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 ([Web]) or the ASHP REMS Resource Center ([Web]).
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
Gouty Arthritis
Treatment to relieve pain in attacks of acute gouty arthritis. Used as a second-line agent in patients who have not responded to or who cannot tolerate other recommended therapy (i.e., NSAIAs, corticosteroids).
Prophylactic treatment of recurrent gouty arthritis. Has no effect on plasma concentrations or urinary excretion of uric acid; use concomitantly with allopurinol or a uricosuric agent (e.g., probenecid, sulfinpyrazone) to decrease serum urate concentrations. Colchicine/probenecid fixed-dosage preparation has limited usefulness for prophylactic therapy because colchicine present exceeds the amount required by most patients.
Perioperatively, used for prevention of an attack that may be precipitated by any surgical procedure.
Familial Mediterranean Fever
Chronic prophylactic therapy to reduce frequency and severity of episodic attacks of painful serositis in patients with familial Mediterranean fever†.
Not curative; manifestations return to pretreatment levels following discontinuance.
Chronic prophylactic therapy appears to prevent amyloidosis (manifested by nephropathy) when there is no evidence of it at initiation of therapy; 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. May prevent deterioration during proteinuric phase of the disease (when amyloid involvement is minimal).
Generally of limited value in altering the effects of amyloid deposits when clinical amyloidosis is evident, particularly when proteinuria has progressed to nephrosis, although a beneficial effect (e.g., restoration of serum albumin concentrations toward normal, slight improvement in renal function) may be evident in some patients.
Primary Biliary Cirrhosis
Has also been used for the treatment of primary biliary cirrhosis†.
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. (See Serious Adverse Effects Related to Colchicine Injection under Cautions and see Preparations.)
Dosage and Administration
General
Gouty Arthritis
Administer prophylactic doses of colchicine before initiation of allopurinol or uricosurics because sudden changes in serum urate concentrations may precipitate acute gout attacks.
May discontinue colchicine and use urate-lowering agents alone after serum urate concentration is reduced to the desired level, and acute gout attacks have not occurred for 3–6 months (some clinicians suggest 1–12 months).
For subsequent acute attacks, patients should become familiar with dosage that provides relief without causing diarrhea.
Administration
Administer orally. Has been administered IV; parenteral preparation no longer available in the US. (See Serious Adverse Effects Related to Colchicine Injection under Cautions.)
Oral Administration
Initiate therapy for acute gouty arthritis at the first sign of an impending attack; initiation in later stages may not completely abate the attack.
Dosage
Pediatric Patients
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
Familial Mediterranean Fever
Chronic Prophylactic Therapy
Oral
Children <5 years of age: 0.5 mg daily has been used.†
Children 5–10 years of age: 1 mg daily has been used.†
Children >10 years of age: 1.5 mg daily has been used.†
Adults
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
Gouty Arthritis
Treatment to Relieve Pain in Acute Attacks
Oral
Initially, 0.6–1.2 mg, followed by 0.6 mg every hour or 1.2 mg every 2 hours.
Alternatively, 0.6–1.2 mg initially, then 0.6 mg every 2–3 hours may be sufficient. Some clinicians recommend 0.6 mg 2 or 3 times daily.
Continue course of therapy until pain is relieved, GI distress or diarrhea occurs, or maximum recommended dosage is attained.
Total amount usually required is 4–8 mg per course.
Allow at least 3 days to elapse between oral courses of therapy to avoid toxicity from drug accumulation.
When ACTH is used for acute attacks, administer at least 1 mg of colchicine daily during ACTH administration and for several days after ACTH is discontinued.
Prophylactic Therapy
Administer prophylactic doses before initiation of allopurinol or uricosurics. (See General under Dosage and Administration.)
Oral
For ≤1 attack per year, usually 0.6 mg daily 3 or 4 times each week.
For >1 attack per year, usually 0.5–0.6 mg daily (no longer commercially available in US as single-entity 0.5-mg preparation; available in 0.5-mg tablet strength only in fixed combination with probenecid); 1–1.8 mg daily may be required.
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.
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. 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).
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.
Perioperative Prophylaxis
Oral
0.6 mg 3 times daily for 3 days before and 3 days after surgery.
Familial Mediterranean Fever
Chronic Prophylactic Therapy
Oral
1–2 mg daily in divided doses.†
Reduce to 0.6 mg daily in patients who develop intolerable adverse GI effects at higher dosages.†
Intermittent Use to Abort an Impending Acute Attack
Oral
Initially, 0.6 mg when attack is first suspected, then 0.6 mg hourly for 3 doses, then 0.6 mg every 2 hours for 2 doses; may continue with 0.6 mg every 12 hours for 2 additional days.†
Relief may occur after the first 4 or 5 doses, and subsequent doses may not be necessary.†
Prescribing Limits
Adults
Gouty Arthritis
Treatment to Relieve Pain in Acute Attacks
Oral
Maximum 8 mg per treatment course. (See Overdosage-related Mortality under Cautions.)
Special Populations
Hepatic Impairment
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
Renal impairment with Clcr >50 mL/minute: 0.6 mg twice daily recommended by some clinicians.
If Clcr 35–50 mL/minute: 0.6 mg daily recommended by some clinicians.
If Clcr 10–34 mL/minute: 0.6 mg every 2–3 days recommended by some clinicians.
If Clcr <10 mL/minute: Avoid use of colchicine.
Prophylactic Treatment of Recurrent Gouty Arthritis
Oral
Do not exceed 0.6 mg daily in patients with Scr ≥1.6 mg/dL or Clcr ≤50 mL/minute; 0.6 mg every other day may be adequate. Generally do not administer to patients undergoing hemodialysis.
Colchicine in fixed combination with probenecid: Fixed-dosage preparation has limited usefulness for prophylactic therapy because colchicine present exceeds the amount required by most patients. Probenecid dosage requirements may be increased in patients with mild renal impairment (Clcr ≥50 mL/minute); not recommended in patients with Clcr <50 mL/minute.
Geriatric Patients
Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.
For prophylactic therapy of recurrent gouty arthritis in patients with reduced muscle mass (e.g., geriatric or debilitated patients), initial dosage of 0.5 mg (no longer commercially available in US) orally once daily (unless Clcr >50 mL/minute) has been recommended.
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
Overdosage-related Mortality
Cumulative IV doses >4 mg (e.g., 7 mg administered acutely) have resulted in irreversible multiple organ failure and death. Oral ingestion of as little as 7 mg has resulted in death, although larger oral doses have been survived.
Serious Adverse Effects Related to Colchicine Injection
Serious adverse events, including some deaths, reported in patients receiving IV colchicine; many events associated with colchicine toxicity. As of June 2007, FDA was aware of 50 reports of adverse effects linked to IV colchicine; 23 of these events were fatal. Neutropenia, acute renal failure, thrombocytopenia, CHF, and pancytopenia reported.
Compounded IV colchicine linked to 3 deaths. Compounded colchicine injection from the same lot as these patients received contained 8 times the labeled amount of colchicine.
FDA is taking enforcement action against all firms, including compounding pharmacies, attempting to manufacture, ship, or deliver colchicine injection. Oral preparations containing colchicine remain on the market; risks believed to be lower with oral preparations. (See Preparations.)
GI symptoms (e.g., abdominal pain, nausea, vomiting, diarrhea) are early signs of toxicity. Discontinue oral colchicine if GI symptoms occur; do not reinstitute therapy until these symptoms disappear (usually within 24–48 hours).
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
Use with caution in geriatric or debilitated patients, and/or in those with early manifestations of GI, renal, hepatic, cardiac, or hematologic disorders.
Hematologic Effects
Bone marrow depression (e.g., agranulocytosis, thrombocytopenia, leukopenia, aplastic anemia) may occur with prolonged administration.
IV administration of 10 mg over a 5-day period has resulted in pancytopenia, bone marrow aplasia, and death.
Monitor blood cell counts periodically in patients receiving long-term therapy.
Prolonged Administration
Loss of body and scalp hair, rashes, vesicular dermatitis, purpura, peripheral neuritis or neuropathy, anuria, renal damage, hematuria, myopathy, and bone marrow depression reported with prolonged administration.
Use of Fixed Combination
When colchicine is used in fixed combination with probenecid, consider the cautions, precautions, and contraindications associated with probenecid.
Specific Populations
Pregnancy
Category C.
Lactation
Distributed into milk. However, AAP states colchicine usually is compatible with breast-feeding; use caution.
Waiting 8–12 hours after a dose to breast-feed may minimize infant exposure.
Pediatric Use
Safety and efficacy not established.
Has been used successfully for the management of familial Mediterranean fever† in children and adolescents.
Geriatric Use
Use with caution in geriatric or debilitated patients (especially those with renal, hepatic, GI, cardiac, or hematologic disorders) because of possible cumulative effects.
Because of age-related decreases in renal function and increased risk of colchicine-induced toxicity, assess renal function, reduce initial dosage, and initiate appropriate precautions; continued monitoring of renal function may be useful. (See Geriatric Patients under Dosage and Administration.)
Hepatic Impairment
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
Use with caution in patients with early manifestation of hepatic disorders. Contraindicated in those with severe hepatic disorders.
Renal Impairment
Use with caution in patients with early manifestation of renal disorders. Clearance may be decreased; dosage adjustment needed. (See Renal Impairment under Dosage and Administration.) Contraindicated in those with severe renal disorders.
Some clinicians recommend monitoring CBC and serum creatine kinase (CK) concentrations at least every 6 months in patients with Clcr ≤50 mL/minute, since risk for myopathy and myelosuppression appears to be increased.
Common Adverse Effects
Abdominal discomfort or pain, nausea, vomiting, diarrhea.
Interactions
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
Drugs Affecting Hepatic Microsomal Enzymes
Inhibitors of CYP3A4: Potential pharmacokinetic interaction (increased plasma colchicine concentrations).
Decreased metabolism and increased plasma concentrations of colchicine; potential for serious and/or life-threatening effects
Monitor for colchicine toxicity, consider alternative macrolide (e.g., azithromycin); alternatively, substitute NSAIA for colchicine if clarithromycin is used
Possible additive nephrotoxic effects; increased concentrations of cyclosporine in biological fluid
Cyclosporine decreases urate clearance, causes hyperuricemia; also may increase intracellular colchicine concentrations
Monitor concentration of cyclosporine in biologic fluid and renal function if colchicine is initiated, discontinued, or dosage altered; adjust cyclosporine dosage accordingly
Use colchicine with caution in patients with renal impairment (e.g., renal transplant)
Rapidly absorbed from the GI tract following oral administration.
Drug and metabolites reenter intestinal tract via biliary and intestinal secretions after partial metabolism in liver.
Unchanged drug may be reabsorbed from the intestine.
Onset
Following oral administration for relief of acute gouty arthritis, articular pain and swelling usually abate within 12 hours; complete relief occurs within 48–72 hours.
Plasma Concentrations
Following oral administration, peak plasma concentrations occur within 0.5–2 hours.
Plasma concentrations of colchicine and its metabolites decline at 1–2 hours after ingestion, then increase, probably as a result of reabsorption of unchanged drug.
Distribution
Extent
Rapidly removed from the plasma after reabsorption; distributed into kidneys, liver, spleen, and intestinal tract; apparently absent in heart, skeletal muscle, and brain.
Concentrates in leukocytes.
Crosses the placenta and is distributed into milk.
Plasma Protein Binding
Apparently not tightly bound to plasma protein.
Elimination
Metabolism
Partly deacetylated in the liver and also is slowly metabolized in other tissues.
Elimination Route
Excreted principally in feces and to a lesser extent (10–20%) in urine. May be detected in urine for ≥9 days after single IV dose.
Half-life
Rapidly cleared from plasma; elimination half-life of about 20 minutes following IV administration (IV preparation no longer commercially available).
About 60 hours in leukocytes.
Special Populations
Clearance is decreased and elimination half-life is increased in patients with renal impairment. Minimal elimination via urine and longer plasma half-life reported in severe renal disease.
Stability
Storage
Oral
Tablets
Tight, light-resistant containers at 15–30°C. Protect from light.
Actions
Has weak anti-inflammatory activity, but no analgesic activity.
Has no effect on urinary excretion of uric acid or on serum urate concentration, solubility, or binding to serum proteins.
Mechanism of principal (antigout) effect is not completely known; apparently reduces inflammatory response to deposition of monosodium urate crystals in joint tissues, possibly by inhibiting polymorphonuclear leukocyte (PMNL) metabolism, mobility, chemotaxis, and/or other leukocyte functions.
Also interferes with sodium urate deposition by directly decreasing lactic acid production by PMNL and indirectly reducing acid production by decreasing phagocytosis.
Inhibits cell division in the metaphase by interfering with the mitotic spindle and with sol-gel transformation; sol-gel transformation also is inhibited in nondividing cells. Antimitotic effect may be responsible for toxic effects on proliferating tissue (e.g., bone marrow, skin, hair).
Possible common mechanism of action for anti-inflammatory and antimitotic effects may be related to the dissolution of PMNL microtubules.
In vitro, inhibits secretion of serum amyloid A protein (synthesized by hepatocytes and the main constituent of amyloid deposits in patients with familial Mediterranean fever).
Administered orally, may alter functional capacity of ileal mucosa and induce a reversible malabsorption syndrome; evidenced by decreased absorption of cyanocobalamin (vitamin B12), fat, sodium, potassium, nitrogen, xylose, and other actively transported sugars, and decreased serum cholesterol and carotene concentrations.
Decreases lactic dehydrogenase and increases lysosomal enzyme activity in intestinal mucosa.
Advice to Patients
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
Importance of learning dosage required to provide relief of an acute gouty arthritis attack without causing diarrhea.
Importance of always having colchicine available to begin therapy at the first sign of an impending acute gouty arthritis attack because later initiation may not completely abate the attack.
Importance of discontinuing the drug if nausea, vomiting, or diarrhea occurs.
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 (e.g., GI, renal, hepatic, cardiovascular, or hematologic disease).
Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.
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.
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. FDA will implement enforcement action against all firms attempting to manufacture or ship colchicine injection products that do not have a National Drug Code (NDC) number on or after February 8, 2008. For colchicine injection products with an NDC number, FDA will take enforcement action against all firms attempting to manufacture such products on or after March 10, 2008, and against firms that ship such products on or after August 6, 2008.
Preparations of colchicine injection have not been approved by FDA. Although colchicine tablets also have not been approved by FDA, FDA did not take action against colchicine tablets in February 2008, since risks associated with use of the tablets are believed to be lower than those associated with use of the injection. Colchicine in fixed combination with probenecid is approved by FDA for the management of recurrent gouty arthritis.
Colchicine
Routes
Dosage Forms
Strengths
Brand Names
Manufacturer
Oral
Tablets
0.6 mg*
Colchicine Tablets
Akyma
* 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
Watson
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Comparative Pricing
This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 09/2009. For the most current and up-to-date pricing information, please visit www.drugstore.com. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.
† Use is not currently included in the labeling approved by the US Food and Drug Administration.
Remember, keep this and all other medicines out of the reach of children,
never share your medicines with others, and use this medication only for the indication prescribed.
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