AN NSAID WITH A BALANCED COX-1 & COX-2 INHIBITORY EFFECT

AN NSAID WITH A BALANCED COX-1 & COX-2 INHIBITORY EFFECT

A balanced cox-1 and cox-2 inhibitor Metabolisim and Bioavailabillty of Lornoxicam (3) Relative selectivity of agents as inhibitors of cox-1 and cox-2 (1) Peak plasma levels Bioavailability With food intake Plasma binding Plasma t1/2 Elimination urine Elimination faeces Liver metabolism % 1-2 h 9% < - 7% 99% 3 h 33% 66% CyP452C9 Plasma concentration time curve for Lornoxicam (4,5) Approximately isopotent inhibition of cox-1 and cox-2 by Lornoxicam (in vitro) (2) Log concentration in plasma (ng/ml) 2 4 6 8 12 14 16 18 2 22 24 Time after administration (hours) Lornoxicam s shorter half-life results in a more rapid clearance and reduced risk of accumulation. Completely metabolised to inactive derrivatives, for reduced accumulation.

A balanced cox-1 and cox-2 inhibitory molecule with high analgesic potency Efficacy superior to Diclofenac and Naproxen (7,8,9,) Decrease in Ritchie Articular lndex from baseline (%) -5 - -15-2 -25-3 -35 Lornoxicam, 8 bid. Diclofenac, 5 tid. Lornoxicam, 8 bid. Naproxen, 5 tid. Lornoxicam vs. Tramadol in post-operative pain (12) TOTPAR 18 16 14 12 8 6 4 2 Xefo Vial (IM) (n=38) Tramadol (IM) (n=35) Total pain relief (P<.5) All patients Xefo IM is significantly superior to Tramadol IM in the treatment of post-operative pain Patients receiving a single dose of Xefo IM 16 experienced significantly greater total pain relief than patients receiving Tramadol 8 hours following the initial dose after arthroscopic reconstruction of the anterior cruciate ligament. Xefo has fewer adverse events than Tramadol (12) Lornoxicam vs. Rofecoxib in Osteoarthritis (11) Reduction in pain (%) 7 6 5 4 3 2 Lornoxicam 42. * Pain at rest 55.8 Rofecoxib (*p<.1) 45.3 Lornoxicam exceeds Rofecoxib in reducing pain on movement, at rest and at night * 55.8 Pain on movement 42.5 * 59.9 Pain at night Number of adverse events 35 3 25 2 15 5 Skin Muscoskeletal Xefo R (n=38) CNS Gastrointestinal Tramadol (n=35) Adverse events Metabolic and nutritional Heart rate and rhythm Urinary General Application site Significantly fewer adverse events with Xefo compared with Tramadol for post-operative pain (p=.3) Distribution of adverse events during treatment with Xefo Vial (IM) (single 16 dose followed by 8 ) or Tramadol (IM) ( tid) for 3 days after anterior cruciate ligament repair.

Balance between Efficacy and Safety (16, 17) Changes in kidney parameters under various NSAID S NSAIDs which inhibit both the cox-1 & cox-2, maintain the thrombotic and vasomotor balances (13) Patients with increased kidney values 3 25 2 15 5 2 BUN Creatinine Lornoxicam Placebo Diclofenac Naproxen The influence of Lornoxicam on kidney laboratory values are within acceptable limits-and less pronounced than that of comparator drugs (16,17) (16, 17) Changes in liver parameters under various NSAID S American Heart Association (14) Stepped Care Approach to Pharmacologic Therapy for Musculoskeletal Symptoms With Known Cardiovascular Disease or Risk Factors for lschemic Heart Disease Select patients at low risk of thrombotic events Prescribe lowest dose required to control symptoms Acetaminophen, ASA, tramadol, narcotic analgesics (short term) Nonacetylated salicylates Add ASA 81 and PPI to patients at increased risk of thrombotic events * * Addition of ASA may not be sufficient protection against thrombotic events Non COX-2 selective NSAIDs NSAIDs with some COX-2 activity COX-2 Selective NSAIDs Regular monitoring for sustained hypertension (or worsening of prior blood pressure control), edema, worsening renal fuction, or gastrointestinal bleeding If these occur, consider reduction of the dose or discontinuation of the offending drug, a different drug, or alternative therapeutic modalities, as dictated by clinical circumstances From the market representing more than 1.5 million patient years of treatment, there is no evidence that lornoxicam is associated with an increased cardiovascular risk - Danish Heart Foundation (15) Patients with increased liver values 2 15 5 No dosage adjustment is needed in liver impairment, unless severe (16,17) Gastrointestinal tolerability of Lornoxicam compared to that of Naproxen in healthy male volunteers (18) Stomach/duodenal bulb Duodenum Lornoxicam Placebo Diclofenac Naproxen Lornoxicam (n=18) Day 1 Day 7 Mean change Day 1 Day 7 Mean change 5 + - 9 81 + 6 + - 88 76 + - 9 197 + - 99 192 + - 9-3 2 + - 3 27 + - 49 Gamma GT GOT GPT Bilirubin 25 + - 48 Naproxen (n=18) 3 + - 5 129 + 126 + - 11.5-116 Lornoxicam 8 bid. caused significantly less mucosal injury than Naproxen 5 bid. in the stomach/duodenal bulb, as well as in the mild/distal duodenum (18) P value.1.1

Balance between Age and Dosing Simple Dosing 8 Lornoxicam, once or twice daily, (Tablet or Injection) No dose adjustment across age range. Perioperative - Injections Continue with Tablets Dosage: 2 vials daily IM or IV Dosage: 2 tablets daily Strong and effective pain killer 8 8 Improved safety and tolerability Dosage Equivalence between Xefo and Opioids Morphine 2 IM 8/16 IM Simple dosing Pethidine 5 IV 8 IV Tramadol tid IM 8 tid IM Dose Equivalence between Xefo and other NSAIDs Diclofenac 5 tid / 75 IM 8 bid / 8 IM Naproxene 5 tid 8 bid Aspirin 65 8 Ibuprofen 4 8 Indomethacin 5 tid 4 tid

FOR ACUTE AND CHRONIC PAIN LOW BACK PAIN EXTRA ARTICULAR INFLAMMATORY PAIN MUSCLE PAIN POST OPERATIVE PAIN DENTAL PAIN PAIN CAUSED BY INJURIES References 1. Antman EM, Demets D, Loscalzo J. Cyclooxygenase inhibition and cardiovascular risk. Circulation 25;112:759-77. 2. Berg J, Fellier H, T Christop, J Grarup. The analgesic NSAID Lornoxicam inhibits Cyclooxygenase. Inflamm Res 1999;48(7):369-79. 3. Ankier SI, et al. Postgrad Med J 1988;64:752. 4. Hitzenberger G, Radholfer-WElte S, Takacs F, Rosenow D, Postgard Med J 199;66 Suppl 4:S22-7. 5. Skjodt N.M., Davies N.M. Clinical pharmacokinetics of Lornoxicam. Clin Pharmacokint 1998;34(6):421-428. 6. Ditrich P, Radhofer Welte S, Magomelschnigg D, Kukovetz WR, Mayerhofer S, Ferber H: Drugs Exp Clin Res. 199;16(2):57-62. 7. Bernstein R.M., Frenzel, W. A comparative study of two dosage regimens of lornoxicam and a standard dosage of naproxen in patients with rheumatoid arthritis. Eur J Clin Res 1995;7:259-73. 8. Kidd, B., Frenzel, W. A multicenter, randomized, double blind study comparing lornoxicam with diclofenac in osteoarthritis. J Rheumatol, 1996;23:165-11. 9. Bugge C. A randomized parallel group trial with Chlortenoxicam (Lornoxicam) and Naproxen in patients with pain due to metastic bone tumours. Clinical Study Report CT 17, 1993;Nycomed Pharma, Denmark.. Caruso I, Montrone F, Boari L., et al. Lornoxicam versus diclofenac in rheumatoid arthritis: a double-blind, multicenter, study. Adv Ther 1994;11:132-8. 11. Peter Rose and Christine Steinhauser. Comparison of Lornoxicam and Rofecoxib in Patients with Activated Osteoarthritis (COLOR Study). Clin Drug Invest 24;24(4):227-236. 12. Staunstrup, H, et al. J Clin Pharmacol. 1999;39:834-41. 13. Segev G, Katz RJ. Selective COX-2 inhibitors and risk of Cardiovascular Events. Hospital Physician 24;2:39-46. 14. Elliott M. Antman, Joel S. Bennett, Alan Daugherty, Curt Furberg, Harold Roberts and Kathryn A. Taubert. Use of Nonsteroidal Anti inflammatory Drugs: An Update for Clinicians: A Scientific Statement from the American Heart Association. Circulation 27;115:1634-1642. 15. Heart Statistic 2/21 Danish Heart Foundation. 16. Nahler G. An open study to determine the effect of renal insufficiency on the pharmacokinetics of Lornoxicam and to assess the tolerability of the drug in patients with renal insufficiency (CT 74). Data on File, editor. 19-8-1993, Nycomed. 17. Radhofer-Welte S. Pharmacokinetics and tolerability of Lornoxicam film-coated tablets on patients suffering from mild, moderate and severe renal impairment. Data on File, editor: 13-5-1993. Nycomed. 18. Aabakken, L., Osnes, M., Frenzel, W. Gastrointestinal tolerability of lornoxicam compared to that of naproxen in healthy male volunteers. Aliment Pharmacol Ther 1996;:151-6. AN NSAID WITH A BALANCED COX-1 & COX-2 INHIBITORY EFFECT www.cts.co.il