CLINICAL PHARMACOLOGY SECTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

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.

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 14C-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) *

NA - not available

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INDICATIONS & USAGE SECTION

Highlight: 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 post-menarchal girls, 10 years to 17 years of age, with heterozygous familial hypercholesterolemia (HeFH), unable to reach LDL-C target levels despite an adequate trial of diet and lifestyle modification ( 1.1).

Limitations of Use ( 1.3):

• Do not use for treatment of type 1 diabetes or for diabetic ketoacidosis.
• Not studied in Fredrickson Type I, III, IV, and V dyslipidemias.

1 INDICATIONS AND USAGE

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 post-menarchal girls, 10 years 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.
• Colesevelam hydrochloride has not been studied in Fredrickson Type I, III, IV, and V dyslipidemias.

DOSAGE & ADMINISTRATION SECTION

Highlight: * Obtain lipid parameters, including serum triglyceride (TG) levels, before starting colesevelam hydrochloride tablets ( 2.1)

• The recommended dosage for adults and for boys and post-menarchal girls aged 10 years to 17 years with primary hyperlipidemia is 3.75 grams daily. Colesevelam hydrochloride tablets should be taken as follows ( 2.2, 2.4):

Take 6 tablets once daily or 3 tablets twice daily with a meal and liquid.

2 DOSAGE AND ADMINISTRATION

2.1 Testing Prior to Initiation of Colesevelam Hydrochloride Tablets

Obtain lipid parameters, including triglyceride (TG) levels, before starting colesevelam hydrochloride tablets. Colesevelam hydrochloride is contraindicated in patients with TG levels > 500 mg/dL [see Contraindications (4) and Warnings and Precautions (5.1)] .

2.2 Recommended Dosage in Primary Hyperlipidemia

The recommended dosage of colesevelam hydrochloride for adults and for boys and post-menarchal girls aged 10 years to 17 years with primary hyperlipidemia is 3.75 grams daily. Colesevelam hydrochloride tablets should be taken as follows:

Take 6 tablets once daily or 3 tablets twice daily. Due to tablet size, colesevelam hydrochloride for oral suspension is recommended for use in the pediatric population.

2.3 Important Dosing Information for Primary Hyperlipidemia

Colesevelam hydrochloride can be dosed at the same time as a statin, or colesevelam hydrochloride and the statin can be dosed apart . Monitor lipid levels within 4 weeks to 6 weeks after initiation of colesevelam hydrochloride.

2.4 Administration Instructions

Take colesevelam hydrochloride tablets with a meal and liquid. For patients with difficulty swallowing tablets, use colesevelam hydrochloride for oral suspension [see Warnings and Precautions (5.2)].

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WARNINGS AND PRECAUTIONS SECTION

Highlight: * 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).

5 WARNINGS AND PRECAUTIONS

5.1 Hypertriglyceridemia and Pancreatitis

Colesevelam hydrochloride, like other bile acid sequestrants, can increase serum TG concentrations. Hypertriglyceridemia can cause acute pancreatitis.

Colesevelam hydrochloride had effects on serum TG (median increase 5% compared to placebo) in trials of patients with primary hyperlipidemia.

Obtain lipid parameters, including TG levels, before starting colesevelam hydrochloride and periodically thereafter. Colesevelam hydrochloride is contraindicated in patients with TG levels > 500 mg/dL or patients with 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)].

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DRUG INTERACTIONS SECTION

Highlight: 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 DRUG INTERACTIONS

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

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

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ADVERSE REACTIONS SECTION

Highlight: 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 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)]

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

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

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%).

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 STUDIES SECTION

14 CLINICAL STUDIES

14.1 Primary Hyperlipidemia

Colesevelam hydrochloride reduces total cholesterol (TC), LDL-C, apolipoprotein B (Apo B), and non-high-density lipoprotein cholesterol (non- HDL-C) when administered alone or in combination with a statin in patients with primary hyperlipidemia. Approximately 1,600 patients were studied in 9 clinical trials with treatment durations ranging from 4 weeks to 50 weeks. With the exception of one open-label, uncontrolled, long-term extension study, all studies were multicenter, randomized, double-blind, and placebo- controlled. A maximum therapeutic response to colesevelam hydrochloride was achieved within 2 weeks and was maintained during long-term therapy.

Monotherapy

In a study in patients with LDL-C between 130 mg/dL and 220 mg/dL (mean 158 mg/dL), colesevelam hydrochloride was given for 24 weeks in divided doses with the morning and evening meals.

As shown in Table 7, the mean LDL-C reductions were 15% and 18% at the 3.8 g and 4.5 g doses. The respective mean TC reductions were 7% and 10%. The mean Apo B reductions were 12% in both treatment groups. Colesevelam hydrochloride at both doses increased HDL-C by 3%. Increases in TG of 9% to 10% were observed at both colesevelam hydrochloride doses, but the changes were not statistically different from placebo.

Table 7 Response to Colesevelam Hydrochloride Monotherapy in a 24-Week Trial - Percent Change in Lipid Parameters from Baseline

In a study in 98 patients with LDL-C between 145 mg/dL and 250 mg/dL (mean 169 mg/dL), colesevelam hydrochloride 3.8 g was given for 6 weeks as a single dose with breakfast, as a single dose with dinner, or as divided doses with breakfast and dinner. The mean LDL-C reductions were 18%, 15%, and 18% for the 3 dosing regimens, respectively. The reductions with these 3 regimens were not statistically different from one another.

Combination Therapy

Co-administration of colesevelam hydrochloride and a statin (atorvastatin, lovastatin, or simvastatin) in 3 clinical studies demonstrated an additive reduction of LDL-C. The mean baseline LDL-C was 184 mg/dL in the atorvastatin study (range 156 mg/dL to 236 mg/dL), 171 mg/dL in the lovastatin study (range 115 mg/dL to 247 mg/dL), and 188 mg/dL in the simvastatin study (range 148 mg/dL to 352 mg/dL). As demonstrated in Table 8, colesevelam hydrochloride doses of 2.3 g to 3.8 g resulted in an additional 8% to 16% reduction in LDL-C above that seen with the statin alone.

Table 8 Response to Colesevelam Hydrochloride in Combination with Atorvastatin, Simvastatin, or Lovastatin - Percent Change in Lipid Parameters

In all 3 studies, the LDL-C reduction achieved with the combination of colesevelam hydrochloride and any given dose of statin therapy was statistically superior to that achieved with colesevelam hydrochloride or that dose of the statin alone. The LDL-C reduction with atorvastatin 80 mg was not statistically significantly different from the combination of colesevelam hydrochloride 3.8 g and atorvastatin 10 mg.

Pediatric Therapy

The safety and efficacy of colesevelam hydrochloride in pediatric patients were evaluated in an 8-week, multi-center, randomized, double-blind, placebo- controlled, parallel-group study followed by an open-label phase, in 194 boys and post-menarchal girls 10 years to 17 years of age (mean age 14.1 years) with HeFH, taking a stable dose of an FDA-approved statin (with LDL-C > 130 mg/dL) or naïve to lipid-lowering therapy (with LDL-C > 160 mg/dL). This study had 3 periods: a single-blind, placebo stabilization period; an 8-week, randomized, double-blind, parallel-group, placebo-controlled treatment period; and an 18-week, open-label treatment period. Forty-seven (24%) patients were taking statins and 147 (76%) patients were statin-naïve at screening. The mean baseline LDL-C at Day 1 was approximately 199 mg/dL.

During the double-blind treatment period, patients were assigned randomly to treatment: Colesevelam hydrochloride 3.8 g/day (n = 64), colesevelam hydrochloride 1.9 g/day (n = 65), or placebo (n = 65). In total, 186 patients completed the double-blind treatment period. After 8 weeks of treatment, colesevelam hydrochloride 3.8 g/day significantly decreased plasma levels of LDL-C, non-HDL-C, TC, and Apo B and significantly increased HDL-C. A moderate, non-statistically significant increase in TG was observed versus placebo (Table 9).

Table 9 Response to Colesevelam Hydrochloride 3.8 g Compared to Placebo in Pediatric Patients 10 Years to 17 Years of Age - Mean Percent Change in Lipid Parameters from Baseline to Week 8

During the open-label treatment period patients were treated with colesevelam hydrochloride 3.8 g/day. In total, 173 (89%) patients completed 26 weeks of treatment. Results at Week 26 were consistent with those at Week 8.

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NONCLINICAL TOXICOLOGY SECTION

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

A 104-week carcinogenicity study with colesevelam hydrochloride was conducted in CD-1 mice, at oral dietary doses up to 3 g/kg/day. This dose was approximately 50 times the maximum recommended human dose of 4.5 g/day, based on body weight, mg/kg. There were no significant drug-induced tumor findings in male or female mice. In a 104-week carcinogenicity study with colesevelam hydrochloride in Harlan Sprague-Dawley rats, a statistically significant increase in the incidence of pancreatic acinar cell adenoma was seen in male rats at doses > 1.2 g/kg/day (approximately 20 times the maximum human dose, based on body weight, mg/kg) (trend test only). A statistically significant increase in thyroid C-cell adenoma was seen in female rats at 2.4 g/kg/day (approximately 40 times the maximum human dose, based on body weight, mg/kg).

Mutagenesis

Colesevelam hydrochloride and 4 degradants present in the drug substance have been evaluated for mutagenicity in the Ames test and a mammalian chromosomal aberration test. The 4 degradants and an extract of the parent compound did not exhibit genetic toxicity in an in vitro bacterial mutagenesis assay in S. typhimurium and E. coli (Ames assay) with or without rat liver metabolic activation. An extract of the parent compound was positive in the Chinese Hamster Ovary (CHO) cell chromosomal aberration assay in the presence of metabolic activation and negative in the absence of metabolic activation. The results of the CHO cell chromosomal aberration assay with 2 of the 4 degradants, decylamine HCl and aminohexyltrimethyl ammonium chloride HCl, were equivocal in the absence of metabolic activation and negative in the presence of metabolic activation. The other 2 degradants, didecylamine HCl and 6-decylamino-hexyltrimethyl ammonium chloride HCl, were negative in the presence and absence of metabolic activation.

Impairment of Fertility

Colesevelam hydrochloride did not impair fertility in rats at doses up to 3 g/kg/day (approximately 50 times the maximum human dose, based on body weight, mg/kg).

13.2 Animal Toxicology and/or Pharmacology

Reproductive Toxicology Studies

Reproduction studies have been performed in rats and rabbits at doses up to 3 g/kg/day and 1 g/kg/day, respectively (approximately 50 and 17 times the maximum human dose, based on body weight, mg/kg) and have revealed no evidence of harm to the fetus due to colesevelam hydrochloride.

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HOW SUPPLIED SECTION

16 HOW SUPPLIED/STORAGE AND HANDLING

Colesevelam hydrochloride tablets, 625 mg are supplied as white to off-white, oval-shaped, film-coated tablets, printed with “COL” on one side with black ink and are available as follows:

• Bottles of 180 - NDC 69452-158-25

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

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