Clozapine Constipation: Laxatives, Warning Signs, and the Risk of Ileus

About one in three people taking clozapine have constipation. A 2016 meta-analysis of 32 studies found a pooled prevalence of 31.2%, which is the share of people constipated when surveyed, and the odds of constipation were about three times those with other antipsychotics (odds ratio 3.02).¹

The FDA strengthened its warning on January 28, 2020, stating that constipation from clozapine can, uncommonly, progress to serious bowel complications. It identified 10 such cases, including five deaths.² The other side effects are covered on the clozapine side effects page.

Clozapine slows the whole gut, often without symptoms

A New Zealand study measured colonic transit time with radiopaque markers in 37 patients, 20 on clozapine and 17 on other antipsychotics.^{3, 2} Median transit time was 104.5 hours on clozapine and 23 hours on other antipsychotics. Eighty percent of the clozapine-treated patients had colonic hypomotility, compared with none of the others, and transit times were positively correlated with clozapine plasma level.³

A second study used a wireless motility capsule in 17 clozapine-treated patients with no known gastrointestinal dysfunction. Dysmotility was evident in at least one region of the gut in 82%, with delayed gastric emptying in 41%, delayed small bowel transit in 71%, and delayed colon transit in 50%.⁴

In that study, patients' own reports of constipation had low sensitivity for predicting dysmotility.⁴ The label states that subjective symptoms may not accurately reflect the degree of hypomotility.⁵ Someone who reports normal bowels can still have slow transit.

What the FDA's January 2020 warning said

The FDA searched its adverse event reports and the medical literature from July 2006 to mid-2016 and identified 10 cases of constipation that progressed to serious complications. The cases resulted in hospitalization, surgery, and five deaths.²

The time to onset of serious bowel events ranged from 3 days to 6 months, with a median of 46 days.²

The agency stated that it can't determine how likely these complications are for a person taking clozapine. It added that the risk is further increased at higher doses and when clozapine is prescribed with anticholinergic medications or other medications that cause constipation, including opioids.²

Ileus over the long term, and its association with mortality

A Finnish register study followed 2,659 people with schizophrenia for up to 25 years after they started clozapine. The cumulative incidence of ileus, meaning severe gastrointestinal hypomotility, was 5.3% at 20 years, and ileus was associated with increased mortality (odds ratio 4.5).⁶

In Australia and New Zealand, 43,132 people started clozapine over 22 years and 160 were reported with serious hypomotility, or 37 per 10,000. At least 29 died, few had received laxatives, and the authors considered 37 per 10,000 a likely underestimate.⁷

An earlier analysis compiled 102 reported cases of suspected life-threatening hypomotility. Mortality among those 102 cases was 27.5%, a figure that applies to people who already had a life-threatening bowel complication. The probable risk factors were a recent start of clozapine, a high dose or serum level, anticholinergic medication, and intercurrent illness.⁸

What the label tells prescribers to do

The Clozaril label tells prescribers to screen for constipation before starting clozapine and to treat it as necessary. If constipation or hypomotility is identified, the label calls for close monitoring and prompt treatment with appropriate laxatives. It also says to consider prophylactic laxatives in high-risk patients.⁵

The FDA communication adds that prescribers should evaluate bowel function before starting, avoid co-prescribing other anticholinergic medications that can cause hypomotility, and consider a prophylactic laxative for patients with a history of constipation or bowel obstruction.² The authors of the New Zealand transit study went further and recommended pre-emptive laxative treatment when starting clozapine.³

Which laxative: the evidence is thin

The Porirua Protocol uses docusate and senna, with macrogol 3350 added in treatment-resistant cases. Its evidence is a before-and-after study of 14 patients with no control group.⁹

Median colonic transit time was 110 hours without laxatives and 62 hours with them. Severe hypomotility decreased from 64% of participants to 21%. Hypomotility of any degree went from 86% to 50%, a change that didn't reach statistical significance (p = 0.061), and patients' own reports of constipation didn't change significantly. The authors called randomized controlled trials the next step.⁹

A 2017 Cochrane review of drug treatment for antipsychotic-related constipation identified two relevant Chinese studies with 480 participants. It found no data comparing the common treatments, such as lactulose, polyethylene glycol, or stool softeners, and rated the available data as very poor quality.¹⁰ The trial evidence doesn't identify a best laxative for clozapine constipation. The choice of laxative is the prescriber's.

Other anticholinergic medications add to the risk

In a registry study of 26,720 patients with schizophrenia, there were 123 cases of ileus. Clozapine (odds ratio 1.99), anticholinergics (1.48), tricyclic antidepressants (2.29), and opioids (2.14) were each associated with an increased risk. Ileus began on average more than 3 years after the first prescription of the drug.¹¹

Nine of those cases were fatal. Clozapine (odds ratio 6.73, 95% CI 1.55 to 29.17) and anticholinergics (odds ratio 5.88, 95% CI 1.47 to 23.58) were associated with fatal ileus.¹¹ The FDA noted that clozapine can cause serious complications of constipation alone, while with other antipsychotics such as olanzapine they were identified only when other anticholinergic medications were also used.²

The same question comes up with some treatments for clozapine drooling.

Symptoms that need urgent assessment

The FDA advises patients to contact the prescriber for any of the following:²

• Bowel movements less frequent than normal, especially fewer than three a week
• Hard or dry stools
• Difficulty passing gas

It advises contacting the prescriber right away for symptoms that can be associated with serious bowel problems, which it says include complete bowel obstruction and paralytic ileus:²

• Nausea and vomiting
• Bloating or belly swelling
• Belly pain

The FDA also notes that patients may not feel or be aware of constipation symptoms.² Any change to clozapine or to a laxative is made with the prescriber.

Limitations of the evidence

This evidence has limitations. First, the FDA and case-report fatality figures come from reported cases, and the FDA states that it can't determine how likely serious complications are. Second, the laxative evidence is a 14-patient study with no control group and transit time as its outcome, and the Cochrane review found no trial data on standard laxatives. Nevertheless, the transit studies and the label agree that clozapine slows the bowel and that symptoms alone can miss it.

Because the label states that symptoms may not reflect the degree of hypomotility, a prescriber's questions about bowel habits are worth answering in detail. Belly pain, vomiting, or swelling needs urgent medical assessment: contact the prescriber right away.

In a crisis: call or text 988, or go to the nearest emergency department. A first episode of psychosis belongs in a hospital-based or coordinated specialty care program.

I start and manage clozapine in an outpatient practice in Chelsea, Manhattan. Details are on the schizophrenia care in NYC page. Clozapine should not be stopped, skipped, or restarted without the prescriber. This page is general information and does not replace an evaluation.

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