COLESEVELAM Drug Interactions: What You Need to Know

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.

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 )

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.