Colchicine

1 INDICATIONS & USAGE Colchicine tablets are 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).

2 DOSAGE & ADMINISTRATION 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 – 2.4 mg; children 6 to 12 years 0.9 – 1.8 mg; children 4 to 6 years 0.3 – 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 increase in colchicine plasma levels*; fatal colchicine toxicity has been reported with clarithromycin, a strong CYP3A4 inhibitor. Similarly, significant increase in colchicine plasma levels is anticipated with other strong CYP3A4 inhibitors. Maximum daily dose of 1.2 – 2.4 mg Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day) Moderate CYP3A4 Inhibitors FMF Drug Noted or Anticipated Outcome Original Intended Dosage Adjusted Dose Amprenavir ‡ Aprepitant Diltiazem Erythromycin Fluconazole Fosamprenavir ‡ (prodrug of Amprenavir) Grapefruit juice Verapamil Significant increase in colchicine plasma concentration is anticipated. Neuromuscular toxicity has been reported with diltiazem and verapamil interactions. Maximum daily dose of 1.2 – 2.4 mg Maximum daily dose of 1.2 mg (may be given as 0.6 mg twice a day) P-gp Inhibitors † FMF Drug Noted or Anticipated Outcome Original Intended Dosage Adjusted Dose Cyclosporine Ranolazine Significant increase in colchicine plasma levels*; fatal colchicine toxicity has been reported with cyclosporine, a P-gp inhibitor. Similarly, significant increase in colchicine plasma levels is anticipated with other P-gp inhibitors. Maximum daily dose of 1.2 –2.4 mg Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day) * 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 Atazanavir sulfate (Reyataz) Patients with renal or hepatic impairment should not be given colchicine with Reyataz. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day) Darunavir (Prezista) Patients with renal or hepatic impairment should not be given colchicine with Prezista/ ritonavir. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day) Fosamprenavir (Lexiva) with Ritonavir Patients with renal or hepatic impairment should not be given colchicine with Lexiva/ritonavir. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day) Fosamprenavir (Lexiva) Patients with renal or hepatic impairment should not be given colchicine with Lexiva/ritonavir. Maximum daily dose of 1.2 mg (may be given as 0.6 mg twice a day) Indinavir (Crixivan) Patients with renal or hepatic impairment should not be given colchicine with Crixivan. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day) Lopinavir/ Ritonavir (Kaletra) Patients with renal or hepatic impairment should not be given colchicine with Kaletra. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day) Nelfinavir mesylate (Viracept) Patients with renal or hepatic impairment should not be given colchicine with Viracept. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day) Ritonavir (Norvir) Patients with renal or hepatic impairment should not be given colchicine with Norvir. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day) Saquinavir mesylate (Invirase) Patients with renal or hepatic impairment should not be given colchicine with Invirase/ ritonavir. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day) Tipranavir (Aptivus) Patients with renal or hepatic impairment should not be given colchicine with Aptivus/ritonavir. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice 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 )]. Clcr in 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 (Clcr 50 to 80 mL/min) and moderate (Clcr 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 (Clcr 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 )].

4 CONTRAINDICATIONS 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).

5 WARNINGS AND PRECAUTIONS · Fatal overdoses have been reported with colchicine in adults and children. Keep colchicine tablets out of the reach of children ( 5.1 , 10 ). · Blood dyscrasias: myelosuppression, leukopenia, granulocytopenia, thrombocytopenia and aplastic anemia have been reported ( 5.2 ). · Monitor for toxicity and if present consider temporary interruption or discontinuation of colchicine ( 5.2 , 5.3 , 5.4 , 6 , 10 ). · Drug interaction P-gp and/or CYP3A4 inhibitors: Coadministration of colchicine with P-gp and/or strong CYP3A4 inhibitors has resulted in life-threatening interactions and death ( 5.3 , 7 ). · Neuromuscular toxicity: Myotoxicity including rhabdomyolysis may occur, especially in combination with other drugs known to cause this effect. Consider temporary interruption or discontinuation of colchicine tablets ( 5.4 , 7 ). 5.1 Fatal Overdose Fatal overdoses, both accidental and intentional, have been reported in adults and children who have ingested colchicine [see Overdosage ( 10 )] . Colchicine tablets 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 tablets 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 ADVERSE REACTIONS FMF Gastrointestinal tract adverse effects are the most frequent side effects in patients initiating colchicine tablets, 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 Ascend Laboratories, LLC at 1-877-ASC-RX01 (877-272-7901) 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

7 DRUG INTERACTIONS 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 tablets 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 tablets 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 tablets toxicity should be evaluated promptly and, if toxicity is suspected, colchicine tablets 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 or Anticipated Outcome Clinical Comment HMG-Co A Reductase Inhibitors: atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin Pharmacokinetic and/or pharmacodynamic interaction: the addition of one drug to a stable long-term regimen of the other has resulted in myopathy and rhabdomyolysis (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 ).

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.

10 OVERDOSAGE The exact dose of colchicine that produces significant toxicity is unknown. Fatalities have occurred after ingestion of a dose as low as 7 mg over a four day period, while other patients have 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 toxicities such as gastrointestinal symptoms, whereas those who took 0.5 to 0.8 mg/kg had more severe reactions such as myelosuppression. There was 100% mortality in those 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 multiorgan failure and its consequences. Death is usually a result of respiratory depression and cardiovascular collapse. If the patient survives, recovery of multiorgan injury may be accompanied by rebound leukocytosis and alopecia starting about one week after the initial ingestion. Treatment of colchicine poisoning 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 dialysis [see Clinical Pharmacology ( 12.3 )] .