Sonaflam

Os comprimidos NAPROSYN, EC-NAPROSYN e ANAPROX DS são indicados para:

o alívio dos sinais e sintomas de :

• artrite reumatóide
• osteoartrite
• espondilite anquilosante
• Artrite idiopática juvenil poliarticular

Os comprimidos NAPROSYN e ANAPROX DS também são indicados para :

o alívio dos sinais e sintomas de :

• tendinite
• bursite
• gota aguda

a gestão de:

• dor
• dismenorreia primária

Adultos:

Tratamento da artrite reumatóide, osteoartrite (artrite degenerativa), espondilite anquilosante, gota aguda, distúrbios músculo-esqueléticos agudos e dismenorreia.

Crianças:

Artrite reumatóide juvenil

Os comprimidos de Sonaflam são indicados para o tratamento de :

• artrite reumatóide (AR)
• osteoartrite (OA)
• espondilite anquilosante (EA)
• tendinite, bursite
• gota aguda
• dismenorreia primária (DP)
• o alívio da dor leve a moderada

.

Os comprimidos de Sonaflam, EC-Sonaflam e ANAPROX DS são indicados para :

o alívio dos sinais e sintomas de :

• artrite reumatóide
• osteoartrite
• espondilite anquilosante
• Artrite idiopática juvenil poliarticular

Sonaflam Tablets e ANAPROX DS também são indicados para :

o alívio dos sinais e sintomas de :

• tendinite
• bursite
• gota aguda

a gestão de:

• dor
• dismenorreia primária

General Dosing Instructions

Carefully consider the potential benefits and risks of NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS and other treatment options before deciding to use NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals.

After observing the response to initial therapy with NAPROSYN Tablets, EC-NAPROSYN or ANAPROX DS, the dose and frequency should be adjusted to suit an individual patient's needs.

To maintain the integrity of the enteric coating, the EC-NAPROSYN tablet should not be broken, crushed or chewed during ingestion.

Naproxen-containing products such as NAPROSYN, EC-NAPROSYN and ANAPROX DS, and other naproxen products should not be used concomitantly since they all circulate in the plasma as the naproxen anion.

Rheumatoid Arthritis, Osteoarthritis And Ankylosing Spondylitis

The recommended dosages of NAPROSYN Tablets, ANAPROX DS, and EC-NAPROSYN are shown in Table 1.

Table 1: Recommended dosages for NAPROSYN Tablets, ANAPROX DS, and EC-NAPROSYN

During long-term administration, the dose of naproxen may be adjusted up or down depending on the clinical response of the patient. A lower daily dose may suffice for long-term administration. The morning and evening doses do not have to be equal in size and the administration of the drug more frequently than twice daily is not necessary.

The morning and evening doses do not have to be equal in size and administration of the drug more frequently than twice daily does not generally make a difference in response.

In patients who tolerate lower doses well, the dose may be increased to naproxen 1500 mg/day for limited periods of up to 6 months when a higher level of anti-inflammatory/analgesic activity is required. When treating such patients with naproxen 1500 mg/day, the physician should observe sufficient increased clinical benefits to offset the potential increased risk.

Polyarticular Juvenile Idiopathic Arthritis

Naproxen solid-oral dosage forms may not allow for the flexible dose titration needed in pediatric patients with polyarticular juvenile idiopathic arthritis. A liquid formulation may be more appropriate for weight-based dosing and due to the need for dose flexibility in children.

In pediatric patients, doses of 5 mg/kg/day produced plasma levels of naproxen similar to those seen in adults taking 500 mg of naproxen. The recommended total daily dose of naproxen is approximately 10 mg/kg given in 2 divided doses. Dosing with NAPROSYN Tablets is not appropriate for children weighing less than 50 kilograms.

Management Of Pain, Primary Dysmenorrhea, And Acute Tendonitis And Bursitis

The recommended starting dose of ANAPROX DS (naproxen sodium) tablets is 550 mg followed by 550 mg every 12 hours or 275 mg (one half of a 550 mg tablet) every 6 to 8 hours as required. The initial total daily dose should not exceed 1375 mg (two and one-half tablets) of naproxen sodium. Thereafter, the total daily dose should not exceed 1100 mg of naproxen sodium. Because the sodium salt of naproxen is more rapidly absorbed, ANAPROX DS is recommended for the management of acute painful conditions when prompt onset of pain relief is desired. NAPROSYN Tablets may also be used. The recommended starting dose of NAPROSYN Tablets is 500 mg followed by 250 mg (one half of a 500 mg NAPROSYN tablet) every 6-8 hours as required.. The total daily dose should not exceed 1250 mg of naproxen.

EC-NAPROSYN is not recommended for initial treatment of acute pain because absorption of naproxen is delayed compared to other naproxen-containing products.

Acute Gout

The recommended starting dose is 750 mg (one and one-half tablets) of NAPROSYN Tablets followed by 250 mg (one-half tablet) every 8 hours until the attack has subsided. ANAPROX DS may also be used at a starting dose of 825 mg (one and one-half tablets) followed by 275 mg (one-half tablet) every 8 hours. EC-NAPROSYN is not recommended because of the delay in absorption.

Non-Interchangeability With Other Formulations Of Naproxen

Different dose strengths and formulations (e.g., tablets, suspension) of naproxen are not interchangeable. This difference should be taken into consideration when changing strengths or formulations.

For oral administration

Elderly: The elderly are at increased risk of the serious consequences of adverse reactions. If an NSAID is considered necessary, the lowest dose should be used and for the shortest possible duration. The patient should be monitored regularly for GI bleeding during NSAID therapy.

To be taken preferably with or after food

Rheumatic Disorders (Adults):

500mg to 1g taken in 2 doses at 12-hour intervals or alternatively, as a single administration. In the following cases a loading dose of 750mg or 1g per day for the acute phase is recommended:

a) In patients reporting severe night-time pain/or morning stiffness.

b) In patients being switched to Naprosyn from a high dose of another anti-rheumatic compound.

c) In osteoarthrosis where pain is the predominant symptom.

Children (over 5 years) : A dose of 10mg per kg body weight daily in two divided doses has been used in children over 5 years of age with juvenile rheumatoid arthritis.

Acute Gout (Adults): In acute gout an initial dose of 750 mg followed by 250mg every 8 hours until attack has passed; has been suggested.

Child: Not recommended in children under 16 years.

Musculoskeletal Disorders and Dysmenorrhoea (Adults); 500mg may be given initially followed by 250mg every 6 to 8 hours as required. Maximum daily dose after first day is 1250mg daily.

Child: Not recommended in children under 16 years.

The lowest recommended dose should be used especially in the elderly to reduce the risk of adverse reactions.

Elderly: Studies indicate that although total plasma concentration of Sonaflam is unchanged, the unbound plasma fraction of Sonaflam is increased in the elderly.

Renal/hepatic impairment: A lower dose should be considered in patients with renal or hepatic impairment. Naprosyn is contraindicated in patients with baseline creatinine clearance less than 30 ml/minute because accumulation of Sonaflam metabolites has been seen in patients with severe renal failure or those on dialysis.

Treatment should be reviewed at regular intervals and discontinued if no benefit is seen or intolerance occurs.

General Dosing Instructions

Carefully consider the potential benefits and risks of Sonaflam and other treatment options before deciding to use Sonaflam. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals.

After observing the response to initial therapy with Sonaflam, the dose and frequency should be adjusted to suit an individual patient's needs.

Rheumatoid Arthritis, Osteoarthritis, And Ankylosing Spondylitis

The recommended starting dose of Sonaflam Tablets in adults is two Sonaflam 375 mg tablets (750 mg) once daily, one Sonaflam 750 mg (750 mg) once daily, or two Sonaflam 500 mg tablets (1,000 mg) once daily. Patients already taking naproxen 250 mg, 375 mg, or 500 mg twice daily (morning and evening) may have their total daily dose replaced with Sonaflam Tablets as a single daily dose.

During long-term administration, the dose of Sonaflam Tablets may be adjusted up or down depending on the clinical response of the patient. In patients who tolerate lower doses of Sonaflam Tablets well, the dose may be increased to two Sonaflam 750 mg tablets (1,500 mg), or three Sonaflam 500 mg tablets (1,500 mg) once daily for limited periods when a higher level of anti-inflammatory/analgesic activity is required. When treating patients, especially at the higher dose levels, the physician should observe sufficient increased clinical benefit to offset the potential increased risk. The lowest effective dose should be sought and used in every patient. Symptomatic improvement in arthritis usually begins within one week; however, treatment for two weeks may be required to achieve a therapeutic benefit.

Management Of Pain, Primary Dysmenorrhea, And Acute Tendinitis and Bursitis

The recommended starting dose is two Sonaflam 500 mg tablets (1,000 mg) once daily. For patients requiring greater analgesic benefit, two Sonaflam 750 mg tablets (1,500 mg) or three Sonaflam 500 mg tablets (1,500 mg) may be used for a limited period. Thereafter, the total daily dose should not exceed two Sonaflam 500 mg tablets (1,000 mg).

Acute Gout

The recommended dose on the first day is two to three Sonaflam 500 mg tablets (1,000 to 1,500 mg) once daily, followed by two Sonaflam 500 mg tablets (1,000 mg) once daily, until the attack has subsided.

Dosage Adjustments In Patients With Hepatic Impairment

A lower dose should be considered in patients with renal or hepatic impairment or in elderly patients. Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. Caution is advised when high doses are required and some adjustment of dosage may be required in elderly patients. As with other drugs used in the elderly it is prudent to use the lowest effective dose.

General Dosing Instructions

Carefully consider the potential benefits and risks of Sonaflam Tablets, EC-Sonaflam and ANAPROX DS and other treatment options before deciding to use Sonaflam Tablets, EC-Sonaflam and ANAPROX DS. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals.

After observing the response to initial therapy with Sonaflam Tablets, EC-Sonaflam or ANAPROX DS, the dose and frequency should be adjusted to suit an individual patient's needs.

To maintain the integrity of the enteric coating, the EC-Sonaflam tablet should not be broken, crushed or chewed during ingestion.

Naproxen-containing products such as Sonaflam, EC-Sonaflam and ANAPROX DS, and other naproxen products should not be used concomitantly since they all circulate in the plasma as the naproxen anion.

Rheumatoid Arthritis, Osteoarthritis And Ankylosing Spondylitis

The recommended dosages of Sonaflam Tablets, ANAPROX DS, and EC-Sonaflam are shown in Table 1.

Table 1: Recommended dosages for Sonaflam Tablets, ANAPROX DS, and EC-Sonaflam

During long-term administration, the dose of naproxen may be adjusted up or down depending on the clinical response of the patient. A lower daily dose may suffice for long-term administration. The morning and evening doses do not have to be equal in size and the administration of the drug more frequently than twice daily is not necessary.

The morning and evening doses do not have to be equal in size and administration of the drug more frequently than twice daily does not generally make a difference in response.

In patients who tolerate lower doses well, the dose may be increased to naproxen 1500 mg/day for limited periods of up to 6 months when a higher level of anti-inflammatory/analgesic activity is required. When treating such patients with naproxen 1500 mg/day, the physician should observe sufficient increased clinical benefits to offset the potential increased risk.

Polyarticular Juvenile Idiopathic Arthritis

Naproxen solid-oral dosage forms may not allow for the flexible dose titration needed in pediatric patients with polyarticular juvenile idiopathic arthritis. A liquid formulation may be more appropriate for weight-based dosing and due to the need for dose flexibility in children.

In pediatric patients, doses of 5 mg/kg/day produced plasma levels of naproxen similar to those seen in adults taking 500 mg of naproxen. The recommended total daily dose of naproxen is approximately 10 mg/kg given in 2 divided doses. Dosing with Sonaflam Tablets is not appropriate for children weighing less than 50 kilograms.

Management Of Pain, Primary Dysmenorrhea, And Acute Tendonitis And Bursitis

The recommended starting dose of ANAPROX DS (naproxen sodium) tablets is 550 mg followed by 550 mg every 12 hours or 275 mg (one half of a 550 mg tablet) every 6 to 8 hours as required. The initial total daily dose should not exceed 1375 mg (two and one-half tablets) of naproxen sodium. Thereafter, the total daily dose should not exceed 1100 mg of naproxen sodium. Because the sodium salt of naproxen is more rapidly absorbed, ANAPROX DS is recommended for the management of acute painful conditions when prompt onset of pain relief is desired. Sonaflam Tablets may also be used. The recommended starting dose of Sonaflam Tablets is 500 mg followed by 250 mg (one half of a 500 mg Sonaflam tablet) every 6-8 hours as required.. The total daily dose should not exceed 1250 mg of naproxen.

EC-Sonaflam is not recommended for initial treatment of acute pain because absorption of naproxen is delayed compared to other naproxen-containing products.

Acute Gout

The recommended starting dose is 750 mg (one and one-half tablets) of Sonaflam Tablets followed by 250 mg (one-half tablet) every 8 hours until the attack has subsided. ANAPROX DS may also be used at a starting dose of 825 mg (one and one-half tablets) followed by 275 mg (one-half tablet) every 8 hours. EC-Sonaflam is not recommended because of the delay in absorption.

Non-Interchangeability With Other Formulations Of Naproxen

Different dose strengths and formulations (e.g., tablets, suspension) of naproxen are not interchangeable. This difference should be taken into consideration when changing strengths or formulations.

Os comprimidos NAPROSYN, EC-NAPROSYN e ANAPROX DS estão contra-indicados nos seguintes pacientes :

• Hipersensibilidade conhecida (por exemplo,., reações anafiláticas e reações cutâneas graves) ao naproxeno ou a qualquer componente do medicamento
• História de asma, urticária ou outras reações alérgicas após tomar aspirina ou outros AINEs. Reações anafiláticas graves, às vezes fatais, a AINEs foram relatadas nesses pacientes
• Na configuração da cirurgia de revascularização do miocárdio (CABG)

- Hipersensibilidade a qualquer um dos constituintes.

- Como existe potencial para reações de sensibilidade cruzada, Sonaflam está contra-indicado em pacientes que mostraram anteriormente reações de hipersensibilidade (por exemplo,. asma, rinite, pólipos nasais, angioedema ou urticária) em resposta ao ibuprofeno, aspirina ou outros anti-inflamatórios não esteróides. Essas reações têm o potencial de serem fatais. Reações anafiláticas graves ao Sonaflam foram relatadas nesses pacientes.

- - Advertências e precauções especiais de uso).

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- História de sangramento ou perfuração gastrointestinal relacionada à terapia anterior com AINEs. História ativa ou de úlcera péptica / ou sangramento gastrointestinal ativo (dois ou mais episódios distintos de ulceração ou sangramento comprovado).

- Em princípio, Sonaflam não deve ser administrado a pacientes com ulcerações gastrointestinais, gastrite congestiva ou gastrite atrófica, sangramento gastrointestinal ou outro sangramento, como sangramento cerebrovascular.

- Hemorróidas ou predisposição para sangramento retal.

Sonaflam está contra-indicado nos seguintes pacientes :

• Hipersensibilidade conhecida (por exemplo,., reações anafiláticas e reações cutâneas graves) ao naproxeno ou a qualquer componente do medicamento
• História de asma, urticária ou outras reações alérgicas após tomar aspirina ou outros AINEs. Reações anafiláticas graves, às vezes fatais, a AINEs foram relatadas nesses pacientes
• Na configuração da cirurgia de revascularização do miocárdio (CABG)

Os comprimidos de Sonaflam, EC-Sonaflam e ANAPROX DS estão contra-indicados nos seguintes pacientes :

• Hipersensibilidade conhecida (por exemplo,., reações anafiláticas e reações cutâneas graves) ao naproxeno ou a qualquer componente do medicamento
• História de asma, urticária ou outras reações alérgicas após tomar aspirina ou outros AINEs. Reações anafiláticas graves, às vezes fatais, a AINEs foram relatadas nesses pacientes
• Na configuração da cirurgia de revascularização do miocárdio (CABG)

AVISO

Incluído como parte do PRECAUÇÕES seção.

PRECAUÇÕES

Eventos trombóticos cardiovasculares

Ensaios clínicos de vários AINEs seletivos e não seletivos de COX-2 com duração de até três anos mostraram um risco aumentado de eventos trombóticos cardiovasculares graves (CV), incluindo infarto do miocárdio (IM) e acidente vascular cerebral, que podem ser fatais. Com base nos dados disponíveis, não está claro que o risco de eventos trombóticos CV seja semelhante para todos os AINEs. O aumento relativo de eventos trombóticos CV graves em relação à linha de base conferida pelo uso de AINEs parece ser semelhante naqueles com e sem doença CV conhecida ou fatores de risco para doença CV. No entanto, pacientes com doença CV conhecida ou fatores de risco tiveram uma incidência absoluta mais alta de eventos trombóticos CV graves em excesso, devido ao aumento da taxa de linha de base. Alguns estudos observacionais descobriram que esse risco aumentado de eventos trombóticos CV graves começou nas primeiras semanas de tratamento. O aumento do risco trombótico CV foi observado de maneira mais consistente em doses mais altas.

Para minimizar o risco potencial de um evento CV adverso em pacientes tratados com AINEs, use a dose eficaz mais baixa pela menor duração possível. Médicos e pacientes devem permanecer alertas para o desenvolvimento de tais eventos, durante todo o curso do tratamento, mesmo na ausência de sintomas CV anteriores. Os pacientes devem ser informados sobre os sintomas de eventos CV graves e as etapas a serem tomadas se ocorrerem.

Não há evidências consistentes de que o uso simultâneo de aspirina atenue o risco aumentado de eventos trombóticos CV graves associados ao uso de AINEs. O uso simultâneo de aspirina e um AINE, como o naproxeno, aumenta o risco de eventos gastrointestinais graves (GI).

Postagem de status Cirurgia do Bypass da artéria coronária (CABG)

Dois grandes ensaios clínicos controlados de um AINE seletivo de COX-2 para o tratamento da dor nos primeiros 10 a 14 dias após a cirurgia de revascularização miocárdica encontraram uma incidência aumentada de infarto do miocárdio e acidente vascular cerebral. Os AINEs são contra-indicados na configuração do CABG

Pacientes pós-IM

Estudos observacionais realizados no Registro Nacional Dinamarquês demonstraram que os pacientes tratados com AINEs no período pós-IM estavam em risco aumentado de reinfarção, morte relacionada ao CV e mortalidade por todas as causas a partir da primeira semana de tratamento. Nesta mesma coorte, a incidência de morte no primeiro ano após o MI foi de 20 por 100 pessoas / ano em pacientes tratados com AINE, em comparação com 12 por 100 pessoas / ano em pacientes não expostos ao AINE. Embora a taxa absoluta de mortalidade tenha diminuído um pouco após o primeiro ano após o MI, o aumento do risco relativo de morte nos usuários de AINEs persistiu durante pelo menos os próximos quatro anos de acompanhamento.

Evite o uso de comprimidos NAPROSYN, EC-NAPROSYN e ANAPROX DS em pacientes com um IM recente, a menos que se espere que os benefícios superem o risco de eventos trombóticos CV recorrentes. Se os comprimidos de NAPROSYN, EC-NAPROSYN e ANAPROX DS forem usados em pacientes com IM recente, monitore os pacientes quanto a sinais de isquemia cardíaca.

Sangramento gastrointestinal, ulceração e perfuração

Os AINEs, incluindo naproxeno, causam eventos adversos gastrointestinais graves (GI), incluindo inflamação, sangramento, ulceração e perfuração do esôfago, estômago, intestino delgado ou intestino grosso, que podem ser fatais. Esses eventos adversos graves podem ocorrer a qualquer momento, com ou sem sintomas de aviso prévio, em pacientes tratados com AINEs.

Apenas um em cada cinco pacientes que desenvolvem um evento adverso grave de IG superior na terapia com AINEs é sintomático. Úlceras gastrointestinais superiores, sangramento grave ou perfuração causada por AINEs ocorreram em aproximadamente 1% dos pacientes tratados por 3-6 meses e em cerca de 2% a 4% dos pacientes tratados por um ano. No entanto, mesmo a terapia com AINEs a curto prazo não deixa de ter riscos.

Fatores de risco para sangramento, ulceração e perfuração de IG

Pacientes com histórico prévio de úlcera péptica e / ou sangramento gastrointestinal que usaram AINEs tiveram um risco maior que 10 vezes maior de desenvolver um sangramento gastrointestinal em comparação com pacientes sem esses fatores de risco. Outros fatores que aumentam o risco de sangramento gastrointestinal em pacientes tratados com AINEs incluem maior duração da terapia com AINEs; uso concomitante de corticosteróides orais, aspirina, anticoagulantes ou inibidores seletivos da recaptação de serotonina (ISRS); fumar; uso de álcool; idade mais velha; e mau estado geral de saúde. A maioria dos relatórios pós-comercialização de eventos fatais de IG ocorreu em pacientes idosos ou debilitados. Além disso, pacientes com doença hepática avançada e / ou coagulopatia apresentam risco aumentado de sangramento gastrointestinal.

Estratégias para minimizar os riscos gastrointestinais em pacientes tratados com AINEs

• Use a menor dose eficaz pela menor duração possível.
• Evite a administração de mais de um AINE por vez.
• Evite o uso em pacientes com maior risco, a menos que se espere que os benefícios superem o risco aumentado de sangramento. Para esses pacientes, bem como aqueles com sangramento GI ativo, considere outras terapias alternativas além dos AINEs.
• Permaneça alerta quanto a sinais e sintomas de ulceração e sangramento gastrointestinais durante o tratamento com AINEs.
• Se houver suspeita de um evento adverso grave de IG, inicie imediatamente a avaliação e o tratamento e interrompa os comprimidos NAPROSYN, EC-NAPROSYN ou ANAPROX DS até que um evento adverso grave de IG seja descartado.
• No cenário de uso concomitante de aspirina em baixa dose para profilaxia cardíaca, monitore os pacientes mais de perto quanto a evidências de sangramento gastrointestinal.

Hepatotoxicidade

Elevações de ALT ou AST (três ou mais vezes o limite superior do normal [LSN]) foram relatadas em aproximadamente 1% dos pacientes tratados com AINE em ensaios clínicos. Além disso, foram relatados casos raros, às vezes fatais, de lesão hepática grave, incluindo hepatite fulminante, necrose hepática e insuficiência hepática.

Elevações de ALT ou AST (menos de três vezes a LSN) podem ocorrer em até 15% dos pacientes tratados com AINEs, incluindo naproxeno.

Informe os pacientes sobre os sinais e sintomas de hepatotoxicidade (por exemplo,., náusea, fadiga, letargia, diarréia, prurido, icterícia, sensibilidade do quadrante superior direito e sintomas "semelhantes à gripe"). Se surgirem sinais e sintomas clínicos consistentes com a doença hepática ou se ocorrerem manifestações sistêmicas (por exemplo,.eosinofilia, erupção cutânea, etc.), interrompa os comprimidos NAPROSYN, ECNAPROSYN ou ANAPROX DS imediatamente e realize uma avaliação clínica do paciente.

Hipertensão

Os AINEs, incluindo os comprimidos NAPROSYN, EC-NAPROSYN e ANAPROX DS, podem levar a um novo início de hipertensão ou agravamento da hipertensão pré-existente, o que pode contribuir para o aumento da incidência de eventos CV. Pacientes que tomam inibidores da enzima de conversão da angiotensina (ECA), diuréticos tiazídicos ou diuréticos de alça podem ter prejudicado a resposta a essas terapias ao tomar AINEs.

Monitore a pressão arterial (PB) durante o início do tratamento com AINEs e durante todo o curso da terapia.

Insuficiência Cardíaca E Edema

A metanálise de Colaboração dos Trialistas de Coxib e NSAID tradicionais de ensaios clínicos randomizados demonstrou um aumento de aproximadamente duas vezes nas hospitalizações por insuficiência cardíaca em pacientes tratados seletivamente com COX-2 e pacientes não seletivos tratados com NSAID em comparação com pacientes tratados com placebo. Em um estudo do Registro Nacional Dinamarquês de pacientes com insuficiência cardíaca, o uso de AINEs aumentou o risco de IM, hospitalização por insuficiência cardíaca e morte.

Além disso, retenção de líquidos e edema foram observados em alguns pacientes tratados com AINEs. O uso de naproxeno pode atenuar os efeitos CV de vários agentes terapêuticos usados para tratar essas condições médicas (por exemplo,.diuréticos, inibidores da ECA ou bloqueadores dos receptores da angiotensina [ARBs]).

Evite o uso de comprimidos NAPROSYN, EC-NAPROSYN ou ANAPROX DS em pacientes com insuficiência cardíaca grave, a menos que se espere que os benefícios superem o risco de agravamento da insuficiência cardíaca. Se os comprimidos de NAPROSYN, EC-NAPROSYN ou ANAPROX DS forem usados em pacientes com insuficiência cardíaca grave, monitore os pacientes quanto a sinais de agravamento da insuficiência cardíaca.

Como cada comprimido ANAPROX DS contém 50 mg de sódio (cerca de 2 mEq por cada 500 mg de naproxeno), isso deve ser considerado em pacientes cuja ingestão geral de sódio deve ser severamente restrita.

Toxicidade renal e hipercalemia

Toxicidade renal

A administração prolongada de AINEs resultou em necrose papilar renal e outras lesões renais.

Toxicidade renal também foi observada em pacientes nos quais as prostaglandinas renais têm um papel compensatório na manutenção da perfusão renal. Nesses pacientes, a administração de um AINE pode causar uma redução dependente da dose na formação de prostaglandinas e, secundariamente, no fluxo sanguíneo renal, que pode precipitar a descompensação renal evidente. Os pacientes com maior risco dessa reação são aqueles com função renal comprometida, desidratação, hipovolemia, insuficiência cardíaca, disfunção hepática, aqueles que tomam diuréticos e inibidores da ECA ou BRAs e idosos. A descontinuação da terapia com AINEs é geralmente seguida pela recuperação do estado de pré-tratamento.

Nenhuma informação está disponível em estudos clínicos controlados sobre o uso de comprimidos NAPROSYN, EC-NAPROSYN ou ANAPROX DS em pacientes com doença renal avançada. Os efeitos renais dos comprimidos de NAPROSYN, EC-NAPROSYN ou ANAPROX DS podem acelerar a progressão da disfunção renal em pacientes com doença renal preexistente.

Status do volume correto em pacientes desidratados ou hipovolêmicos antes de iniciar os comprimidos de NAPROSYN, EC-NAPROSYN, ou ANAPROX DS. Monitore a função renal em pacientes com insuficiência renal ou hepática, insuficiência cardíaca, desidratação, ou hipovolemia durante o uso de comprimidos NAPROSYN, EC-NAPROSYN, e ANAPROX DS. Evite o uso de comprimidos NAPROSYN, EC-NAPROSYN, e ANAPROX DS em pacientes com doença renal avançada, a menos que se espere que os benefícios superem o risco de agravamento da função renal. Se forem utilizados comprimidos de NAPROSYN, EC-NAPROSYN ou ANAPROX DS em pacientes com doença renal avançada, monitore os pacientes quanto a sinais de agravamento da função renal.

Hipercalemia

Aumentos na concentração sérica de potássio, incluindo hipercalemia, foram relatados com o uso de AINEs, mesmo em alguns pacientes sem insuficiência renal. Em pacientes com função renal normal, esses efeitos foram atribuídos a um estado hiporeninêmico-hipoaldosteronismo.

Reações anafiláticas

O naproxeno tem sido associado a reações anafiláticas em pacientes com e sem hipersensibilidade conhecida ao naproxeno e em pacientes com asma sensível à aspirina.

Procure ajuda de emergência se ocorrer uma reação anafilática.

Exacerbação da asma relacionada à sensibilidade à aspirina

Uma subpopulação de pacientes com asma pode ter asma sensível à aspirina, que pode incluir rininosite crônica complicada por pólipos nasais; broncoespasmo grave e potencialmente fatal; e / ou intolerância à aspirina e outros AINEs.

Como a reatividade cruzada entre aspirina e outros AINEs foi relatada em pacientes sensíveis à aspirina, os comprimidos NAPROSYN, EC-NAPROSYN e ANAPROX DS são contra-indicados em pacientes com essa forma de sensibilidade à aspirina. Quando comprimidos de NAPROSYN, EC-NAPROSYN ou ANAPROX DS são usados em pacientes com asma preexistente (sem sensibilidade conhecida à aspirina), monitore os pacientes quanto a alterações nos sinais e sintomas da asma.

Reações cutâneas graves

Os AINEs, incluindo naproxeno, podem causar reações adversas graves na pele, como dermatite esfoliativa, Síndrome de Stevens-Johnson (SJS) e necrólise epidérmica tóxica (RTE), que podem ser fatais. Esses eventos graves podem ocorrer sem aviso prévio. Informe os pacientes sobre os sinais e sintomas de reações cutâneas graves e interrompa o uso de comprimidos NAPROSYN, EC-NAPROSYN ou ANAPROX DS na primeira aparição de erupção cutânea ou qualquer outro sinal de hipersensibilidade. Os comprimidos de NAPROSYN, EC-NAPROSYN e ANAPROX DS estão contra-indicados em pacientes com reações graves da pele anteriores a AINEs.

Encerramento prematuro do ducto fetal arteriosus

O naproxeno pode causar o fechamento prematuro do ducto arterial fetal. Evite o uso de AINEs, incluindo comprimidos NAPROSYN, EC-NAPROSYN e ANAPROX DS, em mulheres grávidas a partir de 30 semanas de gestação (terceiro trimestre).

Toxicidade hematológica

Ocorreu anemia em pacientes tratados com AINEs. Isso pode ser devido à perda de sangue oculta ou bruta, retenção de líquidos ou um efeito incompletamente descrito na eritropoiese. Se um paciente tratado com comprimidos de NAPROSYN, EC-NAPROSYN ou ANAPROX DS tiver algum sinal ou sintoma de anemia, monitore a hemoglobina ou o hematócrito.

AINEs, incluindo comprimidos NAPROSYN, EC-NAPROSYN e ANAPROX DS, podem aumentar o risco de eventos hemorrágicos. Condições co-mórbidas, como distúrbios da coagulação ou uso concomitante de varfarina e outros anticoagulantes, agentes antiplaquetários (por exemplo,., aspirina), inibidores da recaptação de serotonina (ISRS) e inibidores da recaptação de noradrenalina de serotonina (SNRIs) podem aumentar esse risco. Monitore esses pacientes quanto a sinais de sangramento.

Mascaramento de inflamação e febre

A atividade farmacológica dos comprimidos NAPROSYN, EC-NAPROSYN e ANAPROX DS na redução da inflamação e possivelmente febre, pode diminuir a utilidade dos sinais de diagnóstico na detecção de infecções.

Uso a longo prazo e monitoramento de laboratório

Como sangramento grave de IG, hepatotoxicidade e lesão renal podem ocorrer sem sintomas ou sinais de aviso, considere monitorar pacientes em tratamento prolongado com AINEs com um hemograma completo e um perfil químico periodicamente.

Pacientes com valores iniciais de hemoglobina de 10g ou menos que devem receber terapia a longo prazo devem ter valores de hemoglobina determinados periodicamente.

Devido a achados adversos oculares em estudos com animais com medicamentos dessa classe, recomenda-se a realização de estudos oftalmológicos se ocorrer alguma alteração ou perturbação na visão.

Informações de aconselhamento ao paciente

Aconselhe o paciente a ler a rotulagem do paciente aprovada pela FDA (Guia de Medicamentos) que acompanha cada receita dispensada. Informe pacientes, famílias ou seus cuidadores das seguintes informações antes de iniciar o tratamento com comprimidos NAPROSYN, EC-NAPROSYN ou ANAPROX DS e periodicamente durante o curso da terapia em andamento.

Eventos trombóticos cardiovasculares

Aconselhe os pacientes a estarem alertas quanto aos sintomas de eventos trombóticos cardiovasculares, incluindo dor no peito, falta de ar, fraqueza ou insultos da fala, e a relatar qualquer um desses sintomas ao seu médico imediatamente.

Sangramento gastrointestinal, ulceração e perfuração

Aconselhe os pacientes a relatar sintomas de ulcerações e sangramentos, incluindo dor epigástrica, dispepsia, melena e hematemese ao seu médico. No cenário de uso concomitante de aspirina em baixa dose para profilaxia cardíaca, informe os pacientes sobre o aumento do risco e os sinais e sintomas de sangramento gastrointestinal.

Hepatotoxicidade

Informe os pacientes sobre os sinais e sintomas de hepatotoxicidade (por exemplo,., náusea, fadiga, letargia, prurido, diarréia, icterícia, sensibilidade do quadrante superior direito e sintomas "semelhantes à gripe"). Se isso ocorrer, instrua os pacientes a interromper os comprimidos de NAPROSYN, EC-NAPROSYN ou ANAPROX DS e procurar terapia médica imediata.

Insuficiência Cardíaca E Edema

Aconselhe os pacientes a estarem alertas quanto aos sintomas de insuficiência cardíaca congestiva, incluindo falta de ar, ganho de peso inexplicável ou edema e entre em contato com o médico se esses sintomas ocorrerem.

Reações anafiláticas

Informe os pacientes sobre os sinais de uma reação anafilática (por exemplo,., dificuldade em respirar, inchaço da face ou garganta). Instrua os pacientes a procurar ajuda imediata de emergência, se ocorrerem.

Reações cutâneas graves

Aconselhe os pacientes a interromper imediatamente os comprimidos NAPROSYN, EC-NAPROSYN ou ANAPROX DS se desenvolverem algum tipo de erupção cutânea e entrarem em contato com o médico o mais rápido possível.

Fertilidade feminina

Aconselhe as mulheres com potencial reprodutivo que desejam gravidez que os AINEs, incluindo os comprimidos NAPROSYN, ECNAPROSYN e ANAPROX DS, possam estar associados a um atraso reversível na ovulação (ver Use em populações específicas.)

Toxicidade fetal

Informe as mulheres grávidas para evitar o uso de comprimidos NAPROSYN, EC-NAPROSYN ou ANAPROX DS e outros AINEs a partir de 30 semanas de gestação, devido ao risco de fechamento prematuro do ducto arterial fetal.

Evite o uso concomitante de AINEs

Informe os pacientes que o uso concomitante de comprimidos NAPROSYN, EC-NAPROSYN e ANAPROX DS com outros AINEs ou salicilatos (por exemplo,., diflunisal, salsalato) não é recomendado devido ao risco aumentado de toxicidade gastrointestinal e pouco ou nenhum aumento na eficácia. Alerte os pacientes de que os AINEs podem estar presentes em medicamentos "over the counter" para tratamento de resfriados, febre ou insônia.

Uso de AINEs e aspirina em baixa dose

Informe os pacientes a não usar aspirina em baixa dose concomitantemente com os comprimidos NAPROSYN, EC-NAPROSYN e ANAPROX DS até que conversem com seu médico.

Toxicologia Não Clínica

Carcinogênese, Mutagênese, Comprometimento de Fertilidade

Carcinogênese

Foi realizado um estudo de 2 anos em ratos para avaliar o potencial carcinogênico do naproxeno em doses de ratos de 8, 16 e 24 mg / kg / dia (0,05, 0,1 e 0,16 vezes a dose diária humana máxima recomendada [MRHD] de 1500 mg / dia com base em uma comparação da área da superfície corporal). Nenhuma evidência de tumorigenicidade foi encontrada.

Mutagênese

Naproxeno testou positivo no in vivo ensaio de troca cromática irmã para, mas não foi mutagênico no in vitro ensaio de mutação reversa bacteriana (teste de Ames).

Compromisso de fertilidade

Ratos machos foram tratados com 2, 5, 10 e 20 mg / kg de naproxeno por gavagem oral por 60 dias antes do acasalamento e ratos fêmeas foram tratados com as mesmas doses por 14 dias antes do acasalamento e nos primeiros 7 dias de gravidez. Não foram observados efeitos adversos na fertilidade (até 0,13 vezes o MRDH com base na área da superfície corporal).

Use em populações específicas

Gravidez

Resumo do risco

O uso de AINEs, incluindo comprimidos NAPROSYN, EC-NAPROSYN e ANAPROX DS, durante o terceiro trimestre de gravidez aumenta o risco de fechamento prematuro do ducto arterial fetal. Evite o uso de AINEs, incluindo comprimidos NAPROSYN, EC-NAPROSYN e ANAPROX DS, em mulheres grávidas a partir de 30 semanas de gestação (terceiro trimestre).

Não há estudos adequados e bem controlados de comprimidos NAPROSYN, EC-NAPROSYN ou ANAPROX DS em mulheres grávidas. Dados de estudos observacionais sobre os riscos embrionários potenciais do uso de AINEs em mulheres no primeiro ou segundo trimestre de gravidez são inconclusivos. Na população geral dos EUA, todas as gestações clinicamente reconhecidas, independentemente da exposição ao medicamento, têm uma taxa de fundo de 2-4% para as principais malformações e de 15 a 20% para a perda de gravidez. Em estudos de reprodução animal em ratos, coelhos e camundongos, não há evidência de teratogenicidade ou dano fetal quando o naproxeno foi administrado durante o período de organogênese nas doses 0,13, 0,26 e 0,6 vezes a dose diária humana máxima recomendada de 1500 mg / dia, respectivamente. Com base em dados de animais, as prostaglandinas demonstraram ter um papel importante na permeabilidade vascular endometrial, implantação de blastocistos e decidualização. Em estudos com animais, a administração de inibidores da síntese de prostaglandinas, como o naproxeno, resultou em aumento da perda pré e pós-implantação.

Considerações clínicas

Trabalho ou Entrega

Não há estudos sobre os efeitos dos comprimidos NAPROSYN, EC-NAPROSYN ou ANAPROX DS durante o parto ou parto. Em estudos com animais, os AINEs, incluindo naproxeno, inibem a síntese de prostaglandinas, causam atraso no parto e aumentam a incidência de natimortos.

Dados

Dados humanos

Existem evidências que sugerem que, quando inibidores da síntese de prostaglandinas são usados para retardar o parto prematuro, há um risco aumentado de complicações neonatais, como enterocolite necrosante, ducto arterioso patente e hemorragia intracraniana. O tratamento com naproxeno administrado no final da gravidez para retardar o parto tem sido associado a hipertensão pulmonar persistente, disfunção renal e níveis anormais de prostaglandina E em bebês prematuros. Devido aos efeitos conhecidos dos anti-inflamatórios não esteróides no sistema cardiovascular fetal (fechamento do ducto arterioso), deve-se evitar o uso durante a gravidez (particularmente a partir de 30 semanas de gestação ou terceiro trimestre).

Dados em animais

Estudos de reprodução foram realizados em ratos a 20 mg / kg / dia (0,13 vezes a dose diária humana máxima recomendada de 1500 mg / dia, com base na comparação da área da superfície corporal) coelhos a 20 mg / kg / dia (0,26 vezes a dose diária máxima recomendada para humanos, com base na comparação da área da superfície corporal) e camundongos a 170 mg / kg / dia (0,6 vezes a dose diária máxima recomendada para humanos, com base na comparação da área da superfície corporal) sem evidência de fertilidade prejudicada ou dano ao feto devido à droga. Com base em dados de animais, as prostaglandinas demonstraram ter um papel importante na permeabilidade vascular endometrial, implantação de blastocistos e decidualização. Em estudos com animais, a administração de inibidores da síntese de prostaglandinas, como o naproxeno, resultou em aumento da perda pré e pós-implantação.

Lactation

Risk Summary

The naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS and any potential adverse effects on the breastfed infant from the NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS or from the underlying maternal condition.

Females And Males Of Reproductive Potential

Infertility

Females

Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including NAPROSYN Tablets, ECNAPROSYN, and ANAPROX DS, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS, in women who have difficulties conceiving or who are undergoing investigation of infertility.

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 2 years have not been established. Pediatric dosing recommendations for polyarticular juvenile idiopathic arthritis are based on well-controlled studies. There are no adequate effectiveness or dose-response data for other pediatric conditions, but the experience in polyarticular juvenile idiopathic arthritis and other use experience have established that single doses of 2.5 to 5 mg/kg as naproxen suspension, , with total daily dose not exceeding 15 mg/kg/day, are well tolerated in pediatric patients over 2 years of age.

Geriatric Use

The hepatic and renal tolerability of long-term naproxen administration was studied in two double-blind clinical trials involving 586 patients. Of the patients studied, 98 patients were age 65 and older and 10 of the 98 patients were age 75 and older. NAPROXEN was administered at doses of 375 mg twice daily or 750 mg twice daily for up to 6 months. Transient abnormalities of laboratory tests assessing hepatic and renal function were noted in some patients, although there were no differences noted in the occurrence of abnormal values among different age groups.

Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects.

Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. The clinical significance of this finding is unclear, although it is possible that the increase in free naproxen concentration could be associated with an increase in the rate of adverse events per a given dosage in some elderly patients. Caution is advised when high doses are required and some adjustment of dosage may be required in elderly patients. As with other drugs used in the elderly, it is prudent to use the lowest effective dose.

Experience indicates that geriatric patients may be particularly sensitive to certain adverse effects of nonsteroidal anti-inflammatory drugs. Elderly or debilitated patients seem to tolerate peptic ulceration or bleeding less well when these events do occur. Most spontaneous reports of fatal GI events are in the geriatric population.

Naproxen is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Geriatric patients may be at a greater risk for the development of a form of renal toxicity precipitated by reduced prostaglandin formation during administration of nonsteroidal anti-inflammatory drugs.

Hepatic Impairment

Caution is advised when high doses are required and some adjustment of dosage may be required in these patients. It is prudent to use the lowest effective dose.

Renal Impairment

Naproxen-containing products are not recommended for use in patients with moderate to severe and severe renal impairment (creatinine clearance < 30 mL/min).

- )

- A history of gastrointestinal bleeding or perforation related to previous NSAIDs therapy. Active, or history of peptic ulcer/or active gastrointestinal bleeding (two or more distinct episodes of proven ulceration or bleeding).

- In principle, Sonaflam must not be administered to patients with gastrointestinal ulcerations, congestive gastritis or atrophic gastritis, gastrointestinal bleeding or other bleeding such as cerebrovascular bleeding.

- Hemorrhoids or predisposition to rectal bleeding.

In all patients:

Patients treated with NSAIDs long-term should undergo regular medical supervision to monitor for adverse events.

Elderly:

Severe gastrointestinal side effects may occur in patients who use prostaglandin synthetase inhibitors. The risk of developing gastrointestinal ulcers or bleeding increases with the duration of use and dose of Sonaflam. This risk is not limited to a specific patient population, but the elderly and debilitated individuals exhibit poorer tolerance to gastrointestinal ulceration or bleeding than others. The majority of fatal gastrointestinal effects attributed to prostaglandin synthetase inhibitors occurred in this population.

The antipyretic and anti-inflammatory activities of Sonaflam may reduce fever and inflammation, thereby diminishing their utility as diagnostic signs.

Respiratory disorders:

Caution is required if administered to patients suffering from, or with a previous history of, bronchial asthma since NSAIDs have been reported to precipitate bronchospasm in such patients.

Sonaflam decreases platelet aggregation and prolongs bleeding time. This effect should be kept in mind when bleeding times are determined.

Renal and Hepatic Impairment:

There have been reports of impaired renal function, renal failure, acute interstitial nephritis, haematuria, proteinuria, renal papillary necrosis and occasionally nephrotic syndrome associated with Sonaflam.

Renal failure linked to reduced prostaglandin production

The administration of an NSAID may cause a dose dependent reduction in prostaglandin formation and precipitate renal failure.-Contraindications).

Use in patients with impaired renal function

As Sonaflam is eliminated to a large extent (95%) by urinary excretion via glomerular filtration, it should be used with great caution in patients with impaired renal function and the monitoring of serum creatinine and/or creatinine clearance is advised and patients should be adequately hydrated. Sonaflam is contraindicated in patients having a baseline creatinine clearance of less than 30ml/minute.

Haemodialysis does not decrease the plasma concentration of Sonaflam because of the high degree of protein binding.

Certain patients, specifically those whose renal blood flow is compromised, such as in extracellular volume depletion, cirrhosis of the liver, sodium restriction, congestive heart failure, and pre-existing renal disease, should have renal function assessed before and during Sonaflam therapy. Some elderly patients in whom impaired renal function may be expected, as well as patients using diuretics, may also fall within this category. A reduction in daily dosage should be considered to avoid the possibility of excessive accumulation of Sonaflam metabolites in these patients.

Use in patients with impaired liver function

Care should also be exercised in patients with hepatic insufficiency.

Caution is advised when high doses of Sonaflam are administered to elderly patients, because there are indications that the quantity of non-protein-bound Sonaflam increases in such patients. Since Sonaflam has an anti-inflammatory, analgesic and antipyretic effect, certain symptoms of infection can therefore be masked.

Chronic alcoholic liver disease and probably also other forms of cirrhosis reduce the total plasma concentration of Sonaflam, but the plasma concentration of unbound Sonaflam is increased. The implication of this finding for Sonaflam dosing is unknown but it is prudent to use the lowest effective dose.

As with other non-steroidal anti-inflammatory drugs, elevations of one or more liver function tests may occur. Hepatic abnormalities may be the result of hypersensitivity rather than direct toxicity. Severe hepatic reactions, including jaundice and hepatitis (some cases of hepatitis have been fatal) have been reported with this drug as with other non-steroidal anti-inflammatory drugs. Cross reactivity has been reported.

Gastrointestinal bleeding, ulceration and perforation:

GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious GI events.

The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation , when used with alcohol, in smoking and in the elderly. These patients should commence treatment on the lowest dose available.

Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment.

Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroid, or anticoagulants such as warfarin, selective serotonin-reuptake inhibitors or anti-platelet agents such as aspirin. If a corticosteroid is replaced by Sonaflam and the substitution occurs partially or fully, the usual precautions which come into consideration when discontinuing corticosteroid treatment should be applied.

When GI bleeding or ulceration occurs in patients receiving Sonaflam, the treatment should be withdrawn.

Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients, and also for patients requiring concomitant low dose aspirin, or other drugs likely to increase gastrointestinal risk.

Haematological

Patients who have coagulation disorders or are receiving drug therapy that interferes with haemostasis should be carefully observed if Sonaflam-containing products are administered.

Patients at high risk of bleeding or those on full anti-caogulation therapy, e.g. who use coumarin derivatives or heparin alongside Sonaflam have an increased risk of bleeding. The benefits in that case should be weighed up against the risks. In any case concomitant use of Sonaflam with a high dose of heparin (or derivatives thereof) is not recommended.

Anaphylactic (anaphylactoid) reactions

Hypersensitivity reactions may occur in susceptible individuals. Anaphylactic (anaphylactoid) reactions may occur both in patients with and without a history of hypersensitivity or exposure to aspirin, other non-steroidal anti-inflammatory drugs or Sonaflam-containing products. They may also occur in individuals with a history of angio-oedema, bronchospastic reactivity (e.g. asthma), rhinitis and nasal polyps.

Anaphylactoid reactions, like anaphylaxis, may have a fatal outcome.

Steroids

If steroid dosage is reduced or eliminated during therapy, the steroid dosage should be reduced slowly and the patients must be observed closely for any evidence of adverse effects, including adrenal insufficiency and exacerbation of symptoms of arthritis.

Ocular effects

Studies have not shown changes in the eye attributable to Sonaflam administration. In rare cases, adverse ocular disorders including papillitis, retrobulbar optic neuritis and papilloedema, have been reported in users of NSAIDs including Sonaflam, although a cause-and-effect relationship cannot be established; accordingly, patients who develop visual disturbances during treatment with Sonaflam-containing products should have an ophthalmological examination.

Cardiovascular and cerebrovascular effects

Appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy.

Mild peripheral oedema has been observed in a few patients receiving Sonaflam. Although sodium retention has not been reported in metabolic studies, it is possible that patients with questionable or compromised cardiac function may be at a greater risk when taking Sonaflam.

Clinical trial and epidemiological data suggest that use of coxibs and some NSAIDs (particularly at high doses and in long term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). Although data suggest that the use of Sonaflam (1000mg daily) may be associated with a lower risk, some risk cannot be excluded.

Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with Sonaflam after careful consideration. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).

Dermatological

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens- Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs (see 4.8). Patients appear to be at highest risk for these reactions early in the course of therapy: the onset of the reactions occurring in the majority of cases within the first month of treatment. Sonaflam should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity. If the skin becomes delicate or in the event of blistering or other symptoms of pseudoporphyria, treatment should be discontinued and the patient should be carefully monitored.

Combination with other NSAIDs including cyclooxygenase-2 selective inhibitors

The combination of Sonaflam-containing products and other NSAIDs, including cyclooxygenase-2 selective inhibitors, is not recommended, because of the cumulative risks of inducing serious NSAID-related adverse events.

SLE and mixed connective tissue disease:

Female fertility:

The use of Sonaflam, as with any drug known to inhibit cyclooxygenase/prostaglandin synthesis, may impair fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of Sonaflam should be considered.

Interference in tests:

It is suggested that Sonaflam therapy be temporarily discontinued 48 hours before adrenal function tests are performed, because Sonaflam may artifactually interfere with some tests for 17-ketogenic steroids. Similarly, Sonaflam may interfere with some assays of urinary 5-hydroxyindoleacetic acid.

Sporadic abnormalities in laboratory tests (e.g. liver function test) have occurred in patients on Sonaflam therapy, but no definite trend was seen in any test indicating toxicity.

Contains Lactose:

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiencyor glucose-galactose malabsorption should not take this medicine.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Cardiovascular Thrombotic Events

Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses.

To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur.

There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as naproxen, increases the risk of serious gastrointestinal (GI) events.

Status Post Coronary Artery Bypass Graft (CABG) Surgery

Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG.

Post-MI Patients

Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up.

Avoid the use of Sonaflam in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If Sonaflam is used in patients with a recent MI, monitor patients for signs of cardiac ischemia.

Gastrointestinal Bleeding, Ulceration, And Perforation

NSAIDs, including naproxen, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3 to 6 months, and in about 2% to 4% of patients treated for one year. However, even short-term NSAID therapy is not without risk.

Risk Factors For GI Bleeding, Ulceration, And Perforation

Strategies To Minimize The GI Risks In NSAID-Treated Patients

• Use the lowest effective dosage for the shortest possible duration.
• Avoid administration of more than one NSAID at a time.
• Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs.
• Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy.
• If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue Sonaflam until a serious GI adverse event is ruled out.
• In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding.

Hepatotoxicity

Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported.

Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including naproxen.

Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue Sonaflam immediately, and perform a clinical evaluation of the patient.

Hypertension

NSAIDs, including Sonaflam, can lead to new onset or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs.

Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy.

Heart Failure And Edema

The Coxib and traditional NSAID Trialists' Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death.

Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of naproxen may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]).

Avoid the use of Sonaflam in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If Sonaflam is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.

Renal Toxicity And Hyperkalemia

Renal Toxicity

Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.

Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.

No information is available from controlled clinical studies regarding the use of Sonaflam in patients with advanced renal disease. The renal effects of Sonaflam may hasten the progression of renal dysfunction in patients with preexisting renal disease.

Correct volume status in dehydrated or hypovolemic patients prior to initiating Sonaflam. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of Sonaflam. Avoid the use of Sonaflam in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If Sonaflam is used in patients with advanced renal disease, monitor patients for signs of worsening renal function.

Hyperkalemia

Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state.

Anaphylactic Reactions

Naproxen has been associated with anaphylactic reactions in patients with and without known hypersensitivity to naproxen and in patients with aspirin-sensitive asthma.

Seek emergency help if an anaphylactic reaction occurs.

Exacerbation Of Asthma Related To Aspirin Sensitivity

A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, Sonaflam is contraindicated in patients with this form of aspirin sensitivity. When Sonaflam is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.

Serious Skin Reactions

NSAIDs, including naproxen can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of Sonaflam at the first appearance of skin rash or any other sign of hypersensitivity.

Sonaflam is contraindicated in patients with previous serious skin reactions to NSAIDs.

Premature Closure Of Fetal Ductus Arteriosus

Naproxen may cause premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including Sonaflam, in pregnant women starting at 30 weeks of gestation (third trimester).

Hematologic Toxicity

Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with Sonaflam has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.

NSAIDs, including Sonaflam, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders, concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding.

Masking Of Inflammation And Fever

The pharmacological activity of Sonaflam in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.

Laboratory Monitoring

Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with Sonaflam and periodically during the course of ongoing therapy.

Cardiovascular Thrombotic Events

Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately.

Gastrointestinal Bleeding, Ulceration, And Perforation

Sonaflam, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding.

Hepatotoxicity

Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop Sonaflam and seek immediate medical therapy.

Heart Failure And Edema

Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur.

Anaphylactic Reactions

Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur.

Serious Skin Reactions

Sonaflam, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalization and even death. Advise patients to stop Sonaflam immediately if they develop any type of rash and to contact their healthcare provider as soon as possible.

Female Fertility

Advise females of reproductive potential who desire pregnancy that NSAIDs, including Sonaflam, may be associated with a reversible delay in ovulation.

Fetal Toxicity

Inform pregnant women to avoid use of Sonaflam and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus.

Avoid Concomitant Use Of NSAIDs

Inform patients that the concomitant use of Sonaflam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia.

Use Of NSAIDS And Low-Dose Aspirin

Inform patients not to use low-dose aspirin concomitantly with Sonaflam until they talk to their healthcare provider.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

A two year study was performed in rats to evaluate the carcinogenic potential of naproxen at doses of 8 mg/kg/day, 16 mg/kg/day, and 24 mg/kg/day (0.05, 0.1, and 0.16 times the maximum recommended human daily dose of 1,500 mg/day based on a body surface area comparison). No evidence of tumorigenicity was found.

Mutagenesis

Studies to evaluate the mutagenic potential of Naprosyn Suspension have not been completed.

Impairment Of Fertility

Studies to evaluate the impact of naproxen on male or female fertility have not been completed.

Use In Specific Populations

Pregnancy

Risk Summary

Use of NSAIDs, including Sonaflam, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including Sonaflam, in pregnant women starting at 30 weeks of gestation (third trimester).

There are no adequate and well-controlled studies of Sonaflam in pregnant women.

Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In the general U.S. population, all clinically recognized pregnancies, regardless of drug exposure, have a background rate of 2 to 4% for major malformations, and 15 to 20% for pregnancy loss. In animal reproduction studies in rats, rabbit, and mice no evidence of teratogenicity or fetal harm when naproxen was administered during the period of organogenesis at doses 0.13, 0.26, and 0.6 times the maximum recommended human daily dose of 1,500 mg/day, respectively. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as naproxen sodium resulted in increased pre-and post-implantation loss.

Clinical Considerations

Labor Or Delivery

There are no studies on the effects of Sonaflam during labor or delivery. In animal studies, NSAIDS, including naproxen sodium, inhibit prostaglandin synthesis, cause delayed parturition, increase incidence of dystocia and increase the incidence of stillbirth.

Data

Human Data

There is some evidence to suggest that when inhibitors of prostaglandin synthesis are used to delay preterm labor, there is an increased risk of neonatal complications such as necrotizing enterocolitis, patent ductus arteriosus, and intracranial hemorrhage. Naproxen treatment given in late pregnancy to delay parturition has been associated with persistent pulmonary hypertension, renal dysfunction, and abnormal prostaglandin E levels in preterm infants. Because of the known effect of drugs of this class on the human fetal cardiovascular system (closure of the ductus arteriosus), use during third trimester should be avoided.

Animal data

Reproduction studies have been performed in rats at 20 mg/kg/day (0.13 times the maximum recommended human daily dose of 1,500 mg/day based on body surface area comparison) rabbits at 20 mg/kg/day (0.26 times the maximum recommended human daily dose, based on body surface area comparison), and mice at 170 mg/kg/day (0.6 times the maximum recommended human daily dose based on body surface area comparison) with no evidence of impaired fertility or harm to the fetus due to the drug. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as naproxen sodium resulted in increased preand post-implantation loss.

Lactation

Risk Summary

The naproxen anion has been found in the milk of lactating women at a concentration of approximately 1% of that found in the plasma. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Sonaflam and any potential adverse effects on the breastfed infant from the Sonaflam or from the underlying maternal condition.

Females And Males Of Reproductive Potential

Infertility

Females

Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including Sonaflam, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including Sonaflam, in women who have difficulties conceiving or who are undergoing investigation of infertility.

Pediatric Use

The safety and effectiveness of Sonaflam in pediatric populations has not been established.

Geriatric Use

Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects.

Naproxen and its metabolites are known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, use caution in this patient population, and it may be useful to monitor renal function

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Cardiovascular Thrombotic Events

Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses.

To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur.

There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as naproxen, increases the risk of serious gastrointestinal (GI) events.

Status Post Coronary Artery Bypass Graft (CABG) Surgery

Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG.

Post-MI Patients

Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up.

Avoid the use of Sonaflam Tablets, EC-Sonaflam, and ANAPROX DS in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If Sonaflam Tablets, EC-Sonaflam and ANAPROX DS are used in patients with a recent MI, monitor patients for signs of cardiac ischemia.

Gastrointestinal Bleeding, Ulceration, And Perforation

NSAIDs, including naproxen, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs.

Risk Factors For GI Bleeding, Ulceration, And Perforation

Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding.

Strategies To Minimize The GI Risks In NSAID-treated Patients

• Use the lowest effective dosage for the shortest possible duration.
• Avoid administration of more than one NSAID at a time.
• Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs.
• Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy.
• If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue Sonaflam Tablets, EC-Sonaflam, or ANAPROX DS until a serious GI adverse event is ruled out.
• In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding.

Hepatotoxicity

Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported.

Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including naproxen.

Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue Sonaflam Tablets, ECSonaflam, or ANAPROX DS immediately, and perform a clinical evaluation of the patient.

Hypertension

NSAIDs, including Sonaflam Tablets, EC-Sonaflam, and ANAPROX DS, can lead to new onset of hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs.

Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy.

Heart Failure And Edema

The Coxib and traditional NSAID Trialists' Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death.

Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of naproxen may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]).

Avoid the use of Sonaflam Tablets, EC-Sonaflam, or ANAPROX DS in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If Sonaflam Tablets, EC-Sonaflam, or ANAPROX DS is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.

Since each ANAPROX DS tablet contains 50 mg of sodium (about 2 mEq per each 500 mg of naproxen), this should be considered in patients whose overall intake of sodium must be severely restricted.

Renal Toxicity And Hyperkalemia

Renal Toxicity

Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.

Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.

No information is available from controlled clinical studies regarding the use of Sonaflam Tablets, EC-Sonaflam, or ANAPROX DS in patients with advanced renal disease. The renal effects of Sonaflam Tablets, EC-Sonaflam, or ANAPROX DS may hasten the progression of renal dysfunction in patients with preexisting renal disease.

Correct volume status in dehydrated or hypovolemic patients prior to initiating Sonaflam Tablets, EC-Sonaflam, or ANAPROX DS. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of Sonaflam Tablets, EC-Sonaflam, and ANAPROX DS. Avoid the use of Sonaflam Tablets, EC-Sonaflam, and ANAPROX DS in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If Sonaflam Tablets, EC-Sonaflam, or ANAPROX DS is used in patients with advanced renal disease, monitor patients for signs of worsening renal function.

Hyperkalemia

Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state.

Anaphylactic Reactions

Naproxen has been associated with anaphylactic reactions in patients with and without known hypersensitivity to naproxen and in patients with aspirin-sensitive asthma.

Seek emergency help if an anaphylactic reaction occurs.

Exacerbation Of Asthma Related To Aspirin Sensitivity

A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs.

Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, Sonaflam Tablets, EC-Sonaflam, and ANAPROX DS are contraindicated in patients with this form of aspirin sensitivity. When Sonaflam Tablets, EC-Sonaflam, or ANAPROX DS is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.

Serious Skin Reactions

NSAIDs, including naproxen, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of Sonaflam Tablets, EC-Sonaflam, or ANAPROX DS at the first appearance of skin rash or any other sign of hypersensitivity. Sonaflam Tablets, EC-Sonaflam, and ANAPROX DS are contraindicated in patients with previous serious skin reactions to NSAIDs.

Premature Closure Of Fetal Ductus Arteriosus

Naproxen may cause premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including Sonaflam Tablets, EC-Sonaflam, and ANAPROX DS, in pregnant women starting at 30 weeks of gestation (third trimester).

Hematologic Toxicity

Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with Sonaflam Tablets, EC-Sonaflam, or ANAPROX DS has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.

NSAIDs, including Sonaflam Tablets, EC-Sonaflam, and ANAPROX DS, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin and other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding.

Masking Of Inflammation And Fever

The pharmacological activity of Sonaflam Tablets, EC-Sonaflam, and ANAPROX DS in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.

Long-Term Use And Laboratory Monitoring

Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically.

Patients with initial hemoglobin values of 10g or less who are to receive long-term therapy should have hemoglobin values determined periodically.

Because of adverse eye findings in animal studies with drugs of this class, it is recommended that ophthalmic studies be carried out if any change or disturbance in vision occurs.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with Sonaflam Tablets, EC-Sonaflam or ANAPROX DS and periodically during the course of ongoing therapy.

Cardiovascular Thrombotic Events

Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately.

Gastrointestinal Bleeding, Ulceration, And Perforation

Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding.

Hepatotoxicity

Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop Sonaflam Tablets, EC-Sonaflam or ANAPROX DS and seek immediate medical therapy.

Heart Failure And Edema

Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur.

Anaphylactic Reactions

Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur.

Serious Skin Reactions

Advise patients to stop Sonaflam Tablets, EC-Sonaflam or ANAPROX DS immediately if they develop any type of rash and to contact their healthcare provider as soon as possible.

Female Fertility

Advise females of reproductive potential who desire pregnancy that NSAIDs, including Sonaflam Tablets, ECSonaflam, and ANAPROX DS, may be associated with a reversible delay in ovulation (see Use in Specific Populations.)

Fetal Toxicity

Inform pregnant women to avoid use of Sonaflam Tablets, EC-Sonaflam or ANAPROX DS and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus.

Avoid Concomitant Use Of NSAIDs

Inform patients that the concomitant use of Sonaflam Tablets, EC-Sonaflam and ANAPROX DS with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia.

Use Of NSAIDS And Low-Dose Aspirin

Inform patients not to use low-dose aspirin concomitantly with Sonaflam Tablets, EC-Sonaflam and ANAPROX DS until they talk to their healthcare provider.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

A 2-year study was performed in rats to evaluate the carcinogenic potential of naproxen at rat doses of 8, 16, and 24 mg/kg/day (0.05, 0.1, and 0.16 times the maximum recommended human daily dose [MRHD] of 1500 mg/day based on a body surface area comparison). No evidence of tumorigenicity was found.

Mutagenesis

Naproxen tested positive in the in vivo sister chromatid exchange assay for but was not mutagenic in the in vitro bacterial reverse mutation assay (Ames test).

Impairment Of Fertility

Male rats were treated with 2, 5, 10, and 20 mg/kg naproxen by oral gavage for 60 days prior to mating and female rats were treated with the same doses for 14 days prior to mating and for the first 7 days of pregnancy. There were no adverse effects on fertility noted (up to 0.13 times the MRDH based on body surface area).

Use In Specific Populations

Pregnancy

Risk Summary

Use of NSAIDs, including Sonaflam Tablets, EC-Sonaflam, and ANAPROX DS, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including Sonaflam Tablets, EC-Sonaflam, and ANAPROX DS, in pregnant women starting at 30 weeks of gestation (third trimester).

There are no adequate and well-controlled studies of Sonaflam Tablets, EC-Sonaflam or ANAPROX DS in pregnant women. Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In the general U.S. population, all clinically recognized pregnancies, regardless of drug exposure, have a background rate of 2-4% for major malformations, and 15-20% for pregnancy loss. In animal reproduction studies in rats, rabbits, and mice no evidence of teratogenicity or fetal harm when naproxen was administered during the period of organogenesis at doses 0.13, 0.26, and 0.6 times the maximum recommended human daily dose of 1500 mg/day, respectively. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as naproxen, resulted in increased pre-and post-implantation loss.

Clinical Considerations

Labor or Delivery

There are no studies on the effects of Sonaflam Tablets, EC-Sonaflam, or ANAPROX DS during labor or delivery. In animal studies, NSAIDS, including naproxen, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth.

Data

Human Data

There is some evidence to suggest that when inhibitors of prostaglandin synthesis are used to delay preterm labor, there is an increased risk of neonatal complications such as necrotizing enterocolitis, patent ductus arteriosus, and intracranial hemorrhage. Naproxen treatment given in late pregnancy to delay parturition has been associated with persistent pulmonary hypertension, renal dysfunction, and abnormal prostaglandin E levels in preterm infants. Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly starting at 30-weeks of gestation, or third trimester) should be avoided.

Animal data

Reproduction studies have been performed in rats at 20 mg/kg/day (0.13 times the maximum recommended human daily dose of 1500 mg/day based on body surface area comparison), rabbits at 20 mg/kg/day (0.26 times the maximum recommended human daily dose, based on body surface area comparison), and mice at 170 mg/kg/day (0.6 times the maximum recommended human daily dose based on body surface area comparison) with no evidence of impaired fertility or harm to the fetus due to the drug. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as naproxen, resulted in increased pre-and post-implantation loss.

Lactation

Risk Summary

The naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Sonaflam Tablets, EC-Sonaflam, or ANAPROX DS and any potential adverse effects on the breastfed infant from the Sonaflam Tablets, EC-Sonaflam, or ANAPROX DS or from the underlying maternal condition.

Females And Males Of Reproductive Potential

Infertility

Females

Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including Sonaflam Tablets, ECSonaflam, and ANAPROX DS, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including Sonaflam Tablets, EC-Sonaflam and ANAPROX DS, in women who have difficulties conceiving or who are undergoing investigation of infertility.

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 2 years have not been established. Pediatric dosing recommendations for polyarticular juvenile idiopathic arthritis are based on well-controlled studies. There are no adequate effectiveness or dose-response data for other pediatric conditions, but the experience in polyarticular juvenile idiopathic arthritis and other use experience have established that single doses of 2.5 to 5 mg/kg as naproxen suspension, , with total daily dose not exceeding 15 mg/kg/day, are well tolerated in pediatric patients over 2 years of age.

Geriatric Use

The hepatic and renal tolerability of long-term naproxen administration was studied in two double-blind clinical trials involving 586 patients. Of the patients studied, 98 patients were age 65 and older and 10 of the 98 patients were age 75 and older. NAPROXEN was administered at doses of 375 mg twice daily or 750 mg twice daily for up to 6 months. Transient abnormalities of laboratory tests assessing hepatic and renal function were noted in some patients, although there were no differences noted in the occurrence of abnormal values among different age groups.

Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects.

Experience indicates that geriatric patients may be particularly sensitive to certain adverse effects of nonsteroidal anti-inflammatory drugs. Elderly or debilitated patients seem to tolerate peptic ulceration or bleeding less well when these events do occur. Most spontaneous reports of fatal GI events are in the geriatric population.

Naproxen is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Geriatric patients may be at a greater risk for the development of a form of renal toxicity precipitated by reduced prostaglandin formation during administration of nonsteroidal anti-inflammatory drugs.

Hepatic Impairment

Caution is advised when high doses are required and some adjustment of dosage may be required in these patients. It is prudent to use the lowest effective dose.

Renal Impairment

Naproxen-containing products are not recommended for use in patients with moderate to severe and severe renal impairment (creatinine clearance < 30 mL/min).

O naproxeno e o naproxeno sódico são rápida e completamente absorvidos pelo trato gastrointestinal com uma biodisponibilidade in vivo de 95%. As diferentes formas de dosagem de NAPROSYN são bioequivalentes em termos de extensão de absorção (AUC) e pico de concentração (Cmax); no entanto, os produtos diferem em seu padrão de absorção. Essas diferenças entre os produtos de naproxeno estão relacionadas à forma química do naproxeno usado e à sua formulação. Mesmo com as diferenças observadas no padrão de absorção, a meia-vida de eliminação do naproxeno permanece inalterada em produtos que variam de 12 a 17 horas. Níveis de naproxeno em estado estacionário são atingidos em 4 a 5 dias, e o grau de acúmulo de naproxeno é consistente com essa meia-vida. Isso sugere que as diferenças no padrão de liberação desempenham apenas um papel insignificante na obtenção de níveis plasmáticos no estado estacionário.

Absorção

Comprimidos NAPROSYN / ANAPROX DS: Após a administração dos comprimidos NAPROSYN, os níveis plasmáticos máximos são atingidos em 2 a 4 horas. Após administração oral de ANAPROX DS, os níveis plasmáticos máximos são atingidos em 1 a 2 horas. A diferença nas taxas entre os dois produtos se deve ao aumento da solubilidade aquosa do sal de sódio do naproxeno usado no ANAPROX DS

EC-NAPROSYN : O EC-NAPROSYN foi projetado com um revestimento sensível ao pH para fornecer uma barreira à desintegração no ambiente ácido do estômago e perder a integridade no ambiente mais neutro do intestino delgado. O revestimento de polímero entérico selecionado para EC-NAPROSYN se dissolve acima de pH 6. Quando EC-NAPROSYN foi administrado a indivíduos em jejum, os níveis plasmáticos máximos foram atingidos cerca de 4 a 6 horas após a primeira dose (intervalo: 2 a 12 horas). Um in vivo estudo em homens usando comprimidos de ECNAPROSYN radiomarcados demonstrou que o EC-NAPROSYN se dissolve principalmente no intestino delgado e não no estômago, de modo que a absorção do medicamento é retardada até que o estômago seja esvaziado.

Quando os comprimidos EC-NAPROSYN e NAPROSYN foram administrados a indivíduos em jejum (n = 24) em um estudo cruzado após 1 semana de dosagem, foram observadas diferenças no tempo até os níveis plasmáticos máximos (Tmax), mas não houve diferenças na absorção total medida pela Cmax e pela AUC :

Efeitos antiácidos

Quando EC-NAPROSYN foi administrado em dose única com antiácido (capacidade de tamponamento de 54 mEq), os níveis plasmáticos máximos de naproxeno permaneceram inalterados, mas o tempo para atingir o pico foi reduzido (Tmax médio jejuou 5,6 horas, Tmax médio com antiácido 5 horas), embora não significativamente.

Efeitos alimentares

Quando o EC-NAPROSYN foi administrado em dose única com os alimentos, os níveis plasmáticos máximos na maioria dos indivíduos foram atingidos em cerca de 12 horas (intervalo: 4 a 24 horas). O tempo de permanência no intestino delgado até a desintegração era independente da ingestão de alimentos. A presença de alimentos prolongou o tempo em que os comprimidos permaneceram no estômago, o tempo para os primeiros níveis séricos detectáveis de naproxeno e o tempo para os níveis máximos de naproxeno (Tmax), mas não afetou os níveis máximos de naproxeno (Cmax).

Distribuição

Naproxeno tem um volume de distribuição de 0,16 L / kg. Em níveis terapêuticos, o naproxeno é superior a 99% ligado à albumina. Em doses de naproxeno superiores a 500 mg / dia, há um aumento menor que proporcional nos níveis plasmáticos devido a um aumento na depuração causado pela saturação da ligação às proteínas plasmáticas em doses mais altas (calha média Css 36.5, 49,2 e 56,4 mg / L com 500, Doses diárias de 1000 e 1500 mg de naproxeno, respectivamente). O ânion naproxeno foi encontrado no leite de mulheres que amamentam em uma concentração equivalente a aproximadamente 1% da concentração máxima de naproxeno no plasma.

Eliminação

Metabolismo

O naproxeno é extensamente metabolizado no fígado em 6-0-desmetil naproxeno, e os pais e os metabólitos não induzem enzimas metabolizadoras. Tanto o naproxeno quanto o naproxeno 6-0-desmetil são metabolizados ainda mais em seus respectivos metabólitos conjugados com acilglucuronídeo.

Excreção

A depuração do naproxeno é de 0,13 mL / min / kg. Aproximadamente 95% do naproxeno de qualquer dose é excretado na urina, principalmente como naproxeno (<1%), 6-0-desmetil naproxeno (<1%) ou seus conjugados (66% a 92%). A meia-vida plasmática do ânion naproxeno em humanos varia de 12 a 17 horas. As meias-vidas correspondentes dos metabólitos e conjugados do naproxeno são inferiores a 12 horas e verificou-se que suas taxas de excreção coincidem estreitamente com a taxa de depuração do naproxeno do plasma. Pequenas quantidades, 3% ou menos da dose administrada, são excretadas nas fezes. Em pacientes com insuficiência renal, os metabólitos podem se acumular.

Sonaflam é prontamente absorvido pelo trato gastrointestinal e os níveis plasmáticos máximos são atingidos em 2 a 4 horas. Sonaflam está presente no sangue principalmente como droga inalterada. Está extensivamente ligado às proteínas plasmáticas e tem uma meia-vida de cerca de 15 horas. permitindo que um estado estacionário seja alcançado dentro de 3 dias após o início da terapia em um regime de dose duas vezes ao dia. O grau de absorção não é significativamente afetado pelos alimentos ou pela maioria dos antiácidos. A excreção é quase inteiramente via urina, principalmente como Sonaflam conjugado, com alguma droga inalterada. O metabolismo em crianças é semelhante ao dos adultos. A doença hepática alcoólica crônica reduz a concentração plasmática total de Sonaflam, mas a concentração de Sonaflam não ligado aumenta. Em idosos, a concentração plasmática não ligada de Sonaflam é aumentada, embora a concentração plasmática total seja inalterada. Cerca de metade da dose é excretada na urina em 24 horas e cerca de 94% em 5 dias, em grande parte como glucuronida.

Embora o naproxeno em si seja bem absorvido, a forma de sal de sódio é absorvida mais rapidamente, resultando em níveis plasmáticos de pico mais altos para uma determinada dose. Aproximadamente 30% da dose total de naproxeno sódico nos comprimidos de Sonaflam está presente na forma de dosagem como um componente de liberação imediata. O naproxeno sódico restante é revestido como micropartículas para fornecer propriedades de liberação sustentada. Após administração oral, são detectados níveis plasmáticos de naproxeno dentro de 30 minutos após a administração, com níveis plasmáticos máximos ocorrendo aproximadamente 5 horas após a administração. A meia-vida de eliminação terminal observada do naproxeno dos comprimidos de naproxeno sódico e Sonaflam de liberação imediata é de aproximadamente 15 horas. Níveis de estado estacionário de naproxeno são alcançados em 3 dias e o grau de acúmulo de naproxeno no sangue é consistente com isso.

Concentrações plasmáticas de naproxeno Média de 24 indivíduos (+/- 2SD) (estado estacionário, dia 5)

Parâmetros farmacocinéticos no dia 5 do estado estacionário (média de 24 indivíduos)

Absorção

O próprio naproxeno é rápida e completamente absorvido pelo trato GI com uma biodisponibilidade in vivo de 95%. Com base no perfil farmacocinético, a fase de absorção dos comprimidos de Sonaflam ocorre nas primeiras 4 a 6 horas após a administração. Isso coincide com a desintegração do comprimido no estômago, o trânsito das micropartículas de liberação sustentada pelo intestino delgado e no intestino grosso proximal. Um estudo de imagem in vivo foi realizado em voluntários saudáveis que confirma a rápida desintegração da matriz do comprimido e a dispersão das micropartículas.

A taxa de absorção do componente particulado de liberação sustentada dos comprimidos de Sonaflam é mais lenta que a dos comprimidos de naproxeno de sódio convencionais. É esse prolongamento dos processos de absorção de medicamentos que mantém os níveis plasmáticos e permite uma dose diária.

Efeitos alimentares

Não foram observados efeitos alimentares significativos quando vinte e quatro indivíduos receberam uma dose única de Sonaflam Tablets 500 mg após um jejum noturno ou 30 minutos após uma refeição. Em comum com as formulações convencionais de naproxeno e naproxeno sódico, os alimentos causam uma ligeira diminuição na taxa de absorção de naproxeno após a administração de Sonaflam Tablets.

Distribuição

Naproxeno tem um volume de distribuição de 0,16 L / kg. Em níveis terapêuticos, o naproxeno é superior a 99% ligado à albumina. Em doses de naproxeno superiores a 500 mg / dia, há um aumento menor que proporcional nos níveis plasmáticos devido ao aumento da depuração causado pela saturação da ligação às proteínas plasmáticas em doses mais altas. No entanto, a concentração de naproxeno não ligado continua a aumentar proporcionalmente à dose. Os comprimidos de Sonaflam exibem características proporcionais à dose semelhantes.

Eliminação

Metabolismo

O naproxeno é extensamente metabolizado em 6-0-desmetil naproxeno e os pais e os metabólitos não induzem enzimas metabolizadoras.

Excreção

A meia-vida de eliminação dos comprimidos de Sonaflam e do naproxeno convencional é de aproximadamente 15 horas. As condições de estado estacionário são atingidas após 2 a 3 doses de Sonaflam Tablets. A maior parte do medicamento é excretada na urina, principalmente como naproxeno inalterado (menos de 1%), 6-0-desmetil naproxeno (menos de 1%) e seu glucuronídeo ou outros conjugados (66 a 92%). Uma pequena quantidade (<5%) da droga é excretada nas fezes. Verificou-se que a taxa de excreção coincide estreitamente com a taxa de depuração do plasma. Em pacientes com insuficiência renal, os metabólitos podem se acumular.

O naproxeno e o naproxeno sódico são rápida e completamente absorvidos pelo trato gastrointestinal com uma biodisponibilidade in vivo de 95%. As diferentes formas de dosagem do Sonaflam são bioequivalentes em termos de extensão da absorção (AUC) e pico de concentração (Cmax); no entanto, os produtos diferem em seu padrão de absorção. Essas diferenças entre os produtos de naproxeno estão relacionadas à forma química do naproxeno usado e à sua formulação. Mesmo com as diferenças observadas no padrão de absorção, a meia-vida de eliminação do naproxeno permanece inalterada em produtos que variam de 12 a 17 horas. Níveis de naproxeno em estado estacionário são atingidos em 4 a 5 dias, e o grau de acúmulo de naproxeno é consistente com essa meia-vida. Isso sugere que as diferenças no padrão de liberação desempenham apenas um papel insignificante na obtenção de níveis plasmáticos no estado estacionário.

Absorção

Sonaflam Tablets / ANAPROX DS: Após a administração dos comprimidos de Sonaflam, os níveis plasmáticos máximos são atingidos em 2 a 4 horas. Após administração oral de ANAPROX DS, os níveis plasmáticos máximos são atingidos em 1 a 2 horas. A diferença nas taxas entre os dois produtos se deve ao aumento da solubilidade aquosa do sal de sódio do naproxeno usado no ANAPROX DS

EC-Sonaflam : O EC-Sonaflam foi projetado com um revestimento sensível ao pH para fornecer uma barreira à desintegração no ambiente ácido do estômago e perder a integridade no ambiente mais neutro do intestino delgado. O revestimento de polímero entérico selecionado para EC-Sonaflam se dissolve acima de pH 6. Quando EC-Sonaflam foi administrado a indivíduos em jejum, os níveis plasmáticos máximos foram atingidos cerca de 4 a 6 horas após a primeira dose (intervalo: 2 a 12 horas). Um in vivo estudo em homens usando comprimidos radiomarcados de ECSonaflam demonstrou que o EC-Sonaflam se dissolve principalmente no intestino delgado e não no estômago, de modo que a absorção do medicamento é adiada até que o estômago seja esvaziado.

Quando os comprimidos de EC-Sonaflam e Sonaflam foram administrados a indivíduos em jejum (n = 24) em um estudo cruzado após 1 semana de dosagem, foram observadas diferenças no tempo para atingir níveis plasmáticos máximos (Tmax), mas não houve diferenças na absorção total medida pela Cmax e AUC :

Efeitos antiácidos

Quando EC-Sonaflam foi administrado em dose única com antiácido (capacidade de tamponamento de 54 mEq), os níveis plasmáticos máximos de naproxeno permaneceram inalterados, mas o tempo para atingir o pico foi reduzido (o Tmax médio jejuou 5,6 horas, o Tmax médio com antiácido 5 horas), embora não significativamente.

Efeitos alimentares

Quando o EC-Sonaflam foi administrado em dose única com os alimentos, os níveis plasmáticos máximos na maioria dos indivíduos foram atingidos em cerca de 12 horas (intervalo: 4 a 24 horas). O tempo de permanência no intestino delgado até a desintegração era independente da ingestão de alimentos. A presença de alimentos prolongou o tempo em que os comprimidos permaneceram no estômago, o tempo para os primeiros níveis séricos detectáveis de naproxeno e o tempo para os níveis máximos de naproxeno (Tmax), mas não afetou os níveis máximos de naproxeno (Cmax).

Distribuição

Naproxeno tem um volume de distribuição de 0,16 L / kg. Em níveis terapêuticos, o naproxeno é superior a 99% ligado à albumina. Em doses de naproxeno superiores a 500 mg / dia, há um aumento menor que proporcional nos níveis plasmáticos devido a um aumento na depuração causado pela saturação da ligação às proteínas plasmáticas em doses mais altas (calha média Css 36.5, 49,2 e 56,4 mg / L com 500, Doses diárias de 1000 e 1500 mg de naproxeno, respectivamente). O ânion naproxeno foi encontrado no leite de mulheres que amamentam em uma concentração equivalente a aproximadamente 1% da concentração máxima de naproxeno no plasma.

Eliminação

Metabolismo

O naproxeno é extensamente metabolizado no fígado em 6-0-desmetil naproxeno, e os pais e os metabólitos não induzem enzimas metabolizadoras. Tanto o naproxeno quanto o naproxeno 6-0-desmetil são metabolizados ainda mais em seus respectivos metabólitos conjugados com acilglucuronídeo.

Excreção

A depuração do naproxeno é de 0,13 mL / min / kg. Aproximadamente 95% do naproxeno de qualquer dose é excretado na urina, principalmente como naproxeno (<1%), 6-0-desmetil naproxeno (<1%) ou seus conjugados (66% a 92%). A meia-vida plasmática do ânion naproxeno em humanos varia de 12 a 17 horas. As meias-vidas correspondentes dos metabólitos e conjugados do naproxeno são inferiores a 12 horas e verificou-se que suas taxas de excreção coincidem estreitamente com a taxa de depuração do naproxeno do plasma. Pequenas quantidades, 3% ou menos da dose administrada, são excretadas nas fezes. Em pacientes com insuficiência renal, os metabólitos podem se acumular.