Colchicine

Colchicine is a an Antigout agent belonging to pharmacology class of gout suppressant

Colchicine is approved for the treatment of gout flares, Atherosclerotic cardiovascular diseases, Familial Mediterranean fever.

Colchicine is Absorbed quickly and almost entirely. Approximately 45% of bioavailability. 0.5 to 3 hours until plasma concentration reaches its maximum and gets Concentrated in leucocytes, kidney, spleen, and liver (but not in the heart, skeletal muscle, or brain). enters breast milk after crossing the placenta with a distribution volume of around 5-8 L/kg. 39% or so of plasma proteins are bound, mostly albumin, and get metabolized in the liver via demethylation by the CYP3A4 isoenzyme into 2 primary metabolites (2-O-demethylcolchicine and 3-O-demethylcolchicine), and 1 minor metabolite (10-O-demethylcolchicine or known as colchiceine). Undergoes enterohepatic recycling which get excreted mainly via faeces (80%, as unchanged drug and metabolites); urine (10-20%). Elimination half-life: 27-31 hours.

The common side effects associated with Colchicine include Neuromuscular toxicity, rhabdomyolysis (chronic treatment); gastrointestinal effects (e.g. abdominal pain, diarrhea, nausea, vomiting).

Colchicine is available in the form of. oral solid and oral liquid.

The Colchicine is available in India, USA, Japan, Asutralia.

Colchicine belonging to the gout suppressant acts a Antigout Agent.

Hinders the formation of microtubules from -tubulin polymerization, disrupting cytoskeletal activities, and limiting the activation, degranulation, and migration of neutrophils that are thought to be a mediator of various gout symptoms. The inflammasome complex, which is found in neutrophils and monocytes and regulates the activation of interleukin-1, may not be able to assemble properly inside the cells in familial Mediterranean fever.

Onset of action: Approx 18-24 hours.

Tmax :0.5-3 hours.

Colchicine is available in the form of Tablet, Capsules and Solution.

Tablet, Capsules and Solution to be swallowed whole with water/liquid.

Colchicine can be used in the treatment of gout flares, Atherosclerotic cardiovascular diseases, Familial Mediterranean fever. It is also used in the treatment of Pericarditis, recurrent; Behçet syndrome; Calcium pyrophosphate (CPP) crystal arthritis ("pseudogout"); Pericarditis, acute , Sweet syndrome (acute febrile neutrophilic dermatosis); Vasculitis, idiopathic cutaneous small-vessel, Postpericardiotomy syndrome, prevention.

Colchicine functions by suppressing the inflammatory reactions brought on by monosodium urate crystals in synovial fluid that are mediated by neutrophils. Through the inhibition of -tubulin polymerization into microtubules, it disrupts with cytoskeletal activities and hinders neutrophil activation, degranulation, and migration into the inflamed area. It could hinder intracellular assembly of the inflammasome complex, which is present in neutrophils and monocytes and regulates interleukin-1 activation, in familial Mediterranean fever.

Colchicine is approved for use in the following clinical indications

Gout flares: Prophylaxis and treatment of acute gout flares when taken at the first sign of a flare.

Atherosclerotic cardiovascular disease, risk reduction: To lower the risk of myocardial infarction, stroke, coronary revascularization, and cardiovascular death in adults with existing atherosclerotic disease or numerous cardiovascular risk factors.

Familial Mediterranean fever: Treatment of familial Mediterranean fever in adults and children 4 years and older.

Although not approved there have been certain off labelled uses documented for colchicine which include:

Gout, treatment (acute flares):

Day 1: Oral: 1.2 mg at the first sign of flare, followed by 0.6 mg after 1 hour ; maximum total dose: 1.8 mg/day on day 1 . Initiate as soon as possible, ideally within 12 to 24 hours of flare onset; consider alternative agents if >36 hours since flare onset. Note: In patients who were already receiving prophylactic colchicine at the time of their flare, some experts give the higher 1.8 mg/day dosing regimen on day 1 of the flare, in place of the usual prophylactic dose.

Day 2 and thereafter: Oral: 0.6 mg onceparac or twice daily until flare resolves . Some experts continue for 2 to 3 days after flare resolves . Note: In patients who were already receiving prophylaxis at the time of their flare, some experts give 0.6 mg twice daily (total dose: 1.2 mg/day) from day 2 until ~48 hours after flare resolution, and then resume the previous prophylactic dose.

Note: Historically, higher dose regimens have been given for gout flares; however, high-dose regimens have not been proven more effective than low-dose regimens and low-dose regimens have a better safety profile .

Pericarditis, acute or recurrent (off-label use):

Loading dose: Loading doses are not necessary; avoiding loading doses may improve adherence to therapy and reduce adverse effects . If a decision to use a loading dose is made, the following is recommended:

Patients ≥70 kg: Oral: 1 mg (or 1.2 mg) every 12 hours on day 1, followed by maintenance dosing .

Patients <70 kg or unable to tolerate higher dosing regimen: Oral: 0.5 mg (or 0.6 mg) every 12 hours on day 1, followed by maintenance dosing.

Maintenance dosing:

Patients ≥70 kg: Oral: 0.5 mg (or 0.6 mg) twice daily

Patients <70 kg or unable to tolerate higher dosing regimen: Oral: 0.5 mg (or 0.6 mg) once daily

Duration of therapy:

Initial treatment (first occurrence): 3 months

Recurrence treatment (first recurrence or multiple recurrences): 6 months

Concomitant therapy: Use in combination with aspirin or a nonsteroidal anti-inflammatory drug (NSAID); may also add a corticosteroid for refractory cases. Alternatively, colchicine may be used with a corticosteroid alone if aspirin or an NSAID is contraindicated .

Postpericardiotomy syndrome, prevention (off-label use):

Note: Initiate preventive therapy preoperatively (48 to 72 hours prior to surgery) or postoperatively (24 to 72 hours after surgery).

Patients ≥70 kg: Oral: 0.5 mg (or 0.6 mg) twice daily for 1 month

Patients <70 kg: Oral: 0.5 mg (or 0.6 mg) once daily for 1 month

Sweet syndrome (acute febrile neutrophilic dermatosis) (alternative agent )

(off-label use):

Oral: Dosage range studied: 1 to 1.5 mg/day (1.2 to 1.8 mg/day) in 1 to 3 divided doses; the mean duration of therapy in one case series was reported as 15 days (range: 10 to 21 days)

Vasculitis, idiopathic cutaneous small-vessel (alternative agent) (off-label use):

Note: Consider for use in patients who do not respond adequately to initial therapy with corticosteroids .

Oral: Usual dose studied: 0.6 mg twice daily (Callen 1985; Callen 1987); if no response after 1 to 2 weeks, may consider increasing to 0.6 mg 3 times daily ; continue therapy for 2 to 3 months after lesions heal and no new lesions develop, then taper and discontinue therapy over several weeks .

• (Colchicine can be administered orally before/ after meals. The dosage and duration of treatment should be as per the clinical judgement of the treating physician)

Tablet: 0.6 mg

Capsules: 0.6 mg

Solution: 0.6 mg/ 5ml

Tablet, Capsules and Solution.

Dose Adjustment in Kidney Patient:

Dose Adjustment in Hepatic Patient:

Atherosclerotic cardiovascular disease, risk reduction :

Mild to moderate impairment: There are no specific dose adjustments provided in the manufacturer's labeling; however, clearance may be significantly reduced and plasma half-life prolonged in patients with chronic hepatic impairment; monitor closely for adverse effects.

Severe impairment: Use is contraindicated.

Familial Mediterranean fever:

Mild to moderate impairment: Use caution; monitor closely for adverse effects.

Severe impairment: There is no specific dosage adjustment provided in the manufacturer's labeling; dosage adjustment should be considered.

Gout prophylaxis:

Mild to moderate impairment:

Tablet (eg, Colchicine): Dosage adjustment not required; monitor closely for adverse effects.

Capsule (eg, Mitigare) and oral solution (eg, Gloperba): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Severe impairment: There is no specific dosage adjustment provided in the manufacturer's labeling; dosage adjustment should be considered.

Hepatic impairment with concomitant renal impairment: Capsule (eg, Mitigare) and oral solution (eg, Gloperba): Use is contraindicated.

Gout flare treatment:

Note: Treatment of gout flares is not recommended in patients with hepatic impairment who are receiving colchicine for prophylaxis.

Mild to moderate impairment: Dosage adjustment not required; monitor closely for adverse effects.

Severe impairment: Dosage reduction not required but may be considered; treatment course should not be repeated more frequently than every 14 days.

Familial Mediterranean Fever (FMF):

Children 4 to 6 years: Oral: 0.3 to 1.8 mg/day in 1 to 2 divided doses; titrate by increasing or decreasing dose in 0.3 mg/day increments based on efficacy or adverse effects; maximum dose: 2.4 mg/day; some guidelines recommend a lower maximum daily dose (2 mg/day).

Children >6 to 12 years: Oral: 0.9 to 1.8 mg/day in 1 to 2 divided doses; titrate by increasing or decreasing dose in 0.3 mg/day increments based on efficacy or adverse effects; maximum dose: 2.4 mg/day; some guidelines recommend a lower maximum daily dose (2 mg/day).

Children >12 years and Adolescents: Oral: 1.2 to 2.4 mg/day in 1 to 2 divided doses; titrate by increasing or decreasing dose in 0.3 mg/day increments based on efficacy or adverse effects; maximum dose: 2.4 mg/day; some guidelines recommend a lower maximum daily dose (2 mg/day).

Gout: Adolescents >16 years:

Flare treatment: Initial: Oral: 1.2 mg at the first sign of flare, followed in 1 hour with a single dose of 0.6 mg (maximum dose: 1.8 mg over 1 hour). Patients receiving prophylaxis treatment may receive treatment dosing; wait 12 hours before resuming prophylactic dose; wait at least 3 days before repeating treatment dose.

Prophylaxis: Oral: 0.6 mg once or twice daily; maximum daily dose: 1.2 mg/day.

The dietary restriction should be individualized as per patient requirements.

Colchicine may be contraindicated under the following conditions:

Blood dyscrasias. severe renal (including those on dialysis) and hepatic impairment (when used to treat acute gout). birth and breastfeeding. P-glycoprotein (P-gp) inhibitors or potent CYP3A4 inhibitors should be used concurrently in patients with renal or hepatic impairment.

The treating physician must closely monitor the patient and keep pharmacovigilance as follows

Concerns related to adverse effects:

• Blood dyscrasias: Can cause myelosuppression, leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, and aplastic anemia, which can be life-threatening or fatal.

• Neuromuscular toxicity: Can cause neuromuscular toxicity and rhabdomyolysis. If a patient develops signs of neuromuscular toxicity, discontinue therapy, investigate other causes, and treat appropriately.

Disease-related concerns:

• Hepatic impairment: Clearance is decreased in hepatic impairment; may increase risk of adverse effects/toxicity. Dosage adjustments may be considered depending on degree of impairment or indication and may be affected by the use of concurrent medication (CYP3A4 or P-gp inhibitors).

• Renal impairment: Clearance is decreased in renal impairment; may increase risk of adverse effects/toxicity. Dosage adjustments may be required depending on degree of impairment or indication and may be affected by the use of concurrent medication (CYP3A4 or P-gp inhibitors).

Increased blood uric acid levels and risk of gastrointestinal toxicity with alcohol.

Colchicine is present in breast milk.

Colchicine is considered compatible with breastfeeding and use should be continued in women with familial Mediterranean fever. Avoiding breastfeeding 2 to 4 hours after the maternal dose may decrease exposure to the breastfed infant

In a trial involving four mothers who were breastfeeding using colchicine for familial Mediterranean fever, the peak concentrations in both the mother's serum and the breast milk occurred simultaneously. Six hours after the treatment, the concentrations of breast milk were cut in half. The company that manufactures estimates that infants who are exclusively breastfed will receive 10% of the weight-adjusted maternal dose; nevertheless, reported breast milk concentrations might vary greatly. Infants that are breastfed have not seen any negative side effects from usage.

Colchicine is recommended for usage in women with familial Mediterranean fever since it is thought to be compatible with nursing. Avoiding breastfeeding for two to four hours after the mother dose may reduce the infant's exposure.

Grapefruit juice elevates plasma concentrations; prevent concurrent usage.

The adverse reactions related to colchicine can be categorized as

Common Adverse effects: Neuromuscular toxicity, rhabdomyolysis (chronic treatment); gastrointestinal effects (e.g. abdominal pain, diarrhoea, nausea, vomiting).

Less Common Adverse effects: Myotonia, muscle weakness, myopathy, Headache, neuropathy, peripheral neuritis.

Rare Adverse effects: Amenorrhoea, dysmenorrhoea, oligospermia, azoospermia

The clinically relevant drug interactions of colchicine is briefly summarized here

HMG-CoA reductase inhibitors (such as atorvastatin, simvastatin), fibrates, and digoxin increase the risk of myopathy and rhabdomyolysis. B12 absorption issues that are reversible may occur. Acidifying substances, such as ammonium chloride, ascorbic acid, and acid phosphates, have a decreased therapeutic impact. Alkalinizing substances, such as Na bicarbonate and K citrate, have an improved therapeutic impact. may make people more sensitive to CNS depressants (such opiates, sedative hypnotics, and benzodiazepines), according to certain studies. Using phenylbutazone concurrently may raise the risk of leucopenia, thrombocytopenia, or bone marrow depression. Combined use of various NSAIDs may raise the risk of stomach ulcers or hemorrhage. Prophylactic gout therapy with cytolytic antineoplastic drugs has lost effectiveness. The plasma levels of colchicine are raised by tolbutamide and cimetidine.

The common side of colchicine include the following

Neuromuscular toxicity, rhabdomyolysis (chronic treatment); gastrointestinal effects (e.g. abdominal pain, diarrhea, nausea, vomiting).

Pregnancy

Pregnancy Category C.

There are no adequate and well-controlled studies with colchicine in pregnant women. Colchicine crosses the human placenta. While not studied in the treatment of gout flares, data from a limited number of published studies found no evidence of an increased risk of miscarriage, stillbirth or teratogenic effects among pregnant women using colchicine to treat familial Mediterranean fever (FMF). Although animal reproductive and developmental studies were not conducted with Colchicine, published animal reproduction and development studies indicate that colchicine causes embryofetal toxicity, teratogenicity and altered postnatal development at exposures within or above the clinical therapeutic range. Colchicine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Labor and Delivery

The effect of colchicine on labor and delivery is unknown.

Nursing Mothers

Colchicine is excreted into human milk. Limited information suggests that exclusively breastfed infants receive less than 10 percent of the maternal weight-adjusted dose. While there are no published reports of adverse effects in breastfeeding infants of mothers taking colchicine, colchicine can affect gastrointestinal cell renewal and permeability. Caution should be exercised, and breastfeeding infants should be observed for adverse effects when Colchicine is administered to a nursing woman.

Pediatric Use

The safety and efficacy of colchicine in children of all ages with FMF has been evaluated in uncontrolled studies. There does not appear to be an adverse effect on growth in children with FMF treated long-term with colchicine. Gout is rare in pediatric patients; safety and effectiveness of colchicine in pediatric patients has not been established.

Geriatric Use

Clinical studies with colchicine for prophylaxis and treatment of gout flares and for treatment of FMF did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. In general, dose selection for an elderly patient with gout should be cautious, reflecting the greater frequency of decreased renal function, concomitant disease or other drug therapy

Renal Impairment

Colchicine is significantly excreted in urine in healthy subjects. Clearance of colchicine is decreased in patients with impaired renal function. Total body clearance of colchicine was reduced by 75% in patients with end-stage renal disease undergoing dialysis. Prophylaxis of Gout Flares For prophylaxis of gout flares in patients with mild (estimated creatinine clearance Clcr 50 to 80 mL/min) to moderate (Clcr 30 to 50 mL/min) renal function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of colchicine. However, in patients with severe impairment, the starting dose should be 0.3 mg per day and any increase in dose should be done with close monitoring. For the prophylaxis of gout flares in patients undergoing dialysis, the starting doses should be 0.3 mg given twice a week with close monitoring

Treatment of Gout Flares For treatment of gout flares in patients with mild (Clcr 50 to 80 mL/min) to moderate (Clcr 30 to 50 mL/min) renal function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of COLCHICINE. However, in patients with severe impairment, while the dose does not need to be adjusted for the treatment of gout flares, a treatment course should be repeated no more than once every two weeks. For patients with gout flares requiring repeated courses, consideration should be given to alternate therapy. For patients undergoing dialysis, the total recommended dose for the treatment of gout flares should be reduced to a single dose of 0.6 mg (one tablet). For these patients, the treatment course should not be repeated more than once every two weeks [see Dose Modification in Renal Impairment (2.5)]. FMF Although, pharmacokinetics of colchicine in patients with mild (Clcr 50 to 80 mL/min) and moderate (Clcr 30 to 50 mL/min) renal impairment is not known, these patients should be monitored closely for adverse effects of colchicine. Dose reduction may be necessary. In patients with severe renal failure (Clcr less than 30 mL/min) and end-stage renal disease requiring dialysis, Colchicine may be started at the dose of 0.3 mg/day. Any increase in dose should be done with adequate monitoring of the patient for adverse effects of

Hepatic Impairment

The clearance of colchicine may be significantly reduced and plasma half-life prolonged in patients with chronic hepatic impairment compared to healthy subjects

Prophylaxis of Gout Flares

For prophylaxis of gout flares in patients with mild to moderate hepatic function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of colchicine. Dose reduction should be considered for the prophylaxis of gout flares in patients with severe hepatic impairment.

Treatment of Gout Flares

For treatment of gout flares in patients with mild to moderate hepatic function impairment, adjustment of the recommended Colchicine dose is not required, but patients should be monitored closely for adverse effects of Colchicine. However, for the treatment of gout flares in patients with severe impairment, while the dose does not need to be adjusted, the treatment course should be repeated no more than once every two weeks. For these patients, requiring repeated courses for the treatment of gout flares, consideration should be given to alternate. FMF In patients with severe hepatic disease, dose reduction should be considered with careful monitoring.

Symptoms: The following symptoms appear in the first stage (within 24 hours of ingestion): nausea, vomiting, abdominal discomfort, hemorrhagic gastroenteritis, electrolyte imbalance, volume depletion, leucocytosis, and in extreme cases, hypotension. Second stage: life-threatening complications, such as multisystem organ dysfunction, acute renal failure, confusion, coma, ascending peripheral motor and sensory neuropathy, myocardial depression, pancytopenia, dysrhythmias, respiratory failure, and consumption coagulopathy (occurs within 24-72 hours of ingestion).

Management: Symptomatic and supportive treatment. Perform gastric lavage within 1 hour of ingestion. Consider activated charcoal administration within 1 hour of presentation in adults who have ingested doses >0.1 mg/kg and any amount in children.

Pharmacodynamic:

Colchicine acts by blocking the inflammatory reactions brought on by monosodium urate crystals in synovial fluid that are mediated by neutrophils. Through the inhibition of -tubulin polymerization into microtubules, it interacts with cytoskeletal activities and prevents neutrophil activation, degranulation, and migration into the inflamed area. It may prevent intracellular assembly of the inflammasome complex, which is present in neutrophils and monocytes and regulates interleukin-1 activation, in familial Mediterranean fever.

Pharmacokinetics:

Colchicine

Absorption: Absorbed quickly and almost entirely. Approximately 45% of bioavailability. 0.5 to 3 hours until plasma concentration reaches its maximum.

Distribution: Concentrated in leucocytes, kidney, spleen, and liver (but not in the heart, skeletal muscle, or brain). enters breast milk after crossing the placenta. Distribution volume: around 5-8 L/kg. 39% or so of plasma proteins are bound, mostly albumin.

Metabolism: Metabolised in the liver via demethylation by the CYP3A4 isoenzyme into 2 primary metabolites (2-O-demethylcolchicine and 3-O-demethylcolchicine), and 1 minor metabolite (10-O-demethylcolchicine or known as colchiceine). Undergoes enterohepatic recycling.

Excretion: Mainly via faeces (80%, as unchanged drug and metabolites); urine (10-20%). Elimination half-life: 27-31 hours.

1. https://www.uptodate.com/contents/colchicine-drug-information?search=colchicine&source=panel_search_result&selectedTitle=1~148&usage_type=panel&kp_tab=drug_general&display_rank=1#F154338
2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022352s017lbl.pdf
3. https://www.medicaid.nv.gov/Downloads/provider/Colchicine_2015-1215.pdf
4. https://www.mims.com/india/drug/info/colchicine?type=full&mtype=generic#mechanism-of-action