COLCHIMED

Colchicine is an alkaloid drug derived from a plant belonging to the Lily family, known as Colchicum autumnale, or "autumn crocus." 4 Its use was first approved by the FDA in 1961.

Colchicine is used in the treatment of gout flares and Familial Mediterranean fever, 9 and prevention of major cardiovascular events.

It has also been investigated in other inflammatory and fibrotic conditions.

Colchicine is indicated for the prophylaxis and treatment of gout flares.

It is also indicated in Familial

Mediterranean fever (FMF) in children and adults of four years of age and older.

It is also indicated to reduce the risk of myocardial infarction (MI), stroke, coronary revascularization, and cardiovascular death in adult patients with established atherosclerotic disease or with multiple risk factors for cardiovascular disease.

Some off-label uses of colchicine include the treatment of the manifestations of Behcet's syndrome, pericarditis, and postpericardiotomy syndrome. 5,

Colchicine ameliorates the symptoms of gout and Familial Mediterranean fever. 1, 9 It possesses anti-inflammatory, anti-fibrotic, and cardiovascular protective effects.

Colchicine was shown to exhibit anticancer properties, such as the inhibition of cancer cell migration and angiogenesis.

Colchicine is rapidly absorbed after oral administration from the gastrointestinal tract.

The bioavailability of colchicine is about 45%: 9, 12 one study suggests that colchicine bioavailability is highly variable, ranging from 24-88%.

In healthy adults, the mean C max of 2.5 ng/mL (range 1.1-4.4 ng/mL) was achieved in one to two hours (range 0.5-3 hours) after a single dose administered under fasting conditions.

In a multiple-dose study of colchicine administration at a dose of 1 mg per day, steady-state concentrations were achieved by day 8 following administration.

Administration of colchicine with food does not affect the colchicine absorption rate but decreases the extent of colchicine by approximately 15%.

The mean apparent volume of distribution in young and healthy patients is about 5-8 L/kg. It is known to cross the placenta and distribute into the breast milk.

Colchicine has been found to distribute to various tissues, mainly into the bile, liver, and kidney tissues.

Smaller amounts have been detected in the heart, lungs, intestinal tissue, and stomach.

Colchicine is metabolized in the liver.

It undergoes

CYP3A4-mediated demethylation into major metabolites, 2-O-demethylcolchicine and 3-O-demethylcolchicine.

It also forms one minor metabolite, 10-O-demethylcolchicine ( colchiceine ). 9, 11 Plasma levels of these metabolites are less than 5% of parent drug.

Hover over products below to view reaction partners Colchicine 2-Demethylcolchicine 3-Desmethylchochicine Colchiceine.

In a pharmacokinetic study of healthy research subjects who received 1 mg of oral colchicine, about 40% to 65% of the dose was recovered in the urine in the form of an unchanged drug.

Colchicine undergoes enterohepatic recirculation and biliary excretion. 7, 9.

After several doses of 0.6 mg twice daily, the average elimination half-life of colchicine ranges from 26.6-31.2 hours.

Another study reported the elimination half-life ranging to be 20-40 hours.

In one pharmacokinetic study involving patients who received a single oral dose of 0.6 mg colchicine, the clearance was 0.0321 ± 0.0091 mL/min in young, healthy adults and 0.0292 ± 0.0071 mL/min in adults between the ages of and 70 years.

Patients with end-stage renal impairment showed a 75% lower clearance of colchicine.

In a pharmacokinetic study of patients with Familial Mediterranean Fever (FMF), the apparent mean clearance was calculated at 0.726 ± 0.110 L/h/kg.

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The oral

LD of colchicine in mice is 5.87 mg/kg.

Acute overdose exceeding 0.5 mg/kg (35 mg for a 70 kg average adult) is usually fatal.

Fatalities have been reported with as little as 7 mg.

Colchicine poisoning presents in three sequential and usually overlapping phases.

The first stage of acute colchicine toxicity typically occurs 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.

The second stage develops 24-72 hours after ingestion and is characterized by multi-organ failure.

Death is usually a result of respiratory depression and cardiovascular collapse.

Recovery may be accompanied by rebound leukocytosis about one week after ingestion. 9, 12 No specific antidote is known.

Elimination of toxins by gastric lavage followed by activated charcoal should be attempted within 1-2 hours of ingestion.

Colchicine is not effectively removed by hemodialysis. 9, 12.

Patients with renal or hepatic impairment should not be given colchicine tablets 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.

Patients with renal or hepatic impairment should not be given colchicine tablets in conjunction with P-gp or strong CYP3A4 inhibitors ( Error! Hyperlink reference not valid).

In these patients, life-threatening and fatal colchicine toxicity has been reported with colchicine taken in therapeutic doses ( Error! Hyperlink reference not valid).

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 colchicine tablets are different for each indication and must be individualized.

The recommended dosage of colchicine tablets depends on the patient’s age, renal function, hepatic function and use of coadministered drugs.

Colchicine tablets are administered orally without regard to meals.

Colchicine tablets are not an analgesic medication and should not be used to treat pain from other causes.

• Gout Flares: Prophylaxis of Gout Flares: 0.6 mg once or twice daily in adults and adolescents older than 16 years of age ( Error! Hyperlink reference not valid).

Maximum dose 1.2 mg/day. Treatment of Gout Flares: 1.2 mg (two tablets) at the first sign of a gout flare followed by 0.6 mg (one tablet) one hour later ( Error! Hyperlink reference not valid).

• FMF: Adults and children older than 12 years 1.2.

• 2.4 mg; children to 12 years 0.9.

• 1.8 mg; children to 6 years 0.3.

• 1.8 mg ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid). o Give total daily dose in one or two divided doses ( Error! Hyperlink reference not valid). o Increase or decrease the dose as indicated and as tolerated in increments of 0.3 mg/day, not to exceed the maximum recommended daily dose ( Error! Hyperlink reference not valid).

• Colchicine tablets are administered orally without regard to meals.

• See full prescribing information (FPI) for dose adjustment regarding patients with impaired renal function ( Error! Hyperlink reference not valid)., impaired hepatic function ( Error! Hyperlink reference not valid)., the patient’s age ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid). or use of coadministered drugs ( Error! Hyperlink reference not valid). 2.1 Gout Flares Prophylaxis of Gout Flares The recommended dosage of colchicine tablets 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.

Colchicine tablets are 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.

The recommended dose of colchicine tablets 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 1-hour period.

Colchicine tablets 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. 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 Prophylaxis and Treatment of Gout Flares Colchicine tablets are not recommended for pediatric use in prophylaxis or treatment of gout flares.

FMF The recommended dosage of colchicine tablets for FMF in pediatric patients 4 years of age and older is based on age.

• Children to 6 years: 0.3 mg to 1.8 mg daily.

• Children 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 Coadministration of Interacting Drugs Concomitant Therapy Coadministration 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.

Table 1.

Colchicine Tablets Dose Adjustment for Coadministration with Interacting Drugs if No Alternative Available For magnitude of effect on colchicine plasma concentrations Strong CYP3A4 Inhibitors Patients with renal or hepatic impairment should not be given colchicine tablets in conjunction with strong CYP3A4 or P-gp inhibitors Gout Flares Noted or Anticipated Outcome Prophylaxis of Gout Flares Treatment of Gout Flares FMF Drug Original Intended Dosage Adjusted Dose Original Intended Dosage Adjusted Dose Original Intended Dosage Adjusted Dose Atazanavir Clarithromycin Darunavir/ Ritonavir When used in combination with Ritonavir, see dosing recommendations for strong CYP3A4 inhibitors 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 (1/2 tablet) 1 hour later.

Dose to be repeated no earlier than 3 days.

Maximum daily dose of 1.2 mg.

• 2.4 mg Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day) Moderate CYP3A4 Inhibitors Gout Flares Note or Anticipated Outcome Prophylaxis of Gout Flares Treatment of Gout Flares FMF Drug Original Intended Dosage Adjusted Dosage Original Intended Dosage Adjusted Dosage Original Intended Dosage Adjusted Dosage 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. 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.

• 2.4 mg Maximum daily dose of 1.2 mg (may be given as 0.6 mg twice a day) P-gp Inhibitors Gout Flares Note or Anticipated Outcome Prophylaxis of Gout Flares Treatment of Gout Flares FMF Drug Original Intended Dosage Adjusted Dosage Original Intended Dosage Adjusted Dosage Original Intended Dosage Adjusted Dosage 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.

• 2.4 mg Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day) Table 2.

Colchicine Tablets Dose Adjustment for Coadministration with Protease Inhibitors Protease Inhibitor Clinical Comment w/ Colchicine.

• Prophylaxis of Gout Flares w/o 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 (1/2 tablet) 1 hour later.

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.

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.

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.

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.

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.

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.

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.

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.

Dose to be re.

USP, 0.6 mg are purple colored, film-coated, capsule shaped tablets debossed with ‘ 372’ on one side and score line on the other side of the tablet.

Bottles of 5 NDC 71205-687-05 Bottles of 10 NDC 71205-687-10 Bottles of 21 NDC 71205-687-21 Bottles of 30 NDC 71205-687-30 Bottles of 60 NDC 71205-687-60 Bottles of 90 NDC 71205-687-90 logo 16.2 Storage Store at 20° to 25°C (68° to 77°F) .

Protect from light.

Available data from published literature on colchicine use in pregnancy over several decades have not identified any drug associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes.

Colchicine crosses the human placenta.

Although animal reproductive and developmental studies were not conducted with colchicine tablets, 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 to 4% and to 20%, respectively.

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.

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.

Safety and effectiveness of colchicine in pediatric patients with gout has not been established.

Clinical 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.