Az etoricoxib klinikai farmakológiája és farmakokinetikája

Az előadások a következő témára: "Az etoricoxib klinikai farmakológiája és farmakokinetikája"— Előadás másolata:

1 Az etoricoxib klinikai farmakológiája és farmakokinetikája

2 X X NSAID Az NSAID-ek hatásmechanizmusa Arachidonsav
COOH Arachidonsav X X NSAID COX-1 „Konstitutív” COX-2 „Indukálható” Prosztaglandinok Vese Prosztaglandinok Newer nonsteroidal anti-inflammatory drugs (NSAIDs), unlike older ones, can selectively block cyclooxygenase (COX)-2, the inducible isoform of the enzyme associated with pain and inflammation.1,2 Both newer and older NSAIDs block COX, which occurs in COX-1 and COX-2 isoforms.1–4 These two enzymes are differentially expressed and are present in different tissues. COX-1 is constitutively expressed in normal tissues, including renal and endothelial tissues, as part of normal cellular function. COX-2 is believed to be induced by pro-inflammatory cytokines and occurs at elevated levels in inflamed tissues.5,6 COX-2 and COX-1 are also constitutively expressed in some parts of the kidney, in the uterus, and within the spinal cord and brain.1,3,5 Ref 1, p 11S, C2, ¶1, L6, ¶2, L1; p 14S, C1, ¶2, L4 Ref 2, p 368, Fig 1 Ref 1, p 11S, C2, ¶1, L6 C2, ¶2, L1 Ref 3, p 330, C1, ¶2, L9, ¶3, L1 Ref 4, p 18S, C2, ¶1, L1 Ref 5, p 101, ¶2, L2, ¶3, L1 Ref 6, p 1134, C2, ¶1, L1; p 1135, C1, L1 Ref 1, p 12S, C1, ¶1, L9, C2, ¶2, L1 Ref 3, p 330, C1, ¶3, L1 Ref 5, p 102, ¶1, L6; p 103, ¶2, L1; p 104, ¶2, L1 Homeosztázis Fájdalom és láz Gyulladás Gyomor- nyálkahártya védelme NSAID = nonsteroid gyulladáscsökkentő szer Átvéve: Wallace JL Am J Med 1999;107(suppl 6A):11S–17S; Vane JR et al Annu Rev Pharmacol Toxicol 1998;38:97–120; Fung HG et al Clin Ther 1999;21:1131–1157.

3 Az etoricoxib egyedülálló kémiai szerkezete
• Triciklikus metil-szulfon Cl SO2CH3 CH3 N Ref 7, p 2781, ¶4, L1; p 2777, Fig 1, ¶2, L1, ¶1, L14 Ref 8, p 1347, ¶3, L3 Ref 9, p 559, Fig 1 Source A, p 1, ¶2 Ref 10, p 1716, C2, ¶1, L1 A unique chemical structure distinguishes etoricoxib, an optimized pyridinylpyridine tricyclic methlysulfone, from older NSAIDs.7 There are two major classes of new NSAIDs: sulfonamide and sulfone derivatives.8 Etoricoxib is a unique tricyclic methylsulfone NSAID in clinical use.9 In terms of pH, etoricoxib is a basic NSAID, unlike traditional, nonselective NSAIDs, which are weak organic acids.10 Átvéve: Friesen RW et al Bioorg Med Chem Lett 1998;8:2777–2782; Riendeau D et al J Pharmacol Exp Ther 2001;296:558–566.

4 Az etoricoxib plazmakoncentrációja (µmol/l)
A COX-1 és a COX-2 etoricoxibbal végzett ex vivo gátlá-sának összehasonlítása a plazmaszint függvényében 100 PGE2 COX-2 80 TXB2 Napi 100 mg etoricoxibbal mérhető maximális plazmakoncentráció (átlag ± 1 SD) egyen- súlyi állapotban, n=16 (8 fő/panel) 60 Százalékos gátlás 40 COX-1 20 Etoricoxib is highly selective in blocking the activity of COX-2 versus COX-1, as assessed in whole-blood ex vivo assays. Serum-generated thromboxane B2 (TXB2) synthesis is the assay for blockade of COX-1 activity; lipopolysaccharide (LPS)-stimulated prostaglandin E2 (PGE2) synthesis tests for inhibition of COX-2. In these assays, PGE2 levels in LPS-challenged human whole blood and TXB2 levels following blood coagulation are measured as biochemical indices of COX-2 and COX-1 activity, respectively.9 The slide shows pharmacodynamic results of COX-1 and COX-2 assays superimposed on the mean plasma concentration resulting from a single 100 mg dose of etoricoxib. The pharmacodynamic results are from a double-blind, randomized, placebo-controlled, alternating, two-panel, rising single-dose study in which 16 healthy male volunteers received etoricoxib (5, 10, 25, 50, 125, 250, or 500 mg). Blood samples were collected at predose and at 1.5, 4, 8, and 24 hours postdose. Plasma concentrations achieved at steady state after a 100 mg dose coincided with nearly maximal COX-2 inhibition and minimal COX-1 inhibition.11 –20 0.01 0.1 1 10 100 Az etoricoxib plazmakoncentrációja (µmol/l) Ref 9, p 560, C2, ¶3, L1 Ref 11, p 574, C2, ¶2,3; p 575, C1, L1-5, 13-14; p 580, C1, ¶1; p 581, Fig 8 caption Source B, p 1, L1; p 2, L6-20; p 3, L24-25, 28-30; p 4, L1-10 PGE2 = prosztaglandin E2; TXB2 = tromboxán B2 Kettős vak, randomizált, placébókontrollos, egyszeri, emelkedő dózisokkal felváltva kezelt, két paneles – összesen 16 (panelenként 8) egészséges önkéntes férfi bevonásával végzett – vizsgálat, melyben a COX-1- és a COX-2-teszt farmakodinámiás és farmakokinetikai görbéit vetették össze az etoricoxib maximális egyensúlyi koncetrációi mellett mért átlagos plazmaszint függvényében. Átvéve: Dallob A et al J Clin Pharmacol 2003;43:573–585.

5 A COX-1 és a COX-2 gátlása*
COX-1- COX-2- COX-2- gátlás gátlás szelektivitás Etoricoxib ± 18 (12) ± 0.1 (26) Rofecoxib ± 0.9 (211) ± 0.02 (614) 35.0 Valdecoxib ± 4.3 (11) ± 0.11 (14) 30.0 Celecoxib ± 0.9 (13) ± 0.18 (18) 7.6 Diclofenac ± 0.04 (10) ± 0.01 (16) 3.0 Meloxicam ± 0.4 (6) ± 0.28 (5) 2.0 Etoricoxib exhibits much higher COX-2 selectivity than other NSAIDs on whole-blood and enzyme assays.9,12 The selectivity ratio for inhibition of COX-2 by etoricoxib in human whole blood, as measured by 50% inhibitory concentrations (IC50s) for COX-1/ COX-2, was 106.0, compared with respective values of 35.0, 30.0, 7.6, 3.0, and 2.0 for rofecoxib, valdecoxib, celecoxib, diclofenac, and meloxicam. Etoricoxib did not inhibit platelet or human recombinant COX-1 under most assay conditions (IC50 >100 µM). Thus, etoricoxib selectively inhibits COX-2 in human whole-blood assays in vitro, with the lowest potency for COX-1 inhibition compared with other selective agents. Ref 9, p 559, ¶3, L1; p 561, C2, ¶2, L9, ¶3, L1; p 562, Table 2 Ref 12, p 776, Table 1, Row 2, C3,4; p 775, C2, L10, ¶1, L11 A megadott értékek átlagértékek (µmol/l) ± standard hiba (SE). Az elemszámok a zárójelben találhatók. A molekulákat COX-2-szelektivitásuk csökkenő sorrendjében tüntettük fel. A The Journal of Pharmacology and Experimental Therapeutics cikkében olvasható állítások és vélemények az egyes szerzők saját álláspontját tükrözik, és nem az American Society for Pharmacology and Experimental Therapeutics (Amerikai Gyógyszertani és Klinikai Farmakológiai Társaság) álláspontját. Az American Society for Pharmacology and Experimental Therapeutics nem vállal felelősséget akár emberben, akár vagyoni tárgyban bekövetkezett semmilyen kárért, melyek a fenti cikkben szereplő elméletek vagy temékek következményei. *Humán in vitro teljesvér-vizsgálatból származó eredmények Átvéve: Riendeau D et al J Pharmacol Exp Ther 2001;296:558–566.

6 Az etoricoxib farmakokinetikája: Abszorpció és t1/2*
2000 60 mg 120 mg (n=12) 1500 Etoricoxib-koncentráció (ng/ml) 1000 500 Etoricoxib has linear dose-proportional pharmacokinetics and a half-life (t1/2) that permits once-daily dosing. As will be shown in subsequent clinical trial results, etoricoxib is associated with a rapid 24-minute onset of action and a long 24-hour duration of action.13 The pharmacokinetics of oral etoricoxib 5 to 120 mg were evaluated in a randomized, open-label, crossover, rising single-dose study in 12 healthy individuals between 25 and 50 years of age (mean age 36 years). The slide shows data for the 60 and 120 mg doses. Etoricoxib had approximately 100% bioavailability. The maximum plasma concentration (Cmax) and area-under-the-time-versus-plasma- concentration curve (AUC) were dose proportional up to 120 mg. Peak plasma concentrations were observed about one hour after dosing, and the t1/2 was approximately 22 hours.14 Ref 13 (EUSPC), p 10, §5.1, ¶7; p 11, §5.2, ¶1,8 Ref 14, p 269, C2, ¶1, L1-6; p 274, Table III, Fig 3, C1, ¶2, L5; p 275, C2, ¶1, L6-9 12 24 36 48 Idő (óra) t1/2 = felezési idő *Egészséges egyéneknek adott egyszeri orális dózisok Átvéve: Agrawal NGB et al J Clin Pharmacol 2003;43:268–276.

7 Etoricoxib: Tmax és t1/2 Tmax (óra) t1/2 (óra) Etoricoxib 1 22
Rofecoxib 2 17 Celecoxib 2–3 8–12 Valdecoxib 3 8–11 Diclofenac 1–5,25 2 Ibuprofen 0,75–1,5 2 Meloxicam 4–5 20 Naproxen 2–4 12–17 Indomethacin 2 4,5 Nimesulid 2–3 2–5 Ref 13 (EUSPC), p 11, §5.2, ¶1, L2,3, ¶8, L2-4 Source C (WPC, rofecoxib), p 10 §XVIIIb-1, ¶1, L3,4, §XVIIIb-4, ¶2, L3; Ref 15, p 1, ¶6, L6; p 2, ¶8, L3 Ref 16, p 3, ¶5, L4; p 4, ¶7, L4 Ref 17, p1, ¶6, Table 1; p 2, ¶1, L10 Ref 18, p 6, §5.2, ¶1; p 7, L1 Ref 19, p 1, C1, ¶5, Table 1, ¶13, L6 Ref 20, p 2, Fig 1, caption; p 3, Table 1; p 4, ¶8 Ref 21, p1, C1, ¶3, L3; p 3, C1, ¶13, C2, ¶2 Etoricoxib has a distinguishable pharmacokinetic profile. Etoricoxib has a time to maximum plasma concentration (Tmax) of one hour and a t1/2 of 22 hours, which permits once-daily dosing.13 Rofecoxib, celecoxib, and valdecoxib have Tmaxs from two to three hours and t1/2s from eight to 17 hours.15–19 Diclofenac sodium has a Tmax of 2.22–5.25 hours, while diclofenac potassium has a Tmax of one hour; t1/2 is two hours for both.20,21 Ibuprofen, meloxicam, naproxen, indomethacin, and nimesulide have Tmaxs from 0.75 to five hours and t1/2s ranging from two to 20 hours.22–34 Naproxen sodium has a Tmax of two hours.29 Ref 22, p 3, L1, ¶1, L1 Ref 23, p 4, ¶2, L5 Ref 24, p 4, §Pharmacokinetics Ref 25, p 2, ¶1, L2; p 3, ¶1 Ref 26, p 2, ¶18 Ref 27, p 5, §Pharmacokinetics, L7 Ref 28, p 1, §Absorption, ¶2; p 2, ¶3 Ref 29, p 3, Table, ¶5, L3,4 Ref 30, p 7, §5.2 Ref 31, p 3, ¶1, ¶2 Ref 32, p 11, ¶1, ¶4 Ref 33, p 4, Last ¶; p 5, L1, ¶7 Ref 34, p 251, C1, ¶2, L1; p 255, C1, ¶2, L1 p 3, Table Tmax = A maximális plazmakoncentráció eléréséhez szükséges idő

8 Etoricoxib: Metabolizmus
• In vivo kiterjedten metabolizálódik A vizeletből az alapvegyület <1%-a nyerhető vissza A metabolitok nem mutatnak aktivitást A metabolizmus a CYP enzimektől függ A CYP3A4 döntő (~60%) szerepet játszik az in vivo metabolizmusban A maradékot in vitro számos CYP enzim katalizálja (1A2, 2C9, 2C19, és 2D6) A hepatikus CYP3A4-aktivitás nem változik az erythromycin-kilégzési vizsgálatok szerint A CYP 1A2, 2C9, 2C19, 2D6, 2E1 és 3A4 in vitro nem gátlódik • • Etoricoxib is extensively metabolized in the liver but was not shown to inhibit or induce cytochrome P450 (CYP) enzymes in vivo and in vitro.13 Etoricoxib metabolizes into five inactive metabolites.35 Approximately 60% of etoricoxib is metabolized by CYP3A4, the remainder by CYP 1A2, 2C9, 2C19, and 2D6. Less than 1% of the original drug is recovered in the urine. The potential for etoricoxib to inhibit or induce CYP3A4 activity was investigated in healthy volunteers by an erythromycin breath test. Etoricoxib 120 mg daily did not alter hepatic CYP3A4 activity. In in vitro studies, etoricoxib did not inhibit CYP 1A2, 2C9, 2C19, 2D6, or 2E1.36 Ref 13 (EUSPC), p 6, §4.5, ¶7,8; p 7, L1; p 11, §5.2, ¶5,6 Ref 35, p 1060, C1, Scheme 1; p 1061, C2, ¶2, L1 Ref 36, p 817, C1, ¶3, L8; p 818, C1, L5; p 819, C1, ¶5, L1 • CYP = citokróm P450 Átvéve: Chauret N et al Bioorg Med Chem Lett 2001;11:1059–1062; Kassahun K et al Drug Metab Dispos 2001;29:813–820.

9 Az etoricoxib farmakológiája: Együttadás kis dózisú acetil-szalicilsavval (ASA)
100 94,0 92,1** 80 60 Az aggregáció átlagos gátlása* (%) 40 20 Etoricoxib did not affect the antiplatelet activity of low-dose acetylsalicylic acid (ASA). The potential for an interaction between etoricoxib and ASA was evaluated by ex vivo platelet aggregation and serum TXB2 generation using 1.6 mM arachidonic acid and 1 µg/ml collagen agonists. In a double-blind, randomized, placebo-controlled, parallel-group study, healthy individuals received placebo (n=14) or etoricoxib 120 mg once daily (n=13) for 12 days. On days 1 to 5, etoricoxib or placebo was administered without ASA. On days 6 to 12, open-label low-dose ASA (81 mg once daily) was coadministered to all participants. Serum samples tested on day 6 showed no interference with platelet aggregation by etoricoxib. In serum samples tested at steady state (day 12), etoricoxib 120 mg had no effect on the ability of ASA 81 mg to inhibit arachidonic-acid– or collagen-induced platelet aggregation. The mean difference was –2.0% (90% confidence interval [CI] = –4.6%, 0.6%) and 0.5% (90% CI = –4.4%, 6.6%), respectively, for etoricoxib plus ASA and placebo plus ASA.11 COX-2 selective inhibitors are not a substitute for ASA for cardiovascular prophylaxis because of their lack of effect on platelets. Because etoricoxib, a member of this class, does not inhibit platelet aggregation, antiplatelet therapies should not be discontinued and if indicated should be considered in patients at risk for or with a history of cardiovascular or other thrombotic events (prior history of myocardial infarction, angina, ischemic heart disease, atherosclerotic heart disease, cerebrovascular accident, cerebral ischemia, coronary bypass graft surgery, or peripheral vascular surgery). However, concomitant administration of low-dose ASA with etoricoxib may result in an increased rate of GI ulceration or other complications compared to use of etoricoxib alone. Concomitant administration of etoricoxib with doses of ASA above those for cardiovascular prophylaxis or with other NSAIDs is not recommended.13 –3,7 –1,3 –20 Placebo (n=14) Etoricoxib napi 1×120 mg (n=13) Placebo + napi 1×81 mg ASA (n=14) Etoricoxib napi 1×120 mg + napi 1×81 mg ASA (n=13) 6. nap 12. nap *Agonistaként 1,6 mmol/l konc. arachidonsavat használtak; **Az etoricoxib+ASA és a placébó+ASA közötti átlagos különbség –2,0% volt (90%-os konfidencia-intervallum [CI] = –4,6%; +0,6%) Randomizált, kettős vak, placebokontrollos, párhuzamos csoportú vizsgálatban értékelték az etoricoxib és a kis dózisú ASA hatását a thrombocyta-aggregációra és a TXB2 képződésére. Az egészséges önkéntesek napi 1×120 mg etoricoxibot (n=13) vagy placébót (n=14) kaptak 12 napig. A napon minden résztvevő nyílt elrendezésben napi 1×81 mg ASA-t is kapott. Átvéve: Dallob A et al J Clin Pharmacol 2003;43:573–585. Ref 11, p 576, C1, ¶1 (entire); p 581, C2, ¶1, L12-15, ¶2, L7-10; p 582, C1, L1-8; p 583, C2, ¶1, L10-12,19-26 Ref 13 (EUSPC), p 4, §4.4, ¶4; p 5, §4.5, ¶3

10 Az etoricoxib farmakológiája és farmakokinetikája
• Jól felszívódik: magas Cmax, gyors Tmax (~1 óra), és közel 100%-os biohasznosulás jellemzi Lineáris farmakokinetika A plazamakoncentráció a dózis emelésével arányosan növekszik a klinikai dózistartományban Triciklikus metil-szulfon t1/2: kb. 22 óra Napi egyszeri adagolás • • • Pharmacokinetic and pharmacodynamic characteristics make etoricoxib, a tricyclic methylsulfone, highly suitable for the treatment of acute and chronic pain. Etoricoxib is well absorbed, with a high Cmax occurring about one hour after oral administration, and has oral bioavailability of approximately 100%. Etoricoxib also has linear pharmacokinetics across the clinical dose range. The t1/2 of etoricoxib is about 22 hours, consistent with its 24-hour duration of action. Both features are consistent with a convenient once-daily dosing regimen.7,9,13,14 Ref 7, p 2781, ¶4, L1; p 2777, ¶2, L1, ¶1, L14 Ref 9, p 559, C2, Fig 1 Ref 13 (EUSPC), p 11, §5.2, ¶1 (entire), ¶8, L2-4 Ref 14, p 276, C1, ¶2, L8-12 • Cmax = maximális plazmakoncentráció

11 Az etoricoxib hatásának kezdete
Az etoricoxib hatáskezdetének mérését célzó vizsgálatok szerint: A hatás már 24 perccel a bevétel után beállt • In studies specifically designed to measure the onset of action of etoricoxib, the onset of action occurred as early as 24 minutes after dosing.13 Ref 13 (EUSPC), p 10, §5.1, ¶7

12 Fájdalomcsillapító hatás (átlag ± SE) A bevétel óta eltelt idő (óra)
Etoricoxib párhuzamos dózisösszehasonlító vizsgálat: Fájdalomcsillapítás* 24 órán át A 120 mg etoricoxib hatása 24 perc alatt beállt** 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Etoricoxib 120 mg (n=76) Fájdalomcsillapító hatás (átlag ± SE) Etoricoxib 60 mg (n=75) Ibuprofen 400 mg (n=48) In studies specifically designed to measure the onset of action of etoricoxib, the onset of action occurred as early as 24 minutes after dosing.13 Etoricoxib is not indicated for the treatment of postsurgical dental pain in the EU. Placebo (n=49) Ref 13 (EUSPC), p 10, §5.1, ¶7 Ref 37, p 668, C2, ¶3, L1-5; p 669, C1, ¶2, L1-3, ¶3, L10-14, ¶4, L1-3, C2, L1,3-11; p 670, C1, ¶1, L1-3, C2, ¶2, L2, ¶3, L1-3; p 671, C1, L1 Source D, p D-331, Onset of analgesia, Table D-81 p 672, C2, L5-9; p 673, Table II, Rows 9-11 A double-blind, randomized, placebo- and active-comparator–controlled, parallel-group, single-dose study evaluated the efficacy and tolerability of etoricoxib. The 398 adolescents and adults enrolled were experiencing moderate to severe pain following extraction of two or more third molars, at least one of which was partially embedded in mandibular bone. They were randomized to treatment with etoricoxib 60 mg (n=75), 120 mg (n=76), 180 mg (n=74), or 240 mg (n=76) once daily; ibuprofen 400 mg once daily (n=48); or placebo (n=49). Using a diary card, patients reported pain intensity and pain relief during the 24-hour time period after dosing. Onset of analgesia was determined by means of the two-stopwatch method. The primary efficacy variable in the trial was total pain relief over eight hours (TOPAR8).37 Time to perceptible pain relief with etoricoxib 120 mg occurred within 24 minutes or less in 50% of patients. The median time to onset was 24 minutes for the higher doses of etoricoxib (120, 180, and 240 mg) and 30 minutes for etoricoxib 60 mg and ibuprofen 400 mg. The placebo group had a median time to onset longer than four hours.13,37 Etoricoxib had a long 24-hour duration of action in 72% of the patients taking etoricoxib 120 mg. Etoricoxib 120 mg demonstrated significantly greater analgesic efficacy compared with placebo as assessed by TOPAR8, the primary endpoint (p<0.001). Analgesic effect lasted 10.1 hours with ibuprofen 400 mg; 12.1, >24, >24, and >24 hours with etoricoxib 60, 120, 180, and 240 mg; and 2.1 hours with placebo (p<0.05 for all etoricoxib doses vs. placebo).37 1 2 3 4 5 6 7 8 12 24 A bevétel óta eltelt idő (óra) SE = standard hiba *A fájdalomcsillapító hatást egy 0-4 fokozatú skálán (0 = nincs; 4 = teljes) értékelték; **A hatáskezdetig eltelt közepes időtartam (a betegek 50%-ánál) A vizsgálatban az etoricoxib 60, 120, 180, és 240 mg-os dózisait tanulmányozták. Átvéve: Malmstrom K et al Clin Ther 2004;26(5):667–679. Source D, p D-341, Table D-86, Protocol 022, C2, Row 2 + calc Calc: 100–27.6=72.4% Ref 37, p 673, Table II, Rows 16,17, C2, L6,7; p 675, C1, L1-4

13 Referenciák References
1. Wallace JL. Distribution and expression of cyclooxygenase (COX) isoenzymes, their physiological roles, and the categorization of nonsteroidal anti-inflammatory drugs (NSAIDs). Am J Med 1999;107(6A): 11S–17S. 2. Hinz B, Brune K. Cyclooxygenase-2—10 years later. J Pharmacol Exp Ther 2002;300(2):367–375. 3. Vanegas H, Schaible H-G. Prostaglandins and cycloxygenases in the spinal cord. Prog Neurobiol 2001;64:327–363. 4. Furst DE. Pharmacology and efficacy of cyclooxygenase (COX) inhibitors. Am J Med 1999;107(6A): 18S–26S. 5. Vane JR, Bakhle YS, Botting RM. Cyclooxygenases 1 and 2. Annu Rev Pharmacol Toxicol 1998;38: 97–120. 6. Fung HB, Kirschenbaum HL. Selective cyclooxygenase-2 inhibitors for the treatment of arthritis. Clin Ther 1999;21(7):1131–1157. 7. Friesen RW, Brideau C, Chan CC et al. 2-Pyridinyl-3-(4-methylsulfonyl) phenylpyridines: Selective and orally active cyclooxygenase-2 inhibitors. Bioorg Med Chem Lett 1998;8:2777–2782. 8. Penning TD, Talley JJ, Bertenshaw SR et al. Synthesis and biological evaluation of the 1,5 diarylpyrazole class of cyclooxygenase-2 inhibitors: Identification of 4-[5-(4-methylphenyl)–3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (SC-58635, celecoxib). J Med Chem 1997;40: 1347–1365. 9. Riendeau D, Percival MD, Brideau C et al. Etoricoxib (MK-0663): Preclinical profile and comparison with other agents that selectively inhibit cyclooxygenase-2. J Pharmacol Exp Ther 2001;296:558–566. 10. Brooks PM, Day RO. Nonsteroidal antiinflammatory drugs—differences and similarities. N Engl J Med 1991;324(24):1716–1725. 11. Dallob A, Hawkey CJ, Greenberg H et al. Characterization of etoricoxib, a novel, selective COX-2 inhibitor. J Clin Pharmacol 2003;43:573–585. 12. Talley JJ, Brown DL, Carter JS et al. 4-[5-Methyl-3-phenylisoxazol-4-yl]-benzenesulfonamide, valdecoxib: A potent and selective inhibitor of COX-2. J Med Chem 2000;43:775–777. 13. EU Summary of Product Characteristics for ARCOXIA™ (etoricoxib, MSD). May 2004. 14.    Agrawal NGB, Porras AG, Matthews CZ et al. Single- and multiple-dose pharmacokinetics of etoricoxib, a selective inhibitor of cyclooxygenase-2, in man. J Clin Pharmacol 2003;43:268–276. 15. Prescription information for VIOXX® (rofecoxib tablets and oral suspension), United States. Merck & Co., Inc., Whitehouse Station, New Jersey, 1998, 2002. 16. VIOXX® Fachinformation des Arzneimittel – Kompendium der Schweiz. Documed, Corp., Basel, 2001. 17. Prescribing information for Celebrex® (celecoxib), United States. Pfizer Inc., Caguas, Puerto Rico, 2002. 18. Prescribing information for Celebra™ (celecoxib), Sweden. Searle Scandinavia, Malmo, Sweden, 2000. 19. Prescribing information for Bextra™ (valdecoxib). Pfizer Inc., Caguas, Puerto Rico, 2002. 20. Prescribing information for Voltran®-XR tablets (diclofenac), United States. Novartis Pharmaceuticals Corp., East Hanover, New Jersey, 2000. 21. Prescribing information for Motifene™, Voltarol™, Voltarol SR/Retard™, United Kingdom. Novartis Pharmaceuticals UK Limited, 1997. 22. Prescribing information for Motrin® suspension, oral drops, chewable tablets, and caplets (ibuprofen), United States. McNeil Consumer Products Co., Fort Washington, Pennsylvania, 1994. 23. Prescribing information for Brufen™, Brufen Retard™, United Kingdom, 1995. 24. Prescribing information for Brufen®, Sweden. Knoll.

14 Referenciák (folyt.) References (cont’d)
25. Prescribing information for Mobic® (meloxicam), United States. Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, 2003. 26. Prescribing information for Mobic™ (meloxicam), United Kingdom. Boehringer Ingelheim International GmbH, Rhein, Germany, 1998. 27. Prescribing information for Mobic® (meloxicam), Sweden. Boehringer Ingelheim International GmbH, Rhein, Germany, 1998. 28. Prescribing information for Mobicox® (meloxicam), Switzerland. Boehringer Ingelheim International GmbH, Rhein, Germany, 1998. 29. Prescribing information for EC-Naprosyn® (naproxen) delayed-release tablets, Naprosyn® (naproxen) tablets, Anaprox®/Anaprox® DS (naproxen sodium) tablets, Naprosyn® (naproxen) suspension, United States. Roche Laboratories Inc., Nutley, New Jersey, 2003. 30. Prescribing information for Naprosyn™, United Kingdom. Roche Products Limited Available at Accessed January 10, 2002. 31. Prescribing information for INDOCIN™ (indomethacin) oral suspension, United States. Merck & Co., Inc., West Point, Pennsylvania, 1988. 32. Prescribing information for INDOCIN® (indomethacin), France. Merck, Sharp & Dohme-Chibret, Paris, 1994. 33. Prescribing information for Nimed™ (nimesulide), Finland. Helsinn Healthcare SA, Switzerland, 1997. 34. Bernareggi A. Clinical pharmacokinetics of nimesulide. Clin Pharmacokinet 1998;35(4):247–274. 35. Chauret N, Yergey JA, Brideau C et al. In vitro metabolism considerations, including activity testing of metabolites, in discovery and selection of the COX-2 inhibitor etoricoxib (MK-0663). Bioorg Med Chem Lett 2001;11:1059–1062. 36.  Kassahun K, McIntosh IS, Shou M et al. Role of human liver cytochrome P4503A in the metabolism of etoricoxib, a novel cyclooxygenase-2 selective inhibitor. Drug Metab Dispos 2001;29(6):813–820. 37. Malmstrom K, Sapre A, Coughlin H et al. Etoricoxib in acute pain associated with dental surgery: A randomized, double-blind, placebo- and active comparator–controlled dose-ranging study. Clin Ther 2004;26(5):667–679.

15 Lényeges információk I.
Az ARCOXIA (etorikoxib, MSD) csak vényre kiadható gyógyszer. Az ARCOXIA filmtabletta 60 mg 14× és 28×, ill. 90 mg 14× és 28× sorrendben 875, 1707, 927, 1813 Ft-ért kapható (teljes áruk: 2918, 5689, 3089, 6044 Ft, a tb-támogatás: 2043, 3982, 2162, 4231 Ft [az érvényes Eü-pontok alapján; esetleges változásokat ld.: Javallatok: osteoarthritis (OA), rheumatoid arthritis (RA) tüneteinek, ill. akut köszvényes arthritissel járó fájdalom és gyulladás csökkentése. Ellenjavallatok: Túlérzékenység az összetevőkre; 16 év alatti életkor; terhesség; szoptatás; aktív peptikus fekély; gastrointestinalis vérzés; anamnézisben acetilszalicilsav vagy NSAID készítmények – köztük COX-2-gátló – adását követő bronchospasmus, acut rhinitis, orrpolip, angioneuroticus ödema, urticaria, allergiás reakciók; valamint súlyos májelégtelenség (se-albumin <25 g/l vagy Child-Pugh >10); gyulladásos bélbetegség; pangásos szívelégtelenség (NYHA II-IV); 30 ml/perc alatti becsült kreatinin-clearance; nem kellően kontrollált hipertónia; manifeszt ischaemiás szívbetegség, perifériás verőérbetegség és/vagy cerebrovascularis megbetegedés. Update the API please.

16 Lényeges információk II.
Adagolás: maximális napi dózisok: OA-ben 1×60 mg, RA-ben 1×90 mg, akut köszvényes arthritisben max. 8 napig 1×120 mg. Child-Pugh 5-6 esetén max. napi 60 mg, 7-9 esetén másnaponta 60 mg. Főbb mellékhatások (>1%): ödéma/folyadékretenció, szédülés, fejfájás, magas vérnyomás, különféle gastrointestinalis zavarok, asthenia/fáradság, influenzaszerű tünetek, emelkedett ALT-, AST-értékek. Felírás előtt kérjük, olvassa el a teljes alkalmazási előirást, különös tekintettel a pontos indikációkra (4.1), az adagolásra és alkalmazásra (4.2), ill. a figyelmeztetésekre (4.4) (OGYI /55/2006). Update the API please.

17 Az etoricoxib klinikai farmakológiája és farmakokinetikája
Felírás előtt kérjük, olvassa el az érvényes teljes alkalmazási előírást. Az MSD nem javasolja semmilyen gyógyszer alkalmazási előírástól eltérő használatát. Before prescribing, please consult the manufacturers’ prescribing information. Merck does not recommend the use of any product in any different manner than as described in the prescribing information. Copyright © 2008 Merck & Co., Inc., Whitehouse Station, NJ, USA. Minden jog fenntartva. ACX-2007-HU-1802-SC LÁTOGASSON MEG MINKET A VILÁGHÁLÓN Copyright © 2002–2004 Merck & Co., Inc., Whitehouse Station, NJ, USA. All rights reserved ACX 2004-W-6327-SS Printed in USA VISIT US ON THE WORLD WIDE WEB AT