Journal Pre-proof

Select Drug-Drug Interactions with Colchicine and Cardiovascular

Medications: A Review

Dave Dixon PharmD , Jaideep Patel MD , Rowan Spence BS ,

Azita Talasaz PharmD , Antonio Abbate MD, PhD ,
Barbara S. Wiggins PharmD

PII: S0002-8703(22)00126-0
DOI: https://doi.org/10.1016/j.ahj.2022.06.002
Reference: YMHJ 6587

To appear in: American Heart Journal

Received date: May 6, 2022

Accepted date: June 8, 2022

Please cite this article as: Dave Dixon PharmD , Jaideep Patel MD , Rowan Spence BS ,
Azita Talasaz PharmD , Antonio Abbate MD, PhD , Barbara S. Wiggins PharmD , Select Drug-Drug
Interactions with Colchicine and Cardiovascular Medications: A Review, American Heart Journal
(2022), doi: https://doi.org/10.1016/j.ahj.2022.06.002

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 Review Articles

Select Drug-Drug Interactions with Colchicine and Cardiovascular Medications: A Review

Dave Dixona,b,*, PharmD; Jaideep Patelb,c, MD; Rowan Spencea, BS; Azita Talasaza,b, PharmD; Antonio
Abbateb, MD, PhD; Barbara S. Wigginsd, PharmD

a
Department of Pharmacotherapy & Outcomes Science, Virginia Commonwealth University, Richmond,
Virginia
b
Ciccarone Center for the Prevention of Cardiovascular Disease, Baltimore, Maryland
c
Johns Hopkins Heart Center at Greater Baltimore Medical Center, Baltimore, Maryland
d
Department of Pharmacy Services, Medical University of South Carolina, Charleston, South Carolina

*
Corresponding Author: Dave L. Dixon, PharmD, FACC, Nancy L. and Ronald H. McFarlane
Associate Professor of Pharmacy, Chair, Department of Pharmacotherapy & Outcomes Science,
Virginia Commonwealth University School of Pharmacy, 410 N. 12th St., Box 980533, Richmond,
Virginia, Phone: (804) 628-3784 | Email: dldixon@vcu.edu

Funding: none

Disclosures: none

Abstract

Several randomized clinical trials have demonstrated the clinical utility of colchicine in the prevention

and management of various cardiovascular conditions, including secondary prevention of atherosclerotic

cardiovascular disease, acute and chronic pericarditis, and atrial fibrillation. As a result, it is reasonable

to anticipate increased use of colchicine within the cardiovascular specialty. However, colchicine is

metabolized by cytochrome P450 3A4 (CYP3A4) and a substrate of the efflux transporter, P-

glycoprotein (P-gp), creating the potential for clinically significant drug-drug interactions (DDIs).

Therefore, when colchicine is administered concomitantly with other cardiovascular agents that inhibit

CYP3A4 or P-gp, there is an increased risk of significant DDIs, potentially leading to negative sequelae.
1
This article summarizes the evidence supporting the use of colchicine for cardiovascular disease,

describes the mechanisms behind DDIs with select cardiovascular medications, and provides

suggestions regarding colchicine dosing and management of DDIs to minimize the risk of poor

tolerability and colchicine toxicity.

Keywords: colchicine, cardiovascular disease, cytochrome P450, P-glycoprotein, drug interactions

Abbreviations: ABCB1, ATP-binding cassette subfamily B; ASCVD, atherosclerotic cardiovascular

disease; AUC, area under the curve; BCRP, breast cancer resistance protein; Cmax, maximum serum

concentration; CYP450, cytochrome P450; DDI, drug-drug interaction; FDA, Food and Drug

Administration; MDR1, multidrug resistance protein 1; P-gp, p-glycoprotein

Introduction

Colchicine has been used widely for various ailments for a millennium and was originally

derived from the Colchicum autumnale plant (1). The active ingredient, colchicine, was isolated in the

1800’s and subsequently used primarily for the prevention and treatment of gout and Familial

Mediterranean Fever. Despite its extensive use, it was not until 2009 that colchicine gained approval by

the Food and Drug Administration (FDA) (1). More recently, colchicine has been investigated

extensively for a variety of therapeutic applications in oncology, immunology, dermatology, and

cardiology.

2
 The exact mechanism of action for colchicine remains elusive, but is largely based upon its anti-

inflammatory properties, which has recently been shown to have efficacy for inflammatory conditions

beyond gout, including acute and chronic cardiovascular disease (2). It has been postulated that

colchicine produces an anti-inflammatory effect by irreversibly binding tubulin, which blocks

microtubule formation and enables mitosis and regulates intracellular transport (3). As a result,

colchicine impairs the migration of inflammatory cells and the growth of vascular smooth muscle cells

and fibroblasts. Furthermore, the inhibition of intracellular signaling also prevents assembly of the

NLRP3 inflammasome; without this inflammasome, interleukin 1 beta (IL-1β) and other interleukins

cannot be released, blunting the pro-inflammatory response (4). Additional anti-inflammatory effects of

colchicine include impairment of platelet-leukocyte interaction and the activation and adhesion of T

lymphocytes (4).

Role of Colchicine in the Management of Cardiovascular Patients

Acute and Chronic Pericarditis

Colchicine is an effective option for the treatment and prevention of acute and recurrent

pericarditis (5-9). Additional trials have also found colchicine to be effective at preventing post-

pericardiotomy syndrome in patients undergoing cardiac surgery (10-11). Aside from the expected

increased frequency of diarrhea, colchicine was well tolerated in these trials. Currently, there are no

North American guidelines that provide recommendations for the role of colchicine in pericarditis

management; however, European guidelines recommend colchicine as first line adjunct therapy to anti-

inflammatory agents for the treatment of acute pericarditis and recurrences (12). The recommended dose

is 0.5 mg daily in those weighing < 70 kg and 0.5 mg twice daily for those > 70 kg with a treatment

3
duration of 3 months; however, higher doses (~1 mg twice daily) may also be used as a loading dose on

day 1 and for acute flare ups (10). It also should be noted the 0.5 mg dose of colchicine is not available

in the United States and Canada, where 0.6 mg is the only available dose. Although this represents a

20% higher dose, the clinical significance of this is unknown.

Atherosclerotic Cardiovascular Disease (ASCVD)

There is growing evidence to support the use of colchicine in secondary prevention of

atherothrombotic disease. The use of colchicine was given a Class IIb recommendation (i.e.,

usefulness/efficacy is less well established by evidence/opinion), after traditional risk factors are

optimized for the secondary prevention of ASCVD, in the 2021 European Society of Cardiology

Guidelines on Cardiovascular Disease Prevention (13).

The Colchicine Cardiovascular Outcomes Trial (COLCOT) evaluated the efficacy of low-dose

colchicine (0.5 mg daily) in secondary prevention in patients within 30 days of a myocardial infarction

(14). After 22.6 months, the primary composite endpoint of death from cardiovascular causes,

myocardial infarction, resuscitated cardiac arrest, stroke, or urgent hospitalization for angina leading to

coronary revascularization occurred in 5.5% of patients treated with colchicine compared to 7.1% in the

placebo group (P=0.02). Additionally, The Low Dose Colchicine for Secondary Prevention of

Cardiovascular Disease (LoDoCo) found a significant reduction in the primary composite endpoint of

time to first acute coronary syndrome event, cardiac arrest with resuscitation, and non-cardioembolic

ischemic stroke with colchicine compared to placebo (5.3% vs. 16%; P<0.0001) after 3 years of follow

up (15).

4
 A follow up study, Low Dose Colchicine for Secondary Prevention of Cardiovascular Disease 2

(LoDoCo2) also observed a reduction in the primary composite outcome of cardiovascular death,

spontaneous myocardial infarction, ischemic infarction, ischemic stroke, and ischemia driven coronary

revascularization with colchicine 0.5 mg daily compared to placebo (6.8% vs. 9.6%; P<0.001) in

patients with chronic coronary disease (median follow-up, 28.6 months) (16). In the Colchicine to

Improve Cardiovascular Outcomes in ACS Patients (COPS) trial, there was no significant difference in

the occurrence of the primary outcome of all-cause mortality, acute coronary syndrome,

revascularization, and noncardioembolic stroke in those treated with colchicine (6.1%) compared to

placebo (9.5%; P=0.09) (17). It is unclear as to the reasons for the disparity of these findings compared

to the other trials; however, the COPS trial may have been underpowered. Given the growing body of

evidence supporting the role of colchicine in cardiovascular disease, an increase in utilization by

cardiovascular clinicians is expected; however, successful targeting of inflammation for secondary

prevention will likely require an individualized approach (18).

A meta-analysis of 13 randomized controlled trials including 13,125 patients evaluated the effect

of colchicine versus placebo/standard therapy in both acute and chronic coronary artery disease (19).

Colchicine reduces the risk of MI and stroke by 36% (OR 0.64; 95% CI, 0.46–0.90; P=0.01) and 50%

(OR 0.50; 95% CI, 0.31–0.81; P=0.005), respectively. However, colchicine does not appear to reduce

all‐ cause and cardiovascular mortality (OR 0.96; 95% CI, 0.65–1.41; P=0.83; and OR 0.82; 95% CI,

0.55–1.22; P=0.45, respectively). As expected, colchicine was associated with a higher risk of

gastrointestinal side effects (OR 2.21; 95% CI, 1.45–3.36; P=0.0002). Given the increased risk of non-

cardiovascular mortality observed in both the LoDoCo2 and COPS trials, the authors pooled data from 4

5
studies that reported this outcome and found a nonsignificant numerical increase in risk with colchicine

(85 [1.4%] versus 60 [1.0%] cases [OR, 1.35; 95% CI, 0.90–2.02; P=0.15).

Atrial Fibrillation

Proinflammatory processes triggered by catheter ablation or cardiac surgery may contribute to

the development of atrial fibrillation recurrence as well as post-operative atrial fibrillation. Thus, small

studies have explored the potential of colchicine and its anti-inflammatory effects to mitigate these risks.

A randomized controlled trial of 223 patients with paroxysmal atrial fibrillation who were

undergoing catheter ablation received either colchicine 0.5 mg twice daily or placebo (20). After three

months of follow-up, the recurrence rate of atrial fibrillation was 31.1% in the colchicine group

compared to 49.5% in the control group (P=0.10). Furthermore, there were greater improvements in both

physical and psychological health-related quality of life in the colchicine group.

In a sub study of the Colchicine for the Prevention of the Post-Pericardiotomy Syndrome

(COPPS) trial, 336 patients initially in sinus rhythm post-operatively were randomized to colchicine

1mg twice daily starting on postoperative day 3 followed by a maintenance dose of 0.5 mg twice daily

for 1 month in patients ≥70 kg and halved doses for patients <70 kg or intolerant to the highest dose, or

placebo (21). At 1 month, the incidence of post-operative atrial fibrillation was significantly lower in the

colchicine group compared to placebo (12% versus 22%, respectively; P=0.021), as was in-hospital

length of stay (9.4±3.7 versus 10.3±4.3 days; P=0.040) and rehabilitation length of stay (12.1±6.1 versus

13.9±6.5 days; P=0.009).

6
Overview of Drug-Drug Interactions, Enzyme systems and Transporters

Various metabolic pathways and transport mechanisms contribute to drug-drug interactions

(DDIs). The most common DDIs involving colchicine are those mediated by either the cytochrome P450

(CYP450) enzyme and/or the transporter permeability glycoprotein (P-gp) (22).

Cytochrome P450 Enzyme System

Cytochrome P450 enzymes are a superfamily of hemoproteins, and their main function is

oxidative catalysis of both endogenous and exogenous substances. Collectively, they are responsible for

the biotransformation of nearly 80% of all medications currently in use (23). The CYP450 superfamily

is further divided into subfamilies that are dependent upon their similarities (24). While over 50 different

CYP450 enzymes have been isolated in humans, only six (CYP1A2, CYP2C9, CYP2C19, CYP2D6,

CYP3A4, and CYP3A5) have been identified as being responsible for metabolizing the majority of

medications used in clinical practice today, of which CYP3A4 plays the largest role (25). Most of these

enzymes are expressed in the liver, however, some are also expressed in extrahepatic tissues (e.g.

gastrointestinal tract, kidney, brain, pancreas, skin) (26).

Drug interactions involving the CYP450 enzyme system can result in either induction or

inhibition of one or more of these enzymes. Inhibition results in competition between two or more

medications with subsequent increases in serum concentrations of either one or both agents and may

7
lead to toxicity. Induction results in decreased drug serum concentrations that can result in possible loss

of efficacy.

Permeability Glycoprotein (P-gp)

Permeability glycoprotein (P-gp) is an intracellular tissue specific efflux transport system that

belongs to multidrug resistance protein 1 (MDR1) family encoded by the ATP-binding cassette

subfamily B (ABCB1). It is widely distributed throughout the body, but it primarily located in epithelial

cells that have excretory roles that include the apical surface of epithelial cells lining the small intestine,

bile ducts, pancreatic duct, colon, adrenal gland, and the proximal tubule of the kidneys (27-29). The

primary role of P-gp is to remove toxins from the cell membrane and cytoplasm and minimize tissue

exposure of potentially harmful substrates and to promote their removal via transport into the bile, urine,

and intestine (30). Importantly, there is significant structure-activity overlap that exists between CYP450

metabolism, especially CYP3A4, and P-gp and a large number of medications that display affinity for

both proteins (Figure 1). Thus, many DDIs involve both P-gp and CYP3A4.

Quantitative Evaluation of Drug-Drug Interactions

The FDA utilizes two pharmacokinetic parameters when evaluating a DDIs—the maximum

serum concentration (Cmax), which represents the peak concentration achieved by the medication

following administration, and the area under the curve (AUC), which is reflective of total body exposure

to a medication. The AUC serves as a better point of reference, as the magnitude increase in AUC from

co-administration of medications can assist in determining the severity of the DDIs due to a standardized

8
classification system. Weak interactions are those resulting in an AUC increase of 1.25 to <2-fold,

moderate interactions have an AUC increase of 2 to 4.9-fold, while severe interactions may result when

the AUC increase is >5-fold (31). However, the AUC increase should not be used as the sole

determinant regarding the clinical significance of DDIs. Evaluation of DDIs should be done utilizing a

systematic approach also taking into consideration the overall clinical significance and potential

consequence of the interaction prior to making therapy adjustments.

Overview of Colchicine Metabolism and Elimination

Colchicine is primarily metabolized in the liver via CYP3A4 to two major/minor metabolites, 2-

O-demethylcolchicine and 3-O-demethylcolchicine, which make up less than 5% of the parent drug (4).

The elimination of colchicine largely occurs via biliary excretion. Approximately 10-20% of colchicine

is eliminated by the kidneys via the P-gp efflux transporter, which also plays in a role in managing

colchicine concentrations in the plasma through its effect on absorption in the gut (4). Therefore,

colchicine is contraindicated for use with P-gp inhibitors and/or strong CYP3A4 inhibitors, especially in

patients with advanced kidney disease (CrCrl <30 mL/min/1.73m3) or hepatic impairment; however,

colchicine has been used in large clinical trials that included patients with stage 3-4 chronic kidney

disease and concomitantly with potentially interacting medications (e.g., statins, beta-blockers) without

any notable signs of harm. This suggests that the concern may be more theoretical than real, yet it

remains one of the contraindications listed in the prescribing information provided by the FDA.

Colchicine also has a narrow therapeutic index, meaning that there is little difference between

the minimum effective dose and minimum toxic dose; however, this is likely less of a concern with the

9
lower doses of colchicine used for cardiovascular indications (32). The most common adverse effect

associated with colchicine in the clinical trials evaluating colchicine for cardiovascular disease include

gastrointestinal symptoms, which is dose-related and often limits further ingestion and the potential for

rare and severe adverse effects (e.g., pancytopenia, hepatoxicity, rhabdomyolysis) (33). There has also

been concern for colchicine to potentially increase susceptibility to opportunistic infections; however,

the evidence is inconclusive (34). Colchicine may also need to be withheld or initiation paused during

acute illness (e.g., cardiogenic shock) as these patients have generally been excluded from prior studies.

Given the propensity for several cardiovascular medications to be used that also interact with CYP3A4

and P-gp, there is the potential for DDIs to contribute to poor tolerability or colchicine toxicity (Figure

1).

Select Drug-Drug Interactions with Cardiovascular Medications

Statins

Statins are primarily metabolized by the liver, albeit to varying degrees (Table 1) (31). As such,

the statins with the greatest potential for significant DDIs primarily include atorvastatin, lovastatin, and

simvastatin. For example, in murine models, concentration-dependent inhibition of P-gp by atorvastatin,

simvastatin, and lovastatin led to increases in serum colchicine concentrations (35). Observational

experience suggests this interaction may help explain the myopathic-related symptoms suffered by those

taking statins (36). The effect of statins on the AUC for colchicine is variable (31); however, one study

reported a 27% increase in the AUC for colchicine when it was administered to healthy volunteers

already taking atorvastatin 40 mg daily (37). In the LoDoCo-2 trial, participants were allowed to receive

concomitant statin therapy (16). During the trial, 95% of participants were on statin therapy at baseline.

Myalgia was only assessed in the cohort from the Netherlands, but the incidence of myalgia was higher

in the colchicine group compared to placebo (21.2% vs. 18.5%; cumulative incidence ratio, 1.15; 95%
10
CI, 1.01-1.31, P-value not reported) and there was one case of rhabdomyolysis in the colchicine group.

Importantly, colchicine is associated with a small risk of rhabdomyolysis when used alone (38).

Although rhabdomyolysis remains incredibly rare with concomitant use of statins and colchicine, there

is a modest increased risk of muscle symptoms, which could result in statin discontinuation or use of

suboptimal statin intensity. Therefore, it is recommended to closely monitor patient-reported symptoms

of muscle pain, and when possible, use statins not metabolized by CYP3A4 (e.g., rosuvastatin) (Table 2)

(38). Routine monitoring of creatine phosphokinase (CPK) levels is not recommended by current

practice guidelines; however, it is recommended to obtain a CPK in patients reporting severe muscle

symptoms and objective muscle weakness (39).

Fibric Acid Derivatives (Fibrates)

The fibrates, fenofibrate and gemfibrozil, are used primarily for severe hypertriglyceridemia due

to limited evidence supporting their use for ASCVD prevention and increased risk of muscle-related

adverse effects when used in combination with statins (40). Fenofibrate is rapidly hydrolyzed by

esterases to the active metabolite, fenofibric acid, which is then primarily conjugated with glucuronic

acid and excreted in urine. In vitro studies using human liver microsomes indicate that fenofibrate and

fenofibric acid are weak inhibitors of CYP2C19 and CYP2A6, and mild-to-moderate inhibitors of

CYP2C9 (31). Cases of myotoxicity and rhabdomyolysis have been reported, however, are exceedingly

rare (41). Gemfibrozil, on the other hand, is a potent inhibitor of CYP2C9 and undergoes

glucuronidation to become a potent inhibitor of CYP2C8 (31). While there is no cytochrome P450 or

efflux transporter interaction between fibrates and colchicine, there is the potential for

pharmacodynamic synergism given both therapies independently have the potential for muscle toxicity,

albeit rare (42). However, the effect of fenofibrate and gemfibrozil on the AUC of colchicine is

11
unknown. Given the lack of evidence showing clinical benefit with combination fibrate-statin therapy,

this combination should be avoided (Table 2) (39). The benefits and risks of fenofibrate monotherapy

should be considered before adding fibrate therapy to background colchicine and patients should be

counseled to report symptoms of muscle pain, tenderness, or weakness. Patients reporting severe muscle

symptoms and objective muscle weakness should have a CPK level drawn.

β-adrenergic blockers

Beta-adrenergic blockers are frequently used in patients with cardiovascular disease, thus, any

concern for DDIs with colchicine could have significant ramifications. In vitro data suggests that

carvedilol is a strong P-gp inhibitor and influences P-gp similar to verapamil, which may result in

increased levels or effect of colchicine (43). Propranolol may also moderately inhibit P-gp but the

available in vitro data has shown mixed results (43). Metoprolol and atenolol, however, do not interact

with the P-gp system. As such, it has been suggested that carvedilol’s effects on P-gp are not related to

its effect on β-adrenoreceptors but possibly an antioxidant effect, which would reduce the generation of

reactive oxygen species that can induce expression of P-gp (44). Although carvedilol is primarily

metabolized by CYP2D6, it is metabolized partially by CYP3A4, although to a much lesser extent. The

clinical significance of this is unknown (45). Importantly, there are no CYP450-mediated interactions

between β-blockers and colchicine. Beta-blocker use was also quite high in most cardiovascular trials

with colchicine and well tolerated. The prescribing information for colchicine oral solution also

references two pharmacokinetic studies showing no significant increase in colchicine levels when co-

administered with carvedilol (46). It is the opinion of the authors that based on the available data and

primarily theoretical risk, carvedilol and propranolol are likely safe when co-administered with

12
colchicine in patients with stable kidney function (creatinine clearance ≥30 mL/min) (Table 2).

However, routine monitoring for colchicine-related adverse effects, such as gastrointestinal upset, in

patients taking both carvedilol or propranolol and colchicine would still be reasonable. All other beta-

blockers may be safely co-administered with colchicine.

Calcium channel blockers

The non-dihydropyridine calcium channel blockers, verapamil and diltiazem, are moderate inhibitors of

both the CYP3A4 enzyme and P-gp (31). Thus, there is potential for significant interactions with

colchicine. Similar increases in the AUC (~40%) and Cmax (~100%) have been observed with both

diltiazem and verapamil (38). Furthermore, cases of neuromuscular toxicity have been reported with co-

administration of colchicine with either diltiazem or verapamil (22). It should be noted that the protocol

for the LoDoCo2 trial was amended during the study to interrupt colchicine administration in patients

who received verapamil, thus further validating the potential concern with colchicine co-administration

(16). Therefore, diltiazem and verapamil should generally be avoided with colchicine, especially in the

setting of severe kidney or hepatic impairment. If diltiazem or verapamil use is unavoidable, the authors

suggest it may be reasonable to decrease the dose of colchicine to 0.3 mg daily (Table 2).

Dihydropyridine calcium channel blockers, such as amlodipine, however, do not inhibit CYP450

enzymes or P-gp and can be safely co-administered with colchicine.

Amiodarone and Dronedarone

13
 Amiodarone and dronedarone are broad-spectrum anti-arrhythmics that prevent or suppress

arrhythmia burden via 1) a prolongation of the myocardial cell-action potential duration and refractory

period and 2) noncompetitive α- and β-adrenergic inhibition. While amiodarone use has been

complicated by safety issues relating to toxicity of the lungs, thyroid, hepatic, and ocular systems,

dronedarone is contraindicated for use in patients with symptomatic heart failure, those with a recent

hospitalization for heart failure, or New York Heart Association (NYHA) Class IV heart failure,

permanent atrial fibrillation, and may cause hepatotoxicity (47). Amiodarone is metabolized by

CYP3A4 and CYP2C8, and is a potent inhibitor of CYP 3A4, 2C9, 2D6, and 1A2 (48). Dronedarone is

metabolized by and a moderate inhibitor of CYP3A4 and CYP2D6. Considering this, colchicine toxicity

may be augmented with the use of amiodarone or dronedarone, and vice-versa (49). Additionally,

amiodarone and dronedarone are also potent inhibitors of P-gp, which may result in further increases in

colchicine concentrations. However, these are theoretical risks given the limited available clinical data.

Yet, the authors suggest clinicians may consider a lower colchicine dose of 0.3 mg daily to mitigate the

potential risk, especially in patients with severe renal or hepatic impairment (Table 2) (38).

Digoxin

Digoxin is a cardiac glycoside that inhibits sodium-potassium ATPase, an enzyme that regulates

the quantity of sodium and potassium inside cells. The metabolism of digoxin is not dependent upon the

CYP450 system, and digoxin is not known to induce or inhibit the CYP450 system (31). Digoxin is,

however, a substrate of both intestinal and renal P-gp. Further, rhabdomyolysis has been reported with

concomitant use of digoxin and colchicine (38). Considering the narrow therapeutic index of digoxin,

concomitant use with colchicine may theoretically lead to toxic accumulations; however, there is an

absence of evidence to support this. Specifically, drugs that induce or inhibit P-gp have the potential to
14
alter digoxin pharmacokinetics, this is felt to be less likely with colchicine (50). However, close

monitoring for signs and symptoms of muscle toxicity is recommended with concomitant digoxin and

colchicine use (Table 2).

Ranolazine

Ranolazine is an anti-anginal agent that inhibits the late sodium current resulting in reduced calcium

overload and left ventricular diastolic tension. Ranolazine is extensively metabolized by the CYP3A4

enzyme, and to a much lesser extent, CYP2D6 (31). Ranolazine is also a substrate for and transported by

P-gp, thus, significantly increasing the potential for increased colchicine concentrations (38). Although

this is a theoretical risk as there’s no clinical data available, the authors suggest that clinician’s may

consider avoiding concomitant use of ranolazine and colchicine, particularly in the setting of severe

renal or hepatic impairment. If unavoidable, a decrease in colchicine dose to 0.3 mg daily may be

reasonable (Table 2).

Conclusion

Expanding evidence supporting the use colchicine for the management of pericarditis and secondary

prevention of ASCVD is significant and likely to result in increased use. The current data supports the

role of colchicine as a first-line therapy for acute pericarditis and to prevent recurrence. For secondary

prevention of ASCVD, colchicine may be considered but optimization of traditional risk factors should

take priority. Ongoing clinical trials with colchicine (e.g., CLEAR-SYNERGY) will expand upon our

current knowledge of which patients benefit most from colchicine. Cardiovascular clinicians should be

15
aware that colchicine has the potential for significant DDIs with frequently used cardiovascular

medications. Judicious use of colchicine is warranted in patients receiving therapies metabolized by the

CYP3A4 enzyme, which also often utilize P-gp, to minimize the risk of increased adverse effects and

toxicity.

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Figure 1 Colchicine is now used for several cardiovascular conditions. Colchicine is a substrate for P-gp
and metabolized in the liver by CYP3A4 before being eliminated via the kidneys and bile. Clinicians
should be aware that several cardiovascular medications have the potential to interact with colchicine.
CYP3A4 = cytochrome P450 3A4; CL = clearance; P-gp = p-glycoprotein

Table 1. Metabolic Pathways of HMG-CoA Reductase Inhibitors (Statins)

Enzyme Pathway
Statin
CYP2C9 CYP3A4 P-gp
Atorvastatin X X

Fluvastatin X

Lovastatin X X

Pitavastatin X X
*
Pravastatin

Rosuvastatin X

Simvastatin X X

CYP: cytochrome P450; P-gp: p-glycoprotein; X – indicates enzyme pathway activity

*
Metabolism of pravastatin occurs via biliary excretion by active transport and chemical degradation in
the stomach rather than CYP450 dependent metabolism.

Table 2. Recommendations for Drug-Drug Interactions with Colchicine and Select Medications
DDI
Interacting Agent Additional Considerations
Risk
Statins
Atorvastatin  Regardless of which statin is used, closely monitor for new
Fluvastatin onset muscle pain or weakness; check CPK levels in patients
Lovastatin with severe muscle symptoms or objective muscle weakness
Pitavastatin  When possible, it may be reasonable to avoid atorvastatin,
Pravastatin lovastatin, and simvastatin
Rosuvastatin
Simvastatin
21
Fibric acid derivatives
Fenofibrate  Generally safe if not on concomitant statin therapy; check
Gemfibrozil CPK levels in patients with severe muscle symptoms or
objective muscle weakness
 Avoid use with colchicine if on concomitant statin therapy

Beta-blockers
Atenolol  Carvedilol and propranolol are generally safe in patients with
Bisoprolol stable kidney function (creatine clearance ≥30 mL/min)
Carvedilol  Other beta-blockers may be safety administered with
Metoprolol colchicine
Propranolol
Calcium channel
blockers  Avoid diltiazem and verapamil, especially in the setting of
Amlodipine severe kidneya and/or hepaticb impairment
Diltiazem o If unavoidable, decrease colchicine dose to 0.3
Verapamil mg/day

Antiarrhythmics  Strong caution is advised with amiodarone and dronedarone,

Amiodarone especially in the setting of severe kidneya and/or hepaticb
Dronedarone impairment
o Consider decreasing colchicine dose to 0.3 mg/day

Digoxin  Digoxin is a substrate of P-gp and may compete with

colchicine and increase risk of muscle toxicity.
 Close monitoring for signs and symptoms of muscle toxicity
is recommended if used in combination.
o Consider decreasing colchicine dose to 0.3 mg/day

 Avoid, especially in the setting of severe kidneya and/or

hepaticb impairment
Ranolazine o If unavoidable, decrease colchicine dose to 0.3
mg/day

Considered safe Use with caution or limited data

Considered safe but with exceptions Avoid if possible

a
Severe kidney impairment: Creatinine Clearance (Cockcroft-Gault Equation) < 30 mL/min/1.73m2
b
Severe hepatic impairment: Child Pugh Class C
CPK, creatine phosphokinase; DDI, drug-drug interaction; P-gp, P-glycoprotein

22