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Graylands Hospital

DRUG BULLETIN

Pharmacy Department Brockway Road Mount Claremont WA 6010 Telephone (08) 9347 6400 Email [email protected] Fax (08) 9384 4586 Management of Clozapine-Induced Side Effects Graylands Hospital Drug Bulletin 2005 Vol. 13 No. 4 December ISSN 1323-1251 Clozapine may be under-utilised due its adverse effect profile Many adverse effects resolve post-initiation Dose adjustments can result in relief for most adverse effects Adjunctive measures are available for many adverse effects Introduction Haematological Adverse Effects Clozapine has been found to be superior to typical and for treating both positive and Neutropenia and agranulocytosis are serious negative symptoms in treatment–resistant adverse effects that may occur with clozapine (1). Despite its demonstrated therapy. Approximately 2.7% of patients treated efficacy in schizophrenia, widespread use of with clozapine develop neutropenia and 0.7% of clozapine has been limited by the potential for patients develop agranulocytosis(3). ADRAC has adverse effects. Clozapine can cause reversible received 103 case reports of agranulocytosis, with neutropenia, which may progress to a potentially one death and 534 reports of neutropenia fatal agranulocytosis. Other potentially serious including 3 deaths(5). These adverse effects are adverse effects of clozapine include , more likely to occur in the first 6 months of and cardiomyopathy(2). Although treatment, but may occur at any time(6). clozapine shares a similar adverse effect profile to other antipsychotics, the incidence and severity of A compulsory system of regular monitoring and such effects may vary. Antimuscarinic effects, recording of white blood cells and neutrophils and may be more prominent serves as a safeguard against patients developing with clozapine(3). Additional adverse effects of agranulocytosis. The following table details the clozapine include postural , management of patients according to , , urinary haematological test results. incontinence, nausea and tachycardia. It has been Table 1: Haematological Monitoring estimated that up to 17 percent of patients cease Status WBC and neutrophil count Action clozapine therapy due to adverse effects(4). result Green WBC>3.5 x 109/L Continue clozapine This bulletin will review strategies to minimize Range and Neutrophils>2.0 x109/L the impact of the adverse effects of clozapine 9 Amber WBC 3.0-3.5 x10 /L Continue clozapine therapy on quality of life. Where data from the Range And/or Commence twice Australian Adverse Drug Reactions Advisory Neutrophils 1.5-2.0 x109/L weekly blood tests Committee (ADRAC) is presented; these reports until a green range is obtained are suspected reactions to clozapine reported from Red WBC<3.0 x109/L Stop clozapine 1 November 1972 to 5 October 2005. Range And/or Repeat blood tests 9 Neutrophils< 1.5 x10 /L daily until green range is obtained

Graylands Hospital Drug Bulletin 2005 Vol 13 No.2 - 1 - Patients whose blood samples fall in the red range low or falling blood pressure, increased jugular are permanently ineligible for treatment with venous pressure possibly associated with clozapine. Patients with a ‘red range’ status arrhythmias, fever or chest pain(9). should be referred to a haematologist if the WBC and/or neutrophil counts continue to fall Patients with suspected myocarditis or following discontinuation of clozapine. cardiomyopathy should be referred to a Granulocyte colony-stimulating factor, cardiologist. Options for the management of granulocyte-macrophage colony-stimulating myocarditis are limited. It has been reported that factor and antibiotics can be used to treat discontinuation of medication leads to resolution agranulocytosis if necessary(7). of symptoms(9). Treatment of myocarditis involves ceasing clozapine therapy and Eosinophilia commencement on corticosteroids(10). Clozapine-induced eosinophilia is usually benign Management of dilated cardiomyopathy is but can be associated with myocarditis or essentially the same as for congestive heart eosinophilic colitis(4, 8). Overall, the incidence failure(13). Medication used may include a rate for eosinophilia has been estimated to be at combination of angiotensin converting enzyme 0.2%(7). The manufacturers recommend inhibitors, diuretics, digoxin, beta-blockers and discontinuation of clozapine if the eosinophil anticoagulants(14). Patients developing count rises above 3.0 X 109/L. Therapy may be clozapine-induced cardiomyopathy or myocarditis recommenced only after the eosinophil count has must not be re-exposed to clozapine(11). fallen below 1.0X 109/L(9). Tachycardia Cardiovascular Adverse Effects Tachycardia due to clozapine occurs in 25% of Myocarditis/Cardiomyopathy patients, with a mean increase of 10 to 15 beats ADRAC has received 193 case reports of per minute(11, 15). Tachycardia is dose- clozapine-induced myocarditis, including 13 dependent. Tolerance usually develops after 4-6 deaths(5). In 79% of patients who develop weeks of treatment(7). Patients that have myocarditis, the symptoms develop within the persistent tachycardia at rest, especially during the first 6 weeks of clozapine treatment(10). first two months of treatment, should be closely Cardiomyopathy generally occurs later in observed for other signs or symptoms of treatment compared to myocarditis(11). Dilated myocarditis or cardiomyopathy(11). A lower cardiomyopathy may be due to acute myocarditis dose of clozapine and slower upward titration can that was unrecognised in the early stages of limit the occurrence of tachycardia(4). therapy or a more chronic form of Pharmacological management consists of using a myocarditis(12). Although more rare than beta-blocker if necessary(4). myocarditis, 131 cases of clozapine-induced cardiomyopathy including 6 deaths have been Hypotension reported to ADRAC(5). Clozapine related hypotension is related to the alpha- antagonism of clozapine. The following monitoring for cardiac adverse Postural hypotension is more likely to occur effects is recommended(9). during the first days of clozapine therapy and can be accompanied by (16). Clozapine has Table 2 Cardiac Monitoring induced severe enough to Timeline Test cause collapse and respiratory arrest(4). Most Baseline ECG patients develop tolerance to hypotension after 4- I or T and serum creatinine, or CK-MB Day 7 ECG 6 weeks(4). Troponun I or T or CK-MB (Use same test as at baseline) Hypotension can usually be managed by using a Day 14 ECG Troponin I or T or CK-MB slow upward dose titration or by reducing the (Use same test as at baseline) clozapine dose(4). Patients experiencing 6 months Echocardiography orthostatic hypotension should be advised to take Patients should also be monitored for any signs or measures to lessen the impact of postural symptoms of , such as tachypnoea, hypotension such as taking time when standing up

Graylands Hospital Drug Bulletin 2005 Vol 13 No.2 - 2 - and ensuring an adequate fluid intake. Use of Gastrointestinal Adverse Effects support stockings and tilting the head of the bed at Constipation night are second-line management strategies(7). If Constipation occurs in 14 percent of patients non-pharmacological strategies fail, treated with clozapine and can be severe(4). There fludrocortisone or could be have been six deaths reported to ADRAC due to considered(7). There are two case reports of constipation(5). ADRAC has received reports of fludrocortisone being used successfully to colitis, , paralytic ileus, intestinal obstruction, ameliorate clozapine-induced hypotension. intestinal perforation, peritonitis, and Fludrocortisone was well tolerated in both gastrointestinal necrosis induced by clozapine(5). patients, although one patient required a lower Constipation may persist throughout clozapine dose because of emergent hypertension(17). therapy(22). Dihydroergotamine at doses of 10mg daily has been shown to prevent orthostatic hypotension in Considering the potential for serious patients treated with medication(4). complications of constipation, it is advisable to Dihydroergotamine is licensed for short-term or ensure bowel habits are monitored and intermittent treatment of severe hypotension(2). prophylaxis against constipation is provided(23). The following table details the management of Central Nervous System Adverse Effects clozapine-induced constipation(23). Seizures Table 3 Management of Constipation The risk of seizures among clozapine-treated Step 1 Increase exercise, fluid intake and dietary fibre patients increases with high doses, rapid dose Try for 2-4 weeks before initiating therapy titration, concurrent use of drugs that lower the Step 2 Bulk-forming (psyllium mucilloid, threshold and pre-existing seizure ispaghula bark) Agents of choice for chronic constipation. May be used disorders(7). Doses over 600mg daily have been in conjunction with other agents associated with a greater risk of seizures (4.4%) Step 3 Stool softeners (docusate sodium) compared with doses of 300-599mg daily (2.7%) May be required for some patients with chronic and doses below 300mg (1%)(18). constipation Step 4 Osmotic laxatives (sorbitol, magnesium sulphate) Osmotic laxatives are more appropriate for long-term Seizures during clozapine therapy do not require management of constipation than stimulants drug discontinuation(18). If a patient experiences Step 5 Stimulant laxatives (sennosides) For short-term use only, as long-term use can result in a seizure, brief interruption and/or lowering of degenerative changes in colonic muscles and nerves(4). dosage may be all that is required(7). Routine Step 6 Suppositories or Enemas (glycerin suppositories, prophylactic treatment is not bisocodyl suppositories, microlax enema®) currently recommended, although it can be Step 7 Colonic Lavage (Golytely®, Glyco-Prep®, Glyco- considered for patients receiving greater than Prep-C®) 600mg daily of clozapine, or if seizures have Avoid in rectal impaction already occurred(19). If anticonvulsant therapy is For the relief of acute constipation, stimulant indicated, sodium is considered the drug laxatives, suppositories and enemas may be used of choice based on the type of seizures clozapine initially. Once resolved, management of chronic induces, adverse effect profile and interaction constipation should comprise of exercise, potential(20). increased fluid intake, dietary fibre and any of steps of 2, 3 or 4(23). Sedation Sedation is a very common side effect of Nausea clozapine, with an overall incidence of 40%(2). Although antipsychotics have effects Usually sedation occurs at the beginning of due to their D2-blocking properties, paradoxical treatment and gradually decreases over 4-6 nausea has been known to occur in clozapine- weeks(7). Management of sedation includes using treated patients, usually later in treatment(16). the lowest effective dose, giving the majority of Strategies to manage clozapine-induced nausea the dose at night and avoiding other drugs that include using , antacids or H2 cause central nervous system (21). blockers(7). is not recommended, as it can raise clozapine blood levels(2).

Graylands Hospital Drug Bulletin 2005 Vol 13 No.2 - 3 - Autonomic Nervous System Adverse Effects or . Oxybutynin has been used in Hypersalivation doses ranging from 5mg at bedtime to 5mg three Clozapine induced hypersalivation can be socially times a day(32). Desmopressin spray has been embarrassing and potentially life threatening due used at a dose of 10mcg in each nostril at to the risk of asphyxiation. The incidence of bedtime(31). There has been a case report of hypersalivation is estimated to be at 31%(15). hyponatraemia due to desmopressin in a Hypersalivation is particularly worse at night and clozapine-treated patient, which may have been during the early stages of therapy(24). due to ineffective fluid restriction just before and after administration of desmopressin dose(33). Non–pharmacological strategies that can be useful The cost of desmopressin relative to oxybutynin adjuncts include lowering the dose of clozapine may prohibit its use. and the use of sugar-free gum to increase the swallowing rate(24). A variety of Metabolic Adverse Effects pharmacological strategies have been employed to Weight Gain counteract hypersalivation, however there have Of the antipsychotics, those associated with the been no large randomly controlled studies most weight gain are clozapine and completed at this stage. The following agents (34). A recent study of long-stay have been effective in treating clozapine-induced hospital studies showed that patients commenced hypersalivation in a few case reports; on clozapine gained 7% of body weight over two , benzhexol, benztropine, , years(35). Although body weight gain is more hyoscine hydrobromide, , pronounced in the first 4-12 weeks of therapy, , and botulinum toxin(24-30). weight increase may also occur over a prolonged Effective treatment is usually achieved with the period of time(7). use of amitriptyline at a dose of 25-50mg at night. There is a case report of amitriptyline being There is insufficient evidence for pharmacological administered to four patients at a dose of 87- intervention for clozapine-induced weight 100mg and this resulted in either an improvement gain(36). Clozapine-induced weight gain can be or cessation of hypersalivation in all patients(25). managed by informing patients of the potential for Hyoscine hydrobromide tablets sucked and weight gain, dietary modification, increased swallowed three times a day is widely used in physical activity and behavioural clinical practice, however, there are no interventions(36). Drug treatment options for publications supporting its efficacy(24). Caution antipsychotic-induced weight gain was the subject is required when administering clozapine with of the October 2005 Drug Bulletin. other drugs(2). Conclusion Nocturnal Enuresis The scope of this bulletin was to discuss the The incidence of nocturnal enuresis is about 1%, clinically significant adverse effects and their but it may be under-reported because of the management. For a complete list of adverse embarrassing nature of this adverse effect(15). effects of clozapine, please refer to the product The pathophysiological cause requires information. Many of the side effects of investigation, as nocturnal enuresis can be due clozapine are associated with antipsychotic directly to the nature of the medication, therapy in general. There is a wide range of due to epileptic seizures presenting as nocturnal therapeutic benefits to clozapine compared to the enuresis or due to mellitus(31). associated risks. Appropriate management of Nocturnal enuresis can occur at any time during clozapine side effects allows maximisation of the therapy(31). benefits of clozapine therapy.

Patients should be advised to avoid fluids in the Acknowledgment evening and to void before going to bed. This article was prepared by Karolina Golebiewski and Scheduled night awakenings to empty the bladder reviewed by members of the Pharmacy Department and Dr Joseph Lee can be practised. If necessary, an enuresis alarm Comments are welcome at the e-mail address: can be used(4). Pharmacological methods to [email protected] manage nocturnal enuresis include desmopressin References available on request

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