DYNASTAT 40mg powder for injection medication leaflet

Dynastat 40 mg powder for solution for injection

Each vial contains 40 mg parecoxib (as 42.36 mg parecoxib sodium). After reconstitution, theconcentration of parecoxib is 20 mg/ml. Each 2 ml of reconstituted powder contains 40 mg ofparecoxib.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose.

When reconstituted in sodium chloride 9 mg/ml (0.9%) solution, Dynastat contains approximately0.44 mmol of sodium per vial.

For the full list of excipients, see section 6.1.

Powder for solution for injection (powder for injection).

White to off-white powder.

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 anassessment of the individual patient's overall risks (see sections 4.3 and 4.4).

The recommended dose is 40 mg administered intravenously (IV) or intramuscularly (IM), followedevery 6 to 12 hours by 20 mg or 40 mg as required, not to exceed 80 mg/day.

As the cardiovascular risk of COX-2 specific inhibitors may increase with dose and duration ofexposure, the shortest duration possible and the lowest effective daily dose should be used. There islimited clinical experience with Dynastat treatment beyond three days (see section 5.1).

Concomitant use with opioid analgesics

Opioid analgesics can be used concurrently with parecoxib, dosing as described in the paragraphabove. In all clinical assessments parecoxib was administered at a fixed time interval whereas theopioids were administered on as needed basis.

No dose adjustment is generally necessary in elderly patients (≥65 years). However, for elderlypatients weighing less than 50 kg, treatment should be initiated with half the usual recommended doseof Dynastat and reduce the maximum daily dose to 40 mg (see section 5.2).

There is no clinical experience in patients with severe hepatic impairment (Child-Pugh score 10),therefore its use is contraindicated in these patients (see sections 4.3 and 5.2). No dosage adjustment isgenerally necessary in patients with mild hepatic impairment (Child-Pugh score 5-6). Dynastat shouldbe introduced with caution and at half the usual recommended dose in patients with moderate hepaticimpairment (Child-Pugh score 7-9) and the maximum daily dose should be reduced to 40 mg.

In patients with severe renal impairment (creatinine clearance <30 ml/min.) or patients who may bepredisposed to fluid retention, parecoxib should be initiated at the lowest recommended dose (20 mg)and the patient's kidney function should be closely monitored (see sections 4.4 and 5.2). On the basisof pharmacokinetics, no dose adjustment is necessary in patients with mild to moderate renalimpairment (creatinine clearance of 30-80 ml/min.).

The safety and efficacy of parecoxib in children under 18 years old have not been established. No dataare available. Therefore, parecoxib is not recommended in these patients.

The IV bolus injection may be given rapidly and directly into a vein or into an existing IV line. The IMinjection should be given slowly and deeply into the muscle. For instructions on reconstitution of themedicinal product before administration, see section 6.6.

Precipitation may occur when Dynastat is combined in solution with other medicinal products andtherefore Dynastat must not be mixed with any other medicinal product, either during reconstitution orinjection. In those patients where the same IV line is to be used to inject another medicinal product, theline must be adequately flushed prior to and after Dynastat injection with a solution of knowncompatibility.

After reconstitution with acceptable solvents, Dynastat may only be injected IV or IM, or into IV linesdelivering the following:

* sodium chloride 9 mg/ml (0.9%) solution for injection/infusion;

* glucose 50 mg/ml (5%) solution for infusion;

* sodium chloride 4.5 mg/ml (0.45%) and glucose 50 mg/ml (5%) solution forinjection/infusion;or

* Ringer-Lactate solution for injection.

Injection into an IV line delivering glucose 50 mg/ml (5%) in Ringer-Lactate solution for injection, orother IV fluids not listed above, is not recommended as this may cause precipitation from solution.

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 knownhypersensitivity 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 nonsteroidalanti-inflammatory drugs (NSAIDs) including COX-2 inhibitors.

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).

Congestive heart failure (NYHA II-IV).

Treatment of post-operative pain following coronary artery bypass graft (CABG) surgery (see sections4.8 and 5.1).

Established ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease.

Dynastat has been studied in dental, orthopaedic, gynaecologic (principally hysterectomy) andcoronary artery bypass graft surgery. There is limited experience in other types of surgery, for examplegastrointestinal or urological surgery (see section 5.1).

Modes of administration other than IV or IM (e.g. intra-articular, intrathecal) have not been studiedand should not be used.

Because of the possibility for increased adverse reactions at higher doses of parecoxib, other COX-2inhibitors and NSAIDs, patients treated with parecoxib should be reviewed following dose increaseand, in the absence of an increase in efficacy, other therapeutic options should be considered (seesection 4.2). There is limited clinical experience with Dynastat treatment beyond three days (seesection 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.

COX-2 inhibitors have been associated with increased risk of cardiovascular and thrombotic adverseevents when taken long term. The exact magnitude of the risk associated with a single dose has notbeen 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 (seesection 5.1).

Appropriate measures should be taken and discontinuation of parecoxib therapy should be consideredif there is clinical evidence of deterioration in the condition of specific clinical symptoms in thesepatients. Dynastat has not been studied in cardiovascular revascularization procedures other thancoronary artery bypass graft (CABG) procedures. Studies in types of surgery other than CABGprocedures 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 cardiovascularthrombo-embolic diseases because of their lack of antiplatelet effects. Therefore, antiplatelet therapiesshould 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 ofparecoxib with other non- acetylsalicylic acid NSAIDs should be avoided.

Dynastat may mask fever and other signs of inflammation (see section 5.1). In isolated cases, anaggravation of soft tissue infections has been described in connection with the use of NSAIDs and innonclinical studies with Dynastat (see section 5.3). Caution should be exercised with respect tomonitoring the incision for signs of infection in surgical patients receiving Dynastat.

Gastrointestinal

Upper gastrointestinal (GI) complications (perforations, ulcers or bleedings [PUBs]), some of themresulting in fatal outcome, have occurred in patients treated with parecoxib. Caution is advised in thetreatment of patients most at risk of developing a gastrointestinal complication with NSAIDs; theelderly, or patients with a prior history of gastrointestinal disease, such as ulceration and GI bleeding,or patients using acetylsalicylic acid concomitantly. The NSAIDs class is also associated withincreased GI complications when coadministered with glucocorticoids, selective serotonin reuptakeinhibitors, other antiplatelet drugs, other NSAIDs or patients ingesting alcohol. There is furtherincrease in the risk of gastrointestinal adverse effects (gastrointestinal ulceration or othergastrointestinal complications), when parecoxib is taken concomitantly with acetylsalicylic acid (evenat low doses).

Serious skin reactions, including erythema multiforme, exfoliative dermatitis and Stevens-Johnsonsyndrome (some of them fatal) have been reported through post-marketing surveillance in patientsreceiving parecoxib. Additionally, fatal reports of toxic epidermal necrolysis have been reportedthrough post-marketing surveillance in patients receiving valdecoxib (the active metabolite ofparecoxib) and cannot be ruled out for parecoxib (see section 4.8). Some NSAIDs and selective

COX- 2 inhibitors have been associated with an increased risk of generalized bullous fixed drugeruptions (GBFDE). DRESS syndrome may occur with parecoxib exposure based on other seriousskin reactions reported with celecoxib and valdecoxib exposure. Patients appear to be at highest riskfor these reactions early in the course of therapy; the onset of the reaction occurring in the majority ofcases within the first month of treatment.

Appropriate measures should be taken by physicians to monitor for any serious skin reactions withtherapy, e.g. additional patient consultations. Patients should be advised to immediately report anyemergent skin condition to their physician.

Parecoxib should be discontinued at the first appearance of skin rash, mucosal lesions, or any othersign of hypersensitivity. Serious skin reactions are known to occur with NSAIDs including COX-2selective inhibitors as well as other medicinal products. However, the reported rate of serious skinevents appears to be greater for valdecoxib (the active metabolite of parecoxib) as compared to other

COX-2 selective inhibitors. Patients with a history of sulfonamide allergy may be at greater risk ofskin reactions (see section 4.3). Patients without a history of sulfonamide allergy may also be at riskfor serious skin reactions.

Hypersensitivity reactions (anaphylaxis and angioedema) have been reported in post-marketingexperience with valdecoxib and parecoxib (see section 4.8). Some of these reactions have occurred inpatients with a history of allergic-type reactions to sulfonamides (see section 4.3). Parecoxib should bediscontinued at the first sign of hypersensitivity.

Cases of severe hypotension shortly following parecoxib administration have been reported inpost-marketing experience with parecoxib. Some of these cases have occurred without other signs ofanaphylaxis. The physician should be prepared to treat severe hypotension.

Fluid retention, oedema, renal

As with other medicinal products known to inhibit prostaglandin synthesis, fluid retention and oedemahave been observed in some patients taking parecoxib. Therefore, parecoxib should be used withcaution in patients with compromised cardiac function, preexisting oedema, or other conditionspredisposing to, or worsened by, fluid retention including those taking diuretic treatment or otherwiseat risk of hypovolemia. If there is clinical evidence of deterioration in the condition of these patients,appropriate measures including discontinuation of parecoxib should be taken.

Acute renal failure has been reported through post-marketing surveillance in patients receivingparecoxib (see section 4.8). Since prostaglandin synthesis inhibition may result in deterioration ofrenal function and fluid retention, caution should be observed when administering Dynastat in patientswith impaired renal function (see section 4.2) or hypertension, or in patients with compromised cardiacor hepatic function or other conditions predisposing to fluid retention.

Caution should be used when initiating treatment with Dynastat in patients with dehydration. In thiscase, it is advisable to rehydrate patients first and then start therapy with Dynastat.

As with all NSAIDs, parecoxib can lead to the onset of new hypertension or worsening of pre-existinghypertension, either of which may contribute to the increased incidence of cardiovascular events.

Parecoxib should be used with caution in patients with hypertension. Blood pressure should bemonitored closely during the initiation of therapy with parecoxib and throughout the course of therapy.

If blood pressure rises significantly, alternative treatment should be considered.

Dynastat should be used with caution in patients with moderate hepatic impairment (Child-Pughscore 7-9) (see section 4.2).

Use with oral anticoagulants

The concomitant use of NSAIDs with oral anticoagulants increases the risk of bleeding. Oralanticoagulants include warfarin/coumarin-type and novel oral anticoagulants (e.g. apixaban,dabigatran, and rivaroxaban) (see section 4.5).

This medicine contains less than 1 mmol sodium (23 mg) per ml, that is to say essentially‘sodium-free’.

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 anincreased risk of bleeding complications. Therefore, patients receiving oral anticoagulants should beclosely monitored for their prothrombin time INR, particularly in the first few days when therapy withparecoxib 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 bleedingtimes. 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 othergastrointestinal complications compared to use of parecoxib alone was shown for concomitantadministration of low-dose acetylsalicylic acid (see section 5.1).

Coadministration of parecoxib and heparin did not affect the pharmacodynamics of heparin (activatedpartial thromboplastin time) compared to heparin alone.

Inhibition of prostaglandins by NSAIDs, including COX-2 inhibitors, may diminish the effect ofangiotensin converting enzyme (ACE) inhibitors, angiotensin II antagonists, beta-blockers anddiuretics. This interaction should be given consideration in patients receiving parecoxib concomitantlywith ACE-inhibitors, angiotensin II antagonists, beta-blockers and diuretics.

In patients who are elderly, volume-depleted (including those on diuretic therapy), or withcompromised 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.

Therefore, the concomitant administration of these drugs should be done with caution. Patients shouldbe adequately hydrated and the need to monitor the renal function should be assessed at the beginningof the concomitant treatment and periodically thereafter.

Coadministration of NSAIDs and ciclosporin or tacrolimus has been suggested to increase thenephrotoxic 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 arecoadministered.

Dynastat may be coadministered with opioid analgesics. In clinical trials, the daily requirement for

PRN opioids was significantly reduced when coadministered with parecoxib.

Effects of other medicinal products on the pharmacokinetics of parecoxib (or its active metabolitevaldecoxib)

Parecoxib is rapidly hydrolysed to the active metabolite valdecoxib. In humans, studies demonstratedthat valdecoxib metabolism is predominantly mediated via CYP3A4 and 2C9 isozymes.

Plasma exposure (AUC and Cmax) to valdecoxib was increased (62% and 19%, respectively) whencoadministered with fluconazole (predominantly a CYP2C9 inhibitor), indicating that the dose ofparecoxib should be reduced in those patients who are receiving fluconazole therapy.

Plasma exposure (AUC and Cmax) to valdecoxib was increased (38% and 24%, respectively) whencoadministered with ketoconazole (CYP3A4 inhibitor), however, a dosage adjustment should notgenerally be necessary for patients receiving ketoconazole.

The effect of enzyme induction has not been studied. The metabolism of valdecoxib may increasewhen coadministered with enzyme inducers such as rifampicin, phenytoin, carbamazepine, ordexamethasone.

Effect of parecoxib (or its active metabolite valdecoxib) on the pharmacokinetics of other medicinalproducts

Treatment with valdecoxib (40 mg twice daily for 7 days) produced a 3-fold increase in plasmaconcentrations of dextromethorphan (CYP2D6 substrate). Therefore, caution should be observed whencoadministering Dynastat and medicinal products that are predominantly metabolised by CYP2D6 andwhich have narrow therapeutic margins (e.g. flecainide, propafenone, metoprolol).

Plasma exposure of omeprazole (CYP 2C19 substrate) 40 mg once daily was increased by 46%following administration of valdecoxib 40 mg twice daily for 7 days, while the plasma exposure tovaldecoxib was unaffected. These results indicate that although valdecoxib is not metabolised by

CYP2C19, it may be an inhibitor of this isoenzyme. Therefore, caution should be observed whenadministering Dynastat with medicinal products known to be substrates of CYP2C19 (e.g. phenytoin,diazepam, or imipramine).

In two pharmacokinetic interaction studies in rheumatoid arthritis patients receiving a stable weeklymethotrexate dose (5-20 mg/week, as a single oral or intramuscular dose), orally administeredvaldecoxib (10 mg twice daily or 40 mg twice daily) had little or no effect on the steady-state plasmaconcentrations of methotrexate. However caution is advised when methotrexate is administeredconcurrently with NSAIDs, because NSAID administration may result in increased plasma levels ofmethotrexate. Adequate monitoring of methotrexate-related toxicity should be considered whencoadministering parecoxib and methotrexate.

Coadministration of valdecoxib and lithium produced significant decreases in lithium serum clearance(25%) and renal clearance (30%) with a 34% higher serum exposure compared to lithium alone.

Lithium serum concentration should be monitored closely when initiating or changing parecoxibtherapy in patients receiving lithium.

Coadministration of valdecoxib with glibenclamide (CYP3A4 substrate) did not affect either thepharmacokinetics (exposure) or the pharmacodynamics (blood glucose and insulin levels) ofglibenclamide.

Injectable anaesthetics

Coadministration of IV parecoxib 40 mg with propofol (CYP2C9 substrate) or midazolam (CYP3A4substrate) did not affect either the pharmacokinetics (metabolism and exposure) or thepharmacodynamics (EEG effects, psychomotor tests and waking from sedation) of IV propofol or IVmidazolam. Additionally, coadministration of valdecoxib had no clinically significant effect on thehepatic or intestinal CYP 3A4-mediated metabolism of orally administered midazolam.

Administration of IV parecoxib 40 mg had no significant effect on the pharmacokinetics of either IVfentanyl or IV alfentanil (CYP3A4 substrates).

Inhalation anaesthetics

No formal interaction studies have been done. In surgery studies in which parecoxib was administeredpre-operatively, no evidence of pharmacodynamic interaction was observed in patients receivingparecoxib and the inhalation anaesthetic agents nitrous oxide and isoflurane (see section 5.1).

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 epidemiologicalstudies suggest an increased risk of miscarriage after use of prostaglandin synthesis inhibitors in earlypregnancy. In animals, administration of prostaglandin synthesis inhibitors, including parecoxib, hasbeen shown to result in increased pre- and post-implantation loss and embryo-foetal lethality (seesections 5.1 and 5.3). From the 20th week of pregnancy onward, Dynastat use may causeoligohydramnios resulting from foetal renal dysfunction. This may occur shortly after treatmentinitiation and is usually reversible upon discontinuation. In addition, there have been reports of ductusarteriosus constriction following treatment in the second trimester, most of which resolved aftertreatment cessation. Therefore, during the first and second trimester of pregnancy, Dynastat should notbe given unless clearly necessary. If Dynastat is used by a woman attempting to conceive, or duringthe first and second trimester of pregnancy, the dose should be kept as low and duration of treatment asshort as possible. Antenatal monitoring for oligohydramnios and ductus arteriosus constriction shouldbe considered after exposure to Dynastat for several days from gestational week 20 onward. Dynastatshould be discontinued if oligohydramnios or ductus arteriosus constriction are found.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetusto:

* cardiopulmonary toxicity (premature constriction/closure of the ductus arteriosus andpulmonary 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 atvery 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 and5.3).

Administration of a single dose of parecoxib to lactating women following caesarean section resultedin the transfer of a relatively small amount of parecoxib and its active metabolite valdecoxib intohuman milk, and this resulted in a low relative dose for the infant (approximately 1% of theweight-adjusted maternal dose). Dynastat must not be administered to women who breast-feed (seesection 4.3).

The use of Dynastat, as with any medicinal product known to inhibit cyclooxygenase/prostaglandinsynthesis, is not recommended in women attempting to conceive (see sections pct. 4.3, 5.1 and 5.3).

Based on the mechanism of action, the use of NSAIDs, may delay or prevent rupture of ovarianfollicles, which has been associated with reversible infertility in some women. In women who havedifficulties conceiving or who are undergoing investigation of infertility, withdrawal of NSAIDs,including Dynastat should be considered.

Patients who experience dizziness, vertigo or somnolence after receiving Dynastat should refrain fromdriving or operating machines.

The most common adverse reaction for Dynastat is nausea. The most serious reactions occuruncommonly to rarely, and include cardiovascular events such as myocardial infarction and severehypotension, as well as hypersensitivity events such as anaphylaxis, angioedema, and severe skinreactions. Following coronary artery bypass graft surgery, patients administered Dynastat have ahigher risk of adverse reactions such as: cardiovascular/thromboembolic events (including myocardialinfarction, stroke/TIA, pulmonary embolus, and deep vein thrombosis; see sections 4.3 and 5.1), deepsurgical infections, and sternal wound healing complications.

The following adverse reactions were reported for patients who received parecoxib (N=5,402) in28 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 availabledata. Within each frequency grouping, adverse reactions are listed using MedDRA terminology andpresented 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)

Pharyngitis, Abnormal sternalalveolar osteitis serous wound(dry socket) drainage, woundinfection

Anaemia Thrombocytopeniapostoperative

Anaphylactoidreaction

Hypokalaemia Hyperglycaemia,anorexia

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)

Agitation,insomnia

Hypoaesthesia, Cerebrovasculardizziness disorder

Ear and labyrinth disorders

Ear pain

Myocardial Circulatoryinfarction, collapse,bradycardia congestive heartfailure, tachycardia

Hypertension, Hypertensionhypotension (aggravated),orthostatic hypotension

Respiratory Pulmonary Dyspnoeainsufficiency embolism

Nausea Abdominal pain, Gastroduodenal Pancreatitis,vomiting, ulceration, oesophagitis,constipation, gastrooesophageal oedema mouthdyspepsia, reflux disease, dry (perioralflatulence mouth, gastrointestinal swelling)sounds abnormal

Pruritus, Ecchymosis, rash, Stevens-Johnsonhyperhidrosis urticaria syndrome,erythemamultiforme,exfoliativedermatitis

Back pain Arthralgia

Oliguria Renal failure Renal failure,acute

Oedema Asthenia, injection site Hypersensitivityperipheral pain, injection site reactionsreaction includinganaphylaxis andangioedema

Blood Blood CPKcreatinine increased, bloodincreased LDH increased,

SGOT increased,

SGPT increased,

BUN increased.

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)

Post proceduralcomplication (skin)

In post-marketing experience, toxic epidermal necrolysis has been reported in association with the useof valdecoxib, and cannot be ruled out for parecoxib (see section 4.4). In addition, the following rare,serious adverse reactions have been reported in association with the use of NSAIDs and cannot beruled out for Dynastat: bronchospasm and hepatitis.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Reporting of overdose with parecoxib has been associated with adverse reactions which have also beendescribed with recommended doses of parecoxib.

In case of acute overdose, patients should be managed by symptomatic and supportive care. There areno specific antidotes. Parecoxib is a prodrug of valdecoxib. Valdecoxib is not removed byhaemodialysis. Diuresis or alkalisation of urine may not be useful due to high protein binding ofvaldecoxib.

Pharmacotherapeutic group: Anti-inflammatory and antirheumatic products, Coxibs, ATC code:

M01AH04

Parecoxib is a prodrug of valdecoxib. Valdecoxib is a selective COX-2 inhibitor within the clinicaldose range. Cyclooxygenase is responsible for generation of prostaglandins. Two isoforms, COX-1and COX-2, have been identified. COX-2 is the isoform of the enzyme that has been shown to beinduced by pro-inflammatory stimuli and has been postulated to be primarily responsible for thesynthesis of prostanoid mediators of pain, inflammation, and fever. COX-2 is also involved inovulation, implantation, and closure of the ductus arteriosus, regulation of renal function, and centralnervous system functions (fever induction, pain perception, and cognitive function). It may also play arole in ulcer healing. COX-2 has been identified in tissue around gastric ulcers in man but its relevanceto ulcer healing has not been established.

The difference in antiplatelet activity between some COX-1 inhibiting NSAIDs and COX-2 selectiveinhibitors may be of clinical significance in patients at risk of thrombo-embolic reactions. COX-2selective inhibitors reduce the formation of systemic (and therefore possibly endothelial) prostacyclinwithout affecting platelet thromboxane. The clinical relevance of these observations has not beenestablished.

Parecoxib has been used in a range of major and minor surgeries. The efficacy of Dynastat wasestablished in studies of dental, gynaecologic (hysterectomy), orthopaedic (knee and hip replacement),and coronary artery bypass graft surgical pain. The first perceptible analgesic effect occurred in7-13 minutes, with clinically meaningful analgesia demonstrated in 23-39 minutes and a peak effectwithin 2 hours following administration of single doses of 40 mg IV or IM Dynastat. The magnitude ofanalgesic effect of the 40 mg dose was comparable with that of ketorolac 60 mg IM or ketorolac 30 mg

IV. After a single dose, the duration of analgesia was dose and clinical pain model dependent, andranged from 6 to greater than 12 hours.

Use of parecoxib beyond 3 days

Most trials were designed for dosing of parecoxib up to 3 days. Data from 3 randomisedplacebo-controlled trials, where the protocols allowed treatment of parecoxib for >3 days was pooledand analysed. In the pooled analysis of 676 patients, 318 received placebo and 358 received parecoxib.

Of the patients treated with parecoxib, 317 patients received parecoxib for up to 4 days, 32 patients forup to 5 days, while only 8 patients were treated for up to 6 days and 1 patient for 7 or more days. Ofthe patients treated with placebo, 270 patients received placebo for up to 4 days, 43 patients for up to5 days, while only 3 patients were treated for up to 6 days and 2 patients for 7 or more days. Bothgroups had similar demographics. The mean (SD) duration of treatment was 4.1 (0.4) days forparecoxib and 4.2 (0.5) days for placebo, the range was 4-7 days for parecoxib and 4-9 days forplacebo. The occurrence of adverse events in patients receiving parecoxib for 4-7 days (medianduration 4 days) was low after treatment Day 3 and similar to placebo.

Opioid-sparing effects

In a placebo-controlled, orthopedic, and general surgery study (n =1050), patients received Dynastat atan initial parenteral dose of 40 mg IV followed by 20 mg twice daily for a minimum of 72 hours inaddition to receiving standard care including supplemental patient controlled opioids. The reduction inopioid use with Dynastat treatment on Days 2 and 3 was 7.2 mg and 2.8 mg (37% and 28%respectively). This reduction in opioid use was accompanied by significant reductions inpatient-reported opioid symptom distress. Added pain relief compared to opioids alone was shown.

Additional studies in other surgical settings provided similar observations. There are no data indicatingless overall adverse events associated with the use of parecoxib compared to placebo when used inconjunction with opioids.

Gastrointestinal studies

In short-term studies (7 days), the incidence of endoscopically observed gastroduodenal ulcers orerosions in healthy young and elderly (65 years) subjects administered Dynastat (5-21%), althoughhigher than placebo (5-12%), was statistically significantly lower than the incidence observed with

NSAIDs (66-90%).

CABG post-operative safety studies

In addition to routine adverse event reporting, pre-specified event categories, adjudicated by anindependent expert committee, were examined in two placebo-controlled safety studies in whichpatients received parecoxib for at least 3 days and then were transitioned to oral valdecoxib for a totalduration of 10-14 days. All patients received standard of care analgesia during treatment.

Patients received low-dose acetylsalicylic acid prior to randomization and throughout the two CABGsurgery studies.

The first CABG surgery study evaluated patients treated with IV parecoxib 40 mg bid for a minimumof 3 days, followed by treatment with valdecoxib 40 mg bid (parecoxib/valdecoxib group) (n=311) orplacebo/placebo (n=151) in a 14-day, double-blind placebo-controlled study. Nine pre-specifiedadverse event categories were evaluated (cardiovascular thromboembolic events, pericarditis, newonset or exacerbation of congestive heart failure, renal failure/dysfunction, upper GI ulcercomplications, major non-GI bleeds, infections, non-infectious pulmonary complications, and death).

There was a significantly (p <0.05) greater incidence of cardiovascular/thromboembolic events(myocardial infarction, ischemia, cerebrovascular accident, deep vein thrombosis and pulmonaryembolism) detected in the parecoxib/valdecoxib treatment group compared to the placebo/placebotreatment group for the IV dosing period (2.2% and 0.0% respectively) and over the entire studyperiod (4.8% and 1.3% respectively). Surgical wound complications (most involving the sternalwound) were observed at an increased rate with parecoxib/valdecoxib treatment.

In the second CABG surgery study, four pre-specified event categories were evaluated(cardiovascular/thromboembolic; renal dysfunction/renal failure; upper GI ulcer/bleeding; surgicalwound complication). Patients were randomized within 24-hours post-CABG surgery to: parecoxibinitial dose of 40 mg IV, then 20 mg IV Q12H for a minimum of 3 days followed by valdecoxib PO(20 mg Q12H) (n=544) for the remainder of a 10 day treatment period; placebo IV followed byvaldecoxib PO (n=544); or placebo IV followed by placebo PO (n=548). A significantly (p =0.033)greater incidence of events in the cardiovascular/thromboembolic category was detected in theparecoxib/valdecoxib treatment group (2.0%) compared to the placebo/placebo treatment group(0.5%). Placebo/valdecoxib treatment was also associated with a higher incidence of CVthromboembolic events versus placebo treatment, but this difference did not reach statisticalsignificance. Three of the six cardiovascular thromboembolic events in the placebo/valdecoxibtreatment group occurred during the placebo treatment period; these patients did not receivevaldecoxib. Pre-specified events that occurred with the highest incidence in all three treatment groupsinvolved the category of surgical wound complications, including deep surgical infections and sternalwound healing events.

There were no significant differences between active treatments and placebo for any of the otherpre-specified event categories (renal dysfunction/failure, upper GI ulcer complications or surgicalwound complications).

General surgery

In a large (N=1050) major orthopedic/general surgery trial, patients received an initial dose ofparecoxib 40 mg IV, then 20 mg IV Q12H for a minimum of 3 days followed by valdecoxib PO(20 mg Q12H) (n=525) for the remainder of a 10 day treatment period, or placebo IV followed byplacebo PO (n=525). There were no significant differences in the overall safety profile, including thefour pre-specified event categories described above for the second CABG surgery study, forparecoxib/valdecoxib compared to placebo treatment in these post-surgical patients.

Platelet studies

In a series of small, multiple dose studies in healthy young and elderly subjects, Dynastat 20 mg or40 mg twice daily had no effect on platelet aggregation or bleeding compared to placebo. In youngsubjects, Dynastat 40 mg twice daily had no clinically significant effect on acetylsalicylicacid-mediated inhibition of platelet function (see section 4.5).

Following IV or IM injection, parecoxib is rapidly converted to valdecoxib, the pharmacologicallyactive substance, by enzymatic hydrolysis in the liver.

Exposure of valdecoxib following single doses of Dynastat, as measured by both the area under theplasma concentration vs. time curve (AUC) and peak concentration (Cmax), is approximately linear inthe range of clinical doses. AUC and Cmax following twice daily administration is linear up to 50 mg

IV and 20 mg IM. Steady state plasma concentrations of valdecoxib were reached within 4 days withtwice daily dosing.

Following single IV and IM doses of parecoxib 20 mg, Cmax of valdecoxib is achieved inapproximately 30 minutes and approximately 1 hour, respectively. Exposure to valdecoxib was similarin terms of AUC and Cmax following IV and IM administration. Exposure to parecoxib was similarafter IV or IM administration in terms of AUC. Average Cmax of parecoxib after IM dosing was lowercompared to bolus IV dosing, which is attributed to slower extravascular absorption after IMadministration. These decreases were not considered clinically important since Cmax of valdecoxib iscomparable after IM and IV parecoxib administration.

The volume of distribution of valdecoxib after its IV administration is approximately 55 litres. Plasmaprotein binding is approximately 98% over the concentration range achieved with the highestrecommended dose, 80 mg/day. Valdecoxib, but not parecoxib, is extensively partitioned intoerythrocytes.

Parecoxib is rapidly and almost completely converted to valdecoxib and propionic acid in vivo with aplasma half-life of approximately 22 minutes. Elimination of valdecoxib is by extensive hepaticmetabolism involving multiple pathways, including cytochrome P 450 (CYP) 3A4 and CYP2C9isoenzymes and glucuronidation (about 20%) of the sulfonamide moiety. A hydroxylated metabolite ofvaldecoxib (via the CYP pathway) has been identified in human plasma that is active as a COX-2inhibitor. It represents approximately 10% of the concentration of valdecoxib; because of thismetabolite’s low concentration, it is not expected to contribute a significant clinical effect afteradministration of therapeutic doses of parecoxib.

Valdecoxib is eliminated via hepatic metabolism with less than 5% unchanged valdecoxib recovered inthe urine. No unchanged parecoxib is detected in urine and only trace amounts in the faeces. About70% of the dose is excreted in the urine as inactive metabolites. Plasma clearance (CLp) for valdecoxibis about 6 l/hr. After IV or IM dosing of parecoxib, the elimination half-life (t1/2) of valdecoxib isabout 8 hours.

Dynastat has been administered to 335 elderly patients (65-96 years of age) in pharmacokinetic andtherapeutic trials. In healthy elderly subjects, the apparent oral clearance of valdecoxib was reduced,resulting in an approximately 40% higher plasma exposure of valdecoxib compared to healthy youngsubjects. When adjusted for body weight, steady state plasma exposure of valdecoxib was 16% higherin elderly females compared to elderly males (see section 4.2).

In patients with varying degrees of renal impairment administered 20 mg IV Dynastat, parecoxib wasrapidly cleared from plasma. Because renal elimination of valdecoxib is not important to itsdisposition, no changes in valdecoxib clearance were found even in patients with severe renalimpairment or in patients undergoing dialysis (see section 4.2).

Moderate hepatic impairment did not result in a reduced rate or extent of parecoxib conversion tovaldecoxib. In patients with moderate hepatic impairment (Child-Pugh score 7-9), treatment should beinitiated with half the usual recommended dose of Dynastat and the maximum daily dose should bereduced to 40 mg since valdecoxib exposures were more than doubled (130%) in these patients.

Patients with severe hepatic impairment have not been studied and therefore the use of Dynastat inpatients with severe hepatic impairment is not recommended (see sections 4.2 and 4.3).

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology or repeated dose toxicity at 2-fold the maximum human exposure to parecoxib.

However, in the repeated dose toxicity studies in dogs and rats, the systemic exposures to valdecoxib(the active metabolite of parecoxib) were approximately 0.8-fold the systemic exposure in elderlyhuman subjects at the maximum recommended therapeutic dose of 80 mg daily. Higher doses wereassociated with aggravation and delayed healing of skin infections, an effect probably associated with

COX-2 inhibition.

In reproduction toxicity tests, the incidence of post-implantation losses, resorptions and foetal bodyweight retardation occurred at doses not producing maternal toxicity in the rabbit studies. No effects ofparecoxib on male or female fertilities were found in rats.

The effects of parecoxib have not been evaluated in late pregnancy or in the pre- and postnatal period.

Parecoxib administered intravenously to lactating rats as a single dose showed concentrations ofparecoxib, valdecoxib and a valdecoxib active metabolite in milk similar to that of maternal plasma.

The carcinogenic potential of parecoxib has not been evaluated.

Disodium hydrogen phosphate

Phosphoric acid and/or sodium hydroxide (for pH adjustment).

This medicinal product must not be mixed with other medicinal products except for those mentionedin section 6.6.

Dynastat and opioids should not be administered together in the same syringe.

Use of Ringer-Lactate solution for injection or glucose 50 mg/ml (5%) in Ringer Lactate solution forinjection for reconstitution will cause the parecoxib to precipitate from solution and therefore is notrecommended.

Use of water for injection is not recommended, as the resulting solution is not isotonic.

Dynastat should not be injected into an IV line delivering any other medicinal product. The IV linemust be adequately flushed prior to and after Dynastat injection with a solution of knowncompatibility (see section 6.6).

Injection of the reconstituted product into an IV line delivering glucose 50 mg/ml (5%) in Ringer-

Lactate solution for injection, or other IV fluids not listed in section 6.6, is not recommended as thismay cause precipitation from solution.

The shelf life of the unreconstituted product is 3 years.

Chemical and physical in-use stability of the reconstituted solution, which should not be refrigerated orfrozen, have been demonstrated for up to 24 hours at 25°C. Thus, 24 hours should be considered themaximum shelf life of the reconstituted product. However, due to the importance of microbiologicalinfection risk for injectable products, the reconstituted solution should be used immediately unlessreconstitution has taken place in controlled and validated aseptic conditions. Unless such requirementsare met, in-storage times and conditions prior to use are the responsibility of the user, and would notnormally be longer than 12 hours at 25°C.

This medicinal product does not require any special storage conditions prior to reconstitution.

For storage conditions of the reconstituted medicinal product see section 6.3.

Type I colourless glass vials (5 ml) with a butyl rubber stopper, sealed with a purple polypropyleneflip-off cap on the aluminium overseal.

Dynastat is available in packs containing 10 vials.

Dynastat must be reconstituted before use. Dynastat is preservative free. Aseptic technique is requiredfor its preparation.

Reconstitution solvents

Acceptable solvents for reconstitution of Dynastat are:

* sodium chloride 9 mg/ml (0.9%) solution for injection/infusion

* glucose 50 mg/ml (5%) solution for infusion

* sodium chloride 4.5 mg/ml (0.45%) and glucose 50 mg/ml (5%) solution for injection/infusion

Reconstitution process

Use aseptic technique to reconstitute lyophilised parecoxib (as parecoxib).

Remove the purple flip-off cap to expose the central portion of the rubber stopper of the 40 mgparecoxib vial. Withdraw, with a sterile needle and syringe, 2 ml of an acceptable solvent and insertthe needle through the central portion of the rubber stopper transferring the solvent into the 40 mg vial.

Dissolve the powder completely using a gentle swirling motion and inspect the reconstituted productbefore use. The entire contents of the vial should be withdrawn for a single administration.

After reconstitution, the liquid should be a clear solution. Dynastat should be inspected visually forparticulate matter and discoloration prior to administration. The solution should not be used ifdiscolored or cloudy, or if particulate matter is observed. Dynastat should be administered within24 hours of reconstitution (see section 6.3), or discarded.

The reconstituted product is isotonic.

IV line solution compatibility

After reconstitution with acceptable solvents, Dynastat may only be injected IV or IM, or into IV linesdelivering:

* sodium chloride 9 mg/ml (0.9%) solution for injection/infusion;

* glucose 50 mg/ml (5%) solution for infusion;

* sodium chloride 4.5 mg/ml (0.45%) and glucose 50 mg/ml (5%) solution forinjection/infusion;or

* Ringer-Lactate solution for injection.

For single use only. Any unused medicinal product or waste material should be disposed of inaccordance with local requirements.

Pfizer Europe MA EEIG

Boulevard de la Plaine 171050 Bruxelles

Belgium

EU/1/02/209/005

Date of first authorisation: 22 March 2002

Date of latest renewal: 24 January 2012

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.