Summary Of Exposure |
A) USES: Clozapine is used for treatment-resistant schizophrenia. It was first synthesized in 1969, but not widely used until the 1970s. It was withdrawn from the market in 1974 due to cases of fatal agranulocytosis associated with its use, but was reintroduced in 1990. It improves both the positive and negative symptoms of schizophrenia and has a lower likelihood of producing extrapyramidal symptoms compared to typical antipsychotics.
B) PHARMACOLOGY: Unlike typical antipsychotic medications, clozapine has little affinity for dopamine receptors. Clozapine is an antagonist of muscarinic and serotonin receptors at clinically effective doses and blocks peripheral alpha1-adrenergic receptors. In addition, it interferes with the reuptake of catecholamines and antagonizes GABA A receptors.
C) TOXICOLOGY: Overdose is usually an extension of pharmacology effects, which primarily affects the cardiovascular system and central nervous system, including anticholinergic toxidrome (antagonizes muscarinic receptors), hypotension (blocks peripheral alpha1-adrenergic receptors) and, less commonly, seizures (GABA antagonism). Many adverse reactions occur with therapeutic use, and are not dose-dependent.
D) EPIDEMIOLOGY: Clozapine is only indicated for the treatment of resistant schizophrenia and not commonly prescribed. Therefore, poisoning is rare, but may be life-threatening.
E) WITH THERAPEUTIC USE
1) Mild anticholinergic effects are common, including mild sedation, constipation, and urinary retention. Ironically, clozapine can cause increased salivation. Dyslipidemia, hepatic steatosis, and glucose intolerance can occur with long-term antipsychotic use. Clozapine can cause life-threatening agranulocytosis in 0.38% to 2% of patients. Myocarditis and cardiomyopathy have rarely been reported.
2) Extrapyramidal syndrome (ie, acute dystonia, akathisia, parkinsonism, and tardive dyskinesia) more commonly results from typical antipsychotic use, but may occur with clozapine administration. The exact causal mechanism remains unclear. Acute dystonia is involuntary muscle contraction of the head and neck, possibly involving the larynx. Akathisia can be described as a feeling of inner restlessness and anxiety, with may cause difficulty sitting still. Parkinsonism is characterized by rigidity, bradykinesia, and postural instability. Tardive dyskinesia manifests as repetitive masticatory movements, tics, blepharospasm, and chorea after chronic use. Of all of the atypical antipsychotics, clozapine has the lowest rate of tardive dyskinesia.
3) Neuroleptic malignant syndrome (NMS) may occur following overdose, but is much more likely to occur with therapeutic use. Often, NMS occurs in the first 2 weeks of treatment or after a dose increase. It is a potentially life-threatening syndrome of muscular rigidity, autonomic instability, altered mental status, and hyperthermia. NMS should be thought of as a spectrum of disease with symptoms ranging from mild to coma, seizures, and death. The exact cause of NMS is unknown.
F) WITH POISONING/EXPOSURE
1) MILD TO MODERATE POISONING: Somnolence, anticholinergic effects (eg, mydriasis, flushing, fever, dry mouth, decreased bowel sounds), tachycardia, mild hypotension, and nausea and vomiting are common after overdose. Pinpoint pupils are often observed. Agitation, nystagmus, ataxia, confusion, and hallucinations may develop with moderate poisoning.
2) SEVERE POISONING: Generally, toxicity appears to be greater in patients who are not chronically taking clozapine, particularly children. Severe effects involve the central nervous system and cardiovascular system and may include delirium, seizures, coma, hyperthermia, severe hypotension, myoclonus, muscle rigidity and, rarely, ventricular dysrhythmias. Clozapine has a relatively low affinity for cardiac sodium channels, and there is little evidence suggesting cardiac dysrhythmias as a direct effect of clozapine toxicity. Clozapine prolongs the QT interval and, therefore, may cause torsades de pointes, although this has not been reported after overdose. Rhabdomyolysis and renal failure may rarely develop in patients with prolonged agitation, coma, or seizures.
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Vital Signs |
3.3.1) SUMMARY
A) WITH POISONING/EXPOSURE 1) Respiratory depression, tachycardia, hyperthermia, and orthostatic hypotension may occur with clozapine overdose.
3.3.2) RESPIRATIONS
A) WITH POISONING/EXPOSURE 1) Respiratory depression may occur with clozapine overdose; respiratory arrest may occur secondary to severe hypotension (Prod Info CLOZARIL(R) Tablets, 2005).
3.3.3) TEMPERATURE
A) WITH THERAPEUTIC USE 1) Fever was associated with flu-like symptoms following therapeutic dosages of clozapine. Temperature elevation was independent of dose (Blum, 1990).
B) WITH POISONING/EXPOSURE 1) Hypothermia (33.1 C) developed in a 20-year-old woman who ingested approximately 3500 mg clozapine and a few clonazepam. She presented with coma, tachycardia, absent bowel sounds, and areflexia. She gradually recovered over 6 days with supportive care (Thomas & Pollak, 2003).
2) INCIDENCE: In a review of 47 patients with clozapine intoxication, hypothermia developed in 3 of the patients (n=27) with serum clozapine concentrations less than 2000 ng/mL, and in 2 of the patients (n=20) with serum clozapine concentrations of 2000 ng/mL or greater (He et al, 2007).
3.3.4) BLOOD PRESSURE
A) WITH THERAPEUTIC USE 1) Orthostatic hypotension has been reported in patients taking clozapine therapeutically.
3.3.5) PULSE
A) WITH POISONING/EXPOSURE 1) Tachycardia may occur.
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Heent |
3.4.3) EYES
A) WITH THERAPEUTIC USE 1) Accommodation difficulties may be noted (Reynolds, 2000).
B) WITH POISONING/EXPOSURE 1) NYSTAGMUS a) Nystagmus has been reported with clozapine overdose (Goetz et al, 1993).
2) MIOSIS a) CASE REPORT: Miosis with slow pupil reactions has been reported in a 41-year-old patient after ingesting 12,500 mg of clozapine (Sartorius et al, 2002).
b) CASE REPORT: A 40-year-old schizophrenic man was found unconscious, with constricted pupils, sinus tachycardia, and twitching of the limbs after ingesting 3 to 4 grams of clozapine (Renwick et al, 2000).
c) INCIDENCE: In a review of 47 patients with clozapine intoxication, miosis developed in 55.6% (n=27) of the patients with serum clozapine concentrations less than 2000 ng/mL, and in 70% (n=20) of patients with serum clozapine concentrations of 2000 ng/mL or greater (He et al, 2007).
3.4.6) THROAT
A) WITH THERAPEUTIC USE 1) Dry mouth has been reported following therapeutic dosages (Reynolds, 2000).
B) WITH POISONING/EXPOSURE 1) Hypersalivation is a clozapine overdose effect (He et al, 2007; Reith et al, 1998). a) According to a retrospective review of 73 cases of clozapine overdose ingestions reported to the Swiss Toxicological Information Centre from 1995 to 2007, hypersalivation was reported in 6.8% of patients (Kramer et al, 2010).
2) Esophagitis was reported on autopsy in a fatal case of clozapine toxicity (Ferslew et al, 1998). |
Cardiovascular |
3.5.2) CLINICAL EFFECTS
A) TACHYARRHYTHMIA 1) WITH THERAPEUTIC USE a) Sinus tachycardia has been reported as an adverse therapeutic side effect (Wolf & Otten, 1991).
2) WITH POISONING/EXPOSURE a) Sinus tachycardia has been reported following overdoses (Rotella et al, 2014; Reddy et al, 2013; Sartorius et al, 2002; Renwick et al, 2000; Roy & Cutten, 1993; Welber & Nevins, 1995; Mady et al, 1996; Broich et al, 1998). 1) Sinus tachycardia has been reported in several children after ingestion of 50 to 200 mg of clozapine (Goetz et al, 1993; Hadley & Walson, 1993; Mady & Wax, 1993; Mady et al, 1996).
b) INCIDENCE: In a review of 47 patients with clozapine intoxication, tachycardia developed in 77.8% (n=27) of the patients with serum clozapine concentrations less than 2000 ng/mL, and in 95% (n=20) of patients with serum clozapine concentrations of 2000 ng/mL or greater (He et al, 2007). c) CASE REPORT: Mild tachycardia and somnolence were reported in a patient following a clozapine ingestion of 2 g. The serum clozapine concentration, obtained 30 minutes post-ingestion, was 2900 nmol/L (Kramer et al, 2010). d) CASE REPORT: A 26-year-old man developed sinus tachycardia (135 bpm) after ingesting 5 grams of clozapine and 800 mg of citalopram. No specific cardiac treatment was provided. The patient recovered with no sequelae (Sparve et al, 2009). e) According to a retrospective review of 73 cases of clozapine overdose ingestions reported to the Swiss Toxicological Information Centre from 1995 to 2007, tachycardia was reported in 39.7% of patients (Kramer et al, 2010). B) BRADYCARDIA 1) WITH POISONING/EXPOSURE a) CASE REPORT: Bradycardia (50 beats/minute) and acute respiratory failure was reported following an unknown quantity of 100 mg clozapine in a 15-year-old girl who died 4 hours after exposure; postmortem peripheral blood concentration was 8.8 mg/L (Keller et al, 1997).
C) HYPOTENSIVE EPISODE 1) WITH THERAPEUTIC USE a) Orthostatic hypotension has been reported in patients taking clozapine (Battegay et al, 1977; Ayd, 1974; Kane, 1993).
2) WITH POISONING/EXPOSURE a) Severe hypotension has been reported in clozapine overdoses (Reddy et al, 2013; Novikova et al, 2009; Prod Info CLOZARIL(R) Tablets, 2005; Welber & Nevins, 1995; Koppel C, Thurk C & Bertschat F et al, 1994; Broich et al, 1998).
b) INCIDENCE: In a review of 47 patients with clozapine intoxication, hypotension developed in 25.9% (n=27) of the patients with serum clozapine concentrations less than 2000 ng/mL, and in 25% (n=20) of patients with serum clozapine concentrations of 2000 ng/mL or greater (He et al, 2007).
c) CASE REPORT: A 21-year-old woman presented to the emergency department approximately 2 hours after intentionally ingesting 23 100-mg clozapine tablets. Prior to presentation, she experienced a 5-minute generalized tonic-clonic seizure and was found by emergency personnel to be unresponsive with tachycardia (130 beats/min) and hypotension (80 mmHg systolic). Initial laboratory data revealed elevated anion gap metabolic acidosis and respiratory acidosis, and a serum clozapine concentration greater than 1500 mcg/L (therapeutic range 100 to 800 mcg/L). Approximately 20 minutes post-presentation, the patient deteriorated hemodynamically with development of progressive hypotension (73/57 mmHg to 40/34 mmHg) refractory to IV fluids and initial noradrenaline administration. With phenylephrine boluses and continuous noradrenaline infusion, her blood pressure gradually increased to 85/37 mmHg; however marked improvement was observed following initiation of vasopressin treatment, with a blood pressure of 104/55 mmHg after 12 minutes. With continued supportive care, the patient recovered uneventfully (Rotella et al, 2014).
D) HYPERTENSIVE EPISODE 1) WITH THERAPEUTIC USE a) Paradoxical hypertension with tachycardia was reported in a 19-year-old man one week after starting clozapine 175 mg/day, with systolic pressures ranging from 140 to 170 mmHg and diastolic pressures ranging from 90 to 115 mmHg. Clozapine was continued and blood pressure control obtained with atenolol therapy (Ennis & Parker, 1997).
E) CONDUCTION DISORDER OF THE HEART 1) WITH POISONING/EXPOSURE a) Cardiac dysrhythmias and aspiration pneumonia have been reported following overdoses (Prod Info CLOZARIL(R) Tablets, 2005).
b) CASE REPORT: Ventricular tachycardia and hypotension developed in a 33-year-old man after clozapine ingestion (Koppel C, Thurk C & Bertschat F et al, 1994). This deteriorated to electromechanical dissociation despite intensive supportive care and hemoperfusion and the patient died.
c) According to a retrospective review of 73 cases of clozapine overdose ingestions reported to the Swiss Toxicological Information Centre from 1995 to 2007, QT prolongation was reported in 8.2% of patients (Kramer et al, 2010).
d) CASE REPORT: Mild QTc prolongation with ST depression and T-wave flattening was reported in a 23-year-old woman who ingested 2000 mg clozapine, as well as 5 mg clonazepam and 100 mg folic acid (Reddy et al, 2013).
F) CYANOSIS 1) WITH POISONING/EXPOSURE a) CASE REPORT: Cyanosis of the lips and tachycardia were reported in a 21-month-old boy after an overdose of 50 mg (Mady et al, 1996).
G) CARDIOMYOPATHY 1) WITH THERAPEUTIC USE a) CASE REPORT: A case of fatal myocardial failure, preceded by intractable cardiogenic shock, with severe refractory lactic acidosis, hyperglycemia and coma, was reported in a 37-year-old Ashkenazic Jewish male after 12 weeks of clozapine therapy who was admitted with severe agranulocytosis, facial candidiasis and fever (Koren et al, 1997).
b) CASE REPORT: A 26-year-old woman with no previous history of heart problems presented with cardiomyopathy, with signs/symptoms including hypotension, dizziness, dyspnea, hemoptysis, pedal edema, tachycardia and nausea and vomiting. X-rays revealed cardiomegaly with mild pulmonary congestion and left lower lobe atelectasis. Echocardiogram revealed a low ventricular ejection fraction (LVEF) of 18%. Abnormal QRS complexes, and inverted and flattened T-waves were also reported on ECG (Leo et al, 1996).
c) RETROSPECTIVE STUDY: Kilian et al (1999) identified 8 cases of dilated cardiomyopathy and 15 cases of myocarditis associated with clozapine treatment (Kilian et al, 1999). The 15 cases of myocarditis occurred soon after initiation of treatment with clozapine (median 15 days of therapy); 5 of the patients in this group died. For the 8 cases of cardiomyopathy, symptoms occurred later, with a median onset of 12 months; 1 patient died in this group. No confounding illness was found in any of the patients that would have contributed to cardiac disease.
H) MYOCARDITIS 1) WITH THERAPEUTIC USE a) Postmarketing safety data suggested that clozapine is associated with increased risk of fatal myocarditis. This is of greatest concern during the first month of therapy (Prod Info CLOZARIL(R) Tablets, 2005).
2) WITH POISONING/EXPOSURE a) CASE REPORT: Eosinophilic myocarditis occurred in a 25-year-old man following the ingestion of an estimated 2000 mg of clozapine in a suicide attempt; he died 6 hours later despite treatment (Meeker et al, 1992).
I) DEAD - SUDDEN DEATH 1) WITH THERAPEUTIC USE a) The findings of a preliminary investigation suggested that the risk for sudden death in patients treated with clozapine is 3.8 times higher than those on other therapies; however, patients that are not taking clozapine have 5 times greater chance of disease-related death (Modai et al, 2000).
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Respiratory |
3.6.2) CLINICAL EFFECTS
A) ACUTE RESPIRATORY INSUFFICIENCY 1) WITH POISONING/EXPOSURE a) Respiratory depression and apnea may occur following an overdose (Reddy et al, 2013; Prod Info CLOZARIL(R) Tablets, 2005).
b) CASE REPORT: Respiratory depression and acute respiratory failure occurred in a 15-year-old girl following an unknown quantity of 100 mg clozapine tablets; she died within 4 hours of exposure (Keller et al, 1997).
c) CASE REPORT: Respiratory arrest was reported in a 5-year-old boy after ingestion of 200 mg clozapine. The patient recovered after intubation with ventilation for 24 hours and supportive care (Warden & Pace, 1996).
d) CASE REPORT: A patient was comatose with respiratory depression following a clozapine ingestion of 20 g. The serum clozapine concentration, obtained 12 hours post-ingestion, was 10,240 nmol/L (Kramer et al, 2010).
e) INCIDENCE: In a review of 47 patients with clozapine intoxication, respiratory depression developed in 14.8% (n=27) of the patients with serum clozapine concentrations less than 2000 ng/mL, and in 25% (n=20) of patients with serum clozapine concentrations of 2000 ng/mL or greater (He et al, 2007).
f) CASE REPORT: A 16-year-old adolescent developed acute respiratory insufficiency (oxygen saturation 75% on room air and 90% on high flow oxygen) following a suspected overdose ingestion of 10 grams of clozapine. Pulmonary examination revealed bilateral crepitations in her lungs. Despite ventilation and supportive care, the patient's condition continued to deteriorate with the development of respiratory distress syndrome, hypotension, and acute renal failure, resulting in her subsequent death 42 days post-admission (Novikova et al, 2009).
g) According to a retrospective review of 73 cases of clozapine overdose ingestions reported to the Swiss Toxicological Information Centre from 1995 to 2007, respiratory insufficiency (SpO2 less than 90%) was reported in 1.4% of patients (Kramer et al, 2010).
B) PULMONARY ASPIRATION 1) WITH POISONING/EXPOSURE a) Aspiration pneumonia has been reported in acute clozapine overdoses (Prod Info CLOZARIL(R) Tablets, 2005) and is the main complication of poisoning.
b) CASE SERIES: In one case series, 15 of 150 patients with clozapine overdose developed aspiration pneumonia (Anon, 1992).
c) INCIDENCE: In a review of 47 patients with clozapine intoxication, aspiration pneumonia developed in 37% (n=27) of the patients with serum clozapine concentrations less than 2000 ng/mL, and in 65% (n=20) of patients with serum clozapine concentrations of 2000 ng/mL or greater (He et al, 2007).
d) CASE REPORT: A 26-year-old man presented with fever (38 degrees C), confusion, agitation, elevated respiratory rate (36/minute) and tachycardia (135 bpm) approximately 24 hours after ingesting 5 g of clozapine and 800 mg of citalopram. A pulmonary examination indicated crackles, primarily on the left side, and a chest X-ray revealed moderate to severe pulmonary edema. Laboratory data demonstrated leukocytosis and elevated C-reactive protein. Suspecting aspiration pneumonia, supportive therapy, including administration of oxygen and antibiotics, was initiated, resulting in subsequent clinical improvement of the patient (Sparve et al, 2009).
C) ACUTE LUNG INJURY 1) WITH POISONING/EXPOSURE a) Pulmonary edema was reported at autopsy in a case of clozapine toxicity due to a drug interaction (Ferslew et al, 1998).
b) INCIDENCE: In a review of 47 patients with clozapine intoxication, pulmonary edema developed in 1 of the patients (n=27) with serum clozapine concentrations less than 2000 ng/mL, and in 2 of the patients (n=20) with serum clozapine concentrations of 2000 ng/mL or greater (He et al, 2007).
D) PLEURAL EFFUSION 1) WITH THERAPEUTIC USE a) CASE REPORT: A 37-year-old man developed right arm cellulitis after 5 days of clozapine therapy and a left-sided pleural effusion after 12 days. Clozapine was discontinued and he improved with antibiotics. A later trial of clozapine 25 milligrams daily resulted in recurrence of symptoms (Chatterjee & Safferman, 1997).
E) PULMONARY EMBOLISM 1) WITH THERAPEUTIC USE a) Hagg et al (2000) identified 12 cases of thromboembolism associated with clozapine treatment (mean dose of 277 milligrams per day)(Hagg et al, 2000a). Six cases of venous thrombosis and 6 cases of pulmonary embolism were reported; five patients died. No confounding illness was found in any of the patients that would have contributed to thromboembolic disease.
b) A 30-year-old man developed bilateral pulmonary embolism after taking clozapine for five months (Maynes, 2000).
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Neurologic |
3.7.2) CLINICAL EFFECTS
A) SEIZURE 1) WITH THERAPEUTIC USE a) During clinical trials, the reported prevalence of seizures was 5% of patients treated with 600 to 900 milligrams daily (Haller & Binder, 1990). In one case, a 30-year-old man developed a grand mal seizure and liver toxicity after 3 weeks of clozapine therapy which had been increased to 400 mg per day (Panagiotis, 1999).
b) Therapeutic use of clozapine has been reported to lower the seizure threshold, especially in epileptic patients and patients with organic brain disease; these patients may be at greater risk for seizures with overdose (Haller & Binder, 1990).
2) WITH POISONING/EXPOSURE a) Seizures may occur after overdose of clozapine: the effect is dose-dependent (Prod Info CLOZARIL(R) Tablets, 2005; Sartorius et al, 2002; Haag et al, 1999; Haller & Binder, 1990; Simpson & Cooper, 1978; Roy & Cutten, 1993; Pacia & Devinsky, 1994; Anon, 1992).
b) CASE REPORT: A 24-year-old woman, with no history of seizure disorder, developed a grand mal seizure following an overdose of 7300 mg. Previously, she had been on chronic clozapine for 14 months with no problems (Roy & Cutten, 1993).
c) In one study, seizures were reported in up to 8.8% of cases following overdose of clozapine (Reith et al, 1998).
d) INCIDENCE: In a review of 47 patients with clozapine intoxication, seizures developed in 1 of the patients (n=27) with serum clozapine concentrations less than 2000 ng/mL, and in 3 of the patients (n=20) with serum clozapine concentrations of 2000 ng/mL or greater (He et al, 2007).
e) CASE REPORT: A single, generalized seizure, delirium, agitation, and disorientation occurred in a patient following a clozapine ingestion of 19 g (Kramer et al, 2010).
f) CASE REPORT: Generalized tonic-clonic seizures occurred in a 21-year-old woman following an intentional ingestion of 23 100-mg clozapine tablets (Rotella et al, 2014).
B) MYOCLONUS 1) WITH THERAPEUTIC USE a) Myoclonic jerking has developed in patients taking therapeutic doses of clozapine (Antelo et al, 1994).
2) WITH POISONING/EXPOSURE a) Hypotonia, hyporeflexia, myoclonic jerking, muscle rigidity and torticollis have been reported after clozapine overdose (Mady et al, 1996; Anon, 1992; Goetz et al, 1993).
b) CASE REPORT: Periods of myoclonic jerking were reported in a 31-month-old girl after ingestion of 100 or 200 milligrams of clozapine (Mady et al, 1996).
c) CASE REPORT: Agitation, combativeness, and intermittent tremors or fasciculations of all extremities occurred in a 29-year-old man after ingestion of approximately 3750 mg clozapine (Welber & Nevins, 1995).
C) COMA 1) WITH POISONING/EXPOSURE a) Coma may develop in overdose (Prod Info CLOZARIL(R) Tablets, 2005).
b) CASE REPORT: Coma (Glasgow score 7) was reported in a 63-year-old woman following an overdose of over 1000 milligrams clozapine (Jubert, 1994).
c) CASE REPORT: A 40-year-old man had a Glasgow coma score of 4/15 following an overdose of 3 to 4 grams of clozapine. The score improved to 8-10/15 eight hours after admission and symptomatic treatment (Renwick et al, 2000).
d) CASE REPORT: A patient was comatose with respiratory depression following a clozapine ingestion of 20 g. The serum clozapine concentration, obtained 12 hours post-ingestion, was 10,240 nmol/L (Kramer et al, 2010).
e) INCIDENCE: In a review of 47 patients with clozapine intoxication, coma developed in 40.7% (n=27) of the patients with serum clozapine concentrations less than 2000 ng/mL, and in 50% (n=20) of patients with serum clozapine concentrations of 2000 ng/mL or greater (He et al, 2007).
f) CASE REPORT: A 16-year-old adolescent became comatose (Glasgow coma score of 8) following a suspected overdose ingestion of 10 grams of clozapine. Despite supportive therapy, the patient's condition worsened with the development of respiratory distress syndrome, hypotension, and acute renal failure, resulting in her subsequent death 42 days post-admission (Novikova et al, 2009).
g) According to a retrospective review of 73 cases of clozapine overdose ingestions reported to the Swiss Toxicological Information Centre from 1995 to 2007, coma was reported in 11% of patients with a Glasgow Coma Scale (GCS) score of 8 to 9, and in 11% of patients with a GCS score of 7 or less (Kramer et al, 2010).
h) PROLONGED COMA: A 23-year-old woman became comatose (Glasgow coma scale [GCS] score of 6 at presentation) and hypotensive (88/60 mmHg) after ingesting 2000 mg clozapine, as well as 5 mg clonazepam and 100 mg folic acid. Her ECG at admission revealed tachycardia and mild QTc prolongation with ST depression and T-wave flattening. Intubation and mechanical ventilation were initiated after the patient began exhibiting signs of respiratory depression. A chest radiograph indicated right sided pleural effusion without evidence of pulmonary embolization. Decontamination with gastric lavage and activated charcoal was performed; however, she remained comatose for approximately 70 hours. Gradually, the patient regained consciousness (GCS of 13), followed by mood and sensory fluctuations, intermittent disorientation, and paroxysmal drowsiness for the next 3 days. Following initiation of armodafinil 25 mg twice daily, her drowsiness and delirium improved, and she was subsequently discharged by the second week of hospitalization (Reddy et al, 2013).
i) CASE REPORT: A 13-month-old girl presented with tachydyspnea, oropharyngeal rhonchus, peripheral cyanosis, and coma (Glasgow coma scale score of 7 to 8). An EEG indicated moderate encephalopathy and the patient remained comatose with persistent tachycardia and tachypnea. Over the next 24 hours, patient's clinical condition spontaneously improved; however, she continued to alternate between somnolence and awakening, until complete resolution of symptoms approximately 44 hours post-admission. Toxicologic analysis of the patient's blood, performed at admission, and 22 and 118 hours post-admission, revealed serum clozapine concentrations of 736 ng/mL, 185.8 ng/mL, and 1 ng/mL, respectively (Toepfner et al, 2013).
D) EXTRAPYRAMIDAL DISEASE 1) WITH THERAPEUTIC USE a) Extrapyramidal effects are rare or absent following therapeutic dosages (Reynolds, 2000).
2) WITH POISONING/EXPOSURE a) CASE REPORT: Extrapyramidal effects were reported in a 4-year-old girl who ingested 100 mg (Goetz et al, 1993).
b) CASE REPORT: Whole body rigidity, torticollis, and nystagmus were present about 4 hours following ingestion of 100 mg in a 4-year-old girl (Mady et al, 1996). Extrapyramidal effects were absent in a 10-year-old girl who ingested 100 milligrams of clozapine (Borzutzky et al, 2003).
c) CASE REPORT: Myoclonic jerking, difficult tongue control, and decreased muscle tone was apparent in a 31-month-old girl following ingestion of 100 to 200 mg (Mady et al, 1996).
E) ATAXIA 1) WITH POISONING/EXPOSURE a) CASE REPORTS: Ataxia was reported in several children who ingested 50 to 200 milligrams of clozapine (Goetz et al, 1993; Hadley & Walson, 1993; Mady & Wax, 1993; Mady et al, 1996). Ataxic symptoms were absent in a 10-year-old girl who ingested 100 milligrams of clozapine (Borzutzky et al, 2003).
b) CASE REPORT: Ataxia was reported in a 24-year-old woman after an overdose of 7300 milligrams (Roy & Cutten, 1993).
F) DECREASED MUSCLE TONE 1) WITH POISONING/EXPOSURE a) CASE REPORT: A 10-year-old girl developed hypotonicity following an inadvertent ingestion (100 mg) of clozapine. Symptoms fully resolved within 55 hours with supportive care (Borzutzky et al, 2003).
G) ALTERED MENTAL STATUS 1) WITH POISONING/EXPOSURE a) PEDIATRIC 1) CASE REPORT: A 10-year-old girl developed alternating agitation and stupor, hypotonicity, tachycardia, slurred speech and visual hallucinations after an inadvertent exposure to 100 milligrams of clozapine. Unlike earlier pediatric reports, ataxia and extrapyramidal effects did not occur. Symptoms fully resolved within 55 hours with no permanent sequelae (Borzutzky et al, 2003).
2) YOUNG CHILDREN (less than 5 years): Confusion, agitation, ataxia, myoclonic jerking, stupor, slurred speech, somnolence and possible hallucinations have been reported in children after overdose (Goetz et al, 1993; Hadley & Walson, 1993; Mady & Wax, 1993; Mady et al, 1996).
b) ADULT 1) Agitation, delirium, hallucinations and combativeness have been reported following clozapine overdose (Kramer et al, 2010; Sartorius et al, 2002; Broich et al, 1998; Wolf & Otten, 1991; Meeker et al, 1992; Mady et al, 1996; Schuster et al, 1977; Anon, 1992).
2) According to a retrospective review of 73 cases of clozapine overdose ingestions reported to the Swiss Toxicological Information Centre from 1995 to 2007, agitation and restlessness were reported in 16.4% of patients (Kramer et al, 2010).
H) NEUROLEPTIC MALIGNANT SYNDROME 1) WITH THERAPEUTIC USE a) A few cases of neuroleptic malignant syndrome attributed to therapeutic use of clozapine has been reported, some in conjunction with other neuroleptics(Kontaxakis et al, 2002) Campellone et al, 1994; (Anderson & Powers, 1991) Miller et al, 1991; (DasGupta & Young, 1991; Muller et al, 1988).
b) Karagianis et al (1999) reported 2 cases of apparent neuroleptic malignant syndrome (NMS) associated with clozapine use (Karagianis et al, 1999). The authors also performed a review of the literature and stated that clozapine was deemed a highly probable cause in 14 cases of NMS, with most commonly reported effects of tachycardia, mental status changes, and diaphoresis.
c) RETROSPECTIVE REVIEW: In a review of clozapine and cases of presumed neuroleptic malignant syndrome, approximately 9 of the 19 cases were designated as having high probability of actually being neuroleptic malignant syndrome. Alternative diagnoses in low probability cases included benzodiazepine withdrawal, infection, drug-drug interaction, or serotonin syndrome (Hasan & Buckley, 1998).
d) CASE REPORT: A 53-year-old woman, with a history of schizophrenia and who was taking clozapine 500 mg/day for the past 3 years, presented to the emergency department with confusion, shivering, incoherent speech, and urinary incontinence. Vital signs indicated hyperthermia (39.2 degrees C), hypotension (90/50 mmHg) and tachycardia (117 bpm). Laboratory data revealed elevated creatinine and BUN concentrations (1.52 and 23.68 mg/dL, respectively), leukocytosis, thrombocytopenia, and elevated creatine kinase (CK) concentrations (2158 Units/L). CT and MRI scans of the brain were normal and urine and blood cultures and lumbar puncture showed no abnormalities. She continued to have incomprehensible speech with the inability to construct complex sentences. Despite the absence of rigidity, the patient was diagnosed with neuroleptic malignant syndrome (NMS). With supportive care and cessation of clozapine therapy, the patient gradually recovered with normalization of vital signs and CK concentration, and improvement of speech and comprehension. Clozapine levels, taken at presentation, revealed clozapine and nor-clozapine levels of 1439 and 332.6 ng/mL, respectively. There was no evidence of intentional self-harm and family members reported a similar clinical episode 2 years earlier. Eight days later, both clozapine and nor-clozapine levels decreased to less than 40 ng/mL. Clozapine was stopped and the patient was started on olanzapine. It is believed that the symptoms of clozapine toxicity in this patient partially overlapped with symptoms of NMS; measurement of clozapine blood levels are warranted in patients exhibiting atypical signs and symptoms of NMS (Kamis et al, 2014).
I) NYSTAGMUS 1) WITH POISONING/EXPOSURE a) CASE REPORTS: Nystagmus has been reported following overdoses (Welber & Nevins, 1995; Mady et al, 1996; Goetz et al, 1993).
J) HALLUCINATIONS 1) WITH POISONING/EXPOSURE a) CASE REPORT: Visual hallucinations are reported in a 24-year-old woman after an overdose of 7300 milligrams clozapine, following 14 months of chronic therapy (Roy & Cutten, 1993).
b) CASE REPORT: A 41-year-old patient developed agitated delirium with visual and auditory hallucinations after ingesting 12,500 mg of clozapine in a suicide attempt. The patient was symptom free within the first week following exposure (Sartorius et al, 2002).
c) According to a retrospective review of 73 cases of clozapine overdose ingestions reported to the Swiss Toxicological Information Centre from 1995 to 2007, hallucinations were reported in 4.1% of patients (Kramer et al, 2010).
K) DELIRIUM 1) WITH THERAPEUTIC USE a) Delirium may occur, secondary to antimuscarinic side-effects, following therapeutic dosages (Reynolds, 2000). An incidence of 8% was reported in a case series of 391 treatments in 315 inpatients (Gaetner et al, 1989).
2) WITH POISONING/EXPOSURE a) CASE REPORT: A 63-year-old woman developed delirium on the second hospital day following an overdose of over 1000 milligrams clozapine (Jubert, 1994).
b) CASE REPORT: A 41-year-old patient developed agitated delirium with visual and auditory hallucinations after ingesting 12,500 mg of clozapine in a suicide attempt. The patient was symptom free within the first week following exposure (Sartorius et al, 2002).
c) INCIDENCE: In a review of 47 patients with clozapine intoxication, delirium developed in 29.6% (n=27) of the patients with serum clozapine concentrations less than 2000 ng/mL, and in 40% (n=20) of patients with serum clozapine concentrations of 2000 ng/mL or greater (He et al, 2007).
d) According to a retrospective review of 73 cases of clozapine overdose ingestions reported to the Swiss Toxicological Information Centre from 1995 to 2007, delirium was reported in 4.1% of patients (Kramer et al, 2010).
L) CENTRAL NERVOUS SYSTEM DEFICIT 1) WITH THERAPEUTIC USE a) Drowsiness was a common dose-dependent adverse effect of clozapine (Bablenis et al, 1989; Haller & Binder, 1990a) Kirkegaard et al, 1982; (Ayd, 1974; Battegay et al, 1977). .
2) WITH POISONING/EXPOSURE a) CASE SERIES: In a series of 150 cases of clozapine overdose, 50 developed lethargy and 62 became comatose (Anon, 1992). Coma, lethargy, confusion, slurred speech, ataxia, unconsciousness and disorientation have also been reported after clozapine overdose (Prod Info CLOZARIL(R) Tablets, 2005; Sartorius et al, 2002; Renwick et al, 2000; Mady et al, 1996; Hadley & Walson, 1993; Wolf & Otten, 1991; Schuster et al, 1977; Koppel C, Thurk C & Bertschat F et al, 1994).
b) CASE REPORT: Somnolence and mild tachycardia were reported in a patient following a clozapine ingestion of 2 g. The serum clozapine concentration, obtained 30 minutes post-ingestion, was 2900 nmol/L (Kramer et al, 2010).
c) After ingestion of 2.5 grams clozapine, a 64-year-old woman was comatose for 24 hours after admission, followed by prolonged drowsiness and disorientation for 4 days (Haag et al, 1999).
d) INCIDENCE: In a review of 47 patients with clozapine intoxication, lethargy developed in 63% (n=27) of the patients with serum clozapine concentrations less than 2000 ng/mL, and in 40% (n=20) of patients with serum clozapine concentrations of 2000 ng/mL or greater (He et al, 2007).
e) According to a retrospective review of 73 cases of clozapine overdose ingestions reported to the Swiss Toxicological Information Centre from 1995 to 2007, somnolence was reported in 41.1% of patients (Kramer et al, 2010).
M) DIZZINESS 1) WITH THERAPEUTIC USE a) Dizziness and vertigo occur in a significant number of patients taking the drug therapeutically (Prod Info CLOZARIL(R) Tablets, 2005).
N) HYPOREFLEXIA 1) WITH POISONING/EXPOSURE a) INCIDENCE: In a review of 47 patients with clozapine intoxication, hyporeflexia developed in 40.7% (n=27) of the patients with serum clozapine concentrations less than 2000 ng/mL, and in 70% (n=20) of patients with serum clozapine concentrations of 2000 ng/mL or greater (He et al, 2007).
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Gastrointestinal |
3.8.2) CLINICAL EFFECTS
A) EXCESSIVE SALIVATION 1) WITH THERAPEUTIC USE a) Excessive salivation may occur during therapeutic use (Wolf & Otten, 1991).
2) WITH POISONING/EXPOSURE a) CASE SERIES: Excessive drooling was reported in 3 children who ingested 50 to 200 mg of clozapine (Mady et al, 1996; Goetz et al, 1993; Schuster et al, 1977).
b) INCIDENCE: In a review of 47 patients with clozapine intoxication, hypersalivation developed in 44.4% (n=27) of the patients with serum clozapine concentrations less than 2000 ng/mL, and in 75% (n=20) of patients with serum clozapine concentrations of 2000 ng/mL or greater (He et al, 2007).
c) According to a retrospective review of 73 cases of clozapine overdose ingestions reported to the Swiss Toxicological Information Centre from 1995 to 2007, hypersalivation was reported in 6.8% of patients (Kramer et al, 2010).
B) PANCREATITIS 1) WITH POISONING/EXPOSURE a) CASE REPORT: Acute pancreatitis, with serum amylase level of 7000 international units/L and lipase level of 459 international units/L, was reported in a 63-year-old woman following an intentional overdose of greater than 1000 mg clozapine (from her son's prescription). No other drug nor alcohol were consumed in the overdose (Jubert, 1994).
C) CONSTIPATION 1) WITH THERAPEUTIC USE a) Constipation is a common adverse effect associated with clozapine therapy (Haller & Binder, 1990a). Decreased bowel activity is an anticholinergic effect and may occur in overdoses (Broich et al, 1998).
D) DIARRHEA 1) WITH THERAPEUTIC USE a) Diarrhea, associated with decreasing lymphocyte counts, was reported in 3 patients between 13 days and 9 months following initiation of clozapine therapy. Rechallenge in 2 cases did not cause further diarrhea. The mechanism for this is unclear (Harvey et al, 1992).
E) DRUG-INDUCED ILEUS 1) WITH POISONING/EXPOSURE a) Decreased gastrointestinal motility resulting in paralytic ileus and gastroenteritis may be an overdose effect due to anticholinergic properties of clozapine. A fatal case has been reported due to clozapine toxicity. The autopsy revealed paralytic ileus of the sigmoid colonic segment, gastroenteritis, and eosinophilia of the ileocecal valve region (Ferslew et al, 1998a).
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Hepatic |
3.9.2) CLINICAL EFFECTS
A) LIVER ENZYMES ABNORMAL 1) WITH THERAPEUTIC USE a) Clozapine, in therapeutic dosages, has been associated with a rise in liver enzymes in 61% of patients (Gaertner et al, 1989).
b) CASE SERIES: Hummer et al (1997) reported 238 patients, treated with either clozapine or haloperidol, were monitored for increased liver enzyme levels. Increased SGPT (greater than twice the normal level) was evident in 37.3% of clozapine treated patients and in 16.6% of haloperidol treated patients (Hummer et al, 1997). Male patients and patients with higher clozapine plasma levels were at a higher risk for increased serum SGPT. 60% of the hepatic enzyme increase remitted within the first 13 weeks of therapy.
c) CASE REPORT: A case of liver toxicity was reported 4 weeks after monotherapy with clozapine (up to 400 mg/day) was started in a 30-year-old patient. Liver enzymes were 3 to 5 times normal values, and had been normal prior to therapy. Clozapine therapy was stopped, and liver function tests returned to normal (Panagiotis, 1999).
2) WITH POISONING/EXPOSURE a) CASE REPORT: Elevations of ALT (161) and AST (377) have been reported following an overdose of 7300 mg in a 24-year-old woman (Roy & Cutten, 1993).
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Genitourinary |
3.10.2) CLINICAL EFFECTS
A) RETENTION OF URINE 1) WITH POISONING/EXPOSURE a) Wolf & Otten (1991) reported one case of urinary retention following clozapine overdose (Wolf & Otten, 1991).
B) RENAL FAILURE SYNDROME 1) WITH POISONING/EXPOSURE a) Overdoses leading to refractory hypotension may result in complications such as renal failure (Novikova et al, 2009; Broich et al, 1998).
b) Renal impairment developed in 8 of 150 cases of clozapine overdose, usually in association with severe hypotension (Sartorius et al, 2002; Anon, 1992).
C) INTERSTITIAL NEPHRITIS 1) WITH THERAPEUTIC USE a) CASE REPORT: A case of clozapine-induced acute interstitial nephritis was reported 11 days after the introduction of clozapine into the therapy regimen of a 38-year-old woman. Renal biopsy showed a mononuclear-cell interstitial infiltrate with frequent eosinophils and prominent granulomatous component. Following cessation of clozapine, the renal failure rapidly resolved (Elias et al, 1999).
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Acid-Base |
3.11.2) CLINICAL EFFECTS
A) ACIDOSIS 1) WITH THERAPEUTIC USE a) Refractory lactic acidosis (blood pH 6.97, bicarbonate 8 mEq/L, and lactate 92.3 mg/dL), with hyperglycemia and heart failure, agranulocytosis and candidiasis, has been reported following several weeks of clozapine therapy (Koren et al, 1997).
2) WITH POISONING/EXPOSURE a) CASE REPORT: Metabolic acidosis, with blood pH of 7.14, lactate of 17.0 mmol/L, and anion gap of 16.4 mmol/L, was reported in a 67-year-old woman who developed seizures following ingestion of 2.5 grams clozapine (Haag et al, 1999).
b) CASE REPORT: Metabolic and respiratory acidosis (pH 6.93, pCO2 34 mmHg, pO2 70 mmHg, HCO3 7 mmol/L, lactate 20 mmol/L) were reported in a 21-year-old woman who intentionally ingested 23 100-mg clozapine tablets (Rotella et al, 2014).
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Hematologic |
3.13.2) CLINICAL EFFECTS
A) GRANULOCYTOPENIC DISORDER 1) WITH THERAPEUTIC USE a) Clozapine has been associated with a significant risk for granulocytopenia during clinical trials at therapeutic dosages (Modai et al, 2000; Povlsen et al, 1985). 1) ONSET: Between the 6th and 18th week of therapy (Bablenis et al, 1989).
b) PROGNOSIS: Many patients recover once clozapine is discontinued. Some deaths have been reported as a result of secondary infections (Bablenis et al, 1989; Lieberman et al, 1988); up to 35% of granulocytopenia cases have resulted in death (Prod Info CLOZARIL(R) Tablets, 2005). c) INCIDENCE: Approximately 1% to 2% of patients receiving clozapine therapy will experience agranulocytosis (Technical Information, 1991). d) PREDISPOSING FACTORS: Concurrent use of medications with a potential to induce bone marrow suppression is NOT recommended (Technical Information, 1991). See manufacturer's package insert for additional information. e) CASE REPORT: Agranulocytosis (absolute neutrophil count of 120 cells/mm(3)) was reported 11 weeks after initiation of clozapine therapy in a 37-year-old man. It was suggested that his Ashkenazic origin may have been a risk factor, due to proposed HLA linkage as a predisposing factor for clozapine- induced agranulocytosis (Koren et al, 1997). 2) WITH POISONING/EXPOSURE a) CASE REPORT: Leukocyte count of 2000 cells/mm(3) was reported in a 63-year-old woman following an overdose of over 1000 milligrams clozapine. Her leukocyte level increased to 5200 cells/mm(3) by the 5th hospital day (Jubert, 1994).
B) LEUKOCYTOSIS 1) WITH THERAPEUTIC USE a) Leukocytosis has occurred following therapeutic doses (Prod Info CLOZARIL(R) Tablets, 2005).
2) WITH POISONING/EXPOSURE a) CASE REPORT: CBC showed a white blood cell count of 15.4 cells per 10(3)/mcL (5.6% lymphocytes, 89.8% neutrophils) about 12 to 24 hours following an ingestion of approximately 3750 mg of clozapine in a 29-year-old man. Five days later, the leukocyte level decreased to 7.5 cells per 10(3)/mcL (31% lymphocytes, 56% neutrophils) (Welber & Nevins, 1995).
b) CASE REPORT: An acute overdose of 7300 mg is reported in a 24-year-old woman on chronic clozapine for 14 months. A marked rise in neutrophil count (25 x 10(9)/L), which returned to normal after 4 days, was reported. The authors state that this suggests agranulocytosis seen after chronic use is not due to direct toxicity (Roy & Cutten, 1993).
c) Neutrophilia has been reported in one patient who overdosed on clozapine. Neutrophil count returned to normal 4 days after overdose (Roy & Cutten, 1993).
C) COAG./BLEEDING TESTS ABNORMAL 1) WITH THERAPEUTIC USE a) CASE REPORT: Kanjolia et al (1997) reported an increased a PPT of 34.2 sec (control 27 sec) as a result of a positive lupus anticoagulant in a 39-year-old man after therapy with clozapine (225 mg/day), Klonopin, Cogentin, and Lopid (Kanjolia et al, 1997). Normal laboratory tests included PT (14 sec), CBC, TT (21 sec), and a negative ANA titer.
D) THROMBOEMBOLUS 1) WITH THERAPEUTIC USE a) Hagg et al (2000) identified 12 cases of thromboembolism associated with clozapine treatment (mean dose of 277 milligrams per day) (Hagg et al, 2000). Six cases of venous thrombosis and 6 cases of pulmonary embolism were reported; Five patients died. No confounding illness was found in any of the patients that would have contributed to thromboembolic disease.
E) EOSINOPHIL COUNT RAISED 1) WITH THERAPEUTIC USE a) Two cases of eosinophilia have been reported in patients treated therapeutically with clozapine; anecdotal knowledge of several more cases exists (Stricker & Tielens, 1991) Tihonen & Paanila 1992).
F) LEUKOPENIA 1) WITH THERAPEUTIC USE a) Neutropenia has been reported in up to 22% of patients therapeutically treated with clozapine (Hummer et al, 1992).
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Dermatologic |
3.14.2) CLINICAL EFFECTS
A) CELLULITIS 1) WITH THERAPEUTIC USE a) CASE REPORT: A 37-year-old man developed right arm cellulitis and progressively increasing eosinophil count after 5 days of clozapine therapy and a left-sided pleural effusion after 12 days. Clozapine was discontinued and he improved with antibiotics. A later trial of clozapine 25 milligrams daily resulted in recurrence of symptoms (Chatterjee & Safferman, 1997).
B) EXCESSIVE SWEATING 1) WITH THERAPEUTIC USE a) A 31-year-old man developed increased sweating with clozapine therapy. Biperiden, titrated to 6 mg/day resulted in prompt cessation of generalized sweating (Richardson et al, 2001).
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Musculoskeletal |
3.15.2) CLINICAL EFFECTS
A) RHABDOMYOLYSIS 1) WITH POISONING/EXPOSURE a) CASE REPORT: A 40-year-old schizophrenic man was found unconscious, with constricted pupils, sinus tachycardia, and twitching of the limbs after ingesting 3 to 4 grams of clozapine. In addition, he developed lung infection and mild rhabdomyolysis (peak CK 7562 U/L 2 days after admission). He recovered fully (Renwick et al, 2000).
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Endocrine |
3.16.2) CLINICAL EFFECTS
A) HYPERGLYCEMIA 1) WITH THERAPEUTIC USE a) Hyperglycemia, glucose intolerance and new-onset diabetes have been reported with clozapine therapy. Clozapine therapy may modify glucose-insulin homeostasis by increasing insulin secretion, either by a direct effect on the pancreatic beta cells or via induction of peripheral insulin resistance, and impairing growth hormone secretion (Koller et al, 2001; Wehring et al, 2000; Rigalleau et al, 2000; Melkersson et al, 1999; Popli et al, 1997).
b) Lethal diabetic ketoacidosis has also been reported in small number of patients receiving long-term clozapine therapy (greater than 1 year). In each case, there was no history of diabetes; ongoing glucose monitoring every 6 months is recommended in patients treated with clozapine (Wehring et al, 2003).
c) CASE REPORT: Severe hyperglycemia (blood glucose 585 mg/dL) was reported in a 37-year-old man after 11 weeks of clozapine therapy. This was accompanied with refractory lactic acidosis, agranulocytosis, fever, candidiasis and fatal myocardial failure (Koren et al, 1997).
d) CASE SERIES: Popli et al (1997) reported 4 adults who developed increasing glucose intolerance following the initiation of clozapine therapy (Popli et al, 1997). Two of the patients developed severe diabetic ketoacidosis. The other 2 patients developed an exacerbation of their preexisting, well-controlled, diabetes mellitus within 2 weeks of initiation of clozapine therapy. The authors, in their limited experience (treated 147 patients over 10 years), noted a 2.7% incidence of clinically significant changes in glucose tolerance during clozapine therapy.
e) CASE REPORT: A 33-year-old man without past or family history of diabetes mellitus developed diabetic ketoacidosis after taking clozapine (50 mg twice daily) for eight months (Avram et al, 2001).
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Immunologic |
3.19.2) CLINICAL EFFECTS
A) INCREASED IMMUNOGLOBULIN 1) WITH THERAPEUTIC USE a) A positive lupus anticoagulant, with resultant increased aPTT, was reported in an adult male taking clozapine (225 mg/day), Klonopin, Cogentin and Lopid. The etiologic relationship of clozapine to the lupus anticoagulant is probable (Kanjolia et al, 1997).
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Reproductive |
3.20.1) SUMMARY
A) Clozapine is classified as FDA pregnancy category B and is excreted in breast milk. In general, limited data from case reports of clozapine use during pregnancy and during lactation demonstrate no long-term effects to the infant. Third-trimester antipsychotic drug exposure has been associated with extrapyramidal and/or withdrawal symptoms in neonates. Animal studies indicate this agent is excreted in breast milk and may affect the nursing child.
3.20.2) TERATOGENICITY
A) DEVELOPMENTAL EFFECTS 1) In a study of 58 infants, mean adaptive behavior scores, using the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III), at 2 and 6 months of age were significantly lower in infants who were exposed to clozapine in utero compared with infants who were exposed to other atypical antipsychotics (ie, risperidone, olanzapine, or quetiapine). More infants who were exposed to clozapine had delayed development per the adaptive behavior subscale score at 2 and 6 months of age compared with infants who were exposed to other atypical antipsychotics. However, these differences disappeared by 12 months of age, and no differences in cognitive, language, motor, social, and emotional scores were observed between the 2 groups at 2, 6, and 12 months of age. More infants exposed to clozapine (75.8%) had disturbed sleep and labile state at 2 months of age compared with infants exposed to other atypical antipsychotics (26.7%), but these differences disappeared by 6 months of age. While the Apgar score at 1 minute was higher for the clozapine group compared with other atypical antipsychotic group, the Apgar scores at 5 minutes after birth was not significantly different between the 2 groups. The percentage of infants with low birth weight (less than 2.5 kg), and the weight and height at birth, 2, 6, and 12 months of age were also not significantly different (Shao et al, 2015).
B) FETAL/NEONATAL ADVERSE REACTION 1) In 2 separate case reports, serious and irreversible complications were reported to infants exposed to clozapine (150 to 450 mg/day) throughout pregnancy. In both cases, the patient developed gestational diabetes mellitus after treatment with clozapine. Adverse effects in the first case included fetal dysrhythmia, encephalopathy, seizures, floppy infant syndrome, coma, neurodevelopmental delays, left testicle agenesia, and hernia of the white linea. In the second case, adverse effects included neonatal hypoxic respiratory failure, neurodevelopmental delays, craniosynostosis, hypertelorism, hypospadias, and umbilical hernia. Additional cases resulting in shoulder dystocia have also been reported (Gentile, 2014).
2) A 30-year-old woman who was being treated with clozapine throughout her pregnancy delivered a female at 39 weeks gestation with abnormal findings including a cephalhematoma, hyperpigmentation folds, and a coccygeal dimple, all of which were resolving within 2 days of delivery. At 8 days old, the infant was reported to have a seizure and developed gastroenteritis, both of which resolved. At 2 years of age, the child was reported to be healthy with no physical problems (Stoner et al, 1997).
3) A 32-year-old woman, taking clozapine throughout her pregnancy, delivered a female at 40 weeks gestational age with no reported abnormalities except a low-grade fever which resolved prior to hospital discharge (Stoner et al, 1997).
4) A 16-year-old pregnant adolescent presented comatose and hypoxic following a suspected overdose ingestion of approximately 10 grams of clozapine. At the time of presentation, an ultrasound revealed a fetus of 32 weeks gestation with a normal amniotic fluid index and a heart rate of 145 bpm. Approximately 28 hours post-presentation, the patient became hypotensive and a cardiotocogram indicated low variability of the fetal heart rate with an absence of accelerations for 90 minutes, necessitating an immediate delivery by cesarean section. After delivery, the infant had minimal acidosis, abdominal distention and absent bowel sounds that was diagnosed as delayed peristalsis due to the anticholinergic effects of clozapine. With supportive care, the infant completely recovered; however, the mother's condition continued to deteriorate with development of respiratory distress syndrome, worsening hypotension, and renal failure, and she subsequently died 42 days post-admission (Novikova et al, 2009).
5) A 30-year-old woman who was being treated with clozapine 100 mg/day throughout pregnancy delivered a healthy female at term. The patient was maintained on the same clozapine dose while breastfeeding her infant until 1 year of age The infant achieved normal developmental milestones, with the exception of speech (Mendhekar, 2007).
C) LACK OF EFFECT 1) A woman was treated with clozapine 200 mg/day throughout pregnancy. A healthy infant was delivered at term with no abnormalities. In a subsequent pregnancy one and a half years later, the patient was still being treated with clozapine 200 mg/day. Her second child was delivered at term with no abnormalities. (Duran et al, 2008).
2) A woman was treated with clozapine 200 mg/day throughout pregnancy. She delivered healthy twin infants at term with no abnormalities (Duran et al, 2008).
D) ANIMAL STUDIES 1) There are no well-controlled studies of clozapine use during pregnancy. However, studies in animals at doses up to 0.9 times the maximum recommended human dose did not result in teratogenicity (Prod Info CLOZARIL(R) oral tablets, 2014a; Prod Info VERSACLOZ(TM) oral suspension, 2013a; Prod Info FAZACLO(R) oral disintegrating tablets, 2013).
3.20.3) EFFECTS IN PREGNANCY
A) PREGNANCY CATEGORY 1) The manufacturer has classified clozapine as FDA pregnancy category B (Prod Info CLOZARIL(R) oral tablets, 2014a; Prod Info VERSACLOZ(TM) oral suspension, 2013a)
2) Exercise caution when administering to a pregnant woman and use only when clearly needed (Prod Info CLOZARIL(R) oral tablets, 2014a; Prod Info VERSACLOZ(TM) oral suspension, 2013a).
B) FETAL/NEONATAL ADVERSE REACTION 1) Maternal use of antipsychotic drugs during the third trimester of pregnancy has been associated with an increased risk of neonatal extrapyramidal and/or withdrawal symptoms (eg, agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder) following delivery. Severity of these adverse effects have ranged from cases that are self-limiting to cases that required prolonged periods of hospitalization and ICU care (Prod Info CLOZARIL(R) oral tablets, 2014a; Prod Info VERSACLOZ(TM) oral suspension, 2013a).
C) PLACENTAL TRANSFER 1) A woman was treated with clozapine 100 mg/day until the last 9 weeks of pregnancy at which time, the dose was decreased to 50 mg/day. A healthy female was delivered. The infant had normal psychomotor development up to 6 months of age. Maternal clozapine plasma levels were measured monthly during pregnancy, the day of delivery, one day after delivery when the mother began lactating, and one week after delivery. While being treated with 100 mg/day, the mother's clozapine plasma levels were 38 to 55 ng/mL; at 50 mg/day, her level was 15.4 ng/mL. When the infant was delivered, the maternal, amniotic, and fetal plasma levels were 14.1 ng/mL, 11.6 ng/mL, 27 ng/mL, respectively. The accumulation of drug in the fetal plasma can be explained by the higher concentration of albumin in fetal blood which binds clozapine, an acidic, lipophilic drug, and by ion trapping in the fetal compartment which results in a pH gradient in the fetus (Barnas et al, 1994).
D) ANIMAL STUDIES 1) There are no well-controlled studies of clozapine use during pregnancy. However, studies in rats and rabbits at doses 2 to 4 times the normal human dose did not result in teratogenicity or reduced fertility (Prod Info CLOZARIL(R) oral tablets, 2010).
3.20.4) EFFECTS DURING BREAST-FEEDING
A) BREAST MILK 1) Clozapine is present in human milk. Because of the potential for adverse reactions in the nursing infant, either discontinue nursing or discontinue treatment with clozapine (Prod Info CLOZARIL(R) oral tablets, 2014a; Prod Info VERSACLOZ(TM) oral suspension, 2013a).
2) A woman was treated with clozapine 100 mg/day until the last 9 weeks of pregnancy at which time, the dose was decreased to 50 mg/day. A healthy female was delivered. The infant had normal psychomotor development up to 6 months of age. Maternal clozapine plasma levels were measured monthly during pregnancy, the day of delivery, one day after delivery when the mother began lactating, and one week after delivery. While being treated with 100 mg/day, the mother's clozapine plasma levels were 38 to 55 ng/mL; at 50 mg/day, her level was 15.4 ng/mL. When the infant was delivered, the maternal, amniotic, and fetal plasma levels were 14.1 ng/mL, 11.6 ng/mL, 27 ng/mL, respectively. The day after delivery, the concentration of clozapine in the maternal plasma was 14.7 ng/mL and the first portion of the breast milk contained 63.5 ng/mL. At one week postdelivery, the mother was taking clozapine 100 mg/day; the breast milk concentration of drug measured 115.6 ng/mL, and plasma level measured 41.4 ng/mL (Barnas et al, 1994a).
3) A 30-year-old woman who was being treated with clozapine 100 mg/day throughout pregnancy delivered a healthy female at term. The patient was maintained on the same clozapine dose while breastfeeding her infant until 1 year of age The infant achieved normal developmental milestones, with the exception of speech. At the age of 1 year, she began using consonants. At 18 months, she began using combined syllables. She spoke only 6 to 8 words at 2 years of age and would speak only 12 to 15 words until 3 years of age. She was also stuttering. At 4 years of age, she developed speaking skills with small sentences of 2 or 3 words and she could repeat small sentences. She was able to speak fluently by the end of 5 years. Local pathology was ruled out and audiometric assessment was within normal limits. The mother-child relationship was not impaired and there was no evidence of familial phonological disorder or a bilingual environment (Mendhekar, 2007).
3.20.5) FERTILITY
A) ANIMAL STUDIES 1) Fertility of male and female animals exposed to clozapine (at doses up to 0.4 times the maximum recommended human dose of 900 mg/day on a mg/m2 body surface area basis) 70 and 14 days, respectively, before mating was not adversely affected (Prod Info CLOZARIL(R) oral tablets, 2014a; Prod Info VERSACLOZ(TM) oral suspension, 2013a).
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Carcinogenicity |
3.21.2) SUMMARY/HUMAN
A) At the time of this review, the manufacturer did not report any carcinogenic potential.
3.21.4) ANIMAL STUDIES
A) LACK OF EFFECT 1) Long-term studies in mice and rats at respective doses of 0.3 and 0.4 times the maximum recommended human dose of 900 mg/day on a mg/m(2) body surface area basis did not demonstrate carcinogenicity (Prod Info FAZACLO(R) oral disintegrating tablets, 2013; Prod Info CLOZARIL(R) oral tablets, 2013).
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Genotoxicity |
A) There was no evidence of genotoxicity or mutagenicity with the following tests: in vivo micronucleus assay in mice, in vitro unscheduled DNA synthesis in rat hepatocytes, the in vitro mammalian V79 in Chinese hamster cells, or the bacterial Ames test (Prod Info FAZACLO(R) oral disintegrating tablets, 2013; Prod Info CLOZARIL(R) oral tablets, 2013).
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