New Medicines Committee Briefing May 2015 Dynastat® (Parecoxib sodium) 40 mg powder for solution for injection Dynastat® to be reviewed for use within: Primary Care Secondary Care Summary: Parecoxib is a prodrug of valdecoxib a selective cyclooxygenase-2 (COX-2) inhibitor1. Dyloject® (diclofenac) is currently on the formulary but has been discontinued since March 2010. Intravenous parecoxib has been proposed for inclusion in the Joint Formulary as a replacement of Voltarol® (diclofenac) injection. Cochrane review stated that a single dose of parecoxib 20 mg or 40 mg provided effective analgesia for 50 to 60% of those treated compared to about 15% with placebo, and was well tolerated2. A meta-analysis stated that the good postoperative analgesia and minimal interference with platelet function may make parecoxib an alternative to the non-selective NSAID diclofenac in providing pre-emptive analgesia in patients undergoing general surgery3. 1 Application: Neurology: Consultant submitting application: Dr Simon Mills (Consultant Anaesthetist) Clinical Director supporting application: Dr Stephen Merron (Medical Director) Dr Mills states that there is currently no COX-2 NSAID available for use in the operating theatre. He proposed that parecoxib be made available as a single dose for patients undergoing spinal surgery, to be given by the consultant anaesthetist. Dr Mills explained that NSAIDS do not depress respiration nor impair gastrointestinal motility as opioids hence making it clinically useful for treating pain after day surgery, as well as its opiate sparing effect after more major surgery. COX- 1 NSAIDs such as ibuprofen affects platelet function making them unsuitable for perioperative use in spinal surgery where the consequence of a haematoma can be devastating. For patients having less invasive spinal surgery, such as uncomplicated lumber discectomy, the improved analgesia with parecoxib should improve the proportion of patients done as a day case. He noted that for patients having more extensive inpatient surgery, the opioid sparing benefits of parecoxib should reduce the known complications of opioid use such as respiratory depression and reduced gastrointestinal motility thereby improving postoperative recovery and potentially reduce length of stay. Improved analgesia and reduced opioid use will reduce postoperative discomfort and nausea and vomiting and should reduce length of stay. Routine use of parecoxib should increase the proportion of same day discharges and therefore improve bed availability in orthopaedics which currently is a massive problem for the trust, causing loss of revenue through cancellation of elective and emergency surgery. Dr Merron supported the application stating that the anaesthetic department are very keen to develop daycase spinal surgery to reduce on inpatient beds and that parecoxib will be one means of helping to achieve this. Background: Acute pain occurs as a result of tissue damage, commonly accidentally due to an injury or as a result of surgery. Acute postoperative pain is a manifestation of inflammation due to tissue injury. The management of postoperative pain and inflammation is a critical component of patient care. The most common route for administration of postoperative analgesia is by mouth, but some patients are unable to swallow, feel nauseated, or vomit in the immediate postoperative period, and in these patients intravenous or intramuscular administration may be preferred. NSAIDs are one of the most commonly prescribed analgesic medications worldwide, and their efficacy for treating acute pain has been well demonstrated. They reversibly inhibit cyclooxygenase (prostaglandin endoperoxide synthase), the enzyme mediating production of prostaglandins and thromboxane A2. Prostaglandins mediate a variety of physiological functions 2 such as maintenance of the gastric mucosal barrier, regulation of renal blood flow, and regulation of endothelial tone. They also play an important role in inflammatory and nociceptive processes. Cyclooxygenase (COX) activity has been found to be associated with at least two distinct isoenzymes: COX-1 and COX-2. COX- 1 was hypothesized to be involved in the maintenance of physiologic functions such as gastric protection and haemostasis; COX-2 was thought to be involved in pathophysiologic processes such as inflammation, pain and fever. These hypotheses led to the development of the selective COX-2 inhibitors, such as celecoxib, rofecoxib and etoricoxib. These agents have analgesic efficacy comparable with conventional NSAIDs. In addition, they have no antiplatelet activity at therapeutic doses, and therefore may be associated with reduced gastrointestinal adverse effects compared with conventional NSAIDs such as ibuprofen. Concerns about cardiovascular safety in long term use have led to the withdrawal of rofecoxib, and in some countries lumiracoxib. Parecoxib was the first COX-2 to be administered parenterally. It is a prodrug that is rapidly hydrolysed in vivo to its active form, valdecoxib. Clinical trials have indicated that parecoxib is effective in treating postoperative pain resulting from oral surgery, orthopaedic surgery and abdominal hysterectomy pain. Intravenous diclofenac has been included within the North Staffordshire Joint Formulary for prevention and treatment of acute postoperative pain where rapid onset is required. The UHNM with the agreement of the anaesthetists switched over brands of intravenous diclofenac from Voltarol® to Dyloject® in response to NPSA risk assessment of injectable. Voltarol® was assessed as moderate risk product as it requires fresh preparation for each patient and can be irritant during intravenous administration. It is administered by continuous or intermittent infusion. Dyloject® on the contrary was a low risk product as it is a bolus injection. Unfortunately, Dyloject® has been discontinued and theatres have gone back to using Voltarol®. Currently the UHNM surgical guidelines recommend ibuprofen SR 1600 mg oral daily as premedication. Post-operative options include ibuprofen 400 mg oral 8-hrly, or 800 mg SR 12-hrly or naproxen 250 mg oral 6-hrly, or 500 mg 12-hrly or diclofenac 50 mg per rectum 8-hrly – maximum dose 150 mg in 24 hr (not prescribe on discharge) and ibuprofen 400 mg 8-hrly or naproxen 250 mg oral 6-hrly, or 500 mg 12-hrly as drugs to take home. The guideline states that intramuscular diclofenac should be avoided as it is painful and can lead to a sterile abscess. There is no alternative for patients with asthma known to be sensitive to aspirin and NSAIDs or if oral or rectal not available or suitable. Therapeutic class and mode of actionError! Bookmark not defined.: Parecoxib is a prodrug of valdecoxib a selective COX-2 inhibitor. 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, 3 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. Indication: Parecoxib is indicated for short-term treatment of postoperative pain in adults. Contraindication: Hypersensitivity to the active substance Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme or patients with known hypersensitivity to sulphonamide. 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 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 Adverse effects Very common (≥ 1/10); common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000); Very rare (< 1/10,000) Common: Pharyngitis, alveolar osteitis (dry socket), anemia postoperative, hypokalemia, agitation, insomnia, hypoaesthesia, dizziness, respiratory insufficiency, abdominal pain, vomiting, constipation, dyspepsia, flatulence etc. 4 Uncommon: Abnormal sternal serous wound drainage, wound infection, thrombocytopaenia, hyperglycaemia, anorexia, cerebrovascular disorder, myocardial infarction, bradycardia, hypertension (aggravated), orthostatic hypotension etc. Very rare: Anaphylactoid reaction, pancreatitis, oesophagitis, oedema mouth (perioral swelling) etc. Drug interactions Use with Oral Anticoagulants - The concomitant use of NSAIDs with