Clozapine

1) ] . 3) ] .

Table 2:

Clozapine ODT Dosage Modifications Based on ANC Results and Frequency of ANC Testing in Patients with Benign Ethnic Neutropenia Benign Ethnic Neutropenia (BEN) is also known as Duffy-null associated neutrophil count. , patient had neutropenia which required dosage interruption and now their ANC (≥ 1000/µL and ≥ the patient’s ANC baseline prior to treatment) for: < 30 days, continue previous ANC testing frequency ≥ 30 days, obtain ANC tests according to the frequency for patients with BEN who initiate treatment Neutropenia in Patients with BEN (ANC level between 500 to 999/µL) Confirm all initial reports of ANC less than 1500/µL with a repeat ANC measurement within 24 hours Recommend hematology consultation No dosage modification; continue treatment Three times weekly Once ANC ≥ 1000/µL and ≥ the patient’s ANC baseline, obtain ANC tests weekly for 4 weeks If ANC ≥ 1000/µL and ≥ the patient’s baseline after monitoring for 4 weeks, return to the patient’s last Normal ANC Range testing frequency for patients with BEN.

4) ] . Normal or mild neutropenia, reduce the dosage gradually over a period of 1 to 2 weeks, and continue monitoring ANC levels until their ANC is ≥ 1500/µL. 5) ] . ANC within their normal range of ANC reduce the dosage gradually over a period of 1 to 2 weeks.

, profuse sweating, headache, nausea, vomiting, diarrhea). 2) ] . If one day’s dosage is missed, resume Clozapine ODT treatment at 40% to 50% of the previous dosage. If two days of dosing is missed, resume Clozapine ODT treatment at approximately 25% of the previous dosage.

5 mg once or twice daily. If this dosage is well-tolerated, may increase the dosage to the previous dosage more quickly than recommended than for initial Clozapine ODT treatment. 7 Dosage Modifications for Drug Interactions See Table 3 for recommended dosage modifications to reduce the risk of Clozapine ODT-associated adverse reactions or reduce the risk of lower effectiveness [see Drug Interactions (7) ] .

Table 3:

Clozapine ODT Dosage Modifications for Drug Interactions Strong CYP1A2 Inhibitors Administer one third of the Clozapine ODT dosage. Moderate or Weak CYP1A2 Inhibitors Consider reducing the Clozapine ODT dosage if necessary. CYP2D6 or CYP3A4 Inhibitors Strong CYP3A4 Inducers Concomitant use is not recommended.

However, if concomitant use is necessary, it may be necessary to increase the Clozapine ODT dosage. Monitor for decreased effectiveness. Moderate or weak CYP1A2 or CYP3A4 Inducers Consider increasing the Clozapine ODT dosage if necessary.

7) ] .

These rates are not adjusted for duration of exposure.

Table 10:

Adverse Reactions (≥ 2%) Reported in Clozapine-treated Patients (N = 842) Across all Clozapine Studies (excluding the 2 year InterSePT™ Study) Body System Adverse Reaction Clozapine N = 842 Percentage of Patients Central Nervous System Drowsiness/Sedation 39 Dizziness/Vertigo 19 Headache 7 Tremor 6 Syncope 6 Disturbed Sleep/Nightmares 4 Restlessness 4 Hypokinesia/Akinesia 4 Agitation 4 Seizures (convulsions) 3 † Rigidity 3 Akathisia 3 Confusion 3 Fatigue 2 Insomnia 2 Cardiovascular Tachycardia 25 † Hypotension 9 Hypertension 4 Gastrointestinal Constipation 14 Nausea 5 Abdominal Discomfort/Heartburn 4 Nausea/Vomiting 3 Vomiting 3 Diarrhea 2 Urogenital Urinary abnormalities 2 Autonomic Nervous System Salivation 31 Sweating 6 Dry mouth 6 Visual disturbances 5 Skin Rash 2 Hemic/Lymphatic Leukopenia/Decreased WBC/Neutropenia 3 Miscellaneous Fever 5 Weight Gain 4 † Rate based on population of approximately 1700 exposed during premarket clinical evaluation of clozapine.

Table 11 summarizes the most commonly reported adverse reactions (≥ 10% of the clozapine or olanzapine group) in the InterSePT™ Study. This was an adequate and well-controlled, two-year study evaluating the efficacy of clozapine relative to olanzapine in reducing the risk of suicidal behavior in patients with schizophrenia or schizoaffective disorder.

The rates are not adjusted for duration of exposure.

Table 11:

Incidence of Adverse Reactions in Patients Treated with Clozapine or Olanzapine in the InterSePT™ Study (≥ 10% in the clozapine or olanzapine group) Adverse Reactions Clozapine N = 479 % Reporting Olanzapine N = 477 % Reporting Salivary hypersecretion 48% 6% Somnolence 46% 25% Weight increased 31% 56% Dizziness (excluding vertigo) 27% 12% Constipation 25% 10% Insomnia 20% 33% Nausea 17% 10% Vomiting 17% 9% Dyspepsia 14% 8% Dystonia Class effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment.

Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs.

An elevated risk of acute dystonia is observed in males and younger age groups. 2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of clozapine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Central Nervous System Delirium, EEG abnormal, myoclonus, paresthesia, possible cataplexy, status epilepticus, obsessive compulsive symptoms, and post-discontinuation cholinergic rebound adverse reactions. Cardiovascular System Atrial or ventricular fibrillation, ventricular tachycardia, QT interval prolongation, Torsades de Pointes, myocardial infarction, cardiac arrest, pericarditis, and periorbital edema.

Endocrine System Pseudopheochromocytoma. Gastrointestinal System Acute pancreatitis, dysphagia, salivary gland swelling, megacolon, fecal incontinence, and intestinal ischemia, infarction, perforation, ulceration or necrosis. Hepatobiliary System Cholestasis, hepatitis, jaundice, 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 System Acute interstitial nephritis, nocturnal enuresis, priapism, and renal failure. Skin and Subcutaneous Tissue Disorders Hypersensitivity reactions: photosensitivity, vasculitis, erythema multiforme, skin pigmentation disorder, and Stevens-Johnson Syndrome.

Musculoskeletal System and Connective Tissue Disorders Myasthenic syndrome, rhabdomyolysis, and systemic lupus erythematosus. Respiratory System Aspiration, pleural effusion, pneumonia, lower respiratory tract infection. Hemic and Lymphatic System Mild, moderate, or severe leukopenia, agranulocytosis, granulocytopenia, WBC decreased, deep vein thrombosis, elevated hemoglobin/hematocrit, erythrocyte sedimentation rate (ESR) increased, sepsis, thrombocytosis, and thrombocytopenia.

Vision Disorders Narrow-angle glaucoma. Miscellaneous Creatine phosphokinase elevation, hyperuricemia, hyponatremia, and weight loss.

1 ) Interference with Cognitive and Motor Performance: Advise caution when operating machinery, including automobiles. 2) ] and is associated with an increased risk of serious and potentially fatal infections. Severe neutropenia occurred in a small percentage of clozapine-treated patients.

The risk of severe neutropenia appears greatest during the first 18 weeks of Clozapine ODT treatment. The mechanism by which Clozapine ODT causes neutropenia is unknown. Neutropenia is not dose-dependent. Consider a hematology consultation before initiating Clozapine ODT treatment or during treatment.

ANC Monitoring and Dosage Modifications Prior to initiating Clozapine ODT treatment, obtain a baseline ANC. Clozapine ODT initiation is not recommended in patients with a baseline ANC less than 1500/µL. Throughout Clozapine ODT treatment, regularly monitor ANC.

4) ] . ANC Monitoring and Dosage Modification in Patients with Benign Ethnic Neutropenia Patients with Benign Ethnic Neutropenia (BEN) (also known as Duffy-null associated neutrophil count) generally have lower baseline neutrophil counts but they are not at higher risk for developing infections, and they are not at increased risk for developing Clozapine ODT-induced neutropenia.

For patients with documented BEN, obtain at least two baseline ANC levels prior to Clozapine ODT initiation. Clozapine ODT initiation is not recommended in patients with BEN with an ANC less than 1000/µL. There are different ANC dosage modification recommendations in Clozapine ODT-treated patients with BEN due to their lower baseline ANC levels.

4) ] . 5 °C) or greater and obtain an ANC level. If the ANC is less than 1000/µL in patients without BEN, initiate appropriate workup and treatment for infection. 3) ] . 13) for fever. Restarting Clozapine ODT in Patients Who Recovered from Severe Neutropenia Generally, do not rechallenge patients with Clozapine ODT in those who experienced severe neutropenia.

, patients who have no treatment options other than Clozapine ODT). Concomitant Use of Clozapine ODT with Other Drugs Known to Cause Neutropenia If Clozapine ODT is used concomitantly with another drug known to cause neutropenia, consider more frequently ANC monitoring than the recommendations provided in Tables 1 and 2.

2 Orthostatic Hypotension, Bradycardia, and Syncope Hypotension, bradycardia, syncope, and cardiac arrest have occurred with clozapine treatment. The risk is highest during the initial titration period, particularly with rapid dose-escalation.

5 mg. These reactions can be fatal. The syndrome is consistent with neurally mediated reflex bradycardia (NMRB). 5 mg once daily or twice daily. The 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 the end of 2 weeks.

Subsequently, the dose can be increased weekly or twice weekly, in increments of up to 100 mg. The maximum Clozapine ODT dosage is 900 mg per day. 2) ] . Consider reducing the dose if hypotension occurs. When restarting Clozapine ODT in patients who have had even a brief interruption in treatment with Clozapine ODT, the dosage must be reduced.

6) ] . , concomitant use of antihypertensives, dehydration and hypovolemia). 3 Falls Clozapine ODT may cause somnolence, postural hypotension, and 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 treatment. 5%).

The risk of seizure is dose-related. 5 mg), titrate slowly, and use divided dosing. , head trauma or other CNS pathology, use of medications that lower the seizure threshold, or alcohol abuse). , driving an automobile, operating complex machinery, swimming, climbing).

5 Myocarditis, Pericarditis, Cardiomyopathy and Mitral Valve Incompetence Myocarditis, pericarditis, and cardiomyopathy have occurred with the use of clozapine. These reactions can be fatal. Discontinue Clozapine ODT and obtain a cardiac evaluation upon suspicion of myocarditis, pericarditis, or cardiomyopathy.

Generally, patients with a history of clozapine-associated myocarditis, pericarditis or cardiomyopathy should not be rechallenged with Clozapine ODT. However, if the benefit of Clozapine ODT treatment is judged to outweigh the potential risks of recurrence, the clinician may consider rechallenge with Clozapine ODT in consultation with a cardiologist.

Consider the possibility of myocarditis or cardiomyopathy in patients receiving Clozapine ODT 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 and pericarditis most frequently present within the first two months of clozapine treatment. Symptoms of cardiomyopathy generally occur later than clozapine-associated myocarditis and usually after 8 weeks of treatment. However, myocarditis, pericarditis, and cardiomyopathy can occur at any period during treatment with Clozapine ODT.

In patients who are diagnosed with cardiomyopathy while taking clozapine, mitral valve incompetence has been reported. 6 Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.

7 times the risk of death in placebo-treated patients. 6% in the placebo group. , pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality in this population.

The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Clozapine ODT is not approved for the treatment of patients with dementia-related psychosis [see] .

7 Gastrointestinal Hypomotility with Severe Complications Severe gastrointestinal adverse reactions have occurred with the use of clozapine, primarily due to its potent anticholinergic effects and resulting gastrointestinal hypomotility.

In post marketing experience, reported effects range from constipation to paralytic ileus. 2) ] . These reactions have resulted in hospitalization, surgery, and death. 1) ] . Prior to initiating Clozapine ODT, screen for constipation and treat as necessary.

Subjective symptoms of constipation may not accurately reflect the degree of gastrointestinal hypomotility in Clozapine ODT-treated patients. , nausea, vomiting, abdominal distension, abdominal pain). If constipation or gastrointestinal hypomotility are identified, monitor closely and treat promptly with appropriate laxatives, as necessary, to prevent severe complications.

Consider prophylactic laxatives in high risk patients. 8 Eosinophilia Eosinophilia, defined as a blood eosinophil count of greater than 700/μL, has occurred with clozapine treatment. In clinical trials, approximately 1% of patients developed eosinophilia.

Clozapine-related eosinophilia usually occurs during the first month of treatment. In some patients, it has been associated with myocarditis, pancreatitis, hepatitis, colitis, and nephritis. Such organ involvement could be consistent with a drug reaction with eosinophilia and systemic symptoms syndrome (DRESS), also known as drug induced hypersensitivity syndrome (DIHS).

If eosinophilia develops during Clozapine ODT treatment, evaluate promptly for signs and symptoms of systemic reactions, such as rash or other allergic symptoms, myocarditis, or other organ-specific disease associated with eosinophilia.

If clozapine-related systemic disease is suspected, discontinue Clozapine ODT immediately. , asthma, allergies, collagen vascular disease, parasitic infections, and specific neoplasms), treat the underlying cause and continue Clozapine ODT.

Clozapine-related eosinophilia has also occurred in the absence of organ involvement and can resolve without intervention. There are reports of successful rechallenge after discontinuation of Clozapine ODT, without recurrence of eosinophilia.

In the absence of organ involvement, continue Clozapine ODT under careful monitoring. If the total eosinophil count continues to increase over several weeks in the absence of systemic disease, the decision to interrupt Clozapine ODT therapy and rechallenge after the eosinophil count decreases should be based on the overall clinical assessment, in consultation with an internist or hematologist.

9 QT Interval Prolongation QT prolongation, Torsades de Pointes and other life-threatening ventricular arrhythmias, cardiac arrest, and sudden death have occurred with clozapine treatment. When prescribing Clozapine ODT, consider the presence of additional risk factors for QT prolongation and serious cardiovascular reactions.

Conditions that increase these risks include the following: history of QT prolongation, long QT syndrome, family history of long QT syndrome or sudden cardiac death, significant cardiac arrhythmia, recent myocardial infarction, uncompensated heart failure, treatment with other medications that cause QT prolongation, treatment with medications that inhibit the metabolism of clozapine, and electrolyte abnormalities.

Prior to initiating treatment with Clozapine ODT, perform a careful physical examination, medical history, and concomitant medication history. Consider obtaining a baseline ECG and serum chemistry panel. Correct electrolyte abnormalities.

Discontinue Clozapine ODT if the QTc interval exceeds 500 msec. , syncope, presyncope, dizziness, or palpitations), obtain a cardiac evaluation and discontinue Clozapine ODT. Use caution when administering concomitant medications that prolong the QT interval or inhibit the metabolism of clozapine.

, pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus). Clozapine is primarily metabolized by CYP isoenzymes 1A2, 2D6, and 3A4. 3) ] . Hypokalemia and hypomagnesemia increase the risk of QT prolongation.

Hypokalemia can result from diuretic therapy, diarrhea, and other causes. Use caution when treating patients at risk for significant electrolyte disturbance, particularly hypokalemia. Obtain baseline measurements of serum potassium and magnesium levels, and periodically monitor electrolytes.

Correct electrolyte abnormalities before initiating treatment with Clozapine ODT. 10 Metabolic Changes Atypical antipsychotic drugs, including clozapine, have been associated with metabolic changes that can increase cardiovascular and cerebrovascular risk.

These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While atypical antipsychotic drugs may produce some metabolic changes, each drug in the class has its own specific risk profile. Hyperglycemia and Diabetes Mellitus Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including clozapine.

Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population.

Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse reactions is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent, hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics.

Precise risk estimates for hyperglycemia-related adverse reactions in patients treated with atypical antipsychotics are not available. Patients with an established diagnosis of diabetes mellitus who are started on Clozapine ODT should be monitored regularly for worsening of glucose control.

, obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness.

Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.

In a pooled data analysis of 8 studies in adult subjects with schizophrenia, the mean changes in fasting glucose concentration in the clozapine and chlorpromazine groups were +11 mg/dL and +4 mg/dL, respectively. A higher proportion of the clozapine group demonstrated categorical increases from baseline in fasting glucose concentrations, compared to the chlorpromazine group (Table 4).

The clozapine doses were 100 to 900 mg per day (mean modal dose: 512 mg per day). The maximum chlorpromazine dose was 1800 mg per day (mean modal dose: 1029 mg per day). The median duration of exposure was 42 days for clozapine and chlorpromazine.

Table 4:

Categorical Changes in Fasting Glucose Level in Studies in Adult Subjects with Schizophrenia Laboratory Parameter Category Change (at least once) from Baseline Treatment Arm N n (%) Fasting Glucose Normal (< 100 mg/dL) to High (≥ 126 mg/dL) Clozapine 198 53 (27) Chlorpromazine 135 14 (10) Borderline (100 to 125 mg/dL) to High (≥ 126 mg/dL) Clozapine 57 24 (42) Chlorpromazine 43 12 (28) Dyslipidemia Undesirable alterations in lipids have occurred in patients treated with atypical antipsychotics, including clozapine.

Clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using Clozapine ODT, is recommended. In a pooled data analysis of 10 studies in adult subjects with schizophrenia, clozapine treatment was associated with increases in serum total cholesterol.

No data were collected on LDL and HDL cholesterol. The mean increase in total cholesterol was 13 mg/dL in the clozapine group and 15 mg/dL in the chlorpromazine group. In a pooled data analysis of 2 studies in adult subjects with schizophrenia, clozapine treatment was associated with increases in fasting serum triglyceride.

The mean increase in fasting triglyceride was 71 mg/dL (54%) in the clozapine group and 39 mg/dL (35%) in the chlorpromazine group (Table 5). In addition, clozapine treatment was associated with categorical increases in serum total cholesterol and triglyceride, as illustrated in Table 6.

The proportion of patients with categorical increases in total cholesterol or fasting triglyceride increased with the duration of exposure. The median duration of clozapine and chlorpromazine exposure was 45 days and 38 days, respectively.

The clozapine dose range was 100 mg to 900 mg daily; the maximum chlorpromazine dose was 1800 mg daily.

Table 5:

Mean Changes in Total Cholesterol and Triglyceride Concentration in Studies in Adult Subjects with Schizophrenia Treatment Arm Baseline Total Cholesterol Concentration (mg/dL) Change from Baseline mg/dL (%) Clozapine (N = 334) 184 +13 (7) Chlorpromazine (N = 185) 182 +15 (8) Baseline Triglyceride Concentration (mg/dL) Change from Baseline mg/dL (%) Clozapine (N = 6) 130 +71 (54) Chlorpromazine (N = 7) 110 +39 (35) Table 6: Categorical Changes in Lipid Concentrations in Studies in Adult Subjects with Schizophrenia Laboratory Parameter Category Change (at least once) from Baseline Treatment Arm N n (%) Total Cholesterol (random or fasting) Increase by ≥ 40 mg/dL Clozapine 334 111 (33) Chlorpromazine 185 46 (25) Normal (< 200 mg/dL) to High (≥ 240 mg/dL) Clozapine 222 18 (8) Chlorpromazine 132 3 (2) Borderline (200 to 239 mg/dL) to High (≥ 240 mg/dL) Clozapine 79 30 (38) Chlorpromazine 34 14 (41) Triglycerides (fasting) Increase by ≥ 50 mg/dL Clozapine 6 3 (50) Chlorpromazine 7 3 (43) Normal (< 150 mg/dL) to High (≥ 200 mg/dL) Clozapine 4 0 (0) Chlorpromazine 6 2 (33) Borderline (≥ 150 mg/dL and < 200 mg/dL) to High (≥ 200 mg/dL) Clozapine 1 1 (100) Chlorpromazine 1 0 (0) Weight Gain Weight gain has occurred with the use of antipsychotics, including clozapine.

Monitor weight during treatment with Clozapine ODT. Table 7 summarizes the data on weight gain by the duration of exposure pooled from 11 studies with clozapine and active comparators. The median duration of exposure was 609, 728, and 42 days, in the clozapine, olanzapine, and chlorpromazine group, respectively.

7 0 0 Table 8 summarizes pooled data from 11 studies in adult subjects with schizophrenia demonstrating weight gain ≥ 7% of body weight relative to baseline. The median duration of exposure was 609, 728, and 42 days, in the clozapine, olanzapine, and chlorpromazine group, respectively.

11 Neuroleptic Malignant Syndrome Antipsychotic drugs including Clozapine ODT can cause a potentially fatal symptom complex referred to as Neuroleptic Malignant Syndrome (NMS). Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias).

Associated findings can include elevated creatine phosphokinase (CPK), myoglobinuria, rhabdomyolysis, and acute renal failure. The diagnostic evaluation of patients with this syndrome is complicated. , severe neutropenia, infection, heat stroke, primary CNS pathology, central anticholinergic toxicity, extrapyramidal symptoms, and drug fever).

The management of NMS should include (1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, (2) intensive symptomatic treatment and medical monitoring, and (3) treatment of co-morbid medical conditions.

There is no general agreement about specific pharmacological treatments for NMS. If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered.

NMS can recur. Monitor closely if restarting treatment with antipsychotics. NMS has occurred with clozapine monotherapy and with concomitant CNS-active medications, including lithium. 2) ] . Monitor for the 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 ODT. 13 Fever During clozapine therapy, patients have experienced transient, clozapine-related fever.

The peak incidence is within the first 3 weeks of treatment. While this fever is generally benign and self-limited, it may necessitate discontinuing treatment. The fever can be associated with an increase or decrease in WBC count. 1) ] .

11) ] . 14 Pulmonary Embolism Pulmonary embolism and deep vein thrombosis have occurred in patients treated with clozapine. Consider the possibility of pulmonary embolism in patients who present with deep vein thrombosis, acute dyspnea, chest pain, or with other respiratory signs and symptoms.

Whether pulmonary embolus and deep vein thrombosis can be attributed to clozapine or some characteristic(s) of patients is not clear. 15 Anticholinergic Toxicity Clozapine ODT has potent anticholinergic effects. Treatment with Clozapine ODT can result in CNS and peripheral anticholinergic toxicity, especially at higher dosages, or in overdose situations [see Overdosage (10) ] .

Use with caution in patients with a current diagnosis or prior history of constipation, urinary retention, clinically significant prostatic hypertrophy, or other conditions in which anticholinergic effects can lead to significant adverse reactions.

1) ] . 16 Interference with Cognitive and Motor Performance Clozapine ODT can cause sedation and impairment of cognitive and motor performance. Caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain that Clozapine ODT does not affect them adversely.

These reactions may be dose-related. Consider reducing the dose if they occur. 17 Tardive Dyskinesia Tardive dyskinesia (TD) has occurred in patients treated with antipsychotic drugs, including clozapine. The syndrome consists of potentially irreversible, involuntary, dyskinetic movements.

The 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 Clozapine ODT in a manner that is most likely to minimize the risk of developing TD. Use the lowest effective dose and the shortest duration necessary to control symptoms. Periodically assess the need for continued treatment.

Consider discontinuing treatment if TD occurs. However, some patients may require treatment with Clozapine ODT despite the presence of the syndrome. TD may remit partially or completely if treatment is discontinued. Antipsychotic treatment, itself, may suppress (or partially suppress) the signs and symptoms, and it has the potential to mask the underlying process.

The effect of symptom suppression on the long-term course of TD is unknown. 18 Patients with Phenylketonuria Phenylketonuric patients should be informed that Clozapine ODT contain phenylalanine (a component of aspartame). 90 mg phenylalanine.

59 mg phenylalanine. 38 mg phenylalanine. 18 mg phenylalanine. , stroke, transient ischemic attack), including fatalities. The mechanism for this increased risk is not known. An increased risk cannot be excluded for Clozapine ODT or other antipsychotics or other patient populations.

Clozapine ODT should be used with caution in patients with risk factors for cerebrovascular adverse reactions. 1) ] , monitor carefully for the recurrence of psychotic symptoms and adverse reactions related to cholinergic rebound, such as profuse sweating, headache, nausea, vomiting, and diarrhea.