Class: Antigout Agents
VA Class: MS400
CAS Number: 64-86-8
Brands: Colcrys
REMS:
FDA approved a REMS for colchicine to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of colchicine and consists of the following: medication guide. See the FDA REMS page () or the ASHP REMS Resource Center ().
Introduction
Antigout and antimitotic agent.
Uses for Colchicine
Gout Flare
Treatment to relieve pain in attacks of acute gout flare (gouty arthritis).123 124 125 126 127 142 143 152 Initiate at the first sign of gout flare.152 Used as a second-line agent in patients who have not responded to or who cannot tolerate other recommended therapy (i.e., NSAIAs, corticosteroids).142 143
Prophylactic treatment of recurrent gout flare.152 Has no effect on plasma concentrations or urinary excretion of uric acid;123 124 129 130 143 146 use concomitantly with allopurinol or a uricosuric agent (e.g., febuxostat, probenecid, sulfinpyrazone) to decrease serum urate concentrations.123 124 129 130 143 146 Colchicine/probenecid fixed-dosage preparation has limited usefulness for prophylactic therapy because colchicine present exceeds the amount required by most patients.a
Familial Mediterranean Fever
Management of familial Mediterranean fever.100 103 104 105 106 107 108 109 110 111 149 152 Used for chronic prophylactic therapy to reduce frequency and severity of episodic attacks of painful serositis in patients with familial Mediterranean fever.100 103 104 105 106 107 108 109 149 150 152
Not curative; manifestations return to pretreatment levels following discontinuance.100 104 107 108 109
Chronic prophylactic therapy appears to prevent amyloidosis (manifested by nephropathy) when there is no evidence of it at initiation of therapy;100 appears to be effective for preventing amyloidosis regardless of whether patients continue to experience episodic attacks of serositis during chronic prophylactic therapy with the drug.149 150 May prevent deterioration during proteinuric phase of the disease (when amyloid involvement is minimal).100
Regulations Governing Colchicine Injection
On February 8, 2008, FDA announced that it would take enforcement action (e.g., seizure, injunction, other judicial proceeding) against all firms, including compounding pharmacies, attempting to manufacture, ship, or deliver colchicine injection because of potentially serious health risks associated with use of the injection.144 145 (See Serious Adverse Effects Related to Colchicine Injection under Cautions and see Preparations.)
Colchicine Dosage and Administration
General
Gout
Administer prophylactic doses of colchicine before initiation of allopurinol or uricosurics because sudden changes in serum urate concentrations may precipitate acute gout flare.124 125 127 129
May discontinue colchicine and use urate-lowering agents alone after serum urate concentration is reduced to the desired level, and acute gout flares have not occurred for 3–6 months (some clinicians suggest 1–12 months).124 126 143
Administration
Administer orally.152 Has been administered IV; parenteral preparation no longer available in the US.144 145 (See Serious Adverse Effects Related to Colchicine Injection under Cautions.)
Oral Administration
Initiate therapy for acute gout flare at the first sign of an attack.152
Administer without regard to meals.152
Dosage
Dosage depends on the patient’s age, renal and hepatic function, and recent (within 14 days) or concomitant use of moderate or potent CYP3A4 inhibitors or inhibitors of the P-glycoprotein transport system.152
Pediatric Patients
Prophylactic Treatment of Recurrent Gout Flares
Oral
Manufacturer states that adolescents ≥16 years of age may receive adult dosages.152
Familial Mediterranean Fever
Oral
Recommended dosage in children not receiving concomitant therapy with a moderate or potent CYP3A4 inhibitor or a P-glycoprotein inhibitor depends on child’s age (see Table 1).152 Manufacturer makes no specific recommendations for children who are receiving or have recently received therapy with a moderate or potent CYP3A4 inhibitor or an inhibitor of the P-glycoprotein transport system.152
Dosage can be increased in increments of 0.3 mg daily to the maximum recommended dosage or decreased in decrements of 0.3 mg daily in individuals who develop intolerable adverse effects.152
Table 1. Recommended Dosage of Colchicine for Chronic Prophylactic Therapy of Familial Mediterranean Fever in Children Not Receiving Concomitant Therapy with Moderate or Potent CYP3A4 Inhibitors or with P-glycoprotein Inhibitors
Child’s Age (years)
|
Recommended Colchicine Dosage
|
|---|
4–6
|
0.3–1.8 mg daily (given as 1 dose or 2 divided doses)152
|
6–12
|
0.9–1.8 mg daily (given as 1 dose or 2 divided doses)152
|
>12
|
1.2–2.4 mg daily (given as 1 dose or 2 divided doses)152
|
Adults
Treatment of Gout Flare
Oral
Recommended dosage of colchicine depends on whether patient is receiving or has recently (within 14 days) received a moderate or potent CYP3A4 inhibitor or an inhibitor of the P-glycoprotein transport system (see Table 2).152
Use of colchicine for treatment of gout flare is not recommended in patients receiving the drug for prevention of gout flare and also receiving a CYP3A4 inhibitor.152
Do not repeat courses of colchicine therapy (see Table 2) until 3 days have elapsed.152
Table 2. Recommended Adult Dosage of Colchicine for Treatment of Gout Flare
Recent (within 14 days) or Concomitant Therapy
|
Recommended Colchicine Dosage
|
|---|
No recent or concomitant therapy with a moderate or potent CYP3A4 inhibitor or a P-glycoprotein inhibitor
|
1.2 mg at first sign of flare followed by 0.6 mg one hour later;152 wait 12 hours before resuming prophylactic doses of colchicine152
|
Potent CYP3A4 inhibitor (atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin)
|
0.6 mg at first sign of flare followed by 0.3 mg one hour later152
|
Moderate CYP3A4 inhibitor (aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, verapamil)
|
1.2 mg at first sign of flare152
|
P-glycoprotein inhibitor (cyclosporine, ranolazine)
|
0.6 mg at first sign of flare152
|
Prophylactic Treatment of Recurrent Gout Flares
Oral
Recommended dosage of colchicine depends on whether patient is receiving or has recently (within 14 days) received a moderate or potent CYP3A4 inhibitor or an inhibitor of the P-glycoprotein transport system (see Table 3).152
Table 3. Recommended Adult Dosage of Colchicine for Prophylactic Treatment of Recurrent Gout Flares
Recent (within 14 days) or Concomitant Therapy
|
Recommended Colchicine Dosage
|
|---|
No recent or concomitant therapy with a moderate or potent CYP3A4 inhibitor or a P-glycoprotein inhibitor
|
0.6 mg once or twice daily (maximum 1.2 mg daily)152
|
Potent CYP3A4 inhibitor (atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin)
|
0.3 mg daily or every other day152
|
Moderate CYP3A4 inhibitor (aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, verapamil)
|
0.3 mg twice daily, 0.6 mg once daily, or 0.3 mg once daily152
|
P-glycoprotein inhibitor (cyclosporine, ranolazine)
|
0.3 mg once daily or every other day152
|
Colchicine/Probenecid Fixed-Combination Therapy
Oral
Fixed-dosage preparation has limited usefulness for prophylactic therapy because colchicine present exceeds the amount required by most patients.a
Manufacturer recommends initial dosage of colchicine 0.5 mg in fixed combination with probenecid 500 mg (1 tablet) daily for 1 week, then 1 tablet twice daily.146 If gouty arthritis is not controlled or if 24-hour uric acid excretion is ≤700 mg, increase daily dosage by 1 tablet every 4 weeks as tolerated (generally not exceeding 4 tablets [colchicine 2 mg and probenecid 2 g] daily).146
If acute attacks have been absent ≥6 months and serum urate concentrations are controlled, manufacturer recommends reducing dosage by 1 tablet every 6 months as long as serum urate concentrations remain controlled.146
Familial Mediterranean Fever
Oral
Recommended dosage of colchicine depends on whether patient is receiving or has recently (within 14 days) received a moderate or potent CYP3A4 inhibitor or an inhibitor of the P-glycoprotein transport system (see Table 4).152
Dosage can be increased in increments of 0.3 mg daily to the maximum recommended dosage or decreased in decrements of 0.3 mg daily in individuals who develop intolerable adverse effects.152
Table 4. Recommended Adult Dosage of Colchicine for Chronic Prophylactic Therapy of Familial Mediterranean Fever
Recent (within 14 days) or Concomitant Therapy
|
Maximum Recommended Colchicine Dosage
|
|---|
No recent or concomitant therapy with a moderate or potent CYP3A4 inhibitor or a P-glycoprotein inhibitor
|
1.2–2.4 mg daily (given as 1 dose or 2 divided doses)152
|
Potent CYP3A4 inhibitor (atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin)
|
0.6 mg daily (may be given as 0.3 mg twice daily)152
|
Moderate CYP3A4 inhibitor (aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, verapamil)
|
1.2 mg daily (may be given as 0.6 mg twice daily)152
|
P-glycoprotein inhibitor (cyclosporine, ranolazine)
|
0.6 mg daily (may be given as 0.3 mg twice daily)152
|
Special Populations
Hepatic Impairment
Contraindicated in patients with hepatic impairment who are receiving or have recently received therapy with a potent CYP3A4 inhibitor or an inhibitor of the P-glycoprotein transport system.152
Treatment of Gout Flare
Oral
Mild to moderate hepatic impairment: Dosage adjustment is not needed, but monitor for adverse effects.152
Severe hepatic impairment: Dosage adjustment is not needed, but do not repeat courses of colchicine therapy until 2 weeks have elapsed.152 Consider alternative therapy for patients requiring repeat courses of therapy.152
Prophylactic Treatment of Recurrent Gout Flares
Oral
Mild to moderate hepatic impairment: Dosage adjustment is not needed, but monitor for adverse effects.152
Severe hepatic impairment: Consider dosage reduction.152
Familial Mediterranean Fever
Oral
Mild to moderate hepatic impairment: Dosage adjustment is not needed, but monitor for adverse effects.152
Severe hepatic impairment: Consider dosage reduction.152
Renal Impairment
Contraindicated in patients with renal impairment who are receiving or have recently received therapy with a potent CYP3A4 inhibitor or an inhibitor of the P-glycoprotein transport system.152
Treatment of Gout Flare
Oral
Use of colchicine for treatment of gout flare is not recommended in patients with renal impairment who are receiving the drug for prevention of gout flares.152
Mild to moderate renal impairment (Clcr 50–80 or 30–50 mL/minute, respectively): Dosage adjustment is not needed, but monitor for adverse effects.152
Severe renal impairment (Clcr <30 mL/minute): Dosage adjustment is not needed, but do not repeat courses of colchicine therapy until 2 weeks have elapsed.152 Consider alternative therapy for patients requiring repeat courses of therapy.152
Dialysis: 0.6 mg at first sign of gout flare.152 Do not repeat courses of colchicine therapy until 2 weeks have elapsed.152
Prophylactic Treatment of Recurrent Gout Flares
Oral
Mild to moderate renal impairment (Clcr 50–80 or 30–50 mL/minute, respectively): Dosage adjustment is not needed, but monitor for adverse effects.152
Severe renal impairment (Clcr <30 mL/minute): Initial dosage is 0.3 mg daily; monitor closely if dosage is increased.152
Dialysis: Initial dosage is 0.3 mg twice weekly; monitor closely.152
Familial Mediterranean Fever
Oral
Mild to moderate renal impairment (Clcr 50–80 or 30–50 mL/minute, respectively): Monitor for adverse effects; dosage adjustment may be needed.152
Severe renal impairment (Clcr <30 mL/minute) or dialysis: Initial dosage is 0.3 mg daily; dosage can be increased with careful monitoring.152
Geriatric Patients
Select dosage with caution because of age-related decreases in renal function and concomitant disease and drug therapy.152
Cautions for Colchicine
Contraindications
Warnings/Precautions
Warnings
Overdosage-related Mortality
Cumulative IV doses >4 mg (e.g., 7 mg administered acutely) have resulted in irreversible multiple organ failure and death.122 148 Oral ingestion of as little as 7 mg has resulted in death, although larger oral doses have been survived.147 a
Serious Adverse Effects Related to Colchicine Injection
Serious adverse events, including some deaths, reported in patients receiving IV colchicine;144 145 148 many events associated with colchicine toxicity.144 145 As of June 2007, FDA was aware of 50 reports of adverse effects linked to IV colchicine; 23 of these events were fatal.144 145 Neutropenia, acute renal failure, thrombocytopenia, CHF, and pancytopenia reported.144 145 148
Compounded IV colchicine linked to 3 deaths.144 145 148 Compounded colchicine injection from the same lot as these patients received contained 8 times the labeled amount of colchicine.148
FDA is taking enforcement action against all firms, including compounding pharmacies, attempting to manufacture, ship, or deliver colchicine injection.145 Oral preparations containing colchicine remain on the market; risks believed to be lower with oral preparations.144 145 (See Preparations.)
Hematologic Effects
Myelosuppression, leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, and aplastic anemia reported.152
Drug Interactions
Concomitant use with certain drugs is contraindicated or requires particular caution.152 (See Interactions and also see Dosage under Dosage and Administration.)
Neuromuscular Effects
Neuromuscular toxicity and rhabdomyolysis reported with long-term use.152 Individuals with renal impairment and geriatric individuals are at increased risk.152 Concomitant use of certain drugs may increase risk of myotoxicity.152 (See Specific Drugs and Laboratory Tests under Interactions.)
General Precautions
Use of Fixed Combination
When colchicine is used in fixed combination with probenecid, consider the cautions, precautions, and contraindications associated with probenecid.146
Specific Populations
Pregnancy
Category C.152
Lactation
Distributed into milk.152 However, AAP states colchicine usually is compatible with breast-feeding;139 140 use caution.152
Pediatric Use
Safety and efficacy not established for gout.152
Safety and efficacy for familial Mediterranean fever in children evaluated in uncontrolled studies.152 Long-term use of colchicine did not appear to affect growth in children with familial Mediterranean fever.152
Geriatric Use
Clinical studies of colchicine for treatment of gout flares, prophylactic treatment of recurrent gout flares, or management of familial Mediterranean fever did not include sufficient numbers of patients ≥65 years of age to determine whether geriatric patients respond differently than younger patients.152
Select dosage carefully in geriatric patients with gout; consider the greater frequency of decreased renal function and of concomitant disease and drug therapy observed in geriatric patients.152
Hepatic Impairment
Use with caution; dosage adjustment may be needed.152 (See Hepatic Impairment under Dosage and Administration.)
Contraindicated in patients with hepatic impairment receiving therapy with a potent CYP3A4 inhibitor or an inhibitor of the P-glycoprotein transport system.152
Renal Impairment
Use with caution; dosage adjustment may be needed.152 (See Renal Impairment under Dosage and Administration.)
Contraindicated in patients with renal impairment receiving therapy with a potent CYP3A4 inhibitor or an inhibitor of the P-glycoprotein transport system.152
Common Adverse Effects
Treatment of gout flare: Diarrhea, pharyngolaryngeal pain.152
Prophylactic treatment of recurrent gout flares: Diarrhea.152
Familial Mediterranean fever: Abdominal pain, diarrhea, nausea, vomiting.152
Interactions for Colchicine
Metabolized by CYP3A4.152 Does not inhibit or induce CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4.152
A P-glycoprotein substrate.152
Drugs Affecting Hepatic Microsomal Enzymes
CYP3A4 inhibitors: Potential pharmacokinetic interaction (increased plasma colchicine concentrations); increased risk of colchicine toxicity.152 Fatal reactions reported with concomitant use of potent CYP3A4 inhibitors.152 Adjust colchicine dosage if patient is receiving or has recently (within 14 days) received therapy with a moderate or potent CYP3A4 inhibitor (see Dosage under Dosage and Administration).152 Concomitant use of colchicine and potent CYP3A4 inhibitors is contraindicated in renal or hepatic impairment.152
Drugs Affecting P-Glycoprotein Transport
P-glycoprotein inhibitors: Pharmacokinetic interaction (increased plasma concentrations of colchicine) likely; increased risk of colchicine toxicity.152 Fatal reactions reported.152 Adjust colchicine dosage if patient is receiving or has recently (within 14 days) received therapy with a P-glycoprotein inhibitor (see Dosage under Dosage and Administration).152 Concomitant use of colchicine and P-glycoprotein inhibitors is contraindicated in renal or hepatic impairment.152
Specific Drugs and Laboratory Tests
Drug or Test
|
Interaction
|
Comments
|
|---|
Azithromycin
|
Increased plasma concentrations of colchicine152
|
|
Clarithromycin
|
Decreased metabolism and increased plasma concentrations of colchicine; fatal colchicine toxicity reportedc 152
|
Adjust colchicine dosage (see Dosage under Dosage and Administration),152 consider alternative anti-infective,c or substitute NSAIA for colchicine if clarithromycin is usedc
Concomitant use contraindicated in renal or hepatic impairment152
|
Cyclosporine
|
Possible additive nephrotoxic effects; increased concentrations of cyclosporine in biological fluidd g h 152
Increased colchicine concentrations; fatal colchicine toxicity reported152
|
Monitor concentration of cyclosporine in biologic fluid and renal function if colchicine is initiated, discontinued, or dosage altered; adjust cyclosporine dosage accordinglyd
Adjust colchicine dosage (see Dosage under Dosage and Administration)152
Concomitant use contraindicated in renal or hepatic impairment152
|
Digoxin
|
Rhabdomyolysis reported152
|
Weigh potential benefits and risks;120 152 monitor for muscle pain, tenderness, or weakness, especially during the initial phase of such concomitant therapy152
|
Diltiazem
|
Increased plasma concentrations of colchicine; neuromuscular toxicity reported152
|
Adjust colchicine dosage (see Dosage under Dosage and Administration)152
|
Estrogens or progestins
|
Oral contraceptives: No change in plasma concentrations of ethinyl estradiol or norethindrone152
|
|
Fibric acid derivatives (gemfibrozil, fenofibrate)
|
Addition of a fibrate to long-term colchicine therapy or addition of colchicine to long-term fibrate therapy has resulted in myopathy and rhabdomyolysis152
|
Weigh potential benefits and risks; monitor for muscle pain, tenderness, or weakness, especially during the initial phase of such concomitant therapy152
|
Grapefruit juice
|
Minimal change in plasma concentration of colchicine reported152
|
Dosage adjustment may be needed (see Dosage under Dosage and Administration)152
Advise patient to avoid grapefruit juice152
|
HMG-CoA reductase inhibitors (statins)
|
Addition of a statin to long-term colchicine therapy or addition of colchicine to long-term statin therapy has resulted in myopathy and rhabdomyolysis152
|
Weigh potential benefits and risks; monitor for muscle pain, tenderness, or weakness, especially during the initial phase of such concomitant therapy152
|
Ketoconazole
|
Increased plasma concentrations of colchicine152
|
Adjust colchicine dosage (see Dosage under Dosage and Administration)152
Concomitant use contraindicated in renal or hepatic impairment152
|
Ritonavir
|
Increased plasma concentrations of colchicine152
|
Adjust colchicine dosage (see Dosage under Dosage and Administration)152
Concomitant use contraindicated in renal or hepatic impairment152
|
Theophylline
|
No change in plasma concentrations of theophylline152
|
|
Verapamil
|
Increased plasma concentrations of colchicine; neuromuscular toxicity reported152
|
Adjust colchicine dosage (see Dosage under Dosage and Administration)152
|
Colchicine Pharmacokinetics
Absorption
Bioavailability
Rapidly absorbed from the GI tract following oral administration.147 a f
Drug and metabolites reenter intestinal tract via biliary and intestinal secretions after partial metabolism in liver.147 152 a f
Unchanged drug may be reabsorbed from the intestine.a
Food
Administration with food did not affect rate of absorption but decreased extent of absorption by 15%.152
Plasma Concentrations
Following oral administration, peak plasma concentrations occur within 0.5–2 hours.f 152
Absolute bioavailability reported to be about 45%.152
Distribution
Extent
Crosses the placenta and is distributed into milk.139 152
Plasma Protein Binding
39% (mainly albumin).152
Elimination
Metabolism
Demethylated in the liver by CYP3A4.152
Elimination Route
40–65% recovered unchanged in urine.152 Not removed by hemodialysis.152
Half-life
26.6–31.2 hours.152
Special Populations
End-stage renal disease: Colchicine clearance is decreased and elimination half-life increased.152
Stability
Storage
Oral
Tablets
20–25°C.152 Protect from light.152
Actions
Has weak anti-inflammatory activity, but no analgesic activity.a
Has no effect on urinary excretion of uric acid or on serum urate concentration, solubility, or binding to serum proteins.a f
Mechanism of principal (antigout) effect is not completely known; drug appears to disrupt cytoskeletal functions through inhibition of β-tubulin polymerization into microtububules thus preventing activation, degranulation, and migration of neutrophils believed to mediate some gout symptoms.152
Mechanism of beneficial effects in familial Mediterranean fever not fully elucidated.152 Colchicine may interfere with the intracellular assembly of inflammasome complex in neutrophils and monocytes that mediates activation of interleukin-1β.152
Advice to Patients
Possibility of serious adverse effects.152
Importance of informing clinicians of existing or contemplated therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.152
Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.152
Importance of informing patients of other important precautionary information. (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Colchicine
Routes
|
Dosage Forms
|
Strengths
|
Brand Names
|
Manufacturer
|
|---|
Oral
|
Tablets
|
0.6 mg
|
Colcrys (scored)
|
AR Scientific
|
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Probenecid and Colchicine
Routes
|
Dosage Forms
|
Strengths
|
Brand Names
|
Manufacturer
|
|---|
Oral
|
Tablets
|
500 mg Probenecid and Colchicine 0.5 mg*
|
Probenecid and Colchicine Tablets
|
|
Comparative Pricing
This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 10/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.
Colchicine-Probenecid 0.5-500MG Tablets (WATSON LABS): 30/$35.99 or 90/$95.97
Colcrys 0.6MG Tablets (AR SCIENTIFIC): 30/$169.99 or 90/$499.97
Disclaimer
This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.
The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.
AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
References
Only references cited for selected revisions after 1984 are available electronically.
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