- 1. NAME OF THE MEDICINAL PRODUCT
- 2. QUALITATIVE AND QUANTITATIVE COMPOSITION
- 3. PHARMACEUTICAL FORM
- 4. CLINICAL PARTICULARS
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and special precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. PHARMACOLOGICAL PROPERTIES
- 6. PHARMACEUTICAL PARTICULARS
- 7. MARKETING AUTHORISATION HOLDER
- 8. MARKETING AUTHORISATION NUMBER(S)
- 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
- 10. DATE OF REVISION OF THE TEXT
1.NAME OF THE MEDICINAL PRODUCT
Cholestagel 625 mg
2.QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 625 mg colesevelam (as hydrochloride).
For the full list of excipients, see section 6.1.
Cholestagel as monotherapy is indicated as adjunctive therapy to diet for reduction of elevated
Cholestagel can also be used in combination with ezetimibe, with or without a statin, in adult patients with primary hypercholesterolaemia, including patients with familial hypercholesterolaemia (see section 5.1).
4.2Posology and method of administration
The recommended dose of Cholestagel for combination with a statin with or without ezetimibe is 4 to 6 tablets per day. The maximum recommended dose is 6 tablets per day taken as 3 tablets twice per day with meals or 6 tablets taken once per day with a meal. Clinical trials have shown that Cholestagel and statins can be
The recommended starting dose of Cholestagel is 6 tablets per day taken as 3 tablets twice per day with meals or 6 tablets once per day with a meal. The maximum recommended dose is 7 tablets per day.
During therapy, the
When a drug interaction cannot be excluded with a concomitant medicinal product for which minor variations in the therapeutic level would be clinically important, or where no clinical data are available on
hours after the concomitant medication in order to minimize the risk of reduced absorption of the concomitant medication (see section 4.5).
There is no need for dose adjustment when Cholestagel is administered to elderly patients.
The safety and efficacy of Cholestagel in children aged 0 to 17 years have not yet been established. Currently available data are described in section 5.1 but no recommendation on a posology can be made.
Method of administration
Cholestagel tablets should be taken orally with a meal and liquid.
The tablets should be swallowed whole and not broken, crushed or chewed.
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1
Bowel or biliary obstruction
4.4Special warnings and special precautions for use
Secondary causes of hypercholesterolaemia
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.
Interaction with ciclosporin
For patients on ciclosporin starting or stopping Cholestagel or patients on Cholestagel with a need to start ciclosporin: 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
Effects on triglyceride levels
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).
4.5Interaction with other medicinal products and other forms of interaction
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
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.
Oral contraceptive pill
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,
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
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.
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.
Other forms of interaction
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
4.6Fertility, pregnancy and lactation
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
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.
4.7Effects on ability to drive and use machines
Cholestagel has no or negligible influence on the ability to drive and use machines.
Summary of the safety profile
The most frequently occurring adverse reactions are flatulence and constipation, found within the gastrointestinal disorders system organ class.
Tabulated list of adverse reactions
In controlled clinical studies involving approximately 1400 patients and during
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).
Nervous system disorders
Very common: Flatulence*, constipation*
Common: Vomiting, diarrhoea*, dyspepsia*, abdominal pain, abnormal stools, nausea, abdominal distension
Uncommon: Dysphagia Very rare: Pancreatitis
Not known: Intestinal obstruction*,**
Musculoskeletal and connective tissue disorders
Common: Serum triglycerides increased Uncommon :Serum transaminases increased
*see section below for further information
**adverse reactions from
Description of selected adverse events
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 of suspected adverse reactions
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.
Since Cholestagel is not absorbed, the risk of systemic toxicity is low. Gastrointestinal symptoms could occur. Doses in excess of the maximum recommended dose (4.5 g per day (7 tablets)) have not been tested.
Should overdosage occur, however, the chief potential harm would be obstruction of the gastrointestinal tract. The location of such potential obstruction, the degree of obstruction and the presence or absence of normal gut motility would determine treatment.
Pharmacotherapeutic group: Lipid modifying agent, bile acid sequestrants, ATC code: C10A C 04
Mechanism of action
The mechanism of action for the activity of colesevelam, the active substance in Cholestagel, has been evaluated in several in vitro and in vivo studies. These studies have demonstrated that colesevelam binds bile acids, including glycocholic acid, the major bile acid in humans. Cholesterol is the sole precursor of bile acids. During normal digestion, bile acids are secreted into the intestine. A major portion of bile acids is then absorbed from the intestinal tract and returned to the liver via the enterohepatic circulation.
Colesevelam is a
In a 6 week study 129 patients with mixed hyperlipidaemia were randomised to fenofibrate 160 mg plus 3.8 g Cholestagel or fenofibrate alone. The fenofibrate plus Cholestagel group (64 patients) demonstrated a 10% reduction on
(65 patients). Reductions were also seen for
The effect of 3.8 g Cholestagel plus 10 mg ezetimibe versus 10 mg ezetimibe alone on
The addition of Cholestagel 3.8 g daily to
In the paediatric population, the safety and efficacy of 1.9 or 3.8 g/day Cholestagel was assessed in an 8 week
Cholestagel has not been compared directly to other bile acid sequestrants in clinical trials.
So far, no studies have been conducted that directly demonstrate whether treatment with Cholestagel as monotherapy or combination therapy has any effect on cardiovascular morbidity or mortality.
Cholestagel is not absorbed from the gastrointestinal tract.
5.3Preclinical safety data
6.1List of excipients
Cellulose (E460), microcrystalline
Silica, colloidal anhydrous
Iron oxide black (E172)
6.4Special precautions for storage
Keep the bottle tightly closed in order to protect from moisture.
6.5Nature and contents of container
High density polyethylene bottles with a polypropylene cap. Package sizes are: 24 tablets (1 X 24)
100 tablets (2 X 50)
180 tablets (1 X 180)
High density polyethylene bottles with a polypropylene cap without outer carton. Package sizes are: 180 tablets (1 X 180)
Not all pack sizes may be marketed.
6.6Instructions precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7.MARKETING AUTHORISATION HOLDER
Genzyme Europe B.V., Gooimeer 10,
8.MARKETING AUTHORISATION NUMBER(S)
9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 10 March 2004
Date of latest renewal: 12 March 2009
10. DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu/.