European Review for Medical and Pharmacological Sciences 2011; 15: 943-949 2.5% gel: a clinical overview

S. COACCIOLI

Rheumatology Unit, Santa Maria General Hospital, Terni (Italy)

Abstract. – Ketoprofen (KP), a non- therefore, with fewer serious adverse events steroidal anti-inflammatory drug (NSAID), pos- (AEs)2. Current guidelines produced by the Euro- sesses , antipyretic and anti-inflamma- pean League Against Rheumatism (EULAR) and tory properties. Oral KP is widely used in mus- culoskeletal pain and inflammation in muscles the Osteoarthritis Research Society International and joints, including pain, osteoarthritis, (OARSI) suggest that topical NSAIDs are pre- stiffness of the joints, soft tissue rheumatism, ferred over oral NSAIDs for patients with mild to and sports injuries. In common with all NSAIDs, moderate knee or hand OA with few affected oral KP has been associated with systemic ad- joints, and/or a history of sensitivity to oral verse events and in particular gastrointestinal NSAIDs3,4. The favourable benefit/risk ratio of disorders. Topical application of the active ingre- dient is locally effective and at the same time topical NSAIDs has been further confirmed by a minimises the risk of systemic adverse events. recent Cochrane meta-analysis of 47 randomized Pharmacokinetic studies show that serum levels studies5. Because there are a number of topical of the active ingredient following topical KP formulations of NSAIDs currently available, 2.5% gel are less than 1% of those reported after there is a need to summarize the evidence sup- oral dosing, thereby providing good levels of porting the effectiveness and safety of each for- pain relief without the systemic adverse events mulation. In fact, the results of a recent systemat- normally associated with oral NSAIDs. In com- parative studies, topical KP 2.5% gel twice daily ic review highlighted that topical NSAIDs may showed clinical benefits in patients with a range vary significantly in their pharmacokinetic and of musculoskeletal conditions. KP 2.5% gel is pharmacodynamic properties, as well as in their generally well tolerated but the treated skin area efficacy/safety profile1. should not be exposed to direct sunlight, includ- Ketoprofen (KP), a widely used NSAID, is ef- ing solarium (sunbeds), during the treatment fective and well-tolerated in the treatment of and for 2 weeks afterwards as topical photosen- acute and chronic pain, of both rheumatic and sitization has been reported. To our knowledge, 6 this is the first overview on the use of topical KP traumatic origin, as well as postoperative pain . (tKP) 2.5% gel which includes data from both The clinical experience with this drug is exten- clinical trials and from ‘real-life’ clinical practice. sive6, and a number of different formulations are available - including capsules, suppositories, in- Key Words: jectable solutions, sustained release formulations, 7 Ketoprofen, Gel, NSAIDs, Pain, Topical treatment, and a topical gel . To our knowledge, this is the Musculoskeletal. first overview on the use of topical KP (tKP) 2.5% gel which includes data from both clinical trials and from “real-life” clinical practice.

Methodology Introduction We first performed a systematic search using MEDLINE (last updated February 2011). The The use of topical non-steroidal anti-inflam- search terms included, but were not limited to, matory drugs (NSAIDs) in relieving pain in pa- ketoprofen AND gel; topical NSAIDs AND pain tients with acute and chronic musculoskeletal were used. Articles were chosen based on their disorders, including osteoarthritis (OA), ten- relevance, as judged by the Author and search re- donitis, and muscle strains is well established1. sults were supplemented with a search of Com- Topical formulations of NSAIDs have analgesic pany reports held in a proprietary database, by effects similar to that of oral formulations, but manually searching the reference list of identi- are associated with less systemic exposure and, fied articles.

Corresponding Author: Stefano Coaccioli, MD; e-mail: [email protected] 943 S. Coaccioli

Product Development and Indications in the urine following daily application of tKP KP is a NSAIDs which belongs to the group of was 2.6% of the initial dose applied and the ap- substituted 2-phenyl propionic acids [2-(3-ben- parent half-life of unchanged KP was 17.1 ± 9.1 zoylphenyl)-]. It was first synthe- hours, and no accumulation was reported10. An- sized in 1967 at Rhone-Poulenc Research Labo- other study, conducted to determine the concen- ratories, Paris, and was approved for clinical use tration of KP in the synovial fluid following topi- as an oral formulation in France and the United cal application, showed that KP concentrations Kingdom in 1973. It is now available in more were comparable with those following intramus- than 100 countries worldwide. There is a wealth cular administration11. of clinical experience with tKP and it is estimat- In 2002, KP 2.5% gel was used as a standard ed that the therapeutic experience of KP exceeds reference to measure the percutaneous absorption 3 million patient/year8. In the 10 years from Jan- by human skin in two in vitro studies. The first uary 1998 to January 2008, more than 140 mil- study compared the percutaneous absorption (af- lions patients were treated with tKP gel. ter a 24-hour contact) of KP 2.5% gel alone or in The main indication for tKP 2.5% gel is the combination with sunscreen, through human skin local treatment of musculoskeletal pain and in- compared with other two gel formulations (Table flammation in muscles and joints (contusions, I)12. The second study was carried out using ver- distortions, strains, stiff neck, and lumbago). The tical Franz diffusion cells, and the extent of KP topical release of the active molecule is locally diffusion was determined using a validated effective, and because of the low systemic HPLC method13. Systemic absorption of tKP bioavailability is associated with fewer adverse 2.5% gel was relatively low, with the plasma lev- events (AEs) than with systemic formulations1. els about 100-fold lower, and the local tissue lev- Importantly, tKP should only be used on intact els 100-fold higher than those reported following skin (as single or repeated application) to avoid the oral administration. any irritant action on mucosa and scarred skin. In common with other NSAIDs, the pharma- codynamic activity of KP relies on the inhibition Pharmacokinetics and Pharmacodynamics of the metabolism of . KP is one The pharmacokinetic profile of tKP after topi- of the most powerful inhibitors of cyclooxyge- cal application has been extensively studied in nase (COX)14 and the inhibition of vitro and in vivo. In one of the first studies, tKP synthesis gives it its anti-inflammatory, anal- was applied to the entire surface of the knee once gesic, and antipyretic effects1. In addition, KP is a day for three days in patients scheduled for sur- characterized by other pharmacological effects gical intervention. KP concentrations in the plas- that may be relevant to its anti-inflammatory and ma, synovial fluid and tissue were determined by analgesic activities. It is a powerful inhibitor of HPLC9 KP was detected in the plasma 2 hours bradykinin (an important chemical mediator of after the administration and its concentration re- pain and inflammation)15; it stabilises the lysoso- mained constant for 12 hours. Local tissue con- mal membranes against the osmotic damage16 centrations at the site of application were about and it prevents the release of lysosomal enzymes 100-fold higher than the plasma concentrations. that mediate the tissue destruction in the inflam- KP levels in the knee joint were considered to be matory reactions8. In an unpublished report, the a result of a direct transcutaneous diffusion, effect of tKP 2.5% gel on concen- rather than a plasma diffusion. In a 10-day study trations in the synovial fluid and on the platelet in 10 healthy volunteers, the total amount of KP output of tromboxane B2 (TXB2) was measured

Table I. Percutaneous absorption of tKP 2.5% (expressed as µg) gel alone or in combination with sunscreeen, through human skin in comparison with ethylhexyl methoxycinnamate 3% and phenylbenzimidazole sulfonic acid 3% after a 24-hour contact12.

Receptor fluid Epidermis Dermis Total

Ethylhexyl methoxycinnamate 3% 17.16 ± 3.00 9.83 ± 1.85 1.31 ± 1.18 28.30 ± 3.34 KP 2.5% + sunscreen 6.19 ± 1.92 8.77 ± 1.43 0.66 ± 0.32 15.62 ± 3.27 KP 2.5% alone 10.13 ± 3.75 12.23 ± 3.30 0.86 ± 0.48 23.22 ± 5.07 Phenylbenzimidazole sulfonic acid 3% 12.56 ± 4.65 10.60 ± 3.51 1.00 ± 0.54 24.17 ± 9.29

944 Ketoprofen 2.5% gel: a clinical overview in patients with joint effusion17. Inhibition of According to these results, and the overall im- platelet COX activity was comparable to that ob- proved efficacy/safety ratio when compared with served after an oral administration of KP, with a oral administration, the topical treatment with significant reduction in the synovial concentra- NSAIDs, including KP, should be considered as tions of PGE2 and 6-keto-PGF1alpha. a first-line treatment for the management of knee and hand osteoarthritis3,4,36,37.

Efficacy The efficacy of tKP gel has been studied in a Safety and Tolerability series of controlled trials versus placebo or other Overall tKP 2.5% gel is well tolerated38. Re- analgesic drugs such as or etofena- sults of meta-analyses, conducted in a wide range mate, in a broad range of patients, with acute of patients, consistently show that local and sys- and chronic painful conditions (sport lesions, temic adverse events associated with the admin- low back pain, tendonitis, osteoarthritis of the istration of tKP are rare and in most cases knee and hand, soft tissue rheumatic pain). In mild5,34,35. In a double-blind, placebo controlled general, in these studies, tKP 2.5% gel was ap- study no adverse effects were observed over a 7- plied twice daily at dosages ranging from 40- day period19. These findings are consistent with 600 mg (typically 100–300 mg) for 2-42 days those reported in other trials, in which the appli- (typically 7–20 days). In addition, the effects of cation of tKP was not associated with any local tKP 1– 5% gel were investigated in a number of or systemic AEs25,31. In other trials, mild pruritus open studies18-26. Marked improvements were and erythema which did not lead to study a dis- observed in the severity of spontaneous and pal- continuation were the only AEs reported21,22,24. pation pain; in both passive and active articular Importantly the application of tKP gel did not al- mobility and in the signs of inflammation. These ter the blood chemistry parameters32. improvements were significantly more marked Pooled data, collected in the context of post- with tKP 2.5% and 5% gel compared with tKP marketing surveillance reports, from over 273 1% gel, whereas statistical differences between million patients treated with KP 2.5% gel from the two higher concentrations were not reported January 2001 to July 2010 showed a total of 624 for any of the parameters measured. Similar re- reported serious adverse reactions (SDRs) in 437 sults were reported in another series of trials that patients (incidence: 0.16/100,000) (data on file). assessed the efficacy of tKP in association with Most of the ADRs were cutaneous, such as hy- physical therapies including iontophoresis and persensitivity and photosensitivity reactions. sonophoresis27-33. Some cases of photosensitivity, potentially re- The efficacy of tKP, as well as that of other sulting in chronic dermatitis, have been docu- topical NSAIDs has been confirmed in meta- mented following tKP gel treatment39,40. analyses. Moore et al.34 carried out a quantitative Drug interactions are not to be expected when systematic review of 86 randomised controlled using the topical route, and no cases of over- trials, involving 10,160 patients, and reported a dosage have been reported. tKP during pregnan- significant advantage of tKP, with respect to cy and in breastfeeding women should be avoid- placebo, in relieving pain in acute and chronic ed, as well as in children and adolescents under conditions (number needed to treat, NNT, 2.6) 15 years of age. (Table II). In a subsequent meta-analysis by Ma- On the basis of the above, the most relevant son et al. (35) of 26 double-blind, placebo-con- safety issue for KP gel is its potential relation- trolled trials in 2,853 patients, the indirect com- ship with skin disorders, and in particular with parisons of individual topical NSAIDs showed photosensitivity reactions. To reduce the risk of that tKP was significantly better in the treatment these events, patients should be instructed not to of acute pain conditions than all the other topical expose treated skin to sunlight during the appli- NSAIDs studied (Table III). The efficacy of tKP cation period and for the following two weeks. In was also confirmed by a recent Cochrane meta- addition, tKP gel should not be applied near or analysis by Massey et al.5, who concluded that over wounds and contact with the eyes should be topical NSAIDs when used to treat acute muscu- avoided. Overall taking into account the wide loskeletal conditions can provide good levels of clinical experience with tKP collated so far the pain relief, without the systemic adverse events overall safety profile of tKP is favourable and associated with oral NSAIDs. skin disorders are rare events6.

945 S. Coaccioli needed ). 34 produced from Indicates that there may be no benefit with treatment over placebo. with treatment over Indicates that there may be no benefit § Treatment group: Treatment group: Treatment Chronic painful conditions Chronic Average Average Response* Response* Relative Number Relative benefit and number needed to treat in randomized studies of topical NSAIDs acute chronic painful conditions (re benefit Relative Condition/drug Total Total number of with with active benefit treat to acute painful conditions dataCombined efficacy effectsLocal adverse trials effectsSystemic adverse effects due to adverse Withdrawal of quality score 3-5Trials patients 37 patients treated 30 placebo 3239 (%) treatment 2834 (95% CI) 47 52 (95% CI) 39 0.4 38 0.7 3.0 71 0.6 72 1.7 (1.5 to 1.9) 0.8 2.6 0.8 (0.4 to 1.4) 3.9 (3.4 to 4.4) 1.7 (1.5 to 1.9) 1.0 (0.6 to 1.8) 1.2 (0.8 to 1.7) 3.9 (3.4 to 4.4) < 40 patients (pts)40-80 pts> 80 ptsKetoprofenFelbinacIbuprofenPiroxicamBenzydamineIndomethacin 20 dataCombined efficacy effectsLocal adverse effectsSystemic adverse 8 933 effects due to adverse Withdrawal 9 7 of quality score 35Trials 3 4 12 4< 40 pts 810 4 3> 40 pts 1496 724 24 413 9 1097 284 245 589 394 51 123 43 987 35 70 36 31 74 66 6 6 44 55 41 36 76 32 261 34 836 30 62 39 32 0.7 66 1.9 (1.6 to 2.2) 67 74 27 1.3 5.3 22 2.6 (2.3 to 3.1) 66 70 70 65 84 69 1.6 (1.1 to 2.2) 1.6 (1.3 to 1.9) 47 0.7 2.0 (1.5 to 2.6) 5.0 (3.7 to 7.4) 4.6 (3.7 to 5.9) 62 2.0 (1.5 to 2.7) 1.1 2.6 (2.3 to 3.2) 1.9 (1.2 to 3.0) 5.9 2.0 (1.5 to 2.7) 1.4 (0.9 to 2.0) 1.6 (1.2 to 2.2) 31 1.3 (0.9 to 1.8) 3.0 (2.4 to 4.1) 1.0 (0.4 to 3.1) 29 3.5 (2.5 to 5.6) 3.1 (2.7 to 3.8) 6.7 (3.8 to 23) 4.2 (3.1 to 6.1) 2.2 (1.5 to 3.1) 10 (5 to §) 1.1 (0.5 to 2.3) 0.9 (0.4 to 1.7) 3.1 (2.6 to 3.8) 69 61 2.2 (1.5 to 3.1) 2.0 (1.7 to 2.4) 2.6 (2.0 to 3.6) 3.3 (2.8 to 4.3) *Response is either proportion of patients with successful outcome or of patients with adverse effect; effect; *Response is either proportion of patients with successful outcome or adverse Table II. Table

946 Ketoprofen 2.5% gel: a clinical overview 5.2 to infinity) NNH (95 % CI) ). 35 rom Relative benefit NNT Success with 9 22 2511 876/1355 440/1156 1.6 (1.4 to 1.8) 3.8 (3.3 to 4.4) ≥ 9/16 24 2793 969/1501 508/1292 1.5 (1.4 to 1.7) 4.0 (3.5 to 4.6) 3/5 23 2551 893/1375 443/1176 1.6 (1.5 to 1.8) 3.7 (3.2 to 4.3) 3 and validity score 3 and validity ≥ ≥ ≥ Summary data and sensitivity analyses for placebo controlled trials of topical NDAIDs in acute painful conditions (reproduced f analyses for placebo controlled trials of topical NDAIDs Summary data and sensitivity Parameter Trials Patients Treatment Placebo (95% CI) (95% CI) 40 pts per group 15 2279 761/1234 400/1045 1.4 (1.3 to 1.6) 4.3 (3.7 to 5.2) All trials qualityTrial Quality score 26 2853 993/1531 512/1322 1.6 (1.4 to 1.7) 3.8 (3.4 to 4.4) Validity score Validity Quality score Trial size Trial ≥ < 40 pts per group by outcome type Efficacy Preferred outcomes preference outcomesLower by topical NSAIDs Efficacy KetoprofenIbuprofenFelbinacPiroxicamIndomethacin 11 9 17 574 912 1941 6 5 3 3 232/297 3 317/506 676/1025 517 365 112/277 139/406 413 394 563 373/916 203/261 112/183 1.9 (1.6 to 2.2) 1.7 (1.5 to 2.1) 112/210 1.5 (1.3 to 1.6) 179/283 95/197 101/256 2.7 (2.2 to 3.3) 3.5 (2.9 to 4.5) 4.0 (3.4 to 4.8) 67/182 118/280 57/203 76/197 2.1 (1.7 to 2.5) 2.0 (1.5 to 2.6) 1.4 (1.1 to 1.7) 1.6 (1.2 to 2.2) 2.6 (2.2 to 3.3) 1.3 (0.99 to 1.6) 4.1 (2.9 to 6.9) 4.7 (3.4 to 7.7) 4.0 (2.9 to 6.2) ( 10 Adverse events Adverse eventsLocal adverse eventsSystemic adverse withdrawals events Adverse 24 23 23 3011 2685 2741 13/1601 40/1437 65/1464 10/1410 30/1248 60/1277 1.0 (0.8 to 2.4) 1.4 (0.9 to 2.0) 1.6 (1.0 to 2.5) Not calculated Not calculated Not calculated Table III. Table

947 S. Coaccioli

Conclusions References

Oral KP has been widely in the treatment of 1) HAROUTIUNIAN S, DRENNAN DA, LIPMAN AG. Topical NSAID therapy for musculoskeletal pain. Pain patients with rheumatic and muscular pain and Med 2010; 11: 535-549. inflammation. As with all NSAIDs administered 2) ALTMAN R, BARKIN RL. Topical therapy for os- by this route, oral KP is associated with clinical- teoarthritis: clinical and pharmacologic perspec- ly relevant AEs, in particular gastrointestinal dis- tives. Postgrad Med 2009; 121: 139-147. orders. The topical application of the active in- 3) ZHANG W, D OHERTY M, LEEB BF, ALEKSEEVA L, ARDEN gredient is locally effective, but has the advan- NK, BIJLSMA JW, DINÇER F, D ZIEDZIC K, HÄUSELMANN tage lowering the risk of AEs. The efficacy and HJ, HERRERO-BEAUMONT G, KAKLAMANIS P, L OHMANDER safety of tKP have been demonstrated in both S, MAHEU E, MARTÍN-MOLA E, PAVELKA K, PUNZI L, RE- clinical studies and in ‘real-life’ practice. It must ITER S, SAUTNER J, SMOLEN J, VERBRUGGEN G, ZIMMER- MANN-GÓRSKA I. EULAR evidence based recom- be acknowledged that some of the studies which mendations for the management of hand os- investigated the efficacy and safety of tKP 2.5% teoarthritis: report of a Task Force of the EULAR gel belong to the so-called “grey literature” – a Standing Committee for International Clinical term used by medical and research professionals Studies Including Therapeutics (ESCISIT). Ann to refer to a body of materials that cannot be Rheum Dis 2007; 66: 377-388. found easily through conventional channels such 4) ZHANG W, M OSKOWITZ RW, NUKI G, ABRAMSON S, ALT- as that published in international journals. How- MAN RD, ARDEN N, BIERMA-ZEINSTRA S, BRANDT KD, CROFT P, D OHERTY M, DOUGADOS M, HOCHBERG M, ever, these sources of information play a crucial HUNTER DJ, KWOH K, LOHMANDER LS, TUGWELL P. role in conducting a full and comprehensive eval- OARSI recommendations for the management of uation of the drug efficacy and safety41. hip and knee osteoarthritis, part I: critical ap- Pharmacokinetic studies show that serum lev- praisal of existing treatment guidelines and sys- els of the active ingredient following the applica- tematic review of current research evidence. Os- teoarthritis Cartilage 2007; 15: 981-1000. tion of tKP 2.5% gel are less than 1% of those re- ported after oral dosing, thus potentially lowering 5) MASSEY T, D ERRY S, MOORE RA, MCQUAY HJ. Topical NSAIDs for acute pain in adults. Cochrane Data- the risk of systemic AEs. In comparative studies, base Syst Rev 2010; 6: CD007402. 5-15 cm (100-300 mg) of KP 2.5% gel applied 6) SARZI-PUTTINI P, A TZENI F, L ANATA L, BAGNASCO M, twice daily produced a clinical benefit in the ma- COLOMBO M, FISCHER F, D ' I MPORZANO M. Pain and jority of patients with a broad range of symp- ketoprofen: what is its role in clinical practice? toms. In addition, tKP was an useful adjunct to Reumatismo 2010; 62: 172-188. physical therapies in promoting a rehabilitation. 7) VEYS EM. 20 years’ experience with ketoprofen. KP 2.5% gel appears to be well tolerated, with a Scand J Rheumatol Suppl 1991; 90 (Suppl.): 1-44. low potential for systemic adverse effects. Pa- 8) KANTOR TG. Ketoprofen: a review of its pharmaco- tients treated with tKP gel are advised not to ex- logic and clinical properties. 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Pilot study on the anti-inflammatory activity risk/benefit ratio and a low incidence of AEs. of ketoprofen after topical administration of a gel to 20 patients who were undergoing arthroscopy of the knee. FG 14. Company Report, 1994. –––––––––––––––––––– Acknowledgements 12) MARTY JP. Ketoprofen in vitro percutaneous absorp- tion through human skin from 4 gel formulations. The Author wishes to thank Francesca Perretti, PhD, BC/FE-G/069/2002. Company Report, 2002. who contributed to the collection of most of the data 13) PIPPI F. In vitro evaluation on human skin of the inserted in this review. The Author thanks Luca Gia- diffusion of ketoprofen from topical products (Fas- comelli, PhD, who provided editorial assistance in the tum gel, Ketoprofen 2-5% UV gel spray). preparation of this article on behalf of Content Ed Net. RF022MN02.doc. Company Report, 2002.

948 Ketoprofen 2.5% gel: a clinical overview

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