Clozapine Side Effects

Brand Names: FazaClo, Clozaril

Please note - some side effects for Clozapine may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA at http://www.fda.gov/medwatch/ or 1-800-FDA-1088 (1-800-332-1088).

Side Effects of Clozapine - for the Consumer

Clozapine

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Clozapine:

Constipation; dizziness; drowsiness; dry mouth; headache; heartburn; increased sweating or saliva production; lightheadedness when you stand up; nausea; strange dreams; trouble sleeping; weight gain.

Severe allergic reactions (rash; hives; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); agitation; calf pain or tenderness; chest pain; confusion; dark urine; decreased coordination; fainting; fast or irregular heartbeat; fever, chills, or sore throat; increased hunger, thirst, or urination; infection; involuntary movements of the tongue, face, mouth, or jaw (eg, tongue sticking out, puffing of cheeks, mouth puckering, chewing movements); loss of appetite; numbness of an arm or leg; rapid breathing; restlessness; seizures; severe headache, dizziness, or vomiting; severe or persistent nausea or constipation; severe stomach pain; shortness of breath; stiff muscles; sudden, unusual weight gain; swelling of the hands, ankles, or feet; tremor; trouble swallowing; uncontrolled muscle movements; unusual mental or mood changes; unusual tiredness or weakness; vision changes; vomiting; yellowing of the skin or eyes.

Clozapine Orally Disintegrating Tablets

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Clozapine Orally Disintegrating Tablets:

Constipation; dizziness; drowsiness; dry mouth; headache; heartburn; increased sweating or saliva production; lightheadedness when you stand up; nausea; strange dreams; trouble sleeping; weight gain.

Severe allergic reactions (rash; hives; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); agitation; calf pain or tenderness; chest pain; confusion; dark urine; decreased coordination; fainting; fast or irregular heartbeat; fever, chills, or sore throat; increased hunger, thirst, or urination; infection; involuntary movements of the tongue, face, mouth, or jaw (eg, tongue sticking out, puffing of cheeks, mouth puckering, chewing movements); loss of appetite; numbness of an arm or leg; rapid breathing; restlessness; seizures; severe headache, dizziness, or vomiting; severe or persistent nausea or constipation; severe stomach pain; shortness of breath; stiff muscles; swelling of the hands, ankles, or feet; sudden, unusual weight gain; tremor; trouble swallowing; uncontrolled muscle movements; unusual mental or mood changes; unusual tiredness or weakness; vision changes; vomiting; yellowing of the skin or eyes.

Clozapine Side Effects - for the Professional

Clozapine

Associated with Discontinuation of Treatment

Sixteen percent of 1,080 patients who received Clozapine in premarketing clinical trials discontinued treatment due to an adverse event, including both those that could be reasonably attributed to Clozapine treatment and those that might more appropriately be considered intercurrent illness. The more common events considered to be causes of discontinuation included: CNS, primarily drowsiness/sedation, seizures, dizziness/syncope; cardiovascular, primarily tachycardia, hypotension and ECG changes; gastrointestinal, primarily nausea/vomiting; hematologic, primarily leukopenia/granulocytopenia/agranulocytosis; and fever. None of the events enumerated accounts for more than 1.7% of all discontinuations attributed to adverse clinical events.

Extrapyramidal Symptoms

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. Clozapine, an atypical antipsychotic, is associated with a low incidence of dystonia.

Commonly Observed

Adverse events observed in association with the use of Clozapine in clinical trials at an incidence of greater than 5% were: central nervous system complaints, including drowsiness/sedation, dizziness/vertigo, headache and tremor; autonomic nervous system complaints, including salivation, sweating, dry mouth and visual disturbances; cardiovascular findings, including tachycardia, hypotension and syncope; and gastrointestinal complaints, including constipation and nausea; and fever. Complaints of drowsiness/sedation tend to subside with continued therapy or dose reduction. Salivation may be profuse, especially during sleep, but may be diminished with dose reduction.

Incidence in Clinical Trials

The following table enumerates adverse events that occurred at a frequency of 1% or greater among Clozapine patients who participated in clinical trials. These rates are not adjusted for duration of exposure.

The following table enumerates adverse events that occurred at a frequency of 10% for either treatment group in patients who took at least one dose of study medication during their participation in InterSePT, which was an adequate and well controlled 2-year study evaluating the efficacy of Clozapine relative to Zyprexa in reducing the risk of emergent suicidal behavior in patients with schizophrenia or schizoaffective disorder. These rates are not adjusted for duration of exposure.

Other Events Observed During the Premarketing Evaluation of Clozapine

This section reports additional, less frequent adverse events which occurred among the patients taking Clozapine in clinical trials. Various adverse events were reported as part of the total experience in these clinical studies; a causal relationship to Clozapine treatment cannot be determined in the absence of appropriate controls in some of the studies. The table above enumerates adverse events that occurred at a frequency of at least 1% of patients treated with Clozapine. The list below includes all additional adverse experiences reported as being temporally associated with the use of the drug which occurred at a frequency less than 1%, enumerated by organ system.

Central Nervous System: loss of speech, amentia, tics, poor coordination, delusions/hallucinations, involuntary movement, stuttering, dysarthria, amnesia/memory loss, histrionic movements, libido increase or decrease, paranoia, shakiness, Parkinsonism, and irritability.

Cardiovascular System: edema, palpitations, phlebitis/thrombophlebitis, cyanosis, premature ventricular contraction, bradycardia, and nosebleed.

Gastrointestinal System: abdominal distention, gastroenteritis, rectal bleeding, nervous stomach, abnormal stools, hematemesis, gastric ulcer, bitter taste, and eructation.

Urogenital System: dysmenorrhea, impotence, breast pain/discomfort, and vaginal itch/infection.

Autonomic Nervous System: numbness, polydipsia, hot flashes, dry throat, and mydriasis.

Integumentary (Skin): pruritus, pallor, eczema, erythema, bruise, dermatitis, petechiae, and urticaria.

Musculoskeletal System: twitching and joint pain.

Respiratory System: coughing, pneumonia/pneumonia-like symptoms, rhinorrhea, hyperventilation, wheezing, bronchitis, laryngitis, and sneezing.

Hemic and Lymphatic System: anemia and leukocytosis.

Miscellaneous: chills/chills with fever, malaise, appetite increase, ear disorder, hypothermia, eyelid disorder, bloodshot eyes, and nystagmus.

Post-Marketing Clinical Experience

Post-marketing experience has shown an adverse experience profile similar to that presented above. Voluntary reports of adverse events temporally associated with Clozapine not mentioned above that have been received since market introduction and that may have no causal relationship with the drug include the following:

Central Nervous System: delirium; EEG abnormal; exacerbation of psychosis; myoclonus; overdose; paresthesia; possible mild cataplexy; and status epilepticus.

Cardiovascular System: atrial or ventricular fibrillation and periorbital edema.

Gastrointestinal System: acute pancreatitis; dysphagia; fecal impaction; intestinal obstruction/paralytic ileus; and salivary gland swelling.

Hepatobiliary System: cholestasis; hepatitis; and jaundice.

Hepatic System: cholestasis.

Urogenital System: acute interstitial nephritis and priapism.

Integumentary (Skin): hypersensitivity reactions: photosensitivity, vasculitis, erythema multiforme, and Stevens-Johnson Syndrome.

Metabolic and Nutritional Disorders: hypercholesterolemia (very rare); and hypertriglyceridemia (very rare).

Musculoskeletal System: myasthenic syndrome and rhabdomyolysis.

Respiratory System: aspiration and pleural effusion.

Hemic and Lymphatic System: deep vein thrombosis; elevated hemoglobin/hematocrit; ESR increased; pulmonary embolism; sepsis; thrombocytosis; and thrombocytopenia.

Vision Disorders: narrow angle glaucoma.

Miscellaneous: CPK elevation; hyperglycemia; hyperuricemia; hyponatremia; and weight loss.

Side Effects by Body System

Hematologic

Hematologic side effects have included agranulocytosis, leukopenia, neutropenia, and eosinophilia. Anemia and leukocytosis have been reported in less than 1% of patients. Elevated hemoglobin/hematocrit, increased erythrocyte sedimentation rate (ESR), thrombocytosis, and thrombocytopenia have also been reported; however, causality has not been established. Lymphopenia has also been reported.

During premarketing testing, the cumulative incidence of agranulocytosis at one year was approximately 1.3%. A later study has suggested that the cumulative incidence at one year is 0.8%. The incidence of agranulocytosis increases with age and may be higher in women.

The mechanism of clozapine-induced agranulocytosis is not completely understood.

Some investigators have suggested that the presence of HLA-B38 may predispose certain patients to the development of agranulocytosis during clozapine therapy. An increased incidence of clozapine-induced agranulocytosis has been reported in patients of Ashkenazi Jewish ancestry, a population in which HLA-B38 is prevalent.

Another study has suggested that one of the principal metabolites of clozapine, N-desmethylclozapine, is particularly toxic to the bone marrow.

Individuals with a fall in total WBC count to below 2000/mm3 or ANC below 1000/mm3 may not be rechallenged. However, individuals with an initial episode of moderate leukopenia (WBC of at least 2000/mm3 and less than 3000/mm3) have up to a 12- fold increased risk of having a subsequent episode of agranulocytosis upon rechallenge compared to the full cohort of patients treated with clozapine. To reduce the chances of rechallenge occurring in this patient population a report should be filed with the Clozapine National Registry (CNR), phone 1-800-448-5938), a single, national, confidential data base.

Because of the potential of agranulocytosis, clozapine is only available in the United States through distribution systems which ensure that a patient's WBC count and ANC are checked per a predetermined schedule.

Some investigators have suggested that filgrastim, a granulocyte colony stimulating factor, may be useful in the management of clozapine-induced agranulocytosis.

The incidence of agranulocytosis is reported to rise steeply during the first 2 months of therapy, peak at approximately the third month of therapy, and then decrease to approximately 3 per 1000 person-years at 6 months of therapy. After 6 months of therapy the incidence decreases further; however, it never reaches zero.

A 45-year-old African American woman with diagnosis of schizophrenia and mild mental retardation developed agranulocytosis after 6 years of continuous clozapine therapy at a dose of 500 mg per day. At the time of this incident, concomitant therapy for the preceding 4 years consisted of olanzapine, benazepril, and haloperidol decanoate injection. Clozapine was discontinued and the WBC count returned to normal limits two days later. The remaining pharmacological therapy remained constant. Clozapine therapy, without granulocyte colony-stimulating factor, was reinitiated two and a half months later under strict monitoring parameters. The dose was gradually titrated over a 5-month period to 800 mg per day. At the time of report, the patient had received clozapine for 3 years following reinitiation without an abnormal blood event.

Several cases of chronic leukocytosis associated with clozapine use have been reported and all appear to be benign. To date, all reported cases of chronic or persistent leukocytosis have occurred in males. In one case series, chronic leukocytosis was tracked for a period of 2 to 5 years in seven patients receiving clozapine (mean dose 457 mg/day; range 50 to 600 mg daily). Leukocytosis resolved in 2 patients when clozapine was discontinued and returned in 1 when the drug was restarted.

Nervous system

Nervous system side effects have included drowsiness/sedation (39%), dizziness/vertigo (19%), headache (7%), tremor (6%), syncope (6%), disturbed sleep/nightmares (4%), restlessness (4%), hypokinesia/akinesia (4%), agitation (4%), seizures (3%), rigidity (3%), akathisia (3%), confusion (3%), fatigue (2%), insomnia (2%), hyperkinesia (1%), weakness (1%), lethargy (1%), ataxia (1%), slurred speech (1%), depression (1%), epileptiform movements/myoclonic jerks (1%), and anxiety (1%). Loss of speech, amentia, tics, poor coordination, involuntary movement, stuttering, dysarthria, amnesia/memory loss, histrionic movements, changes in libido, shakiness, Parkinsonism, and irritability have been reported in less than 1% of patients. Delirium, EEG abnormalities, myoclonus, overdose, paresthesia, mild cataplexy, and status epilepticus have also been reported; however, causality has not been established. Dyskinesia, coma, dystonia, and neuroleptic malignant syndrome have been reported rarely. One case of clozapine-induced restless legs syndrome (RLS) has been reported. Symptoms (e.g., unpleasant sensation in calves, burning sensation over feet) of RLS developed on the third day of treatment, recurred on rechallenge, and completely resolved following discontinuation. At least one case of reversible Pisa syndrome has also been reported. In addition, clozapine-induced oculogyric crises have also been reported.

Symptoms of dystonia 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. Clozapine, an atypical antipsychotic, is associated with a low incidence of dystonia.

Clozapine may lower the seizure threshold in a dose-dependent fashion.

Rapid dose increase or preexisting epilepsy may increase the incidence of seizures.

Reports of sedation and/or drowsiness appear to decrease with dose reduction or length of clozapine therapy.

Fever, altered consciousness, autonomic dysfunction and muscle rigidity are the hallmarks of the neuroleptic malignant syndrome. The neuroleptic malignant syndrome is associated with a case fatality rate of about 20%. Immediate discontinuation of neuroleptic therapy, consideration of dantrolene therapy, as well as intensive monitoring and supportive care are indicated.

Although considered rare, there have been at least 21 cases of clozapine-associated neuroleptic malignant syndrome (NMS) reported. The mean age of patients who developed NMS has been 40 years, the mean dose of clozapine has been 318 mg daily and the mean number of days to onset of NMS has been 218 days. In approximately half the cases, NMS occurred during a dose increase while the remainder of patients were on stable doses.

In one case report involving a 16-year-old patient, NMS characterized by fever, autonomic changes, muscle rigidity, and elevated creatine kinase developed at a low dose (12.5 mg) within 8 hours of initiation of treatment.

There are reports of possible clozapine-associated atypical neuroleptic malignant syndrome characterized by fever, diaphoresis, no muscle rigidity, and mild or no elevation of creatine kinase level.

Gastrointestinal

Gastrointestinal side effects have included hypersalivation (31% to 80%), salivation (31%), constipation (14%), dry mouth (6%), nausea (5%), abdominal discomfort/heartburn (4%), vomiting (3%), and diarrhea (2%). Abdominal distention, gastroenteritis, rectal bleeding, nervous stomach, abnormal stools, hematemesis, gastric ulcer, bitter taste, eructation, polydipsia, and dry throat have been reported in less than 1% of patients. Acute pancreatitis, dysphagia, fecal impaction, intestinal obstruction, paralytic ileus, and swelling of salivary gland have also been reported; however, causality has not been established. Clozapine has also been associated with rare cases of esophageal dysfunction resulting in dysphagia. One case of clozapine-associated pseudomembranous colitis has been reported after 9 years of therapy.

Elderly patients may be more susceptible to the anticholinergic effects of clozapine, such as constipation.

Hypersalivation may be dose-dependent.

One hypothesis is that hypersalivation may be due to the blockade of alpha-2 adrenoceptors.

Some case reports have suggested that clozapine may rarely cause pancreatitis.

There have been rare reports of severe diarrhea in association with lymphopenia and/or neutropenia.

Cardiovascular

Elderly patients, particularly those with preexisting cardiovascular dysfunction, may be more susceptible to cardiovascular side effects, especially orthostatic hypotension and tachycardia. In addition, an increased risk of mortality, possibly due to heart failure or sudden death, has been reported with the use of atypical antipsychotic agents in the treatment of behavioral disorders in the elderly patient with dementia.

Collective data gathered from 17 placebo-controlled clinical studies (n=5106) involving the use of atypical antipsychotic agents for the treatment of behavioral disorders in the elderly patient with dementia showed a risk of death 1.6 to 1.7 times greater in the drug- treated patient than in the placebo- treated patient. The average length of duration for the trials was 10 weeks with the cause of death in the majority of cases, though not all, reported as either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Although clozapine was not included in these studies, the consistent findings across all three relevant chemical classes support the opinion that these findings are likely to be applicable to all atypical antipsychotic agents. Clozapine is not approved by the FDA for use in the treatment of behavioral disorders in elderly patients with dementia.

The results of a large retrospective cohort study appear to indicate that atypical antipsychotic agents (i.e., risperidone, olanzapine, clozapine, quetiapine) increase the risk of venous thromboembolism in elderly patients; however, these events seem to be rare.

Orthostatic hypotension (sometimes associated with syncope and rarely associated with cardiovascular collapse) has been reported particularly at initial titration in association with rapid dose escalation and has been reported with the first dose.

Case reports have suggested that clozapine may cause a paradoxical increase in blood pressure. A chart review (n=82) revealed the incidence of hypertension to be higher in first six months of clozapine therapy.

One recent study has suggested that mild tachycardia may occur in as many as 51% of treated patients and a case report has suggested that the tachycardia may be associated with PVCs.

There are reports of numerous cases of myocarditis (including eighteen deaths) and forty one cases of cardiomyopathy (including 10 deaths). Clozapine-associated myocarditis has been reported to occur most often within one to two months of starting clozapine, but it may develop at any time while on clozapine and may even occur at very low doses. Fatal myocarditis is reportedly more likely to occur during (but not limited to) the first month of therapy.

One study (n=61) reported that although a substantial portion of patients treated with clozapine developed ECG abnormalities, most of the abnormalities were benign and did not hinder further treatment.

Cardiovascular side effects have included tachycardia (25%), hypotension (9%), hypertension (4%), chest pain/angina (1%), and ECG/cardiac abnormalities (1%). Edema, palpitations, phlebitis/thrombophlebitis, cyanosis, premature ventricular contraction, bradycardia, and nose bleed have been reported in less than 1% of patients. Atrial or ventricular fibrillation, periorbital edema, venous thromboembolism (i.e., deep vein thrombosis), hypercholesterolemia, and hypertriglyceridemia have also been reported. Polyserositis, pericarditis, pericardial tamponade, pericardial effusion, and potentially fatal myocarditis and cardiomyopathy have been reported rarely.

Hepatic

Hepatic side effects have included transient moderate asymptomatic elevations in liver function tests in up to 50% of patients. Cholestasis, hepatitis, and jaundice have also been reported; however, causality has not been established. One case of reversible marked hepatotoxicity has been reported.

Psychiatric

Psychiatric side effects have included delusions, hallucinations, and paranoia in less than 1% of patients. Obsessive-compulsive symptoms, worsening of bulimia nervosa, and exacerbation of psychosis have also been reported. Rebound psychosis (or supersensitivity psychosis) may occur after withdrawal of clozapine therapy.

Hypersensitivity

Hypersensitivity side effects have included photosensitivity, vasculitis, erythema multiforme, and Stevens-Johnson Syndrome. Bronchospasm, respiratory arrest, cardiovascular collapse, polyserosits, and hypersensitivity myocarditis have also been reported.

Genitourinary

Genitourinary side effects have included urinary abnormalities (2%), incontinence (1%), abnormal ejaculation (1%), urinary urgency/frequency (1%), and urinary retention (1%). Dysmenorrhea, impotence, breast pain/discomfort, vaginal itch/infection, hot flashes, and hyperuricemia have been reported in less than 1% of patients. Acute interstitial nephritis and priapism have also been reported; however, causality has not been established.

Elderly patients may be more susceptible to the anticholinergic effects of clozapine, such as urinary retention.

Endocrine

Numerous studies have demonstrated that clozapine treatment is associated with an increased risk for development or exacerbation of diabetes mellitus. Cases of transient hyperglycemia, diabetic ketoacidosis, new onset diabetes, and exacerbation of preexisting diabetes have been reported. In some studies, the prevalence of clozapine-related diabetes has ranged from 4% to 36.6%. In one study, the prevalence of diabetes was considerably higher among patients taking clozapine compared with the general population (25.7% vs 7.9%, respectively). Attempts to associate the frequency of clozapine-related diabetes with specific risk factors, other than those known for the general population (e.g., family history, obesity, age group), have been unsuccessful and in some cases resulted in conflicting data. Compared to conventional antipsychotics (i.e., haloperidol, chlorpromazine), the risk of diabetes is higher among patients receiving clozapine.

A study of U.S. military veterans with schizophrenia has reported that patients on clozapine had 1.48 times as many cases of diabetes when compared to patients taking decades old drugs for psychosis including haloperidol, thioridazine, and others.

A survey of FDA MedWatch reports of the development or exacerbation of diabetes, or hyperglycemia, in patients receiving clozapine therapy (n=384) concluded a possible causal relationship may exist. The results stated the onset of hyperglycemia may be rapid, within the first 3 months of clozapine therapy, and severe. There was no obvious association between dose and severity of hyperglycemia or time to onset of hyperglycemia in this patient population. In addition, the reports that were complete suggest the risk may not end with extended clozapine therapy, and, in some cases, clozapine-induced sedation may delay the diagnosis of hyperglycemia.

Additional studies have confirmed that patients receiving atypical antipsychotics (i.e., clozapine, risperidone, olanzapine, quetiapine, ziprasidone) are at an increased risk of developing hyperglycemia and/or diabetes mellitus.

Endocrine side effects have included hyperglycemia, hyponatremia, clozapine-induced or exacerbated diabetes mellitus, and diabetic ketoacidosis.

Musculoskeletal

Musculoskeletal side effects have included muscle weakness, back, neck, and leg pain, muscle spasm, and muscle pain/ache in 1% of patients. Twitching and joint pain have been reported in less than 1% of patients. Myasthenic syndrome and rhabdomyolysis have been reported; however, causality has not been established. One case report has suggested that clozapine may induce dramatic elevations in creatine phosphokinase (CPK) levels (without other features of the neuroleptic malignant syndrome).

Immunologic

A 55-year-old female with a history of paranoid-hallucinatory schizophrenia developed systemic lupus erythematosus (SLE) following 15 years of continuous therapy with clozapine 200 mg per day. Clinical symptoms resolved and the elevated erythrocyte sedimentation rate (ESR) returned to normal within 2 weeks of discontinuation of clozapine. Subsequently, several pharmacological options were tried to treat the patient's schizophrenia; however, following a risk-benefit analysis clozapine therapy was restarted. The clinical symptoms and lab findings indicating SLE returned within weeks of therapy reinitiation. The patient consented to continue on clozapine therapy with appropriate monitoring.

Clozapine-induced systemic lupus erythematosus has been reported in a 32-year-old patient with schizophrenia and confirmed upon rechallenge. Clinical symptoms and laboratory markers (i.e., antinuclear antibodies (ANA), erythrocyte sedimentation rate (ESR)) completely resolved following discontinuation of clozapine after both the first exposure and the rechallenge.

Immunologic side effects have included asymptomatic antiphospholipid antibodies (1 small study), acute reaction resembling systemic lupus erythematosus (1 case report), and systemic lupus erythematosus.

Ocular

Ocular side effects have included visual disturbances (5%). Mydriasis, eyelid disorder, bloodshot eyes, and nystagmus have been reported in less than 1% of patients. Narrow angle glaucoma has also been reported; however, causality has not been established. Oculogyric crisis has been reported rarely.

Other

Other side effects have included anorexia (1%), sweating (6%), fever (5%), and tongue numb/sore (1%). Chills (with and without a fever), malaise, appetite increase, ear disorder, hypothermia, and numbness have been reported in less than 1% of patients. Sepsis has been reported; however, causality has not been established. Transient hyperthermia has been reported in as many as 50% of patients started on clozapine therapy.

Hyperthermia most commonly occurs between the 8th and 16th days of treatment and may last several days.

Clozapine related fever is generally benign but difficult to assess and manage as it can be confused with much more serious conditions.

Dermatologic

Dermatologic side effects have included rash (2%). Pruritus, pallor, eczema, erythema, bruise, dermatitis, petechiae, and urticaria have been reported in less than 1% of patients. Photosensitivity, vasculitis, erythema multiforme and Stevens-Johnson Syndrome have been reported; however, causality has not been established.

Respiratory

An increased risk of mortality, possibly due to an infection, such as pneumonia, has been reported with the use of atypical antipsychotic agents in the treatment of behavioral disorders in the elderly patient with dementia.

Collective data gathered from 17 placebo-controlled clinical studies (n=5106) involving the use of atypical antipsychotic agents for the treatment of behavioral disorders in the elderly patient with dementia showed a risk of death 1.6 to 1.7 times greater in the drug- treated patient than in the placebo- treated patient. The average length of duration for the trials was 10 weeks with the cause of death in the majority of cases, though not all, reported as either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Although clozapine was not included in these studies, the consistent findings across all three relevant chemical classes support the opinion that these findings are likely to be applicable to all atypical antipsychotic agents. Clozapine is not approved by the FDA for use in the treatment of behavioral disorders in elderly patients with dementia.

Respiratory side effects have included throat discomfort, dyspnea, and nasal congestion in 1% of patients. Coughing, pneumonia, pneumonia- like symptoms, rhinorrhea, hyperventilation, wheezing, bronchitis, laryngitis, and sneezing have been reported in less than 1% of patients. Aspiration, pleural effusion, and pulmonary embolism have also been reported; however, causality has not been established. Pleural inflammation/effusions have been reported rarely.

Metabolic

One study has reported an average weight gain of 8.9% of body weight during the first 16 weeks of clozapine therapy.

Metabolic side effects have included weight gain in up to 67% of patients. Binge eating and increases in food craving have been associated with clozapine. Weight loss has also been reported; however, causality has not been established. Hypercholesterolemia and hypertriglyceridemia have been reported very rarely. Studies have shown that patients receiving clozapine are at an increased risk of developing metabolic syndrome (a clustering of risk factors such as dyslipidemia, hypertension, hyperglycemia for cardiovascular disease).

Renal

A 33-year-old male titrated to clozapine 100 mg per day developed acute interstitial nephritis over seven-to-fourteen days following initiation of clozapine therapy. Concomitant medications included valproic acid, risperidone, and gabapentin. All medications, except valproic acid, were discontinued and the patient improved within one week.

A 49-year-old male developed acute interstitial nephritis within 10 days following initiation of clozapine therapy. The patient recovered following discontinuation of clozapine.

Renal side effects have rarely included acute interstitial nephritis.

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