G-OUT PLUS

Indications

• Acute gout
• Prophylaxis of familial Mediterranean fever (recurrent polyserositis)
• Short-term prophylaxis during initial therapy with allopurinol and uricosuric drugs

Dosage

Children: Refer to the BNF for Children for specific dosing information in children.

Adults: 500 micrograms two to three times daily for acute gout. For prophylaxis of familial Mediterranean fever, 1.0-2.0 mg once daily. Adjustments may be needed based on renal and hepatic function.

Mechanism of action

Colchicine likely interferes with the intracellular assembly of the inflammasome complex in neutrophils and monocytes, mediating activation of interleukin-1β. It also reduces neutrophil adhesion, recruitment, and superoxide production, while disrupting cytoskeletal functions by inhibiting β-tubulin polymerization into microtubules. This action prevents neutrophil activation and migration, mitigating symptoms of gout and reducing inflammatory responses.

Pharmacodynamics

Colchicine exhibits anti-inflammatory properties, effectively ameliorating symptoms of gout and Familial Mediterranean fever. It also demonstrates anti-fibrotic and cardiovascular protective effects, with potential anticancer properties, such as inhibiting cancer cell migration and angiogenesis. However, it is important to note that colchicine has a narrow therapeutic index, which requires careful dosing.

Pharmacokinetics

Colchicine is well absorbed from the gastrointestinal tract, with peak plasma concentrations occurring within 1-2 hours after oral administration. It is extensively metabolized in the liver, primarily via cytochrome P450 enzymes, and has a half-life of about 9-16 hours. The drug is primarily eliminated via biliary excretion, with renal clearance being significant in patients with renal impairment.

Contra-indications

• Severe renal impairment
• Severe hepatic impairment
• Hypersensitivity to colchicine

Adverse effects

• Abdominal pain
• Diarrhoea
• Nausea
• Vomiting
• Agranulocytosis
• Alopecia
• Bone marrow disorders
• Gastrointestinal haemorrhage
• Kidney injury
• Liver injury
• Menstrual cycle irregularities
• Myopathy
• Nerve disorders
• Rash
• Sperm abnormalities
• Thrombocytopenia

Interactions

• Moderate interaction with berotralstat (increases concentration)
• Moderate interaction with sotorasib (increases exposure)
• Moderate interaction with tucatinib (increases exposure)
• Moderate interaction with venetoclax (increases exposure)
• Unknown interaction with apalutamide (decreases exposure)
• Unknown interaction with amiodarone (increases exposure)
• Unknown interaction with dronedarone (increases exposure)
• Unknown interaction with antifungals, azoles (increases exposure)
• Unknown interaction with ceritinib (increases exposure)
• Unknown interaction with ciclosporin (increases exposure)

Precautions

• Use with caution in elderly patients
• Patients with gastrointestinal, cardiac disease
• Patients with renal or hepatic impairment
• Monitor for signs of toxicity or blood disorders

Pregnancy

Use with caution; specialist sources indicate potential risks.

Breast-feeding

No adverse effects reported in breast-fed infants; consider delaying breastfeeding for 6–8 hours after maternal dose.

Storage

Store in a cool, dry place, away from direct sunlight.

Formulations

• Colchicine 500 microgram tablets

Mechanism of action

The exact mechanism of action of colchicine has not been fully established; however, colchicine likely interferes with the intracellular assembly of the inflammasome complex present in neutrophils and monocytes that mediates activation of interleukin-1β, an inflammatory mediator. Colchicine also attenuates neutrophil adhesion and recruitment, as well as superoxide production. Clinical data demonstrate that colchicine reduces high-sensitivity C- reactive protein (hs-CRP). Colchicine is an anti-mitotic drug that disrupts cytoskeletal functions by inhibiting β-tubulin polymerization into microtubules. Consequently, it prevents the activation, degranulation, and migration of neutrophils. This pharmacological action is thought to be related to colchicine ameliorating gout symptoms and preventing major cardiovascular events. Colchicine blocks microtubule growth at low concentrations and causes the depolymerization of microtubules at high concentrations. ... HUVEC cells were exposed to various concentrations of colchicine and were harvested at different time points. Ribonucleic acid was extracted, amplified, reverse transcribed and hybridized to complementary deoxyribonucleic acid microarrrays containing more than 40,000 probes to human expressed sequence tags. This approach enabled us to have a global look at the transcriptional response induced by colchicine treatment. Colchicine changed the expression of many genes in HUVEC cells following exposure to a concentration of 100 ng/ml or higher. Following short exposure (30 or 120 min), colchicine affected genes known to be involved in the cell cycle and its regulation. However, change in expression of genes involved in neutrophil migration or other inflammatory processes were observed mainly after 12 to 24 hr. The anti-inflammatory effect of colchicine may be mediated not only through direct interaction with microtubules but also through changes at the transcriptional level. This latter effect apparently requires a higher concentration and a longer time to occur. Colchicine, long used to treat gout, arrests microtubule assembly and inhibits many cellular functions. At micromolar concentrations, it suppresses monosodium urate crystal-induced NACHT-LRR-PYD-containing protein-3 (NALP3) inflammasome-driven caspase-1 activation, IL-1beta processing and release, and L-selectin expression on neutrophils. At nanomolar concentrations, colchicine blocks the release of a crystal-derived chemotactic factor from neutrophil lysosomes, blocks neutrophil adhesion to endothelium by modulating the distribution of adhesion molecules on the endothelial cells, and inhibits monosodium urate crystal-induced production of superoxide anions from neutrophils. Cyto-chrome P450 3A4, the multidrug transporter P-glycoprotein, and the drugs that bind these proteins influence its pharmacokinetics and pharmacodynamics. Trial evidence supports its efficacy in acute gout and in preventing gout flares, but it has narrow therapeutic index, and overdosage is associated with gastrointestinal, hepatic, renal, neuromuscular, and cerebral toxicity; bone marrow damage; and high mortality. The actions of colchicine were examined with the two-electrode voltage-clamp technique and radioligand binding assays in mouse and human 5-hydroxytryptamine(3A) receptors (5-HT(3A)Rs) expressed in Xenopus laevis oocytes. Colchicine inhibited 5-hydroxytryptamine (5-HT)-evoked currents in oocytes expressing mouse 5-HT(3A)Rs, with an IC(50) of 59.5 +/- 3 uM. In contrast to the mouse receptor, coapplication of colchicine with 5-HT (<1 uM) strongly enhanced 5-HT-evoked currents in oocytes expressing human 5-HT(3A)Rs. Colchicine applied alone did not induce a detectable current. In the presence of 0.5 microM 5-HT, the potentiation was concentration-dependent and reached the maximum (approximately 100%) when 750 microM colchicine was applied. However, colchicine-dependent inhibition can be observed at 5-HT concentrations > 1 uM. In oocyte membranes

Pharmacodynamics

Colchicine ameliorates the symptoms of gout and Familial Mediterranean fever. It possesses anti-inflammatory, anti-fibrotic, and cardiovascular protective effects. Colchicine was shown to exhibit anticancer properties, such as the inhibition of cancer cell migration and angiogenesis. Colchicine has a narrow therapeutic window.