Gloperba (colchicine)

Dosage of colchicine 0.6 mg tablet depends on the patient's age, renal and hepatic function, and whether it is administered concomitantly within 14 days following therapy with other medications that affect hepatic metabolism or the P-glycoprotein transport system.

Colchicine 0.5 mg is also commercially available in a fixed-dose tablet combination with probenecid 500 mg; refer to the full prescribing information for dosing of the combination product.

Colchicine is commercially available as tablets or oral capsules (Mitigare(R)) containing 0.6 mg, an oral solution (Gloperba(R)) containing 0.12 mg/mL , and tablets (Lodoco(R)) containing 0.5 mg.

Colchicine 0.5 mg is also commercially available in a fixed-dose tablet combination with probenecid 500 mg; refer to the full prescribing information for administration details of the combination product.

Colchicine 0.6 mg tablets and capsules, and the oral suspension are administered without regard to meals.

Colchicine 0.6 mg tablets for treatment of an acute gout flare should be initiated at the first sign of an attack.

Patients receiving colchicine 0.6 mg tablets should be instructed on how to resume therapy in the event of a missed dose. Patients with gout who are receiving colchicine 0.6 mg tablets for treatment of an acute flare, but not for prophylaxis of recurrent flares, should be instructed to take the missed dose as soon as possible. Those receiving colchicine 0.6 mg tablets to treat an acute gout flare during colchicine prophylaxis should be instructed to take the missed dose immediately, then wait 12 hours before resuming the previous dosing schedule. Patients receiving colchicine 0.6 mg tablets for treatment of familial Mediterranean fever (FMF) or for prophylaxis of recurrent gout flares (without treatment for an acute gout flare) should be instructed to take the missed dose as soon as possible and then resume their usual dosing schedule. They should not take a double dose to make up for the missed dose.

Patients receiving colchicine 0.6 mg capsules, 0.5 mg tablets, or the oral solution should be instructed to take the missed dose as soon as possible and then resume their usual dosing schedule. They should not take a double dose to make up for the missed dose.

Tablet (0.6 mg): Store at 20-25degreesC; protect from light. Dispense in tight, light-resistant container.

Capsule (0.6 mg): Store at 20-25degreesC; protect from light and moisture.

Oral suspension (0.12 mg/mL): Store at 20-25degreesC (excursions permitted to 15-30degreesC).

Tablet (0.5 mg): Store at 20-25degreesC (excursions permitted to 15-30degreesC). Store in the original package to protect from light.

No dosing information is available for this tab.

Colchicine is a substrate for both CYP3A4 and the P-glycoprotein transport system. Drug interactions, including life-threatening and fatal cases, have been reported in patients receiving colchicine concomitantly with CYP3A4 and/or P-glycoprotein inhibitors.

Consider the potential for serious drug-drug interactions prior to and during colchicine therapy. Concomitant use of colchicine with certain medications is contraindicated or requires particular caution.

Colchicine is metabolized by cytochrome P-450 (CYP) isoenzyme 3A4. In vitro studies indicate that colchicine does not inhibit or induce CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4.

Colchicine is a substrate for the P-glycoprotein (P-gp) transport system.

Colchicine is also commercially available in a fixed-dose combination tablet with probenecid; refer to the full prescribing information for drug interactions with the combination product.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Colchicine/Quinupristin-Dalfopristin, Pristinamycin

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Quinupristin-dalfopristin or pristinamycin may inhibit the metabolism of colchicine by CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of a CYP3A4 inhibitor may result in elevated levels of and toxicity from colchicine. Symptoms of colchicine toxicity include muscle weakness or pain; numbness or tingling in the fingers or toes; myelosuppression; abdominal pain; nausea; severe diarrhea or vomiting; feeling weak or tired; increased infections; and pale or gray color of the lips, tongue, or palms of hands.(1)

PREDISPOSING FACTORS: This interaction is expected to be more severe in patients with renal or hepatic impairment.(1)

PATIENT MANAGEMENT: The manufacturer of pristinamycin state that concurrent use with colchicine is contraindicated.(1) The US manufacturer of quinupristin-dalfopristin recommends caution and monitoring with narrow therapeutic index drugs including colchicine.(4)

DISCUSSION: There are reports of colchicine toxicity(2) and death(3) following the the concomitant administration of colchicine and pristinamycin. In a study in 24 subjects, concurrent administration of quinupristin-dalfopristin (7.5 mg/kg every 8 hours for 2 days) and cyclosporine (300 mg on Day 3, CYP3A4 substrate) resulted in an increase in cyclosporine's area-under-the-curve (AUC) and maximum concentration (Cmax) of 63% and 30%, respectively. Cyclosporine half-life increased 77% while clearance decreased 34%.(4) Concurrent administration of quinupristin-dalfopristin with nifedipine (repeat oral doses, CYP3A4 substrate) in healthy volunteers increased the Cmax and AUC by 18% and 44%. Concurrent midazolam (intravenous bolus dose, CYP3A4 substrate) in healthy volunteers increased the Cmax and AUC by 14% and 33%.(4) In a case report, concurrent administration of cyclosporine and quinupristin-dalfopristin resulted in a 3-fold increase in cyclosporine trough level which was managed by a 33% dose reduction in the cyclosporine dose.(4) There are several other case reports of toxicity and increased cyclosporine trough levels.(5,6) In a case report, concurrent administration of everolimus (CYP3A4 substrate) and pristinamycin resulted in a significant increase in everolimus levels (increased to 33.5 mcg/L on Day 3 of pristinamycin) which was managed by a 25% reduction in the everolimus dose.(7) In a case report, concurrent administration of tacrolimus (CYP3A4 substrate) and pristinamycin resulted in a 5-fold increase in tacrolimus trough level.(8)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Colchicine (For Gout & Fmf)/Moderate Cyp3a4 Inhibitors

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Moderate CYP3A4 inhibitors may inhibit the metabolism of colchicine(1-3)

CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may result in elevated levels of and toxicity from colchicine. Symptoms of colchicine toxicity include muscle weakness or pain; numbness or tingling in the fingers or toes; myelosuppression; abdominal pain; nausea; severe diarrhea or vomiting; feeling weak or tired; increased infections; and pale or gray color of the lips, tongue, or palms of hands.(1-3)

PREDISPOSING FACTORS: This interaction is expected to be more severe in patients with renal and/or hepatic impairment.(1-3)

PATIENT MANAGEMENT: Avoid use of colchicine concurrently with or within 14 days of taking moderate CYP3A4 inhibitors (without ritonavir). If concurrent use is unavoidable, the dosage of colchicine should be reduced.(1-3) For gout flares, the recommended dosage is 1.2 mg (2 tablets) for one dose. This dose should be repeated no earlier than in 3 days.(1-4) For gout prophylaxis, if the original dosage was 0.6 mg twice daily, use 0.3 mg twice daily or 0.6 mg daily. If the original dosage was 0.6 mg daily, use 0.3 mg daily.(1-4) For Familial Mediterranean fever (FMF), the recommended maximum daily dose is 1.2 mg (may be given as 0.6 mg twice a day).(1-4) Patients should be instructed to immediately report any signs of colchicine toxicity, such as muscle weakness/pain, numbness/tingling in fingers/toes, unusual bleeding or bruising, infections, weakness/tiredness, pale/gray color of the lips/tongue/palms of hands, and/or severe diarrhea/vomiting.

DISCUSSION: Fluconazole (400 mg loading dose followed by 200 mg daily for 4 days) increased the area-under-curve (AUC) of colchicine by 40%.(2) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, avacopan, clofazimine, conivaptan, crizotinib, duvelisib, fedratinib, fluconazole, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, ledipasvir, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, stiripentol, and treosulfan.(1,5,6)

Colchicine (For Gout & Fmf)/P-Glycoprotein (P-Gp) Inhibitors

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: P-glycoprotein (P-gp) inhibitors may affect the transport of colchicine, a P-gp substrate.(1,2)

CLINICAL EFFECTS: Concurrent use of a P-gp inhibitor may result in elevated levels of and toxicity from colchicine. Symptoms of colchicine toxicity include abdominal pain; nausea or vomiting; severe diarrhea; muscle weakness or pain; numbness or tingling in the fingers or toes; myelosuppression; feeling weak or tired; increased infections; and pale or gray color of the lips, tongue, or palms of hands.(1,2)

PREDISPOSING FACTORS: This interaction is expected to be more severe in patients with renal and/or hepatic impairment(1,2) and in patients who receive concurrent therapy.

PATIENT MANAGEMENT: The concurrent use of colchicine with P-gp inhibitors is contraindicated in patients with renal or hepatic impairment.(1-3) Avoid concurrent use in other patients, if possible.(3) In patients without renal or hepatic impairment who are currently taking or have taken a P-gp inhibitor in the previous 14 days, the dosage of colchicine should be reduced. For gout flares, the recommended dosage is 0.6 mg (1 tablet) for one dose. This dose should be repeated no earlier than in 3 days.(1,2) For gout prophylaxis, if the original dosage was 0.6 mg twice daily, use 0.3 mg daily. If the original dosage was 0.6 mg daily, use 0.3 mg every other day.(3-12) For Familial Mediterranean fever (FMF), the recommended maximum daily dose is 0.6 mg (may be given as 0.3 mg twice a day).(1,2) Patients should be instructed to immediately report any signs of colchicine toxicity, such as abdominal pain, nausea/significant diarrhea, vomiting; muscle weakness/pain; numbness/tingling in fingers/toes; unusual bleeding or bruising, infections, weakness/tiredness, or pale/gray color of the lips/tongue/palms of hands. The manufacturer of daraxonrasib states P-gp substrates should be administered at least 4 hours apart from daraxonrasib.(13)

DISCUSSION: There are several reports of colchicine toxicity(4-6) and death(7,8) following the addition of clarithromycin to therapy. In a retrospective review of 116 patients who received clarithromycin and colchicine during the same hospitalization, 10.2% (9/88) of patients who received simultaneous therapy died, compared to 3.6% (1/28) of patients who received sequential therapy.(9) An FDA review of 117 colchicine-related deaths that were not attributable to overdose found that 60 deaths (51%) involved concurrent use of clarithromycin.(2) There is one case report of colchicine toxicity with concurrent erythromycin.(10) In a study in 20 subjects, pretreatment with diltiazem (240 mg daily for 7 days) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of colchicine (0.6 mg) by 44.2% (range -46.6% to 318.3%) and by 93.4% (range -30.2% to 338.6%), respectively.(1) In a study in 24 subjects, pretreatment with verapamil (240 mg twice daily for 7 days) increased the Cmax and AUC of a single dose of colchicine (0.6 mg) by 40.1% (range -47.1% to 149.5%) and by 103.3% (range -9.8% to 217.2%), respectively.(1) Colchicine toxicity has been reported with concurrent use of CYP3A4 and P-gp inhibitors such as clarithromycin, cyclosporine, diltiazem, erythromycin, and verapamil.(1,2) P-gp inhibitors include abrocitinib, amiodarone, asciminib, asunaprevir, aumolertinib, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine, danicopan, daraxonrasib, daridorexant, deutivacaftor, diltiazem, diosmin, dronedarone, erythromycin, flibanserin, fluvoxamine, fostamatinib, glecaprevir/pibrentasvir, imlunestrant, ivacaftor, lapatinib, ledipasvir, mavorixafor, neratinib, osimertinib, pirtobrutinib, propafenone, quinidine, ranolazine, schisandra, selpercatinib, sotorasib, tepotinib, valbenazine, velpatasvir, vemurafenib, venetoclax, vepdegestrant, verapamil, vimseltinib, and voclosporin.(1,11,12)

Colchicine (For Gout & Fmf)/Rifampin

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Colchicine is a substrate of CYP3A4 and P-glycoprotein (P-gp).(1) Rifampin is a P-gp inhibitor with short-term use (<7 days) and a CYP3A4 and P-gp inducer with longer use.(2-5)

CLINICAL EFFECTS: The exact course of this interaction is undefined. The addition of rifampin to existing colchicine therapy may initially increase colchicine absorption, resulting in increased colchicine levels and side effects including GI distress, neuropathy, myopathy, and myelosuppression.(1,6) Continued use will cause P-gp and CYP3A4 induction, resulting in decreased colchicine levels and effectiveness.(1,2) The addition of colchicine to a patient already receiving rifampin or who has recently discontinued rifampin may result in induction of colchicine metabolism and decreased levels and efficacy of colchicine.(1,2)

PREDISPOSING FACTORS: This interaction is expected to be more severe in patients with renal and/or hepatic impairment.(1,6)

PATIENT MANAGEMENT: The use of colchicine in patients with renal or hepatic impairment on P-gp inhibitors, including patients starting rifampin therapy, is contraindicated. Avoid concurrent use in other patients, if possible. In patients without renal or hepatic impairment who are starting rifampin, the dosage of colchicine should be reduced. For gout flares, the recommended dosage is 0.6 mg (1 tablet) for one dose. This dose should be repeated no earlier than in 3 days. For gout prophylaxis, if the original dosage was 0.6 mg twice daily, use 0.3 mg daily. If the original dosage was 0.6 mg daily, use 0.3 mg every other day. For Familial Mediterranean fever (FMF), the recommended maximum daily dose is 0.6 mg (may be given as 0.3 mg twice a day).(1,6) Patients should be instructed to immediately report any signs of colchicine toxicity, such as abdominal pain, nausea, significant diarrhea or vomiting, muscle weakness or pain, numbness or tingling in the fingers or toes, unusual bleeding or bruising, infections, weakness, tiredness, or pale or gray color of the lips, tongue, or palms of hands. In patients who have been on rifampin for at least 1 week and require colchicine therapy, monitor for decreased colchicine response.

DISCUSSION: The combination of colchicine and rifampin has not been studied. Colchicine is a known P-gp and CYP3A4 substrate and concurrent therapy with inhibitors of P-gp and/or CYP3A4 increases the risk for colchicine toxicity, including death.(1) An FDA review of 117 colchicine-related deaths that were not attributable to overdose found that 60 deaths (51%) involved concurrent use of clarithromycin (a P-gp and strong CYP3A4 inhibitor).(2) In a study of 11 healthy volunteers, digoxin administered 1 hour after the last dose of a 28-day course of rifampin increased the area-under-curve (AUC(0-3h)) and maximum concentration (Cmax) of digoxin by 45% and 49%, respectively, compared to digoxin administered in the absence of induction. These digoxin levels represent both acute and chronic effects of rifampin on digoxin disposition. Digoxin AUC(0-3h) and Cmax at 1 week after rifampin discontinuation were 68% and 69%, respectively, of the reference values, demonstrating induction effects.(3) A study of 45 healthy volunteers investigated the effects of single-dose rifampin on the pharmacokinetics of a probe-drug cocktail of digoxin, furosemide, metformin, and rosuvastatin. The AUC and Cmax of digoxin were increased by 31% and 118%, respectively.(4) In a physiologically-based pharmacokinetic (PBPK) model, the effects of rifampin on P-gp activity in the liver, intestine, and kidney were predicted. Single-dose rifampin 600 mg is expected to decrease P-gp activity to 28% in the liver, <=5% in the intestine, and 44% in the kidney. Rifampin 600 mg daily at steady state is predicted to increase P-gp activity in the liver to 321%, in the intestine to 276%-284%, and in the kidney to 266%.(5)

Colchicine (For Gout & Fmf)/Strong Cyp3a4 Inhibitors

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of colchicine.(1,2)

CLINICAL EFFECTS: Concurrent use of a strong CYP3A4 inhibitor may result in elevated levels of and toxicity from colchicine. Symptoms of colchicine toxicity include muscle weakness or pain; numbness or tingling in the fingers or toes; myelosuppression; abdominal pain; nausea; severe diarrhea or vomiting; feeling weak or tired; increased infections; and pale or gray color of the lips, tongue, or palms of hands.(1,2)

PREDISPOSING FACTORS: This interaction is expected to be more severe in patients with renal and/or hepatic impairment(1,2) and in patients who receive concurrent therapy.

PATIENT MANAGEMENT: The concurrent use of a strong CYP3A4 inhibitor with colchicine is contraindicated in patients with renal or hepatic impairment.(1-3) Avoid concurrent use in other patients, if possible.(3) In patients without renal or hepatic impairment who are currently taking or have taken strong CYP3A4 inhibitors in the previous 14 days, the dosage of colchicine should be reduced. For gout flares, the recommended colchicine dosage is 0.6 mg (1 tablet) for one dose, then 0.3 mg (half tablet) 1 hour later. This dose should be repeated no earlier than in 3 days.(1,2) For gout prophylaxis, if the original colchicine dosage was 0.6 mg twice daily, use 0.3 mg daily. If the original dosage was 0.6 mg daily, use 0.3 mg every other day.(3-11) For Familial Mediterranean fever (FMF), the recommended maximum daily dose of colchicine is 0.6 mg (may be given as 0.3 mg twice a day).(1,2) Patients should be instructed to immediately report any signs of colchicine toxicity, such as muscle weakness/pain, numbness/tingling in fingers/toes, unusual bleeding or bruising, infections, weakness/tiredness, pale/gray color of the lips/tongue/palms of hands, and/or severe diarrhea/vomiting.

DISCUSSION: In a study in 21 subjects, pretreatment with azithromycin (500 mg Day 1, then 250 mg daily Days 2-5) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of colchicine (0.6 mg) by 21.6% (range -41.7% to 222%) and by 57.1% (range -24.3% to 241.1%), respectively.(1) There are several reports of colchicine toxicity(4-6) and death(7,8) following the addition of clarithromycin to therapy. In a retrospective review of 116 patients who received clarithromycin and colchicine during the same hospitalization, 10.2% (9/88) of patients who received simultaneous therapy died, compared to 3.6% (1/28) of patients who received sequential therapy.(9) An FDA review of 117 colchicine-related deaths that were not attributable to overdose found that 60 deaths (51%) involved concurrent use of clarithromycin.(2) In a study in 23 subjects, pretreatment with clarithromycin (250 mg twice daily for 7 days) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of colchicine (0.6 mg) by 227.2% (range 65.7% to 591.1%) and by 281.5% (range 88.7% to 851.6%), respectively.(1) In a study in 24 subjects, pretreatment with ketoconazole (200 mg twice daily for 5 days) increased the Cmax and AUC of a single dose of colchicine (0.6 mg) by 101.7% (range 19.6% to 219%) and by 212.2% (range 76.7% to 419.6%), respectively.(1) In a study in 18 subjects, pretreatment with ritonavir (100 mg twice daily for 5 days) increased the Cmax and AUC of a single dose of colchicine (0.6 mg) by 184.4% (range 79.2% to 447.4%) and by 296% (range 53.8% to 924.4%), respectively.(1) Colchicine toxicity has been reported with concurrent use of CYP3A4 and P-gp inhibitors such as clarithromycin, cyclosporine, diltiazem, erythromycin, and verapamil.(1,2) Strong inhibitors of CYP3A4 include: adagrasib, atazanavir, boceprevir, ceritinib, clarithromycin, cobicistat, darunavir, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, posaconazole, relacorilant, ribociclib, ritonavir, saquinavir, telaprevir, telithromycin, tipranavir, tucatinib, and voriconazole.(1,10)

Colchicine/Cyclosporine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Colchicine is metabolized and transported by CYP3A4 and P-glycoprotein (P-gp) respectively. Cyclosporine is an inhibitor of both of these pathways. Studies indicate that cyclosporine may inhibit renal secretion(4) of colchicine and decrease the hepatic secretion(5) of colchicine into the bile.

CLINICAL EFFECTS: Concurrent use of cyclosporine may result in elevated levels of and toxicity from colchicine. Symptoms of colchicine toxicity include muscle weakness or pain; numbness or tingling in the fingers or toes; myelosuppression; abdominal pain; nausea; severe diarrhea or vomiting; feeling weak or tired; increased infections; and pale or gray color of the lips, tongue, or palms of hands.(1,2) Patients with familial Mediterranean fever (FMF) may experience a higher incidence of colchicine-related gastrointestinal effects.

PREDISPOSING FACTORS: Serum colchicine levels and the risk of colchicine myopathy may be increased by renal dysfunction,(2) which may occur in renal transplant patients(3) and is common in gout.(2) This interaction is expected to be more severe in patients with renal and/or hepatic impairment(1,2) and may occur more frequently in patients with familial Mediterranean fever (FMF).

PATIENT MANAGEMENT: The concurrent use of strong P-gp inhibitors such as cyclosporine is contraindicated in patients with renal or hepatic impairment.(6,7) In patients without renal or hepatic impairment who are currently taking or have taken strong P-gp inhibitors such as cyclosporine in the previous 14 days, the dosage of colchicine should be reduced. For gout flares, the recommended dosage is 0.6 mg (1 tablet) for one dose. This dose should be repeated no earlier than in 3 days. For gout prophylaxis, if the original dosage was 0.6 mg twice daily, use 0.3 mg daily. If the original dosage was 0.6 mg daily, use 0.3 mg every other day. For Familial Mediterranean fever (FMF), the recommended maximum daily dose is 0.6 mg (may be given as 0.3 mg twice a day).(6,7) Patients should be instructed to immediately report any signs of colchicine toxicity, such as abdominal pain; significant nausea or vomiting; diarrhea; muscle weakness/pain; numbness/tingling in fingers/toes; unusual bleeding or bruising, infections, unusual weakness/tiredness, or pale/gray color of the lips/tongue/palms of hands.

DISCUSSION: In a study in 23 subjects, concurrent administration of a single dose of cyclosporine (100 mg) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of colchicine (0.6 mg) by 270% (range 62% to 606.9%) and by 259% (range 75.8% to 511.9%), respectively.(7) In a case report, a renal transplant patient's cyclosporine level increased more than 9-fold the day after the initiation of colchicine. The patient also developed renal dysfunction.(1) In another report, a renal transplant patient developed renal dysfunction and myopathy two weeks after a three-day course of colchicine.(8) In a case report, a renal transplant patient developed myopathy four weeks after the addition of colchicine to his cyclosporine regimen. Prior to his transplant, he had taken colchicine for almost five years with no adverse effects.(9) In another report, a renal transplant patient developed myopathy two weeks after the addition of colchicine to cyclosporine therapy.(10) Another report describes three cases of myopathy during concurrent cyclosporine and colchicine. The patients had taken the combination for six weeks, one year, and eight years prior to developing myopathy.(11) In a retrospective review, five of ten patients (50%) who received concurrent cyclosporine and colchicine developed myopathy. There were no differences in age, transplant duration, or serum creatinine between those patients who developed myopathy and those who did not.(12) In a study in four patients with familial Mediterranean fever (FMF) who were receiving colchicine, an attempt was made to convert azathioprine to cyclosporine. All four patients developed pronounced side effects, including diarrhea and elevated serum lactic acid; three had elevated serum alanine aminotransferase (ALT) and hyperbilirubinemia; two had elevated serum creatinines; and one was hospitalized with myopathy. No patients reached therapeutic levels of cyclosporine. The authors had previously converted three colchicine-treated FMF patients to cyclosporine.(13) Another article reported that only one of eight patients with FMF tolerated concurrent cyclosporine and colchicine following renal transplantation. Two subjects only had gastrointestinal side effects, the other five had myopathy in addition to gastrointestinal side effects.(14) In another case report, a 59 year-old male renal transplant patient maintained on cyclosporine developed rhabdomyolysis with progressive quadriparesis, hematologic toxicity, and acute renal failure following the addition of colchicine (3 mg daily for 7 days) to his regimen.(15)

Colchicine/Selected Cyp3a4 Inhibitors

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: CYP3A4 inhibitors may inhibit the metabolism of colchicine.(1-3)

CLINICAL EFFECTS: Concurrent use of CYP3A4 inhibitors may result in elevated levels of and toxicity from colchicine. Symptoms of colchicine toxicity include muscle weakness or pain; numbness or tingling in the fingers or toes; myelosuppression; abdominal pain; nausea; severe diarrhea or vomiting; feeling weak or tired; increased infections; and pale or gray color of the lips, tongue, or palms of hands.(1-3)

PREDISPOSING FACTORS: This interaction is expected to be more severe in patients with renal and/or hepatic impairment.(1-3)

PATIENT MANAGEMENT: Monitor patients receiving CYP3A4 inhibitors for signs of colchicine toxicity. Depending on the potency of CYP3A4 inhibition, the indication for colchicine, and the patient's renal and hepatic function, concurrent use may be contraindicated or may require a decreased dosage of colchicine. Refer to colchicine prescribing information for specific recommendations.(1-3) The manufacturers of gepotidacin and sevabertinib state that concurrent use of drugs that are extensively metabolized by CYP3A4 and have a narrow therapeutic window like colchicine should be avoided.(4,5) Patients should be instructed to immediately report any signs of colchicine toxicity, such as muscle weakness/pain, numbness/tingling in fingers/toes, unusual bleeding or bruising, infections, weakness/tiredness, pale/gray color of the lips/tongue/palms of hands, and/or severe diarrhea/vomiting.

DISCUSSION: In a clinical study, coadministration of single-dose midazolam 2 mg (a sensitive CYP3A4 substrate) with gepotidacin (3,000 mg every 12 hours for 2 doses) increased the area-under-curve (AUC) of midazolam by 1.9-fold.(2) Selected CYP3A4 inhibitors linked to this monograph include: camizestrant, gepotidacin, and sevabertinib.

Myelosuppressives; Immunomodulators/Sodium Iodide I 131

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Sodium iodide I 131 can cause depression of the hematopoetic system. Myelosuppressives and immunomodulators also suppress the immune system.(1)

CLINICAL EFFECTS: Concurrent use of sodium iodide I 131 with agents that cause bone marrow depression, including myelosuppressives or immunomodulators, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of sodium iodide I 131 states that concurrent use with bone marrow depressants may enhance the depression of the hematopoetic system caused by large doses of sodium iodide I 131.(1) Sodium iodide I 131 causes a dose-dependent bone marrow suppression, including neutropenia or thrombocytopenia, in the 3 to 5 weeks following administration. Patients may be at increased risk of infections or bleeding during this time. Monitor complete blood counts within one month of therapy. If results indicate leukopenia or thrombocytopenia, dosimetry should be used to determine a safe sodium iodide I 131 activity.(1)

DISCUSSION: Hematologic disorders including death have been reported with sodium iodide I 131. The most common hematologic disorders reported include anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia.(1)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Colchicine/Fibrates

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism of action is not clear. Concurrent use of colchicine and fibrates may result in additive or synergistic risk for myopathy or rhabdomyolysis.(1-2)

CLINICAL EFFECTS: Concurrent use of colchicine and fibrates have been associated with myopathy and rhabdomyolysis.(1-2)

PREDISPOSING FACTORS: This interaction is expected to be more severe in the elderly and in patients with renal impairment.(1-3)

PATIENT MANAGEMENT: The risks and benefits of colchicine should be carefully weighed in patients who are currently taking fibrates. Assure that colchicine dosage has been reduced in patients with a creatinine clearance < 30 mL/min. Patients should be monitored and instructed to report any signs or symptoms of unexpected muscle pain, tenderness or weakness.(1)

DISCUSSION: Neuromyopathy was reported in a patient maintained on bezafibrate who received colchicine for recurrent gout.(4) Rhabdomyolysis was reported in a patient following the addition of gemfibrozil to colchicine therapy. The patient had pre-existing mild renal failure, hepatitis B-related chronic liver disease, and amyloidosis, which may have contributed.(3)

Colchicine/Hmg-Coa Reductase Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Colchicine and HMG-CoA Reductase Inhibitors(statins) each have a risk for myopathy and rhabdomyolysis; these risks may be additive.(1-3)

CLINICAL EFFECTS: Concurrent use of the statin drugs and colchicine may increase the risk of myopathy or rhabdomyolysis, which is characterized by progressive muscle weakness and pain in the presence of a normal neurological exam.(1-8)

PREDISPOSING FACTORS: Long term use of colchicine, generally from weeks to months in duration of use, may predispose patients to myopathy or rhabdomyolysis.(1) The risk for myopathy or rhabdomyolysis may also be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. Patients on fluvastatin who are CYP2C9 intermediate or poor metabolizers may have increased fluvastatin concentrations and risk of myopathy. Patients on rosuvastatin with ABCG2 polymorphisms leading to decreased or poor BCRP transporter function may have increased rosuvastatin concentrations and risk of myopathy.

PATIENT MANAGEMENT: Patients receiving concurrent therapy with colchicine and HMG-CoA reductase inhibitors should be carefully monitored for myopathy or rhabdomyolysis. Patients should be instructed to report any symptoms of myopathy such as unexplained muscle aches, tenderness, weakness, or the onset of tingling/numbness in the fingers or toes.(1-6)

DISCUSSION: The development of myopathy and clinical rhabdomyolysis have been reported in several case reports with concurrent use of colchicine and atorvastatin,(4) fluvastatin,(5) pravastatin,(6) simvastatin(7,8), and rosuvastatin.(2) The incidence and frequency appear to increase in patients with mild to moderate renal insufficiency and length of colchicine therapy.

Colchicine/Tacrolimus

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Tacrolimus may inhibit the metabolism of colchicine through inhibition of CYP3A4 metabolism.

CLINICAL EFFECTS: Concurrent use of tacrolimus, a CYP3A4 inhibitor, may result in elevated levels of and toxicity from colchicine. Approximately 80% of colchicine is metabolized by CYP3A4. Symptoms of colchicine toxicity include abdominal pain; nausea or vomiting; severe diarrhea; muscle weakness or pain; numbness or tingling in the fingers or toes; myelosuppression; feeling weak or tired; increased infections; and pale or gray color of the lips, tongue, or palms of hands.(1-3)

PREDISPOSING FACTORS: This interaction is expected to be more severe in patients with renal and/or hepatic impairment(1,2) and in patients who receive concurrent therapy.

PATIENT MANAGEMENT: The concurrent use of colchicine and tacrolimus should be approached with caution.(3) When concurrent therapy is required, consider following the manufacturer recommendations for dose adjustments. In patients without renal or hepatic impairment who are currently taking or have taken strong CYP3A4 inhibitors in the previous 14 days, the dosage of colchicine should be reduced. For gout flares, the recommended dosage is 0.6 mg (1 tablet) for one dose, then 0.3 mg (half tablet) 1 hour later. This dose should be repeated no earlier than in 3 days. For gout prophylaxis, if the original dosage was 0.6 mg twice daily, use 0.3 mg daily. If the original dosage was 0.6 mg daily, use 0.3 mg every other day. For Familial Mediterranean fever (FMF), the recommended maximum daily dose is 0.6 mg (may be given as 0.3 mg twice a day).(1,2) Patients should be instructed to immediately report any signs of colchicine toxicity, such as abdominal pain, nausea, severe diarrhea/vomiting; muscle weakness/pain; numbness/tingling in fingers/toes; unusual bleeding or bruising, infections, weakness/tiredness, or pale/gray color of the lips/tongue/palms of hands.

DISCUSSION: In a study of 21 patients, treatment with tacrolimus (minimum 4-maximum 10 mg/daily; trough levels minimum 5-maximum 8 ng/ml) in 6 of the kidney transplant recipients increased the maximum concentration (Cmax) 4-fold and area-under-curve (AUC) 3-fold after a single dose of colchicine (1 mg) than those patients with normal renal function.(3) A case report of colchicine-induced myopathy describes a 62-year-old patient on stable tacrolimus therapy for renal transplant immunosuppression who was started on colchicine (0.6 mg twice daily). A few days after initiation of colchicine, the patient reported myopathy and labs showed a 4-fold increase in aspartate aminotransferase and elevated creatine phosphokinase.(4)

Contraindications with the 0.6 mg Tablets

*Patients with hepatic or renal impairment who are receiving strong cytochrome P-450 (CYP) 3A4 (including all protease inhibitors except fosamprenavir) or P-glycoprotein inhibitors; fatal or life-threatening colchicine toxicity has occurred in such patients.

Contraindications with the 0.5 mg Tablets

*Concurrent use of strong CYP3A4 or P-glycoprotein inhibitors, including in patients with hepatic or renal impairment; fatal or life-threatening colchicine toxicity has occurred in such patients.

*Renal failure (creatinine clearance <15 mL/minute).

*Severe hepatic impairment.

*Pre-existing blood dyscrasias.

*Hypersensitivity to the medication or any inactive ingredient.

Contraindications with the Capsules

*Patients with hepatic or renal impairment who are receiving colchicine with concomitant use of CYP3A4 and P-glycoprotein inhibitors; fatal or life-threatening colchicine toxicity has occurred in such patients.

*Both hepatic and renal impairment.

Contraindications with the Oral Solution

*Oral solution: Patients with hepatic or renal impairment who are receiving colchicine with concomitant use of CYP3A4 and P-glycoprotein inhibitors; fatal or life-threatening colchicine toxicity has occurred in such patients.

*Both hepatic and renal impairment.

• Hemolytic anemia from pyruvate kinase and g6PD deficiencies

• Aplastic anemia
• Child-pugh class C hepatic impairment
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Disease of liver
• Renal dialysis

• Bone marrow depression
• Granulocytopenic disorder
• Kidney disease with likely reduction in glomerular filtration rate (GFr)
• Leukopenia
• Myopathy
• Rhabdomyolysis
• Thrombocytopenic disorder

The most common adverse effects of colchicine are GI symptoms (nausea, abdominal discomfort/pain, vomiting, and/or diarrhea) and myalgia. Pharyngolaryngeal pain has also commonly been reported with treatment of gout flares with colchicine.

Rare or Very Rare

• Agranulocytosis
• Allergic dermatitis
• Angioedema
• Aplastic anemia
• Bone marrow depression
• Disseminated intravascular coagulation
• Increased alanine transaminase
• Increased aspartate transaminase
• Leukopenia
• Myopathy
• Pancytopenia
• Peripheral motor neuropathy
• Purpura
• Rhabdomyolysis
• Skin rash
• Thrombocytopenic disorder
• Urticaria

More Frequent

• Abdominal pain with cramps
• Diarrhea
• Nausea
• Sore throat
• Vomiting

Less Frequent

• Abnormal hepatic function tests
• Headache disorder
• Increased creatine kinase level
• Muscle weakness
• Myalgia

Rare or Very Rare

• Alopecia
• Azoospermia
• Maculopapular rash
• Oligospermia
• Peripheral sensory neuropathy

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Safety and efficacy of colchicine in children with gout have not been established as gout is rare in pediatric patients.

Safety and efficacy of colchicine 0.6 mg tablets for the management of FMF in children have been evaluated in uncontrolled studies. Long-term use of colchicine did not appear to affect growth in children with FMF.

Safety and efficacy of colchicine 0.5 mg tablets in children have not been established.

Available human data from published literature on the use of colchicine during pregnancy over several decades have not identified any risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes. Colchicine crosses the placenta in humans. Colchicine has been shown in published animal reproduction and development studies to cause embryofetal toxicity, teratogenic effects, and altered postnatal development at exposure levels within or above the therapeutic range. The effect of colchicine on labor and delivery is not known.

Colchicine should be used during pregnancy only if the potential benefits to the patient outweigh the risks to the fetus. Advise females of child bearing potential to contact their clinician if they become pregnant while taking colchicine.

Colchicine is distributed into human milk. No adverse events in breastfed infants have been reported following administration of colchicine to lactating females. However, colchicine may affect GI cell turnover and function, leading to GI or other unknown adverse effects. There are no data on the effects of colchicine on milk production.

The manufacturer of colchicine oral solution states that use is safe during breastfeeding. Consider the developmental and health benefits of breastfeeding along with the mother's clinical need for colchicine and any potential adverse effects on the breastfed child from the medication or underlying maternal condition.

Capsule: Dosage reduction of colchicine should be considered because of the greater frequency of decreased renal function and of concomitant disease and medication therapy observed in geriatric patients.

Oral solution: Dosage selection should be cautious in geriatric patients; the greater frequency of decreased renal function and of concomitant disease and drug therapy observed in geriatric patients also should be considered.

Tablet (0.5 mg): The manufacturer makes no specific dosage recommendations for geriatric patients. Since geriatric patients are more likely to have decreased renal function, it may be useful to monitor renal function in these patients.

Tablet (0.6 mg): Dosage selection should be cautious in geriatric patients; the greater frequency of decreased renal function and of concomitant disease and drug therapy observed in geriatric patients also should be considered.

Clinical studies of colchicine 0.6 mg tablets and the oral solution did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients.

In the principal efficacy study evaluating colchicine 0.5 mg tablets, 56.1% of patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between geriatric and younger patients. Other reported clinical experience has not identified differences in responses between geriatric and younger patients; however, greater sensitivity of some older individuals cannot be excluded. It may be useful to monitor renal function.

Dosage selection should be cautious in geriatric patients with gout; the greater frequency of decreased renal function and of concomitant disease and medication therapy observed in geriatric patients also should be considered.