Colesevelam hydrochloride

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 colesevelam hydrochloride included constipation, dyspepsia, and nausea ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Nivagen Pharmaceuticals, Inc. at 1-877-977-0687 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 colesevelam hydrochloride 1.5 g/day to 4.5 g/day from 4 to 24 weeks (total exposure 199 patient-years). Table 1 Clinical Studies of Colesevelam Hydrochloride for Primary Hyperlipidemia: Adverse Reactions Reported in ≥ 2% of Patients and More Commonly than in Placebo Colesevelam Hydrochloride 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 colesevelam hydrochloride tablets (1.9-3.8 g, daily) or placebo tablets. Table 2 Clinical Study of Colesevelam Hydrochloride for Primary Hyperlipidemia in HeFH Pediatric Patients: Adverse Reactions Reported in ≥ 2% of Patients and More Commonly than in Placebo Colesevelam Hydrochloride 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 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%). 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 colesevelam hydrochloride. The mean exposure duration was 20 weeks (total exposure 393 patient-years). Patients were to receive 3.8 grams of colesevelam hydrochloride 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 colesevelam hydrochloride in patients with type 2 diabetes. These adverse reactions were not present at baseline, occurred more commonly on colesevelam hydrochloride than on placebo, and occurred in at least 2% of patients treated with colesevelam hydrochloride. Table 3 Clinical Studies of Colesevelam Hydrochloride for Type 2 Diabetes: Adverse Reactions Reported in ≥2% of Patients and More Commonly than in Placebo Colesevelam Hydrochloride 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 colesevelam hydrochloride-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 colesevelam hydrochloride, which may represent a hypersensitivity reaction to colesevelam hydrochloride. 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 colesevelam hydrochloride group and 162 mg/dL in the placebo group. Colesevelam hydrochloride 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, 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. Fasting TG concentrations ≥500 mg/dL occurred in 0.9% of colesevelam hydrochloride-treated patients compared to 0.7% of placebo-treated patients in the diabetes trials. Among these patients, the TG concentrations with colesevelam hydrochloride (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 colesevelam hydrochloride 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 colesevelam hydrochloride 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 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. 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

4 CONTRAINDICATIONS Colesevelam hydrochloride is contraindicated in patients with: • Serum TG concentrations >500 mg/dL [See Warnings and Precautions ( 5.1 )] • History of hypertriglyceridemia-induced pancreatitis [See Warnings and Precautions ( 5.1 )] • A history of bowel obstruction [see Warnings and Precautions ( 5.2 )] • Patients with serum triglyceride levels >500 mg/dL ( 4 ) • Patients with a history of hypertriglyceridemia-induced pancreatitis ( 4 ) • Patients with a history of bowel obstruction ( 4 )

11 DESCRIPTION Colesevelam hydrochloride is a non-absorbed, polymeric, lipid-lowering and glucose-lowering agent for oral administration. Colesevelam hydrochloride is a 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 a decyl group; (d) represents allyl amine units that have been alkylated with a (6-trimethylammonium) hexyl group, and m represents a number ≥ 100 to indicate an extended polymer network. A 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. A large amount of the amines are protonated. The polymer is depicted in the hydrochloride form; a small amount of the halides are bromide. Colesevelam hydrochloride is hydrophilic and insoluble in water. Colesevelam hydrochloride tablets are off-white to light yellow, capsule shaped, coated, tablets each containing 625 mg colesevelam hydrochloride. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, hypromellose 2910, magnesium stearate, microcrystalline cellulose, polyethylene glycol 6000. The tablets are imprinted using a black ink of opacode black S-1-17823 containing ferrosoferric oxide, propylene glycol and shellac. Colesevelam hydrochloride structure

2 DOSAGE AND ADMINISTRATION • Obtain lipid parameters, including serum triglyceride (TG) levels, before starting colesevelam hydrochloride tablets ( 2.1 ). • The recommended dosage for adults and for boys and postmenarchal girls aged 10 to 17 years with primary hyperlipidemia is 3.75 grams daily. The recommended dosage for adults with type 2 diabetes mellitus is 3.75 grams daily. Colesevelam hydrochloride should be taken as follows ( 2.2 , 2.4 ): Tablets Take 6 tablets once daily or 3 tablets twice daily with a meal and liquid. 2.1 Testing Prior to Initiation of Colesevelam Hydrochloride Tablets Obtain lipid parameters, including triglyceride (TG) levels, before starting colesevelam hydrochloride tablets. Colesevelam hydrochloride tablets are contraindicated in patients with TG levels >500 mg/dL [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )] . 2.2 Recommended Dosage in Primary Hyperlipidemia and Type 2 Diabetes Mellitus The recommended dosage of colesevelam hydrochloride tablets for adults and for boys and postmenarchal girls aged 10 to 17 years with primary hyperlipidemia is 3.75 grams daily. The recommended dosage of colesevelam hydrochloride tablets for adults with type 2 diabetes mellitus is 3.75 grams daily. Colesevelam hydrochloride tablets should be taken as follows: Tablets Take 6 tablets once daily or 3 tablets twice daily. Due to tablet size, colesevelam hydrochloride for oral suspension is recommended for use in the pediatric population. 2.3 Important Dosing Information for Primary Hyperlipidemia Colesevelam hydrochloride tablets can be dosed at the same time as a statin, or colesevelam hydrochloride tablets and the statin can be dosed apart. Monitor lipid levels within 4 to 6 weeks after initiation of colesevelam hydrochloride tablets. 2.4 Administration Instructions Tablets Take colesevelam hydrochloride tablets with a meal and liquid. For patients with difficulty swallowing tablets, use colesevelam hydrochloride for oral suspension [see Warnings and Precautions ( 5.2 )] .

1 INDICATIONS AND USAGE Colesevelam hydrochloride is a 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), unable to reach LDL-C target levels despite an adequate trial of diet and lifestyle modification ( 1.1 ). improve glycemic control in adults with type 2 diabetes mellitus ( 1.2 ). Limitations of Use ( 1.3 ): • Do not use for treatment of type 1 diabetes or for diabetic ketoacidosis. • Not studied in Fredrickson Type I, III, IV, and V dyslipidemias 1.1 Primary Hyperlipidemia Colesevelam hydrochloride tablets are indicated as an adjunct to diet and exercise to reduce elevated low-density lipoprotein cholesterol (LDL-C) in adults with primary hyperlipidemia. Colesevelam hydrochloride tablets are 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. 1.2 Type 2 Diabetes Mellitus Colesevelam hydrochloride tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. 1.3 Limitations of Use • Colesevelam hydrochloride should not be used for the treatment of type 1 diabetes or for the treatment of diabetic ketoacidosis. • Colesevelam hydrochloride has not been studied in Fredrickson Type I, III, IV, and V dyslipidemias.

10 OVERDOSAGE Colesevelam hydrochloride is not absorbed and the risk of systemic toxicity is low. Excessive doses of colesevelam hydrochloride may cause more severe local gastrointestinal effects (e.g., constipation).

7 DRUG INTERACTIONS Concomitant use with colesevelam hydrochloride may decrease the exposure of the following drugs : Drugs with a 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 4 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 ). See 17 for PATIENT COUNSELING INFORMATION. 7.1 Colesevelam Hydrochloride Drug Interactions that Decrease the Exposure of the Concomitant Medication Table 4 includes a list of drugs that decrease exposure of the concomitant medication when administered concomitantly with colesevelam hydrochloride and instructions for preventing or managing them. Table 4 Colesevelam Hydrochloride Drug Interactions that Decrease the Exposure of the Concomitant Medication Drugs with a 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 a decrease in exposure of cyclosporine when coadministered with colesevelam hydrochloride [see Clinical Pharmacology ( 12.3 )] . Intervention: Administer the narrow therapeutic index drug at least 4 hours prior to colesevelam hydrochloride. Monitor drug levels when appropriate. Examples: Cyclosporine Phenytoin Clinical 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 4 hours prior to colesevelam hydrochloride. Thyroid Hormone Replacement Therapy Clinical Impact: In vivo drug interactions studies showed a 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 4 hours prior to colesevelam hydrochloride. Warfarin Clinical 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 Norethindrone Clinical Impact: In vivo drug interactions studies showed a 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 4 hours prior to colesevelam hydrochloride. Olmesartan Medoxomil Clinical Impact: In vivo drug interactions studies showed a decrease in olmesartan medoxomil when coadministered with colesevelam hydrochloride [see Clinical Pharmacology ( 12.3 )] . Intervention: Administer olmesartan medoxomil 4 hours prior to colesevelam hydrochloride. Sulfonylureas Clinical Impact: In vivo drug interactions studies showed a decrease in sulfonylureas when coadministered with colesevelam hydrochloride [see Clinical Pharmacology ( 12.3 )] . Intervention: Administer sulfonylureas 4 hours prior to colesevelam hydrochloride. Examples: Glimepiride, glipizide, and glyburide Oral Vitamin Supplements Clinical Impact: Colesevelam hydrochloride may decrease the absorption of fat-soluble vitamins A, D, E, and K [see Warnings and Precautions ( 5.3 )]. Intervention: Patients on oral vitamin supplementation should take their vitamins at least 4 hours prior to colesevelam hydrochloride. 7.2 Colesevelam Hydrochloride Drug Interactions that Increase the Exposure of the Concomitant Medication Table 5 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.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Primary Hyperlipidemia : Colesevelam hydrochloride, the active pharmaceutical ingredient in colesevelam hydrochloride tablets, is a 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-α-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. Type 2 Diabetes Mellitus: The mechanism by which colesevelam hydrochloride improves glycemic control is unknown. 12.2 Pharmacodynamics A maximum therapeutic response to the lipid-lowering effects of colesevelam hydrochloride was achieved within 2 weeks and was maintained during long-term therapy. In the diabetes clinical studies, a therapeutic response to colesevelam hydrochloride, as reflected by a reduction in HbA1c, was initially noted following 4-6 weeks of treatment and reached maximal or near-maximal effect after 12-18 weeks of treatment. 12.3 Pharmacokinetics Absorption Colesevelam hydrochloride is a 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. Elimination Metabolism Colesevelam hydrochloride is not metabolized systemically and does not interfere with systemic drug-metabolizing enzymes such as cytochrome P450. Excretion In 16 healthy volunteers, an average of 0.05% of administered radioactivity from a single 14 C-labeled colesevelam hydrochloride dose was excreted in the urine. Drug Interaction Studies Drug interactions between colesevelam and concomitantly administered drugs were screened through i n 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. Table 6 Mean Change in Drug Exposure (AUC 0-∞ and C max ) when Administered with Colesevelam Hydrochloride (3.75 g)* Drug Dose Co-administered 1 hr prior to Colesevelam Hydrochloride 4 hrs prior to Colesevelam Hydrochloride AUC 0-∞ C max AUC 0-∞ C max AUC 0-∞ C max Cyclosporine 200 mg -34% -44% N/A N/A N/A N/A Ethinyl Estradiol † 0.035 mg -24% -24% -18% -1% -12% 0% Glimepiride 4 mg -18% -8% N/A N/A -6% -3% Glipizide 20 mg -12% -13% N/A N/A -4% 0% Glyburide 3 mg -32% -47% -20% -15% -7% 4% Levothyroxine 600 mcg -22% -33% 6% -2% 1% 8% Metformin ER 1,500 mg 44% 8% N/A N/A N/A N/A Norethindrone † 1 mg -1% -20% 5% -3% 6% 7% Olmesartan Medoxomil 40 mg -39% -28% N/A N/A -15% -4% Repaglinide 2 mg -7% -19% -6% -1% N/A N/A Verapamil Sustained- Release 240 mg -31% -11% N/A N/A N/A N/A * With verapamil, the dose of colesevelam hydrochloride was 4.5 grams † Oral contraceptive containing norethindrone and ethinyl estradiol N/A- Not Available

20231015

4

3 DOSAGE FORMS AND STRENGTHS Tablets: 625 mg tablets are off-white to light yellow, capsule shaped coated tablets imprinted with “083” in black ink on one side and plain on other side and free from physical defects. • Tablets: 625 mg ( 3 )

colesevelam hydrochloride colesevelam hydrochloride CELLULOSE, MICROCRYSTALLINE FERROSOFERRIC OXIDE HYPROMELLOSE 2910 (15 MPA.S) HYPROMELLOSE 2910 (5 MPA.S) HYPROMELLOSE 2910 (50 MPA.S) MAGNESIUM STEARATE POLYETHYLENE GLYCOL 6000 PROPYLENE GLYCOL SHELLAC SILICON DIOXIDE COLESEVELAM HYDROCHLORIDE COLESEVELAM off-white to light yellow capsule shaped 083

13. NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis A 104-week carcinogenicity study with colesevelam hydrochloride was conducted in CD-1 mice, at oral dietary doses up to 3 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 a 104-week carcinogenicity study with colesevelam hydrochloride in Harlan Sprague-Dawley rats, a 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). A 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 4 degradants present in the drug substance have been evaluated for mutagenicity in the Ames test and a mammalian chromosomal aberration test. The 4 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 2 of the 4 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 2 degradants, didecylamine HCl and 6-decylamino-hexyltrimethyl ammonium chloride HCl, were negative in the presence and absence of metabolic activation. Impairment of Fertility Colesevelam hydrochloride did not impair fertility in rats at doses up to 3 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 Studies Reproduction studies have been performed in rats and rabbits at doses up to 3 g/kg/day and 1 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.

ANDA212050

Colesevelam hydrochloride

colesevelam hydrochloride

75834-152

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL 180's HDPE Bottle

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 4 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 )] . Hypertriglyceridemia and Cardiovascular Disease Inform patients that colesevelam hydrochloride may increase serum triglycerides and that the long-term effect of hypertriglyceridemia on the risk of coronary artery disease is uncertain [see Warnings and Precautions ( 5.1 )] . Administration [see Dosage and Administration ( 2.2 , 2.4 )] : Tablets Advise patients to take colesevelam hydrochloride tablets with a meal and liquid. Inform patients that colesevelam hydrochloride tablets can be taken as 6 tablets once daily or 3 tablets twice daily. Females of Reproductive Potential Advise females of reproductive potential that colesevelam hydrochloride may reduce the effectiveness of oral contraceptives, and to take oral contraceptives at least 4 hours before taking colesevelam hydrochloride [see Drug Interactions ( 7.1 ) and Use in Specific Populations ( 8.3 )] . Manufactured by: Inventia Healthcare Limited Plot No. F1-F1/1-F75/1, Additional Ambernath M.I.D.C., Ambernath (East)-421506, Dist. Thane, Maharashtra, India Manufactured for: Nivagen Pharmaceuticals, Inc. Sacramento, CA 95827, USA Toll Free Number: 1-877-977-0687 Revision Date: August 2023

14. CLINICAL STUDIES 14.1 Primary Hyperlipidemia Colesevelam hydrochloride reduces total cholesterol (TC), LDL-C, apolipoprotein B (Apo B), and non-high-density lipoprotein cholesterol (non-HDL-C) when administered alone or in combination with a statin in patients with primary hyperlipidemia. Approximately 1600 patients were studied in 9 clinical trials with treatment durations ranging from 4 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. A maximum therapeutic response to colesevelam hydrochloride was achieved within 2 weeks and was maintained during long-term therapy. Monotherapy In a 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 g and 4.5 g doses. The respective mean TC reductions were 7% and 10%. The mean Apo B 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 7 Response to Colesevelam Hydrochloride Monotherapy in a 24-Week Trial - Percent Change in Lipid Parameters from Baseline Grams/Day N TC LDL-C Apo B HDL-C* Non-HDL-C TG* Placebo 88 +1 0 0 -1 +1 +5 3.8 g (6 tablets) 95 - 7 † -15 † -12 † +3 † -10 † +10 4.5 g (7 tablets) 94 -10 † -18 † -12 † +3 -13 † +9 * Median % change from baseline † p<0.05 for lipid parameters compared to placebo, for Apo B compared to baseline In a study in 98 patients with LDL-C between 145 mg/dL and 250 mg/dL (mean 169 mg/dL), colesevelam hydrochloride 3.8 g was given for 6 weeks as a single dose with breakfast, as a single dose with dinner, or as divided doses with breakfast and dinner. The mean LDL-C reductions were 18%, 15%, and 18% for the 3 dosing regimens, respectively. The reductions with these 3 regimens were not statistically different from one another. Combination Therapy Co-administration of colesevelam hydrochloride and a statin (atorvastatin, lovastatin, or simvastatin) in 3 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 g to 3.8 g resulted in an additional 8% to 16% reduction in LDL-C above that seen with the statin alone. Table 8 Response to Colesevelam Hydrochloride in Combination with Atorvastatin, Simvastatin, or Lovastatin - Percent Change in Lipid Parameters Grams/Day N TC LDL-C Apo B HDL-C* Non-HDL-C TG* Atorvastatin Trial (4-week) Placebo 19 +4 +3 -3 +4 +4 +10 Atorvastatin 10 mg 18 -27 † -38 † -32 † +8 -35 † -24 † Colesevelam Hydrochloride 3.8 g/ Atorvastatin 10 mg 18 -31 † -48 † -38 † +11 -40 † -1 Atorvastatin 80 mg 20 -39 † -53 † -46 † +6 -50 † -33 † Simvastatin Trial (6-week) Placebo 33 -2 -4 -4 † -3 -2 +6 † Simvastatin 10 mg 35 -19 † -26 † -20 † +3 † -24 † -17 † Colesevelam Hydrochloride 3.8 g/ Simvastatin 10 mg 34 -28 † -42 † -33 † +10 † -37 † -12 † Simvastatin 20 mg 39 -23 † -34 † -26 † +7 † -30 † -12 † Colesevelam Hydrochloride 2.3 g/ Simvastatin 20 mg 37 -29 † -42 † -32 † +4 † -37 † -12 † Lovastatin Trial (4-week) Placebo 26 +1 0 0 +1 +1 +1 Lovastatin 10 mg 26 -14 † -22 † -16 † +5 -19 † 0 Colesevelam Hydrochloride 2.3 g/ Lovastatin 10 mg Together 27 -21 † -34 † -24 † +4 -27 † -1 Colesevelam Hydrochloride 2.3 g/ Lovastatin 10 mg Apart 23 -21 † -32 † -24 † +2 -28 † -2 * Median % change from baseline † p<0.05 for lipid parameters compared to placebo, for Apo B compared to baseline In all 3 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 g and atorvastatin 10 mg. Pediatric Therapy The safety and efficacy of colesevelam hydrochloride in pediatric patients were evaluated in an 8-week, multicenter, 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 a stable dose of an FDA-approved statin (with LDL-C >130 mg/dL) or naïve to lipid-lowering therapy (with LDL-C >160 mg/dL). This study had 3 periods: a 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-naïve at screening. The mean baseline LDL-C at Day 1 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 8 weeks of treatment, colesevelam hydrochloride 3.8 g/day significantly decreased plasma levels of LDL-C, non-HDL-C, TC, and Apo B and significantly increased HDL-C. A moderate, non-statistically significant increase in TG was observed versus placebo (Table 9). Table 9 Response to Colesevelam Hydrochloride 3.8 g Compared to Placebo in Pediatric Patients 10-17 Years of Age - Mean Percent Change in Lipid Parameters from Baseline to Week 8 Treatment Difference TC LDL-C Apo B HDL-C Non-HDL-C TG* (N=128) (N=128) (N=124) (N=128) (N=128) (N=128) Colesevelam Hydrochloride 3.8 g vs Placebo -7 † -13 † -8 † -6 † -11 † +5 * For triglycerides, median % change from baseline † p≤0.05 for lipid parameters compared to placebo Values 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 1 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. 14.2 Type 2 Diabetes Mellitus Colesevelam hydrochloride has been studied as monotherapy and in combination with metformin, pioglitazone, sulfonylureas, and insulin. In these studies, colesevelam hydrochloride and placebo were administered either as 3 tablets twice daily with lunch and dinner or as 6 tablets with dinner alone. Monotherapy The efficacy of colesevelam hydrochloride 3.8 g/day as anti-diabetes monotherapy was evaluated in a randomized double-blind, placebo-controlled trial involving 357 patients (176 colesevelam hydrochloride and 181 placebo) with type 2 diabetes mellitus who were treatment-naïve or had not received antihyperglycemic medication within 3 months prior to the start of the study. Statin use at baseline was reported in 13% of the colesevelam hydrochloride - treated patients and 16% of the placebo-treated patients. Colesevelam hydrochloride resulted in a statistically significant reduction in HbA1c of 0.27% compared to placebo (Table 10). The mean baseline LDL-C was 121 mg/dL in the monotherapy trial. Colesevelam hydrochloride treatment resulted in a placebo-corrected 11% reduction in LDL-C. Colesevelam hydrochloride treatment also reduced serum TC, ApoB, and non-HDL-C (Table 11). The mean change in body weight was -0.6 kg for colesevelam hydrochloride and -0.7 kg for placebo treatment groups. Table 10 Glycemic Parameters in a 24-Week Placebo-Controlled Study of Colesevelam Hydrochloride Monotherapy in Patients with Type 2 Diabetes Colesevelam Hydrochloride 3.8 grams/day Placebo HbA1C(%), Mean N 175 169 Baseline 8.25 8.17 Change from baseline* -0.26 0.01 Treatment difference (p-value) -0.27 (p=0.013) FPG (mg/dL), Mean N 172 166 Baseline 172 168 Change from baseline* -4.6 5.7 Treatment difference (p-value) -10.3 (p=0.037 † ) * Least-squares mean change calculated from an Analysis of Covariance model † Nominal p=value, not controlled for multiplicity testing FPG = fasting plasma glucose Table 11 Percent Change in Lipid Parameters in a 24-Week Placebo-Controlled Study of Colesevelam Hydrochloride Monotherapy in Patients with Type 2 Diabetes Dose/Day N* TC LDL-C Apo B HDL-C Non-HDL-C TG † Colesevelam Hydrochloride 3.8 grams 162 -3.3 ‡ -10.0 ‡ -5.6 ‡ 1.7 -4.4 ‡ 15.5 Placebo 160 1.8 1.2 0.9 -0.1 3.0 5.8 * The number of patients with analyzable data, i.e., a baseline and post-treatment value (last observation carried forward), varied slightly among different parameters. The N given represents the smallest number of patients included in the analysis for any parameter. † Median % change from baseline ‡ p<0.001 for lipid parameters compared to placebo (This more stringent criterion for statistical significance accounts for multiplicity testing of the lipid parameters, which were secondary endpoints in the diabetes trials.) Add-on Combination Therapy The efficacy of colesevelam hydrochloride 3.8 g/day in patients with type 2 diabetes mellitus was evaluated in 5 double- blind, placebo-controlled add-on therapy trials involving a total of 1691 patients with baseline HbA1c 7.5­9.5%. Patients were enrolled and maintained on their pre-existing, stable, background anti-diabetic regimen. Statin use at baseline was reported in 41% of the colesevelam hydrochloride-treated patients and 48% of the placebo-treated patients. In 3 add-on combination therapy trials (metformin, sulfonylurea and insulin), treatment with colesevelam hydrochloride resulted in a statistically significant reduction in HbA1c of 0.5% compared to placebo. Similar placebo- corrected reductions in HbA1c occurred in patients who received colesevelam hydrochloride in combination with metformin, sulfonylurea, or insulin monotherapy or combinations of these therapies with other anti- diabetic agents. In the pioglitazone trial, treatment with colesevelam hydrochloride resulted in a statistically significant reduction in HbA1c of 0.32% compared to placebo. In the metformin, pioglitazone, and sulfonylurea trials, treatment with colesevelam hydrochloride also resulted in statistically significant reductions in FPG of at least 14 mg/dL compared to placebo. Colesevelam hydrochloride had consistent effects on HbA1c across subgroups of age, gender, race, body mass index, and baseline HbA1c. Colesevelam hydrochloride’s effects on HbA1c were also similar for the two dosing regimens (3 tablets with lunch and with dinner or 6 tablets with dinner alone). The mean baseline LDL-C was 104 mg/dL in the metformin study (range 32-214 mg/dL), 107 mg/dL in the pioglitazone study (range 48-263 mg/dL), 106 mg/dL in the sulfonylurea study (range 41-264 mg/dL), 102 mg/dL in the insulin study (range 35-204 mg/dL). In these trials, colesevelam hydrochloride treatment was associated with a 12% to 16% reduction in LDL-C levels. The percentage decreases in LDL-C were of similar magnitude to those observed in patients with primary hyperlipidemia. Colesevelam hydrochloride treatment was associated with statistically significant increases in TG levels in the studies of patients on insulin, patients on a sulfonylurea, and patients on pioglitazone but not in the study of patients on metformin. The clinical significance of these increases is unknown. Colesevelam hydrochloride is contraindicated in patients with TG levels >500 mg/dL [see Contraindications ( 4 )] , and periodic monitoring of lipid parameters including TG is recommended [see Warnings and Precautions ( 5.1 ) and Adverse Reactions ( 6.1 )] . Body weight did not significantly increase from baseline with colesevelam hydrochloride therapy, compared with placebo, in any of the add-on combination diabetes studies. Add-on Combination Therapy with Metformin Colesevelam hydrochloride 3.8 g/day or placebo was added to background anti-diabetic therapy in a 26-week trial of 316 patients already receiving treatment with metformin alone (N=159) or metformin in combination with other oral agents (N=157). A total of 60% of these patients were receiving ≥1,500 mg/day of metformin. In combination with metformin, colesevelam hydrochloride resulted in statistically significant placebo-corrected reductions in HbA1c and FPG (Table 12). Colesevelam hydrochloride also reduced TC, LDL-C, Apo B, and non-HDL-C (Table 13). The mean percent change in serum LDL-C levels with colesevelam hydrochloride compared to placebo was -16% among statin users and statin non-users; the median percent change in serum TG levels with colesevelam hydrochloride compared to placebo was -2% among statin users and 10% among statin non-users. The mean change in body weight was -0.5 kg for colesevelam hydrochloride and -0.3 kg for placebo. Table 12 Glycemic Parameters in a 26-Week Placebo-Controlled Study of Colesevelam Hydrochloride in Combination with Metformin in Patients with Type 2 Diabetes Total Patient Population Metformin Alone Metformin in Combination with Other Oral Anti-diabetic Agents Colesevelam Hydrochloride 3.8 grams/day Placebo Colesevelam Hydrochloride 3.8 grams/day Placebo Colesevelam Hydrochloride 3.8 grams/day Placebo HbA1C (%), Mean N 148 152 79 76 69 76 Baseline 8.1 8.1 8.2 8.2 8.1 8.0 Change from baseline* -0.4 0.2 -0.4 0.0 -0.4 0.3 Treatment difference (p‑value) -0.5 (p<0.001) -0.5 (p=0.002) -0.6 (p<0.001) FPG (mg/dL), Mean N 149 152 79 76 70 76 Baseline 178 174 184 180 171 168 Change from baseline* -3 11 -7 8 0 13 Treatment difference (p‑value) -14 (p=0.01) -14 (p=0.07) -14 (p=0.10) * Least-squares mean change calculated from an Analysis of Covariance model. Table 13 Percent Change in Lipid Parameters in a 26-Week Placebo-Controlled Study of Colesevelam Hydrochloride in Combination with Metformin in Patients with Type 2 Diabetes Dose/Day N* TC LDL-C Apo B HDL-C Non-HDL-C TG † Total Patient Population Colesevelam Hydrochloride 3.8 grams/day 125 -4 ‡ -12 ‡ -4 ‡ 1 -6 ‡ 12 Placebo 126 3 4 4 0 5 7 Metformin Alone Colesevelam Hydrochloride 3.8 grams/day 66 -3 -9 -2 1 -4 15 Placebo 61 2 0 1 -2 4 8 Metformin in Combination with Other Oral Anti-diabetic Agents Colesevelam Hydrochloride 3.8 grams/day 59 -6 ‡ -15 ‡ -6 ‡ 1 -7 ‡ 8 Placebo 65 4 7 7 2 6 5 *The number of patients with analyzable data, i.e., a baseline and post-treatment value (last-observation carried forward), varied slightly among different parameters. The N given represents the smallest number of patients included in the analysis for any parameter. † Median % change from baseline. ‡p<0.001 for lipid parameters compared to placebo (this more stringent criterion for statistical significance accounts for multiplicity testing of the lipid parameters, which were secondary endpoints in the diabetes trials) Add-on Combination Therapy with Pioglitazone Colesevelam hydrochloride 3.8 g/day or placebo was added to background anti-diabetic therapy in a 24-week trial of 562 patients already receiving treatment with pioglitazone alone (N=51) or pioglitazone in combination with other oral agents (N=511). Of these, most were on dual therapy with metformin (N=298) or triple therapy with metformin and a sulfonylurea (N=139). In combination with pioglitazone-based therapy, colesevelam hydrochloride resulted in statistically significant reductions in HbA1c and FPG compared to placebo (Table 14). Colesevelam hydrochloride also reduced TC, LDL-C, Apo B, and non-HDL-C but increased serum TG (Table 15). The mean change in body weight was 0.8 kg for colesevelam hydrochloride and 0.4 kg for placebo. Table 14 Glycemic Parameters in a 24-Week Placebo-Controlled Study of Colesevelam Hydrochloride in Combination with Pioglitazone-Based Therapy in Patients with Type 2 Diabetes Colesevelam Hydrochloride 3.8 grams/day Placebo HbA1C(%), Mean N 271 276 Baseline 8.2 8.1 Change from baseline* -0.34 -0.02 Treatment difference (p-value) -0.32 (0.0001) FPG (mg/dL), Mean N 268 270 Baseline 155 157 Change from baseline* -4.8 +9.9 Treatment difference (p-value) -14.7 (<0.0001) * Least-squares mean change calculated from an Analysis of Covariance model. Table 15 Percent Change in Lipid Parameters in a 24-Week Placebo-Controlled Study of Colesevelam Hydrochloride in Combination with Pioglitazone Based Therapy in Patients with Type 2 Diabetes Dose/Day N* TC LDL-C Apo B HDL-C Non-HDL-C TG † Total Patient Cohort Colesevelam Hydrochloride 3.8 grams/day 262 -3 ‡ -9 ‡ -5 ‡ +3 -5 ‡ +14 ‡ Placebo 262 +3 +7 +4 +1 +5 +2 *The N given represents the smallest number of patients included in the analysis for any parameter. † Median % change from baseline. ‡ p<0.001 for lipid parameters compared to placebo Add-on Combination Therapy with Sulfonylurea Colesevelam hydrochloride 3.8 g/day or placebo was added to background anti-diabetic therapy in a 26-week trial of 460 patients already treated with sulfonylurea alone (N=156) or sulfonylurea in combination with other oral agents (N=304). A total of 72% of these patients were receiving at least half-maximal doses of sulfonylurea therapy. In combination with a sulfonylurea, colesevelam hydrochloride resulted in statistically significant placebo-corrected reductions in HbA1c and FPG (Table 16). Colesevelam hydrochloride also reduced TC, LDL-C, Apo B, and non-HDL-C, but increased serum TG (Table 17). The mean percent change in serum LDL-C levels with colesevelam hydrochloride compared to placebo was -18% among statin users and -15% among statin non-users; the median percent increase in serum TG with colesevelam hydrochloride compared to placebo was 29% among statin users and 9% among statin non-users. The mean change in body weight was 0.0 kg for colesevelam hydrochloride and ­0.4 kg for placebo. Table 16 Glycemic Parameters in a 26-Week Placebo-Controlled Study of Colesevelam Hydrochloride in Combination with Sulfonylurea in Patients with Type 2 Diabetes Total Patient Population Sulfonylurea Alone Sulfonylurea in Combination with Other Oral Anti-diabetic Agents Colesevelam Hydrochloride 3.8 grams/day Placebo Colesevelam Hydrochloride 3.8 grams/day Placebo Colesevelam Hydrochloride 3.8 grams/day Placebo HbA1C (%), Mean n 218 218 69 80 149 138 Baseline 8.2 8.3 8.2 8.4 8.2 8.3 Change from baseline* -0.3 0.2 -0.3 0.5 -0.4 0.0 Treatment difference (p-value) -0.5 (p<0.001) -0.8 (p<0.001) -0.4 (p<0.001) FPG (mg/dL), Mean n 218 217 70 80 148 137 Baseline 177 181 181 186 175 178 Change from baseline* -4 10 3 15 -11 4 Treatment difference (p-value) -14 (p=0.009) -12 (p=0.18) -14 (p=0.03) * Least-squares mean change calculated from an Analysis of Covariance model. Table 17 Percent Change in Lipid Parameters in a 26-Week Placebo-Controlled Study of Colesevelam Hydrochloride in Combination with Sulfonylurea in Patients with Type 2 Diabetes Dose/Day N* TC LDL-C Apo B HDL-C Non-HDL-C TG † Total Patient Population Colesevelam Hydrochloride 3.8 grams/day 186 -5 ‡ -16 ‡ -6 ‡ 1 -6 ‡ 20 ‡ Placebo 193 0 1 1 0 1 1 Sulfonylurea Alone Colesevelam Hydrochloride 3.8 grams/day 57 -5 -14 ‡ -5 -1 -6 17 Placebo 68 0 1 1 1 0 -1 Sulfonylurea in Combination with Other Oral Anti-diabetic Agents Colesevelam Hydrochloride 3.8 grams/day 129 -5 -18 ‡ -7 ‡ 1 -6 21 ‡ Placebo 125 0 0 1 0 1 2 *The number of patients with analyzable data, i.e., a baseline and post-treatment value (last-observation carried forward), varied slightly among different parameters. The N given represents the smallest number of patients included in the analysis for any parameter. † Median % change from baseline. ‡ p<0.001 for lipid parameters compared to placebo (this more stringent criterion for statistical significance accounts for multiplicity testing of the lipid parameters, which were secondary endpoints in the diabetes trials) Add-on Combination Therapy with Insulin Colesevelam hydrochloride 3.8 g/day or placebo was added to background anti-diabetic therapy in a 16-week trial of 287 patients already treated with insulin alone (N=116) or insulin in combination with oral agents (N=171). At baseline, the median daily insulin dose was 70 units in the colesevelam hydrochloride group and 65 units in the placebo group. In combination with insulin, colesevelam hydrochloride resulted in a statistically significant placebo-corrected reduction in HbA1c (Table 18). Colesevelam hydrochloride also reduced LDL-C and Apo B, but increased serum TG (Table 19). The mean percent change in serum LDL-C levels with colesevelam hydrochloride compared to placebo was ­ 13% among statin users and statin non-users; the median percent increase in serum TG levels with colesevelam hydrochloride compared to placebo was 24% among statin users and 17% among statin non-users. The mean change in body weight was 0.6 kg for colesevelam hydrochloride and 0.2 kg for placebo. Table 18 Glycemic Parameters in a 16-Week Placebo-Controlled Study of Colesevelam Hydrochloride in Combination with Insulin in Patients with Type 2 Diabetes Total Patient Population Insulin Alone Insulin in Combination with Oral Anti-diabetic Agents Colesevelam Hydrochloride 3.8 grams/day Placebo Colesevelam Hydrochloride 3.8 grams/day Placebo Colesevelam Hydrochloride 3.8 grams/day Placebo HbA1C (%), Mean n 144 136 54 55 90 81 Baseline 8.3 8.2 8.2 8.3 8.3 8.2 Change from baseline* -0.4 0.1 -0.4 0.2 -0.4 0.0 Treatment difference (p-value) -0.5 (p<0.001) -0.6 (p<0.001) -0.4 (p<0.001) FPG (mg/dL), Mean n 144 136 54 55 90 81 Baseline 165 151 165 163 165 143 Change from baseline* 2 16 8 17 -4 14 Treatment difference (p-value) -15 (p=0.08) -9 (p=0.51) -18 (p=0.09) *Least-squares mean change calculated from an Analysis of Covariance model. Table 19 Percent Change in Lipid Parameters in a 16-Week Placebo-Controlled Study of Colesevelam Hydrochloride in Combination with Insulin in Patients with Type 2 Diabetes Dose/Day N* TC LDL-C Apo B HDL-C Non-HDL-C TG † Total Patient Cohort Colesevelam Hydrochloride 3.8 grams/day 129 -3 -12 ‡ -4 -1 -3 23 ‡ Placebo 121 1 1 1 0 1 0 Insulin Alone Colesevelam Hydrochloride 3.8 grams/day 46 -3 -12 -5 0 -3 19 Placebo 48 2 4 2 3 2 -2 Insulin in Combination with Oral Anti-diabetic Agents Colesevelam Hydrochloride 3.8 grams/day 83 -4 -13 -4 -1 -3 25 ‡ Placebo 73 -1 -3 0 -1 -1 2 * The number of patients with analyzable data, i.e., a baseline and post-treatment value (last-observation carried forward), varied slightly among different parameters. The N given represents the smallest number of patients included in the analysis for any parameter. † Median % change from baseline. ‡ p<0.001 for lipid parameters compared to placebo (this more stringent criterion for statistical significance accounts for multiplicity testing of the lipid parameters, which were secondary endpoints in the diabetes trials)

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Colesevelam 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 a 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 8 and 5 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 5 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. Data Human Data There 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 a causal association with congenital anomalies has not been established. Animal Data In pregnant rats given dietary doses of 0.3, 1.0, 3.0 g/kg/day colesevelam hydrochloride from gestation days 7 through 17, no teratogenic effects were observed. Exposures at 3.0 g/kg/day were 8 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 6 through 18, no teratogenic effects were observed. Exposures at 1.0 g/kg/day were 5 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 6 through lactation day 21 (weaning), no adverse effects on survival and development were observed. Exposures at 1.0 g/kg/day were 5 times the human exposure at 3.75 g/day MRHD, based on body surface area (mg/m 2 ). 8.2 Lactation Risk Summary Colesevelam 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 Contraception Use of colesevelam hydrochloride may reduce the efficacy of oral contraceptives. Advise patients to take oral contraceptives at least 4 hours prior to taking colesevelam hydrochloride [see Drug Interactions ( 7 )] . 8.4 Pediatric Use Primary Hyperlipidemia The safety and effectiveness of colesevelam hydrochloride to reduce LDL-C levels in boys and postmenarchal girls 10 to 17 years of age with HeFH who are unable to reach LDL-C target levels despite an adequate trial of dietary therapy and lifestyle modification have been established. Use of colesevelam hydrochloride for this indication is supported by a study in 129 colesevelam hydrochloride -treated pediatric patients aged 10 to 17 years with HeFH [see Clinical Studies ( 14.1 )] . Adverse reactions commonly observed in pediatric patients compared to placebo, but not in adults, included headache (3.9%), creatine phosphokinase increase (2.3%), and vomiting (2.3%) [see Adverse Reactions ( 6.1 )] . There were no significant effects on fat-soluble vitamin levels or clotting factors in the adolescent boys or girls relative to placebo. Due to colesevelam hydrochloride tablet size, colesevelam hydrochloride for oral suspension is recommended for use in the pediatric population [see Dosage and Administration (2.2 , 2.4 )] . The safety and effectiveness of colesevelam hydrochloride in pediatric patients with HeFH less than 10 years of age or in premenarchal females have not been established. Type 2 Diabetes Mellitus The safety and effectiveness of colesevelam hydrochloride to improve glycemic control in pediatric patients with type 2 diabetes mellitus have not been established. Effectiveness was not demonstrated in a 6-month, adequate and well-controlled study conducted in 141 colesevelam hydrochloride-treated pediatric patients aged 10 to 17 years with type 2 diabetes mellitus. 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. Type 2 Diabetes Mellitus Of the 2048 patients enrolled in the six diabetes studies, 397 (19%) were ≥65 years old, and 36 (2%) were ≥75 years old. In these trials, colesevelam hydrochloride 3.8 g/day or placebo was added onto background anti- diabetic therapy. No overall differences in safety or effectiveness were observed between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Renal Impairment Type 2 Diabetes Mellitus Of the 2048 patients enrolled in the six diabetes studies, 807 (39%) had mild renal insufficiency (creatinine clearance [CrCl] 50-<80 mL/min), 61 (3%) had moderate renal insufficiency (CrCl 30-<50 mL/min), and none had severe renal insufficiency (CrCl <30 mL/min), as estimated from baseline serum creatinine using the Modification of Diet in Renal Disease (MDRD) equation. No overall differences in safety or effectiveness were observed between patients with CrCl <50 mL/min (n=53) and those with a CrCl ≥ 50 mL/min (n=1075) in the add-on to metformin, sulfonylureas, and insulin diabetes studies. In the monotherapy study and add-on to pioglitazone study, only 3 and 5 patients, respectively, had moderate renal insufficiency.

16 HOW SUPPLIED/STORAGE AND HANDLING Colesevelam hydrochloride tablets, 625 mg, are supplied as off-white to light yellow, capsule shaped coated tablets imprinted with “083” in black ink on one side and plain on other side and free from physical defects. Colesevelam hydrochloride tablets are available as follows: • Bottles of 180 - NDC 75834-152-18 Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Protect from moisture. Brief exposure to 40°C (104°F) does not adversely affect colesevelam hydrochloride tablets.