tions concomitant drug class or food noted or anticipated outcome clinical comment hmg-co a reductase inhibitors: atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin pharmacokinetic and/or pharmacodynamic interaction: the addition of one drug to a stable long-term regimen of the other has resulted in myopathy and rhabdomyolysis (including a fatality) weigh the potential benefits and risks and carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy; monitoring cpk (creatine phosphokinase) will not necessarily prevent the occurrence of severe myopathy. other lipid-lowering drugs: fibrates, gemfibrozil digitalis glycosides: digoxin p-gp substrate; rhabdomyolysis has been reported co-administration of p-gp and/or cyp3a4 inhibitors (e.g., clarithromycin or cyclosporine) have been demonstrated to alter the concentration of colchicine. the potential for drug-drug interactions must be considered prior to and during therapy. see fpi for a complete list of reported and potential interactions ( 2.4 , 5.3 , 7 ).

colchicine [ see overdosage (10)]. colchicine should be kept out of the reach of children. 5.2 blood dyscrasias myelosuppression, leukopenia, granulocytopenia, thrombocytopenia, pancytopenia and aplastic anemia have been reported with colchicine used in therapeutic doses. 5.3 drug interactions colchicine is a p-gp and cyp3a4 substrate. life-threatening and fatal drug interactions have been reported in patients treated with colchicine given with p-gp and strong cyp3a4 inhibitors. if treatment with a p-gp or strong cyp3a4 inhibitor is required in patients with normal renal and hepatic function, the patient’s dose of colchicine may need to be reduced or interrupted [see drug interactions (7)] . use of colchicine in conjunction with p-gp or strong cyp3a4 inhibitors (this includes all protease inhibitors except fosamprenavir) is contraindicated in patients with renal or hepatic impairment [ see contraindications (4)]. 5.4 neuromuscular toxicity colchicine-induced neuromuscular toxicity and rhabdomyolysis have been reported with chronic treatment in therapeutic doses. patients with renal dysfunction and elderly patients, even those with normal renal and hepatic function, are at increased risk. concomitant use of atorvastatin, simvastatin, pravastatin, fluvastatin, lovastatin, gemfibrozil, fenofibrate, fenofibric acid or benzafibrate (themselves associated with myotoxicity) or cyclosporine with colchicine may potentiate the development of myopathy [ see drug interactions (7)]. once colchicine is stopped, the symptoms generally resolve within one week to several months.

ion (2.5), impaired hepatic function ( 2.6 ), the patient's age ( 2.3 , 8.5 ) or use of co-administered drugs ( 2.4 ). 2.2 fmf the recommended dosage of colchicine tablets for fmf in adults is 1.2 mg to 2.4 mg daily. colchicine tablets should be increased as needed to control disease and as tolerated in increments of 0.3 mg/day to a maximum recommended daily dose. if intolerable side effects develop, the dose should be decreased in increments of 0.3 mg/day. the total daily colchicine tablets dose may be administered in one to two divided doses. 2.3 recommended pediatric dosage fmf the recommended dosage of colchicine tablets for fmf in pediatric patients 4 years of age and older is based on age. the following daily doses may be given as a single or divided dose twice daily: • children 4 to 6 years: 0.3 mg to 1.8 mg daily • children 6 to 12 years: 0.9 mg to 1.8 mg daily • adolescents older than 12 years: 1.2 mg to 2.4 mg daily 2.4 dose modification for co-administration of interacting drugs concomitant therapy co-administration of colchicine tablets with drugs known to inhibit cyp3a4 and/or p-glycoprotein (p-gp) increases the risk of colchicine-induced toxic effects ( table 1 ). if patients are taking or have recently completed treatment with drugs listed in table 1 within the prior 14 days, the dose adjustments are as shown in the table below [see drug interactions ( 7 )]. table 1. colchicine tablets dose adjustment for co-administration with interacting drugs if no alternative available * strong cyp3a4 inhibitors † drug noted or anticipated outcome fmf original intended dosage adjusted dose atazanavir clarithromycin darunavir/ ritonavir ‡ indinavir itraconazole ketoconazole lopinavir/ ritonavir ‡ nefazodone nelfinavir ritonavir saquinavir telithromycin tipranavir/ ritonavir ‡ significant increase in colchicine plasma levels*; fatal colchicine toxicity has been reported with clarithromycin, a strong cyp3a4 inhibitor. similarly, significant increase in colchicine plasma levels is anticipated with other strong cyp3a4 inhibitors. maximum daily dose of 1.2 to 2.4 mg maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day) moderate cyp3a4 inhibitors drug noted or anticipated outcome fmf original intended dosage adjusted dose amprenavir ‡ aprepitant diltiazem erythromycin fluconazole fosamprenavir ‡ (prodrug of amprenavir) grapefruit juice verapamil significant increase in colchicine plasma concentration is anticipated. neuromuscular toxicity has been reported with diltiazem and verapamil interactions. maximum daily dose of 1.2 to 2.4 mg maximum daily dose of 1.2 mg (may be given as 0.6 mg twice a day) p-gp inhibitors † drug noted or anticipated outcome fmf original intended dosage adjusted dose cyclosporine ranolazine significant increase in colchicine plasma levels * ; fatal colchicine toxicity has been reported with cyclosporine, a p-gp inhibitor. similarly, significant increase in colchicine plasma levels is anticipated with other p-gp inhibitors. maximum daily dose of 1.2 to 2.4 mg maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day) * for magnitude of effect on colchicine plasma concentrations [see clinical pharmacology ( 12.3 )] † patients with renal or hepatic impairment should not be given colchicine tablets in conjunction with strong cyp3a4 or p-gp inhibitors [see contraindications ( 4 )] ‡ when used in combination with ritonavir, see dosing recommendations for strong cyp3a4 inhibitors [see contraindications ( 4 )] table 2. colchicine tablets dose adjustment for co-administration with protease inhibitors protease inhibitor clinical comment w/colchicine - treatment of fmf atazanavir sulfate (reyataz) patients with renal or hepatic impairment should not be given colchicine with reyataz. maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day) darunavir (prezista) patients with renal or hepatic impairment should not be given colchicine with prezista/ ritonavir. maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day) fosamprenavir (lexiva) with ritonavir patients with renal or hepatic impairment should not be given colchicine with lexiva/ritonavir maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day) fosamprenavir (lexiva) patients with renal or hepatic impairment should not be given colchicine with lexiva/ritonavir. maximum daily dose of 1.2 mg (may be given as 0.6 mg twice a day) indinavir (crixivan) patients with renal or hepatic impairment should not be given colchicine with crixivan. maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day) lopinavir/ ritonavir (kaletra) patients with renal or hepatic impairment should not be given colchicine with kaletra maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day) nelfinavir mesylate (viracept) patients with renal or hepatic impairment should not be given colchicine with viracept. maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day) ritonavir (norvir) patients with renal or hepatic impairment should not be given colchicine with norvir. maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day) saquinavir mesylate (invirase) patients with renal or hepatic impairment should not be given colchicine with invirase/ ritonavir. maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day) tipranavir (aptivus) patients with renal or hepatic impairment should not be given colchicine with aptivus/ ritonavir. maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). 2.5 dose modification in renal impairment colchicine dosing must be individualized according to the patient's renal function [see use in specific populations (8.6)]. cl cr in ml/minute may be estimated from serum creatinine (mg/dl) determination using the following formula: fmf caution should be taken in dosing patients with moderate and severe renal impairment and in patients undergoing dialysis. for these patients, the dosage should be reduced [ see clinical pharmacology (12.3)]. patients with mild (cl cr 50 to 80 ml/min) and moderate (cl cr 30 to 50 ml/min) renal impairment should be monitored closely for adverse effects of colchicine tablets. dose reduction may be necessary. for patients with severe renal failure (cl cr less than 30 ml/min), start with 0.3 mg/day; any increase in dose should be done with adequate monitoring of the patient for adverse effects of colchicine [ see use in specific populations ( 8.6 )]. for patients undergoing dialysis, the total recommended starting dose should be 0.3 mg (half tablet) per day. dosing can be increased with close monitoring. any increase in dose should be done with adequate monitoring of the patient for adverse effects of colchicine [ see clinical pharmacology (12.3) , use in specific populations (8.6)]. formula-jpg 2.6 dose modification in hepatic impairment fmf patients with mild to moderate hepatic impairment should be monitored closely for adverse effects of colchicine. dose reduction should be considered in patients with severe hepatic impairment [see use in specific populations ( 8.7 )].

se most often occur with excessive accumulation or overdosage [ see overdosage (10)]. the following adverse reactions have been identified with colchicine. these have been generally reversible upon temporarily interrupting treatment or lowering the dose of colchicine. because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. neurological: sensory motor neuropathy dermatological: alopecia, maculopapular rash, purpura, rash digestive: abdominal cramping, abdominal pain, diarrhea, lactose intolerance, nausea, vomiting hematological: leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, aplastic anemia hepatobiliary: elevated ast, elevated alt musculoskeletal: myopathy, elevated cpk, myotonia, muscle weakness, muscle pain, rhabdomyolysis reproductive : azoospermia, oligospermia

tions concomitant drug class or food noted or anticipated outcome clinical comment hmg-co a reductase inhibitors: atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin pharmacokinetic and/or pharmacodynamic interaction: the addition of one drug to a stable long-term regimen of the other has resulted in myopathy and rhabdomyolysis (including a fatality) weigh the potential benefits and risks and carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy; monitoring cpk (creatine phosphokinase) will not necessarily prevent the occurrence of severe myopathy. other lipid-lowering drugs: fibrates, gemfibrozil digitalis glycosides: digoxin p-gp substrate; rhabdomyolysis has been reported co-administration of p-gp and/or cyp3a4 inhibitors (e.g., clarithromycin or cyclosporine) have been demonstrated to alter the concentration of colchicine. the potential for drug-drug interactions must be considered prior to and during therapy. see fpi for a complete list of reported and potential interactions ( 2.4 , 5.3 , 7 ).

s for major birth defects, miscarriage, or adverse maternal or fetal outcomes (see data). colchicine crosses the human placenta. although animal reproductive and developmental studies were not conducted with colchicine, published animal reproduction and development studies indicate that colchicine causes embryofetal toxicity, teratogenicity and altered postnatal development at exposures within or above the clinical therapeutic range. the estimated background risk of major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. data human data available data from published observational studies, case series, and case reports over several decades do not suggest an increased risk for major birth defects or miscarriage in pregnant women with rheumatic diseases (such as rheumatoid arthritis, behcet’s disease, or familial mediterranean fever (fmf) treated with colchicine at therapeutic doses during pregnancy. limitations of these data include the lack of randomization and inability to control for confounders such as underlying maternal disease and maternal use of concomitant medications. 8.2 lactation risk summary colchicine is present in human milk (see data) . adverse events in breastfed infants have not been reported in the published literature after administration of colchicine to lactating women. there are no data on the effects of colchicine on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for colchicine and any potential adverse effects on the breastfed child from colchicine or from the underlying maternal condition. data limited published data from case reports and a small lactation study demonstrate that colchicine is present in breastmilk. a systematic review of literature reported no adverse effects in 149 breastfed children. in a prospective observational cohort study, no gastrointestinal or other symptoms were reported in 38 colchicine-exposed breastfed infants. 8.3 females and males of reproductive potential infertility case reports and epidemiology studies in human male subjects on colchicine therapy indicated that infertility from colchicine is rare and may be reversible. a case report indicated that azoospermia was reversed when therapy was stopped. case reports and epidemiology studies in female subjects on colchicine therapy have not established a clear relationship between colchicine use and female infertility. however, since the progression of fmf without treatment may result in infertility, the use of colchicine needs to be weighed against the potential risks [see nonclinical toxicology ( 13.1 )]. 8.4 pediatric use the safety and efficacy of colchicine in children of all ages with fmf has been evaluated in uncontrolled studies. there does not appear to be an adverse effect on growth in children with fmf treated long-term with colchicine. 8.5 geriatric use clinical studies with colchicine for treatment of fmf did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. in general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased renal function, concomitant disease or other drug therapy [see dosage and administration (2.4), clinical pharmacology ( 12.3 ) . 8.6 renal impairment colchicine is significantly excreted in urine in healthy subjects. clearance of colchicine is decreased in patients with impaired renal function. total body clearance of colchicine was reduced by 75% in patients with end-stage renal disease undergoing dialysis. fmf although, pharmacokinetics of colchicine in patients with mild (clcr 50 to 80 ml/min) and moderate (clcr 30 to 50 ml/min) renal impairment is not known, these patients should be monitored closely for adverse effects of colchicine. dose reduction may be necessary. in patients with severe renal failure (clcr less than 30 ml/min) and end-stage renal disease requiring dialysis, colchicine may be started at the dose of 0.3 mg/day. any increase in dose should be done with adequate monitoring of the patient for adverse effects of colchicine [see clinical pharmacology (12.3) , dosage and administration (2.5)]. 8.7 hepatic impairment the clearance of colchicine may be significantly reduced and plasma half-life prolonged in patients with chronic hepatic impairment compared to healthy subjects [see clinical pharmacology (12.3]. fmf in patients with severe hepatic disease, dose reduction should be considered with careful monitoring [see clinical pharmacology ( 12.3 ), dosage and administration (2.6)].

able data from published observational studies, case series, and case reports over several decades do not suggest an increased risk for major birth defects or miscarriage in pregnant women with rheumatic diseases (such as rheumatoid arthritis, behcet’s disease, or familial mediterranean fever (fmf) treated with colchicine at therapeutic doses during pregnancy. limitations of these data include the lack of randomization and inability to control for confounders such as underlying maternal disease and maternal use of concomitant medications.

y absorbed, reaching mean maximum plasma concentrations of 6.2 ng/ml at a median 1.81 hours (range: 1 to 2.5 hours). following administration of the nonrecommended high-dose regimen (4.8 mg over six hours), mean maximal plasma concentrations were 6.8 ng/ml, at a median 4.47 hours (range: 3.1 to 7.5 hours). after ten days on a regimen of 0.6 mg twice daily, peak concentrations are 3.1 to 3.6 ng/ml (range 1.6 to 6 ng/ml), occurring 1.3 to 1.4 hours postdose (range 0.5 to 3 hours). mean pharmacokinetic parameter values in healthy adults are shown in table 5. table 5. mean (%cv) pharmacokinetic parameters in healthy adults given colchicine c max (colchicine ng/ml) t max* (h) vd/f (l) cl/f (l/hr) t 1/2 (h) colchicine 0.6 mg single dose (n=13) 2.5 (28.7) 1.5 (1 to 3) 341.5 (54.4) 54.1 (31) - colchicine 0.6 mg twice daily x 10 days (n=13) 3.6 (23.7) 1.3 (0.5 to 3) 1150 (18.7) 30.3 (19) 26.6 (16.3) * t max mean (range) cl = dose/auc 0-t (calculated from mean values) vd = cl/ke (calculated from mean values) in some subjects, secondary colchicine peaks are seen, occurring between three and 36 hours postdose and ranging from 39 to 155% of the height of the initial peak. these observations are attributed to intestinal secretion and reabsorption and/or biliary recirculation. absolute bioavailability is reported to be approximately 45%. administration of colchicine with food has no effect on the rate of colchicine absorption but does decrease the extent of colchicine by approximately 15%. this is without clinical significance. distribution the mean apparent volume of distribution in healthy young volunteers is approximately 5 to 8 l/kg. colchicine binding to serum protein is low, 39 ± 5%, primarily to albumin regardless of concentration. colchicine crosses the placenta (plasma levels in the fetus are reported to be approximately 15% of the maternal concentration). colchicine also distributes into breast milk at concentrations similar to those found in the maternal serum [see use in specific populations ( 8.1 , 8.2 )]. metabolism colchicine is demethylated to two primary metabolites, 2-o-demethylcolchicine and 3-o-demethylcolchicine (2- and 3-dmc, respectively) and one minor metabolite, 10-o-demethylcolchicine (also known as colchiceine). in vitro studies using human liver microsomes have shown that cyp3a4 is involved in the metabolism of colchicine to 2-and 3-dmc. plasma levels of these metabolites are minimal (less than 5% of parent drug). elimination/excretion in healthy volunteers (n=12), 40 to 65% of 1 mg orally administered colchicine was recovered unchanged in urine. enterohepatic recirculation and biliary excretion are also postulated to play a role in colchicine elimination. following multiple oral doses (0.6 mg twice daily), the mean elimination half-lives in young healthy volunteers (mean age 25 to 28 years of age) is 26.6 to 31.2 hours. colchicine is a substrate of p-gp. extracorporeal elimination colchicine is not removed by hemodialysis. special populations there is no difference between men and women in the pharmacokinetic disposition of colchicine. pediatric patients: pharmacokinetics of colchicine was not evaluated in pediatric patients. elderly a published report described the pharmacokinetics of 1 mg oral colchicine tablet in four elderly women compared to six young healthy males. the mean age of the four elderly women was 83 years (range 75 to 93), mean weight was 47 kg (38 to 61 kg) and mean creatinine clearance was 46 ml/min (range 25 to 75 ml/min). mean peak plasma levels and auc of colchicine were two times higher in elderly subjects compared to young healthy males. a pharmacokinetic study using a single oral dose of one 0.6 mg colchicine tablet was conducted in young healthy subjects (n=20) between the ages of 18 and 30 years and elderly subjects (n=18) between the ages of 60 and 70 years. elderly subjects in this study had a median age of 62 years and a mean (±sd) age of 62.83 ± 2.83 years. a statistically significant difference in creatinine clearance (mean ± sd) was found between the two age groups (132.56 ± 23.16 ml/min for young vs 87.02 ± 17.92 ml/min for elderly subjects, respectively). the following pharmacokinetic parameter values (mean ± sd) were observed for colchicine in the young and elderly subjects, respectively: auc0-inf (ng/hr/ml) 22.39 ± 6.95 and 25.01 ± 6.92; cmax (ng/ml) 2.61 ± 0.71 and 2.56 ± 0.97; tmax (hr) 1.38 ± 0.42 and 1.25 ± 0.43; apparent elimination half-life (hr) 24.92 ± 5.34 and 30.06 ± 10.78; and clearance (ml/min) 0.0321 ± 0.0091 and 0.0292 ± 0.0071. clinical studies with colchicine for treatment of fmf did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently than younger patients. in general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased renal function, concomitant disease or other drug therapy [see dosage and administration ( 2.4 ), use in specific populations ( 8.5 )]. renal impairment pharmacokinetics of colchicine in patients with mild and moderate renal impairment is not known. a published report described the disposition of colchicine (1 mg) in young adult men and women with fmf who had normal renal function or end-stage renal disease requiring dialysis. patients with end-stage renal disease had 75% lower colchicine clearance (0.17 vs. 0.73 l/hr/kg) and prolonged plasma elimination half-life (18.8 vs 4.4 hours) as compared to subjects with fmf and normal renal function [see dosage and administration ( 2.5 ), use in specific populations ( 8.6 )]. hepatic impairment published reports on the pharmacokinetics of iv colchicine in patients with severe chronic liver disease, as well as those with alcoholic or primary biliary cirrhosis and normal renal function suggest wide interpatient variability. in some subjects with mild to moderate cirrhosis, the clearance of colchicine is significantly reduced and plasma half-life prolonged compared to healthy subjects. in subjects with primary biliary cirrhosis, no consistent trends were noted [see dosage and administration ( 2.6 ), use in specific populations ( 8.7 )]. no pharmacokinetic data are available for patients with severe hepatic impairment (child-pugh c). drug interactions in vitro drug interactions in vitro studies in human liver microsomes have shown that colchicine is not an inhibitor or inducer of cyp1a2, cyp2a6, cyp2b6, cyp2c8, cyp2c9, cyp2c19, cyp2d6, cyp2e1 or cyp3a4 activity. in vivo drug interactions the effects of co-administration of other drugs with colchicine on c max , auc and c min are summarized in table 6 (effect of other drugs on colchicine) and table 7 (effect of colchicine on other drugs). for information regarding clinical recommendations, see table 1 in dose modification for co-administration of interacting drugs [see dosage and administration ( 2.4 )]. table 6. drug interactions: pharmacokinetic parameters for colchicine tablets in the presence of the co-administered drug co-administered drug dose of co-administered drug (mg) dose of colchicine (mg) n % change in colchicine concentrations from baseline (range: min to max) c max auc 0-t cyclosporine 100 mg single dose 0.6 mg single dose 23 270 (62 to 606.9) 259 (75.8 to 511.9) clarithromycin 250 mg twice daily, 7 days 0.6 mg single dose 23 227.2 (65.7 to 591.1) 281.5 (88.7 to 851.6) ketoconazole 200 mg twice daily, 5 days 0.6 mg single dose 24 101.7 (19.6 to 219) 212.2 (76.7 to 419.6) ritonavir 100 mg twice daily, 5 days 0.6 mg single dose 18 184.4 (79.2 to 447.4) 296 (53.8 to 924.4) verapamil 240 mg daily, 5 days 0.6 mg single dose 24 40.1 (-47.1 to 149.5) 103.3 (-9.8 to 217.2) diltiazem 240 mg daily, 7 days 0.6 mg single dose 20 44.2 (-46 to 318.3) 93.4 (-30.2 to 338.6) azithromycin 500 mg x 1 day, then 250 mg x 4 days 0.6 mg single dose 21 21.6 (-41.7 to 222) 57.1 (-24.3 to 241.1) grapefruit juice 240 ml twice daily, 4 days 0.6 mg single dose 21 -2.55 (-53.4 to 55) -2.36 (-46.4 to 62.2) estrogen-containing oral contraceptives: in healthy female volunteers given ethinyl estradiol and norethindrone (ortho-novum 1/35) co-administered with colchicine (0.6 mg twice daily x 14 days), hormone concentrations are not affected. in healthy volunteers given theophylline co-administered with colchicine (0.6 mg twice daily x 14 days), theophylline concentrations were not affected. table 7. drug interactions: pharmacokinetic parameters for co-administration of drug in the presence of colchicine tablets. co-administered drug dose of co-administered drug (mg) dose of colchicine (mg) n % change in co-administered drug concentrations from baseline (range: min to max) c max auc 0-t theophylline 300 mg (elixir) single dose 0.6 mg twice daily x 14 days 27 1.6 (-30.4 to 23.1) 1.6 (-28.5 to 27.1) ethinyl estradiol (ortho-novum 1/35) 21-day cycle (active treatment) + 7-day placebo 0.6 mg twice daily x 14 days 27* -6.7 (-40.3 to 44.7) -3 † (-25.3 to 24.9) norethindrone (ortho-novum 1/35) 0.94 (-37.3 to 59.4) -1.6 † (-32 to 33.7) * conducted in healthy adult females † auc τ

%cv) pharmacokinetic parameters in healthy adults given colchicine c max (colchicine ng/ml) t max* (h) vd/f (l) cl/f (l/hr) t 1/2 (h) colchicine 0.6 mg single dose (n=13) 2.5 (28.7) 1.5 (1 to 3) 341.5 (54.4) 54.1 (31) - colchicine 0.6 mg twice daily x 10 days (n=13) 3.6 (23.7) 1.3 (0.5 to 3) 1150 (18.7) 30.3 (19) 26.6 (16.3) * t max mean (range) cl = dose/auc 0-t (calculated from mean values) vd = cl/ke (calculated from mean values) in some subjects, secondary colchicine peaks are seen, occurring between three and 36 hours postdose and ranging from 39 to 155% of the height of the initial peak. these observations are attributed to intestinal secretion and reabsorption and/or biliary recirculation. absolute bioavailability is reported to be approximately 45%. administration of colchicine with food has no effect on the rate of colchicine absorption but does decrease the extent of colchicine by approximately 15%. this is without clinical significance. distribution the mean apparent volume of distribution in healthy young volunteers is approximately 5 to 8 l/kg. colchicine binding to serum protein is low, 39 ± 5%, primarily to albumin regardless of concentration. colchicine crosses the placenta (plasma levels in the fetus are reported to be approximately 15% of the maternal concentration). colchicine also distributes into breast milk at concentrations similar to those found in the maternal serum [see use in specific populations ( 8.1 , 8.2 )]. metabolism colchicine is demethylated to two primary metabolites, 2-o-demethylcolchicine and 3-o-demethylcolchicine (2- and 3-dmc, respectively) and one minor metabolite, 10-o-demethylcolchicine (also known as colchiceine). in vitro studies using human liver microsomes have shown that cyp3a4 is involved in the metabolism of colchicine to 2-and 3-dmc. plasma levels of these metabolites are minimal (less than 5% of parent drug). elimination/excretion in healthy volunteers (n=12), 40 to 65% of 1 mg orally administered colchicine was recovered unchanged in urine. enterohepatic recirculation and biliary excretion are also postulated to play a role in colchicine elimination. following multiple oral doses (0.6 mg twice daily), the mean elimination half-lives in young healthy volunteers (mean age 25 to 28 years of age) is 26.6 to 31.2 hours. colchicine is a substrate of p-gp. extracorporeal elimination colchicine is not removed by hemodialysis. special populations there is no difference between men and women in the pharmacokinetic disposition of colchicine. pediatric patients: pharmacokinetics of colchicine was not evaluated in pediatric patients. elderly a published report described the pharmacokinetics of 1 mg oral colchicine tablet in four elderly women compared to six young healthy males. the mean age of the four elderly women was 83 years (range 75 to 93), mean weight was 47 kg (38 to 61 kg) and mean creatinine clearance was 46 ml/min (range 25 to 75 ml/min). mean peak plasma levels and auc of colchicine were two times higher in elderly subjects compared to young healthy males. a pharmacokinetic study using a single oral dose of one 0.6 mg colchicine tablet was conducted in young healthy subjects (n=20) between the ages of 18 and 30 years and elderly subjects (n=18) between the ages of 60 and 70 years. elderly subjects in this study had a median age of 62 years and a mean (±sd) age of 62.83 ± 2.83 years. a statistically significant difference in creatinine clearance (mean ± sd) was found between the two age groups (132.56 ± 23.16 ml/min for young vs 87.02 ± 17.92 ml/min for elderly subjects, respectively). the following pharmacokinetic parameter values (mean ± sd) were observed for colchicine in the young and elderly subjects, respectively: auc0-inf (ng/hr/ml) 22.39 ± 6.95 and 25.01 ± 6.92; cmax (ng/ml) 2.61 ± 0.71 and 2.56 ± 0.97; tmax (hr) 1.38 ± 0.42 and 1.25 ± 0.43; apparent elimination half-life (hr) 24.92 ± 5.34 and 30.06 ± 10.78; and clearance (ml/min) 0.0321 ± 0.0091 and 0.0292 ± 0.0071. clinical studies with colchicine for treatment of fmf did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently than younger patients. in general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased renal function, concomitant disease or other drug therapy [see dosage and administration ( 2.4 ), use in specific populations ( 8.5 )]. renal impairment pharmacokinetics of colchicine in patients with mild and moderate renal impairment is not known. a published report described the disposition of colchicine (1 mg) in young adult men and women with fmf who had normal renal function or end-stage renal disease requiring dialysis. patients with end-stage renal disease had 75% lower colchicine clearance (0.17 vs. 0.73 l/hr/kg) and prolonged plasma elimination half-life (18.8 vs 4.4 hours) as compared to subjects with fmf and normal renal function [see dosage and administration ( 2.5 ), use in specific populations ( 8.6 )]. hepatic impairment published reports on the pharmacokinetics of iv colchicine in patients with severe chronic liver disease, as well as those with alcoholic or primary biliary cirrhosis and normal renal function suggest wide interpatient variability. in some subjects with mild to moderate cirrhosis, the clearance of colchicine is significantly reduced and plasma half-life prolonged compared to healthy subjects. in subjects with primary biliary cirrhosis, no consistent trends were noted [see dosage and administration ( 2.6 ), use in specific populations ( 8.7 )]. no pharmacokinetic data are available for patients with severe hepatic impairment (child-pugh c). drug interactions in vitro drug interactions in vitro studies in human liver microsomes have shown that colchicine is not an inhibitor or inducer of cyp1a2, cyp2a6, cyp2b6, cyp2c8, cyp2c9, cyp2c19, cyp2d6, cyp2e1 or cyp3a4 activity. in vivo drug interactions the effects of co-administration of other drugs with colchicine on c max , auc and c min are summarized in table 6 (effect of other drugs on colchicine) and table 7 (effect of colchicine on other drugs). for information regarding clinical recommendations, see table 1 in dose modification for co-administration of interacting drugs [see dosage and administration ( 2.4 )]. table 6. drug interactions: pharmacokinetic parameters for colchicine tablets in the presence of the co-administered drug co-administered drug dose of co-administered drug (mg) dose of colchicine (mg) n % change in colchicine concentrations from baseline (range: min to max) c max auc 0-t cyclosporine 100 mg single dose 0.6 mg single dose 23 270 (62 to 606.9) 259 (75.8 to 511.9) clarithromycin 250 mg twice daily, 7 days 0.6 mg single dose 23 227.2 (65.7 to 591.1) 281.5 (88.7 to 851.6) ketoconazole 200 mg twice daily, 5 days 0.6 mg single dose 24 101.7 (19.6 to 219) 212.2 (76.7 to 419.6) ritonavir 100 mg twice daily, 5 days 0.6 mg single dose 18 184.4 (79.2 to 447.4) 296 (53.8 to 924.4) verapamil 240 mg daily, 5 days 0.6 mg single dose 24 40.1 (-47.1 to 149.5) 103.3 (-9.8 to 217.2) diltiazem 240 mg daily, 7 days 0.6 mg single dose 20 44.2 (-46 to 318.3) 93.4 (-30.2 to 338.6) azithromycin 500 mg x 1 day, then 250 mg x 4 days 0.6 mg single dose 21 21.6 (-41.7 to 222) 57.1 (-24.3 to 241.1) grapefruit juice 240 ml twice daily, 4 days 0.6 mg single dose 21 -2.55 (-53.4 to 55) -2.36 (-46.4 to 62.2) estrogen-containing oral contraceptives: in healthy female volunteers given ethinyl estradiol and norethindrone (ortho-novum 1/35) co-administered with colchicine (0.6 mg twice daily x 14 days), hormone concentrations are not affected. in healthy volunteers given theophylline co-administered with colchicine (0.6 mg twice daily x 14 days), theophylline concentrations were not affected. table 7. drug interactions: pharmacokinetic parameters for co-administration of drug in the presence of colchicine tablets. co-administered drug dose of co-administered drug (mg) dose of colchicine (mg) n % change in co-administered drug concentrations from baseline (range: min to max) c max auc 0-t theophylline 300 mg (elixir) single dose 0.6 mg twice daily x 14 days 27 1.6 (-30.4 to 23.1) 1.6 (-28.5 to 27.1) ethinyl estradiol (ortho-novum 1/35) 21-day cycle (active treatment) + 7-day placebo 0.6 mg twice daily x 14 days 27* -6.7 (-40.3 to 44.7) -3 † (-25.3 to 24.9) norethindrone (ortho-novum 1/35) 0.94 (-37.3 to 59.4) -1.6 † (-32 to 33.7) * conducted in healthy adult females † auc τ

hicine. however, published nonclinical studies demonstrated that colchicine-induced disruption of microtubule formation affects meiosis and mitosis. reproductive studies also reported abnormal sperm morphology and reduced sperm counts in males, and interference with sperm penetration, second meiotic division and normal cleavage in females when exposed to colchicine. colchicine administered to pregnant animals resulted in fetal death and teratogenicity. these effects were dose-dependent, with the timing of exposure critical for the effects on embryofetal development. the nonclinical doses evaluated were generally higher than an equivalent human therapeutic dose, but safety margins for reproductive and developmental toxicity could not be determined.

nonclinical studies demonstrated that colchicine-induced disruption of microtubule formation affects meiosis and mitosis. reproductive studies also reported abnormal sperm morphology and reduced sperm counts in males, and interference with sperm penetration, second meiotic division and normal cleavage in females when exposed to colchicine. colchicine administered to pregnant animals resulted in fetal death and teratogenicity. these effects were dose-dependent, with the timing of exposure critical for the effects on embryofetal development. the nonclinical doses evaluated were generally higher than an equivalent human therapeutic dose, but safety margins for reproductive and developmental toxicity could not be determined.

60 days while treated with colchicine compared to 68 attacks over the course of 60 days while treated with placebo. the third study was discontinued after an interim analysis of six of the 11 patients enrolled had completed the study; results could not be confirmed. open-label experience with colchicine in adults and children with fmf is consistent with the randomized, controlled trial experience and was utilized to support information on the safety profile of colchicine and for dosing recommendations.

y interact with colchicine and some interactions could be fatal. therefore, patients should report to their healthcare provider all of the current medications they are taking and check with their healthcare provider before starting any new medications, particularly antibiotics. patients should also be advised to report the use of nonprescription medication or herbal products. grapefruit and grapefruit juice may also interact and should not be consumed during colchicine treatment. neuromuscular toxicity patients should be informed that muscle pain or weakness, tingling or numbness in fingers or toes may occur with colchicine alone or when it is used with certain other drugs. patients developing any of these signs or symptoms must discontinue colchicine and seek medical evaluation immediately. infertility advise males of reproductive potential that colchicine may rarely and transiently impair fertility [see use in specific populations 8.3 )]. dispense with medication guide is also available at: http://www.granulesindia.com/u.s.productcatalog.php manufactured by: granules pharmaceuticals inc. chantilly, va 20151 distributed by: major® pharmaceuticals livonia, mi 48152 refer to package label for distributor's ndc number rev: 08/2020