Research and analysis

Over-the-counter stimulant laxatives: benefit-risk review

Published 18 August 2020

MHRA UK Public Assessment Report - August 2020

1. Introduction

The Medicines and Healthcare products Regulatory Agency (MHRA) is the government agency responsible for regulating medicines and medical devices in the UK. We continually review the safety of all medicines in the UK and inform healthcare professionals and the public of the latest updates. In our Public Assessment Reports, we discuss evidence-based assessments of safety issues for a particular drug or drug class, and changes made to the product information on the basis of this evidence which will help safeguard public health.

The following MHRA Public Assessment Report discusses new risk minimisation measures which are being put into place for over-the-counter (OTC) stimulant laxatives (bisacodyl, senna and sennosides (isolated as calcium salts) and sodium picosulfate) that are used for the treatment of constipation.

2. Background

OTC stimulant laxatives have been under close review for some time. Previous recommendations have included the addition of warnings that laxatives do not aid weight loss and that taking them for a long time may be harmful. However, these were not consistently added to all stimulant laxatives.

Most recently, the MHRA conducted a comprehensive review to assess the benefits and risks of stimulant laxatives (both orally and rectally administered formulations) and their continued over-the-counter availability. In the light of evidence of misuse/abuse and overuse, and current clinical advice on the treatment of constipation, the review considered: overuse in people with eating disorders, long-term use in the elderly, and use in children. The review looked at evidence from numerous sources, including professional and patient bodies, clinicians working in eating disorder clinics, a submission from the Proprietary Association of Great Britain (PAGB) on behalf of member companies, submissions from marketing authorisation holders (MAHs), and the scientific literature. The review also considered the legal status, product information and pack sizes of these products.

The MHRA review and recommendations were endorsed by the Commission on Human Medicines (CHM; an independent body who gives advice to UK Government Ministers about the safety, quality and efficacy of medicines).

3. Constipation

Constipation is common. It is a symptom not a disease and its exact cause is not fully understood. There may be many factors involved which can include not eating enough fibre, not drinking enough fluids, not moving enough, not exercising, changes to diet or daily routine, adverse effects of medicines, stress, anxiety or depression or rarely an underlying medical condition.

A 1965 study of 1,055 factory workers (Connell, et al., 1965) was set up to define what constitutes “normal” bowel habits and found that 99% of the population had a bowel movement between 3 times day and 3 times a week. This is still quoted as being the normal range.

The 2006 Rome III criteria (a tool for diagnosis) (updated by Lacy, et al., 2016) define chronic constipation as when at least two of the following occur in any 12-week period during the previous 12 months:

• fewer than 3 bowel movements per week
• hard stools in more than 25% of bowel movements
• a sense of incomplete evacuation in more than 25% of bowel movements
• excessive straining in more than 25% of bowel movements
• a need for manual evacuation

The term constipation means different things to different people and this can vary between patients, and between patients and healthcare professionals. A YouGov survey carried out in February 2016 in 2,352 adults reported that nearly 1 in 5 thought that passing stools less than once a day was a symptom of constipation.

Some studies suggest that constipation can reduce quality of life (Irvine, et al., 2002.; Wald, 2007; Belsey et al., 2010). However, the YouGOV survey reported that “a significant proportion of the population does not think constipation is a serious issue” and “many admit they would wait several weeks before addressing the issue.” This difference may be due to the different degrees of constipation experienced by different people, which can range from a minor episode to chronic persistent constipation.

The treatment of constipation depends on the cause. Stimulant laxatives work by stimulating the muscles in the gut lining and helping them to move stools along the gut. They take 6 to 12 hours to work. They are usually recommended when other types of laxatives have not worked. General guidance for patients on both prevention and treatment of constipation, such as NHS Choices advice says that constipation can usually be treated at home with simple changes to diet and lifestyle.

As well as stimulant laxatives, the following are available over-the-counter for the treatment of constipation:

• bulk laxatives (e.g. ispaghula husk, available as a single substance or in combination with mebeverine or senna; methylcellulose; sterculia)
• osmotic laxatives – poorly absorbed ions (e.g. magnesium sulfate, phosphate) and poorly absorbed sugars (e.g. disaccharides - lactulose, sugar alcohols - sorbitol and mannitol, macrogols)
• stool softeners e.g. docusate sodium
• emollients laxatives e.g. mineral oils

Management of constipation in adults

The current NICE Clinical Knowledge Summary on constipation also advises changes to diet and lifestyle, as part of its step-wise approach for treating adults. If dietary and lifestyle changes do not work, they recommend using a bulk-forming laxative such as Fybogel (ispaghula husk), followed by adding or as an alternative using an osmotic laxative such as Lactugel or Duphalac (lactulose) or Movicol (macrogol and electrolytes). Only then do they recommend adding a stimulant laxative, if needed. However, in the case of opioid-induced constipation, bulk-forming laxatives should not be used. Other newer drugs, such as prucalopride or lubiprostone are available under prescription for the treatment of chronic constipation.

The British National Formulary advises that it is important that patients understand that bowel habits can vary considerably in frequency without doing harm and that misconceptions about bowel habits have led to excessive laxative use.

Management of constipation in children

NICE Guidance for children and young people provides advice on a treatment pathway. It also states,

“based on expert consensus, NICE recommend stimulant laxatives only as a second-line intervention as use of macrogol is preferred.

4. Evidence

The reviews of the evidence for efficacy and safety evidence for each of the stimulant laxatives are summarised below:

Efficacy (how well it works)

Bisacodyl

Double-blind, placebo-controlled efficacy studies (Kamm, 2011 and Kienzle-Horn, 2006) and active-controlled studies have demonstrated that bisacodyl is effective for the treatment of constipation. No relevant placebo-controlled efficacy studies on oral bisacodyl in children and adolescents were identified. One uncontrolled trial carried out by one MAH in a small number of children with a wide spread of ages indicated that there may be efficacy in the over-the-counter setting.

Senna and sennosides (as calcium salts)

The Committee on Herbal Medicinal Products (HMPC) Assessment Report on senna leaf and fruit includes a comprehensive review of efficacy. The report concludes that there is no well-designed, non-experimental descriptive study to investigate the use of senna leaf or fruit as a single preparation for the short-term relief of occasional constipation. However, there are well-designed clinical studies for combination products containing senna used for the short term relief of occasional constipation and for products containing high doses of senna for bowel cleansing. Despite the shortcomings of studies reported, they showed that senna containing combination products had a clear laxative effect. The European Union herbal monograph for senna leaf and pods states that these products should not be used in children under 12 years of age.

Sodium picosulfate

Several old studies of poor quality were identified which indicate the efficacy of sodium picosulfate for the treatment of constipation in both adults and children and suggest that it is similarly effective to bisacodyl and senna.

Several published reviews have compared the efficacy of different types of laxatives:

In 2010, Mueller-Lissner and Wald surveyed 51 systematic reviews, randomised controlled trials (RCTs) or observational studies and concluded:

• macrogols improve symptoms of constipation without serious adverse effects. Lactitol and lactulose may be equally effective in improving frequency of bowel movements
• the bulk-forming laxative ispaghula husk seems more effective than lactulose at improving the overall symptoms of constipation
• prucalopride and lubiprostone efficacy has been shown in RCTs but there are relatively frequent adverse events
• the effectiveness of senna, bisacodyl, cascara, docusate and glycerol/glycerine suppositories could not be established
• no evidence examining the efficacy of faecal softeners was found but the authors state that these are “generally considered beneficial”

A 2016 guideline (Emly, M., Marriott, A., 2017) for the management of chronic constipation of adults within the community considers that the strongest evidence is for the use of macrogols solution and psyllium (ispaghula).

They also noted that there is no research evidence to support use of stimulant laxatives, lubricants or stool softeners

In 2005, Ramkumar & Rao carried out a systematic review of the efficacy and safety of traditional medical therapies for chronic constipation in order to make evidence based recommendations. Their results showed:

• good evidence (grade A) was found to support the use of macrogol.
• moderate evidence (grade B) to support the use of ispaghula husk, and lactulose
• a lack of good quality data regarding many commonly used agents including senna and bisacodyl (as well as milk of magnesia and stool softeners).

In summary, stimulant laxatives are well established medicines which have been available for many years. Due to their age, it is not expected that there would be data available from high-quality, modern trials to assess their efficacy. The data which are available, together with their widespread use, suggest that they are effective and well-tolerated when used appropriately. There are reasonable supporting data for other types of laxatives such as lactulose, macrogol and ispaghula husk which can be used to treat constipation in the over-the-counter setting.

Safety

Bisacodyl

Bisacodyl has been widely used for many years and the safety profile of both the tablet and suppository formulation in short-term use were found to be favourable. Up to 31 December 2019, the MHRA had received 149 reports containing 449 suspected adverse drug reactions for bisacodyl; 2 of these reported fatalities. Gastrointestinal side effects such as abdominal cramp, diarrhoea and vomiting were the most frequent reactions reported.

Senna and sennosides (as calcium salts)

Clinical trials involving senna found that most side effects reported were hypersensitivity reactions or gastrointestinal in nature. Up to 31 December 2019, the MHRA had received 424 reports containing 923 suspected adverse drug reactions for senna products; 12 of these reported fatalities. The majority of the reports relate to products which include other active ingredients in combination with senna and allergic adverse reactions relating to the skin were the most frequently reported.

Sodium picosulfate

The adverse events seen in clinical studies involving sodium picosulfate were also mainly gastrointestinal and non-serious, such as stomach pain, diarrhoea, nausea and vomiting. These were found to be more manageable when the dosage was reduced. Up to 31 December 2019, the MHRA had received 279 reports containing 809 suspected adverse drug reactions for sodium picosulfate; 19 of these reported fatalities. Reports were most frequently concerning gastrointestinal side effects. In many of the fatal cases, the patients were taking other medications.

Misuse/abuse

MAHs were requested to provide details of cases of misuse/abuse received in association with stimulant laxatives. These were identified for all three of stimulant laxatives reviewed, although the reports are often incomplete, and it is noted that many cases may not be reported. The cases were often found to occur within the context of eating disorders. The highest number of reports of misuse received related to bisacodyl tablets. MAHs identified 167 relevant reports – 84 of which were serious and 5 fatal. These included a report of a young patient with bulimia who had increased their intake of bisacodyl over 2 years up to 100 tablets daily and experienced non-serious abdominal pain and decreased therapeutic response. There was also a UK HM Coroner’s case (Regulation 28 Prevention of Future Deaths report) of a patient who had overdosed on 80 bisacodyl tablets and was admitted to A&E and subsequently deteriorated and died of multi-organ failure. The patient had a medical history of anorexia nervosa and long-term laxative abuse.

MAHs for senna received 49 reports (53 events) of misuse, abuse or intentional overdose, 7 of which were serious. One of these was a case of a patient with a 23-year history of using maximum strength senna tablets. This included a period where they were taking 90 pills a day and having daily accidents from bowel urgency. Following treatment for the addiction the patient continued to take 10 laxatives a day in order to control their bowels and suffered from several conditions including irritable bowel syndrome, low blood pressure and osteoporosis.

For sodium picosulfate, MAHs identified a total of 12 cases (containing 34 events) associated with eating disorders. In half of these, drug abuse was reported. Several cases did not provide sufficient information, however those which did were indicative of long-term misuse. There were fewer cases of abuse/misuse reported in association with sodium picosulfate than with bisacodyl or senna.

Using laxatives too often or for too long can cause diarrhoea, the bowel to become blocked and unbalanced salts and minerals in the body. Laxative abuse has been found to be associated with several medical complications that affect multiple organ systems (Forney et al., 2016).

Usage

Exposure is difficult to capture accurately as the majority of the usage is from non-prescription sales. It is estimated that the vast majority of sales are as general sale list (GSL) products through supermarkets and other retail outlets. Within pharmacies, most sales are also of GSL stimulant laxatives. Sales volume data for the individual active substances were provided for the review and indicate that GSL senna products are the most frequently purchased, followed by bisacodyl and sodium picosulfate.

Discussion

Stimulant laxatives have been available as OTC products for many years. Constipation and its management have changed considerably since the time of first licensing. The widespread use of these products suggests that they are effective, and the rate of adverse event reports is relatively low. CHM noted that these products are generally used responsibly. However, the serious nature of the cases of misuse and abuse in patients with eating disorders is concerning, particularly within the context of the large GSL pack sizes which have been readily available to patients, including children and adolescents.

In their review, CHM noted that the product information for stimulant laxatives was inconsistent between products and that the large GSL pack sizes are not consistent with their use for short term constipation. They noted current clinical guidance recommends that stimulant laxatives should not be used first line in either adults or children and that they should not be used long-term without medical advice. They also advised that children under the age of 12 years who are experiencing constipation should receive medical advice and noted that macrogol is the recommended first-line treatment. CHM therefore recommended that GSL pack sizes should be reduced, there should be appropriate warnings against overuse and advising that these products do not help with weight loss consistently for all products, and age recommendations should be introduced.

In addition to patients who may deliberately overuse or misuse stimulant laxatives, elderly people may inappropriately overuse them due to misconceptions about constipation. Long-term overuse could mask more serious underlying conditions. Constipation is more common in the elderly and may be caused by a number of different factors. CHM advised that pharmacists are well placed to advise older people who may be taking several medications and/or have underlying medical conditions on the best way to treat their constipation, and on whether they need to seek further medical advice. Smaller GSL pack sizes would provide a large enough supply to treat short-term constipation but if a larger pack size is needed then a pharmacist can provide support and advice.

Several of the efficacy studies which were considered during the review noted the need to understand the underlying cause of constipation, so that the best treatment can be given. CHM advised that pharmacists are well placed to provide guidance to all patients, and to parents and caregivers, on the most appropriate treatment options for constipation. Educational materials have been produced in collaboration with the Royal Pharmaceutical Society to support pharmacists.

5. Expert advice

The Commission on Human Medicines (CHM) – the government’s independent expert advisors on medicinal products – advised the following new risk minimisation measures for over-the-counter stimulant laxatives:

• removal of General Sales List (GSL) availability for children so that they are only licensed for use in adults
• restricting Pharmacy-only (P) availability so they are only licensed for use in patients aged 12 years and above
• harmonising GSL and P indications across the products and in accordance with current clinical practice and removing indications that are not appropriate for the self-care setting
• restriction of GSL pack sizes to two short treatment courses i.e. packs of 20 standard strength bisacodyl or senna tablets, 10 tablets of maximum strength senna and 100ml bottles of senna syrup or sodium picosulfate solution. Any larger pack sizes would only be available through pharmacies
• seeking to restrict the number of packs that can be bought in a single purchase through voluntary best practice
• harmonisation of safety warnings and improving patient information
• educational materials for pharmacists

6. MHRA action

In August 2020, the MHRA announced the comprehensive package of measures set out in the advice from the CHM.

References

Belsey, J., Greenfield, S., Candy, D., Geraint, M., 2010. Systematic review: impact of constipation on quality of life in adults and children. Aliment Pharmacol Ther, 31(9), pp. 938-49.

Connell, A.M, Hilton C., Irvine, G., Lennard-Jones, J.E., Misiewicz, J.J., 1965. Variation of Bowel Habit in Two Population Samples. s.l., s.n.

Emly, M., Marriott, A., 2017. Effective Management of chronic constipation of primary care., s.l.: National Development Team for Inclusion.

Forney, K.J., Buchman-Schmitt, M.S. Keel, P.K., Frank, G.K.W., 2016. The medical complications associated with purging. International Journal of Eating Disorders, 49(3), pp. 249-259.

Irvine, E.J., Ferrazi, S., Pare, P., Thompson, W.G., Rance, L., 2002. Health-related quality of life in functional GI disorders: focus on constipation and resource utilization. The American Journal of Gastroenterology, 97(8), pp. 1986-1993.

Kamm, M.A., Mueller-Lissner, S., Wald, A., Richter, E., Swallow, R., Gessner, U., 2011. Oral Bisacodyl Is Effective and Well-Tolerated in Patients With Chronic Constipation. 9(7).

Kienzle-Horn, S., Vix, J-M, Schuijt, C., Peil, H., Jordan, C.C., Kamm, M.A., 2006. Efficacy and safety of bisacodyl in the acute treatment of constipation: a double-blind, randomized, placebo-controlled study. 23(10).

Lacy B.E., Mearin F., Chang L., Chey, W.D., Lembo, A.J., Simren, M., Spiller, R., 2016. Bowel Disorders. Gastroenterology, pp. 1393-1407.

Mueller-Lissner, S.A., Wald, A., 2010. Constipation in adults. BMJ Clin Evid, Issue Published online Jul 5 2010, p. 0413.

Ramkumar, D., Rao, S.S.C., 2005. Efficacy and Safety of Traditional Medical Therapies for Chronic Constipation: Systematic Review. American Journal of Gastroenterology., Volume 100, pp. 936-971.

Wald A., 2007. Chronic constipation: advances in management. Neurogastroenterol Motil, 19(1), pp. 4-10.

Glossary

British National Formulary (BNF)

A United Kingdom pharmaceutical reference book containing information and advice on prescribing and pharmacology.

General Sales List Medicine

Medicines that can be bought from any shop without a prescription.

Labelling

Information on the immediate or outer packaging of a medicine.

Marketing authorisation holder

The company or other legal entity that has the authorisation to market a medicine in the UK.

Pharmacy medicine

Medicines that can only be sold to a customer by a trained pharmacist.

Proprietary Association of Great Britain (PAGB)

The UK trade association which represents the manufacturers of branded over-the-counter medicines, self-care medical devices and food supplements.

Risk minimisation measure

A public health intervention intended to prevent or reduce the probability of the occurrence of an adverse reaction associated with exposure to a medicine or to reduce its severity if it occurs.

Stimulant laxative

A drug which acts by directly stimulating nerve endings in the colonic mucosa, thereby increasing intestinal motility.