Colchicine

COLCHICINE- colchicine tablet, film coated
Granules Pharmaceuticals Inc.

1 INDICATIONS AND USAGE

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.
The recommended dosage of colchicine tablets depends on the patient’s age, renal function, hepatic function and use of co-administered drugs [see Dosage and Administration (2.4, 2.5, 2.6].


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.

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

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 Co-administration of Interacting Drugs

Concomitant Therapy

Co-administration 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 *

Strong CYP3A4 Inhibitors
Drug Noted or Anticipated Outcome FMF
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. Maximum daily dose of 1.2 to 2.4 mg Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)
Moderate CYP3A4 Inhibitors
Drug Noted or Anticipated Outcome FMF
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. Maximum daily dose of 1.2 to 2.4 mg Maximum daily dose of 1.2 mg (may be given as 0.6 mg twice a day)
P-gp Inhibitors
Drug Noted or Anticipated Outcome FMF
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. Maximum daily dose of 1.2 to 2.4 mg Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)

* For magnitude of effect on colchicine plasma concentrations [see Clinical Pharmacology ( 12.3)]

Patients with renal or hepatic impairment should not be given colchicine tablets in conjunction with strong CYP3A4 or P-gp inhibitors [see Contraindications ( 4)]

When used in combination with Ritonavir, see dosing recommendations for strong CYP3A4 inhibitors [see Contraindications ( 4)]

Table 2. Colchicine Tablets Dose Adjustment for Co-administration with Protease Inhibitors

Protease Inhibitor Clinical Comment

w/Colchicine –

Treatment of FMF

Atazanavir sulfate

Patients with renal or hepatic impairment should not be given colchicine with Reyataz. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)
Darunavir (Prezista) Patients with renal or hepatic impairment should not be given colchicine with Prezista/ ritonavir. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)

Fosamprenavir

(Lexiva) with Ritonavir

Patients with renal or hepatic impairment should not be given colchicine with Lexiva/ritonavir Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)
Fosamprenavir (Lexiva) Patients with renal or hepatic impairment should not be given colchicine with Lexiva/ritonavir. Maximum daily dose of 1.2 mg (may be given as 0.6 mg twice a day)
Indinavir (Crixivan) Patients with renal or hepatic impairment should not be given colchicine with Crixivan. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)

Lopinavir/

Ritonavir

Patients with renal or hepatic impairment should not be given colchicine with Kaletra Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)

Nelfinavir mesylate

Patients with renal or hepatic impairment should not be given colchicine with Viracept. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)
Ritonavir (Norvir) Patients with renal or hepatic impairment should not be given colchicine with Norvir. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)

Saquinavir mesylate

Patients with renal or hepatic impairment should not be given colchicine with Invirase/ ritonavir. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)
Tipranavir (Aptivus) Patients with renal or hepatic impairment should not be given colchicine with Aptivus/ ritonavir. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).

2.5 Dose Modification in Renal Impairment

Colchicine dosing must be individualized according to the patient’s renal function [see Use in Specific Populations (8.6)]. Cl cr in mL/minute may be estimated from serum creatinine (mg/dL) determination using the following formula:

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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 (Cl cr 50 to 80 mL/min) and moderate (Cl cr 30 to 50 mL/min) renal impairment should be monitored closely for adverse effects of colchicine tablets. Dose reduction may be necessary. For patients with severe renal failure (Cl cr less 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 (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), Use in Specific Populations(8.6)].

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