Kompozisyon:
Tedavide kullanılır:
Militian Inessa Mesropovna tarafından tıbbi olarak gözden geçirilmiştir, Eczane Son güncelleme: 27.03.2022
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Aynı bileşenlere sahip en iyi 20 ilaç:
NAPROSYN Tabletler, EC-NAPROSYN ve ANAPROX DS aşağıdakiler için endikedir:
belirtilerinin ve semptomlarının giderilmesi:
- romatoid artrit
- osteoartrit
- ankilozan spondilit
- Poliartiküler Juvenil İdiyopatik Artrit
NAPROSYN Tabletler ve ANAPROX DS ayrıca aşağıdakiler için endikedir:
belirtileri ve semptomlarının giderilmesi:
- tendinit
- bursit
- akut gut
yönetimi:
- Ağrı
- birincil dismenore
Yetişkinler:
Romatoid artrit, osteoartrit (dejeneratif artrit), ankilozan spondilit, akut gut, akut kas-iskelet sistemi bozuklukları ve dismenore tedavisi.
Çocuklar:
Juvenil romatoid artrit
Sonaflam Tabletler aşağıdakilerin tedavisi için endikedir
- romatoid artrit (RA)
- osteoartrit (OA)
- ankilozan spondilit (AS)
- tendinit, bursit
- akut gut
- primer dismenore (PD)
- hafif ila orta derecede ağrının giderilmesi
.
Sonaflam Tabletler, EC-Sonaflam ve ANAPROX DS aşağıdakiler için endikedir:
belirtilerinin ve semptomlarının giderilmesi:
- romatoid artrit
- osteoartrit
- ankilozan spondilit
- Poliartiküler Juvenil İdiyopatik Artrit
Sonaflam Tabletler ve ANAPROX DS ayrıca aşağıdakiler için endikedir:
belirtileri ve semptomlarının giderilmesi:
- tendinit
- bursit
- akut gut
yönetimi:
- Ağrı
- birincil dismenore
Genel Dozlama Talimatları
NAPROSYN Tabletler, EC-NAPROSYN ve ANAPROX DS ve diğer tedavi seçeneklerinin potansiyel faydalarını ve risklerini NAPROSYN Tabletler, EC-NAPROSYN ve ANAPROX DS kullanmaya karar vermeden önce dikkatlice düşünün. Bireysel hasta tedavi hedefleriyle tutarlı olarak en kısa sürede en düşük etkili dozu kullanın.
NAPROSYN Tabletler, EC-NAPROSYN veya ANAPROX DS ile başlangıç tedavisine verilen yanıtı gözlemledikten sonra, doz ve sıklık hastanın ihtiyaçlarına göre ayarlanmalıdır.
Enterik kaplamanın bütünlüğünü korumak için, EC-NAPROSYN tableti yutulması sırasında kırılmamalı, ezilmemeli veya çiğnenmemelidir.
NAPROSYN, EC-NAPROSYN ve ANAPROX DS gibi naproksen içeren ürünler ve diğer naproksen ürünleri, hepsi naproksen anyonu olarak plazmada dolaştığı için birlikte kullanılmamalıdır.
Romatoid Artrit, Osteoartrit ve Ankilozan Spondilit
NAPROSYN Tabletler, ANAPROX DS ve EC-NAPROSYN'nin önerilen dozajları Tablo 1'de gösterilmektedir.
Tablo 1: NAPROSYN Tabletler, ANAPROX DS ve EC-NAPROSYN için önerilen dozajlar
NAPROSYN | 250 mg (bir yarım tablet) 500 mg | günde iki kez |
ANAPROX DS | 275 mg (bir yarım tablet) 550 mg (50 mg sodyum ile 500 mg naproksen) | günde iki kez |
EC-NAPROSYN | 375 mg | günde iki kez |
veya 500 mg | günde iki kez |
Uzun süreli uygulama sırasında, naproksen dozu hastanın klinik yanıtına bağlı olarak yukarı veya aşağı ayarlanabilir. Uzun süreli uygulama için daha düşük bir günlük doz yeterli olabilir. Sabah ve akşam dozlarının boyutu eşit olmak zorunda değildir ve ilacın günde iki kereden daha sık uygulanması gerekli değildir.
Sabah ve akşam dozlarının boyutu eşit olmak zorunda değildir ve ilacın günde iki kereden daha sık uygulanması genellikle yanıtta bir fark yaratmaz.
Daha düşük dozları iyi tolere eden hastalarda, daha yüksek bir anti-enflamatuar / analjezik aktivite gerektiğinde 6 aya kadar sınırlı süreler boyunca doz 1500 mg / gün naproksene yükseltilebilir. Bu tür hastaları 1500 mg / gün naproksen ile tedavi ederken, doktor potansiyel artan riski dengelemek için yeterli artmış klinik faydaları gözlemlemelidir.
Poliartiküler Juvenil İdiyopatik Artrit
Naproksen katı-oral dozaj formları, poliartiküler juvenil idiyopatik artritli pediatrik hastalarda gerekli esnek doz titrasyonuna izin vermeyebilir. Sıvı bir formülasyon, ağırlık bazlı dozlama ve çocuklarda doz esnekliği ihtiyacı nedeniyle daha uygun olabilir.
Pediyatrik hastalarda, 5 mg / kg / gün dozları, 500 mg naproksen alan yetişkinlerde görülenlere benzer plazma naproksen seviyeleri üretti. Önerilen toplam günlük naproksen dozu, 2 bölünmüş dozda verilen yaklaşık 10 mg / kg'dır. NAPROSYN Tabletlerle dozlama, 50 kilogramdan hafif çocuklar için uygun değildir.
Ağrı, Primer Dismenore ve Akut Tendinit ve Bursit Yönetimi
ANAPROX DS (naproksen sodyum) tabletlerinin önerilen başlangıç dozu 550 mg'dır, bunu 12 saatte bir 550 mg veya gerektiğinde her 6 ila 8 saatte bir 275 mg (550 mg tabletin yarısı) takip eder. Başlangıç toplam günlük dozu 1375 mg'ı (iki buçuk tablet) naproksen sodyumunu geçmemelidir. Daha sonra, toplam günlük doz 1100 mg naproksen sodyumunu geçmemelidir. Naproksen sodyum tuzu daha hızlı emildiği için, ağrı kesici derhal başlanması istendiğinde akut ağrılı durumların yönetimi için ANAPROX DS önerilir. NAPROSYN Tabletler de kullanılabilir. NAPROSYN Tabletlerin önerilen başlangıç dozu 500 mg'dır, bunu 6-8 saatte bir 250 mg (500 mg NAPROSYN tabletin yarısı) takip eder.. Toplam günlük doz 1250 mg naproksen'i geçmemelidir.
Akut ağrının ilk tedavisi için EC-NAPROSYN önerilmez, çünkü naproksen emilimi diğer naproksen içeren ürünlere kıyasla gecikir.
Akut Gut
Önerilen başlangıç dozu 750 mg (bir buçuk tablet) NAPROSYN Tablet, ardından saldırı azalıncaya kadar her 8 saatte bir 250 mg (bir buçuk tablet). ANAPROX DS ayrıca 825 mg'lık bir başlangıç dozunda (bir buçuk tablet) ve ardından 8 saatte bir 275 mg (bir buçuk tablet) kullanılabilir. Emilimdeki gecikme nedeniyle EC-NAPROSYN önerilmez.
Naproksen'in Diğer Formülasyonları ile Değiştirilemezlik
Farklı doz güçleri ve formülasyonları (ör., tabletler, süspansiyon) naproksen değiştirilemez. Güçlü yönler veya formülasyonlar değiştirilirken bu fark dikkate alınmalıdır.
Oral uygulama için
Yaşlı: Yaşlılar, advers reaksiyonların ciddi sonuçları açısından yüksek risk altındadır. Bir NSAID gerekli görülürse, en düşük doz ve mümkün olan en kısa süre için kullanılmalıdır. NSAID tedavisi sırasında hasta GI kanaması açısından düzenli olarak izlenmelidir.
Tercihen yiyecekle birlikte veya sonra alınmalıdır
Romatizmal Bozukluklar (Yetişkinler):
12 saatlik aralıklarla veya alternatif olarak tek bir uygulama olarak 2 dozda 500 mg ila 1 g alınır. Aşağıdaki durumlarda akut faz için günde 750 mg veya 1 g'lık bir yükleme dozu önerilir:
a) Şiddetli gece ağrısı / veya sabah sertliği bildiren hastalarda.
b) Yüksek dozda başka bir anti-romatizmal bileşikten Naprosyn'e geçirilen hastalarda.
c) Ağrının baskın semptom olduğu osteoartrozda.
Çocuklar (5 yaş üstü): Juvenil romatoid artritli 5 yaşın üzerindeki çocuklarda günde iki bölünmüş dozda vücut ağırlığının kilogramı başına 10 mg'lık bir doz kullanılmıştır.
Akut Gut (Yetişkinler): Akut gutta 750 mg'lık bir başlangıç dozu ve ardından saldırı geçene kadar her 8 saatte bir 250 mg; önerildi.
Çocuk: 16 yaşın altındaki çocuklarda önerilmez.
Kas-İskelet bozuklukları ve Dismenore (Yetişkinler); Başlangıçta 500 mg verilebilir, ardından her 6 ila 8 saatte bir 250 mg verilebilir. İlk günden sonra maksimum günlük doz günde 1250 mg'dır.
Çocuk: 16 yaşın altındaki çocuklarda önerilmez.
Tavsiye edilen en düşük doz, advers reaksiyon riskini azaltmak için özellikle yaşlılarda kullanılmalıdır.
Yaşlılar: Çalışmalar, Sonaflam'ın toplam plazma konsantrasyonu değişmese de, Sonaflam'ın bağlanmamış plazma fraksiyonunun yaşlılarda arttığını göstermektedir.
Böbrek / karaciğer yetmezliği: Böbrek veya karaciğer yetmezliği olan hastalarda daha düşük bir doz düşünülmelidir. Şiddetli böbrek yetmezliği olan veya diyaliz hastalarında Sonaflam metabolitlerinin birikmesi görüldüğü için, başlangıç kreatinin klerensi 30 ml / dakikadan az olan hastalarda naprosin kontrendikedir.
Tedavi düzenli aralıklarla gözden geçirilmeli ve herhangi bir fayda görülmezse veya hoşgörüsüzlük meydana gelirse kesilmelidir.
Genel Dozlama Talimatları
Sonaflam kullanmaya karar vermeden önce Sonaflam ve diğer tedavi seçeneklerinin potansiyel faydalarını ve risklerini dikkatlice düşünün. Bireysel hasta tedavi hedefleri ile tutarlı olarak en kısa süre için en düşük etkili dozu kullanın.
Sonaflam ile ilk tedaviye yanıtı gözlemledikten sonra, doz ve sıklık bireysel bir hastanın ihtiyaçlarına göre ayarlanmalıdır.
Romatoid Artrit, Osteoartrit ve Ankilozan Spondilit
Yetişkinlerde önerilen Sonaflam Tabletlerin başlangıç dozu günde bir kez iki Sonaflam 375 mg tablet (750 mg), günde bir kez bir Sonaflam 750 mg (750 mg) veya günde bir kez iki Sonaflam 500 mg tablettir (1.000 mg). Halihazırda günde iki kez 250 mg, 375 mg veya 500 mg (sabah ve akşam) naproksen alan hastalar, günlük günlük toplam dozlarını tek bir günlük doz olarak Sonaflam Tabletleri ile değiştirebilir.
Uzun süreli uygulama sırasında, Sonaflam Tabletlerin dozu hastanın klinik yanıtına bağlı olarak yukarı veya aşağı ayarlanabilir. Daha düşük dozlarda Sonaflam Tabletleri iyi tolere eden hastalarda, doz, daha yüksek bir anti-anti-olduğu zaman sınırlı periyotlar için günde bir kez iki Sonaflam 750 mg tablete (1.500 mg) veya üç Sonaflam 500 mg tablete (1.500 mg) yükseltilebilir. inflamatuar / analjezik aktivite gereklidir. Hastaları, özellikle daha yüksek doz seviyelerinde tedavi ederken, doktor potansiyel artan riski dengelemek için yeterli artmış klinik fayda gözlemlemelidir. En düşük etkili doz her hastada aranmalı ve kullanılmalıdır. Artritte semptomatik iyileşme genellikle bir hafta içinde başlar; bununla birlikte, terapötik bir fayda elde etmek için iki hafta boyunca tedavi gerekebilir.
Ağrı, Primer Dismenore ve Akut Tendinit ve Bursit Yönetimi
Önerilen başlangıç dozu günde bir kez iki Sonaflam 500 mg tablettir (1.000 mg). Daha fazla analjezik yarar gerektiren hastalar için, sınırlı bir süre için iki Sonaflam 750 mg tablet (1.500 mg) veya üç Sonaflam 500 mg tablet (1.500 mg) kullanılabilir. Daha sonra, toplam günlük doz iki Sonaflam 500 mg tableti (1.000 mg) geçmemelidir.
Akut Gut
İlk gün önerilen doz günde bir kez iki ila üç Sonaflam 500 mg tablettir (1.000 ila 1.500 mg), ardından saldırı azalıncaya kadar günde bir kez iki Sonaflam 500 mg tablet (1.000 mg) gelir.
Karaciğer yetmezliği olan hastalarda Dozaj Ayarlamaları
Böbrek veya karaciğer yetmezliği olan hastalarda veya yaşlı hastalarda daha düşük bir doz düşünülmelidir. Çalışmalar, naproksen toplam plazma konsantrasyonu değişmese de, naproksen'in bağlanmamış plazma fraksiyonunun yaşlılarda arttığını göstermektedir. Yüksek dozlar gerektiğinde dikkatli olunması ve yaşlı hastalarda doz ayarlaması gerekebilir. Yaşlılarda kullanılan diğer ilaçlarda olduğu gibi, en düşük etkili dozu kullanmak akıllıca olacaktır.
Genel Dozlama Talimatları
Sonaflam Tabletler, EC-Sonaflam ve ANAPROX DS'yi kullanmaya karar vermeden önce Sonaflam Tabletler, EC-Sonaflam ve ANAPROX DS'nin potansiyel faydalarını ve risklerini dikkatlice düşünün. Bireysel hasta tedavi hedefleriyle tutarlı olarak en kısa sürede en düşük etkili dozu kullanın.
Sonaflam Tabletler, EC-Sonaflam veya ANAPROX DS ile başlangıç tedavisine verilen yanıtı gözlemledikten sonra, doz ve sıklık bireysel bir hastanın ihtiyaçlarına göre ayarlanmalıdır.
Enterik kaplamanın bütünlüğünü korumak için, EC-Sonaflam tableti yutulduğunda kırılmamalı, ezilmemeli veya çiğnenmemelidir.
Sonaflam, EC-Sonaflam ve ANAPROX DS gibi naproksen içeren ürünler ve diğer naproksen ürünleri, hepsi naproksen anyonu olarak plazmada dolaştığı için birlikte kullanılmamalıdır.
Romatoid Artrit, Osteoartrit ve Ankilozan Spondilit
Sonaflam Tabletler, ANAPROX DS ve EC-Sonaflam'ın önerilen dozajları Tablo 1'de gösterilmektedir.
Tablo 1: Sonaflam Tabletler, ANAPROX DS ve EC-Sonaflam için önerilen dozajlar
Sonaflam | 250 mg (bir yarım tablet) 500 mg | günde iki kez |
ANAPROX DS | 275 mg (bir yarım tablet) 550 mg (50 mg sodyum ile 500 mg naproksen) | günde iki kez |
EC-Sonaflam | 375 mg | günde iki kez |
veya 500 mg | günde iki kez |
Uzun süreli uygulama sırasında, naproksen dozu hastanın klinik yanıtına bağlı olarak yukarı veya aşağı ayarlanabilir. Uzun süreli uygulama için daha düşük bir günlük doz yeterli olabilir. Sabah ve akşam dozlarının boyutu eşit olmak zorunda değildir ve ilacın günde iki kereden daha sık uygulanması gerekli değildir.
Sabah ve akşam dozlarının boyutu eşit olmak zorunda değildir ve ilacın günde iki kereden daha sık uygulanması genellikle yanıtta bir fark yaratmaz.
Daha düşük dozları iyi tolere eden hastalarda, daha yüksek bir anti-enflamatuar / analjezik aktivite gerektiğinde 6 aya kadar sınırlı süreler boyunca doz 1500 mg / gün naproksene yükseltilebilir. Bu tür hastaları 1500 mg / gün naproksen ile tedavi ederken, doktor potansiyel artan riski dengelemek için yeterli artmış klinik faydaları gözlemlemelidir.
Poliartiküler Juvenil İdiyopatik Artrit
Naproksen katı-oral dozaj formları, poliartiküler juvenil idiyopatik artritli pediatrik hastalarda gerekli esnek doz titrasyonuna izin vermeyebilir. Sıvı bir formülasyon, ağırlık bazlı dozlama ve çocuklarda doz esnekliği ihtiyacı nedeniyle daha uygun olabilir.
Pediyatrik hastalarda, 5 mg / kg / gün dozları, 500 mg naproksen alan yetişkinlerde görülenlere benzer plazma naproksen seviyeleri üretti. Önerilen toplam günlük naproksen dozu, 2 bölünmüş dozda verilen yaklaşık 10 mg / kg'dır. Sonaflam Tabletlerle dozlama, 50 kilogramdan daha hafif çocuklar için uygun değildir.
Ağrı, Primer Dismenore ve Akut Tendinit ve Bursit Yönetimi
ANAPROX DS (naproksen sodyum) tabletlerinin önerilen başlangıç dozu 550 mg'dır, bunu 12 saatte bir 550 mg veya gerektiğinde her 6 ila 8 saatte bir 275 mg (550 mg tabletin yarısı) takip eder. Başlangıç toplam günlük dozu 1375 mg'ı (iki buçuk tablet) naproksen sodyumunu geçmemelidir. Daha sonra, toplam günlük doz 1100 mg naproksen sodyumunu geçmemelidir. Naproksen sodyum tuzu daha hızlı emildiği için, ağrı kesici derhal başlanması istendiğinde akut ağrılı durumların yönetimi için ANAPROX DS önerilir. Sonaflam Tabletler de kullanılabilir. Sonaflam Tabletlerin önerilen başlangıç dozu 500 mg'dır, bunu 6-8 saatte bir 250 mg (500 mg Sonaflam tabletin yarısı) takip eder.. Toplam günlük doz 1250 mg naproksen'i geçmemelidir.
EC-Sonaflam, akut ağrının ilk tedavisi için önerilmez, çünkü naproksen emilimi diğer naproksen içeren ürünlere kıyasla gecikir.
Akut Gut
Önerilen başlangıç dozu 750 mg (bir buçuk tablet) Sonaflam Tablet ve ardından saldırı azalıncaya kadar her 8 saatte bir 250 mg (bir buçuk tablet). ANAPROX DS ayrıca 825 mg'lık bir başlangıç dozunda (bir buçuk tablet) ve ardından 8 saatte bir 275 mg (bir buçuk tablet) kullanılabilir. Emilimdeki gecikme nedeniyle EC-Sonaflam önerilmez.
Naproksen'in Diğer Formülasyonları ile Değiştirilemezlik
Farklı doz güçleri ve formülasyonları (ör., tabletler, süspansiyon) naproksen değiştirilemez. Güçlü yönler veya formülasyonlar değiştirilirken bu fark dikkate alınmalıdır.
NAPROSYN Tabletler, EC-NAPROSYN ve ANAPROX DS aşağıdaki hastalarda kontrendikedir:
- Bilinen aşırı duyarlılık (ör., anafilaktik reaksiyonlar ve ciddi cilt reaksiyonları) naproksen veya ilaç ürününün herhangi bir bileşenine
- Aspirin veya diğer NSAID'leri aldıktan sonra astım, ürtiker veya diğer alerjik tip reaksiyonların öyküsü. Bu hastalarda NSAID'lere şiddetli, bazen ölümcül, anafilaktik reaksiyonlar bildirilmiştir
- Koroner arter baypas greft (KABG) cerrahisi ortamında
- Bileşenlerin herhangi birine karşı aşırı duyarlılık.
- Çapraz duyarlılık reaksiyonları potansiyeli bulunduğundan, daha önce aşırı duyarlılık reaksiyonları gösteren hastalarda (örn. astım, rinit, burun polipleri, anjiyoödem veya ürtiker) ibuprofen, aspirin veya diğer steroidal olmayan antienflamatuar ilaçlara yanıt olarak. Bu reaksiyonların ölümcül olma potansiyeli vardır. Bu hastalarda Sonaflam'a şiddetli anafilaktik benzeri reaksiyonlar bildirilmiştir.
- Özel kullanım uyarıları ve önlemleri).
-)
- Önceki NSAID tedavisi ile ilişkili gastrointestinal kanama veya perforasyon öyküsü. Aktif veya peptik ülser / veya aktif gastrointestinal kanama öyküsü (kanıtlanmış ülserasyon veya kanamanın iki veya daha fazla farklı atakları).
- Prensip olarak, gastrointestinal ülserasyonları, konjestif gastrit veya atrofik gastrit, gastrointestinal kanama veya serebrovasküler kanama gibi diğer kanamaları olan hastalara Sonaflam uygulanmamalıdır.
- Hemoroid veya rektal kanamaya yatkınlık.
Sonaflam aşağıdaki hastalarda kontrendikedir:
- Bilinen aşırı duyarlılık (ör., anafilaktik reaksiyonlar ve ciddi cilt reaksiyonları) naproksen veya ilaç ürününün herhangi bir bileşenine
- Aspirin veya diğer NSAID'leri aldıktan sonra astım, ürtiker veya diğer alerjik tip reaksiyonların öyküsü. Bu hastalarda NSAID'lere şiddetli, bazen ölümcül, anafilaktik reaksiyonlar bildirilmiştir
- Koroner arter baypas greft (KABG) cerrahisi ortamında
Sonaflam Tabletler, EC-Sonaflam ve ANAPROX DS aşağıdaki hastalarda kontrendikedir:
- Bilinen aşırı duyarlılık (ör., anafilaktik reaksiyonlar ve ciddi cilt reaksiyonları) naproksen veya ilaç ürününün herhangi bir bileşenine
- Aspirin veya diğer NSAID'leri aldıktan sonra astım, ürtiker veya diğer alerjik tip reaksiyonların öyküsü. Bu hastalarda NSAID'lere şiddetli, bazen ölümcül, anafilaktik reaksiyonlar bildirilmiştir
- Koroner arter baypas greft (KABG) cerrahisi ortamında
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 NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If NAPROSYN Tablets, EC-NAPROSYN 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.
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 3-6 months, and in about 2%-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
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 NAPROSYN Tablets, EC-NAPROSYN, 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 NAPROSYN Tablets, ECNAPROSYN, or ANAPROX DS immediately, and perform a clinical evaluation of the patient.
Hypertension
NSAIDs, including NAPROSYN Tablets, EC-NAPROSYN, 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 NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If NAPROSYN Tablets, EC-NAPROSYN, 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 NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS in patients with advanced renal disease. The renal effects of NAPROSYN Tablets, EC-NAPROSYN, 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 NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS. Avoid the use of NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If NAPROSYN Tablets, EC-NAPROSYN, 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, NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS are contraindicated in patients with this form of aspirin sensitivity. When NAPROSYN Tablets, EC-NAPROSYN, 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 NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS at the first appearance of skin rash or any other sign of hypersensitivity. NAPROSYN Tablets, EC-NAPROSYN, 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 NAPROSYN Tablets, EC-NAPROSYN, 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 NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.
NSAIDs, including NAPROSYN Tablets, EC-NAPROSYN, 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 NAPROSYN Tablets, EC-NAPROSYN, 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 NAPROSYN Tablets, EC-NAPROSYN 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 NAPROSYN Tablets, EC-NAPROSYN 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 NAPROSYN Tablets, EC-NAPROSYN 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 NAPROSYN Tablets, ECNAPROSYN, 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 NAPROSYN Tablets, EC-NAPROSYN 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 NAPROSYN Tablets, EC-NAPROSYN 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 NAPROSYN Tablets, EC-NAPROSYN 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 NAPROSYN Tablets, EC-NAPROSYN, 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 NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS, in pregnant women starting at 30 weeks of gestation (third trimester).
There are no adequate and well-controlled studies of NAPROSYN Tablets, EC-NAPROSYN 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 NAPROSYN Tablets, EC-NAPROSYN, 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
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.
4.4 Special warnings and precautions for useIn all patients:
Patients treated with NSAIDs long-term should undergo regular medical supervision to monitor for adverse events.
Elderly:
<- Posology and administration). Prolonged use of NSAIDs in these patients is not recommended. Where prolonged therapy is required patients should be reviewed regularly.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.
<- Undesirable effects)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:
<- Undesirable effects).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).
Sonaflam aldıktan sonra baş dönmesi, baş dönmesi, uykusuzluk, uyuşukluk, yorgunluk ve görme bozuklukları veya depresyon gibi istenmeyen etkiler mümkündür. Hasta bu veya benzeri istenmeyen etkileri yaşarsa, makine kullanmamalı veya kullanmamalıdır.
Aşağıdaki advers reaksiyonlar, etiketlemenin diğer bölümlerinde daha ayrıntılı olarak tartışılmaktadır:
- Kardiyovasküler Trombotik Olaylar
- GI Kanama, Ülserasyon ve Perforasyon
- Hepatotoksisite
- Hipertansiyon
- Kalp Yetmezliği ve Ödem
- Böbrek Toksisitesi ve Hiperkalemi
- Anafilaktik Reaksiyonlar
- Ciddi Cilt Reaksiyonları
- Hematolojik Toksisite
Klinik Araştırmalar Deneyimi
Klinik araştırmalar çok çeşitli koşullar altında yapıldığından, bir ilacın klinik çalışmalarında gözlenen advers reaksiyon oranları, başka bir ilacın klinik çalışmalarındaki oranlarla doğrudan karşılaştırılamaz ve uygulamada gözlemlenen oranları yansıtmayabilir.
Bu sınıftaki tüm ilaçlarda olduğu gibi, advers olayların sıklığı ve şiddeti çeşitli faktörlere bağlıdır: ilacın dozu ve tedavi süresi; hastanın yaşı, cinsiyeti, fiziksel durumu; eşzamanlı tıbbi teşhisler veya bireysel risk faktörleri. Aşağıdaki advers reaksiyonlar, frekansa ve ilaç kullanımı ile bu advers olaylar arasında nedensel bir ilişki olup olmadığına bağlı olarak üç bölüme ayrılmıştır. “Olası Nedensel İlişki” olarak listelenen reaksiyonlarda, her bir advers reaksiyon için, ilaç kullanımı ile bildirilen olay arasında nedensel bir ilişki olduğunu gösteren kanıtların bulunduğu en az bir vaka vardır. Bildirilen advers reaksiyonlar, dokuz aylık ek açık etiketli uzatma ile üç aylık iki çift kör kontrollü klinik çalışmanın sonuçlarına dayanmaktadır. Toplam 542 hasta, çift kör dönemde veya dokuz aylık açık etiketli uzatmada Sonaflam Tabletleri aldı. Bu 542 hastanın 232'sinde Sonaflam Tablet, 167'si başlangıçta Naprosyn® ile tedavi edildi ve 143'ü başlangıçta plasebo ile tedavi edildi. Sonaflam Tablet alan hastalar tarafından bildirilen advers reaksiyonlar vücut sistemi ile gösterilir. Naproksen ile gözlenen ancak Sonaflam Tabletler ile yapılan kontrollü çalışmalarda bildirilmeyen bu advers reaksiyonlar italiktir.
Çift kör ve açık etiketli klinik çalışmalardan en sık görülen advers olaylar baş ağrısı (% 15), ardından dispepsi (% 14) ve grip sendromudur (% 10). Hastaların% 3 ila% 9'unda meydana gelen diğer advers olayların insidansı yıldız işareti ile işaretlenmiştir.
Hastaların% 3'ünden daha azında meydana gelen reaksiyonlar işaretlenmemiştir.
İnsidans% 1'den fazla (Olası Nedensel İlişki)
Bir bütün olarak beden - Ağrı (sırt) *, ağrı *, enfeksiyon *, ateş, yaralanma (kaza), asteni, ağrı sandığı, baş ağrısı (% 15), grip sendromu (% 10).
Gastrointestinal - Bulantı *, ishal *, kabızlık *, karın ağrısı *, şişkinlik, gastrit, kusma, disfaji, dispepsi (% 14), mide ekşimesi *, stomatit.
Hematolojik - Anemi, ekimoz.
Solunum - Farenjit *, rinit *, sinüzit *, bronşit, öksürük arttı.
Renal - İdrar yolu enfeksiyonu *, sistit.
Dermatolojik - Deri döküntüsü *, cilt döküntüleri *, ekimozlar *, purpura.
Metabolik ve Beslenme - Periferik ödem, hiperglisemi.
Merkezi Sinir Sistemi - Baş dönmesi, parestezi, uykusuzluk, uyuşukluk *, baş dönmesi.
Kardiyovasküler - Hipertansiyon, ödem *, dispne *, çarpıntı.
Kas-iskelet sistemi - Kramplar (bacak), kas ağrısı, artralji, eklem bozukluğu, tendon bozukluğu.
Özel Duyular - Kulak çınlaması *, işitme bozuklukları, görme bozuklukları.
Genel - Susuzluk.
İnsidans% 1'den Az (Olası Nedensel İlişki)
Bir bütün olarak beden - Apse, monilia, boyun rijit, ağrı boynu, karın genişlemiş, karsinom, selülit, genel ödem, LE sendromu, halsizlik, mukoza zarı bozukluğu, alerjik reaksiyon, ağrı pelvik.
Gastrointestinal - Anoreksiya, kolesistit, kolelitiaz, erütasyon, GI kanaması, rektal kanama, stomatit aftöz, stomatit ülseri, ülser ağzı, ülser mide, periodontal apse, kardiyospazm, kolit, özofajit, gastroenterit, GI bozukluğu, rektal bozukluk, diş bozukluğu, hepatospenomegali.
Renal - Dismenore, dizüri, böbrek fonksiyon anormalliği, noktüri, prostat bozukluğu, piyelonefrit, karsinom göğsü, idrar kaçırma, böbrek hesabı, böbrek yetmezliği, menoraji, metrorrhagia, neoplazm göğsü, nefroskleroz, hematüri, ağrı böbrek, pyuria, idrar anormal, idrar sıklığı, idrar retansiyonu, uterus spazmı, vajinit, glomerüler nefrit, hiperkalemi, interstisyel nefrit, nefrotik sendrom, böbrek hastalığı, böbrek yetmezliği, renal papiller nekroz.
Hematolojik - Lökopeni, kanama süresi arttı, eozinofili, anormal RBC, anormal WBC, trombositopeni, agranülositoz, granülositopeni.
Merkezi Sinir Sistemi - Depresyon, anksiyete, hipertoni, sinirlilik, nevralji, nevrit, baş dönmesi, amnezi, karışıklık, koordinasyon, anormal diplopi, duygusal değişkenlik, hematom subdural, felç, rüya anormallikleri, konsantre olamama, kas zayıflığı.
Dermatolojik: Anjiyodermatit, herpes simpleks, kuru cilt, terleme, ülser derisi, akne, alopesi, dermatit teması, egzama, herpes zoster, tırnak bozukluğu, cilt nekrozu, deri altı nodülü, kaşıntı, ürtiker, neoplazm cilt, ışığa duyarlı dermatit, porfiri benzer ışığa duyarlılık reaksiyonları kutanöz tarda, epidermoliz bullosa.
Özel Duyular - Ambliyopi, sklerit, katarakt, konjonktivit, sağır, kulak bozukluğu, keratokonjonktivit, lakrimasyon bozukluğu, otitis media, ağrı gözü.
Kardiyovasküler - Anjina pektoris, koroner arter hastalığı, miyokard enfarktüsü, derin tromboflebit, vazodilatasyon, vasküler anomali, aritmi, demet dal bloğu, anormal EKG, kalp yetmezliği hakkı, kanama, migren, aort darlığı, senkop, taşikardi, konjestif kalp yetmezliği.
Solunum - Astım, dispne, akciğer ödemi, larenjit, akciğer bozukluğu, burun kanaması, zatürree, solunum sıkıntısı, solunum bozukluğu, eozinofilik pnömonit.
Kas-iskelet sistemi - Miyasteni, kemik bozukluğu, spontan kemik kırığı, fibrotendinit, kemik ağrısı, pitoz, spazm general, bursit.
Metabolik ve Beslenme - Kreatinin artışı, glukozüri, hiperkolesteremi, albüminüri, alkaloz, BUN artışı, dehidrasyon, ödem, glikoz tolerans azalması, hiperürisemi, hipokalemi, SGOT artışı, SGPT artışı, kilo kaybı.
Genel - Anafilaktoid reaksiyonlar, anjiyonörotik ödem, adet bozuklukları, hipoglisemi, pireksi (titreme ve ateş).
İnsidans% 1'den Az (Nedensel İlişki Bilinmiyor)
Naproksen paket etiketinde listelenen ancak Sonaflam Tabletleri alanlar tarafından bildirilmeyen diğer advers reaksiyonlar italik olarak gösterilmiştir. Bu gözlemler doktora uyarı bilgisi olarak listelenmiştir.
Hematolojik - Aplastik anemi, hemolitik anemi.
Merkezi Sinir Sistemi - Aseptik menenjit, bilişsel işlev bozukluğu.
Dermatolojik - Epidermal nekroliz, eritema multiforme, Stevens-Johnson sendromu.
Gastrointestinal - Peptik olmayan GI ülseri, ülseratif stomatit.
Kardiyovasküler - Vaskülit.
Akut NSAID doz aşımlarını takiben semptomlar tipik olarak destekleyici bakım ile geri dönüşümlü olan uyuşukluk, uyuşukluk, bulantı, kusma ve epigastrik ağrı ile sınırlıdır. Gastrointestinal kanama meydana geldi. Hipertansiyon, akut böbrek yetmezliği, solunum depresyonu ve koma meydana gelmiştir, ancak nadirdir.
Birkaç hasta nöbet geçirdi, ancak bunların ilaca bağlı olup olmadığı açık değil. İlacın hangi dozunun hayatı tehdit edici olacağı bilinmemektedir.
NSAID doz aşımını takiben semptomatik ve destekleyici bakımı olan hastaları yönetin. Spesifik bir antidot yoktur. Hemodiyaliz, protein bağlanmasının yüksek derecesi nedeniyle naproksen plazma konsantrasyonunu azaltmaz. Emesis ve / veya aktif kömür düşünün (Yetişkinlerde 60 ila 100 gram, Pediyatrik hastalarda vücut ağırlığının kg'ı başına 1 ila 2 gram) ve / veya dört saat içinde görülen semptomatik hastalarda veya aşırı dozda büyük olan hastalarda ozmotik katartik (Önerilen dozun 5 ila 10 katı). Zorla diürez, idrarın alkalileştirilmesi, hemodiyaliz veya hemoperfüzyon, yüksek protein bağlanması nedeniyle yararlı olmayabilir.
Doz aşımı tedavisi hakkında ek bilgi için bir zehir kontrol merkezine (1-800-2221222) başvurun.
Sonaflam'ın analjezik, antienflamatuar ve anti-piretik eylemleri vardır.
Sonaflam, klasik hayvan test sistemlerinde gösterildiği gibi antipiretik özelliklere sahip steroidal olmayan bir antienflamatuar analjezik bileşiktir. Sonaflam, adrenalektomize hayvanlarda bile anti-enflamatuar etkisini gösterir, bu da etkisinin hipofiz-adrenal eksenden aracılık etmediğini gösterir.
Sonaflam prostaglandin sentetazı inhibe eder (diğer NSAID'ler gibi). Bununla birlikte, diğer NSAID'lerde olduğu gibi, anti-enflamatuar etkisinin kesin mekanizması bilinmemektedir.
Naproksen ve naproksen sodyum,% 95 in vivo biyoyararlanımı ile gastrointestinal sistemden hızla ve tamamen emilir. NAPROSYN'in farklı dozaj formları, emilim derecesi (AUC) ve pik konsantrasyon (Cmax) açısından biyoeşdeğerdir; bununla birlikte, ürünler emilim modellerinde farklılık gösterir. Naproksen ürünleri arasındaki bu farklılıklar, hem kullanılan naproksen kimyasal formu hem de formülasyonu ile ilgilidir. Emilim paterninde gözlenen farklılıklarla bile, naproksen eliminasyon yarılanma ömrü 12 ila 17 saat arasında değişen ürünler arasında değişmez. Kararlı durumdaki naproksen seviyelerine 4 ila 5 gün içinde ulaşılır ve naproksen birikim derecesi bu yarı ömürle tutarlıdır. Bu, salım paternindeki farklılıkların kararlı durum plazma seviyelerine ulaşmada sadece ihmal edilebilir bir rol oynadığını göstermektedir.
Emilim
NAPROSYN Tabletler / ANAPROX DS: NAPROSYN Tabletlerin uygulanmasından sonra, pik plazma seviyelerine 2 ila 4 saat içinde ulaşılır. ANAPROX DS'nin oral uygulamasından sonra, pik plazma seviyelerine 1 ila 2 saat içinde ulaşılır. İki ürün arasındaki oran farkı, ANAPROX DS'de kullanılan naproksen sodyum tuzunun artan sulu çözünürlüğünden kaynaklanmaktadır
EC-NAPROSYN: EC-NAPROSYN, midenin asidik ortamında parçalanmaya karşı bir engel sağlamak ve ince bağırsağın daha nötr ortamında bütünlüğünü kaybetmek için pH'a duyarlı bir kaplama ile tasarlanmıştır. EC-NAPROSYN için seçilen enterik polimer kaplama pH 6'nın üzerinde çözülür. Açlık deneklere EC-NAPROSYN verildiğinde, ilk dozdan yaklaşık 4 ila 6 saat sonra pik plazma seviyelerine ulaşıldı (aralık: 2 ila 12 saat). Bir in vivo radyoaktif işaretli ECNAPROSYN tabletleri kullanan insanlarda yapılan çalışma, EC-NAPROSYN'nin mideden ziyade öncelikle ince bağırsakta çözündüğünü gösterdi, bu nedenle ilacın emilimi mide boşalana kadar ertelendi.
1 haftalık dozlamadan sonra yapılan bir geçiş çalışmasında açlık deneklere (n = 24) EC-NAPROSYN ve NAPROSYN Tabletleri verildiğinde, pik plazma seviyelerine (Tmax) kadar zaman farklılıkları gözlendi, ancak toplam emilimde ölçülen hiçbir fark yoktu. Cmax ve AUC ile:
EC-NAPROSYN * 500 mg teklif | NAPROSYN * 500 mg teklif | |
Cmax (μg / mL) | 94,9 (% 18) | 97,4 (% 13) |
Tmax (saat) | 4 (% 39) | 1.9 (% 61) |
AUC0-12 saat (μg • saat / mL) | 845 (% 20) | 767 (% 15) |
* Ortalama değer (varyasyon katsayısı) |
Antasit Etkileri
EC-NAPROSYN, antasitli (54 mEq tamponlama kapasitesi) tek bir doz olarak verildiğinde, naproksen'in pik plazma seviyeleri değişmedi, ancak zirve süresi azaltıldı (ortalama Tmax 5.6 saat, ortalama Tmax, antasit 5 saat), önemli değil.
Gıda Etkileri
EC-NAPROSYN gıda ile tek bir doz olarak verildiğinde, çoğu denekte pik plazma seviyelerine yaklaşık 12 saat içinde ulaşıldı (aralık: 4 ila 24 saat). Parçalanmaya kadar ince bağırsakta kalma süresi gıda alımından bağımsızdı. Yiyeceklerin varlığı, tabletlerin midede kaldığı süreyi, ilk saptanabilir serum naproksen seviyelerine kadar geçen süreyi ve maksimum naproksen seviyelerine (Tmax) kadar olan süreyi uzattı, ancak pik naproksen seviyelerini (Cmax) etkilemedi.
Dağıtım
Naproksen, 0.16 L / kg'lık bir dağılım hacmine sahiptir. Terapötik seviyelerde naproksen% 99'dan fazla albümine bağlıdır. 500 mg / gün'den daha yüksek naproksen dozlarında, plazma proteinlerine bağlanmanın daha yüksek dozlarda doygunluğundan kaynaklanan klerens artışı nedeniyle plazma seviyelerinde oransaldan daha az artış vardır (ortalama oluk Css 36.5, 500 ile 49.2 ve 56.4 mg / L, Günlük 1000 ve 1500 mg naproksen dozu, sırasıyla). Naproksen anyonu, emziren kadınların sütünde, plazmada maksimum naproksen konsantrasyonunun yaklaşık% 1'ine eşdeğer bir konsantrasyonda bulunmuştur.
Eliminasyon
Metabolizma
Naproksen karaciğerde 6-0-desmetil naproksene yoğun bir şekilde metabolize edilir ve hem ebeveyn hem de metabolitler metabolize edici enzimleri indüklemez. Hem naproksen hem de 6-0-desmetil naproksen, ilgili asilglukuronid konjüge metabolitlerine ayrıca metabolize edilir.
Boşaltım
Naproksen klerensi 0.13 mL / dak / kg'dır. Herhangi bir dozdan naproksen yaklaşık% 95'i idrarda, öncelikle naproksen (<% 1), 6-0-desmetil naproksen (<% 1) veya konjugatları (% 66 ila% 92) olarak atılır. İnsanlarda naproksen anyonunun plazma yarılanma ömrü 12 ila 17 saat arasında değişir. Hem naproksen metabolitlerinin hem de konjugatların karşılık gelen yarılanma ömürleri 12 saatten kısadır ve atılım oranlarının plazmadan naproksen klerensi oranıyla yakından çakıştığı bulunmuştur. Uygulanan dozun% 3'ü veya daha azı küçük miktarlar dışkıya atılır. Böbrek yetmezliği olan hastalarda metabolitler birikebilir.
Sonaflam gastrointestinal sistemden kolayca emilir ve pik plazma seviyelerine 2 ila 4 saat içinde ulaşılır. Sonaflam kanda esas olarak değişmemiş ilaç olarak bulunur. Plazma proteinlerine yoğun bir şekilde bağlıdır ve yaklaşık 15 saatlik bir yarı ömre sahiptir. günde iki kez doz rejiminde tedaviye başlandıktan sonraki 3 gün içinde sabit bir duruma ulaşılmasını sağlar. Emilim derecesi, gıdalardan veya çoğu antasitten önemli ölçüde etkilenmez. Boşaltım neredeyse tamamen değişmemiş bir ilaçla, esas olarak konjuge Sonaflam gibi idrar yoluyla yapılır. Çocuklarda metabolizma yetişkinlerde benzerdir. Kronik alkolik karaciğer hastalığı, Sonaflam'ın toplam plazma konsantrasyonunu azaltır, ancak bağlı olmayan Sonaflam konsantrasyonu artar. Yaşlılarda, toplam plazma konsantrasyonu değişmese de Sonaflam'ın bağlanmamış plazma konsantrasyonu artar. Dozun yaklaşık yarısı 24 saat içinde idrarla ve 5 gün içinde yaklaşık% 94'ü büyük ölçüde glukuronid olarak atılır.
Naproksen'in kendisi iyi emilmiş olsa da, sodyum tuzu formu daha hızlı emilir ve bu da belirli bir doz için daha yüksek pik plazma seviyelerine yol açar. Sonaflam Tabletlerdeki toplam naproksen sodyum dozunun yaklaşık% 30'u dozaj formunda derhal salım bileşeni olarak bulunur. Kalan naproksen sodyum, sürekli salım özellikleri sağlamak için mikropartiküller olarak kaplanır. Oral uygulamadan sonra, dozlamadan yaklaşık 5 saat sonra pik plazma seviyeleri meydana gelen dozlamadan sonraki 30 dakika içinde naproksen plazma seviyeleri tespit edilir. Hem derhal salınan naproksen sodyum hem de Sonaflam Tabletlerden naproksen'in gözlenen terminal eliminasyon yarılanma ömrü yaklaşık 15 saattir. 3 gün içinde sabit durum naproksen seviyelerine ulaşılır ve kandaki naproksen birikim derecesi bununla tutarlıdır.
Plazma Naproksen Konsantrasyonları 24 Konunun Ortalaması (+/- 2SD) (Kararlı Durum, 5. Gün)
Kararlı Durum 5. Gününde Farmakokinetik Parametreler (24 Konunun Ortalaması)
Parametre (birimler) | naproksen 500 mg Q12h / 5 gün (1000 mg) | Sonaflam 2 x 500 mg tablet (1000 mg) Q24h / 5 gün | ||||
Anlamına gelmek | SD | Aralık | Anlamına gelmek | SD | Aralık | |
AUC 0-24 (mcgxh / mL) | 1446 | 168 | 1167-1858 | 1448 | 145 | 1173-1774 |
Cmax (mcg / mL) | 95 | 13 | 71-117 | 94 | 13 | 74-127 |
Cava (mcg / mL) | 60 | 7 | 49-77 | 60 | 6 | 49-74 |
Cmin (mcg / mL) | 36 | 9 | 13-51 | 33 | 7 | 23-48 |
Tmax (saat) | 3 | 1 | 1-4 | 5 | 2 | 2-10 |
Emilim
Naproksen'in kendisi,% 95'lik bir in vivo biyoyararlanımı ile GI yolundan hızla ve tamamen emilir. Farmakokinetik profile dayanarak, Sonaflam Tabletlerin emilim fazı uygulamadan sonraki ilk 4 ila 6 saat içinde ortaya çıkar. Bu, tabletin midede parçalanması, sürekli salimli mikro parçacıkların ince bağırsaktan ve proksimal kalın bağırsağa geçişi ile çakışır. Sağlıklı gönüllülerde, tablet matrisinin hızlı parçalanmasını ve mikro partiküllerin dağılmasını doğrulayan bir in vivo görüntüleme çalışması yapılmıştır.
Sonaflam Tabletlerin sürekli salimli partikül bileşeninden emilim oranı, geleneksel naproksen sodyum tabletlerinkinden daha yavaştır. Plazma seviyelerini koruyan ve günde bir kez dozlamaya izin veren ilaç emilim süreçlerinin bu uzamasıdır.
Gıda Etkileri
Yirmi dört deneğe bir gece hızlı bir şekilde veya bir yemekten 30 dakika sonra tek bir doz Sonaflam Tablet 500 mg verildiğinde önemli bir gıda etkisi gözlenmemiştir. Geleneksel naproksen ve naproksen sodyum formülasyonları ile ortak olarak, gıda Sonaflam Tabletler uygulamasını takiben naproksen emilim oranında hafif bir azalmaya neden olur.
Dağıtım
Naproksen, 0.16 L / kg'lık bir dağılım hacmine sahiptir. Terapötik seviyelerde naproksen,% 99'dan fazla albümine bağlıdır. 500 mg / gün'den daha yüksek naproksen dozlarında, plazma proteinlerine bağlanmanın daha yüksek dozlarda doygunluğundan kaynaklanan klerens artışı nedeniyle plazma seviyelerinde oransaldan daha az bir artış vardır. Bununla birlikte, bağlanmamış naproksen konsantrasyonu doza orantılı olarak artmaya devam etmektedir. Sonaflam Tabletler benzer doz orantılı özellikleri sergiler.
Eliminasyon
Metabolizma
Naproksen, 6-0-desmetil naproksene yoğun bir şekilde metabolize edilir ve hem ebeveyn hem de metabolitler metabolize edici enzimleri indüklemez.
Boşaltım
Sonaflam Tabletlerin ve geleneksel naproksenlerin eliminasyon yarılanma ömrü yaklaşık 15 saattir. 2 ila 3 doz Sonaflam Tablet'ten sonra kararlı durum koşullarına ulaşılır. İlacın çoğu, öncelikle değişmemiş naproksen (% 1'den az), 6-0-desmetil naproksen (% 1'den az) ve glukuronid veya diğer konjugatlar (% 66 ila 92) olarak idrarla atılır. İlacın küçük bir miktarı (<% 5) dışkıya atılır. Boşaltma oranının plazmadan temizleme oranıyla yakından örtüştüğü bulunmuştur. Böbrek yetmezliği olan hastalarda metabolitler birikebilir.
Naproksen ve naproksen sodyum,% 95 in vivo biyoyararlanımı ile gastrointestinal sistemden hızla ve tamamen emilir. Sonaflam'ın farklı dozaj formları, emilim derecesi (AUC) ve pik konsantrasyon (Cmax) açısından biyoeşdeğerdir; bununla birlikte, ürünler emilim modellerinde farklılık gösterir. Naproksen ürünleri arasındaki bu farklılıklar, hem kullanılan naproksen kimyasal formu hem de formülasyonu ile ilgilidir. Emilim paterninde gözlenen farklılıklarla bile, naproksen eliminasyon yarılanma ömrü 12 ila 17 saat arasında değişen ürünler arasında değişmez. Kararlı durumdaki naproksen seviyelerine 4 ila 5 gün içinde ulaşılır ve naproksen birikim derecesi bu yarı ömürle tutarlıdır. Bu, salım paternindeki farklılıkların kararlı durum plazma seviyelerine ulaşmada sadece ihmal edilebilir bir rol oynadığını göstermektedir.
Emilim
Sonaflam Tabletler / ANAPROX DS: Sonaflam Tabletlerin uygulanmasından sonra, pik plazma seviyelerine 2 ila 4 saat içinde ulaşılır. ANAPROX DS'nin oral uygulamasından sonra, pik plazma seviyelerine 1 ila 2 saat içinde ulaşılır. İki ürün arasındaki oran farkı, ANAPROX DS'de kullanılan naproksen sodyum tuzunun artan sulu çözünürlüğünden kaynaklanmaktadır
EC-Sonaflam : EC-Sonaflam, midenin asidik ortamında parçalanmaya karşı bir engel sağlamak ve ince bağırsağın daha nötr ortamında bütünlüğünü kaybetmek için pH'a duyarlı bir kaplama ile tasarlanmıştır. EC-Sonaflam için seçilen enterik polimer kaplama pH 6'nın üzerinde çözülür. Açlık deneklere EC-Sonaflam verildiğinde, ilk dozdan yaklaşık 4 ila 6 saat sonra pik plazma seviyelerine ulaşıldı (aralık: 2 ila 12 saat). Bir in vivo radyoaktif işaretli ECSonaflam tabletleri kullanan insanlarda yapılan çalışma, EC-Sonaflam'ın mideden ziyade öncelikle ince bağırsakta çözündüğünü gösterdi, bu nedenle ilacın emilimi mide boşalana kadar ertelendi.
1 haftalık dozlamadan sonra bir geçiş çalışmasında açlık deneklere (n = 24) EC-Sonaflam ve Sonaflam Tabletler verildiğinde, pik plazma seviyelerine (Tmax) kadar zaman farklılıkları gözlendi, ancak toplam emilimde ölçülen hiçbir fark yoktu. Cmax ve AUC tarafından:
EC-Sonaflam * 500 mg teklif | Sonaflam * 500 mg teklif | |
Cmax (μg / mL) | 94,9 (% 18) | 97,4 (% 13) |
Tmax (saat) | 4 (% 39) | 1.9 (% 61) |
AUC0-12 saat (μg • saat / mL) | 845 (% 20) | 767 (% 15) |
* Ortalama değer (varyasyon katsayısı) |
Antasit Etkileri
EC-Sonaflam antasitli (54 mEq tamponlama kapasitesi) tek bir doz olarak verildiğinde, naproksen'in pik plazma seviyeleri değişmedi, ancak zirve süresi azaltıldı (ortalama Tmax 5.6 saat, ortalama Tmax antasit 5 saat), önemli olmasa da.
Gıda Etkileri
EC-Sonaflam gıda ile tek bir doz olarak verildiğinde, çoğu denekte pik plazma seviyelerine yaklaşık 12 saat içinde ulaşıldı (aralık: 4 ila 24 saat). Parçalanmaya kadar ince bağırsakta kalma süresi gıda alımından bağımsızdı. Yiyeceklerin varlığı, tabletlerin midede kaldığı süreyi, ilk saptanabilir serum naproksen seviyelerine kadar geçen süreyi ve maksimum naproksen seviyelerine (Tmax) kadar olan süreyi uzattı, ancak pik naproksen seviyelerini (Cmax) etkilemedi.
Dağıtım
Naproksen, 0.16 L / kg'lık bir dağılım hacmine sahiptir. Terapötik seviyelerde naproksen% 99'dan fazla albümine bağlıdır. 500 mg / gün'den daha yüksek naproksen dozlarında, plazma proteinlerine bağlanmanın daha yüksek dozlarda doygunluğundan kaynaklanan klerens artışı nedeniyle plazma seviyelerinde oransaldan daha az artış vardır (ortalama oluk Css 36.5, 500 ile 49.2 ve 56.4 mg / L, Günlük 1000 ve 1500 mg naproksen dozu, sırasıyla). Naproksen anyonu, emziren kadınların sütünde, plazmada maksimum naproksen konsantrasyonunun yaklaşık% 1'ine eşdeğer bir konsantrasyonda bulunmuştur.
Eliminasyon
Metabolizma
Naproksen karaciğerde 6-0-desmetil naproksene yoğun bir şekilde metabolize edilir ve hem ebeveyn hem de metabolitler metabolize edici enzimleri indüklemez. Hem naproksen hem de 6-0-desmetil naproksen, ilgili asilglukuronid konjüge metabolitlerine ayrıca metabolize edilir.
Boşaltım
Naproksen klerensi 0.13 mL / dak / kg'dır. Herhangi bir dozdan naproksen yaklaşık% 95'i idrarda, öncelikle naproksen (<% 1), 6-0-desmetil naproksen (<% 1) veya konjugatları (% 66 ila% 92) olarak atılır. İnsanlarda naproksen anyonunun plazma yarılanma ömrü 12 ila 17 saat arasında değişir. Hem naproksen metabolitlerinin hem de konjugatların karşılık gelen yarılanma ömürleri 12 saatten kısadır ve atılım oranlarının plazmadan naproksen klerensi oranıyla yakından çakıştığı bulunmuştur. Uygulanan dozun% 3'ü veya daha azı küçük miktarlar dışkıya atılır. Böbrek yetmezliği olan hastalarda metabolitler birikebilir.
SPC'nin diğer bölümlerinde yer alan verilere ek olarak, reçete yazan ile ilgili klinik öncesi veri yoktur
Kanserojenite
Sonaflam, 24 ay boyunca 8, 16 ve 24 mg / kg / gün dozlarında Sprague-Dawley sıçanlarına gıda ile uygulandı. Sonaflam sıçanlarda kanserojen değildi.
Mutajenite
Mutajenite görülmedi Salmonella typhimurium (5 hücre çizgisi), Sachharomyces cerevisisae (1 hücre çizgisi) ve fare lenfoma testleri.
Doğurganlık
Sonaflam, erkeklere 30 mg / kg / gün ve kadınlara 20 mg / kg / gün dozlarında oral yoldan uygulandığında sıçanların doğurganlığını etkilemedi.
Teratojenisite
Sonaflam, sıçanlara ve tavşanlara organogenez sırasında 20 mg / kg / gün dozunda oral yoldan uygulandığında teratojenik değildi.
Perinatal / Doğum Sonrası Üreme
Gebeliğin üçüncü üç aylık döneminde Sonaflam'ın hamile sıçanlara 2, 10 ve 20 mg / kg / gün dozlarında oral yoldan uygulanması zor işçiliğe neden oldu. Bunlar bu bileşik sınıfının bilinen etkileridir ve aspirin ve indometasinli hamile sıçanlarda gösterilmiştir.
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