Pronunciation: KOL-chi-seen
Class: Agent for gout

Trade Names

Colchicine
- Tablets 0.6 mg

Colcrys
- Tablets 0.6 mg

Colchicine-Odan (Canada)

Pharmacology

The exact mechanism of action of colchicine in gout is not completely known, but it involves a reduction in lactic acid production by leukocytes, which results in a decrease in uric acid deposition, and a reduction in phagocytosis, with abatement of the inflammatory response. In familial Mediterranean fever, colchicine may interfere with the intracellular assembly of the inflammasome complex present in neutrophils and monocytes that mediates activation of interleukin-1beta. Colchicine disrupts cytoskeletal functions through inhibition of beta-tubulin polymerization into microtubules, and consequently prevents the activation, degranulation, and migration of neutrophils.

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Pharmacokinetics

Absorption

Rapidly absorbed. T _max is 1 to 2 h and mean C _max is 2.5 ng/mL (single dose). Absolute bioavailability is approximately 45%. Administration with food has no effect on the rate of absorption, but decreases the extent of absorption by 15%.

Distribution

Large amounts present in bile and intestinal secretions. High concentrations also found in kidney, liver, and spleen. Approximately 39% protein bound. Vd is 5 to 8 L/kg.

Metabolism

Demethylated to 2 primary metabolites by CYP3A4.

Elimination

Mean elimination half-life is 26.6 to 31.2 h. Excreted via enterohepatic recirculation and biliary routes; 40% to 60% excreted unchanged in urine.

Special Populations

Renal Function Impairment

Patients with ESRD had 75% lower Cl and prolonged elimination half-life.

Hepatic Function Impairment

Cl is significantly reduced and plasma half-life prolonged in patients with mild to moderate cirrhosis.

Elderly

Mean peak plasma levels and AUC were 2 times higher in elderly patients; however, this may be caused by decreased renal function.

Children

Pharmacokinetics not evaluated.

Gender

No differences in pharmacokinetics between men and women.

Indications and Usage

For the prophylaxis and the treatment of acute gout flares when taken at the first sign of a flare; treatment of familial Mediterranean fever ( Colcrys only).

Unlabeled Uses

Treatment of Behçet disease; hepatic cirrhosis; primary biliary cirrhosis; pericarditis; scleroderma; Sweet syndrome; amyloidosis; sarcoid arthritis; acute inflammatory calcific tendonitis; arthritis associated with erythema nodosum; leukemia; adenocarcinoma of the GI tract; mycosis fungoides; topically to treat intraurethral condyloma acuminata in men.

Contraindications

Serious GI, renal, hepatic, or cardiac disorders; blood dyscrasias; coadministration with P-glycoprotein (Pgp) or strong CYP3A4 inhibitors in patients with renal or hepatic impairment ( Colcrys only); hypersensitivity to the drug.

Dosage and Administration

Familial Mediterranean Fever ( Colcrys Only)
Adults and Children 13 y of age and older

PO Usual dosage is 1.2 to 2.4 mg daily.

Children 6 to 12 y of age

PO Usual dosage is 0.9 to 1.8 mg daily.

Children 4 to 6 y of age

PO Usual dosage is 0.3 to 1.8 mg daily.

Dosage adjustment

Increase as needed in increments of 0.3 mg/day to a max daily recommended dose to control disease and as tolerated. If intolerable adverse effects develop, the dosage should be decreased in increments of 0.3 mg/day.

Prophylaxis of Gout Flares
Adults

PO 0.6 mg once or twice daily; max dose is 1.2 mg/day

Alternative dosage

The following dosing information is based on product labeling from non–FDA-approved colchicine products.

PO Less than 1 attack per year, 0.6 mg/day 3 or 4 days a week; more than 1 attack per year, 0.6 mg daily. Severe cases may require 1.2 or 1.8 mg daily.

Surgical patients

0.6 mg 3 times daily for 3 days before and 3 days after surgery

Treatment of Gout Flares
Adults

PO 1.2 mg at the first sign of flare, followed by 0.6 mg 1 h later (max dose, 1.8 mg over a 1-h period). If also taking colchicine for prophylaxis of gout flares, wait 12 h after taking the last dose for treatment of the flare, then resume prophylaxis dose.

Alternative dosage

The following dosing information is based on product labeling from non–FDA-approved colchicine products.

PO Initially, 0.6 to 1.2 mg at the first sign of flare, followed by 0.6 mg every h or 1.2 mg every 2 h until pain is relieved or diarrhea ensues. After the initial dose, it is sometimes sufficient to take 0.6 mg every 2 or 3 h. Usual dose is 4 to 8 mg per attack. An interval of 3 days between colchicine courses is advised in order to minimize the possibility of cumulative toxicity.

If corticotropin (ACTH) is administered, it is recommended that colchicine also be given in dosages of at least 1 mg/day, and that the latter be continued for a few days after the hormone is withdrawn.

Renal Function Impairment
Mild (CrCl 50 to 80 mL/min) or moderate (CrCl 30 to 50 mL/min) renal impairment

Dosage adjustment may be necessary in patients with familial Mediterranean fever.

Severe renal impairment (CrCl less than 30 mL/min) renal impairment

Start with 0.3 mg/day in patients with familial Mediterranean fever; any increase in dose should be done with adequate monitoring for adverse reactions.

Gout flares Prophylaxis

Initially, 0.3 mg/day. Any increase should be done with close monitoring.

Treatment

Dosage adjustment is not required, but a treatment course should be repeated no more than once every 2 wk. For patients requiring repeated courses, consider alternate therapy.

Dialysis Familial Mediterranean fever

Initially, 0.3 g/day. Dosing can be increased with close monitoring.

Gout flares Prophylaxis

0.3 mg twice a wk with close monitoring.

Treatment

Single dose of 0.6 mg. A treatment course should not be repeated more than once every 2 wk.

Alternative Dosing Regimen Gout flares CrCl more than 50 mL/min

100% of usual daily dose.

CrCl 10 to 50 mL/min or continuous renal replacement therapy

50% to 100% of usual daily dose.

CrCl less than 10 mL/min or peritoneal dialysis

25% of usual daily dose.

Hepatic Function Impairment
Familial Mediterranean fever

In patients with severe hepatic impairment, dosage reduction should be considered with careful monitoring.

Gout flares Prophylaxis

Dosage adjustment should be considered in patients with severe hepatic disease.

Treatment

In patients with severe hepatic impairment, carefully monitor and do not repeat the treatment course more than once every 2 wk. For patients requiring repeated courses, consider alternate therapy.

Concomitant therapy

Coadministration of colchicine with Pgp inhibitors or strong CYP3A4 inhibitors in patients with renal or hepatic impairment is contraindicated. If patients are taking or have recently completed treatment with a strong or moderate CYP3A4 inhibitor or Pgp inhibitor within the prior 14 days, colchicine dosage adjustments are required.

Strong CYP3A4 inhibitors (eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin) Familial Mediterranean fever

Max daily dose of 0.6 mg.

Gout flares Prophylaxis

If taking 0.6 mg twice daily, decrease dosage to 0.3 mg once daily. If taking 0.6 mg once daily, decrease dosage to 0.3 mg every other day.

Treatment

0.6 mg as 1 dose at the first sign of attack, followed by 0.3 mg 1 h later. Dose to be repeated no earlier than 3 days. Use is not recommended in patients receiving prophylactic dose of colchicine and CYP3A4 inhibitor.

Moderate CYP3A4 inhibitors (eg, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, verapamil) Familial Mediterranean fever

Max daily dose of 1.2 mg.

Gout flares Prophylaxis

If taking 0.6 mg twice daily, decrease dosage to 0.3 mg twice daily. If taking 0.6 mg once daily, decrease dosage to 0.3 mg once daily.

Treatment

1.2 mg as 1 dose at the first sign of attack. Dose to be repeated no earlier than 3 days. Use is not recommended in patients receiving prophylactic dose of colchicine and CYP3A4 inhibitor.

Pgp inhibitors (eg, cyclosporine, ranolazine) Familial Mediterranean fever

Max daily dose of 0.6 mg.

Gout flares Prophylaxis

If taking 0.6 mg twice daily, decrease dosage to 0.3 mg once daily. If taking 0.6 mg once daily, decrease dosage to 0.3 mg every other day.

Treatment

0.6 mg as 1 dose at the first sign of attack. Dose to be repeated no earlier than 3 days.

General Advice

• Colcrys is the only FDA-approved single-ingredient colchicine product.
• Administer orally without regard to meals.
• The total daily dose of Colcrys may be administered in 1 or 2 divided doses.
• Treatment of gout flares is not recommended in patients with renal or hepatic impairment who are receiving colchicine for prophylaxis.

Storage/Stability

Store at 68° to 77°F. Protect from light.

Drug Interactions

Acidifying agents

The action of colchicine is inhibited by acidifying agents. Avoid coadministration.

Alkalinizing agents

The action of colchicine is potentiated by alkalinizing agents. Avoid coadministration.

CNS depressants

Colchicine may increase sensitivity to the action of CNS depressants. Monitor the patient and adjust the CNS depressant dosage as needed.

Cyclosporine, digoxin, fibric acids (eg, fenofibrate, gemfibrozil), HMG-CoA reductase inhibitors (eg, atorvastatin, fluvastatin, pravastatin, simvastatin)

The risk of myopathy or rhabdomyolysis may be increased. If coadministration cannot be avoided, monitor the patient for signs of any unexplained muscle pain, tenderness, or weakness. If colchicine toxicity is suspected, discontinue colchicine.

Grapefruit juice

Colchicine plasma concentrations may be elevated by grapefruit juice ingestion, increasing the risk of toxicity (eg, myopathy). Advise patients taking colchicine not to consume grapefruit juice.

Moderate CYP3A4 inhibitors (eg, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, verapamil)

Colchicine plasma concentrations may be elevated, increasing the risk of toxicity (eg, myopathy). Coadminister with caution, starting at reduced colchicine doses, and increase monitoring of creatine phosphokinase and for adverse reactions. If colchicine toxicity is suspected, discontinue colchicine.

Pgp inhibitors (eg, cyclosporine, ranolazine), strong CYP3A4 inhibitors (eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole)

Life-threatening and fatal drug interactions have been reported in patients receiving colchicine and Pgp inhibitors or strong CYP3A4 inhibitors. Coadministration of colchicine and a Pgp inhibitor or strong CYP3A4 inhibitor to patients with renal or hepatic impairment is contraindicated. If treatment with a Pgp inhibitor or strong CYP3A4 inhibitor is needed in patients with healthy renal and hepatic function, the colchicine dose may need to be reduced or withheld. If colchicine toxicity is suspected, discontinue colchicine.

Sympathomimetics

The action of sympathomimetics may be increased. Monitor the patient and adjust the sympathomimetic dose as needed.

Laboratory Test Interactions

May cause false-positive results in urine tests for RBCs and hemoglobin.

Adverse Reactions

CNS

Fatigue (4%); headache (2%); peripheral neuritis; sensory motor neuropathy (postmarketing).

Dermatologic

Dermatoses; alopecia, maculopapular rash, purpura, rash (postmarketing).

GI

Diarrhea (77%); nausea, vomiting (17%); abdominal cramping, abdominal pain, lactose intolerance (postmarketing).

Genitourinary

Azoospermia, oligospermia (postmarketing).

Hematologic

Bone marrow depression with aplastic anemia, agranulocytosis, or thrombocytopenia; leukopenia, granulocytopenia, pancytopenia (postmarketing).

Hepatic

Elevated AST and ALT (postmarketing)

Musculoskeletal

Myopathy; elevated CPK, myotonia, muscle weakness or pain, rhabdomyolysis (postmarketing).

Miscellaneous

Gout (4%); pharyngolaryngeal pain, respiratory, thoracic mediastinal disorders (3%); hypersensitivity reactions.

Precautions

Monitor Check CBCs periodically in patients undergoing long-term therapy. Assess for signs of toxicity (eg, abdominal pain, alopecia, diarrhea, myopathy, nausea, peripheral neuritis, vomiting). Closely monitor patients with renal or hepatic impairment for adverse reactions.

Pregnancy

Category C .

Lactation

Excreted.

Children

Safety and efficacy not established for gout; not approved for children 3 y of age and younger with familial Mediterranean fever.

Elderly

Administer with great caution.

Renal Function

Monitor patients carefully; dosage adjustment may be required.

Hepatic Function

Monitor patients carefully; dosage adjustment may be required.

Special Risk Patients

Administer with great caution to debilitated patients and to those with early manifestations of GI or cardiac disorders.

Hematologic effects

Myleosuppression, leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, and aplastic anemia have been reported. Use with caution in patients with hematologic disorders.

Neuromuscular toxicity

Has been reported.

Overdosage

Symptoms

Alopecia; ascending paralysis of the CNS; burning sensations of the throat, stomach, and skin; convulsions; delirium; diarrhea (may be bloody); kidney damage; muscular weakness; nausea; peripheral leukocytosis; severe abdominal pain; shock; significant fluid loss leading to volume depletion; vomiting.

Patient Information

• Advise patients taking Colcrys to read the Medication Guide before use for the first time and with each refill.
• Inform patients that fatal overdoses, both accidental and intentional, have been reported.
• Instruct patient to take colchicine regularly to prevent acute attacks.
• Inform patients that bone marrow depression with agranulocytosis, aplastic anemia, and thrombocytopenia may occur.
• Inform patients that muscle pain or weakness, or tingling or numbness in the fingers or toes may occur.
• Advise patients to avoid grapefruit juice during therapy.
• Instruct patient to stop taking drug if nausea, vomiting, diarrhea, or abdominal pain occurs.
• Advise patients that many drugs or other substances may interact with colchicine and some interactions could be fatal. Instruct patients to report all current medications to health care provider and to check with health care provider before starting new medications.

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