FDA label 3e806127-4a87-41cc-9b17-a77e20bb2452

5 WARNINGS AND PRECAUTIONS Hypertriglyceridemia and Pancreatitis: WELCHOL can increase TG. Hypertriglyceridemia can cause acute pancreatitis. Monitor lipids, including TG. Instruct patients to discontinue WELCHOL and seek prompt medical attention if the symptoms of acute pancreatitis occur ( 5.1 ). Gastrointestinal Obstruction: Cases of bowel obstruction have occurred. WELCHOL is not recommended in patients with gastroparesis, other gastrointestinal motility disorders, and in those who have had major gastrointestinal tract surgery and who may be at risk for bowel obstruction ( 5.2 ). Vitamin K or Fat-Soluble Vitamin Deficiencies: WELCHOL may decrease absorption of fat-soluble vitamins. Patients with a susceptibility to deficiencies of vitamin K (e.g., patients on warfarin, patients with malabsorption syndromes) or other fat-soluble vitamins may be at increased risk. Patients on oral vitamin supplementation should take their vitamins at least 4 hours prior to WELCHOL ( 5.3 ). Drug Interactions: Due to the potential for decreased absorption of other drugs that have not been tested for interaction, consider administering at least 4 hours prior to WELCHOL ( 5.4 , 7 , 12.3 ). Risks in Patients with Phenylketonuria (PKU): Phenylalanine can be harmful to patients with phenylketonuria. WELCHOL for oral suspension contains 27 mg phenylalanine per 3.75 gram packet ( 5.5 , 11 ). 5.1 Hypertriglyceridemia and Pancreatitis WELCHOL, like other bile acid sequestrants, can increase serum TG concentrations. Hypertriglyceridemia can cause acute pancreatitis. WELCHOL had effects on serum TG (median increase 5% compared to placebo) in trials of patients with primary hyperlipidemia. In trials in patients with type 2 diabetes, greater increases in TG levels occurred when WELCHOL was used as monotherapy (median increase 9.7% compared to placebo) and when WELCHOL was used in combination with pioglitazone (median increase 11% compared to placebo in combination with pioglitazone), sulfonylureas (median increase 18% compared to placebo in combination with sulfonylureas), and insulin (median increase 22% compared to placebo in combination with insulin) [see Adverse Reactions (6.1) ]. Obtain lipid parameters, including TG levels, before starting WELCHOL and periodically thereafter. WELCHOL is contraindicated in patients with TG levels >500 mg/dL or patients with a history of hypertriglyceridemia-induced pancreatitis [see Contraindications (4) ] . Patients with TG levels greater than 300 mg/dL could have greater increases in serum TG levels with WELCHOL and may require additional TG monitoring. Instruct patients to discontinue WELCHOL and seek prompt medical attention if the symptoms of acute pancreatitis occur (e.g., severe abdominal pain with or without nausea and vomiting). Discontinue WELCHOL if TG levels exceed 500 mg/dL [see Adverse Reactions (6.1) ] . 5.2 Gastrointestinal Obstruction Postmarketing cases of bowel obstruction have occurred with WELCHOL [see Adverse Reactions (6.2) ] . Because of its constipating effects, WELCHOL is not recommended in patients with gastroparesis, other gastrointestinal motility disorders, and in those who have had major gastrointestinal tract surgery and who may be at risk for bowel obstruction. WELCHOL is contraindicated in patients with a history of bowel obstruction [see Contraindications (4) ] . Instruct patients to promptly discontinue WELCHOL and seek medical attention if severe abdominal pain or severe constipation occurs. Because of the tablet size, WELCHOL tablets can cause dysphagia or esophageal obstruction. For patients with difficulty swallowing tablets, use WELCHOL for oral suspension. 5.3 Vitamin K or Fat-Soluble Vitamin Deficiencies WELCHOL may decrease the absorption of fat-soluble vitamins A, D, E, and K. Patients with a susceptibility to deficiencies of vitamin K (e.g., patients on warfarin, patients with malabsorption syndromes) or other fat-soluble vitamins may be at increased risk when taking WELCHOL. Patients on oral vitamin supplementation should take their vitamins at least 4 hours prior to WELCHOL [see Drug Interactions (7.1) ]. 5.4 Drug Interactions WELCHOL reduces gastrointestinal absorption of some drugs. Administer drugs with a known interaction at least 4 hours prior to WELCHOL [see Drug Interactions (7) ] . Due to the potential for decreased absorption of other drugs that have not been tested for interaction, especially those with a narrow therapeutic index, consider administering at least 4 hours prior to WELCHOL [see Clinical Pharmacology (12.3) ]. 5.5 Risks in Patients with Phenylketonuria (PKU) Phenylalanine can be harmful to patients with PKU. WELCHOL for oral suspension contains phenylalanine, a component of aspartame. Each 3.75 gram packet contains 27 mg of phenylalanine. Before prescribing WELCHOL for oral suspension to a patient with PKU, consider the combined daily amount of phenylalanine from all sources, including WELCHOL for oral suspension.

6 ADVERSE REACTIONS The following important adverse reactions are described below and elsewhere in the labeling: Hypertriglyceridemia and Pancreatitis [see Warnings and Precautions (5.1) ] Gastrointestinal Obstruction [see Warnings and Precautions (5.2) ] Vitamin K or Fat-Soluble Vitamin Deficiencies [see Warnings and Precautions (5.3) ] In clinical trials, the most common (incidence ≥2% and greater than placebo) adverse reactions with WELCHOL included constipation, dyspepsia, and nausea ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Daiichi Sankyo, Inc. at 1-877-437-7763 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in clinical studies of another drug and may not reflect the rates observed in practice. Primary Hyperlipidemia In 7 double-blind, placebo-controlled clinical trials, 807 patients with primary hyperlipidemia (age range 18-86 years, 50% women, 90% Caucasians, 7% Blacks, 2% Hispanics, 1% Asians) and elevated LDL-C were treated with WELCHOL 1.5 g/day to 4.5 g/day from 4 to 24 weeks (total exposure 199 patient-years). Table 1 Clinical Studies of WELCHOL for Primary Hyperlipidemia: Adverse Reactions Reported in ≥ 2% of Patients and More Commonly than in Placebo WELCHOL N=807 Placebo N=258 Constipation 11.0% 7.0% Dyspepsia 8.3% 3.5% Nausea 4.2% 3.9% Accidental injury 3.7% 2.7% Asthenia 3.6% 1.9% Pharyngitis 3.2% 1.9% Flu syndrome 3.2% 3.1% Rhinitis 3.2% 3.1% Myalgia 2.1% 0.4% Pediatric Patients 10 to 17 Years of Age In an 8-week double-blind, placebo-controlled study, boys and post-menarchal girls, 10 to 17 years of age, with HeFH (n=194), were treated with WELCHOL tablets (1.9-3.8 g, daily) or placebo tablets. Table 2 Clinical Study of WELCHOL for Primary Hyperlipidemia in HeFH Pediatric Patients: Adverse Reactions Reported in ≥2% of Patients and More Commonly than in Placebo WELCHOL N=129 Placebo N=65 Nasopharyngitis 6.2% 4.6% Headache 3.9% 3.1% Fatigue 3.9% 1.5% Creatine Phosphokinase Increase 2.3% 0.0% Rhinitis 2.3% 0.0% Vomiting 2.3% 1.5% The reported adverse reactions during the additional 18-week open-label treatment period with WELCHOL 3.8 g per day were similar to those during the double-blind period and included headache (7.6%), nasopharyngitis (5.4%), upper respiratory tract infection (4.9%), influenza (3.8%), and nausea (3.8%). Type 2 Diabetes Mellitus In 5 add-on combination and 1 monotherapy double-blind, 12- to 26-week, placebo-controlled clinical trials in patients with type 2 diabetes mellitus, 1022 patients were treated with WELCHOL. The mean exposure duration was 20 weeks (total exposure 393 patient-years). Patients were to receive 3.8 grams of WELCHOL per day. The mean age of patients was 55.7 years, 52.8 percent of the population was male and 61.9% were Caucasian, 4.8% were Asian, and 15.9% were Black or African American. At baseline the population had a mean hemoglobin A1c (HbA1c) of 8.2%, and 26% had past medical history suggestive of microvascular complications of diabetes. Table 3 shows adverse reactions associated with the use of WELCHOL in patients with type 2 diabetes. These adverse reactions were not present at baseline, occurred more commonly on WELCHOL than on placebo, and occurred in at least 2% of patients treated with WELCHOL. Table 3 Clinical Studies of WELCHOL for Type 2 Diabetes: Adverse Reactions Reported in ≥2% of Patients and More Commonly than in Placebo WELCHOL N=1022 Placebo N=1010 Constipation 6.5% 2.2% Hypoglycemia 3.4% 3.1% Dyspepsia 2.8% 1.0% Nausea 2.6% 1.6% Hypertension 2.6% 1.9% Back Pain 2.3% 1.3% A total of 5.3% of WELCHOL-treated patients and 3.6% of placebo-treated patients were discontinued from the diabetes trials due to adverse reactions. This difference was driven mostly by gastrointestinal adverse reactions such as abdominal pain and constipation. One patient in the add-on to sulfonylurea trial discontinued due to body rash and mouth blistering that occurred on the first day of dosing of WELCHOL, which may represent a hypersensitivity reaction to WELCHOL. Hypertriglyceridemia Patients with fasting serum TG levels above 500 mg/dL were excluded from the diabetes clinical trials. In the diabetes trials, 1292 (67.7%) patients had baseline fasting serum TG levels less than 200 mg/dL, 426 (22.3%) had baseline fasting serum TG levels between 200 and less than 300 mg/dL, 175 (9.2%) had baseline fasting serum TG levels between 300 and 500 mg/dL, and 16 (0.8%) had fasting serum TG levels greater than or equal to 500 mg/dL. The median baseline fasting TG concentration for the study population was 160 mg/dL; the median post-treatment fasting TG was 180 mg/dL in the WELCHOL group and 162 mg/dL in the placebo group. WELCHOL therapy resulted in a median placebo-corrected increase in serum TG of 9.7% (p=0.03) in the monotherapy study and of 5% (p=0.22), 11% (p<0.001), 18% (p<0.001), and 22% (p<0.001), when added to metformin, pioglitazone, sulfonylureas, and insulin, respectively. In comparison, WELCHOL resulted in a median increase in serum TG of 5% compared to placebo (p=0.42) in a 24-week monotherapy lipid-lowering trial. Fasting TG concentrations ≥500 mg/dL occurred in 0.9% of WELCHOL-treated patients compared to 0.7% of placebo-treated patients in the diabetes trials. Among these patients, the TG concentrations with WELCHOL (median 606 mg/dL; interquartile range 570-794 mg/dL) were similar to that observed with placebo (median 663 mg/dL; interquartile range 542-984 mg/dL). Five (0.6%) patients on WELCHOL and 3 (0.3%) patients on placebo developed TG elevations ≥1000 mg/dL. Cardiovascular Adverse Reactions During the diabetes trials, the incidence of patients with serious adverse reactions involving the cardiovascular system was 2.2% (22/1022) in the WELCHOL group and 1% (10/1010) in the placebo group. These overall rates included disparate events (e.g., myocardial infarction, aortic stenosis, and bradycardia); therefore, the significance of this imbalance is unknown. 6.2 Post-marketing Experience The following additional adverse reactions have been identified during post-approval use of WELCHOL. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse Reactions Resulting from Drug Interactions [see Drug Interactions (7) ]: Increased seizure activity or decreased phenytoin levels in patients receiving phenytoin, reduced International Normalized Ratio (INR) in patients receiving warfarin therapy, and elevated thyroid-stimulating hormone (TSH) in patients receiving thyroid hormone replacement therapy Gastrointestinal : Bowel obstruction (in patients with a history of bowel obstruction or resection), dysphagia or esophageal obstruction (occasionally requiring medical intervention), fecal impaction, pancreatitis, abdominal distension, exacerbation of hemorrhoids, and increased transaminases Laboratory Abnormalities: Hypertriglyceridemia

<table width="75%"><caption>Table 1 Clinical Studies of WELCHOL for Primary Hyperlipidemia: Adverse Reactions Reported in &#x2265; 2% of Patients and More Commonly than in Placebo</caption><col width="40%" align="left" valign="top"/><col width="30%" align="center" valign="top"/><col width="30%" align="center" valign="top"/><thead><tr><th/><th>WELCHOL N=807</th><th>Placebo N=258</th></tr></thead><tbody><tr styleCode="Botrule"><td>Constipation</td><td>11.0%</td><td>7.0%</td></tr><tr styleCode="Botrule"><td>Dyspepsia</td><td>8.3%</td><td>3.5%</td></tr><tr styleCode="Botrule"><td>Nausea</td><td>4.2%</td><td>3.9%</td></tr><tr styleCode="Botrule"><td>Accidental injury</td><td>3.7%</td><td>2.7%</td></tr><tr styleCode="Botrule"><td>Asthenia</td><td>3.6%</td><td>1.9%</td></tr><tr styleCode="Botrule"><td>Pharyngitis</td><td>3.2%</td><td>1.9%</td></tr><tr styleCode="Botrule"><td>Flu syndrome</td><td>3.2%</td><td>3.1%</td></tr><tr styleCode="Botrule"><td>Rhinitis</td><td>3.2%</td><td>3.1%</td></tr><tr><td>Myalgia</td><td>2.1%</td><td>0.4%</td></tr></tbody></table>

<table width="75%"><caption>Table 2 Clinical Study of WELCHOL for Primary Hyperlipidemia in HeFH Pediatric Patients: Adverse Reactions Reported in &#x2265;2% of Patients and More Commonly than in Placebo</caption><col width="40%" align="left" valign="top"/><col width="30%" align="center" valign="top"/><col width="30%" align="center" valign="top"/><thead><tr><th/><th>WELCHOL N=129</th><th>Placebo N=65</th></tr></thead><tbody><tr styleCode="Botrule"><td>Nasopharyngitis</td><td>6.2%</td><td>4.6%</td></tr><tr styleCode="Botrule"><td>Headache</td><td>3.9%</td><td>3.1%</td></tr><tr styleCode="Botrule"><td>Fatigue</td><td>3.9%</td><td>1.5%</td></tr><tr styleCode="Botrule"><td>Creatine Phosphokinase Increase</td><td>2.3%</td><td>0.0%</td></tr><tr styleCode="Botrule"><td>Rhinitis</td><td>2.3%</td><td>0.0%</td></tr><tr><td>Vomiting</td><td>2.3%</td><td>1.5%</td></tr></tbody></table>

<table width="75%"><caption>Table 3 Clinical Studies of WELCHOL for Type 2 Diabetes: Adverse Reactions Reported in &#x2265;2% of Patients and More Commonly than in Placebo</caption><col width="40%" align="left" valign="top"/><col width="30%" align="center" valign="top"/><col width="30%" align="center" valign="top"/><thead><tr><th/><th>WELCHOL N=1022</th><th>Placebo N=1010</th></tr></thead><tbody><tr styleCode="Botrule"><td>Constipation</td><td>6.5%</td><td>2.2%</td></tr><tr styleCode="Botrule"><td>Hypoglycemia</td><td>3.4%</td><td>3.1%</td></tr><tr styleCode="Botrule"><td>Dyspepsia</td><td>2.8%</td><td>1.0%</td></tr><tr styleCode="Botrule"><td>Nausea</td><td>2.6%</td><td>1.6%</td></tr><tr styleCode="Botrule"><td>Hypertension</td><td>2.6%</td><td>1.9%</td></tr><tr><td>Back Pain</td><td>2.3%</td><td>1.3%</td></tr></tbody></table>