COLCHICINE

Colchicine USP is an alkaloid chemically described as (S)N- (5,6,7,9-tetrahydro- 1,2,3,10-tetramethoxy-9-oxobenzo [alpha] heptalen-7-yl) acetamide with a molecular formula of C 22 H 25 NO 6 and a molecular weight of 399.4. The structural formula of colchicine is given below. Colchicine USP occurs as a pale yellow to pale greenish-yellow amorphous scales or powder or crystalline powder that is soluble in water, freely soluble in alcohol and in chloroform; slightly soluble in ether. Colchicine Tablets USP are supplied for oral administration as light purple to purple capsule-shaped, biconvex film-coated tablets (0.1591” x 0.3039”), debossed with "CO 6" on one side and scored on other side, containing 0.6 mg of the active ingredient colchicine USP. Inactive ingredients: FD&C blue #2, FD&C red #40, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, pregelatinized starch (maize), sodium starch glycolate, titanium dioxide and triacetin. Chemical Structure

Colchicine is an alkaloid indicated for: Familial Mediterranean fever (FMF) in adults and children 4 years or older ( 1.2 ). 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).

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 coadministered 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. FMF: Adults and children older than 12 years 1.2 to 2.4 mg; children 6 to 12 years 0.9 to 1.8 mg; children 4 to 6 years 0.3 to 1.8 mg ( 2.2 , 2.3 ). Give total daily dose in one or two divided doses ( 2.2 ). Increase or decrease the dose as indicated and as tolerated in increments of 0.3 mg/day, not to exceed the maximum recommended daily dose ( 2.2 ). Colchicine tablets are administered orally without regard to meals. See full prescribing information (FPI) for dose adjustment regarding patients with impaired renal function ( 2.5 ), impaired hepatic function ( 2.6 ), the patient’s age ( 2.3 , 8.5 ) or use of coadministered drugs ( 2.4 ). 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 Coadministration of Interacting Drugs Concomitant Therapy Coadministration 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 Coadministration 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 increasein colchicine plasma levels*; fatal colchicine toxicity has beenreported with clarithromycin, a strong CYP3A4 inhibitor. Similarly, significant increasein colchicine plasma levelsisanticipatedwithother strong CYP3A4 inhibitors. Maximum daily dose of1.2 to 2.4mg Maximum daily dose of0.6mg (maybe givenas 0.3mg twice a day) Moderate CYP3A4 Inhibitors Drug Noted or Anticipated Outcome FMF Original Intended Dosage Adjusted Dose Amprenavir ‡ Aprepitant Diltiazem Erythromycin Fluconazole Fosamprenavir ‡ (prodrugof Amprenavir) Grapefruit juice Verapamil Significant increasein colchicine plasma concentrationisanticipated.Neuromuscular toxicity has beenreported withdiltiazemand verapamil interactions. Maximum daily dose of1.2 to2.4mg Maximum daily dose of1.2mg (maybe givenas 0.6mg twice a day) P-gp Inhibitors † Drug Noted or Anticipated Outcome FMF Original Intended Dosage Adjusted Dose Cyclosporine Ranolazine Significant increaseincolchicine plasma levels*;fatal colchicine toxicity has beenreportedwithcyclosporine, a P-gpinhibitor.Similarly, significant increaseincolchicine plasma levelsisanticipatedwithotherP-gpinhibitors. Maximum dailydoseof1.2 to 2.4mg Maximum daily doseof0.6mg (maybe givenas 0.3mgtwice aday) * 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 Coadministration with Protease Inhibitors Protease Inhibitor Clinical Comment w/Colchicine - Treatment of FMF Atazanavirsulfate(Reyataz) Patientswithrenalor hepatic impairment should not be givencolchicinewithReyataz. Maximum daily doseof0.6mg(maybegiven as0.3mgtwice a day) Darunavir (Prezista) Patients with renal or hepatic impairment should not be given colchicine with Prezista/ ritonavir. Maximum daily doseof0.6mg(maybegiven as0.3mgtwice a day) Fosamprenavir(Lexiva)withRitonavir Patientswithrenalor hepatic impairmentshould not begiven colchicinewithLexiva/ritonavir. Maximum daily doseof0.6mg(maybegivenas0.3mgtwice a day) Fosamprenavir(Lexiva) Patientswithrenalor hepatic impairmentshould not begivencolchicinewithLexiva/ritonavir. Maximum daily doseof1.2mg(maybegivenas0.6mgtwice a day) Indinavir(Crixivan) Patientswithrenalor hepatic impairmentshould not begivencolchicinewithCrixivan. Maximum daily doseof0.6mg(maybegivenas0.3mgtwice a day) Lopinavir/Ritonavir (Kaletra) Patientswithrenalor hepatic impairmentshould not begivencolchicinewithKaletra. Maximum daily doseof0.6mg(maybegivenas0.3mgtwice a day) Nelfinavirmesylate(Viracept) Patientswithrenalor hepatic impairmentshould not begivencolchicinewithViracept. Maximum daily doseof0.6mg(maybegivenas0.3mgtwice a day) Ritonavir(Norvir) Patientswithrenalor hepatic impairmentshould not begivencolchicinewithNorvir. Maximum daily doseof0.6mg(maybegivenas0.3mgtwice a day) Saquinavirmesylate(Invirase) Patientswithrenalor hepatic impairmentshould not begivencolchicinewithInvirase/ritonavir. Maximum daily doseof0.6mg(maybegivenas0.3mgtwice a day) Tipranavir(Aptivus) Patientswithrenalor hepatic impairmentshould not begivencolchicinewith Aptivus/ ritonavir. Maximum daily doseof0.6mg(maybegivenas0.3mgtwice 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: Cl cr = [140-age (years) × weight (kg)] 72 × serum creatinine (mg/dL) × 0.85 for female patients 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) ] . 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 [see Use in Specific Populations (8.7)] .

Patients with renal or hepatic impairment should not be given colchicine tablets in conjunction with P-gp or strong CYP3A4 inhibitors (this includes all protease inhibitors except fosamprenavir). In these patients, life-threatening and fatal colchicine toxicity has been reported with colchicine taken in therapeutic doses. Patients with renal or hepatic impairment should not be given colchicine tablets in conjunction with P-gp or strong CYP3A4 inhibitors ( 5.3 ). In these patients, life-threatening and fatal colchicine toxicity has been reported with colchicine taken in therapeutic doses ( 7 ).

FMF Gastrointestinal tract adverse effects are the most frequent side effects in patients initiating colchicine, usually presenting within 24 hours, and occurring in up to 20% of patients given therapeutic doses. Typical symptoms include cramping, nausea, diarrhea, abdominal pain and vomiting. These events should be viewed as dose-limiting if severe, as they can herald the onset of more significant toxicity. FMF: Most common adverse reactions (up to 20%) are abdominal pain, diarrhea, nausea and vomiting. These effects are usually mild, transient and reversible upon lowering the dose ( 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. 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

Colchicine is a substrate of the efflux transporter P-glycoprotein (P-gp). Of the cytochrome P450 enzymes tested, CYP3A4 was mainly involved in the metabolism of colchicine. If colchicine is administered with drugs that inhibit P-gp, most of which also inhibit CYP3A4, increased concentrations of colchicine are likely. Fatal drug interactions have been reported. Physicians should ensure that patients are suitable candidates for treatment with colchicine and remain alert for signs and symptoms of toxicities related to increased colchicine exposure as a result of a drug interaction. Signs and symptoms of colchicine toxicity should be evaluated promptly and, if toxicity is suspected, colchicine should be discontinued immediately. Table 4 provides recommendations as a result of other potentially significant drug interactions. Table 1 provides recommendations for strong and moderate CYP3A4 inhibitors and P-gp inhibitors. Table 4. Other Potentially Significant Drug Interactions Concomitant Drug Class or Food Noted orAnticipated Outcome Clinical Comment HMG-Co A ReductaseInhibitors: atorvastatin,fluvastatin,lovastatin,pravastatin,simvastatin Pharmacokineticand/orpharmacodynamicinteraction: the additionofonedrug to a stablelong­-term regimen of the otherhasresultedinmyopathy andrhabdomyolysis(including a fatality) Weigh the potential benefits and risks and carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy; monitoring CPK (creatine phosphokinase) will not necessarily prevent the occurrence of severe myopathy. Other Lipid-Lowering Drugs: fibrates, gemfibrozil Digitalis Glycosides: digoxin P-gp substrate; rhabdomyolysis has been reported Coadministration of P-gp and/or CYP3A4 inhibitors (e.g., clarithromycin or cyclosporine) have been demonstrated to alter the concentration of colchicine. The potential for drug-drug interactions must be considered prior to and during therapy. See FPI for a complete list of reported and potential interactions ( 2.4 , 5.3 , 7 ).