July 28, 2016
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FazaClo

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Fazaclo




Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Severe Neutropenia

Background

FAZACLO can cause neutropenia (a low absolute neutrophil count [ANC]), defined as a reduction below pre-treatment normal levels of blood neutrophils. The ANC is usually available as a component of the complete blood count (CBC), including differential, and is more relevant to drug-induced neutropenia than is the white blood cell (WBC) count. The ANC may also be calculated using the following formula: ANC equals the Total WBC count multiplied by the total percentage of neutrophils obtained from the differential (neutrophil “segs” plus neutrophil “bands”). Other granulocytes (basophils and eosinophils) contribute minimally to neutropenia and their measurement is not necessary [see ADVERSE REACTIONS]. Neutropenia may be mild, moderate, or severe (see Tables 2 and 3). To improve and standardize understanding, “severe neutropenia” replaces the previous terms severe leukopenia, severe granulocytopenia, or agranulocytosis.

Severe neutropenia, ANC less than ( < ) 500/μL, occurs in a small percentage of patients taking FAZACLO and is associated with an increase in the risk of serious and potentially fatal infections. Risk of neutropenia appears greatest during the first 18 weeks on treatment and then declines. The mechanism by which FAZACLO causes neutropenia is unknown and is not dose-dependent.

Two separate management algorithms are provided below, the first for patients in the general population, and the second for patients identified to have baseline neutropenia.

FAZACLO Treatment and Monitoring in the General Patient Population (see Table 2)

Obtain a CBC, including the ANC value, prior to initiating treatment with FAZACLO to ensure the presence of a normal baseline neutrophil count (equal to or greater than 1500/μL) and to permit later comparisons. Patients in the general population with an ANC equal to or greater than ( ≥ )1500/μL are considered within normal range (Table 2) and are eligible to initiate treatment. Weekly ANC monitoring is required for all patients during the first 6 months of treatment. If a patient's ANC remains equal to or greater than 1500/μL for the first 6 months of treatment, monitoring frequency may be reduced to every 2 weeks for the next 6 months. If the ANC remains equal to or greater than 1500/μL for the second 6 months of continuous therapy, ANC monitoring frequency may be reduced to once every 4 weeks thereafter.

Table 2: FAZACLO Treatment Recommendations Based on Absolute Neutrophil Count (ANC) Monitoring for the General Patient Population

ANC Level FAZACLO Treatment Recommendations ANC Monitoring
Normal range ( ≥ 1500/μL)
  • Initiate treatment
  • If treatment interrupted:
    • < 30 days, continue monitoring as before
    • ≥ 30 days, monitor as if new patient
  • Weekly from initiation to 6 months
  • Every 2 weeks from 6 to 12 months
  • Monthly after 12 months
  • Discontinuation for reasons other than neutropenia
Mild Neutropenia (1000 to 1499/μL)*
  • Continue treatment
  • Three times weekly until ANC ≥ 1500/μL
  • Once ANC ≥ 1500/μL, return to patient’s last “Normal Range” ANC monitoring interval**
Moderate Neutropenia (500 to 999/μL)*
  • Recommend hematology consultation
  • Interrupt treatment for suspected clozapine-induced neutropenia
  • Resume treatment once ANC > 1000/μL
  • Daily until ANC ≥ 1000/μL, then
  • Three times weekly until ANC ≥ 1500/μL
  • Once ANC ≥ 1500/μL, check ANC weekly for 4 weeks, then return to patient’s last “Normal Range” ANC monitoring interval**
Severe Neutropenia (less than 500/μL)*
  • Recommend hematology consultation
  • Interrupt treatment for suspected clozapine-induced neutropenia
  • Do not rechallenge unless prescriber determines benefits outweigh risks
  • Daily until ANC ≥ 1000/μL, then
  • Three times weekly until ANC ≥ 1500/μL
  • If patient rechallenged, resume treatment as a new patient under “Normal Range” monitoring once ANC ≥ 1500/μL
* Confirm all initial reports of ANC less than 1500/μL with a repeat ANC measurement within 24 hours
** If clinically appropriate

FAZACLO Treatment and Monitoring in Patients with Benign Ethnic Neutropenia (see Table 3)

Benign ethnic neutropenia (BEN) is a condition observed in certain ethnic groups whose average ANC values are lower than “standard” laboratory ranges for neutrophils. It is most commonly observed in individuals of African descent (approximate prevalence of 25-50%), some Middle Eastern ethnic groups, and in other non-Caucasian ethnic groups with darker skin. BEN is more common in men. Patients with BEN have normal hematopoietic stem-cell number and myeloid maturation, are healthy, and do not suffer from repeated or severe infections. They are not at increased risk for developing FAZACLO-induced neutropenia. Additional evaluation may be needed to determine if baseline neutropenia is due to BEN. Consider hematology consultation before initiating or during FAZACLO treatment as necessary.

Patients with BEN require a different ANC algorithm for FAZACLO management due to their lower baseline ANC levels. Table 3 provides guidelines for managing FAZACLO treatment and ANC monitoring in patients with BEN.

Table 3: Patients with Benign Ethnic Neutropenia (BEN); FAZACLO Treatment Recommendations Based on Absolute Neutrophil Count (ANC) Monitoring

ANC Level Treatment Recommendations ANC Monitoring
Normal BEN Range (Established ANC baseline > 1000/μL )
  • Obtain at least two baseline ANC levels before initiating treatment
  • If treatment interrupted
    • < 30 days, continue monitoring as before
    • ≥ 30 days, monitor as if new patient
  • Weekly from initiation to 6 months
  • Every 2 weeks from 6 to 12 months
  • Monthly after 12 months
  • Discontinuation of treatment for reasons other than neutropenia
BEN Neutropenia (500 to 999/μL)*
  • Recommend hematology consultation
  • Continue treatment

 

  • Three times weekly until ANC ≥ 1000/μL or ≥ patient’s known baseline
  • Once ANC ≥ 1000/μL or at patient’s known baseline, check ANC weekly for 4 weeks, then return to patient’s last “Normal BEN Range” ANC monitoring interval.**
BEN Severe Neutropenia (less than 500/μL)*
  • Recommend hematology consultation
  • Interrupt treatment for suspected clozapine-induced neutropenia
  • Do not rechallenge unless prescriber determines benefits outweigh risks
  • Daily until ANC ≥ 500/μL, then
  • Three times weekly until ANC ≥ patient’s baseline
  • If patient rechallenged, resume treatment as a new patient under “Normal Range” monitoring once ANC ≥ 1000/μL or at patient’s baseline
* Confirm all initial reports of ANC less than 1500/μL with a repeat ANC measurement within 24 hours
** If clinically appropriate

General Guidelines for Management of All Patients with Fever or with Neutropenia
  • Fever: Interrupt FAZACLO as a precautionary measure in any patient who develops fever, defined as a temperature of 38.5°C [101.3°F] or greater, and obtain an ANC level. Fever is often the first sign of neutropenic infection.
  • ANC less than 1000/μL: If fever occurs in any patient with an ANC less than 1000/μL, initiate appropriate workup and treatment for infection and refer to Tables 2 or 3 for management.
  • Consider hematology consultation.
  • See Neuroleptic Malignant Syndrome (NMS) and Fever under WARNINGS AND PRECAUTIONS and Instructions for Patients, under PATIENT INFORMATION).
Rechallenge after an ANC less than 500/μL (Severe Neutropenia)

For some patients who experience severe FAZACLO-related neutropenia, the risk of serious psychiatric illness from discontinuing FAZACLO treatment may be greater than the risk of rechallenge (e.g., patients with severe schizophrenic illness who have no treatment options other than FAZACLO). A hematology consultation may be useful in deciding to rechallenge a patient. In general, however, do not rechallenge patients who develop severe neutropenia with FAZACLO or a clozapine product.

If a patient will be rechallenged, the clinician should consider thresholds provided in Tables 2 and 3, the patient's medical and psychiatric history, a discussion with the patient and his/her caregiver about the benefits and risks of FAZACLO rechallenge, and the severity and characteristics of the neutropenic episode.

Using FAZACLO with Other Drugs Associated with Neutropenia

It is unclear if concurrent use of other drugs known to cause neutropenia increases the risk or severity of FAZACLO-induced neutropenia. There is no strong scientific rationale to avoid FAZACLO treatment in patients concurrently treated with these drugs. If FAZACLO is used concurrently with an agent known to cause neutropenia (e.g., some chemotherapeutic agents), consider monitoring patients more closely than the treatment guidelines provided in Tables 2 and 3. Consult with the treating oncologist in patients receiving concomitant chemotherapy.

Clozapine REMS Program

FAZACLO is only available through a restricted program under a REMS called the Clozapine REMS Program because of the risk of severe neutropenia.

Notable requirements of the Clozapine REMS Program include:

  • Healthcare professionals who prescribe FAZACLO must be certified with the program by enrolling and completing training.
  • Patients who receive FAZACLO must be enrolled in the program and comply with the ANC testing and monitoring requirements.
  • Pharmacies dispensing FAZACLO must be certified with the program by enrolling and completing training and must only dispense to patients who are eligible to receive FAZACLO.

Further information is available at www.clozapinerems.com or 1-844-267-8678.

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. These reactions can occur with the first dose, at doses as low as 12.5 mg. These reactions can be fatal. The syndrome is consistent with neurally mediated reflex bradycardia (NMRB).

Treatment must begin at a maximum dose of 12.5 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 dose is 900 mg per day. Use cautious titration and a divided dosage schedule to minimize the risk of serious cardiovascular reactions [see DOSAGE AND ADMINISTRATION]. Consider reducing the dose if hypotension occurs. When restarting patients who have had even a brief interval off FAZACLO (i.e., 2 days or more since the last dose), re-initiate treatment at 12.5 mg once daily or twice daily [see DOSAGE AND ADMINISTRATION].

Use FAZACLO cautiously in patients with cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and conditions which would predispose patients to hypotension (e.g., concomitant use of antihypertensives, dehydration and hypovolemia).

Seizures

Seizure has been estimated to occur in association with clozapine use at a cumulative incidence at one year of approximately 5%, based on the occurrence of one or more seizures in 61 of 1743 patients exposed to clozapine during its clinical testing prior to domestic marketing (i.e., a crude rate of 3.5%). The risk of seizure is dose-related. Initiate treatment with a low dose (12.5 mg), titrate slowly, and use divided dosing.

Use caution when administering FAZACLO to patients with a history of seizures or other predisposing risk factors for seizure (e.g., head trauma or other CNS pathology, use of medications that lower the seizure threshold, or alcohol abuse). Because of the substantial risk of seizure associated with FAZACLO use, caution patients about engaging in any activity where sudden loss of consciousness could cause serious risk to themselves or others (e.g., driving an automobile, operating complex machinery, swimming, climbing).

Myocarditis And Cardiomyopathy

Myocarditis and cardiomyopathy have occurred with the use of clozapine. These reactions can be fatal. Discontinue FAZACLO and obtain a cardiac evaluation upon suspicion of myocarditis or cardiomyopathy. Generally, patients with a history of clozapine-associated myocarditis or cardiomyopathy should not be rechallenged with FAZACLO. However, if the benefit of FAZACLO treatment is judged to outweigh the potential risks of recurrent myocarditis or cardiomyopathy, the clinician may consider rechallenge with FAZACLO in consultation with a cardiologist, after a complete cardiac evaluation, and under close monitoring.

Consider the possibility of myocarditis or cardiomyopathy in patients receiving FAZACLO who present with chest pain, dyspnea, persistent tachycardia at rest, palpitations, fever, flu-like symptoms, hypotension, other signs or symptoms of heart failure, or electrocardiographic findings (low voltages, ST-T abnormalities, arrhythmias, right axis deviation, and poor R wave progression). Myocarditis most frequently presents within 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 and cardiomyopathy can occur at any period during treatment with FAZACLO. It is common for nonspecific flu-like symptoms such as malaise, myalgia, pleuritic chest pain, and low-grade fevers to precede more overt signs of heart failure. Typical laboratory findings include elevated troponin I or T, elevated creatinine kinase-MB, peripheral eosinophilia, and elevated C-reactive protein (CRP). Chest roentgenogram may demonstrate cardiac silhouette enlargement, and cardiac imaging (echocardiogram, radionucleotide studies, or cardiac catheterization) may reveal evidence of left ventricular dysfunction.

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. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., 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. FAZACLO is not approved for the treatment of patients with dementia-related psychosis [see BOXED WARNING].

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 FAZACLO 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 FAZACLO immediately.

If a cause of eosinophilia unrelated to clozapine is identified (e.g., asthma, allergies, collagen vascular disease, parasitic infections, and specific neoplasms), treat the underlying cause and continue FAZACLO.

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, without recurrence of eosinophilia. In the absence of organ involvement, continue FAZACLO under careful monitoring. If the total eosinophil count continues to increase over several weeks in the absence of systemic disease, the decision to interrupt FAZACLO therapy and rechallenge after the eosinophil count decreases should be based on the overall clinical assessment, in consultation with an internist or hematologist.

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 FAZACLO, 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 FAZACLO, and electrolyte abnormalities.

Prior to initiating treatment with FAZACLO, perform a careful physical examination, medical history, and concomitant medication history. Consider obtaining a baseline ECG and serum chemistry panel. Correct electrolyte abnormalities. Discontinue FAZACLO if the QTc interval exceeds 500 msec. If patients experience symptoms consistent with Torsades de Pointes or other arrhythmias (e.g., syncope, presyncope, dizziness, or palpitations), obtain a cardiac evaluation and discontinue FAZACLO.

Use caution when administering concomitant medications that prolong the QT interval or inhibit the metabolism of FAZACLO. Drugs that cause QT prolongation include: specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, thioridazine, mesoridazine, droperidol, pimozide), specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin), Class 1A antiarrhythmic medications (e.g., quinidine, procainamide) or Class III antiarrhythmics (e.g., amiodarone, sotalol), and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus). FAZACLO is primarily metabolized by CYP isoenzymes 1A2, 2D6, and 3A4. Concomitant treatment with inhibitors of these enzymes can increase the concentration of FAZACLO [see DRUG INTERACTIONS and CLINICAL PHARMACOLOGY].

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 FAZACLO.

Metabolic Changes

Atypical antipsychotic drugs, including FAZACLO, 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 FAZACLO. 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 FAZACLO should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., 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 100-900 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 FAZACLO. Clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using FAZACLO, 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 - 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 FAZACLO. Monitor weight during treatment with FAZACLO. 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.

Table 7: Mean Change in Body Weight (kg) by duration of exposure from studies in adult subjects with schizophrenia

Metabolic Parameter Exposure Duration Clozapine
(N=669)
Olanzapine
(N=442)
Chlorpromazine
N=155)
n Mean n Mean n Mean
Weight change from baseline 2 weeks (Day 11 - 17) 6 +0.9 3 +0.7 2 -0.5
4 weeks (Day 21 - 35) 23 +0.7 8 +0.8 17 +0.6
8 weeks (Day 49 - 63) 12 + 1.9 13 + 1.8 16 +0.9
12 weeks (Day 70 - 98) 17 +2.8 5 +3.1 0 0
24 weeks (Day 154 - 182) 42 -0.6 12 +5.7 0 0
48 weeks (Day 322 - 350) 3 +3.7 3 +13.7 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.

Table 8: Proportion of adult subjects in schizophrenia studies with weight gain ≥ 7% relative to baseline body weight

Weight Change Clozapine Olanzapine Chlorpromazine
N 669 442 155
≥ 7% (inclusive) 236 (35%) 203 (46%) 13 (8%)

Neuroleptic Malignant Syndrome

Antipsychotic drugs including FAZACLO 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. It is important to consider the presence of other serious medical conditions (e.g., 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.

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. Carefully evaluate patients with fever to rule out severe neutropenia or infection. Consider the possibility of NMS [see Neuroleptic Malignant Syndrome].

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.

Anticholinergic Toxicity

FAZACLO has potent anticholinergic effects. Treatment with FAZACLO can result in CNS and peripheral anticholinergic toxicity. Use with caution in the presence of narrow-angle glaucoma, concomitant anticholinergic medications, prostatic hypertrophy, or other conditions in which anticholinergic effects can lead to significant adverse reactions.

Treatment with FAZACLO can result in gastrointestinal adverse reactions, including constipation, intestinal obstruction, fecal impaction, and paralytic ileus. Such reactions can be fatal. Constipation should be initially treated by ensuring adequate hydration and use of ancillary therapy such as bulk laxatives. Consultation with a gastroenterologist is advisable in more serious cases.

Interference With Cognitive And Motor Performance

FAZACLO can cause sedation and impairment of cognitive and motor performance. Caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain that FAZACLO does not affect them adversely. These reactions may be dose-related. Consider reducing the dose if they occur.

Tardive Dyskinesia

Tardive dyskinesia (TD) has occurred in patients treated with antipsychotic drugs, including FAZACLO. 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 FAZACLO 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 FAZACLO despite the presence of the syndrome.

There is no known treatment for TD. However, the syndrome may remit partially or completely if treatment is discontinued. 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.

Patients With Phenylketonuria

Phenylketonuric patients should be informed that FAZACLO contains phenylalanine (a component of aspartame). Each 12.5 mg, orally disintegrating tablet contains 0.87 mg phenylalanine. Each 25 mg, orally disintegrating tablet contains 1.74 mg phenylalanine. Each 100 mg, orally disintegrating tablet contains 6.96 mg phenylalanine. Each 150 mg, orally disintegrating tablet contains 10.44 mg phenylalanine. Each 200 mg, orally disintegrating tablet contains 13.92 mg phenylalanine.

Cerebrovascular Adverse Reactions

In controlled trials, elderly patients with dementia-related psychosis treated with some atypical antipsychotics had an increased risk (compared to placebo) of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatalities. The mechanism for this increased risk is not known. An increased risk cannot be excluded for FAZACLO or other antipsychotics or other patient populations. FAZACLO should be used with caution in patients with risk factors for cerebrovascular adverse reactions.

Recurrence Of Psychosis And Cholinergic Rebound After Abrupt Discontinuation Of FAZACLO

If abrupt discontinuation of FAZACLO is necessary (because of severe neutropenia or another medical condition, for example) [see DOSAGE AND ADMINISTRATION, Severe Neutropenia], monitor carefully for the recurrence of psychotic symptoms and adverse reactions related to cholinergic rebound, such as profuse sweating, headache, nausea, vomiting, and diarrhea.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

No carcinogenic potential was demonstrated in long-term studies in mice and rats at doses up to 0.3 times and 0.4 times, respectively, the maximum recommended human dose (MRHD) of 900 mg/day on a mg/m² body surface area basis.

Mutagenesis

Clozapine was not genotoxic when tested in the following gene mutation and chromosomal aberration tests: the bacterial Ames test, the in vitro mammalian V79 in Chinese hamster cells, the in vitro unscheduled DNA synthesis in rat hepatocytes, or the in vivo micronucleus assay in mice.

Impairment of Fertility

Clozapine had no effect on any parameters of fertility, pregnancy, fetal weight, or postnatal development when administered orally to male rats 70 days before mating and to female rats for 14 days before mating at doses up to 0.4 times the MRHD of 900 mg/day on a mg/m² body surface area basis.

Use In Specific Populations

Pregnancy

Pregnancy Category B

Risk Summary

There are no adequate or well-controlled studies of clozapine in pregnant women.

Reproduction studies have been performed in rats and rabbits at doses up to 0.4 and 0.9 times, respectively, the maximum recommended human dose (MRHD) of 900 mg/day on a mg/m² body surface area basis. The studies revealed no evidence of impaired fertility or harm to the fetus due to clozapine. Because animal reproduction studies are not always predictive of human response, FAZACLO should be used during pregnancy only if clearly needed.

Clinical Considerations

Consider the risk of exacerbation of psychosis when discontinuing or changing treatment with antipsychotic medications during pregnancy and postpartum. Consider early screening for gestational diabetes for patients treated with antipsychotic medications [see WARNINGS AND PRECAUTIONS]. Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Monitor neonates for symptoms of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding difficulties. The severity of complications can vary from self-limited symptoms to some neonates requiring intensive care unit support and prolonged hospitalization.

Animal Data

In embryofetal developmental studies, clozapine had no effects on maternal parameters, litter sizes, or fetal parameters when administered orally to pregnant rats and rabbits during the period of organogenesis at doses up to 0.4 and 0.9 times, respectively, the MRHD of 900 mg/day on a mg/m² body surface area basis.

In peri/postnatal developmental studies, pregnant female rats were administered clozapine over the last third of pregnancy and until day 21 postpartum. Observations were made on fetuses at birth and during the postnatal period; the offspring were allowed to reach sexual maturity and mated. Clozapine caused a decrease in maternal body weight but had no effects on litter size or body weights of either F1or F2 generations at doses up to 0.4 times the MRHD of 900 mg/day on a mg/m² body surface area basis.

Nursing Mothers

FAZACLO is present in human milk. Because of the potential for serious adverse reactions in nursing infants from FAZACLO, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

There have not been sufficient numbers of geriatric patients in clinical studies utilizing FAZACLO to determine whether those over 65 years of age differ from younger subjects in their response to FAZACLO.

Orthostatic hypotension and tachycardia can occur with clozapine treatment [see BOXED WARNING and WARNINGS AND PRECAUTIONS]. Elderly patients, particularly those with compromised cardiovascular functioning, may be more susceptible to these effects.

Elderly patients may be particularly susceptible to the anticholinergic effects of clozapine, such as urinary retention and constipation [see WARNINGS AND PRECAUTIONS].

Carefully select FAZACLO doses in elderly patients, taking into consideration their greater frequency of decreased hepatic, renal, or cardiac function, as well as other concomitant disease and other drug therapy. Clinical experience suggests that the prevalence of tardive dyskinesia appears to be highest among the elderly; especially elderly women [see WARNINGS AND PRECAUTIONS].

Patients With Renal Or Hepatic Impairment

Dose reduction may be necessary in patients with significant impairment of renal or hepatic function. Clozapine concentrations may be increased in these patients, because clozapine is almost completely metabolized and then excreted [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY].

CYP2D6 Poor Metabolizers

Dose reduction may be necessary in patients who are CYP2D6 poor metabolizers. Clozapine concentrations may be increased in these patients, because clozapine is almost completely metabolized and then excreted [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY].

Hospice Patients

For hospice patients (i.e., terminally ill patients with an estimated life expectancy of 6 months or less), the prescriber may reduce the ANC monitoring frequency to once every 6 months, after a discussion with the patient and his/her caregiver. Individual treatment decisions should weigh the importance of monitoring ANC in the context of the need to control psychiatric symptoms and the patient's terminal illness.

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 10/1/2015

Warnings
Precautions

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