Optimal Colchicine Dosage For Acute Gout Explored
April 15, 2010 By Arthritis Center
Despite being used for decades as a primary treatment for acute gout, optimal colchicine dosing has not been systematically evaluated. This is potentially important, as higher doses of colchicine can frequently be associated with the undesired consequence of severe diarrhea and gastrointestinal distress. Here, Terkeltaub et al : 1060) explore different dosing strategies for colchicine in the first randomized, blinded, placebo controlled trial, named AGREE
Existing Concerns About Colchicine Dosing And Toxicity
Vomiting and diarrhoea commonly occur when colchicine is repeatedly dosed at 1-hour or 2-hour intervals for acute gout.1,3 These are the first signs of colchicine toxicity, and may precede rare adverse effects including muscle damage, neuropathy, multiple organ failure and bone marrow suppression.4 Patients with renal or hepatic impairment may be particularly susceptible to severe colchicine toxicity .2,5-7
Increasing awareness of toxicity led prescribing guidelines to recommend lower colchicine doses and extended dosing intervals.8-10 Case reports and expert opinion suggested that the treatment benefit could be maintained at lower colchicine doses, but no data from controlled trials were available until recently.1,11
Role Of The Study Sponsor
URL Pharma funded the study and choose United BioSource Corporation to be the Contract Research Organization to run the study. Dr. Davis is the Chief Medical Officer for URL Pharma and had key roles in the study design, data collection, data analysis, and writing of the manuscript. Prior to the start of the study, URL Pharma agreed that the authors had full rights to submit the manuscript for publication, URL Pharma approval of the content of the submitted manuscript was not required, and publication of the manuscript was not contingent upon the approval of URL Pharma. The authors had full access to all data, and Dr. Terkeltaub made the final editorial decisions.
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Agree Trial Clinical Investigators
The clinical investigators in the AGREE trial are O. P. Alvarado , K. Ayesu , H. S. Baraf , S. H. Barag , S. Bather , C. A. Birbara , A. G. Captain , J. Christensen , C. F. Colopinto , R. F. Cox , A. Dahdul , C. H. DeBusk , I. A. Diab , R. DiMonte , J. F. Doris , H. S. El-Kadi , D. M. Farmer , M. C. Feinman , J. A. Feinstein , M. Fernandez , J. J. Fiechtner , B. J. Filip-Majewski , M. P. Gimness , J. E. Greenwald , M. S. Hall , N. E. Herrera , C. S. Horn , R. Hymowitz , J. M. Joseph , A. D. Karns , A. Kavanaugh , A. C. Kennedy , B. Kerzner , D. L. Kirby , M. D. Kohen , M. P. Kumar , M. D. Lagwinski , T. A. Lawrence-Ford , C. R. Leach , D. H. Lee , D. M. Levinsky , D. Lewis , S. Longley , R. S. Lorraine , D. R. Mandel , F. M. Mangune , G. B. Maniloff , P. Marchetta , S. Mathews , B. A. McConnehey , W. C. McGarity , D. P. Mehta , H. R. Mena , J. L. Miller , J. Mossell , F. T. Murphy , D. H. Neustadt , P. Q. Nguyen , T. M. Nolen , R. Osborn , D. Pangtay , P. K. Pickrell , G. E. Platt , A. R. Pollack , H. M. Prupas , K. G. Pryhuber , R. M. Pucillo , D. C. Pulver , D. S. Ramstad , L. D. Reed , P. J. Riccardi , D. M. Rice , A. M. Saifi , I. M. Shafik , L. Shandilya , W. J. Shergy , F. E. Smith , R. Z. Surowitz , M. S. Touger , R. Trejo , P. A. Waller , N. Wei , D. I. Weiss , C. W. White , J. M. Wilson , and S. M. Wolfe .
Colchicine 500 Micrograms Tablets
This information is intended for use by health professionals
Colchicine 500 micrograms Tablets.
Colchicine Ph Eur 535 micrograms .
Excipient with known effect:
One tablet contains 56.6mg of lactose
For the full list of excipients, see 6.1.
Prophylaxis of gout attack during initiation of therapy with allopurinol and uricosuric drugs
Treatment of acute gout attack:
1 mg to start followed by 500 micrograms after 1 hour.
No further tablets should be taken for 12 hours.
After 12 hours, treatment can resume if necessary with a maximum dose of 500 micrograms every 8 hours until symptoms are relieved.
The course of treatment should end when symptoms are relieved or when a total of 6 mg has been taken.
No more than 6 mg should be taken as a course of treatment.
After completion of a course, another course should not be started for at least 3 days .
Prophylaxis of gout attack during initiation of therapy with allopurinol and uricosuric drugs:
500 micrograms twice daily.
The treatment duration should be decided after factors such as flare frequency, gout duration and the presence and size of tophi have been assessed.
Patients with renal impairment:
Use with caution in patients with mild renal impairment. For patients with moderate renal impairment, reduce dose or increase interval between doses. Such patients should be carefully monitored for adverse effects of colchicine .
For patients with severe renal impairment, see section 4.3.
Patients with hepatic impairment
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What Side Effects Are Possible With This Medication
Many medications can cause side effects. A side effect is an unwanted response to a medication when it is taken in normal doses. Side effects can be mild or severe, temporary or permanent.
The side effects listed below are not experienced by everyone who takes this medication. If you are concerned about side effects, discuss the risks and benefits of this medication with your doctor.
The following side effects have been reported by at least 1% of people taking this medication. Many of these side effects can be managed, and some may go away on their own over time.
Contact your doctor if you experience these side effects and they are severe or bothersome. Your pharmacist may be able to advise you on managing side effects.
- abdominal pain
Although most of the side effects listed below don’t happen very often, they could lead to serious problems if you do not seek medical attention.
Check with your doctor as soon as possible if any of the following side effects occur:
- frequent infections
- hair loss
- prickling, tingling, or numbness in the arms or legs
- severe diarrhea
- signs of bleeding
- signs of kidney problems
- signs of liver problems
- signs of muscle damage
Stop taking the medication and seek immediate medical attention if any of the following occur:
- signs of a serious allergic reaction
Some people may experience side effects other than those listed. Check with your doctor if you notice any symptom that worries you while you are taking this medication.
Hospitalisation Essential For Suspected Overdose
If there is a high probability of colchicine toxicity, for example because of intentional overdose or dose in excess of 6mg in high risk patients, prompt admission to a facility with access to intensive supportive treatment is essential.
In overdose, early use of activated charcoal will minimise absorption. Repeated doses of charcoal will assist with the elimination of colchicine reabsorbed into the intestines through enterohepatic recycling. Diarrhoea should not be treated as it is the primary route of elimination. The period 24-72 hours after ingestion is critical and multisystem organ failure may occur. The key to patient management is full supportive care.
Serious toxicity with colchicine is an adverse reaction of current concern. Please report all New Zealand cases to the New Zealand Centre for Adverse Reactions Monitoring.
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Agree Statistical Analysis And End Points
The primary end point was the proportion of patients who responded to treatment. Responders were defined as having a pretreatment pain score within 12 hours of flare onset and a â¥50% reduction in pain within 24 hours of the first dose of study medication without the use of rescue medication during that time frame.
The primary analysis compared the proportion of responders in the high-dose colchicine and placebo groups . Comparison of low-dose colchicine with placebo was declared a priori a secondary outcome measure. Additional alternate definitions of response including 1) treatment response based on the target joint pain score 32 hours after the first dose, 2) treatment response based on at least a 2-unit reduction in the target joint pain score 24 hours after the first dose, and 3) treatment response based on at least a 2-unit reduction in the target joint pain score 32 hours after the first dose were declared a priori secondary outcome measures.
Proportions of responders were compared using the unstratified chi-square test by generating the 95% confidence interval around the mean values for the effect of age , serum urate , allopurinol use, diuretic use, time since first diagnosis of gout , number of flares within the last 12 months , admitted alcohol use, and creatinine clearance. All analyses were performed using SAS software, version 9.1 .
Warnings For People With Certain Health Conditions
For people with kidney disease: Your kidneys clear this drug from your body. If theyre not working well, levels of this drug may build up in your body, raising your risk of side effects. To help avoid this, your doctor may lower your dose of colchicine.
For people with liver disease: Your liver processes this drug in your body. If its not working well, levels of this drug may build up in your body, raising your risk of side effects. To help avoid this, your doctor may lower your dose of colchicine.
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Typical Dosing For Colchicine
Prevention of gout flare: The typical dose is 0.6 mg once or twice a day
Treatment of gout flare: The typical dose is 1.2 mg at the first sign of a flare, then 0.6 mg 1 hour later
Familial Mediterranean Fever:
- Adults and children 12 and older: The typical dose is 1.2 mg to 2.4 mg a day
- Children aged 4 to 12: The typical dose ranges from 0.3 mg to 1.8 mg and will be based on the child’s age
Characteristics Of The Agree Study Subjects
A total of 813 patients were screened, and 575 patients were randomized into the trial. Of those, 185 patients had an eligible gout flare and took study medication 52 patients received high-dose colchicine, 74 patients received low-dose colchicine, and 59 patients received placebo. All but 1 patient had a flare confirmed by the Gout Flare Call Center . Demographic and gout characteristics were similar among the 3 treatment groups. The majority of patients were overweight white men â¼50 years of age with an elevated serum urate concentration and a 10-year history of gout. Less than one-third of patients were receiving concurrent urate-lowering therapy at the start of the study. No patient started or altered urate-lowering therapy during the study. Tophi were present in â¼9% of patients . According to investigator assessment, 94.6% of patients were compliant with taking their study medication.
|Â§ OR could not be calculated since zero events occurred in at least 1 treatment group.|
- * Values are the number of patients.
- â Statistically significant difference .
- â¡ No statistically significant difference .
- Â§ OR could not be calculated since zero events occurred in at least 1 treatment group.
- Â¶ Severity of adverse events was determined by a blinded study physician.
- # As defined by Title 21, Code of Federal Regulations, Volume 5, Section 312, Part 32 Revised April 1, 2002.
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Medications Not Recommended With Colchicine
Colcrys, Mitigare and Gloperba are not recommended to take with certain drugs like clarithromycin , conivaptan , Telaprevir , and Verapamil .
A comprehensive list of medicines not recommended to take with colchicine is listed at www.drugs.com.
Additionally, avoid grapefruit while taking colchicine. It can cause a mild increase in colchicine dose, thus, heighten side effects.
A fatal overdose with colchicine is a possibility. The lowest reported lethal doses of oral colchicine are 7-26 mg. Keep in mind, interactions with certain medicines and patient preconditions are significant catalysts.
Always talk to your doctor about your risks of taking colchicine. If side effects persist, get medical help immediately.
Drug Interactions Increase Risk Of Colchicine Toxicity
Concurrently prescribing colchicine and inhibitors of cytochrome P450 3A4 or P-glycoprotein increases the potential for colchicine toxicity .2,5 The US Food and Drug Administration reported that of 117 cases of fatal colchicine toxicity at therapeutic doses , more than half occurred in patients who were taking clarithromycin at the same time.2 However, a possible role for renal impairment or prolonged colchicine dosing cannot be excluded in these cases.
Fatal and non-fatal colchicine toxicity has occurred in patients taking colchicine and concomitant erythromycin, cyclosporin, statins and calcium-channel blockers, including verapamil and diltiazem.2,12
Box 1Common inhibitors of CYP3A4 and/or P-gp that may increase the risk of colchicine toxicity2,12-14
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How To Take Colchicine
- Before you start the treatment, read the manufacturer’s printed information leaflet from inside the pack. It will give you more information about colchicine and will provide you with a full list of the side-effects which you may experience from taking it.
- You must take colchicine exactly as your doctor tells you to. Most doctors will recommend that when a gout attacks starts, you should take one tablet 2-4 times a day until the pain eases. It is important that you do not take more than 12 tablets of colchicine as a course of treatment during any one gout attack. It is also important that you leave at least three days between courses of colchicine. If you find you are having frequent attacks of gout, please let your doctor know about this.
- If you have recently been prescribed a medicine to prevent gout attacks and you have been given colchicine to prevent a flare-up attack of gout, the usual dose for this is one tablet twice each day.
- Take colchicine tablets with a drink of water.
- If you forget to take a dose, take it as soon as you remember unless it is nearly time for your next dose, in which case leave out the missed dose. Do not take two doses together to make up for a forgotten dose.
Dose Modification In Hepatic Impairment
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 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, a 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 therapy .
Treatment of gout flares with Colchicine Tablets, USP is not recommended in patients with hepatic impairment who are receiving Colchicine Tablets, USP for prophylaxis.
Patients with mild to moderate hepatic impairment should be monitored closely for adverse effects of colchicine. Dose reduction should be considered in patients with severe hepatic impairment .
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How Should I Use This Medication
The dose of colchicine and how often it is to be taken depends on the condition being treated and whether it is being used to treat or prevent flare-ups.
Acute gout: Colchicine needs to be started at the first signs of the attack when it is used to treat acute gouty arthritis or an acute attack of gout. The usual adult dose is 1.2 mg at the start of the attack, followed by 0.6 mg 1 hour later. After 12 hours, the normal preventative dose of colchicine may be restarted. This cycle may be repeated in 3 days time, if necessary.
Prevention of acute gout: The usual recommended dose to prevent flare-ups of gout is 0.6 mg taken once or twice daily. The maximum daily dose is 1.2 mg .
Treatment of FMF flare-ups: The usual starting dose of colchicine to prevent and treat FMF is 1.2 mg daily. This may be increased to a maximum of 2.4 mg daily, depending on the effectiveness of the medication.
Many things can affect the dose of medication that a person needs, such as body weight, other medical conditions, and other medications. If your doctor has recommended a dose different from the ones listed here, do not change the way that you are taking the medication without consulting your doctor.
Take this medication with a full glass of water. It may be taken with or without food, but taking it with food may help to reduce upset stomach.
Store this medication at room temperature, protect it from light and moisture, and keep it out of the reach of children.
Why Am I Taking Colchicine
Colchicine is prescribed as either a short-term medication to relieve your acute gout flare or as an ongoing, preventive treatment during the early stages of taking another medication to lower urate. Your doctor can prescribe colchicine to keep on hand in case you do have a gout flare.
Dont take colchicine to relieve other types of arthritis pain or back pain. Its effective in treating treat gout pain, but most types of arthritis dont respond to colchicine. Colchicine comes in a tablet that you swallow. You can take colchicine with or without food, but some people find it easier on the stomach to take with food. For an acute gout attack, its usually taken twice a day. You take one dose of colchicine when you first notice the symptoms, followed by a smaller dose one hour later, with no further doses for at least 12 hours.
This may be followed with doses of 0.6 mg once or twice daily . If you dont get relief within a few days, let your doctor know. You may need to switch to or add another medication.
Let your doctor know if you are allergic to any of these medications that could interact with colchicine:
Also, let your doctor know if you have ever had kidney disease, liver disease, or, for women, if youre pregnant, plan to become pregnant, or are breastfeeding. If you become pregnant while taking colchicine for gout, let your doctor know right away.
If you miss your dose of colchicine, take your dose as soon as you remember. Dont take your next dose for 12 hours.
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