Colchicine

1 INDICATIONS AND USAGE Colchicine capsules are indicated for prophylaxis of gout flares in adults. Limitations of Use : The safety and effectiveness of colchicine capsules for acute treatment of gout flares during prophylaxis has not been studied. Colchicine capsules are not an analgesic medication and should not be used to treat pain from other causes. Colchicine capsules are an alkaloid indicated for prophylaxis of gout flares in adults ( 1 ). Limitations of Use : • The safety and effectiveness of colchicine capsules for acute treatment of gout flares during prophylaxis has not been studied. • Colchicine capsules are not an analgesic medication and should not be used to treat pain from other causes.

2 DOSAGE AND ADMINISTRATION • The recommended dosage is 0.6 mg (one capsule) once or twice daily ( 2 ). Maximum dose 1.2 mg/day. • Colchicine capsules are administered orally, without regard to meals ( 2 ). 2.1 Recommended Dosage for Gout Prophylaxis For prophylaxis of gout flares, the recommended dosage of colchicine capsules is 0.6 mg once or twice daily. The maximum dosage is 1.2 mg per day. Colchicine capsules are administered orally, without regard to meals.

3 DOSAGE FORMS AND STRENGTHS 0.6 mg capsules - Size '4' hard gelatin capsules with green opaque cap imprinted with “V1” in white color and light green opaque body imprinted with “85" in white color filled with white to off white colored granular powder. • 0.6 mg capsules ( 3 ).

4 CONTRAINDICATIONS Patients with renal or hepatic impairment should not be given colchicine capsules with drugs that inhibit both P-glycoprotein and CYP3A4 inhibitors [see Drug Interactions ( 7 )] . Combining these dual inhibitors with colchicine in patients with renal or hepatic impairment has resulted in life-threatening or fatal colchicine toxicity. Patients with both renal and hepatic impairment should not be given colchicine capsules. • Patients with renal or hepatic impairment should not be given colchicine capsules in conjunction with drugs that inhibit both P-gp and CYP3A4 ( 4 ). • Patients with both renal and hepatic impairment should not be given colchicine capsules ( 4 ).

6 ADVERSE REACTIONS Gastrointestinal disorders are the most common adverse reactions with colchicine. They are often the first signs of toxicity and may indicate that the colchicine dosage needs to be reduced or therapy stopped. These include diarrhea, nausea, vomiting, and abdominal pain. Colchicine has been reported to cause neuromuscular toxicity, which may present as muscle pain or weakness [see Warnings and Precautions (5.4) ]. Toxic manifestations associated with colchicine include myelosuppression, disseminated intravascular coagulation, and injury to cells in the renal, hepatic, circulatory, and central nervous system. These most often occur with excessive accumulation or overdosage [see Overdosage (10) ]. The following reactions have been reported with colchicine. These have been generally reversible by interrupting treatment or lowering the dose of colchicine: Digestive : abdominal cramping, abdominal pain, diarrhea, lactose intolerance, nausea, vomiting Neurological : sensory motor neuropathy Dermatological : alopecia, maculopapular rash, purpura, rash 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 The most commonly reported adverse reactions with colchicine are gastrointestinal symptoms, including diarrhea, nausea, vomiting, and abdominal pain ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

7 DRUG INTERACTIONS Colchicine is a substrate of the efflux transporter P-glycoprotein (P-gp), and the CYP3A4 metabolizing enzyme. Fatal drug interactions have been reported when colchicine is administered with clarithromycin, a dual inhibitor of CYP3A4 and P-glycoprotein. 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, erythromycin, verapamil), or inhibitors of P-gp that may not be potent inhibitors of CYP3A4 (e.g., cyclosporine). Patients with renal or hepatic impairment should not be given colchicine capsules with drugs that inhibit both P-glycoprotein and CYP3A4 [see Contraindications ( 4 )] . Combining these dual inhibitors with colchicine capsules in patients with renal and hepatic impairment has resulted in life-threatening or fatal colchicine toxicity. Physicians should ensure that patients are suitable candidates for treatment with colchicine capsules and remain alert for signs and symptoms of toxic reactions associated with increased colchicine exposure due to drug interactions. Signs and symptoms of colchicine toxicity should be evaluated promptly and, if toxicity is suspected, colchicine capsules should be discontinued immediately. • Co-administration of P-gp or CYP3A4 inhibitors or inhibitors of both P-gp and CYP3A4 (e.g., clarithromycin or cyclosporine) have been reported to lead to colchicine toxicity. The potential for drug-drug interactions must be considered prior to and during therapy. • Concomitant use of colchicine capsules and inhibitors of CYP3A4 or P-gp should be avoided if possible. If co-administration of colchicine capsules and an inhibitor of CYP3A4 or P-gp is necessary, the dose of colchicine capsules should be reduced and the patient should be monitored carefully for colchicine toxicity ( 7 , 12.3 ). 7.1 CYP3A4 The concomitant use of colchicine capsules 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 [see Warnings and Precautions ( 5.3 ) and Clinical Pharmacology ( 12 )] . If co-administration of colchicine capsules and a CYP3A4 inhibitor is necessary, the dose of colchicine capsules should be adjusted by either reducing the daily dose or reducing the dose frequency, and the patient should be monitored carefully for colchicine toxicity [see Clinical Pharmacology ( 12 )] . 7.2 P-glycoprotein The concomitant use of colchicine capsules and inhibitors of P-glycoprotein (e.g. clarithromycin, ketoconazole, cyclosporine, etc.) should be avoided due to the potential for serious and life-threatening toxicity [see Warnings and Precautions ( 5.3 ) and Clinical Pharmacology ( 12 )] . If co-administration of colchicine capsules and a P-gp inhibitor is necessary, the dose of colchicine capsules should be adjusted by either reducing the daily dose or reducing the dose frequency, and the patient should be monitored carefully for colchicine toxicity [see Clinical Pharmacology ( 12 )] . 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 colchicine capsules. Complaints of muscle pain or weakness could be an indication to check serum creatinine kinase levels for signs of myopathy. 7.4 Drug-Drug Interaction Studies Four pharmacokinetic studies evaluated the effects of co-administration of voriconazole (200 mg BID), fluconazole (200 mg QD), cimetidine (800 mg BID), and propafenone (225 mg BID) on systemic levels of colchicine. Colchicine can be administered with these drugs at the tested doses without a need for dose adjustment. However, these results should not be extrapolated to other co-administered drugs [ see Drug-Drug Interactions ( 7.1 , 7.2 ) and Pharmacokinetics ( 12.3 ) ].

8 USE IN SPECIFIC POPULATIONS N/A In the presence of renal or hepatic impairment, patients should be monitored closely and dose adjustment should be considered as necessary ( 8.6 , 8.7 ). Pregnancy: Use only if the potential benefit justifies the potential risk to the fetus ( 8.1 ). Lactation: Caution should be exercised when administered to a breastfeeding woman ( 8.2 ). Females and Males of Reproductive Potential: Advise males that colchicine capsules may rarely and transiently impair fertility ( 8.3 ). Geriatric Use: The recommended dosage of colchicine should be based on renal/hepatic function ( 8.5 ). 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 other adverse maternal or fetal outcomes (see Data) . Colchicine crosses the human placenta. Although animal reproductive and developmental studies were not conducted with colchicine capsules, 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 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 capsules and any potential adverse effects on the breastfed child from colchicine capsules or from the underlying maternal condition. Data Human 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. 8.4 Pediatric Use Gout is rare in pediatric patients; the safety and effectiveness of colchicine capsules in pediatric patients has not been evaluated in controlled studies. 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. 8.6 Renal Impairment No dedicated pharmacokinetic study has been conducted using colchicine capsules in patients with varying degrees of renal impairment. Colchicine is known to be …

12.1 Mechanism of Action Colchicine’s effectiveness as a 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.

11 DESCRIPTION Colchicine, USP is an alkaloid obtained from the plant colchicum autumnale. The chemical name for colchicine, USP is (N-[(7 S )-(5,6,7,9-tetrahydro-1,2,3,10-tetramethoxy-9-oxobenzo[a]heptalen-7yl] acetamide with a molecular formula of C 22 H 25 NO 6 and a molecular weight of 399.44. The structural formula of colchicine is represented below: Colchicine, USP consists of pale yellow to pale greenish-yellow crystalline powder; is odorless or nearly so, and darkens on exposure to light. Colchicine is freely soluble in alcohol, in chloroform and soluble in water. Colchicine capsules, USP are supplied for oral administration. Each capsule contains 0.6 mg colchicine, USP and the following inactive ingredients: anhydrous lactose, colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose and sodium starch glycolate. The capsule shell contains FD&C blue No. 1, FD&C yellow No. 6, gelatin, iron oxide yellow and titanium dioxide. The capsules are imprinted with white ink containing ammonia solution, potassium hydroxide, propylene glycol, shellac and titanium dioxide. colchicinecapsstructure

10 OVERDOSAGE The dose of colchicine that would induce significant toxicity for an individual is unknown. Fatalities have been reported in patients after ingesting a dose as low as 7 mg over a 4-day period, while other patients have reportedly 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 adverse reactions, such as gastrointestinal symptoms, whereas those who ingested from 0.5 to 0.8 mg/kg had more severe adverse reactions, including myelosuppression. There was 100% mortality among patients 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 multi-organ failure and its associated consequences. Death usually results from respiratory depression and cardiovascular collapse. If the patient survives, recovery of multi-organ injury may be accompanied by rebound leukocytosis and alopecia starting about 1 week after the initial ingestion. • Treatment of colchicine overdose 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 hemodialysis [see Pharmacokinetics ( 12.3 )] .

16 HOW SUPPLIED/STORAGE AND HANDLING Colchicine Capsules 0.6 mg are light blue cap imprinted with “CO” and light blue body imprinted with “0.6” in black ink filled with white to off-white powder. NDC: 71335-2703-8: 6 Tablets in a BOTTLE NDC: 71335-2703-1: 30 Tablets in a BOTTLE NDC: 71335-2703-2: 10 Tablets in a BOTTLE NDC: 71335-2703-3: 8 Tablets in a BOTTLE NDC: 71335-2703-4: 90 Tablets in a BOTTLE NDC: 71335-2703-5: 60 Tablets in a BOTTLE NDC: 71335-2703-6: 3 Tablets in a BOTTLE NDC: 71335-2703-7: 20 Tablets in a BOTTLE Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Protect from light and moisture. Repackaged/Relabeled by: Bryant Ranch Prepack, Inc. Burbank, CA 91504