Versacloz

Description for Versacloz

Versacloz, an atypical antipsychotic drug, is a tricyclic dibenzodiazepine derivative, 8-chloro-11-(4-methyl-1- piperazinyl)-5H-dibenzo[b,e][1,4]diazepine.

The structural formula is:

C₁₈H₁₉CIN₄    Mol. Wt. 326.83

Versacloz is available as a free-flowing yellow suspension. Each mL contains 50 mg of clozapine.

The active component of Versacloz is clozapine. The remaining components are glycerin, sorbitol (crystallizing), sodium dihydrogen phosphate dihydrate, xanthan gum, sodium methylparaben, sodium propylparaben, povidone, water, and sodium hydroxide to adjust to a pH range of 6.5-7.0.

ADVERSE REACTIONS

The following adverse reactions are discussed in more detail in other sections of the labeling:

• Severe Neutropenia [see Warnings and Precautions (5.1)].
• Orthostatic Hypotension, Bradycardia, and Syncope [see Warnings and Precautions (5.2)].
• Falls [see Warnings and Precautions (5.3)]
• Seizures [seeWarnings and Precautions (5.4)].
• Myocarditis, Pericarditis, Cardiomyopathy and Mitral Valve Incompetence [seeWarnings and Precautions (5.5)].
• Increased Mortality in Elderly Patients with Dementia-Related Psychosis [seeWarnings and Precautions (5.6)].
• Gastrointestinal Hypomotility and Severe Complications [see Warnings and Precautions (5.7)].
• Eosinophilia [seeWarnings and Precautions (5.8)].
• QT Interval Prolongation [seeWarnings and Precautions (5.9)].
• Metabolic Changes (Hyperglycemia and Diabetes Me litus, Dyslipidemia, and Weight Gain) [seeWarnings and Precautions (5.10)].
• Neuroleptic Malignant Syndrome [seeWarnings and Precautions (5.11)].
• Hepatotoxicity [see Warnings and Precautions (5.12)].
• Fever [seeWarnings and Precautions (5.13)].
• Pulmonary Embolism [seeWarnings and Precautions (5.14)].
• Anticholinergic Toxicity [seeWarnings and Precautions (5.15)].
• Interference with Cognitive and Motor Performance [seeWarnings and Precautions (5.16)].
• Tardive Dyskinesia [seeWarnings and Precautions (5.17)].
• Cerebrovascular Adverse Reactions [seeWarnings and Precautions (5.18)].
• Recurrence of Psychosis and Cholinergic Rebound after Abrupt Discontinuation [seeWarnings and Precautions (5.19)].

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.The most commonly reported adverse reactions (>5%) across clozapine clinical trials were: CNS reactions, including sedation, dizziness/vertigo, headache, and tremor; cardiovascular reactions, including tachycardia, hypotension, and syncope; autonomic nervous system reactions, including hypersalivation, sweating, dry mouth, and visual disturbances; gastrointestinal reactions, including constipation and nausea; and fever.

Table 9 summarizes the most commonly reported adverse reactions (>5%) in clozapine- treated patients (compared to chlorpromazine-treated patients) in the pivotal, 6-week, contro led trial in treatment-resistant schizophrenia.

Table 9: Common Adverse Reactions (≥5%) in the 6-Week, Randomized, Chlorpromazine-contro led Trial in Treatment-Resistant Schizophrenia

Adverse Reaction	Clozapine (N=126) (%)	Chlorpromazine (N=142) (%)
Sedation	21	13
Tachycardia	17	11
Constipation	16	12
Dizziness	14	16
Hypotension	13	38
Fever (hyperthermia)	13	4
Hypersalivation	13	1
Hypertension	12	5
Headache	10	10
Nausea/vomiting	10	12
Dry mouth	5	20

Table 10 summarizes the adverse reactions reported in clozapine-treated patients at a frequency of 2% or greater across all clozapine studies (excluding the 2-year InterSePT™ Study). These rates are not adjusted for duration of exposure.

Table 10: Adverse Reactions (≥2%) Reported in Clozapine-treated Patients (N=842) across a l Clozapine Studies (excluding the 2-year InterSePT™ Study)

Body System Adverse Reaction	Clozapine (N = 842) Percentage of Patients
Central Nervous System
Drowsiness/Sedation	39
Dizziness/Vertigo	19
Headache	7
Tremor	6
Syncope	6
Disturbed Sleep/Nightmares	4
Restlessness	4
Hypokinesia/Akinesia	4
Agitation	4
Seizures (convulsions)†	3
Rigidity	3
Akathisia	3
Confusion	3
Fatigue	2
Insomnia	2
Cardiovascular
Tachycardia†	25
Hypotension	9
Hypertension	4
Gastrointestinal
Constipation	14
Nausea	5
Abdominal Discomfort/Heartburn	4
Nausea/Vomiting	3
Vomiting	3
Diarrhea	2
Urogenital
Urinary Abnormalities	2
Autonomic Nervous System
Salivation	31
Sweating	6
Dry Mouth	6
Visual Disturbances	5
Skin
Rash	2
Hemic/Lymphatic
Leukopenia/Decreased WBC/Neutropenia	3
Miscellaneous
Fever	5
Weight Gain	4
† Rate based on population of approximately 1700 exposed during premarket clinical evaluation of clozapine.

Table 11 summarizes the most commonly reported adverse reactions (>10% of the clozapine or olanzapine group) in the InterSePT™ Study. This was an adequate and well- controlled, two-year study evaluating the efficacy of clozapine relative to olanzapine in reducing the risk of suicidal behavior in patients with schizophrenia or schizoaffective disorder. The rates are not adjusted for duration of exposure.

Table 11: Incidence of Adverse Reactions in Patients Treated with Clozapine or Olanzapine in the InterSePT™ Study (≥10% in the clozapine or olanzapine group)

Adverse Reactions	Clozapine N=479 % Reporting	Olanzapine N=477 % Reporting
Salivary hypersecretion	48%	6%
Somnolence	46%	25%
Weight increased	31%	56%
Dizziness (excluding vertigo)	27%	12%
Constipation	25%	10%
Insomnia	20%	33%
Nausea	17%	10%
Vomiting	17%	9%
Dyspepsia	14%	8%

Dystonia

Class effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of clozapine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Central Nervous System

Delirium, EEG abnormal, myoclonus, paresthesia, possible cataplexy, status epilepticus, obsessive compulsive symptoms, and post-discontinuation cholinergic rebound adverse reactions.

Cardiovascular System

Atrial or ventricular fibrillation, ventricular tachycardia, palpitations, QT interval prolongation, Torsades de Pointes, mitral valve incompetence associated with clozapine- related cardiomyopathy, myocardial infarction, cardiac arrest, myocarditis, pericarditis, and periorbital edema.

Endocrine System

Pseudopheochromocytoma.

Gastrointestinal System

Acute pancreatitis, dysphagia, salivary gland swelling, megacolon, fecal incontinence, and intestinal ischemia, infarction, perforation, ulceration or necrosis.

Hepatobiliary System

Cholestasis, hepatitis, jaundice, hepatotoxicity, hepatic steatosis, hepatic necrosis, hepatic fibrosis, hepatic cirrhosis, liver injury (hepatic, cholestatic, and mixed), and liver failure.

Immune System Disorders

Angioedema, leukocytoclastic vasculitis.

Urogenital System

Acute interstitial nephritis, nocturnal enuresis, priapism, renal failure and retrograde ejaculation.

Skin and Subcutaneous Tissue Disorders

Hypersensitivity reactions: photosensitivity, vasculitis, erythema multiforme, skin pigmentation disorder, and Stevens-Johnson Syndrome.

Musculoskeletal System and Connective Tissue Disorders

Myasthenic syndrome, rhabdomyolysis, and systemic lupus erythematosus.

Respiratory System

Aspiration, pleural effusion, pneumonia, lower respiratory tract infection, sleep apnea.

Hemic and Lymphatic System

Mild, moderate, or severe leukopenia, agranulocytosis, granulocytopenia, WBC decreased, deep vein thrombosis, elevated hemoglobin/hematocrit, erythrocyte sedimentation rate (ESR) increased, sepsis, thrombocytosis, and thrombocytopenia.

Vision Disorders

Narrow-angle glaucoma.

Miscellaneous

Creatine phosphokinase elevation, hyperuricemia, hyponatremia, and weight loss.

Drug Interactions for Versacloz

Potential for Other Drugs to Affect VERSACLOZ

Clozapine is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP3A4, and CYP2D6. Use caution when administering VERSACLOZ concomitantly with drugs that are inducers or inhibitors of these enzymes.

CYP1A2 Inhibitors

Concomitant use of VERSACLOZ and CYP1A2 inhibitors can increase plasma levels of clozapine, potentially resulting in adverse reactions. 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). The VERSACLOZ dose should be increased to the original dose when coadministration of strong CYP1A2 inhibitors is discontinued [see Dosage and Administration (2.8), Clinical Pharmacology (12.3)].

Moderate or weak CYP1A2 inhibitors include oral contraceptives and caffeine. Monitor patients closely when VERSACLOZ is coadministered with these inhibitors. Consider reducing the VERSACLOZ dosage if necessary [see Dosage and Administration (2.8)] .

CYP2D6 and CYP3A4 Inhibitors

Concomitant treatment with VERSACLOZ and CYP2D6 or CYP3A4 inhibitors (e.g., cimetidine, escitalopram, erythromycin, paroxetine, bupropion, fluoxetine, quinidine, duloxetine, terbinafine, or sertraline) can increase clozapine levels and lead to adverse reactions [see Clinical Pharmacology (12.3)] . Use caution and monitor patients closely when using such inhibitors. Consider reducing the VERSACLOZ dose [see Dosage and Administration (2.8)] .

CYP1A2 and CYP3A4 Inducers

Concomitant treatment with drugs that induce CYP1A2 or CYP3A4 can decrease the plasma concentration of clozapine, resulting in decreased effectiveness of VERSACLOZ. Tobacco smoke is a moderate inducer of CYP1A2. Strong CYP3A4 inducers include carbamazepine, phenytoin, St. John’s wort, and rifampin. It may be necessary to increase the VERSACLOZ dose if used concomitantly with inducers of these enzymes.

However, concomitant use of VERSACLOZ and strong CYP3A4 inducers is not recommended [see Dosage and Administration (2.8)].

Consider reducing the VERSACLOZ dosage when discontinuing coadministered enzyme inducers, because discontinuation of inducers can result in increased clozapine plasma levels and an increased risk of adverse reactions [seeDosage and Administration (2.8)].

Anticholinergic Drugs

Concomitant treatment with clozapine and other drugs with anticholinergic activity (e.g., benztropine, cyclobenzaprine, diphenhydramine) can increase the risk for anticholinergic toxicity and severe gastrointestinal adverse reactions related to hypomotility. Avoid concomitant use of VERSACLOZ with anticholinergic drugs when possible [see Warnings and Precautions ( 5.7, 5.15)].

Drugs that Cause QT Interval Prolongation

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, and pimozide), specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin), Class 1A antiarrhythmics (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) [seeWarnings and Precautions (5.9)].

Potential for VERSACLOZ to Affect Other Drugs

Concomitant use of VERSACLOZ with other drugs metabolized by CYP2D6 can increase levels of these CYP2D6 substrates. Use caution when coadministering VERSACLOZ with other drugs that are metabolized by CYP2D6. It may be necessary to use lower doses of such drugs than usually prescribed. Such drugs include specific antidepressants, phenothiazines, carbamazepine, and Type 1C antiarrhythmics (e.g., propafenone, flecainide, and encainide).

Warnings for Versacloz

Included as part of the PRECAUTIONS section.

Precautions for Versacloz

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]. 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 2.4
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/^L 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/uL
* 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 2.4
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 and Instructions for Patients, under PATIENT COUNSELING INFORMATION (17).

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.

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 VERSACLOZ in patients who have had even a brief interruption in treatment with VERSACLOZ, the dosage must be reduced. This is necessary to minimize the risk of hypotension, bradycardia, and syncope [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).

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.

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, Cardiomyopathy And Mitral Valve Incompetence

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 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 VERSACLOZ. 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. In patients who are diagnosed with cardiomyopathy while taking clozapine mitral valve incompetence has been reported. These cases reported either mild or moderate mitral regurgitation on two-dimensional echocardiography. In patients with suspected cardiomyopathy, consider a 2D-echo Doppler examination to identify mitral valve incompetence.

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].

Gastrointestinal Hypomotility And Severe Complications

Severe gastrointestinal adverse reactions have occurred with the use of VERSACLOZ, primarily due to its potent anticholinergic effects and resulting gastrointestinal hypomotility. In post marketing experience, reported effects range from constipation to paralytic ileus. Increased frequency of constipation and delayed diagnosis and treatment increased the risk of severe complications of gastrointestinal hypomotility, which can result in, fecal impaction, megacolon, and intestinal obstruction, ischemia, infarction, perforation, ulceration, or necrosis [see ADVERSE REACTION]. These reactions have resulted in hospitalization, surgery, and death. The risk for severe adverse reactions is further increased with anticholinergic medications (and other medications that decrease gastrointestinal peristalsis); therefore, concomitant use should be avoided when possible [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS].

Prior to initiating VERSACLOZ, screen for constipation and treat as necessary. Subjective symptoms of constipation may not accurately reflect the degree of gastrointestinal hypomotility in VERSACLOZ treated patients. Therefore, reassess bowel function frequently with careful attention to any changes in the frequency or character of bowel movements, as well as signs and symptoms of complications of hypomotility (e.g., nausea, vomiting, abdominal distension, abdominal pain). If constipation or gastrointestinal hypomotility are identified, monitor closely and treat promptly with appropriate laxatives, as necessary, to prevent severe complications. Consider prophylactic laxatives in high risk patients.

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 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 VERSACLOZ, 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 VERSACLOZ. 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 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 VERSACLOZ. 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 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 VERSACLOZ. Monitor weight during treatment with VERSACLOZ. 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 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., 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.

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]. 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 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 WARNINGS AND PRECAUTIONS].

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]. 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, DRUG INTERACTIONS].

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 reaction.

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, WARNINGS AND PRECAUTIONS], 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

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION and Instructions for Use).

Severe Neutropenia

• Instruct patients (and caregivers) beginning treatment with VERSACLOZ about the risk of developing severe neutropenia and infection.
• Instruct patients to immediately report to their physician any symptom or sign of infection (e.g., flu-like illness; fever; lethargy; general weakness or malaise; mucus membrane ulceration; skin, pharyngeal, vaginal, urinary, or pulmonary infection; or extreme weakness or lethargy) occurring at any time during VERSACLOZ therapy, to aid in evaluation for neutropenia and to institute prompt and appropriate management. [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]. Advise patients to consult their clinician immediately if they feel faint, lose consciousness or have signs or symptoms suggestive of bradycardia or arrhythmia WARNINGS AND PRECAUTIONS].

Falls

Inform patients of the risk of falls, which may lead to fractures or other injuries [see WARNINGS AND PRECAUTIONS].

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].

Gastrointestinal Hypomotility With Severe Complications

Educate patients and caregivers on the risks, prevention, and treatment of clozapine-induced constipation, including medications to avoid when possible (e.g., drugs with anticholinergic activity). Encourage appropriate hydration, physical activity, and fiber intake and emphasize that prompt attention and treatment to the development of constipation or other gastrointestinal symptoms is critical in preventing severe complications. Advise patients and caregivers to contact their health care provider if they experience symptoms of constipation (e.g., difficulty passing stools, incomplete passage of stool, decreased bowel movement frequency) or other symptoms associated with gastrointestinal hypomotility (e.g., nausea, abdominal distension or pain, vomiting) [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS].

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].

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].

Interference With Cognitive And Motor Performance

Because VERSACLOZ may have the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that VERSACLOZ therapy does not affect them adversely [see WARNINGS AND PRECAUTIONS].

Hepatotoxicity

Instruct patients to immediately report to their physician any symptoms or signs of potential liver injury (e.g. fatigue, malaise, anorexia, nausea, jaundice, bilirubinemia, coagulopathy, and hepatic encephalopathy). [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, he or she should not restart his or her medication at the same dosage but should contact their physician for dosing instructions [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].

Pregnancy

Advise pregnant women to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with VERSACLOZ. Advise patients that VERSACLOZ may cause extrapyramidal and/or withdrawal symptoms (agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder) in a neonate. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to clozapine during pregnancy [see Use In Specific Populations].

Lactation

Advise breastfeeding women using VERSACLOZ to monitor infants for excess sedation and to seek medical care if they notice this sign [see Use In Specific Populations].

Concomitant Medication

Advise patients to inform their healthcare provider if they are taking, or plan to take, any prescription or over-the-counter drugs; there is a potential for significant drug-drug interactions [see DOSAGE AND ADMINISTRATION, DRUG INTERACTIONS].

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

PregnancyExposureRegistry

There is a pregnancy exposureregistry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including clozapine, during pregnancy. Health care providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at1-866-961-2388 or visit https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.

Risk Summary

Neonates exposed to antipsychotic drugs, including VERSACLOZ, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations). Overall, available data from published epidemiologic studies of pregnant women exposed to clozapine have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). There are risks to the mother associated with untreated schizophrenia and with exposure to antipsychotics, including VERSACLOZ, during pregnancy (see Clinical Considerations).

In animal reproduction studies, no adverse developmental effects were observed when clozapine was administered orally to pregnant rats or rabbits during the period of organogenesis, or to pregnant rats during pregnancy and lactation, at doses up to approximately 0.4 and 0.9 times the maximum recommended human dose (MRHD) of 900 mg/day, for rats and rabbits respectively, based on mg/m² body surface area (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Disease-Associated Maternal And/Or Embryo/Fetal Risk

There is a risk to the mother from untreated schizophrenia, including increased risk of relapse, hospitalization, and suicide. Schizophrenia is associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors.

Fetal/Neonatal Adverse Reactions

Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who have been exposed to antipsychotic drugs, including VERSACLOZ, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization.

Data

Human Data

Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics do not report a clear association with antipsychotics and major birth defects. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects.

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 F1 or F2 generations at doses up to 0.4 times the MRHD of 900 mg/day on a mg/m² body surface area basis.

Lactation

Risk Summary

Clozapine is present in human milk. There are reports of sedation and a report of agranulocytosis in an infant exposed to clozapine through human milk (see Clinical Considerations). There is no information on the effects of clozapine on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for VERSACLOZ and any potential adverse effects on the breastfed-child from VERSACLOZ or from the underlying maternal condition.

Clinical Considerations

Infants exposed to VERSACLOZ should be monitored for excess sedation.

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].

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.

OVERDOSES

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

There are no specific antidotes for VERSACLOZ. Establish and maintain an airway; ensure adequate oxygenation and ventilation. Monitor cardiac status and vital signs. Use general symptomatic and supportive measures. Consider the possibility of multiple-drug involvement.

Contact a Certified Poison Control Center for the most up to date information on the management of overdosage (1-800-222-1222).

Contraindications for Versacloz

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)] .

Clinical Pharmacology for Versacloz

Mechanism Of Action

The mechanism of action of clozapine is unknown. However, it has been proposed that the therapeutic efficacy of clozapine in schizophrenia is mediated through antagonism of the dopamine type 2 (D 2) and the serotonin type 2A (5-HT 2A) receptors. VERSACLOZ also acts as an antagonist at adrenergic, cholinergic, histaminergic and other dopaminergic and serotonergic receptors.

Pharmacodynamics

Clozapine demonstrated binding affinity to the following receptors: histamine H 1(K i1.1 nM), adrenergic α 1A(K i1.6 nM), serotonin 5-HT 6(K i4 nM), serotonin 5-HT 2A(K i5.4 nM), muscarinic M 1(K i6.2 nM), serotonin 5-HT 7(K i6.3 nM), serotonin 5-HT 2C(K i9.4 nM), dopamine D 4(K i24 nM), adrenergic α 2A(K i90 nM), serotonin 5-HT 3 (K i95 nM), serotonin 5-HT 1A(K i120 nM), dopamine D 2(K i160 nM), dopamine D 1(K i270 nM), dopamine D 5(K i454 nM), and dopamine D 3(K i555 nM).

Clozapine causes little or no prolactin elevation.

Clinical electroencephalogram (EEG) studies demonstrated that clozapine increases delta and theta activity and slows dominant alpha frequencies. Enhanced synchronization occurs. Sharp wave activity and spike and wave complexes may also develop. Patients have reported an intensification of dream activity during clozapine therapy. REM sleep was found to be increased to 85% of the total sleep time. In these patients, the onset of REM sleep occurred almost immediately after falling asleep.

Pharmacokinetics

Absorption

In man, clozapine tablets (25 mg and 100 mg) are equally bioavailable relative to a clozapine solution. VERSACLOZ Oral Suspension is bioequivalent to clozapine marketed tablets.

Following oral administration of 100 mg to 800 mg VERSACLOZ, once daily, the average steady-state peak plasma concentration was 275 ng/mL (range: 105 - 723 ng/mL), occurring at the average of 2.2 hours (range: 1 - 3.5 hours) after dosing. The average minimum concentration at steady-state was 75 ng/mL (range: 11 - 198 ng/mL).

When VERSACLOZ was administered after a high fat meal there was no effect on the AUC_ss or C_{min, ss}, however C_max was reduced about 20%, and there was a slight delay in T_max of 0.5 hour from a median T_max of 2.0 hours under fasted conditions to 2.5 hours under fed conditions. The decrease in C_max is not considered clinically relevant.

Therefore VERSACLOZ may be taken without regard to meals.

Distribution

Clozapine is approximately 97% bound to serum proteins. The interaction between clozapine and other highly protein-bound drugs has not been fully evaluated but may be important [see Drug Interactions (7)].

Metabolism and Excretion

VERSACLOZ is almost completely metabolized prior to excretion, and only trace amounts of unchanged drug are detected in the urine and feces. VERSACLOZ is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP2D6, and CYP3A4. Approximately 50% of the administered dose is excreted in the urine and 30% in the feces. The demethylated, hydroxylated, and N-oxide derivatives are components in both urine and feces. Pharmacological testing has shown the desmethyl metabolite (norclozapine) to have only limited activity, while the hydroxylated and N-oxide derivatives were inactive. The mean elimination half-life of clozapine after a single 75 mg dose was 8 hours (range: 4-12 hours), compared to a mean elimination half-life of 12 hours (range: 4-66 hours), after achieving steady-state with 100 mg twice daily dosing.

A comparison of single-dose and multiple-dose administration of clozapine demonstrated that the elimination half-life increased significantly after multiple dosing relative to that after single-dose administration, suggesting the possibility of concentration-dependent pharmacokinetics. However, at steady-state, approximately dose-proportional changes with respect to AUC (area under the curve), peak, and minimum clozapine plasma concentrations were observed after administration of 37.5, 75, and 150 mg twice daily.

Drug-Drug Interaction Studies

Fluvoxamine

A pharmacokinetic study was conducted in 16 patients with schizophrenia who received clozapine under steady-state conditions. After coadministration of fluvoxamine for 14 days, mean trough concentrations of clozapine and its metabolites, N- desmethylclozapine and clozapine N-oxide, were elevated about three-fold compared to baseline steady-state concentrations.

Paroxetine, Fluoxetine, and Sertraline

In a study of patients with schizophrenia (n=14) who received clozapine under steady-state conditions, coadministration of paroxetine produced only minor changes in the levels of clozapine and its metabolites. However, other published reports describe modest elevations (less than two-fold) of clozapine and metabolite concentrations when clozapine was taken with paroxetine, fluoxetine, and sertraline.

Specific Populations

Renal or Hepatic Impairment

No specific pharmacokinetic studies were conducted to investigate the effects of renal or hepatic impairment on the pharmacokinetics of clozapine. Higher clozapine plasma concentrations are likely in patients with significant renal or hepatic impairment when given usual doses.

CYP2D6 Poor Metabolizers

A subset (3%–10%) of the population has reduced activity of CYP2D6 (CYP2D6 poor metabolizers). These individuals may develop higher than expected plasma concentrations of clozapine when given usual doses.

Patients with Pneumonia and other Inflammatory Conditions

Published case reports describe examples where pneumonia or other inflammatory- conditions may increase clozapine concentrations. The clinical significance, the impact of treatments to modulate this inflammation, and mechanism of this potential increase in clozapine concentrations have not been fully characterized but may involve reduced cytochrome P450 1A2 activity.

INSTRUCTIONS FOR USE

Supplies you wi l need to take your VERSACLOZ dose:

• VERSACLOZ^® oral Suspension bottle
• a bottle neck adaptor
• the correct oral syringe to measure your dose
  • If your dose is 1 mL (50 mg) or less, use the smaller 1 mL oral syringe.
  • If your dose is more than 1 mL (50 mg),use the larger 9 mL oral syringe.

 

Disposal of your oral syringe, empty VERSACLOZ bottle and bottle neck adaptor:

Place the cap back on the empty VERSACLOZ bottle before you throw it away. The oral syringe, empty bottle and bottle neck adaptor should be placed in your household trash when you finish your bottle of VERSACLOZ. The oral syringe should not be shared with other people or used for medicines other than VERSACLOZ.

Distributed by:
TruPharma, LLC
Tampa, FL 33609

This Patient Information and the Instructions for Use have been approved by the U.S. Food and Drug Administration.