ADVERSE REACTIONS SECTION.

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 or Fat-Soluble Vitamin Deficiencies [see Warnings and Precautions (5.3)] Hypertriglyceridemia and Pancreatitis [see Warnings and Precautions (5.1)] Gastrointestinal Obstruction [see Warnings and Precautions (5.2)] Vitamin 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 colesevelam hydrochloride included constipation, dyspepsia, and nausea 6.1). To report SUSPECTED ADVERSE REACTIONS, contact Tris Pharma, Inc., at 732-940-0358 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 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 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 colesevelam hydrochloride 1.5 g/day to 4.5 g/day from to 24 weeks (total exposure 199 patient-years).Table Clinical Studies of Colesevelam Hydrochloride for Primary Hyperlipidemia: Adverse Reactions Reported in >= 2% of Patients and More Commonly than in PlaceboColesevelam Hydrochloride = 807 Placebo = 258 Constipation11.0%7.0%Dyspepsia8.3%3.5%Nausea4.2%3.9%Accidental injury3.7%2.7%Asthenia3.6%1.9%Pharyngitis3.2%1.9%Flu syndrome3.2%3.1%Rhinitis3.2%3.1%Myalgia2.1%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 colesevelam hydrochloride tablets (1.9-3.8 g, daily) or placebo tablets.Table Clinical Study of Colesevelam Hydrochloride for Primary Hyperlipidemia in HeFH Pediatric Patients: Adverse Reactions Reported in >=2% of Patients and More Commonly than in PlaceboColesevelam Hydrochloride = 129 Placebo = 65 Nasopharyngitis6.2%4.6%Headache3.9%3.1%Fatigue3.9%1.5%Creatine Phosphokinase Increase2.3%0.0%Rhinitis2.3%0.0%Vomiting2.3%1.5%The reported adverse reactions during the additional 18-week open-label treatment period with colesevelam hydrochloride 3.8 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%).. 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 population of uncertain size, it is generally not possible to reliably estimate their frequency or establish 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 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.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenesis 104-week carcinogenicity study with colesevelam hydrochloride was conducted in CD-1 mice, at oral dietary doses up to g/kg/day. This dose was approximately 50 times the maximum recommended human dose of 4.5 g/day, based on body weight, mg/kg. There were no significant drug-induced tumor findings in male or female mice. In 104-week carcinogenicity study with colesevelam hydrochloride in Harlan Sprague-Dawley rats, statistically significant increase in the incidence of pancreatic acinar cell adenoma was seen in male rats at doses >1.2 g/kg/day (approximately 20 times the maximum human dose, based on body weight, mg/kg) (trend test only). statistically significant increase in thyroid C-cell adenoma was seen in female rats at 2.4 g/kg/day (approximately 40 times the maximum human dose, based on body weight, mg/kg).Mutagenesis Colesevelam hydrochloride and degradants present in the drug substance have been evaluated for mutagenicity in the Ames test and mammalian chromosomal aberration test. The degradants and an extract of the parent compound did not exhibit genetic toxicity in an in vitro bacterial mutagenesis assay in S. typhimurium and E. coli (Ames assay) with or without rat liver metabolic activation. An extract of the parent compound was positive in the Chinese Hamster Ovary (CHO) cell chromosomal aberration assay in the presence of metabolic activation and negative in the absence of metabolic activation. The results of the CHO cell chromosomal aberration assay with of the degradants, decylamine HCl and aminohexyltrimethyl ammonium chloride HCl, were equivocal in the absence of metabolic activation and negative in the presence of metabolic activation. The other degradants, didecylamine HCl and 6-decylamino-hexyltrimethyl ammonium chloride HCl, were negative in the presence and absence of metabolic activation. Impairment of FertilityColesevelam hydrochloride did not impair fertility in rats at doses up to g/kg/day (approximately 50 times the maximum human dose, based on body weight, mg/kg).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Primary Hyperlipidemia: Colesevelam hydrochloride, the active pharmaceutical ingredient in colesevelam hydrochloride, is non-absorbed, lipid-lowering polymer that binds bile acids in the intestine, impeding their reabsorption. As the bile acid pool becomes depleted, the hepatic enzyme, cholesterol 7--hydroxylase, is upregulated, which increases the conversion of cholesterol to bile acids. This causes an increased demand for cholesterol in the liver cells, resulting in the dual effect of increasing transcription and activity of the cholesterol biosynthetic enzyme, HMG-CoA reductase, and increasing the number of hepatic LDL receptors. These compensatory effects result in increased clearance of LDL-C from the blood, resulting in decreased serum LDL-C levels. Serum TG levels may increase or remain unchanged. 12.2 Pharmacodynamics. maximum therapeutic response to the lipid-lowering effects of colesevelam hydrochloride was achieved within weeks and was maintained during long-term therapy. 12.3 Pharmacokinetics. Absorption Colesevelam hydrochloride is hydrophilic, water-insoluble polymer that is not hydrolyzed by digestive enzymes and is not absorbed.Distribution Colesevelam hydrochloride is not absorbed, and therefore, its distribution is limited to the gastrointestinal tract.EliminationMetabolismColesevelam hydrochloride is not metabolized systemically and does not interfere with systemic drug-metabolizing enzymes such as cytochrome P-450.Excretion: In 16 healthy volunteers, an average of 0.05% of administered radioactivity from single 14C-labeled colesevelam hydrochloride dose was excreted in the urine. Drug Interaction Studies Drug interactions between colesevelam and concomitantly administered drugs were screened through in vitro studies and confirmed in in vivo studies. In vitro studies demonstrated that cephalexin, metformin, and ciprofloxacin had negligible binding to colesevelam hydrochloride. Therefore, an in vivo pharmacokinetic interaction of colesevelam hydrochloride with these drugs is unlikely. Colesevelam hydrochloride was found to have no significant effect on the bioavailability of aspirin, atenolol, digoxin, enalapril, fenofibrate, lovastatin, metoprolol, phenytoin, pioglitazone, quinidine, rosiglitazone, sitagliptin, valproic acid, and warfarin. The results of additional in vivo drug interactions of colesevelam hydrochloride are presented in Table 6. DrugDoseCo-administered1 hr prior to Colesevelam Hydrochloride4 hr prior to Colesevelam HydrochlorideAUC 0- max AUC 0- max AUC 0- max Table Mean Change in Drug Exposure (AUC0- and max) when Administered with Colesevelam Hydrochloride (3.75 g) Cyclosporine200 mg-34%-44%N/AN/AN/AN/AEthinyl Estradiol 0.035 mg-24%-24%-18%-1%-12%0%Glimepiride4 mg-18%-8%N/AN/A-6%3%Glipizide20 mg-12%-13%N/AN/A-4%0%Glyburide3 mg-32%-47%-20%-15%-7%4%Levothyroxine600 ug-22%-33%6%-2%1%8%Metformin ER1500 mg44%8%N/AN/AN/AN/ANorethindrone 1 mg-1%-20%5%-3%6%7%Olmesartan Medoxomil40 mg -39%-28%N/AN/A-15%-4%Repaglinide2 mg-7%-19%-6%-1%N/AN/AVerapamil sustained-release240 mg-31%-11%N/AN/AN/AN/A With verapamil, the dose of colesevelam hydrochloride was 4.5 + Oral contraceptive containing norethindrone and ethinyl estradiolN/A Not Available.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Primary Hyperlipidemia. Colesevelam hydrochloride reduces total cholesterol (TC), LDL-C, apolipoprotein (Apo B), and non-high-density lipoprotein cholesterol (non-HDL-C) when administered alone or in combination with statin in patients with primary hyperlipidemia.Approximately 1600 patients were studied in clinical trials with treatment durations ranging from to 50 weeks. With the exception of one open-label, uncontrolled, long-term extension study, all studies were multicenter, randomized, double-blind, and placebo-controlled. maximum therapeutic response to colesevelam hydrochloride was achieved within weeks and was maintained during long-term therapy.Monotherapy In study in patients with LDL-C between 130 mg/dL and 220 mg/dL (mean 158 mg/dL), colesevelam hydrochloride was given for 24 weeks in divided doses with the morning and evening meals.As shown in Table 7, the mean LDL-C reductions were 15% and 18% at the 3.8 and 4.5 doses. The respective mean TC reductions were 7% and 10%. The mean Apo reductions were 12% in both treatment groups. Colesevelam hydrochloride at both doses increased HDL-C by 3%. Increases in TG of 9-10% were observed at both colesevelam hydrochloride doses but the changes were not statistically different from placebo.Table Response to Colesevelam Hydrochloride Monotherapy in 24-Week Trial Percent Change in Lipid Parameters from BaselineGrams/DayNTCLDL-CApo BHDL-C Non-HDL-CTG Placebo88+100-1+1+53.8 (6 tablets)95-7 -15 -12 +3 -10 +104.5 (7 tablets)94-10 -18 -12 +3-13 +9 Median change from baseline. p<0.05 for lipid parameters compared to placebo, for Apo compared to baseline.In study in 98 patients with LDL-C between 145 mg/dL and 250 mg/dL (mean 169 mg/dL), colesevelam hydrochloride 3.8 was given for weeks as single dose with breakfast, as single dose with dinner, or as divided doses with breakfast and dinner. The mean LDL-C reductions were 18%, 15%, and 18% for the dosing regimens, respectively. The reductions with these regimens were not statistically different from one another.Combination Therapy Co-administration of colesevelam hydrochloride and statin (atorvastatin, lovastatin, or simvastatin) in clinical studies demonstrated an additive reduction of LDL-C. The mean baseline LDL-C was 184 mg/dL in the atorvastatin study (range 156-236 mg/dL), 171 mg/dL in the lovastatin study (range 115-247 mg/dL), and 188 mg/dL in the simvastatin study (range 148-352 mg/dL). As demonstrated in Table 8, colesevelam hydrochloride doses of 2.3 to 3.8 resulted in an additional 8% to 16% reduction in LDL-C above that seen with the statin alone.Dose/DayNTCLDL-CApo BHDL-C Non-HDL-CTG Table Response to Colesevelam Hydrochloride in Combination with Atorvastatin, Simvastatin, or Lovastatin Percent Change in Lipid ParametersAtorvastatin Trial (4-week)Placebo19+4+3-3+4+4+10Atorvastatin 10 mg18-27 -38 -32 +8-35 -24 Colesevelam Hydrochloride 3.8 g/Atorvastatin 10 mg18-31 -48 -38 +11-40 -1Atorvastatin 80 mg20-39 -53 -46 +6-50 -33 Simvastatin Trial (6-week)Placebo33-2-4-4 -3-2+6 Simvastatin 10 mg35-19 -26 -20 +3 -24 -17 Colesevelam Hydrochloride 3.8 g/Simvastatin 10 mg34-28 -42 -33 +10 -37 -12 Simvastatin 20 mg39-23 -34 -26 +7 -30 -12 Colesevelam Hydrochloride 2.3 g/Simvastatin 20 mg37-29 -42 -32 +4 -37 -12 Lovastatin Trial (4-week)Placebo26+100+1+1+1Lovastatin 10 mg26-14 -22 -16 +5-19 0Colesevelam Hydrochloride 2.3 g/Lovastatin 10 mg Together27-21 -34 -24 +4-27 -1Colesevelam Hydrochloride 2.3 g/Lovastatin 10 mg Apart23-21 -32 -24 +2-28 -2 Median change from baseline. p<0.05 for lipid parameters compared to placebo, for Apo compared to baseline.In all studies, the LDL-C reduction achieved with the combination of colesevelam hydrochloride and any given dose of statin therapy was statistically superior to that achieved with colesevelam hydrochloride or that dose of the statin alone. The LDL-C reduction with atorvastatin 80 mg was not statistically significantly different from the combination of colesevelam hydrochloride 3.8 and atorvastatin 10 mg.Pediatric Therapy The safety and efficacy of colesevelam hydrochloride in pediatric patients were evaluated in an 8-week, multi-center, randomized, double-blind, placebo-controlled, parallel-group study followed by an open-label phase, in 194 boys and postmenarchal girls 10-17 years of age (mean age 14.1 years) with HeFH, taking stable dose of an FDA-approved statin (with LDL-C >130 mg/dL) or naive to lipid-lowering therapy (with LDL-C >160 mg/dL). This study had periods: single-blind, placebo stabilization period; an 8-week, randomized, double-blind, parallel-group, placebo-controlled treatment period; and an 18-week, open-label treatment period. Forty-seven (24%) patients were taking statins and 147 (76%) patients were statin-naive at screening. The mean baseline LDL-C at Day was approximately 199 mg/dL.During the double-blind treatment period, patients were assigned randomly to treatment: colesevelam hydrochloride 3.8 g/day (n=64), colesevelam hydrochloride 1.9 g/day (n=65), or placebo (n=65). In total, 186 patients completed the double-blind treatment period. After weeks of treatment, colesevelam hydrochloride 3.8 g/day significantly decreased plasma levels of LDL-C, non-HDL-C, TC, and Apo and significantly increased HDL-C. moderate, non-statistically significant increase in TG was observed versus placebo (Table 9).Treatment DifferenceTC (N=128) LDL-C (N=128) Apo (N=124) HDL-C (N=128) Non-HDL-C (N=128) TG (N=128) Table Response to Colesevelam Hydrochloride 3.8 Compared to Placebo in Pediatric Patients 10-17 Years of Age Mean Percent Change in Lipid Parameters from Baseline to Week 8Colesevelam Hydrochloride 3.8 vs Placebo-7 -13 -8 +6 -11 +5 For triglycerides, median change from baseline p<=0.05 for lipid parameters compared to placeboValues represent LS mean. Only patients with values at both study baseline and endpoint are included in this table. Study baseline was defined as the last value measured before or on Day prior to the first dose of randomized study medication.Results were based on the ITT population with LOCF.During the open-label treatment period patients were treated with colesevelam hydrochloride 3.8 g/day. In total, 173 (89%) patients completed 26 weeks of treatment. Results at Week 26 were consistent with those at Week 8.

DESCRIPTION SECTION.

11 DESCRIPTION. Colesevelam hydrochloride is non-absorbed, polymeric, lipid-lowering agent for oral administration. Colesevelam hydrochloride is high-capacity bile acid-binding molecule.Colesevelam hydrochloride is poly(allylamine hydrochloride) cross-linked with epichlorohydrin and alkylated with 1-bromodecane and (6-bromohexyl)-trimethylammonium bromide. The chemical name (IUPAC) of colesevelam hydrochloride is allylamine polymer with 1-chloro-2,3-epoxypropane, [6-(allylamino)-hexyl]trimethylammonium chloride and N-allyldecylamine, hydrochloride. The chemical structure of colesevelam hydrochloride is represented by the following formula:wherein (a) represents allyl amine monomer units that have not been alkylated by either of the 1-bromodecane or (6-bromohexyl)-trimethylammonium bromide alkylating agents or cross-linked by epichlorohydrin; (b) represents allyl amine units that have undergone cross-linking with epichlorohydrin; (c) represents allyl amine units that have been alkylated with decyl group; (d) represents allyl amine units that have been alkylated with (6-trimethylammonium) hexyl group, and represents number >= 100 to indicate an extended polymer network. small amount of the amines are dialkylated, and are not depicted in the formula above. No regular order of the groups is implied by the structure; cross-linking and alkylation are expected to occur randomly along the polymer chains. large amount of the amines are protonated. The polymer is depicted in the hydrochloride form; small amount of the halides are bromide. Colesevelam hydrochloride is hydrophilic and insoluble in water.Colesevelam hydrochloride tablets are an off-white, capsule-shaped, film-coated, solid tablet each containing 625 mg colesevelam hydrochloride. In addition, each tablet contains the following inactive ingredients: ammonia, N-butyl alcohol, diacetylated monoglycerides, ferrosoferric oxide, isopropyl alcohol, hypromellose 2910 (5 MPA.S), hypromellose 2910 (15 MPA.S), magnesium stearate, microcrystalline cellulose, propylene glycol, shellac and silicon dioxide.. structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Obtain lipid parameters, including serum triglyceride (TG) levels, before starting colesevelam hydrochloride 2.1) The recommended dosage for adults and children 10 to 17 years old with primary hyperlipidemia is 3.75 grams daily. Colesevelam hydrochloride tablets should be taken as follows 2.2, 2.4): TabletsTake tablets once daily or tablets twice daily with meal and liquid. Obtain lipid parameters, including serum triglyceride (TG) levels, before starting colesevelam hydrochloride 2.1) The recommended dosage for adults and children 10 to 17 years old with primary hyperlipidemia is 3.75 grams daily. Colesevelam hydrochloride tablets should be taken as follows 2.2, 2.4): 2.1 Testing Prior to Initiation of Colesevelam Hydrochloride. Obtain lipid parameters, including triglyceride (TG) levels, before starting colesevelam hydrochloride. Colesevelam hydrochloride is contraindicated in patients with TG levels >500 mg/dL [see Contraindications (4) and Warnings and Precautions (5.1)] . 2.2 Recommended Dosage in PrimaryHyperlipidemia The recommended dosage of colesevelam hydrochloride for adults and children 10 to 17 years old with primary hyperlipidemia is 3.75 grams daily. Colesevelam hydrochloride should be taken as follows:TabletsTake tablets once daily or tablets twice daily. Due to tablet size, colesevelam hydrochloride for oral suspension is recommended for use in the pediatric population.. 2.3 Important Dosing Informationfor Primary Hyperlipidemia. Colesevelam hydrochloride can be dosed at the same time as statin or colesevelam hydrochloride and the statin can be dosed apart Monitor lipid levels within to weeks after initiation of colesevelam hydrochloride. 2.4 Administration Instructions. Tablets:Take colesevelam hydrochloride tablets with meal and liquid. For patients with difficulty swallowing tablets use colesevelam hydrochloride for oral suspension [see Warnings and Precautions (5.2)].

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Concomitant use with colesevelam hydrochloride may decrease the exposure of the following drugs: Drugs with narrow therapeutic index (e.g., cyclosporine), phenytoin, thyroid hormone replacement therapy, warfarin, oral contraceptives containing ethinyl estradiol and norethindrone, olmesartan medoxomil, and sulfonylureas (glimepiride, glipizide, glyburide). Administer these drugs hours prior to colesevelam hydrochloride. For patients on warfarin, monitor International Normalized Ratio (INR) frequently during initiation then periodically 7.1). Concomitant use with colesevelam hydrochloride may increase the exposure of the following drugs: Metformin extended release. Monitor patients glycemic control 7.2). 7.1 Colesevelam hydrochloride DrugInteractions that Decrease the Exposure of the Concomitant Medication. Table includes list of drugs that decrease exposure of the concomitant medication when administered concomitantly with colesevelam hydrochloride and instructions for preventing or managing them.Table Colesevelam Hydrochloride Drug Interactions that Decrease the Exposure of the Concomitant Medication Drugs with Narrow Therapeutic Index Clinical Impact:Concomitant use with colesevelam hydrochloride may decrease the exposure of the narrow therapeutic index drug. In vivo drug interactions studies showed decrease in exposure of cyclosporine when coadministered with colesevelam hydrochloride [see Clinical Pharmacology (12.3)]. Intervention:Administer the narrow therapeutic index drug at least hours prior to colesevelam hydrochloride. Monitor drug levels when appropriate.Examples:CyclosporinePhenytoinClinical Impact:There have been postmarketing reports of increased seizure activity or decreased phenytoin levels in patients receiving phenytoin [see Adverse Reactions (6.2)]. Intervention:Administer phenytoin hours prior to colesevelam hydrochloride.Thyroid Hormone Replacement TherapyClinical Impact:In vivo drug interactions studies showed decrease in exposure of levothyroxine when coadministered with colesevelam hydrochloride [see Clinical Pharmacology (12.3)]. There have been postmarketing reports of elevated thyroid-stimulating hormone (TSH) in patients receiving thyroid hormone replacement therapy [see Adverse Reactions (6.2)]. Intervention:Administer thyroid hormone replacement therapy hours prior to colesevelam hydrochloride.WarfarinClinical Impact:There have been postmarketing reports of reduced INR in patients receiving warfarin therapy [see Adverse Reactions (6.2)]. Intervention:Monitor INR frequently during colesevelam hydrochloride initiation then periodically thereafter.Oral Contraceptives Containing Ethinyl Estradiol and NorethindroneClinical Impact:In vivo drug interactions studies showed decrease in exposure of ethinyl estradiol and norethindrone when coadministered with colesevelam hydrochloride [see Clinical Pharmacology (12.3)]. Intervention:Administer oral contraceptives containing ethinyl estradiol and norethindrone hours prior to colesevelam hydrochloride.Olmesartan MedoxomilClinical Impact:In vivo drug interactions studies showed decrease in olmesartan medoxomil when coadministered with colesevelam hydrochloride [see Clinical Pharmacology (12.3)]. Intervention:Administer olmesartan medoxomil hours prior to colesevelam hydrochloride.Sulfonylureas Clinical Impact:In vivo drug interactions studies showed decrease in sulfonylureas when coadministered with colesevelam hydrochloride [see Clinical Pharmacology (12.3)]. Intervention:Administer sulfonylureas hours prior to colesevelam hydrochloride.Examples:Glimepiride, glipizide, and glyburideOral Vitamin SupplementsClinical Impact:Colesevelam hydrochloride may decrease the absorption of fat-soluble vitamins A, D, E, and [see Warnings and Precautions (5.3)]. Intervention:Patients on oral vitamin supplementation should take their vitamins at least hours prior to colesevelam hydrochloride.. 7.2 Colesevelam Hydrochloride DrugInteractions that Increase the Exposure of the Concomitant Medication. Table Colesevelam Hydrochloride Drug Interactions that Increase the Exposure of the Concomitant Medication Metformin Extended-Release (ER) Clinical Impact: In vivo drug interactions studies showed an increase in metformin extended release (ER) when coadministered with colesevelam hydrochloride [see Clinical Pharmacology (12.3)]. Intervention: Monitor patients glycemic control.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Colesevelam hydrochloride is bile acid sequestrant indicated as an adjunct to diet and exercise to: reduce elevated low-density lipoprotein cholesterol (LDL-C) in adults with primary hyperlipidemia 1.1). reduce LDL-C levels in boys and postmenarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia (HeFH) 1.1). Limitations of Use 1.3): Do not use for treatment of type diabetes or for diabetic ketoacidosis. The effect on cardiovascular morbidity and mortality has not been determined. Not studied in type diabetes with dipeptidyl peptidase inhibitor. Not studied in Fredrickson Type I, III, IV, and dyslipidemias. Not studied in children less than 10 years of age or in pre-menarchal girls. reduce elevated low-density lipoprotein cholesterol (LDL-C) in adults with primary hyperlipidemia 1.1). reduce LDL-C levels in boys and postmenarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia (HeFH) 1.1). Do not use for treatment of type diabetes or for diabetic ketoacidosis. The effect on cardiovascular morbidity and mortality has not been determined. Not studied in type diabetes with dipeptidyl peptidase inhibitor. Not studied in Fredrickson Type I, III, IV, and dyslipidemias. Not studied in children less than 10 years of age or in pre-menarchal girls. 1.1 Primary Hyperlipidemia. Colesevelam hydrochloride is indicated as an adjunct to diet and exercise to reduce elevated low-density lipoprotein cholesterol (LDL-C) in adults with primary hyperlipidemia. Colesevelam hydrochloride is indicated to reduce LDL-C levels in boys and postmenarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia (HeFH) who are unable to reach LDL-C target levels despite an adequate trial of dietary therapy and lifestyle modification.. 1.3 Limitations of Use. Colesevelam hydrochloride should not be used for the treatment of type diabetes or for the treatment of diabetic ketoacidosis. The effect of colesevelam hydrochloride on cardiovascular morbidity and mortality has not been determined. Colesevelam hydrochloride has not been studied in type diabetes in combination with dipeptidyl peptidase inhibitor. Colesevelam hydrochloride has not been studied in Fredrickson Type I, III, IV, and dyslipidemias. Colesevelam hydrochloride has not been studied in children younger than 10 years of age or in pre-menarchal girls. Colesevelam hydrochloride should not be used for the treatment of type diabetes or for the treatment of diabetic ketoacidosis. The effect of colesevelam hydrochloride on cardiovascular morbidity and mortality has not been determined. Colesevelam hydrochloride has not been studied in type diabetes in combination with dipeptidyl peptidase inhibitor. Colesevelam hydrochloride has not been studied in Fredrickson Type I, III, IV, and dyslipidemias. Colesevelam hydrochloride has not been studied in children younger than 10 years of age or in pre-menarchal girls.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Hypertriglyceridemia and Pancreatitis Inform patients that colesevelam hydrochloride may increase their serum triglycerides which can lead to hypertriglyceridemia and pancreatitis. Instruct patients to discontinue colesevelam hydrochloride and seek prompt medical attention if the symptoms of acute pancreatitis occur (e.g., severe abdominal pain with or without nausea and vomiting) [see Warnings and Precautions (5.1)]. Gastrointestinal Inform patients that colesevelam hydrochloride may cause bowel obstruction. Instruct patients to promptly discontinue colesevelam hydrochloride and seek medical attention if severe abdominal pain or severe constipation occurs [see Warnings and Precautions (5.2)]. Drug and Vitamin interactions: Advise patients that colesevelam hydrochloride has drug interactions and colesevelam hydrochloride may decrease the absorption of fat-soluble vitamins A, D, E, and K. Instruct patients to take oral vitamins at least hours prior to colesevelam hydrochloride. Instruct patients to inform their physician about all the drugs and vitamins that they are prescribed or take over the counter [see Warnings and Precautions (5.3) and Drug Interactions (7)]. Administration [see Dosage and Administration (2.4)]: Tablets:Advise patients to take colesevelam hydrochloride tablets with meal and liquid. Inform patients that colesevelam hydrochloride tablets can be taken as tablets once daily or tablets twice daily.Females of Reproductive PotentialAdvise females of reproductive potential that colesevelam hydrochloride may reduce the effectiveness of oral contraceptives, and to take oral contraceptives at least hours before taking colesevelam hydrochloride [see Drug Interactions (7) and Use in Specific Populations (8.3)]. Manufactured by:Zhejiang Jingxin Pharmaceutical Co., Ltd.No. 800 Xinchang East RoadZhejiang Province, P.R. ChinaFor: Tris Pharma, Inc.Monmouth Junction, NJ 08852 USAwww.trispharma.comRevised: May 2020Marketed/Packaged by: GSMS, Inc. Camarillo, CA USA 93012.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenesis 104-week carcinogenicity study with colesevelam hydrochloride was conducted in CD-1 mice, at oral dietary doses up to g/kg/day. This dose was approximately 50 times the maximum recommended human dose of 4.5 g/day, based on body weight, mg/kg. There were no significant drug-induced tumor findings in male or female mice. In 104-week carcinogenicity study with colesevelam hydrochloride in Harlan Sprague-Dawley rats, statistically significant increase in the incidence of pancreatic acinar cell adenoma was seen in male rats at doses >1.2 g/kg/day (approximately 20 times the maximum human dose, based on body weight, mg/kg) (trend test only). statistically significant increase in thyroid C-cell adenoma was seen in female rats at 2.4 g/kg/day (approximately 40 times the maximum human dose, based on body weight, mg/kg).Mutagenesis Colesevelam hydrochloride and degradants present in the drug substance have been evaluated for mutagenicity in the Ames test and mammalian chromosomal aberration test. The degradants and an extract of the parent compound did not exhibit genetic toxicity in an in vitro bacterial mutagenesis assay in S. typhimurium and E. coli (Ames assay) with or without rat liver metabolic activation. An extract of the parent compound was positive in the Chinese Hamster Ovary (CHO) cell chromosomal aberration assay in the presence of metabolic activation and negative in the absence of metabolic activation. The results of the CHO cell chromosomal aberration assay with of the degradants, decylamine HCl and aminohexyltrimethyl ammonium chloride HCl, were equivocal in the absence of metabolic activation and negative in the presence of metabolic activation. The other degradants, didecylamine HCl and 6-decylamino-hexyltrimethyl ammonium chloride HCl, were negative in the presence and absence of metabolic activation. Impairment of FertilityColesevelam hydrochloride did not impair fertility in rats at doses up to g/kg/day (approximately 50 times the maximum human dose, based on body weight, mg/kg).. 13.2 Animal Toxicology and/or Pharmacology. Reproductive Toxicology StudiesReproduction studies have been performed in rats and rabbits at doses up to g/kg/day and g/kg/day, respectively (approximately 50 and 17 times the maximum human dose, based on body weight, mg/kg) and have revealed no evidence of harm to the fetus due to colesevelam hydrochloride.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryColesevelam hydrochloride is not absorbed systemically following oral administration, and maternal use is not expected to result in fetal exposure to the drug. Limited available data on the use of colesevelam hydrochloride are insufficient to determine drug-associated risk of major congenital malformations or miscarriage. In animal reproduction studies, no evidence of either maternal or fetal toxicity was found in rats or rabbits exposed to colesevelam hydrochloride during the period of fetal organogenesis at and times, respectively, the maximum recommended human dose (MRHD) of 3.75 g/day, based on body surface area (mg/m 2). No adverse effects on offspring survival and development were observed in rats administered times the MRHD (see Data). Colesevelam hydrochloride may decrease the absorption of fat-soluble vitamins [see Warnings and Precautions (5.3)]. There are no data available on the effect of colesevelam hydrochloride on the absorption of fat-soluble vitamins in pregnant women. If the patient becomes pregnant while taking colesevelam hydrochloride, the patient should be advised of the lack of known clinical benefit with continued use during pregnancy. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.DataHuman DataThere are no adequate and well-controlled studies of colesevelam hydrochloride use in pregnant women. In the postmarketing setting there have been infrequent reports of pregnancy with use of colesevelam hydrochloride and causal association with congenital anomalies has not been established.Animal DataIn pregnant rats given dietary doses of 0.3, 1.0, 3.0 g/kg/day colesevelam hydrochloride from gestation days through 17, no teratogenic effects were observed. Exposures at 3.0 g/kg/day were times the human exposure at 3.75 g/day MRHD, based on body surface area (mg/m 2). In pregnant rabbits given oral gavage doses of 0.1, 0.5, 1.0 g/kg/day colesevelam hydrochloride from gestation days through 18, no teratogenic effects were observed. Exposures at 1.0 g/kg/day were times the human exposure at 3.75 g/day MRHD, based on body surface area (mg/m 2). In pregnant rats given oral gavage doses of 0.1, 0.3, 1.0 g/kg/day colesevelam hydrochloride from gestation day through lactation day 21 (weaning), no adverse effects on survival and development were observed. Exposures at 1.0 g/kg/day were times the human exposure at 3.75 g/day MRHD, based on body surface area (mg/m 2).

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryColesevelam hydrochloride is not absorbed systemically following oral administration, and maternal use is not expected to result in fetal exposure to the drug. Limited available data on the use of colesevelam hydrochloride are insufficient to determine drug-associated risk of major congenital malformations or miscarriage. In animal reproduction studies, no evidence of either maternal or fetal toxicity was found in rats or rabbits exposed to colesevelam hydrochloride during the period of fetal organogenesis at and times, respectively, the maximum recommended human dose (MRHD) of 3.75 g/day, based on body surface area (mg/m 2). No adverse effects on offspring survival and development were observed in rats administered times the MRHD (see Data). Colesevelam hydrochloride may decrease the absorption of fat-soluble vitamins [see Warnings and Precautions (5.3)]. There are no data available on the effect of colesevelam hydrochloride on the absorption of fat-soluble vitamins in pregnant women. If the patient becomes pregnant while taking colesevelam hydrochloride, the patient should be advised of the lack of known clinical benefit with continued use during pregnancy. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.DataHuman DataThere are no adequate and well-controlled studies of colesevelam hydrochloride use in pregnant women. In the postmarketing setting there have been infrequent reports of pregnancy with use of colesevelam hydrochloride and causal association with congenital anomalies has not been established.Animal DataIn pregnant rats given dietary doses of 0.3, 1.0, 3.0 g/kg/day colesevelam hydrochloride from gestation days through 17, no teratogenic effects were observed. Exposures at 3.0 g/kg/day were times the human exposure at 3.75 g/day MRHD, based on body surface area (mg/m 2). In pregnant rabbits given oral gavage doses of 0.1, 0.5, 1.0 g/kg/day colesevelam hydrochloride from gestation days through 18, no teratogenic effects were observed. Exposures at 1.0 g/kg/day were times the human exposure at 3.75 g/day MRHD, based on body surface area (mg/m 2). In pregnant rats given oral gavage doses of 0.1, 0.3, 1.0 g/kg/day colesevelam hydrochloride from gestation day through lactation day 21 (weaning), no adverse effects on survival and development were observed. Exposures at 1.0 g/kg/day were times the human exposure at 3.75 g/day MRHD, based on body surface area (mg/m 2). 8.2 Lactation. Risk SummaryColesevelam hydrochloride is not absorbed systemically by the mother following oral administration, and breastfeeding is not expected to result in exposure of the child to colesevelam hydrochloride.. 8.3 Females and Males of Reproductive Potential. ContraceptionUse of colesevelam hydrochloride may reduce the efficacy of oral contraceptives. Advise patients to take oral contraceptives at least hours prior to taking colesevelam hydrochloride [see Drug Interactions (7)]. 8.4 Pediatric Use. The safety and effectiveness of colesevelam hydrochloride as monotherapy or in combination with statin were evaluated in children, 10 to 17 years of age, with HeFH [see Clinical Studies (14.1)] The adverse reaction profile was similar to that of patients treated with placebo. In this limited controlled study, there were no significant effects on growth, sexual maturation, fat-soluble vitamin levels or clotting factors in the adolescent boys or girls relative to placebo [see Adverse Reactions (6.1) ]. Due to tablet size, colesevelam hydrochloride for oral suspension is recommended for use in the pediatric population. Dose adjustments are not required when colesevelam hydrochloride is administered to children 10 to 17 years of age.Colesevelam hydrochloride has not been studied in children younger than 10 years of age or in pre-menarchal girls.. 8.5 Geriatric Use. Primary Hyperlipidemia Of the 1350 patients enrolled in the hyperlipidemia clinical studies, 349 (26%) were >=65 years old, and 58 (4%) were >=75 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Hypertriglyceridemia and Pancreatitis: Colesevelam hydrochloride can increase TG. Hypertriglyceridemia can cause acute pancreatitis. Monitor lipids, including TG. Instruct patients to discontinue colesevelam hydrochloride and seek prompt medical attention if the symptoms of acute pancreatitis occur 5.1). Gastrointestinal Obstruction: Cases of bowel obstruction have occurred. 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 5.2). Vitamin or Fat-Soluble Vitamin Deficiencies: Colesevelam hydrochloride may decrease absorption of fat-soluble vitamins. Patients with susceptibility to deficiencies of vitamin (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 hours prior to colesevelam hydrochloride 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 hours prior to colesevelam hydrochloride 5.4, 7, 12.3). Hypertriglyceridemia and Pancreatitis: Colesevelam hydrochloride can increase TG. Hypertriglyceridemia can cause acute pancreatitis. Monitor lipids, including TG. Instruct patients to discontinue colesevelam hydrochloride and seek prompt medical attention if the symptoms of acute pancreatitis occur 5.1). Gastrointestinal Obstruction: Cases of bowel obstruction have occurred. 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 5.2). Vitamin or Fat-Soluble Vitamin Deficiencies: Colesevelam hydrochloride may decrease absorption of fat-soluble vitamins. Patients with susceptibility to deficiencies of vitamin (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 hours prior to colesevelam hydrochloride 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 hours prior to colesevelam hydrochloride 5.4, 7, 12.3). 5.1 Hypertriglyceridemia andPancreatitis. Colesevelam hydrochloride, like other bile acid sequestrants, can increase serum TG concentrations. Hypertriglyceridemia can cause acute pancreatitis.Colesevelam hydrochloride had effects on serum TG (median increase 5% compared to placebo) in trials of patients with primary hyperlipidemia.Obtain lipid parameters, including TG levels, before starting colesevelam hydrochloride and periodically thereafter. Colesevelam hydrochloride is contraindicated in patients with TG levels >500 mg/dL or patients with 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 colesevelam hydrochloride and may require additional TG monitoring. Instruct patients to discontinue colesevelam hydrochloride and seek prompt medical attention if the symptoms of acute pancreatitis occur (e.g., severe abdominal pain with or without nausea and vomiting). Discontinue colesevelam hydrochloride if TG levels exceed 500 mg/dL [see Adverse Reactions (6.1)] . 5.2 Gastrointestinal Obstruction. Postmarketing cases of bowel obstruction have occurred with colesevelam hydrochloride [see Adverse Reactions (6.2)] 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. Colesevelam hydrochloride is contraindicated in patients with history of bowel obstruction [see Contraindications (4)] Instruct patients to promptly discontinue colesevelam hydrochloride and seek medical attention if severe abdominal pain or severe constipation occurs. Because of the tablet size, colesevelam hydrochloride tablets can cause dysphagia or esophageal obstruction. For patients with difficulty swallowing tablets use colesevelam hydrochloride for oral suspension.. 5.3 Vitamin or Fat-SolubleVitamin Deficiencies. Colesevelam hydrochloride may decrease the absorption of fat-soluble vitamins A, D, E, and K. Patients with susceptibility to deficiencies of vitamin (e.g., patients on warfarin, patients with malabsorption syndromes) or other fat-soluble vitamins may be at increased risk when taking colesevelam hydrochloride.Patients on oral vitamin supplementation should take their vitamins at least hours prior to colesevelam hydrochloride [see Drug Interactions (7.1)]. 5.4 Drug Interactions. Colesevelam hydrochloride reduces gastrointestinal absorption of some drugs. Administer drugs with known interaction at least hours prior to colesevelam hydrochloride [see Drug Interactions (7)] Due to the potential for decreased absorption of other drugs that have not been tested for interaction, especially those with narrow therapeutic index, consider administering at least hours prior to colesevelam hydrochloride [see Clinical Pharmacology (12.3)]. 5.6 Macrovascular Outcomes. There have been no clinical studies establishing conclusive evidence of macrovascular disease risk reduction with colesevelam hydrochloride.