243 - Clozapine uncommon or unusual adverse effects

Clozapine: uncommon or unusual adverse effects

Schizophrenia and related psychoses CHAPTER 1 Clozapine: uncommon or unusual adverse effects Adverse effect Time course Comment Agranulocytosis (delayed)1–4 Usually first 3 months but may occur at any time Occasional reports of apparent clozapine-­related blood dyscrasia even after 1 year of treatment. Some suggest risk may be elevated for up to 9 years.5 It is very likely that clozapine is not the causative agent in most, if not all late cases6,7 (see section on clozapine: serious haematological adverse effects in this chapter). Colitis/gastrointestinal necrosis8–15 Usually within the first month but may be any time16 Growing body of case reports. Any severe or chronic diarrhoea should prompt specialist referral as there is a substantial risk of death. Use of drugs with anticholinergic effects probably increases risk of colitis and necrosis.17 Delirium18–20 Any time Reported rates vary (0.1–10%)18,21,22 but rarely seen in practice if dose is titrated slowly and plasma level determinations are used. Older age and medical comorbidity increase the risk of delirium. Ensure common causes of delirium are treated. Cholinergic rebound resulting from abrupt cessation of clozapine can cause delirium. Eosinophilia23–25 First week,26,27 but can be any time Reasonably common but significance unclear. Eosinophilia may predict neutropenia but this is disputed. Usually benign but investigate for signs of inflammatory organ damage28 (myocarditis,29 interstitial nephritis,27,30 interstitial lung disease, hepatitis, pancreatitis).31 May be associated with colitis and related symptoms.15,32 DRESS syndrome described in case reports.33,34 Successful rechallenge is possible.35 Concomitant antidepressants may increase risk.36,37 Heat stroke38,39 Any time Two cases reported, both occurred during a heatwave. May be mistaken for NMS (CK was elevated in both cases). Hepatic failure/enzyme abnormalities40–46 First few months Benign changes in LFTs are common (up to 50% of patients) but worth monitoring because of the very small risk of fulminant hepatic failure.47 Rash may be associated with clozapine-­related hepatitis48 (see section on hepatic impairment in Chapter 8). Hypothermia49 Any time A few case reports and events in pharmacovigilance databases. Can be fatal. Interstitial nephritis50,51 Usually first 3 weeks, possibly up to 3 months27 A handful of reports implicating clozapine. Probably immune mediated. May occur after only a few doses. Symptoms include fever, tachycardia, nausea, vomiting, diarrhoea, raised creatinine, urinary difficulties and eosinophilia. The classic nephritis-­ associated rash may not be present.27 There are no published cases of successful rechallenge.27 Interstitial lung disease Usually first few months, possibly later in treatment Six case reports.52 May be caused by aspiration or an immune reaction. Symptoms are non-­specific: shortness of breath, fever, cough, fatigue. Pneumonitis has also been reported.53 Knee-­buckling54,55 Usually at the start of treatment Several cases reported. May be mistaken for postural hypotension. Ocular effects56 Any time Single case report of ocular pigmentation,57 five of periorbital oedema.58 Clozapine may cause dry eye syndrome.59 (Continued)

246 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Adverse effect Time course Comment Pancreatitis60–69 Usually first 6 weeks, possibly later in treatment70 Several reports of asymptomatic and symptomatic pancreatitis. Symptoms include fever, abdominal pain and distension, nausea and vomiting, raised CRP and raised lipase and/or amylase. Concomitant valproate may increase the risk.27 The majority of attempts to rechallenge fail63,71–74 but one successful case is reported.75 Parotid gland swelling76–80 Usually first few weeks, but may occur later81 Several case reports. Unclear mechanism, possibly immunological or thickening of saliva leading to calcium precipitation. Can be recurrent. May resolve spontaneously.82 Terazosin in combination with benztropine may be helpful. Pericarditis and pericardial effusion69,83–90 Any time Several reports in the literature. Symptoms include fatigue, chest pain, dyspnoea, orthostatic hypotension and tachycardia, but may be asymptomatic.91 Signs include raised inflammatory markers (specifically trop I) and pro-­BNP levels.91 Use echocardiogram to confirm/rule out effusion. Successful rechallenge possible.92–94 Stuttering95,96 Any time Case reports only. Check plasma levels, consider dose reduction and/or antiseizure drugs – may be a warning sign for impending generalised seizures.97 Thrombocytopenia98–101 First 3 months Few data but apparently fairly common (incidence over 1 year of 3102–8%103). Probably transient and clinically unimportant, but persistent in some cases104,105 and recurrent on rechallenge in others.106,107 Thrombocytosis also reported.108 Skin reactions109 Any time Presence of skin diseases in general is higher in those with schizophrenia.110 Four reports of vasculitis111–114 in which patients developed confluent erythematous rash on lower limbs. One report of Stevens–Johnson syndrome,115 two of pityriasis rosea,116,117 one of a papular rash,118 one of exanthematic pustulosis,119 one of cholinergic urticaria120 and two of Sweet’s syndrome,121 one fatal.122 Rash is often reported in DRESS syndrome.123 Thromboembolism124–126 Any time127 Weight increase and sedation may contribute to risk. Mechanism may be increased platelet aggregation via 5HT2A receptor activation.128 Clozapine increases risk of pulmonary thromboembolism by 28 times compared with the general population.129 The risk may be dose related130 but cases are reported across the dose range.131,132 Consider prophylactic antithrombotic treatment where additional risk factors are present (surgery, immobility). Continuation of therapy after embolism may be possible133 but consult haematologist as without prophylactic antithrombotic treatment recurrence is likely134,135 and may be fatal.131,136 Polyserositis Usually first few weeks, but can occur at any time Case reports describe a wide variety of symptoms related to inflammatory processes, including flu-­like symptoms, fever, eosinophilia, diarrhoea, shortness of breath, tachycardia, thoracic pain.137 Other inflammatory conditions may be present (hepatitis, pancreatitis, dermatosis). Suggested to be either IgE-­mediated hypersensitivity or an immunomodulatory effect.138 All reported cases have resolved on discontinuation of clozapine.138 CK, creatine kinase; CRP, C-­reactive protein; DRESS, drug rash with eosinophilia and systemic symptoms; IgE, immunoglobulin E; NMS, neuroleptic malignant syndrome; pro-­BNP, pro-­brain natriuretic peptide. (Continued)