Safety concerns in practice

There is a general lack of awareness of clozapine-induced constipation and its fast onset. There are reports of fatal cases still occurring.

Intestinal obstruction, faecal impaction and paralytic ileus

A Medicines and Healthcare products Regulatory Agency (MHRA) safety alert (2017) reminds healthcare professionals of the potentially fatal risk of intestinal obstruction, faecal impaction, and paralytic ileus with using clozapine and the importance of recognising and actively treating constipation.

To reduce the risk of fatalities, the MHRA advise:

• clozapine is contraindicated in patients with paralytic ileus
• advise patients to report constipation immediately
• actively treat any constipation that occurs

Clozapine toxicity

A second MHRA safety alert (2020) on clozapine indicates blood clozapine monitoring is required in certain clinical scenarios such as when a patient stops smoking. In addition to blood monitoring, it is equally important to monitor bowels as severe constipation can be precipitated. The reason for this is because slowed gastrointestinal transit time (gastrointestinal hypomotility) likely increases with higher clozapine levels.

Incidence of constipation

Clozapine can cause varying degrees of gastrointestinal hypomotility. The effects can range from:

• Constipation, which is very common (≥1/10)
• Intestinal obstruction, faecal impaction, and paralytic ileus, which are very rare (< 1/10,000).

The reported fatality rate for severe clozapine-induced constipation is around 20%.

All healthcare professionals should be aware of the common incidence of constipation with clozapine and recognise early signs of constipation.

Preventing constipation

Consider the following strategies to prevent constipation in people taking clozapine.

Counsel people about constipation

• Advise people taking clozapine to report constipation immediately.
• Ensure family members or carers are aware of this side effect.
• A handy patient fact sheet on clozapine, slow gut and constipation is available on Choice and Medication (subscription only).
• Keep a stool chart.

Encourage people taking clozapine or their carer to keep a note of the bowel movements (day, time of stool, amount and Bristol Stool Chart number for each movement). Advise to record daily for the first 4 weeks and weekly or monthly thereafter. This is because the risk of constipation is the highest in the first four months of starting clozapine.

Give dietary advice

• Advise people taking clozapine to gradually increase fibre intake. The NHS website provides tips on how to get more fibre into your diet.
• Encourage people to drink at least 2 litres per day of non-caffeinated liquid such as water or water diluted with low sugar squash.
• Avoid caffeinated drinks as they can increase clozapine plasma levels.
• Consider increasing mobility or exercise e.g. daily walk or run. Keeping active can help regulate bowel movements.
• The NHS website provides a summary on how to prevent constipation.

Active early interventions

For people recently started on clozapine consider the following points.

Review other medicines taken by the individual which can contribute to constipation. Take particular care in people:

• receiving other medicines known to cause constipation (especially those with anticholinergic and antihistaminergic properties e.g. opioids)
• with a history of colonic disease or lower abdominal surgery
• aged 60 years and older

Consider providing a rescue pack of stimulant laxatives and an osmotic laxative or a stool softener.

Some individuals may need long-term laxatives to prevent constipation. Laxatives are safe to use long-term in people on clozapine. This can be helpful in people who may not realise they are constipated.

Recognising constipation and faecal impaction

Signs to watch out for include:

• Change in usual bowel pattern per week. Monitor for stool types 1, 2, 6 or 7 on the Bristol Stool Chart. Note: diarrhoea can be a sign of faecal impaction.
• Straining to pass a stool
• Stomach aches which improve after a bowel movement
• Feeling sick, less hungry, bloated or full
• Smelly wind
• Stools getting dry, hard or lumpy

When to refer

Direct the individual to seek immediate medical attention at their local A&E if they experience any of the following red flag symptoms:

• Medium to severe abdominal pain or discomfort lasting over an hour
• Swollen or distended stomach (also known as ‘clozapine belly’)
• Overflow diarrhoea (particularly if there is blood in the stools)
• Sickness or vomiting (particularly if it smells of stool)
• Absent bowel sounds
• Symptoms of sepsis

There are case reports of death occurring only hours after the above symptoms present.

Treating constipation

The following clozapine-induced constipation management advice is based on clinical experience and The Maudsley Prescribing Guidelines in Psychiatry (log in required).

Actively treat constipation if the individual has not passed a bowel movement in two days and intestinal obstruction has been excluded.

• Start stimulant laxatives (e.g. senna or bisacodyl or sodium picosulfate). Check with the individual whether the laxative is working after 24 hours.
• Add an osmotic laxative (macrogols or lactulose) or stool softener (docusate sodium) if necessary. Confirm with the individual whether the laxative regimen is having the desired effect after 48 hours. Note: advise to take lactulose regularly and with plenty of fluid.
• Avoid bulk-forming laxatives because the cause of constipation in this case is gastric hypomotility.
• Increase laxative doses every 48 hours until resolution of symptoms. Consider the maximum licensed doses.
• Faecal impaction may require treatment with high dose macrogol or repeated doses of suppositories.

NICE CKS Constipation provides a useful table summarising the factors affecting choice of laxative.

Ensure you do the following:

• Inform the individual’s mental health team to ensure they are aware of the constipation episode.
• In severe cases of constipation, liaise with a gastroenterologist for advice.
• Develop a plan with the individual to prevent future episodes of constipation.

Mitigation of risk

Organisations may wish to consider the following strategies to mitigate the severe consequences of constipation in people taking clozapine.

Report an adverse drug reaction

Report constipation and obstruction adverse drug reactions in people taking clozapine to the MHRA by completing a Yellow Card.

Flags in prescribing systems

A reminder in prescribing systems highlighting the risk of constipation with clozapine. This can help healthcare professionals take prompt action when people taking clozapine report the side effect of constipation.

Liaising on discharge

Inform the relevant primary care healthcare professionals on discharge communication when initiating clozapine or continuing clozapine. This includes all transfer of care to ensure the relevant healthcare professionals are informed. Remind them of key side effects including constipation and agranulocytosis (severe reduction in white blood cell count).