Colesevelam

Colesevam is a lipid-lowering substance from the group of anion exchange resins, which is used to lower elevated cholesterol levels (LDL-C).

Anion exchange resins are the oldest group of lipid-lowering substances. However, they have become considerably less important in the treatment of hypercholesterolemia with the introduction of statins. Other disadvantages are the dosage form and administration modalities as well as gastrointestinal intolerance.

Colesevelam was approved in 2004. It is available in an improved dosage form as tablets and should therefore be easier to use and better tolerated than colestyramine.

Colesevelam is a non-absorbable, lipid-lowering polymer that binds bile acids in the intestine and inhibits their reabsorption. The enterohepatic circulation is interrupted, more bile acids are excreted in the stool and bile acid re-synthesis, which requires cholesterol as a precursor, is increased in the liver. This in turn lowers the cholesterol level.

In detail, the reduction in bile acids leads to increased activity of the liver enzyme cholesterol-7- α-hydroxylase and more cholesterol is converted into bile acids. Due to the increased demand for cholesterol in the liver cells, there is an increase in the transcription and activity of hydroxy-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, the key enzyme in cholesterol biosynthesis, as well as an increase in the number of hepatic low-density lipoprotein (LDL) receptors. In addition to increased synthesis of cholesterol in the liver, this also leads to increased absorption of LDL-C from the blood, which lowers the LDL-C level in the blood.

It can also lead to an increase in very low-density lipoprotein (VLDL) synthesis and an increase in triglycerides (caution with already elevated triglyceride levels).

Reduction of LDL-C levels by approx. 15-18%

Reduction of total C by approx. 7 to 10%,

Increase in HDL-C by approx. 3%

Increase in triglycerides by approx. 9 to 10 %.

Reduction of Apo-B by approx. 12 %

The effect can be expected within a few weeks.

When administered in combination with statins, an additional effect of approximately the same magnitude can be expected. The same applies to combination therapy for FH.

Colesevelam has a slightly lower effect on the LDL-C value than cholestyramine or colestipol (no longer commercially available in Germany).

Active substance: Colesevelam hydrochloride

Colesevelam is not absorbed from the gastrointestinal tract. However, colesevelam can affect the absorption and the entero-hepatic circulation and therefore the bioavailability of other orally administered drugs in different ways (see WW).

Combination therapy: in addition to statins and ezetimibe and lifestyle changes (diet, exercise) to reduce LDL-C in hypercholesterolemia or increased cardiovascular risk(SCORE2/SCORE2-OP) as part of primary and secondary prevention, if a sufficient LDL-C reduction to the target value cannot be achieved by other substances alone. Here too, colesevam tends to be used less frequently, as other substances with greater efficacy and proven risk reduction are also available in combination.

Monotherapy: in addition to lifestyle changes (diet, exercise) to lower LDL-C in hypercholesterolemia, only secondary if other substances to lower cholesterol cannot be used or are not tolerated.

Causes of secondary hypercholesterolemia (type 2 DM, hypothyroidism, nephrotic syndrome, CKD, medication, etc.) should first be treated causally.

For the treatment of FH, colesevelam can be used in combination with ezetimibe with or without a statin (EMA approval).

Safety and efficacy have only been studied in adults aged 18 and over.

Use in children (0-17 years) is only possible off-label. There is insufficient data on this (see expert information).

However, approved substances (statins, etc.) are now also available for first-line therapy in children, so that the use of colesevelam will only be a secondary consideration here too.

Combination therapy: with colesevelam in combination with a statin, with or without ezetimibe recommended daily dose 4 to 6 tablets daily; recommended maximum dose 6 tablets daily (2x3 tablets with each meal or 6 tablets once daily with
a meal). Cholestagel can be administered separately or simultaneously with both statins and ezetimibe (for clinical studies, see specialist information).

Monotherapy: recommended starting dose for colesevelam 6 tablets daily (2x3 tablets with meals or 6 tablets once daily with a meal); recommended maximum dose 7 tablets per day.

Take orally with food and liquid; tablets should be swallowed whole and not broken, crushed or chewed!

If substances with a possible impairment of absorption (WW) are taken at the same time, especially those with a low therapeutic range (antiarrhythmics, etc.), a time interval of at least 4 hours should be observed before and after taking colesevelam!

Verify response to therapy by laboratory checks; if there is no response, therapy should not be continued.

For further information, see specialist information.

Most common NW are gastrointestinal complaints: flatulence, constipation, vomiting, diarrhea, dyspepsia, abdominal pain, stool abnormalities, nausea, flatulence; occasionally also dysphagia and intestinal obstruction; very rarely: pancreatitis.

Frequently also headache.

occasionally myalgia

Often there is an increase in triglycerides and occasionally an increase in liver values.

It should be noted that the absorption of fat-soluble vitamins may be reduced (substitution may be necessary).

In addition to the adverse effects described for the individual substances, additional adverse effects are not to be expected from the combination with statins and ezetimibe.

Colesevelam can affect the bioavailability of many other orally administered drugs both by impairing absorption and by interrupting the entero-hepatic circulation.

If an interaction with a concomitant medicinal product for which minor variations in therapeutic levels are clinically significant cannot be excluded, colesevelam should be administered at least 4 hours before or at least 4 hours after the concomitant medicinal product in order to minimize the risk of reduced absorption of the concomitant medicinal product.

If other medicinal products are administered in divided doses, it should be noted that the required colesevelam dose can be administered once daily.

For substances with a risk of clinically effective impairment of bioavailability, blood level control or close clinical monitoring if necessary.

Selection of individual substances with impaired bioavailability:

Olmesartan intake with a 4-hour interval necessary.

Phenytoin Take 4 hours apart; monitor phenytoin levels.

Anticoagulant therapy Close laboratory monitoring, anticoagulant effect may be impaired (vitamin K resorption reduced).

Levothyroxine must be taken 4 hours apart.

Oral contraceptives are strongly subject to the entero-hepatic circulation, therefore bioavailability may be limited and efficacy impaired; intake with a 4-hour interval necessary.

Ciclosporin significant impairment of bioavailability; must be taken 4 hours apart; close monitoring of levels necessary. Always take colesevelam and ciclosporin at the same time to minimize the risk of impairment.

Oral antidiabetics Bioavailability may be reduced; take 4 hours apart.

Metformin ER (delayed release) Exposure of metformin may be increased!

Fat-soluble vitamins Vit.E, D, K, A, may be reduced, especially in the case of pre-existing malabsorption, malnutrition; laboratory control and substitution may be necessary.

If WW leads to dose adjustment of concomitantly administered substances, this must also be taken into account when stopping therapy with colesevelam and the dose must be adjusted again if necessary (otherwise certain drugs may have a greatly increased or toxic effect of the increased dose after increasing the dose when colesevelam is discontinued).

For further information, see specialist information!

Colesevelam Fachinfo ^{Cholestagel®}

Karow T, Lang-Roth R. General and special pharmacology 32nd ed. 2024/25.