cholinergic rebound adverse reactions, tardive dyskinesia, neuroleptic malignant syndrome, restless leg syndrome Cardiovascular: Atrial or ventricular tachycardia or fibrillation, periorbital edema, myocardial infarction, cardiac arrest, QT prolongation, Torsades de pointes, hypertension, mitral valve incompetence, bradycardia, cardiomyopathy, myocarditis Endocrine system: Pseudopheochromocytoma Gastrointestinal system: Acute pancreatitis, dysphagia, salivary gland swelling, colitis, hypersalivation, dry mouth, megacolon, intestinal obstruction, ischemia, infarction, perforation, ulceration or necrosis Hepatobiliary: Hepatotoxicity, hepatic steatosis, hepatic necrosis, hepatic fibrosis, hepatic cirrhosis, liver injury (hepatic, cholestatic, and mixed), and liver failure Immune system disorders: Angioedema, leukocytoclastic vasculitis Urogenital: Renal failure, nocturnal enuresis, acute interstitial nephritis, priapism, retrograde ejaculation Hemic and lymphatic system: DVT; elevated hemoglobin/hematocrit, ESR; sepsis, pulmonary embolism, thrombocytosis, thrombocytopenia, angioedema, leukocytoclastic vasculitis, eosinophilia Vision disorders: Narrow-angle glaucoma Miscellaneous: CPK elevation, hyperuricemia, hyponatremia, weight loss, polyserositis Black Box Warnings Agranulocytosis Available only through a restricted program called the Clozapine REMS Severe neutropenia, defined as an absolute neutrophil count (ANC) <500/mm3, has been reported Severe neutropenia can lead to serious infection and death Before initiating, baseline ANC must be ≥1500/mm3 for the general population and ≥1000/mm3 for patients with documented benign ethnic neutropenia Regularly monitor ANC during treatment Advise patients to immediately report symptoms consistent with severe neutropenia or infection (eg, fever, weakness, lethargy, sore throat) Seizures Caution with history of seizure or other factors predisposing to seizure Risk is dose-related Myocarditis, cardiomyopathy, and mitral valve incompetence Fatal myocarditis and cardiomyopathy reported; discontinue and obtain cardiac evaluation if suspected Measuring brain NP levels may offer a means of monitoring to detect early, asymptomatic myocarditis Generally, patients with a history of clozapine-associated myocarditis or cardiomyopathy should not be rechallenged; however, if benefit of treatment is judged to outweigh potential risks of recurrent myocarditis or cardiomyopathy, the clinician may consider rechallenging in consultation with a cardiologist, after a complete cardiac evaluation, and under close monitoring Orthostatic hypotension, bradycardia, syncope Orthostatic hypotension, bradycardia, syncope, and cardiac arrest may occur Risk is highest during initial titration period, particularly with rapid dose escalation May occur with the first dose, and with doses as low as 12.5 mg/day or when restarting patients who have had even a brief interruption in treatment; initiate treatment at 12.5 mg once or twice daily; titrate slowly; and use divided dosages to minimize risk Caution with history of cardiovascular or cerebrovascular disease or conditions predisposing to hypotension Increased mortality in elderly with dementia-related psychosis Not approved for dementia-related psychosis; patients with dementia-related psychosis who are treated with antipsychotic drugs are at increased risk of death, as shown in short-term controlled trials; deaths in these trials appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature Contraindications Hypersensitivity (eg, photosensitivity, vasculitis, erythema multiforme, Stevens-Johnson syndrome) Cautions Increased risk of dose-related seizures Eosinophilia (blood eosinophil count >700/mm3) reported; associated in some patients with myocarditis, pancreatitis, hepatitis, colitis, and nephritis; organ involvement could be consistent with a drug reaction with eosinophilia and systemic symptoms syndrome (DRESS) Increased risk of cerebrovascular adverse events reported with some atypical antipsychotics (mechanism unknown) FDA warning regarding off-label use for dementia-related psychosis in elderly patients; increased risk of death Antipsychotic drugs can cause the potentially fatal symptom complex referred to as neuroleptic malignant syndrome (NMS); if NMS occurs, immediately discontinue antipsychotic drug, and other drugs not essential to therapy; implement intensive symptomatic treatment and medical monitoring Possible QT prolongation; use with caution in patients with history of long QT syndrome or other conditions that may increase risk (eg, hypokalemia, hypomagnesemia) Severe, life threatening, and in some cases fatal hepatotoxicity including hepatic failure, hepatic necrosis, and hepatitis reported in post marketing studies; monitor for appearance of signs and symptoms of hepatotoxicity such as fatigue, malaise, anorexia, nausea, jaundice, bilirubinemia, coagulopathy, and hepatic encephalopathy; perform serum tests for liver injury and consider permanently discontinuing treatment if hepatitis or transaminase elevations combined with other systemic symptoms are due to clozapine Transient fever reported; peak incidence is within first 3 weeks of treatment; although this fever is generally benign and self-limited, it may necessitate discontinuing treatment since fever can be associated with an increase or decrease in WBC count; evaluate patients with fever to rule out severe neutropenia or infection; consider possibility of NMS Treatment must begin at maximum dose of 12.5 mg once daily or twice daily; total daily dose can be increased in increments of 25 mg to 50 mg per day, if well-tolerated, to a target dose of 300 mg to 450 mg per day (administered in divided doses) by end of 2 weeks; subsequently, the dose can be increased weekly or twice weekly, in increments of up to 100 mg; the maximum dose is 900 mg per day; use cautious titration and a divided dosage schedule to minimize risk of serious cardiovascular reactions Consider reducing the dose if hypotension occurs; when restarting therapy in patients who have had even a brief interruption in treatment, the dosage must be reduced; this is necessary to minimize the risk of hypotension, bradycardia, and syncope Pulmonary embolism (PE) and DVT reported; unclear whether PE and DVT can be attributed to clozapine Myocarditis, cardiomyopathy and mitral valve incompetence Myocarditis, cardiomyopathy, and mitral valve incompetence reported, including fatalities; discontinue and obtain cardiac evaluation upon suspicion of myocarditis or cardiomyopathy Consider the possibility of myocarditis or cardiomyopathy in patients receiving therapy who present with chest pain, dyspnea, persistent tachycardia at rest, palpitations, fever, flu-like symptoms, hypotension, other signs or symptoms of heart failure, or electrocardiographic findings (low voltages, ST-T abnormalities, arrhythmias, right axis deviation, and poor R wave progression) Myocarditis most frequently presents within first two months of clozapine treatment; symptoms generally occur later than clozapine-associated myocarditis and usually after 8 weeks of treatment However, myocarditis and cardiomyopathy can occur at any period during treatment; it is common for nonspecific flu- like symptoms such as malaise, myalgia, pleuritic chest pain, and low-grade fevers to precede more overt signs of heart failure Typical laboratory findings include elevated troponin I or T, elevated creatinine kinase-MB, peripheral eosinophilia, and elevated C-reactive protein (CRP) Chest roentgenogram may demonstrate cardiac silhouette enlargement, and cardiac imaging (echocardiogram, radionucleotide studies, or cardiac catheterization) may reveal evidence of left ventricular dysfunction In patients who are diagnosed with cardiomyopathy while taking clozapine mitral valve incompetence has been reported; these cases reported either mild or moderate mitral regurgitation on two-dimensional echocardiography In patients with suspected cardiomyopathy, consider a 2D-echo Doppler examination to identify mitral valve incompetence Neutropenia Only available through a restricted access program because of risk for neutropenia (ie, low ANC); patients must be registered, prescriber must enroll and complete training, and pharmacies dispensing clozapine must be certified and complete training Severe neutropenia (ANC <500/mm³) occurs in a small percentage of patients and is associated with increased risk of serious and potentially fatal infections; risk is greatest during the first 18 weeks of treatment and then declines; see prescribing information for detailed information regarding monitoring ANC, including patients with benign ethnic neutropenia Benign transient elevation of temperature reported, peaking within first 3 weeks of treatment (rule out agranulocytosis, infection, NMS) Metabolic changes Increased risk of hyperglycemia and diabetes; in some cases, hyperglycemia concomitant with use of atypical antipsychotics has been associated with esophageal dysmotility, ketoacidosis, hyperosmolar coma, or death; monitor blood glucose of high-risk patients Dyslipidemia and weight gain reported with atypical antipsychotics Anticholinergic effects Potent anticholinergic effects can occur that can result in CNS and peripheral anticholinergic toxicity Caution with narrow-angle glaucoma, concomitant anticholinergic medications, prostatic hypertrophy, or other conditions in which anticholinergic effects can lead to significant adverse reactions Impaired core body temperature regulation may occur; caution with strenuous exercise, dehydration, heat exposure, and concomitant medication possessing anticholinergic effects Gastrointestinal adverse reactions, including increased frequency of constipation, risk of severe complications of gastrointestinal hypomotility, which can result in fecal impaction, megacolon, and intestinal obstruction, ischemia, infarction, perforation, ulceration or necrosis reported; such reactions can be fatal Constipation should be initially treated by ensuring adequate hydration and use of ancillary therapy (eg, bulk laxatives); consult with gastroenterologist in more serious cases Evaluate bowel function before initiating treatment Instruct patients on preventive measures and to seek medical help if constipation occurs Cognitive and motor abilities May cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries; for patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long- term antipsychotic therapy May cause CNS depression, which may impair physical or mental abilities; caution patients about performing tasks that require mental alertness Tardive dyskinesia Tardive dyskinesia (TD) has occurred with antipsychotic drugs Syndrome consists of potentially irreversible, involuntary, dyskinetic movements Risk of TD and the likelihood that it will become irreversible are believed to increase with greater durations of treatment and higher total cumulative doses; however, the syndrome can develop after relatively brief treatment periods at low doses Prescribe drug in a manner that is most likely to minimize TD risk Use the lowest effective dose and the shortest duration necessary to control symptoms Periodically assess need for continued treatment; consider discontinuing treatment if TD occurs Some patients may require treatment despite the presence of the syndrome There is no known treatment for TD; however, the syndrome may remit partially or completely if treatment is discontinued Drug interaction overview CYP inhibitors and inducers Clozapine is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP2D6, and CYP3A4 Clozapine dosage modification may be required if coadministered with drugs that inhibit or induce metabolism of clozapine (eg, CYP 1A2, 2D6, and 3A4 inhibitors) QT prolongation Clozapine associated with QT prolongation Caution if coadministered with other drugs that prolong QT interval CYP2D6 substrates Clozapine inhibits CYP2D6 Coadministration with CYP2D6 substrates can increase levels of these substrate; lower dose of CYP2D6 substrate may be required Anticholinergic drugs Caution if coadministered with other drugs that elicit anticholinergic effects Monitor carefully for additive anticholinergic effects Pregnancy There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including clozapine, during pregnancy; health care providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmental health.org/clinical-and-research-programs/pregnancyregistry/ Neonates exposed to antipsychotic drugs during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery; overall, available data from published epidemiologic studies of pregnant women exposed to clozapine have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes; there are risks to the mother associated with untreated schizophrenia and with exposure to antipsychotics, during pregnancy Animal data In animal reproduction studies, no adverse developmental effects were observed with drug administered to pregnant rats or rabbits during period of organogenesis, or to pregnant rats during pregnancy and lactation, at doses up to approximately 0.4 and 0.9 times the maximum recommended human dose (MRHD) of 900 mg/day, for rats and rabbits respectively, based on mg/m2 body surface area There is risk to mother from untreated schizophrenia, including increased risk of relapse, hospitalization, and suicide; schizophrenia is associated with increased adverse perinatal outcomes, including preterm birth; it is not known if this is a direct result of the illness or other comorbid factors Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder reported in neonates exposed to antipsychotic drugs during third trimester of pregnancy; these symptoms have varied in severity; monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately; some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization Lactation Clozapine is present in human milk; there are reports of sedation and a report of agranulocytosis in an infant exposed to clozapine through human milk; there is no information on effects of clozapine on milk production; the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for therapy and any potential adverse effects on breastfed-child from drug or from underlying maternal condition Infants exposed to drug should be monitored for excess sedationPregnancy Categories A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk. B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.