Table 3.
Management options for colchicine drug interactions
| Drugs | Evidence for drug interaction (DDI) | ORCA classa and management options | Management if concurrent use needed |
|---|---|---|---|
| Antiarrhythmics | |||
| Amiodarone | Amiodarone inhibits CYP3A4/P-gp and would be expected to ↑ colchicine AUC; [61] several case reports suggest that a DDI may occurb |
ORCA Class 2: Avoid if possiblec Use alternative: other than amiodarone and dronedarone, most other antiarrhythmics are not known to inhibit CYP3A4 and P-gp Or consider alternative to colchicined |
Reduce colchicine dose 50–75% Monitor for colchicine toxicity Advise patient about colchicine toxicitye |
| Dronedarone | Dronedarone inhibits CYP3A4/P-gp and theoretically would be expected to ↑ colchicine AUC [62, 63] |
ORCA Class 2: Avoid if possiblec Use alternative: other than amiodarone and dronedarone, most other antiarrhythmics are not known to inhibit CYP3A4 and P-gp Or consider alternative to colchicined |
Reduce colchicine dose 50–75% Monitor for colchicine toxicity Advise patient about colchicine toxicitye |
| Propafenone | Propafenone inhibits P-gp but has little effect on CYP3A4; no colchicine DDI was found in healthy subjects with propafenone 450 mg/d × 5 days [30, 56] |
ORCA Class 4: Low risk Concurrent use need not be avoided, but some patients might have increased colchicine levels especially if they have low CYP3A4 activity due to other drugs or genetics |
Normal monitoring for colchicine toxicity |
| Quinidine | Quinidine is a potent inhibitor of P-gp, but not CYP3A4 [64]; it is not known if P-gp inhibition alone affects colchicine pharmacokinetics, no clinical data are available |
ORCA Class 3: Assess risk; take action if needed Concurrent use need not be avoided, but increased colchicine levels possible, especially in predisposed patients (e.g., on CYP3A4 inhibitors, severe renal or hepatic impairment)c |
Monitor for altered colchicine effect if quinidine is started, stopped or changed in dosage Advise patient about colchicine toxicitye |
| Ranolazine | Ranolazine appears to be a modest inhibitor of CYP3A4 and P-gp [65–67]; it is not known if inhibition of CYP3A4 and P-gp is large enough for interaction |
ORCA Class 3: Assess risk; take action if needed Concurrent use need not be avoided, but increased colchicine levels possible, especially in predisposed patients (e.g., on CYP3A4 inhibitors, severe renal or hepatic impairment)c |
Monitor for altered colchicine effect if ranolazine is started, stopped or changed in dosage Advise patient about colchicine toxicitye |
| Azole antifungals | |||
| Fluconazole | Fluconazole is a dose-dependent inhibitor of CYP3A4 that probably has little effect on P-gp [27, 68–70]; fluconazole 400 mg on day 1 and 200 mg on days 2–5 ↑ colchicine AUC by 40% in healthy subjects [56]; one case of colchicine toxicity with fluconazole in patient with renal failureb |
ORCA Class 3: Assess risk; take action if needed Concurrent use need not be avoided, but increased risk with renal impairmentc,f or if patient has low P-gp activityg Or consider alternative to fluconazole: voriconazole may be less likely to interact with colchicine (see below); terbinafine does not inhibit CYP3A4 |
If no renal impairment or ↓ P-pg activity: Monitor for colchicine toxicity particularly during start of fluconazole therapy Advise patient about colchicine toxicitye With renal impairment or ↓ P-gp activity: Reduce colchicine dose 50–75% Monitor for colchicine toxicity Advise patient about colchicine toxicitye |
| Itraconazole | Itraconazole inhibits CYP3A4/P-gp [27] and would be expected to ↑ colchicine AUC as does ketoconazole (see below) |
ORCA Class 2: Avoid if possiblec Consider stopping colchicine during short-term itraconazole Or use alternative. Fluconazole (see above) and voriconazole (see below) are less likely to interact; terbinafine does not inhibit CYP3A4 Or consider alternative to colchicined |
Reduce colchicine dose 50–75% Monitor for colchicine toxicity Advise patient about colchicine toxicitye |
| Ketoconazole | Ketoconazole inhibits CYP3A4/P-gp. A study in 24 healthy subjects found a mean 212% ↑ in colchicine AUC after ketoconazole 200 mg BID for 5 days; one subject had a 420% ↑ in AUC [25] |
ORCA Class 2: Avoid if possiblec Consider stopping colchicine during short-term ketoconazole Or use alternative. Fluconazole (see above) and voriconazole (see below) are less likely to interact; terbinafine does not inhibit CYP3A4 Or consider alternative to colchicined |
Reduce colchicine dose 50–75% Monitor for colchicine toxicity Advise patient about colchicine toxicitye |
| Voriconazole | Voriconazole is a strong CYP3A4 inhibitor, but appears to have little effect on P-gp [27–29]; a study in healthy subjects found no effect of voriconazole 200 mg BID for 5 days on colchicine AUC [30] |
ORCA Class 4: Low risk Concurrent use need not be avoided, but some patients might have increased colchicine levels, especially if P-gp activity is lowg |
Normal monitoring for colchicine toxicity |
| Antivirals—protease inhibitors and adjuvants | |||
|
Atazanavir Cobicistat Darunavirh Fosamprenavir Indinavir Nelfinavir Ritonavir Saquinavir Telaprevir |
These agents inhibit CYP3A4 and P-gp and would be expected to ↑ colchicine AUC; a study in 18 healthy subjects found a mean 296% ↑ in colchicine AUC after ritonavir 100 mg/day for 5 days; one subject had a 924% ↑ in colchicine AUCi [25, 45] |
ORCA Class 2: Avoid if possiblec Use alternative: For most patients it may be easier to avoid colchicine than the antiviral agentd. Stop colchicine before antiviral is started, and for 3–4 days after antiviral is stopped. If concurrent use is deemed necessary (which should very rarely be the case), see column to the right. Ritonavir + nirmatrelvir (Paxlovid) is normally given for 5 days, so stopping colchicine during Paxlovid therapy would usually be the best management |
Reduce colchicine dose 50–75% Monitor for colchicine toxicity Advise patient about colchicine toxicitye |
| Tipranavir | Unlike many other protease inhibitors, tipranavir tends to ↑ P-gp activity, which might reduce colchicine AUCj [71] |
ORCA Class 3: Assess risk; take action if needed Concurrent use need not be avoided, but some patients may have reduced colchicine concentrations; more data are needed |
Monitor for altered colchicine effect if tipranavir is started, stopped, or changed in dosage; adjust colchicine dose as needed; note that the onset and offset of enzyme induction may occur slowly over 1–2 weeks |
| Antivirals—miscellaneous | |||
| Boceprevir | Boceprevir inhibits CYP3A4 [72], but its effect on P-pg is not known. Effect on colchicine requires further study |
ORCA Class 3: Assess risk; take action if needed Concurrent use need not be avoided, but some patients might have increased colchicine levels, especially if P-gp activity is lowg |
Monitor for altered colchicine effect if boceprevir is started, stopped or changed in dosage Advise patient about colchicine toxicitye |
| Letermovir | Letermovir inhibits CYP3A4 [73], but may not affect P-pg [74]. Effect on colchicine requires further study |
ORCA Class 3: Assess risk; take action if needed Concurrent use need not be avoided, but some patients might have increased colchicine levels, especially if P-gp activity is lowg |
Monitor for altered colchicine effect if letermovir is started, stopped or changed in dosage Advise patient about colchicine toxicitye |
|
Efavirenz Etravirine Nevirapine |
These enzyme inducers are known to induce CYP3A4, and are likely to reduce colchicine serum concentrations |
ORCA Class 3: Assess risk; take action if needed Concurrent use need not be avoided, but some patients may have reduced colchicine concentrations; more data are needed |
Monitor for altered colchicine effect if these agents are started, stopped, or changed in dosage; adjust colchicine dose as needed; note that the onset and offset of enzyme induction may occur slowly over 1–2 weeks |
| Calcineurin inhibitors | |||
| Cyclosporine | Cyclosporine inhibits CYP3A4 and P-gp; a study in 23 healthy subjects found a mean 259% ↑ in colchicine AUC after a single 100-mg dose of cyclosporine; one subject had a 512% ↑ [25, 45, 75]; possible additive myopathyk; over 30 cases of colchicine–cyclosporine DDI reportedb |
ORCA Class 2: Avoid if possiblec The risk would almost always outweigh the benefit Use alternative: If appropriate, tacrolimus appears less likely to interact with colchicine (see below); many other immunosuppressants are not known to inhibit CYP3A4 and P-gp Or consider alternative to colchicined |
Reduce colchicine dose 50–75% Monitor for colchicine toxicity, especially for signs of myopathy Advise patient about colchicine toxicitye |
| Tacrolimus | Tacrolimus inhibits P-gp somewhat, but may be only weak inhibitor of CYP3A4; Two small studies found increased colchicine AUC with tacrolimus, but less than with cyclosporine [16, 75] |
ORCA Class 3. Assess risk; take action if needed Colchicine levels are likely to increase somewhat, especially in predisposed patients (e.g., on CYP3A4 inhibitors, or with severe renal or hepatic impairment)c Consider alternative to tacrolimus or colchicined |
Monitor for altered colchicine effect if tacrolimus started, stopped, or changed in dosage Advise patient about colchicine toxicitye |
| Calcium-channel blockers (CCBs) | |||
| Diltiazem | Diltiazem inhibits CYP3A4 and P-gp; in 20 healthy subjects, diltiazem 240 mg BID for 7 days ↑ colchicine AUC by 93%; one subject had a 339% increase [25, 45]; a patient on diltiazem developed fatal colchicine toxicity, but causality was not establishedb |
ORCA Class 2: Avoid if possiblec Use alternative. If appropriate, use an alternative to diltiazem or verapamil; most other CCBs such as dihydropyridines appear to have little effect on CYP3A4 or P-gp Or consider alternative to colchicined |
Reduce colchicine dose 50–75% Monitor for colchicine toxicity, especially for signs of myopathy Advise patient about colchicine toxicitye |
| Verapamil | Verapamil inhibits CYP3A4 and P-gp; in 24 healthy subjects, verapamil 240 mg BID for 5 days ↑ colchicine AUC by 103%; one subject had a 217% increase [25, 45]; a patient on verapamil developed serious colchicine toxicityb |
ORCA Class 2: Avoid if possiblec Use alternative. If appropriate, use an alternative to verapamil or diltiazem; most other CCBs such as dihydropyridines appear to have little effect on CYP3A4 or P-gp Or consider alternative to colchicined |
Reduce colchicine dose 50–75% Monitor for colchicine toxicity, especially for signs of myopathy Advise patient about colchicine toxicitye |
| Enzyme inducers | |||
| Carbamazepine (CBZ) | Carbamazepine induces CYP3A4 and P-gp, and would be expected to reduce colchicine AUC; case report of very low colchicine levels in patient on CBZb |
ORCA Class 2: Avoid if possible It may be difficult to achieve therapeutic colchicine levels in presence of CBZ Use alternative. If appropriate, use an alternative to the CBZ or colchicined |
Monitor for altered colchicine effect if CBZ is started, stopped, or changed in dosage; adjust colchicine dose as needed; note that the onset and offset of enzyme induction may occur slowly over 1–2 weeks |
| Rifampin | Rifampin induces CYP3A4 and P-gp, and would be expected to reduce colchicine AUC; case report of low colchicine levels in patient on rifampinb |
ORCA Class 2: Avoid if possible It may be difficult to achieve therapeutic colchicine levels in presence of rifampin Use alternative. If appropriate, use an alternative to rifampin or colchicined |
Monitor for altered colchicine effect if CBZ is started, stopped, or changed in dosage; adjust colchicine dose as needed; note that the onset and offset of enzyme induction may occur slowly over 1–2 weeks |
|
Barbiturates Bosentan Dabrafenib Lumacaftor Phenytoin Primidone Rifabutin Rifapentine St. John’s wort Topiramate |
These enzyme inducers are known to induce CYP3A4, and are likely to reduce colchicine serum concentrations |
ORCA Class 2: Avoid if possible It may be difficult to achieve therapeutic colchicine levels in presence of these enzyme inducers Use alternative. If appropriate, use an alternative to the enzyme inducer or colchicined |
Monitor for altered colchicine effect if inducer is started, stopped, or changed in dosage; adjust colchicine dose as needed; note that the onset and offset of enzyme induction may occur slowly over 1–2 weeks |
| Foods | |||
| Grapefruit | Grapefruit inhibits CYP3A4, but appears to be a weak P-gp inhibitor; a single case of life-threatening colchicine toxicity was reported in an 8-year-old girlb and in vitro evidence [76] suggest a DDI; but study in 21 healthy subjects given 240 mL grapefruit juice BID for 4 days found no effect on colchicine AUCl [24] |
ORCA Class 3. Assess risk; take action if needed Although evidence for an interaction is weak, it might occur in patients with low P-gp activityg It would be prudent to advise patents to drink juices other than grapefruit |
If the patient drinks grapefruit juice, advise them to avoid ingesting more than 240 mL/day |
| Seville oranges | A study in 23 healthy subjects given 240 mL Seville orange juice BID for 4 days found a small decrease in colchicine AUC [24] |
ORCA Class 4. Low risk Concurrent use need not be avoided, but a slight reduction in colchicine AUC may occur |
Normal monitoring for colchicine toxicity |
| HMG-CoA reductase inhibitors | |||
| Atorvastatin | A study in 24 healthy subjects found a mean 24% ↑ in colchicine AUC after atorvastatin 40 mg/day for 14 days [77]; due to weak P-gp inhibition by atorvastatin? 7 case reports of myopathy with combinationb; additive myotoxicity? [58, 59] |
ORCA Class 3. Assess risk; take action if needed Concurrent use need not be avoided, especially if the colchicine dose is 0.6 mg/day or less If colchicine dose is > 0.6 mg/day, myopathy risk may be increased in predisposed patients, (i.e. impaired renal function, elevated statin levels due to dose, DDIs, etc.)c,m Consider alternative: fluvastatin, pravastatin, and rosuvastatin may be less likely to interact |
Monitor for colchicine toxicity, especially for signs of myopathy Advise patient to report evidence of myopathy (muscle weakness, myalgia, dark urine) |
| Fluvastatin | Not expected to affect colchicine AUC; isolated cases of rhabdomyolysis reported with combination, but causality was not establishedb; additive myotoxicity? [58, 59] |
ORCA Class 4: Low risk Concurrent use need not be avoided; it is possible that the myopathy risk is increased in predisposed patients, but more data are neededn |
Normal monitoring for colchicine toxicity, with emphasis on signs of myopathy (muscle weakness, myalgia, dark urine) |
| Lovastatin | Possible P-gp inhibitory effect of lovastatin? [78] Possible additive myotoxicity? [58, 59]. Isolated cases of myopathyb; lovastatin has similar pharmacokinetic properties as simvastatin (see below) |
ORCA Class 3: Assess risk; take action if needed Concurrent use need not be avoided, especially if the colchicine dose is 0.6 mg/day or less If colchicine dose is > 0.6 mg/day, myopathy risk may be increased with renal impairment or elevated statin levels due to dose, DDIs, etc.)c,m Consider alternative: fluvastatin, pravastatin, and rosuvastatin may be less likely to interact |
Monitor for colchicine toxicity, especially for signs of myopathy Advise patient to report evidence of myopathy (muscle weakness, myalgia, dark urine) |
| Pravastatin | Not expected to affect colchicine AUC; isolated cases of myopathy reported with combination, but causality was not establishedb; additive myotoxicity? [58, 59] |
ORCA Class 4: Low risk Concurrent use need not be avoided; it is possible that the myopathy risk is increased in predisposed patients, but more data are neededn |
Normal monitoring for colchicine toxicity, with emphasis on signs of myopathy (muscle weakness, myalgia, dark urine) |
| Rosuvastatin | Not expected to affect colchicine AUC; isolated cases of myopathy reported, but causality was not establishedb; additive myotoxicity? [58, 59] Combination has been used to treat COVID [79] |
ORCA Class 4: Low risk Concurrent use need not be avoided; it is possible that the myopathy risk is increased in predisposed patients, but more data are neededn |
Normal monitoring for colchicine toxicity, with emphasis on signs of myopathy (muscle weakness, myalgia, dark urine) |
| Simvastatin | Possible P-gp inhibitory effect of simvastatin? [80] Numerous case reports of myopathy reported with combination, usually in patients with preexisting renal impairmentb; possible additive myotoxicity [58, 59] |
ORCA Class 3: Assess risk; take action if needed Concurrent use need not be avoided, especially if the colchicine dose is 0.6 mg/day or less If colchicine dose is > 0.6 mg/day, myopathy risk may be increased with renal impairment or elevated statin levels due to dose, DDIs, etc.c,m Consider alternative: fluvastatin , pravastatin, and rosuvastatin may be less likely to interact |
Monitor for colchicine toxicity, especially for signs of myopathy Advise patient to report evidence of myopathy (muscle weakness, myalgia, dark urine) |
| Macrolide antibiotics | |||
| Azithromycin | A study in 21 healthy subjects found a mean 57% ↑ in colchicine AUC after azithromycin 500 mg on day 1, then 250 mg/day for 4 days; one subject had a 241% increase [25, 45]; azithromycin is a modest P-gp inhibitor |
ORCA Class 3. Assess risk; take action if needed Colchicine levels are likely to increase somewhat, especially in predisposed patients (e.g., on CYP3A4 inhibitors, or with severe renal or hepatic impairment)c Consider alternative to antibiotic or colchicined |
Monitor for altered colchicine effect if azithromycin is started, stopped or changed in dosage Advise patient about colchicine toxicitye |
| Clarithromycin | A study in 23 healthy subjects found a mean 282% ↑ in colchicine AUC after clarithromycin 500 mg/day for 7 days; one subject had a 852% ↑; clarithromycin inhibits both CYP3A4 and P-gp; fatalities reported in case series [19], among >2 dozen case reports,b and ADR reporting systems [18, 81] |
ORCA Class 1. Avoid combination The risk would almost always outweigh the benefit Consider stopping colchicine during clarithromycin therapy Or use alternative to clarithromycin; azithromycin has a smaller effect on colchicine (see above); many other antibiotics have little effect on CYP3A4 or P-gp |
It should not be necessary to use colchicine and clarithromycin together. If it is absolutely necessary: Reduce colchicine dose by 75% Monitor for colchicine toxicity Advise patient about colchicine toxicitye |
| Erythromycin | Erythromycin inhibits CYP3A4 but may inhibit P-gp less than clarithromycin; isolated DDI case reportsb |
ORCA Class 2: Avoid if possiblec Consider stopping colchicine during erythromycin therapy Or use alternative. Consider an alternative to erythromycin; azithromycin has a smaller effect on colchicine (see above); many other antibiotics have little effect on CYP3A4 or P-gp |
Reduce colchicine dose 50–75% Monitor for colchicine toxicity, especially for signs of myopathy Advise patient about colchicine toxicitye |
| Miscellaneous CYP3A4 inhibitors | |||
|
Aprepitant Ceritinib Conivaptan Crizotinib Fedratinib Idelalisib Imatinib Lapatinib Lomitapide Lefamulin Mifapristone Nefazodone Quinupristin Ribociclib Telithromycin |
All of these drugs inhibit CYP3A4 and many are also known to inhibit P-gp; no information is available on the effect of these drugs on colchicine AUC, but interactions should be considered possible until proven otherwise |
ORCA Class 2: Avoid if possiblec Use alternative. If appropriate, us an alternative to the CYP3A4 inhibitor that does not inhibit CYP3A4 Or consider alternative to colchicined |
Reduce colchicine dose 50–75% Monitor for altered colchicine response if CYP3A4 inhibitor started, stopped, or changed in dosage Advise patient about colchicine toxicityd |
| Quinolines | |||
| Chloroquine | Chloroquine alone can cause myopathy [82], so additive myotoxicity with colchicine is possible; no supporting clinical data |
ORCA Class 4. Low risk Concurrent use need not be avoided; it is possible that the myopathy risk is increased in predisposed patients, but more data are needed |
Normal monitoring for colchicine toxicity, with emphasis on signs of myopathy |
| Hydroxychloroquine (HQ) | HQ alone can cause myopathy; additive myotoxicity possible and single case of myopathy reportedb; HQ might inhibit P-gp, but no PK studies with colchicine; HQ has been used with colchicine to treat various disorders [83–85] |
ORCA Class 4. Low risk Concurrent use need not be avoided; it is possible that the myopathy risk is increased in predisposed patients, but more data are needed |
Normal monitoring for colchicine toxicity, with emphasis on signs of myopathy |
| Other drugs | |||
| Digoxin | Digoxin is purported to cause myopathy when combined with colchicine [25, 55] but supporting evidence is lacking; the fact that digoxin is a P-gp substrate is not proof that it inhibits P-gp |
ORCA Class 4. Low risk Concurrent use need not be avoided |
Normal monitoring for colchicine toxicity |
| Disulfiram | Evidence that disulfiram inhibits P-gp or CYP3A4 is weak [86, 87]; single case report of DDI with colchicine, but causal relationship doubtfulb |
ORCA Class 4. Low risk Concurrent use need not be avoided |
Normal monitoring for colchicine toxicity |
| Fibrates | Fenofibrate and gemfibrozil known to cause myopathy, with or without statins [88]; additive myotoxic effect with colchicine? Evidence that fenofibrate inhibits P-gp is weak [89]; one case of myopathy with gemfibrozil + colchicineb |
ORCA Class 3: Assess risk; take action if needed Concurrent use need not be avoided; it is possible that the myopathy risk is increased in predisposed patients, but more data are needed. Risk may be increased if patient is also taking a statin |
Monitor for colchicine toxicity, especially for signs of myopathy Advise patient to report evidence of myopathy (muscle weakness, myalgia, dark urine) |
| Lesinurad | Lesinurad may be a modest CYP3A4 inducer [90]; PK study in healthy subjects found modest ↓ in colchicine AUC, but lesinurad dose was high (400–600 mg/day) [33] |
ORCA Class 3: Assess risk; take action if needed Concurrent use need not be avoided, but some patients may have reduced colchicine concentrations; more data are needed |
Monitor for altered colchicine effect if lesinurad is started, stopped, or changed in dosage. Adjust colchicine dose as needed |
| Nivolumab | Thrombocytopenia reported in a patient on nivolumab and colchicineb; nivolumab may inhibit CYP3A4 by upregulating cytokines [91] but an effect on colchicine is speculative |
ORCA Class 3: Assess risk; take action if needed This DDI is largely theoretical, and concurrent use need not be avoided, some patients might have increased colchicine AUC, but more data are needed to establish a causal effect |
Monitor for altered colchicine effect if nivolumab is started, stopped, or changed in dosage. Adjust colchicine dose as needed |
| Sunitinib | Colchicine toxicity reported in a patient on sunitinibb, but the colchicine toxicity was more likely due to the excessive dose of colchicine, and the effect of concurrent diltiazem (see above) |
ORCA Class 4: Low risk Concurrent use need not be avoided |
Normal monitoring for colchicine toxicity |
ADRs adverse drug reactions, AUC area under the concentration–time curve, BID twice daily, DDIs drug–drug interactions, P-gp P-glycoprotein, PK pharmacokinetics, ↑ indicates increase, ↓ indicates decrease
aORCA: OpeRational ClassificAtion of drug interactions [92]: Class 1 = Avoid combination; Class 2 = Avoid combination unless benefit outweighs risk; Class 3 = Assess risk and take action if needed; Class 4 = Low risk: no special precautions; Class 5 = No interaction
bCase report details, including evaluation of causality, are presented in Online Resource (see ESM)
cDrug interactions that result in elevated colchicine plasma concentrations tend to be more dangerous in patients with renal impairment. Consider patients with significant renal impairment (e.g., creatinine clearance [CrCl] < 60 mL/min) to be at somewhat higher risk, and patients with severe renal disease (e.g., CrCl < 30 mL/min) at much higher risk of colchicine toxicity from drug interactions. For all drug interactions listed as ‘Class 2’, consider them contraindicated in patients with severe renal disease. The effect of liver disease is more theoretical, but assume ORCA class 2 DDIs are contraindicated if patient has a Child-Pugh score of C
dIf colchicine is being used for acute gout, consider using alternative gout therapy. If colchicine is being used chronically for gout prophylaxis, consider the risk of colchicine toxicity vs the expected benefit of gout prevention. If colchicine is being used for familial Mediterranean fever, cardiovascular disease, dermatologic disorders, Covid-19, or other disorders, it may be more difficult to find alternatives for colchicine. For some disorders such as pericarditis, colchicine may be deemed necessary
ePatient should report colchicine toxicity such as severe diarrhea, protracted vomiting, muscle weakness, muscle pain, dark urine, fever or other signs of infection, unusual bleeding or bruising, severe fatigue
fFluconazole and colchicine are both eliminated renally, so patients with severe renal impairment will have increased serum concentrations of both drugs. And since the ability of fluconazole to inhibit CYP3A4 is related to serum concentrations, there will be increased CYP3A4 inhibition
gBased on available evidence, drugs that inhibit CYP3A4 but not P-gp have little effect on colchicine AUC. But the risk of a DDI with colchicine would theoretically be increased if CYP3A4 inhibitors are given to patients with low P-gp activity due to other drugs or genetics
hDarunavir inhibits CYP3A4, but may induce P-gp somewhat. Theoretically, this might mitigate any increase in colchicine serum concentrations
iLong-term ritonavir therapy can result in enzyme induction [93], so it is not clear if these results apply to patients on chronic ritonavir
jTipranavir is generally given with ritonavir, but the result (CYP3A4 inhibition with P-gp induction) does not seem likely to increase colchicine serum concentrations based on study of tipranavir/ritonavir with other CYP3A4/P-gp substrates [71]
kBoth colchicine and cyclosporine can cause myopathy, and all case reports of colchicine–cyclosporine DDI had evidence of myopathy (e.g., some combination of muscle pain, muscle weakness, dark urine)
lThe lack of effect of grapefruit juice in the healthy subject study is consistent with the theory that inhibition of both CYP3A4 and P-gp is necessary for a DDI with colchicine. It is possible that the huge amount of grapefruit juice ingested by the 8-year-old girl (1 L/day for 2 months) was enough to inhibit P-gp. It is also possible that the grapefruit juice used in the healthy subject study did not contain sufficient quantities of the CYP3A4-inhibiting phytochemicals to affect colchicine pharmacokinetics. Different types of grapefruit are known to contain differing amounts of CYP3A4-inhibiting compounds [94, 95]
mAtorvastatin, lovastatin, and simvastatin are all metabolized by CYP3A4, so patients on CYP3A4 inhibitors are likely to be at increased risk
nPitavastatin, pravastatin, and rosuvastatin are all substrates for OATP transporters, so patients on OATP inhibitors may be at increased risk