Copyright 2012 Oregon State University. All Rights Reserved Drug Use Research & Management Program Oregon State University, 500 Summer Street NE, E35 Salem, Oregon 97301-1079 Phone 503-947-5220 Fax 503-947-1119 Literature Scan: NSAIDs Date of Review: March 2016 Date of Last Review: November 2014 Current Status of PDL Class: See Appendix 1. Conclusions: Since the last NSAID scan, there is limited new comparative evidence from three Cochrane systematic reviews and two randomized controlled trials (RCTs). There is also one new FDA safety alert regarding cardiovascular risk with oral NSAIDs. There is low quality evidence that NSAIDs are more effective than placebo for treating chronic low back pain, with a mean difference in the pain intensity score using the 100 point visual analog scale (VAS) from baseline of 3.30 (95% CI 5.33 to 1.27). The clinical significance of this change remains unclear. There is high quality evidence of a significant reduction in pain with NSAIDs compared to placebo in the treatment of ankylosing spondylitis (AS). There is low quality evidence of no difference between specific NSAIDs for both the treatment of chronic low back pain and AS. Recommendations: No further review or research needed. Evaluate comparative drug costs in the executive session. Previous Conclusions/Conclusions: No further review or research needed. Evaluate comparative drug costs in the executive session. Methods: An OHSU Drug Effectiveness Review Project literature scan was used to identify randomized controlled trials (RCTs) and systematic reviews through November 2015. A Medline literature search for new systematic reviews and RCTs assessing clinically relevant outcomes to active controls, or placebo if needed, was conducted to present date. A summary of the clinical trials is available in Appendix 2 with abstracts presented in Appendix 3. The Medline search strategy used for this literature scan is available in Appendix 4, which includes dates, search terms and limits used. The OHSU Drug Effectiveness Review Project, Agency for Healthcare Research and Quality (AHRQ), Cochrane Collection, National Institute for Health and Clinical Excellence (NICE), Department of Veterans Affairs, BMJ Clinical Evidence, and the Canadian Agency for Drugs and Technologies in Health (CADTH) resources were manually searched for high quality and relevant systematic reviews. When necessary, systematic reviews are critically appraised for quality using the AMSTAR tool and clinical practice guidelines using the AGREE tool. The FDA website was searched for new drug approvals, indications, and pertinent safety alerts. Finally, the AHRQ National Guideline Clearinghouse (NGC) was searched for updated and recent evidence based guidelines.
The primary focus of the evidence is on high quality systematic reviews and evidence based guidelines. Randomized controlled trials will be emphasized if evidence is lacking or insufficient from those preferred sources. New Systematic Reviews: A recent Cochrane Systematic Review compared the efficacy and harms of NSAIDs compared with other oral analgesics for treating acute soft tissue injury. 1 Sixteen trials (n=2144) were included. The evidence was either low quality or very low quality with study limitations including suboptimal dosing of single comparators, imprecision, and indirectness. Nine studies compared NSADs with acetaminophen (APAP). There were no significant differences between the two groups in pain at any time point measured, swelling, and return to function. There was also low quality evidence of no difference in gastrointestinal adverse events (RR 1.76; 95% CI 0.99 to 3.14) between NSAIDs and APAP. Four studies compared opioids to NSAIDs. There was low quality evidence for a lack of clinically important differences between the groups for pain or swelling. No studies compared NSAIDs with complementary and alternative medicines and the review did not evaluate the comparative effectiveness of different NSAIDs or COX 2 inhibitors. 1 Another Cochrane Systematic Review evaluated the use of NSAIDs for chronic low back pain. 2 There was low quality evidence from six studies (n=1354) that NSAIDs are more effective than placebo, with a mean difference in pain intensity score from baseline of 3.30 mm (95% CI 5.33 to 1.27). The clinical significance of this is unclear as studies have suggested that a 13 mm difference on the 0 100 visual analogue scale (VAS) is the minimum clinically significant difference. 3 In addition, patients with more severe pain require a greater change in the VAS to demonstrate clinically significant lessening of pain. There was also low quality evidence that NSAIDs are modestly more effective than placebo at reducing disability on a scale from 0 24 (mean difference from baseline 0.85; 95% CI 1.30 to 0.40) with a median follow up of 84 days. Although there was no significant difference in adverse events between the NSAID and placebo groups (RR 1.04; 95% CI 0.92 to 1.17), it is likely this is underestimated in trials due to the their short duration follow up. Comparative trials were limited and demonstrated no difference for ibuprofen versus diclofenac and piroxicam versus indomethacin. A third Cochrane Review compared oral NSAIDs for the treatment of ankylosing spondylitis (AS). 4 Compared to placebo, there was high quality evidence of a significant reduction in pain using the VAS with NSAIDs. Pain in the control group ranged from 57 to 64 on the 100 mm VAS and was 16.5 points lower in the NSAID group (95% CI 12.2 to 20.8). There was moderate quality evidence of improved disease activity with NSAIDs. There was no significant difference in withdrawals due to adverse events (RR 0.75; 95% CI 0.46 to 1.21) or serious adverse events (RR 1.69; 95% CI 0.36 to 7.97). There were no significant differences in pain or harms between NSAID classes. New Guidelines: None identified. New FDA Drug Approvals: None identified.
New FDA Safety Alerts: After a recent review of the current safety data, the FDA opted to strengthen the label warning that non aspirin NSAIDs increase the chance of a myocardial infarction and stroke. 5 A review of a meta analysis of RCTs and observational trials were reviewed by the FDA Advisory Committee in 2014. Based on this review, the following conclusions were made: 1) a multitude of studies support the finding that NSAIDs can cause serious cardiovascular (CV) thrombotic events (RR 10% 50%) and this risk is also evident in healthy individuals; 2) there could be a significant risk within days to weeks of initiation and there may be a higher risk with longer NSAID use; 3) some observational data suggests that naproxen may have a lower CV risk compared to other NSAIDs. However, this is based on limited data from studies not designed to compare safety between NSAIDs. The ongoing randomized safety trial comparing CV events with celecoxib, naproxen and ibuprofen among high CV risk patients will help determine if there are differences between individual agents; and 4) there is an approximately 2 fold increase in hospitalizations due to heart failure with use of both COX 2 selective and nonselective NSAIDs. References: 1. Jones P, Dalziel SR, Lamdin R, Miles Chan JL, Frampton C. Oral non steroidal anti inflammatory drugs versus other oral analgesic agents for acute soft tissue injury. In: Cochrane Database of Systematic Reviews. John Wiley & Sons, Ltd; 2015. http://onlinelibrary.wiley.com/doi/10.1002/14651858.cd007789.pub2/abstract. Accessed February 10, 2016. 2. Enthoven WT, Roelofs PD, Deyo RA, van Tulder MW, Koes BW. Non steroidal anti inflammatory drugs for chronic low back pain. Cochrane Database Syst Rev. 2016;2:CD012087. doi:10.1002/14651858.cd012087. 3. Bird SB, Dickson EW. Clinically significant changes in pain along the visual analog scale. Ann Emerg Med. 2001;38(6):639 643. doi:10.1067/mem.2001.118012. 4. Kroon FPB, van der Burg LRA, Ramiro S, et al. Non steroidal anti inflammatory drugs (NSAIDs) for axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis). Cochrane Database Syst Rev. 2015;7:CD010952. doi:10.1002/14651858.cd010952.pub2. 5. US Food and Drug Administration. FDA Drug Safety Communication: FDA strengthens warning that non aspirin nonsteroidal anti inflammatory drugs (NSAIDs) can cause heart attacks or strokes. July 2015. Available at http://www.fda.gov/drugs/drugsafety/ucm451800.htm. Accessed 1/7/2016. 6. Essex MN, Behar R, O Connell MA, Brown PB. Efficacy and tolerability of celecoxib and naproxen versus placebo in Hispanic patients with knee osteoarthritis. Int J Gen Med. 2014;7:227 235. doi:10.2147/ijgm.s61297. 7. Huang F, Gu J, Liu Y, et al. Efficacy and safety of celecoxib in chinese patients with ankylosing spondylitis: a 6 week randomized, double blinded study with 6 week open label extension treatment. Curr Ther Res Clin Exp. 2014;76:126 133. doi:10.1016/j.curtheres.2014.08.002.
Appendix 1: Current Status on Preferred Drug List ROUTE FORMULATION BRAND GENERIC PDL ORAL TABLET DICLOFENAC POTASSIUM DICLOFENAC POTASSIUM Y ORAL TABLET DR DICLOFENAC SODIUM DICLOFENAC SODIUM Y ORAL TABLET ETODOLAC ETODOLAC Y ORAL TABLET FLURBIPROFEN FLURBIPROFEN Y ORAL TABLET PROVIL IBUPROFEN Y ORAL CAPSULE ADVIL IBUPROFEN Y ORAL CAPSULE ADVIL LIQUI-GELS IBUPROFEN Y ORAL CAPSULE ADVIL MIGRAINE IBUPROFEN Y ORAL CAPSULE IBUPROFEN IBUPROFEN Y ORAL DROPS SUSP IBU-DROPS IBUPROFEN Y ORAL DROPS SUSP INFANTS IBU-DROPS IBUPROFEN Y ORAL DROPS SUSP INFANTS IBUPROFEN IBUPROFEN Y ORAL DROPS SUSP INFANT'S IBUPROFEN IBUPROFEN Y ORAL DROPS SUSP INFANTS' IBUPROFEN IBUPROFEN Y ORAL ORAL SUSP CHILD IBUPROFEN IBUPROFEN Y ORAL ORAL SUSP CHILDREN'S ADVIL IBUPROFEN Y ORAL ORAL SUSP CHILDREN'S IBUPROFEN IBUPROFEN Y ORAL ORAL SUSP IBUPROFEN IBUPROFEN Y ORAL TAB CHEW ADVIL IBUPROFEN Y ORAL TAB CHEW IBUPROFEN IBUPROFEN Y ORAL TAB CHEW IBUPROFEN IB IBUPROFEN Y ORAL TABLET ADVIL IBUPROFEN Y ORAL TABLET IBUPROFEN IBUPROFEN Y ORAL TABLET IBUPROFEN IB IBUPROFEN Y ORAL CAPSULE INDOMETHACIN INDOMETHACIN Y ORAL CAPSULE KETOPROFEN KETOPROFEN Y ORAL TABLET KETOROLAC TROMETHAMINE KETOROLAC TROMETHAMINE Y ORAL TABLET MELOXICAM MELOXICAM Y ORAL TABLET MOBIC MELOXICAM Y ORAL TABLET NABUMETONE NABUMETONE Y ORAL TABLET ALL DAY PAIN RELIEF NAPROXEN SODIUM Y ORAL TABLET ALL DAY RELIEF NAPROXEN SODIUM Y ORAL TABLET ANAPROX NAPROXEN SODIUM Y ORAL TABLET ANAPROX DS NAPROXEN SODIUM Y ORAL TABLET NAPROSYN NAPROXEN Y ORAL TABLET NAPROXEN NAPROXEN Y
ORAL TABLET NAPROXEN SODIUM NAPROXEN SODIUM Y ORAL TABLET DR EC-NAPROSYN NAPROXEN Y ORAL TABLET DR NAPROXEN NAPROXEN Y ORAL TABLET OXAPROZIN OXAPROZIN Y ORAL TABLET DAYPRO OXAPROZIN Y ORAL TABLET SULINDAC SULINDAC Y ORAL CAPSULE CELEBREX CELECOXIB N ORAL CAPSULE CELECOXIB CELECOXIB N ORAL CAPSULE ZIPSOR DICLOFENAC POTASSIUM N ORAL CAPSULE ZORVOLEX DICLOFENAC SUBMICRONIZED N ORAL POWD PACK CAMBIA DICLOFENAC POTASSIUM N ORAL TAB ER 24H DICLOFENAC SODIUM ER DICLOFENAC SODIUM N ORAL TAB IR DR ARTHROTEC 50 DICLOFENAC SODIUM/MISOPROSTOL N ORAL TAB IR DR ARTHROTEC 75 DICLOFENAC SODIUM/MISOPROSTOL N ORAL TAB IR DR DICLOFENAC SODIUM-MISOPROSTOL DICLOFENAC SODIUM/MISOPROSTOL N ORAL TABLET DIFLUNISAL DIFLUNISAL N ORAL CAPSULE ETODOLAC ETODOLAC N ORAL TAB ER 24H ETODOLAC ER ETODOLAC N ORAL TABLET FENOPROFEN CALCIUM FENOPROFEN CALCIUM N ORAL CAPSULE NALFON FENOPROFEN CALCIUM N ORAL TABLET DUEXIS IBUPROFEN/FAMOTIDINE N ORAL CAPSULE ER INDOMETHACIN INDOMETHACIN N ORAL ORAL SUSP INDOCIN INDOMETHACIN N ORAL CAPSULE TIVORBEX INDOMETHACIN, SUBMICRONIZED N ORAL CAP24H PEL KETOPROFEN KETOPROFEN N NASAL SPRAY SPRIX KETOROLAC TROMETHAMINE N ORAL CAPSULE MECLOFENAMATE SODIUM MECLOFENAMATE SODIUM N ORAL CAPSULE MEFENAMIC ACID MEFENAMIC ACID N ORAL CAPSULE PONSTEL MEFENAMIC ACID N ORAL ORAL SUSP MELOXICAM MELOXICAM N ORAL ORAL SUSP MOBIC MELOXICAM N ORAL CAPSULE NAPROXEN SODIUM NAPROXEN SODIUM N ORAL ORAL SUSP NAPROXEN NAPROXEN N ORAL TBMP 24HR NAPRELAN NAPROXEN SODIUM N ORAL TBMP 24HR NAPROXEN SODIUM CR NAPROXEN SODIUM N ORAL TAB IR DR VIMOVO NAPROXEN/ESOMEPRAZOLE MAG N ORAL CAPSULE FELDENE PIROXICAM N ORAL CAPSULE PIROXICAM PIROXICAM N ORAL CAPSULE TOLMETIN SODIUM TOLMETIN SODIUM N ORAL TABLET TOLMETIN SODIUM TOLMETIN SODIUM N
Appendix 2: New Clinical Trials A total of 177 citations were manually reviewed from the literature search. After further review, 175 trials were excluded because of wrong study design (observational), comparator (placebo), or outcome studied (non clinical). The remaining 2 trials are briefly described in the table below. Full abstracts are included in Appendix 3. Table 1: Description of Clinical Trials Study Comparison Population Primary Outcome Results Essex, et al. 6 DB, PG, NI, RCT Celecoxib 200 mg daily vs. naproxen 500 mg twice daily(noninferiority study) Hispanics with knee osteoarthritis age 45 years (n=239) Change in patient s assessment of arthritis pain at 6 weeks compared with baseline Reduction in OA Pain (least squares mean change from baseline): Celecoxib: 39.7 mm Naproxen: 36.9 mm P=NS (noninferior) Huang, et al. 7 DB, PG, et al. Celecoxib 200 mg 400 mg daily vs. diclofenac 75 mg daily Chinese subjects with ankylosing spondylitis (n=240) Noninferiority of celecoxib compared with diclofenac in global assessment of pain using the VAS Also no statistically significant differences in GI tolerability, and patient s and physician s global assessments of arthritis Change from baseline in VAS pain scale Celecoxib: 23.8 mm Diclofenac: 27.1 mm Treatment difference: 3.3 mm (95% CI 2.2 to 8.8) Abbreviations: DB = double blind; NI = non inferiority study; OA = osteoarthritis; PG = parallel group; NS = not statistically significant; RCT = randomized controlled trial; VAS = visual analog scale.
Appendix 3: Abstracts of Clinical Trials 1. Essex, et al. Efficacy and Tolerability of celecoxib and naproxen versus placebo in Hispanic patients with knee osteoarthritis. Int J Gen Med. 2014 May 16:7;227 35. BACKGROUND: Celecoxib is an effective treatment for osteoarthritis (OA). However, information on its efficacy and safety profile in different racial/ethnic groups is limited. Noticeable differences among racial groups are found in other disease states, but a thorough investigation of OA is lacking. The objective of this study was to determine if celecoxib 200 mg once daily is as effective as naproxen 500 mg twice daily in the treatment of OA of the knee in Hispanic patients. METHODS: Hispanic patients aged 45 years with knee OA were randomized to receive celecoxib 200 mg once daily, naproxen 500 mg twice daily, or placebo for 6 weeks. The primary efficacy variable was the change in Patient's Assessment of Arthritis Pain at 6 weeks compared with baseline. Secondary variables were change in Patient's and Physician's Global Assessments of Arthritis from baseline to week 6/early termination, change in Western Ontario and McMaster Universities OA Index (WOMAC) from baseline to week 6/early termination, change in American Pain Society pain score, Pain Satisfaction Scale, Patient Health Questionnaire (PHQ 9), and measurements of upper gastrointestinal tolerability. RESULTS: In total, 239 patients completed the trial (96 celecoxib, 96 naproxen, 47 placebo). Celecoxib was as effective as naproxen in reducing OA pain (least squares mean change from baseline [standard error] 39.7 [2.7] for celecoxib and 36.9 [2.6] for naproxen). Patient's and Physician's Global Assessments of Arthritis, WOMAC scores, upper gastrointestinal tolerability, Pain Satisfaction Scale, and PHQ 9 showed no statistically significant differences between the celecoxib and naproxen groups. The incidence of adverse events and treatment related adverse events were similar among the treatment groups. CONCLUSION: Celecoxib 200 mg once daily was as effective as naproxen 500 mg twice daily in the treatment of signs and symptoms of knee OA in Hispanic patients. Celecoxib was shown to be safe and well tolerated in this patient population. 2. Huang, et al. Efficacy and Safety of celecoxib in chinese patients with ankylosing spondylitis: a 6 week randomized, double blinded study with 6 week openlabel extension treatment. Curr Ther Res Clin Exp. 2014 Dec 5:76:126 33. BACKGROUND: Nonsteroidal anti inflammatory drugs are the first line option for treating ankylosing spondylitis (AS) in China. However, no large scale controlled trials have been conducted in this ethnic population. OBJECTIVE: To evaluate the efficacy and safety of 6 weeks' treatment with celecoxib in patients with AS in China. METHODS: This Phase 3, double blind, parallel group study randomized patients with AS aged 18 to 65 years 1:1 to receive celecoxib 200 mg once daily or diclofenac sustained release 75 mg once daily. After 6 weeks, patients could use celecoxib 400 mg once daily or maintain blinded therapy. The primary efficacy end point was mean change from baseline at Week 6 for Patient's Global Assessment of Pain Intensity score (100 mm visual analog scale). Noninferiority was established if the upper bound of the CI was <10 mm. Secondary objectives included patients' and physicians' assessments of disease activity, change from baseline in C reactive protein level, and safety.
RESULTS: In the per protocol analysis set the least squares mean change from baseline in the Patient's Global Assessment of Pain Intensity score at Week 6 was 23.8 mm and 27.1 mm in patients receiving celecoxib (n = 111) and diclofenac (n = 108), respectively. The 2 sided 95% CI for the treatment difference (celecoxib diclofenac) was 2.2 to 8.8. Overall, 4.2% and 6.7% of patients in the celecoxib and diclofenac groups, respectively, reported treatment related adverse events. All were mild to moderate in severity. CONCLUSIONS: Celecoxib 200 mg once daily is noninferior to diclofenac sustained release 75 mg once daily for pain treatment in Chinese patients with AS. ClinicalTrials.gov identifier: NCT00762463. Appendix 4: Medline Search Strategy 1 NSAID.mp or Anti inflammatory agents, non steroidal/ 47484 2 ibuprofen.mp or ibuprofen/ 7309 3 naproxen.mp 3308 4 celecoxib.mp 4870 5 indomethacin/ 14704 6 Ketolrac or ketorolac.mp 1733 7 Nabumetone.mp 256 8 diclofenac.mp 7311 9 etodolac 394 10 meloxicam.mp 1451 11 piroxicam.mp 1758 12 Tolmentin.mp 388 13 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 70056 14 limit 13 to (English language and yr=2015 Current clinical trial, all or clinical trial or comparative study or controlled clinical trial or meta analysis or practice guideline or pragmatic clinical trial or randomized controlled trial or systematic reviews) 177
Appendix 5: Prior Authorization Criteria Analgesics, Non-Steroidal Anti-Inflammatory Drugs Goal(s): To ensure that non-preferred NSAIDs are used for conditions funded by the OHP. Restrict ketorolac to short-term use (5-day supply every 60 days) per the FDA black boxed warning. Length of Authorization: Up to 12 months Requires PA: Non-preferred NSAIDs. Ketorolac: Maximum of one claim per 60 days, with a maximum 20 tablets/5-day supply (maximum 5-day supply every 60 days). Preferred Alternatives: Preferred alternatives listed at www.orpdl.org/drugs/ Approval Criteria 1. What diagnosis is being treated? Record ICD10 code. 2. Is the diagnosis funded by the Oregon Health Plan? Yes: Go to #3 No: Pass to RPh; Deny (not funded by the OHP) 3. Is this a continuation of current therapy (i.e. filled prescription within prior 90 days)? Verify via pharmacy claims. 4. Is request for more than a 5-day supply of ketorolac within 60 days (200 mg total over 5 days for tablets, 630 mg total over 5 days for the nasal spray)? Yes: Document prior therapy in PA record. Go to #4. Yes: Pass to RPh. Deny for medical appropriateness. No: Go to #5 No: Go to #5
Approval Criteria 5. Will the prescriber consider switching to a preferred product? Message: Preferred products do not require PA or copay. Preferred products are evidence-based reviewed for comparative effectiveness & safety by the Pharmacy and Therapeutics (P&T) Committee. Yes: Inform prescriber of covered alternatives in class. No: Approve for up to 12 months. P&T / DUR Review: 3/16 (MH); 11/14; 9/13; 2/12; 9/09; 2/06 Implementation: 10/15, 1/1/15, 1/1/14, 5/14/12, 1/1/10