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warnings and cautions
5 WARNINGS AND PRECAUTIONS The effect of colesevelam hydrochloride on cardiovascular morbidity and mortality has not been determined ( 5.1 ). Colesevelam hydrochloride can increase TG, particularly when used with insulin or sulfonylureas. Marked hypertriglyceridemia can cause acute pancreatitis. The effect of hypertriglyceridemia on the risk of coronary artery disease is uncertain. Monitor lipids, including TG and non-high density lipoprotein cholesterol (non-HDL-C) ( 5.2 ). Bile acid sequestrants may decrease absorption of fat-soluble vitamins. Use caution in patients susceptible to fat-soluble vitamin deficiencies ( 5.3 ). Because of its constipating effects, colesevelam hydrochloride is not recommended in patients at risk of bowel obstruction (e.g., patients with gastroparesis, other gastrointestinal motility disorders or a history of major gastrointestinal surgery) ( 5.4 ). Colesevelam hydrochloride reduces gastrointestinal absorption of some drugs. Administer drugs with a known interaction with colesevelam at least 4 hours prior to colesevelam hydrochloride. Drugs that have not been tested for interaction with colesevelam, especially those with a narrow therapeutic index, should also be administered at least 4 hours prior to colesevelam hydrochloride. Alternatively, monitor drug levels of the co-administered drug. ( 5.5 , 7 , 12.3 ) 5.1 General The effect of colesevelam hydrochloride on cardiovascular morbidity and mortality has not been determined. 5.2 Serum Triglycerides Colesevelam hydrochloride, like other bile acid sequestrants, can increase serum TG concentrations. Colesevelam hydrochloride had small effects on serum TG (median increase 5% compared to placebo) in trials of patients with primary hyperlipidemia [see Adverse Reactions (6.1) and Clinical Studies (14.1) ] . Hypertriglyceridemia of sufficient severity can cause acute pancreatitis. The long-term effect of hypertriglyceridemia on the risk of coronary artery disease is uncertain. Caution should be exercised when treating patients with TG levels greater than 300 mg/dL. Because most patients in the colesevelam hydrochloride clinical trials had baseline TG <300 mg/dL, it is unknown whether patients with more uncontrolled baseline hypertriglyceridemia would have greater increases in serum TG levels with colesevelam hydrochloride. In addition, the use of colesevelam hydrochloride is contraindicated in patients with TG levels >500 mg/dL [see Contraindications (4) ] . Lipid parameters, including TG levels and non-HDL-C, should be obtained before starting colesevelam hydrochloride and periodically thereafter. Colesevelam hydrochloride should be discontinued if TG levels exceed 500 mg/dL or if the patient develops hypertriglyceridemia-induced pancreatitis [see Adverse Reactions (6.1) ] . 5.3 Vitamin K or Fat-Soluble Vitamin Deficiencies Precautions Bile acid sequestrants may decrease the absorption of fat-soluble vitamins A, D, E, and K. No specific clinical studies have been conducted to evaluate the effects of colesevelam hydrochloride on the absorption of co-administered dietary or supplemental vitamin therapy. In nonclinical safety studies, rats administered colesevelam hydrochloride at doses greater than 30-fold the projected human clinical dose experienced hemorrhage from vitamin K deficiency. Patients on oral vitamin supplementation should take their vitamins at least 4 hours prior to colesevelam hydrochloride. Caution should be exercised when treating patients with a susceptibility to deficiencies of vitamin K (e.g., patients on warfarin, patients with malabsorption syndromes) or other fat-soluble vitamins. 5.4 Gastrointestinal Disorders Because of its constipating effects, colesevelam hydrochloride 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. Because of the tablet size, colesevelam hydrochloride tablets can cause dysphagia or esophageal obstruction and should be used with caution in patients with dysphagia or swallowing disorders. 5.5 Drug Interactions Colesevelam hydrochloride reduces gastrointestinal absorption of some drugs. Drugs with a known interaction with colesevelam should be administered at least 4 hours prior to colesevelam hydrochloride. Drugs that have not been tested for interaction with colesevelam, especially those with a narrow therapeutic index, should also be administered at least 4 hours prior to colesevelam hydrochloride. Alternatively, the physician should monitor drug levels of the co-administered drug [see Drug Interactions (7) and Clinical Pharmacology (12.3) ] . 5.7 Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular disease risk reduction with colesevelam hydrochloride or any other antidiabetic drugs.
6 ADVERSE REACTIONS In clinical trials, the most common (incidence ≥2% and greater than placebo) adverse reactions with colesevelam hydrochloride included constipation, dyspepsia, and nausea. Post-marketing reports with concomitant colesevelam hydrochloride administration include: Increased seizure activity or decreased phenytoin levels in patients receiving phenytoin. Administer phenytoin 4 hours prior to colesevelam hydrochloride. Reduced International Normalized Ratio (INR) in patients receiving warfarin. Monitor INR. Elevated thyroid-stimulating hormone (TSH) in patients receiving thyroid hormone replacement therapy. Administer thyroid hormones 4 hours prior to colesevelam hydrochloride. Other post-marketing reports include bowel obstruction, dysphagia, esophageal obstruction, fecal impaction, hypertriglyceridemia, pancreatitis, and increased transaminases ( 5.5 , 6.2 , 7 , 12.3 ). To report SUSPECTED ADVERSE REACTIONS, contact AvKARE, Inc. at 1-855-361-3993; email drugsafety@avkare.com; 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 to 86 years, 50% women, 90% Caucasians, 7% Blacks, 2% Hispanics, 1% Asians) and elevated LDL-C were treated with colesevelam hydrochloride 1.5 g/day to 4.5 g/day from 4 to 24 weeks (total exposure 199 patient-years). In clinical trials for the reduction of LDL-C, 68% of patients receiving colesevelam hydrochloride vs. 64% of patients receiving placebo reported an adverse reaction. Table 1 Placebo-Controlled Clinical Studies of Colesevelam Hydrochloride for Primary Hyperlipidemia: Adverse Reactions Reported in ≥2% of Patients and More Commonly than in Patients Given Placebo, Regardless of Investigator Assessment of Causality Number of Patients (%) Colesevelam Hydrochloride N=807 Placebo N=258 Constipation 89 (11.0) 18 (7.0) Dyspepsia 67 (8.3) 9 (3.5) Nausea 34 (4.2) 10 (3.9) Accidental injury 30 (3.7) 7 (2.7) Asthenia 29 (3.6) 5 (1.9) Pharyngitis 26 (3.2) 5 (1.9) Flu syndrome 26 (3.2) 8 (3.1) Rhinitis 26 (3.2) 8 (3.1) Myalgia 17 (2.1) 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 heterozygous familial hypercholesterolemia (heFH) (n=129), were treated with colesevelam hydrochloride tablets (1.9 to 3.8 g, daily) or placebo tablets [see Clinical Studies (14.1) ] . Table 2 Placebo-Controlled Clinical Study of Colesevelam Hydrochloride for Primary Hyperlipidemia in heFH Pediatric Patients: Adverse Reactions Reported in ≥2% of Patients and More Commonly than in Patients Given Placebo, Regardless of Investigator Assessment of Causality Number of Patients (%) Colesevelam Hydrochloride N=129 Placebo N=65 Nasopharyngitis 8 (6.2) 3 (4.6) Headache 5 (3.9) 2 (3.1) Fatigue 5 (3.9) 1 (1.5) Creatine Phosphokinase Increase 3 (2.3) 0 (0.0) Rhinitis 3 (2.3) 0 (0.0) Vomiting 3 (2.3) 1 (1.5) The reported adverse reactions during the additional 18-week open-label treatment period with colesevelam hydrochloride 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%) [see Clinical Studies (14.1) ] . Hypertriglyceridemia: Colesevelam hydrochloride resulted in a median increase in serum TG of 5% compared to placebo (p=0.42) in a 24-week monotherapy lipid-lowering trial [see Clinical Studies (14.1) ] . 6.2 Post-Marketing Experience The following additional adverse reactions have been identified during post-approval use of colesevelam hydrochloride. 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. Drug Interactions with concomitant colesevelam hydrochloride administration include: Increased seizure activity or decreased phenytoin levels in patients receiving phenytoin. Phenytoin should be administered 4 hours prior to colesevelam hydrochloride. Reduced International Normalized Ratio (INR) in patients receiving warfarin therapy. In warfarin-treated patients, INR should be monitored frequently during colesevelam hydrochloride initiation then periodically thereafter. Elevated thyroid-stimulating hormone (TSH) in patients receiving thyroid hormone replacement therapy. Thyroid hormone replacement should be administered 4 hours prior to colesevelam hydrochloride [see Drug Interactions (7) ] . Gastrointestinal Adverse Reactions 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