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Special Alerts
Colchicine: FDA Approved Oral Product (Colcrys™) and Safety Issues Associated With Colchicine Use - July 2009
The Food and Drug Administration (FDA) has approved an oral colchicine product, Colcrys™, for the treatment of familial Mediterranean fever (FMF) and acute gout flares. Prior to the approval of Colcrys™, colchicine had been available as an unapproved medication without FDA-approved prescribing information. In addition, the FDA is also notifying healthcare professionals of two new safety concerns associated with colchicine involving drug interactions and the safety of doses historically used in the treatment of acute gout.
The FDA analyzed safety data from published literature, pharmacokinetic and drug interaction studies, as well as previously reported adverse events, and discovered cases of fatal colchicine toxicity in certain patients. The cases occurred in patients receiving concomitant medications that interact with colchicine, such as clarithromycin (despite receiving standard therapeutic doses of colchicine). These reports suggest a role of concomitant medications which affect the gastrointestinal absorption and/or hepatic metabolism of colchicine in the development of toxicity (particularly in patients with renal or hepatic impairment).
In addition, the FDA analysis of safety and efficacy data of colchicine in acute gout revealed that a substantially lower dose of colchicine (total cumulative dose: 1.8 mg) demonstrated efficacy compared to the higher dose (total cumulative dose: 4.8 mg) traditionally used. There were also fewer adverse events reported with the lower dose.
In light of the safety issues, the FDA is recommending that colchicine not be used concurrently with P-glycoprotein (P-gp) or strong CYP3A4 inhibitors in patients with renal or hepatic impairment, and a dose reduction or interruption of colchicine therapy be considered in those patients without renal or hepatic impairment. A medication guide has also been developed for patient distribution.
For additional information, please refer to http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm174596.ht
Medication Safety Issues
Sound-alike/look-alike issues:
Colchicine may be confused with Cortrosyn®
Pronunciation
(KOL chi seen)
U.S. Brand Names
Generic Available
Yes
Pharmacologic Category
Use: Labeled Indications
Treatment of acute gout flares and familial Mediterranean fever (FMF)
Use: Unlabeled/Investigational
Primary biliary cirrhosis; pericarditis; prophylaxis of acute gout flares during initiation of antihyperuricemic therapy
Pregnancy Risk Factor
C
Lactation
Enters breast milk/use caution (AAP rates “compatible”)
Contraindications
Concomitant use of a P-glycoprotein (P-gp) or strong CYP3A4 inhibitor in presence of renal or hepatic impairment
Warnings/Precautions
Concerns related to adverse effects:
• Blood dyscrasias: Myelosuppression (eg, thrombocytopenia, leukopenia, granulocytopenia, pancytopenia) and aplastic anemia have been reported in patients receiving therapeutic doses.
• Gastrointestinal symptoms: Dosage reduction is recommended in patients who develop gastrointestinal symptoms (anorexia, diarrhea, nausea, vomiting) related to drug therapy.
• Neuromuscular toxicity: Myotoxicity (including rhabdomyolysis) has been reported in patients receiving therapeutic doses; patients with renal dysfunction and elderly patients are at increased risk. Concomitant use of cyclosporine, diltiazem, verapamil, fibrates, and statins may increase the risk of myopathy.
Disease-related concerns:
• Hepatic impairment: Clearance is decreased in hepatic impairment; monitor closely for adverse effects/toxicity. Dosage adjustments may be considered depending on degree of impairment or indication, and may be affected by the use of concurrent medication (CYP3A4 or P-gp inhibitors). Concurrent use of P-gp or strong CYP3A4 inhibitors is contraindicated in hepatic impairment. Fatal toxicity has been reported.
• Renal impairment: Clearance is decreased in renal impairment; monitor closely for adverse effects/toxicity. Dosage adjustments may be required depending on degree of impairment or indication, and may be affected by the use of concurrent medication (CYP3A4 or P-gp inhibitors). Concurrent use of P-gp or strong CYP3A4 inhibitors is contraindicated in renal impairment. Fatal toxicity has been reported.
Concurrent drug therapy issues:
• High potential for interactions: Use with caution in patients taking P-gp or moderate or strong CYP3A4 inhibitors; significant increase in colchicine serum concentrations and fatal toxicity have been reported; dosage adjustment required.
Special populations:
• Elderly: Use with caution in the elderly; literature suggests dosage adjustments should be considered.
Other warnings/precautions:
• Appropriate use: Colchicine does not have analgesic activity and should not be used to treat pain from other causes.
• Fatal overdose: Accidental and intentional fatal overdoses have been reported. Dosage associated with fatal toxicity is variable (eg, wide dosage range).
Adverse Reactions
>10%: Gastrointestinal: Diarrhea (up to 23%), abdominal pain, cramping, nausea, vomiting
1% to 10%:
Central nervous system: Fatigue
Gastrointestinal: Anorexia
Respiratory: Pharyngolaryngeal pain
<1%, postmarketing, and/or case reports: Alopecia, ALT increased, aplastic anemia, AST increased, azoospermia, bone marrow suppression, CPK increased, dermatosis, granulocytopenia, hepatotoxicity, hypersensitivity reaction, leukopenia, maculopapular rash, muscle weakness, myalgia, myopathy, myotonia, neuropathy, oligospermia, pancytopenia, peripheral neuritis, purpura, rash, rhabdomyolysis, thrombocytopenia
Metabolism/Transport Effects
Substrate of CYP3A4 (major); Induces CYP2C8 (weak), 2C9 (weak), 2E1 (weak), 3A4 (weak)
Drug Interactions
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Colchicine. Management: Reduce colchicine dose as directed when using with a moderate CYP3A4 inhibitor, and increase monitoring for colchicine-related toxicity. Use extra caution in patients with impaired renal and/or hepatic function. Risk D: Consider therapy modification
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Colchicine. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a strong CYP3A4 inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. Risk D: Consider therapy modification
Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Fibric Acid Derivatives: May enhance the myopathic (rhabdomyolysis) effect of Colchicine. Risk C: Monitor therapy
HMG-CoA Reductase Inhibitors: Colchicine may enhance the myopathic (rhabdomyolysis) effect of HMG-CoA Reductase Inhibitors. Colchicine may increase the serum concentration of HMG-CoA Reductase Inhibitors. Risk D: Consider therapy modification
P-Glycoprotein Inducers: May decrease the serum concentration of P-Glycoprotein Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
P-Glycoprotein Inhibitors: May increase the serum concentration of Colchicine. Colchicine distribution into certain tissues (e.g., brain) may also be increased. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a p-glycoprotein inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. Risk D: Consider therapy modification
Saxagliptin: CYP3A4 Inducers may decrease the serum concentration of Saxagliptin. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Ethanol: Avoid ethanol.
Food: Cyanocobalamin (vitamin B12): Malabsorption of the substrate. May result in macrocytic anemia or neurologic dysfunction. Grapefruit juice may increase colchicine serum concentrations.
Herb/Nutraceutical: Vitamin B12 absorption may be decreased by colchicine.
Storage
Store at 20°C to 25°C (68°F to 77°F). Protect from light.
Mechanism of Action
Disrupts cytoskeletal functions by inhibiting ?-tubulin polymerization into microtubules, preventing activation, degranulation, and migration of neutrophils associated with mediating some gout symptoms. In familial Mediterranean fever, may interfere with intracellular assembly of the inflammasome complex present in neutrophils and monocytes that mediate activation of interleukin-1?.
Pharmacodynamics/Kinetics
Onset of action: Oral: Pain relief: ~18-24 hours
Distribution: Concentrates in leukocytes, kidney, spleen, and liver; does not distribute in heart, skeletal muscle, and brain
Vd: 5-8 L/kg
Protein binding: ~39%
Metabolism: Hepatic via CYP3A4; 3 metabolites (2 primary, 1 minor)
Bioavailability: 45%
Half-life elimination: 27-31 hours (multiple oral doses; young, healthy volunteers)
Time to peak, serum: Oral: 0.5-3 hours
Excretion: Urine (40% to 65% as unchanged drug); enterohepatic recirculation and biliary excretion also possible
Dosage
Oral:
Familial Mediterranean fever (FMF):
Children:
4-6 years: 0.3-1.8 mg/day in 1-2 divided doses
6-12 years: 0.9-1.8 mg/day in 1-2 divided doses
Children >12 years and Adults: 1.2-2.4 mg/day in 1-2 divided doses. Titration: Increase or decrease dose in 0.3 mg increments based on efficacy or adverse effects
Gout: Adults:
Flares: Initial: 1.2 mg at the first sign of flare, followed in 1 hour with a single dose of 0.6 mg (maximum: 1.8 mg within 1 hour). Note: Current FDA-approved dose for gout flare is substantially lower than what has been historically used clinically. Doses larger than the currently recommended dosage for gout flare have not been proven to be more effective.
Prophylaxis of acute attacks (unlabeled use): 0.6 mg twice daily; initial and/or subsequent dosage may be decreased (eg, 0.6 mg once daily) in patients who are intolerant (diarrhea) (Terkeltaub, 2009)
Pericarditis (unlabeled use): Adults: 0.6 mg twice daily (Antman, 2004)
Primary biliary cirrhosis (unlabeled use): Adults: 0.6 mg twice daily (Kaplan, 2005); Note: Use reserved for patients refractory to ursodiol.
Elderly: Use caution; reduce prophylactic daily dose by 50% in individuals >70 years (Terkeltaub, 2009)
Dosage adjustment for concomitant therapy with CYP3A4 or P-glycoprotein (P-gp) inhibitors: Dosage adjustment also required in patients receiving CYP3A4 or P-gp inhibitors up to 14 days prior to initiation of colchicine.
Coadministration of strong CYP3A4 inhibitor (eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin):
FMF: Maximum dose: 0.6 mg/day (0.3 mg twice daily)
Gout flare: Initial: 0.6 mg, followed in 1 hour by a single dose of 0.3 mg; do not repeat for at least 3 days
Coadministration of moderate CYP3A4 inhibitor (eg, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, verapamil):
FMF: Maximum dose: 1.2 mg/day (0.6 mg twice daily)
Gout flare: 1.2 mg as a single dose; do not repeat for at least 3 days
Coadministration of P-gp inhibitor (eg, cyclosporine, ranolazine):
FMF: Maximum dose: 0.6 mg/day (0.3 mg twice daily)
Gout flare: Initial: 0.6 mg as a single dose; do not repeat for at least 3 days
Dosing adjustment in renal impairment: Concurrent use of colchicine and P-gp or strong CYP3A4 inhibitors is contraindicated in renal impairment. Fatal toxicity has been reported.
FMF:
Clcr 30-80 mL/minute: Monitor closely for adverse effects; dose reduction may be necessary
Clcr <30 mL/minute: Initial dose: 0.3 mg/day; use caution if dose titrated; monitor for adverse effects
Dialysis: 0.3 mg as a single dose; use caution if dose titrated; monitor for adverse effects. Not removed by dialysis.
Gout flares:
Clcr 30-80 mL/minute: Dosage adjustment not required; monitor closely for adverse effects
Clcr <30 mL/minute: Dosage reduction not required but may be considered; treatment course should not be repeated more frequently than every 14 days
Dialysis: 0.6 mg as a single dose; treatment course should not be repeated more frequently than every 14 days. Not removed by dialysis.
Gout prophylaxis (Terkeltaub, 2009):
Clcr 35-49 mL/minute: 0.6 mg once daily
Clcr 10-34 mL/minute: 0.6 mg every 2-3 days
Clcr <10 mL/minute: Avoid chronic use of colchicine.
Hemodialysis: Avoid chronic use of colchicine.
Dosage adjustment in hepatic impairment: Concurrent use of colchicine and P-gp or strong CYP3A4 inhibitors is contraindicated in hepatic impairment. Fatal toxicity has been reported.
FMF:
Mild-to-moderate impairment: Use caution; monitor closely for adverse effects
Severe impairment: Consider dosage reduction
Gout flares:
Mild-to-moderate impairment: Dosage adjustment not required; monitor closely for adverse effects
Severe impairment: Dosage reduction not required but may be considered; treatment course should not be repeated more frequently than every 14 days
Administration: Oral
Administer orally with water and maintain adequate fluid intake.
Monitoring Parameters
CBC, renal and hepatic function tests
Test Interactions
May cause false-positive results in urine tests for erythrocytes or hemoglobin
Dietary Considerations
May need to supplement with vitamin B12. Avoid grapefruit juice.
Patient Education
Take as directed; do not exceed recommended dosage. Consult prescriber about a low-purine diet. Maintain adequate hydration unless instructed to restrict fluid intake. Do not use alcohol or aspirin-containing medication without consulting prescriber. You may experience nausea, vomiting, or anorexia (small frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); hair loss (reversible). Stop medication and report to prescriber if severe vomiting, watery or bloody diarrhea, or abdominal pain occurs. Report muscle tremors or weakness; fatigue; easy bruising or bleeding; yellowing of eyes or skin; or pale stool or dark urine. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Consult prescriber if breast-feeding.
Geriatric Considerations
Colchicine appears to be more toxic in older adults, particularly in the presence of renal, gastrointestinal, or cardiac disease. The most predictable oral side effects are gastrointestinal (eg, vomiting, abdominal pain, and nausea). If colchicine is stopped at this point, other more severe adverse effects may be avoided, such as bone marrow suppression, peripheral neuritis, etc.
Additional Information
Oral colchicine had been available as an unapproved medication without FDA-approved prescribing information. In August 2009, the FDA approved prescribing information for a brand name colchicine product. The currently approved prescribing information recommends a lower than historically used dosage for the treatment of acute gout. This recommendation is based on data from the AGREE trial. In this trial, low-dose colchicine (1.8 mg total) had similar efficacy to high dose colchicine (4.8 mg total). Additionally, the low dosage regimen was associated with a lower incidence (26% vs 77%) of GI adverse events. Parenteral formulation of colchicine is no longer available in the U.S.; serious life-threatening complications (eg, neutropenia, acute renal failure, thrombocytopenia, heart failure) associated with intravenous colchicine have occurred prior to market withdrawal. The risks associated with oral colchicine are believed to be lower compared to intravenous use.
Dental Health: Effects on Dental Treatment
No significant effects or complications reported
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May cause drowsiness
Mental Health: Effects on Psychiatric Treatment
Rare reports of agranulocytosis; use caution with clozapine and carbamazepine; CNS depressant effects may be enhanced
Nursing: Physical Assessment/Monitoring
Assess effectiveness and interactions of other medications patient may be taking. Monitor therapeutic effectiveness, laboratory values, and adverse reactions at beginning of therapy and periodically with long-term use. Assess knowledge/teach patient appropriate use, interventions to reduce side effects, and adverse symptoms to report.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet: 0.6 mg
Pricing: U.S. (www.drugstore.com)
Tablets (Colchicine)
0.6 mg (30): $12.99
References
Antman EM, Anbe SC, Alpert JS, et al, “ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction - Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction),” Circulation, 2004, 110(5):588-636. Available at: http://www.circulationaha.org/cgi/content/full/110/5/588. Last accessed October 26, 2004.
Borstad GC, Bryant LR, Abel MP, et al, “Colchicine for Prophylaxis of Acute Flares When Initiating Allopurinol for Chronic Gouty Arthritis,” J Rheumatol, 2004, 31(12):2429-32.
Centers for Disease Control and Prevention (CDC), “Deaths From Intravenous Colchicine Resulting From a Pharmacy Compounding Error - Oregon And Washington, 2007,” MMWR Morb Mortal Wkly Rep, 2007, 56(40):1050-2.
Emmerson BT, “The Management of Gout,” N Engl J Med, 1996, 334(7):445-51.
Kaplan MM and Gershwin ME, “Primary Biliary Cirrhosis,” N Engl J Med, 2005, 353(12):1261-73.
Kaplan MM, Schmid C, Provenzale D, et al, “A Prospective Trial of Colchicine and Methotrexate in the Treatment of Primary Biliary Cirrhosis,” Gastroenterology, 1999, 117(5):1173-80.
Levy M, Spino M, and Read SE, “Colchicine: A State-of-the-Art Review,” Pharmacotherapy, 1991, 11(3):196-211.
Majeed HA, Carroll JE, Khuffash FA, et al, “Long-Term Colchicine Prophylaxis in Children With Familial Mediterranean Fever (Recurrent Hereditary Polyserositis),” J Pediatr, 1990, 116(6):997-9.
Terkeltaub RA, “Colchicine Update: 2008,” Semin Arthritis Rheum, 2009, 38(6):411-9.
Terkeltaub RA, “Gout,” N Engl J Med, 2003, 349(17):1647-55.
Wallace SL, Singer JZ, Duncan GJ, et al, “Renal Function Predicts Colchicine Toxicity: Guidelines for the Prophylactic Use of Colchicine in Gout,” J Rheumatol, 1991, 18(2):264-9.
International Brand Names
Lexi-Comp.com
Last full review/revision September 2009
Content last modified September 2009
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