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    Celebrex 200 MG Capsule, Hard - SPC - Medicines - Ie

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    jacksddu
    SPC

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    © All Rights Reserved
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    4a 42 SUMMARY OF PRODUCT CHARACTERISTICS NAME OF THE MEDICINAL PRODUCT (Celebrex 200 mg hard capsules QUALITATIVE AND QUANTITATIVE COMPOSITION Each capsule contains 200 mg celecoxib. Excipient with known effect ‘Lactose each capsule contains 49.8 mg lactose monohydrate; se section 4.) For the fll ist of excipients, se section 6.1 PHARMACEUTICAL FORM ‘Hard capsules (capsule. Opaque, white with two gold bands marked 7767 and 200, CLINICAL PARTICULARS “Therapeutic indications (Celebrex is indicated in adults forthe symptomatic reli in the treatment of osteoarthritis, sheumatoid atts and ankylosing spondylitis “The decision to prescribe a selective cyclooxygenase-2 (COX-2) iaibitor should bebased on ‘an assessment of the individual patent's overall risks (ee sections 4.3 and 4.4), Posology anid method of administration Posology AAs the cardiovascular (CV) risks of celecoxib may increase with dose and duration of ‘exposure, the shortest duration posible andthe lowest effetive daily dose should be used. “The patients need for symptomatic relief and response to therapy should be re-evaluated periodically, especially in patient with ostecartiitis (see sections 4.3, 4.4 48 and 5.1) Osteoarthritis “The usual recommended dally dose is 200 mg taken once daily or in two divided doses. tn some patients, with insufTiciet relief from symptoms, an increased dose of 200 mg twice lily may increase efficacy. In the absence of an increase in therapewticbetefit ater two ‘weeks, other therapeutic options shouldbe considered Rheumatoid arthritis ‘The intial recommended daily doe is 200 mg taken in two divided doses, The dose may, if needed, later be increased to 200 mg twice dally. In the absence ofan increase in therapeutic, benoit after two weeks, other therspeutic options shoul be considers, Page of 16 43 Anipiosing sponds “The recommended daily dose is 200 mg taken once daily or in wo divided doses. In. few patients, wit insufficient relief from symptoms, an increased dase of 400 mg once daily or in {wo civided doses may increase efficacy. Inthe absence of an inrease in therspeutic benefit aftr two weeks, other therapeutic options shouldbe considered “The maxin ma recommended daily dose is 400 mg forall indications. Soecial papulaions Elderly ‘As in younger adult, 200 mg per day shouldbe usd iitilly. Tae dose may, if weeded, Later be increased to 200 mg twice daily, Particular caution should be exercised in elderly with @ body weigh less than £0 kg (see sections 4.4 and 5.2, Paedlotre population (Celecoxib is aor indicated for use in ehildren, CIP2C9 poor merabolisers Patients who are known, or suspected to be CYP2C9 poor metabolisrs based on genotyping. fr previous histry'experience with other CYP2C9 substrates should be administered {eleconib with caution ss the risk of dose-dependent adverse effects is increased. Consider ‘reducing the dose to half he lowest recommended dose (see section 5.2) Hlopotic impairment ‘Treatment should be initiated at half the recommended dose in patients with established moderate liver impairment witha serum albumin of 25-38 gl. Experience in sch patients is limited to cirhotie patients (se sections 4.3, 4.4 and 5.2) Renal impairment Experience With celecosib in patents with mild or moderate renal impairment is Limited, ‘therefore sul patents shouldbe treated with caution (682 sections 4.3, 4.4 and $.2) ‘Method of adminisration Oral nse CColabrex may be takea with or without food. For patients who have difficulty wallowing capsules, the contents ofa celecaxi capsule can be added fo applesauce rice gruel, yogurt oF ‘mashed banana. To do s the entre capsule contents must be carefully emptied oato level ‘teaspoon of cool or room temperature applestuce, rice gruel, yogurt or mashed bansua and should be ingested immediately with 240 ml of water. The sprinkled capsule contents on applesauce, rice gruel ot yogurt aze sable for up to 6 hours Under refiigerted coaditions @:8°O). The sprinkled capsule contents on mashed banana should not be stoced under ‘efrigerated conditions and should be ingested immediately. Contraindications Hypersensitivity tothe active substance orto any ofthe excipients listed in section 6.1, ‘Kaown hypersensitivity to sulfonamides. Active peptic ulceration or gastrointestinal (GI) bleeding Posed of 16 44 Patients who have experienced asthma, acute shins, nasal polyps, angionenrotic oedema, ‘urticaria or other allergc-type reactions after taking acetylsalicylic acid (asprin) or other ‘non-steroidal aat-inflammatory drugs (NSAIDs) including COX-2 inhibitors, In pregnancy and in women of childbearing potential unless using an effective method of ‘contraception (se section 4.6), Celecoxib has besa shown to cause malformations in the two animal species studied (see Secitons 4.6 and 8.3) The potential for human rskin pregnancy is ‘unknown, but eannot be excluded, Breast-Feeding (se sections 4.6 and 5.3). Severe hepatic dysfunction (serum albumin <25 g/l or Child-Pugh score =10) Patients with estimated creatinine clearance <30 ml/min, Inflammatory bowel diseae (Congestive her failure (NYHA ILIV), Established ischaemic heat disease, peripheral arterial disease and/or cerebrovascular disease, ‘Special warnings and precautions for use Gastrointestinal (GI eff ‘Upper and lower gastrointestinal complications (perforations, ulcers or bleedings (PUBS)), some of them resulting in fatal outcome, have occurred in patients treted with celecoxib Caution is advised with teatment of patients most at risk of developing a gasrointestinal ‘complication with NSAIDs; the elderly, patiets using any other NSAID o anvplatelet drugs (Gach as aceylsaliylic acid) or glucocorticoids concomitantly, patients using alcohol, oF patients witha prior history of gastrointestinal disease, suchas ulceration and GI bleeding ‘There is further increase in the risk of gastrointestinal adverse effects for celecoxib (gastrointestinal ulceration or otter gastrointestinal complications), when celecoxib is taken ‘concomitantly with acetylsalicylic aie (even tle doses) A signiican difference in GI safety brween selective CON-2 inhibitors + acetylsalicylic acid ‘ve NSAIDs + acetylalielic acid has not beea demonstrated in long-term clinical tals (see section $1) “The concomitant use celecoxib and a noa-aspria NSAID should be avoided. Cardiovascular effects Increased umber of serious cardiovascular (CV) events, mainly myocardial infarction, has ‘been found in a long-term placebo-contolleé study in subjets with sporadic adenomatous polyps treated with celecoxib at doses of 200 mg bs indie BID) and 400 mg BID compared toplacebo (ste section 5.1), As the cardiovascular isk of celecoxib may inerease wit dose and duration of exposure, the ‘Shortest durstion possible and the lowest effective daily dose should be used, NSAIDs, including COX:2 selective inhibitors, have been associated with increased risk of cardiovascular ad thrombotic adverse events when taken long-term, The exact magaitude of the risk associated with a single-dose has not heen determined, nor has the exact duration of ‘therapy associted with increased risk. Tae patient's need for symptomatic relief and response Pose sof 16 to therapy should be re-evaluated periodically, especially in patients with osteoarthritis (see sections 4.2,4.3,48.and 5.1), Patients with significant risk factors for cardiovascular events (e.g. hypertension, hhyperlipidcomia, disbotes mellitus, smoking) should only be teated with celecoxib after catefil consideration see section 5.1), COX-2 selective inhibitors are not a substitute for acetyslicyic acid for prophylaxis of cardiovascular thrombo-embolic diseases because of their lack of antiplatelet effects ‘Therefore, antiplatelet therapies should not be discontinved (se section 5.1). Fluid retention and oedema |As with other medicinal products known to inhibit prostaglandin synthesis hid retention and ‘edema have been observed in patiats taking celsowio, Therefore, celesoxi should be used ‘with caution in patients with history of cardioe failure, left ventricular dysfunction or hypertension, and in patients with pre-existing ordema from any other reason, since prostaglandin inhibition may result in deterioration of renal funtion and fluid retention Caution is also required in patients taking diuretic trestment or otherwise at risk of nypovolsemis, Hypertension [As with all NSAIDS, celeconicaa lead tothe onset of new hypertension or worsening of pre- existing hypertension, ether of which may contribute to the increased incidence of cardiovascular events’ Therefore, blood pressure should be monitored closely during the Initiation of therapy with celeconib and trough the course of therapy. Hepatic and onal effets ‘Compromised renal or hepatic function and especially cardiac dysfunction are more Likely in the elderly and therefore medically appropriate supervision should be maintained. NSAIDs, including colecoxib, may cause renal toxicity. Clinical rials with cloeoxib have show renal effets similar to those observed with comparator NSAIDS. Patients at greatest "sk for renal toxicity are those with impaired renal fusction, heart failure liver dysfunction, those taking diuretics, angiotensin converting enzyme (ACE)-inhibitors, angiotensin Tt receptor antagonists, andthe elderly (se section 4). Such patients should be eaefully ‘monitored wiile receiving treatment with celecoxib. Some cases of severe hepatic reactions, including folminant hepatitis (some with fatal foutcame), liver necrosis and, hepatic faifure (some with fatal outcome or requiring liver ‘ransplant), have been reported with celecoxib, Among the cases that reported time to onset, most of the severe adverse hepatic events developed within one month after ination of celecoxib treatment (se section 48). 1 during trootaent, patients deteriorate in any of the organ system functions decribed above appropriate measies should be taken and discontinuation of celecoxib therapy should be considered XPD inhibition ‘Gelecoxid inhibis CYP2D6. Although it is not a strong inhibitor oF this enzyme, a dase reduction may be necessary for individually dose-titrated macicinal products that are metabolised by CYP2D6 (see section 4.5). ©¥P2C9 por metabolisers Patients Know (o be CYP2C9 poor metabolisers should be treated with caution (see section 52), Page of 16 4s Skin and systemic hypersensitivity reactions Serious skin reactions, seme of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, ad toxic epidermal necrolysis, have been reported very rarely in asociation with thouse of celocoxib (see section 4.8). Paion's appear 1 be at highest risk for these reactions curly in the course of therapy: the onset of the faction occurring ia the majority of cases ‘within tho frst mouth of treatment. Serious hypersensitivity reactions including anaphylaxis, angioedema and drug rash with eosinophilia and systemic symptoms (DRESS), of hypersensitivity synérome), have been reported in patients receiving celecoxib (see section 4.8) Patents with a history of sulfonamide allergy or any drug allergy may beat greater risk ‘of serious skin reactions or hypersensitivity reactions (See section 43). Celecaxib should be slscoatiaved at the first appearance of skin rash, mucosal lesions, or any other siga of Inspersensitivity. General (Celecoxib may mak fever and other signs of inflammation, ‘Use with oral anticoagu [Inpatients on concurrent therapy with warfarin, serious bleeding events, some of them fatal, have been reported. Incteased prothrombin time (INR) with eoacurzent therapy has been reported, Therefore, this sould be closely monitored inpatients receiving ‘warfarinicoumarin-type oral anticeagulants particularly when therapy with colecoxib is inated or celecoxib dose is changed (see section 4.5), Concomitant tse of anticoagulants ‘with NSAIDS may increase the risk of bleeding. Caution shouldbe exercised when combining celecoxib with warfarin or other oral anticoagulants, including novel anticoagulants (eg apixaban, dabigaran, and rivaroxaben) Excipiens Celebrex 100 mg and 200 mg capsules contin lactose (149.7 mg snd 49.8 mg, respectively). Patients with rate herectary problems of galoctose intolerance, total laciase deficiency or _lucose-galactose malebeorpion should act take this medicine, (Celebrex 100 mg and 200 mg contains les thaa 1 mumol sodium (23 mg) per capsule, thet eto ‘ay essentially “Socium-free Interaction with other medicinal products and other forms of interaction Pharmacodvnamic interactions Anicoogutants ‘Anticoagulant activity should be monitored particulary inthe first fev: days ater initiating oF ‘changing the dose of celesosib in patients receiving warferia or other anticoagulants since these patients have an increased risk of bleeding complications. Therefore, patients receiving ‘oral enticoagulants shouldbe closely nzonitored fr their prothrombin ime INR, particule ely in the first few days when therapy with celeconib is initiated or the dose of celecoxib is changed (80 section 44), Bleeding eveats i association with incteases in proheombia time hnave been reported, predominantly inte eldery, in patients receiving celecoxib concurrently ‘with warfarin, some of them Fatal Anviohypenensives SSAIDe my reduce the eect of antiypertensive meticiml products including ACE-inhibors, angiotensin TT receptor anagoniss, dizetcs and bets-blockers. As for NSAIDs th rink of ate real aifiency, hich sully reverabl, ny be sree some patents with compromised renal functon (eg deivrted patients, patients On eis. x elery pte) when ACE inher, angiotensin rsceplor antagonists, andor dts Piss S08 18 are combined with NSAIDs, including celecoxib (see section 4.4), Therefor, the combinstion ‘should fe administered with caution, especially inthe eldesly. Patients shoald he adequately lnyérated and consideration should be given to monitoring of renal function efter initiation of ‘concomitant therapy, and periodically thereater, In a 28-day clinical study in patients with lisipopril-controlled Stage I and II hypertension, ‘administration of celecoxib 200 mg BID rosuted in no clinically significant increases, when compared to placebo teaimest, ia mea daly sjsiolic or diastolic blood pressure as determined using 24-hour ambulatory blood pressure monitoring. Among patients treated ‘ith celecoxib 200 mg BID, 48% were considered unresponsive to lisinopril a the Final clinic Visit (defined a5 ether eufT diastolic blood pressure >90 mmHg or cuit diastolic blood pressure increased 10% compared to baseline), compared t0 27% of patients treated with placebo; this difference was statistically significant. CCiclasporin and tacrolimus (Covadministation of NSAIDs and ciclosporin or tacrolimus may incvease the nephrotoxic effect of ciclosporin or tacrolimus, respectively. Renal function should be monitored when celecoxib and any ofthese medicinal products ave combined. Acetylalieslic acid CCelecoxid can be used with low-dose acetylsalicylic acid but is not @ substitute for acetylsalicylic acid for CV prophylaxis. In the submittad suies, as with other NSAIDs, an increased risk of gastrointestinal ulceration or other gastrointestinal complications compared to use of celecoxib lane was shown for concomitant administration of low-dose acetylsalicylic acid (see section §.1). Phasmacokinctic interactions Effects of celecoxib on other medicinal products 1s a inhibitor of CYP2D6. The plasma concentrations of medicinal produc that fare subsrstes of thie enzyme may be increased when celecoxib is used concomitantly. Examples of medicinal products Which are metabolised by CYPID6 aze aatidepressats (Gricyelics and SSRI), neuroleptics, anti-arraythmic medicinal products, ete. The dose of individually dose-titzated CYP2DS substrates may aved to be reduced when treatment with celecoxib is initiated or increased if teatment with celecoxib is terminated Concomitant administration of celecoxib 200 mg twice daily resulted in 2.6-fold and 1.$-fold increases in plasma concentrations of dexiromethorphan aad metoprolol (CYP2D6 substrates), respectively. These increases are dve to celecoxib inhibition of the CYP2D6 subsirste sctabolis. CAP 2C19 whibaion {vitro studies have shown some poteatial for celecoxib 10 inhibit CYP2C19 catalysed nietabolis, The clinical significance of this i vire Finding is wakaota, Examples of ‘medicinal products which are metabolised by CYP2CI9 are diazepam, citalopram and imipramine. Methorecote I patients with rheumatoid arthritis celecosib had uo statistically sigaificant effect om the pharmacokinetics (plasma of renal cleaauce) of methotrexate (in rheumatologic doses) However, adequate monitoring for methotrexaterelated toxicity should be coasidered wien combining these two medicinal products. Paar of 16 46 Lithium a healthy subjects, co-adminisration of celecoxib 200 mg evce daily with 450 mg twice dlily of lithium resulted ina mean increas in Cam of 16% and in area under the curve (AUC) ‘of 18% of litum. Therefor, ptienson lithium treatment should be closely monitored when celeconib i introduced or withdrawn, Oral comaceptines [an nteracuon study, celecoxib had no clinically relevant effects on the pharmacokinetics of ‘oral contraceptives (Img torethisterone/35 micrograms ethinylestradic). Glibenctamiderotbuamide {Celecoxib does not affect the pharmacokinetics of tolbutamide (CYP2C9 substrata), or _libenclamide toa clinically relevant extent Effects of other medicinal products on celecoxib C¥P2C9 poor metabolisors In individuals who are CYP2C9 poor metabolisers and demonstrate increased systemic lexpomure to celacoxib, concomitant testment with CYP2CO inhibitors such as fluconazole ‘oud result ia Turther increases i celecoxib exposure, Such combinations should be avoided in known CYP2C9 poor mietabolisers see sections 4. and 5.2) Since celecoxib is predominansly metabolised by CYP2CO it should be used at half the ‘recommended dose in patients receiving fluconazole. Concomitant se of 200 mg sixgle-dose ‘of celecoxib and 200 mg once daly of fluconazole, a potest CYP2C% inhibitor, resulted in a ‘mean increas in eleeoxib Cau Of 60% and in AUC of 130%, Concomitant use of induces of CYP2CD such a5 rifampicin, carbamazepine and barbiturates may reduce plasma concentrations of eeleconib Ketoconazole and antacid ‘Ketoconazole or antacids have aot heen observe to affect the pharmacokinetics of clecoxib Paediatric population Interaction stdies have only bee performed in adults, Fertility, pregnaney and lactation Pregnancy Studies in animals (rats and rabbits) have shown reproductive toxicity, including ‘malformations (see scctions 43 and 5.3). Inhibition of prostglandin synthesis might adversely atfet pregnancy. Data from epidemiological studies sugges an increased rise of spoataneous abortion after use of prostaglandin synthesis inhibitors in early pregnancy. The potential for human risk in pregnancy is unknown, but cannot be excluded, Celecoxib a with ‘ther medicinal products inhibiting prosiglandin synthesis, may eause uterine inert and ‘premature closure ofthe ductus arteriosus duriag the lst wimester During the second or thicd trimester of pregnancy, NSAIDs including celecoxib may cause fetal renal dysfunction which may result in reduction of amniotic fluid volume or oligotiydramaios in severe cass, Such effects may occur shortly after treatment initiation and are usually reversible upon dseoatinuation Page of 16 a7 48 Celecoxib is containdicated in pregnancy and in women who can become pregnant (see sections 4.3 and 4.4). Ifa woman becomes pregaant during trestment, celecoxib should be sliscontinned Broost-fesding (Celeconi is excreted inthe milk of lactating rts at concentration similar to those in plasma. “Administration of celecoxib to a limited number of lactating women has shown a very low ‘taasier of celecoxib into breast mill: Wonen who take Celebeex should not breasfeed Ferlite Based on the mechanism of ation, the use of NSAIDs, including celecoxib, may delay of ‘prevent rupture of ovarian follicles, which has been associated with reversible inert in [Effects on ability to driveand use machines (Celebrex may have minor influence onthe ability to drive and use machines. Patients Who ‘experience dizines, vertigo or somoleace wile taking Celebrex should gefrin from driving ‘or operating machinery Undesirable eects Adverse rections ae listed by sytem organ clas and canked by frequency ‘electing data tom the following sources: ‘+ Adverse reactions reported in osteoarthritis patents and rheumatoid atts patients at incidence rates greater than 0.01% and greater than those reported fr placebo during 12 placebo- aad or ative-coatrolled clinical trials of duration up {fo 12 weeks at celesosib daily doses From 100 mg up 0 800 mg. In additional studies using non-selective NSAID comparators approximately 7 400 artri patlats have boon treed with celecoab a daily doves vp to S00 mg, inclncing approximately 2300 patents treated for | year or longer, The adverse reactions ‘observed with celacorb in these additonal smudiae were consent with those Tor oxeoartritis and sheumaroid ates patients listed in Table 1 ‘+ Adverse reactions reported at incidence rates greater than placebo for subjects Uweated with eelecoxib 400 mg daily in long-term polyp. prevention tals of uration up t0 3 years (the Adenoma Prevention with Celecoxib (APC) and Prevention of Colorectal Sporadic Adenomatous Polyps (PreSAP) wials, see section $.1, Cardiovascular safety — long-term studies involving patients ‘with sporadic adenomatous polyps) + Adverse drug eetctions from pos-marketing surveillance as spontaneously reported during period ia which an estimated >70 million paiens were treated ‘ith celecoxib (various doses, durations, and indications). Eventhough these ‘were identified as reactions from pest-marketing reports, teil data was consulted to estimate frequency. Frequencies are based on a cumulative meta- fnalysis with pooling of tile represnting exponire in 38102 patients. ia Table 1, Pose of 16 ‘Table 1. Adverse drug reactions in celecont clinical tials and surveillance ‘experience (MedDRA preferred terms)? acm onan | var] Common] Uncommon] Rae Vere Nevin chs commen Je inoow | cui.conws | incon. | crieaon | ‘eanaerie iio)” | 00) Sin), Poa ines woe Pinna Bid aa Taam Tatopena | aro ce Some ‘horas cry ORE sopiyhe Te aa pee Praanie Teoma | an Coal Iieatache* | paraesthesia, (Gasvding fod crip acing Sang hordes 7 intwesoa!| pabinions ee (eching fing Page of 18 ‘vere Drag Reston Freq) cass common Jc vino | einconte= | ersoonom | cannon | eymonte cers [Sag | Fass 1000) ssi ay GaatreaT Ramer Cong | Gao Sirs. | Simin ee fencer, | seeritant,| Sern Sateen, | cviot wie patents ‘ican Teas Tapa hacian | Hapa” — Tas Sooner ‘norm (oman oor ‘ie Feat ome Sensi S0or nih locos. ison Mpeacnecose Solr Sind Tam Tarn] anasto | De Err) Svenohavon Scab” ‘vere Drag Reston Freq) fonmon Fe viv0m | evicone | crsnos0e | c130.000) eto [Erna | Too) Siitobo) steey sactesed, bod | sete npo> | nepsiteaepbiote ‘ores treningened | tatseaut | Syndrome” Biren Repro Senay Teeny = Shaner Pele tertiisy serene’)? Tatieaar | Fa oclen Heeithess, | sherpa Sieceane eigen ajar ay Dotsoning end (Gece Procedural ‘ss compte SGOT sem gnuans oalnarciswanraaaare $OPE osm tam celco 40 gd nai] wal of dnetonup to yen (be APC snd eS AP tl). The ‘vere degree Inte above fore polyp preveton wn oe eal thovedatseeee Irons mgidinpostnnten els nnn obec re ny Farmer te following prvonhunbrow advection seruedin ply prevention ih seprvetng objects weve waheeeonb 400 gaily sinc sivefSuronep 3 yee (he ARC nod esAP nl): Comms saga etry, nine bowel yom ep lithins, bod resinie rnd Denia, frovatelyperpanaeiitineencd. Uavommenbelesbace fection beper sot ysl ‘ronshnpueumoaie iba, siliafeston, Epos viveus Moses conical > Women intense become prgmatrexcied femal inh te contin of thet Satan forthe Reuensy oft event ns notvesronle In final data (adjudeated from the APC sud PreSAP alsin patents ieated with celecoxib 400 m, 1 daily for up to 3 years (pooled data from both wrals; se section S.1 for results from individual trials), the excess rate over placebo for myocardial infarction was 7.6 events per 1.000) oveepl patients (uncommon) and there was no exces ate fr stroke (types no differentiated) aebo, sing of a Werserenctions Pose of 8 49 sa Reporting. suspected adverse reactions after authorisation of the medicinal product is impoctant. [allows continied monitoring ofthe benafit nae halanceof the medicinal pros. Healthcare professionals are asked to report any sispected adverse reactions via HPRA Pharmacovigilance, Website: www hpra Overdose ‘There i no clinical experience of overdose, Single-doses upto 1200 mg and multiple doses up to 1200 mg twice daly have been administered to healthy subjects for nine days without clinically significa adverse effects. Ta the event of suspected overdose, appropriate supportive medical care should be provided e-. by eliminating te gastric contents, clinical Supervision and, if necessary, the istittion of eymiptomati trestment Dialysis isualikely t0 ‘be an efficient method of medicial product removal due to high proteim binding. PHARMACOLOGICAL PROPERTIES Pharmacodynamic properties Pharmacotherapeuiic group: Nonsteroidal. aati-iaflammatory and anticheumatic deugs, NSAIDs, Coxibs, ATC code: MOLAHOL Mechanism of ation Celecoxib is an orl, selective, COX-2 inhibitor within the clinical dose range (200-400 mg dally). No statistically significant inhibition of COX-1 (assessed as ex vio inhibition of ‘thromboxane B: [TXB] formation) was observed inthis dse rauge in healthy volunteers Pharmacodvnamic effects ‘Cyeloosygenase is responsible for generation of prostagladins. Two isoforms, COX-1 and ‘COX-2, have been identified. COX-2 iste isoform of the enzyme that has been showa to be induced by pro-inflammatory stim snd has been postulated fo be primarily responsible for the synthesis of prostanoid mediators of psin, inflammation, and fever. COX-2 is also involved in ovulation, implantation and closure of the ductus arteriosus, repulsion of renal function, and central nervous system functions (fever induction, palu perception and cognitive function), It may also play arolin ulcer healing. COX? has boon identified in tise around {gastric ulcers in humais but tsrelevance to uler healing has not beet establised, “The difference in antiplatelet activity between some COX-1 inhibiting NSAIDs and CO? sectve inhibitors may be of clinical significance in patients at risk of thrombo-embolic reactions, CON-2 selective inhibitors reduce the formation of systemic (and therefore possibly endothelial) prostacyclin without affecting platelet thromboxane, Celecoxib is a diaryL-spsituteé pyrazole, chemically similar to other noa-arylmine sulfonamides (e.g. thiazids, furosemide) but differs from arylamine sulfonamides (eg sulfamethoxizole and otber sulfonamide atibioues). ‘A dose-dependent effect on TxB: formation as been observed after high doses of celecoxib. “Hovwever, in healthy subjects, in small multiple dose staies with 600 mg BID (thre times the highest recommended dose) celecoxib sd no effect on platelet agerepation and bleeding time compared 19 placebo (Clinical efficacy and safer Several clinical studies have boon performed confirming officacy and safety in osteoarthritis, ‘sheumatoid arthritis and ankylosing spondylitis. Celecoxib was evaluated forthe treatment of Pope of 8 ‘the inflammation and pain of osteoarthritis of the knee and hip i approximately 4200 patients in placebo and acive-contolla trils of wp to 12 week duration. Tt ws also evaltatad for {westmient of the inflammation and pin of rheumatoid artis in approsimately 2100 patints in placebo and active-controlled trials of upto 24 weeks duration. Celecoxib at éily doses of 1200 mg ~ 400 mg provided pain reli within 24 hours of dosing. Celooxi was evaluated for the symptomatic treatment of ankylosing spondylitis in $96 patients in placebo and active- 2 {BL}, confirmed by cepeat testing, was signicaatly Tower in patents on celecoxib compared to the NSAID group, relative risk 0.29, 95% CT0.17- 0.48 The significantly lower incidence ‘ofthis even with celecoxib was maintained with or without acetylsalieylic acid use Ina prospective randomised 24 week safety stay inpatients who were aged 260 years or had a history of gastroduodenal uleers [users of acetylsalicylic acid (ASA) escluded], the percentages of patients with decreases in hemoglobin (22 gL) and/or haematocrit (210%) ‘of defined or presumed GI origin were lower in patients weated with celecoxib 200 mg twice ‘daily (N=2238) compared to patients ated With diclofenac SR 75 mg twice daily plus ‘omeprazole 20 mg once daily (N=2246) (0.2% vs. 1186 for defined GI origin, p= 0.004; 0. Ws. 2.4% for presumed GI origin, p = 0.0001). The rates of clincaly manifest GL complications sich as perforation, obstruction of haemorrhage Were very low With no lfferences benween the rentment groups (4-5 per group) Cardiovascalar safety — long-term studios involving subject with

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