Pro-Bextra

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.

Posology

The recommended dose is 40 mg administered intravenously (IV) or intramuscularly (IM), followed every 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 of exposure, the shortest duration possible and the lowest effective daily dose should be used. There is limited clinical experience with Pro-Bextra treatment beyond three days.

Concomitant use with opioid analgesics

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

Elderly

No dose adjustment is generally necessary in elderly patients (>65 years). However, for elderly patients weighing less than 50 kg, treatment should be initiated with half the usual recommended dose of Pro-Bextra and reduce the maximum daily dose to 40 mg.

Hepatic impairment

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

Renal impairment

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

Paediatric population

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

Method of administration

The IV bolus injection may be given rapidly and directly into a vein or into an existing IV line.

Precipitation may occur when Pro-Bextra is combined in solution with other medicinal products and therefore Pro-Bextra must not be mixed with any other medicinal product, either during reconstitution or injection. In those patients where the same IV line is to be used to inject another medicinal product, the line must be adequately flushed prior to and after Pro-Bextra injection with a solution of known compatibility.

After reconstitution with acceptable solvents, Pro-Bextra may only be injected IV or IM, or into IV lines delivering 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 for injection/infusion; or

- Ringer-Lactate solution for injection.

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

History of previous serious allergic drug reaction of any type, especially cutaneous reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme or patients with known hypersensitivity to sulfonamides.

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 NSAIDs including COX-2 (cyclooxygenase-2) inhibitors.

The third trimester of pregnancy and breast-feeding.

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.

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

Pro-Bextra has been studied in dental, orthopaedic, gynaecologic (principally hysterectomy) and coronary artery bypass graft surgery. There is little experience in other types of surgery, for example gastrointestinal or urological surgery.

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. There is limited clinical experience with Pro-Bextra treatment beyond three days.

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.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, and is therefore considered essentially 'sodium- free'.

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.

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. Pro-Bextra has not been studied in cardiovascular revascularization procedures other than CABG (coronary artery bypass graft procedures). Studies in types of surgery other than CABG procedures included patients with ASA (American Society of Anaesthesiology) Physical Status Class I-III only.

Acetylsalicyclic 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. Caution should be exercised when co-administering Pro-Bextra with warfarin and other oral anticoagulants. The concomitant use of parecoxib with other non- acetylsalicylic acid NSAIDs should be avoided.

Pro-Bextra may mask fever and other signs of inflammation. In isolated cases, an aggravation of soft tissue infections has been described in connection with the use of NSAIDs and in nonclinical studies with Pro-Bextra. Caution should be exercised with respect to monitoring the incision for signs of infection in surgical patients receiving Pro-Bextra.

Gastrointestinal

Upper gastrointestinal (GI) complications [perforations, ulcers or bleedings (PUBs)], some of them resulting in fatal outcome, have occurred in patients treated with parecoxib. Caution is advised in the treatment of patients most at risk of developing a gastrointestinal complication with NSAIDs; the elderly, patients using any other NSAID or acetylsalicylic acid concomitantly, glucocorticoids, selective serotonin reuptake inhibitors, patients ingesting alcohol or patients with a prior history of gastrointestinal disease, such as ulceration and GI bleeding. There is further increase in the risk of gastrointestinal adverse effects (gastrointestinal ulceration or other gastrointestinal complications), when parecoxib is taken concomitantly with acetylsalicylic acid (even at low doses).

Skin reactions

Serious skin reactions, including erythema multiforme, exfoliative dermatitis and Stevens-Johnson syndrome (some of them fatal) have been reported through post-marketing surveillance in patients receiving parecoxib. Additionally, fatal reports of toxic epidermal necrolysis have been reported through post-marketing surveillance in patients receiving valdecoxib (the active metabolite of parecoxib) and cannot be ruled out for parecoxib. Patients appear to be at highest risk for these reactions early in the course of therapy; the onset of the reaction occurring in the majority of cases within the first month of treatment.

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

Parecoxib should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity. Serious skin reactions are known to occur with NSAIDs including COX-2 selective inhibitors as well as other medicinal products. However, the reported rate of serious skin events 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 of skin reactions. Patients without a history of sulfonamide allergy may also be at risk for serious skin reactions.

Hypersensitivity

Hypersensitivity reactions (anaphylaxis and angioedema) have been reported in post-marketing experience with valdecoxib and parecoxib. Some of these reactions have occurred in patients with a history of allergic-type reactions to sulfonamides. Parecoxib should be discontinued at the first sign of hypersensitivity.

Cases of severe hypotension shortly following parecoxib administration have been reported in post-marketing experience with parecoxib. Some of these cases have occurred without other signs of anaphylaxis. 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 oedema have been observed in some patients taking parecoxib. Therefore, parecoxib should be used with caution in patients with compromised cardiac function, pre-existing oedema, or other conditions predisposing to, or worsened by, fluid retention including those taking diuretic treatment or otherwise at 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 receiving parecoxib. Since prostaglandin synthesis inhibition may result in deterioration of renal function and fluid retention, caution should be observed when administering Pro-Bextra in patients with impaired renal function or hypertension, or in patients with compromised cardiac or hepatic function or other conditions predisposing to fluid retention.

Caution should be used when initiating treatment with Pro-Bextra in patients with dehydration. In this case, it is advisable to rehydrate patients first and then start therapy with Pro-Bextra.

Hypertension

As with all NSAIDs, parecoxib can lead to the onset of new hypertension or worsening of pre-existing hypertension, 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 be monitored closely during the initiation of therapy with parecoxib and throughout the course of therapy. If blood pressure rises significantly, alternative treatment should be considered.

Hepatic impairment

Pro-Bextra should be used with caution in patients with moderate hepatic impairment (Child-Pugh score 7-9).

Use with oral anticoagulants

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

Patients who experience dizziness, vertigo or somnolence after receiving Pro-Bextra should refrain from driving or operating machines.

Summary of the safety profile

The most common adverse reaction for Pro-Bextra 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 Pro-Bextra have a higher risk of adverse reactions such as: cardiovascular/ thromboembolic events , 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.

Description of selected adverse reactions

In post-marketing experience, toxic epidermal necrolysis has been reported in association with the use of valdecoxib, and cannot be ruled out for parecoxib. In addition, the following rare, serious adverse reactions have been reported in association with the use of NSAIDs and cannot be ruled out for Pro-Bextra: bronchospasm and hepatitis.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

United Kingdom

Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Ireland

Healthcare professionals are asked to report any suspected adverse reactions via:

HPRA Pharmacovigilance,

Earlsfort Terrace,

IRL - Dublin 2,

Tel: +353 1 6764971,

Fax: +353 1 6762517,

Website: www.hpra.ie

E-mail: [email protected]

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

In case of overdose, patients should be managed by symptomatic and supportive care. Valdecoxib is not removed by haemodialysis. Diuresis or alkalisation of urine may not be useful due to high protein binding of valdecoxib.

Pharmacotherapeutic group: Antiinflammatory and antirheumatic products, Coxibs, ATC code: M01AH04

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

The difference in antiplatelet activity between some COX-1 inhibiting NSAIDs and COX-2 selective inhibitors may be of clinical significance in patients at risk of thrombo-embolic reactions. COX-2 selective inhibitors reduce the formation of systemic (and therefore possibly endothelial) prostacyclin without affecting platelet thromboxane. The clinical relevance of these observations has not been established.

The efficacy of Pro-Bextra was established in studies of dental, gynaecologic (hysterectomy), orthopaedic (knee and hip replacement), and coronary artery bypass graft surgical pain. The first perceptible analgesic effect occurred in 7 -13 minutes, with clinically meaningful analgesia demonstrated in 23-39 minutes and a peak effect within 2 hours following administration of single doses of 40 mg IV or IM Pro-Bextra. The magnitude of analgesic 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, and ranged from 6 to greater than 12 hours.

Opioid-sparing effects

In a placebo-controlled, orthopedic and general surgery study (n =1050), patients received Pro-Bextra at an initial parenteral dose of 40 mg IV followed by 20 mg twice daily for a minimum of 72 hours in addition to receiving standard care including supplemental patient controlled opioids. The reduction in opioid use with Pro-Bextra 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 in patient-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 indicating less overall adverse events associated with the use of parecoxib compared to placebo when used in conjunction with opioids.

Gastrointestinal studies

In short-term studies (7 days), the incidence of endoscopically observed gastroduodenal ulcers or erosions in healthy young and elderly (> 65 years) subjects administered Pro-Bextra (5-21%), although higher 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 an independent expert committee, were examined in two placebo-controlled safety studies in which patients received parecoxib for at least 3 days and then were transitioned to oral valdecoxib for a total duration 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 CABG surgery studies.

The first CABG surgery study evaluated patients treated with IV parecoxib 40 mg bid for a minimum of 3 days, followed by treatment with valdecoxib 40 mg bid (parecoxib/valdecoxib group) (n=311) or placebo/placebo (n=151) in a 14-day, double-blind placebo-controlled study. Nine pre-specified adverse event categories were evaluated (cardiovascular thromboembolic events, pericarditis, new onset or exacerbation of congestive heart failure, renal failure/dysfunction, upper GI ulcer complications, 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 pulmonary embolism) detected in the parecoxib/valdecoxib treatment group compared to the placebo/placebo treatment group for the IV dosing period (2.2% and 0.0% respectively) and over the entire study period (4.8% and 1.3% respectively). Surgical wound complications (most involving the sternal wound) 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; surgical wound complication). Patients were randomized within 24-hours post-CABG surgery to: parecoxib initial 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 by valdecoxib 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 the parecoxib /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 CV thromboembolic events versus placebo treatment, but this difference did not reach statistical significance. Three of the six cardiovascular thromboembolic events in the placebo/valdecoxib treatment group occurred during the placebo treatment period; these patients did not receive valdecoxib. Pre-specified events that occurred with the highest incidence in all three treatment groups involved the category of surgical wound complications, including deep surgical infections and sternal wound healing events.

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

General surgery

In a large (N=1050) major orthopedic/general surgery trial, patients received an initial dose of parecoxib 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 by placebo PO (n=525). There were no significant differences in the overall safety profile, including the four pre-specified event categories described above for the second CABG surgery study, for parecoxib/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, Pro-Bextra 20 mg or 40 mg twice daily had no effect on platelet aggregation or bleeding compared to placebo. In young subjects, Pro-Bextra 40 mg twice daily had no clinically significant effect on acetylsalicylic acid - mediated inhibition of platelet function.

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

Absorption

Exposure of valdecoxib following single doses of Pro-Bextra, as measured by both the area under the plasma concentration vs. time curve (AUC) and peak concentration (C_max), is approximately linear in the range of clinical doses. AUC and C_max 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 with twice daily dosing.

Following single IV and IM doses of parecoxib 20 mg, C_max of valdecoxib is achieved in approximately 30 minutes and approximately 1 hour, respectively. Exposure to valdecoxib was similar in terms of AUC and C_max following IV and IM administration. Exposure to parecoxib was similar after IV or IM administration in terms of AUC. Average C_max of parecoxib after IM dosing was lower compared to bolus IV dosing, which is attributed to slower extravascular absorption after IM administration. These decreases were not considered clinically important since C_max of valdecoxib is comparable after IM and IV parecoxib administration.

Distribution

The volume of distribution of valdecoxib after its IV administration is approximately 55 litres. Plasma protein binding is approximately 98% over the concentration range achieved with the highest recommended dose, 80 mg/day. Valdecoxib, but not parecoxib, is extensively partitioned into erythrocytes.

Biotransformation

Parecoxib is rapidly and almost completely converted to valdecoxib and propionic acid in vivo with a plasma half-life of approximately 22 minutes. Elimination of valdecoxib is by extensive hepatic metabolism involving multiple pathways, including cytochrome P 450 (CYP) 3A4 and CYP2C9 isoenzymes and glucuronidation (about 20%) of the sulfonamide moiety. A hydroxylated metabolite of valdecoxib (via the CYP pathway) has been identified in human plasma that is active as a COX-2 inhibitor. It represents approximately 10% of the concentration of valdecoxib; because of this metabolite's low concentration, it is not expected to contribute a significant clinical effect after administration of therapeutic doses of parecoxib.

Elimination

Valdecoxib is eliminated via hepatic metabolism with less than 5% unchanged valdecoxib recovered in the urine. No unchanged parecoxib is detected in urine and only trace amounts in the faeces. About 70% of the dose is excreted in the urine as inactive metabolites. Plasma clearance (CL_p) for valdecoxib is about 6 l/hr. After IV or IM dosing of parecoxib, the elimination half-life (t_1/2) of valdecoxib is about 8 hours.

Elderly

Pro-Bextra has been administered to 335 elderly patients (65-96 years of age) in pharmacokinetic and therapeutic 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 young subjects. When adjusted for body weight, steady state plasma exposure of valdecoxib was 16% higher in elderly females compared to elderly males.

Renal impairment

In patients with varying degrees of renal impairment administered 20 mg IV Pro-Bextra, parecoxib was rapidly cleared from plasma. Because renal elimination of valdecoxib is not important to its disposition, no changes in valdecoxib clearance were found even in patients with severe renal impairment or in patients undergoing dialysis.

Hepatic impairment

Moderate hepatic impairment did not result in a reduced rate or extent of parecoxib conversion to valdecoxib. In patients with moderate hepatic impairment (Child-Pugh score 7-9), treatment should be initiated with half the usual recommended dose of Pro-Bextra and the maximum daily dose should be reduced 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 Pro-Bextra in patients with severe hepatic impairment is not recommended.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology 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 elderly human subjects at the maximum recommended therapeutic dose of 80 mg daily. Higher doses were associated 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 body weight retardation occurred at doses not producing maternal toxicity in the rabbit studies. No effects of parecoxib 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 of parecoxib, valdecoxib and a valdecoxib active metabolite in milk similar to that of maternal plasma.

The carcinogenic potential of parecoxib has not been evaluated.

Pro-Bextra 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 for injection for reconstitution will cause the parecoxib to precipitate from solution and therefore is not recommended.

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

Pro-Bextra should not be injected into an IV line delivering any other medicinal product. The IV line must be adequately flushed prior to and after Pro-Bextra injection with a solution of known compatibility.

Pro-Bextra must be reconstituted before use. Pro-Bextra is preservative free. Aseptic technique is required for its preparation.

Reconstitution solvents

Acceptable solvents for reconstitution of Pro-Bextra 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

Reconstitute Pro-Bextra 40 mg with 2 ml sodium chloride 9 mg/ml (0.9%) solution.

The only other acceptable solvents for reconstitution are:

- 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 mg parecoxib vial. Withdraw, with a sterile needle and syringe, 2 ml of an acceptable solvent and insert the 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 product before use. The entire contents of the vial should be withdrawn for a single administration.

After reconstitution, the liquid should be a clear solution. Pro-Bextra should be inspected visually for particulate matter and discoloration prior to administration. The solution should not be used if discolored or cloudy, or if particulate matter is observed. Pro-Bextra should be administered within 24 hours of reconstitution , or discarded.

The reconstituted product is isotonic.

IV line solution compatibility

After reconstitution with acceptable solvents, Pro-Bextra may only be injected IV or IM, or into IV lines delivering:

- 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;

or

- Ringer-Lactate solution for injection.

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