Colchicine

Article Author:
Kenneth Robinson
Article Editor:
Steve Bhimji
Updated:
10/18/2018 9:30:19 AM
PubMed Link:
Colchicine

Indications

Colchicine is approved for gout prophylaxis and treatment of acute gouty flares.  It is also approved for treatment of familial Mediterranean fever.[1][2]

While not approved for the following conditions, colchicine has been used off-label to treat the following:

  • Acute and recurrent pericarditis
  • Prevention of post pericardial syndrome
  • Primary biliary cirrhosis
  • Hepatic cirrhosis
  • Dermatitis herpetiformis
  • Paget's disease of bone
  • Chronic immune thrombocytopenia and idiopathic thrombocytopenia purpura
  • Pseudogout
  • Idiopathic pulmonary fibrosis

Colchicine is not recommended for prophylaxis or treatment of gout flares in the pediatric population. It can be used to treat familial Mediterranean fever in children four years of age and older.

Mechanism of Action

Colchicine has primarily anti-inflammatory properties. It disrupts cytoskeletal functions by inhibiting beta-tubulin polymerization into microtubules, preventing activation, degranulation, and migration of neutrophils associated with mediating some gout symptoms.  Colchicine does not inhibit phagocytosis of uric acid crystals, but it does seem to prevent the release of an inflammatory glycoprotein from phagocytes. Colchicine blocks metaphase due to two separate anti-mitotic effects, disruption of mitotic spindle formation and disruption of the sol-gel formation. The toxic effects of colchicine are related to this anti-mitotic activity within proliferating tissue such as skin, hair and bone marrow.[3][4]

The mechanism of action of colchicine in the treatment of familial Mediterranean fever is less well understood, it may interfere with intracellular assembly of the inflammasome complex present in neutrophils and monocytes that mediate the activation or interleukin-1beta.

Administration

Colchicine is available as a tablet, capsule, and a gel.  In tablet form, it is available in a generic 0.6 mg tablet and as Colcrys 0.6 mg tablet. It is available as a capsule in a generic form of 0.6 mg and as Mitigare 0.6 mg capsule. There is a topical gel form of Colchicum autumnale, available as ColciGel.

Colchicine is commonly administered orally, and use of the topical gel is rare. Due to the toxicity, the injectable form is no longer available in the United States.

Dosing

Prophylaxis of gout: 0.6 mg once or twice a day in adults and adolescents older than 16 years old, the maximum dose of 1.2 mg per day.

Treatment of acute gout flare: 1.2 mg at the first sign of a gout flare followed by 0.6 mg one hour later.

Familial Mediterranean fever: 1.2 mg to 2.4 mg for adults and children over 12 years old, the daily dose is divided into one or two doses.

Adverse Effects

The most common adverse reactions are related to the gastrointestinal tract. Diarrhea is the most commonly reported symptom (23%), followed by vomiting (17%) and nausea (4% to 17%). Central nervous system symptoms such as fatigue and headache have been reported.  Endocrine and metabolic conditions such as gout have been reported with the use of colchicine, as has pharyngolaryngeal pain.[5][6]

While less common, the following adverse reactions have been reported with colchicine and are thought to be reversible upon discontinuation of the medication or lowering the dose:

  • Neurologic - sensorimotor neuropathy
  • Dermatologic - alopecia, maculopapular rash, purpura, rash
  • Gastrointestinal - abdominal cramping, abdominal pain, lactose intolerance
  • Hematologic - leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, aplastic anemia
  • Hepatobiliary - elevated AST, elevated ALT
  • Musculoskeletal - myopathy, elevated CPK, myotonia, muscle weakness, muscle pain, rhabdomyolysis
  • Reproductive - azoospermia, oligospermia

Drug Interactions

Colchicine is a substrate for the efflux transporter P-glycoprotein (P–gp). Of the cytochrome P450 enzymes tested, CYP3A4 was mainly involved in the metabolism of colchicine. If colchicine is administered with drugs that inhibit P-glycoprotein, most of which also inhibit CYP3A4, increased concentrations of colchicine are likely and fatal drug interactions have been reported.

When co-administered with drugs known to inhibit CYP3A4 and/or P-glycoprotein, the dose of colchicine should be adjusted.

The following medications should be used with caution when co-administered with colchicine:

Strong CYP3A4 inhibitors – Atazanavir, clarithromycin, Indinavir, Itraconazole, Ketoconazole, Nefazodone, Nelfinavir, Ritonavir, Saquinavir, and Telithromycin

Moderate CYP3A4 inhibitors  - Amprenavir, Aprepitant, diltiazem, erythromycin, fluconazole, Fosamprenavir, grapefruit juice, and verapamil

P-glycoprotein inhibitors – Cyclosporine, Ranolazine

Food Interactions

Grapefruit juice may increase the serum concentration of colchicine.  Therefore, the dose of colchicine may require adjustment when taking grapefruit juice. Grapefruit juice should be avoided in patients with a hepatic or renal impairment who are taking colchicine.

Contraindications

Contraindications

Colchicine is metabolized by the liver and other tissues and is dependent on the P-glycoprotein transport and CYP 384 isoenzymes. It is eliminated unchanged in urine and via metabolism. P-glycoprotein and CYP3A4 inhibitors can decrease the metabolism of colchicine and therefore result in increased plasma levels of colchicine. Impairment of renal and hepatic function can decrease the metabolism and clearance of colchicine and result in elevated concentrations. The elevated levels can cause adverse reactions, including death.[7][8][9]

The concomitant use of a P-glycoprotein (p-gp) or CYP3A4 inhibitor and colchicine, in the presence of renal or hepatic impairment is contraindicated. Dose adjustments or alternative therapies should be considered for patients with renal or hepatic impairment, who are not taking a P-glycoprotein (p-gp) or CYP3A4 inhibitor.

Precautions

Biliary obstruction, renal impairment, hepatic disease and renal disease

Dosage adjustments are needed in patients with normal renal and hepatic function taking interacting medications and in patients who have either renal or hepatic impairment.  Patients with renal impairment or elevated plasma concentrations of colchicine, due to renal disease can develop myeloneuropathy characterized by proximal weakness and elevated serum creatinine, and possibly rhabdomyolysis.  Colchicine is eliminated through biliary pathways. Therefore, patients with hepatic disease or hepatic biliary obstruction should have alternate therapies considered.

Alcoholism, Gastrointestinal Disease

Colchicine-induced gastrointestinal tissue damage may be a greater risk in patients with preexisting alcoholism or gastrointestinal disease.  Therefore, adjustments in dosing should be considered.

Bone Marrow Suppression

Colchicine taken over an extended period has been associated with bone marrow suppression. Therefore, colchicine should be used cautiously in patients with preexisting bone marrow suppression.  Therapeutic doses of colchicine have been reported to be associated with myelosuppression, leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, and aplastic anemia.  Also, these types of blood dyscrasias may be worsened by colchicine.

Dialysis

Dialysis does not remove colchicine, patients receiving dialysis required a dosage reduction secondary to their impaired renal function.

Dental Disease

Colchicine can cause myelosuppression and therefore should be used with caution with patients with dental disease. It is recommended that the dental work be performed before the initiation of therapy with colchicine or delayed until blood count returned to normal.

Neuromuscular Toxicity

Colchicine-induced neuromuscular toxicity and rhabdomyolysis have been reported with chronic treatment in therapeutic doses of colchicine.  Patients with renal dysfunction and elderly patients, even those with normal renal and hepatic function, are at increased risk. Concomitant use of colchicine and atorvastatin, simvastatin, pravastatin, fluvastatin, gemfibrozil and fenofibric acid or cyclosporine may potentiate the development of myopathy.

Geriatric

Geriatric patients, with or without preexisting renal or hepatic impairment, have an increased risk of neuromuscular toxicity and rhabdomyolysis when taking colchicine. Caution should be used, and a dose adjustment may be appropriate when colchicine is used for geriatric patients.

Pregnancy

Colchicine is classified as pregnancy category C. Colchicine should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

Breast Feeding

Colchicine is excreted into human breast milk.  Colchicine can affect gastrointestinal cell renewal and permeability; however, no adverse effects have been reported in progress breast-fed human infants.  The American Academy of Pediatrics considers colchicine usually compatible with breastfeeding.

Monitoring

There is no blood test available to determine colchicine serum concentration.  In patients with hepatic or renal impairment or disease, or patients taking a P-glycoprotein (p-gp) or CYP3A4 inhibitor parameters that should be monitored include complete blood count, renal, and hepatic function tests.

Toxicity

The exact dose of colchicine that produces significant toxicity is unknown. Toxicity has occurred after ingestion of a dose as low as 7 mg over a four day period, while other patients have survived after ingesting more than 60 mg. In a review of 150 patients who overdosed on colchicine, there was 100% mortality in those who ingested more than 0.8 mg/kg.

Acute colchicine toxicity typically begins within 24 hours of ingestion and includes gastrointestinal symptoms which eventually lead to significant fluid loss and volume depletion. In this initial phase, peripheral leukocytosis may also be present. Life-threatening complications often occur 24 to 72 hours after drug administration and are usually attributed to multi-organ failure. Death is usually a result of respiratory depression and cardiovascular collapse.

Treatment of colchicine poisoning should begin with gastric lavage and measures to prevent shock.  Otherwise, treatment is symptomatic and supportive.  There is no known specific antidote, and colchicine is not effectively removed by dialysis.

Enhancing Healthcare Team Outcomes

While the use of colchicine has declined over the past two decades, physicians, nurses, and pharmacists still need to know about the dosing requirements. Prior to administering colchicine to any patient, it is imperative that one be aware of the current dosing recommendations and the patient' age, renal and liver function. At least 30% of all colchicine related medication errors are related to incorrect dosing regimens. In addition, it is important to know what else the patient is taking to prevent lethal drug interactions. One should also ensure that the patient knows how to take colchicine and that it is not an analgesic agent. Many errors have occurred with colchicine simply because patients were not told that the drug effects might take 24-36 hours to develop, and one should avoid taking repeated doses within this time period. Further,  patients should be instructed to discontinue colchicine if they develop gastrointestinal side effects or paresthesias. Finally, all patients should be educated on how to safely store colchicine in the home; away from the reach of children. Colchicine has a very high mortality rate within a short time when a high dose is ingested.[10][1]