COLCHICINE

Colchicine is an alkaloid obtained from the plant colchicum autumnale . The chemical name for colchicine is ( S)-N- (5,6,7,9- tetrahydro-1,2,3,10-tetramethoxy-9 oxobenzol[a]heptalen-7-yl) acetamide. The structural formula is represented below: Colchicine consists of pale yellow to pale greenish-yellow amorphous scales or powder or crystalline powder; it darkens on exposure to light. Colchicine is soluble in water, freely soluble in alcohol and in chloroform; slightly soluble in ether. Colchicine capsules are supplied for oral administration. Each capsule contains 0.6 mg colchicine, USP and the following inactive ingredients: colloidal silicon dioxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The capsule shell contains FD&C Blue No. 1, FD&C Red No. 40, gelatin and titanium dioxide. The capsules are imprinted with black ink containing black iron oxide, potassium hydroxide and shellac.

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.

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 dose is 1.2 mg per day. Colchicine capsules are administered orally, without regard to meals.

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 ).

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 Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 with drugs that inhibit both P-glycoprotein and CYP3A4 [see Contraindications (4) ]. Combining these dual inhibitors with colchicine 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 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 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 and inhibitors of CYP3A4 or P-gp should be avoided if possible. If co-administration of colchicine and an inhibitor of CYP3A4 or P-gp is necessary, the dose of colchicine should be reduced and the patient should be monitored carefully for colchicine toxicity ( 7 , 12.3 ). 7.1 CYP3A4 The concomitant use of colchicine 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 and a CYP3A4 inhibitor is necessary, the dose of colchicine 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 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 and a P-gp inhibitor is necessary, the dose of colchicine 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. 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) ].