Colchicine

Colchicine tablets are an alkaloid indicated for:

•   Prophylaxis and treatment of gout flares in adults (
  1.1 Gout Flares

  Colchicine tablets are indicated for prophylaxis and the treatment of acute gout flares.

  • Prophylaxis of Gout Flares:

  Colchicine tablets are indicated for prophylaxis of gout flares.

  • Treatment of Gout Flares:

  Colchicine tablets are indicated for treatment of acute gout flares when taken at the first sign of a flare.
  ).
•   Familial Mediterranean fever (FMF) in adults and children 4 years or older (
  1.2 Familial Mediterranean Fever (FMF)

  Colchicine tablets are indicated in adults and children four years or older for treatment of familial Mediterranean fever (FMF).
  ).

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 colchicine tablets are different for each indication and must be individualized.

The recommended dosage of colchicine tablets depends on the patient's age, renal function, hepatic function and use of coadministered drugs

[see Dosage and Administration (

2.4 Dose Modification for Coadministration of Interacting Drugs

Concomitant Therapy

Coadministration of colchicine tablets 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 in the table below

[see Drug Interactions ]

.

Table 1  Colchicine Tablets Dose Adjustment for Coadministration with Interacting Drugs if No Alternative Available^*

*For magnitude of effect on colchicine plasma concentrations [see Clinical Pharmacology ]
†Patients with renal or hepatic impairment should not be given colchicine in conjunction with strong CYP3A4 or P-gp inhibitors [see Contraindications ]
‡When used in combination with Ritonavir, see dosing recommendations for strong CYP3A4 inhibitors [see Contraindications ]
Strong CYP3A4 Inhibitors†
		Gout Flares				FMF
		Prophylaxis of Gout Flares		Treatment of Gout Flares
Drug	Noted or Anticipated Outcome	Original Intended Dosage	Adjusted Dose	Original Intended Dosage	Adjusted Dose	Original Intended Dosage	Adjusted Dose
Atazanavir Clarithromycin Darunavir/ Ritonavir‡Indinavir Itraconazole Ketoconazole Lopinavir/ Ritonavir‡Nefazodone Nelfinavir Ritonavir Saquinavir Telithromycin Tipranavir/ Ritonavir‡	Significant increase in colchicine plasma levels*; fatal colchicine toxicity has been reported with clarithromycin, a strong CYP3A4 inhibitor. Similarly, significant increase in colchicine plasma levels is anticipated with other strong CYP3A4 inhibitors.	0.6 mg twice a day 0.6 mg once a day	0.3 mg once a day 0.3 mg once every other day	1.2 mg (two tablets) followed by 0.6 mg (one tablet) 1 hour later. Dose to be repeated no earlier than 3 days.	0.6 mg (one tablet) x 1 dose, followed by 0.3 mg (1/2 tablet) 1 hour later. Dose to be repeated no earlier than 3 days.	Maximum daily dose of 1.2 mg to 2.4 mg	Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)
Moderate CYP3A4 Inhibitors
		Gout Flares				FMF
		Prophylaxis of Gout Flares		Treatment of Gout Flares
Drug	Noted or Anticipated Outcome	Original Intended Dosage	Adjusted Dose	Original Intended Dosage	Adjusted Dose	Original Intended Dosage	Adjusted Dose
Amprenavir‡Aprepitant Diltiazem Erythromycin Fluconazole Fosamprenavir‡(prodrug of Amprenavir) Grapefruit juice Verapamil	Significant increase in colchicine plasma concentration is anticipated. Neuromuscular toxicity has been reported with diltiazem and verapamil interactions.	0.6 mg twice a day 0.6 mg once a day	0.3 mg twice a day or 0.6 mg once a day 0.3 mg once a day	1.2 mg (two tablets) followed by 0.6 mg (one tablet) 1 hour later. Dose to be repeated no earlier than 3 days.	1.2 mg (two tablets) x 1 dose. Dose to be repeated no earlier than 3 days.	Maximum daily dose of 1.2 mg to 2.4 mg	Maximum daily dose of 1.2 mg (may be given as 0.6 mg twice a day)
P-gp Inhibitors†
		Gout Flares				FMF
		Prophylaxis of Gout Flares		Treatment of Gout Flares
Drug	Noted or Anticipated Outcome	Original Intended Dosage	Adjusted Dose	Original Intended Dosage	Adjusted Dose	Original Intended Dosage	Adjusted Dose
Cyclosporine Ranolazine	Significant increase in colchicine plasma levels*; fatal colchicine toxicity has been reported with cyclosporine, a P-gp inhibitor. Similarly, significant increase in colchicine plasma levels is anticipated with other P-gp inhibitors.	0.6 mg twice a day 0.6 mg once a day	0.3 mg once a day 0.3 mg once every other day	1.2 mg (two tablets) followed by 0.6 mg (one tablet) 1 hour later. Dose to be repeated no earlier than 3 days.	0.6 mg (one tablet) x 1 dose. Dose to be repeated no earlier than 3 days.	Maximum daily dose of 1.2 mg to 2.4 mg	Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)

Table 2 Colchicine Tablets Dose Adjustment for Coadministration with Protease Inhibitors

Protease Inhibitor	Clinical Comment	w/Colchicine -Prophylaxis of Gout Flares		w/Colchicine   -Treatment of Gout Flares	w/Colchicine   -Treatment of FMF
Atazanavir sulfate (Reyataz)	Patients with renal or hepatic impairment should not be given colchicine with Reyataz.	Original dose	Adjusted dose	0.6 mg (one tablet) x 1 dose, followed by 0.3 mg (1/2 tablet) 1 hour later. Dose to be repeated no earlier than 3 days.	Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)
		0.6 mg twice a day	0.3 mg once a day
		0.6 mg once a day	0.3 mg once every other day
Darunavir (Prezista)	Patients with renal or hepatic impairment should not be given colchicine with Prezista/ ritonavir.	Original dose	Adjusted dose	0.6 mg (one tablet) x 1 dose, followed by 0.3 mg (1/2 tablet) 1 hour later. Dose to be repeated no earlier than 3 days.	Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)
		0.6 mg twice a day	0.3 mg once a day
		0.6 mg once a day	0.3 mg once every other day
Fosamprenavir (Lexiva) with Ritonavir	Patients with renal or hepatic impairment should not be given colchicine with Lexiva/ritonavir.	Original dose	Adjusted dose	0.6 mg (one tablet) x 1 dose, followed by 0.3 mg (1/2 tablet) 1 hour later. Dose to be repeated no earlier than 3 days.	Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)
		0.6 mg twice a day	0.3 mg once a day
		0.6 mg once a day	0.3 mg once every other day
Fosamprenavir (Lexiva)	Patients with renal or hepatic impairment should not be given colchicine with Lexiva/ritonavir.	Original dose	Adjusted dose	1.2 mg (two tablets) x 1 dose. Dose to be repeated no earlier than 3 days.	Maximum daily dose of 1.2 mg (may be given as 0.6 mg twice a day)
		0.6 mg twice a day	0.3 mg twice a day or 0.6 mg once a day
		0.6 mg once a day	0.3 mg once a day
Indinavir (Crixivan)	Patients with renal or hepatic impairment should not be given colchicine with Crixivan.	Original dose	Adjusted dose	0.6 mg (one tablet) x 1 dose, followed by 0.3 mg (1/2 tablet) 1 hour later. Dose to be repeated no earlier than 3 days.	Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)
		0.6 mg twice a day	0.3 mg once a day
		0.6 mg once a day	0.3 mg once every other day
Lopinavir/ Ritonavir (Kaletra)	Patients with renal or hepatic impairment should not be given colchicine with Kaletra	Original dose	Adjusted dose	0.6 mg (one tablet) x 1 dose, followed by 0.3 mg (1/2 tablet) 1 hour later. Dose to be repeated no earlier than 3 days.	Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)
		0.6 mg twice a day	0.3 mg once a day
		0.6 mg once a day	0.3 mg once every other day
Nelfinavir mesylate (Viracept)	Patients with renal or hepatic impairment should not be given colchicine with Viracept.	Original dose	Adjusted dose	0.6 mg (one tablet) x 1 dose, followed by 0.3 mg (1/2 tablet) 1 hour later. Dose to be repeated no earlier than 3 days.	Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)
		0.6 mg twice a day	0.3 mg once a day
		0.6 mg once a day	0.3 mg once every other day
Ritonavir (Norvir)	Patients with renal or hepatic impairment should not be given colchicine with Norvir.	Original dose	Adjusted dose	0.6 mg (one tablet) x 1 dose, followed by 0.3 mg (1/2 tablet) 1 hour later. Dose to be repeated no earlier than 3 days.	Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)
		0.6 mg twice a day	0.3 mg once a day
		0.6 mg once a day	0.3 mg once every other day
Saquinavir mesylate (Invirase)	Patients with renal or hepatic impairment should not be given colchicine with Invirase/ ritonavir.	Original dose	Adjusted dose	0.6 mg (one tablet) x 1 dose, followed by 0.3 mg (1/2 tablet) 1 hour later. Dose to be repeated no earlier than 3 days.	Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)
		0.6 mg twice a day	0.3 mg once a day
		0.6 mg once a day	0.3 mg once every other day
Tipranavir (Aptivus)	Patients with renal or hepatic impairment should not be given colchicine with Aptivus/ ritonavir.	Original dose	Adjusted dose	0.6 mg (one tablet) x 1 dose, followed by 0.3 mg (1/2 tablet) 1 hour later. Dose to be repeated no earlier than 3 days.	Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)
		0.6 mg twice a day	0.3 mg once a day
		0.6 mg once a day	0.3 mg once every other day

Treatment of gout flares with colchicine tablets are not recommended in patients receiving prophylactic dose of colchicine tablets and CYP3A4 inhibitors.

,

2.5 Dose Modification in Renal Impairment

Colchicine dosing must be individualized according to the patient's renal function

[see Use in Specific Populations ].

Cl_crin 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 [Cl_cr] 50 mL/min to 80 mL/min) to moderate (Cl_cr30 mL/min 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/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 , Use in Specific Populations ]

.

Treatment of Gout Flares

For treatment of gout flares in patients with mild (Cl_cr50 mL/min to 80 mL/min) to moderate (Cl_cr30 mL/min 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 Clinical Pharmacology , Use in Specific Populations ]

.

Treatment of gout flares with colchicine tablets are not recommended in patients with renal impairment who are receiving colchicine tablets 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 Use in Specific Populations ]

. Patients with mild (Cl_cr50 mL/min to 80 mL/min) and moderate (Cl_cr30 mL/min to 50 mL/min) renal impairment should be monitored closely for adverse effects of colchicine. Dose reduction may be necessary. For patients with severe renal failure (Cl_crless than 30 mL/min), 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 Use in Specific Populations ]

. 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 , Use in Specific Populations ].

,

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 Use in Specific Populations ]

.

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

[see Use in Specific Populations ]

.

Treatment of gout flares with colchicine tablets are not recommended in patients with hepatic impairment who are receiving colchicine tablets 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 Use in Specific Populations ]

.

)].

Colchicine tablets are administered orally without regard to meals.

Colchicine tablets are not an analgesic medication and should not be used to treat pain from other causes.

Colchicine tablets, USP 0.6 mg are purple, capsule-shaped, film-coated tablets, debossed with '1351' on one side and scored on the other side.

• 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 (
  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 Cl_cr50 mL/min to 80 mL/min) to moderate (Cl_cr30 mL/min 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

  [see Dosage and Administration ].

  Treatment of Gout Flares

  For treatment of gout flares in patients with mild (Cl_cr50 mL/min to 80 mL/min) to moderate (Cl_cr30 mL/min 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 Dosage and Administration ].

  FMF

  Although pharmacokinetics of colchicine in patients with mild (Cl_cr50 mL/min to 80 mL/min) and moderate (Cl_cr30 mL/min 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 (Cl_crless 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 colchicine

  [see Clinical Pharmacology , Dosage and Administration ]

  .
  ).
• 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 two weeks. In FMF patients, start with 0.3 mg/day, and any increase in dose should be done with close monitoring (
  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 Cl_cr50 mL/min to 80 mL/min) to moderate (Cl_cr30 mL/min 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

  [see Dosage and Administration ].

  Treatment of Gout Flares

  For treatment of gout flares in patients with mild (Cl_cr50 mL/min to 80 mL/min) to moderate (Cl_cr30 mL/min 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 Dosage and Administration ].

  FMF

  Although pharmacokinetics of colchicine in patients with mild (Cl_cr50 mL/min to 80 mL/min) and moderate (Cl_cr30 mL/min 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 (Cl_crless 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 colchicine

  [see Clinical Pharmacology , Dosage and Administration ]

  .
  ).
• 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 two weeks (
  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 Cl_cr50 mL/min to 80 mL/min) to moderate (Cl_cr30 mL/min 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

  [see Dosage and Administration ].

  Treatment of Gout Flares

  For treatment of gout flares in patients with mild (Cl_cr50 mL/min to 80 mL/min) to moderate (Cl_cr30 mL/min 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 Dosage and Administration ].

  FMF

  Although pharmacokinetics of colchicine in patients with mild (Cl_cr50 mL/min to 80 mL/min) and moderate (Cl_cr30 mL/min 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 (Cl_crless 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 colchicine

  [see Clinical Pharmacology , Dosage and Administration ]

  .
  ,
  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 Clinical Pharmacology ]

  .

  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 Dosage and Administration ]

  .

  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 therapy

  [see Dosage and Administration ]

  .

  FMF

  In patients with severe hepatic disease, dose reduction should be considered with careful monitoring

  [see Clinical Pharmacology , Dosage and Administration ]

  .
  ).
• 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 (one tablet) x 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/day and dosing can be increased with close monitoring (
  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 Cl_cr50 mL/min to 80 mL/min) to moderate (Cl_cr30 mL/min 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

  [see Dosage and Administration ].

  Treatment of Gout Flares

  For treatment of gout flares in patients with mild (Cl_cr50 mL/min to 80 mL/min) to moderate (Cl_cr30 mL/min 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 Dosage and Administration ].

  FMF

  Although pharmacokinetics of colchicine in patients with mild (Cl_cr50 mL/min to 80 mL/min) and moderate (Cl_cr30 mL/min 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 (Cl_crless 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 colchicine

  [see Clinical Pharmacology , Dosage and Administration ]

  .
  ).
• Females and Males of Reproductive Potential: Advise males that colchicine tablets may transiently impair fertility (
  8.3 Females and Males of Reproductive Potential

  Infertility

  Case reports and epidemiology studies in human male subjects on colchicine therapy indicated that infertility from colchicine is rare and may be reversible. A case report indicated that azoospermia was reversed when therapy was stopped. Case reports and epidemiology studies in female subjects on colchicine therapy have not established a clear relationship between colchicine use and female infertility. However, since the progression of FMF without treatment may result in infertility, the use of colchicine needs to be weighed against the potential risks

  [see Nonclinical Toxicology ].
  ).
• Geriatric Use: The recommended dose of colchicine should be based on renal function (
  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 Dosage and Administration , Clinical Pharmacology ]

  .
  ).

• Fatal overdoses
  have been reported with colchicine in adults and children. Keep colchicine out of the reach of children (
  5.1 Fatal Overdose

  Fatal overdoses, both accidental and intentional, have been reported in adults and children who have ingested colchicine

  [see Overdosage ]

  . Colchicine should be kept out of the reach of children.
  ,
  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 four 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 multiorgan failure and its consequences. Death is usually a result of respiratory depression and cardiovascular collapse. If the patient survives, recovery of multiorgan injury may be accompanied by rebound leukocytosis and alopecia starting about one 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 Clinical Pharmacology ]

  .
  ).
• Blood dyscrasias:
  myelosuppression, leukopenia, granulocytopenia, thrombocytopenia and aplastic anemia have been reported (
  5.2 Blood Dyscrasias

  Myelosuppression, leukopenia, granulocytopenia, thrombocytopenia, pancytopenia and aplastic anemia have been reported with colchicine used in therapeutic doses.
  ).
• Monitor for toxicity and if present consider temporary interruption or discontinuation of colchicine (
  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 ]

  . Use of colchicine 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 ].
  ,
  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 colchicine may potentiate the development of myopathy

  [see Drug Interactions ]

  . Once colchicine is stopped, the symptoms generally resolve within one 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 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 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.

  • 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 .

  To report SUSPECTED ADVERSE REACTIONS, contact Northstar Rx LLC at 1-800-206-7821 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

  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 one hour) of colchicine compared to 77% of patients taking a nonrecommended high dose (4.8 mg over six 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 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 nonrecommended high-dose colchicine regimen but did not occur in the recommended low-dose colchicine regimen.

  Table 3 Number (%) of Patients with at Least One Drug-Related Treatment-Emergent Adverse Event with an Incidence of ≥ 2% of Patients in Any Treatment Group

  MedDRA System Organ Class MedDRA Preferred Term	Colchicine Dose		Placebo (N=59) n (%)
  	High (N=52) n (%)	Low (N=74) n (%)
  Number of Patients with at Least One Drug-Related TEAE	40 (77)	27 (37)	16 (27)
  Gastrointestinal Disorders	40 (77)	19 (26)	12 (20)
  Diarrhea	40 (77)	17 (23)	8 (14)
  Nausea	9 (17)	3 (4)	3 (5)
  Vomiting	9 (17)	0	0
  Abdominal Discomfort	0	0	2 (3)
  General Disorders and Administration Site Conditions	4 (8)	1 (1)	1 (2)
  Fatigue	2 (4)	1 (1)	1 (2)
  Metabolic and Nutrition Disorders	0	3 (4)	2 (3)
  Gout	0	3 (4)	1 (2)
  Nervous System Disorders	1 (2)	1 (1.4)	2 (3)
  Headache	1 (2)	1 (1)	2 (3)
  Respiratory Thoracic Mediastinal Disorders	1 (2)	2 (3)	0
  Pharyngolaryngeal Pain	1 (2)	2 (3)	0

  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 ]

  .

  The following adverse reactions have been identified with colchicine. These have been generally reversible upon temporarily interrupting treatment or lowering the dose of colchicine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

  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
  ,
  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 four 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 multiorgan failure and its consequences. Death is usually a result of respiratory depression and cardiovascular collapse. If the patient survives, recovery of multiorgan injury may be accompanied by rebound leukocytosis and alopecia starting about one 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 Clinical Pharmacology ]

  .
  ).
• Drug interaction P-gp and/or CYP3A4 inhibitors:
  Coadministration of colchicine with P-gp and/or strong CYP3A4 inhibitors has resulted in life-threatening interactions and death (
  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 ]

  . Use of colchicine 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 ].
  ,
  7 DRUG INTERACTIONS

  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 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 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 colchicine toxicity should be evaluated promptly and, if toxicity is suspected, 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.

  Table 4 Other Potentially Significant Drug Interactions

  Concomitant Drug Class or Food	Noted or Anticipated Outcome	Clinical Comment
  HMG-Co A Reductase Inhibitors: atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin	Pharmacokinetic and/or pharmacodynamic interaction: the addition of one drug to a stable long-term regimen of the other has resulted in myopathy and rhabdomyolysis (including a fatality)	Weigh the potential benefits and risks and carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy; monitoring CPK (creatine phosphokinase) will not necessarily prevent the occurrence of severe myopathy.
  Other Lipid-Lowering Drugs: fibrates, gemfibrozil
  Digitalis Glycosides: digoxin	P-gp substrate; rhabdomyolysis has been reported

  Coadministration 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 FPI for a complete list of reported and potential interactions .

  ).
• Neuromuscular toxicity:
  Myotoxicity including rhabdomyolysis may occur, especially in combination with other drugs known to cause this effect. Consider temporary interruption or discontinuation of colchicine (
  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 colchicine may potentiate the development of myopathy

  [see Drug Interactions ]

  . Once colchicine is stopped, the symptoms generally resolve within one week to several months.
  ,
  7 DRUG INTERACTIONS

  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 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 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 colchicine toxicity should be evaluated promptly and, if toxicity is suspected, 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.

  Table 4 Other Potentially Significant Drug Interactions

  Concomitant Drug Class or Food	Noted or Anticipated Outcome	Clinical Comment
  HMG-Co A Reductase Inhibitors: atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin	Pharmacokinetic and/or pharmacodynamic interaction: the addition of one drug to a stable long-term regimen of the other has resulted in myopathy and rhabdomyolysis (including a fatality)	Weigh the potential benefits and risks and carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy; monitoring CPK (creatine phosphokinase) will not necessarily prevent the occurrence of severe myopathy.
  Other Lipid-Lowering Drugs: fibrates, gemfibrozil
  Digitalis Glycosides: digoxin	P-gp substrate; rhabdomyolysis has been reported

  Coadministration 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 FPI for a complete list of reported and potential interactions .

  ).