DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Tablets: 625 mg tablets are off-white, oval, film-coated and imprinted with Sankyo and C01 on one side.For Oral Suspension: 3.75 gram packet containing white to pale yellow powder with yellow granules.. Tablets: 625 mg tablets are off-white, oval, film-coated and imprinted with Sankyo and C01 on one side.. For Oral Suspension: 3.75 gram packet containing white to pale yellow powder with yellow granules.. Tablets: 625 mg (3)For Oral Suspension: 3.75 gram packet (3). Tablets: 625 mg (3). For Oral Suspension: 3.75 gram packet (3).

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 Daiichi Sankyo, Inc. at 1-877-437-7763 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1Clinical 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 18-86 years, 50% women, 90% Caucasians, 7% Blacks, 2% Hispanics, 1% Asians) and elevated LDL-C were treated with colesevelam hydrochloride 1.5 g/day to 4.5 g/day from to 24 weeks (total exposure 199 patient-years).Table Clinical Studies of Colesevelam Hydrochloride for Primary Hyperlipidemia: Adverse Reactions Reported in >= 2% of Patients and More Commonly than in PlaceboColesevelam HydrochloridePlaceboN=807N=258Constipation11.0%7.0%Dyspepsia8.3%3.5%Nausea4.2%3.9%Accidental injury3.7%2.7%Asthenia3.6%1.9%Pharyngitis3.2%1.9%Flu syndrome3.2%3.1%Rhinitis3.2%3.1%Myalgia2.1%0.4%. Pediatric Patients 10 to 17 Years of 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 PlaceboColesevelam HydrochloridePlaceboN=129N=65Nasopharyngitis6.2%4.6%Headache3.9%3.1%Fatigue3.9%1.5%Creatine Phosphokinase Increase2.3%0.0%Rhinitis2.3%0.0%Vomiting2.3%1.5%The reported adverse reactions during the additional 18-week open-label treatment period with colesevelam hydrochloride 3.8 per day were similar to those during the double-blind period and included headache (7.6%), nasopharyngitis (5.4%), upper respiratory tract infection (4.9%), influenza (3.8%), and nausea (3.8%).. Type Diabetes MellitusIn add-on combination and monotherapy double-blind, 12- to 26-week, placebo-controlled clinical trials in patients with type 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 mean hemoglobin A1c (HbA1c) of 8.2%, and 26% had past medical history suggestive of microvascular complications of diabetes.Table shows adverse reactions associated with the use of colesevelam hydrochloride in patients with type 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 Clinical Studies of Colesevelam Hydrochloride for Type Diabetes: Adverse Reactions Reported in >=2% of Patients and More Commonly than in PlaceboColesevelam HydrochloridePlaceboN=1022N=1010Constipation6.5%2.2%Hypoglycemia3.4%3.1%Dyspepsia2.8%1.0%Nausea2.6%1.6%Hypertension 2.6%1.9%Back Pain2.3%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 hypersensitivity reaction to colesevelam hydrochloride.. HypertriglyceridemiaPatients 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 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 median increase in serum TG of 5% compared to placebo (p=0.42) in 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 (0.3%) patients on placebo developed TG elevations >=1000 mg/dL.. Cardiovascular Adverse ReactionsDuring 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.. 6.2Post-marketing Experience. The following additional adverse reactions have been identified during post-approval use of colesevelam hydrochloride. Because these reactions are reported voluntarily from population of uncertain size, it is generally not possible to reliably estimate their frequency or establish causal relationship to drug exposure.Adverse Reactions Resulting from Drug Interactions [see Drug Interactions (7)]: Increased seizure activity or decreased phenytoin levels in patients receiving phenytoin, reduced International Normalized Ratio (INR) in patients receiving warfarin therapy, and elevated thyroid-stimulating hormone (TSH) in patients receiving thyroid hormone replacement therapyGastrointestinal: Bowel obstruction (in patients with history of bowel obstruction or resection), dysphagia or esophageal obstruction (occasionally requiring medical intervention), fecal impaction, pancreatitis, abdominal distension, exacerbation of hemorrhoids, and increased transaminasesLaboratory Abnormalities: Hypertriglyceridemia.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2Animal 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.

13.1Carcinogenesis, 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. 12.1Mechanism of Action. Primary Hyperlipidemia: Colesevelam hydrochloride, the active pharmaceutical ingredient, 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.. Type Diabetes Mellitus: The mechanism by which colesevelam hydrochloride improves glycemic control is unknown.. 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. In the diabetes clinical studies, therapeutic response to colesevelam hydrochloride, as reflected by 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. 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.. Elimination. MetabolismColesevelam hydrochloride is not metabolized systemically and does not interfere with systemic drug-metabolizing enzymes such as cytochrome P450.. 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 Interaction StudiesDrug 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)With verapamil, the dose of colesevelam hydrochloride was 4.5 g. DrugDoseCo-administered1 hr prior to Colesevelam Hydrochloride4 hrs prior to Colesevelam HydrochlorideAUC0- Cmax AUC0- Cmax AUC0- Cmax N/A not availableCyclosporine200 mg-34%-44%N/AN/AN/AN/AEthinyl EstradiolOral contraceptive containing norethindrone and ethinyl estradiol 0.035 mg-24%-24%-18%-1%-12%0%Glimepiride4 mg-18%-8%N/AN/A-6%3%Glipizide20 mg-12%-13%N/AN/A-4%0%Glyburide3 mg-32%-47%-20%-15%-7%4%Levothyroxine600 ug-22%-33%6%-2%1%8%Metformin ER1500 mg44%8%N/AN/AN/AN/ANorethindrone mg-1%-20%5%-3%6%7%Olmesartan Medoxomil40 mg -39%-28%N/AN/A-15%-4%Repaglinide2 mg-7%-19%-6%-1%N/AN/AVerapamil Sustained Release240 mg-31%-11%N/AN/AN/AN/A.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1Primary 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 9-10% were observed at both colesevelam hydrochloride doses, but the changes were not statistically different from placebo.Table Response to Colesevelam Hydrochloride Monotherapy in 24-Week Trial Percent Change in Lipid Parameters from BaselineGrams/DayNTCLDL-CApo BHDL-CMedian change from baseline Non-HDL-CTG Placebo88+100-1+1+53.8 (6 tablets)95-7p<0.05 for lipid parameters compared to placebo, for Apo compared to baseline -15 -12 +3 -10 +104.5 (7 tablets)94-10 -18 -12 +3-13 +9In 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 TherapyCo-administration of colesevelam hydrochloride and statin (atorvastatin, lovastatin, or simvastatin) in clinical studies demonstrated an additive reduction of LDL-C. The mean baseline LDL-C was 184 mg/dL in the atorvastatin study (range 156-236 mg/dL), 171 mg/dL in the lovastatin study (range 115-247 mg/dL), and 188 mg/dL in the simvastatin study (range 148-352 mg/dL). As demonstrated in Table 8, colesevelam hydrochloride doses of 2.3 to 3.8 resulted in an additional 8% to 16% reduction in LDL-C above that seen with the statin alone.Table Response to Colesevelam Hydrochloride in Combination with Atorvastatin, Simvastatin, or Lovastatin Percent Change in Lipid ParametersDose/DayNTCLDL-CApo BHDL-CMedian change from baseline Non-HDL-CTG Atorvastatin Trial (4-week)Placebo19+4+3-3+4+4+10Atorvastatin 10 mg18-27p<0.05 for lipid parameters compared to placebo, for Apo compared to baseline -38 -32 +8-35 -24 Colesevelam hydrochloride 3.8 g/Atorvastatin 10 mg18-31 -48 -38 +11-40 -1Atorvastatin 80 mg20-39 -53 -46 +6-50 -33 Simvastatin Trial (6-week)Placebo33-2-4-4 -3-2+6 Simvastatin 10 mg35-19 -26 -20 +3 -24 -17 Colesevelam hydrochloride 3.8 g/Simvastatin 10 mg34-28 -42 -33 +10 -37 -12 Simvastatin 20 mg39-23 -34 -26 +7 -30 -12 Colesevelam hydrochloride 2.3 g/Simvastatin 20 mg37-29 -42 -32 +4 -37 -12 Lovastatin Trial (4-week)Placebo26+100+1+1+1Lovastatin 10 mg26-14 -22 -16 +5-19 0Colesevelam hydrochloride 2.3 g/Lovastatin 10 mg Together27-21 -34 -24 +4-27 -1Colesevelam hydrochloride 2.3 g/Lovastatin 10 mg Apart23-21 -32 -24 +2-28 -2In 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 10-17 years of age (mean age 14.1 years) with HeFH, taking stable dose of an FDA-approved statin (with LDL-C >130 mg/dL) or naive to lipid-lowering therapy (with LDL-C >160 mg/dL). This study had periods: single-blind, placebo stabilization period; an 8-week, randomized, double-blind, parallel-group, placebo-controlled treatment period; and an 18-week, open-label treatment period. Forty-seven (24%) patients were taking statins and 147 (76%) patients were statin-naive at screening. The mean baseline LDL-C at Day was approximately 199 mg/dL.During the double-blind treatment period, patients were assigned randomly to treatment: colesevelam hydrochloride 3.8 g/day (n=64), colesevelam hydrochloride 1.9 g/day (n=65), or placebo (n=65). In total, 186 patients completed the double-blind treatment period. After weeks of treatment, colesevelam hydrochloride 3.8 g/day significantly decreased plasma levels of LDL-C, non-HDL-C, TC, and Apo and significantly increased HDL-C. moderate, non-statistically significant increase in TG was observed versus placebo (Table 9).Table Response to Colesevelam Hydrochloride 3.8 Compared to Placebo in Pediatric Patients 10-17 Years of Age Mean Percent Change in Lipid Parameters from Baseline to Week 8Treatment DifferenceTCLDL-CApo BHDL-CNon-HDL-CTGFor triglycerides, median change from baseline (N=128)(N=128)(N=124)(N=128)(N=128)(N=128)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 prior to the first dose of randomized study medication.Results were based on the ITT population with LOCF.Colesevelam hydrochloride 3.8 vs Placebo-7p<=0.05 for lipid parameters compared to placebo -13 -8 +6 -11 +5During 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.. 14.2Type 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 tablets twice daily with lunch and dinner or as tablets with dinner alone.. MonotherapyThe efficacy of colesevelam hydrochloride 3.8 g/day as anti-diabetes monotherapy was evaluated in randomized double-blind, placebo-controlled trial involving 357 patients (176 colesevelam hydrochloride and 181 placebo) with type diabetes mellitus who were treatment-naive or had not received antihyperglycemic medication within 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 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 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 24-Week Placebo-Controlled Study of Colesevelam Hydrochloride Monotherapy in Patients with Type DiabetesColesevelam Hydrochloride3.8 g/dayPlaceboFPG fasting plasma glucoseHbA1c (%), MeanN175169Baseline8.258.17Change from baselineLeast-squares mean change calculated from an Analysis of Covariance model -0.260.01Treatment difference (p-value)-0.27 (p=0.013)FPG (mg/dL), MeanN172166Baseline172168Change from baseline -4.65.7Treatment difference (p-value)-10.3 (p=0.037Nominal p=value, not controlled for multiplicity testing)Table 11 Percent Change in Lipid Parameters in 24-Week Placebo-Controlled Study of Colesevelam Hydrochloride Monotherapy in Patients with Type DiabetesDose/DayNThe number of patients with analyzable data, i.e., baseline and post-treatment value (last observation carried forward), varied slightly among different parameters. The given represents the smallest number of patients included in the analysis for any parameter. TCLDL-CApo BHDL-CNon-HDL-CTGMedian change from baseline Colesevelam hydrochloride 3.8 g162-3.3p<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.) -10.0 -5.6 1.7-4.4 15.5Placebo1601.81.20.9-0.13.05.8. Add-on Combination TherapyThe efficacy of colesevelam hydrochloride 3.8 g/day in patients with type diabetes mellitus was evaluated in double-blind, placebo-controlled add-on therapy trials involving total of 1691 patients with baseline HbA1c 7.5-9.5%. 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 add-on combination therapy trials (metformin, sulfonylurea and insulin), treatment with colesevelam hydrochloride resulted in 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 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 hydrochlorides effects on HbA1c were also similar for the two dosing regimens (3 tablets with lunch and with dinner or 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 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 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 MetforminColesevelam hydrochloride 3.8 g/day or placebo was added to background anti-diabetic therapy in 26-week trial of 316 patients already receiving treatment with metformin alone (N=159) or metformin in combination with other oral agents (N=157). 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 26-Week Placebo-Controlled Study of Colesevelam Hydrochloride in Combination with Metformin in Patients with Type DiabetesTotal Patient PopulationMetformin AloneMetformin in Combination with Other Oral Anti-diabetic AgentsColesevelam Hydrochloride3.8 g/dayPlaceboColesevelam Hydrochloride3.8 g/dayPlaceboColesevelam Hydrochloride3.8 g/dayPlaceboHbA1c (%), MeanN14815279766976Baseline8.18.18.28.28.18.0Change from baselineLeast-squares mean change calculated from an Analysis of Covariance model -0.40.2-0.40.0-0.40.3Treatment difference (p-value)-0.5 (p<0.001)-0.5 (p=0.002)-0.6 (p<0.001)FPG (mg/dL), MeanN14915279767076Baseline178174184180171168Change from baseline -311-78013Treatment difference (p-value)-14 (p=0.01)-14 (p=0.07)-14 (p=0.10)Table 13 Percent Change in Lipid Parameters in 26-Week Placebo-Controlled Study of Colesevelam Hydrochloride in Combination with Metformin in Patients with Type DiabetesDose/DayNThe number of patients with analyzable data, i.e., baseline and post-treatment value (last observation carried forward), varied slightly among different parameters. The given represents the smallest number of patients included in the analysis for any parameter. TCLDL-CApo BHDL-CNon-HDL-CTGMedian change from baseline Total Patient PopulationColesevelam hydrochloride 3.8 g125-4p<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.) -12 -4 1-6 12Placebo126344057Metformin AloneColesevelam hydrochloride 3.8 g66-3-9-21-415Placebo61201-248Metformin in Combination with Other Oral Anti-diabetic AgentsColesevelam hydrochloride 3.8 g59-6 -15 -6 1-7 8Placebo65477265. Add-on Combination Therapy with PioglitazoneColesevelam hydrochloride 3.8 g/day or placebo was added to background anti-diabetic therapy in 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 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 24-Week Placebo-Controlled Study of Colesevelam Hydrochloride in Combination with Pioglitazone-Based Therapy in Patients with Type DiabetesColesevelam Hydrochloride3.8 g/dayPlaceboHbA1c (%), MeanN271276Baseline8.28.1Change from baselineLeast-squares mean change calculated from an Analysis of Covariance model -0.34-0.02Treatment difference (p-value)-0.32 (0.0001)FPG (mg/dL), MeanN268270Baseline155157Change from baseline -4.8+9.9Treatment difference (p-value)-14.7 (<0.0001)Table 15 Percent Change in Lipid Parameters in 24-Week Placebo-Controlled Study of Colesevelam Hydrochloride in Combination with Pioglitazone-Based Therapy in Patients with Type DiabetesDose/DayNThe given represents the smallest number of patients included in the analysis for any parameter. TCLDL-CApo BHDL-CNon-HDL-CTGMedian change from baseline Total Patient CohortColesevelam hydrochloride 3.8 g262-3p<0.001 for lipid parameters compared to placebo -9 -5 +3-5 +14 Placebo262+3+7+4+1+5+2. Add-on Combination Therapy with SulfonylureaColesevelam hydrochloride 3.8 g/day or placebo was added to background anti-diabetic therapy in 26-week trial of 460 patients already treated with sulfonylurea alone (N=156) or sulfonylurea in combination with other oral agents (N=304). total of 72% of these patients were receiving at least half-maximal doses of sulfonylurea therapy. In combination with 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 26-Week Placebo-Controlled Study of Colesevelam Hydrochloride in Combination with Sulfonylurea in Patients with Type DiabetesTotal Patient PopulationSulfonylurea AloneSulfonylurea in Combination with Other Oral Anti-diabetic AgentsColesevelam Hydrochloride3.8 g/dayPlaceboColesevelam Hydrochloride3.8 g/dayPlaceboColesevelam Hydrochloride3.8 g/dayPlaceboHbA1c (%), Meann2182186980149138Baseline8.28.38.28.48.28.3Change from baselineLeast-squares mean change calculated from an Analysis of Covariance model -0.30.2-0.30.5-0.40.0Treatment difference-0.5-0.8-0.4(p-value)(p<0.001)(p<0.001)(p<0.001)FPG (mg/dL), Meann2182177080148137Baseline177181181186175178Change from baseline -410315-114Treatment difference-14-12-14(p-value)(p=0.009)(p=0.18)(p=0.03)Table 17 Percent Change in Lipid Parameters in 26-Week Placebo-Controlled Study of Colesevelam Hydrochloride in Combination with Sulfonylurea in Patients with Type DiabetesDose/DayNThe number of patients with analyzable data, i.e., baseline and post-treatment value (last observation carried forward), varied slightly among different parameters. The given represents the smallest number of patients included in the analysis for any parameter. TCLDL-CApo BHDL-CNon-HDL-CTG Median change from baseline Total Patient PopulationColesevelam hydrochloride 3.8 g186-5p<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.) -16 -6 1-6 20 Placebo193011011Sulfonylurea AloneColesevelam hydrochloride 3.8 g57-5-14 -5-1-617Placebo6801110-1Sulfonylurea in Combination with Other Oral Anti-diabetic AgentsColesevelam hydrochloride 3.8 g129-5-18 -7 1-621 Placebo125001012. Add-on Combination Therapy with InsulinColesevelam hydrochloride 3.8 g/day or placebo was added to background anti-diabetic therapy in 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 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 16-Week Placebo-Controlled Study of Colesevelam Hydrochloride in Combination with Insulin in Patients with Type DiabetesTotal Patient PopulationInsulin AloneInsulin in Combination with Oral Anti-diabetic AgentsColesevelam Hydrochloride3.8 g/dayPlaceboColesevelam Hydrochloride3.8 g/dayPlaceboColesevelam Hydrochloride3.8 g/dayPlaceboHbA1c (%), Meann14413654559081Baseline8.38.28.28.38.38.2Change from baselineLeast-squares mean change calculated from an Analysis of Covariance model -0.40.1-0.40.2-0.40.0Treatment difference-0.5-0.6-0.4(p-value)(p<0.001)(p<0.001)(p<0.001)FPG (mg/dL), Meann14413654559081Baseline165151165163165143Change from baseline 216817-414Treatment difference(p-value)-15 (p=0.08)-9 (p=0.51)-18 (p=0.09)Table 19 Percent Change in Lipid Parameters in 16-Week Placebo-Controlled Study of Colesevelam Hydrochloride in Combination with Insulin in Patients with Type DiabetesDose/DayNThe number of patients with analyzable data, i.e., baseline and post-treatment value (last observation carried forward), varied slightly among different parameters. The given represents the smallest number of patients included in the analysis for any parameter. TCLDL-CApo BHDL-CNon-HDL-CTGMedian change from baseline Total Patient CohortColesevelam hydrochloride 3.8 g129-3-12p<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.) -4-1-323 Placebo121111010Insulin AloneColesevelam hydrochloride 3.8 g46-3-12-50-319Placebo4824232-2Insulin in Combination with Oral Anti-diabetic AgentsColesevelam hydrochloride 3.8 g83-4-13-4-1-325 Placebo73-1-30-1-12.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1Clinical 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 18-86 years, 50% women, 90% Caucasians, 7% Blacks, 2% Hispanics, 1% Asians) and elevated LDL-C were treated with colesevelam hydrochloride 1.5 g/day to 4.5 g/day from to 24 weeks (total exposure 199 patient-years).Table Clinical Studies of Colesevelam Hydrochloride for Primary Hyperlipidemia: Adverse Reactions Reported in >= 2% of Patients and More Commonly than in PlaceboColesevelam HydrochloridePlaceboN=807N=258Constipation11.0%7.0%Dyspepsia8.3%3.5%Nausea4.2%3.9%Accidental injury3.7%2.7%Asthenia3.6%1.9%Pharyngitis3.2%1.9%Flu syndrome3.2%3.1%Rhinitis3.2%3.1%Myalgia2.1%0.4%. Pediatric Patients 10 to 17 Years of 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 PlaceboColesevelam HydrochloridePlaceboN=129N=65Nasopharyngitis6.2%4.6%Headache3.9%3.1%Fatigue3.9%1.5%Creatine Phosphokinase Increase2.3%0.0%Rhinitis2.3%0.0%Vomiting2.3%1.5%The reported adverse reactions during the additional 18-week open-label treatment period with colesevelam hydrochloride 3.8 per day were similar to those during the double-blind period and included headache (7.6%), nasopharyngitis (5.4%), upper respiratory tract infection (4.9%), influenza (3.8%), and nausea (3.8%).. Type Diabetes MellitusIn add-on combination and monotherapy double-blind, 12- to 26-week, placebo-controlled clinical trials in patients with type 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 mean hemoglobin A1c (HbA1c) of 8.2%, and 26% had past medical history suggestive of microvascular complications of diabetes.Table shows adverse reactions associated with the use of colesevelam hydrochloride in patients with type 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 Clinical Studies of Colesevelam Hydrochloride for Type Diabetes: Adverse Reactions Reported in >=2% of Patients and More Commonly than in PlaceboColesevelam HydrochloridePlaceboN=1022N=1010Constipation6.5%2.2%Hypoglycemia3.4%3.1%Dyspepsia2.8%1.0%Nausea2.6%1.6%Hypertension 2.6%1.9%Back Pain2.3%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 hypersensitivity reaction to colesevelam hydrochloride.. HypertriglyceridemiaPatients 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 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 median increase in serum TG of 5% compared to placebo (p=0.42) in 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 (0.3%) patients on placebo developed TG elevations >=1000 mg/dL.. Cardiovascular Adverse ReactionsDuring 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.

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 poly(allylamine hydrochloride) cross-linked with epichlorohydrin and alkylated with 1-bromodecane and (6-bromohexyl)-trimethylammonium bromide. The chemical name (IUPAC) of colesevelam hydrochloride is allylamine polymer with 1-chloro-2,3-epoxypropane, [6-(allylamino)-hexyl]trimethylammonium chloride and N-allyldecylamine, hydrochloride. The chemical structure of colesevelam hydrochloride is represented by the following formula:wherein (a) represents allyl amine monomer units that have not been alkylated by either of the 1-bromodecane or (6-bromohexyl)-trimethylammonium bromide alkylating agents or cross-linked by epichlorohydrin; (b) represents allyl amine units that have undergone cross-linking with epichlorohydrin; (c) represents allyl amine units that have been alkylated with decyl group; (d) represents allyl amine units that have been alkylated with (6-trimethylammonium) hexyl group, and represents number >=100 to indicate an extended polymer network. small amount of the amines are dialkylated and are not depicted in the formula above. No regular order of the groups is implied by the structure; cross-linking and alkylation are expected to occur randomly along the polymer chains. large amount of the amines are protonated. The polymer is depicted in the hydrochloride form; small amount of the halides are bromide. Colesevelam hydrochloride is hydrophilic and insoluble in water.Colesevelam hydrochloride tablets are off-white, oval, film-coated, solid tablets each containing 625 mg colesevelam hydrochloride. In addition, each tablet contains the following inactive ingredients: magnesium stearate, microcrystalline cellulose, silicon dioxide, HPMC (hydroxypropyl methylcellulose), and acetylated monoglyceride. The tablets are imprinted using water-soluble black ink (<5 calories per tablets).Colesevelam hydrochloride for oral suspension is citrus-flavored, white to pale yellow powder containing yellow granules packaged in packet containing 3.75 gram colesevelam hydrochloride. In addition, each packet contains the following inactive ingredients: lemon flavor, orange flavor, propylene glycol alginate, simethicone, aspartame, citric acid, medium chain triglycerides, and magnesium trisilicate (<5 calories per 3.75 gram single-dose packet). PHENYLKETONURICS: Colesevelam hydrochloride for oral suspension contains 27 mg phenylalanine per 3.75 gram dose.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Obtain lipid parameters, including serum triglyceride (TG) levels, before starting colesevelam hydrochloride (2.1).The recommended dosage for adults and 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 diabetes mellitus is 3.75 grams daily. Colesevelam hydrochloride should be taken as follows (2.2, 2.4):TabletsTake tablets once daily or tablets twice daily with meal and liquid.For Oral SuspensionTake one packet once daily with meal. To prepare, empty the entire contents of one packet into glass or cup. Add cup of water, fruit juice, or diet soft drinks. Stir well and drink.. 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. The recommended dosage for adults with type diabetes mellitus is 3.75 grams daily. Colesevelam hydrochloride should be taken as follows (2.2, 2.4):. 2.1Testing Prior to Initiation of Colesevelam Hydrochloride. Obtain lipid parameters, including triglyceride (TG) levels, before starting colesevelam hydrochloride. Colesevelam hydrochloride is contraindicated in patients with TG levels >500 mg/dL [see Contraindications (4) and Warnings and Precautions (5.1)].. 2.2Recommended Dosage in Primary Hyperlipidemia and Type Diabetes Mellitus. 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. The recommended dosage of colesevelam hydrochloride for adults with type diabetes mellitus is 3.75 grams daily. Colesevelam hydrochloride should be taken as follows:. TabletsTake tablets once daily or tablets twice daily. Due to tablet size, colesevelam hydrochloride for oral suspension is recommended for use in the pediatric population.. For Oral SuspensionTake one packet once daily.. 2.3Important 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.. 2.4Administration Instructions. TabletsTake 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)]. For Oral SuspensionTo prepare, empty the entire contents of one packet into glass or cup. Add cup (8 ounces) of water, fruit juice, or diet soft drinks. Stir well and drink. Take colesevelam hydrochloride oral suspension with meals. Do not take colesevelam hydrochloride oral suspension in its dry form. Due to tablet size, colesevelam hydrochloride for oral suspension is recommended for use in the pediatric population.

DRUG INTERACTIONS SECTION.

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

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

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)].

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.. Type Diabetes MellitusOf 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.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Colesevelam hydrochloride 625 mg tablets are supplied as off-white, solid tablets imprinted with the word Sankyo and C01 on one side and are available as follows:Bottles of 180 NDC 51660-996-28Colesevelam hydrochloride 3.75 gram packets for oral suspension contain white to pale yellow powder containing yellow granules and are available as follows:Cartons of 30 packets NDC 51660-995-30. Bottles of 180 NDC 51660-996-28. Cartons of 30 packets NDC 51660-995-30. Store at 25C (77F); excursions permitted to 15-30C (59-86F) [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). improve glycemic control in adults with type diabetes mellitus (1.2).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 dyslipidemias. 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 diabetes mellitus (1.2).. Do not use for treatment of type diabetes or for diabetic ketoacidosis.. Not studied in Fredrickson Type I, III, IV, and dyslipidemias. 1.1Primary Hyperlipidemia. Colesevelam hydrochloride is indicated as an adjunct to diet and exercise to reduce elevated low-density lipoprotein cholesterol (LDL-C) in adults with primary hyperlipidemia. Colesevelam hydrochloride is indicated to reduce LDL-C levels in boys and postmenarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia (HeFH) who are unable to reach LDL-C target levels despite an adequate trial of dietary therapy and lifestyle modification. 1.2Type Diabetes Mellitus. Colesevelam hydrochloride is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type diabetes mellitus. 1.3Limitations 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 (2.2, 2.4)]:. TabletsAdvise 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.. For Oral SuspensionInstruct patients to empty the entire contents of one packet into glass or cup and add cup (8 ounces) of water, fruit juice, or diet soft drinks. Stir well and drink. Advise patients to take colesevelam hydrochloride oral suspension with meals. Advise patient to not take colesevelam hydrochloride oral suspension in its dry form.. 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)].

LACTATION SECTION.

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.

MECHANISM OF ACTION SECTION.

12.1Mechanism of Action. Primary Hyperlipidemia: Colesevelam hydrochloride, the active pharmaceutical ingredient, 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.. Type Diabetes Mellitus: The mechanism by which colesevelam hydrochloride improves glycemic control is unknown.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1Carcinogenesis, 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).. 13.2Animal 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.

PRINCIPAL DISPLAY PANEL. NDC 51660-996-28Colesevelam Hydrochloride Tablets625 mgRx only 180 Tablets. PRINCIPAL DISPLAY PANEL NDC 51660-996-28 Colesevelam Hydrochloride Tablets 625 mg 180 Tablets Rx Only.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Primary HyperlipidemiaThe 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.. Type Diabetes MellitusThe safety and effectiveness of colesevelam hydrochloride to improve glycemic control in pediatric patients with type diabetes mellitus have not been established. Effectiveness was not demonstrated in 6-month, adequate and well-controlled study conducted in 141 colesevelam hydrochloride-treated pediatric patients aged 10 to 17 years with type diabetes mellitus.

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. In the diabetes clinical studies, therapeutic response to colesevelam hydrochloride, as reflected by 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.

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.. Elimination. MetabolismColesevelam hydrochloride is not metabolized systemically and does not interfere with systemic drug-metabolizing enzymes such as cytochrome P450.. 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 Interaction StudiesDrug 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)With verapamil, the dose of colesevelam hydrochloride was 4.5 g. DrugDoseCo-administered1 hr prior to Colesevelam Hydrochloride4 hrs prior to Colesevelam HydrochlorideAUC0- Cmax AUC0- Cmax AUC0- Cmax N/A not availableCyclosporine200 mg-34%-44%N/AN/AN/AN/AEthinyl EstradiolOral contraceptive containing norethindrone and ethinyl estradiol 0.035 mg-24%-24%-18%-1%-12%0%Glimepiride4 mg-18%-8%N/AN/A-6%3%Glipizide20 mg-12%-13%N/AN/A-4%0%Glyburide3 mg-32%-47%-20%-15%-7%4%Levothyroxine600 ug-22%-33%6%-2%1%8%Metformin ER1500 mg44%8%N/AN/AN/AN/ANorethindrone mg-1%-20%5%-3%6%7%Olmesartan Medoxomil40 mg -39%-28%N/AN/A-15%-4%Repaglinide2 mg-7%-19%-6%-1%N/AN/AVerapamil Sustained Release240 mg-31%-11%N/AN/AN/AN/A.

POSTMARKETING EXPERIENCE SECTION.

6.2Post-marketing Experience. The following additional adverse reactions have been identified during post-approval use of colesevelam hydrochloride. Because these reactions are reported voluntarily from population of uncertain size, it is generally not possible to reliably estimate their frequency or establish causal relationship to drug exposure.Adverse Reactions Resulting from Drug Interactions [see Drug Interactions (7)]: Increased seizure activity or decreased phenytoin levels in patients receiving phenytoin, reduced International Normalized Ratio (INR) in patients receiving warfarin therapy, and elevated thyroid-stimulating hormone (TSH) in patients receiving thyroid hormone replacement therapyGastrointestinal: Bowel obstruction (in patients with history of bowel obstruction or resection), dysphagia or esophageal obstruction (occasionally requiring medical intervention), fecal impaction, pancreatitis, abdominal distension, exacerbation of hemorrhoids, and increased transaminasesLaboratory Abnormalities: Hypertriglyceridemia.

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.. Data. Human DataThere are no adequate and well-controlled studies of colesevelam hydrochloride use in pregnant women. In the postmarketing setting there have been infrequent reports of pregnancy with use of colesevelam hydrochloride and causal association with congenital anomalies has not been established.. Animal DataIn pregnant rats given dietary doses of 0.3, 1.0, 3.0 g/kg/day colesevelam hydrochloride from gestation days through 17, no teratogenic effects were observed. Exposures at 3.0 g/kg/day were times the human exposure at 3.75 g/day MRHD, based on body surface area (mg/m2).In pregnant rabbits given oral gavage doses of 0.1, 0.5, 1.0 g/kg/day colesevelam hydrochloride from gestation days through 18, no teratogenic effects were observed. Exposures at 1.0 g/kg/day were times the human exposure at 3.75 g/day MRHD, based on body surface area (mg/m2).In pregnant rats given oral gavage doses of 0.1, 0.3, 1.0 g/kg/day colesevelam hydrochloride from gestation day through lactation day 21 (weaning), no adverse effects on survival and development were observed. Exposures at 1.0 g/kg/day were times the human exposure at 3.75 g/day MRHD, based on body surface area (mg/m2).

RENAL IMPAIRMENT SUBSECTION.

8.6Renal Impairment. Type Diabetes MellitusOf 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 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 and patients, respectively, had moderate renal insufficiency.

SPL UNCLASSIFIED SECTION.

1.1Primary Hyperlipidemia. Colesevelam hydrochloride is indicated as an adjunct to diet and exercise to reduce elevated low-density lipoprotein cholesterol (LDL-C) in adults with primary hyperlipidemia. Colesevelam hydrochloride is indicated to reduce LDL-C levels in boys and postmenarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia (HeFH) who are unable to reach LDL-C target levels despite an adequate trial of dietary therapy and lifestyle modification.

STORAGE AND HANDLING SECTION.

Store at 25C (77F); excursions permitted to 15-30C (59-86F) [see USP Controlled Room Temperature]. Protect from moisture. Brief exposure to 40C (104F) does not adversely affect colesevelam hydrochloride tablets.

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.. Data. Human DataThere are no adequate and well-controlled studies of colesevelam hydrochloride use in pregnant women. In the postmarketing setting there have been infrequent reports of pregnancy with use of colesevelam hydrochloride and causal association with congenital anomalies has not been established.. Animal DataIn pregnant rats given dietary doses of 0.3, 1.0, 3.0 g/kg/day colesevelam hydrochloride from gestation days through 17, no teratogenic effects were observed. Exposures at 3.0 g/kg/day were times the human exposure at 3.75 g/day MRHD, based on body surface area (mg/m2).In pregnant rabbits given oral gavage doses of 0.1, 0.5, 1.0 g/kg/day colesevelam hydrochloride from gestation days through 18, no teratogenic effects were observed. Exposures at 1.0 g/kg/day were times the human exposure at 3.75 g/day MRHD, based on body surface area (mg/m2).In pregnant rats given oral gavage doses of 0.1, 0.3, 1.0 g/kg/day colesevelam hydrochloride from gestation day through lactation day 21 (weaning), no adverse effects on survival and development were observed. Exposures at 1.0 g/kg/day were times the human exposure at 3.75 g/day MRHD, based on body surface area (mg/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 HyperlipidemiaThe 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.. Type Diabetes MellitusThe safety and effectiveness of colesevelam hydrochloride to improve glycemic control in pediatric patients with type diabetes mellitus have not been established. Effectiveness was not demonstrated in 6-month, adequate and well-controlled study conducted in 141 colesevelam hydrochloride-treated pediatric patients aged 10 to 17 years with type diabetes mellitus.. 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.. Type Diabetes MellitusOf 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.. 8.6Renal Impairment. Type Diabetes MellitusOf 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 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 and patients, respectively, had moderate renal insufficiency.

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).Risks in Patients with Phenylketonuria (PKU): Phenylalanine can be harmful to patients with phenylketonuria. Colesevelam hydrochloride for oral suspension contains 27 mg phenylalanine per 3.75 gram packet (5.5, 11).. 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).. Risks in Patients with Phenylketonuria (PKU): Phenylalanine can be harmful to patients with phenylketonuria. Colesevelam hydrochloride for oral suspension contains 27 mg phenylalanine per 3.75 gram packet (5.5, 11).. 5.1Hypertriglyceridemia 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. In trials in patients with type diabetes, greater increases in TG levels occurred when colesevelam hydrochloride was used as monotherapy (median increase 9.7% compared to placebo) and when colesevelam hydrochloride was used in combination with pioglitazone (median increase 11% compared to placebo in combination with pioglitazone), sulfonylureas (median increase 18% compared to placebo in combination with sulfonylureas), and insulin (median increase 22% compared to placebo in combination with insulin) [see Adverse Reactions (6.1)]. Obtain lipid parameters, including TG levels, before starting 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)].. 5.2Gastrointestinal 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.. 5.3Vitamin 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)]. 5.5 Risks in Patients with Phenylketonuria (PKU). Phenylalanine can be harmful to patients with PKU. Colesevelam hydrochloride for oral suspension contains phenylalanine, component of aspartame. Each 3.75 gram packet contains 27 mg of phenylalanine. Before prescribing colesevelam hydrochloride for oral suspension to patient with PKU, consider the combined daily amount of phenylalanine from all sources, including colesevelam hydrochloride for oral suspension.