Colchicine tablets are an alkaloid indicated for:

• Prophylaxis and treatment of gout flares in adults (1.1).
• Familial Mediterranean fever (FMF) in adults and children 4 years or older (1.2).

Colchicine tablets are indicated for prophylaxis and the treatment of acute gout flares.

•  Prophylaxis of Gout Flares:

   Colchicine tablets is indicated for prophylaxis of gout flares.

•  Treatment of Gout Flares:

   Colchicine tablets are indicated for treatment of acute gout flares when taken at the first sign of a flare.

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 and the prophylaxis of gout flares, but the safety and efficacy of repeat treatment for gout flares has not been evaluated. The dosing regimens for colchicine tablets are different for each indication and must be individualized.

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 is not an analgesic medication and should not be used to treat pain from other causes.

• Gout Flares :

Prophylaxis of Gout Flares: 0.6 mg once or twice daily in adults and adolescents older than 16 years of age (2.1). Maximum dose 1.2 mg/day.

Treatment of Gout Flares: 1.2 mg (two tablets) at the first sign of a gout flare followed by 0.6 mg (one tablet) one hour later (2.1).

• 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).

Prophylaxis of Gout Flares

The recommended dosage of colchicine tablets for prophylaxis of gout flares for adults and adolescents older than 16 years of age is 0.6 mg once or twice daily. The maximum recommended dose for prophylaxis of gout flares is 1.2 mg/day.

An increase in gout flares may occur after initiation of uric acid-lowering therapy, including pegloticase, febuxostat and allopurinol, due to changing serum uric acid levels resulting in mobilization of urate from tissue deposits. Colchicine tablets is recommended upon initiation of gout flare prophylaxis with uric acid-lowering therapy. Prophylactic therapy may be beneficial for at least the first six months of uric acid-lowering therapy.

Treatment of Gout Flares

The recommended dose of colchicine tablets for treatment of a gout flare is 1.2 mg (two tablets) at the first sign of the flare followed by 0.6 mg (one tablet) one hour later. Higher doses have not been found to be more effective. The maximum recommended dose for treatment of gout flares is 1.8 mg over a 1-hour period. Colchicine tablets may be administered for treatment of a gout flare during prophylaxis at doses not to exceed 1.2 mg (two tablets) at the first sign of the flare followed by 0.6 mg (one tablet) one hour later. Wait 12 hours and then resume the prophylactic dose.

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.

Prophylaxis and Treatment of Gout Flares

Colchicine tablets is not recommended for pediatric use in prophylaxis or treatment of gout flares.

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

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 Co-administration with Interacting Drugs if no Alternative Available*

Treatment of gout flares with colchicine tablets is not recommended in patients receiving prophylactic dose of Colchicine and CYP3A4 inhibitors.

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:

            [140-age (years) × weight (kg)]

Cl_cr = --------------------------------------------

            72 × serum creatinine (mg/dL) x 0.85 for female patients

Gout Flares

Prophylaxis of Gout Flares

For prophylaxis of gout flares in patients with mild (estimated creatinine clearance [Cl_cr] 50 to 80 mL/min) to moderate (Cl_cr 30 to 50 mL/min) renal function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of colchicine. However, in patients with severe impairment, the starting dose should be 0.3 mg/day and any increase in dose should be done with close monitoring. For the prophylaxis of gout flares in patients undergoing dialysis, the starting doses should be 0.3 mg given twice a week with close monitoring [see Clinical Pharmacology (12.3), Use in Specific Populations (8.6)].

Treatment of Gout Flares

For treatment of gout flares in patients with mild (Cl_cr 50 to 80 mL/min) to moderate (Cl_cr 30 to 50mL/min) renal function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of colchicine. However, in patients with severe impairment, while the dose does not need to be adjusted for the treatment of gout flares, a treatment course should be repeated no more than once every two weeks. For patients with gout flares requiring repeated courses, consideration should be given to alternate therapy. For patients undergoing dialysis, the total recommended dose for the treatment of gout flares should be reduced to a single dose of 0.6 mg (one tablet). For these patients, the treatment course should not be repeated more than once every two weeks [see Clinical Pharmacology (12.3), Use in Specific Populations (8.6)].

Treatment of gout flares with Colchicine tablets is not recommended in patients with renal impairment who are receiving Colchicine tablets for prophylaxis.

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)].

Gout Flares

Prophylaxis of Gout Flares

For prophylaxis of gout flares in patients with mild to moderate hepatic function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of colchicine. Dose reduction should be considered for the prophylaxis of gout flares in patients with severe hepatic impairment [see Use in Specific Populations (8.7)].

Treatment of Gout Flares

For treatment of gout flares in patients with mild to moderate hepatic function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of colchicine. However, for the treatment of gout flares in patients with severe impairment, while the dose does not need to be adjusted, a treatment course should be repeated no more than once every two weeks. For these patients, requiring repeated courses for the treatment of gout flares, consideration should be given to alternate therapy [see Use in Specific Populations (8.7)].

Treatment of gout flares with Colchicine is not recommended in patients with hepatic impairment who are receiving Colchicine for prophylaxis.

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).

• 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).

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.

Myelosuppression, leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, and aplastic anemia have been reported with colchicine used in therapeutic doses.

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 tablets 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)].

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 may potentiate the development of myopathy [see Drug Interactions (7)]. Once colchicine is stopped, the symptoms generally resolve within one week to several months.

• Prophylaxis of Gout Flares: The most commonly reported adverse reaction in clinical trials for the prophylaxis of gout was diarrhea.

• Treatment of Gout Flares: The most common adverse reactions reported in the clinical trial for gout were diarrhea (23%) and pharyngolaryngeal pain (3%).

• 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 Strides Pharma Inc. at 1-877-244-9825 or go to www.strides.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Prophylaxis of Gout Flares

The most commonly reported adverse reaction in clinical trials of colchicine for the prophylaxis of gout was diarrhea.

Treatment of Gout Flares

The most common adverse reactions reported in the clinical trial with colchicine for treatment of gout flares were diarrhea (23%) and pharyngolaryngeal pain (3%).

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.

Because clinical studies are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice.

In a randomized, double-blind, placebo-controlled trial in patients with a gout flare, gastrointestinal adverse reactions occurred in 26% of patients using the recommended dose (1.8 mg over one hour) of colchicine compared to 77% of patients taking a nonrecommended high dose (4.8 mg over six hours) of colchicine and 20% of patients taking placebo. Diarrhea was the most commonly reported drug-related gastrointestinal adverse event. As shown in Table 3, diarrhea is associated with colchicine treatment. Diarrhea was more likely to occur in patients taking the high-dose regimen than the low-dose regimen. Severe diarrhea occurred in 19% and vomiting occurred in 17% of patients taking the nonrecommended high-dose colchicine regimen but did not occur in the recommended low-dose colchicine regimen.

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