Additional Important Safety Information

Contraindications include:

• VERSACLOZ is contraindicated in patients with a history of serious 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

Background

VERSACLOZ 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 (6.2) of the Prescribing Information]. 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 VERSACLOZ 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 VERSACLOZ 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.

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

Obtain a CBC, including the ANC value, prior to initiating treatment with VERSACLOZ 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: VERSACLOZ Treatment Recommendations Based on Absolute Neutrophil Count (ANC) Monitoring for the General Patient Population

ANC Level	VERSACLOZ 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	See Section 2.5 of the Prescribing Information
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

VERSACLOZ 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 VERSACLOZ-induced neutropenia. Additional evaluation may be needed to determine if baseline neutropenia is due to BEN. Consider hematology consultation before initiating or during VERSACLOZ treatment as necessary.

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

Table 3: Patients with Benign Ethnic Neutropenia (BEN); VERSACLOZ 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	See Section 2.5 of the Prescribing Information
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 VERSACLOZ 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 (5) and Instructions for Patients, under PATIENT COUNSELING INFORMATION (17) of the Prescribing Information.

Rechallenge after an ANC less than 500/µL (severe neutropenia)

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

Using VERSACLOZ 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 VERSACLOZ-induced neutropenia. There is no strong scientific rationale to avoid VERSACLOZ treatment in patients concurrently treated with these drugs. If VERSACLOZ 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.

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.

Gastrointestinal Hypomotility

Gastrointestinal hypomotility can range from constipation to paralytic ileus. Severe complications of gastrointestinal hypomotility can result in intestinal obstruction, fecal impaction, megacolon and intestinal ischemia or infarction. 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.

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 clozapine, 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 clozapine.
• 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 clozapine. 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 agranulocytosis, 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. Consider the possibility of NMS [see Warnings and Precautions (5.12) of the 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. Use with caution in patients with 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.

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.

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 severe neutropenia or another medical condition, for example) [see Dosage and Administration (2.5), 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 VERSACLOZ dose to one-third when coadministered with strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, 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 (5.3) 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 (5.16) 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 (5.18) 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 (2.8), 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 (2.8), Clinical Pharmacology (12.3) of the Prescribing Information].

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.

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.

You may contact the Clozapine REMS Program at 1-888-586-0758 or Fax: 1-800-878-5927
or at https://www.newclozapinerems.com.

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

Reference: 1. Versacloz^® Prescribing Information, Warminister, PA: Tasman Pharma Inc. 2021