Eforex sistólica e diastólica

Effexor XR ADVERTÊNCIA: PENSAMENTOS E COMPORTAMENTOS SUICIDAS 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 um aumento no risco de pensamentos suicidas e comportamento com o uso de antidepressivos em pacientes com mais de 24 anos. Houve uma redução no risco com o uso de antidepressivos em pacientes com 65 anos ou mais ver Advertências e Precauções (5.1). Em pacientes de todas as idades que iniciaram a terapia antidepressiva, monitore atentamente o agravamento clínico e o surgimento de pensamentos e comportamentos suicidas. Aconselhe as famílias e os cuidadores sobre a necessidade de observação e comunicação com o prescritor (ver Advertências e Precauções) e informações sobre aconselhamento ao paciente (17). Indicações e uso para Effexor XR Transtorno Depressivo Maior Effexor XR (cloridrato de venlafaxina) cápsulas de liberação prolongada são indicados para o tratamento do transtorno depressivo maior (MDD). A eficácia foi estabelecida em três ensaios de manutenção de curto prazo (4, 8 e 12 semanas) e dois de longo prazo. Transtorno de Ansiedade Generalizada Effexor XR é indicado para o tratamento do Transtorno de Ansiedade Generalizada (TAG). A eficácia foi estabelecida em dois ensaios de 8 semanas e dois de 26 semanas controlados por placebo. 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 estudos de 12 semanas e um de 26 semanas, controlados por placebo. Transtorno de Pânico Effexor XR é indicado para o tratamento do Transtorno de Pânico (TP), com ou sem agorafobia. A eficácia foi estabelecida em dois ensaios de 12 semanas controlados por placebo. Dosagem e administração de Effexor XR Effexor XR deve ser administrado numa dose única com alimentos, de manhã ou à noite, aproximadamente à mesma hora, todos os dias, em Farmacologia Clínica (12.3). Cada cápsula deve ser engolida inteira com líquido 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 molho de maçã. Esta mistura de drogas / alimentos deve ser engolida imediatamente sem mastigar e seguida com um copo de água para garantir a deglutição completa dos pellets (esferóides). Transtorno Depressivo Maior Para a maioria dos pacientes, a dose inicial recomendada para Effexor XR é de 75 mg por dia, administrada em dose única. Para alguns pacientes, pode ser desejável começar com 37,5 mg por dia por 4 a 7 dias para permitir que novos pacientes se ajustem ao medicamento antes de aumentar para 75 mg por dia. Os doentes que não respondem à dose inicial de 75 mg por dia podem beneficiar do aumento da dose até um máximo de 225 mg por dia. O aumento da dose deve ser em incrementos de até 75 mg por dia, conforme necessário, e deve ser feito em intervalos não inferiores a 4 dias, uma vez que os níveis plasmáticos de venlafaxina no estado estacionário e seus principais metabólitos são alcançados na maioria dos pacientes no dia 4 veja Farmacologia Clínica (12.3). Nos estudos clínicos que estabelecem a eficácia, a titulação ascendente foi permitida em intervalos de 2 semanas ou mais. Deve-se notar que, enquanto a dose máxima recomendada para pacientes ambulatoriais moderadamente deprimidos também é de 225 mg por dia para Effexor (liberação imediata), pacientes deprimidos mais severamente internados 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). Não se sabe se doses mais altas de Effexor XR são necessárias para pacientes mais gravemente deprimidos, no entanto, 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 dose única. Para alguns pacientes, pode ser desejável começar com 37,5 mg por dia por 4 a 7 dias para permitir que novos pacientes se ajustem ao medicamento antes de aumentar para 75 mg por dia. Os doentes que não respondem à dose inicial de 75 mg por dia podem beneficiar do aumento da dose até um máximo de 225 mg por dia. O aumento da dose deve ser em incrementos de até 75 mg por dia, conforme necessário, e deve ser feito em intervalos não inferiores a 4 dias, uma vez que os níveis plasmáticos de venlafaxina no estado estacionário e seus principais metabólitos são alcançados na maioria dos pacientes no dia 4 veja Farmacologia Clínica (12.3). Transtorno de Ansiedade Social (Fobia Social) A dose recomendada é de 75 mg por dia, administrada em dose única. Não houve evidência de que doses mais altas conferem qualquer benefício adicional. Perturbação de Pânico A dose inicial recomendada é de 37,5 mg por dia de Effexor XR durante 7 dias. Os doentes que não respondem a 75 mg por dia podem beneficiar do aumento da dose até um máximo de aproximadamente 225 mg por dia. O aumento da dose deve ser em incrementos de até 75 mg por dia, conforme necessário, e deve ser feito em intervalos não inferiores a 7 dias. Troca de Pacientes de Comprimidos Effexor Pacientes deprimidos que estão sendo tratados atualmente com uma dose terapêutica com Effexor (liberação imediata) podem ser transferidos para Effexor XR na dose equivalente mais próxima (mg por dia), por ex. 37,5 mg de venlafaxina duas vezes por dia para 75 mg de Effexor XR uma vez por dia. Entretanto, ajustes individuais de dosagem podem ser necessários. Populações Específicas Doentes com Insuficiência Hepática A dose diária total deve ser reduzida em 50 doentes com compromisso hepático ligeiro (Child-Pugh5ndash6) a moderado (Child-Pugh7ndash9). Em doentes com compromisso hepático grave (Child-Pugh10ndash15) ou cirrose hepática, pode ser necessário reduzir a dose em 50 ou mais Ver Uso em Populações Específicas (8.7). Doentes com Insuficiência Renal A dose diária total deve ser reduzida em 25 a 50 em doentes com compromisso renal ligeiro (CLcr 60 a 85 mL / min) ou moderado (CLcr 30 e 59 mL / min). Em pacientes submetidos a hemodiálise ou com insuficiência renal grave (CLcr 30 mL / min), a dose diária total deve ser reduzida em 50 ou mais. Como havia muita variabilidade individual na depuração entre pacientes com comprometimento renal, a individualização da dose pode ser desejável em alguns pacientes, ver Uso em populações específicas (8.7). Tratamento de manutenção Não há nenhum corpo de evidência disponível a partir de estudos controlados para indicar por quanto tempo os pacientes com TDM, TAG, TAG ou DP devem ser tratados com Effexor XR. É geralmente aceito que os episódios agudos de TDM requerem vários meses ou mais de terapia farmacológica sustentada além da resposta ao episódio agudo. Effexor XR / Effexor demonstrou continuação da resposta em estudos clínicos até 52 semanas, na mesma dose em que os doentes 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 idêntica à dose necessária para obter uma resposta inicial. Os pacientes devem ser reavaliados periodicamente para determinar a necessidade de tratamento de manutenção e a dose apropriada para tal tratamento. Em doentes com GAD e SAD, o Effexor XR demonstrou ser eficaz em estudos clínicos de 6 meses. A necessidade de continuar a medicação em pacientes com GAD e SAD que melhoram com o tratamento com Effexor XR deve ser reavaliada periodicamente. Em um estudo clínico para DP, os pacientes que continuaram com Effexor XR na mesma dose em que responderam durante as 12 semanas iniciais de tratamento tiveram um tempo estatisticamente mais longo de recidiva do que os pacientes randomizados para placebo, ver Estudos Clínicos (14.4). A necessidade de continuar a medicação em pacientes com DP que melhoram com o tratamento com Effexor XR deve ser reavaliada periodicamente. Descontinuação do Effexor XR Recomenda-se uma redução gradual da dose, em vez de uma interrupção abrupta, sempre que possível. Em estudos clínicos com Effexor XR, a redução gradual foi alcançada reduzindo a dose diária em 75 mg em intervalos de uma semana. A individualização do afilamento pode ser necessária, veja Advertências e Precauções (5.7). Trocar os pacientes de ou para um inibidor da monoamina oxidase (IMAO) destinado a tratar distúrbios psiquiátricos Devem decorrer pelo menos 14 dias entre a interrupção de um IMAO (destinado a tratar perturbações do foro psiquiátrico) e o início da terapia com Effexor XR. Além disso, devem ser permitidos pelo menos 7 dias após a interrupção do Effexor XR antes de iniciar um IMAO destinado ao tratamento de transtornos psiquiátricos. Ver Contra-indicações (4.2). Advertências e Precauções (5.2). e Interações Medicamentosas (7.2). Utilização de Effexor XR com outros inibidores da MAO, tais como Linezolide ou Intravenous Methylene Blue Não inicie Effexor XR num doente que esteja a ser tratado com linezolide ou azul de metileno intravenoso, porque existe um risco aumentado de síndrome da serotonina. Em um paciente que requer tratamento mais urgente de uma condição psiquiátrica, outras intervenções, incluindo hospitalização, devem ser consideradas (ver Contra-indicações 4.2). Em alguns casos, um paciente que já esteja recebendo a terapia com Effexor XR pode necessitar de tratamento urgente com linezolide ou azul de metileno intravenoso. Se alternativas aceitáveis ​​para linezolide ou azul de metileno intravenoso não estiverem disponíveis e se os benefícios potenciais do tratamento com linezolide ou azul de metileno intravenoso excederem os riscos da síndrome serotoninérgica em um paciente em particular, Effexor XR deve ser interrompido imediatamente e linezolida ou azul de metileno intravenoso pode ser administrado. Monitore o paciente em busca de sintomas da síndrome da serotonina por 7 dias ou até 24 horas após a última dose de linezolida ou azul de metileno intravenoso, o que ocorrer primeiro. A terapêutica com Effexor XR pode ser retomada 24 horas após a última dose de linezolide ou azul de metileno intravenoso, vide Advertências e Precauções (5.2). O risco de administrar azul de metileno por via não intravenosa (como comprimidos orais ou por injecção local) ou em doses intravenosas muito inferiores a 1 mg / kg concomitantemente com Effexor XR não é claro. O clínico deve, no entanto, estar ciente da possibilidade de sintomas emergentes da síndrome serotoninérgica com tal uso, ver Advertências e Precauções (5.2). Formas de Dosagem e Forças Effexor XR reg (cloridrato de venlafaxina) cápsulas de liberação prolongada estão disponíveis nas seguintes dosagens: cápsulas de 37,5 mg (tampa cinzenta / corpo de pêssego com W e Effexor XR na tampa e 37,5 no corpo) cápsulas de 75 mg tampa e corpo com W e Effexor XR na tampa e 75 no corpo) Cápsulas de 150 mg (tampa laranja escura 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 quaisquer excipientes na formulação Uso concomitante com inibidores da monoamina oxidase (IMAOs) O uso de inibidores da MAO (destinados a tratar perturbações do foro psiquiátrico) concomitantemente com Effexor XR ou nos 7 dias seguintes à descontinuação do tratamento com Effexor XR é contra-indicado devido ao aumento do risco de síndrome serotoninérgica . A utilização de Effexor XR no prazo de 14 dias após a interrupção do tratamento com um IMAO (destinado a tratar perturbações do foro psiquiátrico) também é contraindicada, ver Dosagem e Administração (2.9). Advertências e Precauções (5.2). e Interações Medicamentosas (7.2). Iniciar Effexor XR em um paciente que está sendo tratado com um IMAO, como linezolida ou azul de metileno intravenoso, também é contraindicado, devido ao aumento do risco de síndrome serotoninérgica, ver Dosagem e administração (2,9). Advertências e Precauções (5.2). e Interações Medicamentosas (7.3). Advertências e precauções Pensamentos e comportamentos suicidas em crianças, adolescentes e adultos jovens Os pacientes com transtorno depressivo maior (MDD), adulto e pediátrico, podem apresentar piora da depressão e / ou o surgimento de ideação e comportamento suicida (tendência suicida) ou incomuns mudanças no comportamento, se eles estão ou não tomando medicamentos antidepressivos, e esse risco pode persistir até que ocorra remissão significativa. O suicídio é um risco conhecido de depressão e certos outros distúrbios psiquiátricos, e esses distúrbios em si são os mais fortes indicadores de suicídio. Há uma preocupação de longa data, no entanto, que os antidepressivos podem ter um papel na indução de agravamento da depressão e o surgimento de tendências suicidas em certos pacientes durante as fases iniciais do tratamento. Análises agrupadas de estudos de curto prazo controlados por placebo sobre drogas antidepressivas (ISRSs e outros) mostraram que essas drogas aumentam o risco de pensamentos e comportamentos suicidas (suicidalidade) em crianças, adolescentes e adultos jovens (18 e 24 anos) com TDM e outras doenças psiquiátricas. distúrbios Estudos de curto prazo não mostraram um aumento no risco de suicidalidade com antidepressivos em comparação com placebo em adultos além dos 24 anos, houve uma 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 TDM, Transtorno Obsessivo-Compulsivo (TOC) ou outros transtornos psiquiátricos incluíram um total de 24 estudos de curto prazo de 9 antidepressivos em mais de 4.400 pacientes. As análises agrupadas de estudos controlados por placebo em adultos com TDM ou outros transtornos psiquiátricos incluíram um total de 295 estudos de curto prazo (duração mediana de 2 meses) de 11 antidepressivos em mais de 77.000 pacientes. Houve considerável variação no risco de suicidalidade entre as drogas, mas uma tendência a um aumento nos pacientes mais jovens para quase todas as drogas estudadas. Houve diferenças no risco absoluto de suicidalidade entre as diferentes indicações, com a maior incidência em TDM. As diferenças de risco (droga versus placebo), no entanto, foram relativamente estáveis ​​dentro dos estratos etários e entre as indicações. Estas diferenças de risco (diferença placebo-droga no número de casos de suicídio por 1.000 pacientes tratados) são apresentadas na Tabela 1. Tabela 1: Diferença no Número de Casos de Suicidalidade por 1.000 Pacientes Tratados versus aumentos de Placebo Comparados ao Placebo Não ocorreram suicídios em qualquer um dos estudos pediátricos. Houve suicídios nos estudos com adultos, mas o número não foi suficiente para se chegar a uma conclusão sobre o efeito do medicamento no suicídio. Não se sabe se o risco de suicídio se estende a um 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 de que o uso de antidepressivos pode retardar a recorrência da depressão. Todos os pacientes em tratamento com antidepressivos para qualquer indicação devem ser adequadamente monitorados e observados de perto quanto a piora clínica, tendências suicidas e mudanças incomuns no comportamento, especialmente durante os poucos meses iniciais de um tratamento medicamentoso, ou em momentos de mudança de dose, ou diminui. Foram relatados os seguintes sintomas, ansiedade, agitação, ataques de pânico, insônia, irritabilidade, hostilidade, agressividade, impulsividade, acatisia (agitação psicomotora), hipomania e mania em pacientes adultos e pediátricos em tratamento com antidepressivos para MDD, bem como para outras indicações, tanto psiquiátricas como não psiquiátricas. Embora não tenha sido estabelecido um nexo causal entre o surgimento de tais sintomas e o agravamento da depressão e / ou o surgimento de impulsos suicidas, existe a preocupação de que tais sintomas possam representar precursores da tendência suicida emergente. Deve-se considerar a possibilidade de mudar o regime terapêutico, incluindo possivelmente interromper a medicação, em pacientes cuja depressão seja persistentemente pior ou que estejam experimentando uma tendência suicida emergente ou sintomas que possam ser precursores do agravamento da depressão ou tendência suicida, especialmente se esses sintomas forem graves, abruptos. no início, ou não faziam parte dos pacientes que apresentavam sintomas. Se a decisão tiver sido tomada para descontinuar o tratamento, a medicação deve ser reduzida o mais rapidamente possível, mas com o reconhecimento de que a interrupção abrupta pode estar associada a certos sintomas, consulte Advertências e precauções (5.7) e Posologia e administração (2.8). Famílias e cuidadores de pacientes em tratamento com antidepressivos para MDD ou outras indicações, tanto psiquiátricas quanto não psiquiátricas, devem ser alertados sobre a necessidade de monitorar pacientes para o surgimento de agitação, irritabilidade, mudanças incomuns no comportamento e os outros sintomas descritos acima, como bem como o surgimento de tendências suicidas e relatar tais sintomas imediatamente aos profissionais de saúde. Esse monitoramento deve incluir a observação diária de familiares e cuidadores. As prescrições do Effexor XR devem ser escritas para a menor quantidade de cápsulas consistente com o bom manejo do paciente, a fim de reduzir o risco de overdose. Triagem de pacientes para transtorno bipolar Um episódio depressivo maior pode ser a apresentação inicial do transtorno bipolar. Acredita-se geralmente (embora não estabelecido em estudos controlados) que tratar tal episódio com um antidepressivo sozinho pode aumentar a probabilidade de precipitação de um episódio misto / maníaco em pacientes com risco de transtorno bipolar. Se algum dos sintomas descritos acima representa tal conversão é desconhecido. No entanto, antes de iniciar o tratamento com um antidepressivo, os pacientes com sintomas depressivos devem ser adequadamente selecionados para determinar se estão em risco para transtorno bipolar. Esse rastreamento deve incluir uma história psiquiátrica detalhada, incluindo história familiar de suicídio, transtorno bipolar e depressão. Deve notar-se que Effexor XR não está aprovado para uso no tratamento da depressão bipolar. Síndrome Serotoninérgica 8203 O desenvolvimento de uma síndrome serotoninérgica potencialmente fatal foi relatado com ISRNs e ISRSs, incluindo Effexor XR isolado, mas particularmente com o uso concomitante de outros medicamentos serotoninérgicos (incluindo triptanos, antidepressivos tricíclicos, fentanil, lítio, tramadol, triptofano, buspirona, anfetaminas e erva de São João) e com drogas que prejudicam particularmente o metabolismo da serotonina, os inibidores da MAO, tanto aqueles destinados ao tratamento de distúrbios psiquiátricos como outros, como a linezolida ou o azul de metileno intravenoso). Os sintomas da síndrome da serotonina podem incluir alterações do estado mental (por exemplo, agitação, alucinações, delírio, coma), instabilidade autonômica (por exemplo, taquicardia, pressão arterial lábil, hipertermia, diaforese, rubor e tontura), sintomas neuromusculares (tremor, rigidez, mioclonia, hiperreflexia, incoordenação) convulsões e sintomas gastrointestinais (por exemplo, náuseas, vômitos, diarréia). Os pacientes devem ser monitorados para o surgimento da síndrome serotoninérgica. A utilização concomitante de Effexor XR com inibidores da MAO (destinados a tratar perturbações do foro psiquiátrico) é contraindicada. Effexor XR também não deve ser iniciado em um paciente que está sendo tratado com inibidores da MAO, como linezolide ou azul de metileno intravenoso. Todos os relatos com azul de metileno que forneceram informações sobre a via de administração envolveram administração intravenosa na faixa de dose de 1 mg / kg a 8 mg / kg. Nenhum relato envolveu a administração de azul de metileno por outras vias (como comprimidos orais ou injeção de tecido local) ou em doses menores. Pode haver circunstâncias em que é necessário iniciar o tratamento com um IMAO, como linezolide ou azul de metileno intravenoso, em um paciente que esteja tomando Effexor XR. Effexor XR deve ser descontinuado antes de iniciar o tratamento com o IMAO ver Contra-indicações (4.2). Dosagem e Administração (2.6). e Interações Medicamentosas (7.3). Se o uso concomitante de Effexor XR com outros fármacos serotoninérgicos (por exemplo, triptanos, antidepressivos tricíclicos, mirtazapina, fentanil, lítio, tramadol, buspirona, anfetaminas, triptofano ou hipericão) é clinicamente necessário, recomenda-se uma observação cuidadosa do doente, particularmente Durante o início do tratamento e aumento da dose, ver Interacções Medicamentosas (7.3). Os pacientes devem estar cientes do risco potencial de síndrome serotoninérgica. O tratamento com Effexor XR e quaisquer agentes serotoninérgicos concomitantes deve ser descontinuado imediatamente caso ocorram os acontecimentos acima descritos, devendo ser iniciado tratamento sintomático de suporte. Elevações da pressão arterial Em ensaios controlados, houve aumentos relacionados com a dose na pressão arterial sistólica e diastólica, bem como nos casos de hipertensão sustentada, ver Reações Adversas (6.2). Monitorize a pressão arterial antes de iniciar o tratamento com Effexor XR e regularmente durante o tratamento. Controlar a hipertensão pré-existente antes de iniciar o tratamento com Effexor XR. Tenha cuidado no tratamento de pacientes com hipertensão pré-existente ou condições cardiovasculares ou cerebrovasculares que possam ser comprometidas pelo aumento da pressão arterial. A elevação sustentada da pressão arterial pode levar a resultados adversos. Casos de pressão arterial elevada que requerem tratamento imediato foram relatados com Effexor XR. Considere a redução da dose ou a descontinuação do tratamento para pacientes que experimentam um aumento sustentado da pressão arterial. Em todos os estudos clínicos com Effexor, 1,4 dos doentes tratados com Effexor XR experimentaram um aumento de 15 mmHg na pressão arterial diastólica em supino (SDBP) de 105 mmHg, comparativamente com 0,9 dos doentes nos grupos do placebo. Da mesma forma, 1 dos doentes tratados com Effexor XR apresentou um aumento de 20 mm Hg na pressão arterial sistólica em posição supina (SSBP) com pressão arterial de 180 mmHg, comparativamente com 0,3 dos doentes nos grupos de placebo, ver Quadro 10 das Reações Adversas ( 6.2). O tratamento com Effexor XR foi associado a hipertensão sustentada (definida como SDBP emergente do tratamento com 90 mm Hg e 10 mm Hg acima do valor basal durante três visitas consecutivas ao tratamento, ver Tabela 11 em Reações Adversas (6.2). doses de Effexor XR superiores a 300 mg por dia em estudos clínicos para avaliar completamente a incidência de aumentos sustentados da pressão arterial com estas doses mais elevadas. Os ISRSs com Sangramento Anormal e ISRNs, incluindo Effexor XR, podem aumentar o risco de eventos hemorrágicos, variando de equimoses, hematomas, epistaxe, petéquias e hemorragia gastrointestinal a hemorragia com risco de vida O uso concomitante de aspirina, medicamentos antiinflamatórios não-esteroidais (AINEs), varfarina e outros anticoagulantes ou outras drogas que afetam a função plaquetária podem aumentar esse risco. Relatos de casos e estudos epidemiológicos (caso-controle e coorte) demonstraram uma associação entre o uso de drogas que interferem na recaptação da serotonina e a ocorrência de sangramento gastrintestinal. Preste atenção aos pacientes sobre o risco de sangramento associado ao uso concomitante de Effexor XR e AINEs, aspirina ou outras drogas que afetam a coagulação. Glaucoma de Fechamento Angular A dilatação pupilar que ocorre após o uso de muitos antidepressivos, incluindo o Effexor XR, pode desencadear um ataque de fechamento de ângulo em um paciente com ângulos anatomicamente estreitos que não possuem uma iridectomia patente. A ativação de mania / hipomania mania ou hipomania foi relatada em pacientes tratados com Effexor XR nos estudos de pré-comercialização em TDM, TAS e DP (ver Tabela 2). Mania / hipomania 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 utilizado com precaução em doentes com história de mania ou hipomania. Tabela 2: Incidência () de Mania ou Hipomania Relatada em Pacientes Tratados com Effexor XR na Síndrome de Descontinuação de Estudos de Pré-comercialização Os sintomas de descontinuação foram sistematicamente avaliados em pacientes sob venlafaxina, incluindo análises prospectivas de estudos clínicos em TAG e levantamentos retrospectivos de estudos em MDD e SAD . Descontinuidade abrupta ou redução da dose de venlafaxina em várias doses tem sido associada ao aparecimento de novos sintomas, cuja frequência aumentou com o aumento do nível de dose e com maior duração do tratamento. Os sintomas relatados incluem agitação, anorexia, ansiedade, confusão, dificuldade de coordenação e equilíbrio, diarréia, tontura, boca seca, humor disfórico, fasciculação, fadiga, sintomas semelhantes aos da gripe, dores de cabeça, hipomania, insônia, náusea, nervosismo, pesadelos, distúrbios sensoriais ( incluindo sensações elétricas semelhantes a choque), sonolência, sudorese, tremor, vertigem e vômitos. Durante a comercialização de Effexor XR, outros SNRIs e SSRIs, houve relatos espontâneos de eventos adversos que ocorreram após a descontinuação desses medicamentos, particularmente quando abruptos, incluindo os seguintes: humor disfórico, irritabilidade, agitação, tontura, 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 autolimitados, houve relatos de sintomas graves de descontinuação. Os doentes devem ser monitorizados quanto a estes sintomas quando interromperem o tratamento com Effexor XR. Recomenda-se uma redução gradual da dose, em vez de cessação abrupta, sempre que possível. Se ocorrerem sintomas intoleráveis ​​após uma diminuição da dose ou após a descontinuação do tratamento, pode ser considerada a continuação da dose previamente prescrita. Posteriormente, o médico pode continuar diminuindo a dose, mas a uma taxa mais gradual, ver Dosagem e Administração (2.8). Convulsões ocorreram com a terapia venlafaxina. Effexor XR, como muitos antidepressivos, deve ser usado com cautela em pacientes com histórico de convulsões e deve ser descontinuado em qualquer paciente que desenvolva convulsões. Deve mitigar o risco: Fatores de risco, medicamentos concomitantes que reduzem o limiar convulsivo. Hiponatremia A hiponatremia pode ocorrer como resultado do tratamento com ISRSs e IRSNs, incluindo Effexor XR. Em muitos casos, a hiponatremia parece ser o resultado da secreção da Síndrome da Hormônio Antidiurético Inapropriado (SIADH). Casos com sódio sérico menor que 110 mmol / L foram relatados. Pacientes idosos podem estar em maior risco de desenvolver hiponatremia com ISRSs e SNRIs ver Uso em Populações Específicas (8.5). Além disso, os pacientes que tomam diuréticos, ou aqueles que são depletados de volume, podem estar em maior risco. Considerar a descontinuação de Effexor XR em pacientes com hiponatremia sintomática e instituir uma intervenção médica apropriada. Sinais e sintomas de hiponatremia incluem cefaleia, dificuldade de concentração, comprometimento da memória, confusão, fraqueza e instabilidade, o que pode levar a quedas. Sinais e sintomas associados a casos mais graves e / ou agudos incluem alucinações, síncope, convulsões, coma, parada respiratória e morte. Alterações de peso e altura em pacientes pediátricos A variação média no peso corporal e a incidência de perda de peso (porcentagem de pacientes que perderam 3,5 ou mais) nos estudos pediátricos controlados por placebo em MDD, GAD e SAD são mostradas nas Tabelas 3 e 4. Tabela 3: Variação média no peso corporal (kg) desde o início do tratamento em doentes pediátricos em estudos controlados por placebo com Effecor XR A perda de peso não se limitou a doentes com anorexia emergente no tratamento (Advertências e precauções) (5.11). Os riscos associados ao uso prolongado 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 adolescentes do estudo tiveram aumentos de peso abaixo do esperado, com base em dados de pares pareados por idade e sexo. A diferença entre o ganho de peso observado e o ganho de peso esperado foi maior para crianças (lt 12 anos) do que para adolescentes (ge 12 anos). A Tabela 5 mostra o aumento médio da altura em pacientes pediátricos nos estudos de curto prazo, controlados por placebo, MDD, GAD e SAD. As diferenças nos aumentos de altura nos estudos GAD e MDD foram mais notáveis ​​em pacientes com menos de doze anos. Tabela 5: Aumentos médios de altura (cm) em doentes pediátricos em estudos controlados com placebo de Effexor XR No estudo MDD aberto de seis meses, as crianças e adolescentes tiveram aumentos de altura inferiores aos esperados, com base em dados de e pares de sexo. A diferença entre as taxas de crescimento observadas e esperadas foi maior para crianças (lt 12 anos) do que para adolescentes (com 12 anos). Alterações no apetite em pacientes pediátricos O apetite diminuído (relatado como anorexia emergente do tratamento) foi mais comumente observado 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 interrupção para perda de peso foram de 0,7 para pacientes que receberam Effexor XR ou placebo. TDM e TAG (pool, 8 semanas) Doença Pulmonar Intersticial e Pneumonia Eosinofílica A doença intersticial pulmonar e a pneumonia eosinofílica associadas à terapia com venlafaxina foram raramente relatadas. A possibilidade desses eventos adversos deve ser considerada em pacientes tratados com venlafaxina que apresentam dispneia progressiva, tosse ou desconforto torácico. Esses pacientes devem ser submetidos a uma avaliação médica imediata, e a descontinuação da terapia com venlafaxina deve ser considerada. Reações Adversas As seguintes reações adversas são discutidas em maiores detalhes em outras seções do rótulo: Experiência em Estudos Clínicos Como os estudos clínicos são conduzidos em condições muito variadas, as taxas de reações adversas observadas nos estudos clínicos de um medicamento não podem ser comparadas diretamente às taxas. estudos clínicos de outra droga e podem não refletir as taxas observadas na prática. Reações adversas mais comuns As reações adversas mais comumente observadas na base de dados de estudos clínicos em pacientes tratados com Effexor XR em TDM, TAG, TAG e DP (incidência 5 e pelo menos o dobro da taxa de placebo) foram: náusea (30,0), sonolência (15,3), boca seca (14,8), sudorese (11,4), ejaculação anormal (9,9), anorexia (9,8), obstipação (9,3), impotência (5,3) e diminuição da libido (5,1). Reações Adversas Relatadas como Razões para a Descontinuação do Tratamento Combinados em todos os estudos de pré-comercialização controlados por placebo de curto prazo para todas as indicações, 12 dos 3.558 pacientes que receberam Effexor XR (37.5ndash225 mg) interromperam o tratamento devido a uma experiência adversa, comparados com 4 os 2.197 pacientes tratados com placebo nesses estudos. As reacções adversas mais frequentes que conduziram à descontinuação da dose em 1 dos doentes tratados com Effexor XR nos estudos de curta duração (até 12 semanas) entre as indicações estão apresentadas na Tabela 7. Tabela 7: Incidência () dos doentes que relataram reacções adversas que conduziram a Descontinuação em estudos clínicos controlados com placebo (duração até 12 semanas) Reação adversa do sistema corporal Effexor XR n3.558 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 pré-comercialização de cada 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 (beats/min) in Effexor XR Premarketing Placebo-controlled St udies (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 (mg/dL) 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 mg/dL compared with a mean final decrease of 7.4 mg/dL 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 mg/dL and 2.3 mg/dL, respectively while placebo subjects experienced mean final decreases of 4.9 mg/dL and 7.7 mg/dL, 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 mg/dL and 5.6 mg/dL, respectively, compared with mean final decreases of 2.9 and 4.2 mg/dL, 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 mg/dL compared with a mean final decrease of 3.7 mg/dL 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 mg/dL compared with a decrease of 7.1 mg/dL 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 mg/dL from baseline and to a value ge261 mg/dL, or 2) an average on-therapy increase in serum cholesterol ge50 mg/dL from baseline and to a value ge261 mg/dL, 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 (mg/dL) 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 Hemic/Lymphatic system ndash Mucous membrane bleeding see Warnings and Precautions (5.4 ) , blood dyscrasias (including agranulocytosis, aplastic anemia, neutropenia and pancytopenia), prolonged bleeding time, thrombocytopenia Metabolic/Nutritional 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 Preca utions (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 chromatography/mass 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 mg/m 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 (mg/m 2 ) the maximum human daily dose. The no effect dose for rat pup mortality was 0.25 times the human dose on a mg/m 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, and/or 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 and/or 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 and/or 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 (R/S)-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 mg/mL 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 L/h/kg, 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 L/kg, 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 (ng/mL) 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 mg/kg per day, which was 1.7 times the maximum recommended human dose on a mg/m 2 basis. Venlafaxine was also given to rats by oral gavage for 24 months at doses up to 120 mg/kg per day. In rats receiving the 120 mg/kg 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 500/300 mg/kg/day (dosage lowered after 45 weeks of dosing). The exposure at the 300 mg/kg/day dose is 9 times that of a human dose of 225 mg/day. Rats received ODV at dosages up to 300 mg/kg/day (males) or 500 mg/kg/day (females). The exposure at the highest dose is approximately 8 (males) or 11 (females) times that of a human dose of 225 mg/day. Venlafaxine and the major human metabolite, ODV, were not mutagenic in the Ames reverse mutation assay in Salmonella bacteria or the Chinese hamster ovary/HGPRT mammalian cell forward gene mutation assay. Venlafaxine was also not mutagenic or clastogenic in the in vitro BALB/c-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 mg/day on a mg/m 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 mg/day. 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, fixed/flexible-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 Supplied/Storage and Handling Effexor XR reg (venlafaxine hydrochloride) extended-release capsules are available as follows: 37.5 mg, grey cap/peach 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 Mania/Hypomania Advise patients, their families and caregivers to observe for signs of activation of mania/hypomania 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. Manic/hypomanic 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