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12.1 Mechanism of Action The mechanism by which colchicine tablets exert its beneficial effect in patients with FMF has not been fully elucidated; however, evidence suggests that colchicine may interfere with the intracellular assembly of the inflammasome complex present in neutrophils and monocytes that mediates activation of interleukin-1β. Additionally, colchicine disrupts cytoskeletal functions through inhibition of β-tubulin polymerization into microtubules and consequently prevents the activation, degranulation and migration of neutrophils thought to mediate some gout symptoms.

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 ( Error! Hyperlink reference not valid. ). 1.1 Gout Flares Colchicine tablets are indicated for prophylaxis and the treatment of acute gout flares. • Prophylaxis of Gout Flares: Colchicine tablets are 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. 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 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 Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. ] . 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. • Gout Flares: Prophylaxis of Gout Flares: 0.6 mg once or twice daily in adults and adolescents older than 16 years of age ( Error! Hyperlink reference not valid. ). 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 ( Error! Hyperlink reference not valid. ). • 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 ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. ). o Give total daily dose in one or two divided doses ( Error! Hyperlink reference not valid. ). o 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 ( Error! Hyperlink reference not valid. ). • Colchicine tablets are administered orally without regard to meals. • See full prescribing information (FPI) for dose adjustment regarding patients with impaired renal function ( Error! Hyperlink reference not valid. ), impaired hepatic function ( Error! Hyperlink reference not valid. ), the patient’s age ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. ) or use of coadministered drugs ( Error! Hyperlink reference not valid. ). 2.1 Gout Flares 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....

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 reported in the clinical trial with colchicine tablets 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. • 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 reported in the clinical trial for gout were diarrhea (23%) and pharyngolaryngeal pain (3%). • FMF: Most common (up to 20%) are abdominal pain, diarrhea, nausea and vomiting. These effects are usually mild, transient and reversible upon lowering the dose ( Error! Hyperlink reference not valid. ). To report SUSPECTED , contact Dr. Reddy’s Laboratories Inc., at 1-888- 375-3784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience in Gout 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 occurred in 26% of patients using the recommended dose (1.8 mg over one hour) of colchicine tablets 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 tablets treatment. Diarrhea was more likely to occur in patients taking the high-dose regimen than the low-dose regimen....

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 ( Error! Hyperlink reference not valid. ). In these patients, life-threatening and fatal colchicine toxicity has been reported with colchicine taken in therapeutic doses ( Error! Hyperlink reference not valid. ).