Colcrys Information
Colcrys (Colchicine) Dosage And Administration
The long term use of colchicine is established for FMF and the prophylaxis of gout flares but the safety and efficacy of repeat treatment for gout flares has not been evaluated. The dosing regimens for Colcrys (Colchicine) are different for each indication and must be individualized.
The recommended dosage of Colcrys (Colchicine) depends on the patient's age, renal function, hepatic function, and use of co-administered drugs [].
Colcrys (Colchicine) tablets are administered orally, without regard to meals.
Colcrys (Colchicine) is not an analgesic medication and should not be used to treat pain from other causes.
Colcrys (Colchicine) Dosage Forms And Strengths
0.6 mg tablets — purple capsule-shaped, film-coated with AR 374 debossed on one side and scored on the other side.
Colcrys (Colchicine) Contraindications
Patients with renal or hepatic impairment should not be given Colcrys (Colchicine) in conjunction with P-gp or strong CYP3A4 inhibitors (this includes all protease inhibitors, except fosamprenavir). In these patients, life-threatening and fatal colchicine toxicity has been reported with colchicine taken in therapeutic doses.
Colcrys (Colchicine) Adverse Reactions
Prophylaxis of Gout Flares:
The most commonly reported adverse reaction in clinical trials of colchicine for the prophylaxis of gout was diarrhea.
Treatment of Gout Flares:
The most common adverse reactions reported in the clinical trial with Colcrys (Colchicine) for treatment of gout flares were diarrhea (23%) and pharyngolaryngeal pain (3%).
FMF:
Gastrointestinal tract adverse effects are the most frequent side effects in patients initiating Colcrys (Colchicine) , usually presenting within 24 hours, and occurring in up to 20% of patients given therapeutic doses. Typical symptoms include cramping, nausea, diarrhea, abdominal pain, and vomiting. These events should be viewed as dose-limiting if severe as they can herald the onset of more significant toxicity.
Because clinical studies are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug, and may not predict the rates observed in a broader patient population in clinical practice.
In a randomized, double-blind, placebo-controlled trial in patients with a gout flare, gastrointestinal adverse reactions occurred in 26% of patients using the recommended dose (1.8 mg over 1 hour) of Colcrys (Colchicine) compared to 77% of patients taking a non-recommended high-dose (4.8 mg over 6 hours) of colchicine and 20% of patients taking placebo. Diarrhea was the most commonly reported drug-related gastrointestinal adverse event. As shown in Table 3, diarrhea is associated with Colcrys (Colchicine) treatment. Diarrhea was more likely to occur in patients taking the high-dose regimen than the low-dose regimen. Severe diarrhea occurred in 19% and vomiting occurred in 17% of patients taking the non-recommended high-dose colchicine regimen but did not occur in the recommended low-dose Colcrys (Colchicine) regimen.
Serious toxic manifestations associated with colchicine include myelosuppression, disseminated intravascular coagulation, and injury to cells in the renal, hepatic, circulatory, and central nervous systems.
These most often occur with excessive accumulation or overdosage [].
The following adverse reactions have been reported with colchicine. These have been generally reversible upon temporarily interrupting treatment or lowering the dose of colchicine.
Colcrys (Colchicine) Drug Interactions
Colcrys (Colchicine) is a substrate of the efflux transporter P-glycoprotein (P-gp). Of the cytochrome P450 enzymes tested, CYP3A4 was mainly involved in the metabolism of colchicine. If Colcrys (Colchicine) is administered with drugs that inhibit P-gp, most of which also inhibit CYP3A4, increased concentrations of colchicine are likely. Fatal drug interactions have been reported.
Physicians should ensure that patients are suitable candidates for treatment with Colcrys (Colchicine) and remain alert for signs and symptoms of toxicities related to increased colchicine exposure as a result of a drug interaction. Signs and symptoms of Colcrys (Colchicine) toxicity should be evaluated promptly and, if toxicity is suspected, Colcrys (Colchicine) should be discontinued immediately.
Table 4 provides recommendations as a result of other potentially significant drug interactions. Table 1 provides recommendations for strong and moderate CYP3A4 inhibitors and P-gp inhibitors.
Colcrys (Colchicine) Drug Abuse And Dependence
Tolerance, abuse, or dependence with colchicine has not been reported.
Colcrys (Colchicine) Overdosage
The exact dose of colchicine that produces significant toxicity is unknown. Fatalities have occurred after ingestion of a dose as low as 7 mg over a 4-day period, while other patients have survived after ingesting more than 60 mg. A review of 150 patients who overdosed on colchicine found that those who ingested less than 0.5 mg/kg survived and tended to have milder toxicities, such as gastrointestinal symptoms, whereas those who took 0.5 to 0.8 mg/kg had more severe reactions, such as myelosuppression. There was 100% mortality in those who ingested more than 0.8 mg/kg.
The first stage of acute colchicine toxicity typically begins within 24 hours of ingestion and includes gastrointestinal symptoms, such as abdominal pain, nausea, vomiting, diarrhea, and significant fluid loss, leading to volume depletion. Peripheral leukocytosis may also be seen. Life-threatening complications occur during the second stage, which occurs 24 to 72 hours after drug administration, attributed to multi-organ failure and its consequences. Death is usually a result of respiratory depression and cardiovascular collapse. If the patient survives, recovery of multi-organ injury may be accompanied by rebound leukocytosis and alopecia starting about 1 week after the initial ingestion.
Treatment of colchicine poisoning should begin with gastric lavage and measures to prevent shock. Otherwise, treatment is symptomatic and supportive. No specific antidote is known. Colchicine is not effectively removed by dialysis [].
Colcrys (Colchicine) Description
Colchicine is an alkaloid chemically described as (S)N- (5,6,7,9-tetrahydro- 1,2,3, 10-tetramethoxy-9-oxobenzo [alpha] heptalen-7-yl) acetamide with a molecular formula of CHNO and a molecular weight of 399.4. The structural formula of colchicine is given below.
Colchicine occurs as a pale yellow powder that is soluble in water.
Colcrys (Colchicine) (colchicine, USP) tablets are supplied for oral administration as purple, film-coated, capsule-shaped tablets (0.1575" × 0.3030"), debossed with 'AR 374' on one side and scored on the other, containing 0.6 mg of the active ingredient colchicine USP. Inactive ingredients: carnauba wax, FD&C blue #2, FD&C red #40, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, pregelatinized starch, sodium starch glycolate, titanium dioxide, and triacetin.
Colcrys (Colchicine) Clinical Studies
The evidence for the efficacy of colchicine in patients with chronic gout is derived from the published literature. Two randomized clinical trials assessed the efficacy of colchicine 0.6 mg twice a day for the prophylaxis of gout flares in patients with gout initiating treatment with urate lowering therapy. In both trials, treatment with colchicine decreased the frequency of gout flares.
The efficacy of a low dosage regimen of oral colchicine (Colcrys (Colchicine) total dose 1.8 mg over 1 hour) for treatment of gout flares was assessed in a multicenter, randomized, double-blind, placebo-controlled, parallel group, 1 week, dose comparison study. Patients meeting American College of Rheumatology criteria for gout were randomly assigned to three groups: high-dose colchicine (1.2 mg, then 0.6 mg hourly × 6 hours [4.8 mg total]); low-dose colchicine (1.2 mg, then 0.6 mg in 1 hour [1.8 mg total] followed by 5 placebo doses hourly); or placebo (2 capsules, then 1 capsule hourly × 6 hours). Patients took the first dose within 12 hours of the onset of the flare and recorded pain intensity (11-point Likert scale) and adverse events over 72 hours. The efficacy of colchicine was measured based on response to treatment in the target joint, using patient self assessment of pain at 24 hours following the time of first dose as recorded in the diary. A responder was one who achieved at least a 50% reduction in pain score at the 24-hour post-dose assessment relative to the pre-treatment score and did not use rescue medication prior to the actual time of 24-hour post-dose assessment.
Rates of response were similar for the recommended low-dose treatment group (38%) and the non-recommended high-dose group (33%) but were higher as compared to the placebo group (16%) as shown in Table 8.
Figure 1 below shows the percentage of patients achieving varying degrees of improvement in pain from baseline at 24 hours.
The evidence for the efficacy of colchicine in patients with FMF is derived from the published literature. Three randomized, placebo-controlled studies were identified. The three placebo-controlled studies randomized a total of 48 adult patients diagnosed with FMF and reported similar efficacy endpoints as well as inclusion and exclusion criteria.
One of the studies randomized 15 patients with FMF to a 6-month crossover study during which 5 patients discontinued due to study non-compliance. The 10 patients completing the study experienced 5 attacks over the course of 90 days while treated with colchicine compared to 59 attacks over the course of 90 days while treated with placebo. Similarly, the second study randomized 22 patients with FMF to a 4-month crossover study during which 9 patients discontinued due to lack of efficacy while receiving placebo or study non-compliance. The 13 patients completing the study experienced 18 attacks over the course of 60 days while treated with colchicine compared to 68 attacks over the course of 60 days while treated with placebo. The third study was discontinued after an interim analysis of 6 of the 11 patients enrolled had completed the study; results could not be confirmed.
Open-label experience with colchicine in adults and children with FMF is consistent with the randomized, controlled trial experience, and was utilized to support information on the safety profile of colchicine and for dosing recommendations.
Colcrys (Colchicine) How Supplied / Storage And Handling
Store at 20° to 25°C (68° to 77°F).[See USP Controlled Room Temperature]Protect from light.
DISPENSE IN TIGHT, LIGHT-RESISTANT CONTAINER.
Colcrys (Colchicine) Patient Counseling Information
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Colcrys (Colchicine) is a registered U.S. trademark of the URL Pharma, Inc. group of companies. © 2009 AR Holding Company, Inc., a URL Pharma, Inc. companyU.S. Patent Nos. 7,601,758; 7,619,004 and other patents pending
Manufactured for:AR SCIENTIFIC, INC.Philadelphia, PA 19124 USAby:MUTUAL PHARMACEUTICAL COMPANY, INC.Philadelphia, PA 19124 USA
Rev 10, July 2011
Colcrys (Colchicine)
Colcrys (Colchicine)
