2.1       Gout Prophylaxis

For prophylaxis of gout flares, the recommended dosage of GLOPERBA is 0.6 mg (5 mL) once or twice daily.  The maximum dose is 1.2 mg/day.

GLOPERBA is administered orally, without regard to meals.

5.1Fatal Overdose

Fatal overdoses, both accidental and intentional, have been reported in adults and children who have ingested colchicine [ see Overdosage (10)]. GLOPERBA 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.

5.3Drug Interactions

Because colchicine is a substrate for both the CYP3A4 metabolizing enzyme and the P-gp efflux transporter, inhibition of either of these pathways may lead to colchicine-related toxicity. Inhibition of both CYP3A4 and P-gp by dual inhibitors (i.e., clarithromycin) has been reported to produce life-threatening or fatal colchicine toxicity due to significant increases in systemic colchicine levels. Therefore, concomitant use of GLOPERBA with inhibitors of both CYP3A4 and P-gp should be avoided. If treatment with colchicine is necessary, a reduced daily dose should be considered and the patient should be closely monitored for colchicine toxicity [ see Drug Interactions (7)].

Use of GLOPERBA in conjunction with drugs that inhibit both CYP3A4 and P-gp 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, especially in combination with other drugs known to cause this effect.  Patients with impaired renal function and elderly patients, even those with normal renal and hepatic function, are at increased risk. Once colchicine treatment is stopped, the symptoms generally resolve within one week to several months.

7.1CYP3A4

The concomitant use of GLOPERBA and CYP3A4 inhibitors (e.g., clarithromycin, ketoconazole, grapefruit juice, erythromycin, verapamil, etc.) should be avoided due to the potential for serious and life-threatening toxicity [ seeWarnings andPrecautions(5.3) and ClinicalPharmacology(12.3)].

If co-administration of GLOPERBA and a CYP3A4 inhibitor is necessary, the dose of GLOPERBA should be adjusted by either reducing the daily dose or reducing the dose frequency, and the patient should be monitored carefully for colchicine toxicity [ seeClinicalPharmacology(12.3)].

7.2P- Glycoprotein

The concomitant use of GLOPERBA and inhibitors of P-glycoprotein (e.g. clarithromycin, ketoconazole, cyclosporine, etc.) should be avoided due to the potential for serious and life-threatening toxicity [ seeWarnings andPrecautions(5.3) and ClinicalPharmacology(12.3)].

If co-administration of GLOPERBA and a P-gp inhibitor is necessary, the dose of GLOPERBA should be adjusted by either reducing the daily dose or reducing the dose frequency, and the patient should be monitored carefully for colchicine toxicity [ seeClinicalPharmacology(12.3)].

7.3       HMG- CoA Reductase Inhibitors and Fibrates

Some drugs such as HMG-CoA reductase inhibitors and fibrates may increase the risk of myopathy when combined with GLOPERBA.  Complaints of muscle pain or weakness could be an indication to check serum creatinine kinase levels for signs of myopathy.

7.4       Drug Interaction Studies

Two pharmacokinetic studies evaluated the effects of co-administration of posaconazole (300 mg QD), ciprofloxacin (500 mg BID), amlodipine (5 to 10 mg QD), and carvedilol (20 to 40 mg QD) on the systemic levels of colchicine.

GLOPERBA can be administered with amlodipine, carvedilol, and ciprofloxacin at the tested doses without a need for dose adjustment.  However, the results should not be extrapolated to other co-administered drugs.  Colchicine plasma levels were markedly elevated when GLOPERBA was co-administered with posaconazole. The recommended dose of GLOPERBA when co-administered with posaconazole is 0.24 mg (2 mL).

8.1Pregnancy

Risk Summary

Available human 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). Although animal reproduction and development studies were not conducted with GLOPERBA, published animal reproduction and development studies indicate that colchicine causes embryofetal toxicity 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

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, Behçet’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 GLOPERBA and any potential adverse effects on the breastfed infant from GLOPERBA 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 and advised to reconsider breastfeeding if the infant has diarrhea. 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 indicate that infertility from colchicine is rare and may be reversible.

8.4       Pediatric Use

Gout is rare in pediatric patients; safety and effectiveness of GLOPERBA in pediatric patients has not been established.

8.5       Geriatric Use

Because of the increased incidence of decreased renal function in the elderly population, and the higher incidence of other co-morbid conditions in the elderly population requiring the use of other medications, reducing the dosage of colchicine when elderly patients are treated with colchicine should be carefully considered [ see Clinical Pharmacology (12.3)].

8.6       Renal Impairment

No dedicated pharmacokinetic study has been conducted using GLOPERBA in patients with varying degrees of renal impairment.  Colchicine is known to be excreted in urine in humans and the presence of severe renal impairment has been associated with colchicine toxicity.  Urinary clearance of colchicine and its metabolites may be decreased in patients with impaired renal function.  Dose reduction or alternatives should be considered for the prophylaxis of gout flares in patients with severe renal impairment.  Colchicine is not effectively removed by hemodialysis.  Patients who are undergoing hemodialysis should be monitored carefully for colchicine toxicity.

8.7       Hepatic Impairment

No dedicated pharmacokinetic study using GLOPERBA has been conducted in patients with varying degrees of hepatic impairment.  Colchicine is known to be metabolized in humans and the presence of severe hepatic impairment has been associated with colchicine toxicity.  Hepatic clearance of colchicine may be significantly reduced and plasma half-life prolonged in patients with chronic hepatic impairment.

Dose reduction or alternatives should be considered for the prophylaxis of gout flares in patients with severe hepatic impairment.

12.1       Mechanism of Action 

Colchicine’s effectiveness as a prophylactic treatment for gout has been postulated to be due to its ability to block neutrophil-mediated inflammatory responses induced by monosodium urate crystals in synovial fluid.  Colchicine disrupts the polymerization of β-tubulin into microtubules, thereby preventing the activation, degranulation and migration of neutrophils to sites of inflammation.  Colchicine also interferes with the inflammasome complex found in neutrophils and monocytes that mediates interleukin-1β (IL-1β) activation.

12.2       Pharmacodynamics

The pharmacodynamics of colchicine are unknown.

12.3Pharmacokinetics

Absorption

In healthy adults, GLOPERBA reached a mean C max of 2.16 ± 0.87 ng/mL in 1 hour (range 0.5 to 2 hours) after a single dose administered under fasting conditions. A minimal food effect was observed when GLOPERBA was administered following a high fat, high calorie meal. A slight decrease in C max was observed; however, the overall extent of absorption based on AUC 0- t and AUC 0- inf, was similar in the fed and fasted states. The absolute bioavailability of colchicine is reported to be approximately 45%. Mean pharmacokinetic parameter values for GLOPERBA in healthy adults are shown in Table1.

Distribution

The mean apparent volume of distribution(V z/F) of GLOPERBA in healthy adults was approximately 1420 L. Colchicine binding to serum protein is reported to be low (39%) primarily due to albumin regardless of concentration.

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

Metabolism

In vitro studies using human liver microsomes have shown that CYP3A4 is involved in the metabolism of colchicine to 2- O-demethylcolchicine (2-DMC) and 3- O-demethylcolchicine (3-DMC). Glucuronidation is also believed to be a metabolic pathway for colchicine.

Elimination

The mean elimination half-life of GLOPERBA in healthy adults is 31 hours (± 6 hours). In a published study in healthy adults approximately 40 to 65% of a single 1-mg oral dose of colchicine was reported to be recovered unchanged in urine. Enterohepatic recirculation and biliary excretion are postulated to play a role in colchicine elimination. Colchicine is also a substrate of P-gp, and P-gp efflux is postulated to play an important role in colchicine disposition.

Specific Populations

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

Pediatric Patients: Pharmacokinetics of colchicine were not evaluated in pediatric patients.

Geriatric Patients: Pharmacokinetics of GLOPERBA have not been determined in elderly patients. A published report described the pharmacokinetics of a 1-mg oral colchicine tablet dose 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/minute (range 25 to 75 mL/minute). Mean peak plasma levels and AUC of colchicine were two times higher in elderly subjects compared to young healthy males. It is possible that the higher exposure in the elderly subjects was due to decreased renal function.

Patients with 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 patients who had end-stage renal disease requiring dialysis compared to patients with normal renal function. 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 hours vs. 4.4 hours) as compared to subjects with normal renal function [s ee Use in Specific Populations(8.6)].

Patients with Hepatic Impairment: Published reports on the pharmacokinetics of intravenous colchicine in patients with severe chronic liver disease, as well as those with alcoholic or primary biliary cirrhosis, and normal renal function suggest wide inter-patient 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 [s ee Use in Specific Populations (8.7)]. No pharmacokinetic data are available for patients with severe hepatic impairment (Child-Pugh C).

Drug Interactions

Pharmacokinetic studies evaluating changes in systemic levels of colchicine when co-administered with CYP3A4 and P-gp inhibitors in healthy subjects have been conducted with GOLPERBA. Carvedilol 20 to 40 mg QD (considered a P-gp inhibitor), amlodipine 5 to 10 mg QD (considered a weak inhibitor of CYP3A4) and ciprofloxacin 500 mg BID (considered a moderate CYP3A4 inhibitor) did not cause any significant changes in colchicine systemic levels. Co-administration with posaconazole 300 mg QD (considered a strong CYP3A4 inhibitor) increased AUC by approximately 3-fold.

These results should not be extrapolated to other inhibitors as colchicine is known to be a substrate for CYP3A4 and P-gp, and case reports of colchicine toxicity associated with the co-administration of CYP3A4 and P-gp inhibitors (i.e., clarithromycin) have been published.

Fatal drug interactions have been reported when colchicine is administered with clarithromycin, a dual inhibitor of CYP3A4 and P-gp. Toxicities have also been reported when colchicine is administered with inhibitors of CYP3A4 that may not be potent inhibitors of P-gp (e.g., grapefruit juice), or inhibitors of P-gp that may not be potent inhibitors of CYP3A4 (e.g., cyclosporine). If treatment with a P-gp and CYP3A4 inhibitor is required in patients with normal renal and hepatic function, the patients’ dose of colchicine may need to be reduced or interrupted.

13.1       Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Carcinogenicity studies of colchicine have not been conducted.  Due to the potential for colchicine to produce aneuploid cells (cells with an unequal number of chromosomes), colchicine presents a theoretical increased risk of malignancy.

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

There were no studies conducted of the effects of GLOPERBA on fertility. Published nonclinical studies have demonstrated that colchicine-induced disruption of microtubule formation affects meiosis and mitosis. Published colchicine reproductive studies have reported abnormal sperm morphology and reduced sperm counts in males and interference with sperm penetration, second meiotic division and normal cleavage in females.

16.1How Supplied

GLOPERBA (colchicine) Oral Solution is a slightly hazy, red liquid with a cherry odor and the strength of 0.6 mg/5 mL. GLOPERBA (150 mL) is provided in a white, oblong, high density polyethylene bottle with a child-resistant cap.

150 mL: NDC 75854-801-01

16.2Storage

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15°-30°C (59°-86°F). [See USP Controlled Room Temperature].