Effexor XR AVISO: PENSAMENTOS SUICIDOS E COMPORTAMENTOS Os antidepressivos aumentaram o risco de pensamentos e comportamentos suicidas em crianças, adolescentes e adultos jovens em estudos de curto prazo. Esses estudos não mostraram aumento no risco de pensamentos e comportamentos suicidas com uso de antidepressivos em pacientes com idade superior a 24 anos, com redução de risco com uso de antidepressivos em pacientes com idade igual ou superior a 65 anos, ver Advertências e Precauções (5.1). Em pacientes de todas as idades que iniciaram a terapia com antidepressivos acompanham de perto o empeoramento clínico eo surgimento de pensamentos e comportamentos suicidas. Aconselhe as famílias e os cuidadores sobre a necessidade de uma observação próxima e a comunicação com a pessoa que prescreve, veja Avisos e Precauções (5.1) e Informação de Aconselhamento do Paciente (17). Indicações e uso para o transtorno depressivo principal de Effexor XR As cápsulas de liberação prolongada de Effexor XR (cloridrato de venlafaxina) são indicadas para o tratamento de transtorno depressivo maior (MDD). A eficácia foi estabelecida em três testes de manutenção a curto prazo (4, 8 e 12 semanas) e dois a longo prazo. Transtorno de ansiedade generalizada Effexor XR é indicado para o tratamento do transtorno de ansiedade generalizada (GAD). A eficácia foi estabelecida em dois estudos de 8 semanas e dois controlados com placebo de 26 semanas. Transtorno de Ansiedade Social O Effexor XR é indicado para o tratamento do Transtorno de Ansiedade Social (SAD), também conhecido como fobia social. A eficácia foi estabelecida em quatro ensaios controlados com placebo de 12 semanas e uma de 26 semanas. Transtorno de pânico Effexor XR é indicado para o tratamento do transtorno de pânico (PD), com ou sem agorafobia. A eficácia foi estabelecida em dois ensaios controlados com placebo de 12 semanas. Dosagem e administração de Effexor XR Effexor XR deve ser administrado em uma única dose com alimentos, tanto pela manhã quanto na noite, aproximadamente na mesma hora, todos os dias, ver Clinical Pharmacology (12.3). Cada cápsula deve ser engolida inteira com fluido e não dividida, esmagada, mastigada ou colocada em água ou pode ser administrada abrindo cuidadosamente a cápsula e espalhando todo o conteúdo em uma colher de compota de maçã. Esta mistura de alimentos para droga deve ser engolida imediatamente sem mastigar e seguida com um copo de água para garantir a ingestão completa dos grânulos (esferóides). Transtorno depressivo maior Para a maioria dos pacientes, a dose inicial recomendada para Effexor XR é de 75 mg por dia, administrada em uma única dose. Para alguns pacientes, pode ser desejável começar com 37,5 mg por dia durante 4 a 7 dias para permitir que novos pacientes se adaptem à medicação antes de aumentar para 75 mg por dia. Os doentes que não respondem à dose inicial de 75 mg por dia podem beneficiar dos aumentos de dose até um máximo de 225 mg por dia. Os aumentos de dose devem ser em incrementos de até 75 mg por dia, conforme necessário, e devem ser feitos em intervalos não inferiores a 4 dias, uma vez que os níveis plasmáticos estacionários de venlafaxina e seus principais metabolitos são alcançados na maioria dos pacientes no dia 4 Ver Clinical Pharmacology (12.3). Nos estudos clínicos que estabelecem eficácia, a titulação ascendente foi permitida em intervalos de 2 semanas ou mais. Deve notar-se que, embora a dose máxima recomendada para pacientes ambulatoriais moderadamente deprimidos seja também de 225 mg por dia para Effexor (liberação imediata), pacientes com problemas mais intensos em um estudo do programa de desenvolvimento para esse produto responderam a uma dose média de 350 Mg por dia (intervalo de 150 a 375 mg por dia). Se é necessário ou não doses mais elevadas de Effexor XR para pacientes mais deprimidos, a experiência com doses de Effexor XR superiores a 225 mg por dia é muito limitada. Transtorno de ansiedade generalizada Para a maioria dos pacientes, a dose inicial recomendada para Effexor XR é de 75 mg por dia, administrada em uma única dose. Para alguns pacientes, pode ser desejável começar com 37,5 mg por dia durante 4 a 7 dias para permitir que novos pacientes se adaptem à medicação antes de aumentar para 75 mg por dia. Os doentes que não respondem à dose inicial de 75 mg por dia podem beneficiar dos aumentos de dose até um máximo de 225 mg por dia. Os aumentos de dose devem ser em incrementos de até 75 mg por dia, conforme necessário, e devem ser feitos em intervalos não inferiores a 4 dias, uma vez que os níveis plasmáticos estacionários de venlafaxina e seus principais metabolitos são alcançados na maioria dos pacientes no dia 4 Ver Clinical Pharmacology (12.3). Transtorno de Ansiedade Social (Fobia Social) A dose recomendada é de 75 mg por dia, administrada em uma única dose. Não houve evidência de que doses mais elevadas conferissem algum benefício adicional. Transtorno de pânico A dose inicial recomendada é de 37,5 mg por dia de Effexor XR por 7 dias. Os doentes que não respondem a 75 mg por dia podem beneficiar dos aumentos de dose até um máximo de aproximadamente 225 mg por dia. Os aumentos de dose devem ser em incrementos de até 75 mg por dia, conforme necessário, e devem ser feitos em intervalos não inferiores a 7 dias. Alternar pacientes de Comprimidos Effexor Pacientes deprimidos que estão sendo tratados atualmente em uma dose terapêutica com Effexor (liberação imediata) podem ser comutados para Effexor XR na dose equivalente mais próxima (mg por dia), e. 37,5 mg de venlafaxina duas vezes ao dia a 75 mg de Effexor XR uma vez por dia. No entanto, ajustes de dosagem individuais podem ser necessários. Populações específicas Pacientes com insuficiência hepática A dose diária total deve ser reduzida em 50 em pacientes com insuficiência hepática leve (Child-Pugh5ndash6) a moderada (Child-Pugh7ndash9). Em pacientes com insuficiência hepática grave (Child-Pugh10ndash15) ou cirrose hepática, pode ser necessário reduzir a dose em 50 ou mais Ver Uso em Populações Específicas (8.7). Pacientes com insuficiência renal A dose diária total deve ser reduzida em 25 a 50 em pacientes com insuficiência renal moderada (CLcr 30ndash59 mLmin) em pacientes com insuficiência renal leve (CLcr 60ndash89 mLmin) ou moderada (CLcr 30ndash59 mLmin). Em pacientes submetidos a hemodiálise ou com insuficiência renal grave (CLcr lt 30 mLmin), a dose diária total deve ser reduzida em 50 ou mais. Como houve muita variabilidade individual na depuração entre pacientes com insuficiência renal, a individualização da dosagem pode ser desejável em alguns pacientes, ver Uso em Populações Específicas (8.7). Tratamento de manutenção Não há evidência disponível de estudos controlados para indicar quanto tempo pacientes com MDD, GAD, SAD ou PD devem ser tratados com Effexor XR. Em geral, concorda-se que os episódios agudos de MDD requerem vários meses ou mais de terapia farmacológica sustentada além da resposta ao episódio agudo. O Effexor XREffexor demonstrou a continuação da resposta em estudos clínicos até 52 semanas, na mesma dose em que os pacientes responderam durante o tratamento inicial, ver Estudos Clínicos (14.1). Não se sabe se a dose de Effexor XR necessária para o tratamento de manutenção é ou não idêntica à dose necessária para obter uma resposta inicial. Os pacientes devem ser periodicamente reavaliados para determinar a necessidade de tratamento de manutenção e a dose apropriada para esse tratamento. Em pacientes com GAD e SAD, Effexor XR mostrou-se eficaz em estudos clínicos de 6 meses. A necessidade de medicação contínua em pacientes com GAD e SAD que melhorem com o tratamento com Effexor XR deve ser periodicamente reavaliada. Em um estudo clínico para PD, os pacientes que continuaram com Effexor XR na mesma dose em que responderam durante as 12 semanas iniciais de tratamento apresentaram tempo estatisticamente significantemente mais longo para recidiva do que os pacientes randomizados para placebo, ver Estudos Clínicos (14,4). A necessidade de medicação contínua em pacientes com PD que melhoram com o tratamento com Effexor XR deve ser periodicamente reavaliada. Descontinuação de Effexor XR É recomendável uma redução gradual da dose, em vez de uma cessação abrupta, sempre que possível. Em estudos clínicos com Effexor XR, o afilamento foi conseguido reduzindo a dose diária em 75 mg em intervalos de uma semana. A individualização do afunilamento pode ser necessária, ver Advertências e Precauções (5.7). Alternar Pacientes para ou de um Inibidor de Oxidase de Monoamina (IMAO) Destinado a Tratar Distúrbios Psiquiátricos Pelo menos 14 dias devem decorrer entre a descontinuação de um IMAO (destinado a tratar transtornos psiquiátricos) e início de terapia com Effexor XR. Além disso, pelo menos 7 dias devem ser permitidos após a interrupção de Effexor XR antes de iniciar um IMAO destinado a tratar distúrbios psiquiátricos ver Contra-indicações (4.2). Avisos e Precauções (5.2). E Interações medicamentosas (7.2). Uso de Effexor XR com outros MAOIs, como Linezolid ou Methylene Blue Intravenous. Não inicie Effexor XR em um paciente que esteja sendo tratado com linezolid ou azul de metileno por via intravenosa, pois existe um risco aumentado de síndrome de serotonina. Em um paciente que requer um tratamento mais urgente de uma condição psiquiátrica, outras intervenções, incluindo a hospitalização, devem ser consideradas, ver Contra-indicações 4.2). Em alguns casos, um paciente que já recebe terapêutica com Effexor XR pode exigir tratamento urgente com linezolid ou azul de metileno por via intravenosa. Se as alternativas aceitáveis ao linezolid ou ao azul de metileno por via intravenosa não estiverem disponíveis e os benefícios potenciais do tratamento com linhisozol ou azul de metileno por via intravenosa forem considerados superiores aos riscos da síndrome da serotonina em um paciente específico, o Effexor XR deve ser interrompido prontamente e o azul de metileno linezolido ou intravenoso Pode ser administrado. Monitore o paciente para sintomas de síndrome de serotonina por 7 dias ou até 24 horas após a última dose de linezolid ou azul de metileno por via intravenosa, o que ocorrer primeiro. A terapia com Effexor XR pode ser retomada 24 horas após a última dose de linezolid ou azul de metileno por via intravenosa, ver Advertências e Precauções (5.2). O risco de administração de azul de metileno por rotas não intravenosas (como comprimidos orais ou por injeção local) ou em doses intravenosas muito inferiores a 1 mgkg concomitantemente com Effexor XR não está claro. O clínico deve, no entanto, estar ciente da possibilidade de sintomas emergentes da síndrome da serotonina com tal uso, ver Advertências e Precauções (5.2). Formulários de Dosagem e Forças As cápsulas de libertação prolongada de Effexor XR reg (venlafaxine hydrochloride) estão disponíveis nos seguintes pontos fortes: cápsulas de 37,5 mg (corpo cappeach cinzento com W e Effexor XR na tampa e 37,5 no corpo) cápsulas de 75 mg (cápsula de pessego e Corpo com W e Effexor XR na tampa e 75 no corpo) cápsulas de 150 mg (tampão de laranja escuro e corpo com W e Effexor XR na tampa e 150 no corpo) Contra-indicações Hipersensibilidade Hipersensibilidade ao cloridrato de venlafaxina, succinato de desvenlafaxina ou a qualquer Excipientes na formulação Uso concomitante com inibidores de monoaminoamidase (IMAOs) O uso de MAOIs (destinados a tratar distúrbios psiquiátricos) concomitantemente com Effexor XR ou dentro de 7 dias após a interrupção do tratamento com Effexor XR está contra-indicado devido ao aumento do risco de síndrome de serotonina. O uso de Effexor XR dentro de 14 dias após a interrupção do tratamento com um IMAO (destinado a tratar distúrbios psiquiátricos) também está contra-indicado. Veja a Dosagem e Administração (2.9). Avisos e Precauções (5.2). E Interações medicamentosas (7.2). Iniciando Effexor XR em um paciente que está sendo tratado com um MAOI, como linezolid ou azul de metileno por via intravenosa, também está contra-indicado, devido ao aumento do risco de síndrome de serotonina, ver Dosagem e Administração (2.9). Avisos e Precauções (5.2). E Interações medicamentosas (7.3). Avisos e precauções suicidas Pensamentos e comportamentos suicidas em crianças, adolescentes e adultos jovens Os pacientes com transtorno depressivo maior (MDD), adultos e pediátricos, podem sofrer um agravamento da depressão ou o surgimento de ideias e comportamentos suicidas (alterações suicidas) ou mudanças incomuns em Comportamento, quer estejam ou não tomando medicamentos antidepressivos, e esse risco pode persistir até ocorrer remissão significativa. O suicídio é um risco conhecido de depressão e certos outros distúrbios psiquiátricos, e esses distúrbios são os preditores mais fortes do suicídio. Entretanto, tem uma preocupação de longa data, que os antidepressivos podem ter um papel na indução de piora da depressão e no surgimento de suicídio em certos pacientes durante as primeiras fases do tratamento. As análises conjuntas de estudos de curto prazo controlados por placebo de drogas antidepressivas (SSRIs e outros) mostraram que esses fármacos aumentam o risco de pensamento suicida e comportamento (suicídio) em crianças, adolescentes e adultos jovens (idade 18ndash24) com MDD e outras doenças psiquiátricas Desordens. Estudos de curto prazo não mostraram aumento no risco de suicídio com antidepressivos em comparação com placebo em adultos com idade superior a 24 anos houve redução com antidepressivos em comparação com placebo em adultos com 65 anos ou mais. As análises agrupadas de estudos controlados com placebo em crianças e adolescentes com MDD, Transtorno Obsessivo Compulsivo (TOC) ou outros transtornos psiquiátricos incluíram 24 estudos de curto prazo de 9 drogas antidepressivas em mais de 4.400 pacientes. As análises agrupadas de estudos controlados com placebo em adultos com MDD ou outros distúrbios psiquiátricos incluíram um total de 295 estudos de curto prazo (duração média de 2 meses) de 11 drogas antidepressivas em mais de 77.000 pacientes. Houve uma variação considerável no risco de suicídio entre as drogas, mas uma tendência para um aumento nos pacientes mais jovens para quase todas as drogas estudadas. Houve diferenças no risco absoluto de suicídio nas diferentes indicações, com a maior incidência em MDD. As diferenças de risco (fármaco versus placebo), no entanto, foram relativamente estáveis em estratos de idade e em todas as indicações. Estas diferenças de risco (diferença de placebo do fármaco no número de casos de suicídio por 1.000 pacientes tratados) são fornecidos na Tabela 1. Tabela 1: Diferença no número de casos de suicídio por 1.000 pacientes tratados versus placebo Aumentos comparados ao placebo Não ocorreram suicídios Em qualquer um dos estudos pediátricos. Houve suicídios nos estudos para adultos, mas o número não foi suficiente para chegar a qualquer conclusão sobre o efeito da droga sobre o suicídio. Desconhece-se se o risco de suicídio se estende ao uso de longo prazo, ou seja, além de vários meses. No entanto, há evidências substanciais de estudos de manutenção controlados por placebo em adultos com depressão que o uso de antidepressivos pode atrasar a recorrência da depressão. Todos os pacientes que estão sendo tratados com antidepressivos para qualquer indicação devem ser monitorados adequadamente e observados de perto para o empeoramento clínico, o suicídio e as mudanças incomuns no comportamento, especialmente durante os primeiros meses de um curso de terapia medicamentosa, ou em momentos de mudanças de dose, quer aumenta Ou diminui. Os seguintes sintomas, ansiedade, agitação, ataques de pânico, insônia, irritabilidade, hostilidade, agressividade, impulsividade, akathisia (inquietação psicomotora), hipomania e mania, foram relatados em pacientes adultos e pediátricos tratados com antidepressivos para MDD, bem como Para outras indicações, tanto psiquiátricas como não psiquiátricas. Embora não tenha sido estabelecida uma ligação causal entre o surgimento de tais sintomas e o agravamento da depressão ou o surgimento de impulsos suicidas, há preocupação de que tais sintomas possam representar precursores para o suicídio emergente. Deve-se considerar a alteração do regime terapêutico, incluindo, possivelmente, a interrupção da medicação, em pacientes cuja depressão seja persistentemente pior ou que estejam experimentando suicídio emergente ou sintomas que possam ser precursores de piora da depressão ou suicídio, especialmente se esses sintomas forem graves, abruptos No início, ou não faziam parte dos pacientes apresentando sintomas. Se a decisão foi tomada para interromper o tratamento, a medicação deve diminuir, tão rapidamente quanto possível, mas com reconhecimento de que a descontinuação abrupta pode ser associada a certos sintomas, ver Advertências e Precauções (5.7) e Dosagem e Administração (2.8). As famílias e cuidadores de pacientes que estão sendo tratados com antidepressivos para MDD ou outras indicações, tanto psiquiátricas como não psiquiátricas, devem ser alertados sobre a necessidade de monitorar os pacientes para o surgimento de agitação, irritabilidade, alterações incomuns no comportamento e os outros sintomas descritos acima, como Bem como o surgimento do suicídio, e relatar esses sintomas imediatamente aos profissionais de saúde. Esse monitoramento deve incluir a observação diária de famílias e cuidadores. As prescrições para Effexor XR devem ser escritas para a menor quantidade de cápsulas consistente com o bom gerenciamento do paciente, a fim de reduzir o risco de sobredosagem. Triagem de pacientes para transtorno bipolar Um episódio depressivo maior pode ser a apresentação inicial do transtorno bipolar. Geralmente, acredita-se (embora não estabelecido em estudos controlados) que tratar esse episódio com um antidepressivo sozinho pode aumentar a probabilidade de precipitação de um episódio misturado em pacientes com risco de transtorno bipolar. Se algum dos sintomas descritos acima representa tal conversão é desconhecida. No entanto, antes de iniciar o tratamento com um antidepressivo, os pacientes com sintomas depressivos devem ser adequadamente rastreados para determinar se eles estão em risco de transtorno bipolar, o rastreio deve incluir uma história psiquiátrica detalhada, incluindo história familiar de suicídio, transtorno bipolar e depressão. Deve notar-se que o Effexor XR não está aprovado para uso no tratamento da depressão bipolar. Síndrome de Serotonina 8203 O desenvolvimento de uma síndrome de serotonina potencialmente morta foi relatado com SNRIs e SSRIs, incluindo Effexor XR sozinho, mas particularmente com o uso concomitante de outros medicamentos serotoninérgicos (incluindo triptanos, antidepressivos tricíclicos, fentanil, lítio, tramadol, triptofano, Buspirona, anfetaminas e erva de St. Johns) e com drogas que prejudicam o metabolismo da serotonina em particular, MAOIs, tanto aqueles destinados a tratar transtornos psiquiátricos como outros, como linezolid ou azul de metileno por via intravenosa). Os sintomas da síndrome de serotonina podem incluir alterações no estado mental (por exemplo, agitação, alucinações, delírio, coma), instabilidade autonômica (por ex., Taquicardia, pressão arterial lábil, hipertermia, diaforese, rubor e tonturas), sintomas neuromusculares (por exemplo, tremor, rigidez, mioclonia, hiperreflexia, Incoordação) convulsões e sintomas gastrointestinais (por exemplo, náuseas, vômitos, diarréia). Os pacientes devem ser monitorados para o surgimento da síndrome da serotonina. O uso concomitante de Effexor XR com MAOIs (destinado a tratar distúrbios psiquiátricos) está contra-indicado. Effexor XR também não deve ser iniciado em um paciente que está sendo tratado com MAOIs, como linezolid ou azul de metileno por via intravenosa. Todos os relatórios com azul de metileno que forneceram informações sobre a via de administração envolveram administração intravenosa na dose de 1 mgkg a 8 mgkg. Nenhum relatório envolveu a administração de azul de metileno por outras rotas (como comprimidos orais ou injeção local de tecido) ou em doses mais baixas. Pode haver circunstâncias em que é necessário iniciar o tratamento com um MAOI, como linezolid ou azul de metileno por via intravenosa em um paciente que tome Effexor XR. Effexor XR deve ser interrompido antes de iniciar o tratamento com o MAOI, ver Contra-indicações (4.2). Dosagem e administração (2.6). E Interações medicamentosas (7.3). Se o uso concomitante de Effexor XR com outros medicamentos serotonérgicos (por exemplo triptanos, antidepressivos tricíclicos, mirtazapina, fentanil, lítio, tramadol, buspirona, anfetaminas, triptofano ou erva de St. Johns) é clinicamente justificado, é recomendada uma observação cuidadosa do paciente, particularmente Durante a iniciação do tratamento e os aumentos de dose, ver Interações medicamentosas (7.3). Os pacientes devem ser conscientizados do risco potencial de síndrome da serotonina. O tratamento com Effexor XR e quaisquer agentes serotonérgicos concomitantes devem ser descontinuados imediatamente se os eventos acima ocorrerem e o tratamento sintomático de suporte deve ser iniciado. Elevação na pressão arterial Em ensaios controlados, houve aumento na dose de pressão arterial sistólica e diastólica relacionada à dose, bem como casos de hipertensão sustentada, ver Reações adversas (6.2). Monitorar a pressão arterial antes de iniciar o tratamento com Effexor XR e regularmente durante o tratamento. Controle a hipertensão pré-existente antes de iniciar o tratamento com Effexor XR. Tenha cuidado no tratamento de pacientes com hipertensão pré-existente ou doenças cardiovasculares ou cerebrovasculares que possam ser comprometidas pelo aumento da pressão arterial. A elevação da pressão arterial sustentada pode levar a resultados adversos. Os casos de pressão sanguínea elevada que requerem tratamento imediato foram relatados com Effexor XR. Considere a redução da dose ou a descontinuação do tratamento para pacientes que sofrem um aumento sustentado da pressão arterial. Em todos os estudos clínicos com Effexor, 1,4 dos pacientes nos grupos tratados com Effexor XR experimentaram um aumento de ge15 mm Hg na pressão arterial diastólica supina (SDBP) ge 105 mm Hg, em comparação com 0,9 dos pacientes nos grupos placebo. Da mesma forma, 1 dos pacientes nos grupos tratados com Effexor XR experimentou um aumento de 20 mm Hg na pressão arterial sistólica supina (SSBP) com pressão arterial ge 180 mm Hg, em comparação com 0,3 dos pacientes nos grupos placebo, ver Tabela 10 em Reações adversas ( 6.2). O tratamento com Effexor XR foi associado a hipertensão sustentada (definida como SDBP emergente do tratamento ge 90 mm Hg e ge 10 mm Hg acima da linha de base para três visitas consecutivas em terapia, ver Tabela 11 em Reações adversas (6.2). Um número insuficiente de pacientes recebeu média Doses de Effexor XR superiores a 300 mg por dia em estudos clínicos para avaliar completamente a incidência de aumentos sustentados na pressão arterial nessas doses mais elevadas. Síndromes anormais Os ISRSs e SNRIs, incluindo Effexor XR, podem aumentar o risco de eventos hemorrágicos, variando de equimoses, Hematomas, epistaxis, petequias e hemorragia gastrointestinal para hemorragias com risco de vida. O uso concomitante de aspirina, antiinflamatórios não esteróides (AINE), varfarina e outros anti-coagulantes ou outras drogas que podem afetar a função plaquetária podem aumentar esse risco. Relatos de casos e estudos epidemiológicos (caso-controle e design de coorte) demonstraram associação entre o uso de drogas que interferem com a recaptação de serotonina E a ocorrência de sangramento gastrointestinal. Cuide pacientes sobre o risco de sangramento associado ao uso concomitante de Effexor XR e AINEs, aspirina ou outros medicamentos que afetam a coagulação. Glaucoma de fechamento de ângulo A dilatação pupilar que ocorre após o uso de muitos medicamentos antidepressivos, incluindo Effexor XR, pode desencadear um ataque de fechamento de ângulo em um paciente com ângulos anatômicos estreitos que não possui uma patente de iridectomia. A ativação de ManiaHypomania Mania ou hipomania foi relatada em pacientes tratados com Effexor XR nos estudos de pré-comercialização em MDD, SAD e PD (ver Tabela 2). Maniahypomania também foi relatada em uma pequena proporção de pacientes com transtornos de humor que foram tratados com outros medicamentos comercializados para tratar MDD. Effexor XR deve ser usado com cautela em pacientes com história de mania ou hipomania. Tabela 2: Incidência () de mania ou hipomania relatada em pacientes tratados com Effexor XR nos estudos de pré-comercialização Síndrome de descontinuação Os sintomas de descontinuação foram avaliados sistematicamente em pacientes que tomaram venlafaxina, incluindo análises prospectivas de estudos clínicos em GAD e levantamentos retrospectivos de estudos em MDD e SAD . A descontinuação abrupta ou redução da dose de venlafaxina em várias doses foi associada à aparência de novos sintomas, cuja freqüência aumentou com o aumento do nível de dose e com maior duração do tratamento. Os sintomas relatados incluem agitação, anorexia, ansiedade, confusão, comprometimento da coordenação e equilíbrio, diarréia, tonturas, boca seca, humor disfórico, fasciculação, fadiga, sintomas gripais, dores de cabeça, hipomania, insônia, náuseas, nervosismo, pesadelos, distúrbios sensoriais ( Incluindo sensações elétricas semelhantes a choques), sonolência, transpiração, tremor, vertigem e vômitos. Durante a comercialização de Effexor XR, outros SNRIs e SSRIs, houve relatos espontâneos de eventos adversos ocorridos após a interrupção desses medicamentos, particularmente quando abruptos, incluindo o seguinte: humor disfórico, irritabilidade, agitação, tonturas, distúrbios sensoriais (por exemplo, parestesia, Tais como sensações de choque elétrico), ansiedade, confusão, dor de cabeça, letargia, labilidade emocional, insônia, hipomania, zumbido e convulsões. Embora esses eventos sejam geralmente auto-limitantes, houve relatos de sintomas graves de descontinuação. Os pacientes devem ser monitorados por esses sintomas ao interromper o tratamento com Effexor XR. É recomendável uma redução gradual da dose, em vez de uma cessação brusca, sempre que possível. Se os sintomas intoleráveis ocorrerem após uma diminuição da dose ou após a interrupção do tratamento, a retomada da dose previamente prescrita pode ser considerada. Posteriormente, o médico pode continuar a diminuir a dose, mas a uma taxa mais gradual, veja Dosagem e Administração (2.8). Ocorreram convulsões com a terapia com venlafaxina. Effexor XR, como muitos antidepressivos, deve ser usado cautelosamente em pacientes com história de convulsões e deve ser descontinuado em qualquer paciente que desenvolva convulsões. Deve atenuar o risco: fatores de risco, medicações concomitantes que reduzem o limiar de convulsão. Hiponatremia Hiponatremia pode ocorrer como resultado do tratamento com SSRI e SNRIs, incluindo Effexor XR. Em muitos casos, a hiponatremia parece ser o resultado da síndrome de secreção inadequada de hormona antidiurética (SIADH). Foram relatados casos com soro de sódio inferior a 110 mmolL. Os pacientes idosos podem estar em maior risco de desenvolver hiponatremia com SSRIs e SNRIs, ver Uso em Populações Específicas (8.5). Além disso, os pacientes que tomam diuréticos, ou aqueles que de outra forma estão empobrecidos em volume, podem estar em maior risco. Considere a descontinuação do Effexor XR em pacientes com hiponatremia sintomática e institua uma intervenção médica apropriada. Sinais e sintomas de hiponatremia incluem dor de cabeça, dificuldade de concentração, comprometimento da memória, confusão, fraqueza e instabilidade, o que pode levar a quedas. Os sinais e sintomas associados a casos mais intensos ou agudos incluem alucinações, síncope, convulsão, coma, parada respiratória e morte. Alterações de peso e altura em pacientes pediátricos A variação média no peso corporal e na incidência de perda de peso (porcentagem de pacientes que perderam 3,5 ou mais) nos estudos pediátricos controlados com placebo em MDD, GAD e SAD são mostradas nas Tabelas 3 e 4. Tabela 3: Variação média do peso corporal (kg) Desde o início do tratamento em pacientes pediátricos em estudos duplo-cegos, controlados por placebo de Effexor XR A perda de peso não se limitou a pacientes com anorexia emergente do tratamento, ver Advertências e Precauções (5.11). Os riscos associados ao uso de longo prazo de Effexor XR foram avaliados em um estudo MDD aberto de crianças e adolescentes que receberam Effexor XR por até seis meses. As crianças e os adolescentes no estudo apresentaram aumentos de peso que foram menos do que o esperado, com base em dados de pares correspondentes à idade e ao sexo. A diferença entre o aumento de peso observado e o aumento de peso esperado foi maior para crianças (12 anos) do que para adolescentes (idade geográfica de 12 anos). A Tabela 5 mostra o aumento médio de altura em pacientes pediátricos nos estudos de MDD, GAD e SAD de curto prazo, controlados por placebo. As diferenças de aumento de altura nos estudos de GAD e MDD foram mais notáveis em pacientes com menos de doze. Tabela 5: Aumentos médios de altura (cm) em pacientes pediátricos em estudos controlados com placebo de Effexor XR No estudo de MDD open-label de seis meses, crianças e adolescentes tiveram aumentos de altura que eram menores do que o esperado, com base em dados de idade - E pares correspondentes ao sexo. A diferença entre taxas de crescimento observadas e esperadas foi maior para crianças (12 anos) do que para adolescentes (idade geográfica 12 anos). Mudanças de apetite em pacientes pediátricos A diminuição do apetite (relatada como anorexia emergente do tratamento) foi mais comumente observada em pacientes tratados com Effexor XR versus pacientes tratados com placebo na avaliação pré-comercialização de Effexor XR para MDD, GAD e SAD (ver Tabela 6). Tabela 6: Incidência () de Diminuição do Apetite e Taxas de Descontinuação Associadas () em Pacientes Pediátricos em Estudos Controlados por Placebo de Effexor XR Incidência de Effexor XR As taxas de descontinuação para perda de peso foram 0,7 para pacientes que receberam Effexor XR ou placebo. MDD e GAD (em conjunto, 8 semanas) Doença pulmonar intersticial e pneumonia eosinofílica A doença pulmonar intersticial e a pneumonia eosinofílica associada à terapia com venlafaxina raramente foram relatadas. A possibilidade desses eventos adversos deve ser considerada em pacientes tratados com venlafaxina que apresentam dispnéia progressiva, tosse ou desconforto no tórax. Esses pacientes devem ser submetidos a uma pronta avaliação médica, e a descontinuação da terapia com venlafaxina deve ser considerada. Reações adversas As seguintes reações adversas são discutidas em maior detalhe em outras seções do rótulo: Experiência em Estudos Clínicos Uma vez que os estudos clínicos são conduzidos em condições amplamente variáveis, as taxas de reação adversas observadas nos estudos clínicos de um medicamento não podem ser diretamente comparadas às taxas na Estudos clínicos de outro medicamento e podem não refletir as taxas observadas na prática. Reações adversas mais comuns As reações adversas mais comumente observadas no banco de dados de estudos clínicos em pacientes tratados com Effexor XR em MDD, GAD, SAD e PD (incidência ge 5 e pelo menos duas vezes a taxa de placebo) foram: náuseas (30,0), sonolência (15,3), boca seca (14,8), sudação (11,4), ejaculação anormal (9,9), anorexia (9,8), constipação (9,3), impotência (5,3) e diminuição da libido (5,1). Reações adversas relatadas como razões para a interrupção do tratamento Combinado em estudos de pré-comercialização controlados por placebo em curto prazo para todas as indicações, 12 dos 3.558 pacientes que receberam Effexor XR (37.5ndash225 mg) descontinuaram o tratamento devido a uma experiência adversa, em comparação com 4 Os 2.197 doentes tratados com placebo nesses estudos. As reacções adversas mais frequentes que conduzem à descontinuação na ge 1 dos doentes tratados com Effexor XR nos estudos de curto prazo (até 12 semanas) em todas as indicações são mostradas na Tabela 7. Tabela 7: Incidência () de Pacientes Relatando Reações Adversas Levando para Descontinuação em Estudos Clínicos Controlados por Placebo (até 12 Semanas de Duração) Reacção Adversa do Sistema do Corpo Effexor XR n 3,558 Placebo n 2,197 Reações Adversas Comuns em Estudos Controlados por Placebo O número de pacientes que receberam doses múltiplas de Effexor XR durante a avaliação de pré-comercialização para cada um aprovado indication is shown in Table 8. The conditions and duration of exposure to venlafaxine in all development programs varied greatly, and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient (Effexor only) and outpatient studies, fixed-dose, and titration studies. Table 8: Patients Receiving Effexor XR in Premarketing Clinical Studies In addition, in the premarketing assessment of Effexor, multiple doses were administered to 2,897 patients in studies for MDD. The incidences of common adverse reactions (those that occurred in ge 2 of Effexor XR treated patients 357 MDD patients, 1,381 GAD patients, 819 SAD patients, and 1,001 PD patients and more frequently than placebo) in Effexor XR treated patients in short-term, placebo-controlled, fixed - and flexible-dose clinical studies (doses 37.5 to 225 mg per day) are shown in Table 9. The adverse reaction profile did not differ substantially between the different patient populations. Table 9: Common Adverse Reactions: Percentage of Patients Reporting Adverse Reactions (ge 2 and gt placebo) in Placebo-controlled Studies (up to 12 Weeks Duration) across All Indications Body System Adverse Reaction Effexor XR n 3,558 Placebo n 2,197 Percentages based on the number of men (Effexor XR, n 1,440 placebo, n 923) dagger Percentages based on the number of women (Effexor XR, n 2,118 placebo, n 1,274) Other Adverse Reactions Observed in Clinical Studies Body as a whole ndash Photosensitivity reaction, chills Cardiovascular system ndash Postural hypotension, syncope, hypotension, tachycardia Digestive system ndash Gastrointestinal hemorrhage see Warnings and Precautions (5.4) , bruxism Nervous system ndash Seizures see Warnings and Precautions (5.8) , manic reaction see Warnings and Precautions (5.6) , agitation, confusion, akathisia, hallucinations, hypertonia, myoclonus, depersonalization, apathy Skin and appendages ndash Urticaria, pruritus, rash, alopecia Special senses ndash Mydriasis, abnormality of accommodation, tinnitus, taste perversion Urogenital system ndash Urinary retention, urination impaired, urinary incontinence, urinary frequency increased, menstrual disorders associated with increased bleeding or increased irregular bleeding (e. g. menorrhagia, metrorrhagia) Vital Sign Changes In placebo-controlled premarketing studies, there were increases in mean blood pressure (see Table 10 ). Across most indications, a dose-related increase in mean supine systolic and diastolic blood pressure was evident in patients treated with Effexor XRs. Across all clinical studies in MDD, GAD, SAD and PD, 1.4 of patients in the Effexor XR groups experienced an increase in SDBP of ge15 mm Hg along with a blood pressure ge 105 mm Hg, compared to 0.9 of patients in the placebo groups. Similarly, 1 of patients in the Effexor XR groups experienced an increase in SSBP of ge 20 mm Hg with a blood pressure ge 180 mm Hg, compared to 0.3 of patients in the placebo groups. Table 10: Final On-therapy Mean Changes From Baseline in Supine Systolic (SSBP) and Diastolic (SDBP) Blood Pressure (mm Hg) in Placebo-controlled Studies Effexor XR treatment was associated with sustained hypertension (defined as treatment-emergent Supine Diastolic Blood Pressure SDBP ge 90 mm Hg and ge 10 mm Hg above baseline for three consecutive on-therapy visits (see Table 11 ). An insufficient number of patients received mean doses of Effexor XR over 300 mg per day in clinical studies to fully evaluate the incidence of sustained increases in blood pressure at these higher doses. Table 11: Sustained Elevations in SDBP in Effexor XR Premarketing Studies Dose Range (mg per day) Effexor XR was associated with mean increases in pulse rate compared with placebo in premarketing placebo-controlled studies (see Table 12 ) see Warnings and Precautions (5.3. 5.4) . Table 12: Approximate Mean Final On-therapy Increase in Pulse Rate (beatsmin) in Effexor XR Premarketing Placebo-controlled Stu dies (up to 12 Weeks Duration) Laboratory Changes Effexor XR was associated with mean final increases in serum cholesterol concentrations compared with mean final decreases for placebo in premarketing MDD, GAD, SAD and PD clinical studies (Table 13). Table 13: Mean Final On-therapy Changes in Cholesterol Concentrations (mgdL) in Effexor XR Premarketing Studies Effexor XR (venlafaxine hydrochloride) extended-release capsules treatment for up to 12 weeks in premarketing placebo-controlled trials for major depressive disorder was associated with a mean final on-therapy increase in serum cholesterol concentration of approximately 1.5 mgdL compared with a mean final decrease of 7.4 mgdL for placebo. Effexor XR treatment for up to 8 weeks and up to 6 months in premarketing placebo-controlled GAD trials was associated with mean final on-therapy increases in serum cholesterol concentration of approximately 1.0 mgdL and 2.3 mgdL, respectively while placebo subjects experienced mean final decreases of 4.9 mgdL and 7.7 mgdL, respectively. Effexor XR treatment for up to 12 weeks and up to 6 months in premarketing placebo-controlled Social Anxiety Disorder trials was associated with mean final on-therapy increases in serum cholesterol concentration of approximately 7.9 mgdL and 5.6 mgdL, respectively, compared with mean final decreases of 2.9 and 4.2 mgdL, respectively, for placebo. Effexor XR treatment for up to 12 weeks in premarketing placebo-controlled panic disorder trials was associated with mean final on-therapy increases in serum cholesterol concentration of approximately 5.8 mgdL compared with a mean final decrease of 3.7 mgdL for placebo. Patients treated with Effexor (immediate release) for at least 3 months in placebo-controlled 12-month extension trials had a mean final on-therapy increase in total cholesterol of 9.1 mgdL compared with a decrease of 7.1 mgdL among placebo-treated patients. This increase was duration dependent over the study period and tended to be greater with higher doses. Clinically relevant increases in serum cholesterol, defined as 1) a final on-therapy increase in serum cholesterol ge50 mgdL from baseline and to a value ge261 mgdL, or 2) an average on-therapy increase in serum cholesterol ge50 mgdL from baseline and to a value ge261 mgdL, were recorded in 5.3 of venlafaxine-treated patients and 0.0 of placebo-treated patients. Effexor XR was associated with mean final on-therapy increases in fasting serum triglycerides compared with placebo in premarketing clinical studies of SAD and PD up to 12 weeks (pooled data) and 6 months duration (Table 14). Table 14: Mean Final On-therapy Increases in Triglyceride Concentrations (mgdL) in Effexor XR Premarketing Studies Pediatric Patients In general, the adverse reaction profile of venlafaxine (in placebo-controlled clinical studies) in children and adolescents (ages 6 to 17) was similar to that seen for adults. As with adults, decreased appetite, weight loss, increased blood pressure, and increased serum cholesterol were observed see Warnings and Precautions (5.3. 5.10. 5.11 ) and Use in Specific Populations (8.4) . In pediatric clinical studies, the adverse reaction, suicidal ideation, was observed. Particularly, the following adverse reactions were observed in pediatric patients: abdominal pain, agitation, dyspepsia, ecchymosis, epistaxis, and myalgia. Adverse Reactions Identified During Postapproval Use The following adverse reactions have been identified during postapproval use of Effexor XR. 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 as a whole ndash Anaphylaxis, angioedema Cardiovascular system ndash QT prolongation, ventricular fibrillation, ventricular tachycardia (including torsade de pointes) Digestive system ndash Pancreatitis HemicLymphatic system ndash Mucous membrane bleeding see Warnings and Precautions (5.4 ) , blood dyscrasias (including agranulocytosis, aplastic anemia, neutropenia and pancytopenia), prolonged bleeding time, thrombocytopenia MetabolicNutritional ndash Hyponatremia see Warnings and Precautions (5.9) , Syndrome of Inappropriate Antidiuretic Hormone (SIADH) secretion see Warnings and Precautions (5.9) , abnormal liver function tests, hepatitis, prolactin increased Musculoskeletal ndash Rhabdomyolysis Nervous system ndash Neuroleptic Malignant Syndrome (NMS) see Warnings and Precaut ions (5.2) , serotonergic syndrome see Warnings and Precautions (5.2) , delirium, extrapyramidal reactions (including dystonia and dyskinesia), impaired coordination and balance, tardive dyskinesia Respiratory system ndash Dyspnea, interstitial lung disease, pulmonary eosinophilia see Warnings and Precautions (5.12) Skin and appendages ndash Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme Special senses ndash Angle-closure glaucoma see Warnings and Precautions (5.5) Drug Interactions Central Nervous System (CNS)-Active Drugs The risk of using venlafaxine in combination with other CNS-active drugs has not been systematically evaluated. Consequently, caution is advised when Effexor XR is taken in combination with other CNS-active drugs. Monoamine Oxidase Inhibitors Adverse reactions, some of which were serious, have been reported in patients who have recently been discontinued from an MAOI and started on antidepressants with pharmacological properties similar to Effexor XR (SNRIs or SSRIs), or who have recently had SNRI or SSRI therapy discontinued prior to initiation of an MAOI see Dosage and Administration (2.9). Contraindications (4.2) and Warnings and Precautions (5.2) . Serotonergic Drugs Based on the mechanism of action of Effexor XR and the potential for serotonin syndrome, caution is advised when Effexor XR is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, SSRIs, other SNRIs, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St. Johns wort. If concomitant treatment with Effexor XR and these drugs is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. The concomitant use of Effexor XR with tryptophan supplements is not recommended see Dosage and Administration (2.9). Contraindications (4.2). and Warnings and Precautions (5.2) . Drugs that Interfere with Hemostasis (e. g. NSAIDs, Aspirin, and Warfarin) Serotonin release by platelets plays an important role in hemostasis. The use of psychotropic drugs that interfere with serotonin reuptake is associated with the occurrence of upper gastrointestinal bleeding and concurrent use of an NSAID or aspirin may potentiate this risk of bleeding see Warnings and Precautions (5.4) . Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when Effexor XR is initiated or discontinued. Weight Loss Agents The safety and efficacy of venlafaxine therapy in combination with weight loss agents, including phentermine, have not been established. Coadministration of Effexor XR and weight loss agents is not recommended. Effexor XR is not indicated for weight loss alone or in combination with other products. Effects of Other Drugs on Effexor XR Figure 1: Effect of interacting drugs on the pharmacokinetics of venlafaxine and active metabolite O-desmethylvenlafaxine (ODV). Abbreviations: AUC, area under the curve Cmax, peak plasma concentrations OH, hydroxyl Data for 2-OH desipramine were not plotted to enhance clarity the fold change and 90 CI for Cmax and AUC of 2-OH desipramine were 6.6 (5.5, 7.9) and 4.4 (3.8, 5.0), respectively. Note: : Administration of venlafaxine in a stable regimen did not exaggerate the psychomotor and psychometric effects induced by ethanol in these same subjects when they were not receiving venlafaxine. Drug-Laboratory Test Interactions False-positive urine immunoassay screening tests for phencyclidine (PCP) and amphetamine have been reported in patients taking venlafaxine. This is due to lack of specificity of the screening tests. False positive test results may be expected for several days following discontinuation of venlafaxine therapy. Confirmatory tests, such as gas chromatographymass spectrometry, will distinguish venlafaxine from PCP and amphetamine. USE IN SPECIFIC POPULATIONS Teratogenic Effects ndash Pregnancy Category C Venlafaxine did not cause malformations in offspring of rats or rabbits given doses up to 2.5 times (rat) or 4 times (rabbit) the maximum recommended human daily dose on a mgm 2 basis. However, in rats, there was a decrease in pup weight, an increase in stillborn pups, and an increase in pup deaths during the first 5 days of lactation, when dosing began during pregnancy and continued until weaning. The cause of these deaths is not known. These effects occurred at 2.5 times (mgm 2 ) the maximum human daily dose. The no effect dose for rat pup mortality was 0.25 times the human dose on a mgm 2 basis. In reproductive developmental studies in rats and rabbits with O-desmethylvenlafaxine (ODV), the major human metabolite of venlafaxine, evidence of teratogenicity was not observed at exposure margins of 13 in rats and 0.3 in rabbits. There are no adequate and well-controlled studies in pregnant women. Effexor XR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Neonates exposed to Effexor XR, other SNRIs, or SSRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs, or possibly a drug discontinuation syndrome. It should be noted, that in some cases the clinical picture is consistent with serotonin syndrome see Warnings and Precautions (5.2) and Drug Interactions (7.3) . When treating a pregnant woman with Effexor XR during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. Labor and Delivery The effect of venlafaxine on labor and delivery in humans is unknown. Nursing Mothers Venlafaxine and ODV have been reported to be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Effexor XR, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Two placebo-controlled trials in 766 pediatric patients with MDD and two placebo-controlled trials in 793 pediatric patients with GAD have been conducted with Effexor XR, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of Effexor XR in a child or adolescent must balance the potential risks with the clinical need see Boxed Warning. Warnings and Precautions (5.1. 5.10. 5.11 ) and Adverse Reactions (6.4 ) . Although no studies have been designed to primarily assess Effexor XRs impact on the growth, development, and maturation of children and adolescents, the studies that have been done suggest that Effexor XR may adversely affect weight and height (see Warnings and Precautions (5.10) ). Should the decision be made to treat a pediatric patient with Effexor XR, regular monitoring of weight and height is recommended during treatment, particularly if treatment is to be continued long-term see Warnings and Precautions (5.10. 5.11) . The safety of Effexor XR treatment for pediatric patients has not been systematically assessed for chronic treatment longer than six months in duration. In the studies conducted in pediatric patients (ages 6ndash17), the occurrence of blood pressure and cholesterol increases considered to be clinically relevant in pediatric patients was similar to that observed in adult patients. Consequently, the precautions for adults apply to pediatric patients see Warnings and Precautions (5.3 ,6.3) . Geriatric Use The percentage of patients in clinical studies for Effexor XR for MDD, GAD, SAD, and PD who were 65 years of age or older are shown in Table 15. Table 15: Percentage (and Number of Patients Studied) of Patients 65 Years of Age and Older by Indication No overall differences in effectiveness or safety were observed between geriatric patients and younger patients, and other reported clinical experience generally has not identified differences in response between the elderly and younger patients. However, greater sensitivity of some older individuals cannot be ruled out. SSRIs and SNRIs, including Effexor XR, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event see Warnings and Precautions (5.9) . The pharmacokinetics of venlafaxine and ODV are not substantially altered in the elderly see Clinical Pharmacology (12.3) and (see Figure 3) . No dose adjustment is recommended for the elderly on the basis of age alone, although other clinical circumstances, some of which may be more common in the elderly, such as renal or hepatic impairment, may warrant a dose reduction see Dosage and Administration (2.6) . Age and Gender A population pharmacokinetic analysis of 404 Effexor-treated patients from two studies involving both twice daily and three times daily regimens showed that dose-normalized trough plasma levels of either venlafaxine or ODV were unaltered by age or gender differences. Dosage adjustment based on the age or gender of a patient is generally not necessary see Dosage and Administration (2.6) (see Table 15 ). Use in Patient Subgroups Figure 3: Pharmacokinetics of venlafaxine and its metabolite O-desmethylvenlafaxine (ODV) in special populations. Abbreviations: ODV, O-desmethylvenlafaxine AUC, area under the curve Cmax, peak plasma concentrations Similar effect is expected with strong CYP2D6 inhibitors Drug Abuse and Dependence Controlled Substance Effexor XR is not a controlled substance. While venlafaxine has not been systematically studied in clinical studies for its potential for abuse, there was no indication of drug-seeking behavior in the clinical studies. However, it is not possible to predict on the basis of premarketing experience the extent to which a CNS-active drug will be misused, diverted, andor abused once marketed. Consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of venlafaxine (e. g. development of tolerance, incrementation of dose, drug-seeking behavior). Dependence In vitro studies revealed that venlafaxine has virtually no affinity for opiate, benzodiazepine, phencyclidine (PCP), or N-methyl-D-aspartic acid (NMDA) receptors. Venlafaxine was not found to have any significant CNS stimulant activity in rodents. In primate drug discrimination studies, venlafaxine showed no significant stimulant or depressant abuse liability. Discontinuation effects have been reported in patients receiving venlafaxine see Dosage and Administration (2.8) . Overdosage Human Experience During the premarketing evaluations of Effexor XR (for MDD, GAD, SAD, and PD) and Effexor (for MDD), there were twenty reports of acute overdosage with Effexor (6 and 14 reports in Effexor XR and Effexor patients, respectively), either alone or in combination with other drugs andor alcohol. Somnolence was the most commonly reported symptom. Among the other reported symptoms were paresthesia of all four limbs, moderate dizziness, nausea, numb hands and feet, and hot-cold spells 5 days after the overdose. In most cases, no signs or symptoms were associated with overdose. The majority of the reports involved ingestion in which the total dose of venlafaxine taken was estimated to be no more than several-fold higher than the usual therapeutic dose. One patient who ingested 2.75 g of venlafaxine was observed to have two generalized convulsions and a prolongation of QTc to 500 msec, compared with 405 msec at baseline. Mild sinus tachycardia was reported in two of the other patients. Actions taken to treat the overdose included no treatment, hospitalization and symptomatic treatment, and hospitalization plus treatment with activated charcoal. All patients recovered. In postmarketing experience, overdose with venlafaxine has occurred predominantly in combination with alcohol andor other drugs. The most commonly reported events in overdosage include tachycardia, changes in level of consciousness (ranging from somnolence to coma), mydriasis, seizures, and vomiting. Electrocardiogram changes (e. g. prolongation of QT interval, bundle branch block, QRS prolongation), ventricular tachycardia, bradycardia, hypotension, rhabdomyolysis, vertigo, liver necrosis, serotonin syndrome, and death have been reported. Published retrospective studies report that venlafaxine overdosage may be associated with an increased risk of fatal outcomes compared to that observed with SSRI antidepressant products, but lower than that for tricyclic antidepressants. Epidemiological studies have shown that venlafaxine-treated patients have a higher preexisting burden of suicide risk factors than SSRI-treated patients. The extent to which the finding of an increased risk of fatal outcomes can be attributed to the toxicity of venlafaxine in overdosage, as opposed to some characteristic(s) of venlafaxine-treated patients, is not clear. Prescriptions for Effexor XR should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose. Management of Overdosage Consult a Certified Poison Control Center for up-to-date guidance and advice (1-800-222-1222 or poison. org). In case of an overdose, provide supportive care, including close medical supervision and monitoring. Treatment should consist of those general measures employed in the management of overdosage with any drug. Consider the possibility of multiple drug overdose. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Provide supportive and symptomatic measures. Effexor XR Description Effexor XR is an extended-release capsule for once-a-day oral administration that contains venlafaxine hydrochloride, a serotonin and norepinephrine reuptake inhibitor (SNRI). Venlafaxine is designated (RS)-1-2-(dimethylamino)-1-(4-methoxyphenyl)ethyl cyclohexanol hydrochloride or (plusmn)-1-alpha - (dimethylamino)methyl-p-methoxybenzyl cyclohexanol hydrochloride and has the empirical formula of C 17 H 27 NO 2 HCl. Its molecular weight is 313.86. The structural formula is shown as follows: Venlafaxine hydrochloride is a white to off-white crystalline solid, with a solubility of 572 mgmL in water (adjusted to ionic strength of 0.2 M with sodium chloride). Its octanol:water (0.2 M sodium chloride) partition coefficient is 0.43. Drug release is controlled by diffusion through the coating membrane on the spheroids and is not pH-dependent. Capsules contain venlafaxine hydrochloride equivalent to 37.5 mg, 75 mg, or 150 mg venlafaxine. Inactive ingredients consist of cellulose, ethylcellulose, gelatin, hypromellose, iron oxide, and titanium dioxide. Effexor XR - Clinical Pharmacology Mechanism of Action The exact mechanism of the antidepressant action of venlafaxine in humans is unknown, but is thought to be related to the potentiation of serotonin and norepinephrine in the central nervous system, through inhibition of their reuptake. Non - clinical studies have demonstrated that venlafaxine and its active metabolite, ODV, are potent and selective inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake. Pharmacodynamics Venlafaxine and ODV have no significant affinity for muscarinic-cholinergic, H 1 - histaminergic, or alpha 1 - adrenergic receptors in vitro. Pharmacologic activity at these receptors is hypothesized to be associated with the various anticholinergic, sedative, and cardiovascular effects seen with other psychotropic drugs. Venlafaxine and ODV do not possess monoamine oxidase (MAO) inhibitory activity. Pharmacokinetics Steady-state concentrations of venlafaxine and ODV in plasma are attained within 3 days of oral multiple-dose therapy. Venlafaxine and ODV exhibited linear kinetics over the dose range of 75 to 450 mg per day. MeanplusmnSD steady-state plasma clearance of venlafaxine and ODV is 1.3plusmn0.6 and 0.4plusmn0.2 Lhkg, respectively apparent elimination half-life is 5plusmn2 and 11plusmn2 hours, respectively and apparent (steady-state) volume of distribution is 7.5plusmn3.7 and 5.7plusmn1.8 Lkg, respectively. Venlafaxine and ODV are minimally bound at therapeutic concentrations to plasma proteins (27 and 30, respectively). Absorption and Distribution Venlafaxine is well absorbed and extensively metabolized in the liver. ODV is the major active metabolite. On the basis of mass balance studies, at least 92 of a single oral dose of venlafaxine is absorbed. The absolute bioavailability of venlafaxine is approximately 45. Administration of Effexor XR (150 mg once daily) generally resulted in lower C max and later T max values than for Effexor (immediate release) administered twice daily (Table 16). When equal daily doses of venlafaxine were administered as either an immediate-release tablet or the extended-release capsule, the exposure to both venlafaxine and ODV was similar for the two treatments, and the fluctuation in plasma concentrations was slightly lower with the Effexor XR capsule. Therefore, Effexor XR provides a slower rate of absorption, but the same extent of absorption compared with the immediate-release tablet. Table 16: Comparison of C max and T max Values for Venlafaxine and ODV Following Oral Administration of Effexor XR and Effexor (Immediate Release) Venlafaxine C max (ngmL) Food did not affect the bioavailability of venlafaxine or its active metabolite, ODV. Time of administration (AM versus PM) did not affect the pharmacokinetics of venlafaxine and ODV from the 75 mg Effexor XR capsule. Venlafaxine is not highly bound to plasma proteins therefore, administration of Effexor XR to a patient taking another drug that is highly protein-bound should not cause increased free concentrations of the other drug. Metabolism and Elimination Following absorption, venlafaxine undergoes extensive presystemic metabolism in the liver, primarily to ODV, but also to N-desmethylvenlafaxine, N, O-didesmethylvenlafaxine, and other minor metabolites. In vitro studies indicate that the formation of ODV is catalyzed by CYP2D6 this has been confirmed in a clinical study showing that patients with low CYP2D6 levels (poor metabolizers) had increased levels of venlafaxine and reduced levels of ODV compared to people with normal CYP2D6 levels (extensive metabolizers) see Use in Specific Populations 8.7 . Approximately 87 of a venlafaxine dose is recovered in the urine within 48 hours as unchanged venlafaxine (5), unconjugated ODV (29), conjugated ODV (26), or other minor inactive metabolites (27). Renal elimination of venlafaxine and its metabolites is thus the primary route of excretion. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility Tumors were not increased by venlafaxine treatment in mice or rats. Venlafaxine was given by oral gavage to mice for 18 months at doses up to 120 mgkg per day, which was 1.7 times the maximum recommended human dose on a mgm 2 basis. Venlafaxine was also given to rats by oral gavage for 24 months at doses up to 120 mgkg per day. In rats receiving the 120 mgkg dose, plasma concentrations of venlafaxine at necropsy were 1 times (male rats) and 6 times (female rats) the plasma concentrations of patients receiving the maximum recommended human dose. Plasma levels of the O-desmethyl metabolite (ODV) were lower in rats than in patients receiving the maximum recommended dose. O-desmethylvenlafaxine (ODV), the major human metabolite of venlafaxine, administered by oral gavage to mice and rats for 2 years did not increase the incidence of tumors in either study. Mice received ODV at dosages up to 500300 mgkgday (dosage lowered after 45 weeks of dosing). The exposure at the 300 mgkgday dose is 9 times that of a human dose of 225 mgday. Rats received ODV at dosages up to 300 mgkgday (males) or 500 mgkgday (females). The exposure at the highest dose is approximately 8 (males) or 11 (females) times that of a human dose of 225 mgday. Venlafaxine and the major human metabolite, ODV, were not mutagenic in the Ames reverse mutation assay in Salmonella bacteria or the Chinese hamster ovaryHGPRT mammalian cell forward gene mutation assay. Venlafaxine was also not mutagenic or clastogenic in the in vitro BALBc-3T3 mouse cell transformation assay, the sister chromatid exchange assay in cultured Chinese hamster ovary cells, or in the in vivo chromosomal aberration assay in rat bone marrow. ODV was not clastogenic in the in vitro Chinese hamster ovary cell chromosomal aberration assay or in the in vivo chromosomal aberration assay in rats. Impairment of Fertility Reproduction and fertility studies of venlafaxine in rats showed no adverse effects of venlafaxine on male or female fertility at oral doses of up to 2 times the maximum recommended human dose of 225 mgday on a mgm 2 basis. However, reduced fertility was observed in a study in which male and female rats were treated with O-desmethylvenlafaxine (ODV), the major human metabolite of venlafaxine, prior to and during mating and gestation. This occurred at an ODV exposure (AUC) approximately 2 to 3 times that associated with a human venlafaxine dose of 225 mgday. Clinical Studies Major Depressive Disorder The efficacy of Effexor XR (venlafaxine hydrochloride) extended-release capsules as a treatment for Major Depressive Disorder (MDD) was established in two placebo-controlled, short-term (8 weeks for study 1 12 weeks for study 2), flexible-dose studies, with doses starting at 75 mg per day and ranging to 225 mg per day in adult outpatients meeting DSM-III-R or DSM-IV criteria for MDD. In moderately depressed outpatients, the initial dose of venlafaxine was 75 mg per day. In both studies, Effexor XR demonstrated superiority over placebo on the primary efficacy measure defined as change from baseline in the HAM-D-21 total score to the endpoint visit, Effexor XR also demonstrated superiority over placebo on the key secondary efficacy endpoint, the Clinical Global Impressions (CGI) Severity of Illness scale. Examination of gender subsets of the population studied did not reveal any differential responsiveness on the basis of gender. A 4-week study of inpatients meeting DSM-III-R criteria for MDD with melancholia utilizing Effexor in a range of 150 to 375 mg per day (divided in a three-times-a-day schedule) demonstrated superiority of Effexor over placebo based on the HAM-D-21 total score. The mean dose in completers was 350 mg per day (study 3). In a longer-term study, adult outpatients with MDD who had responded during an 8-week open-label study on Effexor XR (75, 150, or 225 mg, once daily every morning) were randomized to continuation of their same Effexor XR dose or to placebo, for up to 26 weeks of observation for relapse. Response during the open-label phase was defined as a CGI Severity of Illness item score of le3 and a HAM-D-21 total score of le10 at the day 56 evaluation. Relapse during the double-blind phase was defined as follows: (1) a reappearance of major depressive disorder as defined by DSM-IV criteria and a CGI Severity of Illness item score of ge4 (moderately ill), (2) 2 consecutive CGI Severity of Illness item scores of ge4, or (3) a final CGI Severity of Illness item score of ge4 for any patient who withdrew from the study for any reason. Patients receiving continued Effexor XR treatment experienced statistically significantly lower relapse rates over the subsequent 26 weeks compared with those receiving placebo (study 4). In a second longer term trial, adult outpatients with MDD, recurrent type, who had responded (HAM-D-21 total score le 12 at the day 56 evaluation) and continued to be improved defined as the following criteria being met for days 56 through 180: (1) no HAM-D-21 total score ge 20 (2) no more than 2 HAM-D-21 total scores gt 10, and (3) no single CGI Severity of Illness item score ge 4 (moderately ill) during an initial 26 weeks of treatment on Effexor 100 to 200 mg per day, on a twice daily schedule were randomized to continuation of their same Effexor dose or to placebo. The follow-up period to observe patients for relapse, defined as a CGI Severity of Illness item score ge 4, was for up to 52 weeks. Patients receiving continued Effexor treatment experienced statistically significantly lower relapse rates over the subsequent 52 weeks compared with those receiving placebo (study 5). Table 17: Major Depressive Disorder Studies: Generalized Anxiety Disorder The efficacy of Effexor XR as a treatment for Generalized Anxiety Disorder (GAD) was established in two 8-week, placebo-controlled, fixed-dose studies (75 to 225 mg per day), one 6-month, placebo-controlled, flexible-dose study (75 to 225 mg per day), and one 6-month, placebo-controlled, fixed-dose study (37.5, 75, and 150 mg per day) in adult outpatients meeting DSM-IV criteria for GAD. In one 8-week study, Effexor XR demonstrated superiority over placebo for the 75, 150, and 225 mg per day doses as measured by the Hamilton Rating Scale for Anxiety (HAM-A) total score, both the HAM-A anxiety and tension items, and the Clinical Global Impressions (CGI) scale. However, the 75 and 150 mg per day doses were not as consistently effective as the highest dose (study 1). A second 8-week study evaluating doses of 75 and 150 mg per day and placebo showed that both doses were more effective than placebo on some of these same outcomes however, the 75 mg per day dose was more consistently effective than the 150 mg per day dose (study 2). A dose-response relationship for effectiveness in GAD was not clearly established in the 75 to 225 mg per day dose range studied. Two 6-month studies, one evaluating Effexor XR doses of 37.5, 75, and 150 mg per day (study 3) and the other evaluating Effexor XR doses of 75 to 225 mg per day (study 4), showed that daily doses of 75 mg or higher were more effective than placebo on the HAM-A total, both the HAM-A anxiety and tension items, and the CGI scale during 6 months of treatment. While there was also evidence for superiority over placebo for the 37.5 mg per day dose, this dose was not as consistently effective as the higher doses. Examination of gender subsets of the population studied did not reveal any differential responsiveness on the basis of gender. Table 18: Generalized Anxiety Disorder Studies: Primary Efficacy Measure: HAM-A Score Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo Subtracted Difference (95 CI) SD: standard deviation SE: standard error LS Mean: least-squares mean CI: confidence interval. Doses statistically significantly superior to placebo. Difference (drug minus placebo) in least-squares mean change from baseline Social Anxiety Disorder (also known as Social Phobia) The efficacy of Effexor XR as a treatment for Social Anxiety Disorder (SAD) was established in four double-blind, parallel-group, 12-week, multicenter, placebo-controlled, flexible-dose studies (studies 1ndash4) and one double-blind, parallel-group, 6-month, placebo-controlled, fixedflexible-dose study, which included doses in a range of 75 to 225 mg per day in adult outpatients meeting DSM-IV criteria for SAD (study 5). In these five studies, Effexor XR was statistically significantly more effective than placebo on change from baseline to endpoint on the Liebowitz Social Anxiety Scale (LSAS) total score. There was no evidence for any greater effectiveness of the 150 to 225 mg per day group compared to the 75 mg per day group in the 6-month study. Examination of subsets of the population studied did not reveal any differential responsiveness on the basis of gender. There was insufficient information to determine the effect of age or race on outcome in these studies. Table 19: Social Anxiety Disorder Studies Primary Efficacy Measure: LSAS Score Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo Subtracted Difference (95 CI) SD: standard deviation SE: standard error LS Mean: least-squares mean CI: confidence interval. Doses statistically significantly superior to placebo. Difference (drug minus placebo) in least-squares mean change from baseline Panic Disorder The efficacy of Effexor XR as a treatment for Panic Disorder (PD) was established in two double-blind, 12-week, multicenter, placebo-controlled studies in adult outpatients meeting DSM-IV criteria for PD, with or without agoraphobia. Patients received fixed doses of 75 or 150 mg per day in one study (study 1) and 75 or 225 mg per day in the other study (study 2). Efficacy was assessed on the basis of outcomes in three variables: (1) percentage of patients free of full-symptom panic attacks on the Panic and Anticipatory Anxiety Scale (PAAS) (2) mean change from baseline to endpoint on the Panic Disorder Severity Scale (PDSS) total score and (3) percentage of patients rated as responders (much improved or very much improved) on the Clinical Global Impressions (CGI) Improvement scale. In these two studies, Effexor XR was statistically significantly more effective than placebo (for each fixed dose) on all three endpoints, but a dose-response relationship was not clearly established. Examination of subsets of the population studied did not reveal any differential responsiveness on the basis of gender. There was insufficient information to determine the effect of age or race on outcome in these studies. In a longer term study (study 3), adult outpatients meeting DSM-IV criteria for PD who had responded during a 12-week open phase with Effexor XR (75 to 225 mg per day) were randomly assigned to continue the same Effexor XR dose (75, 150, or 225 mg) or switch to placebo for observation for relapse under double-blind conditions. Response during the open phase was defined as le 1 full-symptom panic attack per week during the last 2 weeks of the open phase and a CGI Improvement score of 1 (very much improved) or 2 (much improved). Relapse during the double-blind phase was defined as having 2 or more full-symptom panic attacks per week for 2 consecutive weeks or having discontinued due to loss of effectiveness as determined by the investigators during the study. Randomized patients were in response status for a mean time of 34 days prior to being randomized. In the randomized phase following the 12-week open-label period, patients receiving continued Effexor XR experienced a statistically significantly longer time to relapse. Table 20: Panic Disorder Studies: Primary Efficacy Measure: Whether Free of Full-symptom Panic Attacks Percent of patients Free of Full symptom panic attack Adjusted Odds Ratio to placebo Adjusted Odds Ratio 95 Confidence Interval 95CI: 95 confidence interval without adjusting for multiple dose arms. Odds ratio (drug to placebo) in terms of probability of free of full-symptom panic attacks based on logistic regression model. dagger Doses statistically significantly superior to placebo. Pediatric Patients Two placebo-controlled studies in 766 pediatric patients with MDD and two placebo-controlled studies in 793 pediatric patients with GAD have been conducted with Effexor XR, and the data were not sufficient to support a claim for use in pediatric patients. How SuppliedStorage and Handling Effexor XR reg (venlafaxine hydrochloride) extended-release capsules are available as follows: 37.5 mg, grey cappeach body with W and Effexor XR on the cap and 37.5 on the body. NDC 0008-0837-20, bottle of 15 capsules in unit-of-use package. NDC 0008-0837-21, bottle of 30 capsules in unit-of-use package. NDC 0008-0837-22, bottle of 90 capsules in unit-of-use package. NDC 0008-0837-03, carton of 10 Redipak reg blister strips of 10 capsules each. 75 mg, peach cap and body with W and Effexor XR on the cap and 75 on the body. NDC 0008-0833-20, bottle of 15 capsules in unit-of-use package. NDC 0008-0833-21, bottle of 30 capsules in unit-of-use package. NDC 0008-0833-22, bottle of 90 capsules in unit-of-use package. NDC 0008-0833-03, carton of 10 Redipak reg blister strips of 10 capsules each. 150 mg, dark orange cap and body with W and Effexor XR on the cap and 150 on the body. NDC 0008-0836-20, bottle of 15 capsules in unit-of-use package. NDC 0008-0836-21, bottle of 30 capsules in unit-of-use package. NDC 0008-0836-22, bottle of 90 capsules in unit-of-use package. NDC 0008-0836-03, carton of 10 Redipak reg blister strips of 10 capsules each. Store at controlled room temperature, 20deg to 25degC (68deg to 77degF). The unit-of-use package is intended to be dispensed as a unit. The appearance of these capsules is a trademark of Wyeth Pharmaceuticals. Patient Counseling Information See FDA-approved patient labeling (Medication Guide ). Prescribers or other healthcare professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Effexor XR and should counsel them in its appropriate use. A patient Medication Guide about Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions is available for Effexor XR. The prescriber or healthcare professional should instruct patients, their families, and their caregivers to read the Medication Guide and should 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. Patients should be advised of the following issues and should be asked to alert their prescriber if these occur while taking Effexor XR. Suicidal Thoughts and Behaviors Advise patients, their families and caregivers to look for the emergence of suicidality, worsening of depression, and other psychiatric symptoms (anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, psychomotor restlessness, hypomania, mania, other unusual changes in behavior), especially early during treatment and when the dose is adjusted up or down. Such symptoms should be reported to the patients prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patients 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 see Boxed Warning and Warnings and Precautions (5.1) . Advise patients taking Effexor XR not to use concomitantly other products containing venlafaxine or desvenlafaxine. Healthcare professionals should instruct patients not to take Effexor XR with an MAOI or within 14 days of stopping an MAOI and to allow 7 days after stopping Effexor XR before starting an MAOI see Contraindications (4.2) . Patients should be cautioned about the risk of serotonin syndrome, with the concomitant use of Effexor XR and triptans, tramadol, amphetamines, tryptophan supplements, with antipsychotics or other dopamine antagonists, or other serotonergic agents s ee Warnings and Precautions (5.2) and Drug Interactions (7.3) . Elevated Blood Pressure Advise patients that they should have regular monitoring of blood pressure when taking Effexor XR see Warnings and Precautions (5.3) . Patients should be cautioned about the concomitant use of Effexor XR and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding see Warnings and Precautions (5.4) . Angle Closure Glaucoma Patients should be advised that taking Effexor XR 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 see Warnings and Precautions (5.5) . Activation of ManiaHypomania Advise patients, their families and caregivers to observe for signs of activation of maniahypomania see Warnings and Precautions (5.6) . Caution is advised in administering Effexor XR to patients with cardiovascular, cerebrovascular, or lipid metabolism disorders see Adverse Reactions (6.1) . Serum Cholesterol and Triglyceride Elevation Advise patients that elevations in total cholesterol, LDL and triglycerides may occur and that measurement of serum lipids may be considered see Warnings and Precautions (6.3) . Advise patients not to stop taking Effexor XR without talking first with their healthcare professional. Patients should be aware that discontinuation effects may occur when stopping Effexor XR see Warnings and Precautions (5.7) and Adverse Reactions (6.1) . Interference with Cognitive and Motor Performance Caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain that Effexor XR therapy does not adversely affect their ability to engage in such activities. Advise patients to avoid alcohol while taking Effexor XR see Drug Interactions (7.6) . Advise patients to notify their physician if they develop allergic phenomena such as rash, hives, swelling, or difficulty breathing. Advise patients to notify their physician if they become pregnant or intend to become pregnant during therapy see Use in Specific Populations (8.1) . Advise patients to notify their physician if they are breast-feeding an infant see Use in Specific Populations (8.3) . Effexor XR contains spheroids, which release the drug slowly into the digestive tract. The insoluble portion of these spheroids is eliminated, and patients may notice spheroids passing in the stool or via colostomy. Patients should be informed that the active medication has already been absorbed by the time the patient sees the spheroids. Medication Guide Effexor XR (e-fex-or) (venlafaxine hydrochloride) (Extended-Release Capsules) Read the Medication Guide that comes with Effexor XR before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment. Talk with your healthcare provider if there is something you do not understand or want to learn more about. What is the most important information I should know about Effexor XR Effexor XR and other antidepressant medicines may cause serious side effects, including: 1. Suicidal thoughts or actions: Effexor XR and other antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, or young adults within the first few months of treatment or when the dose is changed. Depression or other serious mental illnesses are the most important causes of suicidal thoughts or actions. Watch for these changes and call your healthcare provider right away if you notice: New or sudden changes in mood, behavior, actions, thoughts, or feelings, especially if severe. Pay particular attention to such changes when Effexor XR is started or when the dose is changed. Keep all follow-up visits with your healthcare provider and call between visits if you are worried about symptoms. Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency, especially if they are new, worse, or worry you: attempts to commit suicide acting on dangerous impulses acting aggressive or violent thoughts about suicide or dying new or worse depression new or worse anxiety or panic attacks feeling agitated, restless, angry or irritable trouble sleeping an increase in activity or talking more than what is normal for you other unusual changes in behavior or mood Visual problems eye pain changes in vision swelling or redness in or around the eye Only some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are. Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency. Effexor XR may be associated with these serious side effects : 2. Serotonin Syndrome This condition can be life-threatening and may include : agitation, hallucinations, coma or other changes in mental status coordination problems or muscle twitching (overactive reflexes) racing heartbeat, high or low blood pressure sweating or fever nausea, vomiting, or diarrhea muscle rigidity 3. Changes in blood pressure. Effexor XR may: increase your blood pressure. Control high blood pressure before starting treatment and monitor blood pressure regularly 4. Enlarged pupils (mydriasis). 5. Anxiety and insomnia. 6. Changes in appetite or weight. 7. Manichypomanic episodes: greatly increased energy severe trouble sleeping racing thoughts reckless behavior unusually grand ideas excessive happiness or irritability talking more or faster than usual 8. Low salt (sodium) levels in the blood. Elderly people may be at greater risk for this. Symptoms may include: headache weakness or feeling unsteady confusion, problems concentrating or thinking or memory problems 9. Seizures or convulsions. 10. Abnormal bleeding. Effexor XR and other antidepressant medicines may increase your risk of bleeding or bruising, especially if you take the blood thinner warfarin (Coumadin reg. Jantoven reg ), a non-steroidal anti-inflammatory drug (NSAIDs, like ibuprofen or naproxen), or aspirin. 11. Elevated cholesterol. 12. Lung disease and pneumonia. Effexor XR may cause rare lung problems. Symptoms include: worsening shortness of breath cough chest discomfort 13. Severe allergic reactions: trouble breathing swelling of the face, tongue, eyes or mouth rash, itchy welts (hives) or blisters, alone or with fever or joint pain. Do not stop Effexor XR without first talking to your healthcare provider. Stopping Effexor XR too quickly or changing from another antidepressant too quickly may cause serious symptoms including: anxiety, irritability feeling tired, restless or problems sleeping headache, sweating, dizziness electric shock-like sensations, shaking, confusion, nightmares vomiting, nausea, diarrhea What is Effexor XR Effexor XR is a prescription medicine used to treat depression. It is important to talk with your healthcare provider about the risks of treating depression and also the risks of not treating it. You should discuss all treatment choices with your healthcare provider. Effexor XR is also used to treat: Generalized Anxiety Disorder (GAD) Social Anxiety Disorder (SAD) Panic Disorder (PD) Talk to your healthcare provider if you do not think that your condition is getting better with Effexor XR treatment. Who should not take Effexor XR Do not take Effexor XR if you: are allergic to Effexor XR or any of the ingredients in Effexor XR. See the end of this Medication Guide for a complete list of ingredients in Effexor XR . have uncontrolled angle-closure glaucoma take a Monoamine Oxidase Inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid. Do not take an MAOI within 7 days of stopping Effexor XR unless directed to do so by your physician. Do not start Effexor XR if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your physician. People who take Effexor XR close in time to an MAOI may have serious or even life-threatening side effects. Get medical help right away if you have any of these symptoms: high fever uncontrolled muscle spasms stiff muscles rapid changes in heart rate or blood pressure confusion loss of consciousness (pass out) What should I tell my healthcare provider before taking Effexor XR Ask if you are not sure. Before starting Effexor XR. tell your healthcare provider if you: Are taking certain drugs such as: Amphetamines Medicines used to treat migraine headaches such as: triptans Medicines used to treat mood, anxiety, psychotic or thought disorders, such as: tricyclic antidepressants lithium SSRIs SNRIs antipsychotic drugs Medicines used to treat pain such as: tramadol Medicines used to thin your blood such as: warfarin Medicines used to treat heartburn such as: Cimetidine Over-the-counter medicines or supplements such as: Aspirin or other NSAIDs Tryptophan St. Johns Wort have heart problems have diabetes have liver problems have kidney problems have thyroid problems have or had seizures or convulsions have bipolar disorder or mania have low sodium levels in your blood have high blood pressure have high cholesterol have or had bleeding problems are pregnant or plan to become pregnant. It is not known if Effexor XR will harm your unborn baby. Talk to your healthcare provider about the benefits and risks of treating depression during pregnancy are breast-feeding or plan to breast-feed. Some Effexor XR may pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby while taking Effexor XR . Tell your healthcare provider about all the medicines that you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Effexor XR and some medicines may interact with each other, may not work as well, or may cause serious side effects. Your healthcare provider or pharmacist can tell you if it is safe to take Effexor XR with your other medicines. Do not start or stop any medicine while taking Effexor XR without talking to your healthcare provider first. If you take Effexor XR. you should not take any other medicines that contain (venlafaxine) including: venlafaxine HCl. How should I take Effexor XR Take Effexor XR exactly as prescribed. Your healthcare provider may need to change the dose of Effexor XR until it is the right dose for you. Effexor XR is to be taken with food. If you miss a dose of Effexor XR. take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of Effexor XR at the same time. If you take too much Effexor XR. call your healthcare provider or poison control center right away, or get emergency treatment. When switching from another antidepressant to Effexor XR your doctor may want to lower the dose of the initial antidepressant first to avoid side effects What should I avoid while taking Effexor XR Effexor XR can cause sleepiness or may affect your ability to make decisions, think clearly, or react quickly. You should not drive, operate heavy machinery, or do other dangerous activities until you know how Effexor XR affects you. Do not drink alcohol while using Effexor XR . What are the possible side effects of Effexor XR Effexor XR may cause serious side effects, including: See What is the most important information I should know about Effexor XR Increased cholesterol - have your cholesterol checked regularly Newborns whose mothers take Effexor XR in the third trimester may have problems right after birth including: problems feeding and breathing seizures shaking, jitteriness or constant crying Angle-closure glaucoma Common possible side effects in people who take Effexor XR include. unusual dreams sexual problems loss of appetite, constipation, diarrhea, nausea or vomiting, or dry mouth feeling tired, fatigued or overly sleepy change in sleep habits, problems sleeping yawning tremor or shaking dizziness, blurred vision sweating feeling anxious, nervous or jittery headache increase in heart rate Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of Effexor XR. For more information, ask your healthcare provider or pharmacist. CALL YOUR DOCTOR FOR MEDICAL ADVICE ABOUT SIDE EFFECTS. YOU MAY REPORT SIDE EFFECTS TO THE FDA AT 1-800-FDA-1088. How should I store Effexor XR Store Effexor XR at room temperature between 68degF and 77degF (20degC to 25degC). Keep Effexor XR in a dry place. Keep Effexor XR and all medicines out of the reach of children. General information about EFFEXOR Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Effexor XR for a condition for which it was not prescribed. Do not give Effexor XR to other people, even if they have the same condition. It may harm them. This Medication Guide summarizes the most important information about Effexor XR. If you would like more information, talk with your healthcare provider. You may ask your healthcare provider or pharmacist for information about Effexor XR that is written for healthcare professionals. For more information about Effexor XR call 1-800-438-1985 or go to Effexor XR . What are the ingredients in Effexor XR Active ingredient: (venlafaxine) Extended-Release Capsules. cellulose, ethylcellulose, gelatin, hypromellose, iron oxides, and titanium dioxide. This Medication Guide has been approved by the U. S. Food and Drug Administration for all antidepressants. This products label may have been updated. For current full prescribing information, please visit pfizer PRINCIPAL DISPLAY PANEL - 37.5 mg Capsule Bottle Label ALWAYS DISPENSE WITH MEDICATION GUIDE Pfizer NDC 0008-0837-20 Effexor XR reg (venlafaxine HCl) Extended-Release Capsules 15 Capsules Rx only PRINCIPAL DISPLAY PANEL - 37.5 mg Capsule Blister Pack Effexor XR reg (venlafaxine HCl) Extended-Release Capsules 37.5 mg Wyeth reg Phila. PA 19101 PRINCIPAL DISPLAY PANEL - 37.5 mg Capsule Blister Pack Carton ALWAYS DISPENSE WITH MEDICATION GUIDE NDC 0008-0837-03 Effexor XR reg (venlafaxine HCl) Extended-Release Capsules 10 Redipak reg Blister Strips of 10 Capsules 100 Capsules PRINCIPAL DISPLAY PANEL - 75 mg Capsule Bottle Label ALWAYS DISPENSE WITH MEDICATION GUIDE Effexor XR reg (venlafaxine HCl) Extended-Release Capsules PRINCIPAL DISPLAY PANEL - 75 mg Capsule Blister Pack Effexor XR reg (venlafaxine HCl) Extended-Release Capsules 75 mg Wyeth reg Phila. PA 19101 PRINCIPAL DISPLAY PANEL - 75 mg Capsule Blister Pack Carton ALWAYS DISPENSE WITH MEDICATION GUIDE NDC 0008-0833-03 Effexor XR reg (venlafaxine HCl) Extended-Release Capsules 10 Redipak reg Blister Strips of 10 Capsules 100 Capsules PRINCIPAL DISPLAY PANEL - 150 mg Capsule Bottle Label ALWAYS DISPENSE WITH MEDICATION GUIDE Effexor XR reg (venlafaxine HCl) Extended-Release Capsules PRINCIPAL DISPLAY PANEL - 150 mg Capsule Blister Pack Effexor XR reg (venlafaxine HCl) Extended-Release Capsules 150 mg Wyeth reg Phila. PA 19101 PRINCIPAL DISPLAY PANEL - 150 mg Capsule Blister Pack Carton ALWAYS DISPENSE WITH MEDICATION GUIDE NDC 0008-0836-03 Effexor XR reg (venlafaxine HCl) Extended-Release Capsules 10 Redipak reg Blister Strips of 10 Capsules 100 Capsules
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