Rediscovering Clozapine: Adverse Effects Develop—What Should You Do Now?

SECOND OF 3 PARTS Rediscovering clozapine: Adverse effects develop—what should you do now?

Benefit comes at the expense of monitoring for, and treating, an array of potential problems

lozapine is a highly effective antipsychotic with supe- rior efficacy in treatment-resistant schizophrenia, but Cits side effect profile is daunting (Figure 1).1 Adverse reactions lead to approximately 17% of patients who take clozapine eventually discontinuing the medication.1 As we noted in Part 1 of this 3-part series,2 clozapine remains the most efficacious, but most tedious, antipsychotic available to psychiatrists because of its monitoring requirements and potential side effects. A powerful rationale for prescribing clozapine, despite its drawbacks, is its association with a reduced risk of all-cause mortality.3,4 People with serious mental illness, including schizophrenia, have a median 10-year shorter life expectancy CAP PANNELL than the general population.5 Brianne M. Newman, MD A recent cohort study6 examined electronic health records William J. Newman, MD to test whether intensive monitoring or lower suicide risk might account for the reduced mortality with clozapine. • • • • The authors found that the reduced mortality rate was not Associate Professors of Psychiatry directly related to clozapine’s clinical monitoring or other Department of Psychiatry Saint Louis University School of Medicine confounding factors. They did find an association between St. Louis, Missouri clozapine use and reduced risk of death from both natural Dr. W. J. Newman is a member of the Editorial Board and unnatural causes. of Current Psychiatry. This second article in our series examines clozapine’s adverse effects from a systems perspective. Severe neutropenia, myocarditis, sedation, weight gain, orthostatic hypotension, and sialorrhea appear to be the most studied adverse effects, but myriad others can occur.7 We offer guidance to help the astute clinician continue this effective antipsychotic

Disclosures Current Psychiatry The authors report no financial relationships with any company whose products are mentioned in 40 August 2016 this article or with manufacturers of competing products. Figure 1 Common side effects of clozapine

Sedation (21%) Tachycardia (17%) Constipation (16%) Dizziness (14%) Hypotension (13%) Fever (13%) Sialorrhea (13%) Hypertension (12%) Headache (10%) Clinical Point Concomitant treatment with Source: Adapted from reference 1 clozapine and lithium can affect white blood cell and absolute neutrophil by monitoring carefully, treating side effects significant—change in ANC values.11 The early, and managing potential drug interac- authors noted that viral infection might count values tions (Table 1, page 42).8 lead to blood dyscrasia early in illness, and that oseltamivir has been associated with a small incidence of blood dyscrasia.11-13 This Hematologic events information might be useful when treat- Severe neutropenia, defined as abso- ing influenza in patients taking clozapine, lute neutrophil count (ANC) <500/µL, is although no specific change in manage- a well-known adverse effect of clozapine ment is recommended. that requires specific clinical monitoring, a Similarly, concomitant treatment with requirement that was updated by the FDA clozapine and lithium can affect both in 2015.2 The incidence of severe neutrope- white blood cell and ANC values.14,15 nia peaks in the first 2 months of clozap- Lithium-treated patients often demon- ine therapy and tapers after 6 months, but strate increased circulating neutrophils some risk always remains. via enhancement of granulocyte-colony Older efficacy studies in the United States stimulating factor.16 Case studies describe gauged the 1-year cumulative incidence of how initiating lithium treatment enabled severe clozapine-induced neutropenia to some patients to continue clozapine after be 2%.9 A 1998 study of the effects of using developing neutropenia.14,17 Leukocytosis a clozapine registry reported a lower inci- can affect blood monitoring, possibly mask- dence—0.38%—than the 2% noted above.10 ing other blood dyscrasias, when lithium is Early recognition and recommended inter- used concurrently with clozapine. Discuss this article at ventions can improve clinical outcomes.2 Eosinophilia (blood eosinophil count www.facebook.com/ CurrentPsychiatry >700/µL) occurs in approximately 1% of clo- Drug interactions and neutropenia. A ret- zapine users, usually in the first 4 weeks of rospective study of mental health inpatients treatment.18 It can be benign and transient or taking clozapine concurrently with oselta- a harbinger of a more rare adverse reaction mivir during an influenza outbreak found such as myocarditis, pancreatitis, hepatitis, Current Psychiatry a statistically significant—but not clinically colitis, or nephritis.19 If a patient taking clo- Vol. 15, No. 8 41 Table 1 Clinically relevant drug interactions with clozapine Mechanism of interaction Medications and other substances involved Effect on clozapine CYP1A2 strong Fluvoxamine, ciprofloxacin ↑ Clozapine levels inhibitors CYP1A2 weak or Oral contraceptives, caffeine May ↑ clozapine levels Clozapine moderate inhibitors CYP2D6 and CYP3A4 Antidepressants (escitalopram, paroxetine, May ↑ clozapine levels inhibitors bupropion, fluoxetine, duloxetine, sertraline) Antibiotic (erythromycin) Miscellaneous (cimetidine, quinidine, terbinafine) CYP1A2 moderate Smoking ↓ Clozapine levels inducer CYP3A4 strong Carbamazepine, phenytoin, St. John’s wort, ↓ Clozapine levels inducersa rifampin Clinical Point CYP2D6 substrates Certain antidepressants (fluoxetine), Clozapine may ↑ levels phenothiazines, carbamazepine, Type 1C of these medications Reducing the dosage antiarrhythmics (propafenone, flecainide) aClozapine dosing instructions recommend against concurrent use of clozapine with strong CYP3A4 inducers of clozapine or CYP: cytochrome P450 enzymes slowing titration Source: Adapted from reference 8 could reverse common cardiac side effects zapine develops eosinophilia, clozapine’s sion (Figure 1, page 41).1 Orthostatic hypo- package insert recommends that you: tension, bradycardia, and syncope also can • evaluate promptly for other systemic occur, especially with rapid clozapine titra- involvement (rash, other evidence of tion. Baseline electrocardiogram (ECG) allergic reaction, myocarditis, other organ- can help differentiate whether abnormali- specific disease) ties are clozapine-induced or related to a • stop clozapine immediately if any of preexisting condition. these are found. Reducing the dosage of clozapine or If other causes of eosinophilia are iden- slowing titration could reverse cardiac tified (asthma, allergies, collagen vascular side effects.8 If dosage reduction is not an disease, parasitic infection, neoplasm), treat option or is ineffective, first consider treat- these and continue clozapine. ing the side effect rather than discontinu- The manufacturer also mentions the ing clozapine.20 occurrence of clozapine-related eosino- Sinus tachycardia is one of the most philia without organ involvement that can common side effects of clozapine. First, rule resolve without intervention, with care- out serious conditions—myocarditis, car- ful monitoring over several weeks.8 In diomyopathy, neuroleptic malignant syn- this scenario, there is flexibility to judge drome (NMS)—then consider waiting and whether clozapine should be stopped or monitoring for the first few months of clo- re-challenged, or if close monitoring is zapine treatment. If tachycardia continues, adequate. Consulting with an internal consider dosage reduction. Slower titra- medicine or hematology specialist might tion, or treatment with a cardio-selective be helpful. beta blocker such as atenolol.21,22 Note that a recent Cochrane Review concluded that there is not enough randomized evidence Cardiovascular side effects to support any particular treatment for Most common events. Three of the 10 most clozapine-induced tachycardia; the pre- common clozapine side effects are cardiac: scriber must therefore make a case-by-case Current Psychiatry 42 August 2016 tachycardia, hypotension, and hyperten- clinical judgment.22 Similarly, orthostatic hypotension can risk. Tonic-clonic seizures are the most com- be managed with a reduced dosage of clo- mon type associated with clozapine. zapine or slower titration. Increased fluid The manufacturer recommends caution intake, compression stockings, and, if neces- when using clozapine in patients with a sary, fludrocortisone also can be initiated.20 known seizure disorder, alcohol use disorder, or other CNS pathology.8 Patients with Rare, potentially fatal events. Myocarditis, a seizure disorder may be at increased risk pericarditis, and cardiomyopathy are of experiencing clozapine-induced seizures, among the rare but potentially fatal adverse but this is not an absolute contraindica- effects of clozapine. A recent study reported tion.26 Smoking cessation increases clozap- the incidence of myocarditis with clozapine ine blood levels by an average of 57.4%, at a range of 0.015% to 1.3%; cardiomyopa- further increasing seizure risk.26,27 thy was even more rare.23 Pulmonary embo- Discontinuing clozapine is unneces- lism and deep venous thrombosis also are sary when a patient experiences a seizure. very rare possibilities; keep them in mind, Instead, you can: however, when patients taking clozapine • halve the dosage prescribed at the time report new cardiovascular symptoms. of the seizure (or at least reduce to the last Clinical Point Patients with clozapine-induced car- seizure-free dosage) To reduce sedation, diovascular effects most commonly report • consider any medications or medical shortness of breath (60%), palpitations problems that might have contributed to a consider instructing (36%), cough (16%), fatigue (16%), and lower seizure threshold the patient to take chest pain (8%).7,24 • consider prophylaxis with an anti- all or most of Clozapine’s “black-box” warning specif- epileptic medication (eg, valproic acid has the clozapine dosage ically recommends discontinuing clozapine efficacy for both myoclonic and tonic-clonic at bedtime and consulting cardiology when myocardi- seizures).20,26 tis or cardiomyopathy is suspected. In 50% of cases, myocarditis symptoms present in Sedation is the most common side effect the first few weeks of clozapine treatment.23 of clozapine.1 Patients experiencing severe The manufacturer states that myocarditis sedation should not drive or operate heavy usually presents in the first 2 months, and machinery. To reduce sedation, consider cardiomyopathy after 8 weeks of treatment; instructing the patient to take all or most of however, either can present at any time.8 the clozapine dosage at bedtime. A critical Figure 2 (page 44) provides a clinical refer- review of modafinil for sedation caused by ence for monitoring a clozapine patient for antipsychotics in schizophrenia found only cardiomyopathy.24 1 open-label study that showed any posi- Laboratory findings that support a diagno- tive effects; the authors concluded that fur- sis of clozapine-related myocarditis include: ther study is needed.28 • elevated C-reactive protein Cognitive and motor slowing are pos- • elevated troponin I or T sible neurologic side effects of clozapine. • elevated creatine kinase-MB Caution patients about the risk of partici- • peripheral eosinophilia.8,25 pating in activities that require cognitive ECG, echocardiography, and cardiac or motor performance until the individual MRI can be helpful in diagnosis, in consul- effects of clozapine are known.8 tation with a cardiologist. Tardive dyskinesia. Clozapine carries some risk of tardive dyskinesia, although Neurologic side effects that risk is lower than with other antipsy- Seizures are listed in the “black-box” chotics. Similarly, all antipsychotics includ- warning for clozapine. Seizure incidence ing clozapine are associated with a risk of with clozapine is 5% per year, with higher NMS. In the rare case of clozapine-induced incidence at dosages ≥600 mg/d.8 Because NMS, stop clozapine immediately and clozapine-induced seizures are dosage- initiate supportive therapy. Clozapine- Current Psychiatry dependent, slow titration can mitigate this induced NMS is not an absolute contrain- Vol. 15, No. 8 43 Figure 2 Monitoring strategy for clozapine-associated cardiomyopathy

• Full cardiac history and review of symptoms Initiation of • Physical exam with weight and vital signs clozapine

Clozapine • CBC with differential, CMP, weight, fasting lipid panel, fasting glucose, Check orthostatic blood pressure baseline • Baseline ECG if clinical indicated labs

• Routine follow-up at least every 3 months (if possible) Routine • Document cardiac review of symptoms (dyspnea, edema, fatigue, etc.) follow-up

New • Order ECG, echocardiogram, chest radiograph cardiac signs/ • Consult with cardiology Clinical Point symptoms • If clozapine-induced, stop clozapine immediately In the rare case of Cardiac side effects • Evaluate for other causes in conjuction with cardiology clozapine-induced present neuroleptic malignant syndrome, CBC: complete blood count; CMP: comprehensive metabolic panel; ECG: electrocardiogram Source: Adapted from reference 24 stop clozapine immediately, initiate supportive therapy dication to re-challenging a patient with As a result, Ms. B is embarrassed to con- clozapine, however, if doing so is clinically tinue her usual activities. She asks to stop appropriate.20 clozapine, even though her psychotic symptoms have improved and she is functioning Cerebrovascular events. In older people at her highest level in years. with dementia, the use of antipsychotics— Ms. B already is taking trihexyphenidyl, including clozapine—has been shown to 5 mg, 3 times daily, to manage extrapyra- increase the risk of cerebrovascular events. midal symptoms related to haloperidol dec- Because most antipsychotics are not FDA- anoate treatment. After discussing other approved for treating psychosis associated medication options for sialorrhea, she agrees with dementia (only pimavanserin is FDA- to a trial of glycopyrrolate, 1 mg, twice daily. approved for symptoms of psychosis in She experiences significant improvement Parkinson’s disease), a risk-benefit analysis and continues taking clozapine. should be documented when prescribing any antipsychotic in this population. In Sialorrhea develops in 13% of patients practice, clozapine’s benefits may outweigh taking clozapine.1 As in Ms. B’s case, the mortality risks in specific situations.29,30 this side effect can be embarrassing, can limit social or occupational functioning, CASE Sialorrhea puts progress at risk and might lead patients to discontinue Ms. B, age 40, has a history of treatment- clozapine treatment despite efficacy. resistant schizophrenia and is starting clozap- Nonpharmacotherapeutic options include ine because of residual psychosis during trials covering the pillow with a towel, lowering of other antipsychotics. She develops severe the clozapine dosage or titrating slowly (or persistent drooling, mostly at night, during both), and using sugarless gum or candy clozapine titration. Sugar-free candy, multiple to increase swallowing. bed pillows, and changing the dosing sched- If the benefits of additional medications Current Psychiatry 44 August 2016 ule do not significantly improve the sialorrhea. targeting side effects outweigh the risks, Table 2 Medications for managing clozapine-induced sialorrhea Medication Class Dosage Locally administered Atropine sulfate ophthalmic Antimuscarinic 1 drop sublingually at bedtime solution, 1% Ipratropium bromide spray, 0.06% Antimuscarinic 1 spray sublingually at bedtime Oral systemic Glycopyrrolate Antimuscarinic 1 mg, twice daily Benztropine Antimuscarinic 1 mg, twice daily Trihexyphenidyl Antimuscarinic 5 to 15 mg at bedtime Amitriptyline Tricyclic antidepressant 75 to 100 mg at bedtime

Clonidine α2-adrenergic agonist 0.05 to 0.1 mg, once daily

Terazosin α1-adrenergic antagonist 2 mg at bedtime Benztropine-terazosin Antimuscarinic plus Benztropine, 1 mg, twice Clinical Point combination α1-adrenergic antagonist daily, plus terazosin, 2 mg at bedtime Behavioral weight Source: Adapted from reference 31 management and exercise are recommended as pharmacotherapeutic intervention may be ing clozapine-induced sialorrhea. Monitor initial therapy to appropriate. Options include the tricyclic blood pressure when prescribing terazosin control metabolic antidepressant amitriptyline31; alpha-adren- or clonidine, which could potentiate clozap- ergic agonists or antagonists (clonidine, ine’s hypotensive effects. side effects terazosin); and anti-muscarinic medications (benztropine, atropine, trihexyphenidyl, glycopyrrolate) (Table 231). Scopolamine trans- Endocrine side effects dermal patch is another possible treatment Among antipsychotics, clozapine is asso- strategy; however, the scopolamine patch ciated with the greatest weight gain— was used for clozapine-induced sialorrhea averaging nearly 10% of body weight.33,34 in only a few case reports, and it is not con- Similarly, the risk of new-onset diabetes sidered a first-line treatment choice.30 mellitus is highest with clozapine in rela- When prescribing, consider the possibility tion to other antipsychotics: 43% reported of combined side effects with clozapine and in a 10-year naturalistic study.35 The risk of adjunct medications having antimuscarinic hyperlipidemia also increases with clozap- or alpha-adrenergic activity, or both. Even ine treatment.36 These metabolic changes atropine ophthalmic drops, administered increase the risk of cardiovascular-related sublingually, are readily absorbed and cross death, with a 10-year mortality rate from the blood–brain barrier.31 Another antimus- cardiovascular disease reported at 9% in carinic agent, glycopyrrolate, is less likely to clozapine-treated patients.35 cross the blood–brain barrier and therefore Despite clozapine’s metabolic side is less likely to cause cognitive side effects. effects, patients with schizophrenia who Glycopyrrolate is 5 times more potent at are treated with clozapine show a sig- blocking the muscarinic receptor than atro- nificant reduction in overall mortality pine.31,32 Ipratropium bromide, another non- compared with patients not treated with selective muscarinic receptor antagonist, clozapine.6 Effective identification and has less systemic absorption than atropine management of metabolic side effects can drops, with less anticholinergic side effects prevent the need to discontinue clozapine. when administered sublingually. Behavioral weight management and Limited evidence supports the efficacy exercise are recommended as initial ther- Current Psychiatry of alpha-adrenergic medications for manag- apy.20 If, based on clinical judgment, these Vol. 15, No. 8 45 alone are insufficient, data support the Obstetricians and Gynecologists Practice use of pharmacotherapeutic interventions. Bulletin on the use of psychiatric medica- Metformin demonstrates a positive effect tions during pregnancy and lactation can on body weight, insulin resistance, and lip- be a useful resource.42 ids, making it the first choice for adjunctive Be aware that the FDA very recently treatment of clozapine-induced metabolic made major changes to the format and con- side effects.37-39 tent of pregnancy and lactation labeling, Clozapine removing the letter categories that have been used for medications approved on or Gastrointestinal side effects after June 30, 2001. The manufacturers of Clozapine’s anticholinergic activity can lead medications (such as clozapine) that were to serious gastrointestinal (GI) side effects, approved before June 30, 2001, have 3 years including constipation, intestinal obstruc- to comply with new requirements.43 tion, fecal impaction, and paralytic ileus.8 The FDA had rated clozapine a preg- Ileus has produced more fatal adverse nancy risk category B medication, meaning reactions with clozapine than has severe no evidence of risk in humans. In 2011, the Clinical Point neutropenia.20,40 Co-administered anticho- FDA issued a general warning that antipsy- When treating linergic medications could increase the risk chotic use in pregnancy can cause extra- of ileus. Obtaining a GI review of systems pyramidal symptoms and discontinuation a pregnant patient, and monitoring bowel movements (in inpa- symptoms in newborns.44,45 weigh the benefits of tient or residential facilities) can aid in early A 2015 review of psychotropic medica- clozapine against identification and limit morbidity and mor- tions and pregnancy noted that approxi- risk of adverse events, tality from GI adverse events. A high-fiber mately 60% of women with schizophrenia diet, adequate hydration, bulk laxatives in became pregnant, with an increased inci- and clearly document patients who can reliably maintain hydra- dence of unplanned pregnancy. A high your analysis tion, and GI consultation (if needed) may risk of psychotic relapse (65%) during help manage GI side effects.20 pregnancy and in the postpartum period may lead to insufficient prenatal care, drug use, and obstetric complications.45 Some Constitutional side effects data suggest low fetal birth weight and an Fever can occur with clozapine, most often increased rate of therapeutic abortions in in the first month of treatment, but the inci- women with schizophrenia.42,46 dence is quite variable (0.5% to 55%).20,41 When treating a pregnant patient, weigh Although benign fever is common, agranu- the benefits of clozapine against the risks of locytosis with infection, NMS, and other adverse events, and clearly document the systemic illness must be ruled out. The rec- analysis. Clozapine treatment is not recom- ommended workup when a patient devel- mended during breast-feeding because of ops fever while taking clozapine includes the risk of side effects for newborns.8 physical examination and relevant test- We highly recommend keeping updated ing (urinalysis, measurement of ANC and on the literature regarding pregnancy and serum creatine kinase, chest radiograph, lactation information with antipsychotics, ECG, and, possibly, blood cultures).41 including clozapine, because prescribing If evidence supports a serious adverse information will likely be updated in the reaction, stop clozapine immediately.20 If near future to comply with recent FDA benign clozapine-related fever is suspected, labeling changes. acetaminophen or another antipyretic might provide symptomatic relief; discontinuing clozapine is then unnecessary.41 Final installment: Using clozapine off-label Pregnancy. When a patient with schizo- Clozapine is FDA-approved for refractory phrenia requires clozapine treatment schizophrenia and for reducing the risk of during pregnancy, reliable clinical guid- recurrent suicidal behavior in schizophre- Current Psychiatry 46 August 2016 ance is limited. The American College of nia or schizoaffective disorder. In Part 3 of continued on page 48 continued from page 46

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The effect of content/themes/eyesite/pi/Clozaril-2015A507-10022015- clozapine on premature mortality: an assessment of clinical Approved.pdf. monitoring and other potential confounders. Schizophr • Smith TL, Mican LM. What to do when your patient who Bull. 2015;41(3):644-655. takes clozapine enters a smoke-free facility. Current 7. De Fazio P, Gaetano R, Caroleo M, et al. Rare and very rare Psychiatry. 2014;13(5):47-48,57. adverse effects of clozapine. Neuropsychiatr Dis Treat. 2015;11:1995-2003. • U.S. Food and Drug Administration. Pregnancy and Lactation 8. Novartis Pharmaceuticals Corporation. Clozaril (clozapine). Labeling (Drugs) Final Rule. https://s3.amazonaws.com/ Prescribing information. http://clozaril.com/wp- public-inspection.federalregister.gov/2014-28241.pdf. content/themes/eyesite/pi/Clozaril-2015A507-10022015- Approved.pdf. Accessed June 29, 2016. Drug Brand Names 9. Lieberman JA, Johns CA, Kane JM, et al. 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