Continuing Education Activity

Colchicine has FDA approval for gout prophylaxis and treatment of acute gouty flares. It also has approval for the treatment of familial Mediterranean fever. Colchicine has been used off-label to treat several other conditions, including hepatic cirrhosis, primary biliary cirrhosis, and pseudogout. Colchicine has primarily anti-inflammatory properties. This activity reviews the mechanism of action, adverse event profile, toxicity, dosing, pharmacodynamics, and monitoring of colchicine for gout and other indications for interprofessional team members.

Objectives:

• Identify the various hypothesized mechanisms of action of colchicine.
• Outline the primary and secondary indications for colchicine.
• Review the potential adverse events profile of colchicine.
• Summarize the importance of interprofessional communication improving care coordination among the interprofessional team when initiating antibiotic therapy with colchicine.

Indications

Colchicine has FDA approval for gout prophylaxis and treatment of acute gouty flares. It also has approval for the 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 thrombocytopenic purpura
• Pseudogout
• Idiopathic pulmonary fibrosis

Recommendations for colchicine do not include 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-1-beta.

Administration

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

Colchicine administration is usually via the oral route, and the use of the topical gel is rare. Due to toxicity, the injectable form is no longer available in the United States.

Dosing

Prophylaxis of gout: Colchicine dosing is 0.6 mg once or twice a day in adults and adolescents older than 16 years old; the maximum dose is 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 gets administered in 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%). There are reports of central nervous system symptoms such as fatigue and headache. Endocrine and metabolic conditions such as gout have been reported when using 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. Of the cytochrome P450 enzymes tested, CYP3A4 is the primary enzyme involved in the metabolism of colchicine. If administering colchicine with drugs that inhibit P-glycoprotein, most of which also inhibit CYP3A4 increased concentrations of colchicine are likely, and there are reports of fatal drug interactions.

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

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

Potent 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. Patients should avoid grapefruit juice if they have hepatic or renal impairment and are taking colchicine.

Contraindications

Contraindications

Colchicine metabolism is via the liver and other tissues and is dependent on the P-glycoprotein transport and CYP 384 isoenzymes. It is eliminated unchanged in the 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. These elevated levels can cause adverse reactions, including death.[7][8][9]

The concomitant use of a P-glycoprotein or CYP3A4 inhibitor and colchicine in the presence of renal or hepatic impairment is contraindicated. Dose adjustments or alternative therapies are considerations for patients with renal or hepatic impairment who are not taking a P-glycoprotein or CYP3A4 inhibitor.

Precautions

Biliary obstruction, renal impairment, hepatic disease, and renal disease

Dosage adjustments are necessary for patients with normal renal and hepatic function, taking interacting medications, and patients with 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, elevated serum creatinine, and possibly rhabdomyolysis.  Colchicine gets eliminated through biliary pathways. Therefore, patients with hepatic disease or hepatic biliary obstruction should have alternate therapies considered.

Alcoholism, Gastrointestinal Disease

The risk for colchicine-induced gastrointestinal tissue damage may be higher in patients with preexisting alcoholism or gastrointestinal disease. Therefore, the clinician should consider adjustments in dosing.

Bone Marrow Suppression

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

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, its use requires caution with patients with dental disease. The recommendation is that the dental work is performed before initiating therapy with colchicine or delayed until blood count returned to normal.

Neuromuscular Toxicity

Reports exist of colchicine-induced neuromuscular toxicity and rhabdomyolysis with chronic treatment in therapeutic doses of colchicine. Patients with renal impairment 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

With or without preexisting renal or hepatic impairment, geriatric patients have an increased risk of neuromuscular toxicity and rhabdomyolysis when taking colchicine. Caution is necessary, and a dose adjustment may be appropriate when dosing colchicine in geriatric patients.

Pregnancy

Colchicine classifies as pregnancy category C. Colchicine use during pregnancy should only be if the potential benefit to the mother justifies the possible risk to the fetus.

Breast Feeding

Colchicine is excreted into human breast milk. Colchicine can alter gastrointestinal cell renewal and permeability; however, there are no reported adverse effects in breastfed 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 or CYP3A4 inhibitor, parameters that require monitoring include a complete blood count and renal and hepatic function tests.

Toxicity

The precise dose of colchicine that results in significant toxicity is unknown. Toxicity has occurred after the ingestion of a dose as low as 7 mg over four days, while other patients survived after taking more than 60 mg. In a review of 150 patients with a colchicine overdose, there was 100% mortality in those who ingested over 0.8 mg/kg.

Acute colchicine toxicity usually begins within 24 hours of ingestion and includes gastrointestinal symptoms, eventually leading 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 typically a result of respiratory depression and cardiovascular collapse.

Treatment of colchicine poisoning should start 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 and restrictions. Before administering colchicine to any patient, one must be aware of the current dosing recommendations and the patient's age, renal, and liver function. At least 30% of all colchicine-related medication errors are related to incorrect dosing regimens. Also, 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 did not know that the drug effects might take 24 to 36 hours to develop, and the patient should avoid taking repeated doses within this period. Further,  patients should understand to discontinue colchicine if they develop gastrointestinal side effects or paresthesias. Finally, all patients require education 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 ingesting a high dose.[10][1]

Given the above, prescribers should work closely with the pharmacist and the nursing staff when initiating colchicine therapy. All three disciplines need to provide patient counseling so that the crucial points receive emphasis. The prescriber and pharmacist should review all patient parameters and make sure dose adjustments are not necessary. Nurses should be familiar with signs of toxicity or adverse events to monitor the patient and inform the prescriber should any issues arise. With an interprofessional team approach, colchicine can still be an effective agent in specific cases. [Level 5]