(cid:47)(cid:56)(cid:51)(cid:44)(cid:49)(cid:3)(cid:40)(cid:59)(cid:17)(cid:3)(cid:20)(cid:19)(cid:20)(cid:21)
`(cid:47)(cid:88)(cid:83)(cid:76)(cid:81)(cid:3)(cid:89)(cid:17)(cid:3)(cid:76)(cid:38)(cid:72)(cid:88)(cid:87)(cid:76)(cid:70)(cid:68)
`(cid:56)(cid:54)(cid:3)(cid:51)(cid:68)(cid:87)(cid:72)(cid:81)(cid:87)(cid:3)(cid:49)(cid:82)(cid:17)(cid:3)(cid:28)(cid:15)(cid:19)(cid:20)(cid:26)(cid:15)(cid:26)(cid:21)(cid:20)
`
`Page 1
`
`

`
`164
`
`Moore
`
`5.¢ Summary of Comparative Safety and Tolerobiliiy .
`6. Conclusion .
`,
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`. 190
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`. .. 191
`
`AbSi'l'ClC‘l'
`
`Non-prescription (over-the-counter [OTCl) analgesics are used for the short-
`term treatment of acute painful conditions of mild to moderate intensity in
`
`everyday life. Well documented safety and efficacy, a rapid onset of action and a
`
`flexible daily dosing regimen are essential in this context. Film—t:oated, immedi-
`
`ate-release.
`
`low-dose diclofenac potassium, developed for OTC use, offers a
`
`flexible daily dosing regimen with an initial dose of two tablets (2 X l2.5mg)
`
`followed by one or two tablets up to a maximum daily dose of six tablets ("£5 mg’
`
`day). The maximum plasma drug concentration is reached 30 minutes after
`
`administration. and the mean terminal half-life is I-2 hours. allowing a 4- to
`
`6-hour duration of activity. depending on the condition.
`
`Thirteen randomised. douhle—blind trials with both placebo and active controls
`
`have demonstrated the efficacy of diclofenac potassium l2.5mg tablets in condi-
`
`tions suitable for treatment with OTC medication, for example, acute lower back
`
`pain. headache. acute pain after dental extraction. symptoms of cold and influenza
`
`{including fever). and dysmenorrhoea. A single dose of dielofenac potassium
`
`l2.5mg is the lowest recommended effective dose. A two-tablet single dose of
`
`25mg is at least as effective as ibuprofen 400mg. A flexible dosing regimen of an
`
`initial two tablets followed by one or two tablets up to a total daily dose of 75mg is
`
`as effective as ibuprofen used in comparable fashion Up to a total daily dose of
`
`1200111 g.
`
`The incidence of adverse events in patients taking single or multiple doses of
`
`diclofenac potassium is similar to that of ibuprofen and placebo. In a safety study
`
`conducted to compare diclofenac potassium with ibuprofen for up to 3 months in
`
`patients with osteoarthritis of the knee, no differences in the pattern of adverse
`
`events were noted. There was no evidence of either hepatic injury or cardiovascu-
`
`lar safety—related issues at any time during the study.
`
`Patients are generally capable of taking dielofenac potassium appropriately. A
`
`maximum OTC treatment duration of 5 days for pain and 3 days for fever is
`recommended.
`
`1. Introduction
`
`formulations. Diclofenac sodium was first marketed
`
`Diclofenac is a potent NSAID with anti-inflarn-
`
`ry use. Since its introduction. diclofenac sodium has
`
`matory. analgesic and antipyretic properties. Chemi— been used by >1 billion patients. Dielofenae potassi-
`
`cally it
`
`is a phenylacetic acid derivative. Ural
`
`um was introduced in the early l98Us as Cat,atlarn®r'
`
`diclofenac is available in sodium— or potassium—salt
`
`Voltaren Rapid®, primarily for analgesic indica-
`
`in Japan in 1974 as Voltaren® ' for anti—inllammato—
`
`l The use of trade names is for product identification purposes only and does not imply endorsement.
`
`-'21 200? Adis Data Information av. All rights reserved.
`
`Clin Drug Invest 200?; 2? (3)
`
`Page 2
`Page 2
`
`

`
`Diclofena-C Potassiunt 125mg Tablets in Mild to Moderate Pain and Fever
`
`165
`
`12.5
`
`25
`
`50
`
`‘ID
`
`9 B '
`
`.-’
`
`E
`5
`
`43 2 I O
`
`b
`
`10
`
`D-osaimgi
`
`
`M0:4.‘:U1at--.1D2:to
`
`dE
`
`E5
`
`U2
`
`AUGturnol-h.tL)
`
`tions. Currently.
`
`it
`
`is approved as an over-the-
`
`counter (OTC) medication in many countries around
`
`the world. forexatnple Germany. Switzerland. Italy.
`
`Spain, The Netherlands. Norway. Sweden. Hungary,
`
`Poland. Iceland. Czech Republic. Slovakia. Latvia.
`Lithuania. Russia. Australia. New Zealand and sev-
`
`eral countries in South America.
`
`This article gives an overview of the relevant
`
`pharmacological aspects, clinical efficacy and toler-
`
`ahility ot' low-dose diclofenac and underlines its
`
`suitability for non-prescription use.
`
`2. Phctrmctcodynarnics
`
`Diclofenac is a typical. potent. non-selective in-
`
`hibitor of cyclo-oxygcnasc (COX). which reduces
`
`the formation oi‘ the proinflammalory and nocicep-
`
`rive prostaglandins. In addition. diclofenac inhibits
`
`the synthesis of prostacycliu and thromb-oxane and
`
`downregulates the lipoxygenasc pathwayl” Fur-
`
`thermore, it has been reported to decrease levels of
`
`the proinflatnlnatory cylol-tine interleukin-6 and sub-
`
`stance P in the synovial fluid and plasma of patients
`with rheumatoid arthritislii
`
`The concentrations required to produce 50% in-
`
`12.5
`
`25
`
`50
`
`hibition of enzyme activity {IC5n) of diclofettae for
`COX-I and COX-2 in vitro in a human whole blood
`
`assay are 0.075 t1molfL and 0.038 ].tmo|}L, respec-
`
`tively. and the concentratiort of diclofenac that in-
`
`hibits COX-2 activity by 80% (ICgn} produces ap-
`proximately '.-’t)% inhibition of COX-l.l3' The con-
`
`centrations reached in viva during an ascending dose
`
`pharmacokinctic study [figure I) were well within
`
`the range of the in vttm and ex vivo COX inhibitory
`concentrations!“ Diclofenac helongs to the class of
`
`drugs presenting almost a similar level of inhibition
`
`for both COX-I and COX-2 {<5-fold COX-2 selec-
`
`Dose (mg)
`Fig. 1. Ascending dose pharmacokineties of dicloitanac in study
`F339“: (a) maximum concentration {Cruz} and {bi area under the
`plasma concentration-tlrna curve {AUG} at dlflarsnt closes.
`
`Diclofenac is highly bound to serum protein
`
`(99.7 96], mainly albumin. and it is a weak acid {pKa
`
`= 4.0) and amphiphilic. Because of these character-
`
`istics. diclofennc distributes unequally.
`
`it reaches
`
`high concentrations and persists in inflamed tissue,
`
`as is demonstrated by its measured concentration in
`
`the synovial tiuid in rheumatic diseases. while the
`
`tivc).i-*1 The IQ“: of diclofcnac indicates that
`
`it is
`
`eiimination in the central body compartment such as
`
`slightly more specific in inhibiting the activity of
`
`COX-2 than COX-I: however, no major difference
`
`blood, liver and kidney is fast with a half-life of l—2
`hours.‘-""’i NSAlDs such as diclofenac associate and
`
`is observed at the therapeutically relevant inhibition
`
`dissociate with alhutnin rapidly. The ongoing disso-
`
`potency lC3o.
`
`ciation rnakes hound drug available for transvascu-
`
`-Q 2603'’ Anti: Dcrta ln1'orI'nertion BV. All rigt't1'5ra:t:ewacI_
`
`Clin Drug Invest 200?; 2? (3)
`
`Page 3
`Page 3
`
`

`
`166
`
`Moore
`
`lar exchange towards the target compartment and
`
`salts are equivalent with respect
`
`to the rate and
`
`thereby diminishes
`
`the pharmacokinetic signifi-
`
`extent of absorption, as measured by maximum con-
`
`cance of binding measured in 1.-'r'Iro.l°l
`
`centration (Cmax) and area under the plasma concen-
`
`[t
`
`is now well established that COX-2 plays a
`
`tration-time
`
`curve
`
`(AUC),
`
`respectively, when
`
`major role in no-cieeption if inflammatory processes
`are involved. However, there is also evidence that
`
`COX-l may play an important
`
`role in the local
`
`transmission and central integration of pain, and that
`simultaneous inhibition of both COX-1 and COX-2
`
`is generally superior to inhibition of either alone.l7l
`
`This is especially relevant because the anti-inflam-
`
`matory effect of diclofenac is minimal at the doses
`
`used in OTC medications. and the objective in this
`
`setting is pain relief rather than an anti—inflammato—
`
`ry action.
`
`3. Phormacokinelic Properties
`
`normalised by dose.l3l Dose-normalised AUCs were
`
`27.7 i 8.6 nmol - l1.fL - tune] for diclofenac sodium
`
`and 24 i 6.3 nmol - h!L - ttmol for diclofenac potas-
`sium.
`
`Diclofenac is completely absorbed. First—pass
`
`metabolism accounts for approximately 40% of an
`
`oral dose, which means that about 60% of the ad-
`
`ministered dose reaches the systemic circulation as
`
`unchanged die|ofenac.l'3"l Absolute bioavailability of
`
`low-dose diclofenac potassium from tablet formula-
`tions was investigated by Hinz et al.“9l The mean
`
`absolute bioavailability of diclofenac potassium
`
`12.5mg (administered as a single dose of a 12.5mg
`
`Immediate—rclease, sugar-coated diclofenac po-
`
`capsule-shaped tablet] and 25mg [ administered as a
`
`tassium tablets dissolve rapidly in the stomach and
`
`single dose of two l2.5mg tablets) was 63. I % in the
`
`the time to maximum concentration (tum) is approx-
`
`12.5mg group and 65.1% in the 25mg group, results
`
`imately 30 minutes.
`
`In contrast, enteric-coated
`
`that were consistent with those of a previous investi-
`
`diclofenac sodium (Voltarcn®, Voltarol®) dissolves
`in the more alkaline environment of the duodenum
`
`gation“”3l showing 5{)—6[l‘;‘/E.- oral availability. The
`9(l";’l:.- Cls for the AUCM and AUCI (t = 4h) ratios for
`
`(tmax >2 hours}. The two salts of diclofenac,
`
`the two oral regimens were 82.6, 103.4 (point esti-
`
`diclofenac potassium and diclofenac sodium. have
`
`mate 92.4) and 86.2, 112.9 (point estimate 98.6),
`
`the same mechanism of action and identical pharma-
`
`respectively, which are within the acceptance crite-
`
`codynamic effects, are absorbed to the same extent
`
`ria for bioequivalencc (80, 125).”-"1 In conclusion.
`
`following oral administration?“ and are distributed,
`biotransformed and eliminated in identical fashion.
`
`the study demonstrated that diclofenac potassium is
`
`rapidly and well absorbed at low doses of 12.5 and
`
`3.] Absorption
`
`The bioequivalence of diclofenac potassium has
`
`not been tested in a pharmaeokinctic study of stan-
`
`25mg and shows linear pharmacokinetics.
`
`After ingestion of one or two diclofenac potassi-
`
`um l2.5mg tablets the median tmax was approxi-
`mately 30 minutes.l'°*"'l5l With increasing doses of
`
`dard crossover design. However, Several trials have
`
`diclofenac potassium the corresponding AUC as
`
`measured plasma concentrations after various doses
`
`well as the Cmax were proportionally increased and
`
`of either diclofenac sodium or diclofenac potassium
`were administe1°ed to lasted individuals in either
`
`dose linearity has been confirmed for the low-dose
`
`range of l2.5—50mg {figure l).l4l In volunteers given
`
`buffered solution (pH 7.5) or plain water. An analy-
`sis of the combined data from these studies (95
`
`a high—l"at breakfast, the Cm.-ix of a single dose of
`
`diclofenac potassium l2.5mg was decreased and the
`
`individuals given diclofenac sodium and 2t given
`
`tmax increased.“-‘J The AUC and the elimination
`
`diclofenac potassium) shows that the two diclofenac
`
`half-life (tips), on the other hand, were not affected.
`
`-'21 200? Adis Doro Information av. All rights reserved.
`
`Clin Drug Invest 200?.‘ 2? (3)
`
`Page 4
`Page 4
`
`

`
`Diclofenac Potassium 125mg Tablets in Mild to Moderate Pain and Fever
`
`113'?
`
`Thus. the total amount of drug absorbed does not
`
`3.4 Elimlnotion
`
`seem to be affected by the presence of food in the
`stomach.
`
`The bioequivalence of several rapid—re|ease for-
`
`mulations of low-dose diclofenac potassium (cap-
`
`sules, and sugar-— or ti|m—coat.ed tablets in a variety
`
`of shapes) has been confirmed in several bic-avai-
`
`lability studies taking into account intra-subject va-
`riability.“"‘6l The film-coated tablets were used in
`
`the diclofenac potassium |2.5mg phase III develop-
`
`ment programme.
`
`Since the quantities of diclofenac potassium ad-
`
`ministered are
`
`usually
`
`lower
`
`than
`
`those of
`
`diclofenac sodium, the potential for end—organ fail-
`
`ure or metabolic interaction with diclofenae poten-
`
`tial is accordingly lower. Thus, it is relevant to note
`
`that the pharmacokinetic data presented in the fol-
`
`Total systemic clearance of diclofenac from plas-
`
`ma is 263 i 56 lTIl.ufITlll'I.ll2l The terminal
`
`tv,[3 in
`
`plasma is 1-2 hours. Four of the metabolites, includ-
`
`ing the two active ones, also have a short plasma tv,[5
`
`of 1-3 hours. A fifth, virtually inactive. metabolite
`
`(3'—hydroxy—4'—methoxy—cliclofenac) has a much
`
`longer plasma half-life. Approximately 60% of the
`
`administered dose of diclofenac potassium is excret-
`
`ed in the urine as the glucuronide of the intact
`molecule and as metabolites, most of which are also
`
`converted to glucuronide conjugates?“ Less than
`
`1% is excreted unchanged. The remainder of the
`
`dose is eliminated as metabolites through the bile in
`the faeces.l”l
`
`lowing sections are from studies of high—dose
`
`3.5 Influence of Age and Renal or
`
`diclofenac sodium, not low-dose diclofenac potassi-
`urn.
`
`Hepatic Function
`
`3.2 Distribution
`
`DieloI'enae is 99.7% protein bound with a volume
`of distribution of U. l 2-0. I 7 Li'kg.“7l
`
`3.3 Biotronsformotion
`
`After absorption. diclofcnac is metabolised by
`both phase I and II enzyines.'”“ The biotI'ansforma-
`
`No relevant age—dependent differences in the ab-
`
`sorption, metabolism or excretion of diclofenac
`
`impairment does not
`have been observed. Renal
`result in accumulation of diclofenac with the usual
`
`dosage schedule.l3°1 At a creatinine
`
`clearance
`
`<10 n1Lfmin_. the steady-state plasma concentrations
`
`of the hydroxy metabolites are about four times
`
`higher than in healthy individuals. However, these
`
`metabolites are ultimately cleared through the bile.
`
`Lion ofdielofenac includes glucuronidation of sever-
`
`Nevertheless. neither chronic hepatitis nor non-de-
`
`al phenolic metabolites, which a1'e generated by
`
`single and multiple hydroxylation and methoxyla-
`
`compensated cirrhosis affect the pharmacokinetics
`or ntetabolism of diclofenaelz" While active alco-
`
`tion. Two of these phenolic metabolites are biologi-
`
`holic cirrhosis may increase the AUC of diclofenac,
`
`cally active, but
`
`to a much lesser extent
`
`than
`
`diclofenac. The aromatic hydroxylated metabolite
`
`chronic active hepatitis has also been shown to not
`affect the pharmacokinetics of diclofenaelfll
`
`and the conjugated metabolites have been reported
`to be pharmacologically inactive.“3l The metabo-
`lism of dielofenac in. viva and in liver microsomcs
`
`3.6 Pregnancy and Lcictotion
`
`has recently been demonstrated to be similar in six
`
`During
`
`pregnancy,
`
`as with
`
`all NSAlDs,
`
`different cytochrome P450 {CYP) enzyme 20‘? ge-
`notypes,l'°l with no evidence of polymorphism [fig-
`
`diclofenac should he used only for compelling rea-
`
`sons and only in the lowest effective dose, particu-
`
`ure 2).[‘3l
`
`larly in the last
`
`trimester because of the risk of
`
`-'21 200? Adis Data Information sv. All rights reserved.
`
`Clin Drug Invest 200?: 2? (3)
`
`Page 5
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`
`

`
`168
`
`Moore
`
`CUOH
`
`OH
`
`Acyl glucuronide 1:
`UG T2 B?
`
`NH
`
` cooHN H
`
`Cl
`
`Cl
`
`Cl
`
`4', 5-Dihydroxy-d iclofenac
`Cl
`
`OH
`
`4'AHydrox~_-Hiiclofenac
`
`COMT
`
`COOH
`
`CYPZCB
`C‘i’F’2C9
`
`C‘r'F'2C9
`
`H
`
`COOH
`
`OH
`
`CUDH
`
`NH
`
`CI
`
`CI
`
`OCH;
`
`OH
`
`4'-H ydroxy-3' -rnethoxy—
`
`diclotenac
`
`NH
`
`Cl
`
`0'
`
`CY P2C9
`
`To
`CYF’2CB.r’1Bf19
`cvpzaa
`CY PSA4
`
`NH
`
`Cl
`
`Cl
`
`Dial Man“
`
`5'-Hydroxy-diclote nae
`
` oooH OH
` COOH
`Ola i :0‘ \.
`
`Cl
`
`Cl
`
`OH
`
`CIH
`
`3 '— Hyd noxy—d lclofenac
`
`DC
`
`Hg:
`
`3'-Hydroxy~4' —metho>:y—
`die lotenac
`
`COOH
`
`N—OH
`i
`CI
`
`Cl-.
`
`N.5-Dihydroxy-dtclofenae
`
`Fig. 2. Blotransformation oi diclofenae. COMT = catechoI—D—methyltransferase; CYP = cytochrome P450; UGT = uricline diphosphate
`Ql uCu1’Or‘lU$\;|l1"al'|SiE:I'a59.
`
`uterine inertia andfor premature closure of the duc-
`
`3.7 Summary
`
`tus arteriosus.'33'
`
`Diclofenac passes into breast milk in very low
`
`quantities when oral doses of 50mg are taken every
`
`8 l‘lU111'$'.[24l The risk to the infant of diclofenac—
`
`The pharmacokincties of diclofenac, including its
`
`potassium salt, are well known. Diclofenac potassi-
`
`um 12.5rng is provided in a rapid—rcleasc formula-
`
`tion, which means that it has a more rapid onset of
`
`related adverse effects should therefore be minimal,
`
`pharniaeodynamic activity. The elimination of
`
`especially with the recommended OTC dosing regi-
`
`men (S75 mg/day). Although in
`
`two studies
`
`diclofenac could not be detected in breast milk, the
`
`diclofenac is complete. At low doses it is unlikely
`
`that other exogenous t"actors such as commonly used
`
`drugs or endogenous factors such as age or impaired
`
`clea1‘ing—organ functions cause any critical changes
`
`presence of diclofenac metabolites in breast milk
`
`in the pharmacokineties of diclofenac. Based on the
`
`has not yet been excluded.”
`
`wide therapeutic experience with dielofenac and
`
`E3 200? Adis Data Informenion BV. All rights reserved.
`
`Clin Drug Invest 200?: 2? (3)
`
`Page 6
`Page 6
`
`

`
`Diclofenac Potassium 125mg Tablets in Mild to Moderate Pain and Fever
`
`169
`
`Table I. Comparison of some characteristic phannacokinetic parameters of non-prescription analgesics and diclofenac
`
`Compound
`
`Half-life {hi
`
`trrlayi (hi
`
`Aspirin iacetylsalicyllc acid)
`Salicylic acid
`
`Ibuprofen {Fli'S)l*5'39l
`
`0.25
`2-33
`15-30”
`1 5—3D”
`
`2-3
`
`1-2
`
`1-2
`
`Naproxen
`
`12-25
`
`2~4l3°-311
`
`0.4-0.8
`
`14.
`Diclofenac potassium
`a
`For low doses of salieylates.
`b Because of saturable kinetics, half-life increases to 15—3t]h.
`CYP : cytochrome 450 enzyme; RIS = racemic {containing equal quantities of Ft{—)— and S{+)—ibuproten}', tmu = time to maximum
`ooncerltration.
`
`Metabolism (e.g. site, metabolites and
`enzymes}
`Liver and other tissue
`
`Excretion
`
`Flenal
`
`Salicylunc acid. salicyl phenolic glucuronicle
`
`he-nal
`
`Hydroxylation, carboxylation (2-hydro>ty-
`ibuprofen and carb-oxy-ibuprofen) followed by
`ccnjugationml formation of Ft(-Hhioesters
`6—O—clesmethylnaproxenl3?l (CYPECQ.
`CYP2C13)
`Liver: CYPECB, CYFECQ, CYP3A4
`
`Flenal
`
`Flenal
`
`Flenal
`
`taking into account
`
`the known pharmacokinetics
`
`ibuprofen lnay represent an additional
`
`lnetabolic
`
`of
`
`the
`
`drug,
`
`low—dose
`
`diclofenac
`
`potassium
`
`load for the organism. Additionally. metabolic in-
`
`pharmaeokinetics seem appropriate for a non-pre-
`
`version may be impaired in hepatic dysfunction,
`
`scription status.
`
`resulting in delayed elimination of ll)LlpI‘L‘ll'CIl.l33l
`
`3.8 Comparison of the Pharmacokinetics of
`Low—Dose Dlclofenac: Potassium with
`
`Established Non-Prescription Analgesics
`
`There
`
`are
`
`relatively
`
`few
`
`nonprescription
`
`analgesics containing chemically defined com-
`
`pounds on the market. Aspirin (acctylsalicylic acid"),
`
`Rapid onset of analgesia is essential in the treat-
`
`ment of acute pain. The observed tnm for diclofenac
`
`is.
`
`in general. shorter than that of naproxen and
`
`similar to that of ibuprofen, indicating that the onset
`
`of the analgesic effect of diclofenac should occur
`
`rapidly, as confirmed by several clinical
`ieS_[s4—3'l]
`
`stud-
`
`paracetamol. ibuprofen and naproxen appear to be
`
`The available OTC analgesics differ markedly in
`
`the most relevant compounds for comparison with
`
`their metabolism. Diclofenac is mctabolised by
`
`diclofenac potassium.
`
`phase 1 hydroxylation and by phase 1] conjugation,
`
`Important comparative pharmacokinctic para-
`
`with the CYP enzyme 2C subfamily (CYP2C9,
`
`meters of diclofenac and other OTC analgesics are
`summarised in table I.l15'-*2]
`
`Diclofenac is a non-chiral compound. Naproxen
`
`CYPECS]
`
`playing
`
`a
`
`key
`
`role. Naproxen
`
`is
`
`metaboliscd to a 6—CI—dcsmcthyl derivative and then
`with
`
`glucuronide. When
`
`racelnic
`
`conjugated
`
`is a stcreoehemically pure drug, of which the S-
`
`ibuprofen is administered to humans. a substantial
`
`enantiomer is available on the market. Ibuprofen is
`
`fraction 60-90%) of the dose of RI:-)-ibuprofen
`
`chiral and the marketed product is racernic, contain-
`
`ing equal quantities of R(—)- and S(+)-ibuprofen.
`
`The active S(+)—enantiomer (eutomer) is capable of
`
`inversion to yield S{+)—
`undergoes metabolic
`ihuprofen.l29'i‘3' However. the degree of this inver-
`sion varies from individual to individual. Moreover,
`
`inhibiting COX at clinically relevant concentrations.
`
`the extent of inversion appears to be reduced when
`
`R(—)—ibuprc-fen is not a COX inhibitor. Even if the
`
`inactive enantiolner [distomer) undergoes metabolic
`
`the racematc is given to patients experiencing acute
`pain.”-"1 The chiral inversion is unidirectional from
`
`inversion to the active cutomcr,
`
`inactive R(—)—
`
`the inactive R{—)— to the active S(+)—enantiomcr.l4Ul
`
`-e 200? Adis Data Information av. All rights reserved.
`
`Clin Drug Invest 200?.‘ 2? E3}
`
`Page 7
`Page 7
`
`

`
`170
`
`Moore
`
`Both isomers are nietabolised in the liver by hydrox-
`
`4. Therapeutic Efficacy
`
`ylation and carboxylation to 2—hydroxyibuprofen
`
`and carboxyibuprofen followed by conjugation.l39J
`
`The Rl[—)-enantiomer of ibuprofen becomes in-
`
`volved in pathways of lipid metabolism by forming
`
`coenzyme A thioesters.l“"-42] The resulting interac-
`
`tion leads to the formation of hybrid triglycerides,
`
`which may impair membrane function or endoge-
`
`nous lipid synthesis.[43l Additionally, hybrid ni-
`
`glycerides result
`
`in depots of slowly eliminated
`
`ibuprofen ttvgp >100 hours}.
`
`The therapeutic efficacy and safety of diclofenac
`
`potassium administered as a single dose (l2.5mg.
`
`25mg). or in multiple doses of 25mg up to 7'5 mg]
`
`day, has been demonstrated in randomised, double-
`
`blind, placebo-cont.rol led trials with active compara-
`
`tors (ibuprofen, paracetamol, aspirin) in established
`
`pain and fever models. These include dental pain
`
`after extraction of impacted third molars, acute he-
`
`nign lower back pain tlumbagol. episodic tension-
`
`type headache, fever and sore throat, cold and influ-
`
`There are also marked differences in the tv_43. The
`
`enza-like symptoms, and menstrual pain arising
`
`apparent tvip of aspirin is approximately l8—-40 min-
`utes.l4“'45l Aspirin is rapidly hydrolysed in the body
`
`from primary dysmenorrhoea. An overview of the
`
`clinical trials and a summary of the outcomes are
`
`to salicylic acid. Correspondingly, the decrease in
`
`presented in table II.
`
`plasma aspirin concentration is associated with a
`
`All the efficacy studies described in this article
`
`rapid increase in salicylic acid concentration.”“' The
`
`included timed evaluations of pain intensity and
`
`average plasma half—life of salicylic acid is about 3
`
`hours.'‘““ Salicylate, but not aspirin itself. exhibits
`
`Michaelis-Menten isaturable) phamtacokinetics. At
`low doses. the elimination is first order and the half-
`
`life remains constant at 2-3 hours. However, at
`
`higher doses, the enzymes become saturated and the
`
`apparent half—|i'fe can increase to l5—3O hours. The
`
`effect of aspirin is therefore prolonged as a result of
`
`irreversible aeetylation of COX and metabolism to
`
`salicylate. Similarly, the half—life for naproxen with
`
`values between [2 and 25 hours is also relatively
`
`long, resulting in prolonged inhibition of gastric
`
`COX-1. Scharf et
`
`al. have hypothesised that
`
`NSAIDs with longer half-live-s are of particular con-
`
`eern as they may be more toxic in the gastrointesti-
`
`nal (Gll tract, particularly in the elderly, and that
`NSAIDS with short half-lives are associated with
`
`lower GI toxicity than NSAIDs with long hall'-
`
`lives.l‘”] This, combined with the low doses used
`
`and the common lack of risk factors. could be a
`
`factor contributing to the excellent GI tolerability of
`
`ibuprofen and diclofenac, which are among the
`NSAIDs with the shortest half-lives.
`
`pain relief or fever reduction over the first 6 hours
`
`after the first dose. In those studies that emphasised
`
`pain relief. the primary outcome for first-dose effl-
`
`cacy was either the pain-relief assessment at a spe-
`
`cific timepoinl or an aggregated total pain relief
`(TOTPAR—ta) outcome, defined as the area under
`
`the pain relief-versus-time curve from hour zero t.o a
`
`fixed post—dosing timepoint. The secondary out-
`
`come. sum of pain intensity difference (SPID-ta], is
`
`defined as the area under the pain—intcnsity dit'fer—
`ence from the baseline-versus-time curve from hour
`
`zero to a fixed post—dosing timepoint.
`
`4.l Dentol Pclin
`
`Dental pain is widely accepted as a validated
`
`model for documenting the efficacy of analgesics.
`
`The efficacy of low doses of diclofenac potassium
`
`against moderate-to-severe pain after the extraction
`
`of impacted third—molar teeth has been evaluated in
`
`several randomised. placebo-controlled studies in-
`
`volving 1259 patients aged l6—75 years (table
`ll).“3‘-“"531 Single-dose, dose-ranging studies con-
`
`ducted with diclofenac potassium 6.25. 12.5 and
`
`-'21 200? Adis Data Information av. All rights reserved.
`
`Clin Drug Invest 200?: 2? (3)
`
`Page 8
`Page 8
`
`

`
`Page 9ao
`
`mum
`
`171
`
`Dielofenac Potassium 125mg Tablets in Mild to Moderate Pain and Fever
`
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`Clin Dlug |rw6S’r 2007: 2}‘ (3)
`
`

`
`Page 10o
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`E3 200? Adis Data Informefiom BV. All righis reserved.
`
`Clin Dlug |rw6’3’r 2007: 2}‘ E3}
`
`

`
`Diclofenac Potassium 125mg Tablets in Mild to Moderate Pain and Fever
`
`173
`
`4 _
`
`3 —.
`
`I Diclofenac potassium
`A Paracetamol
`El Placebo
`
`
`
`Meanpainrelief
`
`
`
`Time (h)
`
`Fig. 3. Mean relief ol pain with diclofenac potassium, paracetamol
`or placebo at different
`timepoints following dental extraction in
`study P34.[“31 The pain relief scores in both active groups were
`significantly higher than placebo at all timepolnts (p < 0.01}. At 30
`minutes only, pain relief was significantly greater for paracetamol
`than for dlelofenae potassium (p < -0.01). Pain relief scale is: 0 = no
`relief;
`1 = a little; 2 = some: 3 = a lot; 4 = complete.
`
`25mg evidenced the logarithmic dose-response pro-
`file of diclofenac potassium.[“35°'53l TiInepoint-by-
`
`timepoint comparisons of least square means for
`
`pain relief. and pain-intensity differences for each
`
`treatment group, show a classic dose-proportionality
`
`profile with regularly increasing efficacy and a flat
`
`placebo line.
`
`Over 6 hours a single dose of diclofenac potassi-
`
`um 25mg tended to provide better relief than the two
`
`comparator drugs. aspirin 650mg and ibuprofen
`
`200mg. and the two lower doses of diclofenac potas-
`
`sium 6.25 and l2.5n1g, especially between I and 3
`l'1()l.1t'S.l48‘5O'52l
`
`tion for up to 6 hours (figure 3) and that the flexible
`
`multiplc—dose regimen is suitable for managing pain
`
`over the normal course of 2 days. This study also
`
`demonstrated that after the initial dose and during
`
`re-medication. multiple doses ofdiclofenac pot.assi-
`
`um 125mg, given as one or two tablets as needed,
`
`provided a consistent profile of analgesia similar to
`
`that obtained with paracetamol 100-0mg tablets and
`
`significantly better than placebo.
`
`4.2 Acute Lower Bock Poin
`
`The efficacy of the flexible dosing regimen of
`
`dielofenac potassium l2.5mg in a daily dose of
`
`25—'?5mg versus ibuprofen 2 X 200mg in a daily
`
`dose of 400—l20(lmg or placebo was investigated in
`
`study P40, a 7-day trial in 370 patients with at least
`
`moderately acute lower back pain, such as lumbago
`(table l[).l-lg‘ This study showed that diclofenac po-
`
`tassiurn was at least as effective as ibuprofen, with a
`
`suggestion of superior efficacy based on statistically
`
`significant superiority in a subset of efficacy out-
`
`comes. The primary efficacy outcome for the first
`dose of two tablets was TOTPAR—3 — the time-
`
`weighted sum of the pain relief scores after 3
`
`included
`hours. Secondary first—dose outcomes
`TOTPAR-6, SPID-3 and SPID-6, time to rescue or
`
`re—medication, and the cnd—of—first—dose global effi-
`
`cacy assessment. Diclofenac potassium 2 X |2.5ntg
`
`was significantly superior to placebo on TOTPAR-3
`
`(p = 0.03). Diclofenac potassium was also superior
`
`on all other first—dose outcomes, except for time to
`rescue or re-medication, for which the three treat-
`
`Efficacy was confirmed in the multiple—dose
`study P3493‘ This randomised. double-blind, doub-
`
`ments did not differ. Diclofenac potassium was also
`
`significantly superior to ibuprofen 2 X 200mg on
`
`le-dummy, placebo-controlled. multicentre, paral-
`
`SPlD—?i (p : 0.04). Ibuprofen 2 X 200mg was superi-
`
`lel—group trial compared the efficacy of an initial
`
`or to placebo only on the end-of-first-dose global
`
`dose of diclofenac potassium 25mg up to 75 mg.-‘day
`
`efficacy assessment.
`
`with an initial dose of paracetamol
`
`lf}0(lmg up to
`
`Flexible dosing outcomes in this study included
`
`3000 mgfday and placebo over 2 days. This study
`
`daily and end-ollstudy global efficacy assessments,
`
`showed that an initial dose of diclofenac potassium
`
`time to rescue or re-tnedication. and pain-intensity
`
`25mg effectively relieves pain from dental extrac-
`
`assessment on a visual analogue scale (VAS)
`
`-e 200? Adis Data Information Bv. All rights reserved.
`
`Cliri Drug Invest 200?: 2? (3)
`
`Page 11
`Page 11
`
`

`
`174
`
`Moore
`
`I Diclofenac potassium
`A Paracetamol
`El Placebo
`
`4 _
`
`3 —.
`
`I
`
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