a new ketoprofen lysine salt formulation: 40 mg ...october 2012 volume 12 number 4 trends in...

October 2012 Volume 12 Number 4 Trends in Medicine 159

Review

A new ketoprofen lysine salt formulation: 40 mgorodispersible granules

Alberto E Panerai1, LuigiLanata2, Mauro Ferrari3,Michela Bagnasco2

1Department of Pharmacological andBiomolecular Sciences, University ofMilan, Via Balzaretti 9, 20133 Milan2Dompé SpA, Medical Department,Milan3Dompé SpA, Research &Development, Milan

Alberto PaneraiDipartimento di ScienzeFarmacologiche e Biomolecolari,Università degli Studi di Milano, ViaBalzaretti 9, 20133 MilanoTel. 02-50316934Fax 02-50316933Email: [email protected]

SummaryKetoprofen is a well established non steroidal anti-inflammatory drug (NSAID) approved for a broad range ofpainful conditions. Its salification with lysine aminoacid enables rapid and almost complete absorption of thecompound ensuring a rapid onset of action. The new formulation ketoprofen lysine salt 40 mg orodispersiblegranules (okitask®) is specifically designed for easy use in everyday life, as no water is required for its ingestionand has shown to be effective in controlling mild to moderate pain, such as in particular, tension-type heada-che. Pharmacological studies demonstrates that the onset of action of ketoprofen lysine salt oral products isvery rapid, meaning that in few minutes the drug is already producing its analgesic effect, that shows within 6minutes from oral administration with the new formulation of 40 mg orodispersible granules and in about 3minutes with the well known the sachet formulation (OKi®).

Panerai AE, Lanata L, Ferrari M, et al. A new ketoprofen lysine salt formulation: 40 mg orodispersible granules.Trends Med 2012; 12(4):159-167.©2012 Pharma Project Group srl. ISSN: 1594-2848

Ketoprofen lysine salt:Importance of theformulation for earlyonset of action

Ketoprofen is a propionic deri-vative with analgesic, anti-in-flammatory and antipyretic pro-perties belonging to the wellknown nonsteroidal anti-in-flammatory class of drugs(NSAIDs). The main mechani-sm of action of ketoprofen isthe inhibition of cyclooxygena-se (COX), resulting in a redu-ced biosynthesis of prostaglan-dins from arachidonic acid1.Further activities of ketoprofenthat may contribute to the anti-inflammatory and analgesic ac-tivities are: inhibition of bra-dykinin, stabilization of lysoso-mal membranes against osmo-tic damage and prevention ofthe release of lysosomal enzy-mes that mediate tissue destruc-tion during inflammation2-4.These pharmacodynamic activi-

ties have proved to determinethe control of clinical signs ofinflammation and marked anal-gesic effects5.Salification with the lysine ami-noacid does not alter the phar-macological properties of con-ventional acid ketoprofen in anyway and remarkably increasesthe solubility of the compound,improving both rate and extentof absorption as compared tothe conventional formulation:after oral administration, peakserum concentrations are twiceas high and are achieved after15 minutes instead of after 60minutes, enabling a much fasteronset of action (Figure 1)6.Following oral administration,ketoprofen is rapidly and almostcompletely absorbed. The abso-lute bioavailability of oral keto-profen is generally accepted tobe 90% or higher7. Thanks toits high lipophilicity, ketoprofenreadily distributes also withinthe brain, where it possibly par-

Key words:ketoprofenlysine salt

160 Trends in Medicine October 2012 Volume 12 Number 4

A.E. Panerai, L. Lanata, M. Ferrari, M. Bagnasco

tially develops its action. Linea-rity in the absorption kinetic hasbeen demonstrated in the rangeof doses of ketoprofen betwe-en 12.5 mg and 200 mg.Ketoprofen is rapidly and ex-tensively metabolized in the li-ver, largely by conjugation andit also undergoes hydroxylationand subsequent conjugationwith glucuronic acid. No acti-ve metabolites have been iden-tified to date. Ketoprofen is ap-proximately 99% bound to pla-sma proteins, mostly to albu-min, and plasma concentra-tions of ketoprofen appear todecline in a biphasic manner,with a mean elimination half-life of 1.1-4.0 h7.Ketoprofen lysine salt orodi-spersible granules is a newpharmaceutical presentation ofketoprofen lysine salt (KLS),containing 40 mg of ketopro-fen lysine salt in the form oforodispersible granules to bedissolved into the mouth andswallowed with or without wa-ter.Ketoprofen lysine salt orodi-spersible granules (okitask®)

contains 40 mg of ketoprofenlysine salt and has been demon-strated to be bio-equivalent to25 mg of ketoprofen; it is pro-posed for use in adults and ado-lescents above 15 years for thetreatment of painful conditionsof different nature and originsuch as headache, toothache,neuralgia, dysmenhorrea, mu-scular and osteoarticular pain.The orodispersible granulesformulation is specifically de-signed for convenient use ineveryday life, as no water is re-quired for its ingestion9.A two-way crossover, randomi-zed, single-dose pharmacokine-tic study in 69 healthy subjects(34 females and 35 males, mean± SD age 33.6 ± .9 years) com-paring the novel KSL 40 mgorodispersible granules takenwithout water and KLS 80 mgsachets (half a 80 mg sachettaken with 240 ml of water) hasshown that the two treatmentsare bioequivalent, in both rate(mean peak plasma concentra-tion – Cmax: 2.77 ± 0.82 mcg/ml and 3.16 ± 0.75 mcg/ml re-spectively) and extent of ab-

Figure 1. Ketoprofen plasma levels after administration of ketoprofen capsule 50 mg and ketoprofenlysine salt (KLS) sachet or drops 80 mg.

10.000

8.000

6.000

4.000

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0

Keto

pro

fen p

lasm

a levels

(ng/m

l)

0 15’ 30’ 45’ 60’ 1,5 2 3 4 6 8 12

KLS

Ketoprofen

Minutes Hours

sorption (Area under the con-centration curve – AUC: 4.82± 1.02 mcg/mLxh and 4.62 ±1.08 mcg/mLxh, respectively9

(Figure 2). In fact, the 90% CIsof the evaluated parameterswere inside the bioequivalenceacceptance range 80.00-125.00in compliance with the Euro-pean guideline on bioequivalen-ce studies.An analgesic effect-concentra-tion relationship for ketopro-fen was established in an oralsurgery pain study with keto-profen. The effect-site rateconstant (keo) was estimated tobe 0.9 hour - 1 (95% confiden-ce limits: 0 to 2.1), and the con-centration of ketoprofen thatproduced 50% the maximumpain intensity difference (PID)(Ce50) was 0.3 mcg/ml (95%confidence limits: 0.1 to 0.5)8.This concentration, Ce50, isconsidered as a clinically signi-ficant indicator of ketoprofen’seffect on pain.The Ce50 of 0.3 mcg/ml wasachieved very rapidly and, inparticular, within 6 minutes af-ter the administration of KSL


A new ketoprofen lysine salt formulation: 40 mg orodispersible granules

40 mg orodispersible granulestaken without water9. Therefo-re, based on this data analysis,KSL 40 mg orodispersible gra-nules (okitask®) is rapidly ab-sorbed and rapidly achieves thedesired effective plasmatic con-centrations, thus exerting itsanalgesic effect, in about 6 mi-nutes from oral administration.In the same way, also KSL 80mg sachet (adult dosage, OKi®

80 mg sachet) reaches the Ce50in about three minutes showingits analgesic effect6. Taken to-gheter, these data indicate thatthe onset of action of KSL oralproducts is very rapid meaningthat in few minutes the drug isalready producing its analgesiceffect, demonstrated with the 40mg orodispersible granules (oki-task®) and with the sachet for-mulation (OKi®).

Figure 2. Mean (+SD) plasma ketoprofen concentration (µg/ml) vs.time profiles after administration of ketoprofen lysine salt (KLS)orodispersible granules (okitask®, solid line) and ketoprofen lysinesalt sachet for oral solution (OKi®, dotted line).

6

5

4

3

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1

00 1 2 3 4 5 6 7 8

Time (hr)

Keto

pro

fen (

µg/m

l)Ketoprofen lysine salt80 mg sachet: efficacyin a broad range ofpainful conditions

Pain is a very common symptomthat occurs in many conditions.According to WHO chronic painis the most underestimated he-althcare problem in the world,about 20% of people experien-ce moderate to severe pain re-gularly; out of these one thirdcannot lead an independent lifebecause of pain10. It has beenclaimed that that the prevalen-ce of chronic pain in Europe isas high as 50%6.Ketoprofen is a well establishedNSAID that has been on themarket for therapeutic use since1973. Extensive evidence of ef-ficacy of oral ketoprofen in con-trolling pain is available in a broadrange of conditions. Ketoprofenlysine salt 80 mg three times daily(tid) demonstrated to be signifi-cantly more effective in terms ofimproving pain intensity, tender-ness and functional limitation,than placebo in 120 patients suf-fering from soft tissue disorders,such as tendinitis, bursitis andperiarthritis. Also pain relief wasachieved rapidly (Figure 3)6.Moreover, oral ketoprofen offe-red a significantly more rapidonset of pain relief after thefirst dose in patients with spor-ts traumatic injuries (by 1.1hours) as compared to ibupro-fen, with a responder rate, defi-ned as the proportion of su-bjects who experienced at least50% pain relief, significantly hi-gher than ibuprofen (76% vs58% p=0.05)6. Similarly, in 155patients with chronic lumbarpain oral ketoprofen achievedhigher improvement rates afterone week of treatment than di-clofenac, with a faster onset ofanalgesic relief (71.4% impro-vement rate versus 62.3%)6.

Figure 3. Analgesic effect on spontaneous pain measured with Scott-Huskisson (0-8hrs) scale after single administration of ketoprofenlysine salt 80 mg and placebo.

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50

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0Baseline 30 min 1 hr 2 hr 4 hr 6 hr 8 hr

Placebo

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Efficacy of ketoprofenlysine salt 40 mgorodispersiblegranules

Ketoprofen lysine salt 40 mgorodispersible granules, corre-sponding and equivalent also inefficacy to 25 mg of ketopro-fen, have proved to be effectivein controlling pain in a numberof conditions: headache, posto-perative dental pain, toothacheand dysmenorrhea9.

Tension-type Headache

Five randomized, double-blind,parallel-group studies con-ducted in 1694 patients with ten-sion-type headaches, out ofwhom 425 treated with ketopro-fen 25 mg have shown to be sta-tistically significant superior ver-sus NSAIDs, such as ibuprofen(200 mg), naproxen (275 mg)and paracetamol (500 and 1000mg), and offer the advantage ofa significantly faster onset ofaction11-15. Comparisons betwe-en ketoprofen 25 mg and 12.5mg demonstrated a dose-re-sponse effect showing that the25 mg dosage is more effectiveor offers faster onset of ac-tion11,14 indicating, thus, that thisis the minimum truly effectivedose.In particular, the evidence sup-ports the recommendation ofketoprofen 25 mg as a first linechoice for acute therapy of ten-sion-type headache in the gui-delines of the European Fede-ration of Neurological Societies(EFNS). Ketoprofen is the onlydrug that is recommended witha specific indication of the dose(okitask®), instead of a range16.The largest clinical trial, in thisclinical condition, was con-ducted by Mehlisch et al11 in 703subjects (631 eligible for analy-sis) suffering from tension hea-daches, given single doses of

ketoprofen 12.5 mg (n=158),ketoprofen 25 mg (n=156), pa-racetamol 1000 mg (n=166)and placebo (n=151). The su-bjects were recruited from anadult out-patient populationwho reported at least a one-year history of tension-typeheadaches, as defined in theInternational Headache So-ciety’s Classification and Dia-gnostic Criteria for HeadacheDisorders17 with an average fre-quency of 1-10 headaches permonth. The headaches had tobe at least of moderate inten-sity and to respond to OTCanalgesics.Ketoprofen 25 mg was signifi-cantly more effective in con-trolling pain due to tension hea-dache than ketoprofen 12.5 mg,paracetamol 1000 mg and pla-cebo (p<0.05) (Figure 4). Re-sults from this study suggest adose response effect for keto-profen 12.5 mg and 25 mg, de-monstrating a more rapid on-set of analgesia and a strongeranalgesic efficacy of ketoprofen

25 mg compared to acetami-nophen 1000 mg.The patients’ rate of excellent /good global assessments for ke-toprofen 25 mg group showedsuperior profiles compared toplacebo treatment and demon-strated a trend of superiority vsthe acetaminophen group(62.8% vs 56.1% respectively).Worthy of mention is also asmaller study in 159 adult su-bjects, which was home moni-tored using an electronic patientdiary12. Subjects had regular ten-sion headaches and had expe-rienced on average 13.6 to 14.7episodes in the last two monthsand mean VAS score was 0.45to 0.51 (range 0.26 to 0.96).Patients were randomly assignedto a single dose of ketoprofen25 mg (n=39), ketoprofen 50mg (n=40), ibuprofen 200 mg(n=41) or placebo (n=39).Both ketoprofen doses (25 mgand 50 mg) were significantlymore effective than placebo(p<0.05) in controlling the se-verity of headache, expressed as

Figure 4. Sum of pain relief intensity differences (SPRID) scores (4hours). Vertical bars indicate standard error of the mean; asterisk,significant difference from placebo (p<0.05).

18,5

18,0

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4h S

PRID

Ketoprofenn=156

Paracetamoln=166

Placebon=151

*

*p<0,05 vs placebo



change in VAS score over 4hours, whereas ibuprofen didnot reached the statistical signi-ficance.Two hours after administration,a clinically significant improve-ment in tension-type headachewas observed in 41% of patien-ts treated with ketoprofen 25mg, 18% with ibuprofen 200 mgand 17% with placebo (Figure 5,p<0,001). Moreover, ibuprofen200 mg after 2 hours from in-take does not produce any im-provement in pain and it is su-perimposable to the placebo tre-ated group. These results clear-ly demonstrate how ketoprofen25 mg is, compared to ibupro-fen, more rapid in onset of ac-tion and more effective in redu-cing pain starting acting on painsymptoms 1 hour before ibu-profen.Only one patient in the placebogroup (3%) became headache-free (VAS-score=0) after 3hours versus 10% in the ibupro-fen group, 18% in the ketopro-fen 25 mg group and 28% in theketoprofen 50 mg group(p=0.003 vs placebo; n.s. vs ibu-profen).In particular, strong improve-

ment, defined as headache re-lief ratings (HRR, a 5-item re-lief semiquantitative rating sca-le) score “+4” (highest HRR),occurred significantly morecommonly with the two stren-gths of ketoprofen (n=22 –55% with 50 mg and n=24 –62% with 25 mg) than with pla-cebo (n=7 – 18%) and with ibu-profen (n=16 – 39%) (ketopro-fen 50 mg vs placebo p<0.001and ketoprofen 25 mg vs place-bo p=0.001, ibuprofen vs pla-cebo n.s.), showing a significantsuperiority of this low-dose ke-toprofen versus ibuprofen12.

Post-operative dentalpain

Several randomized, single-dose, double-blind dose-findingclinical trials have been carriedout to establish the best stren-gth of ketoprofen preparationsfor controlling postoperativedental pain for a total of 1152participants.A trial by Sunshine et al compa-red 6.25 mg, 12.5 mg and 25 mgwith active and inactive referen-ce treatment (ibuprofen 200 mgand placebo) in 175 patientswith moderate to severe post-

operative pain secondary to theextraction of third molars. Ba-sed on SPID scores, pain reliefscores, time to peak pain reliefand patient global assessmentsof study medication a dose-re-sponse relationship was recor-ded, the two higher doses beingmore effective than the lowestdose. In particular, faster onsetof relief was achieved with 12.5mg and 25 mg than with keto-profen 6.25 mg and ibuprofen200 mg (p<0.05). Thus, 12.5 mgand 25 mg were considered tobe suitable for analgesic treat-ment18 .A trial by Cooper et al19 compa-red ketoprofen 25 mg, 50 mg100 mg to active and inactivereferences (aspirin 650 mg andplacebo) in 153 out-patientsundergoing surgical removal ofimpacted teeth during local ane-sthesia. The Pain Intensity Dif-ference score - time curvesshowed that all three strengthsof ketoprofen were significan-tly more effective than aspirinand placebo (all p<0.001). The-re also was a significant linearregression for ketoprofen 25mg, 50 mg and 100 mg (p<0.05)The same was true for pain re-lief - time curves (Figure 6) andfor the overall evaluation: allthree ketoprofen strengths wereconsidered to be significantlybetter than both placebo andaspirin (all p<0.001). The timeto remedication was significan-tly longer with all three ketopro-fen strengths as compared toboth aspirin and placebo.A second study by the same re-search team compared ketopro-fen 25, 50, and 100 mg with co-deine 90 mg and placebo in 129patients, using the same metho-ds. Ketoprofen appeared tohave a more rapid onset, higherpeak effect, and longer durationof pain relief than codeine withat least 70% of patients in each

Figure 5. Reduction in VAS-ratio after 2 hours in 159 adult subjectssuffering from tension type headaches

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0

2h V

AS-r

atio (

%)

Ketoprofen Ibuprofen Placebo

41%

18% 17%

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*Significant difference from placebo (p<0.001)



of the ketoprofen groups ratingthe test medication as very goodor excellent, compared with only7% of the patients in the codei-ne group. For the TOPAR (To-tal pain relief) significant(p<0.05) differences betweenketoprofen and codeine, favo-ring ketoprofen, were found20.Overall these dose-finding stu-dies show that ketoprofen 25mg is the correct dose for mildto moderate postoperative den-tal pain, which can be increa-sed to 50 mg and even more incases of more severe pain.Twenty-five mg (25 mg) was thedose selected for a single-dose,double-blind, triple-dummy,parallel group efficacy trialcomparing ketoprofen with anovel liquid formulation ofibuprofen 400 mg designed toprovide a faster onset of actionand active and inactive referen-ce treatments (paracetamol1000 mg and placebo) in 239adult patients with moderate orsevere pain following thirdmolar extractions21. Patientswere mostly young women

(68.2%) who experienced seve-re pain (88%) after a surgicalprocedure that lasted on ave-rage 17 minutes to extract twoteeth in most cases (96.2%).Median times to meaningfulrelief, to a lot of relief and tocomplete relief showed that allthree active treatments provi-ded relief significantly fasterthan placebo (p<0.05) and thatthe time to onset of relief wassimilar with liquid ibuprofenand ketoprofen 25 mg.All the three active treatmentswere significantly more effec-tive than placebo by 30 minu-tes (p<0.05) and remained soup to the end of the observa-tion period (6 hours), in termsof all the variables assessed,namely pain relief, difference inpain intensity and the sum ofthe two variables. Thus, in thisstudy ketoprofen was found tooffer faster time to relief andsuperior overall efficacy mea-sured as pain relief, pain inten-sity difference (PID) and painrelief intensity difference(PRID) as compared to para-

Figure 6. Time-effect curves for placebo, aspirin 650 mg and ketoprofen 25 mg. Mean Pain ReliefScores are plotted against time in hours.

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ain

relief

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Hours

cetamol 1000 mg and placebo(p<0.05)21.A Cochrane review assessed theefficacy and safety of ketopro-fen and dexketoprofen in thetreatment of acute postopera-tive pain22. Randomised, dou-ble blind, placebo-controlledtrials of orally administered,single doses of ketoprofen anddexketoprofen conducted inadults with moderate to severeacute postoperative pain wereincluded. Overall, 18 studieswere included, out of whicheight studies with 535 partici-pants provided data on keto-profen 25 mg, mainly in posto-perative dental pain. The pro-portion of participants expe-riencing at least 50% pain re-lief over 4 to 6 hours was 62%versus 12% with placebo. Thenumber of patients who needto be treated (NNT, numberneeded to treat) for at least 50%pain relief over 4 to 6 hours was2.0 (1.8 to 2.3), showing howketoprofen 25 mg is an effecti-ve treatment for pain with a su-perior evidence of efficacy, me-



smenorrhoea and represent themost commonly used treatmen-ts for this type of disturbances23.Two clinical trials support effi-cacy of ketoprofen in control-ling menstrual pain: a double-blind, cross-over, single dosetrial comparing ketoprofen (25,50 or 75 mg) with naproxen (500mg) and placebo in 63 womensuffering from dysmenorrhea.

Results showed that all activetreatments were superior to pla-cebo; ketoprofen 50 mg and 75mg offered earlier onset and lon-ger duration of pain relief thanketoprofen 25 mg and napro-xen24. Another study by Dawo-od suggests that ketoprofen 25mg is as effective as ibuprofen200 mg25.

Safety: The importanceof dosage

Ketoprofen is approved for oraltherapeutic use at daily dosagesup to 200 mg daily.It is well known that the mostcommon untoward effects ofNSAIDs are gastrointestinal di-sorders and that their gastroin-testinal toxicity can lead to pep-tic ulcer and gastrointestinal ble-eding. The risk of upper gastro-intestinal bleeding was assessedin a multicentre case-controlstudy that reviewed all incidentcommunity cases of upper ga-strointestinal bleeding from agastric or duodenal lesion inadult patients, by recording the

asured as NNT, compared toother NSAIDs, such as ibupro-fen 400 mg (NNT=2.5), diclo-fenac 50 mg (NNT=2.7) anddexketoprofen 25 mg(NNT=3.6) (Figure 7).

Dysmenorrhea

Nonsteroidal antiinflammatorydrugs (NSAIDs) should be con-sidered first-line therapy for dy-

Figure 7. Number needed to treat (NNT) for ketoprofen 25 mg,ibuprofen 400 mg, diclofenac 50 mg and dexketoprofen 25 mg.

4

3,5

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T

Ketoprofen25 mg

Ibuprofen400 mg

Diclofenac50 mg

Dexketoprofen25 mg

Figure 8. Odds ratio estimates (OR) for the risk of upper gastrointestinal bleeding of most commonlyused NSAIDs at therapeutical dosages.

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0KT

<200 mg/die

IBU1200-1799

mg/die

IBU≥1800mg/die

NPX≤750 mg/die

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DCF75-149mg/die

Legenda: KT=ketoprofene, IBU=ibuprofene, NPX=naproxene, NMS=nimesulide, DCF=diclofenac

Odds R

atio (

OR)



outcome of all endoscopic pro-cedures and checking lists ofadmission diagnoses at 10 ho-spitals in Spain and 8 hospitalsin Italy26. For each case up tothree hospital controls were ran-domly selected and matched ac-cording to center, date of ad-mission, sex and age (± 5 years).The odds ratio of upper gastro-intestinal bleeding for eachNSAID and analgesic was cal-culated separately. They foundthat the incidence of upper ga-strointestinal bleeding was 401.4per million adult inhabitants;38% were attributable to NSAI-Ds. Importantly, they esta-blished that the risk related tothe individual drugs was dose-dependent and calculated thecut-off dose of each NSAID,below which the risk is modest.In the case of ketoprofen thecut-off dose is 200 mg daily26,27

(Figure 8).The dose of ketoprofen contai-ned in 40 mg orodispersible gra-nules is 8 times lower than thecut-off dose; moreover, the re-commended maximum dailydose of KSL 80mg sachets(three times/day = 240 mg KSL= 150 mg ketoprofen) ensuresthat the cut-off dose is neverexceeded.

Safety of ketoprofen 40mg

A large study28 was carried outto assess the safety, tolerabilityand efficacy of low-dose keto-profen (75-150 mg daily for 5to 15 days) in a general practicesetting. Four thousand and six-ty-eight (4068) patients, of allages (13-93 years), 1009 withEar-Nose-Throat (ENT) disea-ses (mean age 38.8 (13-83) ye-ars, 53% female), 978 with dys-menorrhoea (mean age 30.3 (13-60) years), 2081 with musculo-skeletal disorders (mean age 49.6(16-93) years, 54% female) wereincluded in the trial. Less than1% of the patients were lost tofollow-up. None of the adverseevents (AEs) reported were life-threatening and treatment wasstopped prematurely in only3.3% of patients because ofadverse events; in 17.1% of ca-ses therapy was stopped prema-turely because of early successof therapy. Gastrointestinalevents were the most frequentadverse events, occurring in10% of patients. They weremore frequent in patients withmusculoskeletal pain, who wereolder and had more associateddiseases. The authors came to

the conclusion that low-doseketoprofen is generally well to-lerated and not associated withsevere adverse reactions.In the trials conducted with ke-toprofen 25 mg in tension-typeheadache and in postoperativedental pain, the rate of AEs re-ported with the product was si-milar or slightly higher than therate reported with placebo (5.1to 26.7% versus 5 to 26.7%).The most common AEs, as ex-pected, were gastrointestinal di-sturbances, and tiredness.

Conclusions

The efficacy of oral ketoprofenin the treatment of pain of dif-ferent origin and nature is well-established as documented bythe numerous clinical trials pu-blished.The novel formulation as keto-profen lysine salt 40 mg orodi-spersible granules (okitask®)has proved to be safe, well tole-rated and effective in the con-trol of mild to moderate pain,such as tension-type headache,dental pain and postoperativedental pain. The recent Cochra-ne review confirmed the strongefficacy even when compared toother NSAIDs.

References

1. Williams RL, Upton RA. The cli-

nical pharmacology of ketoprofen.

J Clin Pharmacol 1988; 28 (12 Sup-

pl): S13-S22.

2. Julou L, Guyonnet JC, Ducrot R,

et al. Ketoprofen (2-(3-benzoyl-

phenyl)-proprionic acid): main

pharmacological properties. Scand

J Rheumatol Suppl 1976; 14:33-42.

3. Kantor TG. Ketoprofen: a review

of its pharmacology and clinical

properties. Pharmatherapy 1986;

6:93-103.

4. Tamisier JN. Ketoprofen. Clin

Rheum Dis 1979; 5:381-391.

5. Veys EM. 20 years’ experience

with ketoprofen. Scand J Rheuma-

tol Suppl 1991; 90:1-44.

6. Sarzi-Puttini P, Atzeni F, Lana-

ta l, et al. Pain and ketoprofen:

what is its role in clinical practice?

Reumatismo 2010; 62:172-188.

7. Jamali F, Brocks DR. Clinical

pharmacokinetics of ketoprofen

and its enantiomers. Clin Pharma-

cokinet 1990; 19: 197-217.

8. Roda A, Sabatini L, Mirasoli M,

et al. Bioavailability of a new ke-

toprofen formulation for once-dai-

ly oral administration. Int J Pharm

2002; 241:165-172.

9. Study report CRO-PK-11-262

(MAA dossier, Module 5.3.1.2.2).

10. WHO, website. http://

www.who.int/mediacentre/news/

releases/2004/pr70/en/8.

11. Mehlisch DR, Weaver M, Flau-

dung B. Ketoprofen, acetami-

nophen, and placebo in the treat-

ment of tension headache. Heada-

che 1998; 38:579-589.

12. Van Gerven JMA, Schoemaker

RC, Jacobs LD, et al. Self-medi-

cation of a single headache episo-

de with ketoprofen, ibuprofen or

placebo, home-monitored with an

electronic patient diary. Br J Clin

TiM



Pharmacol 1996; 42:475-481.

13. Steiner TJ. Ketoprofen (25 mg)

in the symptomatic treatment of

episodic tension-type headache:

double-blind placebo-controlled

comparison with acetaminophen

(1000 mg). Cephalalgia 1998;

18:38-43.

14. Lange R, Lentz R. Comparison

of ketoprofen, ibuprofen and na-

proxen sodium in the treatment of

tension-type headache. Drugs Exp-

tl Clin Res 1995; XXI (3) 89-96.

15. Dahlöf CGH, Jacobs LD. Keto-

profen, paracetamol and placebo in

the treatment of episodic tension-

type headache. Cephalalgia 1996;

16. 117-123.

16. Bendtsen L, Evers S, Linde M,

Mitsikostas DD, et al. EFNS

guidelines on the treatment of ten-

sion-type headache - Report of an

EFNS task-force. Europ J Neurol

2010; 17: 1318-1325.

17. Headache Classification Com-

mittee of the International Hea-

dache Society. Classification and

diagnostic criteria for headache di-

sorders, cranial neuralgias and fa-

cial pain. Cephalalgia 1988; 8 (sdup-

pl 7): 1-96.

18. Sunshine A, Olson NZ, Marre-

ro I, et al. Onset and duration of

analgesia for low-dose ketoprofen

in the treatment of postoperative

dental pain. J Clin Pharmacol. 1998;

38:1155-1164.

19. Cooper SA, Gelb SB, Maggio

Cavaliere MB, et al. An analgesic

relative potency assay comparing

ketoprofen and aspirin in postope-

rative dental pain. Adv Therapy

1984; 1:410-418.

20. Cooper SA. Ketoprofen in oral

surgery pain: a review. J Clin Phar-

macol 1988; 28 (12 Suppl): S40-46

21. Olson NZ, Otero AM, Marrero

I, et al. Onset of analgesia for li-

quigel ibuprofen 400 mg, acetami-

nophen 1000 mg, ketoprofen 25

mg, and placebo in the treatment

of postoperative dental pain. J Clin

Pharmacol. 2001;41:1238-1247.

22. Barden J, Derry S, McQuay HJ,

et al. Single dose oral ketoprofen

and dexketoprofen for acute posto-

perative pain in adults. Cochrane

Database Syst Rev 2009 Oct 7: 4.

23. Ezcurdia M, Cortejoso FJ, Lan-

zón R, et al. Comparison of the

efficacy and tolerability of dexke-

toprofen and ketoprofen in the tre-

atment of primary dysmenorrhea.

J Clin Pharmacol 1998; 38:65S-73S.

24. Mehlisch DR. Double-blind cros-

sover comparison of ketoprofen,

naproxen, and placebo in patients

with primary dysmenorrhea. Clin

Ther 1990; 12: 398-409.

25. Dawood MY. Primary dysmenor-

rhea advances in pathogenesis and

management Obstet Gynecol

2006;108:428-441.

26. Laporte JR, Ibañez L, Vidal X,

et al. Upper gastrointestinal blee-

ding associated with the use of

NSAIDs. Drug Safety 2004; 27:

411-420.

27. Panerai AE. The management of

pain-inflammatory conditions.

Trends Med 2011; 11(4):163-177.

28. Moore N, Vuillemin N, Abite-

boul M, et al. Large scale safety

study of ketoprofen 25 mg (To-

prec) in febrile and painful condi-

tions. Pharmacoepidemiol Drug

Saf 1996; 5:295-302.

a new ketoprofen lysine salt formulation: 40 mg ...october 2012 volume 12 number 4 trends in...

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