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Colchicine is an alkaloid extracted from the bulb of the meadow saffron or Colchicum. It has been used for centuries as an antiinflammatory agent in the treatment of gouty arthritis. Its approved indications are:
1. Treatment of acute attacks of gouty arthritis.
2. Prevention of acute gout attacks
3. Managementg of familial Mediterranean fever (FMF)
More recently, the use of colchicine expanded to include many off-label indications such as primary biliary cirrhosis (PBC), alcohol-induced cirrhosis, scleroderma, sarcoidosis, amyloidosis, Behcet's syndrome, and many more
Colchicine has multiple biological effects:
• Interferes with most leukocyte functions including diapedesis (ameboid movement), mobilization, lysosomal degranulation, and most importantly leukocyte chemotaxis. These effects may be mediated at least in part by a decrease in the expression of adhesion molecules on neutrophil membranes.
• Binds to and inhibits the assembley of microtubules, thereby interfering with secretory mechanisms such as the release of histamine from the mast cells.
• Colchicine reduces the inflammation and relieves the pain associated with acute gout, and it is primarily used for this purpose. It is most effective when used at the onset of symptoms.
• Inhibits proliferation of fibroblasts and decreases IL-1 production in patients with PBC.
• Inhibits collagen transport to the extracellular space, hence its use in the prevention or treatment of amyloidosis and scleroderma.

Available As

• Injectable: 0.5 mg/mL (2 mL)
• PO: Tablets (0.5 mg or 0.6 mg)

Dose

• Acute gout attack in adults (with normal renal and hepatic functions): start with 1.2 mg PO x 1 then 0.5 or 0.6 mg PO q2h until desired response is achieved or GI side effects (n/v, diarrhea, cramps) occur or a maximum oral dose of 8 mg is reached. In all case, a waiting period of 3 days is recommended before starting either a colchicine maintenance regimen or attempting another loading course. The corresponding iv dosage is as follows: 1 mg x 1, then 0.5 mg iv q6h until response or a maximum dose of 4 mg. A waiting period of 7 days after iv loading is recommended before resuming colchicine administation by any route. Each iv dose should be given over a period of 2-5 min.
• The administration of iv colchicine is contraindicated in patients with renal failure, extrahepatic biliary obstruction, or patients with combined renal and hepatic insufficiency.
• Prophylaxis of recurrent attacks of gouty arthritis (adults): 0.5 or 0.6 mg PO qd or every other day.
• Familial Mediterrean Fever:
  • Children £ 5 yrs: 0.5 ng qd
  • Children > 5 yrs: 0.5 mg bid or tid
  • Adults: 1-2 mg/day in divided doses
• Behcet's Syndrome (adults): 1 - 1.5 mg PO qday.
• Other conditions (PBC, alcoholic cirrhosis, HB, etc): Adequate dosage regimens are yet to be established. However, a doses ranging from 0.5 to 1.5 mg/day have been used.
• General dosing guidelines for patients with renal impairment:

  GFR (mL/min/m2)	Recommendation
  >60	Use normal dosage
  20 - 60	Use 65 - 75% of normal dose. Avoid chronic administration.
  £20	Use 50% of normal dose. Avoid chronic administration. Do not use iv preparation

  
  The above recommendations are not based on any particular study; they are based on personal obsevations and interpretation of conflicting kinetic studies (for references see the reviews listed below].

Pharmacokinetics

• Absorption of oral form is rapid but incomplete (time to max = 2 hrs; bioavailability = 25 - 50%) . However, absorption can be highly variable.
• Absorption is thought to occur in the ileum, and there is significant enterohepatic recirculation.
• Onset of action (relief of gout pain): IV 8 hrs and PO 24 hrs
• Colchicine distributes into leukocytes (granulocytes in partricular), spleen, liver, and kidney (Vd=4L/kg).
• Plasma protein binding = 50%..
• Colchicine is not removed by conventional hemodialysis.
• Colchicine does not penetrate brain tissue, heart muscle, or skeletal muscle.
• ~30% of an iv dose is eliminated in the urine in 24 hrs.
• At least 10% of a colchicine dose is metabolized (demethylated) by hepatic Cytochrome P450 3A4.
• Terminal half-life after an oral dose in patients with normal renal and hepatic functions = 9 hrs.
• Half-life in pts with renal failure = 2 - 3 times normal (about 24 hrs)
• Half-life in cirrhotic pts with renal failure = 10 times normal (about 4 days).
• Colchicine transfers through the placenta, and passes into breast milk.

Main Side Effects

• GI (> 10% of pts): Abdominal pain, nausea, vomiting, increased motility, & diarrhea.
• Hematologic: bone marrow depression (pancytopenia); aplastic anemia
• Dermatologic: rash; alopecia
• CNS: anorexia
• Liver: hepatotoxicity
• Miscellaneous: peripheral neuritis; myopathy; azoospermia

Precautions and Warnings

• Do not administer IM or SC
• Do not use IV route in patients with severe renal impairment and/or hepatic impairment
• It is essential to monitor for signs of GI toxicity and discontinue drug therapy if they occur. GI symptoms should taken as early signs of potentially serious colchicine toxicity.
• Overdose ð cholera-like syndrome, severe dehydration, ARF, metabolic acidosis, respiratory failure, shock, bone marrow failure (pancytopenia], hepatic failure, alopecia, disseminated intravascular coagulation (DIC), seizures, coma, and death.

Drug Interactions

• Colchicine may inhibit the gastrointestinal absortption of some drugs such as isoniazid, quinidine, and sulfisoxazole.
• Colchicine induces vitamin B12 malabsorption (possibly by reducing the number of intrinsic factor receptors in the intestinal mucosa)
• Inhibitors of cytochrome P450 (cimetidine, ketoconazole, erythromycin, diltiazem, grape fruit, etc) Þ ò Colchicine metabolism Þñ Colchicine blood level.
• Inducers of cytochrome P450 (rifampin, phenobarbital, phenytoin, etc) Þñ Colchicine metabolism and clearance Þ ò Colchicine blood level.
• Substrates of cytochrome P450 3A4 such as cyclosporin and tacrolimus may be affected by the coadministration of colchicine.

References

1. Levy et al. Colchicine: a state-of-the-art review. Pharmacotherapy 1991; 11:196-211
2. Ben-Chitrit and Levy. Colchicine: 1998 Update. Semin Arthritis Rheum 1998; 28(1):48-59].