Colesevelam

INDICATIONS & USAGE Colesevelam hydrochloride is a bile acid sequestrant indicated as an adjunct to diet and exercise to: reduce elevated low-density lipoprotein cholesterol (LDL-C) in adults with primary hyperlipidemia ( 1.1 ). reduce LDL-C levels in boys and postmenarchal girls, 10 to 17 years of age, with heteroz ygous familial hypercholesterolemia (HeFH) ( 1.1 ). Limitations of Use ( 1.3 ): Do not use for treatment of type 1 diabetes or for diabetic ketoacidosis. The effect on cardiovascular morbidity and mortality has not been determined. Not studied in type 2 diabetes with a dipeptidyl peptidase 4 inhibitor. Not studied in Fredrickson Type I, III, IV, and V dyslipidemias. Not studied in children less than 10 years of age or in premenarchal girls. 1.1 Primary Hyperlipidemia Colesevelam hydrochloride for oral suspension 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 for oral suspension is indicated to reduce LDL-C levels in boys and postmenarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia (HeFH) who are unable to reach LDL-C target levels despite an adequate trial of dietary therapy and lifestyle modification. 1.3 Limitations of Use Colesevelam hydrochloride should not be used for the treatment of type 1 diabetes or for the treatment of diabetic ketoacidosis. The effect of colesevelam hydrochloride on cardiovascular morbidity and mortality has not been determined. Colesevelam hydrochloride has not been studied in type 2 diabetes in combination with a dipeptidyl peptidase 4 inhibitor. Colesevelam hydrochloride has not been studied in Fredrickson Type I, III, IV, and V dyslipidemias. Colesevelam hydrochloride has not been studied in children younger than 10 years of age or in premenarchal girls.

DOSAGE AND ADMINISTRATION • Obtain lipid parameters, including serum triglyceride (TG) levels, before starting colesevelam hydrochloride for oral suspension ( 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 or one 1.875 grams packet twice daily. The recommended dosage for adults with type 2 diabetes mellitus is 3.75 grams daily or one 1.875 grams packet twice daily. Colesevelam hydrochloride for oral suspension should be taken as follows ( 2.2 , 2.4 ): For Oral Suspension Take one 3.75 grams packet once daily or one 1.875 grams packet twice daily with a meal. To prepare, empty the entire contents of one packet into the glass or cup. Add ½ cup to 1 cup of water, fruit juice, or diet soft drinks. Stir well and drink. 2.1 Testing Prior to Initiation of Colesevelam Hydrochloride for Oral Suspension Obtain lipid parameters, including triglyceride (TG) levels, before starting colesevelam hydrochloride for oral suspension. Colesevelam hydrochloride for oral suspension is contraindicated in patients with TG levels >500 mg/dL [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )] . 2.2 Recommended Dosage in Primary Hyperlipidemia and Type 2 Diabetes Mellitus The recommended dosage of colesevelam hydrochloride for oral suspension for adults and for boys and postmenarchal girls aged 10 to 17 years with primary hyperlipidemia is 3.75 grams daily or one 1.875 grams packet twice daily. The recommended dosage of colesevelam hydrochloride for oral suspension for adults with type 2 diabetes mellitus is 3.75 grams daily or one 1.875 grams packet twice daily. Colesevelam hydrochloride for oral suspension should be taken as follows: For Oral Suspension 1.875 gm – Take one packet twice daily 3.75 gm - Take one packet once daily. 2.3 Important Dosing Information for Primary Hyperlipidemia Colesevelam hydrochloride for oral suspension can be dosed at the same time as a statin, or colesevelam hydrochloride for oral suspension and the statin can be dosed apart . Monitor lipid levels within 4 to 6 weeks after initiation of colesevelam hydrochloride for oral suspension. 2.4 Administration Instructions For Oral Suspension To prepare, empty the entire contents of one packet into a glass or cup. Add ½ to 1 cup (4 to 8 ounces) of water, fruit juice, or diet soft drinks. Stir well and drink. Take colesevelam hydrochloride for oral suspension with meals. Do not take colesevelam hydrochloride for oral suspension in its dry form. Due to tablet size, colesevelam hydrochloride for oral suspension is recommended for use in the pediatric population.

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 K or Fat-Soluble Vitamin Deficiencies: Colesevelam hydrochloride 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 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 4 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 ). 5.1 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 >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) ]. 5.5 Risks in Patients with Phenylketonuria (PKU) Phenylalanine can be harmful to patients with PKU. Colesevelam hydrochloride for oral suspension contains phenylalanine, a component of aspartame. Each 3.75 gram packet contains 27 mg of phenylalanine. Before prescribing colesevelam hydrochloride for oral suspension to a patient with PKU, consider the combined daily amount of phenylalanine from all sources, including colesevelam hydrochloride for oral suspension.

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

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

ADVERSE REACTIONS The following important adverse reactions are described below and elsewhere in the labeling: Hypertriglyceridemia and Pancreatitis [see Warnings and Precautions (5.1) ] Gastrointestinal Obstruction [see Warnings and Precautions (5.2) ] Vitamin K or Fat-Soluble Vitamin Deficiencies [see Warnings and Precautions (5.3) ] In clinical trials, the most common (incidence ≥ 2% and greater than placebo) adverse reactions with colesevelam hydrochloride included constipation, dyspepsia, and nausea ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Bionpharma Inc. at 1-888-235-BION or 1-888-235-2466 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 years 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 weeks 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% 7% Dyspepsia 8.3% 3.5% Nausea 4.2% 3.9% Accidental injury 3.7% 2.7% Asthenia 3.6% 1.9% Pharyngitis 3.2% 1.9% Flu syndrome 3.2% 3.1% Rhinitis 3.2% 3.1% Myalgia 2.1% 0.4% Pediatric Patients 10 Years to 17 Years of Age In an 8-week double-blind, placebo-controlled study, boys and post-menarchal girls, 10 years to 17 years of age, with HeFH (n = 194), were treated with colesevelam hydrochloride tablets (1.9 g 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% Rhinitis 2.3% 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 = 1,022 Placebo N = 1,010 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, 1,292 (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 mg/dL 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 mg/dL to 794 mg/dL) were similar to that observed with placebo (median 663 mg/dL; interquartile range 542 mg/dL to 984 mg/dL). Five (0.6%) patients on colesevelam hydrochloride and 3 (0.3%) patients on placebo developed TG elevations > 1,000 mg/dL. Cardiovascular Adverse Reactions During the diabetes trials, the incidence of patients with serious adverse reactions involving the cardiovascular system was 2.2% (22/1,022) in the colesevelam hydrochloride group and 1% (10/1,010) 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

CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 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. 12.2 Pharmacodynamics A maximum therapeutic response to the lipid-lowering effects of colesevelam hydrochloride was achieved within 2 weeks and was maintained during long-term therapy. In the diabetes clinical studies, a therapeutic response to colesevelam hydrochloride, as reflected by a reduction in HbA1c, was initially noted following 4-6 weeks of treatment and reached maximal or near-maximal effect after 12-18 weeks of treatment. 12.3 Pharmacokinetics Absorption Colesevelam hydrochloride is a hydrophilic, water-insoluble polymer that is not hydrolyzed by digestive enzymes and is not absorbed. Distribution Colesevelam hydrochloride is not absorbed, and therefore, its distribution is limited to the gastrointestinal tract. Elimination Metabolism Colesevelam hydrochloride is not metabolized systemically and does not interfere with systemic drug-metabolizing enzymes such as cytochrome P450. Excretion In 16 healthy volunteers, an average of 0.05% of administered radioactivity from a single 14 C-labeled colesevelam hydrochloride dose was excreted in the urine. Drug Interaction Studies Drug interactions between colesevelam and concomitantly administered drugs were screened through 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 6 Mean Change in Drug Exposure (AUC 0-∞ and C max ) when Administered with Colesevelam Hydrochloride (3.75 g) * Drug Dose Co-administered 1 hr prior to Colesevelam Hydrochloride 4 hrs prior to Colesevelam Hydrochloride AUC 0-∞ C max AUC 0-∞ C max AUC 0-∞ C max Cyclosporine 200 mg -34% -44% N/A N/A N/A N/A Ethinyl Estradiol † 0.035 mg -24% -24% -18% -1% -12% 0% Glimepiride 4 mg -18% -8% N/A N/A -6% 3% Glipizide 20 mg -12% -13% N/A N/A -4% 0% Glyburide 3 mg -32% -47% -20% -15% -7% 4% Levothyroxine 600 μg -22% -33% 6% -2% 1% 8% Metformin ER 1500 mg 44% 8% N/A N/A N/A N/A Norethindrone † 1 mg -1% -20% 5% -3% 6% 7% Olmesartan Medoxomil 40 mg -39% -28% N/A N/A -15% -4% Repaglinide 2 mg -7% -19% -6% -1% N/A N/A Verapamil Sustained Release 240 mg -31% -11% N/A N/A N/A N/A * With verapamil, the dose of colesevelam hydrochloride was 4.5 g. † Oral contraceptive containing norethindrone and ethinyl estradiol N/A – not available