Colesevelam Hydrochloride

Colesevelam hydrochloride is a bile acid sequestrant indicated as an adjunct to diet and exercise to:

• reduce elevated low-density lipoprotein cholesterol (LDL-C) in adults with primary hyperlipidemia ( 1.1 ).
• reduce LDL-C levels in boys and postmenarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia (HeFH), unable to reach LDL-C target levels despite an adequate trial of diet and lifestyle modification ( 1.1 ).
• improve glycemic control in adults with type 2 diabetes mellitus ( 1.2 ). Limitations of Use ( 1.3 ):
• Do not use for treatment of type 1 diabetes or for diabetic ketoacidosis.
• Not studied in Fredrickson Type I, III, IV, and V dyslipidemias

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

1.2 Type 2 Diabetes Mellitus Colesevelam hydrochloride is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

1.3 Limitations of Use Colesevelam hydrochloride should not be used for the treatment of type 1 diabetes or for the treatment of diabetic ketoacidosis. Colesevelam hydrochloride has not been studied in Fredrickson Type I, III, IV, and V dyslipidemias.

Off-white to light yellow colored, oval, film coated tablets imprinted "C625" on one side. Tablets: 625 mg ( 3 )

Colesevelam hydrochloride is contraindicated in patients with: Serum TG concentrations greater than 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 greater than 500 mg/dL ( 4 ) Patients with a history of hypertriglyceridemia-induced pancreatitis ( 4 ) Patients with a history of bowel obstruction ( 4 )

Hypertriglyceridemia and Pancreatitis: Colesevelam hydrochoride can increase TG. Hypertriglyceridemia can cause acute pancreatitis. Monitor lipids, including TG . Instruct patients to discontinue colesevelam hydrochoride and seek prompt medical attention if the symptoms of acute pancreatitis occur ( 5.1 ). Gastrointestinal Obstruction: Cases of bowel obstruction have occurred. Colesevelam hydrochoride 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 K or Fat-Soluble Vitamin Deficiencies: Colesevelam hydrochoride may decrease absorption of fat-soluble vitamins. Patients with a susceptibility to deficiencies of vitamin K (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 4 hours prior to colesevelam hydrochoride ( 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 4 hours prior to colesevelam hydrochoride ( 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. In trials in patients with type 2 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 greater than 500 mg/dL or patients with a 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 a 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 K or Fat-Soluble Vitamin Deficiencies Colesevelam hydrochloride may decrease the absorption of fat-soluble vitamins A, D, E, and K. Patients with a susceptibility to deficiencies of vitamin K (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 4 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 a known interaction at least 4 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 a narrow therapeutic index, consider administering at least 4 hours prior to colesevelam hydrochloride [see Clinical Pharmacology ( 12.3 )].

The following important adverse reactions are described below and elsewhere in the labeling: Hypertriglyceridemia and Pancreatitis [see Warnings and Precautions ( 5.1 )] Gastrointestinal Obstruction [see Warnings and Precautions ( 5.2 )] Vitamin K or Fat-Soluble Vitamin Deficiencies [see Warnings and Precautions ( 5.3 )] In clinical trials, the most common (incidence ≥2% and greater than placebo) adverse reactions with Colesevelam hydrochloride included constipation, dyspepsia, and nausea ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Ascend Laboratories, LLC at 1-877-272-7901 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Studies Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in clinical studies of another drug and may not reflect the rates observed in practice. Primary Hyperlipidemia In 7 double-blind, placebo-controlled clinical trials, 807 patients with primary hyperlipidemia (age range 18 to 86 years, 50% women, 90% Caucasians, 7% Blacks, 2% Hispanics, 1% Asians) and elevated LDL-C were treated with colesevelam hydrochloride 1.5 g/day to 4.5 g/day from 4 to 24 weeks (total exposure 199 patient-years). Table 1 Clinical Studies of Colesevelam Hydrochloride for Primary Hyperlipidemia: Adverse Reactions Reported in ≥ 2% of Patients and More Commonly than in Placebo Colesevelam hydrochloride N = 807 Placebo N = 258 Constipation 11.0% 7.0% Dyspepsia 8.3% 3.5% Nausea 4.2% 3.9% Accidental injury 3.7% 2.7% Asthenia 3.6% 1.9% Pharyngitis 3.2% 1.9% Flu syndrome 3.2% 3.1% Rhinitis 3.2% 3.1% Myalgia 2.1% 0.4% Pediatric Patients 10 to 17 Years of Age In an 8-week double-blind, placebo-controlled study, boys and post-menarchal girls, 10 to 17 years of age, with HeFH (n=194), were treated with colesevelam hydrochloride tablets (1.9 to 3.8 g, daily) or placebo tablets. Table 2 Clinical Study of Colesevelam Hydrochloride for Primary Hyperlipidemia in HeFH Pediatric Patients: Adverse Reactions Reported in ≥2% of Patients and More Commonly than in Placebo Colesevelam Hydrochloride N = 129 Placebo N = 65 Nasopharyngitis 6.2% 4.6% Headache 3.9% 3.1% Fatigue 3.9% 1.5% Creatine Phosphokinase Increase 2.3% 0.0% Rhinitis 2.3% 0.0% Vomiting 2.3% 1.5% The reported adverse reactions during the additional 18-week open-label treatment period with colesevelam hydrochloride 3.8 g per day were similar to those during the double-blind period and included headache (7.6%), nasopharyngitis (5.4%), upper respiratory tract infection (4.9%), influenza (3.8%), and nausea (3.8%). Type 2 Diabetes Mellitus In 5 add-on combination and 1 monotherapy double-blind, 12- to 26-week, placebo-controlled clinical trials in patients with type 2 diabetes mellitus, 1022 patients were treated with colesevelam hydrochloride. The mean exposure duration was 20 weeks (total exposure 393 patient-years). Patients were to receive 3.8 grams of colesevelam hydrochloride per day. The mean age of patients was 55.7 years, 52.8 percent of the population was male and 61.9% were Caucasian, 4.8% were Asian, and 15.9% were Black or African American. At baseline the population had a mean hemoglobin A1c (HbA1c) of 8.2%, and 26% had past medical history suggestive of microvascular complications of diabetes. Table 3 shows adverse reactions associated with the use of colesevelam hydrochloride in patients with type 2 diabetes. These adverse reactions were not present at baseline, occurred more commonly on colesevelam hydrochloride than on placebo, and occurred in at least 2% of patients treated with colesevelam hydrochloride. Table 3 Clinical Studies of Colesevelam Hydrochloride for Type 2 Diabetes: Adverse Reactions Reported in ≥ 2% of Patients and More Commonly than in Placebo Colesevelam Hydrochloride N=1022 Placebo N= 1010 Constipation 6.5% 2.2% Hypoglycemia 3.4% 3.1% Dyspepsia 2.8% 1.0% Nausea 2.6% 1.6% Hypertension 2.6% 1.9% Back Pain 2.3% 1.3% A total of 5.3% of colesevelam hydrochloride-treated patients and 3.6% of placebo-treated patients were discontinued from the diabetes trials due to adverse reactions. This difference was driven mostly by gastrointestinal adverse reactions such as abdominal pain and constipation. One patient in the add-on to sulfonylurea trial discontinued due to body rash and mouth blistering that occurred on the first day of dosing of colesevelam hydrochloride, which may represent a hypersensitivity reaction to colesevelam hydrochloride. Hypertriglyceridemia Patients with fasting serum TG levels above 500 mg/dL were excluded from the diabetes clinical trials. In the diabetes trials, 1292 (67.7%) patients had baseline fasting serum TG levels less than 200 mg/dL, 426 (22.3%) had baseline fasting serum TG levels between 200 and less than 300 mg/dL, 175 (9.2%) had baseline fasting serum TG levels between 300 and 500 mg/dL, and 16 (0.8%) had fasting serum TG levels greater than or equal to 500 mg/dL. The median baseline fasting TG concentration for the study population was 160 mg/dL; the median post-treatment fasting TG was 180 mg/dL in the colesevelam hydrochloride group and 162 mg/dL in the placebo group. Colesevelam hydrochloride therapy resulted in a median placebo-corrected increase in serum TG of 9.7% (p=0.03) in the monotherapy study and of 5% (p=0.22), 11% (p<0.001), 18% (p<0.001), and 22% (p<0.001), when added to metformin, pioglitazone, sulfonylureas, and insulin, respectively. In comparison, colesevelam hydrochloride resulted in a median increase in serum TG of 5% compared to placebo (p=0.42) in a 24-week monotherapy lipid-lowering trial. Fasting TG concentrations ≥500 mg/dL occurred in 0.9% of colesevelam hydrochloride -treated patients compared to 0.7% of placebo-treated patients in the diabetes trials. Among these patients, the TG concentrations with colesevelam hydrochloride (median 606 mg/dL; interquartile range 570-794 mg/dL) were similar to that observed with placebo (median 663 mg/dL; interquartile range 542-984 mg/dL). Five (0.6%) patients on colesevelam hydrochloride and 3 (0.3%) patients on placebo developed TG elevations >1000 mg/dL. Cardiovascular Adverse Reactions During the diabetes trials, the incidence of patients with serious adverse reactions involving the cardiovascular system was 2.2% (22/1022) in the colesevelam hydrochloride group and 1% (10/1010) in the placebo group. These overall rates included disparate events (e.g., myocardial infarction, aortic stenosis, and bradycardia); therefore, the significance of this imbalance is unknown.

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

Concomitant use with colesevelam hydrochoride may decrease the exposure of the following drugs: Drugs with a narrow therapeutic index (e.g., cyclosporine), phenytoin, thyroid hormone replacement therapy, warfarin, oral contraceptives containing ethinyl estradiol and norethindrone, olmesartan medoxomil, and sulfonylureas (glimepiride, glipizide, glyburide). Administer these drugs 4 hours prior to colesevelam hydrochloride tablets. For patients on warfarin, monitor International Normalized Ratio (INR) frequently during initiation then periodically ( 7.1 ). Concomitant use with colesevelam hydrochoride may increase the exposure of the following drugs: Metformin extended release. Monitor patients' glycemic control ( 7.2 ).

7.1 Colesevelam Hydrochloride Drug Interactions that Decrease the Exposure of the Concomitant Medication Table 4 includes a list of drugs that decrease exposure of the concomitant medication when administered concomitantly with colesevelam hydrochloride and instructions for preventing or managing them. Table 4 Colesevelam Hydrochloride Drug Interactions that Decrease the Exposure of the Concomitant Medication Drugs with a Narrow Therapeutic Index Clinical Impact: Concomitant use with colesevelam hydrochloride may decrease the exposure of the narrow therapeutic index drug. In vivo drug interactions studies showed a decrease in exposure of cyclosporine when coadministered with colesevelam hydrochloride [see Clinical Pharmacology ( 12.3 )]. Intervention: Administer the narrow therapeutic index drug at least 4 hours prior to colesevelam hydrochloride. Monitor drug levels when appropriate. Examples: Cyclosporine Phenytoin Clinical Impact: There have been postmarketing reports of increased seizure activity or decreased phenytoin levels in patients receiving phenytoin [see Adverse Reactions ( 6.2 )]. Intervention: Administer phenytoin 4 hours prior to colesevelam hydrochloride. Thyroid Hormone Replacement Therapy Clinical Impact: In vivo drug interactions studies showed a decrease in exposure of levothyroxine when coadministered with colesevelam hydrochloride [see Clinical Pharmacology ( 12.3 )]. There have been postmarketing reports of elevated thyroid-stimulating hormone (TSH) in patients receiving thyroid hormone replacement therapy [see Adverse Reactions ( 6.2 )]. Intervention: Administer thyroid hormone replacement therapy 4 hours prior to colesevelam hydrochloride. Warfarin Clinical Impact: There have been postmarketing reports of reduced INR in patients receiving warfarin therapy [see Adverse Reactions ( 6.2 )]. Intervention: Monitor INR frequently during colesevelam hydrochloride initiation then periodically thereafter. Oral Contraceptives Containing Ethinyl Estradiol and Norethindrone Clinical Impact: In vivo drug interactions studies showed a decrease in exposure of ethinyl estradiol and norethindrone when coadministered with colesevelam hydrochloride [see Clinical Pharmacology ( 12.3 )]. Intervention: Administer oral contraceptives containing ethinyl estradiol and norethindrone 4 hours prior to colesevelam hydrochloride. Olmesartan Medoxomil Clinical Impact: In vivo drug interactions studies showed a decrease in olmesartan medoxomil when coadministered with colesevelam hydrochloride [see Clinical Pharmacology ( 12.3 )]. Intervention: Administer olmesartan medoxomil 4 hours prior to colesevelam hydrochloride. Sulfonylureas Clinical Impact: In vivo drug interactions studies showed a decrease in sulfonylureas when coadministered with colesevelam hydrochloride [see Clinical Pharmacology ( 12.3 )]. Intervention: Administer sulfonylureas 4 hours prior to colesevelam hydrochloride. Examples: Glimepiride, glipizide, and glyburide Oral Vitamin Supplements Clinical Impact: Colesevelam hydrochloride may decrease the absorption of fat-soluble vitamins A, D, E, and K [see Warnings and Precautions ( 5.3 )]. Intervention: Patients on oral vitamin supplementation should take their vitamins at least 4 hours prior to colesevelam hydrochloride.

7.2 Colesevelam Hydrochloride Drug Interactions that Increase the Exposure of the Concomitant Medication Table 5 Colesevelam Hydrochloride Drug Interactions that Increase the Exposure of the Concomitant Medication Metformin Extended Release (ER) Clinical Impact: In vivo drug interactions studies showed an increase in metformin extended release (ER) when coadministered with colesevelam hydrochloride [see Clinical Pharmacology ( 12.3 )]. Intervention: Monitor patients' glycemic control.

8.1 Pregnancy Risk Summary Colesevelam hydrochloride is not absorbed systemically following oral administration, and maternal use is not expected to result in fetal exposure to the drug. Limited available data on the use of colesevelam hydrochloride are insufficient to determine a drug-associated risk of major congenital malformations or miscarriage. In animal reproduction studies, no evidence of either maternal or fetal toxicity was found in rats or rabbits exposed to colesevelam hydrochloride during the period of fetal organogenesis at 8 and 5 times, respectively, the maximum recommended human dose (MRHD) of 3.75 g/day, based on body surface area (mg/m 2 ). No adverse effects on offspring survival and development were observed in rats administered 5 times the MRHD (see Data).Colesevelam hydrochloride may decrease the absorption of fat-soluble vitamins [see Warnings and Precautions ( 5.3 )]. There are no data available on the effect of colesevelam hydrochloride on the absorption of fat-soluble vitamins in pregnant women. If the patient becomes pregnant while taking colesevelam hydrochloride, the patient should be advised of the lack of known clinical benefit with continued use during pregnancy. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Human Data There are no adequate and well-controlled studies of colesevelam hydrochloride use in pregnant women. In the postmarketing setting there have been infrequent reports of pregnancy with use of colesevelam hydrochloride and a causal association with congenital anomalies has not been established. Animal Data In pregnant rats given dietary doses of 0.3, 1.0, 3.0 g/kg/day colesevelam hydrochloride from gestation days 7 through 17, no teratogenic effects were observed. Exposures at 3.0 g/kg/day were 8 times the human exposure at 3.75 g/day MRHD, based on body surface area (mg/m 2 ). In pregnant rabbits given oral gavage doses of 0.1, 0.5, 1.0 g/kg/day colesevelam hydrochloride from gestation days 6 through 18, no teratogenic effects were observed. Exposures at 1.0 g/kg/day were 5 times the human exposure at 3.75 g/day MRHD, based on body surface area (mg/m 2 ). In pregnant rats given oral gavage doses of 0.1, 0.3, 1.0 g/kg/day colesevelam hydrochloride from gestation day 6 through lactation day 21 (weaning), no adverse effects on survival and development were observed. Exposures at 1.0 g/kg/day were 5 times the human exposure at 3.75 g/day MRHD, based on body surface area (mg/m 2 ).

8.2 Lactation Risk Summary Colesevelam hydrochloride is not absorbed systemically by the mother following oral administration, and breastfeeding is not expected to result in exposure of the child to colesevelam hydrochloride.

8.3 Females and Males of Reproductive Potential Contraception Use of colesevelam hydrochloride may reduce the efficacy of oral contraceptives. Advise patients to take oral contraceptives at least 4 hours prior to taking colesevelam hydrochloride [see Drug Interactions ( 7 )].

8.4 Pediatric Use Primary Hyperlipidemia The safety and effectiveness of colesevelam hydrochloride to reduce LDL-C levels in boys and postmenarchal girls 10 to 17 years of age with HeFH who are unable to reach LDL-C target levels despite an adequate trial of dietary therapy and lifestyle modification have been established. Use of colesevelam hydrochloride for this indication is supported by a study in 129 colesevelam hydrochloride-treated pediatric patients aged 10 to 17 years with HeFH [see Clinical Studies ( 14.1 )]. Adverse reactions commonly observed in pediatric patients compared to placebo, but not in adults, included headache (3.9%), creatine phosphokinase increase (2.3%), and vomiting (2.3%) [see Adverse Reactions ( 6.1 )]. There were no significant effects on fat-soluble vitamin levels or clotting factors in the adolescent boys or girls relative to placebo. Due to colesevelam hydrochloride tablet size, colesevelam hydrochloride for oral suspension is recommended for use in the pediatric population [see Dosage and Administration ( 2.2 , 2.4 )]. The safety and effectiveness of colesevelam hydrochloride in pediatric patients with HeFH less than 10 years of age or in premenarchal females have not been established. Type 2 Diabetes Mellitus The safety and effectiveness of colesevelam hydrochloride to improve glycemic control in pediatric patients with type 2 diabetes mellitus have not been established. Effectiveness was not demonstrated in a 6-month, adequate and well-controlled study conducted in 141 colesevelam hydrochloride -treated pediatric patients aged 10 to 17 years with type 2 diabetes mellitus.

8.5 Geriatric Use Primary Hyperlipidemia Of the 1350 patients enrolled in the hyperlipidemia clinical studies, 349 (26%) were ≥65 years old, and 58 (4%) were ≥75 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Type 2 Diabetes Mellitus Of the 2048 patients enrolled in the six diabetes studies, 397 (19%) were ≥65 years old, and 36 (2%) were ≥75 years old. In these trials, colesevelam hydrochloride 3.8 g/day or placebo was added onto background anti-diabetic therapy. No overall differences in safety or effectiveness were observed between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.6 Renal Impairment Type 2 Diabetes Mellitus Of the 2048 patients enrolled in the six diabetes studies, 807 (39%) had mild renal insufficiency (creatinine clearance [CrCl] 50-<80 mL/min), 61 (3%) had moderate renal insufficiency (CrCl 30-<50 mL/min), and none had severe renal insufficiency (CrCl <30 mL/min), as estimated from baseline serum creatinine using the Modification of Diet in Renal Disease (MDRD) equation. No overall differences in safety or effectiveness were observed between patients with CrCl <50 mL/min (n=53) and those with a CrCl ≥50 mL/min (n=1,075) in the add-on to metformin, sulfonylureas, and insulin diabetes studies. In the monotherapy study and add-on to pioglitazone study, only 3 and 5 patients, respectively, had moderate renal insufficiency.

Primary Hyperlipidemia : Colesevelam hydrochloride, the active pharmaceutical ingredient in colesevelam hydrochloride, is a non-absorbed, lipid-lowering polymer that binds bile acids in the intestine, impeding their reabsorption. As the bile acid pool becomes depleted, the hepatic enzyme, cholesterol 7-α-hydroxylase, is upregulated, which increases the conversion of cholesterol to bile acids. This causes an increased demand for cholesterol in the liver cells, resulting in the dual effect of increasing transcription and activity of the cholesterol biosynthetic enzyme, HMG-CoA reductase, and increasing the number of hepatic LDL receptors. These compensatory effects result in increased clearance of LDL-C from the blood, resulting in decreased serum LDL-C levels. Serum TG levels may increase or remain unchanged. Type 2 Diabetes Mellitus: The mechanism by which colesevelam hydrochloride improves glycemic control is unknown.