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).

2.2 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 1within the prior 14 days, the dose adjustments are as shown in the table below [see Drug Interactions( 7)].

*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)]

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

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 cr50 to 80 mL/min) and moderate (Cl cr30 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 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(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)].

2.6 Dose Modification in Hepatic Impairment

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 [seeUse in Specific Populations(8.7)].

5.1 Fatal Overdose

Fatal overdoses, both accidental and intentional, have been reported in adults and children who have ingested colchicine [ seeOverdosage (10)].Colchicine 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 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 (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 colchicine may potentiate the development of myopathy [ see Drug Interactions (7)].Once colchicine is stopped, the symptoms generally resolve within one week to several months.

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 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

8.1 Pregnancy

Risk Summary
Available data from published literature on colchicine use in pregnancy over several decades have not identified any drug associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data).Colchicine crosses the human placenta. Although animal reproductive and developmental studies were not conducted with colchicine, 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.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data
Human Data
Available data from published observational studies, case series, and case reports over several decades do not suggest an increased risk for major birth defects or miscarriage in pregnant women with rheumatic diseases (such as rheumatoid arthritis, Behcet’s disease, or Familial Mediterranean Fever (FMF) treated with colchicine at therapeutic doses during pregnancy. Limitations of these data include the lack of randomization and inability to control for confounders such as underlying maternal disease and maternal use of concomitant medications.

8.2 Lactation

Risk Summary
Colchicine is present in human milk (see Data). Adverse events in breastfed infants have not been reported in the published literature after administration of colchicine to lactating women. There are no data on the effects of colchicine on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for colchicine and any potential adverse effects on the breastfed child from colchicine or from the underlying maternal condition.

Data
Limited published data from case reports and a small lactation study demonstrate that colchicine is present in breastmilk. A systematic review of literature reported no adverse effects in 149 breastfed children. In a prospective observational cohort study, no gastrointestinal or other symptoms were reported in 38 colchicine-exposed breastfed infants.

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( 13.1)].

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.

8.5 Geriatric Use

Clinical studies with colchicine 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 should be cautious, reflecting the greater frequency of decreased renal function, concomitant disease or other drug therapy [see Dosage and Administration(2.4),Clinical Pharmacology(12.3).

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.

FMF

Although, pharmacokinetics of colchicine in patients with mild (Clcr 50 to 80 mL/min) and moderate (Clcr 30 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 (Clcr less 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(12.3), Dosage and Administration(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 Clinical Pharmacology(12.3].

FMF

In patients with severe hepatic disease, dose reduction should be considered with careful monitoring [see Clinical Pharmacology(12.3), Dosage and Administration(2.6)].

12.1 Mechanism of Action

The mechanism by which colchicine exerts its beneficial effect in patients with FMF has not been fully elucidated; however, evidence suggests that colchicine may interfere with the intracellular assembly of the inflammasome complex present in neutrophils and monocytes that mediates activation of interleukin-1β. Additionally, colchicine disrupts cytoskeletal functions through inhibition of β-tubulin polymerization into microtubules and consequently prevents the activation, degranulation and migration of neutrophils.

12.3 Pharmacokinetics

Absorption

In healthy adults, colchicine is absorbed when given orally, reaching a mean C maxof 2.5 ng/mL (range 1.1 to 4.4 ng/mL) in one to two hours (range 0.5 to 3 hours) after a single dose administered under fasting conditions.

Following oral administration of colchicine given as 1.8 mg colchicine over one hour to healthy, young adults under fasting conditions, colchicine appears to be readily absorbed, reaching mean maximum plasma concentrations of 6.2 ng/mL at a median 1.81 hours (range: 1 to 2.5 hours). Following administration of the nonrecommended high-dose regimen (4.8 mg over six hours), mean maximal plasma concentrations were 6.8 ng/mL, at a median 4.47 hours (range: 3.1 to 7.5 hours).

After ten days on a regimen of 0.6 mg twice daily, peak concentrations are 3.1 to 3.6 ng/mL (range 1.6 to 6 ng/mL), occurring 1.3 to 1.4 hours postdose (range 0.5 to 3 hours). Mean pharmacokinetic parameter values in healthy adults are shown in Table 5.

*T maxmean (range)

CL = Dose/AUC 0-t(calculated from mean values)

Vd = CL/Ke (calculated from mean values)

In some subjects, secondary colchicine peaks are seen, occurring between three and 36 hours postdose and ranging from 39 to 155% of the height of the initial peak. These observations are attributed to intestinal secretion and reabsorption and/or biliary recirculation.

Absolute bioavailability is reported to be approximately 45%.

Administration of colchicine with food has no effect on the rate of colchicine absorption but does decrease the extent of colchicine by approximately 15%. This is without clinical significance.

Distribution

The mean apparent volume of distribution in healthy young volunteers is approximately 5 to 8 L/kg.

Colchicine binding to serum protein is low, 39 ± 5%, primarily to albumin regardless of concentration.

Colchicine crosses the placenta (plasma levels in the fetus are reported to be approximately 15% of the maternal concentration). Colchicine also distributes into breast milk at concentrations similar to those found in the maternal serum [see Use in Specific Populations( 8.1, 8.2)].

Metabolism

Colchicine is demethylated to two primary metabolites, 2-O-demethylcolchicine and 3-O-demethylcolchicine (2- and 3-DMC, respectively) and one minor metabolite, 10-O-demethylcolchicine (also known as colchiceine). In vitro studies using human liver microsomes have shown that CYP3A4 is involved in the metabolism of colchicine to 2-and 3-DMC. Plasma levels of these metabolites are minimal (less than 5% of parent drug).

Elimination/Excretion

In healthy volunteers (n=12), 40 to 65% of 1 mg orally administered colchicine was recovered unchanged in urine. Enterohepatic recirculation and biliary excretion are also postulated to play a role in colchicine elimination. Following multiple oral doses (0.6 mg twice daily), the mean elimination half-lives in young healthy volunteers (mean age 25 to 28 years of age) is 26.6 to 31.2 hours. Colchicine is a substrate of P-gp.

Extracorporeal Elimination

Colchicine is not removed by hemodialysis.

Special Populations

There is no difference between men and women in the pharmacokinetic disposition of colchicine.

Pediatric Patients:

Pharmacokinetics of colchicine was not evaluated in pediatric patients.

Elderly

A published report described the pharmacokinetics of 1 mg oral colchicine tablet in four elderly women compared to six young healthy males. The mean age of the four elderly women was 83 years (range 75 to 93), mean weight was 47 kg (38 to 61 kg) and mean creatinine clearance was 46 mL/min (range 25 to 75 mL/min). Mean peak plasma levels and AUC of colchicine were two times higher in elderly subjects compared to young healthy males.

A pharmacokinetic study using a single oral dose of one 0.6 mg colchicine tablet was conducted in young healthy subjects (n=20) between the ages of 18 and 30 years and elderly subjects (n=18) between the ages of 60 and 70 years. Elderly subjects in this study had a median age of 62 years and a mean (±SD) age of 62.83 ± 2.83 years. A statistically significant difference in creatinine clearance (mean ± SD) was found between the two age groups (132.56 ± 23.16 mL/min for young vs 87.02 ± 17.92 mL/min for elderly subjects, respectively). The following pharmacokinetic parameter values (mean ± SD) were observed for colchicine in the young and elderly subjects, respectively: AUC0-inf (ng/hr/mL) 22.39 ± 6.95 and 25.01 ± 6.92; Cmax (ng/mL) 2.61 ± 0.71 and 2.56 ± 0.97; Tmax (hr) 1.38 ± 0.42 and 1.25 ± 0.43; apparent elimination half-life (hr) 24.92 ± 5.34 and 30.06 ± 10.78; and clearance (mL/min) 0.0321 ± 0.0091 and 0.0292 ± 0.0071.

Clinical studies with colchicine for treatment of FMF did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently than younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased renal function, concomitant disease or other drug therapy [see Dosage and Administration( 2.4), Use in Specific Populations( 8.5)].

Renal Impairment

Pharmacokinetics of colchicine in patients with mild and moderate renal impairment is not known. A published report described the disposition of colchicine (1 mg) in young adult men and women with FMF who had normal renal function or end-stage renal disease requiring dialysis. Patients with end-stage renal disease had 75% lower colchicine clearance (0.17 vs. 0.73 L/hr/kg) and prolonged plasma elimination half-life (18.8 vs 4.4 hours) as compared to subjects with FMF and normal renal function [see Dosage and Administration( 2.5), Use in Specific Populations( 8.6)].

Hepatic Impairment

Published reports on the pharmacokinetics of IV colchicine in patients with severe chronic liver disease, as well as those with alcoholic or primary biliary cirrhosis and normal renal function suggest wide interpatient variability. In some subjects with mild to moderate cirrhosis, the clearance of colchicine is significantly reduced and plasma half-life prolonged compared to healthy subjects. In subjects with primary biliary cirrhosis, no consistent trends were noted [see Dosage and Administration( 2.6), Use in Specific Populations( 8.7)]. No pharmacokinetic data are available for patients with severe hepatic impairment (Child-Pugh C).

Drug Interactions

In Vitro Drug Interactions

In vitro studies in human liver microsomes have shown that colchicine is not an inhibitor or inducer of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4 activity.

In Vivo Drug Interactions

The effects of co-administration of other drugs with colchicine on C max, AUC and C minare summarized in Table 6(effect of other drugs on colchicine) and Table 7(effect of colchicine on other drugs). For information regarding clinical recommendations, see Table 1in Dose Modification for Co-administration of Interacting Drugs [see Dosage and Administration( 2.4)].

Estrogen-containing oral contraceptives: In healthy female volunteers given ethinyl estradiol and norethindrone (Ortho-Novum 1/35) co-administered with colchicine (0.6 mg twice daily X 14 days), hormone concentrations are not affected.

In healthy volunteers given theophylline co-administered with colchicine (0.6 mg twice daily X 14 days), theophylline concentrations were not affected.

*Conducted in healthy adult females

†AUC τ

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Two-year studies were conducted in mice and rats to assess the carcinogenic potential of colchicine. No evidence of colchicine-related tumorigenicity was observed in mice or rats at colchicine oral doses up to 3 and 2 mg/kg/day, respectively (approximately six and eight times, respectively, the maximum recommended human dose of 2.4 mg on a mg/m 2basis).

Mutagenesis

Colchicine was negative for mutagenicity in the bacterial reverse mutation assay. In a chromosomal aberration assay in cultured human white blood cells, colchicine treatment resulted in the formation of micronuclei. Since published studies demonstrated that colchicine induces aneuploidy from the process of mitotic nondisjunction without structural DNA changes, colchicine is not considered clastogenic, although micronuclei are formed.

Impairment of Fertility

No studies of colchicine effects on fertility were conducted with colchicine. However, published nonclinical studies demonstrated that colchicine-induced disruption of microtubule formation affects meiosis and mitosis. Reproductive studies also reported abnormal sperm morphology and reduced sperm counts in males, and interference with sperm penetration, second meiotic division and normal cleavage in females when exposed to colchicine. Colchicine administered to pregnant animals resulted in fetal death and teratogenicity. These effects were dose-dependent, with the timing of exposure critical for the effects on embryofetal development. The nonclinical doses evaluated were generally higher than an equivalent human therapeutic dose, but safety margins for reproductive and developmental toxicity could not be determined.

16.1 How Supplied

Colchicine tablets, USP 0.6 mg are purple, film-coated, capsule-shaped tablets debossed with "G 02" on one side and scored on the other side.

Bottles of 30 NDC 51407-082-30

Bottles of 100 NDC 51407-082-01

16.2 Storage

Store at 20°C to 25°C (68°F to 77°F) [See USP Controlled Room Temperature].
Protect from light.

DISPENSE IN TIGHT, LIGHT-RESISTANT CONTAINER.