Advice

Overview for healthcare professionals

Overview for healthcare professionals

Regulatory status of colesevelam

Colesevelam (Cholestagel, Sanofi) is licensed by the European Medicines Agency to reduce levels of total cholesterol and low-density lipoprotein cholesterol in people with primary hypercholesterolaemia. Colesevelam can be prescribed in combination with statins and/or ezetimibe, or as monotherapy if statins are inappropriate or not tolerated.

Colesevelam is not licensed to treat bile acid malabsorption; therefore, the use of colesevelam for this indication is off-label.

In line with the guidance from the General Medical Council (GMC), it is the responsibility of the prescriber to determine the clinical need of the patient and the suitability of using colesevelam outside its authorised indications.

Evidence statements

No randomised controlled trials (RCTs) were identified that compared colesevelam with placebo or other treatments in people with bile acid malabsorption. One RCT was identified that compared colesevelam with placebo in 24 women with diarrhoea-predominant irritable bowel syndrome, 4 of whom had evidence of bile acid malabsorption. Two case series were identified that reported on the efficacy of colesevelam for bile acid malabsorption.

  • A small RCT compared the effects of colesevelam with placebo in 24 women with diarrhoea-predominant irritable bowel syndrome. Four of the women had raised fasting serum 7-hydroxy-4-cholesten-3-one (7C4), a marker for bile acid malabsorption. After treatment, there was no statistically significant difference in gastric, small bowel and overall colonic transit, or ascending colonic emptying, with colesevelam compared with placebo. Stool passage was statistically significantly easier in women who received colesevelam compared with those who received placebo. However, it is unclear whether this difference is of clinical importance. There was no difference between the groups in stool frequency or consistency (Odunsi-Shiyanbade et al. 2010).

  • According to a retrospective review of electronic patient records and a patient questionnaire, colesevelam improved diarrhoea, frequency and urgency of defecation, steatorrhoea, abdominal pain and faecal incontinence in 45 people with a diagnosis of cancer and symptoms of bile acid malabsorption for 3 months or more (Wedlake et al. 2009). The most common reasons for bile acid malabsorption were pelvic radiotherapy (64%) and small-bowel resection or right hemicolectomy (27%). Symptoms had not responded to prior colestyramine treatment in 30 people (67%).

  • Colesevelam resolved diarrhoea in 5 people with bile acid malabsorption who could not tolerate colestyramine (Puleston et al. 2005).

  • According to the summary of product characteristics for Cholestagel, the most frequent adverse effects are flatulence and constipation, which affect at least 1 in 10 people. Other common adverse effects include headache, vomiting, diarrhoea, dyspepsia, abdominal pain, abnormal stools, nausea and abdominal distension.

Summary of the evidence

This section gives a brief summary of the main evidence. A more thorough analysis is given in the Evidence review section.

Efficacy

No RCTs were identified that compared colesevelam with placebo or other treatments in people with bile acid malabsorption.

One RCT was identified that compared the effects of colesevelam with placebo in 24 women with diarrhoea-predominant irritable bowel syndrome, 4 of whom had evidence of bile acid malabsorption.

Two case series were identified that reported on the efficacy of colesevelam for treating bile acid malabsorption. One included people who developed bile acid malabsorption after cancer treatment; the other included people with bile acid malabsorption who could not tolerate colestyramine.

Colesevelam compared with placebo in diarrhoea-predominant irritable bowel syndrome

Odunsi-Shiyanbade et al. (2010) conducted a small double-blind RCT that assessed the effect of colesevelam on gastrointestinal and colonic transit, bowel function, and colonic permeability in 24 women with diarrhoea-predominant irritable bowel syndrome. The women were randomised to receive 1.875 g colesevelam or placebo twice daily for 12–14 days. Three women in the placebo group and 1 in the colesevelam group had evidence of bile acid malabsorption (fasting serum 7C4 61 nanograms/ml or more [an indirect measure of bile acid synthesis that is used to screen for bile acid malabsorption]). However, the results for these women were not reported separately.

The primary end points were colonic geometric centre at 24 hours (a measure of colonic transit, with a higher geometric centre implying a faster colonic transit) and ascending colon emptying half-life (the time taken for 50% of a radiolabeled meal to empty from the colon). Other outcomes included bowel function (for example, daily bowel frequency and consistency) and colonic mucosal permeability.

After treatment, there was no statistically significant difference in gastric, small bowel and overall colonic transit, or ascending colonic emptying with colesevelam compared with placebo. Higher baseline fasting serum levels of 7C4 were associated with higher ascending colon half-lives (a marker for reduced colonic transit times; p<0.001) after colesevelam treatment. The authors suggested that 7C4 levels may predict responsiveness to colesevelam in women with diarrhoea-predominant irritable bowel syndrome.

There was no difference between the colesevelam and placebo groups in the number of bowel movements (mean 2 per day in both groups; statistical significance not reported) or in stool consistency (Bristol Stool Form Scale, mean score 4.57 with placebo and 3.78 with colesevelam, p=0.12). Stool passage was statistically significantly easier in women who received colesevelam, compared with women who received placebo (4.18 with colesevelam compared with 4.39 with placebo, on a scale of 1 to 7, with 1 representing manual disimpaction and 7 incontinence; p=0.047). However, it is unclear whether this difference is of clinical importance. There was no significant difference in colonic mucosal permeability between the colesevelam and placebo groups.

See table 1 for a summary of the results.

Colesevelam for treating bile acid malabsorption (case series)

Wedlake et al. (2009) reported a retrospective review of 45 people (37 women) who had completed cancer treatment or were undergoing treatment for ongoing or relapsed cancer, and who had chronic symptoms of bile acid malabsorption for 3 months or more for which they had been prescribed colesevelam (1.25 g 3 times daily with or after food). The most common reasons for bile acid malabsorption were pelvic radiotherapy (64%) and small-bowel resection or right hemicolectomy (27%). Bile acid malabsorption was confirmed by SeHCAT scan in 27 people (60%). Symptoms had not responded to prior colestyramine treatment in 30 people (67%).

Hospital electronic patient records were reviewed retrospectively for all 45 people to assess the effects of 2−6 weeks of colesevelam treatment on 6 gastrointestinal symptoms, which had been recorded prospectively in the patient record. Outcomes were also assessed by a patient questionnaire, which was sent to 36 of the 45 people included in the case series (excluding those who were terminally ill). Out of 36 people, 30 (83%) responded. The median treatment period in these people was 27 months. When data from the electronic patient records and questionnaires were combined, it was found that 30 people (67%) were still taking colesevelam at their last follow-up (up to 4 years).

In people who experienced each symptom, the following were improved after colesevelam treatment (proportions of people):

  • diarrhoea (record review 88%; questionnaire 80%)

  • frequency of defecation (record review 77%; questionnaire 83%)

  • steatorrhoea (record review 76%; questionnaire 80%)

  • urgency of defecation (record review 76%; questionnaire 80%)

  • abdominal pain (record review 74%; questionnaire 58%)

  • faecal incontinence (record review 69%; questionnaire 74%).

Based on the review of patient records, of the 30 people whose symptoms did not respond to prior colestyramine treatment, colesevelam improved diarrhoea in 83%, urgency of defecation in 74%, frequency of defecation in 72%, steatorrhoea in 71%, abdominal pain in 68% and faecal incontinence in 62%.

Puleston et al. (2005) reported on the use of colesevelam in 5 people with bile acid malabsorption who could not tolerate colestyramine. Colesevelam resolved diarrhoea with no adverse effects at doses between 1.25 g and 3.75 g per day for 2–7 months.

Table 1 Summary of Odunsi-Shiyanbade et al. (2010)

Placebo

Colesevelam

Analysis

Randomised

n=12

n=12

Efficacy

n=12

n=12

Geometric centre at 24 hoursa

3.30±0.3

2.68±0.32

p=0.18

Ascending colon emptying half-lifeb

14.9±3.58

18.85±2.88

NR

Stool frequency per day (mean ± standard error)

2.25±0.34

2.14±0.31

NR

Stool consistency (Bristol Stool Form Scale; mean ± standard error)

4.57±0.35

3.78±0.27

p=0.12

Ease of stool passage (scale, 1−7; mean ± standard error)

4.39±0.11

4.18±0.14

p=0.047

Safety

n=12

n=12

People reporting serious adverse events

0

0

NR

Headache

33%

4/12

40%

5/12

NR

Lower abdominal cramps

0%

0/12

17%

2/12

NR

Flatulence

8%

1/12

24%

3/12

NR

Green-coloured stools

17%

2/12

17%

2/12

NR

Nausea

24%

3/12

17%

2/12

NR

n, number of people; NR, not reported.

a A measure of colonic transit: a higher geometric centre implies a faster colonic transit.

b The time taken for 50% of a radiolabeled meal to empty from the colon.

Safety

The summary of product characteristics for colesevelam states that the most frequent adverse effects are flatulence and constipation. These affected at least 1 in 10 people in controlled clinical studies and during post-approval use for hypercholesterolaemia. Other common adverse effects (affecting between 1 in 100 and 1 in 10 people) are headache, vomiting, diarrhoea, dyspepsia, abdominal pain, abnormal stools, nausea, abdominal distension and raised serum triglycerides.

The summary of product characteristics notes that colesevelam may affect the bioavailability of other medicines. Therefore, when a clinically important drug interaction cannot be excluded, colesevelam should be taken at least 4 hours before or 4 hours after the other medicine to minimise the risk of reduced absorption. Colesevelam tablets can be taken once a day if needed. However, it is not known whether a once-daily dose is effective for treating bile acid malabsorption. In Odunsi-Shiyanbade et al. (2010), 1.875 g colesevelam was taken twice daily and, in Wedlake et al. (2009), 1.25 g was taken 3 times daily. The exact dosage regimens were not reported in Puleston et al. (2005).

In Odunsi-Shiyanbade et al. (2010), the most common adverse effects seen with colesevelam were headache (40%), flatulence (24%), nausea (17%), lower abdominal cramps (17%) and green-coloured stools (17%). The authors state that these adverse effects occurred at similar rates in the placebo group, although the statistical significance of any differences between the groups was not reported. There were no serious adverse events and no women had to stop the study because of an adverse event. See table 1 for more details.

Wedlake et al. (2009) reported bloating, constipation, heartburn, abdominal pain, flatulence, perianal soreness, weight gain, and leg and facial oedema in people treated with colesevelam. Each of these adverse effects occurred in 7% or fewer people treated with colesevelam. After at least 1 year of treatment, 9 people (20%) developed vitamin D deficiency.

Adverse effects led to 5 people stopping colesevelam (11%). Other reasons for stopping treatment were lack of efficacy (n=5); having to take too many tablets or finding them difficult to swallow (n=3); resolution of symptoms (n=2); and switching to another medicine (n=1). One person was lost to follow-up.

In Puleston et al. (2005), no adverse effects were reported by the 5 people with bile acid malabsorption who had not previously tolerated colestyramine.

Cost effectiveness and cost

According to the Drug Tariff (September 2013), 180 colesevelam tablets (625 mg) cost £87.36.

In the studies reported in this evidence summary, between 2 and 6 colesevelam tablets (625 mg) were taken daily. Current costs for 1.25 g colesevelam per day are £0.97, and for 3.75 g per day £2.91.