FDA label 1ebe06e0-d306-62d2-e063-6394a90a8534

5 WARNINGS AND PRECAUTIONS 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, USP 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 Tablets, USP 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, USP 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 To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals at 1-877-825-3327 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 Tablets, USP 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, USP, 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. 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 adverse reactions occurred in 26% of patients using the recommended dose (1.8 mg over one hour) of Colchicine Tablets, USP 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, USP 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 Tablets, USP regimen. Table 3. Number (%) of Patients with at Least One Drug-Related Treatment- Emergent Adverse Event with an Incidence of ≥2% of Patients in Any Treatment Group MedDRA System Organ Class MedDRA Preferred Term Colchicine Tablets, USP Dose Placebo (N=59) n (%) High (N=52) n (%) Low (N=74) n (%) Number of Patients with at Least One Drug-Related TEAE 40 (77) 27 (37) 16 (27) Gastrointestinal Disorders 40 (77) 19 (26) 12 (20) Diarrhea 40 (77) 17 (23) 8 (14) Nausea 9 (17) 3 (4) 3 (5) Vomiting 9 (17) 0 0 Abdominal Discomfort 0 0 2 (3) General Disorders and Administration Site Conditions 4 (8) 1 (1) 1 (2) Fatigue 2 (4) 1 (1) 1 (2) Metabolic and Nutrition Disorders 0 3 (4) 2 (3) Gout 0 3 (4) 1 (2) Nervous System Disorders 1 (2) 1 (1.4) 2 (3) Headache 1 (2) 1 (1) 2 (3) Respiratory Thoracic Mediastinal Disorders 1 (2) 2 (3) 0 Pharyngolaryngeal Pain 1 (2) 2 (3) 0 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 reported with colchicine. These have been generally reversible upon temporarily interrupting treatment or lowering the dose of colchicine. 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

<table ID="table3" width="90%"><caption>Table 3. Number (%) of Patients with at Least One Drug-Related Treatment- Emergent Adverse Event with an Incidence of &#x2265;2% of Patients in Any Treatment Group</caption><col width="52%" align="left" valign="top"/><col width="16%" align="center" valign="top"/><col width="16%" align="center" valign="top"/><col width="16%" align="center" valign="top"/><thead><tr><th align="center" rowspan="2" styleCode="Lrule Rrule" valign="bottom">MedDRA System Organ Class MedDRA Preferred Term </th><th align="center" colspan="2" styleCode="Rrule Botrule">Colchicine Tablets, USP Dose</th><th rowspan="2" styleCode="Rrule" valign="bottom">Placebo (N=59) n (%) </th></tr><tr><th align="center" styleCode="Rrule">High (N=52) n (%) </th><th align="center" styleCode="Rrule">Low (N=74) n (%) </th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Number of Patients with at Least One Drug-Related TEAE</td><td styleCode="Rrule">40 (77)</td><td styleCode="Rrule">27 (37)</td><td styleCode="Rrule">16 (27)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Gastrointestinal Disorders</td><td styleCode="Rrule">40 (77)</td><td styleCode="Rrule">19 (26)</td><td styleCode="Rrule">12 (20)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Diarrhea</td><td styleCode="Rrule">40 (77)</td><td styleCode="Rrule">17 (23)</td><td styleCode="Rrule">8 (14)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Nausea</td><td styleCode="Rrule">9 (17)</td><td styleCode="Rrule">3 (4)</td><td styleCode="Rrule">3 (5)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Vomiting</td><td styleCode="Rrule">9 (17)</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Abdominal Discomfort</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td><td styleCode="Rrule">2 (3)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">General Disorders and Administration Site Conditions</td><td styleCode="Rrule">4 (8)</td><td styleCode="Rrule">1 (1)</td><td styleCode="Rrule">1 (2)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Fatigue</td><td styleCode="Rrule">2 (4)</td><td styleCode="Rrule">1 (1)</td><td styleCode="Rrule">1 (2)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Metabolic and Nutrition Disorders </td><td styleCode="Rrule">0</td><td styleCode="Rrule">3 (4)</td><td styleCode="Rrule">2 (3)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Gout</td><td styleCode="Rrule">0</td><td styleCode="Rrule">3 (4)</td><td styleCode="Rrule">1 (2)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nervous System Disorders</td><td styleCode="Rrule">1 (2)</td><td styleCode="Rrule">1 (1.4)</td><td styleCode="Rrule">2 (3)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Headache</td><td styleCode="Rrule">1 (2)</td><td styleCode="Rrule">1 (1)</td><td styleCode="Rrule">2 (3)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Respiratory Thoracic Mediastinal Disorders</td><td styleCode="Rrule">1 (2)</td><td styleCode="Rrule">2 (3)</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Pharyngolaryngeal Pain</td><td styleCode="Rrule">1 (2)</td><td styleCode="Rrule">2 (3)</td><td styleCode="Rrule">0</td></tr></tbody></table>