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 Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 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 HyperlipidemiaIn double-blind, placebo-controlled clinical trials, 807 patients with primary hyperlipidemia (age range 18 to 86 years, 50% women, 90% Caucasians, 7% Blacks, 2% Hispanics, 1% Asians) and elevated LDL-C were treated with colesevelam hydrochloride 1.5 g/day to 4.5 g/day from 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 Placebo Colesevelam Hydrochloride = 807 Placebo = 258 Constipation 11 7 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 AgeIn 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 Placebo Colesevelam Hydrochloride = 129 Placebo = 65 Nasopharyngitis 6.2% 4.6% Headache 3.9% 3.1% Fatigue 3.9% 1.5% Creatine Phosphokinase Increase 2.3% % Rhinitis 2.3% % Vomiting 2.3% 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 Postmarketing 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 therapyGastrointestinalBowel 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 AbnormalitiesHypertriglyceridemia.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

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.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisA 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).MutagenesisColesevelam 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 HyperlipidemiaColesevelam 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. AbsorptionColesevelam hydrochloride is hydrophilic, water-insoluble polymer that is not hydrolyzed by digestive enzymes and is not absorbed.DistributionColesevelam hydrochloride is not absorbed, and therefore, its distribution is limited to the gastrointestinal tract.MetabolismColesevelam hydrochloride is not metabolized systemically and does not interfere with systemic drug-metabolizing enzymes such as cytochrome P-450.ExcretionIn 16 healthy volunteers, an average of 0.05% of administered radioactivity from single 14C-labeled colesevelam hydrochloride dose was excreted in the urine.Drug InteractionsDrug 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. Table Mean Change in Drug Exposure (AUC0- and Cmax) when Administered with Colesevelam Hydrochloride(3.75 g)a With verapamil, the dose of colesevelam hydrochloride was 4.5 gOral contraceptive containing norethindrone and ethinyl estradiol N/A Not Available Drug Dose Coadministered hr prior to Colesevelam Hydrochloride hr prior to Colesevelam Hydrochloride AUC0- Cmax AUC0- Cmax AUC0- Cmax 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 mg -18% -8% N/A N/A -6% 3% Glipizide 20 mg -12% -13% N/A N/A -4% 0% Glyburide mg -32% -47% -20% -15% -7% 4% Levothyroxine 600 ug -22% -33% 6% -2% 1% 8% Metformin ER 1500 mg 44% 8% N/A N/A N/A N/A Norethindrone mg -1% -20% 5% -3% 6% 7% Olmesartan Medoxomil 40 mg -39% -28% N/A N/A -15% -4% Repaglinide mg -7% -19% -6% -1% N/A N/A Verapamil Sustained-Release 240 mg -31% -11% N/A N/A N/A N/A.

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.MonotherapyIn 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 to 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 Baseline aMedian change from baseline.p 0.05 for lipid parameters compared to placebo, for Apo compared to baseline. Grams/Day TC LDL-C Apo HDL-Ca Non-HDL-C TGa Placebo 88 +1 0 -1 +1 +5 3.8 (6 tablets) 95 -7 -15 -12 +3 -10 +10 4.5 (7 tablets) 94 -10 -18 -12 +3 -13 +9 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 TherapyCoadministration 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 to 236 mg/dL), 171 mg/dL in the lovastatin study (range 115 to 247 mg/dL), and 188 mg/dL in the simvastatin study (range 148 to 352 mg/dL). As demonstrated in Table 8, colesevelam hydrochloride doses of 2.3g to 3.8g resulted in an additional 8% to 16% reduction in LDL-C above that seen with the statin alone. Table Response to Colesevelam Hydrochloride in Combination with Atorvastatin, Simvastatin, or Lovastatin Percent Change in Lipid Parameters Median change from baseline.p 0.05 for lipid parameters compared to placebo, for Apo compared to baseline. Dose/Day TC LDL-C Apo HDL-Ca Non-HDL-C TGa 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 +1 +1 +1 Lovastatin 10 mg 26 -14 -22 -16 +5 -19 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 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 TherapyThe 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 to 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.A moderate, non-statistically significant increase in TG was observed versus placebo (Table 9). Table Response to Colesevelam Hydrochloride 3.8 Compared to Placebo in Pediatric Patients 10 to 17 Years of Age Mean Percent Change in Lipid Parameters from Baseline to Week a 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 Treatment Difference TC (N=128) LDL-C (N=128) Apo (N=124) HDL-C (N=128) Non-HDL-C (N=128) TGa (N=128) Colesevelam Hydrochloride 3.8 vs Placebo -7 -13 -8 +6 -11 +5 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.

CONTRAINDICATIONS SECTION.

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)] history of bowel obstruction [see Warnings and Precautions (5.2)] 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 history of hypertriglyceridemia-induced pancreatitis (4). Patients with history of bowel obstruction (4).. Patients with serum triglyceride levels >500 mg/dL (4).. Patients with history of hypertriglyceridemia-induced pancreatitis (4).. Patients with history of bowel obstruction (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Colesevelam hydrochloride is non-absorbed, polymeric, lipid-lowering and glucose-lowering agent for oral administration. Colesevelam hydrochloride is high-capacity bile acid-binding molecule.Colesevelam hydrochloride is polymer with off-white to light yellow color powder, which is insoluble in water and any organic solvent.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 tablet contains 625 mg colesevelam hydrochloride. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, crospovidone, hypromellose, iron oxide yellow, iron oxide red, magnesium stearate, methacrylic acid copolymer, microcrystalline cellulose, povidone, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, sodium bicarbonate. The tablet is printed with black pharmaceutical ink which contains ammonium hydroxide, ferrosoferric oxide, propylene glycol and shellac (< calories per tablets).. Image.

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 for boys and postmenarchal girls aged 10 to 17 years with primary hyperlipidemia is 3.75 grams daily. Colesevelam hydrochloride should be taken as follows (2.2, 2.4):Tablets Take 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 for boys and postmenarchal girls aged 10 to 17 years with primary hyperlipidemia is 3.75 grams daily. Colesevelam hydrochloride should be taken as follows (2.2, 2.4):. 2.1 Testing Prior to Initiation of Colesevelam Hydrochloride Tablets. 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 Primary Hyperlipidemia. The recommended dosage of colesevelam hydrochloride for adults and for boys and postmenarchal girls aged 10 to 17 years with primary hyperlipidemia is 3.75 grams daily. Colesevelam hydrochloride should be taken as follows:Take 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 Information for 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. 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)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Colesevelam Hydrochloride Tablets, 625 mg are cream to light yellow colored with or without matte appearance, modified capsule shaped, biconvex, film-coated tablets, imprinted 619 on one side and plain on other side.. Colesevelam Hydrochloride Tablets, 625 mg are cream to light yellow colored with or without matte appearance, modified capsule shaped, biconvex, film-coated tablets, imprinted 619 on one side and plain on other side.. Tablets: 625 mg (3). Tablets: 625 mg (3).

DRUG INTERACTIONS SECTION.

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)].

GERIATRIC USE SECTION.

8.5 Geriatric Use. Primary HyperlipidemiaOf 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.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Colesevelam Hydrochloride Tablets, 625 mg are cream to light yellow colored with or without matte appearance, modified capsule shaped, biconvex, film-coated tablets, imprinted 619 on one side and plain on other side and are supplied as follows:NDC 68382-619-28 in bottle of 180 tabletsNDC 68382-619-10 in bottle of 1000 tabletsNDC 68382-619-77 in carton of 100 tablets (10 10 unit-dose)StorageStore at 20 to 25C (68 to 77F) [See USP Controlled Room Temperature]. Protect from moisture. Brief exposure to 40C (104F) does not adversely affect colesevelam hydrochloride tablets.

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), unable to reach LDL-C target levels despite an adequate trial of diet and lifestyle modification (1.1).Limitations of Use (1.3)Do not use for treatment of type diabetes or for diabetic ketoacidosis.Not studied in Fredrickson Type I, III, IV, and V.. 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).. Do not use for treatment of type diabetes or for diabetic ketoacidosis.. Not studied in Fredrickson Type I, III, IV, and V.. 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.. 1.3 Limitations of Use. Colesevelam hydrochloride should not be used for the treatment of type diabetes or for the treatment of diabetic ketoacidosis.Colesevelam hydrochloride has not been studied in Fredrickson Type I, III, IV, and dyslipidemias.. Colesevelam hydrochloride should not be used for the treatment of type diabetes or for the treatment of diabetic ketoacidosis.. Colesevelam hydrochloride has not been studied in Fredrickson Type I, III, IV, and dyslipidemias.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Hypertriglyceridemia and PancreatitisInform 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)].GastrointestinalInform 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 InteractionsAdvise 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)].Hypertriglyceridemia and Cardiovascular DiseaseInform 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 (2.4)]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 (7.1) and Use in Specific Populations (8.3)].Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Primary HyperlipidemiaColesevelam 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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisA 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).MutagenesisColesevelam 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.

OVERDOSAGE SECTION.

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).

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL. Colesevelam Hydrochloride Tablets, 625 mgNDC 68382-619-28180 TabletsRx only. image.

PEDIATRIC USE SECTION.

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 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.

PHARMACODYNAMICS SECTION.

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.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionColesevelam hydrochloride is hydrophilic, water-insoluble polymer that is not hydrolyzed by digestive enzymes and is not absorbed.DistributionColesevelam hydrochloride is not absorbed, and therefore, its distribution is limited to the gastrointestinal tract.MetabolismColesevelam hydrochloride is not metabolized systemically and does not interfere with systemic drug-metabolizing enzymes such as cytochrome P-450.ExcretionIn 16 healthy volunteers, an average of 0.05% of administered radioactivity from single 14C-labeled colesevelam hydrochloride dose was excreted in the urine.Drug InteractionsDrug 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. Table Mean Change in Drug Exposure (AUC0- and Cmax) when Administered with Colesevelam Hydrochloride(3.75 g)a With verapamil, the dose of colesevelam hydrochloride was 4.5 gOral contraceptive containing norethindrone and ethinyl estradiol N/A Not Available Drug Dose Coadministered hr prior to Colesevelam Hydrochloride hr prior to Colesevelam Hydrochloride AUC0- Cmax AUC0- Cmax AUC0- Cmax 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 mg -18% -8% N/A N/A -6% 3% Glipizide 20 mg -12% -13% N/A N/A -4% 0% Glyburide mg -32% -47% -20% -15% -7% 4% Levothyroxine 600 ug -22% -33% 6% -2% 1% 8% Metformin ER 1500 mg 44% 8% N/A N/A N/A N/A Norethindrone mg -1% -20% 5% -3% 6% 7% Olmesartan Medoxomil 40 mg -39% -28% N/A N/A -15% -4% Repaglinide mg -7% -19% -6% -1% N/A N/A Verapamil Sustained-Release 240 mg -31% -11% N/A N/A N/A N/A.

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/m2). 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 g/kg/day, g/kg/day, g/kg/day colesevelam hydrochloride from gestation days through 17, no teratogenic effects were observed. Exposures at g/kg/day were times the human exposure at 3.75 g/day MRHD, based on body surface area (mg/m2).In pregnant rabbits given oral gavage doses of 0.1 g/kg/day, 0.5 g/kg/day, g/kg/day colesevelam hydrochloride from gestation days through 18, no teratogenic effects were observed. Exposures at g/kg/day were times the human exposure at 3.75 g/day MRHD, based on body surface area (mg/m2).In pregnant rats given oral gavage doses of 0.1 g/kg/day, 0.3 g/kg/day, g/kg/day colesevelam hydrochloride from gestation day through lactation day 21 (weaning), no adverse effects on survival and development were observed. Exposures at g/kg/day were times the human exposure at 3.75 g/day MRHD, based on body surface area (mg/m2).

SPL UNCLASSIFIED SECTION.

Manufactured by:Cadila Healthcare Ltd.Ahmedabad, India.Distributed by:Zydus Pharmaceuticals (USA) Inc.Pennington, NJ 08534Rev.: 01/22.

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/m2). 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 g/kg/day, g/kg/day, g/kg/day colesevelam hydrochloride from gestation days through 17, no teratogenic effects were observed. Exposures at g/kg/day were times the human exposure at 3.75 g/day MRHD, based on body surface area (mg/m2).In pregnant rabbits given oral gavage doses of 0.1 g/kg/day, 0.5 g/kg/day, g/kg/day colesevelam hydrochloride from gestation days through 18, no teratogenic effects were observed. Exposures at g/kg/day were times the human exposure at 3.75 g/day MRHD, based on body surface area (mg/m2).In pregnant rats given oral gavage doses of 0.1 g/kg/day, 0.3 g/kg/day, g/kg/day colesevelam hydrochloride from gestation day through lactation day 21 (weaning), no adverse effects on survival and development were observed. Exposures at g/kg/day were times the human exposure at 3.75 g/day MRHD, based on body surface area (mg/m2).. 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. 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 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.. 8.5 Geriatric Use. Primary HyperlipidemiaOf 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 and Pancreatitis. 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-Soluble Vitamin 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)].