. While the data suggest that most people using concurrent statins and low-dose colchicine do not develop myopathy, reasonable precautions are warranted as discussed in Table 3.

In addition to improving the information on colchicine DDIs, it may be necessary to raise awareness in health care professionals on how serious these DDIs can be. In one study, over 90% of the alerts for colchicine with strong CYP3A4 inhibitors flagged in clinical decision support systems were overridden by prescribers [60]. It seems likely that more than 10% of these patients were at risk, and these results suggest a lack of awareness regarding the potentially life-threatening nature of colchicine DDIs.

9 Conclusion

Colchicine is a useful drug for a wide range of disorders and is usually safe when used in appropriate doses given the patient’s renal function. Numerous drugs are capable of causing colchicine toxicity, however, and given that colchicine toxicity is potentially fatal and difficult to treat, it is imperative that every effort be made to avoid placing patients at risk from these drug interactions. Currently available information on colchicine DDIs can be confusing and inconsistent, and in this paper we have tried to present recommendations based on the empirical evidence. Enough is known about colchicine drug interactions so that virtually every case of colchicine toxicity could have been prevented had the appropriate precautions been taken.