241 - Clozapine common adverse effects

Clozapine: common adverse effects

Schizophrenia and related psychoses CHAPTER 1 CLOZAPINE ADVERSE EFFECTS Clozapine: common adverse effects This section provides a summary of management of the common adverse effects of clozapine. Adverse effect Time course Action Constipation First 4 months are the highest risk.1 Usually persists and so requires continuous monitoring and treatment. Advise patients of the risks before starting, screen regularly, ensure adequate fibre, fluid and exercise. Consider early or even prophylactic laxatives. Stimulant laxatives (senna or bisacodyl) are first-­line treatments, with emollients (docusate) and/or osmotics (macrogols).2 Bulk-­forming laxatives should be avoided. Stop other medicines that may be contributing and reduce clozapine dose if possible. Effective treatment or prevention of constipation is essential, as death may result.3,4 See section on clozapine-­induced gastrointestinal hypomotility in this chapter. Fever5 First 4 weeks6 Clozapine induces inflammatory response (increased CRP, interleukin-­6 and eosinophils).7–9 Give paracetamol but check FBC for neutropenia. Reduce rate of dose titration.10 Concurrent valproate or quetiapine may increase risk.11 This fever is not usually related to blood dyscrasias12 but beware myocarditis, NMS, pneumonia and other rarer types of inflammatory organ damage (see section on clozapine: uncommon or unusual adverse effects in this chapter). Gastro-­esophageal reflux disease13,14 Any time Proton pump inhibitors often prescribed but some are CYP1A2 inducers and possibly increase risk of neutropenia and agranulocytosis.15,16 Reasons for GERD association unclear – clozapine is an H2 antagonist.17 Hypersalivation First few months. Usually persists but sometimes wears off. Often very troublesome at night. Reduce dose if possible.18 Many options available19 (see section on clozapine-­induced hypersalivation in this chapter). Systemic anticholinergic drugs worsen constipation and cognition and so should not be used first line. Hypertension20 First 4 weeks, sometimes longer Monitor closely and increase dose as slowly as is necessary. Hypotensive therapy is sometimes necessary.21 Hypotension First 4 weeks Advise patient to stand up in stages. Reduce dose or slow down rate of increase. Ensure fluid intake of >2L daily.22 If severe, consider fludrocortisone 0.05–0.3mg daily first line (monitor fluid intake, potassium and sodium) or midodrine 2.5–5mg three times a day (maximum 30mg/day).23 Other options include moclobemide and Bovril® in combination or etilefrine.23 Myoclonus24–27 During dose titration or plasma level increases May precede full tonic-­clonic seizure. May present as knee-­ buckling.28 Reduce dose. Antiseizure drugs may help and will reduce the likelihood of progression to seizures. Valproate is first choice but has limited utility. Referral to neurology specialist is advised. Nausea First 6 weeks May give anti-­emetic. Avoid prochlorperazine if previous EPS. Avoid domperidone if underlying cardiac risk or QTc prolongation. Ondansetron is a good choice, but it may worsen constipation. Metoclopramide may help with hypersalivation. Nausea and vomiting can be the only presenting symptoms of myocarditis.29 (Continued)

242 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Adverse effect Time course Action Nocturnal enuresis May occur at any time Try reducing the dose or manipulating dose schedule to avoid periods of deep sedation. Avoid fluids before bedtime. Consider scheduled night-­time toileting. May resolve spontaneously,30 but may persist for months or years.31 Seems to affect 1 in 5 people on clozapine.32 Try aripiprazole (10–15mg daily) or desmopressin (10mcg/mL nasal spray into each nostril at night, or 200–400mcg orally at night).33 Monitoring for hyponatraemia is essential. Other options include oxybutynin, trihexyphenidyl, imipramine, amitriptyline and verapamil.33 Pneumonia34,35 Usually early in treatment, but may be any time May result from saliva aspiration (this may be why pneumonia appears to be dose related),36,37 and very rarely from constipation.38 Pneumonia is a common cause of death in people on clozapine.39 Infections in general may be more common in those on clozapine40 and use of antibiotics is also increased.41 Obesity,34 anticholinergic burden35 and treatment-­resistant schizophrenia itself may also contribute to risk.34 Respiratory infections may give rise to elevated clozapine levels.42,43–45 This may be an artefact: smoking usually ceases during an infection and inflammation itself causes a reduction in CYP1A2 activity.46,47 Clozapine is often successfully continued after the pneumonia has resolved, but recurrence may be more likely.48–50 Sedation First few months. May persist, but usually wears off to some extent. Give smaller dose in the morning. Give evening dose earlier if morning waking is troublesome. Once daily dosing in the evening seems effective and well tolerated.51,52 Case reports of successful use of psychostimulants (methylphenidate53) and betahistine.54 Modafinil does not appear to be effective.55 Aripiprazole may help.56 Seizures57 May occur at any time58 Related to dose, plasma level and rapid dose escalation.25 There is no step-­change in risk at a particular dose or level. Consider prophylactic, topiramate, lamotrigine, gabapentin or valproate* if there are risk factors for seizures and or plasma level is high (≥600mcg/L). Some suggest risk of seizures below 1300mcg/L is not enough to support primary prophylaxis.59 After a seizure: withhold clozapine for one day; restart at half previous dose; give antiseizure medication.** Tachycardia First 4 weeks, but usually persists Very common in early stages of treatment but usually benign. May be dose-­related.60 Tachycardia, if persistent at rest and associated with fever, hypotension or chest pain, may indicate myocarditis or pericarditis (see section on clozapine: serious cardiovascular adverse effects in this chapter). Referral to a cardiologist is advised. Benign sinus tachycardia can be treated with bisoprolol61 or atenolol,62 although evidence base is poor.63,64 Ivabradine may be used if hypotension or contraindications limit the use of beta blockers.65 Prolonged tachycardia can itself precipitate cardiomyopathy66 or other cardiovascular consequences.22 Weight gain Usually during the first year of treatment, but may continue Dietary counselling is essential. Advice may be more effective if given before weight gain occurs. Weight gain is common and often profound (4.5kg in the first 10 weeks).67 Many treatments available (see section on treatment of antipsychotic-­induced weight gain in this chapter). * Usual dose is 1000–2000mg/day. Plasma levels may be useful as a rough guide to dosing – aim for 50–100mg/L. Use of modified-­release preparation (Epilim Chrono) may aid compliance: can be given once daily and may be better tolerated. ** Lamotrigine may be helpful if poor response to clozapine or continued negative symptoms; topiramate if weight loss required (but beware cognitive adverse effects); gabapentin if other anticonvulsants are poorly tolerated.25 Valproate should be avoided in most cases because of the risks of neurodevelopmental disorders and birth defects if valproate is taken during pregnancy or prior to conception (in the case of men). EEG abnormalities are common in those on clozapine.68,69 CRP, C-­reactive protein; EPS, extrapyramidal symptoms; GERD, gastro-­esophageal reflux disease. (Continued)