Source: European Medicines Agency (EU) Revision Year: 2018 Publisher: Genzyme Europe B.V., Gooimeer 10, NL-1411 DD Naarden, The Netherlands
Prior to initiating therapy with Cholestagel, if secondary causes of hypercholesterolaemia (i.e. poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinaemias, obstructive liver disease) are considered, these should be diagnosed and properly treated.
Cholestagel reduces the bioavailability of ciclosporin (see also section 4.5). Patients starting on ciclosporin already taking Cholestagel should have their ciclosporin blood concentrations monitored as normal and their dose adjusted as normal. Patients starting on Cholestagel already taking ciclosporin should have their blood concentrations monitored prior to combination therapy and frequently monitored immediately starting co-therapy with the ciclosporin dose adjusted accordingly. It should be noted that stopping Cholestagel therapy will result in increased ciclosporin blood concentrations. Therefore, patients taking both ciclosporin and Cholestagel should have their blood concentrations monitored prior to and frequently after when Cholestagel therapy is stopped with their ciclosporin dose adjusted accordingly.
Caution should be exercised when treating patients with triglyceride levels greater than 3.4 mmol/L due to the triglyceride increasing effect with Cholestagel. Safety and efficacy are not established for patients with triglyceride levels greater than 3.4 mmol/L, since such patients were excluded from the clinical studies.
The safety and efficacy of Cholestagel in patients with dysphagia, swallowing disorders, severe gastrointestinal motility disorders, inflammatory bowel disease, liver failure or major gastrointestinal tract surgery have not been established. Consequently, caution should be exercised when Cholestagel is used in patients with these disorders.
Cholestagel can induce or worsen present constipation. The risk of constipation should especially be considered in patients with coronary heart disease and angina pectoris.
Anticoagulant therapy should be monitored closely in patients receiving warfarin or similar agents, since bile acid sequestrants, like Cholestagel, have been shown to reduce absorption of vitamin K and therefore interfere with warfarin’s anticoagulant effect (see also section 4.5).
Cholestagel can affect the bioavailability of the oral contraceptive pill when administered simultaneously. It is important to ensure that Cholestagel is administered at least 4 hours after the oral contraceptive pill to minimise the risk of any interaction (see also section 4.5).
Cholestagel may affect the bioavailability of other medicinal products. Therefore when a drug interaction cannot be excluded with a concomitant medicinal product for which minor variations in the therapeutic level would be clinically important, Cholestagel should be administered at least four hours before or at least four hours after the concomitant medication to minimize the risk of reduced absorption of the concomitant medication. For concomitant medications which require administration via divided doses, it should be noted that the required dose of Cholestagel can be taken once a day.
When administering medicinal products for which alterations in blood levels could have a clinically significant effect on safety or efficacy, physicians should consider monitoring serum levels or effects.
Interaction studies have only been performed in adults.
In interaction studies in healthy volunteers, Cholestagel had no effect on the bioavailability of digoxin, metoprolol, quinidine, valproic acid, and warfarin. Cholestagel decreased the Cmax and AUC of sustained-release verapamil by approximately 31% and 11%, respectively. Since there is a high degree of variability in the bioavailability of verapamil, the clinical significance of this finding is unclear.
Co-administration of colesevelam and olmesartan decreases the exposure of olmesartan. Olmesartan should be administered at least 4 hours prior to colesevelam.
There have been very rare reports of reduced phenytoin levels in patients who have received Cholestagel administered with phenytoin.
Anticoagulant therapy should be monitored closely in patients receiving warfarin or similar agents, since bile acid sequestrants, like Cholestagel, have been shown to reduce absorption of vitamin K and therefore interfere with warfarin’s anticoagulant effect. Specific clinical interaction studies with colesevelam and vitamin K have not been performed.
In an interaction study in healthy volunteers, Cholestagel reduced the AUC and Cmax of levothyroxine when administered either concomitantly or after 1 hour. No interaction was observed when Cholestagel was administered at least four hours after levothyroxine.
In an interaction study in healthy volunteers, Cholestagel reduced the Cmax of norethindrone as well as the AUC and Cmax of ethinylestradiol when administered simultaneously with the oral contraceptive pill. This interaction was also observed when Cholestagel was administered one hour after the oral contraceptive pill. However no interaction was observed when Cholestagel was administered four hours after the oral contraceptive pill.
In an interaction study in healthy volunteers, co-administration of Cholestagel and ciclosporin significantly reduced the AUC0-inf and Cmax of ciclosporin by 34% by 44%, respectively. Therefore advice is given to closely monitor ciclosporin blood concentrations (see also section 4.4). In addition, based on theoretical grounds Cholestagel should be administered at least 4 hours after ciclosporin in order to further minimise the risks related to the concomitant administration of ciclosporin and Cholestagel. Furthermore, Cholestagel should always be administered at the same times consistently since the timing of intake of Cholestagel and ciclosporin could theoretically influence the degree of reduced bioavailability of ciclosporin.
When Cholestagel was co-administered with statins in clinical studies, an expected add-on LDL-C lowering effect was observed, and no unexpected effects were observed. Cholestagel had no effect on the bioavailability of lovastatin in an interaction study.
Co-administration of colesevelam and metformin extended-release (ER) tablets increases the exposure of metformin. Patients receiving concomitant metformin ER and colesevelam should be monitored for clinical response as is usual for the use of anti-diabetes drugs.
Colesevelam binds to glimepiride and reduces glimepiride absorption from the gastrointestinal tract. No interaction was observed when glimepiride was taken at least 4 hours before colesevelam. Therefore glimepiride should be administered at least 4 hours prior to colesevelam.
Co-administration of colesevelam and glipizide decreases the exposure of glipizide. Glipizide should be administered at least 4 hours prior to colesevelam.
Co-administration of Cholestagel and glyburide (also known as glibenclamide) caused a decrease in the AUC0-inf and Cmax of glyburide by 32% and 47%, respectively. No interaction was observed when Cholestagel was administered four hours after glyburide.
Co-administration of Cholestagel and repaglinide had no effect on the AUC and caused a 19% reduction in the Cmax of repaglinide, the clinical significance of which is unknown. No interaction was observed when Cholestagel was administered one hour after repaglinide.
No interaction was observed when Cholestagel and pioglitazone were administered simultaneously in healthy volunteers
Cholestagel predominantly binds hydrophobic bile acids. In a clinical study Cholestagel did not affect the faecal excretion of endogenous (hydrophilic) ursodeoxycholic acid. However, formal interaction studies with ursodeoxycholic acid have not been performed. As noted in general, when a drug interaction cannot be excluded with a concomitant medicinal product, Cholestagel should be administered at least four hours before or at least four hours after the concomitant medication to minimise the risk of reduced absorption of the concomitant medication. Monitoring of the clinical effects of treatment with ursodeoxycholic acid should be considered.
Cholestagel did not induce any clinically significant reduction in the absorption of vitamins A, D, E or K during clinical studies of up to one year. However, caution should be exercised when treating patients with a susceptibility to vitamin K or fat-soluble vitamin deficiencies, such as patients with malabsorption. In these patients, monitoring vitamin A, D and E levels and assessing vitamin K status through the measurement of coagulation parameters is recommended and the vitamins should be supplemented if necessary.
No clinical data are available on the use of Cholestagel in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonic/foetal development, parturition or postnatal development (see section 5.3). Caution should be exercised when prescribing to pregnant women.
The safety of Cholestagel has not been established in breast-feeding women. Caution should be exercised when prescribing to breast-feeding women.
There are no data on the effect of Cholestagel on fertility in humans. A study conducted in rats did not result in any differences in reproductive parameters between the groups that might imply reproductive effects attributable to colesevelam.
Cholestagel has no or negligible influence on the ability to drive and use machines.
The most frequently occurring adverse reactions are flatulence and constipation, found within the gastrointestinal disorders system organ class.
In controlled clinical studies involving approximately 1400 patients and during post-approval use, the following adverse reactions were reported in patients given Cholestagel.
The reporting rate is classified as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data).
Common: Headache
Very common: Flatulence*, constipation*
Common: Vomiting, diarrhoea*, dyspepsia*, abdominal pain, abnormal stools, nausea, abdominal distension
Uncommon: Dysphagia
Very rare: Pancreatitis
Not known: Intestinal obstruction*,**
Uncommon: Myalgia
Common: Serum triglycerides increased
Uncommon: Serum transaminases increased
* see section below for further information
** adverse reactions from post-marketing experience
The background incidence of flatulence and diarrhoea were higher in patients receiving placebo in the same controlled clinical studies. Only constipation and dyspepsia were reported by a higher percentage among those receiving Cholestagel, compared with placebo.
The incidence of intestinal obstruction is likely to be increased among patients with a history of bowel obstruction or removal.
Cholestagel in combination with statins and in combination with ezetimibe was well tolerated and the adverse reactions observed were consistent with the known safety profile of statins or ezetimibe alone.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
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