Additional Important Safety Information

Contraindications include:

• VERSACLOZ is contraindicated in patients with a history of hypersensitivity to clozapine (e.g., photosensitivity, vasculitis, erythema multiforme, or Stevens-Johnson Syndrome) or any other component of VERSACLOZ [see Adverse Reactions (6.2) of the Prescribing Information].

Severe Neutropenia

VERSACLOZ has caused severe neutropenia (absolute neutrophil count (ANC) less than 500/μL) [see Adverse Reactions (6.1, 6.2) of the Full Prescribing Information] and is associated with an increased risk of serious and potentially fatal infections. Severe neutropenia occurred in a small percentage of VERSACLOZ-treated patients. The risk of severe neutropenia appears greatest during the first 18 weeks of VERSACLOZ treatment. The mechanism by which VERSACLOZ causes neutropenia is unknown. Neutropenia is not dose dependent.

Consider a hematology consultation before initiating VERSACLOZ treatment or during treatment.

ANC Monitoring and Dosage Modifications

Prior to initiating VERSACLOZ treatment, obtain a baseline ANC. VERSACLOZ initiation is not recommended in patients with a baseline ANC less than 1500/μL. Throughout VERSACLOZ treatment, regularly monitor ANC.

Table 1 under the Dosage and Administration section of this website provides recommendations for dosage modifications (dosage interruption and treatment discontinuation), based on ANC levels, during VERSACLOZ treatment and frequency of ANC monitoring [see Dosage and Administration (2.4) in the Full Prescribing Information].

ANC Monitoring and Dosage Modification in Patients with Benign Ethnic Neutropenia

Patients with Benign Ethnic Neutropenia (BEN) (also known as Duffy-null associated neutrophil count) generally have lower baseline neutrophil counts but they are not at higher risk for developing infections, and they are not at increased risk for developing VERSACLOZ-induced neutropenia.

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

Table 2 under the Dosage and Administration section of this website provides recommendations on dosage modifications (dosage interruption and treatment discontinuation), based on ANC monitoring, during VERSACLOZ treatment in patients with BEN and recommended frequency of ANC testing [see Dosage and Administration (2.5) in the Full Prescribing Information].

Management of VERSACLOZ-Treated Patients Who Develop a Fever

For patients who develop a fever during VERSACLOZ treatment:

• Interrupt VERSACLOZ in those who develop a temperature of 101.3°F (38.5°C) or greater and obtain an ANC level.
• If the ANC is less than 1000/μL in patients without BEN, initiate appropriate workup and treatment for infection. Table 1 under the Dosage and Administration section of this website provides dosage modifications based on ANC monitoring [see Dosage and Administration (2.4) of the Full Prescribing Information].

In patients with fever and a normal neutrophil count, see Warnings and Precautions (5.11) for neuroleptic malignant syndrome and Warnings and Precautions (5.13) for fever, of the Full Prescribing Information.

Restarting VERSACLOZ in Patients Who Recovered from Severe Neutropenia

Generally, do not rechallenge patients with VERSACLOZ in those who experienced severe neutropenia. However, for some patients who had resolution of their VERSACLOZ-related severe neutropenia after stopping VERSACLOZ, the risk of schizophrenia exacerbation from not restarting VERSACLOZ treatment may be greater than the risk of neutropenia reoccurrence from restarting VERSACLOZ (e.g., patients who have no treatment options other than VERSACLOZ).

Concomitant Use of VERSACLOZ with Other Drugs Known to Cause Neutropenia

If VERSACLOZ is used concomitantly with another drug known to cause neutropenia, consider more frequently ANC monitoring than the recommendations provided in Table 1 and Table 2 (refer to the Dosage and Administration section of this website).

Gastrointestinal Hypomotility

Gastrointestinal hypomotility can range from constipation to paralytic ileus. Severe complications of gastrointestinal hypomotility can result in fecal impaction, megacolon, and intestinal obstruction, ischemia, infarction, perforation, ulceration, or necrosis. These reactions have resulted in hospitalization, surgery and death. Reassess bowel function frequently with careful attention to any changes in the frequency or character of bowel movements or symptoms of hypomotility (nausea, vomiting, abdominal distension, or abdominal pain) and treat promptly with laxatives as necessary.

Falls

VERSACLOZ may cause somnolence, postural hypotension, and motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic treatment.

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 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 (7.1) and Clinical Pharmacology (12.3) of the Prescribing Information].

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 VERSACLOZ, have been associated with metabolic changes that can increase cardiovascular and cerebrovascular risk. These include:

• Hyperglycemia and Diabetes Mellitus: Monitor all patients for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Monitor glucose prior to starting treatment and periodically thereafter in patients with diabetes or at risk for diabetes. Hyperglycemia, in some cases extreme and associated with ketoacidosis and hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including VERSACLOZ.
• Dyslipidemia: Undesirable alterations in lipids have occurred in patients treated with atypical antipsychotics. Baseline and periodic follow-up lipid evaluations are recommended.
• Weight Gain: Significant weight gain has occurred. Monitor weight during treatment with VERSACLOZ.

Neuroleptic Malignant Syndrome (NMS)

NMS, a potentially fatal symptom complex, has been reported with administration of antipsychotic drugs, including VERSACLOZ. Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). Additional signs may include elevated creatine phosphokinase, myoglobinuria, rhabdomyolysis, and acute renal failure. Management should include immediate discontinuation of antipsychotics and other drugs not essential to concurrent therapy, intensive symptomatic treatment and medical monitoring, and treatment of comorbidities, including severe neutropenia, infection, heat stroke, primary CNS pathology, central anticholinergic toxicity, extrapyramidal symptoms, and drug fever. If a patient requires antipsychotic therapy after recovery from NMS, monitor closely. NMS can reoccur.

Hepatotoxicity

Severe, life threatening, and in some cases fatal hepatotoxicity including hepatic failure, hepatic necrosis, and hepatitis have been reported in patients treated with clozapine [see Adverse Reactions (6.2) of the Prescribing Information]. Monitor for the appearance of signs and symptoms of hepatotoxicity such as fatigue, malaise, anorexia, nausea, jaundice, bilirubinemia, coagulopathy, and hepatic encephalopathy. Perform serum tests for liver injury and consider permanently discontinuing treatment if hepatitis or transaminase elevations combined with other systemic symptoms are due to clozapine.

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 severe neutropenia or infection [see Warnings and Precautions (5.1)]. Consider the possibility of NMS [see Warnings and Precautions (5.11) of the Full Prescribing Information].

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, especially at higher dosages or in overdose situations [see Overdosage (10) of the Full Prescribing Information]. Use with caution in patients with a current diagnosis or prior history of constipation, urinary retention, clinically significant prostatic hypertrophy, or other conditions in which anticholinergic effects can lead to significant adverse reactions. When possible, avoid concomitant use with other anticholinergic medications because the risk for anticholinergic toxicity or severe gastrointestinal adverse reactions is increased [see Warnings and Precautions (5.7), Drug Interactions (7.1) of the Full Prescribing Information].

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 VERSACLOZ. 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.

TD may remit partially or completely if treatment is discontinued. Antipsychotic treatment, itself, may suppress (or partially suppress) the signs and symptoms, and it has the potential to mask the underlying process. The effect of symptom suppression on the long-term course of TD is unknown.

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 severe neutropenia or another medical condition, for example) [see Dosage and Administration (2.6), Warnings and Precautions (5.1) of the Prescribing Information], monitor carefully for the recurrence of psychotic symptoms and adverse reactions related to cholinergic rebound, such as profuse sweating, headache, nausea, vomiting, and diarrhea.

ADVERSE REACTIONS

Most common adverse reactions (≥5%) were: CNS reactions (sedation, dizziness/vertigo, headache, and tremor); cardiovascular reactions (tachycardia, hypotension, and syncope); autonomic nervous system reactions (hypersalivation, sweating, dry mouth, and visual disturbances); gastrointestinal reactions (constipation and nausea); and fever.

DRUG INTERACTIONS

• CYP1A2 Inhibitors: Reduce the VERSACLOZ dose to one third of the original dose when VERSACLOZ is coadministered with strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, or enoxacin). Dose reduction may be necessary with concomitant use of moderate or weak CYP1A2 inhibitors (e.g., oral contraceptives or caffeine).
• CYP2D6 or CYP3A4 Inhibitors. Dose reduction may be necessary with concomitant use of CYP2D6 or CYP3A4 inhibitors (e.g., cimetidine, escitalopram, erythromycin, paroxetine, bupropion, fluoxetine, quinidine, duloxetine, terbinafine, or sertraline).
• CYP1A2 or CYP3A4 Inducers. Concomitant use with strong CYP3A4 inducers (carbamazepine, phenytoin, St. John's wort, rifampin) is not recommended. Dose increase may be necessary with concomitant use of moderate CYP1A2 (e.g., tobacco smoke) or CYP3A4 inducers. Consider reducing VERSACLOZ dose when CYP1A2 (e.g., tobacco smoke) or CYP3A4 (e.g., carbamazepine) inducers are discontinued.

Pregnancy

VERSACLOZ should be used during pregnancy only if clearly needed.

Lactation

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 (5.2) of the Prescribing Information]. 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 (5.15) of the Prescribing Information].

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 (5.17) of the Prescribing Information].

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 (2.9), Clinical Pharmacology (12.3) of the Prescribing Information].

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 (2.9), Clinical Pharmacology (12.3) of the Prescribing Information].

OVERDOSAGE

Overdosage Experience

The most commonly reported signs and symptoms associated with clozapine overdose are: sedation, delirium, coma, tachycardia, hypotension, respiratory depression or failure, and hypersalivation. There are reports of aspiration pneumonia, cardiac arrhythmias, and seizure. Fatal overdoses have been reported with clozapine, generally at doses above 2500 mg. There have also been reports of patients recovering from overdoses well in excess of 4 g.

Management of Overdosage

For the most up-to-date information on the management of VERSACLOZ overdosage, contact a certified Regional Poison Control Center (1-800-222-1222). Telephone numbers of certified Regional Poison Control Centers are listed in the Physician’s Desk Reference^®, a registered trademark of PDR Network. Establish and maintain an airway; ensure adequate oxygenation and ventilation. Monitor cardiac status and vital signs. Use general symptomatic and supportive measures. There are no specific antidotes for VERSACLOZ.

In managing overdosage, consider the possibility of multiple-drug involvement.

Please see the full Prescribing Information for Important Safety Information, including
BOXED Warning.

Reference: 1. Versacloz^® Prescribing Information, Douglas Pharmaceuticals America Ltd. 2025