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Colchicine - Indications, Dosage, and Side Effects

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Colchicine is used in the treatment of gout flares and familial Mediterranean fever. This article elaborates on Colchicine and its usage with effects.

Medically reviewed by

Dr. Nagaraj

Published At March 2, 2023
Reviewed AtAugust 18, 2023

Overview:

Colchicine has been approved by the Food and Drug Administration (FDA) for the prevention of gout and treatment of acute gouty flares. It is also used to treat familial Mediterranean fever and other hepatic cirrhosis, primary biliary cirrhosis, and pseudogout (arthritis). Unfortunately, it does not have any anti-inflammatory properties.

Indications of Colchicine:

  • It is approved to be used in prophylaxis and treatment of acute gout flares.

  • It is also approved to treat familial Mediterranean fever in children of four years and older.

  • But it has been used off-label to treat a few not approved conditions, like acute and recurrent pericarditis, prevention of post pericardial syndrome, hepatic cirrhosis, dermatitis herpetiformis (bumps and blisters over the skin), Paget's disease of bone (chronic diseases in which bone break down and then regrows), chronic immune thrombocytopenia (easy excessive bleeding on injury), and idiopathic thrombocytopenic purpura (abnormal decrease in platelets), pseudogout, and idiopathic pulmonary fibrosis (lung tissues get damaged and scarred).

Mechanism of Actions:

  • Colchicine has anti-inflammatory effects. Ideally, it disturbs the cytoskeletal functions by inhibiting beta-tubulin polymerization into microtubules, preventing activation, degranulation, and migration of neutrophils with mediating gout symptoms. Colchicine prevents the release of inflammatory glycoprotein from phagocytes, although it does not stop the phagocytosis of the uric acid crystals. Colchicine blocks the metaphase due to two separate antimitotic effects, along with disruption of mitotic spindle formation and disruption of sol-gel formation. The toxic effects of Colchicine are antimitotic, with proliferating tissues such as skin, hair, and bone marrow.

  • The mechanism of action of Colchicine in familial Mediterranean fever treatment is unknown. It interferes with the intercellular assembly of the inflammasome complex in the neutrophils, and monocytes mediate the interleukin-1 beta.

Dosing:

  • Dosage Form - Tablets, capsules, and gel. A purple color capsule-shaped with one side debossed and scored on the other side.

  • Dosage Strength - 0.6 mg in the form of tablets and capsules.

For Gout Flares

  • Prophylaxis of Gout Flares - 0.6 mg once or twice daily given to adults who are older than 16 or a maximum dose of up to 1.2 mg.

  • Treatment of Gout Flares - 1.2 mg, two tablets to be taken during the first sign of gout, followed by 0.6 mg, another tablet taken at one hour.

  • For Familial Mediterranean Fever - Children and adults older than 12 are given 1.2 to 2.4 mg. Children who are six to 12 years are given 0.9 to 1.8 mg. Children aged four to six years are given 0.3 to 1.8 mg.

Dose Recommendation

  1. The total daily dose in one or two divided doses.

  2. Increase or decrease the dose as recommended as it is incremented as 0.3 mg/day, but not to increase the maximum recommended daily dose.

  3. Tablets are taken orally.

Warning and Precautions :

  • Fatal Overdose - It is recommended to keep the drug out of reach of children, as the chances of fatal overdoses are reported.

  • Blood Dyscrasias - Myelosuppression (bone marrow activity decrease), leukopenia (low levels of white blood cells), granulocytopenia (low levels of granulocytes), and thrombocytopenia (low levels of platelets) can occur.

  • Drug Interaction P-Gp and CYP3A4 Inhibitors - Co-administration of Colchicine with P-gp and strong CYP3A4 inhibitors can be threatening interactions leading to death.

  • Neuromuscular Toxicity - The patient can develop myotoxicity, including rhabdomyolysis (syndrome due to muscle injury). In such cases, discontinuation should be done.

Special Considerations

  • Hepatic Impairment - Mild to moderate impairment does not require dosage adjustments, but Colchicine should be used cautiously. Severe hepatic impairment cases require a dose reduction; the repeated dose should not be more than once every two weeks.

  • Renal Impairments - Patients need to start the dose with 0.3 mg/day for severe renal impairments. No dose adjustments are required, but they should not repeat more than once every two weeks.

  • Pregnancy - Cautious use of Colchicine is done in pregnant women.

  • Breastfeeding Mothers - Colchicine is used in breastfeeding mothers cautiously.

  • Older Population - Colchicine is used in older people based on their renal considerations.

  • Pediatric - It is only recommended for children who are the age of four or older.

For Patients

The doctor recommends Colchicine because it prevents gout attacks. Gout attacks are sudden severe joint pain that is caused by increased levels of uric acid in the blood (hyperuricemia). It is used to relieve the pains occurring during gout attacks. It is categorized in the class of anti-gout agents; it is not anti-inflammatory. Colchicine works by blocking the process of swelling and other symptoms. It also treats familial Mediterranean fever, which causes pain, fever, and swelling of the stomach, lungs, and joints.

How to Use Medicine?

  • Use the medicine as recommended by the doctor. Usually, it is taken orally in the form of a tablet or solution with or without food.

  • When it is taken to prevent gout, it is taken once or twice daily. And if the patient gets any gout attacks during the treatment, consult the doctor, and take an extra dose of Colchicine, followed by a smaller one hour later. If an extra dose of Colchicine is taken to treat gout attacks, avoid the next scheduled dose of Colchicine until the next 12 hours.

  • If it is taken to relieve the pain of the gout attacks, the first dose is usually taken at the first sign of the pain, followed by the second one hour later than the previous dose but with a smaller dosage.

  • It is taken orally by syringe to measure the amount of dose correctly.

  • If it is taken to treat familial Mediterranean fever, it should start from a low dose and gradually increase the dose.

What Are the Precautions Taken While Colchicine Usage?

Precautions are taken while Colchicine usage is:

  • If the patient is allergic to Colchicine, avoid the medicine.

  • The patient should inform the doctor of the medication taken for the past 14 days, like antibiotics, antifungals, statins, HIV, or any drugs. The doctor will adjust the dosage accordingly.

  • The patient should inform the doctor about the medical conditions, including renal and liver diseases.

  • The patient should inform the doctor about the pregnancy or breastfeeding to the doctor.

What Are the Side Effects of Colchicine?

Side effects of Colchicine are:

  • Nausea.

  • Vomiting.

  • Diarrhea.

  • Stomach cramps.

Some severe side effects that require a doctor's attention immediately are:

  • Numbness in the fingers or toes.

  • Muscle weakness or pain.

  • Unusual bleeding.

  • Unusual bruising.

  • Sore throat.

  • Fever.

  • Infection.

  • Paleness or grayness of lips, tongue, or palms.

  • Decreases the fertility of the man.

How to Store and Dispose of Colchicine?

The storage of the Colchicine is done in a tightly closed container. It is to be kept at room temperature. It is kept out of reach of the children with tightly locked caps. The unneeded medicine is disposed of in particular ways to ensure that pets, children, and people unintentionally do not consume it. Special take-back programs are provided to dispose of the medicine. Do not flush the medicine into the toilets.

What Happens if the Colchicine Causes an Overdose?

Symptoms of overdose appear, such as:

  • Stomach pain.

  • Nausea.

  • Vomiting.

  • Diarrhea.

  • Decreased breathing.

  • Slow heart rate.

  • Unusual bruising and bleeding.

  • Sore throat, fever, and chills.

  • Signs of infections.

  • Paleness or grayness of lips, tongue, or throat.

For Doctors

Indication and Usage of Colchicine:

  • Gout Flares - Colchicine is used in a tablet form for prophylaxis and treatment of gout flares (acute gout flare).

  • Familial Mediterranean Fever - Colchicine is indicated for adults and children from four years and older to treat familial Mediterranean fever.

Dosage and Administration:

The dosing regimens for Colchicine are different for each indication. The recommended dosage depends upon the patient's age, renal function, hepatic function, and use of the co-administered drugs. It is usually given in the form of tablets orally without regard to meals.

  • Gout Flares:

  • The Prophylaxis of Gout Flares - Recommended dosage of Colchicine for prophylaxis of gout flares for adults who are older than 16 years of age is 0.6 mg delivered once daily or twice daily. The maximum dose for prophylaxis is 1.2 mg/day. Colchicine is used to initiate gout flare prophylaxis with uric acid-lowering therapy. It is beneficial for at least the first six months of uric acid-lowering therapy.

  • Treatment of Gout Flares - Colchicine's recommended dose for treating gout flares is 1.2 mg; two tablets are given, firstly at the first sign of the flare and second at 0.6 mg (one tablet) tablet after one hour. A higher dosage is not effective in these cases. The maximum recommended dosage for the treatment of gout flares is 1.8 mg tablet given over a time period of a one-hour gap. It can be administered for the treatment of gout flares during the prophylaxis, but doses should not exceed 1.2 mg; two tablets are given, firstly at the first sign of the flare and second at 0.6 mg (one tablet) tablet after one hour, then wait for 12 hours and then resume the prophylactic dose.

  • For Familial Mediterranean Fever: The Colchicine dose is recommended in adults as 1.2 mg to 2.4 mg daily. The dosage of the Colchicine is increased as needed to control the disease. 0.3 mg/day is recommended in increments and is tolerated to the maximum recommended daily dose. If side effects appear, the dose is decreased in increments of 0.3 mg/day. The total daily Colchicine dose may be administered in one to two divided doses.

For Pediatric Patients

  • For Prophylaxis and Treatment of Gout Flares - Colchicine is not used for the prophylaxis and treatment of gout flares in child patients.

  • For Familial Mediterranean Fever - The recommended dose for patients four years and older is based on age. The daily doses may be given as a single or divided dose twice daily:

  • Children aged four to six years are given 0.3 mg to 1.8 mg daily.

  • Children aged six to 12 years are given 0.9 mg to 1.8 mg daily.

  • Adolescents and children older than 12 are given 1.2 mg to 2.4 mg daily.

Dose Modification for Co-administration of the Interacting Drugs

  • Concomitant Therapy: Co-administration of the Colchicine with drugs known to inhibit CYP3A4 and P-glycoprotein (P-GP) increases the risk of the Colchicine-induced toxic effects. The doctor will adjust the dose if patients take or have recent drug treatment within 14 days. Drugs like Atazanavir, Clarithromycin, and Ritonavir are strong CYP3A4 inhibitors; Moderate CYP3A4 inhibitors are Diltiazem, Erythromycin, Verapamil; P-GP inhibitors drugs like Cyclosporine and Ranolazine, all require dose adjustment.

Treatment of gout flares with Colchicine is not recommended in patients who are already administered with a prophylactic dose of Colchicine and CYP3A4 inhibitors.

Dose Modification in Renal Impairment

Colchicine dosing is done individually according to the patient's renal function.

Clcr in mL/minute is estimated from serum creatinine (mg/dL) levels.

creatinine clearance [140 age (years) × weight (kg)

Clcr = --------------------------------------- × 0.85 for female patients

( mL/minute) 72 × serum creatinine (mg/dL)

  • Gout Flares

  • For the Prophylaxis of the Gout Flares - For the prophylaxis of the gout flares in patients with mild (creatinine clearance of 50 to 80 mL/min) to moderate (clearance of 30 to 50 mL/min) for renal impairment patients, dose adjustment is not made. Still, the patient is under supervision for any adverse effects if found. The patient with severe impairments is started with a dose of 0.3 mg/day, and further increasing is done with doctor supervision and monitoring. And for the patient with dialysis, the dose should be 0.3 mg given twice a week with close monitoring.

  • For Treatment of Gout Flares: The patient with mild to moderate renal function impairment does not require dose adjustment but requires close monitoring of the patient who is given Colchicine. With severe impairment patients, treatment should be repeated not more than once every two weeks. Alternate therapy can be given for a patient with gout flare that requires repeated courses. For dialysis patients, the total recommended dose for the treatment of gout flares should be decreased to a single dose of 0.6 mg (one tablet); the treatment dose should not be repeated more than once every two weeks.

  • Familial Mediterranean Fever: Caution should be taken while using Colchicine in renal impairment patients. Therefore, the dose is reduced for these patients. Severe impairments should start with a 0.3 mg/day dose and slowly increase with adequate monitoring. Patients with dialysis should be given 0.3 mg (half tablet), and increasing the dose requires close monitoring.

Dose Modifications in Hepatic Impairment

  • Gout Flare

  • Prophylaxis of the Gout Flares - No dose adjustment is required for mild to moderate hepatic impairment. But the severe cases require dose reduction.

  • Treatment of Gout Flares - The patient with mild to moderate hepatic adjustment does not require dose adjustment, but close monitoring is required. However, for severe cases, treatment should repeat no more than once every two weeks. In cases of a repeated course, the patient should be made to go for alternate therapy.

  • Familial Mediterranean Fever: Mild to moderate are monitored closely for adverse effects of Colchicine. Dose reduction is made only in severe impairments of hepatic function.

Pharmacokinetics:

  • Absorption: Colchicine is orally taken after taking a mean Cmax of 2.5 ng/mL for 1 to 2 hours after a single dose of administration under fasting. Further, Colchicine is given 1.8 mg over one hour, reaching plasma concentrations of 6.2 ng/mL in 1.81 hours. The mean plasma concentration reaches 6.8 ng/mL in an average of 4.47 hours. The bioavailability of Colchicine is reported to be approximately 45 %.

  • Distribution: The volume of the drug distribution in the young volunteers is 5 to 8 L/kg. The Colchicine binding to protein levels is low, nearly 39%. It is distributed in breast milk and serum in pregnancy.

  • Metabolism: It is metabolized into two primary metabolites, 2-O-demethyl Colchicine and 3-O-demethyl Colchicine, and one minor metabolite.

  • Elimination: 40 to 65 % of 1 mg orally is administered. Colchicine is recovered unchanged in the urine. Enterohepatic recirculation and biliary excretion play a role in Colchicine elimination. The multiple oral doses of 0.6 mg twice daily and the mean elimination of half-lives in young, healthy people is 26.6 to 31.2 hours. Colchicine is a substrate of P-GP.

Contraindication:

  • Patients with hepatic or renal impairment are not given Colchicine with P-GP or strong CYP3A4 inhibitors because the effects after their use can be fatal or life-threatening.

Drug Interactions:

If administering Colchicine with drugs that inhibit P-glycoprotein, which also inhibits CYP3A4, increases the concentration of the Colchicine, they can cause fatal drug interactions. While co-administering, the Colchicine dosage is adjusted. When co-administered with drugs known to inhibit CYP3A4, it can be fatal.

  • Concomitant classes or food that have shown fatality in long-term use of Colchicine are HMG-CoA reductase inhibitors (Atorvastatin, Fluvastatin, Lovastatin, Pravastatin, Simvastatin); other lipid-lowering drugs (Gemfibrozil, Fibrates); Digitalis glycosides (Digoxin).

Specific Considerations:

  • Pregnancy - There are no adequate or well-controlled studies with Colchicine in pregnant women. It crosses the placenta. However, animal studies have reported teratogenicity and altered postnatal developments. It should be used in pregnancy cautiously, only after justifying the benefits than the risks.

  • Labor and Delivery - There is no data on the effects of Colchicine on labor and delivery.

  • Nursing Mothers - Colchicine is excreted in breast milk. Little information regarding breastfed infants is present; less than ten percent of material weight in dosage infants have Colchicine. Caution should be taken while prescribing Colchicine to breastfeeding mothers.

  • Pediatric Use - The safety and efficacy in children have been evaluated with familial Mediterranean fever in uncontrolled studies. There is no adverse effect on growth in children with Colchicine usage. For gout patients, its efficacy and safety are not established.

  • Geriatric Patients - The dose selection for elderly patients with gout should be cautious to have decreased frequency of renal function, concomitant disease, or drug therapy. No sufficient studies are present to evaluate the results.

  • Renal Impairments - Colchicine is excreted in the urine. Its clearance is decreased in patients with renal impairments. Reduced total body clearance to 75 % in end-stage renal disease patients undergoing dialysis.

Nonclinical Toxicology:

  • Carcinogenesis - The use of Colchicine to produce aneuploid cells; thus, there is theoretically a risk of malignancy.

  • Mutagenesis - Although the results were negative based on mutagenicity, the Colchicine treatment resulted in micronuclei formation. So, it is not considered clastogenic (agents that break the chromosome and cause mutation) on the micronuclei formation, even if it has reported an aneuploidy.

  • Impairment of Fertility - It has been reported that abnormal sperm formation and decreased sperm counts in males, along with sperm penetration, will get interfered with, and second meiotic division and normal cleavage in females on Colchicine use. Also, administering Colchicine to pregnant animals has detected fetal death and teratogenicity.

Clinical Trials:

  • Two randomized clinical trials assessed the effectiveness of Colchicine 0.6 mg twice daily for prophylaxis of gout flares in the patient. In both trials, treatment with Colchicine decreases the frequency of the gout flares.

  • A low-dosage regimen of oral Colchicine with a total dose of 1.8 mg over one hour for the treatment of the gout flares was determined. It was a multicenter, randomized, double-blind, placebo-controlled, parallel-group, one-week, dose-comparison study. The patient was assigned to three groups: high dosage with Colchicine 1.2 mg, then 0.6 mg in six hours (4.8 mg total); low dosage of 1.2 mg, then 0.6 mg in the 1-hour gap (1.8 mg total) then following the five placebo doses hourly with two capsules, then one capsule every one hour in six hours. The patient reported taking the first dose within 12 hours of the flare's onset and recorded pain intensity and adverse effects over 72 hours. The efficacy was measured depending upon the treatment in the target joint by the patient in 24 hours. This resulted in a 50 % improvement in the pain score in 24 hours.

Results - The response was similar in the recommended low-dose group (38 %) and high-dose group (33 %) but higher in the placebo group (16 %).

  • Three randomized, placebo-controlled studies were performed. The three placebo groups randomized with 48 patients who were diagnosed with familial Mediterranean fever reported the same efficacy results.

  • One of the randomized studies with 15 patients with a familial Mediterranean fever over a six-month crossover study. Among them, five patients discontinued due to non-compliance; ten patients completing the study had five attacks within 90 days while treated with Colchicine and 59 attacks on treatment with a placebo. A similar study with 22 randomized familial Mediterranean fever patients with a four-month crossover study with nine patients was discontinued because of efficacy. In comparison, 13 other patients completed the study with 18 attacks over the 60 days of course treatment with Colchicine and 68 attacks on the 60 days course with placebo. The third study discontinued the analysis of six patients out of 11 who had completed the study but confirmed no results.

Frequently Asked Questions

1.

Does Colchicine Reduce Uric Acid Levels?

Colchicine is an anti-inflammatory and analgesic drug. It works by lowering the swelling caused by the uric acid crystals that amass in the joints when one has gout. One can lessen the likelihood of attacks by taking low doses of Colchicine every day. Due to Colchicine's inability to reduce uric acid levels in the blood, this will not, however, prevent the formation of crystals or stop long-term joint injury.

2.

Is Colchicine an Analgesic?

Colchicine belongs to the group of drugs known as anti-gout agents. It functions by halting the organic processes that result in swelling and other gout and familial Mediterranean fever symptoms. Multiple pro- and anti-inflammatory mechanisms linked to gouty arthritis are modulated by Colchicine. Inflammasome activation, microtubule-based inflammatory cell chemotaxis, the production of leukotrienes and cytokines, and phagocytosis are all disrupted by Colchicine's prevention of microtubule assembly.

3.

Why Is Colchicine Not Used for Gout Nowadays?

Within the first 36 hours of the gout attack, medication should be started. Due to the fact that Colchicine; might take up to 24 hours to fully take effect, it is not utilized as frequently these days. It is, however, a different choice for those who cannot take the other prescriptions due to other health issues or intolerances. Colchicine is used to treat and prevent gout flare-ups, but due to its expense and adverse effects, it is not widely utilized.

4.

Does Colchicine Affect Kidneys?

The kidneys excrete Colchicine. Patients with chronic kidney disease are more susceptible to the toxicity of Colchicine, hence dosage reduction is necessary depending on kidney function. If the glomerular filtration rate is less than 50 mL/minute, patients taking Colchicine for prophylaxis must be closely monitored; otherwise, Colchicine should be avoided.

5.

What Conditions Does Colchicine Treat?

The Food and Drug Administration (FDA) has given Colchicine permission to prevent gout attacks and treat acute gout flares. Additionally, it is authorized to treat familial Mediterranean fever. Colchicine has been used off-label to treat a number of different illnesses, such as pseudogout, primary biliary cirrhosis, and hepatic cirrhosis. Colchicine is typically used to treat or prevent bouts of gout, commonly known as gouty arthritis. Too much uric acid in the blood is the root cause of this illness. A gout attack happens when uric acid flames in a joint, resulting in discomfort (pain, redness, edema, and heat).

6.

Can a Person Take Colchicine Every Day?

Colchicine should be started within 24 hours of a gout attack for optimal outcomes. Do not take any additional Colchicine for at least three days after taking pills to treat an attack. Do not take any more Colchicine (tablets or injections) for at least seven days after obtaining the medication through injection for an attack. If one is taking Colchicine for longer than ten days and one has weak kidney function, one might need to take a reduced dose every day.

7.

Who Should Avoid Taking Colchicine?

If a person has stomach ulcers or other severe stomach issues, Colchicine might not be recommended. If people have significant kidney issues or irregular blood counts, Colchicine might not be the best choice for them. This medication leaves the body through the kidneys. The body's levels of this medication may increase if they are not acting properly, increasing the chance of negative effects. The doctor might reduce the dosage of Colchicine to help prevent this.

8.

Is Colchicine Safe?

Rhabdomyolysis, a significant (and occasionally deadly) muscle injury, can occasionally be caused by Colchicine. When muscles are damaged, chemicals are released that can seriously damage the kidneys. When Colchicine is used with other medications that have the potential to cause rhabdomyolysis, the risk may increase. Colchicine should be started within 24 hours of a gout attack for optimal outcomes. If people will be taking Colchicine for more than ten days and they have weak kidney function, they could need to lower the daily dose.

9.

Can Colchicine Cause High Blood Pressure?

The probability of contracting an infection rises due to Colchicine's ability to temporarily reduce the amount of white blood cells in the blood. Furthermore, it can lower platelet counts, which are crucial for proper blood coagulation. Calcium channel blockers are used to treat irregular heartbeats, excessive blood pressure, and chest discomfort. Colchicine may interact with the calcium channel blockers Diltiazem and Verapamil. The enzyme that metabolizes Colchicine is blocked by these calcium channel blockers. Blood pressure, however, has not been found to be affected.

10.

How Long Does Colchicine Take for Its Onset?

It may take a day or two for the discomfort to start to subside after taking Colchicine, which begins to work after around 30 minutes to two hours. It is crucial to take the medication exactly as directed. Symptoms frequently surface before pain alleviation does, usually two to 12 hours after consumption. 

11.

Why Should Colchicine Not Be Taken With NSAIDs?

Non-steroidal anti-inflammatory medications or corticosteroids may exacerbate Colchicine toxicity via resulting pharmacokinetic and pharmacodynamic interaction in the gut wall when used to treat acute gouty arthritis. NSAIDs and Colchicine both have the potential to harm the kidneys. Despite being an NSAID, acetylsalicylic acid (the active ingredient in medications like Aspirin) is not a good choice for treating gout. 
Dr. Nagaraj
Dr. Nagaraj

Diabetology

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