Cholestyramine (cholestyramine (with sugar))

Dosage of cholestyramine is expressed in terms of the anhydrous (i.e., dried) resin. Each 9 g of Questran(R) or generic (nonproprietary) cholestyramine, 5.5 g of Prevalite(R), or 5 g of Questran Light(R) or generic cholestyramine light powder contains about 4 g of anhydrous cholestyramine resin. In calculating pediatric dosages, each 100 mg of Questran(R), generic cholestyramine, Prevalite(R), Questran(R) Light, or generic cholestyramine light powder contains 44.4, 44.4, 72.7, 80, or 80 mg, respectively, of anhydrous cholestyramine resin. Dosage must be carefully adjusted according to the condition being treated and the patient's response and tolerance.

For the management of primary hypercholesterolemia, the usual adult dosage of anhydrous cholestyramine resin is 4-24 g (1-6 packets or level scoops) daily taken once or in divided doses. To optimize antilipemic effects while minimizing the risk of adverse GI effects (e.g., fecal impaction), dosage should be adjusted carefully and titrated slowly. Cholestyramine therapy generally is initiated in adults with 4 g (1 packet or level scoop) once or twice daily; if the initial dosage is well tolerated, the dosage may be titrated upward as necessary at intervals of no less than 4 weeks. In patients with preexisting constipation, the initial dosage of anhydrous cholestyramine resin should be 4 g (1 packet or level scoop) daily for 5-7 days, increasing to 4 g twice daily with monitoring of constipation and of serum lipoprotein values, at least twice, 4-6 weeks apart; if the initial dosage is well tolerated, the dosage may be increased as needed by one dose (i.e., 4 g) per day at monthly intervals. Serum lipoprotein concentrations should be determined periodically and dosage adjusted accordingly to achieve the desired effect while avoiding excessive dosage. The usual maintenance dosage recommended by the manufacturers is 8-16 g (2-4 packets or level scoops) daily, given in 2 divided doses; the usual dosage range suggested by the Third Report of the National Cholesterol Education Program (NCEP) (Adult Treatment Panel (ATP) III) is 4-16 g daily. The maximum recommended dosage is 24 g (6 packets or level scoops) daily. If constipation worsens or the desired effect is not achieved with acceptable adverse effects within the usual dosage range of 1-6 doses (i.e., 4-24 g) per day, substitution or addition of another antilipemic agent should be considered.

The manufacturers state that the optimal dosage of cholestyramine resin for pediatric patients has not been established. Pediatric dosages of anhydrous cholestyramine resin generally have ranged from 8-16 g daily in 2 or 3 divided doses before meals. The usual pediatric dosage suggested by the manufacturers and some clinicians is 240 mg/kg daily, given in 2 or 3 divided doses, not to exceed 8 g daily. Some clinicians suggest that children older than 6 years of age be given 80 mg/kg or 2.35 g/m2 3 times daily. Alternatively, some clinicians suggest initiating cholestyramine at a pediatric dosage of 2 or 4 g twice daily before meals, and then gradually increasing the dosage until a serum total cholesterol concentration of 250 mg/dL or less is achieved or intolerable adverse effects occur.

Cholestyramine resin is administered orally as a suspension prepared from the powder. Cholestyramine suspension should be administered at mealtime. Patients should be instructed to take other drugs at least 1 hour before or 4-6 hours (or as long an interval as possible) after taking cholestyramine suspension to minimize possible interference with absorption. Although the recommended dosing schedule is twice daily, cholestyramine may be administered in 1-6 doses per day.

Cholestyramine powder should not be taken in its dry form; the resin should always be mixed with water or other fluids before ingesting. Just prior to administration, each packet or level scoop of cholestyramine powder (containing 4 g of dried cholestyramine resin) should be mixed with 60-180 mL of water or another noncarbonated beverage (e.g., fruit juice). Some clinicians suggest that palatability and compliance may be increased if the entire next-day's dose is mixed in one of these liquids in the evening and then refrigerated. Use of a heavy or pulpy fruit juice may minimize complaints about consistency of suspensions of the drug. To minimize excessive swallowing of air, patients should be advised to avoid rapid ingestion of suspensions of the drug. If a carbonated beverage is used, excessive foaming can be minimized by mixing the powder slowly in a large glass. Alternatively, cholestyramine resin may be mixed with a highly fluid soup or a pulpy fruit with a high moisture content such as applesauce or crushed pineapple.

There is no enhanced messaging for this drug.

There are no contraindication interactions for this drug.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Al Antacids;Bile Acid Seq/Sodium Phenylbutyrate-Taurursodiol

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Aluminum-based antacids and bile acid sequestrants (including cholestyramine, colestipol, and colesevelam) may bind to sodium phenylbutyrate-taurursodiol (sodium phenylbutyrate-ursodoxicoltaurine), which may decrease gastrointestinal absorption and impair enterohepatic recirculation of sodium phenylbutyrate-taurursodiol.(1)

CLINICAL EFFECTS: Simultaneous administration of an aluminum-based antacid or bile acid sequestrants (including cholestyramine, colestipol, or colesevelam) may result in decreased absorption and effectiveness of sodium phenylbutyrate-taurursodiol (sodium phenylbutyrate-ursodoxicoltaurine).(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of sodium phenylbutyrate-taurursodiol (sodium phenylbutyrate-ursodoxicoltaurine) states that concurrent therapy with aluminum-based antacids or bile acid sequestrants should be avoided. Consider alternative acid lowering agents or cholesterol lowering agents in patients taking sodium phenylbutyrate-taurursodiol.(1) The Canadian manufacturer of sodium phenylbutyrate-taurursodiol recommends not using bile acid sequestrants with sodium phenylbutyrate-taurursodiol.(2) The Canadian manufacturer of sodium phenylbutyrate-taurursodiol states that if aluminum-based antacids are required, administer antacids at least 2 hours prior to or 2 hours after the administration of sodium phenylbutyrate-taurursodiol.(2)

DISCUSSION: Aluminum-based antacids have been shown to adsorb bile acids in vitro. Bile acid sequestrants (including cholestyramine, colestipol, or colesevelam) reduce bile acid absorption.(1)

Bile Acid Sequestrants And Ion Exchange Resins/Tiratricol

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Bile acid sequestrants and ion exchange resins may decrease the gastrointestinal absorption of tiratricol.(1,2)

CLINICAL EFFECTS: Simultaneous administration of a bile acid sequestrants and ion exchange resins may result in decreased absorption and effectiveness of tiratricol.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of tiratricol states concurrent use of bile acid sequestrants and ion exchange resins with tiratricol should be avoided.(1) The UK manufacturer of tiratricol states use of antacids, charcoal, calcium, cationic resins (e.g. cholestyramine), iron, sucralfate, and other gastrointestinal agents may interfere with the gastrointestinal absorption of tiratricol should be taken before or after tiratricol (more than 2 hours before or after if possible). For cholestyramine, tiratricol should be taken 1 hour before or 4 hours after the resin dose. Adjustment of the tiratricol dose may be required to obtain the desired effect.(2)

DISCUSSION: Bile acid sequestrants and ion exchange resins decrease thyroid hormone exposure by binding and delaying or preventing absorption.(1,2)

Bile Acid Sequestrants/Deferasirox

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Bile acid sequestrants may interfere with the enterohepatic recycling of deferasirox.(1)

CLINICAL EFFECTS: Concurrent use of bile acid sequestrants may result in decreased levels and effectiveness of deferasirox, even when the administration times are separated.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the use of bile acid sequestrants with deferasirox. If concurrent therapy is warranted, consider increasing the initial dose of deferasirox by 50%. Further dosage adjustments should be made based upon serum ferritin levels and clinical response. Doses above 40 mg/kg are not recommended.(1)

DISCUSSION: In a study in healthy subjects, administration of cholestyramine (12 g twice daily, 4 and 10 hours after deferasirox) decreased the area-under-curve (AUC) of a single dose of deferasirox (dosage not stated) by 45%.(1)

Bile Acid Sequestrants/Leflunomide; Teriflunomide

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Bile acid sequestrants may interfere with the enterohepatic recycling of teriflunomide.(1-4) Leflunomide is metabolized to teriflunomide.(2-3)

CLINICAL EFFECTS: Concurrent use of bile acid sequestrants may result in decreased levels and effectiveness of leflunomide and teriflunomide, even when the administration times are separated. Coadministration may result in return of disease activity.(1-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the use of bile acid sequestrants with leflunomide and teriflunomide. Teriflunomide has a prolonged half-life and staggering administration times will not prevent the drug interaction.(1-4) Teriflunomide may be coadministered with bile acid sequestrants in order to accelerate elimination for suspected drug-induced liver injury, pregnancy occurs during teriflunomide therapy, patient taking teriflunomide wants to become pregnant or father a child, or other situations requiring accelerated removal of teriflunomide.(4)

DISCUSSION: After 11 days of cholestyramine administration, plasma concentrations of teriflunomide are reduced by greater than 98%.(4) In an open-label study in 18 healthy subjects, administration of teriflunomide (days 1-5; five 14 mg tablets once daily) followed by colesevelam (days 6-16, four 625 mg tablets in morning, three 625 mg tablets in evening) decreased the teriflunomide plasma concentration an average of 96.1% after 11 days.(5) In a study in 14 healthy subjects, administration of teriflunomide (70 mg daily for 3 days; 14 mg daily for 11 days) followed by colestipol (8 g twice daily for 15 days) decreased the teriflunomide plasma concentration an average of 96.9% after 11 days.(6)

Bile Acid Sequestrants/Mycophenolate

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Bile acid sequestrants may bind mycophenolate in the intestine, preventing the absorption of the oral formulation of mycophenolate and the enterohepatic recirculation of both the oral and intravenous formulations of mycophenolate.(1)

CLINICAL EFFECTS: The concurrent administration of mycophenolate and a bile acid sequestrant may decrease the levels and clinical effects of mycophenolate.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturers of mycophenolate state that the concurrent administration of mycophenolate and bile acid sequestrants is not recommended.(1,2) Consider the use of other agents in patients receiving mycophenolate therapy.

DISCUSSION: In a study in 12 healthy subjects, the administration of mycophenolate (1.5 grams) following pretreatment with cholestyramine (4 grams three times daily) resulted in a 40% decrease in the area-under-curve (AUC) of mycophenolate. The interaction is also expected to occur with intravenous mycophenolate, because it also undergoes enterohepatic circulation.(1)

Bile Acid Sequestrants/Raloxifene

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Bile acid sequestrants may reduce the absorption and enterohepatic recycling of raloxifene.(1)

CLINICAL EFFECTS: Concurrent use may result in decreased levels and clinical effects of raloxifene.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of raloxifene states that concurrent use with cholestyramine is not recommended, and raloxifene should not be coadministered with other anion exchange resins.(1)

DISCUSSION: Cholestyramine was found to decrease the absorption and enterohepatic circulation of raloxifene by 60% after only one dose. Other anion exchange resins, such as colestipol and colesevelam, are thought to produce similar effects.(1) In a study, cholestyramine given at 4 hours and 10 hours after raloxifene administration decreased raloxifene AUC by 40%.(2)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Aluminum-Based Antacids; Bile Acid Sequestrants/Chenodiol

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Aluminum-based antacids, cholestyramine, or colestipol may bind to chenodiol, which may decrease gastrointestinal absorption and impair enterohepatic recirculation of chenodiol.(1,2)

CLINICAL EFFECTS: Simultaneous administration of an aluminum-based antacid, cholestyramine, or colestipol may result in decreased absorption and effectiveness of chenodiol.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If concomitant therapy with aluminum-based antacids or colestipol is necessary, administer chenodiol at least 2 hours before or after the antacid or colestipol. If concomitant therapy with cholestyramine is necessary, administer chenodiol at least 1 hour before or 4-6 hours after cholestyramine.(2)

DISCUSSION: Aluminum-based antacids have been shown to adsorb bile acids in vitro. Bile acid sequestrants reduce bile acid absorption.(1)

Aluminum-Based Antacids; Bile Acid Sequestrants/Cholic Acid

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Aluminum-based antacids and bile acid sequestrants may decrease the gastrointestinal absorption of cholic acid.(1)

CLINICAL EFFECTS: Simultaneous administration of an aluminum-based antacid or a bile acid sequestrant may result in decreased absorption and effectiveness of cholic acid.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: For maximal bioavailability in patients receiving both medications, administer cholic acid at least 1 hour before or 4-6 hours after (or as great an interval as possible) a bile acid sequestrant or aluminum-based antacid.(1)

DISCUSSION: Aluminum-based antacids have been shown to adsorb cholic acid in vitro. Bile acid sequestrants reduce bile acid absorption.(1)

Bile Acid Sequestrant/Ileal Bile Acid Transporter Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Bile acid sequestrants may bind to linerixibat, maralixibat and odevixibat in the gut, resulting in decreased absorption of the IBAT inhibitor.(1-3)

CLINICAL EFFECTS: Coadministration of bile acid sequestrants with IBAT inhibitors may cause reduced efficacy of IBAT inhibitors.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturers state to administer bile acid sequestrants (cholestyramine, colesevelam, and colestipol) at least 4 hours before or 4 hours after administration of IBAT inhibitors.(1-3)

DISCUSSION: Bile acid sequestrants are known to bind to drugs when given concurrently. Administration with IBAT inhibitors may result in decreased systemic absorption.(1-3)

Bile Acid Sequestrants/Elafibranor

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Bile acid sequestrants may bind to elafibranor in the gut, resulting in decreased absorption of elafibranor.(1)

CLINICAL EFFECTS: Coadministration of bile acid sequestrants with elafibranor may cause reduced efficacy of elafibranor.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer states to administer bile acid sequestrants (cholestyramine, colesevelam, and colestipol) at least 4 hours before or 4 hours after administration of elafibranor, or at as great an interval as possible.(1)

DISCUSSION: Bile acid sequestrants are known to bind to drugs when given concurrently. Administration with elafibranor may result in decreased systemic absorption.(1)

Bile Acid Sequestrants/Ezetimibe

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Bile acid sequestrants may prevent the absorption of ezetimibe.(1)

CLINICAL EFFECTS: Simultaneous administration of a bile acid sequestrant and ezetimibe may result in decreased levels and clinical effectiveness of ezetimibe.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: In patients receiving concurrent therapy, the manufacturer of ezetimibe recommends that ezetimibe be administered either 2 or more hours before or 4 or more hours after a bile acid sequestrant.(1)

DISCUSSION: In a study in 40 subjects, the simultaneous administration of ezetimibe and cholestyramine decreased the area-under-curve (AUC) of total ezetimibe and ezetimibe by 55% and 80%, respectively. This may reduce the effectiveness of ezetimibe. Therefore, the manufacturer of ezetimibe recommends that ezetimibe be administered either 2 or more hours before or 4 or more hours after a bile acid sequestrant.(1)

Bile Acid Sequestrants/Fenofibrate; Gemfibrozil

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Bile acid sequestrants may bind to fenofibrate and gemfibrozil resulting in decreased absorption of fenofibrate and gemfibrozil.(1,2)

CLINICAL EFFECTS: Concurrent use of fenofibrate and gemfibrozil with bile acid sequestrants may result in decreased fenofibrate absorption and clinical effects.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer states that fenofibrate should be administered 1 hour before or 4-6 hours after administration of bile acid sequestrants.(1) The US manufacturer states that gemfibrozil should be administered 2 hours apart from bile acid sequestrants.(2)

DISCUSSION: Bile acid sequestrants are known to bind to drugs when given concurrently. Administration with fenofibrate and gemfibrozil may result in decreased systemic absorption.(1,2)

Bile Acid Sequestrants/Oral Vancomycin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Bile acid sequestrants bind to vancomycin when the medications are coadministered.(1,2)

CLINICAL EFFECTS: When using both medications concurrently, bile acid sequestrants may bind to oral vancomycin, causing a decrease in its unbound concentration and potentially affecting the antibiotic activity of the medication.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: It has been suggested when using both medications that the course of bile acid sequestrants follow the course of oral vancomycin in order to avoid a reduction in vancomycin concentration by preventing the binding of vancomycin to the bile acid sequestrant.(2,3)

DISCUSSION: One study found when oral vancomycin and cholestyramine were coadministered that the active concentration of vancomycin decreased by as much as 80%.(2) Conversely another study suggests when both medications are used concurrently that vancomycin antibacterial activity is unaffected by cholestyramine binding.(1) Two additional studies looked at the combination of cholestyramine and oral vancomycin for the treatment of C. difficile associated pseudomembranous colitis. One looked at the results from both in vitro and hamster models(4) while the other recorded results from hamster as well as clinical studies.(3) Both of the studies had similar results noting a 10-fold decrease in therapeutically active vancomycin concentration when used in combination with cholestyramine. Both studies also found no clinical benefit from coadministration of the medications versus the use of oral vancomycin alone. Another study found the in vitro combination of cholestyramine and oral vancomycin resulted in substantially decreased vancomycin concentrations potentially hindering its therapeutic activity.(5)

Bile Acid Sequestrants/Seladelpar

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Bile acid sequestrants may bind to seladelpar in the gut, resulting in decreased absorption of seladelpar.(1)

CLINICAL EFFECTS: Coadministration of bile acid sequestrants with seladelpar may result in reduced efficacy of seladelpar.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of seladelpar states to administer bile acid sequestrants (cholestyramine, colesevelam, and colestipol) at least 4 hours before or 4 hours after administration of seladelpar, or at as great an interval as possible.(1)

DISCUSSION: Bile acid sequestrants are known to bind to drugs when given concurrently. Administration with seladelpar may result in decreased systemic absorption.(1)

Bile Acid Sequestrants/Ursodiol

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Bile acid sequestrants may bind to ursodiol in the gastrointestinal tract, preventing its absorption.(1)

CLINICAL EFFECTS: Simultaneously administering ursodiol and a bile acid sequestrant may decrease the effectiveness of ursodiol.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Separate the administration time of ursodiol and bile acid sequestrants by as much time as possible.(2)

DISCUSSION: In a study in 5 healthy subjects, simultaneous administration of cholestyramine (4 grams daily) and ursodiol (12.5 mg/kg daily) decreased ursodiol levels by 60%. Separation of the dosage times by 5 hours decreased this effect.(2) In a study in 5 healthy subjects, simultaneous administration of colestimide (1.5 grams) and ursodiol (200 mg) decreased ursodiol by more than 50% in 4 of the 5 subjects.(3)

Bile Acid Sequestrants; Lanthanum; Sevelamer/Thyroid Preps

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Bile acid sequestrants, lanthanum and sevelamer may decrease the gastrointestinal absorption of thyroid drugs.(1)

CLINICAL EFFECTS: Simultaneous administration of a bile acid sequestrant, lanthanum or sevelamer may result in decreased absorption and effectiveness of thyroid drugs.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: For maximal bioavailability, thyroid preparations should be taken on an empty stomach at least 4 hours apart from bile acid sequestrants and sevelamer.(1-3) Thyroid preparations should be taken at least 2 hours apart from lanthanum.(4)

DISCUSSION: The effect of cholestyramine on the absorption of thyroid drugs appears to be clinically significant, resulting in approximately a 50% decrease in thyroid absorption. Cholestyramine has been used to treat thyroid overdoses. When administered with colesevelam (3.75 g), the area-under-curve (AUC) and maximum concentration (Cmax) of levothyroxine (600 mcg) decreased by 22% and by 33%, respectively. When administered 1 hour prior to colesevelam, the AUC of levothyroxine increased by 6% and the Cmax of levothyroxine decreased by 2%, respectively. When administered 4 hours prior to colesevelam, the AUC and Cmax of levothyroxine increased by 1% and 8%, respectively. Although used for hyperphosphatemia, sevelamer is linked to this monograph due to its structural and pharmacologic similarities to colesevelam. Both agents are non-absorbed cross linked polymers with a high affinity for bile acids.(2,3) An in vivo study in healthy subjects evaluated the bioavailability of levothyroxine 1 mg when given with or without sevelamer 800 mg. Concomitant administration of sevelamer decreased levothyroxine AUC by 46%.(13) One case report described a newly diagnosed hypothyroid patient with a TSH of 297 mU/L (reference 0.03 - 4.20 mU/L). She took her daily levothyroxine with her morning blood pressure medications, acetaminophen, B-vitamins and sevelamer 3200 mg. Over 3 months of treatment her levothyroxine dose was increased to 150 mcg daily but the TSH remained high at 196 mU/L. Her levothyroxine dose was changed to an evening dose taken at least 4 hours after medications. Three weeks later she was symptomatically improved and TSH had decreased to 19 mU/L. She was inadvertently rechallenged on the morning levothyroxine and sevelamer regimen due to a hospitalization. After the hospital stay her TSH risen to 76 mU/L; on return to her evening regimen her TSH again normalized.(14)

Bile Acid Sequestrants; Sevelamer/Lomitapide

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Bile acid sequestrants and sevelamer may decrease the gastrointestinal absorption of lomitapide.

CLINICAL EFFECTS: Simultaneous administration of a bile acid sequestrant or sevelamer may result in decreased absorption and effectiveness of lomitapide.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: For maximal bioavailability, the manufacturer of lomitapide states lomitapide and bile acid sequestrant administration should be separated by at least 4 hours.(1) Although used for hyperphosphatemia, sevelamer is linked to this monograph due to its structural and pharmacologic similarities to colesevelam. Both agents are non-absorbed cross linked polymers with a high affinity for bile acids.(2)

DISCUSSION: Lomitapide maximal systemic concentrations occur approximately 6 hours after administration. Although an interaction study has not been performed, the manufacturer of lomitapide recommends separating bile acid sequestrant administration for a minimum of 4 hours before or after lomitapide dose.(1)

Bile Acid Sequestrants; Sevelamer/Obeticholic Acid

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Bile acid sequestrants and sevelamer may decrease the gastrointestinal absorption of obeticholic acid.

CLINICAL EFFECTS: Simultaneous administration of a bile acid sequestrant or sevelamer may result in decreased absorption and effectiveness of obeticholic acid.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: For maximal bioavailability, the manufacturer of obeticholic acid states obeticholic acid should be administered at least 4 hours before or after a bile acid sequestrant or sevelamer.(1) Although used for hyperphosphatemia, sevelamer is linked to this monograph due to its structural and pharmacologic similarities to colesevelam. Both agents are non-absorbed cross linked polymers with a high affinity for bile acids.(2)

DISCUSSION: Bile acid sequestrants may be needed to treat pruritis due to primary biliary cholangitis and/or obeticholic acid therapy.(1,3) In a clinical trial of patients receiving obeticholic acid and bile acid sequestrants, obeticholic acid trough concentrations were slightly lower compared with patients who did not receive bile acid sequestrants. This resulted in a modest attenuation of efficacy in obeticholic acid 5mg, but did not appear to affect efficacy in patients receiving obeticholic acid 10 mg.(3)

Bile Acid Sequestrants; Sevelamer/Roxadustat

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Bile acid sequestrants and sevelamer may decrease the gastrointestinal absorption of roxadustat.(1)

CLINICAL EFFECTS: Simultaneous administration of a bile acid sequestrant or sevelamer may result in decreased absorption and effectiveness of roxadustat.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: For maximal bioavailability, the manufacturer of roxadustat states roxadustat should be administered at least 1 hour before or 1 hour after a bile acid sequestrant or sevelamer.(1) Although used for hyperphosphatemia, sevelamer is linked to this monograph due to its structural and pharmacologic similarities to colesevelam. Both agents are non-absorbed cross linked polymers with a high affinity for bile acids.(2)

DISCUSSION: In a study in health subjects, concurrent use of roxadustat with sevelamer carbonate or calcium acetate decreased roxadustat area-under-curve (AUC) by 67% and 46% and concentration maximum (Cmax) by 66% and 52%, respectively.(1)

Cholestyramine/Paricalcitol

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Cholestyramine may impair intestinal absorption of fat-soluble vitamins. Paricalcitol is an analogue of a fat-soluble vitamin and therefore cholestyramine may interfere with absorption of paricalcitol.(1)

CLINICAL EFFECTS: Concurrent use may result in decreased levels and clinical effects of paricalcitol.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of paricalcitol capsules recommends that paricalcitol be taken at least 1 hour before or 4-6 hours after taking cholestyramine.(1)

DISCUSSION: The manufacturer recommends that administration of paricalcitol capsules be separated from concurrent administration with drugs that impair intestinal absorption of fat-soluble vitamins.(1)

Cholestyramine/Troglitazone

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown; however, cholestyramine may bind with troglitazone in the gastrointestinal tract and prevent its absorption.

CLINICAL EFFECTS: Concurrent administration may result in decreased levels of troglitazone and decreased clinical effects.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of troglitazone states that concurrent administration is not recommended.(1) If concurrent therapy is necessary, the administration of troglitazone and cholestyramine should be separated as much as possible.

DISCUSSION: There is no published documentation to support this interaction. The manufacturer of troglitazone states that concurrent administration of troglitazone and cholestyramine decreased the absorption of troglitazone by 70%.(1)

Cholestyramine; Colesevelam/Slt Anticoagulants (Vit K Antag)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Cholestyramine and colesevelam may bind to anticoagulants, which may lead to reduced GI absorption and impaired enterohepatic circulation. Decreased absorption of vitamin K may also occur.

CLINICAL EFFECTS: Concurrent use of cholestyramine or colesevelam may result in decreased effectiveness of anticoagulants.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Changes in therapy may not be required. However, INR levels should be monitored and anticoagulant dose adjusted as necessary during initiation and discontinuation of cholestyramine or colesevelam therapy. Staggering doses of these two drugs may reduce problems, but may be unreliable because of the possibility of altering vitamin K absorption. Colestipol may be an alternative to cholestyramine or colesevelam in patients maintained on warfarin therapy who require treatment with a bile acid sequestrant.

DISCUSSION: In healthy volunteers, oral administration of cholestyramine decreased the anticoagulant effect of intravenously administered warfarin by 25% suggesting that cholestyramine interferes with the enterohepatic recirculation of warfarin. Cholestyramine has been used to treat anticoagulant overdoses. In healthy volunteers absorption of warfarin was 95% complete when administered with colestipol compared to 68% absorption when warfarin was given with cholestyramine. Although an in vivo study found no effect from colesevelam on warfarin levels, INR values were not assessed and there are post-marketing reports of decreased INR levels during concurrent therapy. If patient is receiving treatment with cholestyramine and an anticoagulant and the cholestyramine is stopped, serum anticoagulant concentrations may increase, increasing the hypoprothrombinemic effect of the anticoagulant.

Cholestyramine; Colestipol/Digitalis Glycosides, Oral

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Digitalis glycosides bind to cholestyramine and colestipol in the gastrointestinal tract reducing digitalis absorption and enterohepatic recirculation.

CLINICAL EFFECTS: Reduced therapeutic response to digitalis.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Separate the administration times of the two drugs by at least two hours, or more if possible. Adjust the digitalis dose as needed based on serum drug levels and patient response. The dosage of digoxin may need to be increased by 20% to 40%.

DISCUSSION: Documentation supports routine monitoring of this interaction. Serum concentrations may increase when the cholesterol lowering resin is discontinued. Because of the longer half-life of digitoxin over that of digoxin, the extent of the interaction may be more profound in digitoxin.

Cholestyramine; Colestipol/Thiazide & Related Diuretics

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Cholestyramine and colestipol, anionic exchange resins, bind thiazides and furosemide, preventing their absorption.

CLINICAL EFFECTS: Concurrent administration may result in decreased absorption of the diuretic, as well as decreased clinical effects. Decreased absorption of furosemide by 80-90% has been reported.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Available data suggest that colestipol may be preferable to cholestyramine. Separating administration times lessens the the extent of this interaction but still remains significant. Separate the administration of cholestyramine and the thiazide by at least four hours and that of colestipol by at least two hours. Separate the administration of furosemide and cholestyramine or colestipol by two to three hours.

DISCUSSION: Administration of cholestyramine or colestipol decreased total urinary excretion of hydrochlorothiazide by 85% and 43% respectively. These studies indicate that no dosing schedule will eliminate this interaction. Even four hours of separation reduces the absorption of hydrochlorothiazide by 35%. Similar reductions occurred to serum hydrochlorothiazide concentrations. In a study in six subjects, the concurrent administration of cholestyramine and furosemide resulted in a decrease in furosemide area-under-curve (AUC) by 90% and a decrease in furosemide's diuretic effects. Concurrent administration of furosemide and colestipol resulted in a decrease in furosemide AUC by 80% and a decrease in furosemide's diuretic effects.

Polyvalent Cations And Phosphate Binders/Vadadustat

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Vadadustat may form a chelate with iron supplements, phosphate binders, and other medicinal products whose primary component consists of polyvalent cations such as aluminum, calcium, magnesium, selenium, and zinc.(1)

CLINICAL EFFECTS: Simultaneous administration of vadadustat and polyvalent cations and phosphate binders decreases the exposure and effectiveness of vadadustat.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of vadadustat states that it should be administered at least 1 hour before or 2 hours after any medications or products whose primary component consists of iron, phosphate binders and polyvalent cations.(1)

DISCUSSION: Two studies evaluating the pharmacokinetics, safety, and tolerability of a single oral dose of vadadustat coadministered with a phosphate binder or iron supplement were conducted in healthy adult participants. Vadadustat exposure was reduced by coadministration with sevelamer carbonate, calcium acetate, ferric citrate, and ferrous sulfate. Geometric least squares mean ratios for area under the concentration-time curve (AUC) were reduced 37% to 55% by phosphate binders and 46% by ferrous sulfate. However, when vadadustat was administered 1 hour before phosphate binders, 90% confidence intervals for vadadustat exposure were within the no-effect boundaries of +50% to -33%, indicating that drug-drug interactions can be reduced by administering vadadustat 1 hour before phosphate binders.(2)

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• Complete biliary obstruction

• Constipation
• Hypovolemia
• Pregnancy

• Hemorrhoids
• Increased risk of bleeding due to coagulation disorder
• Kidney disease with reduction in glomerular filtration rate (GFr)

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More Frequent

• Constipation
• Severe constipation

Rare or Very Rare

• Acute pancreatitis
• Biliary calculus
• Gastrointestinal hemorrhage
• Gastrointestinal obstruction
• Hypoprothrombinemia
• Malabsorption states
• Osteoporosis
• Peptic ulcer
• Steatorrhea

More Frequent

• Abdominal pain with cramps
• Heartburn
• Nausea
• Vomiting

Less Frequent

• Diarrhea
• Dizziness
• Flatulence
• Headache disorder
• Perianal irritation

Rare or Very Rare

• Abdominal distension
• Anorexia
• Eructation
• Skin rash

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Since cholestyramine resin is not absorbed systemically, the drug is not expected to cause fetal harm when administered in usual dosages to pregnant women. However, there are no adequate and controlled studies to date using cholestyramine resin in pregnant women, and the known interference with absorption of fat-soluble vitamins may cause fetal harm even in the presence of supplementation. Currently, most experts recommend that dyslipidemias in pregnant women be managed with dietary measures; consultation with a lipid specialist may be indicated for pregnant women with severe forms of dyslipidemia.

Cholestyramine resin should be used with caution in nursing women, and the potential effect on the nursing infant of cholestyramine-induced interference with maternal absorption of fat-soluble vitamins should be considered.

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