Uspen

Esquizofrenia resistente ao tratamento

FAZACLO está indicado no tratamento de pacientes gravemente doentes com esquizofrenia que não respondem adequadamente ao tratamento antipsicótico padrão. Devido aos riscos de neutropenia grave e de convulsões associadas ao seu uso, o FAZACLO deve ser usado apenas em pacientes que não responderam adequadamente ao tratamento antipsicótico padrão.

A eficácia da clozapina na esquizofrenia resistente ao tratamento foi demonstrada em um estudo de 6 semanas, randomizado, duplo-cego e controlado por ativos, comparando clozapina e clorpromazina em pacientes que falharam com outros antipsicóticos.

Redução do risco de comportamento suicida recorrente na esquizofrenia ou transtorno esquizoafetivo

FAZACLO está indicado para reduzir o risco de comportamento suicida recorrente em pacientes com esquizofrenia ou distúrbio esquizoafetivo que são considerados de risco crônico por reexperiência de comportamento suicida, com base na história e no estado clínico recente. O comportamento suicida refere-se a ações de um paciente que se coloca em risco de morte.

A eficácia da clozapina na redução do risco de comportamento suicida recorrente foi demonstrada durante um período de tratamento de dois anos no estudo InterSePT ™.

Esquizofrenia resistente ao tratamento

Uspen é indicado para o tratamento de pacientes gravemente enfermos com esquizofrenia que não respondem adequadamente ao tratamento antipsicótico padrão. Devido aos riscos de neutropenia grave e de convulsões associadas ao seu uso, o Uspen deve ser usado apenas em pacientes que não responderam adequadamente ao tratamento antipsicótico padrão.

A eficácia da clozapina na esquizofrenia resistente ao tratamento foi demonstrada em um estudo de 6 semanas, randomizado, duplo-cego e controlado por ativos, comparando clozapina e clorpromazina em pacientes que falharam com outros antipsicóticos.

Redução do risco de comportamento suicida recorrente na esquizofrenia ou transtorno esquizoafetivo

Uspen é indicado para reduzir o risco de comportamento suicida recorrente em pacientes com esquizofrenia ou distúrbio esquizoafetivo que são considerados de risco crônico por reexperimentar o comportamento suicida, com base na história e no estado clínico recente. O comportamento suicida refere-se a ações de um paciente que se coloca em risco de morte.

A eficácia da clozapina na redução do risco de comportamento suicida recorrente foi demonstrada durante um período de tratamento de dois anos no estudo InterSePT ™.

Teste de laboratório necessário antes da iniciação e durante a terapia

Antes de iniciar o tratamento com FAZACLO, um ANC basal deve ser obtido. O ANC basal deve ser de pelo menos 1500 / μL para a população em geral e de pelo menos 1000 / μL para pacientes com Neutropenia Étnica Benina (BEN) documentada. Para continuar o tratamento, o ANC deve ser monitorado regularmente.

Instruções importantes para administração

Os comprimidos desintegrantes por via oral FAZACLO devem ser imediatamente colocados na boca após a remoção do comprimido da embalagem ou frasco. O comprimido se desintegra rapidamente após a colocação na boca. Os comprimidos podem se desintegrar ou podem ser mastigados. Eles podem ser engolidos com saliva. Nenhuma água é necessária para administração.

Os comprimidos desintegrantes oralmente em uma embalagem blister devem ser deixados no blister fechado até o momento do uso. Pouco antes de usar, retire a folha do blister e remova suavemente o comprimido desintegrador por via oral. Não empurre os comprimidos através da folha, pois isso pode danificar o comprimido.

Informações de dosagem

A dose inicial é de 12,5 mg uma vez ao dia ou duas vezes ao dia. A dose diária total pode ser aumentada em incrementos de 25 mg a 50 mg por dia, se bem tolerada, para atingir uma dose alvo de 300 mg a 450 mg por dia (administrada em doses divididas) até o final de 2 semanas. Posteriormente, a dose pode ser aumentada uma vez por semana ou duas vezes por semana, em incrementos de até 100 mg. A dose máxima é de 900 mg por dia. Para minimizar o risco de hipotensão ortostática, bradicardia e síncope, é necessário usar essa dose inicial baixa, esquema de titulação gradual e dosagens divididas.

FAZACLO pode ser tomado com ou sem alimentos.

Tratamento de manutenção

Geralmente, os pacientes que respondem ao FAZACLO devem continuar o tratamento de manutenção em sua dose efetiva além do episódio agudo.

Descontinuação do tratamento

O método de descontinuação do tratamento varia de acordo com o último ANC do paciente :

• Consulte as Tabelas 2 ou 3 para obter um monitoramento adequado do ANC com base no nível de neutropenia se for necessária uma interrupção abrupta do tratamento devido a neutropenia moderada a grave.
• Reduza a dose gradualmente por um período de 1 a 2 semanas se o término da terapia com FAZACLO estiver planejado e não houver evidência de neutropenia moderada a grave.
• Para a descontinuação abrupta da clozapina por um motivo não relacionado à neutropenia, recomenda-se a continuação do monitoramento existente do ANC para pacientes em geral até que seu ANC seja ≥ 1500 / μL e para pacientes com BEN até que seu ANC seja ≥ 1000 / μL ou acima da linha de base.
• É necessário monitoramento adicional do ANC para qualquer paciente que relate o início da febre (temperatura de 38,5 ° C ou 101,3 ° F ou superior) durante as 2 semanas após a descontinuação.
• Monitore todos os pacientes cuidadosamente quanto à recorrência de sintomas psicóticos e sintomas relacionados à recuperação colinérgica, como transpiração profusa, dor de cabeça, náusea, vômito e diarréia.

Re-iniciação do tratamento

Ao reiniciar o FAZACLO em pacientes que interromperam o FAZACLO (ou seja,., 2 dias ou mais desde a última dose), reinicie com 12,5 mg uma vez ao dia ou duas vezes ao dia. Isso é necessário para minimizar o risco de hipotensão, bradicardia e síncope. Se essa dose for bem tolerada, a dose poderá ser aumentada para a dose terapêutica anterior mais rapidamente do que o recomendado para o tratamento inicial.

Ajustes de dosagem com uso concomitante de inibidores do CYP1A2, CYP2D6, CYP3A4 ou indutores do CYP1A2, CYP3A4

Podem ser necessários ajustes de dose em pacientes com uso concomitante de: inibidores fortes do CYP1A2 (por exemplo,., fluvoxamina, ciprofloxacina ou enoxacina); inibidores moderados ou fracos do CYP1A2 (por exemplo,.contraceptivos orais ou cafeína); Inibidores do CYP2D6 ou CYP3A4 (por exemplo,., cimetidina, escitalopram, eritromicina, paroxetina, bupropiona, fluoxetina, quinidina, duloxetina, terbinafina ou sertralina); Indutores do CYP3A4 (por exemplo,., fenitoína, carbamazepina, St. Erva de João e rifampicina); ou indutores do CYP1A2 (por exemplo,., tabagismo) (Tabela 1).

Tabela 1: Ajuste da dose em pacientes que tomam medicamentos concomitantes

Compromisso renal ou hepático ou metabolizadores pobres do CYP2D6

Pode ser necessário reduzir a dose de FAZACLO em pacientes com insuficiência renal ou hepática significativa ou em metabolizadores fracos do CYP2D6.

Teste de laboratório necessário antes da iniciação e durante a terapia

Antes de iniciar o tratamento com Uspen, um ANC basal deve ser obtido. O ANC basal deve ser de pelo menos 1500 / μL para a população em geral e de pelo menos 1000 / μL para pacientes com Neutropenia Étnica Benina (BEN) documentada. Para continuar o tratamento, o ANC deve ser monitorado regularmente.

Instruções importantes para administração

Os comprimidos desintegrantes por via oral devem ser imediatamente colocados na boca após a remoção do comprimido da embalagem ou frasco. O comprimido se desintegra rapidamente após a colocação na boca. Os comprimidos podem se desintegrar ou podem ser mastigados. Eles podem ser engolidos com saliva. Nenhuma água é necessária para administração.

Os comprimidos desintegrantes oralmente em uma embalagem blister devem ser deixados no blister fechado até o momento do uso. Pouco antes de usar, retire a folha do blister e remova suavemente o comprimido desintegrador por via oral. Não empurre os comprimidos através da folha, pois isso pode danificar o comprimido.

Informações de dosagem

A dose inicial é de 12,5 mg uma vez ao dia ou duas vezes ao dia. A dose diária total pode ser aumentada em incrementos de 25 mg a 50 mg por dia, se bem tolerada, para atingir uma dose alvo de 300 mg a 450 mg por dia (administrada em doses divididas) até o final de 2 semanas. Posteriormente, a dose pode ser aumentada uma vez por semana ou duas vezes por semana, em incrementos de até 100 mg. A dose máxima é de 900 mg por dia. Para minimizar o risco de hipotensão ortostática, bradicardia e síncope, é necessário usar essa dose inicial baixa, esquema de titulação gradual e dosagens divididas.

Uspen pode ser tomado com ou sem alimentos.

Tratamento de manutenção

Geralmente, os pacientes que respondem ao Uspen devem continuar o tratamento de manutenção em sua dose efetiva além do episódio agudo.

Descontinuação do tratamento

O método de descontinuação do tratamento varia de acordo com o último ANC do paciente :

• Consulte as Tabelas 2 ou 3 para obter um monitoramento adequado do ANC com base no nível de neutropenia se for necessária uma interrupção abrupta do tratamento devido a neutropenia moderada a grave.
• Reduza a dose gradualmente por um período de 1 a 2 semanas se o término da terapia com Uspen estiver planejado e não houver evidência de neutropenia moderada a grave.
• Para a descontinuação abrupta da clozapina por um motivo não relacionado à neutropenia, recomenda-se a continuação do monitoramento existente do ANC para pacientes em geral até que seu ANC seja ≥ 1500 / μL e para pacientes com BEN até que seu ANC seja ≥ 1000 / μL ou acima da linha de base.
• É necessário monitoramento adicional do ANC para qualquer paciente que relate o início da febre (temperatura de 38,5 ° C ou 101,3 ° F ou superior) durante as 2 semanas após a descontinuação.
• Monitore todos os pacientes cuidadosamente quanto à recorrência de sintomas psicóticos e sintomas relacionados à recuperação colinérgica, como transpiração profusa, dor de cabeça, náusea, vômito e diarréia.

Re-iniciação do tratamento

Ao reiniciar o Uspen em pacientes que interromperam o Uspen (ou seja,., 2 dias ou mais desde a última dose), reinicie com 12,5 mg uma vez ao dia ou duas vezes ao dia. Isso é necessário para minimizar o risco de hipotensão, bradicardia e síncope. Se essa dose for bem tolerada, a dose poderá ser aumentada para a dose terapêutica anterior mais rapidamente do que o recomendado para o tratamento inicial.

Ajustes de dosagem com uso concomitante de inibidores do CYP1A2, CYP2D6, CYP3A4 ou indutores do CYP1A2, CYP3A4

Podem ser necessários ajustes de dose em pacientes com uso concomitante de: inibidores fortes do CYP1A2 (por exemplo,., fluvoxamina, ciprofloxacina ou enoxacina); inibidores moderados ou fracos do CYP1A2 (por exemplo,.contraceptivos orais ou cafeína); Inibidores do CYP2D6 ou CYP3A4 (por exemplo,., cimetidina, escitalopram, eritromicina, paroxetina, bupropiona, fluoxetina, quinidina, duloxetina, terbinafina ou sertralina); Indutores do CYP3A4 (por exemplo,., fenitoína, carbamazepina, St. Erva de João e rifampicina); ou indutores do CYP1A2 (por exemplo,., tabagismo) (Tabela 1).

Tabela 1: Ajuste da dose em pacientes que tomam medicamentos concomitantes

Compromisso renal ou hepático ou metabolizadores pobres do CYP2D6

Pode ser necessário reduzir a dose de Uspen em pacientes com insuficiência renal ou hepática significativa ou em metabolizadores fracos do CYP2D6.

Hipersensibilidade

FAZACLO está contra-indicado em pacientes com histórico de hipersensibilidade grave à clozapina (por exemplo,., fotosensibilidade, vasculite, eritema multiforme ou Síndrome de Stevens-Johnson) ou qualquer outro componente do FAZACLO

Hipersensibilidade

Uspen está contra-indicado em pacientes com histórico de hipersensibilidade grave à clozapina (por exemplo,., fotosensibilidade, vasculite, eritema multiforme ou Síndrome de Stevens-Johnson) ou qualquer outro componente de Uspen.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Severe Neutropenia

Background

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

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

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

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

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

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

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

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

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

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

General Guidelines for Management of All Patients with Fever or with Neutropenia

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

Rechallenge after an ANC less than 500/μL (Severe Neutropenia)

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

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

Using FAZACLO with Other Drugs Associated with Neutropenia

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

Clozapine REMS Program

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

Notable requirements of the Clozapine REMS Program include:

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

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

Orthostatic Hypotension, Bradycardia, And Syncope

Hypotension, bradycardia, syncope, and cardiac arrest have occurred with clozapine treatment. The risk is highest during the initial titration period, particularly with rapid dose-escalation. These reactions can occur with the first dose, at doses as low as 12.5 mg. These reactions can be fatal. The syndrome is consistent with neurally mediated reflex bradycardia (NMRB).

Treatment must begin at a maximum dose of 12.5 mg once daily or twice daily. The total daily dose can be increased in increments of 25 mg to 50 mg per day, if well-tolerated, to a target dose of 300 mg to 450 mg per day (administered in divided doses) by the end of 2 weeks. Subsequently, the dose can be increased weekly or twice weekly, in increments of up to 100 mg. The maximum dose is 900 mg per day. Use cautious titration and a divided dosage schedule to minimize the risk of serious cardiovascular reactions. Consider reducing the dose if hypotension occurs. When restarting patients who have had even a brief interval off FAZACLO (i.e., 2 days or more since the last dose), re-initiate treatment at 12.5 mg once daily or twice daily.

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

Seizures

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

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

Myocarditis And Cardiomyopathy

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

Consider the possibility of myocarditis or cardiomyopathy in patients receiving FAZACLO who present with chest pain, dyspnea, persistent tachycardia at rest, palpitations, fever, flu-like symptoms, hypotension, other signs or symptoms of heart failure, or electrocardiographic findings (low voltages, ST-T abnormalities, arrhythmias, right axis deviation, and poor R wave progression). Myocarditis most frequently presents within the first two months of clozapine treatment. Symptoms of cardiomyopathy generally occur later than clozapine-associated myocarditis and usually after 8 weeks of treatment. However, myocarditis and cardiomyopathy can occur at any period during treatment with FAZACLO. It is common for nonspecific flu-like symptoms such as malaise, myalgia, pleuritic chest pain, and low-grade fevers to precede more overt signs of heart failure. Typical laboratory findings include elevated troponin I or T, elevated creatinine kinase-MB, peripheral eosinophilia, and elevated C-reactive protein (CRP). Chest roentgenogram may demonstrate cardiac silhouette enlargement, and cardiac imaging (echocardiogram, radionucleotide studies, or cardiac catheterization) may reveal evidence of left ventricular dysfunction.

Increased Mortality In Elderly Patients With Dementia-Related Psychosis

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality in this population. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. FAZACLO is not approved for the treatment of patients with dementia-related psychosis.

Eosinophilia

Eosinophilia, defined as a blood eosinophil count of greater than 700/μL, has occurred with clozapine treatment. In clinical trials, approximately 1% of patients developed eosinophilia. Clozapine-related eosinophilia usually occurs during the first month of treatment. In some patients, it has been associated with myocarditis, pancreatitis, hepatitis, colitis, and nephritis. Such organ involvement could be consistent with a drug reaction with eosinophilia and systemic symptoms syndrome (DRESS), also known as drug induced hypersensitivity syndrome (DIHS).

If eosinophilia develops during FAZACLO treatment, evaluate promptly for signs and symptoms of systemic reactions, such as rash or other allergic symptoms, myocarditis, or other organ-specific disease associated with eosinophilia. If clozapine-related systemic disease is suspected, discontinue FAZACLO immediately.

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

Clozapine-related eosinophilia has also occurred in the absence of organ involvement and can resolve without intervention. There are reports of successful rechallenge after discontinuation of clozapine, without recurrence of eosinophilia. In the absence of organ involvement, continue FAZACLO under careful monitoring. If the total eosinophil count continues to increase over several weeks in the absence of systemic disease, the decision to interrupt FAZACLO therapy and rechallenge after the eosinophil count decreases should be based on the overall clinical assessment, in consultation with an internist or hematologist.

QT Interval Prolongation

QT prolongation, Torsades de Pointes and other life-threatening ventricular arrhythmias, cardiac arrest, and sudden death have occurred with clozapine treatment. When prescribing FAZACLO, consider the presence of additional risk factors for QT prolongation and serious cardiovascular reactions. Conditions that increase these risks include the following: history of QT prolongation, long QT syndrome, family history of long QT syndrome or sudden cardiac death, significant cardiac arrhythmia, recent myocardial infarction, uncompensated heart failure, treatment with other medications that cause QT prolongation, treatment with medications that inhibit the metabolism of FAZACLO, and electrolyte abnormalities.

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

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

Hypokalemia and hypomagnesemia increase the risk of QT prolongation. Hypokalemia can result from diuretic therapy, diarrhea, and other causes. Use caution when treating patients at risk for significant electrolyte disturbance, particularly hypokalemia. Obtain baseline measurements of serum potassium and magnesium levels, and periodically monitor electrolytes. Correct electrolyte abnormalities before initiating treatment with FAZACLO.

Metabolic Changes

Atypical antipsychotic drugs, including FAZACLO, have been associated with metabolic changes that can increase cardiovascular and cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While atypical antipsychotic drugs may produce some metabolic changes, each drug in the class has its own specific risk profile.

Hyperglycemia and Diabetes Mellitus

Patients with an established diagnosis of diabetes mellitus who are started on FAZACLO should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.

In a pooled data analysis of 8 studies in adult subjects with schizophrenia, the mean changes in fasting glucose concentration in the clozapine and chlorpromazine groups were +11 mg/dL and +4 mg/dL respectively. A higher proportion of the clozapine group demonstrated categorical increases from baseline in fasting glucose concentrations, compared to the chlorpromazine group (Table 4). The clozapine doses were 100-900 mg per day (mean modal dose: 512 mg per day). The maximum chlorpromazine dose was 1800 mg per day (mean modal dose: 1029 mg per day). The median duration of exposure was 42 days for clozapine and chlorpromazine.

Table 4: Categorical Changes in Fasting Glucose Level in Studies in Adult Subjects with Schizophrenia

Dyslipidemia

Undesirable alterations in lipids have occurred in patients treated with atypical antipsychotics, including FAZACLO. Clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using FAZACLO, is recommended.

In a pooled data analysis of 10 studies in adult subjects with schizophrenia, clozapine treatment was associated with increases in serum total cholesterol. No data were collected on LDL and HDL cholesterol. The mean increase in total cholesterol was 13 mg/dL in the clozapine group and 15 mg/dL in the chlorpromazine group. In a pooled data analysis of 2 studies in adult subjects with schizophrenia, clozapine treatment was associated with increases in fasting serum triglyceride. The mean increase in fasting triglyceride was 71 mg/dL (54%) in the clozapine group and 39 mg/dL (35%) in the chlorpromazine group (Table 5). In addition, clozapine treatment was associated with categorical increases in serum total cholesterol and triglyceride, as illustrated in Table 6. The proportion of patients with categorical increases in total cholesterol or fasting triglyceride increased with the duration of exposure. The median duration of clozapine and chlorpromazine exposure was 45 days and 38 days, respectively. The clozapine dose range was 100 mg to 900 mg daily; the maximum chlorpromazine dose was 1800 mg daily.

Table 5: Mean Changes in Total Cholesterol and Triglyceride Concentration in Studies in Adult Subjects with Schizophrenia

Table 6: Categorical Changes in Lipid Concentrations in Studies in Adult Subjects with Schizophrenia

Weight Gain

Weight gain has occurred with the use of antipsychotics, including FAZACLO. Monitor weight during treatment with FAZACLO. Table 7 summarizes the data on weight gain by the duration of exposure pooled from 11 studies with clozapine and active comparators. The median duration of exposure was 609, 728, and 42 days, in the clozapine, olanzapine, and chlorpromazine group, respectively.

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

Table 8 summarizes pooled data from 11 studies in

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Severe Neutropenia

Background

Uspen 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. 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 Uspen 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 Uspen 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.

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

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

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

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

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

General Guidelines for Management of All Patients with Fever or with Neutropenia

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

Rechallenge after an ANC less than 500/μL (Severe Neutropenia)

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

Using Uspen 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 Uspen-induced neutropenia. There is no strong scientific rationale to avoid Uspen treatment in patients concurrently treated with these drugs. If Uspen is used concurrently with an agent known to cause neutropenia (e.g., some chemotherapeutic agents), consider monitoring patients more closely than the treatment guidelines provided in Tables 2 and 3. Consult with the treating oncologist in patients receiving concomitant chemotherapy.

Clozapine REMS Program

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

Notable requirements of the Clozapine REMS Program include:

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

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

Orthostatic Hypotension, Bradycardia, And Syncope

Hypotension, bradycardia, syncope, and cardiac arrest have occurred with clozapine treatment. The risk is highest during the initial titration period, particularly with rapid dose-escalation. These reactions can occur with the first dose, at doses as low as 12.5 mg. These reactions can be fatal. The syndrome is consistent with neurally mediated reflex bradycardia (NMRB).

Treatment must begin at a maximum dose of 12.5 mg once daily or twice daily. The total daily dose can be increased in increments of 25 mg to 50 mg per day, if well-tolerated, to a target dose of 300 mg to 450 mg per day (administered in divided doses) by the end of 2 weeks. Subsequently, the dose can be increased weekly or twice weekly, in increments of up to 100 mg. The maximum dose is 900 mg per day. Use cautious titration and a divided dosage schedule to minimize the risk of serious cardiovascular reactions. Consider reducing the dose if hypotension occurs. When restarting patients who have had even a brief interval off Uspen (i.e., 2 days or more since the last dose), re-initiate treatment at 12.5 mg once daily or twice daily.

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

Seizures

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

Use caution when administering Uspen 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 Uspen use, caution patients about engaging in any activity where sudden loss of consciousness could cause serious risk to themselves or others (e.g., driving an automobile, operating complex machinery, swimming, climbing).

Myocarditis And Cardiomyopathy

Myocarditis and cardiomyopathy have occurred with the use of clozapine. These reactions can be fatal. Discontinue Uspen 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 Uspen. However, if the benefit of Uspen treatment is judged to outweigh the potential risks of recurrent myocarditis or cardiomyopathy, the clinician may consider rechallenge with Uspen in consultation with a cardiologist, after a complete cardiac evaluation, and under close monitoring.

Consider the possibility of myocarditis or cardiomyopathy in patients receiving Uspen 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 Uspen. It is common for nonspecific flu-like symptoms such as malaise, myalgia, pleuritic chest pain, and low-grade fevers to precede more overt signs of heart failure. Typical laboratory findings include elevated troponin I or T, elevated creatinine kinase-MB, peripheral eosinophilia, and elevated C-reactive protein (CRP). Chest roentgenogram may demonstrate cardiac silhouette enlargement, and cardiac imaging (echocardiogram, radionucleotide studies, or cardiac catheterization) may reveal evidence of left ventricular dysfunction.

Increased Mortality In Elderly Patients With Dementia-Related Psychosis

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 Uspen 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 Uspen 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 Uspen.

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

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

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

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 Uspen.

Metabolic Changes

Atypical antipsychotic drugs, including Uspen, 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 Uspen. 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 Uspen 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

Dyslipidemia

Undesirable alterations in lipids have occurred in patients treated with atypical antipsychotics, including Uspen. Clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using Uspen, 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

Table 6: Categorical Changes in Lipid Concentrations in Studies in Adult Subjects with Schizophrenia

Weight Gain

Weight gain has occurred with the use of antipsychotics, including Uspen. Monitor weight during treatment with Uspen. 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

Table 8 summarizes pooled data from 11 studies in

Experiência de superdosagem

Os sinais e sintomas mais comumente relatados associados à sobredosagem com clozapina são: sedação, delírio, coma, taquicardia, hipotensão, depressão respiratória ou insuficiência; e hipersalivação. Há relatos de pneumonia por aspiração, arritmias cardíacas e convulsões. Foram relatadas sobredosagens fatais com clozapina, geralmente em doses acima de 2500 mg. Também houve relatos de pacientes se recuperando de overdoses bem acima de 4 g.

Gerenciamento de superdosagem

Para obter as informações mais atualizadas sobre o gerenciamento da superdosagem da FAZACLO, entre em contato com um Centro Regional de Controle de Venenos certificado (1-800-222-1222). Os números de telefone dos Centros Regionais de Controle de Venenos certificados estão listados no Physicians 'Desk Reference®, uma marca registrada da PDR Network. Estabelecer e manter uma via aérea; garantir oxigenação e ventilação adequadas. Monitore o estado cardíaco e os sinais vitais. Use medidas gerais sintomáticas e de suporte. Não há antídotos específicos para FAZACLO

Ao gerenciar a superdosagem, considere a possibilidade de envolvimento com vários medicamentos.

Experiência de superdosagem

Os sinais e sintomas mais comumente relatados associados à sobredosagem com clozapina são: sedação, delírio, coma, taquicardia, hipotensão, depressão respiratória ou insuficiência; e hipersalivação. Há relatos de pneumonia por aspiração, arritmias cardíacas e convulsões. Foram relatadas sobredosagens fatais com clozapina, geralmente em doses acima de 2500 mg. Também houve relatos de pacientes se recuperando de overdoses bem acima de 4 g.

Gerenciamento de superdosagem

Para obter as informações mais atualizadas sobre o gerenciamento da superdosagem de Uspen, entre em contato com um Centro Regional de Controle de Venenos certificado (1-800-222-1222). Os números de telefone dos Centros Regionais de Controle de Venenos certificados estão listados no Physicians 'Desk Reference®, uma marca registrada da PDR Network. Estabelecer e manter uma via aérea; garantir oxigenação e ventilação adequadas. Monitore o estado cardíaco e os sinais vitais. Use medidas gerais sintomáticas e de suporte. Não há antídotos específicos para Uspen.

Ao gerenciar a superdosagem, considere a possibilidade de envolvimento com vários medicamentos.

Absorção

No homem, os comprimidos de clozapina (25 mg e 100 mg) são igualmente biodisponíveis em relação a uma solução de clozapina. Os comprimidos desintegrantes por via oral FAZACLO® (clozapina) são bioequivalentes aos comprimidos Clozaril® (clozapina), marca registrada da Novartis Pharmaceuticals Corporation. Após uma dose de 100 mg b.i.d., a concentração plasmática média máxima no estado estacionário foi de 413 ng / mL (variação: 132-854 ng / mL), ocorrendo na média de 2,3 horas (variação: 1-6 horas) após a administração. A concentração mínima média no estado estacionário foi de 168 ng / mL (variação: 45-574 ng / mL), após 100 mg b.i.d. dosagem.

Um estudo comparativo de bioequivalência / biodisponibilidade foi realizado em 32 pacientes (com esquizofrenia ou distúrbio esquizoafetivo) comparando os comprimidos de FAZACLO 200 mg a 2 comprimidos de FAZACLO 100 mg (produto de referência aprovado) em condições de jejum. O estudo também avaliou o efeito dos alimentos e da mastigação na farmacocinética do comprimido de 200 mg. Em condições de jejum, a AUCss média e Cmin, ss de clozapina para os comprimidos de 200 mg foram equivalentes aos dos comprimidos de 2 x 100 mg. A Cmax média, ss de clozapina para os comprimidos de FAZACLO 200 mg foi de 85% para 2 comprimidos de FAZACLO de 100 mg. Esta diminuição na Cmax, ss para os comprimidos de FAZACLO 200 mg não é clinicamente significativa.

Para os comprimidos de FAZACLO 200 mg, os alimentos aumentaram significativamente a Cmin, ss da clozapina em 21%. No entanto, esse aumento não é clinicamente significativo. A AUCss média e a Cmax, ss de clozapina em condições alimentadas foram equivalentes às condições em jejum. Os alimentos atrasaram a absorção de clozapina em 1,5 horas, de um Tmax médio de 2,5 horas em condições de jejum para 4 horas em condições de alimentação.

A Cmax média, ss de clozapina em condições mastigadas para os comprimidos de FAZACLO 200 mg foi de cerca de 86% que para os comprimidos de FAZACLO de 2 x 100 mg em condições não mastigadas, enquanto os valores de AUCss e Cmin, ss foram semelhantes entre os mastigados e não mastigados condições.

Num estudo de efeito alimentar, uma dose única de comprimidos desintegrantes por via oral de FAZACLO (clozapina) 12,5 mg foi administrada a voluntários saudáveis em condições de jejum e após uma refeição rica em gordura. Quando o FAZACLO foi administrado após uma refeição rica em gordura, a Cmax da clozapina e seu metabólito ativo, desmetilclozapina, diminuiu aproximadamente 20%, em comparação com a administração em condições de jejum, enquanto os valores da AUC permaneceram inalterados. Esta diminuição na Cmax não é clinicamente significativa. Portanto, os comprimidos desintegrantes por via oral FAZACLO (clozapina) podem ser tomados sem levar em consideração as refeições.

Distribuição

A clozapina está aproximadamente 97% ligada às proteínas séricas. A interação entre a clozapina e outros medicamentos altamente ligados a proteínas não foi totalmente avaliada, mas pode ser importante.

Metabolismo e excreção

A clozapina é quase completamente metabolizada antes da excreção, e apenas quantidades vestigiais de drogas inalteradas são detectadas na urina e nas fezes. A clozapina é um substrato para muitas isozimas do citocromo P450, em particular o CYP1A2, CYP2D6 e CYP3A4. Aproximadamente 50% da dose administrada é excretada na urina e 30% nas fezes. Os derivados desmetilados, hidroxilados e N-óxido são componentes na urina e nas fezes. Os testes farmacológicos mostraram que o metabolito desmetil (norclozapina) tem apenas atividade limitada, enquanto os derivados hidroxilados e N-óxido estavam inativos. A meia-vida média de eliminação da clozapina após uma dose única de 75 mg foi de 8 horas (intervalo: 4-12 horas), em comparação com uma meia-vida média de eliminação de 12 horas (intervalo: 4-66 horas), após atingir o estado estacionário com 100 mg duas vezes ao dia.

Uma comparação da administração de dose única e de doses múltiplas de clozapina demonstrou que a meia-vida de eliminação aumentou significativamente após doses múltiplas em relação à administração após dose única, sugerindo a possibilidade de farmacocinética dependente da concentração. No entanto, no estado estacionário, foram observadas alterações aproximadamente proporcionais à dose em relação à AUC (área sob a curva), pico e concentrações plasmáticas mínimas de clozapina após a administração de 37,5, 75 e 150 mg duas vezes ao dia.

Absorção

No homem, os comprimidos de clozapina (25 mg e 100 mg) são igualmente biodisponíveis em relação a uma solução de clozapina. Os comprimidos desintegrantes orais de Uspen® (clozapina) são bioequivalentes aos comprimidos de Clozaril® (clozapina), marca registrada da Novartis Pharmaceuticals Corporation. Após uma dose de 100 mg b.i.d., a concentração plasmática média máxima no estado estacionário foi de 413 ng / mL (variação: 132-854 ng / mL), ocorrendo na média de 2,3 horas (variação: 1-6 horas) após a administração. A concentração mínima média no estado estacionário foi de 168 ng / mL (variação: 45-574 ng / mL), após 100 mg b.i.d. dosagem.

Um estudo comparativo de bioequivalência / biodisponibilidade foi realizado em 32 pacientes (com esquizofrenia ou distúrbio esquizoafetivo) comparando os comprimidos de Uspen 200 mg com 2 comprimidos de Uspen 100 mg (o produto de referência aprovado) em condições de jejum. O estudo também avaliou o efeito dos alimentos e da mastigação na farmacocinética do comprimido de 200 mg. Em condições de jejum, a AUCss média e Cmin, ss de clozapina para os comprimidos de 200 mg foram equivalentes aos dos comprimidos de 2 x 100 mg. A Cmax média, ss de clozapina para comprimidos de Uspen 200 mg foi de 85% para 2 comprimidos de Uspen de 100 mg. Esta diminuição na Cmax, ss para comprimidos de Uspen 200 mg não é clinicamente significativa.

Para os comprimidos de Uspen 200 mg, os alimentos aumentaram significativamente a Cmin, ss da clozapina em 21%. No entanto, esse aumento não é clinicamente significativo. A AUCss média e a Cmax, ss de clozapina em condições alimentadas foram equivalentes às condições em jejum. Os alimentos atrasaram a absorção de clozapina em 1,5 horas, de um Tmax médio de 2,5 horas em condições de jejum para 4 horas em condições de alimentação.

A Cmax média, ss de clozapina em condições mastigadas para comprimidos de Uspen 200 mg foi de cerca de 86% que para comprimidos de Uspen de 2 x 100 mg em condições não mastigadas, enquanto os valores de AUCss e Cmin, ss foram semelhantes entre os mastigados e não mastigados condições.

Num estudo de efeito alimentar, uma dose única de comprimidos desintegrantes por via oral de Uspen (clozapina) 12,5 mg foi administrada a voluntários saudáveis em condições de jejum e após uma refeição rica em gordura. Quando o Uspen foi administrado após uma refeição rica em gordura, a Cmax da clozapina e seu metabólito ativo, desmetilclozapina, diminuiu aproximadamente 20%, em comparação com a administração em condições de jejum, enquanto os valores da AUC permaneceram inalterados. Esta diminuição na Cmax não é clinicamente significativa. Portanto, os comprimidos de desintegração oral de Uspen (clozapina) podem ser tomados sem levar em consideração as refeições.

Distribuição

A clozapina está aproximadamente 97% ligada às proteínas séricas. A interação entre a clozapina e outros medicamentos altamente ligados a proteínas não foi totalmente avaliada, mas pode ser importante.

Metabolismo e excreção

A clozapina é quase completamente metabolizada antes da excreção, e apenas quantidades vestigiais de drogas inalteradas são detectadas na urina e nas fezes. A clozapina é um substrato para muitas isozimas do citocromo P450, em particular o CYP1A2, CYP2D6 e CYP3A4. Aproximadamente 50% da dose administrada é excretada na urina e 30% nas fezes. Os derivados desmetilados, hidroxilados e N-óxido são componentes na urina e nas fezes. Os testes farmacológicos mostraram que o metabolito desmetil (norclozapina) tem apenas atividade limitada, enquanto os derivados hidroxilados e N-óxido estavam inativos. A meia-vida média de eliminação da clozapina após uma dose única de 75 mg foi de 8 horas (intervalo: 4-12 horas), em comparação com uma meia-vida média de eliminação de 12 horas (intervalo: 4-66 horas), após atingir o estado estacionário com 100 mg duas vezes ao dia.

Uma comparação da administração de dose única e de doses múltiplas de clozapina demonstrou que a meia-vida de eliminação aumentou significativamente após doses múltiplas em relação à administração após dose única, sugerindo a possibilidade de farmacocinética dependente da concentração. No entanto, no estado estacionário, foram observadas alterações aproximadamente proporcionais à dose em relação à AUC (área sob a curva), pico e concentrações plasmáticas mínimas de clozapina após a administração de 37,5, 75 e 150 mg duas vezes ao dia.