Mitigare

Drug overview for MITIGARE (colchicine):

Generic name: COLCHICINE (KOL-chi-seen)
Drug class: Hyperuricemia Agents (antimitotic)
Therapeutic class: Gout and Hyperuricemia Therapy

Colchicine is an antigout and antimitotic agent.

No enhanced Uses information available for this drug.

DRUG IMAGES

MITIGARE 0.6 MG CAPSULE

The following indications for MITIGARE (colchicine) have been approved by the FDA:

Indications:
Prevention of acute gout attack

Professional Synonyms:
Acute gout attack prophylaxis
Prevention of acute gout flare

The following dosing information is available for MITIGARE (colchicine):

Dosing
Administration
MITIGARE
COLCHICINE

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

Use of colchicine in combination with a potent CYP3A4 inhibitor, such as atazanavir, boceprevir, clarithromycin, ritonavir-boosted darunavir, ritonavir-boosted fosamprenavir, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telaprevir, telithromycin, ritonavir-boosted tipranavir, lopinavir/ritonavir, or the fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir, or with a P-glycoprotein inhibitor, such as cyclosporine or ranolazine, in patients with renal impairment is contraindicated.

Use of colchicine in combination with a potent CYP3A4 inhibitor, such as atazanavir, boceprevir, clarithromycin, ritonavir-boosted darunavir, ritonavir-boosted fosamprenavir, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telaprevir, telithromycin, ritonavir-boosted tipranavir, lopinavir/ritonavir, the fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir, or with a P-glycoprotein inhibitor, such as cyclosporine or ranolazine, in patients with hepatic impairment is contraindicated.

Colchicine is administered orally without regard to meals. Colchicine has been administered by IV injection; however, IV preparations of colchicine have been withdrawn from the US market because of safety concerns. (See Uses: Regulatory Actions Affecting Colchicine and see Cautions.) Patients receiving colchicine should be instructed on how to resume therapy in the event of a missed dose.

Patients with gout who are receiving colchicine 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 the drug to treat an acute gout flare during colchicine prophylaxis should be instructed to take the missed dose immediately and then wait 12 hours before resuming the previous dosing schedule. Patients receiving colchicine for treatment of familial Mediterranean fever 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, but not to take a double dose to make up for the missed dose.

Dosing information for MITIGARE
DRUG LABEL	DOSING TYPE	DOSING INSTRUCTIONS
MITIGARE 0.6 MG CAPSULE	Maintenance	Adults take 1 capsule (0.6 mg) by oral route once daily

Generic dosing information for COLCHICINE
DRUG LABEL	DOSING TYPE	DOSING INSTRUCTIONS
COLCHICINE 0.6 MG CAPSULE	Maintenance	Adults take 1 capsule (0.6 mg) by oral route once daily

The following drug interaction information is available for MITIGARE (colchicine):

Contraindicated
Severe
Moderate

There are 0 contraindications.

There are 6 severe interactions. These drug interactions can produce serious consequences in most patients. Actions required for severe interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration scheduling, and providing additional patient monitoring. Review the full interaction monograph for more information.

Drug Interaction	Drug Names
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)	CYCLOSPORINE, CYCLOSPORINE MODIFIED, GENGRAF, NEORAL, SANDIMMUNE
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, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, posaconazole, ribociclib, ritonavir, saquinavir, telaprevir, telithromycin, tipranavir, tucatinib, and voriconazole.(1,10)	APTIVUS, ATAZANAVIR SULFATE, CLARITHROMYCIN, CLARITHROMYCIN ER, DARUNAVIR, EVOTAZ, GENVOYA, ITRACONAZOLE, ITRACONAZOLE MICRONIZED, KALETRA, KETOCONAZOLE, KISQALI, KORLYM, KRAZATI, LANSOPRAZOL-AMOXICIL-CLARITHRO, LOPINAVIR-RITONAVIR, MIFEPREX, MIFEPRISTONE, NEFAZODONE HCL, NORVIR, NOXAFIL, OMECLAMOX-PAK, PAXLOVID, POSACONAZOLE, PREZCOBIX, PREZISTA, RECORLEV, REYATAZ, RITONAVIR, SPORANOX, STRIBILD, SYMTUZA, TOLSURA, TUKYSA, TYBOST, VFEND, VFEND IV, VIRACEPT, VOQUEZNA TRIPLE PAK, VORICONAZOLE, ZOKINVY, ZYDELIG, ZYKADIA
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, and treosulfan.(1,5,6)	AKYNZEO, APONVIE, APREPITANT, CINVANTI, CLOFAZIMINE, CONIVAPTAN-D5W, COPIKTRA, CRESEMBA, DANZITEN, DIFLUCAN, EMEND, FLUCONAZOLE, FLUCONAZOLE-NACL, FOSAMPRENAVIR CALCIUM, GLEEVEC, GRAFAPEX, IMATINIB MESYLATE, IMKELDI, INREBIC, NILOTINIB HCL, PREVYMIS, SUNLENCA, TASIGNA, TAVNEOS, VAPRISOL-5% DEXTROSE, XALKORI
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. 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, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine, danicopan, daridorexant, diltiazem, diosmin, dronedarone, erythromycin, flibanserin, fluvoxamine, fostamatinib, glecaprevir/pibrentasvir, lapatinib, ledipasvir, mavorixafor, neratinib, osimertinib, pirtobrutinib, propafenone, quinidine, ranolazine, schisandra, selpercatinib, sotorasib, tepotinib, tezacaftor, valbenazine, velpatasvir, vemurafenib, verapamil, vimseltinib, and voclosporin.(1,11,12)	ADDYI, ALYFTREK, AMIODARONE HCL, AMIODARONE HCL-D5W, ASPRUZYO SPRINKLE, AZITHROMYCIN, CARDIZEM, CARDIZEM CD, CARDIZEM LA, CARTIA XT, CARVEDILOL, CARVEDILOL ER, CIBINQO, CIMETIDINE, COREG, COREG CR, DILT-XR, DILTIAZEM 12HR ER, DILTIAZEM 24HR ER, DILTIAZEM 24HR ER (CD), DILTIAZEM 24HR ER (LA), DILTIAZEM 24HR ER (XR), DILTIAZEM HCL, DILTIAZEM HCL-0.7% NACL, DILTIAZEM HCL-0.9% NACL, DILTIAZEM HCL-NACL, DILTIAZEM-D5W, E.E.S. 200, E.E.S. 400, EPCLUSA, ERY-TAB, ERYPED 200, ERYPED 400, ERYTHROCIN LACTOBIONATE, ERYTHROCIN STEARATE, ERYTHROMYCIN, ERYTHROMYCIN ESTOLATE, ERYTHROMYCIN ETHYLSUCCINATE, ERYTHROMYCIN LACTOBIONATE, FLIBANSERIN, FLUVOXAMINE MALEATE, FLUVOXAMINE MALEATE ER, HARVONI, INGREZZA, INGREZZA INITIATION PK(TARDIV), INGREZZA SPRINKLE, JAYPIRCA, LAPATINIB, LEDIPASVIR-SOFOSBUVIR, LUMAKRAS, LUPKYNIS, MATZIM LA, MAVYRET, MULTAQ, NERLYNX, NEXTERONE, NUEDEXTA, PACERONE, PROPAFENONE HCL, PROPAFENONE HCL ER, QUINIDINE GLUCONATE, QUINIDINE SULFATE, QUVIVIQ, RANOLAZINE ER, RETEVMO, REZUROCK, ROMVIMZA, SCEMBLIX, SOFOSBUVIR-VELPATASVIR, SYMDEKO, TABRECTA, TAGRISSO, TAVALISSE, TEPMETKO, TIADYLT ER, TIAZAC, TRANDOLAPRIL-VERAPAMIL ER, TRIKAFTA, TYKERB, VERAPAMIL ER, VERAPAMIL ER PM, VERAPAMIL HCL, VERAPAMIL SR, VOSEVI, VOYDEYA, XOLREMDI, ZELBORAF, ZITHROMAX, ZITHROMAX TRI-PAK
Sodium Iodide I 131/Myelosuppressives; Immunomodulators 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)	HICON, SODIUM IODIDE I-131
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)	RIFADIN, RIFAMPIN

There are 3 moderate interactions. The clinician should assess the patient’s characteristics and take action as needed. Actions required for moderate interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration.

Drug Interaction	Drug Names
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.	ALTOPREV, AMLODIPINE-ATORVASTATIN, ATORVALIQ, ATORVASTATIN CALCIUM, CADUET, CRESTOR, EZALLOR SPRINKLE, EZETIMIBE-SIMVASTATIN, FLOLIPID, FLUVASTATIN ER, FLUVASTATIN SODIUM, LESCOL XL, LIPITOR, LIVALO, LOVASTATIN, PITAVASTATIN CALCIUM, PRAVASTATIN SODIUM, ROSUVASTATIN CALCIUM, ROSUVASTATIN-EZETIMIBE, ROSZET, SIMVASTATIN, VYTORIN, ZOCOR, ZYPITAMAG
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)	FENOFIBRATE, FENOFIBRIC ACID, FIBRICOR, GEMFIBROZIL, LIPOFEN, LOPID, TRICOR, TRILIPIX
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)	ASTAGRAF XL, ENVARSUS XR, PROGRAF, TACROLIMUS, TACROLIMUS XL

The following contraindication information is available for MITIGARE (colchicine):

Overview
Contraindicated
Severe
Moderate

Drug contraindication overview.

No enhanced Contraindications information available for this drug.

There are 1 contraindications. Absolute contraindication.

Contraindication List
Hemolytic anemia from pyruvate kinase and g6PD deficiencies

There are 6 severe contraindications. Adequate patient monitoring is recommended for safer drug use.

Severe List
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

There are 7 moderate contraindications. Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.

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

The following adverse reaction information is available for MITIGARE (colchicine):

Overview
Severe
Less Severe

Adverse reaction overview.

No enhanced Common Adverse Effects information available for this drug.

There are 17 severe adverse reactions.

More Frequent	Less Frequent
None.	None.

Rare/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

There are 15 less severe adverse reactions.

More Frequent	Less Frequent
Abdominal pain with cramps Diarrhea Nausea Sore throat Vomiting	Abnormal hepatic function tests Headache disorder Increased creatine kinase level Muscle weakness Myalgia

Rare/Very Rare
Alopecia Azoospermia Maculopapular rash Oligospermia Peripheral sensory neuropathy

The following precautions are available for MITIGARE (colchicine):

Pediatric
Pregnant
Lactation
Geriatric

No enhanced Pediatric Use information available for this drug.

Contraindicated

None

Severe Precaution

None

Management or Monitoring Precaution

None

Chromosomal aberrations have been reported in a limited number of patients receiving prolonged colchicine therapy. Colchicine crosses the placenta in humans and has been shown in animal reproduction and development studies to cause embryofetal toxicity, teratogenic effects, and altered postnatal development at exposure levels within or above the therapeutic range. Although there are no adequate and controlled studies to date in humans, results of one study suggest that patients receiving prolonged colchicine therapy may have a greater risk of producing trisomic offspring if conception occurs during therapy with the drug.

Other clinicians, however, contend that this study is inconclusive and at most merely suggestive of a probable increased risk to the offspring. Data from a limited number of published studies indicate that use of colchicine for the treatment of familial Mediterranean fever in pregnant women was not associated with increased risk of miscarriage, stillbirth, or teratogenic effects. Colchicine should be used during pregnancy only if the potential benefits outweigh the risks. The effect of colchicine on labor and delivery is not known.

Colchicine is distributed into milk. (See Pharmacokinetics: Distribution.) Limited information suggests that exclusively breast-fed infants receive less than 10% of the maternal weight-adjusted dose. Although the drug can affect GI cell renewal and permeability, some experts state that the actual amounts of the drug distributed into breast milk are not high enough to warrant cessation of nursing.

No adverse effects have been reported to date in breast-fed infants of women receiving colchicine therapy who were observed over periods of up to 10 months. The American Academy of Pediatrics (AAP) states that the drug usually is compatible with breast-feeding. Some clinicians have suggested that exposure of the infant to the drug could be minimized by waiting 8-12 hours after a dose to breast-feed the infant. The manufacturer states that caution is advised; the infant should be observed for adverse effects.

No enhanced Geriatric Use information available for this drug.

The following icd codes are available for MITIGARE (colchicine)'s list of indications:

Prevention of acute gout attack
E79.0	Hyperuricemia without signs of inflammatory arthritis and tophaceous disease
M10	Gout
M10.00	Idiopathic gout, unspecified site
M10.30	Gout due to renal impairment, unspecified site
M10.40	Other secondary gout, unspecified site
M10.9	Gout, unspecified
M1A.00x1	Idiopathic chronic gout, unspecified site, with tophus (tophi)
M1A.20x1	Drug-induced chronic gout, unspecified site, with tophus (tophi)
M1A.30x1	Chronic gout due to renal impairment, unspecified site, with tophus (tophi)
M1A.40x1	Other secondary chronic gout, unspecified site, with tophus (tophi)
M1A.9xx0	Chronic gout, unspecified, without tophus (tophi)
M1A.9xx1	Chronic gout, unspecified, with tophus (tophi)