Colcrys

Takeda Pharmaceuticals America, Inc.

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use colchicine safely and effectively. See full prescribing information for COLCRYS. COLCRYS (colchicine, USP) tablets for Oral useInitial U.S. Approval: 1961INDICATIONS AND USAGECOLCRYS (colchicine, USP) tablets are an alkaloid indicated for: •Prophylaxis and Treatment of Gout Flares in adults (1.1). •Familial Mediterranean fever (FMF) in adults and children 4 years or older (1.2). COLCRYS is not an analgesic medication and should not be used to treat pain from other causes.DOSAGE AND ADMINISTRATION • Gout Flares:   Prophylaxis of Gout Flares: 0.6 mg once or twice daily in adults and adolescents older than 16 years of age (2.1). Maximum dose 1.2 mg/day.   Treatment of Gout Flares: 1.2 mg (2 tablets) at the first sign of a gout flare followed by 0.6 mg (1 tablet) one hour later (2.1). • FMF: Adults and Children older than 12 years 1.2 – 2.4 mg; Children 6 to 12 years 0.9 – 1.8 mg; Children 4 to 6 years 0.3 – 1.8 mg (2.2, 2.3). ∘Give total daily dose in one or two divided doses (2.2). ∘Increase or decrease the dose as indicated and as tolerated in increments of 0.3 mg/day, not to exceed the maximum recommended daily dose (2.2). Colchicine tablets are administered orally, without regard to meals.See full prescribing information for dose adjustment regarding patients with impaired renal function (2.5), impaired hepatic function (2.6), the patient's age (2.3, 8.5), or use of co-administered drugs (2.4).DOSAGE FORMS AND STRENGTHS •0.6 mg tablets (3). CONTRAINDICATIONSPatients with renal or hepatic impairment should not be given COLCRYS in conjunction with P-gp or strong CYP3A4 inhibitors (5.3). In these patients, life-threatening and fatal colchicine toxicity has been reported with colchicine taken in therapeutic doses (7).WARNINGS AND PRECAUTIONS • Fatal overdoses have been reported with colchicine in adults and children. Keep COLCRYS out of the reach of children (5.1, 10). • Blood dyscrasias: myelosuppression, leukopenia, granulocytopenia, thrombocytopenia, and aplastic anemia have been reported (5.2). •Monitor for toxicity and if present consider temporary interruption or discontinuation of colchicine (5.2, 5.3, 5.4, 6, 10). • Drug interaction P-gp and/or CYP3A4 inhibitors: Co-administration of colchicine with P-gp and/or strong CYP3A4 inhibitors has resulted in life-threatening interactions and death (5.3, 7). • Neuromuscular toxicity: Myotoxicity including rhabdomyolysis may occur, especially in combination with other drugs known to cause this effect. Consider temporary interruption or discontinuation of COLCRYS (5.4, 7). Side Effects Prophylaxis of Gout Flares: The most commonly reported adverse reaction in clinical trials for the prophylaxis of gout was diarrhea.  Treatment of Gout Flares: The most common adverse reactions reported in the clinical trial for gout were diarrhea (23%) and pharyngolaryngeal pain (3%).   FMF: Most common adverse reactions (up to 20%) are abdominal pain, diarrhea, nausea, and vomiting. These effects are usually mild, transient, and reversible upon lowering the dose (6).   To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals America, Inc. at 1-877-825-3327 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONSCo-administration of P-gp and/or CYP3A4 inhibitors (e.g., clarithromycin or cyclosporine) have been demonstrated to alter the concentration of colchicine. The potential for drug-drug interactions must be considered prior to and during therapy. See full prescribing information for a complete list of reported and potential interactions (2.4, 5.3, 7).USE IN SPECIFIC POPULATIONS •In the presence of mild to moderate renal or hepatic impairment, adjustment of dosing is not required for treatment of gout flare, prophylaxis of gout flare, and FMF but patients should be monitored closely (2.5, 8.6). •In patients with severe renal impairment for prophylaxis of gout flares the starting dose should be 0.3 mg/day, for gout flares no dose adjustment is required but a treatment course should be repeated no more than once every 2 weeks. In FMF patients, start with 0.3 mg/day and any increase in dose should be done with close monitoring (2.5, 8.6). •In patients with severe hepatic impairment, a dose reduction may be needed in prophylaxis of gout flares and FMF patients; while a dose reduction may not be needed in gout flares, a treatment course should be repeated no more than once every 2 weeks (2.5, 2.6, 8.6, 8.7). •For patients undergoing dialysis, the total recommended dose for prophylaxis of gout flares should be 0.3 mg given twice a week with close monitoring. For treatment of gout flares, the total recommended dose should be reduced to 0.6 mg (1 tablet) × 1 dose and the treatment course should not be repeated more than once every two weeks. For FMF patients the starting dose should be 0.3 mg per day and dosing can be increased with close monitoring (2.5, 8.6). •Pregnancy: Use only if the potential benefit justifies the potential risk to the fetus (8.1). •Nursing Mothers: Caution should be exercised when administered to a nursing woman (8.3). •Geriatric Use: The recommended dose of colchicine should be based on renal function (2.5, 8.5).

FULL PRESCRIBING INFORMATION: CONTENTS*

• 1 COLCRYS INDICATIONS AND USAGE
  • 1.1 Gout Flares
  • 1.2 Familial Mediterranean fever (FMF)
• 2 COLCRYS DOSAGE AND ADMINISTRATION
  • 2.1 Gout Flares
  • 2.2 FMF
  • 2.3 Recommended Pediatric Dosage
  • 2.4 Dose Modification for Co-administration of Interacting Drugs
  • 2.5 Dose Modification in Renal Impairment
  • 2.6 Dose Modification in Hepatic Impairment
• 3 DOSAGE FORMS AND STRENGTHS
• 4 COLCRYS CONTRAINDICATIONS
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Fatal Overdose
  • 5.2 Blood Dyscrasias
  • 5.3 Drug Interactions
  • 5.4 Neuromuscular Toxicity
• 6 COLCRYS ADVERSE REACTIONS
  • 6.1 Clinical Trials Experience in Gout
  • 6.2 Postmarketing Experience
• 7 DRUG INTERACTIONS
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.2 Labor and Delivery
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
  • 8.6 Renal Impairment
  • 8.7 Hepatic Impairment
• 9 DRUG ABUSE AND DEPENDENCE
• 10 OVERDOSAGE
• 11 COLCRYS DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.3 Pharmacokinetics
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
• 14 CLINICAL STUDIES
• 16 HOW SUPPLIED/STORAGE AND HANDLING
  • 16.1 How Supplied
  • 16.2 Storage
• 17 PATIENT COUNSELING INFORMATION
  • 17.1 Dosing Instructions
  • 17.2 Fatal Overdose
  • 17.3 Blood Dyscrasias
  • 17.4 Drug and Food Interactions
  • 17.5 Neuromuscular Toxicity
  • 17.6 Medication Guide

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 Gout Flares

COLCRYS^® (colchicine, USP) tablets are indicated for prophylaxis and the treatment of acute gout flares.

•   Prophylaxis of Gout Flares:
  COLCRYS is indicated for prophylaxis of gout flares.
•   Treatment of Gout Flares:
  COLCRYS tablets are indicated for treatment of acute gout flares when taken at the first sign of a flare.

1.2 Familial Mediterranean fever (FMF)

COLCRYS^® (colchicine, USP) tablets are indicated in adults and children 4 years or older for treatment of familial Mediterranean fever (FMF).

2 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 are different for each indication and must be individualized.

The recommended dosage of COLCRYS depends on the patient's age, renal function, hepatic function, and use of co-administered drugs [see Dose Modification for Co-administration of Interacting Drugs (2.4) ].

COLCRYS tablets are administered orally, without regard to meals.

COLCRYS is not an analgesic medication and should not be used to treat pain from other causes.

2.1 Gout Flares

Prophylaxis of Gout Flares:

The recommended dosage of COLCRYS for prophylaxis of gout flares for adults and adolescents older than 16 years of age is 0.6 mg once or twice daily. The maximum recommended dose for prophylaxis of gout flares is 1.2 mg/day.

Treatment of Gout Flares:

The recommended dose of COLCRYS for treatment of a gout flare is 1.2 mg (2 tablets) at the first sign of the flare followed by 0.6 mg (1 tablet) one hour later. Higher doses have not been found to be more effective. The maximum recommended dose for treatment of gout flares is 1.8 mg over a 1 hour period. COLCRYS may be administered for treatment of a gout flare during prophylaxis at doses not to exceed 1.2 mg (2 tablets) at the first sign of the flare followed by 0.6 mg (1 tablet) one hour later. Wait 12 hours and then resume the prophylactic dose.

2.2 FMF

The recommended dosage of COLCRYS for FMF in adults is 1.2 mg to 2.4 mg daily.

COLCRYS should be increased as needed to control disease and as tolerated in increments of 0.3 mg/day to a maximum recommended daily dose. If intolerable side effects develop, the dose should be decreased in increments of 0.3 mg/day. The total daily COLCRYS dose may be administered in one to two divided doses.

2.3 Recommended Pediatric Dosage

Prophylaxis and Treatment of Gout Flares:

COLCRYS is not recommended for pediatric use in prophylaxis or treatment of gout flares.

FMF:

The recommended dosage of COLCRYS for FMF in pediatric patients 4 years of age and older is based on age. The following daily doses may be given as a single or divided dose twice daily:

• • Children 4 – 6 years: 0.3 mg to 1.8 mg daily
• • Children 6 – 12 years: 0.9 mg to 1.8 mg daily
• • Adolescents older than 12 years: 1.2 mg to 2.4 mg daily

2.4 Dose Modification for Co-administration of Interacting Drugs

Concomitant Therapy:

Co-administration of COLCRYS with drugs known to inhibit CYP3A4 and/or P-glycoprotein (P-gp) increases the risk of colchicine-induced toxic effects (Table 1). If patients are taking or have recently completed treatment with drugs listed in Table 1 within the prior 14 days, the dose adjustments are as shown on the table below [see DRUG INTERACTIONS (7) ].

Treatment of gout flares with COLCRYS is not recommended in patients receiving prophylactic dose of COLCRYS and CYP3A4 inhibitors.

2.5 Dose Modification in Renal Impairment

Colchicine dosing must be individualized according to the patient's renal function [see Renal Impairment (8.6) ].

Clcr in mL/minute may be estimated from serum creatinine (mg/dL) determination using the following formula:

Gout Flares:

Prophylaxis of Gout Flares:

For prophylaxis of gout flares in patients with mild (estimated creatinine clearance Clcr 50 – 80 mL/min) to moderate (Clcr 30 – 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 [see Clinical Pharmacology (12.3) and Renal Impairment (8.6) ].

Treatment of Gout Flares:

For treatment of gout flares in patients with mild (Clcr 50 – 80 mL/min) to moderate (Clcr 30 – 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 2 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 (1 tablet). For these patients, the treatment course should not be repeated more than once every 2 weeks [see Clinical Pharmacology (12.3) and Renal Impairment (8.6) ].

Treatment of gout flares with COLCRYS is not recommended in patients with renal impairment who are receiving COLCRYS for prophylaxis.

FMF:

Caution should be taken in dosing patients with moderate and severe renal impairment and in patients undergoing dialysis. For these patients, the dosage should be reduced [see Clinical Pharmacology (12.3) ]. Patients with mild (Clcr 50 – 80 mL/min) and moderate (Clcr 30 – 50 mL/min) renal impairment should be monitored closely for adverse effects of COLCRYS. Dose reduction may be necessary. For patients with severe renal failure (Clcr less than 30 mL/minute), start with 0.3 mg/day; any increase in dose should be done with adequate monitoring of the patient for adverse effects of colchicine [see Renal Impairment (8.6) ]. For patients undergoing dialysis, the total recommended starting dose should be 0.3 mg (half tablet) per day. Dosing can be increased with close monitoring. Any increase in dose should be done with adequate monitoring of the patient for adverse effects of colchicine [see Clinical Pharmacology (12.3) and Renal Impairment (8.6) ].

2.6 Dose Modification in Hepatic Impairment

Gout Flares

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 [see Hepatic Impairment (8.7) ].

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, but a treatment course should be repeated no more than once every 2 weeks. For these patients, requiring repeated courses for the treatment of gout flares, consideration should be given to alternate therapy [see Hepatic Impairment (8.7) ].

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

FMF:

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 [see Hepatic Impairment (8.7) ].

3 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.

4 CONTRAINDICATIONS

Patients with renal or hepatic impairment should not be given COLCRYS 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.

5 WARNINGS AND PRECAUTIONS

5.1 Fatal Overdose

Fatal overdoses, both accidental and intentional, have been reported in adults and children who have ingested colchicine [see OVERDOSAGE (10) ]. COLCRYS should be kept out of the reach of children.

5.2 Blood Dyscrasias

Myelosuppression, leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, and aplastic anemia have been reported with colchicine used in therapeutic doses.

5.3 Drug Interactions

Colchicine is a P-gp and CYP3A4 substrate. Life-threatening and fatal drug interactions have been reported in patients treated with colchicine given with P-gp and strong CYP3A4 inhibitors. If treatment with a P-gp or strong CYP3A4 inhibitor is required in patients with normal renal and hepatic function, the patient's dose of colchicine may need to be reduced or interrupted [see DRUG INTERACTIONS (7) ]. Use of COLCRYS in conjunction with P-gp or strong CYP3A4 inhibitors (this includes all protease inhibitors, except fosamprenavir) is contraindicated in patients with renal or hepatic impairment [see CONTRAINDICATIONS (4) ].

5.4 Neuromuscular Toxicity

Colchicine-induced neuromuscular toxicity and rhabdomyolysis have been reported with chronic treatment in therapeutic doses. Patients with renal dysfunction and elderly patients, even those with normal renal and hepatic function, are at increased risk. Concomitant use of atorvastatin, simvastatin, pravastatin, fluvastatin, lovastatin, gemfibrozil, fenofibrate, fenofibric acid, or benzafibrate (themselves associated with myotoxicity) or cyclosporine with COLCRYS may potentiate the development of myopathy [see DRUG INTERACTIONS (7) ]. Once colchicine is stopped, the symptoms generally resolve within 1 week to several months.

6 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 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, 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.

6.1 Clinical Trials Experience in Gout

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 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 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 regimen.

6.2 Postmarketing Experience

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 [see OVERDOSAGE (10) ].

The following adverse reactions have been reported with colchicine. These have been generally reversible upon temporarily interrupting treatment or lowering the dose of colchicine.

•   Neurological: sensory motor neuropathy
•   
•   Dermatological: alopecia, maculopapular rash, purpura, rash
•   
•   Digestive: abdominal cramping, abdominal pain, diarrhea, lactose intolerance, nausea, vomiting
•   
•   Hematological: leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, aplastic anemia
•   
•   Hepatobiliary: elevated AST, elevated ALT
•   
•   Musculoskeletal: myopathy, elevated CPK, myotonia, muscle weakness, muscle pain, rhabdomyolysis
•   
•   Reproductive: azoospermia, oligospermia

7 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 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 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 toxicity should be evaluated promptly and, if toxicity is suspected, COLCRYS 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.

8 USE IN SPECIFIC POPULATIONS

8.1 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 COLCRYS, 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. COLCRYS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

8.2 Labor and Delivery

The effect of colchicine on labor and delivery is unknown.

8.3 Nursing Mothers

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

8.4 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.

8.5 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 [see Dose Modification for Co-administration of Interacting Drugs (2.4) ].

8.6 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 – 80 mL/min) to moderate (Clcr 30 – 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 [see Dose Modification in Renal Impairment (2.5) ].

Treatment of Gout Flares:

For treatment of gout flares in patients with mild (Clcr 50 – 80 mL/min) to moderate (Clcr 30 – 50 mL/min) renal function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of COLCRYS. 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 2 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 (1 tablet). For these patients, the treatment course should not be repeated more than once every 2 weeks [see Dose Modification in Renal Impairment (2.5) ].

FMF

Although, pharmacokinetics of colchicine in patients with mild (Clcr 50 – 80 mL/min) and moderate (Clcr 30 – 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/minute) and end-stage renal disease requiring dialysis, COLCRYS 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 COLCRYS [see Pharmacokinetics (12.3) and Dose Modification in Renal Impairment (2.5) ].

8.7 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 [see Pharmacokinetics (12.3) ].

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 [see Dose Modification in Hepatic Impairment (2.6) ].

Treatment of Gout Flares:

For treatment of gout flares in patients with mild to moderate hepatic function impairment, adjustment of the recommended COLCRYS dose is not required, but patients should be monitored closely for adverse effects of COLCRYS. 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 2 weeks. For these patients, requiring repeated courses for the treatment of gout flares, consideration should be given to alternate therapy [see Dose Modification in Hepatic Impairment (2.6) ].

FMF

In patients with severe hepatic disease, dose reduction should be considered with careful monitoring [see Pharmacokinetics (12.3) and Dose Modification in Hepatic Impairment (2.6) ].

9 DRUG ABUSE AND DEPENDENCE

Tolerance, abuse, or dependence with colchicine has not been reported.

10 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 [see Pharmacokinetics (12.3) ].

11 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 C₂₂H₂₅NO₆ and a molecular weight of 399.4. The structural formula of colchicine is given below.