Management of OsteoarthritisA Case-Based Approach copy.pptx

Management of OA

1. Management of Osteoarthritis: A Case-Based Approach

2. Disclaimer The Content in this presentation is only intended for healthcare professionals in India . The medical information in this presentation is provided as an information resource only, and is not to be used or relied on for any diagnostic or treatment purpose. “ “The views and opinions mentioned in the presentation is strictly that of the author and the individuals expressing the same and Pfizer may not necessarily endorse the same. Pfizer (including its parent, subsidiary and affiliate entities) makes no representation or warranties of any kind, expressed or implied; as to the content used in the presentation and/or the accuracy, completeness of its content.” Pfizer Limited, The Capital- A Wing, 1802, 18th Floor, Plot No. C-70, G Block, Bandra - Kurla Complex, Bandra (East), Mumbai 400 051, India  For the use only of Registered Medical Practitioners or a Hospital or a Laboratory PP-DGM-IND-0272 12/01/2021 See the summary of prescribing information on last slide

3. Learning Objectives To make a strong case for individualizing therapy for the management of osteoarthritis in adults via case-based discussions

4. Case Presentation Section 1

5. Case Presentation Clinical presentation Medical history Clinical presentation This is a hypothetical case for representation purpose only.

6. Osteoarthritis: Overview Section 2

7. Burden of Osteoarthritis (OA) Global scenario Indian scenario OA: Osteoarthritis; EPI: Epidemiological. Nearly 80% of patients affected by OA 3 78.27% Uttar Pradesh Andhra Pradesh West Bengal 68% 49.8% 47.3% Delhi 43% Assam Karnataka 41.3% Bihar / Uttarakhand 21.2% 10.2% Maharashtra 56.6% Rural 2 32.6% Urban 2 Asians have a greater risk for knee OA vs. Americans and Europeans. 2 An estimated 250 million people are affected by OA globally. 1 Knee OA accounts ~85% of total OA. 1 Osteoarthritis is a major cause of disability in older adults worldwide. Osteoarthritis: EPI shift pattern A higher prevalence for radiographic osteoarthritis than for symptomatic osteoarthritis, and for knee and hand osteoarthritis than for hip osteoarthritis. 1 A higher prevalence symptomatic knee and hand osteoarthritis noted in women than men 1 The prevalence of OA is increasing globally and its burden will rise continually. 1 The knee is the most common site of OA, followed by the hand and hip. 1 At a global level, OA is a leading cause of disability. 1 Hunter D, et al . Lancet. 2019;393:1745–1759. 2. Venkatachalam J, et al . Indian J Public Health . 2018;62:117–122. 3. Azad CS, et al . Int J Recent Sci Res . 2017;8(10):20918–20922.

8. Classification of Osteoarthritis Primary osteoarthritis It arises due to specific cause (factors that damage cartilage). 2  Risk factors for secondary osteoarthritis: 1 Congenital joint structure abnormalities (e.g. hypermobility and abnormally shaped joint surfaces) Trauma (obesity, fractures along joint surfaces, and surgery) Crystal deposition Presence of abnormal cartilage Gout, rheumatoid and septic arthritis     It is mechanical consequence of wear and tear of the articular cartilage 1 It is associated with aging and occurs in older age 1,2 It is a more commonly diagnosed form of arthritis 1 1. Pizzorno JE, et al. Osteoarthritis . 3rd Edition. 2016:706–720. 2. Jerosch J. Int J Rheumatol . 2011;1–17. Secondary osteoarthritis

9. Kaur R, et al . Int J Med Sci Public Health. 2018;7(10):825–830. 2. Palazzo C, et al . Ann Phys Rehabil Med . 2016;59(3):134–138. Genetic factors responsible for hand OA in 60% of cases, knee and hip OA in 40% of cases 2 Genetic susceptibility Lower levels of vitamins D, C, and K lead to OA. 2 Diet Osteoarthritis affects every age group; the prevalence rises dramatically in men aged >50 years and women aged >40 years. 1 Age Women are more prone to OA. 2 Gender BMI >30 kg/m 2 or e very 5-unit increase in BMI is strongly associated with the risk of knee OA. 2 Obesity Early-onset knee OA due to rupture of anterior cruciate ligament 2 Injury Risk Factors for Osteoarthritis OA; Osteoarthritis.

10. Clinical Features of Osteoarthritis Pain Stiffness Locomotor restriction Early morning stiffness (short-lived <30 min) Inactivity-related stiffness of short duration (gelling may occur) Abhishek A, Doherty M. Rheum Dis Clin North Am . 2013;39(1):45 – 66. Pain worse with joint use and relieved by rest Pain may be intermittent and relapsing Pain intensity varies all over the day and the week Symptoms of osteoarthritis Locomotor restriction and functional impairment: Depend on the site and severity of OA Knee or hip OA: Impair ability to get up from a chair and walk Carpometacarpal joint OA: May cause difficulty in gripping Osteoarthritis symptoms can vary depending on the cause and location of the problem. OA: Osteoarthritis.

11. 01 02 03 40% Constant dull or aching pain Punctuated by short episodes of often unpredictable intense, exhausting pain Severe functional limitations Stage 3 - Advanced Predictable sharp pain Pain due to mechanical insult Minimal effect on joint function Limits high-impact activities Experience of pain on regular basis Affects daily activities Unpredictable episodes of stiffness Advanced 2 Mild-moderate 2 Early 2 Hunter D, et al. Lancet . 2019;393:1745–1759. 2. Abhishek A, Doherty M. Rheum Dis Clin North Am . 2013;39(1):45 – 66. Stages of Pain in Osteoarthritis Pain is the most disabling symptom in patients with osteoarthritis. 1 Adapted from: Abhishek A, Doherty M. Rheum Dis Clin North Am . 2013;39(1):45 – 66.

12. Clinical Features of Osteoarthritis Abhishek A and Doherty M. Rheum Dis Clin North Am . 2013;39(1):45 – 66. Signs of osteoarthritis Joint effusion: If present, usually small and cool Joint-line tenderness : Evident around the joint (suggests articular disorder) Periarticular tenderness : A way from joint line and evident in knee and hip No palpable warmth Crepitus : Crunching sensation or sound due to friction between damaged articular cartilages Decreased range of movement : Due to marginal osteophytosis and capsular thickening Bony swelling : Caused by bony remodeling, marginal osteophytosis, and joint subluxation Bony deformity : Signs of joint damage Muscle wasting : Suggests advanced stage of OA Appearance Feeling Movement OA: Osteoarthritis.

13. Investigations Case Continued... Investigations On inspection: No erythema, bruising, or discoloration of left knee was noted. Slight bulging was seen on the medial aspect of left knee joint. Popliteal bulging was seen at at the posterior aspect of left knee. Musculature of both knees appeared bilaterally symmetrical. No bone deformity was observed. On palpation : T he left knee joint was not warm or tender. Mild effusion was felt. Range of movement of the left knee was reduced. Crepitus was noted in both legs. Pedal pulses were present. Findings of radiography of knee were suggestive of osteoarthritis of left knee

14. History of injury, trauma, previous surgery, medications, occupation, and symptoms 1 Physical examination for presence of crepitus, restricted or painful movement and joint tenderness 1,2 Identifying effects of OA on quality of life, mood, occupation, and sleep 3 Osteoarthritis can be diagnosed clinically based on history and physical examination. 1 Diagnosis of Osteoarthritis : History and Physical Examination Lespasio MJ, et al . Perm J . 2017;21:16–183. 2. Hunter DJ, et al . BMJ . 2006;332:639–42. 3. National Clinical Guideline Centre (UK). Osteoarthritis: Care and Management in Adults. Available at: https://www.ncbi.nlm.nih.gov/books/NBK333054 / . Accessed on 26 December 2020. OA: Osteoarthritis Joint pain and one of the following: 1 Age >50 years Stiffness <30 minutes Crepitus Osteophytes Three symptoms (persistent pain, limited morning stiffness, and reduced function) 1 Three signs (crepitus, restricted range of motion, and bony enlargement) 1 Diagnosis of knee OA according to: History and physical examination American College of Rheumatology European League Against Rheumatism

15. Inflammatory markers: C-reactive protein, erythrocyte sedimentation rate, and plasma viscosity 2 X-ray: In advanced stages, X-ray shows narrowing of joint space, osteophytes, and sometimes changes in the subchondral bone. 3 Other imaging : Bone scan, computed tomography, and MRIs are usually not required. These may be needed to rule out other conditions of bone and soft tissues of joints 1 Diagnosis of Osteoarthritis : Laboratory and Radiographic Investigations Laboratory tests Radiographic investigations Lespasio MJ, et al. Perm J . 2017;21:16–183. 2. Abhishek A, et al. Rheum Dis Clin North Am . 2013;39(1):45 – 66. 3. Hunter DJ, et al . BMJ . 2006;332:639–42. Useful in excluding other diagnoses 2 To support a clinical diagnosis and defining prognosis 3 Useful in case of strong clinical suspicion of co-crystal deposition 2 Joint aspiration: Monosodium urate and calcium pyrophosphate crystal deposition associated with OA and may cause acute synovitis or more chronic inflammation in osteoarthritis joints 2 Osteoarthritis can be confirmed by radiography 1 MRIs: Magnetic resonance imagings

16. Radiographic investigations revealed osteoarthritis of left knee. Case Continued... Diagnosis

17. Abhishek A, et al . Rheum Dis Clin North Am . 2013;39(1):45 – 66. 2. De Rooij M, et al. Arthritis Care Res (Hoboken). 2016;68(4):481–492. Poor prognosis of knee OA Joint laxity, muscle wasting, and weakness 1 Ageing 1 Obesity 1 Knee malalignment 1 Excess or no joint use 1 Bilateral knee OA 2 Higher pain at baseline 2 Psychosocial factors and poor social support 1,2 Factors for Poor Prognosis of Knee Osteoarthritis OA: Osteoarthritis.

18. Localized OA : Involves only 1–2 joint regions GOA : Involves 3 joint regions with spine or hands being one of the regions affected (nodal GOA if nodes present) Abhishek A, et al . Rheum Dis Clin North Am . 2013;39(1):45–66. Crystal deposition : Calcium pyrophosphate crystal deposition and gout (OA encourages deposition of both crystal types) Coexistent inflammatory arthritis : Rheumatoid arthritis and seronegative spondyloarthropathy Erosive OA : Targets hand interphalangeal joints OA: Osteoarthritis; GOA: Generalized osteoarthritis. Clinical Approach to Identify Subtypes of Osteoarthritis Atypical OA : Unusual distribution, young age of onset (<45 years), rapid progression Number of joints involved Clinical joint inflammation Classic or atypical OA

19. Abhishek A, et al . Rheum Dis Clin North Am . 2013;39(1):45 – 66. 2. Messier SP, et al . Osteoarthritis Cartilage . 2016;24(5):807–813. 3. Nilmart P. J Nov Physiother . 2018;8:62. 4. Riddle DL, et al . Rheumatology (Oxford ). 2013;52(12):2229–2237. Clinical Features: Bilateral knee versus Unilateral knee Osteoarthritis The knee is an important target site for OA, and OA affects one or both knees. 1 Bilateral knee OA Unilateral knee OA Gait Symmetric gait 2 Asymmetric gait 2 Duration of pain Significantly longer duration of knee pain 3 Shorter duration of knee pain 3 Functional Greater functional loss 4 Lesser functional loss 4 Influence on daily activities Greater difficulty with daily activities 4 Pain severity influences daily activities 4 OA: Osteoarthritis.

20. Abhishek A, et al . Rheum Dis Clin North Am . 2013;39(1):45 – 66. 2. Musumeci G. J. Funct. Morphol. Kinesiol . 2017;2(8):1–5. Knee OA affects two main compartments of the knee joint: patellofemoral joint and tibiofemoral joint. 2 OA: Osteoarthritis; COMP: Cartilage oligomeric matrix protein. Patellofemoral knee OA Pain noted in anterior and posterior aspects of the patella 1 Higher frequency of radiographic osteophytes 2 Lower levels of serum COMP due to small articular cartilage volume in the latter 2 Pain worsens by prolonged sitting, standing up from low chairs, climbing stairs or inclines 1 Tibiofemoral knee OA Clinical Features: Patellofemoral and Tibiofemoral knee Osteoarthritis Pain occurs in anteromedial part of knee joint 1 Presence of osteophytes is often not painful. 2 Higher levels of serum COMP and biomarkers of cartilage damage 2

21. Comparative Effectiveness Review. Treatment of Osteoarthritis of the Knee: An Update Review (2017). Available at. https://www.ncbi.nlm.nih.gov/books/NBK447530/. Accessed on: 26 December 2020. Fibel KH, et al . World J Clin Cases. 2015;3(2):89–101 Management of Osteoarthritis: Goals Reduce inflammation 1 Improve mobility and function 1 Delay disease progression 2 Delay or avert surgery 1 Improve patients' quality of life 1 Decrease joint pain 1

22. Hunter D, et al. Lancet . 2019;393:1745–1759. Management of Osteoarthritis : Treatment Strategies Non-pharmacological Pharmacological Surgery Education and self-management Exercise (strengthening and general aerobic) Weight loss, if overweight Nonsteroidal anti-inflammatory drugs Intra-articular corticosteroid injections Disease-modifying agents Joint replacement surgery for end-stage OA Osteotomy Knee joint distraction Arthroscopic knee surgery OA: Osteoarthritis.

23. Etoricoxib in the treatment of osteoarthritis over 52-weeks The aim of this study was to evaluate the long-term efficacy and tolerability of etoricoxib , a COX-2 selective inhibitor, in osteoarthritis (OA) patients WOMAC: Western Ontario and McMaster Universities Osteoarthritis Index, COX-2: Cyclooxygenase 2 Curtis SP, Bockow B, Fisher C, Olaleye J, Compton A, Ko AT, Reicin AS. Etoricoxib in the treatment of osteoarthritis over 52-weeks: a double-blind, active-comparator controlled trial [NCT00242489]. BMC Musculoskeletal Disorders. 2005 Dec;6(1):1-0. Double-blind, randomized, multicenter study was conducted in 617 patients with OA of the knee Treatment duration: consecutive 12 and 26 week extensions Primary efficacy endpoints: WOMAC Visual Analogue (VA) 3.0 pain subscale Investigator global assessment of disease status

24. Etoricoxib in the treatment of osteoarthritis over 52-weeks Compared with placebo, the etoricoxib groups displayed significant (p < 0.05) dose dependent efficacy for all primary endpoints in Part I Efficacy was maintained throughout the 52 weeks of the study During the 46-week active-comparator controlled period, the etoricoxib groups demonstrated clinical efficacy that was similar to that of diclofenac 150 mg Etoricoxib had a lower incidence of gastrointestinal (GI) nuisance symptoms compared with diclofenac (13.1, 14.7% for etoricoxib 30, 60mg respectively compared with 22.5% for diclofenac) Adapted from: Curtis SP, Bockow B, Fisher C, Olaleye J, Compton A, Ko AT, Reicin AS. Etoricoxib in the treatment of osteoarthritis over 52-weeks: a double-blind, active-comparator controlled trial [NCT00242489]. BMC Musculoskeletal Disorders. 2005 Dec;6(1):1-0. n=102 n=198 n=102

25. Etoricoxib in the treatment of osteoarthritis over 52-weeks Curtis SP, Bockow B, Fisher C, Olaleye J, Compton A, Ko AT, Reicin AS. Etoricoxib in the treatment of osteoarthritis over 52-weeks: a double-blind, active-comparator controlled trial [NCT00242489]. BMC Musculoskeletal Disorders. 2005 Dec;6(1):1-0. Conclusion: Etoricoxib , at doses ranging from 30 to 60 mg, demonstrated a maintenance of significant clinical efficacy in patients with OA through 52 weeks of treatment Etoricoxib displayed clinical efficacy similar to diclofenac 150 mg and was generally well tolerated

26. Etoricoxib 30mg vs. Celecoxib 200mg in the Treatment of OA To compare the efficacy of etoricoxib 30 mg with the generally maximum recommended dose of celecoxib, 200 mg, in the treatment of osteoarthritis (OA) in two identically designed studies OA: Osteoarthritis, NSAID: Non-Steroidal Anti-Inflammatory Drug, qd : quaque die, OD: once daily Bingham III CO, Sebba AI, Rubin BR, Ruoff GE, Kremer J, Bird S, Smugar SS, Fitzgerald BJ, O’Brien K, Tershakovec AM. Efficacy and safety of etoricoxib 30 mg and celecoxib 200 mg in the treatment of osteoarthritis in two identically designed, randomized, placebo-controlled, non-inferiority studies. Rheumatology. 2007 Mar 1;46(3):496-507. Two multi- centre , 26-week, double-blind, placebo-controlled, non-inferiority studies were conducted, enrolling patients who were prior non-steroidal anti-inflammatory drug (NSAID) or acetaminophen users Study 1 599 patients Study 2 608 patients Randomized 4:4:1:1 to etoricoxib 30 mg qd , celecoxib 200 mg qd OR one of two placebo groups Placebo patients were evenly distributed to etoricoxib or celecoxib based on their initial enrollment randomization schedule 12 weeks

27. Etoricoxib 30mg vs. Celecoxib 200mg in the Treatment of OA Primary hypothesis: Etoricoxib 30 mg would be at least as effective as celecoxib 200 mg for the time-weighted average change from baseline over 12 weeks for: Western Ontario and McMaster (WOMAC) Pain Subscale WOMAC Physical Function Subscale Patient Global Assessment of Disease Status Bingham III CO, Sebba AI, Rubin BR, Ruoff GE, Kremer J, Bird S, Smugar SS, Fitzgerald BJ, O’Brien K, Tershakovec AM. Efficacy and safety of etoricoxib 30 mg and celecoxib 200 mg in the treatment of osteoarthritis in two identically designed, randomized, placebo-controlled, non-inferiority studies. Rheumatology. 2007 Mar 1;46(3):496-507. In both studies, etoricoxib was non-inferior to celecoxib for all three efficacy outcomes over 12 and 26 weeks; both were superior to placebo (P<0.001) for all three outcomes in each study over 12 weeks

28. Etoricoxib Improves Pain, Function and Quality of Life: Results of a Real-world Effectiveness Trial Multicenter, prospective, open-label, single-arm study OA patients (n = 500) taking nonsteroidal anti-inflammatory drugs (NSAIDs) or other analgesics who had inadequate response as determined by their physicians (≥ 40 mm on a 0–100 mm pain scale) were switched directly to etoricoxib 60 mg once daily for 4 weeks without prior medication washout Results: 52% of patients reported a clinically meaningful reduction (≥ 30%) for WOMAC pain walking on a flat surface In the post hoc analysis, examining the subgroup with patient-reported baseline pain intensity >= 40 mm, the percentage of responders (n = 240) increased to 66.4% The most commonly reported adverse event was peripheral edema of the leg, hand, eyelid or face (4.2%) Conclusion: In OA patients experiencing inadequate relief from a wide variety of analgesics, pain, function, quality of life, and treatment satisfaction significantly improved when switched to etoricoxib Lin Hy, Cheng TT, Wang JH, Lee CS, Chen MH, Lei V, Lac C, Gammaitoni AR, Smugar SS, CHEN WJ. Etoricoxib improves pain, function and quality of life: results of a real‐world effectiveness trial. International Journal of Rheumatic Diseases. 2010 May;13(2):144-50.

29. Adapted from Lin Hy, Cheng TT, Wang JH, Lee CS, Chen MH, Lei V, Lac C, Gammaitoni AR, Smugar SS, CHEN WJ. Etoricoxib improves pain, function and quality of life: results of a real‐world effectiveness trial. International Journal of Rheumatic Diseases. 2010 May;13(2):144-50.

30. MEDAL Programme : Cardiovascular outcomes of Etoricoxib and Diclofenac Cannon CP, Curtis SP, FitzGerald GA, Krum H, Kaur A, Bolognese JA, Reicin AS, Bombardier C, Weinblatt ME, Van Der Heijde D, Erdmann E. Cardiovascular outcomes with etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme : a randomised comparison. The Lancet. 2006 Nov 18;368(9549):1771-81. Objective: To provide a precise estimate of thrombotic cardiovascular events with the COX-2 selective inhibitor etoricoxib versus the traditional NSAID diclofenac Pooled analysis of data from three trials in which patients with osteoarthritis or rheumatoid arthritis were randomly assigned to etoricoxib (60 mg or 90 mg daily) or diclofenac (150 mg daily) Background: Cyclo-oxygenase-2 (COX-2) selective inhibitors have been associated with an increased risk of thrombotic cardiovascular events in placebo-controlled trials No clinical trial has been reported with the primary aim of assessing relative cardiovascular risk of these drugs compared with traditional non-steroidal anti-inflammatory drugs (NSAIDs) The MEDAL programme was designed to provide a precise estimate of thrombotic cardiovascular events with the COX-2 selective inhibitor etoricoxib versus the traditional NSAID diclofenac

31. MEDAL Programme : Cardiovascular outcomes of Etoricoxib and Diclofenac The MEDAL programme was done between June, 2002, and May, 2006, at 1380 sites in 46 countries The MEDAL programme was prospectively designed to pool data from three randomised , double-blind clinical trials: the MEDAL study, the Etoricoxib versus Diclofenac Sodium Gastrointestinal Tolerability and Effectiveness (EDGE) study, and the EDGE II study Cannon CP, Curtis SP, FitzGerald GA, Krum H, Kaur A, Bolognese JA, Reicin AS, Bombardier C, Weinblatt ME, Van Der Heijde D, Erdmann E. Cardiovascular outcomes with etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme : a randomised comparison. The Lancet. 2006 Nov 18;368(9549):1771-81. Patients: Patients with osteoarthritis or rheumatoid arthritis aged 50 years or older with clinical diagnosis of osteoarthritis of the knee, hip, hand, or spine, or a clinical diagnosis of rheumatoid arthritis that satisfied at least four of seven of the American Rheumatism Association 1987 revised criteria and in the judgment of the investigator, would need chronic treatment with an NSAID These patients were not candidates for paracetamol as first-line therapy because of the severity of their symptoms Patients with a history of myocardial infarction, coronary artery bypass graft surgery, or percutaneous coronary intervention more than 6 months preceding enrolment were allowed to participate.

32. MEDAL Programme : Cardiovascular outcomes of Etoricoxib and Diclofenac Etoricoxib (n = 17412) Diclofenac (n = 17289) Age, mean (SD) 63.2 (8.5) 63.2 (8.5) < 65 years 10178 (58.5%) 10127 (58.6%) ≥65 to < 75 years 5201 (29.9%) 5261 (30.4%) ≥75 years 2033 (11.7%) 1901 (11.0%) Sex, women (%) 12925 (74.2%) 12823 (74.2%) Arthritis type* Osteoarthritis 12533 (72.0%) 12380 (71.6%) Rheumatoid Arthritis 4878 (28.0%) 4909 (28.4%) Weight in kg, mean (SD) 78.9 (18.6) 78.9 (18.5) BMI in kg/m 2 , mean (SD) 29.5 (6.1) 29.5 (6.0) Diabetes 1810 (10.4%) 1855 (10.7%) Hypertension‡ 8109 (46.6%) 8221 (47.6%) Dyslipidemia‡ 5097 (29.3%) 5034 (29.1%) Current cigarette smoker 2034 (11.7%) 2037 (11.8%) Established atherosclerotic CV disease § 2014 (11.6%) 2010 (11.6%) ≥2 CV risk factors¶ or established atherosclerotic CV disease 6586 (37.8%) 6639 (38.4%) Low-dose aspirin use 6030 (34.6%) 5976 (34.6%) Reference in notes ‡Clinical history at time of screening. §Includes clinical history of myocardial infarction, angina pectoris, cerebral vascular accident, transient ischaemic attack, angioplasty, carotid artery disease, peripheral vascular disease, or coronary artery bypass surgery. ¶Includes two or more of the following risk factors: history of hypertension, diabetes, dyslipidaemia , family history of CV disease, current cigarette smoking *Data missing for one patient Adapted from Cannon CP, Curtis SP, FitzGerald GA, Krum H, Kaur A, Bolognese JA, Reicin AS, Bombardier C, Weinblatt ME, Van Der Heijde D, Erdmann E. Cardiovascular outcomes with etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme : a randomised comparison. The Lancet. 2006 Nov 18;368(9549):1771-81.

33. MEDAL Programme : Cardiovascular outcomes of Etoricoxib and Diclofenac Cannon CP, Curtis SP, FitzGerald GA, Krum H, Kaur A, Bolognese JA, Reicin AS, Bombardier C, Weinblatt ME, Van Der Heijde D, Erdmann E. Cardiovascular outcomes with etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme : a randomised comparison. The Lancet. 2006 Nov 18;368(9549):1771-81. Conclusion: Rates of thrombotic cardiovascular events in patients with arthritis on etoricoxib are similar to those in patients on diclofenac with long-term use of these drugs Results: 34701 patients (24913 with osteoarthritis and 9787 with rheumatoid arthritis) were enrolled Average treatment duration was 18 months 320 patients in the etoricoxib group and 323 in the diclofenac group had thrombotic cardiovascular events, yielding event rates of 1·24 and 1·30 per 100 patient-years - a hazard ratio of 0·95 (95% CI 0·81–1·11) for etoricoxib compared with diclofenac Rates of upper gastrointestinal clinical events (perforation, bleeding, obstruction, ulcer) were lower with etoricoxib than with diclofenac ( 0·67 vs 0·97 per 100 patient-years) (hazard ratio 0·69 [0·57–0·83]), but the rates of complicated upper gastrointestinal events were similar for etoricoxib (0·30) and diclofenac (0·32).

34. Etoricoxib vs. nonselective NSAIDs Upper GI AEs in clinical trials : an updated combined analysis GI: Gastro Intestinal, AE: Adverse Events, NSAIDs-Non- Steroidsl Anti-Inflammatory Drugs, PUB: Peptic Ulcer Bleeding Adapted from Dena R. Ramey, Douglas J. Watson, Chang Yu, James A. Bolognese, Sean P. Curtis & Alise S. Reicin (2005) The incidence of upper gastrointestinal adverse events in clinical trial s of etoricoxib vs. non-selective NSAIDs: an updated combined analysis, Current Medical Research and Opinion, 21:5, 715-722, DOI: 10.1185/030079905X43686 NSAID* diclofenac, Naproxen , Ibuprofen n=5441, 10 studies The overall relative risk for Etoricoxib vs. NSAIDs was 0.48 (95% CI 0.32, 0.73)

35. This study demonstrates that COX-2 specific inhibition etoricoxib is associated with a significantly lower risk of PUBs relative to non-selective NSAIDs. The risk reduction with etoricoxib pertained to important subgroups of patients with and without risk factors for PUB and in patients using concomitant gastroprotective therapy. Etoricoxib may provide an effective alternative for patients at high risk of gastrointestinal complications with non-selective NSAIDs. Conclusion COX-2: Cyclooxygenase 2; PUB: Peptic Ulcer Bleeding, NSAID: Non-Steroidal Anti-Inflammatory Drug Dena R. Ramey, Douglas J. Watson, Chang Yu, James A. Bolognese, Sean P. Curtis & Alise S. Reicin (2005) The incidence of upper gastrointestinal adverse events in clinical trial s of etoricoxib vs. non-selective NSAIDs: an updated combined analysis, Current Medical Research and Opinion, 21:5, 715-722, DOI: 10.1185/030079905X43686 NSAID* diclofenac, Naproxen , Ibuprofen n=5441, 10 studies

36. Renal Effects of Etoricoxib and Comparator NSAIDS Adapted from: Curtis SP, Ng J, Yu Q, Shingo S, Bergman G, McCormick CL, Reicin AS. Renal effects of etoricoxib and comparator nonsteroidal anti-inflammatory drugs in controlled clinical trials. Clinical therapeutics. 2004 Jan 1;26(1):70-83. Incidence of investigator-reported renal adverse events AE Placebo (n=1491) Etoricoxib 60mg (n=658) Naproxen 1000 mg/d (n=1034) Ibuprofen 2400 mg/d (n=226) Hypertension 30 (2.0) 26 (4.0) 30 (2.9) 15 (6.6) Lower extremity edema (LEE) 28 (1.9) 21 (3.2) 24 (2.3) 4 (1.8) Elevated SCC 4 (0.3) 5 (0.8) 7 (0.7) 0 (0.0) Congestive heart failure (CHF) 0 (0.0) 1 (0.2) 1 (0.1) 0 (0.0) SCC, serum creatinine concentration data Based on this combined data review, the risks for renal AEs ( ie , hypertension, LEE, elevated SCC changes, and CHF) with etoricoxih 60 were low, with a shallow dose response, and were generally similar to those found with the comparator NSAIDs naproxen 1000 mg/d and ibuprofen 2400 mg/d.

37. The patient was started on Etoricoxib 60 mg OD along with physiotherapy. A follow-up visit was scheduled for 10 days later. The patient showed improvement in her symptoms. The patient was asked to continue Etoricoxib 60 mg OD and continue physiotherapy. The patient was advised to return for a follow-up visit again, after 12 days. The patient showed complete resolution of symptoms. Case Continued… Management OD; Once daily.

38. Piroxicam: A Nonsteroidal Anti-inflammatory Agent Section 3

39. Piroxicam: A Nonsteroidal Anti-inflammatory Agent It is widely used for the treatment of pain in osteoarthritis, and has proven efficacy and safety. 1,3 Ando GA, et al . Eur J Rheumatol Inflamm . 1983;6(1):3 – 23. 2. Mohammed Y, et al . J Nat Sc Biol Med . 2018;9:180–184. 3. Lindén B, et al. Br J Rheumatol . 1996;35(1):35–38. 4. Hochberg MC, et al. Arthritis Care Res (Hoboken ). 2012;64(4):465–474. American College of Rheumatology recommends oral and topical NSAIDs drugs for osteoarthritis of the hand and knee 4 Piroxicam is a nonsteroidal anti-inflammatory drug of the oxicam derivative. 1,2 It is chemically unique from other NSAIDs with longer half-life. 1,2 It blocks cyclooxygease enzymes which further inhibits the production of prostaglandin, which is the main mediator of pain. 1,2 NSAIDs: Nonsteroidal anti-inflammatory drug

40. Pharmacokinetic Properties of Piroxicam Orally well absorbed, reaches peak plasma concentration within 3 to 5 hours Produces peak plasma levels of 1.5 µ g/mL to 2 µg /mL Upon daily administration (20 mg), attains maximum drug plasma concentrations (usually stabilize at 3 µg /mL to 8 µg /mL) No effect on plasma levels when co-administered with antacids Local product document of Dolonex® LPDDLN032019. Absorption Bioavailability of the injectable form with the oral capsules after intramuscular administration of piroxicam: Plasma levels are significantly higher than those obtained after ingestion of capsules during the 45 minutes; following administration the first day, during 30 minutes the second day and 15 minutes on the seventh day. Bioequivalence exists between the two dosage forms. Metabolism of piroxicam occurs by hydroxylation. Cytochrome P450 (CYP2C9) is the main enzyme involved in the metabolism of piroxicam, in the liver. Plasma half life ≈ 50 hours, in men. Excreted in urine and feces. Approximately 5% of the piroxicam dose is excreted unchanged. Distribution Metabolism Excretion

41. Characteristics of Piroxicam That Enhance Patient Adherence Once-daily dose enables 24-hour control of symptoms 1 Potent anti-inflammatory and analgesic effects 1 Efficacy; reduces scores for joint pain, total joint swelling; and improves functional activity 2,3 Patient preference for and compliance with piroxicam therapy consistently high 1 Globally safer as compared to other NSAIDs as class* 3 Ando GA, et al . Eur J Rheumatol Inflamm . 1983;6(1):3 – 23. Zizic TM, et al . Semin Arthritis Rheum. 1985 Feb;14(3 Suppl 1):14-9. Richy F, et al . Pharmacol Res . 2009;60(4):254-63. *S alicylates , naproxen, indomethacin

42. Clinical Evidence on Use of Piroxicam for Pain Management in Osteoarthritis Section 4

43. Ravaud P, et al. J Rheumatol . 1998;25(12):2425–2431. Efficacy of Piroxicam in Reducing Pain in Knee Osteoarthritis (1/2) Multicenter, randomized, double-blind study; 1905 patients with knee OA and synovial effusion received piroxicam 20 mg once daily To compare the efficacy and safety of piroxicam 20 mg OD for 14 or 28 days in patients with knee osteoarthritis and synovial effusion Patients classified at day 28 Improved (Decrease in VAS and Lequesne's functional index by at least 30% from Day 14) Worsened (Increase in VAS and Lequesne's functional index by at least 30% from Day 14) Unchanged Study objective Study design and patients Changes in synovial effusion, pain on a 100 mm VAS, and Lequesne's functional index to assess impairment. Outcomes OA: Osteoarthritis; OD: Once daily’ VAS: mm visual analog scale .

44. Ravaud P, et al. J Rheumatol . 1998;25(12):2425–2431. Efficacy of Piroxicam in Reducing Pain in Knee Osteoarthritis (2/2) Significantly decreased pain, synovial effusion and functional impairment (p<0.001) Piroxicam at 14 days vs. baseline Higher percentage of patients with reduction in pain and functional improvement (Figure) n=280 n=298 n=233 p<0.0001 p<0.0001 n=339 Results Piroxicam significantly decreased pain, synovial effusion and functional impairment Piroxicam at 28 days vs. 14 days

45. Zizic TM, et al . Semin Arthritis Rheum. 1985 Feb;14(3 Suppl 1):14-9. . Long-term Efficacy and Safety of Piroxicam in the Treatment of Osteoarthritis (1/2) A total of 30 patients (all women, age 53–86 years ) All patients had either knee or hip involvement, and some had additional joints affected as well. Piroxicam 20 mg/day; n = 30 To establish the continued efficacy and safety of long-term, continuous piroxicam therapy in an elderly population of patients with osteoarthritis Study objective Study design and patients Outcome In all, 28 (93%) of the 30 patients reported feeling well at the last evaluation visit, while 12 (40%) of the 30 females stated that they were asymptomatic or had only mild symptoms of OA. Physicians’ overall assessment placed 15 (50%) patients in the asymptomatic or minimal disease activity category. OA: Osteoarthritis.

46. Long-term Efficacy and Safety of Piroxicam in the Treatment of Osteoarthritis (2/2) The mean total number of painful joints remains low, when the patients are grouped on the basis of duration of piroxicam therapy. The specific activity levels according to duration of therapy confirm the continuing long-term efficacy of piroxicam. Throughout the course of piroxicam therapy , no significant liver toxicity in any of the patients was found. Patients experienced sufficient benefits to prefer remaining on piroxicam (20 mg/day) for a mean of 6 years rather than changing to alternative forms of therapy available to them. Zizic TM, et al . Semin Arthritis Rheum . 1985;14(1):14 –1 9. Duration of therapy (mean total joint pain) Duration of therapy (mean specific activity) Mean total joint pain score (during last 12 months) Mean specific activity levels (during last 12 months) n=30

47. 1. Zizic TM, et al . Semin Arthritis Rheum . 1985;14(1):14 –1 9. 2. Richy F, et al. Pharmacological research . 2009;60(4):254–263. 3. Lapeyre-Mestre M, et al . Fundam Clin Pharmacol . 2013;27(2):223–230. 4. Ando GA, et al. Eur J Rheumatol Inflamm . 1983;6(1):3 – 23. 5. McGettigan P, et al . JAMA . 2006;296(13):1633 – 1644. Safety of Long-Term Piroxicam Use # Serious ADRs: Cutaneous, gastrointestinal, hepatic, renal and, rarely, cardiovascular events. 01 Piroxicam Had favorable g astrointestinal safety profile than other NSAIDs* 2 Well tolerated in patients with osteoarthritis and rheumatoid arthritis 4 Has low risk of cardiovascular events than other NSAIDs^ 5 Has numerically lower rate of serious ADRs # vs. other NSAIDs** (Figure) 3 NSAIDs: Nonsteroidal anti-inflammatory drugs; ADRs: Adverse drug reactions Piroxicam showed favorable safety profile where the patients preferred to continue taking it for a mean of six years rather than switch to alternative therapies 1 *NSAIDs: indomethacin, naproxen, salicylates; **NSAIDs: naproxen, nimesulide, diclofenac, ketoprofen; ^NSAIDs: Diclofenac, naproxen Adapted from Lapeyre-Mestre M, et al . Fundam Clin Pharmacol . 2013;27(2):223–230.

48. The patient was started on piroxicam 20 mg OD along with physiotherapy. A follow-up visit was scheduled for 10 days later. The patient showed improvement in her symptoms. The patient was asked to continue piroxicam 20 mg OD and continue physiotherapy. The patient was advised to return for a follow-up visit again, after 12 days. The patient showed complete resolution of symptoms. Case Continued… Management OD; Once daily.

49. Key Takeaways Osteoarthritis is a leading cause of disability in older adults and its prevalence is increasing globally. Guidelines recommend nonsteroidal anti-inflammatory drugs for the treatment of osteoarthritis Piroxicam is effective for reducing scores for joint pain, reducing total joint swelling, and improving functional activity Piroxicam has a favorable safety profile as patients showed complete improvement in their symptoms Osteoarthritis is typically diagnosed on the basis of clinical findings or with combination of laboratory or radiographic investigations NSAIDs: Nonsteroidal anti-inflammatory drugs *Diclofenac, ibuprofen, naproxen, indomethacin etc., combined as class

50. Summary of Prescribing Information of DOLONEX ® /DOLONEX ® DT/DOLONEX ® IM COMPOSITION: Dolonex 20 mg Capsules: piroxicam 20 mg per capsule; Dolonex 20 mg Dispersible Tablets: piroxicam 20 mg per tablet; Dolonex Intramuscular Solution 1 ml and 2 ml Ampules: piroxicam 20 mg per ml. INDICATIONS: Rheumatoid arthritis, osteoarthritis (arthrosis, degenerative joint disease), ankylosing spondylitis, juvenile rheumatoid arthritis, post-operative and post-traumatic pain, fever and pain associated with acute upper respiratory tract inflammation. CONTRAINDICATIONS: Active peptic ulceration, hypersensitivity to the drug or excipients, patients in whom aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) induce symptoms of asthma, nasal polyps, angioedema, or urticaria as potential for cross sensitivity to aspirin and other NSAIDs exists, peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery, patients with severe renal and hepatic failure, patients with severe heart failure. ADVERSE REACTIONS: Gastrointestinal symptoms are the most common, e.g., stomatitis, anorexia, epigastric distress, nausea, vomiting, constipation, abdominal pain/discomfort, flatulence, diarrhoea, indigestion; rarely, dyspnea, gastrointestinal bleeding (including hematemesis and melena), perforation, pancreatitis, and peptic ulceration have been reported. Other side effects include: tinnitus, malaise, palpitation, ankle edema, dizziness, mood alterations, dermal hypersensitivity reactions, metabolic abnormalities, reversible alterations in renal function, aseptic meningitis, changes in hematological and liver function tests. Swollen eyes, blurred vision, and eye irritation have been reported. It can reduce the efficacy of diuretics and other anti-hypertensive drugs including ACE. inhibitors, AIIA and beta-blockers.. Effect of coumarin anticoagulants may be enhanced. Being highly protein-bound, Dolonex may displace other protein-bound drugs; plasma levels of lithium may be increased. Piroxicam interferes with the antiplatelet effect of low-dose aspirin, and thus may interfere with aspirin’s prophylactic treatment of CV disease. WARNINGS & PRECAUTIONS: NSAIDs may cause an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. To minimize the potential risk for an adverse CV event in patients treated with piroxicam, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV toxicity and the steps to take if they occur Piroxicam can lead to the onset of new hypertension or worsening of pre-existing hypertension. Piroxicam, should be used with caution in patients with hypertension. Blood pressure should be monitored closely during the initiation of therapy with piroxicam and throughout the course of therapy.  Fluid retention and edema have been observed in some patients taking NSAIDs. Therefore, Piroxicam should be used with caution in patients with compromised cardiac function and other conditions predisposing to, or worsened by, fluid retention. Piroxicam can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. Administration of doses of greater than 20 mg/day carries an increased risk of gastrointestinal side effects. Piroxicam may be associated with a high risk of serious gastrointestinal toxicity, relative to other NSAIDs. When GI bleeding or ulceration occurs in patients receiving piroxicam, the treatment should be withdrawn. Piroxicam should be used with caution in patients a risk of developing GI complications such as elderly, patients with CV disease, patients using concomitant corticosteroids, antiplatelet drugs, selective serotonin reuptake inhibitors, patients ingesting alcohol or patients with a prior history of, or active GI disease, such as ulceration, GI bleeding or inflammatory conditions. Dolonex administration in patients with history of upper gastrointestinal disease, hypertension, congestive heart failure, liver cirrhosis, nephrotic syndrome, and overt renal disease, should be carefully monitored. Bleeding time may be prolonged. Concomitant use of other NSAIDs is not advised. Visual complaints during therapy should receive ophthalmic evaluation. To minimize the potential risk for an adverse cardiovascular event or a gastrointestinal event in patients treated with piroxicam, the lowest effective dose should be used for the shortest duration possible. Piroxicam should not be used during the third trimester of Pregnancy. If used during second or third trimester of pregnancy, NSAIDs may cause fetal renal dysfunction which may result in reduction of amniotic fluid volume or oligohydramnios in severe cases. Such effects may occur shortly after treatment initiation and are usually reversible. Pregnant women on piroxicam should be closely monitored for amniotic fluid volume. DOSAGE: Rheumatoid arthritis, osteoarthritis, ankylosing spondylitis: 20 mg daily as a single dose. Juvenile rheumatoid arthritis: Recommended once-daily doses based on body weight are - less than 15 kg -5mg, 16-25 kg - 10mg, 26-45 kg - 15mg, 46 kg and above - 20mg. Upper respiratory tract inflammation: 10-20 mg once daily for five to seven days; Dolonex Dispersible Tablets can be swallowed whole, or after dispersal in 50 ml water. ® Trademark Proprietor; Pfizer Products Inc, USA. Licensed User: Pfizer Limited, India Adapted from approved local product document of Dolonex® /Dolonex® DT Dolonex® IM; (LPDDLN032019). Full Prescribing information available on request

51. Summary of Prescribing Information of DOLONEX ® E Full Prescribing information available on request