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Published: 10 June 2015

Clozapine ­ Close Monitoring Required

Prescriber Update 36(2): 18-21
June 2015

Key Messages

  • Clozapine is effective in treatment-resistant schizophrenia, but is associated with significant adverse reactions.
  • Close monitoring, particularly in the first few months of treatment, is essential to reduce the occurrence of serious, sometimes fatal adverse reactions.
  • Permanent discontinuation of clozapine treatment is recommended for patients showing evidence of agranulocytosis, myocarditis, cardiomyopathy, or QT prolongation greater than 500 ms if no alternative causes can be found.
  • Treatment interruption and review is recommended for patients showing evidence of neutropenia, severe constipation/ileus, venous thromboembolism, severe diabetes/metabolic abnormalities, seizures or severe orthostatic hypertension.

 

Clozapine is an atypical antipsychotic used for treatment-resistant schizophrenia. A number of serious adverse reactions are associated with its use including: agranulocytosis, myocarditis, cardiomyopathy, and severe constipation (ileus).

Agranulocytosis and neutropenia1,2

Agranulocytosis, defined as an absolute neutrophil count (ANC) less than 500/µL, is the most widely recognised serious adverse reaction of clozapine and warrants regular blood monitoring (weekly for 18 weeks, then monthly for the duration of treatment). Monitoring reduces the risk of agranulocytosis approximately 20-fold (from 0.7% to 0.03%). This is why pharmacists will not dispense clozapine without an up-to-date white cell count1.

Neither dose nor plasma concentration of clozapine have been found to be associated with the risk of agranulocytosis2. Elderly patients appear to be at higher risk and are more likely to die when agranulocytosis occurs2.

Agranulocytosis tends to develop during the first six months of treatment, whereas neutropenia (ANC between 500 and 1500/µL) may occur at any time1. Agranulocytosis is a medical emergency and clozapine should be stopped immediately and patients referred for acute medical assessment2. Patients showing evidence of a drop in white cell counts should be investigated and monitored closely and (usually) have their treatment interrupted if neutropenia occurs1.

Between 1 January 2000 and 31 December 2014, the New Zealand Centre for Adverse Reactions Monitoring (CARM) received 166 reports of agranulocytosis and neutropenia in patients prescribed clozapine (13% of the total reports for clozapine). Where reported, the onset time to agranulocytosis/neutropenia ranged from one day to more than 20 years of clozapine treatment. The reported age range of the patients was between 15 and 92 years.

Myocarditis

Myocarditis generally occurs within the first few weeks after clozapine initiation. The absolute risk has been estimated at 0.015% to 0.188% of patients1. Mortality rates as high as 50% have been reported3. Cases occurring later in treatment are more often fatal3. Unsurprisingly, a delayed diagnosis results in worse outcomes4. There are also case reports of later onset myocarditis, apparently associated with the re-introduction of clozapine5.

The pathophysiology of clozapine-associated myocarditis is poorly understood but may be a hypersensitivity reaction and as such is not dose-dependent4.

Myocarditis has a variety of non-specific presenting symptoms. Those most commonly reported include fever, tachycardia and chest pain3. Other symptoms include: shortness of breath, dry cough, elevated white cell count, peripheral eosinophilia, diarrhoea, vomiting, dysuria and rash3.

Diagnosis is not straightforward, and suspected cases should be referred urgently for a cardiology opinion. C-reactive protein (CRP) elevation occurs as one of the earliest signs of myocarditis, around five days prior to troponin elevation. Where available, echocardiography is recommended as an initial diagnostic step.

A comparison has been made of differences between fatal and non-fatal myocarditis in patients taking clozapine6. Obesity, longer duration of clozapine use and creatine kinase >1000 U/L were all significantly associated with death6.

CARM received 63 reports of myocarditis associated with clozapine between 1 January 2000 and 31 December 2014. Time to onset of myocarditis, where provided, ranged from four days to over a year. The most frequently reported onset time was 12 to 16 days. In 48 of 56 cases where the onset time was reported, symptoms developed within one month of starting clozapine.

In 34 cases, the patient was reported to have recovered or be improving. At least three cases were fatal. The age of patients with clozapine-associated myocarditis ranged from 16 to 81years.

Cardiomyopathy

Cardiomyopathy usually occurs later in clozapine treatment than myocarditis2. Symptoms include signs of heart failure, flu-like symptoms, cough, fever, sinus tachycardia/ palpitations, fatigue, hypotension and chest discomfort7. Prescribers should maintain a high index of suspicion for cardiomyopathy throughout treatment2.

In a systematic review of published cases, the mean age of patients with clozapine-associated cardiomyopathy was 33.5 years with a mean clozapine dose of 360 mg/day7. The average onset latency was 14.4 months, with a range of three weeks to four years7. The mortality rate was around 15% in this review7.

Diagnosis of clozapine-associated cardiomyopathy is generally made on the basis of echocardiographic evidence of reduced ejection fraction. Electrocardiograms (ECGs) and blood tests, including raised B-type natriuretic peptide (BNP), provide supportive evidence. In general, patients with an ejection fraction of <25% at the time of diagnosis have a poor prognosis7.

Treatment includes cessation of clozapine and usual treatment for heart failure7.

Between 1 January 2000 and 31 December 2014, CARM received 30 reports of cardiomyopathy associated with clozapine. In four cases, the reported onset time was less than a month. This may have been due to underlying cardiac problems or that the patient had recently restarted clozapine. In 22 of the 28 cases with reported onset time, diagnosis of cardiomyopathy occurred after at least a year of treatment.

The youngest patient experiencing cardiomyopathy was 20 and the oldest 73. In two cases, the patient was reported to have died.

Constipation

Constipation can develop at any stage of treatment and has been estimated to occur in 14% to 60% of patients. The risk is likely to be dose-related. Severe constipation can cause bowel obstruction, sepsis and death. More deaths are caused by clozapine-induced ileus/megacolon than by agranulocytosis1.

The most commonly reported signs and symptoms associated with severe constipation include moderate to severe abdominal pain, abdominal distension, vomiting, paradoxical ‘overflow’ diarrhoea, reduced appetite and nausea. However, many patients with schizophrenia have abnormally high pain tolerance, and may not report symptoms associated with constipation.

Many patients require routine use of a laxative, and this is often commenced during clozapine initiation. There is no clear evidence indicating which laxative is best. However, bulk forming and stimulant laxatives should be avoided in patients with suspected intestinal obstruction2.

Patients' bowel habits should be routinely monitored and those with suspected severe constipation should be referred urgently to gastroenterology or general medicine. Further information is available in an earlier edition of Prescriber Update, 'Clozapine: impacts on the colon'8.

Between 1 January 2000 and 31 December 2014 CARM received reports of 74 cases of constipation and more serious bowel conditions such as ileus, megacolon and intestinal ischaemia, necrosis, obstruction and perforation. The onset time (when reported) ranged from five days to over 10 years. The affected patients were 18 to 71 years of age.

Monitoring clozapine patients

Prior to initiation

Before starting clozapine, patients should have a thorough medical evaluation, including baseline ECG, chest X-ray and possibly an echocardiogram. However, there is no evidence that routine repetition of ECG or echocardiograms will reliably detect clozapine induced cardiac toxicity3,7.

Baseline blood tests should check white cell count, troponins, CRP and possibly BNP3.

Patients with a history of cardiac disease or abnormal cardiac findings on examination (such as QT prolongation) should be referred to a cardiologist7.

Any pre-existing constipation should be effectively treated before starting clozapine. Co-prescription of other constipating medicines should be avoided whenever possible. Patients should be warned about the risks of constipation and given information on diet, exercise and fluid intake2.

First few months

For the first 18 weeks after initiation, patients require routine weekly blood tests to detect emergent agranulocytosis or neutropenia. Troponins and CRP should be included in weekly blood work for the first four weeks of treatment (ie, on days 7, 14, 21 and 28)3.

Patients should be monitored at least weekly for the first four months, and/or co-prescribed a laxative, to avoid constipation.

Longer term

Patients should be assessed at least four times a year for symptoms of heart failure and constipation. Any patients with new symptoms consistent with heart failure/cardiomyopathy or constipation should be investigated further.

Monitoring for constipation should be continued regularly throughout treatment as the risk of constipation usually persists2.

When to discontinue clozapine treatment permanently

Clozapine should be permanently discontinued if no alternative causes for the following events are identified.

Agranulocytosis, (ANC less than 500/µL) should always lead to prompt permanent discontinuation of clozapine1.

If myocarditis is suspected, and troponin is more than twice the upper limit of normal or CRP is over 100 mg/L, clozapine should be discontinued permanently. Left ventricular function recovers rapidly on withdrawal of clozapine and significant improvement is usually seen within five days3.

A diagnosis of cardiomyopathy should result in prompt, permanent discontinuation of clozapine1,7.

In addition, permanent termination of clozapine treatment is recommended when the QT prolongation is greater than 500 ms using the correct (usually Fridericia) correction formula1.

When to interrupt treatment1

If neutropenia (ANC between 500 and 1500/µL) develops, clozapine therapy should be interrupted until the ANC normalises.

Clozapine withdrawal is indicated for severe constipation and ileus. Clozapine may be reintroduced after addressing inadequate dietary and bowel habits if present. A stimulant laxative may also be needed in the short term. Patients with no bowel movement in five days despite the use of laxatives should be admitted to hospital for treatment.

Other situations in which clozapine treatment should be interrupted, but may potentially be restarted with appropriate surveillance and management, include: venous thromboembolism, severe diabetes and metabolic abnormalities, seizures and orthostatic hypotension.

Benefits of clozapine

Clozapine has unique efficacy in patients with treatment-resistant schizophrenia, including anti-suicidal and anti-aggressive properties. Many clozapine-treated patients and their relatives report a substantial positive effect on their lives and wellbeing1.

Despite the serious adverse reactions of clozapine, a study of patients in Finland found that all-cause mortality with clozapine treatment was significantly lower than for any other antipsychotic9. New Zealand data confirm the benefits of clozapine in treatment resistant psychosis10.

References
  1. Nielsen J, Correll CU, Manu P, et al. 2013. Termination of clozapine treatment due to medical reasons: when is it warranted and how can it be avoided? The Journal of Clinical Psychiatry 74: 603–613.
  2. Bishara D, Taylor D. 2014. Adverse effects of clozapine in older patients: epidemiology, prevention and management. Drugs & Aging 31: 11–20.
  3. Ronaldson KJ, Fitzgerald PB, Taylor AJ, et al. 2011. A new monitoring protocol for clozapine-induced myocarditis based on an analysis of 75 cases and 94 controls. The Australian and New Zealand Journal of Psychiatry 45: 458–465.
  4. Munshi TA, Volochniouk D, Hassan T, et al. 2014. Clozapine-induced myocarditis: is mandatory monitoring warranted for its early recognition? Case Reports in Psychiatry 2014: 513108.
  5. Smith LT, Symons E, Hare JL, et al. 2014. Asymptomatic myocarditis during clozapine re-titration, in a patient who had previously been stable on clozapine for 10 years. Australasian Psychiatry 22: 539–542.
  6. Ronaldson KJ, Fitzgerald PB, Taylor AJ, et al. 2011. Clinical course and analysis of ten fatal cases of clozapine-induced myocarditis and comparison with 66 surviving cases. Schizophrenia research 128: 161–165.
  7. Alawami M, Wasywich C, Cicovic A, et al. 2014. A systematic review of clozapine induced cardiomyopathy. International Journal of Cardiology 176: 315–320.
  8. Medsafe. 2011. Clozapine: impacts on the colon. Prescriber Update 32(2): 14–15. URL: www.medsafe.govt.nz/profs/PUArticles/ClozapineJune2011.htm (accessed 20 May 2015).
  9. Tiihonen J, Lonnqvist J, Wahlbeck K, et al. 2009. 11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study). Lancet 374: 620–627.
  10. Wheeler A, Humberstone V, Robinson G. 2009. Outcomes for schizophrenia patients with clozapine treatment: how good does it get? Journal of Psychopharmacology 23: 957–965.
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