Nirva

Esquizofrenia resistente al tratamiento

FAZACLO está indicado para el tratamiento de pacientes gravemente enfermos con esquizofrenia que no responden adecuadamente al tratamiento antipsicótico estándar. Debido a los riesgos de neutropenia grave y de convulsiones asociadas con su uso, FAZACLO debe usarse solo en pacientes que no han respondido adecuadamente al tratamiento antipsicótico estándar.

La efectividad de la clozapina en la esquizofrenia resistente al tratamiento se demostró en un estudio aleatorizado, doble ciego, controlado activo de 6 semanas que compara la clozapina y la clorpromazina en pacientes que habían fallado otros antipsicóticos.

Reducción del riesgo de comportamiento suicida recurrente en esquizofrenia o trastorno esquizoafectivo

FAZACLO está indicado para reducir el riesgo de comportamiento suicida recurrente en pacientes con esquizofrenia o trastorno esquizoafectivo que se consideran con riesgo crónico de volver a experimentar el comportamiento suicida, según la historia y el estado clínico reciente. El comportamiento suicida se refiere a las acciones de un paciente que se pone en riesgo de muerte.

La efectividad de la clozapina para reducir el riesgo de comportamiento suicida recurrente se demostró durante un período de tratamiento de dos años en el ensayo InterSePT ™.

Esquizofrenia resistente al tratamiento

Nirva está indicado para el tratamiento de pacientes gravemente enfermos con esquizofrenia que no responden adecuadamente al tratamiento antipsicótico estándar. Debido a los riesgos de neutropenia grave y de convulsiones asociadas con su uso, Nirva debe usarse solo en pacientes que no han respondido adecuadamente al tratamiento antipsicótico estándar.

La efectividad de la clozapina en la esquizofrenia resistente al tratamiento se demostró en un estudio aleatorizado, doble ciego, controlado activo de 6 semanas que compara la clozapina y la clorpromazina en pacientes que habían fallado otros antipsicóticos.

Reducción del riesgo de comportamiento suicida recurrente en esquizofrenia o trastorno esquizoafectivo

Nirva está indicado para reducir el riesgo de comportamiento suicida recurrente en pacientes con esquizofrenia o trastorno esquizoafectivo que se consideran con riesgo crónico de volver a experimentar el comportamiento suicida, según la historia y el estado clínico reciente. El comportamiento suicida se refiere a las acciones de un paciente que se pone en riesgo de muerte.

La efectividad de la clozapina para reducir el riesgo de comportamiento suicida recurrente se demostró durante un período de tratamiento de dos años en el ensayo InterSePT ™.

Pruebas de laboratorio requeridas antes de la iniciación y durante la terapia

Antes de iniciar el tratamiento con FAZACLO, se debe obtener un ANC basal. El ANC basal debe ser de al menos 1500 / μL para la población general, y al menos 1000 / μL para pacientes con neutropenia étnica benigna (BEN) documentada. Para continuar el tratamiento, el ANC debe ser monitoreado regularmente.

Instrucciones de administración importantes

Las tabletas de desintegración oral de FAZACLO deben colocarse inmediatamente en la boca después de retirar la tableta del blister o frasco. La tableta se desintegra rápidamente después de colocarla en la boca. Se puede permitir que las tabletas se desintegren o se pueden masticar. Se pueden tragar con saliva. No se necesita agua para la administración.

Las tabletas que se desintegran por vía oral en un blister deben dejarse en la ampolla sin abrir hasta el momento del uso. Justo antes de su uso, retire la lámina de la ampolla y retire suavemente la tableta de desintegración oral. No empuje las tabletas a través de la lámina, ya que esto podría dañar la tableta.

Información de dosificación

La dosis inicial es de 12.5 mg una vez al día o dos veces al día. La dosis diaria total se puede aumentar en incrementos de 25 mg a 50 mg por día, si se tolera bien, para lograr una dosis objetivo de 300 mg a 450 mg por día (administrada en dosis divididas) al final de 2 semanas. Posteriormente, la dosis se puede aumentar una vez por semana o dos veces por semana, en incrementos de hasta 100 mg. La dosis máxima es de 900 mg por día. Para minimizar el riesgo de hipotensión ortostática, bradicardia y síncope, es necesario usar esta dosis inicial baja, un programa de titulación gradual y dosis divididas.

FAZACLO se puede tomar con o sin alimentos.

Tratamiento de mantenimiento

En general, los pacientes que responden a FAZACLO deben continuar el tratamiento de mantenimiento con su dosis efectiva más allá del episodio agudo.

Interrupción del tratamiento

El método de interrupción del tratamiento variará según el último ANC del paciente:

• Consulte las Tablas 2 o 3 para obtener un monitoreo adecuado del ANC basado en el nivel de neutropenia si es necesaria la interrupción brusca del tratamiento debido a la neutropenia moderada a grave.
• Reduzca la dosis gradualmente durante un período de 1 a 2 semanas si se planea la finalización de la terapia con FAZACLO y no hay evidencia de neutropenia moderada a grave.
• Para la interrupción abrupta de la clozapina por una razón no relacionada con la neutropenia, se recomienda la continuación de la monitorización del ANC existente para pacientes de población general hasta que su ANC sea ≥ 1500 / μL y para pacientes con BEN hasta que su ANC sea ≥ 1000 / μL o superior a su valor inicial.
• Se requiere un monitoreo adicional de ANC para cualquier paciente que informe el inicio de la fiebre (temperatura de 38.5 ° C o 101.3 ° F, o mayor) durante las 2 semanas posteriores a la interrupción.
• Controle cuidadosamente a todos los pacientes para detectar la recurrencia de síntomas psicóticos y síntomas relacionados con el rebote colinérgico, como sudoración profusa, dolor de cabeza, náuseas, vómitos y diarrea.

Reiniciación del tratamiento

Al reiniciar FAZACLO en pacientes que han descontinuado FAZACLO (es decir,., 2 días o más desde la última dosis), reinicie con 12.5 mg una vez al día o dos veces al día. Esto es necesario para minimizar el riesgo de hipotensión, bradicardia y síncope. Si esa dosis es bien tolerada, la dosis puede aumentarse a la dosis terapéutica previa más rápidamente de lo recomendado para el tratamiento inicial.

Ajustes de dosis con uso concomitante de inhibidores de CYP1A2, CYP2D6, CYP3A4 o inductores de CYP1A2, CYP3A4

Los ajustes de dosis pueden ser necesarios en pacientes con uso concomitante de: inhibidores potentes de CYP1A2 (p. Ej., fluvoxamina, ciprofloxacina o enoxacina); inhibidores moderados o débiles de CYP1A2 (p. ej., anticonceptivos orales o cafeína); Inhibidores de CYP2D6 o CYP3A4 (p. ej., cimetidina, escitalopram, eritromicina, paroxetina, bupropión, fluoxetina, quinidina, duloxetina, terbinafina o sertralina); Inductores de CYP3A4 (p. ej., fenitoína, carbamazepina, St. Hierba de John y rifampicina); o inductores de CYP1A2 (p. ej., fumar tabaco) (Tabla 1).

Tabla 1: Ajuste de dosis en pacientes que toman medicamentos concomitantes

Insuficiencia renal o hepática o metabolizadores pobres de CYP2D6

Puede ser necesario reducir la dosis de FAZACLO en pacientes con insuficiencia renal o hepática significativa, o en metabolizadores lentos de CYP2D6.

Pruebas de laboratorio requeridas antes de la iniciación y durante la terapia

Antes de iniciar el tratamiento con Nirva, se debe obtener un ANC basal. El ANC basal debe ser de al menos 1500 / μL para la población general, y al menos 1000 / μL para pacientes con neutropenia étnica benigna (BEN) documentada. Para continuar el tratamiento, el ANC debe ser monitoreado regularmente.

Instrucciones de administración importantes

Las tabletas de desintegración oral de Nirva deben colocarse inmediatamente en la boca después de retirar la tableta del blister o frasco. La tableta se desintegra rápidamente después de colocarla en la boca. Se puede permitir que las tabletas se desintegren o se pueden masticar. Se pueden tragar con saliva. No se necesita agua para la administración.

Las tabletas que se desintegran por vía oral en un blister deben dejarse en la ampolla sin abrir hasta el momento del uso. Justo antes de su uso, retire la lámina de la ampolla y retire suavemente la tableta de desintegración oral. No empuje las tabletas a través de la lámina, ya que esto podría dañar la tableta.

Información de dosificación

La dosis inicial es de 12.5 mg una vez al día o dos veces al día. La dosis diaria total se puede aumentar en incrementos de 25 mg a 50 mg por día, si se tolera bien, para lograr una dosis objetivo de 300 mg a 450 mg por día (administrada en dosis divididas) al final de 2 semanas. Posteriormente, la dosis se puede aumentar una vez por semana o dos veces por semana, en incrementos de hasta 100 mg. La dosis máxima es de 900 mg por día. Para minimizar el riesgo de hipotensión ortostática, bradicardia y síncope, es necesario usar esta dosis inicial baja, un programa de titulación gradual y dosis divididas.

Nirva se puede tomar con o sin alimentos.

Tratamiento de mantenimiento

En general, los pacientes que responden a Nirva deben continuar el tratamiento de mantenimiento con su dosis efectiva más allá del episodio agudo.

Interrupción del tratamiento

El método de interrupción del tratamiento variará según el último ANC del paciente:

• Consulte las Tablas 2 o 3 para obtener un monitoreo adecuado del ANC basado en el nivel de neutropenia si es necesaria la interrupción brusca del tratamiento debido a la neutropenia moderada a grave.
• Reduzca la dosis gradualmente durante un período de 1 a 2 semanas si se planea la finalización de la terapia con Nirva y no hay evidencia de neutropenia moderada a grave.
• Para la interrupción abrupta de la clozapina por una razón no relacionada con la neutropenia, se recomienda la continuación de la monitorización del ANC existente para pacientes de población general hasta que su ANC sea ≥ 1500 / μL y para pacientes con BEN hasta que su ANC sea ≥ 1000 / μL o superior a su valor inicial.
• Se requiere un monitoreo adicional de ANC para cualquier paciente que informe el inicio de la fiebre (temperatura de 38.5 ° C o 101.3 ° F, o mayor) durante las 2 semanas posteriores a la interrupción.
• Controle cuidadosamente a todos los pacientes para detectar la recurrencia de síntomas psicóticos y síntomas relacionados con el rebote colinérgico, como sudoración profusa, dolor de cabeza, náuseas, vómitos y diarrea.

Reiniciación del tratamiento

Al reiniciar Nirva en pacientes que han descontinuado Nirva (p. Ej., 2 días o más desde la última dosis), reinicie con 12.5 mg una vez al día o dos veces al día. Esto es necesario para minimizar el riesgo de hipotensión, bradicardia y síncope. Si esa dosis es bien tolerada, la dosis puede aumentarse a la dosis terapéutica previa más rápidamente de lo recomendado para el tratamiento inicial.

Ajustes de dosis con uso concomitante de inhibidores de CYP1A2, CYP2D6, CYP3A4 o inductores de CYP1A2, CYP3A4

Los ajustes de dosis pueden ser necesarios en pacientes con uso concomitante de: inhibidores potentes de CYP1A2 (p. Ej., fluvoxamina, ciprofloxacina o enoxacina); inhibidores moderados o débiles de CYP1A2 (p. ej., anticonceptivos orales o cafeína); Inhibidores de CYP2D6 o CYP3A4 (p. ej., cimetidina, escitalopram, eritromicina, paroxetina, bupropión, fluoxetina, quinidina, duloxetina, terbinafina o sertralina); Inductores de CYP3A4 (p. ej., fenitoína, carbamazepina, St. Hierba de John y rifampicina); o inductores de CYP1A2 (p. ej., fumar tabaco) (Tabla 1).

Tabla 1: Ajuste de dosis en pacientes que toman medicamentos concomitantes

Insuficiencia renal o hepática o metabolizadores pobres de CYP2D6

Puede ser necesario reducir la dosis de Nirva en pacientes con insuficiencia renal o hepática significativa, o en metabolizadores lentos de CYP2D6.

Hipersensibilidad

FAZACLO está contraindicado en pacientes con antecedentes de hipersensibilidad grave a la clozapina (p. Ej., fotosensibilidad, vasculitis, eritema multiforme o síndrome de Stevens-Johnson) o cualquier otro componente de FAZACLO

Hipersensibilidad

Nirva está contraindicado en pacientes con antecedentes de hipersensibilidad grave a la clozapina (p. Ej., fotosensibilidad, vasculitis, eritema multiforme o síndrome de Stevens-Johnson) o cualquier otro componente de Nirva.

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

Nirva 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 Nirva 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 Nirva 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.

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

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

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

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

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

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

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

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

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

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 Nirva (i.e., 2 days or more since the last dose), re-initiate treatment at 12.5 mg once daily or twice daily.

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

Consider the possibility of myocarditis or cardiomyopathy in patients receiving Nirva 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 Nirva. 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 Nirva 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 Nirva 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 Nirva.

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

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

Use caution when administering concomitant medications that prolong the QT interval or inhibit the metabolism of Nirva. 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). Nirva is primarily metabolized by CYP isoenzymes 1A2, 2D6, and 3A4. Concomitant treatment with inhibitors of these enzymes can increase the concentration of Nirva.

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 Nirva.

Metabolic Changes

Atypical antipsychotic drugs, including Nirva, 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 Nirva. 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 Nirva 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 Nirva. Clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using Nirva, 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 Nirva. Monitor weight during treatment with Nirva. 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

Experiencia de sobredosis

Los signos y síntomas más comúnmente reportados asociados con la sobredosis de clozapina son: sedación, delirio, coma, taquicardia, hipotensión, depresión respiratoria o insuficiencia; e hipersalivación. Hay informes de neumonía por aspiración, arritmias cardíacas y convulsiones. Se han notificado sobredosis fatales con clozapina, generalmente a dosis superiores a 2500 mg. También ha habido informes de pacientes que se recuperan de sobredosis superiores a 4 g.

Gestión de sobredosis

Para obtener la información más actualizada sobre el manejo de la sobredosis de FAZACLO, comuníquese con un Centro Regional de Control de Envenenamiento certificado (1-800-222-1222). Los números de teléfono de los Centros Regionales de Control de Envenenamiento certificados se enumeran en Physicians 'Desk Reference®, una marca registrada de PDR Network. Establecer y mantener una vía aérea; Garantizar la oxigenación y ventilación adecuadas. Monitoree el estado cardíaco y los signos vitales. Use medidas generales sintomáticas y de apoyo. No hay antídotos específicos para FAZACLO

Al controlar la sobredosis, considere la posibilidad de participación de múltiples medicamentos.

Experiencia de sobredosis

Los signos y síntomas más comúnmente reportados asociados con la sobredosis de clozapina son: sedación, delirio, coma, taquicardia, hipotensión, depresión respiratoria o insuficiencia; e hipersalivación. Hay informes de neumonía por aspiración, arritmias cardíacas y convulsiones. Se han notificado sobredosis fatales con clozapina, generalmente a dosis superiores a 2500 mg. También ha habido informes de pacientes que se recuperan de sobredosis superiores a 4 g.

Gestión de sobredosis

Para obtener la información más actualizada sobre el manejo de la sobredosis de Nirva, comuníquese con un Centro Regional de Control de Envenenamiento certificado (1-800-222-1222). Los números de teléfono de los Centros Regionales de Control de Envenenamiento certificados se enumeran en Physicians 'Desk Reference®, una marca registrada de PDR Network. Establecer y mantener una vía aérea; Garantizar la oxigenación y ventilación adecuadas. Monitoree el estado cardíaco y los signos vitales. Use medidas generales sintomáticas y de apoyo. No hay antídotos específicos para Nirva.

Al controlar la sobredosis, considere la posibilidad de participación de múltiples medicamentos.

Absorción

En el hombre, las tabletas de clozapina (25 mg y 100 mg) están igualmente biodisponibles en relación con una solución de clozapina. Las tabletas desintegratorias por vía oral de FAZACLO® (clozapina) son bioequivalentes a las tabletas Clozaril® (clozapina), una marca registrada de Novartis Pharmaceuticals Corporation. Después de una dosis de 100 mg b.i.d., la concentración plasmática máxima promedio en estado estacionario fue de 413 ng / ml (rango: 132-854 ng / ml), que ocurrió en el promedio de 2.3 horas (rango: 1-6 horas) después de la dosificación. La concentración mínima promedio en estado estacionario fue de 168 ng / ml (rango: 45-574 ng / ml), después de 100 mg b.i.d. dosificación.

Se realizó un estudio comparativo de bioequivalencia / biodisponibilidad en 32 pacientes (con esquizofrenia o trastorno esquizoafectivo) que compararon tabletas FAZACLO de 200 mg con tabletas de 2 Ã - FAZACLO de 100 mg (el producto de referencia aprobado) en condiciones de ayuno. El estudio también evaluó el efecto de los alimentos y la masticación en la farmacocinética de la tableta de 200 mg. En condiciones de ayuno, el AUCss medio y Cmin, ss de clozapina para las tabletas de 200 mg fueron equivalentes a los de las tabletas de 2 x 100 mg. La Cmáx media, ss de clozapina para tabletas FAZACLO 200 mg fue del 85% que para tabletas FAZACLO de 2 x 100 mg. Esta disminución en Cmax, ss para tabletas FAZACLO 200 mg no es clínicamente significativa.

Para las tabletas de FAZACLO 200 mg, los alimentos aumentaron significativamente la Cmin, ss de clozapina en un 21%. Sin embargo, este aumento no es clínicamente significativo. El AUCss medio y el Cmax, ss de clozapina en condiciones de alimentación fueron equivalentes a los de condiciones de ayuno. Los alimentos retrasaron la absorción de clozapina en 1,5 horas, desde una mediana de Tmax de 2,5 horas en condiciones de ayuno hasta 4 horas en condiciones de alimentación.

La Cmax media, ss de clozapina en condiciones masticadas para tabletas FAZACLO 200 mg fue aproximadamente del 86% que para tabletas FAZACLO de 2 x 100 mg en condiciones no masticadas, mientras que los valores de AUCss y Cmin, ss fueron similares entre las masticadas y las no masticadas condiciones.

En un estudio de efectos alimentarios, se administró una dosis única de FAZACLO (clozapina) tabletas de desintegración oral de 12.5 mg a voluntarios sanos en condiciones de ayuno y después de una comida rica en grasas. Cuando se administró FAZACLO después de una comida rica en grasas, la Cmáx de clozapina y su metabolito activo, desmetilclozapina, disminuyó en aproximadamente un 20%, en comparación con la administración en condiciones de ayuno, mientras que los valores de AUC no cambiaron. Esta disminución en la Cmáx no es clínicamente significativa. Por lo tanto, se pueden tomar tabletas desintegratorias por vía oral de FAZACLO (clozapina) sin tener en cuenta las comidas.

Distribución

La clozapina se une aproximadamente en un 97% a las proteínas séricas. La interacción entre la clozapina y otros fármacos altamente unidos a proteínas no se ha evaluado completamente, pero puede ser importante.

Metabolismo y excreción

La clozapina se metaboliza casi por completo antes de la excreción, y solo se detectan pequeñas cantidades de fármaco inalterado en la orina y las heces. La clozapina es un sustrato para muchas isoenzimas del citocromo P450, en particular CYP1A2, CYP2D6 y CYP3A4. Aproximadamente el 50% de la dosis administrada se excreta en la orina y el 30% en las heces. Los derivados desmetilados, hidroxilados y de N-óxido son componentes tanto en orina como en heces. Las pruebas farmacológicas han demostrado que el metabolito desmetil (norclozapina) tiene una actividad limitada, mientras que los derivados hidroxilados y de N-óxido estaban inactivos. La vida media de eliminación de clozapina después de una dosis única de 75 mg fue de 8 horas (rango: 4-12 horas), en comparación con una vida media de eliminación de 12 horas (rango: 4-66 horas), después de alcanzar el estado estacionario con 100 mg dos veces al día.

Una comparación de la administración de dosis única y dosis múltiples de clozapina demostró que la vida media de eliminación aumentó significativamente después de la administración de dosis múltiples en relación con la administración de dosis única, lo que sugiere la posibilidad de una farmacocinética dependiente de la concentración. Sin embargo, en estado estacionario, se observaron cambios aproximadamente proporcionales a la dosis con respecto al AUC (área bajo la curva), el pico y las concentraciones plasmáticas mínimas de clozapina después de la administración de 37.5, 75 y 150 mg dos veces al día.

Absorción

En el hombre, las tabletas de clozapina (25 mg y 100 mg) están igualmente biodisponibles en relación con una solución de clozapina. Las tabletas desintegratorias por vía oral de Nirva® (clozapina) son bioequivalentes a las tabletas Clozaril® (clozapina), una marca registrada de Novartis Pharmaceuticals Corporation. Después de una dosis de 100 mg b.i.d., la concentración plasmática máxima promedio en estado estacionario fue de 413 ng / ml (rango: 132-854 ng / ml), que ocurrió en el promedio de 2.3 horas (rango: 1-6 horas) después de la dosificación. La concentración mínima promedio en estado estacionario fue de 168 ng / ml (rango: 45-574 ng / ml), después de 100 mg b.i.d. dosificación.

Se realizó un estudio comparativo de bioequivalencia / biodisponibilidad en 32 pacientes (con esquizofrenia o trastorno esquizoafectivo) que compararon tabletas de Nirva 200 mg con tabletas de 2 Ã - Nirva 100 mg (el producto de referencia aprobado) en condiciones de ayuno. El estudio también evaluó el efecto de los alimentos y la masticación en la farmacocinética de la tableta de 200 mg. En condiciones de ayuno, el AUCss medio y Cmin, ss de clozapina para las tabletas de 200 mg fueron equivalentes a los de las tabletas de 2 x 100 mg. La Cmáx media, ss de clozapina para tabletas de Nirva 200 mg fue del 85% que para tabletas de Nirva de 2 x 100 mg. Esta disminución en Cmax, ss para tabletas de Nirva 200 mg no es clínicamente significativa.

Para las tabletas de Nirva 200 mg, los alimentos aumentaron significativamente la Cmin, ss de clozapina en un 21%. Sin embargo, este aumento no es clínicamente significativo. El AUCss medio y el Cmax, ss de clozapina en condiciones de alimentación fueron equivalentes a los de condiciones de ayuno. Los alimentos retrasaron la absorción de clozapina en 1,5 horas, desde una mediana de Tmax de 2,5 horas en condiciones de ayuno hasta 4 horas en condiciones de alimentación.

La Cmáx media, ss de clozapina en condiciones masticadas para tabletas de Nirva 200 mg fue aproximadamente del 86% que para tabletas de Nirva de 2 x 100 mg en condiciones no masticadas, mientras que los valores de AUCss y Cmin, ss fueron similares entre las masticadas y las no masticadas condiciones.

En un estudio de efectos alimentarios, se administró una dosis única de Nirva (clozapina) tabletas de desintegración oral de 12.5 mg a voluntarios sanos en condiciones de ayuno y después de una comida rica en grasas. Cuando se administró Nirva después de una comida rica en grasas, la Cmáx de clozapina y su metabolito activo, desmetilclozapina, disminuyó en aproximadamente un 20%, en comparación con la administración en condiciones de ayuno, mientras que los valores de AUC no cambiaron. Esta disminución en la Cmáx no es clínicamente significativa. Por lo tanto, se pueden tomar tabletas de desintegración oral de Nirva (clozapina) sin tener en cuenta las comidas.

Distribución

La clozapina se une aproximadamente en un 97% a las proteínas séricas. La interacción entre la clozapina y otros fármacos altamente unidos a proteínas no se ha evaluado completamente, pero puede ser importante.

Metabolismo y excreción

La clozapina se metaboliza casi por completo antes de la excreción, y solo se detectan pequeñas cantidades de fármaco inalterado en la orina y las heces. La clozapina es un sustrato para muchas isoenzimas del citocromo P450, en particular CYP1A2, CYP2D6 y CYP3A4. Aproximadamente el 50% de la dosis administrada se excreta en la orina y el 30% en las heces. Los derivados desmetilados, hidroxilados y de N-óxido son componentes tanto en orina como en heces. Las pruebas farmacológicas han demostrado que el metabolito desmetil (norclozapina) tiene una actividad limitada, mientras que los derivados hidroxilados y de N-óxido estaban inactivos. La vida media de eliminación de clozapina después de una dosis única de 75 mg fue de 8 horas (rango: 4-12 horas), en comparación con una vida media de eliminación de 12 horas (rango: 4-66 horas), después de alcanzar el estado estacionario con 100 mg dos veces al día.

Una comparación de la administración de dosis única y dosis múltiples de clozapina demostró que la vida media de eliminación aumentó significativamente después de la administración de dosis múltiples en relación con la administración de dosis única, lo que sugiere la posibilidad de una farmacocinética dependiente de la concentración. Sin embargo, en estado estacionario, se observaron cambios aproximadamente proporcionales a la dosis con respecto al AUC (área bajo la curva), el pico y las concentraciones plasmáticas mínimas de clozapina después de la administración de 37.5, 75 y 150 mg dos veces al día.