The exact dose of colchicine that produces significant toxicity is unknown. Fatalities have occurred after ingestion of a dose as low as 7 mg over a four-day period, while other patients have survived after ingesting more than 60 mg. A review of 150 patients who overdosed on colchicine found that those who ingested less than 0.5 mg/kg survived and tended to have milder toxicities such as gastrointestinal symptoms, whereas those who took 0.5 to 0.8 mg/kg had more severe reactions such as myelosuppression. There was 100% mortality in those who ingested more than 0.8 mg/kg.
The first stage of acute colchicine toxicity typically begins within 24 hours of ingestion and includes gastrointestinal symptoms such as abdominal pain, nausea, vomiting, diarrhea and significant fluid loss, leading to volume depletion. Peripheral leukocytosis may also be seen. Life-threatening complications occur during the second stage, which occurs 24 to 72 hours after drug administration, attributed to multiorgan failure and its consequences. Death is usually a result of respiratory depression and cardiovascular collapse. If the patient survives, recovery of multiorgan injury may be accompanied by rebound leukocytosis and alopecia starting about one week after the initial ingestion.
Treatment of colchicine poisoning should begin with gastric lavage and measures to prevent shock. Otherwise, treatment is symptomatic and supportive. No specific antidote is known. Colchicine is not effectively removed by dialysis.
Patients with renal or hepatic impairment should not be given COLCRYS in conjunction with P-gp or strong CYP3A4 inhibitors (this includes all protease inhibitors except fosamprenavir). In these patients, life-threatening and fatal colchicine toxicity has been reported with colchicine taken in therapeutic doses.
The most commonly reported adverse reaction in clinical trials of colchicine for the prophylaxis of gout was diarrhea.
Treatment of Gout FlaresThe most common adverse reactions reported in the clinical trial with COLCRYS for treatment of gout flares were diarrhea (23%) and pharyngolaryngeal pain (3%).
FMFGastrointestinal tract adverse effects are the most frequent side effects in patients initiating COLCRYS, usually presenting within 24 hours, and occurring in up to 20% of patients given therapeutic doses. Typical symptoms include cramping, nausea, diarrhea, abdominal pain and vomiting. These events should be viewed as dose-limiting if severe, as they can herald the onset of more significant toxicity.
Clinical Trials Experience In GoutBecause clinical studies are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice.
In a randomized, double-blind, placebo-controlled trial in patients with a gout flare, gastrointestinal adverse reactions occurred in 26% of patients using the recommended dose (1.8 mg over one hour) of COLCRYS compared to 77% of patients taking a nonrecommended high dose (4.8 mg over six hours) of colchicine and 20% of patients taking placebo. Diarrhea was the most commonly reported drug-related gastrointestinal adverse event. As shown in Table 3, diarrhea is associated with COLCRYS treatment. Diarrhea was more likely to occur in patients taking the high-dose regimen than the lowdose regimen. Severe diarrhea occurred in 19% and vomiting occurred in 17% of patients taking the nonrecommended high-dose colchicine regimen but did not occur in the recommended low-dose COLCRYS regimen.
Table 3: Number (%) of Patients with at Least One
Drug-Related Treatment-Emergent Adverse Event with an Incidence of ≥ 2% of
Patients in Any Treatment Group
| MedDRA System Organ Class MedDRA Preferred Term |
COLCRYS Dose | Placebo (N=59) n (%) |
|
| High (N=52) n (%) |
Low (N=74) n (%) |
||
| Number of Patients with at Least One Drug-Related TEAE | 40 (77) | 27 (37) | 16 (27) |
| Gastrointestinal Disorders | 40 (77) | 19 (26) | 12 (20) |
| Diarrhea | 40 (77) | 17 (23) | 8 (14) |
| Nausea | 9 (17) | 3 (4) | 3 (5) |
| Vomiting | 9 (17) | 0 | 0 |
| Abdominal Discomfort | 0 | 0 | 2 (3) |
| General Disorders and Administration Site Conditions | 4 (8) | 1 (1) | 1 (2) |
| Fatigue | 2 (4) | 1 (1) | 1 (2) |
| Metabolic and Nutrition Disorders | 0 | 3 (4) | 2 (3) |
| Gout | 0 | 3 (4) | 1 (2) |
| Nervous System Disorders | 1 (2) | 1 (1.4) | 2 (3) |
| Headache | 1 (2) | 1 (1) | 2 (3) |
| Respiratory Thoracic Mediastinal Disorders | 1 (2) | 2 (3) | 0 |
| Pharyngolaryngeal Pain | 1 (2) | 2 (3) | 0 |
Serious toxic manifestations associated with colchicine include myelosuppression, disseminated intravascular coagulation and injury to cells in the renal, hepatic, circulatory and central nervous systems.
These most often occur with excessive accumulation or overdosage.
The following adverse reactions have been reported with colchicine. These have been generally reversible upon temporarily interrupting treatment or lowering the dose of colchicine.
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
COLCRYS (colchicine, USP) tablets are indicated for prophylaxis and the treatment of acute gout flares.
COLCRYS (colchicine, USP) tablets are indicated in adults and children 4 years or older for treatment of familial Mediterranean fever (FMF).
In healthy adults, COLCRYS is absorbed when given orally, reaching a mean Cmax of 2.5 ng/mL (range 1.1 to 4.4 ng/mL) in one to two hours (range 0.5 to three hours) after a single dose administered under fasting conditions.
Following oral administration of COLCRYS given as 1.8 mg colchicine over one hour to healthy, young adults under fasting conditions, colchicine appears to be readily absorbed, reaching mean maximum plasma concentrations of 6.2 ng/mL at a median 1.81 hours (range: 1.0 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 10 days on a regimen of 0.6 mg twice daily, peak concentrations are 3.1 to 3.6 ng/mL (range 1.6 to 6.0 ng/mL), occurring 1.3 to 1.4 hours post dose (range 0.5 to 3.0 hours). Mean pharmacokinetic parameter values in healthy adults are shown in Table 5.
Table 5: Mean (%CV) Pharmacokinetic Parameters in
Healthy Adults Given COLCRYS
| Cmax (Colchicine ng/mL) | Tmax* (h) | Vd/F (L) | CL/F (L/hr) | t½ (h) |
| COLCRYS 0.6 mg Single Dose (N=13) | ||||
| 2.5 (28.7) | 1.5 (1.0 - 3.0) | 341.5 (54.4) | 54.1 (31.0) | -- |
| COLCRYS 0.6 mg Twice Daily x 10 Days (N=13) | ||||
| 3.6 (23.7) | 1.3 (0.5 - 3.0) | 1150 (18.7) | 30.3 (19.0) | 26.6 (16.3) |
| *Tmax mean (range) CL = Dose/AUC0-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 post dose 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 COLCRYS 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.
DistributionThe 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.
MetabolismColchicine 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/ExcretionIn 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 EliminationColchicine is not removed by hemodialysis.
There are no adequate and well-controlled studies with colchicine in pregnant women. Colchicine crosses the human placenta. While not studied in the treatment of gout flares, data from a limited number of published studies found no evidence of an increased risk of miscarriage, stillbirth or teratogenic effects among pregnant women using colchicine to treat familial Mediterranean fever (FMF). Although animal reproductive and developmental studies were not conducted with COLCRYS, 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. COLCRYS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
0.6 mg tablets — purple capsule-shaped, film-coated with “AR 374” debossed on one side and scored on the other side.
Storage And HandlingCOLCRYS (colchicine, USP) tablets 0.6 mg are purple, film-coated, capsule-shaped tablets debossed with “AR 374” on one side and scored on the other side.
Bottles of 30 NDC 64764-119-07
Bottles of 60 NDC 64764-119-06
Bottles of 100 NDC 64764-119-01
Bottles of 250 NDC 64764-119-03
Bottles of 500 NDC 64764-119-05
Bottles of 1000 NDC 64764-119-10
Store at 20° to 25°C (68° to 77°F). Protect from light.
DISPENSE IN TIGHT, LIGHT-RESISTANT CONTAINER.
Distributed by: Takeda Pharmaceuticals America, Inc., Deerfield, IL 60015. Revised: December 2015
Included as part of the PRECAUTIONS section.
PRECAUTIONS Fatal OverdoseFatal overdoses, both accidental and intentional, have been reported in adults and children who have ingested colchicine. COLCRYS should be kept out of the reach of children.
Blood DyscrasiasMyelosuppression, leukopenia, granulocytopenia, thrombocytopenia, pancytopenia and aplastic anemia have been reported with colchicine used in therapeutic doses.
Drug InteractionsColchicine 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. Use of COLCRYS 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.
Neuromuscular ToxicityColchicine-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 COLCRYS may potentiate the development of myopathy. Once colchicine is stopped, the symptoms generally resolve within one week to several months.
Patient Counseling InformationAdvise the patient to read the FDA-approved patient labeling (Medication Guide).
Dosing InstructionsPatients should be advised to take COLCRYS as prescribed, even if they are feeling better. Patients should not alter the dose or discontinue treatment without consulting with their doctor. If a dose of COLCRYS is missed:
Instruct patient that fatal overdoses, both accidental and intentional, have been reported in adults and children who have ingested colchicine. COLCRYS should be kept out of the reach of children.
Blood DyscrasiasPatients should be informed that bone marrow depression with agranulocytosis, aplastic anemia and thrombocytopenia may occur with COLCRYS.
Drug and Food InteractionsPatients should be advised that many drugs or other substances may interact with COLCRYS 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 COLCRYS treatment.
Neuromuscular ToxicityPatients should be informed that muscle pain or weakness, tingling or numbness in fingers or toes may occur with COLCRYS alone or when it is used with certain other drugs. Patients developing any of these signs or symptoms must discontinue COLCRYS and seek medical evaluation immediately.
Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility CarcinogenesisTwo-year studies were conducted in mice and rats to assess the carcinogenic potential of colchicine. No evidence of colchicine-related tumorigenicity was observed in mice or rats at colchicine oral doses up to 3 mg/kg/day and 2 mg/kg/day, respectively (approximately 6 and 8 times, respectively, the maximum recommended human dose of 2.4 mg on a mg/m² basis).
MutagenesisColchicine was negative for mutagenicity in the bacterial reverse mutation assay. In a chromosomal aberration assay in cultured human white blood cells, colchicine treatment resulted in the formation of micronuclei. Since published studies demonstrated that colchicine induces aneuploidy from the process of mitotic nondisjunction without structural DNA changes, colchicine is not considered clastogenic, although micronuclei are formed.
Impairment of FertilityNo studies of colchicine effects on fertility were conducted with COLCRYS. 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.
Case reports and epidemiology studies in human male subjects on colchicine therapy indicated that infertility from colchicine is rare. 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.
Use In Specific Populations Pregnancy Pregnancy Category CThere are no adequate and well-controlled studies with colchicine in pregnant women. Colchicine crosses the human placenta. While not studied in the treatment of gout flares, data from a limited number of published studies found no evidence of an increased risk of miscarriage, stillbirth or teratogenic effects among pregnant women using colchicine to treat familial Mediterranean fever (FMF). Although animal reproductive and developmental studies were not conducted with COLCRYS, 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. COLCRYS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Labor And DeliveryThe effect of colchicine on labor and delivery is unknown.
Nursing MothersColchicine is excreted into human milk. Limited information suggests that exclusively breastfed infants receive less than 10 percent of the maternal weight-adjusted dose. While there are no published reports of adverse effects in breastfeeding infants of mothers taking colchicine, colchicine can affect gastrointestinal cell renewal and permeability. Caution should be exercised, and breastfeeding infants should be observed for adverse effects when COLCRYS is administered to a nursing woman.
Pediatric UseThe 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. Gout is rare in pediatric patients; safety and effectiveness of colchicine in pediatric patients has not been established.
Geriatric UseClinical studies with colchicine for prophylaxis and treatment of gout flares and 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 with gout should be cautious, reflecting the greater frequency of decreased renal function, concomitant disease or other drug therapy.
Renal ImpairmentColchicine is significantly excreted in urine in healthy subjects. Clearance of colchicines is decreased in patients with impaired renal function. Total body clearance of colchicines was reduced by 75% in patients with end-stage renal disease undergoing dialysis.
Prophylaxis of Gout FlaresFor prophylaxis of gout flares in patients with mild (estimated creatinine clearance Clcr 50 to 80 mL/min) to moderate (Clcr 30 to 50 mL/min) renal function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of colchicine. However, in patients with severe impairment, the starting dose should be 0.3 mg per day and any increase in dose should be done with close monitoring. For the prophylaxis of gout flares in patients undergoing dialysis, the starting doses should be 0.3 mg given twice a week with close monitoring.
Treatment of Gout FlaresFor treatment of gout flares in patients with mild (Clcr 50 to 80 mL/min) to moderate (Clcr 30 to 50 mL/min) renal function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of COLCRYS. However, in patients with severe impairment, while the dose does not need to be adjusted for the treatment of gout flares, a treatment course should be repeated no more than once every two weeks. For patients with gout flares requiring repeated courses, consideration should be given to alternate therapy. For patients undergoing dialysis, the total recommended dose for the treatment of gout flares should be reduced to a single dose of 0.6 mg (one tablet). For these patients, the treatment course should not be repeated more than once every two weeks.
FMFAlthough, 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, COLCRYS 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 COLCRYS.
Hepatic ImpairmentThe clearance of colchicine may be significantly reduced and plasma half-life prolonged in patients with chronic hepatic impairment compared to healthy subjects.
Prophylaxis of Gout FlaresFor prophylaxis of gout flares in patients with mild to moderate hepatic function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of colchicine. Dose reduction should be considered for the prophylaxis of gout flares in patients with severe hepatic impairment.
Treatment of Gout FlaresFor treatment of gout flares in patients with mild to moderate hepatic function impairment, adjustment of the recommended COLCRYS dose is not required, but patients should be monitored closely for adverse effects of COLCRYS. However, for the treatment of gout flares in patients with severe impairment, while the dose does not need to be adjusted, the treatment course should be repeated no more than once every two weeks. For these patients, requiring repeated courses for the treatment of gout flares, consideration should be given to alternate therapy.
FMFIn patients with severe hepatic disease, dose reduction should be considered with careful monitoring.
The long-term use of colchicine is established for FMF and the prophylaxis of gout flares, but the safety and efficacy of repeat treatment for gout flares has not been evaluated. The dosing regimens for COLCRYS are different for each indication and must be individualized.
The recommended dosage of COLCRYS depends on the patient's age, renal function, hepatic function and use of coadministered drugs .
COLCRYS tablets are administered orally without regard to meals.
COLCRYS is not an analgesic medication and should not be used to treat pain from other causes.
Gout Flares Prophylaxis Of Gout FlaresThe recommended dosage of COLCRYS for prophylaxis of gout flares for adults and adolescents older than 16 years of age is 0.6 mg once or twice daily. The maximum recommended dose for prophylaxis of gout flares is 1.2 mg/day.
An increase in gout flares may occur after initiation of uric acid-lowering therapy, including pegloticase, febuxostat and allopurinol, due to changing serum uric acid levels resulting in mobilization of urate from tissue deposits. COLCRYS is recommended upon initiation of gout flare prophylaxis with uric acid-lowering therapy. Prophylactic therapy may be beneficial for at least the first six months of uric acid-lowering therapy.
Treatment of Gout FlaresThe recommended dose of COLCRYS for treatment of a gout flare is 1.2 mg (two tablets) at the first sign of the flare followed by 0.6 mg (one tablet) one hour later. Higher doses have not been found to be more effective. The maximum recommended dose for treatment of gout flares is 1.8 mg over a one-hour period. COLCRYS may be administered for treatment of a gout flare during prophylaxis at doses not to exceed 1.2 mg (two tablets) at the first sign of the flare followed by 0.6 mg (one tablet) one hour later. Wait 12 hours and then resume the prophylactic dose.
FMFThe recommended dosage of COLCRYS for FMF in adults is 1.2 mg to 2.4 mg daily.
COLCRYS 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 COLCRYS dose may be administered in one to two divided doses.
Recommended Pediatric Dosage Prophylaxis and Treatment of Gout FlaresCOLCRYS is not recommended for pediatric use in prophylaxis or treatment of gout flares.
FMFThe recommended dosage of COLCRYS 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:
Coadministration of COLCRYS 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.
Table 1: COLCRYS Dose Adjustment for Coadministration
with Interacting Drugs if no Alternative Available*
| Strong CYP3A4 Inhibitors† | |||||||
| Drug | Noted or Anticipated Outcome | Gout Flares | FMF | ||||
| Prophylaxis of Gout Flares | Treatment of Gout Flares | ||||||
| Original Intended Dosage | Adjusted Dose | Original Intended Dosage | Adjusted Dose | 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. | 0.6 mg twice a day 0.6 mg once a day | 0.3 mg once a day 0.3 mg once every other day | 1.2 mg (2 tablets) followed by 0.6 mg (1 tablet) 1 hour later. Dose to be repeated no earlier than 3 days. | 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (½ tablet) 1 hour later. Dose to be repeated no earlier than 3 days. | Maximum daily dose of 1.2 -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 | Gout Flares | |||||
| Prophylaxis of Gout Flares | Treatment of Gout Flares | FMF | |||||
| Original Intended Dosage | Adjusted Dose | Original Intended Dosage | Adjusted Dose | Original Intended Dosage | Adjusted Dose | ||
| Amprenavir‡ Aprepitant Diltiazem Erythromycin Fluconazole Fosamprenavir‡ (pro-drug of Amprenavir) Grapefruit juice Verapamil | Significant increase in colchicine plasma concentration is anticipated. Neuromuscular toxicity has been reported with diltiazem and verapamil interactions. | 0.6 mg twice a day 0.6 mg once a day | 0.3 mg twice a day or 0.6 mg once a day 0.3 mg once a day | 1.2 mg (2 tablets) followed by 0.6 mg (1 tablet) 1 hour later. Dose to be repeated no earlier than 3 days. | 1.2 mg (2 tablets) x 1 dose. Dose to be repeated no earlier than 3 days. | Maximum daily dose of 1.2 -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 | Gout Flares | FMF | ||||
| Prophylaxis of Gout Flares | Treatment of Gout Flares | ||||||
| Original Intended Dosage | Adjusted Dose | Original Intended Dosage | Adjusted Dose | 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. | 0.6 mg twice a day 0.6 mg once a day | 0.3 mg once a day 0.3 mg once every other day | 1.2 mg (2 tablets) followed by 0.6 mg (1 tablet) 1 hour later. Dose to be repeated no earlier than 3 days. | 0.6 mg (1 tablet) x 1 dose. Dose to be repeated no earlier than 3 days. | Maximum daily dose of 1.2 -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 †Patients with renal or hepatic impairment should not be given COLCRYS in conjunction with strong CYP3A4 or P-gp inhibitors ‡When used in combination with Ritonavir, see dosing recommendations for strong CYP3A4 inhibitors |
Table 2: COLCRYS Dose Adjustment for Coadministration
with Protease Inhibitors
| Protease Inhibitor | Clinical Comment | w/Colchicine - Prophylaxis of Gout Flares | w/Colchicine -Treatment of Gout Flares | w/Colchicine -Treatment of FMF | |
| Atazanavir sulfate (Reyataz) | Patients with renal or hepatic impairment should not be given colchicine with Reyataz. | Original dose | Adjusted dose | 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (½ tablet) 1 hour later. Dose to be repeated no earlier than 3 days. | Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day) |
| 0.6 mg twice a day 0.6 mg once a day | 0.3 mg once a day 0.3 mg once every other day | ||||
| Darunavir (Prezista) | Patients with renal or hepatic impairment should not be given colchicine with Prezista/ ritonavir. | Original dose | Adjusted dose | 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (½ tablet) 1 hour later. Dose to be repeated no earlier than 3 days. | Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day) |
| 0.6 mg twice a day 0.6 mg once a day | 0.3 mg once a day 0.3 mg once every other day | ||||
| Fosamprenavir (Lexiva) with Ritonavir | Patients with renal or hepatic impairment should not be given colchicine with Lexiva/ritonavir. | Original dose | Adjusted dose | 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (½ tablet) 1 hour later. Dose to be repeated no earlier than 3 days. | Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day) |
| 0.6 mg twice a day 0.6 mg once a day | 0.3 mg once a day 0.3 mg once every other day | ||||
| Fosamprenavir (Lexiva) | Patients with renal or hepatic impairment should not be given colchicine with Lexiva/ritonavir. | Original dose | Adjusted dose | 1.2 mg (2 tablets) x 1 dose. Dose to be repeated no earlier than 3 days. | Maximum daily dose of 1.2 mg (may be given as 0.6 mg twice a day) |
| 0.6 mg twice a day 0.6 mg once a day | 0.3 mg twice a day or 0.6 mg once a day 0.3 mg once a day | ||||
| Indinavir (Crixivan) | Patients with renal or hepatic impairment should not be given colchicine with Crixivan. | Original dose | Adjusted dose | 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (½ tablet) 1 hour later. Dose to be repeated no earlier than 3 days. | Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day) |
| 0.6 mg twice a day 0.6 mg once a day | 0.3 mg once a day 0.3 mg once every other day | ||||
| Lopinavir/ Ritonavir (Kaletra) | Patients with renal or hepatic impairment should not be given colchicine with Kaletra. | Original dose | Adjusted dose | 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (½ tablet) 1 hour later. Dose to be repeated no earlier than 3 days. | Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day) |
| 0.6 mg twice a day 0.6 mg once a day | 0.3 mg once a day 0.3 mg once every other day | ||||
| Nelfinavir mesylate (Viracept) | Patients with renal or hepatic impairment should not be given colchicine with Viracept. | Original dose | Adjusted dose | 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (½ tablet) 1 hour later. Dose to be repeated no earlier than 3 days. | Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day) |
| 0.6 mg twice a day 0.6 mg once a day | 0.3 mg once a day 0.3 mg once every other day | ||||
| Ritonavir (Norvir) | Patients with renal or hepatic impairment should not be given colchicine with Norvir. | Original dose | Adjusted dose | 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (½ tablet) 1 hour later. Dose to be repeated no earlier than 3 days. | Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day) |
| 0.6 mg twice a day 0.6 mg once a day | 0.3 mg once a day 0.3 mg once every other day | ||||
| Saquinavir mesylate (Invirase) | Patients with renal or hepatic impairment should not be given colchicine with Invirase/ ritonavir. | Original dose | Adjusted dose | 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (½ tablet) 1 hour later. Dose to be repeated no earlier than 3 days. | Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day) |
| 0.6 mg twice a day 0.6 mg once a day | 0.3 mg once a day 0.3 mg once every other day | ||||
| Tipranavir (Aptivus) | Patients with renal or hepatic impairment should not be given colchicine with Aptivus/ ritonavir. | Original dose | Adjusted dose | 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (1/2 tablet) 1 hour later. Dose to be repeated no earlier than 3 days. | Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day) |
| 0.6 mg twice a day 0.6 mg once a day | 0.3 mg once a day 0.3 mg once every other day |
Treatment of gout flares with COLCRYS is not recommended in patients receiving prophylactic dose of COLCRYS and CYP3A4 inhibitors.
Dose Modification In Renal ImpairmentColchicine dosing must be individualized according to the patient's renal function.
Clcr in mL/minute may be estimated from serum creatinine (mg/dL) determination using the following formula:
| Males: | (weight in kg) x (140 – age) |
| (72) x serum creatinine (mg/100 mL) | |
| Females | (0.85) x (above value) |
Prophylaxis of Gout Flares
For prophylaxis of gout flares in patients with mild (estimated creatinine clearance [Clcr] 50 to 80 mL/min) to moderate (Clcr 30 to 50 mL/min) renal function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of colchicine. However, in patients with severe impairment, the starting dose should be 0.3 mg/day and any increase in dose should be done with close monitoring. For the prophylaxis of gout flares in patients undergoing dialysis, the starting doses should be 0.3 mg given twice a week with close monitoring.
Treatment of Gout Flares
For treatment of gout flares in patients with mild (Clcr 50 to 80 mL/min) to moderate (Clcr 30 to 50 mL/min) renal function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of colchicine. However, in patients with severe impairment, while the dose does not need to be adjusted for the treatment of gout flares, a treatment course should be repeated no more than once every two weeks. For patients with gout flares requiring repeated courses, consideration should be given to alternate therapy. For patients undergoing dialysis, the total recommended dose for the treatment of gout flares should be reduced to a single dose of 0.6 mg (one tablet). For these patients, the treatment course should not be repeated more than once every two weeks.
Treatment of gout flares with COLCRYS is not recommended in patients with renal impairment who are receiving COLCRYS for prophylaxis.
FMFCaution 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. Patients with mild (Clcr 50 to 80 mL/min) and moderate (Clcr 30 to 50 mL/min) renal impairment should be monitored closely for adverse effects of COLCRYS. Dose reduction may be necessary. For patients with severe renal failure (Clcr 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. 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.
Dose Modification In Hepatic Impairment Gout FlaresProphylaxis of Gout Flares
For prophylaxis of gout flares in patients with mild to moderate hepatic function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of colchicine. Dose reduction should be considered for the prophylaxis of gout flares in patients with severe hepatic impairment.
Treatment of Gout Flares
For treatment of gout flares in patients with mild to moderate hepatic function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of colchicine. However, for the treatment of gout flares in patients with severe impairment, while the dose does not need to be adjusted, a treatment course should be repeated no more than once every two weeks. For these patients, requiring repeated courses for the treatment of gout flares, consideration should be given to alternate therapy.
Treatment of gout flares with COLCRYS is not recommended in patients with hepatic impairment who are receiving COLCRYS for prophylaxis.
FMFPatients 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.
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. Use of COLCRYS 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.
