Componentes:
Método de ação:
Opção de tratamento:
Medicamente revisado por Kovalenko Svetlana Olegovna, Farmácia Última atualização em 12.03.2022
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20 principais medicamentos com os mesmos componentes:
20 principais medicamentos com os mesmos tratamentos:
Transtorno Depressivo Maior
WELLBUTRIN XL® (comprimidos de liberação prolongada de cloridrato de bupropiona) é indicado para o tratamento de transtorno depressivo maior (MDD), conforme definido pelo Manual Diagnóstico e Estatístico (DSM).
A eficácia da formulação de bupropiona de liberação imediata foi estabelecida em dois ensaios internados controlados por 4 semanas e em um estudo ambulatorial controlado por 6 semanas de pacientes adultos com MDD. A eficácia da formulação de bupropiona de liberação sustentada no tratamento de manutenção do MDD foi estabelecida a longo prazo (até 44 semanas) estudo controlado por placebo em pacientes que responderam à bupropiona em um estudo de 8 semanas de tratamento agudo.
Transtorno Afetivo Sazonal
WELLBUTRIN XL é indicado para a prevenção de episódios depressivos maiores sazonais em pacientes com diagnóstico de transtorno afetivo sazonal (DAU).
A eficácia dos comprimidos de liberação prolongada de cloridrato de bupropiona na prevenção de episódios depressivos maiores sazonais foi estabelecida em 3 ensaios controlados por placebo em pacientes ambulatoriais adultos com histórico de MDD com um padrão sazonal outono-inverno, conforme definido no DSM
Transtorno Depressivo Maior
O Zyntabac® (comprimidos de liberação prolongada de cloridrato de bupropiona) é indicado para o tratamento de transtorno depressivo maior (MDD), conforme definido pelo Manual Diagnóstico e Estatístico (DSM).
A eficácia da formulação de bupropiona de liberação imediata foi estabelecida em dois ensaios internados controlados por 4 semanas e em um estudo ambulatorial controlado por 6 semanas de pacientes adultos com MDD. A eficácia da formulação de bupropiona de liberação sustentada no tratamento de manutenção do MDD foi estabelecida a longo prazo (até 44 semanas) estudo controlado por placebo em pacientes que responderam à bupropiona em um estudo de 8 semanas de tratamento agudo.
Transtorno Afetivo Sazonal
Zyntabac é indicado para a prevenção de episódios depressivos maiores sazonais em pacientes com diagnóstico de transtorno afetivo sazonal (DAU).
A eficácia dos comprimidos de liberação prolongada de cloridrato de bupropiona na prevenção de episódios depressivos maiores sazonais foi estabelecida em 3 ensaios controlados por placebo em pacientes ambulatoriais adultos com histórico de MDD com um padrão sazonal outono-inverno, conforme definido no DSM
O Zyntabac (cloridrato de bupropiona) é indicado para o tratamento do transtorno depressivo maior (MDD), conforme definido pelo Manual Diagnóstico e Estatístico (DSM).
A eficácia da bupropiona no tratamento de um episódio depressivo maior foi estabelecida em dois ensaios internados controlados por 4 semanas e em um estudo ambulatorial controlado por 6 semanas de indivíduos adultos com MDD
A eficácia do Zyntabac na manutenção de uma resposta antidepressiva por até 44 semanas após 8 semanas de tratamento agudo foi demonstrada em um estudo controlado por placebo.
Instruções gerais de uso
Para minimizar o risco de convulsão, aumente a dose gradualmente.
WELLBUTRIN XL deve ser engolido inteiro e não esmagado, dividido ou mastigado.
WELLBUTRIN XL deve ser administrado de manhã e pode ser tomado com ou sem alimentos.
Dosagem para transtorno depressivo maior (MDD)
A dose inicial recomendada para MDD é de 150 mg uma vez ao dia pela manhã. Após 4 dias de administração, a dose pode ser aumentada para a dose alvo de 300 mg uma vez ao dia pela manhã.
É geralmente aceito que episódios agudos de depressão requerem vários meses ou mais de tratamento antidepressivo além da resposta no episódio agudo. Não se sabe se a dose de WELLBUTRIN XL necessária para o tratamento de manutenção é idêntica à dose que forneceu uma resposta inicial. Reavalie periodicamente a necessidade de tratamento de manutenção e a dose apropriada para esse tratamento.
Dosagem para Transtorno Afetivo Sazonal (SAD)
A dose inicial recomendada para SAD é de 150 mg uma vez ao dia. Após 7 dias de administração, a dose pode ser aumentada para a dose alvo de 300 mg uma vez ao dia pela manhã. Doses acima de 300 mg de liberação prolongada de HCl de bupropiona não foram avaliadas nos ensaios de DAU.
Para a prevenção de episódios sazonais de MDD associados ao SAD, inicie o WELLBUTRIN XL no outono, antes do início dos sintomas depressivos. Continue o tratamento durante o inverno. Diminua e interrompa o WELLBUTRIN XL no início da primavera. Para pacientes tratados com 300 mg por dia, diminua a dose para 150 mg uma vez ao dia antes de interromper o WELLBUTRIN XL. Individualize o momento da iniciação e a duração do tratamento deve ser individualizada, com base no padrão histórico do paciente de episódios sazonais de MDD.
Trocar pacientes de comprimidos WELLBUTRIN ou de comprimidos de liberação sustentada WELLBUTRIN SR
Ao trocar pacientes de comprimidos WELLBUTRIN para WELLBUTRIN XL ou de comprimidos de liberação sustentada WELLBUTRIN SR para WELLBUTRIN XL, administre a mesma dose diária total quando possível.
Para descontinuar o WELLBUTRIN XL, afine a dose
Ao interromper o tratamento em pacientes tratados com WELLBUTRIN XL 300 mg uma vez ao dia, diminua a dose para 150 mg uma vez ao dia antes da descontinuação.
Ajuste da dose em pacientes com comprometimento hepático
Em doentes com compromisso hepático moderado a grave (escore de Child-Pugh: 7 a 15), a dose máxima é de 150 mg em dias alternados. Em pacientes com insuficiência hepática leve (escore de Child-Pugh: 5 a 6), considere reduzir a dose e / ou a frequência da administração.
Ajuste da dose em pacientes com comprometimento renal
Considere reduzir a dose e / ou frequência de WELLBUTRIN em pacientes com insuficiência renal (taxa de filtragem glomerular inferior a 90 mL / min).
Mudando um paciente para ou de um antidepressivo inibidor da monoamina oxidase (MAOI)
Pelo menos 14 dias devem decorrer entre a descontinuação de um MAOI destinado a tratar a depressão e o início da terapia com WELLBUTRIN XL. Por outro lado, pelo menos 14 dias devem ser permitidos após a interrupção do WELLBUTRIN XL antes de iniciar um antidepressivo MAOI.
Uso de WELLBUTRIN XL com MAOIs reversíveis, como Linezolid ou Milethylene Blue
Não inicie o WELLBUTRIN XL em um paciente que esteja sendo tratado com um MAOI reversível, como azul de metileno linezolida ou intravenosa. As interações medicamentosas podem aumentar o risco de reações hipertensas. Em um paciente que requer tratamento mais urgente de uma condição psiquiátrica, intervenções não farmacológicas, incluindo hospitalização, devem ser consideradas.
Em alguns casos, um paciente que já está recebendo terapia com WELLBUTRIN XL pode precisar de tratamento urgente com azul de metileno linezolida ou intravenosa. Se não houver alternativas aceitáveis para o tratamento com azul de metileno linezolida ou intravenosa, os benefícios potenciais do tratamento com azul de metileno linezolida ou intravenosa superam os riscos de reações hipertensas em um paciente em particular, WELLBUTRIN XL deve ser interrompido imediatamente, e azul de metileno linezolida ou intravenoso pode ser administrado. O paciente deve ser monitorado por 2 semanas ou até 24 horas após a última dose de azul de metileno linezolida ou intravenosa, o que ocorrer primeiro. A terapia com WELLBUTRIN XL pode ser retomada 24 horas após a última dose de azul de metileno linezolida ou intravenosa.
O risco de administrar azul de metileno por vias não intravenosas (como comprimidos orais ou injeção local) ou em doses intravenosas muito inferiores a 1 mg por kg com WELLBUTRIN XL não é claro. O clínico deve, no entanto, estar ciente da possibilidade de interação medicamentosa com esse uso.
Instruções gerais de uso
Para minimizar o risco de convulsão, aumente a dose gradualmente.
Zyntabac deve ser engolido inteiro e não esmagado, dividido ou mastigado.
Zyntabac deve ser administrado de manhã e pode ser tomado com ou sem alimentos.
Dosagem para transtorno depressivo maior (MDD)
A dose inicial recomendada para MDD é de 150 mg uma vez ao dia pela manhã. Após 4 dias de administração, a dose pode ser aumentada para a dose alvo de 300 mg uma vez ao dia pela manhã.
É geralmente aceito que episódios agudos de depressão requerem vários meses ou mais de tratamento antidepressivo além da resposta no episódio agudo. Não se sabe se a dose de Zyntabac necessária para o tratamento de manutenção é idêntica à dose que forneceu uma resposta inicial. Reavalie periodicamente a necessidade de tratamento de manutenção e a dose apropriada para esse tratamento.
Dosagem para Transtorno Afetivo Sazonal (SAD)
A dose inicial recomendada para SAD é de 150 mg uma vez ao dia. Após 7 dias de administração, a dose pode ser aumentada para a dose alvo de 300 mg uma vez ao dia pela manhã. Doses acima de 300 mg de liberação prolongada de HCl de bupropiona não foram avaliadas nos ensaios de DAU.
Para a prevenção de episódios sazonais de MDD associados ao SAD, inicie o Zyntabac no outono, antes do início dos sintomas depressivos. Continue o tratamento durante o inverno. Afine e interrompa o Zyntabac no início da primavera. Para pacientes tratados com 300 mg por dia, diminua a dose para 150 mg uma vez ao dia antes de interromper o Zyntabac. Individualize o momento da iniciação e a duração do tratamento deve ser individualizada, com base no padrão histórico do paciente de episódios sazonais de MDD.
Trocar pacientes de comprimidos WELLBUTRIN ou de comprimidos de liberação sustentada WELLBUTRIN SR
Ao trocar pacientes de comprimidos WELLBUTRIN para Zyntabac ou de comprimidos de liberação sustentada WELLBUTRIN SR para Zyntabac, administre a mesma dose diária total quando possível.
Para descontinuar Zyntabac, afunde a dose
Ao interromper o tratamento em pacientes tratados com WELLBUTRIN XL 300 mg uma vez ao dia, diminua a dose para 150 mg uma vez ao dia antes da descontinuação.
Ajuste da dose em pacientes com comprometimento hepático
Em doentes com compromisso hepático moderado a grave (escore de Child-Pugh: 7 a 15), a dose máxima é de 150 mg em dias alternados. Em pacientes com insuficiência hepática leve (escore de Child-Pugh: 5 a 6), considere reduzir a dose e / ou a frequência da administração.
Ajuste da dose em pacientes com comprometimento renal
Considere reduzir a dose e / ou frequência de WELLBUTRIN em pacientes com insuficiência renal (taxa de filtragem glomerular inferior a 90 mL / min).
Mudando um paciente para ou de um antidepressivo inibidor da monoamina oxidase (MAOI)
Pelo menos 14 dias devem decorrer entre a descontinuação de um MAOI destinado a tratar a depressão e o início da terapia com WELLBUTRIN XL. Por outro lado, pelo menos 14 dias devem ser permitidos após a interrupção do Zyntabac antes de iniciar um antidepressivo MAOI.
Uso de Zyntabac com MAOIs reversíveis, como Linezolid ou Methylene Blue
Não inicie o Zyntabac em um paciente que esteja sendo tratado com um MAOI reversível, como azul de metileno linezolido ou intravenoso. As interações medicamentosas podem aumentar o risco de reações hipertensas. Em um paciente que requer tratamento mais urgente de uma condição psiquiátrica, intervenções não farmacológicas, incluindo hospitalização, devem ser consideradas.
Em alguns casos, um paciente que já está recebendo terapia com Zyntabac pode precisar de tratamento urgente com azul de metileno linezolida ou intravenosa. Se não houver alternativas aceitáveis para o tratamento com azul de metileno linezolida ou intravenosa, os benefícios potenciais do tratamento com azul de metileno linezolida ou intravenosa superam os riscos de reações hipertensas em um paciente em particular, Zyntabac deve ser parado imediatamente, e azul de metileno linezolida ou intravenoso pode ser administrado. O paciente deve ser monitorado por 2 semanas ou até 24 horas após a última dose de azul de metileno linezolida ou intravenosa, o que ocorrer primeiro. A terapia com Zyntabac pode ser retomada 24 horas após a última dose de azul de metileno linezolida ou intravenosa.
O risco de administrar azul de metileno por vias não intravenosas (como comprimidos orais ou injeção local) ou em doses intravenosas muito inferiores a 1 mg por kg com Zyntabac não é claro. O clínico deve, no entanto, estar ciente da possibilidade de interação medicamentosa com esse uso.
Instruções gerais de uso
Para minimizar o risco de convulsão, aumente a dose gradualmente. Os comprimidos de Zyntabac devem ser engolidos inteiros e não esmagados, divididos ou mastigados. Zyntabac pode ser tomado com ou sem alimentos.
A dose alvo habitual para adultos de Zyntabac é de 300 mg por dia, administrada em 150 mg duas vezes ao dia. Inicie a administração com 150 mg por dia, administrada em dose diária única pela manhã. Após 3 dias de administração, a dose pode ser aumentada para a dose alvo de 300 mg por dia, administrada em 150 mg duas vezes ao dia. Deve haver um intervalo de pelo menos 8 horas entre doses sucessivas. Um máximo de 400 mg por dia, administrado em 200 mg duas vezes ao dia, pode ser considerado em pacientes nos quais não há melhora clínica após várias semanas de tratamento a 300 mg por dia. Para evitar altas concentrações máximas de bupropiona e / ou seus metabólitos, não exceda 200 mg em uma dose única.
É geralmente aceito que episódios agudos de depressão requerem vários meses ou mais de tratamento medicamentoso antidepressivo além da resposta no episódio agudo. Não se sabe se a dose de Zyntabac necessária para o tratamento de manutenção é idêntica à dose que forneceu uma resposta inicial. Reavalie periodicamente a necessidade de tratamento de manutenção e a dose apropriada para esse tratamento.
Ajuste da dose em pacientes com comprometimento hepático
Em doentes com compromisso hepático moderado a grave (escore de Child-Pugh: 7 a 15), a dose máxima de Zyntabac é de 100 mg por dia ou 150 mg todos os dias. Em pacientes com insuficiência hepática leve (escore de Child-Pugh: 5 a 6), considere reduzir a dose e / ou a frequência da administração.
Ajuste da dose em pacientes com comprometimento renal
Considere reduzir a dose e / ou frequência de WELLBUTRIN SR em pacientes com insuficiência renal (taxa de filtragem glomerular inferior a 90 mL por min).
Mudando um paciente para ou de um antidepressivo inibidor da monoamina oxidase (MAOI)
Pelo menos 14 dias devem decorrer entre a descontinuação de um MAOI destinado a tratar a depressão e o início da terapia com WELLBUTRIN SR. Por outro lado, pelo menos 14 dias devem ser permitidos após a interrupção do Zyntabac antes de iniciar um antidepressivo MAOI.
Uso de Zyntabac com MAOIs reversíveis, como Linezolid ou Methylene Blue
Não inicie o Zyntabac em um paciente que esteja sendo tratado com um MAOI reversível, como azul de metileno linezolido ou intravenoso. As interações medicamentosas podem aumentar o risco de reações hipertensas. Em um paciente que requer tratamento mais urgente de uma condição psiquiátrica, intervenções não farmacológicas, incluindo hospitalização, devem ser consideradas.
Em alguns casos, um paciente que já está recebendo terapia com WELLBUTRIN SR pode precisar de tratamento urgente com azul de metileno linezolida ou intravenosa. Se não houver alternativas aceitáveis para o tratamento com azul de metileno linezolida ou intravenosa, os benefícios potenciais do tratamento com azul de metileno linezolida ou intravenosa superam os riscos de reações hipertensas em um paciente em particular, Zyntabac deve ser parado imediatamente, e azul de metileno linezolida ou intravenoso pode ser administrado. O paciente deve ser monitorado por 2 semanas ou até 24 horas após a última dose de azul de metileno linezolida ou intravenosa, o que ocorrer primeiro. A terapia com Zyntabac pode ser retomada 24 horas após a última dose de azul de metileno linezolida ou intravenosa.
O risco de administrar azul de metileno por vias não intravenosas (como comprimidos orais ou injeção local) ou em doses intravenosas muito inferiores a 1 mg por kg com Zyntabac não é claro. O clínico deve, no entanto, estar ciente da possibilidade de interação medicamentosa com esse uso.
- WELLBUTRIN XL está contra-indicado em pacientes com transtorno convulsivo.
- WELLBUTRIN XL está contra-indicado em pacientes com diagnóstico atual ou prévio de bulimia ou anorexia nervosa, pois foi observada uma maior incidência de convulsões nesses pacientes tratados com WELLBUTRIN XL
- WELLBUTRIN XL está contra-indicado em pacientes submetidos à descontinuação abrupta de álcool, benzodiazepínicos, barbitúricos e medicamentos antiepiléticos.
- O uso de MAOIs (destinado ao tratamento de distúrbios psiquiátricos) concomitantemente com WELLBUTRIN XL ou dentro de 14 dias após a interrupção do tratamento com WELLBUTRIN XL é contra-indicado. Existe um risco aumentado de reações hipertensivas quando o WELLBUTRIN XL é usado concomitantemente com MAOIs. O uso de WELLBUTRIN XL dentro de 14 dias após a interrupção do tratamento com um MAOI também é contra-indicado. Iniciar o WELLBUTRIN XL em um paciente tratado com MAOIs reversíveis, como linezolida ou azul de metileno intravenoso, é contra-indicado.
- WELLBUTRIN XL está contra-indicado em pacientes com hipersensibilidade conhecida à bupropiona ou outros ingredientes de WELLBUTRIN XL. Foram relatadas reações anafilactóides / anafiláticas e síndrome de Stevens-Johnson.
- Zyntabac está contra-indicado em pacientes com transtorno convulsivo.
- Zyntabac está contra-indicado em pacientes com diagnóstico atual ou prévio de bulimia ou anorexia nervosa, pois foi observada uma maior incidência de convulsões nesses pacientes tratados com Zyntabac.
- O zyntabac está contra-indicado em pacientes submetidos à descontinuação abrupta de álcool, benzodiazepínicos, barbitúricos e medicamentos antiepiléticos.
- O uso de MAOIs (destinado ao tratamento de distúrbios psiquiátricos) concomitantemente com Zyntabac ou dentro de 14 dias após a interrupção do tratamento com Zyntabac é contra-indicado. Existe um risco aumentado de reações hipertensivas quando o Zyntabac é usado concomitantemente com MAOIs. O uso de Zyntabac dentro de 14 dias após a interrupção do tratamento com um MAOI também é contra-indicado. O início do Zyntabac em um paciente tratado com MAOIs reversíveis, como o azul de metileno linezolida ou intravenoso, é contra-indicado.
- Zyntabac está contra-indicado em pacientes com hipersensibilidade conhecida à bupropiona ou a outros ingredientes de Zyntabac. Foram relatadas reações anafilactóides / anafiláticas e síndrome de Stevens-Johnson.
- Zyntabac está contra-indicado em pacientes com um distúrbio convulsivo.
- O zyntabac é contra-indicado em pacientes com diagnóstico atual ou prévio de bulimia oranorexia nervosa, pois foi observada uma maior incidência de convulsões nesses pacientes tratados com a formulação de bupropiona de liberação imediata.
- O zyntabac está contra-indicado em pacientes submetidos à descontinuação abrupta de álcool, benzodiazepínicos, barbitúricos e medicamentos antiepiléticos.
- O uso de MAOIs (destinado ao tratamento de distúrbios psiquiátricos) concomitantemente com Zyntabac ou dentro de 14 dias após a interrupção do tratamento com Zyntabac é contra-indicado. Existe um risco aumentado de reações hipertensivas quando o Zyntabac é usado concomitantemente com MAOIs. O uso de Zyntabac dentro de 14 dias após a interrupção do tratamento com um MAOI também é contra-indicado. O início do Zyntabac em um paciente tratado com MAOIs reversíveis, como o azul de metileno linezolida ou intravenoso, é contra-indicado.
- Zyntabac está contra-indicado em pacientes com hipersensibilidade conhecida à bupropiona ou a outros ingredientes de Zyntabac. Foram relatadas reações anafilactóides / anafiláticas e síndrome de Stevens-Johnson.
WARNINGS
Included as part of the PRECAUTIONS section.
PRECAUTIONS
Suicidal Thoughts And Behaviors In Children, Adolescents, And Young Adults
Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.
Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (Selective Serotonin Reuptake Inhibitors [SSRIs] and others) show that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.
Table 1: Risk Differences in the Number of Suicidality Cases by Age Group in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients
Age Range | Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated |
Increases Compared to Placebo | |
< 18 years | 14 additional cases |
18-24 years | 5 additional cases |
Decreases Compared to Placebo | |
25-64 years | 1 fewer case |
> 65 years | 6 fewer cases |
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for WELLBUTRIN XL should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
Neuropsychiatric Symptoms And Suicide Risk In Smoking Cessation Treatment
WELLBUTRIN XL is not approved for smoking cessation treatment; however, bupropion HCl sustained-release is approved for this use. Serious neuropsychiatric symptoms have been reported in patients taking bupropion for smoking cessation. These have included changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, hostility, agitation, aggression, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide. Observe patients for the occurrence of neuropsychiatric reactions. Instruct patients to contact a healthcare professional if such reactions occur.
In many of these cases, a causal relationship to bupropion treatment is not certain, because depressed mood can be a symptom of nicotine withdrawal. However, some of the cases occurred in patients taking bupropion who continued to smoke.
Seizure
WELLBUTRIN XL can cause seizure. The risk of seizure is dose-related. The dose should not exceed 300 mg once daily. Increase the dose gradually. Discontinue WELLBUTRIN XL and do not restart treatment if the patient experiences a seizure.
The risk of seizures is also related to patient factors, clinical situations, and concomitant medications that lower the seizure threshold. Consider these risks before initiating treatment with WELLBUTRIN XL. WELLBUTRIN XL is contraindicated in patients with a seizure disorder or conditions that increase the risk of seizure (e.g., severe head injury, arteriovenous malformation, CNS tumor or CNS infection, severe stroke, anorexia nervosa or bulimia, or abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs. The following conditions can also increase the risk of seizure: concomitant use of other medications that lower the seizure threshold (e.g., other bupropion products, antipsychotics, tricyclic antidepressants, theophylline, and systemic corticosteroids), metabolic disorders (e.g., hypoglycemia, hyponatremia, severe hepatic impairment, and hypoxia), or use of illicit drugs (e.g., cocaine) or abuse or misuse of prescription drugs such as CNS stimulants. Additional predisposing conditions include diabetes mellitus treated with oral hypoglycemic drugs or insulin, use of anorectic drugs, excessive use of alcohol, benzodiazepines, sedative/hypnotics, or opiates.
Incidence Of Seizure With Bupropion Use
The incidence of seizure with WELLBUTRIN XL has not been formally evaluated in clinical trials. In studies using bupropion HCl sustained-release up to 300 mg per day the incidence of seizure was approximately 0.1% (1/1000 patients). In a large prospective, follow-up study, the seizure incidence was approximately 0.4% (13/3200) with bupropion HCl immediate-release in the range of 300 mg to 450 mg per day.
Additional data accumulated for bupropion immediate-release suggests that the estimated seizure incidence increases almost tenfold between 450 and 600 mg/day. The risk of seizure can be reduced if the WELLBUTRIN XL dose does not exceed 450 mg once daily and the titration rate is gradual.
Hypertension
Treatment with WELLBUTRIN XL can result in elevated blood pressure and hypertension.
Assess blood pressure before initiating treatment with WELLBUTRIN XL, and monitor periodically during treatment. The risk of hypertension is increased if WELLBUTRIN XL is used concomitantly with MAOIs or other drugs that increase dopaminergic or noradrenergic activity.
Data from a comparative trial of the sustained-release formulation of bupropion HCl, nicotine transdermal system (NTS), the combination of sustained-release bupropion plus NTS, and placebo as an aid to smoking cessation suggest a higher incidence of treatment-emergent hypertension in patients treated with the combination of sustained-release bupropion and NTS. In this trial, 6.1% of subjects treated with the combination of sustained-release bupropion and NTS had treatment-emergent hypertension compared to 2.5%, 1.6%, and 3.1% of subjects treated with sustained-release bupropion, NTS, and placebo, respectively. The majority of these subjects had evidence of pre-existing hypertension. Three subjects (1.2%) treated with the combination of sustained-release bupropion and NTS and 1 subject (0.4%) treated with NTS had study medication discontinued due to hypertension compared with none of the subjects treated with sustained-release bupropion or placebo. Monitoring of blood pressure is recommended in patients who receive the combination of bupropion and nicotine replacement.
In the 3 trials of bupropion HCl extended-release in seasonal affective disorder, there were significant elevations in blood pressure. Hypertension was reported as an adverse reaction for 2% of the bupropion group (11/537) and none in the placebo group (0/511). In the SAD trials, 2 patients treated with bupropion discontinued from the study because they developed hypertension. None of the placebo group discontinued because of hypertension. The mean increase in systolic blood pressure was 1.3 mmHg in the bupropion group and 0.1 mmHg in the placebo group. The difference was statistically significant (p=0.013). The mean increase in diastolic blood pressure was 0.8 mmHg in the bupropion group and 0.1 mmHg in the placebo group. The difference was not statistically significant (p=0.075). In the SAD trials, 82% of patients were treated with 300 mg per day, and 18% were treated with 150 mg per day. The mean daily dose was 270 mg per day. The mean duration of bupropion exposure was 126 days.
In a clinical trial of bupropion immediate-release in MDD subjects with stable congestive heart failure (N=36), bupropion was associated with an exacerbation of pre-existing hypertension in 2 subjects, leading to discontinuation of bupropion treatment. There are no controlled studies assessing the safety of bupropion in patients with a recent history of myocardial infarction or unstable cardiac disease.
Activation Of Mania/Hypomania
Antidepressant treatment can precipitate a manic, mixed, or hypomanic manic episode. The risk appears to be increased in patients with bipolar disorder or who have risk factors for bipolar disorder. Prior to initiating WELLBUTRIN XL, screen patients for a history of bipolar disorder and the presence of risk factors for bipolar disorder (e.g., family history of bipolar disorder, suicide, or depression). WELLBUTRIN XL is not approved for the treatment of bipolar depression.
Psychosis And Other Neuropsychiatric Reactions
Depressed patients treated with bupropion have had a variety of neuropsychiatric signs and symptoms, including delusions, hallucinations, psychosis, concentration disturbance, paranoia, and confusion. Some of these patients had a diagnosis of bipolar disorder. In some cases, these symptoms abated upon dose reduction and/or withdrawal of treatment. Discontinue WELLBUTRIN XL if these reactions occur.
Angle-Closure Glaucoma
Angle-Closure Glaucoma: The pupillary dilation that occurs following use of many antidepressant drugs including WELLBUTRIN XL may trigger an angle-closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.
Hypersensitivity Reactions
Anaphylactoid/anaphylactic reactions have occurred during clinical trials with bupropion. Reactions have been characterized by pruritus, urticaria, angioedema, and dyspnea, requiring medical treatment. In addition, there have been rare, spontaneous postmarketing reports of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock associated with bupropion. Instruct patients to discontinue WELLBUTRIN XL and consult a healthcare provider if they develop an allergic or anaphylactoid/anaphylactic reaction (e.g., skin rash, pruritus, hives, chest pain, edema, and shortness of breath) during treatment.
There are reports of arthralgia, myalgia, fever with rash and other symptoms of serum sickness suggestive of delayed hypersensitivity.
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Inform patients, their families, and their caregivers about the benefits and risks associated with treatment with WELLBUTRIN XL and counsel them in its appropriate use.
A patient Medication Guide about “Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions,” “Quitting Smoking, Quit-Smoking Medications, Changes in Thinking and Behavior, Depression, and Suicidal Thoughts or Actions,” and “What Other Important Information Should I Know About WELLBUTRIN XL?” is available for WELLBUTRIN XL. Instruct patients, their families, and their caregivers to read the Medication Guide and assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.
Advise patients regarding the following issues and to alert their prescriber if these occur while taking WELLBUTRIN XL.
Suicidal Thoughts And Behaviors
Instruct patients, their families, and/or their caregivers to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Advise families and caregivers of patients to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.
Neuropsychiatric Symptoms And Suicide Risk In Smoking Cessation Treatment
Although WELLBUTRIN XL is not indicated for smoking cessation treatment, it contains the same active ingredient as ZYBAN® which is approved for this use. Advise patients, families and caregivers that quitting smoking, with or without ZYBAN, may trigger nicotine withdrawal symptoms (e.g., including depression or agitation) or worsen pre-existing psychiatric illness. Some patients have experienced changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide when attempting to quit smoking while taking ZYBAN. If patients develop agitation, hostility, depressed mood, or changes in thinking or behavior that are not typical for them, or if patients develop suicidal ideation or behavior, they should be urged to report these symptoms to their healthcare provider immediately.
Severe Allergic Reactions
Educate patients on the symptoms of hypersensitivity and to discontinue WELLBUTRIN XL if they have a severe allergic reaction.
Seizure
Instruct patients to discontinue and not restart WELLBUTRIN XL if they experience a seizure while on treatment. Advise patients that the excessive use or the abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can increase the risk of seizure. Advise patients to minimize or avoid the use of alcohol.
Angle-Closure Glaucoma
Patients should be advised that taking WELLBUTRIN XL can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angleglaucoma is not a risk factor for angle-closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible.
Bupropion-Containing Products
Educate patients that WELLBUTRIN XL contains the same active ingredient (bupropion) found in ZYBAN, which is used as an aid to smoking cessation treatment, and that WELLBUTRIN XL should not be used in combination with ZYBAN or any other medications that contain bupropion hydrochloride (such as WELLBUTRIN SR, the sustained-release formulation, WELLBUTRIN, the immediate-release formulation, and APLENZIN, a bupropion hydrobromide formulation). In addition, there are a number of generic bupropion HCl products for the immediate, sustained, and extended-release formulations.
Potential For Cognitive And Motor Impairment
Advise patients that any CNS-active drug like WELLBUTRIN XL Tablets may impair their ability to perform tasks requiring judgment or motor and cognitive skills. Advise patients that until they are reasonably certain that WELLBUTRIN XL Tablets do not adversely affect their performance, they should refrain from driving an automobile or operating complex, hazardous machinery. WELLBUTRIN XL treatment may lead to decreased alcohol tolerance.
Concomitant Medications
Counsel patients to notify their healthcare provider if they are taking or plan to take any prescription or over-the-counter drugs, because WELLBUTRIN XL Tablets and other drugs may affect each other's metabolism.
Pregnancy
Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during therapy.
Precautions For Nursing Mothers
Communicate with the patient and pediatric healthcare provider regarding the infant's exposure to bupropion through human milk. Instruct patients to immediately contact the infant's healthcare provider if they note any side effect in the infant that concerns them or is persistent.
Administration Information
Instruct patients to swallow WELLBUTRIN XL Tablets whole so that the release rate is not altered. Instruct patients if they miss a dose, not to take an extra tablet to make up for the missed dose and to take the next tablet at the regular time because of the dose-related risk of seizure. Instruct patients that WELLBUTRIN XL tablets should be swallowed whole and not crushed, divided, or chewed. WELLBUTRIN XL should be administered in the morning and may be taken with or without food.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Bupropion produced a positive response (2 to 3 times control mutation rate) in 2 of 5 strains in one Ames bacterial mutagenicity assay, but was negative in another. Bupropion produced an increase in chromosomal aberrations in 1 of 3 in vivo rat bone marrow cytogenetic studies.
A fertility study in rats at doses up to 300 mg/kg/day revealed no evidence of impaired fertility.
Use In Specific Populations
Pregnancy
Pregnancy Category C
Risk Summary
Data from epidemiological studies including pregnant women exposed to bupropion in the first trimester indicate no increased risk of congenital malformations overall. All pregnancies regardless of drug exposure have a background rate of 2% to 4% for major malformations and 15% to 20% for pregnancy loss. No clear evidence of teratogenic activity was found in reproductive developmental studies conducted in rats and rabbits. However, in rabbits, slightly increased incidences of fetal malformations and skeletal variations were observed at doses approximately equal to the maximum recommended human dose (MRHD) and greater and decreased fetal weights were seen at doses twice the MRHD and greater. WELLBUTRIN XL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Clinical Considerations
Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medications during pregnancy and postpartum.
Human Data
Data from an international bupropion Pregnancy registry (675 first trimester exposures) and a retrospective cohort study using the United Healthcare database (1,213 first trimester exposures) did not show an increased risk for malformations overall.
No increased risk for cardiovascular malformations overall has been observed after bupropion exposure during the first trimester. The prospectively observed rate of cardiovascular malformations in pregnancies with exposure to bupropion in the first trimester from the international Pregnancy Registry was 1.3% (9 cardiovascular malformations/675 first-trimester maternal bupropion exposures), which is similar to the background rate of cardiovascular malformations (approximately 1%). Data from the United Healthcare database and a case-controlled study (6,853 infants with cardiovascular malformations and 5,753 with non-cardiovascular malformations) from the National Birth Defects Prevention Study (NBDPS) did not show an increased risk for cardiovascular malformations overall after bupropion exposure during the first trimester.
Study findings on bupropion exposure during the first trimester and risk left ventricular outflow tract obstruction (LVOTO) are inconsistent and do not allow conclusions regarding possible association. The United Healthcare database lacked sufficient power to evaluate this association; the NBDPS found increased risk for LVOTO (n = 10; adjusted OR = 2.6; 95% CI 1.2, 5.7) and the Slone Epidemiology case control study did not find increased risk for LVOTO.
Study findings on bupropion exposure during the first trimester and risk for ventricular septal defect (VSD) are inconsistent and do not allow conclusions regarding a possible association. The Slone Epidemiology Study found an increased risk for VSD following first trimester maternal bupropion exposure (n = 17; adjusted OR = 2.5; 95% CI: 1.3, 5.0) but did not find an increased risk for any other cardiovascular malformations studied (including LVOTO as above). The NBDPS and United Healthcare database study did not find an association between first trimester maternal bupropion exposure and VSD.
For the findings of LVOTO and VSD, the studies were limited by the small number of exposed cases, inconsistent findings among studies, and the potential for chance findings from multiple comparisons in case control studies.
Animal Data
In studies conducted in rats and rabbits, bupropion was administered orally at doses of up to 450 and 150 mg/kg/day, respectively (approximately 11 and 7 times the MRHD, respectively, on a mg/m² basis), during the period of organogenesis. No clear evidence of teratogenic activity was found in either species; however, in rabbits, slightly increased incidences of fetal malformations and skeletal variations were observed at the lowest dose tested (25 mg/kg/day, approximately equal to the MRHD on a mg/m² basis) and greater. Decreased fetal weights were observed at 50 mg/kg and greater. When rats were administered bupropion at oral doses of up to 300 mg/kg/day (approximately 7 times the MRHD on a mg/m² basis) prior to mating and throughout pregnancy and lactation, there were no apparent adverse effects on offspring development.
Nursing Mothers
Bupropion and its metabolites are present in human milk. In a lactation study of ten women, levels of orally dosed bupropion and its active metabolites were measured in expressed milk. The average daily infant exposure (assuming 150 mL/kg daily consumption) to bupropion and its active metabolites was 2% of the maternal weight-adjusted dose. Exercise caution when WELLBUTRIN XL is administered to a nursing woman.
Pediatric Use
Safety and effectiveness in the pediatric population have not been established. When considering the use of WELLBUTRIN XL in a child or adolescent, balance the potential risks with the clinical need.
Geriatric Use
Of the approximately 6000 patients who participated in clinical trials with bupropion hydrochloride sustained-release tablets (depression and smoking cessation studies), 275 were ≥ 65 years old and 47 were ≥ 75 years old. In addition, several hundred patients ≥ 65 years of age participated in clinical trials using the immediate-release formulation of bupropion hydrochloride (depression studies). No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Bupropion is extensively metabolized in the liver to active metabolites, which are further metabolized and excreted by the kidneys. The risk of adverse reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be necessary to consider this factor in dose selection; it may be useful to monitor renal function.
Renal Impairment
Consider a reduced dose and/or dosing frequency of WELLBUTRIN XL in patients with renal impairment (Glomerular Filtration Rate: < 90 mL/min). Bupropion and its metabolites are cleared renally and may accumulate in such patients to a greater extent than usual. Monitor closely for adverse reactions that could indicate high bupropion or metabolite exposures.
Hepatic Impairment
In patients with moderate to severe hepatic impairment (Child-Pugh score: 7 to 15), the maximum WELLBUTRIN XL dose is 150 mg every other day. In patients with mild hepatic impairment (Child-Pugh score: 5 to 6), consider reducing the dose and/or frequency of dosing.
WARNINGS
Included as part of the PRECAUTIONS section.
PRECAUTIONS
Suicidal Thoughts And Behaviors In Children, Adolescents, And Young Adults
Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.
Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (Selective Serotonin Reuptake Inhibitors [SSRIs] and others) show that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.
Table 1: Risk Differences in the Number of Suicidality Cases by Age Group in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients
Age Range | Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated |
Increases Compared to Placebo | |
< 18 years | 14 additional cases |
18-24 years | 5 additional cases |
Decreases Compared to Placebo | |
25-64 years | 1 fewer case |
> 65 years | 6 fewer cases |
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Zyntabac should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
Neuropsychiatric Symptoms And Suicide Risk In Smoking Cessation Treatment
Zyntabac is not approved for smoking cessation treatment; however, bupropion HCl sustained-release is approved for this use. Serious neuropsychiatric symptoms have been reported in patients taking bupropion for smoking cessation. These have included changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, hostility, agitation, aggression, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide. Observe patients for the occurrence of neuropsychiatric reactions. Instruct patients to contact a healthcare professional if such reactions occur.
In many of these cases, a causal relationship to bupropion treatment is not certain, because depressed mood can be a symptom of nicotine withdrawal. However, some of the cases occurred in patients taking bupropion who continued to smoke.
Seizure
Zyntabac can cause seizure. The risk of seizure is dose-related. The dose should not exceed 300 mg once daily. Increase the dose gradually. Discontinue Zyntabac and do not restart treatment if the patient experiences a seizure.
The risk of seizures is also related to patient factors, clinical situations, and concomitant medications that lower the seizure threshold. Consider these risks before initiating treatment with Zyntabac. Zyntabac is contraindicated in patients with a seizure disorder or conditions that increase the risk of seizure (e.g., severe head injury, arteriovenous malformation, CNS tumor or CNS infection, severe stroke, anorexia nervosa or bulimia, or abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs. The following conditions can also increase the risk of seizure: concomitant use of other medications that lower the seizure threshold (e.g., other bupropion products, antipsychotics, tricyclic antidepressants, theophylline, and systemic corticosteroids), metabolic disorders (e.g., hypoglycemia, hyponatremia, severe hepatic impairment, and hypoxia), or use of illicit drugs (e.g., cocaine) or abuse or misuse of prescription drugs such as CNS stimulants. Additional predisposing conditions include diabetes mellitus treated with oral hypoglycemic drugs or insulin, use of anorectic drugs, excessive use of alcohol, benzodiazepines, sedative/hypnotics, or opiates.
Incidence Of Seizure With Bupropion Use
The incidence of seizure with Zyntabac has not been formally evaluated in clinical trials. In studies using bupropion HCl sustained-release up to 300 mg per day the incidence of seizure was approximately 0.1% (1/1000 patients). In a large prospective, follow-up study, the seizure incidence was approximately 0.4% (13/3200) with bupropion HCl immediate-release in the range of 300 mg to 450 mg per day.
Additional data accumulated for bupropion immediate-release suggests that the estimated seizure incidence increases almost tenfold between 450 and 600 mg/day. The risk of seizure can be reduced if the Zyntabac dose does not exceed 450 mg once daily and the titration rate is gradual.
Hypertension
Treatment with Zyntabac can result in elevated blood pressure and hypertension.
Assess blood pressure before initiating treatment with Zyntabac, and monitor periodically during treatment. The risk of hypertension is increased if Zyntabac is used concomitantly with MAOIs or other drugs that increase dopaminergic or noradrenergic activity.
Data from a comparative trial of the sustained-release formulation of bupropion HCl, nicotine transdermal system (NTS), the combination of sustained-release bupropion plus NTS, and placebo as an aid to smoking cessation suggest a higher incidence of treatment-emergent hypertension in patients treated with the combination of sustained-release bupropion and NTS. In this trial, 6.1% of subjects treated with the combination of sustained-release bupropion and NTS had treatment-emergent hypertension compared to 2.5%, 1.6%, and 3.1% of subjects treated with sustained-release bupropion, NTS, and placebo, respectively. The majority of these subjects had evidence of pre-existing hypertension. Three subjects (1.2%) treated with the combination of sustained-release bupropion and NTS and 1 subject (0.4%) treated with NTS had study medication discontinued due to hypertension compared with none of the subjects treated with sustained-release bupropion or placebo. Monitoring of blood pressure is recommended in patients who receive the combination of bupropion and nicotine replacement.
In the 3 trials of bupropion HCl extended-release in seasonal affective disorder, there were significant elevations in blood pressure. Hypertension was reported as an adverse reaction for 2% of the bupropion group (11/537) and none in the placebo group (0/511). In the SAD trials, 2 patients treated with bupropion discontinued from the study because they developed hypertension. None of the placebo group discontinued because of hypertension. The mean increase in systolic blood pressure was 1.3 mmHg in the bupropion group and 0.1 mmHg in the placebo group. The difference was statistically significant (p=0.013). The mean increase in diastolic blood pressure was 0.8 mmHg in the bupropion group and 0.1 mmHg in the placebo group. The difference was not statistically significant (p=0.075). In the SAD trials, 82% of patients were treated with 300 mg per day, and 18% were treated with 150 mg per day. The mean daily dose was 270 mg per day. The mean duration of bupropion exposure was 126 days.
In a clinical trial of bupropion immediate-release in MDD subjects with stable congestive heart failure (N=36), bupropion was associated with an exacerbation of pre-existing hypertension in 2 subjects, leading to discontinuation of bupropion treatment. There are no controlled studies assessing the safety of bupropion in patients with a recent history of myocardial infarction or unstable cardiac disease.
Activation Of Mania/Hypomania
Antidepressant treatment can precipitate a manic, mixed, or hypomanic manic episode. The risk appears to be increased in patients with bipolar disorder or who have risk factors for bipolar disorder. Prior to initiating Zyntabac, screen patients for a history of bipolar disorder and the presence of risk factors for bipolar disorder (e.g., family history of bipolar disorder, suicide, or depression). Zyntabac is not approved for the treatment of bipolar depression.
Psychosis And Other Neuropsychiatric Reactions
Depressed patients treated with bupropion have had a variety of neuropsychiatric signs and symptoms, including delusions, hallucinations, psychosis, concentration disturbance, paranoia, and confusion. Some of these patients had a diagnosis of bipolar disorder. In some cases, these symptoms abated upon dose reduction and/or withdrawal of treatment. Discontinue Zyntabac if these reactions occur.
Angle-Closure Glaucoma
Angle-Closure Glaucoma: The pupillary dilation that occurs following use of many antidepressant drugs including Zyntabac may trigger an angle-closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.
Hypersensitivity Reactions
There are reports of arthralgia, myalgia, fever with rash and other symptoms of serum sickness suggestive of delayed hypersensitivity.
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Zyntabac and counsel them in its appropriate use.
A patient Medication Guide about “Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions,” “Quitting Smoking, Quit-Smoking Medications, Changes in Thinking and Behavior, Depression, and Suicidal Thoughts or Actions,” and “What Other Important Information Should I Know About Zyntabac?” is available for Zyntabac. Instruct patients, their families, and their caregivers to read the Medication Guide and assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.
Advise patients regarding the following issues and to alert their prescriber if these occur while taking Zyntabac.
Suicidal Thoughts And Behaviors
Instruct patients, their families, and/or their caregivers to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Advise families and caregivers of patients to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.
Neuropsychiatric Symptoms And Suicide Risk In Smoking Cessation Treatment
Although Zyntabac is not indicated for smoking cessation treatment, it contains the same active ingredient as ZYBAN® which is approved for this use. Advise patients, families and caregivers that quitting smoking, with or without ZYBAN, may trigger nicotine withdrawal symptoms (e.g., including depression or agitation) or worsen pre-existing psychiatric illness. Some patients have experienced changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide when attempting to quit smoking while taking ZYBAN. If patients develop agitation, hostility, depressed mood, or changes in thinking or behavior that are not typical for them, or if patients develop suicidal ideation or behavior, they should be urged to report these symptoms to their healthcare provider immediately.
Severe Allergic Reactions
Educate patients on the symptoms of hypersensitivity and to discontinue Zyntabac if they have a severe allergic reaction.
Seizure
Instruct patients to discontinue and not restart Zyntabac if they experience a seizure while on treatment. Advise patients that the excessive use or the abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can increase the risk of seizure. Advise patients to minimize or avoid the use of alcohol.
Angle-Closure Glaucoma
Patients should be advised that taking Zyntabac can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angleglaucoma is not a risk factor for angle-closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible.
Bupropion-Containing Products
Educate patients that Zyntabac contains the same active ingredient (bupropion) found in ZYBAN, which is used as an aid to smoking cessation treatment, and that Zyntabac should not be used in combination with ZYBAN or any other medications that contain bupropion hydrochloride (such as WELLBUTRIN SR, the sustained-release formulation, WELLBUTRIN, the immediate-release formulation, and APLENZIN, a bupropion hydrobromide formulation). In addition, there are a number of generic bupropion HCl products for the immediate, sustained, and extended-release formulations.
Potential For Cognitive And Motor Impairment
Advise patients that any CNS-active drug like WELLBUTRIN XL Tablets may impair their ability to perform tasks requiring judgment or motor and cognitive skills. Advise patients that until they are reasonably certain that Zyntabac Tablets do not adversely affect their performance, they should refrain from driving an automobile or operating complex, hazardous machinery. Zyntabac treatment may lead to decreased alcohol tolerance.
Concomitant Medications
Counsel patients to notify their healthcare provider if they are taking or plan to take any prescription or over-the-counter drugs, because Zyntabac Tablets and other drugs may affect each other's metabolism.
Pregnancy
Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during therapy.
Precautions For Nursing Mothers
Communicate with the patient and pediatric healthcare provider regarding the infant's exposure to bupropion through human milk. Instruct patients to immediately contact the infant's healthcare provider if they note any side effect in the infant that concerns them or is persistent.
Administration Information
Instruct patients to swallow Zyntabac Tablets whole so that the release rate is not altered. Instruct patients if they miss a dose, not to take an extra tablet to make up for the missed dose and to take the next tablet at the regular time because of the dose-related risk of seizure. Instruct patients that Zyntabac tablets should be swallowed whole and not crushed, divided, or chewed. Zyntabac should be administered in the morning and may be taken with or without food.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Lifetime carcinogenicity studies were performed in rats and mice at doses up to 300 and 150 mg/kg/day bupropion hydrochloride, respectively. These doses are approximately 7 and 2 times the maximum recommended human dose (MRHD), respectively, on a mg/m² basis. In the rat study there was an increase in nodular proliferative lesions of the liver at doses of 100 to 300 mg/kg/day of bupropion hydrochloride (approximately 2 to 7 times the MRHD on a mg/m² basis); lower doses were not tested. The question of whether or not such lesions may be precursors of neoplasms of the liver is currently unresolved. Similar liver lesions were not seen in the mouse study, and no increase in malignant tumors of the liver and other organs was seen in either study.
Bupropion produced a positive response (2 to 3 times control mutation rate) in 2 of 5 strains in one Ames bacterial mutagenicity assay, but was negative in another. Bupropion produced an increase in chromosomal aberrations in 1 of 3 in vivo rat bone marrow cytogenetic studies.
A fertility study in rats at doses up to 300 mg/kg/day revealed no evidence of impaired fertility.
Use In Specific Populations
Pregnancy
Pregnancy Category C
Risk Summary
Data from epidemiological studies including pregnant women exposed to bupropion in the first trimester indicate no increased risk of congenital malformations overall. All pregnancies regardless of drug exposure have a background rate of 2% to 4% for major malformations and 15% to 20% for pregnancy loss. No clear evidence of teratogenic activity was found in reproductive developmental studies conducted in rats and rabbits. However, in rabbits, slightly increased incidences of fetal malformations and skeletal variations were observed at doses approximately equal to the maximum recommended human dose (MRHD) and greater and decreased fetal weights were seen at doses twice the MRHD and greater. Zyntabac should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Clinical Considerations
Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medications during pregnancy and postpartum.
Human Data
Data from an international bupropion Pregnancy registry (675 first trimester exposures) and a retrospective cohort study using the United Healthcare database (1,213 first trimester exposures) did not show an increased risk for malformations overall.
No increased risk for cardiovascular malformations overall has been observed after bupropion exposure during the first trimester. The prospectively observed rate of cardiovascular malformations in pregnancies with exposure to bupropion in the first trimester from the international Pregnancy Registry was 1.3% (9 cardiovascular malformations/675 first-trimester maternal bupropion exposures), which is similar to the background rate of cardiovascular malformations (approximately 1%). Data from the United Healthcare database and a case-controlled study (6,853 infants with cardiovascular malformations and 5,753 with non-cardiovascular malformations) from the National Birth Defects Prevention Study (NBDPS) did not show an increased risk for cardiovascular malformations overall after bupropion exposure during the first trimester.
Study findings on bupropion exposure during the first trimester and risk left ventricular outflow tract obstruction (LVOTO) are inconsistent and do not allow conclusions regarding possible association. The United Healthcare database lacked sufficient power to evaluate this association; the NBDPS found increased risk for LVOTO (n = 10; adjusted OR = 2.6; 95% CI 1.2, 5.7) and the Slone Epidemiology case control study did not find increased risk for LVOTO.
Study findings on bupropion exposure during the first trimester and risk for ventricular septal defect (VSD) are inconsistent and do not allow conclusions regarding a possible association. The Slone Epidemiology Study found an increased risk for VSD following first trimester maternal bupropion exposure (n = 17; adjusted OR = 2.5; 95% CI: 1.3, 5.0) but did not find an increased risk for any other cardiovascular malformations studied (including LVOTO as above). The NBDPS and United Healthcare database study did not find an association between first trimester maternal bupropion exposure and VSD.
For the findings of LVOTO and VSD, the studies were limited by the small number of exposed cases, inconsistent findings among studies, and the potential for chance findings from multiple comparisons in case control studies.
Animal Data
In studies conducted in rats and rabbits, bupropion was administered orally at doses of up to 450 and 150 mg/kg/day, respectively (approximately 11 and 7 times the MRHD, respectively, on a mg/m² basis), during the period of organogenesis. No clear evidence of teratogenic activity was found in either species; however, in rabbits, slightly increased incidences of fetal malformations and skeletal variations were observed at the lowest dose tested (25 mg/kg/day, approximately equal to the MRHD on a mg/m² basis) and greater. Decreased fetal weights were observed at 50 mg/kg and greater. When rats were administered bupropion at oral doses of up to 300 mg/kg/day (approximately 7 times the MRHD on a mg/m² basis) prior to mating and throughout pregnancy and lactation, there were no apparent adverse effects on offspring development.
Nursing Mothers
Bupropion and its metabolites are present in human milk. In a lactation study of ten women, levels of orally dosed bupropion and its active metabolites were measured in expressed milk. The average daily infant exposure (assuming 150 mL/kg daily consumption) to bupropion and its active metabolites was 2% of the maternal weight-adjusted dose. Exercise caution when Zyntabac is administered to a nursing woman.
Pediatric Use
Safety and effectiveness in the pediatric population have not been established. When considering the use of Zyntabac in a child or adolescent, balance the potential risks with the clinical need.
Geriatric Use
Of the approximately 6000 patients who participated in clinical trials with bupropion hydrochloride sustained-release tablets (depression and smoking cessation studies), 275 were ≥ 65 years old and 47 were ≥ 75 years old. In addition, several hundred patients ≥ 65 years of age participated in clinical trials using the immediate-release formulation of bupropion hydrochloride (depression studies). No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Bupropion is extensively metabolized in the liver to active metabolites, which are further metabolized and excreted by the kidneys. The risk of adverse reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be necessary to consider this factor in dose selection; it may be useful to monitor renal function.
Renal Impairment
Consider a reduced dose and/or dosing frequency of Zyntabac in patients with renal impairment (Glomerular Filtration Rate: < 90 mL/min). Bupropion and its metabolites are cleared renally and may accumulate in such patients to a greater extent than usual. Monitor closely for adverse reactions that could indicate high bupropion or metabolite exposures.
Hepatic Impairment
In patients with moderate to severe hepatic impairment (Child-Pugh score: 7 to 15), the maximum Zyntabac dose is 150 mg every other day. In patients with mild hepatic impairment (Child-Pugh score: 5 to 6), consider reducing the dose and/or frequency of dosing.
WARNINGS
Included as part of the PRECAUTIONS section.
PRECAUTIONS
Suicidal Thoughts And Behaviors In Children, Adoles cents , and Young Adults
Patients with MDD, both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.
Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (selective serotonin reuptake inhibitors [SSRIs] and others) show that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with MDD and other psychiatric disorders. Short-term clinical trials did not show an increase in the risk of suicidality with antidepressants compared with placebo in adults beyond age 24; there was a reduction with antidepressants compared with placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4,400 subjects. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 subjects. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger subjects for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 subjects treated) are provided in Table 1.
Table 1: Risk Differences in the Number of Suicidality Cases by Age Group in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Subjects
Age Range | Drug-Placebo Difference in Number of Cases of Suicidality per 1,000 Subjects Treated |
Increases Compared with Placebo | |
< 18 | 14 additional cases |
18-24 | 5 additional cases |
Decreases Compared with Placebo | |
25-64 | 1 fewer case |
≥ 65 | 6 fewer cases |
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
Families and caregivers of patients being treated with antidepressants for MDD or other indications , both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Zyntabac should be written for the smallest quantity of tablets cons is tent with good patient management, in order to reduce the risk of overdose.
Neuropsychiatric Symptoms And Suicide Risk In Smoking Cessation Treatment
In many of these cases, a causal relationship to bupropion treatment is not certain, because depressed mood can be a symptom of nicotine withdrawal. However, some of the cases occurred in patients taking bupropion who continued to smoke.
Seizure
Zyntabac can cause seizure. The risk of seizure is dose-related. The dose should not exceed 400 mg per day. Increase the dose gradually. Discontinue Zyntabac and do not restart treatment if the patient experiences a seizure.
The risk of seizures is also related to patient factors, clinical situations, and concomitant medications that lower the seizure threshold. Consider these risks before initiating treatment with Zyntabac. WELLBUTRIN SR is contraindicated in patients with a seizure disorder, current or prior diagnosis of anorexia nervosa or bulimia, or undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs. The following conditions can also increase the risk of seizure: severe head injury; arteriovenous malformation; CNS tumor or CNS infection; severe stroke; concomitant use of other medications that lower the seizure threshold (e.g., other bupropion products, antipsychotics, tricyclic antidepressants, theophylline, and systemic corticosteroids); metabolic disorders (e.g., hypoglycemia, hyponatremia, severe hepatic impairment, and hypoxia); use of illicit drugs (e.g., cocaine); or abuse or misuse of prescription drugs such as CNS stimulants. Additional predisposing conditions include diabetes mellitus treated with oral hypoglycemic drugs or insulin; use of anorectic drugs; and excessive use of alcohol, benzodiazepines, sedative/hypnotics, or opiates.
Incidence Of Seizure With Bupropion Use
When Zyntabac is dosed up to 300 mg per day, the incidence of seizure is approximately 0.1% (1/1,000) and increases to approximately 0.4% (4/1,000) at the maximum recommended dose of 400 mg per day.
The risk of seizure can be reduced if the dose of Zyntabac does not exceed 400 mg per day, given as 200 mg twice daily, and the titration rate is gradual.
Hypertension
Treatment with Zyntabac can result in elevated blood pressure and hypertension. Assess blood pressure before initiating treatment with Zyntabac, and monitor periodically during treatment. The risk of hypertension is increased if Zyntabac is used concomitantly with MAOIs or other drugs that increase dopaminergic or noradrenergic activity.
Data from a comparative trial of the sustained-release formulation of bupropion HCl, nicotine transdermal system (NTS), the combination of sustained-release bupropion plus NTS, and placebo as an aid to smoking cessation suggest a higher incidence of treatment-emergent hypertension in patients treated with the combination of sustained-release bupropion and NTS. In this trial, 6.1% of subjects treated with the combination of sustained-release bupropion and NTS had treatment-emergent hypertension compared with 2.5%, 1.6%, and 3.1% of subjects treated with sustained-release bupropion, NTS, and placebo, respectively. The majority of these subjects had evidence of pre-existing hypertension. Three subjects (1.2%) treated with the combination of sustained-release bupropion and NTS and 1 subject (0.4%) treated with NTS had study medication discontinued due to hypertension compared with none of the subjects treated with sustained-release bupropion or placebo. Monitoring of blood pressure is recommended in patients who receive the combination of bupropion and nicotine replacement.
In a clinical trial of bupropion immediate-release in MDD subjects with stable congestive heart failure (N = 36), bupropion was associated with an exacerbation of pre-existing hypertension in 2 subjects, leading to discontinuation of bupropion treatment. There are no controlled trials assessing the safety of bupropion in patients with a recent history of myocardial infarction or unstable cardiac disease.
Activation Of Mania/Hypomania
Antidepressant treatment can precipitate a manic, mixed, or hypomanic manic episode. The risk appears to be increased in patients with bipolar disorder or who have risk factors for bipolar disorder. Prior to initiating Zyntabac, screen patients for a history of bipolar disorder and the presence of risk factors for bipolar disorder (e.g., family history of bipolar disorder, suicide, or depression). Zyntabac is not approved for use in treating bipolar depression.
Psychosis And Other Neuropsychiatric Reactions
Depressed patients treated with Zyntabac have had a variety of neuropsychiatric signs and symptoms, including delusions, hallucinations, psychosis, concentration disturbance, paranoia, and confusion. Some of these patients had a diagnosis of bipolar disorder. In some cases, these symptoms abated upon dose reduction and/or withdrawal of treatment. Instruct patients to contact a healthcare professional if such reactions occur.
Angle-Closure Glaucoma
The pupillary dilation that occurs following use of many antidepressant drugs including Zyntabac may trigger an angle-closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.
Hypersensitivity Reactions
Anaphylactoid/anaphylactic reactions have occurred during clinical trials with bupropion. Reactions have been characterized by pruritus, urticaria, angioedema, and dyspnea requiring medical treatment. In addition, there have been rare, spontaneous postmarketing reports of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock associated with bupropion. Instruct patients to discontinue Zyntabac and consult a healthcare provider if they develop an allergic or anaphylactoid/anaphylactic reaction (e.g., skin rash, pruritus, hives, chest pain, edema, and shortness of breath) during treatment.
There are reports of arthralgia, myalgia, fever with rash and other serum sickness-like symptoms suggestive of delayed hypersensitivity.
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Zyntabac and counsel them in its appropriate use.
A patient Medication Guide about “Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions,” “Quitting Smoking, Quit-Smoking Medications, Changes in Thinking and Behavior, Depression, and Suicidal Thoughts or Actions,” and “What Other Important Information Should I Know About Zyntabac?” is available for Zyntabac. Instruct patients, their families, and their caregivers to read the Medication Guide and assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.
Advise patients regarding the following issues and to alert their prescriber if these occur while taking Zyntabac.
Suicidal Thoughts And Behaviors
Instruct patients, their families, and/or their caregivers to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Advise families and caregivers of patients to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or healthcare professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.
Neuropsychiatric Symptoms And Suicide Risk In Smoking Cessation Treatment
Although Zyntabac is not indicated for smoking cessation treatment, it contains the same active ingredient as ZYBAN which is approved for this use. Advise patients, families and caregivers that quitting smoking, with or without ZYBAN, may trigger nicotine withdrawal symptoms (e.g., including depression or agitation), or worsen pre-existing psychiatric illness. Some patients have experienced changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide when attempting to quit smoking while taking ZYBAN. If patients develop agitation, hostility, depressed mood, or changes in thinking or behavior that are not typical for them, or if patients develop suicidal ideation or behavior, they should be urged to report these symptoms to their healthcare provider immediately.
Severe Allergic Reactions
Educate patients on the symptoms of hypersensitivity and to discontinue Zyntabac if they have a severe allergic reaction.
Seizure
Instruct patients to discontinue and not restart Zyntabac if they experience a seizure while on treatment. Advise patients that the excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can increase the risk of seizure. Advise patients to minimize or avoid use of alcohol.
As the dose is increased during initial titration to doses above 150 mg per day, instruct patients to take Zyntabac in 2 divided doses, preferably with at least 8 hours between successive doses, to minimize the risk of seizures.
Angle-Closure Glaucoma
Patients should be advised that taking Zyntabac can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible.
Bupropion-Containing Products
Educate patients that Zyntabac contains the same active ingredient (bupropion hydrochloride) found in ZYBAN, which is used as an aid to smoking cessation treatment, and that Zyntabac should not be used in combination with ZYBAN or any other medications that contain bupropion (such as WELLBUTRIN®, the immediate-release formulation and WELLBUTRIN XL ® or FORFIVO XL®, the extended-release formulations, and APLENZIN®, the extended-release formulation of bupropion hydrobromide). In addition, there are a number of generic bupropion HCl products for the immediate-, sustained-, and extended-release formulations.
Potential For Cognitive And Motor Impairment
Advise patients that any CNS-active drug like Zyntabac may impair their ability to perform tasks requiring judgment or motor and cognitive skills. Advise patients that until they are reasonably certain that Zyntabac does not adversely affect their performance, they should refrain from driving an automobile or operating complex, hazardous machinery. Zyntabac may lead to decreased alcohol tolerance.
Concomitant Medications
Counsel patients to notify their healthcare provider if they are taking or plan to take any prescription or over-the-counter drugs because Zyntabac sustained-release tablets and other drugs may affect each others’ metabolisms.
Pregnancy
Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during therapy.
Precautions For Nursing Mothers
Advise patients that Zyntabac is present in human milk in small amounts.
Storage Information
Instruct patients to store Zyntabac at room temperature, between 59°F and 86°F (15°C to 30°C) and keep the tablets dry and out of the light.
Administration Information
Instruct patients to swallow Zyntabac tablets whole so that the release rate is not altered. Do not chew, divide, or crush tablets; they are designed to slowly release drug in the body. When patients take more than 150 mg per day, instruct them to take Zyntabac in 2 doses at least 8 hours apart, to minimize the risk of seizures. Instruct patients if they miss a dose, not to take an extra tablet to make up for the missed dose and to take the next tablet at the regular time because of the dose-related risk of seizure. Instruct patients that Zyntabac tablets may have an odor. Zyntabac can be taken with or without food.
WELLBUTRIN, Zyntabac, WELLBUTRIN XL, and ZYBAN are registered trademarks of the GSK group of companies. The other brands listed are trademarks of their respective owners and are not trademarks of the GSK group of companies. The makers of these brands are not affiliated with and do not endorse the GSK group of companies or its products.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Lifetime carcinogenicity studies were performed in rats and mice at bupropion doses up to 300 and 150 mg per kg per day, respectively. These doses are approximately 7 and 2 times the MRHD, respectively, on a mg per m² basis. In the rat study there was an increase in nodular proliferative lesions of the liver at doses of 100 to 300 mg per kg per day (approximately 2 to 7 times the MRHD on a mg per m² basis); lower doses were not tested. The question of whether or not such lesions may be precursors of neoplasms of the liver is currently unresolved. Similar liver lesions were not seen in the mouse study, and no increase in malignant tumors of the liver and other organs was seen in either study.
Bupropion produced a positive response (2 to 3 times control mutation rate) in 2 of 5 strains in the Ames bacterial mutagenicity assay. Bupropion produced an increase in chromosomal aberrations in 1 of 3 in vivo rat bone marrow cytogenetic studies.
A fertility study in rats at doses up to 300 mg per kg per day revealed no evidence of impaired fertility.
Use In Specific Populations
Pregnancy
Pregnancy Category C
Risk Summary
Data from epidemiological studies of pregnant women exposed to bupropion in the first trimester indicate no increased risk of congenital malformations overall. All pregnancies, regardless of drug exposure, have a background rate of 2% to 4% for major malformations, and 15% to 20% for pregnancy loss. No clear evidence of teratogenic activity was found in reproductive developmental studies conducted in rats and rabbits; however, in rabbits, slightly increased incidences of fetal malformations and skeletal variations were observed at doses approximately equal to the maximum recommended human dose (MRHD) and greater and decreased fetal weights were seen at doses twice the MRHD and greater. Zyntabac should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Clinical Considerations
Consider the risks of untreated depression when discontinuing or changing treatment with antidepressant medications during pregnancy and postpartum.
Human Data
Data from the international bupropion Pregnancy Registry (675 first trimester exposures) and a retrospective cohort study using the United Healthcare database (1,213 first trimester exposures) did not show an increased risk for malformations overall.
No increased risk for cardiovascular malformations overall has been observed after bupropion exposure during the first trimester. The prospectively observed rate of cardiovascular malformations in pregnancies with exposure to bupropion in the first trimester from the international Pregnancy Registry was 1.3% (9 cardiovascular malformations/675 first-trimester maternal bupropion exposures), which is similar to the background rate of cardiovascular malformations (approximately 1%). Data from the United Healthcare database and a case-control study (6,853 infants with cardiovascular malformations and 5,763 with non-cardiovascular malformations) from the National Birth Defects Prevention Study (NBDPS) did not show an increased risk for cardiovascular malformations overall after bupropion exposure during the first trimester.
Study findings on bupropion exposure during the first trimester and risk for left ventricular outflow tract obstruction (LVOTO) are inconsistent and do not allow conclusions regarding a possible association. The United Healthcare database lacked sufficient power to evaluate this association; the NBDPS found increased risk for LVOTO (n = 10; adjusted OR = 2.6; 95% CI: 1.2, 5.7), and the Slone Epidemiology case control study did not find increased risk for LVOTO.
Study findings on bupropion exposure during the first trimester and risk for ventricular septal defect (VSD) are inconsistent and do not allow conclusions regarding a possible association. The Slone Epidemiology Study found an increased risk for VSD following first trimester maternal bupropion exposure (n = 17; adjusted OR = 2.5; 95% CI: 1.3, 5.0) but did not find increased risk for any other cardiovascular malformations studied (including LVOTO as above). The NBDPS and United Healthcare database study did not find an association between first trimester maternal bupropion exposure and VSD.
For the findings of LVOTO and VSD, the studies were limited by the small number of exposed cases, inconsistent findings among studies, and the potential for chance findings from multiple comparisons in case control studies.
Animal Data
In studies conducted in rats and rabbits, bupropion was administered orally during the period of organogenesis at doses of up to 450 and 150 mg per kg per day, respectively (approximately 11 and 7 times the MRHD, respectively, on a mg per m² basis). No clear evidence of teratogenic 2 activity was found in either species; however, in rabbits, slightly increased incidences of fetal malformations and skeletal variations were observed at the lowest dose tested (25 mg per kg per day, approximately equal to the MRHD on a mg per m² basis) and greater. Decreased fetal weights were observed at 50 mg per kg and greater.
When rats were administered bupropion at oral doses of up to 300 mg per kg per day (approximately 7 times the MRHD on a mg per m basis) prior to mating and throughout pregnancy and lactation, there were no apparent adverse effects on offspring development.
Nursing Mothers
Bupropion and its metabolites are present in human milk. In a lactation study of 10 women, levels of orally dosed bupropion and its active metabolites were measured in expressed milk. The average daily infant exposure (assuming 150 mL per kg daily consumption) to bupropion and its active metabolites was 2% of the maternal weight-adjusted dose. Exercise caution when Zyntabac is administered to a nursing woman.
Pediatric Use
Safety and effectiveness in the pediatric population have not been established.
Geriatric Use
Of the approximately 6,000 subjects who participated in clinical trials with bupropion sustained-release tablets (depression and smoking cessation trials), 275 were aged ≥ 65 years and 47 were aged ≥ 75 years. In addition, several hundred subjects aged ≥ 65 years participated in clinical trials using the immediaterelease formulation of bupropion (depression trials). No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Renal Impairment
Consider a reduced dose and/or dosing frequency of Zyntabac in patients with renal impairment (Glomerular Filtration Rate: less than 90 mL per min). Bupropion and its metabolites are cleared renally and may accumulate in such patients to a greater extent than usual. Monitor closely for adverse reactions that could indicate high bupropion or metabolite exposures.
Hepatic Impairment
In patients with moderate to severe hepatic impairment (Child-Pugh score: 7 to 15), the maximum dose of Zyntabac is 100 mg per day or 150 mg every other day. In patients with mild hepatic impairment (Child-Pugh score: 5 to 6), consider reducing the dose and/or frequency of dosing.
The following adverse reactions are discussed in greater detail in other sections of the labeling:
- Suicidal thoughts and behaviors in children, adolescents, and young adults
- Neuropsychiatric symptoms and suicide risk in smoking cessation treatment
- Seizure
- Hypertension
- Activation of mania or hypomania
- Psychosis and other neuropsychiatric events
- Angle-Closure Glaucoma
- Hypersensitivity reactions
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Commonly Observed Adverse Reactions In Controlled Clinical Trials Of Sustained-Release Bupropion Hydrochloride
Adverse reactions that occurred in at least 5% of patients treated with bupropion HCl sustained-release (300 mg and 400 mg per day) and at a rate at least twice the placebo rate are listed below.
300 mg/day of bupropion HCl sustained-release: anorexia, dry mouth, rash, sweating, tinnitus, and tremor.
400 mg/day of bupropion HCl sustained-release: abdominal pain, agitation, anxiety, dizziness, dry mouth, insomnia, myalgia, nausea, palpitation, pharyngitis, sweating, tinnitus, and urinary frequency.
WELLBUTRIN XL has been demonstrated to have similar bioavailability both to the immediate-release and sustained-release formulations of bupropion. The information included under this subsection and under subsection 6.2 is based primarily on data from controlled clinical trials with the sustained-release and extended-release formulations of bupropion hydrochloride.
Major Depressive Disorder
Adverse Reactions Leading to Discontinuation of Treatment with Bupropion HCl Immediate-Release, Bupropion HCl Sustained-Release, and Bupropion HCl Extended-Release in Major Depressive Disorder Trials
In placebo-controlled clinical trials with bupropion HCl sustained-release, 4%, 9%, and 11% of the placebo, 300 mg/day and 400 mg/day groups, respectively, discontinued treatment because of adverse reactions. The specific adverse reactions leading to discontinuation in at least 1% of the 300 mg/day or 400 mg/day groups and at a rate at least twice the placebo rate are listed in Table 2.
Table 2: Treatment Discontinuation Due to Adverse Reactions in Placebo-Controlled Trials in MDD
Adverse Reaction Term | Placebo (n=385) | Bupropion HCl Sustained-Release 300 mg/day (n=376) | Bupropion HCl Sustained-Release 400 mg/day (n=114) |
Rash | 0.0% | 2.4% | 0.9% |
Nausea | 0.3% | 0.8% | 1.8% |
Agitation | 0.3% | 0.3% | 1.8% |
Migraine | 0.3% | 0.0% | 1.8% |
In clinical trials with bupropion HCl immediate-release, 10% of patients and volunteers discontinued due to an adverse reaction. Reactions resulting in discontinuation (in addition to those listed above for the sustained-release formulation) included vomiting, seizures, and sleep disturbances.
Adverse Reactions Occurring at an Incidence of > 1% in Patients Treated with Bupropion HCl Immediate-Release or Bupropion HCl Sustained-Release in MDD
Table 3 summarizes the adverse reactions that occurred in placebo-controlled trials in patients treated with bupropion HCl sustained-release 300 mg/day and 400 mg/day. These include reactions that occurred in either the 300 mg or 400 mg group at an incidence of 1% or more and were more frequent than in the placebo group.
Table 3: Adverse Reactions in Placebo-Controlled Trials in Patients with MDD
Body System/ Adverse Reaction | Placebo (n=385) | Bupropion HCl Sustained-Release 300 mg/day (n=376) | Bupropion HCl Sustained-Release 400 mg/day (n=114) |
Body (General) | |||
Headache | 23% | 26% | 25% |
Infection | 6% | 8% | 9% |
Abdominal pain | 2% | 3% | 9% |
Asthenia | 2% | 2% | 4% |
Chest pain | 1% | 3% | 4% |
Pain | 2% | 2% | 3% |
Fever | — | 1% | 2% |
Cardiovascular | |||
Palpitation | 2% | 2% | 6% |
Flushing | — | 1% | 4% |
Migraine | 1% | 1% | 4% |
Hot flashes | 1% | 1% | 3% |
Digestive | |||
Dry mouth | 7% | 17% | 24% |
Nausea | 8% | 13% | 18% |
Constipation | 7% | 10% | 5% |
Diarrhea | 6% | 5% | 7% |
Anorexia | 2% | 5% | 3% |
Vomiting | 2% | 4% | 2% |
Dysphagia | 0% | 0% | 2% |
Musculoskeletal | |||
Myalgia | 3% | 2% | 6% |
Arthralgia | 1% | 1% | 4% |
Arthritis | 0% | 0% | 2% |
Twitch | — | 1% | 2% |
Nervous System | |||
Insomnia | 6% | 11% | 16% |
Dizziness | 5% | 7% | 11% |
Agitation | 2% | 3% | 9% |
Anxiety | 3% | 5% | 6% |
Tremor | 1% | 6% | 3% |
Nervousness | 3% | 5% | 3% |
Somnolence | 2% | 2% | 3% |
Irritability | 2% | 3% | 2% |
Memory decreased | 1% | — | 3% |
Paresthesia | 1% | 1% | 2% |
Central nervous system stimulation | 1% | 2% | 1% |
Respiratory | |||
Pharyngitis | 2% | 3% | 11% |
Sinusitis | 2% | 3% | 1% |
Increased cough | 1% | 1% | 2% |
Skin | |||
Sweating | 2% | 6% | 5% |
Rash | 1% | 5% | 4% |
Pruritus | 2% | 2% | 4% |
Urticaria | 0% | 2% | 1% |
Special Senses | |||
Tinnitus | 2% | 6% | 6% |
Taste perversion | — | 2% | 4% |
Blurred vision or diplopia | 2% | 3% | 2% |
Urogenital | |||
Urinary frequency | 2% | 2% | 5% |
Urinary urgency | 0% | — | 2% |
Vaginal hemorrhage1 | — | 0% | 2% |
Urinary tract infection | —2 | 1% | 0% |
1Incidence based on the number of female patients. 2Hyphen denotes adverse reactions occurring in greater than 0 but less than 0.5% of patients |
The following additional adverse reactions occurred in controlled trials of bupropion HCl immediate-release (300 to 600 mg per day) at an incidence of at least 1% more frequently than in the placebo group were: cardiac arrhythmia (5% vs. 4%), hypertension (4% vs. 2%), hypotension (3% vs. 2%), menstrual complaints (5% vs. 1%), akathisia (2% vs. 1%), impaired sleep quality (4% vs. 2%), sensory disturbance (4% vs. 3%), confusion (8% vs. 5%), decreased libido (3% vs. 2%), hostility (6% vs. 4%), auditory disturbance (5% vs. 3%), and gustatory disturbance (3% vs. 1%).
Seasonal Affective Disorder
In placebo-controlled clinical trials in SAD, 9% of patients treated with WELLBUTRIN XL and 5% of patients treated with placebo discontinued treatment because of adverse reactions. The adverse reactions leading to discontinuation in at least 1% of patients treated with bupropion and at a rate numerically greater than the placebo rate were insomnia (2% vs. < 1%) and headache (1% vs. < 1%).
Table 4 summarizes the adverse reactions that occurred in patients treated with WELLBUTRIN XL for up to approximately 6 months in 3 placebo-controlled trials. These include reactions that occurred at an incidence of 2% or more and were more frequent than in the placebo group.
Table 4: Adverse Reactions in Placebo-Controlled Trials in Patients with SAD
System Organ Class/ Preferred Term | Placebo (n=511) | Bupropion HCl Extended-Release (n=537) |
Gastrointestinal Disorder | ||
Dry mouth | 15% | 26% |
Nausea | 8% | 13% |
Constipation | 2% | 9% |
Flatulence | 3% | 6% |
Abdominal pain | < 1% | 2% |
Nervous System Disorders | ||
Headache | 26% | 34% |
Dizziness | 5% | 6% |
Tremor | < 1% | 3% |
Infections and Infestations | ||
Nasopharyngitis | 12% | 13% |
Upper respiratory tract infection | 8% | 9% |
Sinusitis | 4% | 5% |
Psychiatric Disorders | ||
Insomnia | 13% | 20% |
Anxiety | 5% | 7% |
Abnormal dreams | 2% | 3% |
Agitation | < 1% | 2% |
Musculoskeletal and Connective Tissue Disorders | ||
Myalgia | 2% | 3% |
Pain in extremity | 2% | 3% |
Respiratory, Thoracic, and Mediastinal Disorders | ||
Cough | 3% | 4% |
General Disorders and Administration Site Conditions | ||
Feeling jittery | 2% | 3% |
Skin and Subcutaneous Tissue Disorders | ||
Rash | 2% | 3% |
Metabolism and Nutrition Disorders | ||
Decreased appetite | 1% | 4% |
Reproductive System and Breast Disorders | ||
Dysmenorrhea | < 1% | 2% |
Ear and Labyrinth Disorders | ||
Tinnitus | < 1% | 3% |
Vascular Disorders | ||
Hypertension | 0% | 2% |
Changes In Body Weight
Table 5 presents the incidence of body weight changes ( ≥ 5 lbs) in the short-term MDD trials using bupropion HCl sustained-release. There was a dose-related decrease in body weight.
Table 5: Incidence of Weight Gain or Weight Loss ( ≥ 5 lbs) in MDD Trials Using Bupropion HClSustained-Release
Weight Change | Bupropion HCl Sustained-Release 300 mg/day (n=339) | Bupropion HCl Sustained-Release 400 mg/day (n=112) | Placebo (n=347) |
Gained > 5 lbs | 3% | 2% | 4% |
Lost > 5 lbs | 14% | 19% | 6% |
Table 6 presents the incidence of body weight changes ( ≥ 5 lbs) in the 3 SAD trials using bupropion HCl extended-release. A higher proportion of subjects in the bupropion group (23%) had a weight loss ≥ 5 lbs, compared to the placebo group (11%). These were relatively long-term trials (up to 6 months).
Table 6: Incidence of Weight Gain or Weight Loss ( ≥ 5 lbs) in SAD Trials Using Bupropion HCl Extended-Release
Weight Change | Bupropion HCl Extended-Release 150 to 300 mg/day (n=537) | Placebo (n=511) |
Gained > 5 lbs | 11% | 21% |
Lost > 5 lbs | 23% | 11% |
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of WELLBUTRIN XL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Body (General)
Chills, facial edema, edema, peripheral edema, musculoskeletal chest pain, photosensitivity, and malaise.
Cardiovascular
Postural hypotension, hypertension, stroke, vasodilation, syncope, complete atrioventricular block, extrasystoles, myocardial infarction, phlebitis, and pulmonary embolism.
Digestive
Abnormal liver function, bruxism, gastric reflux, gingivitis, glossitis, increased salivation, jaundice, mouth ulcers, stomatitis, thirst, edema of tongue, colitis, esophagitis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, intestinal perforation, liver damage, pancreatitis, and stomach ulcer.
Endocrine
Hyperglycemia, hypoglycemia, and syndrome of inappropriate antidiuretic hormone secretion.
Hemic And Lymphatic
Ecchymosis, anemia, leukocytosis, leukopenia, lymphadenopathy, pancytopenia, and thrombocytopenia. Altered PT and/or INR, associated with hemorrhagic or thrombotic complications, were observed when bupropion was coadministered with warfarin.
Metabolic And Nutritional
Glycosuria.
Musculoskeletal
Leg cramps, fever/rhabdomyolysis, and muscle weakness.
Nervous System
Abnormal coordination, depersonalization, emotional lability, hyperkinesia, hypertonia, hypesthesia, vertigo, amnesia, ataxia, derealization, abnormal electroencephalogram (EEG), aggression, akinesia, aphasia, coma, dysarthria, dyskinesia, dystonia, euphoria, extrapyramidal syndrome, hypokinesia, increased libido, neuralgia, neuropathy, paranoid ideation, restlessness, suicide attempt, and unmasking tardive dyskinesia.
Respiratory
Bronchospasm and pneumonia.
Skin
Maculopapular rash, alopecia, angioedema, exfoliative dermatitis, and hirsutism.
Special Senses
Accommodation abnormality, dry eye, deafness, increased intraocular pressure, angle-closure glaucoma, and mydriasis.
Urogenital
Impotence, polyuria, prostate disorder, abnormal ejaculation, cystitis, dyspareunia, dysuria, gynecomastia, menopause, painful erection, salpingitis, urinary incontinence, urinary retention, and vaginitis.
The following adverse reactions are discussed in greater detail in other sections of the labeling:
- Suicidal thoughts and behaviors in children, adolescents, and young adults
- Neuropsychiatric symptoms and suicide risk in smoking cessation treatment
- Seizure
- Hypertension
- Activation of mania or hypomania
- Psychosis and other neuropsychiatric events
- Angle-Closure Glaucoma
- Hypersensitivity reactions
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Commonly Observed Adverse Reactions In Controlled Clinical Trials Of Sustained-Release Bupropion Hydrochloride
Adverse reactions that occurred in at least 5% of patients treated with bupropion HCl sustained-release (300 mg and 400 mg per day) and at a rate at least twice the placebo rate are listed below.
300 mg/day of bupropion HCl sustained-release: anorexia, dry mouth, rash, sweating, tinnitus, and tremor.
400 mg/day of bupropion HCl sustained-release: abdominal pain, agitation, anxiety, dizziness, dry mouth, insomnia, myalgia, nausea, palpitation, pharyngitis, sweating, tinnitus, and urinary frequency.
Zyntabac has been demonstrated to have similar bioavailability both to the immediate-release and sustained-release formulations of bupropion. The information included under this subsection and under subsection 6.2 is based primarily on data from controlled clinical trials with the sustained-release and extended-release formulations of bupropion hydrochloride.
Major Depressive Disorder
Adverse Reactions Leading to Discontinuation of Treatment with Bupropion HCl Immediate-Release, Bupropion HCl Sustained-Release, and Bupropion HCl Extended-Release in Major Depressive Disorder Trials
In placebo-controlled clinical trials with bupropion HCl sustained-release, 4%, 9%, and 11% of the placebo, 300 mg/day and 400 mg/day groups, respectively, discontinued treatment because of adverse reactions. The specific adverse reactions leading to discontinuation in at least 1% of the 300 mg/day or 400 mg/day groups and at a rate at least twice the placebo rate are listed in Table 2.
Table 2: Treatment Discontinuation Due to Adverse Reactions in Placebo-Controlled Trials in MDD
Adverse Reaction Term | Placebo (n=385) | Bupropion HCl Sustained-Release 300 mg/day (n=376) | Bupropion HCl Sustained-Release 400 mg/day (n=114) |
Rash | 0.0% | 2.4% | 0.9% |
Nausea | 0.3% | 0.8% | 1.8% |
Agitation | 0.3% | 0.3% | 1.8% |
Migraine | 0.3% | 0.0% | 1.8% |
In clinical trials with bupropion HCl immediate-release, 10% of patients and volunteers discontinued due to an adverse reaction. Reactions resulting in discontinuation (in addition to those listed above for the sustained-release formulation) included vomiting, seizures, and sleep disturbances.
Adverse Reactions Occurring at an Incidence of > 1% in Patients Treated with Bupropion HCl Immediate-Release or Bupropion HCl Sustained-Release in MDD
Table 3 summarizes the adverse reactions that occurred in placebo-controlled trials in patients treated with bupropion HCl sustained-release 300 mg/day and 400 mg/day. These include reactions that occurred in either the 300 mg or 400 mg group at an incidence of 1% or more and were more frequent than in the placebo group.
Table 3: Adverse Reactions in Placebo-Controlled Trials in Patients with MDD
Body System/ Adverse Reaction | Placebo (n=385) | Bupropion HCl Sustained-Release 300 mg/day (n=376) | Bupropion HCl Sustained-Release 400 mg/day (n=114) |
Body (General) | |||
Headache | 23% | 26% | 25% |
Infection | 6% | 8% | 9% |
Abdominal pain | 2% | 3% | 9% |
Asthenia | 2% | 2% | 4% |
Chest pain | 1% | 3% | 4% |
Pain | 2% | 2% | 3% |
Fever | — | 1% | 2% |
Cardiovascular | |||
Palpitation | 2% | 2% | 6% |
Flushing | — | 1% | 4% |
Migraine | 1% | 1% | 4% |
Hot flashes | 1% | 1% | 3% |
Digestive | |||
Dry mouth | 7% | 17% | 24% |
Nausea | 8% | 13% | 18% |
Constipation | 7% | 10% | 5% |
Diarrhea | 6% | 5% | 7% |
Anorexia | 2% | 5% | 3% |
Vomiting | 2% | 4% | 2% |
Dysphagia | 0% | 0% | 2% |
Musculoskeletal | |||
Myalgia | 3% | 2% | 6% |
Arthralgia | 1% | 1% | 4% |
Arthritis | 0% | 0% | 2% |
Twitch | — | 1% | 2% |
Nervous System | |||
Insomnia | 6% | 11% | 16% |
Dizziness | 5% | 7% | 11% |
Agitation | 2% | 3% | 9% |
Anxiety | 3% | 5% | 6% |
Tremor | 1% | 6% | 3% |
Nervousness | 3% | 5% | 3% |
Somnolence | 2% | 2% | 3% |
Irritability | 2% | 3% | 2% |
Memory decreased | 1% | — | 3% |
Paresthesia | 1% | 1% | 2% |
Central nervous system stimulation | 1% | 2% | 1% |
Respiratory | |||
Pharyngitis | 2% | 3% | 11% |
Sinusitis | 2% | 3% | 1% |
Increased cough | 1% | 1% | 2% |
Skin | |||
Sweating | 2% | 6% | 5% |
Rash | 1% | 5% | 4% |
Pruritus | 2% | 2% | 4% |
Urticaria | 0% | 2% | 1% |
Special Senses | |||
Tinnitus | 2% | 6% | 6% |
Taste perversion | — | 2% | 4% |
Blurred vision or diplopia | 2% | 3% | 2% |
Urogenital | |||
Urinary frequency | 2% | 2% | 5% |
Urinary urgency | 0% | — | 2% |
Vaginal hemorrhage1 | — | 0% | 2% |
Urinary tract infection | —2 | 1% | 0% |
1Incidence based on the number of female patients. 2Hyphen denotes adverse reactions occurring in greater than 0 but less than 0.5% of patients |
The following additional adverse reactions occurred in controlled trials of bupropion HCl immediate-release (300 to 600 mg per day) at an incidence of at least 1% more frequently than in the placebo group were: cardiac arrhythmia (5% vs. 4%), hypertension (4% vs. 2%), hypotension (3% vs. 2%), menstrual complaints (5% vs. 1%), akathisia (2% vs. 1%), impaired sleep quality (4% vs. 2%), sensory disturbance (4% vs. 3%), confusion (8% vs. 5%), decreased libido (3% vs. 2%), hostility (6% vs. 4%), auditory disturbance (5% vs. 3%), and gustatory disturbance (3% vs. 1%).
Seasonal Affective Disorder
In placebo-controlled clinical trials in SAD, 9% of patients treated with Zyntabac and 5% of patients treated with placebo discontinued treatment because of adverse reactions. The adverse reactions leading to discontinuation in at least 1% of patients treated with bupropion and at a rate numerically greater than the placebo rate were insomnia (2% vs. < 1%) and headache (1% vs. < 1%).
Table 4 summarizes the adverse reactions that occurred in patients treated with Zyntabac for up to approximately 6 months in 3 placebo-controlled trials. These include reactions that occurred at an incidence of 2% or more and were more frequent than in the placebo group.
Table 4: Adverse Reactions in Placebo-Controlled Trials in Patients with SAD
System Organ Class/ Preferred Term | Placebo (n=511) | Bupropion HCl Extended-Release (n=537) |
Gastrointestinal Disorder | ||
Dry mouth | 15% | 26% |
Nausea | 8% | 13% |
Constipation | 2% | 9% |
Flatulence | 3% | 6% |
Abdominal pain | < 1% | 2% |
Nervous System Disorders | ||
Headache | 26% | 34% |
Dizziness | 5% | 6% |
Tremor | < 1% | 3% |
Infections and Infestations | ||
Nasopharyngitis | 12% | 13% |
Upper respiratory tract infection | 8% | 9% |
Sinusitis | 4% | 5% |
Psychiatric Disorders | ||
Insomnia | 13% | 20% |
Anxiety | 5% | 7% |
Abnormal dreams | 2% | 3% |
Agitation | < 1% | 2% |
Musculoskeletal and Connective Tissue Disorders | ||
Myalgia | 2% | 3% |
Pain in extremity | 2% | 3% |
Respiratory, Thoracic, and Mediastinal Disorders | ||
Cough | 3% | 4% |
General Disorders and Administration Site Conditions | ||
Feeling jittery | 2% | 3% |
Skin and Subcutaneous Tissue Disorders | ||
Rash | 2% | 3% |
Metabolism and Nutrition Disorders | ||
Decreased appetite | 1% | 4% |
Reproductive System and Breast Disorders | ||
Dysmenorrhea | < 1% | 2% |
Ear and Labyrinth Disorders | ||
Tinnitus | < 1% | 3% |
Vascular Disorders | ||
Hypertension | 0% | 2% |
Changes In Body Weight
Table 5 presents the incidence of body weight changes ( ≥ 5 lbs) in the short-term MDD trials using bupropion HCl sustained-release. There was a dose-related decrease in body weight.
Table 5: Incidence of Weight Gain or Weight Loss ( ≥ 5 lbs) in MDD Trials Using Bupropion HClSustained-Release
Weight Change | Bupropion HCl Sustained-Release 300 mg/day (n=339) | Bupropion HCl Sustained-Release 400 mg/day (n=112) | Placebo (n=347) |
Gained > 5 lbs | 3% | 2% | 4% |
Lost > 5 lbs | 14% | 19% | 6% |
Table 6 presents the incidence of body weight changes ( ≥ 5 lbs) in the 3 SAD trials using bupropion HCl extended-release. A higher proportion of subjects in the bupropion group (23%) had a weight loss ≥ 5 lbs, compared to the placebo group (11%). These were relatively long-term trials (up to 6 months).
Table 6: Incidence of Weight Gain or Weight Loss ( ≥ 5 lbs) in SAD Trials Using Bupropion HCl Extended-Release
Weight Change | Bupropion HCl Extended-Release 150 to 300 mg/day (n=537) | Placebo (n=511) |
Gained > 5 lbs | 11% | 21% |
Lost > 5 lbs | 23% | 11% |
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of Zyntabac. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Body (General)
Chills, facial edema, edema, peripheral edema, musculoskeletal chest pain, photosensitivity, and malaise.
Cardiovascular
Postural hypotension, hypertension, stroke, vasodilation, syncope, complete atrioventricular block, extrasystoles, myocardial infarction, phlebitis, and pulmonary embolism.
Digestive
Abnormal liver function, bruxism, gastric reflux, gingivitis, glossitis, increased salivation, jaundice, mouth ulcers, stomatitis, thirst, edema of tongue, colitis, esophagitis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, intestinal perforation, liver damage, pancreatitis, and stomach ulcer.
Endocrine
Hyperglycemia, hypoglycemia, and syndrome of inappropriate antidiuretic hormone secretion.
Hemic And Lymphatic
Ecchymosis, anemia, leukocytosis, leukopenia, lymphadenopathy, pancytopenia, and thrombocytopenia. Altered PT and/or INR, associated with hemorrhagic or thrombotic complications, were observed when bupropion was coadministered with warfarin.
Metabolic And Nutritional
Glycosuria.
Musculoskeletal
Leg cramps, fever/rhabdomyolysis, and muscle weakness.
Nervous System
Abnormal coordination, depersonalization, emotional lability, hyperkinesia, hypertonia, hypesthesia, vertigo, amnesia, ataxia, derealization, abnormal electroencephalogram (EEG), aggression, akinesia, aphasia, coma, dysarthria, dyskinesia, dystonia, euphoria, extrapyramidal syndrome, hypokinesia, increased libido, neuralgia, neuropathy, paranoid ideation, restlessness, suicide attempt, and unmasking tardive dyskinesia.
Respiratory
Bronchospasm and pneumonia.
Skin
Maculopapular rash, alopecia, angioedema, exfoliative dermatitis, and hirsutism.
Special Senses
Accommodation abnormality, dry eye, deafness, increased intraocular pressure, angle-closure glaucoma, and mydriasis.
Urogenital
The following adverse reactions are discussed in greater detail in other sections of the labeling:
- Suicidal thoughts and behaviors in adolescents and young adults
- Neuropsychiatric symptoms and suicide risk in smoking cessation treatment
- Seizure
- Hypertension
- Activation of mania or hypomania
- Psychosis and other neuropsychiatric reactions
- Angle-closure glaucoma
- Hypersensitivity reactions
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Adverse Reactions Leading To Discontinuation Of Treatment
In placebo-controlled clinical trials, 4%, 9%, and 11% of the placebo, 300-mg-per-day, and 400-mg per- day groups, respectively, discontinued treatment due to adverse reactions. The specific adverse reactions leading to discontinuation in at least 1% of the 300-mg-per-day or 400-mg-per-day groups and at a rate at least twice the placebo rate are listed in Table 2.
Table 2: Treatment Discontinuations Due to Adverse Reactions in Placebo-Controlled Trials
Adverse Reaction | Placebo (n = 385) | Zyntabac 300 mg/day (n=376) | Zyntabac 400 mg/day (n = 114) |
Rash | 0.0% | 2.4% | 0.9% |
Nausea | 0.3% | 0.8% | 1.8% |
Agitation | 0.3% | 0.3% | 1.8% |
Migraine | 0.3% | 0.0% | 1.8% |
Commonly Observed Adverse Reactions
Adverse reactions from Table 3 occurring in at least 5% of subjects treated with Zyntabac and at a rate at least twice the placebo rate are listed below for the 300- and 400-mg-per-day dose groups.
Zyntabac 300 mg per day: Anorexia, dry mouth, rash, sweating, tinnitus, and tremor.
Zyntabac 400 mg per day: Abdominal pain, agitation, anxiety, dizziness, dry mouth, insomnia, myalgia, nausea, palpitation, pharyngitis, sweating, tinnitus, and urinary frequency.
Adverse reactions reported in placebo-controlled trials are presented in Table 3. Reported adverse reactions were classified using a COSTART-based Dictionary.
Table 3: Adverse Reactions Reported by at Least 1% of Subjects and at a Greater Frequency than Placebo in Controlled Clinical Trials
Body System/ Adverse Reaction | Zyntabac 300 mg/day (n=376) | Zyntabac 400 mg/day (n = 114) | Placebo (n = 385) |
Body (General) | |||
Headache | 26% | 25% | 23% |
Infection | 8% | 9% | 6% |
Abdominal pain | 3% | 9% | 2% |
Asthenia | 2% | 4% | 2% |
Chest pain | 3% | 4% | 1% |
Pain | 2% | 3% | 2% |
Fever | 1% | 2% | — |
Cardiovascular | |||
Palpitation | 2% | 6% | 2% |
Flushing | 1% | 4% | — |
Migraine | 1% | 4% | 1% |
Hot flashes | 1% | 3% | 1% |
Digestive | |||
Dry mouth | 17% | 24% | 7% |
Nausea | 13% | 18% | 8% |
Constipation | 10% | 5% | 7% |
Diarrhea | 5% | 7% | 6% |
Anorexia | 5% | 3% | 2% |
Vomiting | 4% | 2% | 2% |
Dysphagia | 0% | 2% | 0% |
Musculoskeletal | |||
Myalgia | 2% | 6% | 3% |
Arthralgia | 1% | 4% | 1% |
Arthritis | 0% | 2% | 0% |
Twitch | 1% | 2% | — |
Nervous system | |||
Insomnia | 11% | 16% | 6% |
Dizziness | 7% | 11% | 5% |
Agitation | 3% | 9% | 2% |
Anxiety | 5% | 6% | 3% |
Tremor | 6% | 3% | 1% |
Nervousness | 5% | 3% | 3% |
Somnolence | 2% | 3% | 2% |
Irritability | 3% | 2% | 2% |
Memory decreased | — | 3% | 1% |
Paresthesia | 1% | 2% | 1% |
Central nervous system stimulation | 2% | 1% | 1% |
Respiratory | |||
Pharyngitis | 3% | 11% | 2% |
Sinusitis | 3% | 1% | 2% |
Increased cough | 1% | 2% | 1% |
Skin | |||
Sweating | 6% | 5% | 2% |
Rash | 5% | 4% | 1% |
Pruritus | 2% | 4% | 2% |
Urticaria | 2% | 1% | 0% |
Special senses | |||
Tinnitus | 6% | 6% | 2% |
Taste perversion | 2% | 4% | — |
Blurred vision or diplopia | 3% | 2% | 2% |
Urogenital | |||
Urinary frequency | 2% | 5% | 2% |
Urinary urgency | — | 2% | 0% |
Vaginal hemorrhagea | 0% | 2% | — |
Urinary tract infection | 1% | 0% | — |
aIncidence based on the number of female subjects. — Hyphen denotes adverse events occurring in greater than 0 but less than 0.5% of subjects. |
Other Adverse Reactions Observed During The Clinical Development Of Bupropion
In addition to the adverse reactions noted above, the following adverse reactions have been reported in clinical trials with the sustained-release formulation of bupropion in depressed subjects and in nondepressed smokers, as well as in clinical trials with the immediate-release formulation of bupropion.
Adverse reaction frequencies represent the proportion of subjects who experienced a treatment-emergent adverse reaction on at least one occasion in placebo-controlled trials for depression (n = 987) or smoking cessation (n = 1,013), or subjects who experienced an adverse reaction requiring discontinuation of treatment in an open-label surveillance trial with Zyntabac (n = 3,100). All treatment-emergent adverse reactions are included except those listed in Table 3, those listed in other safety-related sections of the prescribing information, those subsumed under COSTART terms that are either overly general or excessively specific so as to be uninformative, those not reasonably associated with the use of the drug, and those that were not serious and occurred in fewer than 2 subjects.
Adverse reactions are further categorized by body system and listed in order of decreasing frequency according to the following definitions of frequency: Frequent adverse reactions are defined as those occurring in at least 1/100 subjects. Infrequent adverse reactions are those occurring in 1/100 to 1/1,000 subjects, while rare events are those occurring in less than 1/1,000 subjects.
Body (General): Infrequent were chills, facial edema, and photosensitivity. Rare was malaise.
Cardiovascular: Infrequent were postural hypotension, stroke, tachycardia, and vasodilation. Rare were syncope and myocardial infarction.
Digestive: Infrequent were abnormal liver function, bruxism, gastric reflux, gingivitis, increased salivation, jaundice, mouth ulcers, stomatitis, and thirst. Rare was edema of tongue.
Hemic and Lymphatic: Infrequent was ecchymosis.
Metabolic and Nutritional: Infrequent were edema and peripheral edema.
Musculoskeletal: Infrequent were leg cramps.
Nervous System: Infrequent were abnormal coordination, decreased libido, depersonalization, dysphoria, emotional lability, hostility, hyperkinesia, hypertonia, hypesthesia, suicidal ideation, and vertigo. Rare were amnesia, ataxia, derealization, and hypomania.
Respiratory: Rare was bronchospasm.
Special Senses: Infrequent were accommodation abnormality and dry eye.
Urogenital: Infrequent were impotence, polyuria, and prostate disorder.
Changes In Body Weight
In placebo-controlled trials, subjects experienced weight gain or weight loss as shown in Table 4.
Table 4: Incidence of Weight Gain and Weight Los s ( ≥ 5 lbs ) in Placebo-Controlled Trials
Weight Change | Zyntabac 300 mg/day (n=339) | Zyntabac 400 mg/day (n = 112) | Placebo (n=347) |
Gained > 5 lbs | 3% | 2% | 4% |
Lost > 5 lbs | 14% | 19% | 6% |
In clinical trials conducted with the immediate-release formulation of bupropion, 35% of subjects receiving tricyclic antidepressants gained weight, compared with 9% of subjects treated with the immediate-release formulation of bupropion. If weight loss is a major presenting sign of a patient's depressive illness, the anorectic and/or weight-reducing potential of Zyntabac should be considered.
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of Zyntabac and are not described elsewhere in the label. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Body (General)
Arthralgia, myalgia, and fever with rash and other symptoms suggestive of delayed hypersensitivity. These symptoms may resemble serum sickness.
Cardiovascular
Complete atrioventricular block, extrasystoles, hypotension, hypertension (in some cases severe), phlebitis, and pulmonary embolism.
Digestive
Colitis, esophagitis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, intestinal perforation, pancreatitis, and stomach ulcer.
Endocrine
Hyperglycemia, hypoglycemia, and syndrome of inappropriate antidiuretic hormone.
Hemic and Lymphatic
Anemia, leukocytosis, leukopenia, lymphadenopathy, pancytopenia, and thrombocytopenia. Altered PT and/or INR, infrequently associated with hemorrhagic or thrombotic complications, were observed when bupropion was coadministered with warfarin.
Metabolic and Nutritional
Glycosuria.
Musculoskeletal
Muscle rigidity/fever/rhabdomyolysis and muscle weakness.
Nervous System
Abnormal electroencephalogram (EEG), aggression, akinesia, aphasia, coma, completed suicide, delirium, delusions, dysarthria, euphoria, extrapyramidal syndrome (dyskinesia, dystonia, hypokinesia, parkinsonism), hallucinations, increased libido, manic reaction, neuralgia, neuropathy, paranoid ideation, restlessness, suicide attempt, and unmasking tardive dyskinesia.
Respiratory
Pneumonia.
Skin
Alopecia, angioedema, exfoliative dermatitis, hirsutism, and Stevens-Johnson syndrome.
Special Senses
Deafness, increased intraocular pressure, and mydriasis.
Urogenital
Abnormal ejaculation, cystitis, dyspareunia, dysuria, gynecomastia, menopause, painful erection, salpingitis, urinary incontinence, urinary retention, and vaginitis.
Experiência em overdose humana
Sobredosagens de até 30 gramas ou mais de bupropiona foram relatadas. A apreensão foi relatada em aproximadamente um terço de todos os casos. Outras reações graves relatadas apenas com overdoses de bupropiona incluíram alucinações, perda de consciência, taquicardia sinusal e alterações no ECG, como distúrbios de condução (incluindo prolongamento do QRS) ou arritmias. Febre, rigidez muscular, rabdomiólise, hipotensão, estupor, coma e insuficiência respiratória foram relatadas principalmente quando a bupropiona fazia parte de várias overdoses de drogas.
Embora a maioria dos pacientes tenha se recuperado sem sequelas, foram relatadas mortes associadas a overdoses de bupropiona em pacientes que ingeriram grandes doses do medicamento. Várias convulsões não controladas, bradicardia, insuficiência cardíaca e parada cardíaca antes da morte foram relatadas nesses pacientes.
Gerenciamento de overdosage
Consulte um Centro de Controle de Venenos Certificado para obter orientações e conselhos atualizados. Os números de telefone dos centros de controle de intoxicações certificados estão listados na Referência de mesa do médico (PDR). Ligue para 1-800-222-1222 ou consulte www.poison.org.
Não há antídotos conhecidos para bupropiona. Em caso de sobredosagem, forneça cuidados de suporte, incluindo supervisão e monitoramento médicos próximos. Considere a possibilidade de overdose múltipla de drogas. Garanta uma via aérea, oxigenação e ventilação adequadas. Monitore o ritmo cardíaco e os sinais vitais. A indução de emese não é recomendada.
Bupropion is a racemic mixture. The pharmacologic activity and pharmacokinetics of the individual enantiomers have not been studied.
Following chronic dosing, the mean steady-state plasma concentration of bupropion was reached within 8 days. The mean elimination half-life (±SD) of bupropion 21 (±9) hours.
In a study comparing 14-day dosing with WELLBUTRIN XL, 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with WELLBUTRIN XL 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites.
Absorption
Following single oral administration of WELLBUTRIN XL tablets to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion.
Distribution
In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg/mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that of bupropion.
Metabolism
Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance, because the plasma concentrations of the metabolites are as high or higher than those of bupropion.
At steady state, peak plasma concentration of hydroxybupropion occurred approximately 7 hours after administration of WELLBUTRIN XL, and it was approximately 7 times the peak level of the parent drug. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours, and its AUC at steady state is about 13 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of hydroxybupropion. However, the elimination half-lives of erythrohydrobupropion and threohydrobupropion are longer, approximately 33 (±10) and 37 (±13) hours, respectively, and steady-state AUCs were 1.4 and 7 times that of bupropion, respectively.
Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg/day.
Elimination
Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. Only 0.5% of the oral dose was excreted as unchanged bupropion.
Bupropion is a racemic mixture. The pharmacologic activity and pharmacokinetics of the individual enantiomers have not been studied.
Following chronic dosing, the mean steady-state plasma concentration of bupropion was reached within 8 days. The mean elimination half-life (±SD) of bupropion 21 (±9) hours.
In a study comparing 14-day dosing with Zyntabac, 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with Zyntabac 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites.
Absorption
Following single oral administration of Zyntabac tablets to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion.
Distribution
In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg/mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that of bupropion.
Metabolism
Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance, because the plasma concentrations of the metabolites are as high or higher than those of bupropion.
At steady state, peak plasma concentration of hydroxybupropion occurred approximately 7 hours after administration of Zyntabac, and it was approximately 7 times the peak level of the parent drug. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours, and its AUC at steady state is about 13 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of hydroxybupropion. However, the elimination half-lives of erythrohydrobupropion and threohydrobupropion are longer, approximately 33 (±10) and 37 (±13) hours, respectively, and steady-state AUCs were 1.4 and 7 times that of bupropion, respectively.
Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg/day.
Elimination
Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. Only 0.5% of the oral dose was excreted as unchanged bupropion.
Bupropion is a racemic mixture. The pharmacological activity and pharmacokinetics of the individual enantiomers have not been studied. The mean elimination half-life (±SD) of bupropion after chronic dosing is 21 (±9) hours, and steady-state plasma concentrations of bupropion are reached within 8 days.
Absorption
The absolute bioavailability of Zyntabac in humans has not been determined because an intravenous formulation for human use is not available. However, it appears likely that only a small proportion of any orally administered dose reaches the systemic circulation intact. In rat and dog studies, the bioavailability of bupropion ranged from 5% to 20%. In humans, following oral administration of Zyntabac, peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours.
In a trial comparing chronic dosing with Zyntabac 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after WELLBUTRIN SR administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, WELLBUTRIN SR given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites.
Zyntabac can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when Zyntabac was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant.
Distribution
In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion; whereas, the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion.
Metabolism
Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion.
Following a single-dose administration of Zyntabac in humans, Cmax of hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33 (±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively.
Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day.
Elimination
Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. Only 0.5% of the oral dose was excreted as unchanged bupropion.