Versacloz

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Agranulocytosis

Background

Agranulocytosis, defined as an ANC of less than 500/mm³, has been estimated to occur in association with clozapine use at a cumulative incidence at 1 year of approximately 1.3%, based on the occurrence of 15 US cases out of 1743 patients exposed to clozapine during its clinical testing prior to domestic marketing. All of these cases occurred at a time when the need for close monitoring of WBC counts was already recognized. A hematologic risk analysis was conducted based upon the available information in the Clozapine National Registry for US patients. Based upon a cut-off date of April 30, 1995, the incidence rates of agranulocytosis based upon a weekly monitoring schedule rose steeply during the first two months of therapy, peaking in the third month. Among clozapine patients who continued the drug beyond the third month, the weekly incidence of agranulocytosis fell a substantial degree. After 6 months, the weekly incidence of agranulocytosis declines still further; however, it never reaches zero. It should be noted that any type of reduction in the frequency of monitoring WBC counts may result in an increased incidence of agranulocytosis.

Risk Factors

Experience from clinical development, as well as from examples in the medical literature, suggests that patients who have developed agranulocytosis during VERSACLOZ therapy are at increased risk of subsequent episodes of agranulocytosis. Analysis of WBC count data from the Clozapine National Registry also suggests that patients who have an initial episode of moderate leukopenia (3000/mm³ > WBC count ≥ 2000/mm³) are at an increased risk of subsequent episodes of agranulocytosis. Except for bone-marrow suppression during initial clozapine therapy, there are no other established risk factors based on worldwide experience for the development of agranulocytosis in association with clozapine use. However, a disproportionate number of the US cases of agranulocytosis occurred in patients of Jewish background compared to the overall proportion of such patients exposed during domestic development of clozapine. Most of the US cases of agranulocytosis occurred within 4–10 weeks of exposure, but neither dose nor duration is a reliable predictor of this problem. Agranulocytosis associated with other antipsychotic drugs has been reported to occur with a greater frequency in women, the elderly, and in patients who are cachectic or have serious underlying medical illness; such patients may also be at particular risk with VERSACLOZ, although this has not been definitively demonstrated.

WBC Count and ANC Clinical Monitoring Schedule

VERSACLOZ is available only through a distribution system that ensures monitoring of WBC count and ANC according to the schedule described below prior to delivery of the next supply of medication.

As described in Table 2, patients who are being treated with VERSACLOZ must have a baseline WBC count and ANC before initiation of treatment, and a WBC count and ANC every week for the first 6 months. Thereafter, if acceptable WBC counts and ANCs (WBC count ≥ 3500/mm³ and ANC ≥ 2000/mm³) have been maintained during the first 6 months of continuous therapy, WBC counts and ANCs can be monitored every 2 weeks for the next 6 months. Thereafter, if acceptable WBC counts and ANCs (WBC count ≥ 3500/mm³ and ANC ≥ 2000/mm³) have been maintained during the second 6 months of continuous therapy, WBC count and ANC can be monitored every 4 weeks.

When treatment with VERSACLOZ is discontinued (regardless of the reason), WBC count and ANC must be monitored weekly for at least 4 weeks from the day of discontinuation or until WBC count ≥ 3500/mm³ and ANC ≥ 2000/mm³.

Table 2 provides a summary of the frequency of monitoring that should occur based on various stages of therapy (e.g., initiation of therapy) or results from WBC count and ANC monitoring tests (e.g., moderate leukopenia). The text that follows should be consulted for additional details regarding the treatment of patients under the various conditions (e.g., severe leukopenia).

Advise patients to immediately report the appearance of signs/symptoms consistent with agranulocytosis or infection (e.g., fever, weakness, lethargy, or sore throat) at any time during VERSACLOZ therapy. Such patients should have a WBC count and an ANC performed promptly.

Table 2: Frequency of Monitoring Based on Stage of Therapy or Results from WBC Count and ANC Monitoring Tests

Situation Hematological Values for Monitoring Frequency of WBC Count and ANC Monitoring
Initiation of therapy WBC count ≥ 3500/mm³ and ANC ≥ 2000/mm³
Note: Do not initiate in patients with a history of clozapine-induced agranulocytosis or severe granulocytopenia.
Weekly for 6 months
6 to 12 months of therapy WBC ≥ 3500/mm³ and ANC ≥ 2000/mm³ Every 2 weeks for 6 months
12 months of therapy WBC ≥ 3500/mm³ and ANC ≥ 2000/mm³ Every 4 weeks ad infinitum
Immature forms present N/A Repeat WBC and ANC
Discontinuation of therapy N/A Weekly for at least 4 weeks from day of discontinuation or until WBC ≥ 3500/mm³ and ANC ≥ 2000/mm³
Substantial drop in WBC or ANC Single drop or cumulative drop within 3 weeks of: WBC ≥ 3000/mm³ or ANC ≥ 1500/mm³
  1. Repeat WBC and ANC
  2. If repeat values are: WBC 3000/mm³ to 3500/mm³ and ANC > 2000/mm³, then monitor twice weekly
Mild leukopenia and/or Mild granulocytopenia If WBC 3000/mm³ to < 3500/mm³ and/or ANC 1500/mm³ to < 2000/mm³ Twice weekly until WBC > 3500/mm³ and ANC > 2000/mm³ then return to previous monitoring frequency
Moderate leukopenia and/or Moderate granulocytopenia WBC 2000/mm³ to < 3000/mm³ and/or ANC 1000/mm³ to < 1500/mm³
  1. Interrupt therapy
  2. Daily until WBC > 3000/mm³ and ANC > 1500/mm³
  3. Twice weekly until WBC > 3500/mm³ and ANC > 2000/mm³
  4. May rechallenge when WBC > 3500/mm³ and ANC > 2000/mm³
  5. If rechallenged, monitor weekly for 1 year before returning to the usual monitoring schedule of every 2 weeks for 6 months and then every 4 weeks ad infinitum
Severe leukopenia and/or Severe granulocytopenia WBC count < 2000/mm³ and/or ANC < 1000/mm³
  1. Discontinue treatment and do not rechallenge patient
  2. Monitor until normal and for at least four weeks from day of discontinuation as follows:
  • Daily until WBC > 3000/mm³ and ANC > 1500/mm³
  • Twice weekly until WBC > 3500/mm³ and ANC > 2000/mm³
  • Weekly after WBC > 3500/mm³
Agranulocytosis ANC < 500/mm³
  1. Discontinue treatment and do not rechallenge patient
  2. Monitor until normal and for at least four weeks from day of discontinuation as follows:
  • Daily until WBC > 3000/mm³ and ANC > 1500/mm³
  • Twice weekly until WBC > 3500/mm³ and ANC > 2000/mm³
  • Weekly after WBC > 3500/mm³
WBC = White blood cell
ANC = Absolute neutrophil count

Decrements in WBC Count and/or ANC

Consult Table 2 above to determine how to monitor patients who experience decrements in WBC count and/or ANC at any point during treatment. Additionally, patients should be carefully monitored for flu-like symptoms or other symptoms suggestive of infection.

Nonrechallengeable Patients

If the total WBC count falls below 2000/mm³ or the ANC falls below 1000/mm³, bone-marrow aspiration should be considered to ascertain granulopoietic status and patients should not be rechallenged with VERSACLOZ. Protective isolation with close observation may be indicated if granulopoiesis is determined to be deficient. Should evidence of infection develop, the patient should have appropriate cultures performed and an appropriate antibiotic regimen instituted.

Patients discontinued from clozapine therapy due to significant granulopoietic suppression have been found to develop agranulocytosis upon rechallenge, often with a shorter latency on reexposure. To reduce the chances of rechallenge occurring in patients who have experienced significant bone-marrow suppression during VERSACLOZ therapy, a single, national master file (i.e., Nonrechallengeable Database) is confidentially maintained.

Treatment of Rechallengeable Patients

Patients may be rechallenged with VERSACLOZ if their WBC count does not fall below 2000/mm³ and the ANC does not fall below 1000/mm³. However, analysis of the data from the Clozapine National Registry suggests that patients who have an initial episode of moderate leukopenia (3000/mm³ > WBC count ≥ 2000/mm³) have up to a 12-fold increased risk of having a subsequent episode of agranulocytosis when rechallenged as compared to the full cohort of patients treated with clozapine. Although VERSACLOZ therapy may be resumed if no symptoms of infection develop and when the WBC count rises above 3500/mm³ and the ANC rises above 2000/mm³, prescribers are strongly advised to consider whether the benefit of continuing VERSACLOZ treatment outweighs the increased risk of agranulocytosis.

Analyses of the Clozapine National Registry have shown an increased risk of having a subsequent episode of granulopoietic suppression up to a year after recovery from the initial episode. Therefore, as noted in Table 2, patients must undergo weekly WBC count and ANC monitoring for one year following recovery from an episode of moderate leukopenia and/or moderate granulocytopenia regardless of when the episode develops. If acceptable WBC counts and ANC (WBC count ≥ 3500/mm³ and ANC ≥ 2000/mm³) have been maintained during the year of weekly monitoring, WBC counts can be monitored every 2 weeks for the next 6 months. If acceptable WBC counts and ANC (WBC count ≥ 3500/mm³ and ANC ≥ 2000/mm³) continue to be maintained during the 6 months of every-2-week monitoring, WBC counts can be monitored every 4 weeks thereafter, ad infinitum.

Interruptions in Therapy

Figure 1 provides instructions regarding re-initiating therapy and subsequently the frequency of WBC count and ANC monitoring after a period of interruption.

Figure 1: Resuming Monitoring Frequency after Interruption of Therapy

Resuming Monitoring Frequency after Interruption of Therapy - Illustration

*Transitions to reduce frequency of monitoring only permitted if all WBC counts ≥ 3500/mm³ and ANCs ≥ 2000/mm³.

VERSACLOZ Patient Registry Because Of The Risk Of Agranulocytosis

Because of the risk of agranulocytosis, VERSACLOZ is available only through a restricted program called the VERSACLOZ Patient Registry. Under the VERSACLOZ Patient Registry, prescribers, patients, pharmacies, and distributors must enroll in the program.

Required components of the VERSACLOZ Patient Registry are:

  • Healthcare professionals who prescribe VERSACLOZ must enroll in the program and comply with the Registry requirements.
  • Pharmacies that dispense VERSACLOZ must enroll in the program and comply with the Registry requirements.
  • Routine monitoring and submission of laboratory results (WBC and ANC) is required during treatment with VERSACLOZ.
  • Patients that receive VERSACLOZ must be enrolled in a registry.

Further information is available at http://www.versaclozregistry.com or 1-877-329-2256.

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 VERSACLOZ (i.e., 2 days or more since the last dose), re-initiate treatment at 12.5 mg dose once daily or twice daily [see DOSAGE AND ADMINISTRATION].

Use VERSACLOZ 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 VERSACLOZ 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 VERSACLOZ 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 VERSACLOZ 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 VERSACLOZ. However, if the benefit of VERSACLOZ treatment is judged to outweigh the potential risks of recurrent myocarditis or cardiomyopathy, the clinician may consider rechallenge with VERSACLOZ in consultation with a cardiologist, after a complete cardiac evaluation, and under close monitoring.

Consider the possibility of myocarditis or cardiomyopathy in patients receiving VERSACLOZ 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 VERSACLOZ 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 VERSACLOZ. It is common for nonspecific flulike 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. VERSACLOZ 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/mm³, 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 VERSACLOZ 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 VERSACLOZ 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 VERSACLOZ.

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 VERSACLOZ under careful monitoring. If the total eosinophil count continues to increase over several weeks in the absence of systemic disease, the decision to interrupt VERSACLOZ 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 VERSACLOZ, 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 VERSACLOZ, and electrolyte abnormalities.

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

Use caution when administering concomitant medications that prolong the QT interval or inhibit the metabolism of VERSACLOZ. 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 antiarrhythmic (e.g., amiodarone, sotalol), and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus). VERSACLOZ is primarily metabolized by CYP isoenzymes 1A2, 2D6, and 3A4. Concomitant treatment with inhibitors of these enzymes can increase the concentration of VERSACLOZ [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 VERSACLOZ.

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 VERSACLOZ 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 3). 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 3: 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 VERSACLOZ, 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 4). In addition, clozapine treatment was associated with categorical increases in serum total cholesterol and triglyceride, as illustrated in Table 5.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 4: 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 5: 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 clozapine. Monitor weight during treatment with VERSACLOZ. Table 6 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 6: 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 (154 - 182) 42 -0.6 12 +5.7 0 0
48 weeks (Day 322 -350) 3 +3.7 3 +13.7 0 0

Table 7 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 7: 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 VERSACLOZ 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., agranulocytosis, 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 comorbid 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 selflimited, 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 agranulocytosis or infection. Consider the possibility of NMS.

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

VERSACLOZ has potent anticholinergic effects. Treatment with VERSACLOZ 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 VERSACLOZ 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

VERSACLOZ can cause sedation and impairment of cognitive and motor performance. Caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain that VERSACLOZ 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 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 VERSACLOZ 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 VERSACLOZ 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.

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 VERSACLOZ or other antipsychotics or other patient populations. VERSACLOZ should be used with caution in patients with risk factors for cerebrovascular adverse reactions.

Recurrence Of Psychosis And Cholinergic Rebound After Abrupt Discontinuation Of VERSACLOZ

If abrupt discontinuation of VERSACLOZ is necessary (because of agranulocytosis or another medical condition, for example), monitor carefully for the recurrence of psychotic symptoms and adverse reactions related to cholinergic rebound, such as profuse sweating, headache, nausea, vomiting and diarrhea.

Patient Counseling Information

See FDA-approved patient labeling (Patient Information and Instructions for Use).

Discuss the following issues with patients and caregivers:

  • Agranulocytosis: Prior to initiating treatment, educate patients and caregivers about the significant risk of developing agranulocytosis. Advise them to immediately report the appearance of signs or symptoms consistent with agranulocytosis or infection (e.g., fever; mucus membrane ulcers; skin, pharyngeal, vaginal, urinary, or pulmonary infection; or extreme weakness or lethargy) at any time during VERSACLOZ therapy [see WARNINGS AND PRECAUTIONS].
    • Inform patients and caregivers that VERSACLOZ Oral Suspension will be made available only through a special program designed to ensure the required blood monitoring in order to reduce the risk of developing agranulocytosis. Inform patients and caregivers the WBC count and ANC will be monitored as follows:
      • Weekly blood tests are required for the first 6 months.
      • If acceptable WBC counts and ANCs (WBC count ≥ 3500/mm³ and ANC ≥ 2000/mm³) have been maintained during the first 6 months of continuous therapy, then WBC counts and ANCs can be monitored every 2 weeks for the next 6 months.
      • Thereafter, if acceptable WBC counts and ANCs have been maintained during the second 6 months of continuous therapy, WBC counts and ANCs can be monitored every 4 weeks.
  • Seizures: Inform patients and caregivers about the significant risk of seizure during VERSACLOZ treatment. Caution them about driving and any other potentially hazardous activity while taking VERSACLOZ [see WARNINGS AND PRECAUTIONS].
  • Metabolic Changes (hyperglycemia and diabetes mellitus, dyslipidemia, weight gain): Educate patients and caregivers about the risk of metabolic changes and the need for specific monitoring. The risks include hyperglycemia and diabetes mellitus, dyslipidemia, weight gain, and cardiovascular reactions. Educate patients and caregivers about the symptoms of hyperglycemia (high blood sugar) and diabetes mellitus (e.g., polydipsia, polyuria, polyphagia, and weakness). Monitor all patients for these symptoms. Patients who are diagnosed with diabetes or have risk factors for diabetes (obesity, family history of diabetes) should have their fasting blood glucose monitored before beginning treatment and periodically during treatment. Patients who develop symptoms of hyperglycemia should have assessments of fasting glucose. Clinical monitoring of weight is recommended [see WARNINGS AND PRECAUTIONS].
  • Orthostatic Hypotension, Bradycardia, and Syncope: Inform patients and caregivers about the risk of orthostatic hypotension and syncope, especially during the period of initial dose titration. Instruct them to strictly follow the clinician's instructions for dosage and administration [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].
  • Interference with Cognitive and Motor Performance: Caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain that VERSACLOZ does not affect them adversely [see WARNINGS AND PRECAUTIONS].
  • Missed Doses and Re-initiating Treatment: Inform patients and caregivers that if the patient misses taking VERSACLOZ for more than 2 days, they should not restart their medication at the same dosage but should contact their physician for dosing instructions [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].
  • QT Interval Prolongation: Advise patients to consult their clinician immediately if they feel faint, lose consciousness or have signs or symptoms suggestive of arrhythmia. Instruct patients to not take VERSACLOZ with other drugs that cause QT interval prolongation. Instruct patients to inform their clinicians that they are taking VERSACLOZ before any new drug [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].
  • Concomitant Medication: Advise patients and caregivers to notify the physician if they are taking or plan to take any prescription or over-the-counter drugs or alcohol [see DRUG INTERACTIONS].
  • Pregnancy: Patients and caregivers should notify the physician if the patient becomes pregnant or intends to become pregnant during therapy [see Use In Specific Populations].
  • Nursing: Advise patients and caregivers that the patient should not breast feed an infant if they are taking VERSACLOZ [see Use in Specific Populations].
  • Patient Instructions for Use: Educate the patient and caregiver about the Patient Instructions for Use if VERSACLOZ will be administered at home. Discuss the specific steps for administering the prescribed dose using the oral syringe [see DOSAGE AND ADMINISTRATION].

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, VERSACLOZ 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 selflimited 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

VERSACLOZ is present in human milk. Because of the potential for serious adverse reactions in nursing infants from VERSACLOZ, 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 VERSACLOZ to determine whether those over 65 years of age differ from younger subjects in their response to VERSACLOZ.

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 VERSACLOZ 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].

Last reviewed on RxList: 1/23/2014
This monograph has been modified to include the generic and brand name in many instances.

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