parecoxib sodium

HOS-093194 · has-adverse-reaction-information · PDF-Seite 9

Summary of the safety profile The most common adverse reaction for Dynastat is nausea. The most serious reactions occur uncommonly to rarely, and include cardiovascular events such as myocardial infarction and severe hypotension, as well as hypersensitivity events such as anaphylaxis, angioedema, and severe skin reactions. Following coronary artery bypass graft surgery, patients administered Dynastat have a higher risk of adverse reactions such as: cardiovascular/thromboembolic events (including myocardial infarction, stroke/TIA, pulmonary embolus, and deep vein thrombosis; see sections 4.3 and 5.1), deep surgical infections, and sternal wound healing complications. Tabulated list of adverse reactions The following adverse reactions were reported for patients who received parecoxib (N=5,402) in 28 placebo-controlled clinical trials. Reports from post-marketing experience have been listed as “frequency not known” because the respective frequencies cannot be estimated from the available data. Within each frequency grouping, adverse reactions are listed using MedDRA terminology and presented in order of decreasing seriousness. Adverse Drug Reaction Frequency Very Common Common Uncommon Rare (1/10,000 Not known (1/10) (1/100 to (1/1000 to <1/100) to <1/1000) <1/10) Infections and infestations Pharyngitis, Abnormal sternal alveolar osteitis serous wound (dry socket) drainage, wound infection Blood and lymphatic system disorders Anaemia Thrombocytopenia postoperative Immune system disorders Anaphylactoid reaction Metabolism and nutrition disorders Hypokalaemia Hyperglycaemia, anorexia 9 Adverse Drug Reaction Frequency Very Common Common Uncommon Rare (1/10,000 Not known (1/10) (1/100 to (1/1000 to <1/100) to <1/1000) <1/10) Psychiatric disorders Agitation, insomnia Nervous system disorders Hypoaesthesia, Cerebrovascular dizziness disorder Ear and labyrinth disorders

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HOS-093200 · has-adverse-reaction-information · PDF-Seite 25

Summary of the safety profile The most common adverse reaction for Dynastat is nausea. The most serious reactions occur uncommonly to rarely, and include cardiovascular events such as myocardial infarction and severe hypotension, as well as hypersensitivity events such as anaphylaxis, angioedema and severe skin reactions. Following coronary artery bypass graft surgery, patients administered Dynastat have a higher risk of adverse reactions such as: cardiovascular/thromboembolic events (including myocardial infarction, stroke/TIA, pulmonary embolus, and deep vein thrombosis; see sections 4.3 and 5.1), deep surgical infections, and sternal wound healing complications. Tabulated list of adverse reactions The following adverse reactions were reported for patients who received parecoxib (N=5,402) in 28 placebo-controlled clinical trials. Reports from post-marketing experience have been listed as “frequency not known” because the respective frequencies cannot be estimated from the available data. Within each frequency grouping, adverse reactions are listed using MedDRA terminology and presented in order of decreasing seriousness. Adverse Drug Reaction Frequency Very Common Common Uncommon Rare (1/10,000 Not known (1/10) (1/100 to (1/1000 to <1/100) to <1/1000) <1/10) Infections and infestations Pharyngitis, Abnormal sternal alveolar osteitis serous wound (dry socket) drainage, wound infection Blood and lymphatic system disorders Anaemia Thrombocytopenia postoperative Immune system disorders Anaphylactoid reaction Metabolism and nutrition disorders Hypokalaemia Hyperglycaemia, anorexia 25 Adverse Drug Reaction Frequency Very Common Common Uncommon Rare (1/10,000 Not known (1/10) (1/100 to (1/1000 to <1/100) to <1/1000) <1/10) Psychiatric disorders Agitation, insomnia Nervous system disorders Hypoaesthesia, Cerebrovascular dizziness disorder Ear and labyrinth disorders Ear pain C

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HOS-093196 · has-contraindication-information · PDF-Seite 19

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. History of previous serious allergic drug reaction of any type, especially cutaneous reactions such as Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms syndrome (DRESS syndrome), toxic epidermal necrolysis, erythema multiforme or patients with known hypersensitivity to sulfonamides (see sections 4.4 and 4.8). Active peptic ulceration or gastrointestinal (GI) bleeding. Patients who have experienced bronchospasm, acute rhinitis, nasal polyps, angioneurotic oedema, urticaria or other allergic-type reactions after taking acetylsalicylic acid or nonsteroidal anti-inflammatory drugs (NSAIDs) including COX-2 inhibitors. 19 The third trimester of pregnancy and breast-feeding (see sections 4.6 and 5.3). Severe hepatic impairment (serum albumin <25 g/l or Child-Pugh score 10). Inflammatory bowel disease. Congestive heart failure (NYHA II-IV). Treatment of post-operative pain following coronary artery bypass graft (CABG) surgery (see sections 4.8 and 5.1). Established ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease.

HOS-093190 · has-contraindication-information · PDF-Seite 3

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. History of previous serious allergic drug reaction of any type, especially cutaneous reactions such as Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms syndrome (DRESS syndrome), toxic epidermal necrolysis, erythema multiforme or patients with known hypersensitivity to sulfonamides (see sections 4.4 and 4.8). Active peptic ulceration or gastrointestinal (GI) bleeding. Patients who have experienced bronchospasm, acute rhinitis, nasal polyps, angioneurotic oedema, urticaria or other allergic-type reactions after taking acetylsalicylic acid or nonsteroidal anti-inflammatory drugs (NSAIDs) including COX-2 inhibitors. 3 The third trimester of pregnancy and breast-feeding (see sections 4.6 and 5.3). Severe hepatic impairment (serum albumin <25 g/l or Child-Pugh score 10). Inflammatory bowel disease. Congestive heart failure (NYHA II-IV). Treatment of post-operative pain following coronary artery bypass graft (CABG) surgery (see sections 4.8 and 5.1). Established ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease.

HOS-093195 · has-indication-information · PDF-Seite 18

For the short-term treatment of postoperative pain in adults. The decision to prescribe a selective cyclooxygenase-2 (COX-2) inhibitor should be based on an assessment of the individual patient's overall risks (see sections 4.3 and 4.4).

HOS-093189 · has-indication-information · PDF-Seite 2

For the short-term treatment of postoperative pain in adults. The decision to prescribe a selective cyclooxygenase-2 (COX-2) inhibitor should be based on an assessment of the individual patient's overall risks (see sections 4.3 and 4.4).

HOS-093198 · has-interaction-information · PDF-Seite 22

Pharmacodynamic interactions Anticoagulant therapy should be monitored, particularly during the first few days after initiating Dynastat therapy in patients receiving warfarin or other anticoagulants, since these patients have an increased risk of bleeding complications. Therefore, patients receiving oral anticoagulants should be closely monitored for their prothrombin time INR, particularly in the first few days when therapy with parecoxib is initiated or the dose of parecoxib is changed (see section 4.4). Dynastat had no effect on acetylsalicylic acid-mediated inhibition of platelet aggregation or bleeding times. Clinical trials indicate that Dynastat can be given with low dose acetylsalicylic acid (325 mg). In the submitted studies, as with other NSAIDs, an increased risk of gastrointestinal ulceration or other gastrointestinal complications compared to use of parecoxib alone was shown for concomitant administration of low-dose acetylsalicylic acid (see section 5.1). Coadministration of parecoxib and heparin did not affect the pharmacodynamics of heparin (activated partial thromboplastin time) compared to heparin alone. Inhibition of prostaglandins by NSAIDs, including COX-2 inhibitors, may diminish the effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin II antagonists, beta-blockers and diuretics. This interaction should be given consideration in patients receiving parecoxib concomitantly with ACE-inhibitors, angiotensin II antagonists, beta-blockers and diuretics. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDs, including selective COX-2 inhibitors, with 22 ACE inhibitors or Angiotensin-II antagonists, may result in further deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Therefore, the concomitant administration of these drugs should be done with caution. Patients should be adequately hydrated and the need to monitor the renal function should be assessed at the beginning of the concomitant treatment and periodically thereafter. Coadministration of NSAIDs and ciclosporin or tacrolimus has been suggested to increase the nephrotoxic effect of ciclosporin and tacrolimus because of NSAID effects on renal prostaglandins. Renal function should be monitored when parecoxib and any of these medicinal products are coadminister

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HOS-093192 · has-interaction-information · PDF-Seite 6

Pharmacodynamic interactions Anticoagulant therapy should be monitored, particularly during the first few days after initiating Dynastat therapy in patients receiving warfarin or other anticoagulants, since these patients have an increased risk of bleeding complications. Therefore, patients receiving oral anticoagulants should be closely monitored for their prothrombin time INR, particularly in the first few days when therapy with parecoxib is initiated or the dose of parecoxib is changed (see section 4.4). Dynastat had no effect on acetylsalicylic acid-mediated inhibition of platelet aggregation or bleeding times. Clinical trials indicate that Dynastat can be given with low dose acetylsalicylic acid (325 mg). In the submitted studies, as with other NSAIDs, an increased risk of gastrointestinal ulceration or other gastrointestinal complications compared to use of parecoxib alone was shown for concomitant administration of low-dose acetylsalicylic acid (see section 5.1). Coadministration of parecoxib and heparin did not affect the pharmacodynamics of heparin (activated partial thromboplastin time) compared to heparin alone. Inhibition of prostaglandins by NSAIDs, including COX-2 inhibitors, may diminish the effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin II antagonists, beta-blockers and diuretics. This interaction should be given consideration in patients receiving parecoxib concomitantly with ACE-inhibitors, angiotensin II antagonists, beta-blockers and diuretics. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors or Angiotensin-II antagonists, may result in further deterioration of renal function, including possible acute renal failure. These effects are usually reversible. 6 Therefore, the concomitant administration of these drugs should be done with caution. Patients should be adequately hydrated and the need to monitor the renal function should be assessed at the beginning of the concomitant treatment and periodically thereafter. Coadministration of NSAIDs and ciclosporin or tacrolimus has been suggested to increase the nephrotoxic effect of ciclosporin and tacrolimus because of NSAID effects on renal prostaglandins. Renal function should be monitored when parecoxib and any of these medicinal products are coadministered

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HOS-093193 · has-pregnancy-information · PDF-Seite 8

Pregnancy There are no adequate data from the use of parecoxib in pregnant women or during labour. However, inhibition of prostaglandin synthesis might adversely affect pregnancy. Data from epidemiological studies suggest an increased risk of miscarriage after use of prostaglandin synthesis inhibitors in early pregnancy. In animals, administration of prostaglandin synthesis inhibitors, including parecoxib, has been shown to result in increased pre- and post-implantation loss and embryo-foetal lethality (see sections 5.1 and 5.3). From the 20th week of pregnancy onward, Dynastat use may cause oligohydramnios resulting from foetal renal dysfunction. This may occur shortly after treatment initiation and is usually reversible upon discontinuation. In addition, there have been reports of ductus arteriosus constriction following treatment in the second trimester, most of which resolved after treatment cessation. Therefore, during the first and second trimester of pregnancy, Dynastat should not be given unless clearly necessary. If Dynastat is used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept as low and duration of treatment as short as possible. Antenatal monitoring for oligohydramnios and ductus arteriosus constriction should be considered after exposure to Dynastat for several days from gestational week 20 onward. Dynastat should be discontinued if oligohydramnios or ductus arteriosus constriction are found. During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to: • cardiopulmonary toxicity (premature constriction/closure of the ductus arteriosus and pulmonary hypertension); • renal dysfunction (see above); the mother and the neonate, at the end of pregnancy, to: • possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses; • inhibition of uterine contractions resulting in delayed or prolonged labour. Consequently, Dynastat is contraindicated during the third trimester of pregnancy (see sections 4.3 and 5.3). Breast-feeding Administration of a single dose of parecoxib to lactating women following caesarean section resulted in the transfer of a relatively small amount of parecoxib and its active metabolite valdecoxib into 8 human milk, and this resulted in a low relative dose for the i

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HOS-093199 · has-pregnancy-information · PDF-Seite 24

Pregnancy There are no adequate data from the use of parecoxib in pregnant women or during labour. However, inhibition of prostaglandin synthesis might adversely affect pregnancy. Data from epidemiological studies suggest an increased risk of miscarriage after use of prostaglandin synthesis inhibitors in early pregnancy. In animals, administration of prostaglandin synthesis inhibitors, including parecoxib, has been shown to result in increased pre- and post-implantation loss and embryo-foetal lethality (see sections 5.1 and 5.3). From the 20th week of pregnancy onward, Dynastat use may cause oligohydramnios resulting from foetal renal dysfunction. This may occur shortly after treatment initiation and is usually reversible upon discontinuation. In addition, there have been reports of ductus arteriosus constriction following treatment in the second trimester, most of which resolved after treatment cessation. Therefore, during the first and second trimester of pregnancy, Dynastat should not be given unless clearly necessary. If Dynastat is used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept as low and duration of treatment as short as possible. Antenatal monitoring for oligohydramnios and ductus arteriosus constriction should be considered after exposure to Dynastat for several days from gestational week 20 onward. Dynastat should be discontinued if oligohydramnios or ductus arteriosus constriction are found. During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to: • cardiopulmonary toxicity (premature constriction/closure of the ductus arteriosus and pulmonary hypertension); • renal dysfunction (see above); the mother and the neonate, at the end of pregnancy, to: • possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses; • inhibition of uterine contractions resulting in delayed or prolonged labour. Consequently, Dynastat is contraindicated during the third trimester of pregnancy (see sections 4.3 and 5.3). 24 Breast-feeding Administration of a single dose of parecoxib to lactating women following caesarean section resulted in the transfer of a relatively small amount of parecoxib and its active metabolite valdecoxib into human milk, and this resulted in a low relative dose for the

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HOS-093197 · has-warning-information · PDF-Seite 20

Dynastat has been studied in dental, orthopaedic, gynaecologic (principally hysterectomy) and coronary artery bypass graft surgery. There is limited experience in other types of surgery, for example gastrointestinal or urological surgery (see section 5.1). Modes of administration other than IV or IM (e.g. intra-articular, intrathecal) have not been studied and should not be used. Because of the possibility for increased adverse reactions at higher doses of parecoxib, other COX-2 inhibitors and NSAIDs, patients treated with parecoxib should be reviewed following dose increase and, in the absence of an increase in efficacy, other therapeutic options should be considered (see section 4.2). There is limited clinical experience with Dynastat treatment beyond three days (see section 5.1). If, during treatment, patients deteriorate in any of the organ system functions described below, appropriate measures should be taken and discontinuation of parecoxib therapy should be considered. Cardiovascular COX-2 inhibitors have been associated with increased risk of cardiovascular and thrombotic adverse events when taken long term. The exact magnitude of the risk associated with a single dose has not been determined, nor has the exact duration of therapy associated with increased risk. Patients with significant risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking) should only be treated with parecoxib after careful consideration (see section 5.1). Appropriate measures should be taken and discontinuation of parecoxib therapy should be considered if there is clinical evidence of deterioration in the condition of specific clinical symptoms in these patients. Dynastat has not been studied in cardiovascular revascularization procedures other than coronary artery bypass graft (CABG) procedures. Studies in types of surgery other than CABG procedures included patients with American Society of Anaesthesiology (ASA) Physical Status Class I-III only. Acetylsalicylic acid and other NSAIDs COX-2 inhibitors are not a substitute for acetylsalicylic acid for prophylaxis of cardiovascular thrombo-embolic diseases because of their lack of antiplatelet effects. Therefore, antiplatelet therapies should not be discontinued (see section 5.1). Caution should be exercised when coadministering Dynastat with warfarin and other oral anticoagulants (see section 4.5). The concomitant use of parecoxib with other non- acetylsalicylic acid NSAIDs

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HOS-093191 · has-warning-information · PDF-Seite 4

Dynastat has been studied in dental, orthopaedic, gynaecologic (principally hysterectomy) and coronary artery bypass graft surgery. There is limited experience in other types of surgery, for example gastrointestinal or urological surgery (see section 5.1). Modes of administration other than IV or IM (e.g. intra-articular, intrathecal) have not been studied and should not be used. Because of the possibility for increased adverse reactions at higher doses of parecoxib, other COX-2 inhibitors and NSAIDs, patients treated with parecoxib should be reviewed following dose increase and, in the absence of an increase in efficacy, other therapeutic options should be considered (see section 4.2). There is limited clinical experience with Dynastat treatment beyond three days (see section 5.1). If, during treatment, patients deteriorate in any of the organ system functions described below, appropriate measures should be taken and discontinuation of parecoxib therapy should be considered. Cardiovascular COX-2 inhibitors have been associated with increased risk of cardiovascular and thrombotic adverse events when taken long term. The exact magnitude of the risk associated with a single dose has not been determined, nor has the exact duration of therapy associated with increased risk. Patients with significant risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking) should only be treated with parecoxib after careful consideration (see section 5.1). Appropriate measures should be taken and discontinuation of parecoxib therapy should be considered if there is clinical evidence of deterioration in the condition of specific clinical symptoms in these patients. Dynastat has not been studied in cardiovascular revascularization procedures other than coronary artery bypass graft (CABG) procedures. Studies in types of surgery other than CABG procedures included patients with American Society of Anaesthesiology (ASA) Physical Status Class I-III only. Acetylsalicylic acid and other NSAIDs COX-2 inhibitors are not a substitute for acetylsalicylic acid for prophylaxis of cardiovascular thrombo-embolic diseases because of their lack of antiplatelet effects. Therefore, antiplatelet therapies should not be discontinued (see section 5.1). Caution should be exercised when coadministering Dynastat with warfarin and other oral anticoagulants (see section 4.5). The concomitant use of parecoxib with other non- acetylsalicylic acid NSAIDs

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