Colchicine

COLCHICINE — colchicine tablet, film coated
Heritage Pharmaceuticals Inc. d/b/a Avet Pharmaceuticals Inc.

1 INDICATIONS AND USAGE

1.1 Gout Flares

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

• Prophylaxis of Gout Flares:

Colchicine tablets is 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.

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).

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 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, 2.5, 2.6)].

Colchicine tablets are administered orally without regard to meals.

Colchicine tablets 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 colchicine tablets 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.

An increase in gout flares may occur after initiation of uric acid-lowering therapy, including pegloticase, febuxostat and allopurinol, due to changing serum uric acid levels resulting in mobilization of urate from tissue deposits. Colchicine tablets is recommended upon initiation of gout flare prophylaxis with uric acid-lowering therapy. Prophylactic therapy may be beneficial for at least the first six months of uric acid-lowering therapy.

Treatment of Gout Flares

The recommended dose of colchicine tablets for treatment of a gout flare is 1.2 mg (two tablets) at the first sign of the flare followed by 0.6 mg (one 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. Colchicine tablets may be administered for treatment of a gout flare during prophylaxis at doses not to exceed 1.2 mg (two tablets) at the first sign of the flare followed by 0.6 mg (one tablet) one hour later. Wait 12 hours and then resume the prophylactic dose.

2.2 FMF

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

Colchicine tablets 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 Colchicine tablets dose may be administered in one to two divided doses.

2.3 Recommended Pediatric Dosage

Prophylaxis and Treatment of Gout Flares

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

FMF

The recommended dosage of Colchicine tablets 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 to 6 years: 0.3 mg to 1.8 mg daily
• Children 6 to 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 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 (7)].

Table 1: Colchicine tablets Dose Adjustment for Co-administration with Interacting Drugs if no Alternative Available*

* For magnitude of effect on colchicine plasma concentrations [see Clinical Pharmacology (12.3)]
† When used in combination with Ritonavir, see dosing recommendations for strong CYP3A4 inhibitors [see Contraindications (4)]
‡ Patients with renal or hepatic impairment should not be given colchicine tablets in conjunction with strong CYP3A4 or P-gp inhibitors [see Contraindications (4)]
Strong CYP3A4 Inhibitors†
Drug	Noted or Anticipated Outcome	Gout Flares				FMF
		Prophylaxis of Gout Flares		Treatment of Gout Flares
		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	0.3 mg once a day	1.2 mg (2 tablets) followed by 0.6 mg (1 tablet) 1 hour later. Dose to be repeated no earlier than 3 days.	0.6 mg (1 tablet) × 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 – 2.4 mg	Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)
		0.6 mg once a day	0.3 mg once every other day
Moderate CYP3A4 Inhibitors
Drug	Noted or Anticipated Outcome	Gout Flares				FMF
		Prophylaxis of Gout Flares		Treatment of Gout Flares
		Original Intended Dosage	Adjusted Dose	Original Intended Dosage	Adjusted Dose	Original Intended Dosage	Adjusted Dose
Amprenavir † Aprepitant Diltiazem Erythromycin Fluconazole Fosamprenavir † (pro-drug 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	0.3 mg twice a day or 0.6 mg once a day	1.2 mg (2 tablets) followed by 0.6 mg (1 tablet) 1 hour later. Dose to be repeated no earlier than 3 days.	1.2 mg (2 tablets) × 1 dose. Dose to be repeated no earlier than 3 days.	Maximum daily dose of 1.2 – 2.4 mg.	Maximum daily dose of 1.2 mg (may be given as 0.6 mg twice a day)
		0.6 mg once a day	0.3 mg once a day
P-gp Inhibitors‡
Drug	Noted or Anticipated Outcome	Gout Flares				FMF
		Prophylaxis of Gout Flares		Treatment of Gout Flares
		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	0.3 mg once a day	1.2 mg (2 tablets) Followed by 0.6 mg (1 tablet) 1 hour later. Dose to be repeated no earlier than 3 days.	0.6 mg (1 tablet) × 1 dose. Dose to be repeated no earlier than 3 days.	Maximum daily dose of 1.2 – 2.4 mg	Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)
		0.6 mg once a day	0.3 mg once every other day

Table 2. Colchicine 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 (1 tablet) × 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 0.6 mg once a day	0.3 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 (1 tablet) × 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 0.6 mg once a day	0.3 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 (1 tablet) × 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 0.6 mg once a day	0.3 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 (2 tablets) × 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 0.6 mg once a day	0.3 mg twice a day or 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 (1 tablet) × 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 0.6 mg once a day	0.3 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 (1 tablet) × 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 0.6 mg once a day	0.3 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 (1 tablet) × 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 0.6 mg once a day	0.3 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 (1 tablet) × 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 0.6 mg once a day	0.3 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 (1 tablet) × 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 0.6 mg once a day	0.3 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 (1 tablet) × 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 0.6 mg once a day	0.3 mg once a day 0.3 mg once every other day

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