COLESEVELAM: 3,271 Adverse Event Reports & Safety Profile

Colesevelam hydrochloride is a non-absorbed, polymeric, lipid-lowering and glucose-lowering agent for oral administration. Colesevelam hydrochloride is a 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 a decyl group; (d) represents allyl amine units that have been alkylated with a (6-trimethylammonium) hexyl group, and m represents a number ≥100 to indicate an extended polymer network. A 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. A large amount of the amines are protonated. The polymer is depicted in the hydrochloride form; a 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 a water-soluble black ink (<5 calories per 6 tablets). Colesevelam hydrochloride for oral suspension is a citrus-flavored, white to pale yellow powder containing yellow granules packaged in a 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

1 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.

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 &gt;500 mg/dL <span class="opacity-50 text-xs">[see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )]</span> .

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.

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 )

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

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) <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span>. Obtain lipid parameters, including TG levels, before starting colesevelam hydrochloride and periodically thereafter. Colesevelam hydrochloride is contraindicated in patients with TG levels &gt;500 mg/dL or patients with a history of hypertriglyceridemia-induced pancreatitis <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> . 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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> .

5.2 Gastrointestinal Obstruction Postmarketing cases of bowel obstruction have occurred with colesevelam hydrochloride <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) ]</span> . 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 <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> . 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 <span class="opacity-50 text-xs">[see Drug Interactions (7.1) ]</span>.

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 <span class="opacity-50 text-xs">[see Drug Interactions (7) ]</span> . 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span>.

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.

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 )] .

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.