Keldor

Les comprimés NAPROSYN, EC-NAPROSYN et ANAPROX DS sont indiqués pour:

le soulagement des signes et symptômes de:

• polyarthrite rhumatoïde
• arthrose
• spondylarthrite ankylosante
• Arthrite juvénile idiopathique polyarticulaire

Les comprimés NAPROSYN et ANAPROX DS sont également indiqués pour:

le soulagement des signes et symptômes de:

• tendinite
• bursite
• goutte aiguë

la gestion de:

• douleur
• dysménorrhée primaire

Adultes:

Traitement de la polyarthrite rhumatoïde, de l'arthrose (arthrite dégénérative), de la spondylarthrite ankylosante, de la goutte aiguë, des troubles musculo-squelettiques aigus et de la dysménorrhée.

Enfants:

Polyarthrite rhumatoïde juvénile

Les comprimés Keldor sont indiqués pour le traitement de:

• polyarthrite rhumatoïde (PR)
• arthrose (OA)
• spondylarthrite ankylosante (AS)
• tendinite, bursite
• goutte aiguë
• dysménorrhée primaire (PD)
• le soulagement de la douleur légère à modérée

.

Les comprimés Keldor, EC-Keldor et ANAPROX DS sont indiqués pour:

le soulagement des signes et symptômes de:

• polyarthrite rhumatoïde
• arthrose
• spondylarthrite ankylosante
• Arthrite juvénile idiopathique polyarticulaire

Les tablettes Keldor et ANAPROX DS sont également indiquées pour:

le soulagement des signes et symptômes de:

• tendinite
• bursite
• goutte aiguë

la gestion de:

• douleur
• dysménorrhée primaire

Instructions générales de dosage

Considérez attentivement les avantages et les risques potentiels des comprimés NAPROSYN, EC-NAPROSYN et ANAPROX DS et d'autres options de traitement avant de décider d'utiliser les comprimés NAPROSYN, EC-NAPROSYN et ANAPROX DS. Utilisez la dose efficace la plus faible pour la durée la plus courte compatible avec les objectifs de traitement individuels des patients.

Après avoir observé la réponse au traitement initial avec les comprimés NAPROSYN, EC-NAPROSYN ou ANAPROX DS, la dose et la fréquence doivent être ajustées en fonction des besoins d'un patient individuel.

Pour maintenir l'intégrité du revêtement entérique, le comprimé EC-NAPROSYN ne doit pas être cassé, broyé ou mâché pendant l'ingestion.

Les produits contenant du naproxène tels que NAPROSYN, EC-NAPROSYN et ANAPROX DS, et d'autres produits à base de naproxène ne doivent pas être utilisés en concomitance car ils circulent tous dans le plasma sous forme d'anion naproxène.

Arthrite rhumatoïde, arthrose et spondylarthrite ankylosante

Les doses recommandées des comprimés NAPROSYN, ANAPROX DS et EC-NAPROSYN sont présentées dans le tableau 1.

Tableau 1: Dosages recommandés pour les comprimés NAPROSYN, ANAPROX DS et EC-NAPROSYN

NAPROSYN	250 mg (un demi-comprimé) 500 mg	deux fois par jour
ANAPROX DS	275 mg (un demi-comprimé) 550 mg (naproxène 500 mg avec 50 mg de sodium)	deux fois par jour
EC-NAPROSYN	375 mg	deux fois par jour
	ou 500 mg	deux fois par jour

Pendant l'administration à long terme, la dose de naproxène peut être ajustée vers le haut ou vers le bas en fonction de la réponse clinique du patient. Une dose quotidienne plus faible peut suffire pour une administration à long terme. Les doses du matin et du soir ne doivent pas être de taille égale et l'administration du médicament plus fréquemment que deux fois par jour n'est pas nécessaire.

Les doses du matin et du soir ne doivent pas être égales en taille et l'administration du médicament plus fréquemment que deux fois par jour ne fait généralement pas de différence de réponse.

Chez les patients qui tolèrent bien des doses plus faibles, la dose peut être augmentée à 1500 mg / jour de naproxène pendant des périodes limitées allant jusqu'à 6 mois lorsqu'un niveau plus élevé d'activité anti-inflammatoire / analgésique est requis. Lors du traitement de ces patients avec du naproxène à 1500 mg / jour, le médecin doit observer des avantages cliniques accrus suffisants pour compenser le risque potentiel accru.

Arthrite juvénile idiopathique polyarticulaire

Les formes posologiques de Naproxène à oralité solide peuvent ne pas permettre le titrage flexible de la dose nécessaire chez les patients pédiatriques atteints d'arthrite juvénile idiopathique polyarticulaire. Une formulation liquide peut être plus appropriée pour un dosage en fonction du poids et en raison du besoin de flexibilité de la dose chez les enfants.

Chez les patients pédiatriques, des doses de 5 mg / kg / jour ont produit des taux plasmatiques de naproxène similaires à ceux observés chez les adultes prenant 500 mg de naproxène. La dose quotidienne totale recommandée de naproxène est d'environ 10 mg / kg administrée en 2 doses divisées. Le dosage avec des comprimés NAPROSYN ne convient pas aux enfants pesant moins de 50 kilogrammes.

Gestion de la douleur, de la dysménorrhée primaire et de la tendinite aiguë et de la bursite

La dose initiale recommandée de comprimés ANAPROX DS (naproxène sodique) est de 550 mg suivie de 550 mg toutes les 12 heures ou 275 mg (la moitié d'un comprimé à 550 mg) toutes les 6 à 8 heures selon les besoins. La dose quotidienne totale initiale ne doit pas dépasser 1375 mg (deux comprimés et demi) de naproxène sodique. Par la suite, la dose quotidienne totale ne doit pas dépasser 1100 mg de naproxène sodique. Le sel de sodium du naproxène étant absorbé plus rapidement, ANAPROX DS est recommandé pour la gestion des affections douloureuses aiguës lorsque l'apparition rapide du soulagement de la douleur est souhaitée. Des comprimés NAPROSYN peuvent également être utilisés. La dose initiale recommandée de comprimés NAPROSYN est de 500 mg suivie de 250 mg (la moitié d'un comprimé de 500 mg NAPROSYN) toutes les 6 à 8 heures au besoin.. La dose quotidienne totale ne doit pas dépasser 1250 mg de naproxène.

EC-NAPROSYN n'est pas recommandé pour le traitement initial de la douleur aiguë car l'absorption du naproxène est retardée par rapport aux autres produits contenant du naproxène.

Goutte aiguë

La dose initiale recommandée est de 750 mg (un comprimé et demi) de comprimés NAPROSYN suivis de 250 mg (un demi-comprimé) toutes les 8 heures jusqu'à ce que l'attaque se soit apaisée. ANAPROX DS peut également être utilisé à une dose initiale de 825 mg (un comprimé et demi) suivie de 275 mg (un demi-comprimé) toutes les 8 heures. EC-NAPROSYN n'est pas recommandé en raison du retard d'absorption.

Non-interchangeabilité avec d'autres formulations de naproxène

Différentes dosages et formulations (par ex., comprimés, suspension) de naproxène ne sont pas interchangeables. Cette différence doit être prise en considération lors de l'évolution des forces ou des formulations.

Pour administration orale

Personnes âgées: Les personnes âgées courent un risque accru de conséquences graves des effets indésirables. Si un AINS est jugé nécessaire, la dose la plus faible doit être utilisée et pour la durée la plus courte possible. Le patient doit être surveillé régulièrement pour les saignements gastro-intestinaux pendant le traitement par AINS.

À prendre de préférence avec ou après la nourriture

Troubles rhumatismaux (adultes):

500 mg à 1 g pris en 2 doses à des intervalles de 12 heures ou alternativement, en une seule administration. Dans les cas suivants, une dose de charge de 750 mg ou 1 g par jour pour la phase aiguë est recommandée:

a) Chez les patients signalant une douleur nocturne sévère / ou une raideur matinale.

b) Chez les patients passés à Naprosyn à partir d'une dose élevée d'un autre composé antirhumatismal.

c) Dans l'ostéoarthrose où la douleur est le symptôme prédominant.

Enfants (plus de 5 ans): Une dose de 10 mg par kg de poids corporel par jour en deux doses divisées a été utilisée chez les enfants de plus de 5 ans atteints de polyarthrite rhumatoïde juvénile.

Goutte aiguë (adultes): Dans la goutte aiguë, une dose initiale de 750 mg suivie de 250 mg toutes les 8 heures jusqu'à ce que l'attaque soit passée; a été suggéré.

Enfant: Non recommandé chez les enfants de moins de 16 ans.

Troubles musculo-squelettiques et dysménorrhée (adultes); 500 mg peuvent être administrés initialement suivis de 250 mg toutes les 6 à 8 heures selon les besoins. La dose quotidienne maximale après le premier jour est de 1250 mg par jour.

Enfant: Non recommandé chez les enfants de moins de 16 ans.

La dose recommandée la plus faible doit être utilisée en particulier chez les personnes âgées pour réduire le risque d'effets indésirables.

Personnes âgées: Des études indiquent que bien que la concentration plasmatique totale de Keldor soit inchangée, la fraction plasmatique non liée de Keldor est augmentée chez les personnes âgées.

Insuffisance rénale / hépatique: Une dose plus faible doit être envisagée chez les patients atteints d'insuffisance rénale ou hépatique. Naprosyn est contre-indiqué chez les patients dont la clairance de la créatinine est inférieure à 30 ml / minute car une accumulation de métabolites de Keldor a été observée chez les patients atteints d'insuffisance rénale sévère ou sous dialyse.

Le traitement doit être revu à intervalles réguliers et interrompu si aucun avantage n'est observé ou si une intolérance se produit.

Instructions générales de dosage

Considérez attentivement les avantages et les risques potentiels de Keldor et d'autres options de traitement avant de décider d'utiliser Keldor. Utilisez la posologie efficace la plus faible pour la durée la plus courte compatible avec les objectifs de traitement individuels des patients.

Après avoir observé la réponse au traitement initial par Keldor, la dose et la fréquence doivent être ajustées en fonction des besoins d'un patient individuel.

Arthrite rhumatoïde, arthrose et spondylarthrite ankylosante

La dose initiale recommandée de comprimés Keldor chez l'adulte est de deux comprimés Keldor 375 mg (750 mg) une fois par jour, un Keldor 750 mg (750 mg) une fois par jour ou deux comprimés Keldor 500 mg (1000 mg) une fois par jour. Les patients qui prennent déjà du naproxène 250 mg, 375 mg ou 500 mg deux fois par jour (matin et soir) peuvent voir leur dose quotidienne totale remplacée par les comprimés Keldor en une seule dose quotidienne.

Pendant l'administration à long terme, la dose de comprimés Keldor peut être ajustée vers le haut ou vers le bas en fonction de la réponse clinique du patient. Chez les patients qui tolèrent bien des doses plus faibles de comprimés de Keldor, la dose peut être augmentée à deux comprimés de Keldor 750 mg (1 500 mg), ou à trois comprimés de Keldor 500 mg (1 500 mg) une fois par jour pendant des périodes limitées lorsqu'un niveau plus élevé d'anti- inflammatoire / l'activité analgésique est nécessaire. Lors du traitement des patients, en particulier à des doses plus élevées, le médecin doit observer un bénéfice clinique accru suffisant pour compenser le risque potentiel accru. La dose efficace la plus faible doit être recherchée et utilisée chez chaque patient. L'amélioration symptomatique de l'arthrite commence généralement dans la semaine; cependant, un traitement de deux semaines peut être nécessaire pour obtenir un bénéfice thérapeutique.

Gestion de la douleur, de la dysménorrhée primaire et de la tendinite aiguë et de la bursite

La dose initiale recommandée est de deux comprimés de Keldor 500 mg (1 000 mg) une fois par jour. Pour les patients nécessitant un bénéfice analgésique plus important, deux comprimés de Keldor 750 mg (1 500 mg) ou trois comprimés de Keldor 500 mg (1 500 mg) peuvent être utilisés pendant une période limitée. Par la suite, la dose quotidienne totale ne doit pas dépasser deux comprimés de Keldor 500 mg (1 000 mg).

Goutte aiguë

La dose recommandée le premier jour est de deux à trois comprimés de Keldor 500 mg (1 000 à 1 500 mg) une fois par jour, suivis de deux comprimés de Keldor 500 mg (1 000 mg) une fois par jour, jusqu'à ce que l'attaque se soit apaisée.

Ajustements posologiques chez les patients présentant une insuffisance hépatique

Une dose plus faible doit être envisagée chez les patients atteints d'insuffisance rénale ou hépatique ou chez les patients âgés. Des études indiquent que bien que la concentration plasmatique totale de naproxène soit inchangée, la fraction plasmatique non liée du naproxène est augmentée chez les personnes âgées. La prudence est recommandée lorsque des doses élevées sont nécessaires et qu'un certain ajustement de la posologie peut être nécessaire chez les patients âgés. Comme pour les autres médicaments utilisés chez les personnes âgées, il est prudent d'utiliser la dose efficace la plus faible.

Instructions générales de dosage

Considérez attentivement les avantages et les risques potentiels des comprimés Keldor, EC-Keldor et ANAPROX DS et d'autres options de traitement avant de décider d'utiliser les comprimés Keldor, EC-Keldor et ANAPROX DS. Utilisez la dose efficace la plus faible pendant la durée la plus courte compatible avec les objectifs de traitement individuels des patients.

Après avoir observé la réponse au traitement initial avec les comprimés Keldor, EC-Keldor ou ANAPROX DS, la dose et la fréquence doivent être ajustées en fonction des besoins d'un patient individuel.

Pour maintenir l'intégrité du revêtement entérique, le comprimé EC-Keldor ne doit pas être cassé, broyé ou mâché pendant l'ingestion.

Les produits contenant du naproxène tels que Keldor, EC-Keldor et ANAPROX DS, et d'autres produits à base de naproxène ne doivent pas être utilisés en concomitance car ils circulent tous dans le plasma sous forme d'anion naproxène.

Arthrite rhumatoïde, arthrose et spondylarthrite ankylosante

Les doses recommandées des comprimés Keldor, ANAPROX DS et EC-Keldor sont présentées dans le tableau 1.

Tableau 1: Dosages recommandés pour les comprimés Keldor, ANAPROX DS et EC-Keldor

Keldor	250 mg (un demi-comprimé) 500 mg	deux fois par jour
ANAPROX DS	275 mg (un demi-comprimé) 550 mg (naproxène 500 mg avec 50 mg de sodium)	deux fois par jour
EC-Keldor	375 mg	deux fois par jour
	ou 500 mg	deux fois par jour

Pendant l'administration à long terme, la dose de naproxène peut être ajustée vers le haut ou vers le bas en fonction de la réponse clinique du patient. Une dose quotidienne plus faible peut suffire pour une administration à long terme. Les doses du matin et du soir ne doivent pas être de taille égale et l'administration du médicament plus fréquemment que deux fois par jour n'est pas nécessaire.

Les doses du matin et du soir ne doivent pas être égales en taille et l'administration du médicament plus fréquemment que deux fois par jour ne fait généralement pas de différence de réponse.

Chez les patients qui tolèrent bien des doses plus faibles, la dose peut être augmentée à 1500 mg / jour de naproxène pendant des périodes limitées allant jusqu'à 6 mois lorsqu'un niveau plus élevé d'activité anti-inflammatoire / analgésique est requis. Lors du traitement de ces patients avec du naproxène à 1500 mg / jour, le médecin doit observer des avantages cliniques accrus suffisants pour compenser le risque potentiel accru.

Arthrite juvénile idiopathique polyarticulaire

Les formes posologiques de Naproxène à oralité solide peuvent ne pas permettre le titrage flexible de la dose nécessaire chez les patients pédiatriques atteints d'arthrite juvénile idiopathique polyarticulaire. Une formulation liquide peut être plus appropriée pour un dosage en fonction du poids et en raison du besoin de flexibilité de la dose chez les enfants.

Chez les patients pédiatriques, des doses de 5 mg / kg / jour ont produit des taux plasmatiques de naproxène similaires à ceux observés chez les adultes prenant 500 mg de naproxène. La dose quotidienne totale recommandée de naproxène est d'environ 10 mg / kg administrée en 2 doses divisées. Le dosage avec des comprimés Keldor ne convient pas aux enfants pesant moins de 50 kilogrammes.

Gestion de la douleur, de la dysménorrhée primaire et de la tendinite aiguë et de la bursite

La dose initiale recommandée de comprimés ANAPROX DS (naproxène sodique) est de 550 mg suivie de 550 mg toutes les 12 heures ou 275 mg (la moitié d'un comprimé à 550 mg) toutes les 6 à 8 heures selon les besoins. La dose quotidienne totale initiale ne doit pas dépasser 1375 mg (deux comprimés et demi) de naproxène sodique. Par la suite, la dose quotidienne totale ne doit pas dépasser 1100 mg de naproxène sodique. Le sel de sodium du naproxène étant absorbé plus rapidement, ANAPROX DS est recommandé pour la gestion des affections douloureuses aiguës lorsque l'apparition rapide du soulagement de la douleur est souhaitée. Les comprimés Keldor peuvent également être utilisés. La dose initiale recommandée de comprimés Keldor est de 500 mg suivie de 250 mg (la moitié d'un comprimé de Keldor à 500 mg) toutes les 6 à 8 heures au besoin.. La dose quotidienne totale ne doit pas dépasser 1250 mg de naproxène.

EC-Keldor n'est pas recommandé pour le traitement initial de la douleur aiguë car l'absorption du naproxène est retardée par rapport aux autres produits contenant du naproxène.

Goutte aiguë

La dose initiale recommandée est de 750 mg (un comprimé et demi) de comprimés de Keldor, suivie de 250 mg (un demi-comprimé) toutes les 8 heures jusqu'à ce que l'attaque se soit apaisée. ANAPROX DS peut également être utilisé à une dose initiale de 825 mg (un comprimé et demi) suivie de 275 mg (un demi-comprimé) toutes les 8 heures. EC-Keldor n'est pas recommandé en raison du retard d'absorption.

Non-interchangeabilité avec d'autres formulations de naproxène

Différentes dosages et formulations (par ex., comprimés, suspension) de naproxène ne sont pas interchangeables. Cette différence doit être prise en considération lors de l'évolution des forces ou des formulations.

Les comprimés NAPROSYN, EC-NAPROSYN et ANAPROX DS sont contre-indiqués chez les patients suivants:

• Hypersensibilité connue (par ex., réactions anaphylactiques et réactions cutanées graves) au naproxène ou à tout composant du produit médicamenteux
• Antécédents d'asthme, d'urticaire ou d'autres réactions de type allergique après la prise d'aspirine ou d'autres AINS. Des réactions anaphylactiques sévères, parfois mortelles, aux AINS ont été rapportées chez ces patients
• Dans le cadre de la chirurgie de pontage aortocoronarien (CABG)

- Hypersensibilité à l'un des constituants.

- Étant donné que le potentiel existe pour les réactions de sensibilité croisée, Keldor est contre-indiqué chez les patients qui ont déjà montré des réactions d'hypersensibilité (par ex. asthme, rhinite, polypes nasaux, œdème de Quincke ou urticaire) en réponse à l'ibuprofène, à l'aspirine ou à d'autres anti-inflammatoires non stéroïdiens. Ces réactions peuvent être fatales. De graves réactions anaphylactiques à Keldor ont été rapportées chez ces patients.

- - Mises en garde spéciales et précautions d'emploi).

- )

- Antécédents de saignement gastro-intestinal ou de perforation liés au traitement antérieur par les AINS. Actif ou antécédents d'ulcère gastro-duodénal / ou de saignement gastro-intestinal actif (deux épisodes distincts ou plus d'ulcération ou de saignement prouvés).

- En principe, Keldor ne doit pas être administré aux patients présentant des ulcérations gastro-intestinales, une gastrite congestive ou une gastrite atrophique, des saignements gastro-intestinaux ou d'autres saignements tels que des saignements cérébrovasculaires.

- Hémorroïdes ou prédisposition aux saignements rectaux.

Keldor est contre-indiqué chez les patients suivants:

• Hypersensibilité connue (par ex., réactions anaphylactiques et réactions cutanées graves) au naproxène ou à tout composant du produit médicamenteux
• Antécédents d'asthme, d'urticaire ou d'autres réactions de type allergique après la prise d'aspirine ou d'autres AINS. Des réactions anaphylactiques sévères, parfois mortelles, aux AINS ont été rapportées chez ces patients
• Dans le cadre de la chirurgie de pontage aortocoronarien (CABG)

Les comprimés Keldor, EC-Keldor et ANAPROX DS sont contre-indiqués chez les patients suivants:

• Hypersensibilité connue (par ex., réactions anaphylactiques et réactions cutanées graves) au naproxène ou à tout composant du produit médicamenteux
• Antécédents d'asthme, d'urticaire ou d'autres réactions de type allergique après la prise d'aspirine ou d'autres AINS. Des réactions anaphylactiques sévères, parfois mortelles, aux AINS ont été rapportées chez ces patients
• Dans le cadre de la chirurgie de pontage aortocoronarien (CABG)

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).

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- 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, Keldor 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 use

In 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 Keldor. 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 Keldor 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.

Keldor 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 Keldor.

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 Keldor 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. Keldor is contraindicated in patients having a baseline creatinine clearance of less than 30ml/minute.

Haemodialysis does not decrease the plasma concentration of Keldor 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 Keldor 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 Keldor 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 Keldor are administered to elderly patients, because there are indications that the quantity of non-protein-bound Keldor increases in such patients. Since Keldor 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 Keldor, but the plasma concentration of unbound Keldor is increased. The implication of this finding for Keldor 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 Keldor 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 Keldor, 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 Keldor-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 Keldor have an increased risk of bleeding. The benefits in that case should be weighed up against the risks. In any case concomitant use of Keldor 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 Keldor-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 Keldor administration. In rare cases, adverse ocular disorders including papillitis, retrobulbar optic neuritis and papilloedema, have been reported in users of NSAIDs including Keldor, although a cause-and-effect relationship cannot be established; accordingly, patients who develop visual disturbances during treatment with Keldor-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 Keldor. 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 Keldor.

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 Keldor (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 Keldor 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. Keldor 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 Keldor-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 Keldor, 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 Keldor should be considered.

Interference in tests:

It is suggested that Keldor therapy be temporarily discontinued 48 hours before adrenal function tests are performed, because Keldor may artifactually interfere with some tests for 17-ketogenic steroids. Similarly, Keldor 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 Keldor 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 Keldor in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If Keldor 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 Keldor 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 Keldor immediately, and perform a clinical evaluation of the patient.

Hypertension

NSAIDs, including Keldor, 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 Keldor in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If Keldor 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 Keldor in patients with advanced renal disease. The renal effects of Keldor may hasten the progression of renal dysfunction in patients with preexisting renal disease.

Correct volume status in dehydrated or hypovolemic patients prior to initiating Keldor. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of Keldor. Avoid the use of Keldor in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If Keldor 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, Keldor is contraindicated in patients with this form of aspirin sensitivity. When Keldor 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 Keldor at the first appearance of skin rash or any other sign of hypersensitivity.

Keldor 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 Keldor, 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 Keldor has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.

NSAIDs, including Keldor, 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 Keldor 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 Keldor 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

Keldor, 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 Keldor 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

Keldor, 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 Keldor 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 Keldor, may be associated with a reversible delay in ovulation.

Fetal Toxicity

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

There are no adequate and well-controlled studies of Keldor 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 Keldor 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 Keldor and any potential adverse effects on the breastfed infant from the Keldor 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 Keldor, 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 Keldor, in women who have difficulties conceiving or who are undergoing investigation of infertility.

Pediatric Use

The safety and effectiveness of Keldor 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 Keldor Tablets, EC-Keldor, and ANAPROX DS in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If Keldor Tablets, EC-Keldor 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.

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 treat