What are the management strategies for constipation in patients taking Clozapine (clozapine)?

From the Guidelines

Managing constipation in patients taking clozapine requires a proactive approach, starting with preventive measures and escalating to medications when needed, with a focus on stimulant laxatives or polyethylene glycol as first-line treatments. The management of constipation in these patients is crucial due to the high risk of severe complications such as ileus or bowel obstruction, which can be fatal. When considering the management of constipation, it's essential to prioritize the most recent and highest quality evidence available. According to the NCCN Guidelines for Adult Cancer Pain 1, for prophylaxis, a stimulant laxative or a heaping tablespoon (17 g) of polyethylene glycol with 8 oz of water 2 times daily along with maintaining adequate fluid intake is recommended.

Some key points to consider in the management of constipation in patients taking clozapine include:

• Encouraging lifestyle modifications such as increased fluid intake and regular physical activity
• The use of prophylactic bowel regimens, with stimulant laxatives or polyethylene glycol being preferred over stool softeners like docusate, which has not shown benefit 1
• Monitoring bowel movements regularly to assess the effectiveness of the treatment and adjust as necessary
• Avoiding bulk-forming laxatives like psyllium, which may worsen constipation
• Considering combination therapy with both osmotic and stimulant agents for severe cases, or adding lubiprostone for refractory constipation

It's also important to note that clozapine causes constipation through strong anticholinergic effects, reducing gut motility and intestinal secretions, with constipation rates of 30-60% in these patients 1. Therefore, a proactive and aggressive approach to managing constipation is essential to prevent severe complications. Dose reduction of clozapine may be necessary in refractory cases, but only in consultation with the prescribing psychiatrist.

From the FDA Drug Label

Severe gastrointestinal adverse reactions have occurred with the use of clozapine, primarily due to its potent anticholinergic effects and resulting gastrointestinal hypomotility. In post marketing experience, reported effects range from constipation to paralytic ileus Increased frequency of constipation and delayed diagnosis and treatment increased the risk of severe complications of gastrointestinal hypomotility, which can result in fecal impaction, megacolon, and intestinal obstruction, ischemia, infarction, perforation, ulceration, or necrosis [see Adverse Reaction (6. 2)]. Prior to initiating clozapine, screen for constipation and treat as necessary. Subjective symptoms of constipation may not accurately reflect the degree of gastrointestinal hypomotility in clozapine treated patients Therefore, reassess bowel function frequently with careful attention to any changes in the frequency or character of bowel movements, as well as signs and symptoms of complications of hypomotility (e.g., nausea, vomiting, abdominal distension, abdominal pain). If constipation or gastrointestinal hypomotility are identified, monitor closely and treat promptly with appropriate laxatives, as necessary, to prevent severe complications. Consider prophylactic laxatives in high risk patients. Educate patients and caregivers on the risks, prevention and treatment of clozapine-induced constipation, including medications to avoid when possible (e.g., drugs with anticholinergic activity). Encourage appropriate hydration, physical activity, and fiber intake and emphasize that prompt attention and treatment to the development of constipation or other gastrointestinal symptoms is critical in preventing severe complications.

To manage constipation in patients taking clozapine, the following steps should be taken:

• Screen for constipation before initiating clozapine and treat as necessary.
• Monitor bowel function frequently and reassess for changes in bowel movements or signs of complications.
• Treat constipation promptly with appropriate laxatives to prevent severe complications.
• Consider prophylactic laxatives in high-risk patients.
• Educate patients and caregivers on the risks, prevention, and treatment of clozapine-induced constipation, including the importance of hydration, physical activity, and fiber intake. 2 2

From the Research

Managing Constipation in Patients Taking Clozapine

• Constipation is a common side effect of clozapine, affecting 50-80% of patients, and can lead to severe complications such as ileus, bowel obstruction, and death 3, 4.
• The Porirua Protocol, which involves the use of docusate and senna augmented by macrogol 3350, has been shown to be effective in reducing colonic transit times in patients with clozapine-induced constipation 3.
• Self-reported constipation has been found to have low sensitivity in diagnosing clozapine-induced gastrointestinal hypomotility, and therefore, prophylactic laxatives are suggested for patients taking clozapine 4.
• Senna, a stimulant laxative, has been shown to be effective in improving colonic motility and reducing constipation in various patient populations, including children with anorectal malformations 5 and adults with chronic constipation 6, 7.
• Polyethylene glycol (PEG) is another effective osmotic laxative that can be used to treat constipation, and has been recommended as a first-line laxative for chronic constipation 6, 7.
• Other agents, such as fiber supplements, fruit-based laxatives, and magnesium-based products, may also be effective in managing constipation, although the evidence is modest 6, 7.