Why must Questran (cholestyramine) be administered an hour before other medications in adults with a history of cardiovascular disease or high cholesterol?

Why Questran Must Be Spaced from Other Medications

Questran (cholestyramine) is a bile acid sequestrant that physically binds to other medications in the gastrointestinal tract, preventing their absorption—therefore, other medications must be taken at least 1 hour before or 4-6 hours after Questran to avoid impeding their absorption. 1, 2

Mechanism of Drug Interaction

• Cholestyramine is a positively-charged resin that works by binding bile acids in the intestine, but this binding mechanism is non-selective 2
• The resin can bind to and sequester other orally administered medications, physically trapping them and preventing their absorption from the gastrointestinal tract 1
• This interaction is unavoidable for drugs that undergo enterohepatic circulation, as cholestyramine will continue to bind these medications even when properly spaced 2

FDA-Mandated Timing Recommendations

The FDA drug label explicitly states: "SINCE CHOLESTYRAMINE RESIN MAY BIND OTHER DRUGS GIVEN CONCURRENTLY, IT IS RECOMMENDED THAT PATIENTS TAKE OTHER DRUGS AT LEAST 1 HOUR BEFORE OR 4 TO 6 HOURS AFTER CHOLESTYRAMINE RESIN (OR AT AS GREAT AN INTERVAL AS POSSIBLE) TO AVOID IMPEDING THEIR ABSORPTION." 2

• The American College of Cardiology guidelines reinforce this timing: other medications should be given at least 4 hours before bile acid sequestrants 1
• When ezetimibe is used with cholestyramine, it must be taken either 2 hours before or 4 hours after the bile acid sequestrant 1

High-Risk Medication Interactions

Certain medications require particularly careful attention to timing with cholestyramine 1, 2:

• Warfarin: Cholestyramine interferes with warfarin absorption and its enterohepatic circulation; spacing by 2 hours before or 6 hours after only partially mitigates this interaction 1, 2
• Thyroid replacement therapy: Absorption is significantly reduced without proper spacing 1
• Oral contraceptives (ethinyl estradiol and norethindrone): Must be given 4 hours before cholestyramine 1
• Cyclosporine: Known to have decreased absorption, though one study showed 4g cholestyramine at noon did not interfere with morning cyclosporine dosing 1, 3
• Cardiovascular medications: Olmesartan, phenytoin, sulfonylureas all require the 4-hour spacing 1
• Digitalis: Particularly dangerous as the drug may have been titrated to maintenance levels while on cholestyramine; discontinuing cholestyramine could result in toxic digitalis levels 2

Fat-Soluble Vitamin Considerations

• Cholestyramine interferes with normal fat digestion and absorption, preventing absorption of fat-soluble vitamins A, D, E, and K 1, 2
• For long-term cholestyramine therapy, concomitant supplementation with water-miscible or parenteral forms of fat-soluble vitamins should be considered 2
• Oral vitamins should be given at least 4 hours before cholestyramine 1

Clinical Pitfalls to Avoid

• Do not assume proper spacing eliminates all interactions: For drugs undergoing enterohepatic circulation, some interaction is unavoidable 2
• Monitor INR frequently when initiating cholestyramine in patients on warfarin, then periodically thereafter 1
• For patients on digitalis: Discontinuing cholestyramine poses a hazard if digitalis has been titrated to maintenance levels while the patient was taking cholestyramine 2
• Pregnant patients: Regular prenatal vitamin supplementation may be inadequate due to interference with fat-soluble vitamin absorption 2

Practical Dosing Strategy

The most practical approach is to administer all other medications either 1 hour before breakfast or 4-6 hours after the cholestyramine dose, with cholestyramine typically given with meals 1, 2. This maximizes the interval between cholestyramine and other medications while maintaining adherence.