Componentes:
Método de ação:
Opção de tratamento:
Medicamente revisado por Militian Inessa Mesropovna, Farmácia Última atualização em 17.03.2022
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Os comprimidos de Valdex são indicados:
- Para alívio dos sinais e sintomas de osteoartrite e artrite reumatóide adulta.
- Para o tratamento da dismenorreia primária.
Osteoartrite e artrite reumatóide adulta
A dose recomendada de comprimidos de Valdex para o alívio dos sinais e sintomas da artrite é de 10 mg uma vez ao dia.
Dismenorreia primária
A dose recomendada de comprimidos de Valdex para o tratamento da dismenorreia primária é de 20 mg duas vezes ao dia, conforme necessário.
Valdex não deve ser administrado a pacientes que demonstraram reações alérgicas às sulfonamidas.
Os comprimidos de Valdex estão contra-indicados em pacientes com hipersensibilidade conhecida ao valdecoxibe. Valdex não deve ser administrado a pacientes que apresentaram asma, urticária ou reações alérgicas após tomar aspirina ou AINEs. Reações graves, raramente fatais, do tipo anafilático a AINEs são possíveis nesses pacientes (ver AVISO - Reações anafilactóides, e PRECAUÇÕES - Asma preexistente).
Valdex está contra-indicado para o tratamento da dor pós-operatória imediatamente após a cirurgia do revascularização do miocárdio (CABG) e não deve ser usado nesta configuração. (Vejo Estudos clínicos - Estudos de segurança).
WARNINGS
Gastrointestinal (GI) Effects — Risk Of GI Ulceration, Bleeding, And Perforation
Serious gastrointestinal toxicity such as bleeding, ulceration and perforation of the stomach, small intestine or large intestine can occur at any time with or without warning symptoms in patients treated with nonsteroidal anti-inflammatory drugs (NSAIDs). Minor gastrointestinal problems such as dyspepsia are common and may also occur at any time during NSAID therapy. Therefore, physicians and patients should remain alert for ulceration and bleeding even in the absence of previous GI tract symptoms. Patients should be informed about the signs and symptoms of serious GI toxicity and the steps to take if they occur. The utility of periodic laboratory monitoring has not been demonstrated, nor has it been adequately assessed. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. It has been demonstrated that upper GI ulcers, gross bleeding or perforation caused by NSAIDs appear to occur in approximately 1% of patients treated for 3 to 6 months and 2–4% of patients treated for one year. These trends continue, thus increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk.
NSAIDs should be prescribed with extreme caution in patients with a prior history of ulcer disease or gastrointestinal bleeding. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore special care should be taken in treating this population. For high risk patients, alternate therapies that do not involve NSAIDs should be considered.
Studies have shown that patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding and who use NSAIDs, have a greater than 10-fold higher risk for developing a GI bleed than patients with neither of these risk factors. In addition to a past history of ulcer disease, pharmacoepidemiological studies have identified several other co-therapies or co-morbid conditions that may increase the risk for GI bleeding such as: treatment with oral corticosteroids, treatment with anticoagulants, longer duration of NSAID therapy, smoking, alcoholism, older age, and poor general health status. (See Clinical Studies — Safety Studies.)
Serious Skin Reactions
Valdecoxib contains a sulfonamide moiety and patients with a known history of a sulfonamide allergy may be at a greater risk of skin reactions. Patients without a history of sulfonamide allergy may also be at risk for serious skin reactions.
Serious skin reactions, including erythema multiforme, Stevens -Johnson syndrome, and toxic epidermal necrolysis, have been reported through postmarketing surveillance in patients receiving Valdex (see ADVERSE REACTIONS — Postmarketing Experience). Fatalities due to Stevens -Johnson syndrome and toxic epidermal necrolys is have been reported. Patients appear to be at higher risk for these events early in the course of therapy, with the onset of the event occurring in the majority of cases within the first two weeks of treatment. Valdex should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity. Serious skin reactions have been reported with other COX-2 inhibitors during postmarketing experience. The reported rate of these events appears to be greater for Valdex as compared to other COX-2 agents (see BOXED WARNING — Serious Skin Reactions).
Anaphylactoid Reactions
In postmarketing experience, cases of hypersensitivity reactions (anaphylactic reactions and angioedema) have been reported in patients receiving Valdex (see ADVERSE REACTIONS — Postmarketing Experience). These cases have occurred in patients with and without a history of allergic-type reactions to sulfonamides (see CONTRAINDICATIONS). Valdex should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS — Preexisting Asthma).
Emergency help should be sought in cases where an anaphylactoid reaction occurs.
Coronary Artery Bypass Graft Surgery
Patients treated with Valdex for pain following coronary artery bypass graft surgery have a higher risk for cardiovascular/thromboembolic events, deep s urgical infections or s ternal wound complications. Valdex is therefore contraindicated for the treatment of postoperative pain following CABG surgery. (See CONTRAINDICATIONS and Clinical Studies-Safety Studies).
Advanced Renal Disease
No information is available regarding the safe use of Valdex Tablets in patients with advanced kidney disease. Therefore, treatment with Valdex is not recommended in these patients. If therapy with Valdex must be initiated, close monitoring of the patient's kidney function is advisable (PRECAUTIONS — Renal Effects).
Pregnancy
In late pregnancy, Valdex should be avoided because it may cause premature closure of the ductus arteriosus.
PRECAUTIONS
General
Valdex Tablets cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to exacerbation of corticosteroidresponsive illness. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.
The pharmacological activity of valdecoxib in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.
Hepatic Effects
Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. These laboratory abnormalities may progress, may remain unchanged, or may remain transient with continuing therapy. Rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure (some with fatal outcome) have been reported with NSAIDs. In controlled clinical trials of valdecoxib, the incidence of borderline (defined as 1.2- to 3.0-fold) elevations of liver tests was 8.0% for valdecoxib and 8.4% for placebo, while approximately 0.3% of patients taking valdecoxib, and 0.2% of patients taking placebo, had notable (defined as greater than 3-fold) elevations of ALT or AST.
A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be monitored carefully for evidence of the development of a more severe hepatic reaction while on therapy with Valdex. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash), Valdex should be discontinued.
Renal Effects
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and Angiotensin Converting Enzyme (ACE) inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
Caution should be used when initiating treatment with Valdex in patients with considerable dehydration. It is advisable to rehydrate patients first and then start therapy with Valdex. Caution is also recommended in patients with preexisting kidney disease. (See WARNINGS — Advanced Renal Disease.)
Hematological Effects
Anemia is sometimes seen in patients receiving Valdex. Patients on long-term treatment with Valdex should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.
Valdex does not generally affect platelet counts, prothrombin time (PT), or activated partial thromboplastin time (APTT), and does not appear to inhibit platelet aggregation at indicated dosages (see Clinical Studies — Safety Studies — Platelets).
Fluid Retention And Edema
Fluid retention and edema have been observed in some patients taking Valdex (see ADVERSE REACTIONS). Therefore, Valdex should be used with caution in patients with fluid retention, hypertension, or heart failure.
Preexisting Asthma
Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirinsensitive asthma has been associated with severe bronchospasm, which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, Valdex should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.
Laboratory Tests
Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs and symptoms of GI bleeding.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Valdecoxib was not carcinogenic in rats given oral doses up to 7.5 mg/kg/day for males and 1.5 mg/kg/day for females (equivalent to approximately 2- to 6-fold human exposure at 20 mg QD as measured by the AUC(0–24hr)) or in mice given oral doses up to 25 mg/kg/day for males and 50 mg/kg/day for females (equivalent to approximately 0.6- to 2.4-fold human exposure at 20 mg QD as measured by the AUC(0–24hr)) for two years.
Valdecoxib was not mutagenic in an Ames test or a mutation assay in Chinese hamster ovary (CHO) cells, nor was it clastogenic in a chromosome aberration assay in CHO cells or in an in vivo micronucleus test in rat bone marrow.
Valdecoxib did not impair male rat fertility at oral doses up to 9.0 mg/kg/day (equivalent to approximately 3- to 6-fold human exposure at 20 mg QD as measured by the AUC(0–24hr)). In female rats, a decrease in ovulation with increased pre- and post-implantation loss resulted in decreased live embryos/fetuses at doses ≥2 mg/kg/day (equivalent to approximately 2-fold human exposure at 20 mg QD as measured by the AUC(0–24hr) for valdecoxib). The effects on female fertility were reversible. This effect is expected with inhibition of prostaglandin synthesis and is not the result of irreversible alteration of female reproductive function.
Pregnancy
Teratogenic Effects
Pregnancy Category C
The incidence of fetuses with skeletal anomalies such as semi-bipartite thoracic vertebra centra and fused sternebrae was slightly higher in rabbits at an oral dose of 40 mg/kg/day (equivalent to approximately 72-fold human exposures at 20 mg QD as measured by the AUC(0–24hr)) throughout organogenesis. Valdecoxib was not teratogenic in rabbits up to an oral dose of 10 mg/kg/day (equivalent to approximately 8-fold human exposures at 20 mg QD as measured by the AUC(0–24hr)).
Valdecoxib was not teratogenic in rats up to an oral dose of 10 mg/kg/day (equivalent to approximately 19-fold human exposure at 20 mg QD as measured by the AUC(0–24hr)). There are no studies in pregnant women. However, valdecoxib crosses the placenta in rats and rabbits. Valdex should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Non-Teratogenic Effects
Valdecoxib caused increased pre- and post-implantation loss with reduced live fetuses at oral doses ≥10 mg/kg/day (equivalent to approximately 19-fold human exposure at 20 mg QD as measured by the AUC(0–24hr)) in rats and an oral dose of 40 mg/kg/day (equivalent to approximately 72-fold human exposure at 20 mg QD as measured by the AUC(0–24hr)) in rabbits throughout organogenesis. In addition, reduced neonatal survival and decreased neonatal body weight when rats were treated with valdecoxib at oral doses ≥6 mg/kg/day (equivalent to approximately 7-fold human exposure at 20 mg QD as measured by the AUC(0–24hr)) throughout organogenesis and lactation period. No studies have been conducted to evaluate the effect of valdecoxib on the closure of the ductus arteriosus in humans. Therefore, as with other drugs known to inhibit prostaglandin synthesis, use of Valdex during the third trimester of pregnancy should be avoided.
Labor And Delivery
Valdecoxib produced no evidence of delayed labor or parturition at oral doses up to 10 mg/kg/day in rats (equivalent to approximately 19-fold human exposure at 20 mg QD as measured by the AUC(0–24hr)). The effects of Valdex on labor and delivery in pregnant women are unknown.
Nursing Mothers
Valdecoxib and its active metabolite are excreted in the milk of lactating rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for adverse reactions in nursing infants from Valdex, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother and the importance of nursing to the infant.
Pediatric Use
Safety and effectiveness of Valdex in pediatric patients below the age of 18 years have not been evaluated.
Geriatric Use
Of the patients who received Valdex in arthritis clinical trials of three months duration, or greater, approximately 2100 were 65 years of age or older, including 570 patients who were 75 years or older. No overall differences in effectiveness were observed between these patients and younger patients.
Dos pacientes tratados com Valdex Tablets em ensaios controlados de artrite, 2665 eram pacientes com OA e 2684 eram pacientes com AR. Mais de 4000 pacientes receberam uma dose diária total crônica de Valdex 10 mg ou mais. Mais de 2800 pacientes receberam Valdex 10 mg / dia, ou mais, por pelo menos 6 meses e 988 deles receberam Valdex por pelo menos 1 ano.
Osteoartrite e artrite reumatóide
A Tabela 4 lista todos os eventos adversos, independentemente da causalidade, que ocorreram em ≥2,0% dos pacientes que receberam Valdex 10 e 20 mg / dia em estudos de três meses ou mais a partir de 7 estudos controlados realizados em pacientes com OA ou AR que incluíram um placebo e / ou um grupo controle positivo.
Tabela 4 Eventos adversos com incidência ≥2,0% nos grupos de tratamento com Valdecoxib: ensaios de artrite controlada de três meses ou mais
(Dose diária total) | ||||||
Valdecoxib | Diclofenaco | Ibuprofeno | Naproxeno | |||
Evento adverso Número tratado | Placebo 973 | 10 mg 1214 | 20 mg 1358 | 150 mg 711 | 2400 mg 207 | 1000 mg 766 |
Distúrbios autonômicos do sistema nervoso | ||||||
Hipertensão | 0.6 | 1.6 | 2.1 | 2.5 | 2.4 | 1.7 |
Corpo como um todo | ||||||
Dor nas costas | 1.6 | 1.6 | 2.7 | 2.8 | 1.4 | 1.0 |
Edema periférico | 0,7 | 2.4 | 3.0 | 3.2 | 2.9 | 2.1 |
Como a gripe sintomas | 2.2 | 2.0 | 2.2 | 3.1 | 2.9 | 2.0 |
Lesão acidental | 2.8 | 4.0 | 3.7 | 3.9 | 3.9 | 3.0 |
Distúrbios do sistema nervoso central e periférico | ||||||
Tontura | 2.1 | 2.6 | 2.7 | 4.2 | 3.4 | 2.7 |
Dor de cabeça | 7.1 | 4.8 | 8.5 | 6.6 | 4.3 | 5.5 |
Distúrbios do sistema gastrointestinal | ||||||
Plenitude abdominal | 2.0 | 2.1 | 1.9 | 3.0 | 2.9 | 2.5 |
Dor abdominal | 6.3 | 7.0 | 8.2 | 17,0 | 8.2 | 10.1 |
Diarréia | 4.2 | 5.4 | 6.0 | 10,8 | 3.9 | 4.7 |
Dispepsia | 6.3 | 7.9 | 8.7 | 13.4 | 15,0 | 12,9 |
Flatulência | 4.1 | 2.9 | 3.5 | 3.1 | 7.7 | 5.4 |
Náusea | 5.9 | 7.0 | 6.3 | 8.4 | 7.7 | 8.7 |
Distúrbios do sistema músculo-esquelético | ||||||
Mialgia | 1.6 | 2.0 | 1.9 | 2.4 | 2.4 | 1.4 |
Distúrbios do sistema respiratório | ||||||
Sinusite | 2.2 | 2.6 | 1.8 | 1.1 | 3.4 | 3.4 |
Infecção do trato respiratório superior | 6.0 | 6.7 | 5.7 | 6.3 | 4.3 | 6.4 |
Distúrbios da pele e dos apêndices | ||||||
Erupção cutânea | 1.0 | 1.4 | 2.1 | 1.5 | 0,5 | 1.4 |
Nestes ensaios clínicos controlados por placebo e ativo, a taxa de descontinuação devido a eventos adversos foi de 7,5% para pacientes com artrite que receberam valdecoxibe 10 mg por dia, 7,9% para pacientes com artrite que receberam valdecoxibe 20 mg por dia e 6,0% para pacientes que receberam placebo.
Nos sete estudos controlados de OA e AR, os seguintes eventos adversos ocorreram em 0,1 a 1,9% dos pacientes tratados com Valdex 10 a 20 mg por dia, independentemente da causalidade.
Distúrbios do local da aplicação: Celulite, contato com dermatite
Cardiovascular: Hipertensão agravada, aneurisma, angina de peito, arritmia, cardiomiopatia, insuficiência cardíaca congestiva, distúrbio da artéria coronária, sopro cardíaco, hipotensão
Sistema nervoso central e periférico: Distúrbio cerebrovascular, hipertonia, hipoestesia, enxaqueca, neuralgia, neuropatia, parestesia, tremor, espasmos, vertigem
Endócrino: Goiter
Reprodutivo feminino: Amenorréia, dismenorreia, leucorréia, mastite, distúrbio menstrual, menorragia, inchaço menstrual, hemorragia vaginal
Gastrointestinal: Fezes anormais, constipação, diverticulose, boca seca, úlcera duodenal, duodenite, eructação, esofagite, incontinência fecal, úlcera gástrica, gastrite, gastroenterite, refluxo gastroesofágico, hematemese, hematochezia, hemorróidas, hemorróidas sangrando, hiatal e melena,
Geral: Alergia agravada, reação alérgica, astenia, dor no peito, calafrios, SOE do cisto, edema generalizado, edema facial, fadiga, febre, afrontamentos, halitose, mal-estar, dor, inchaço periorbital, dor periférica
Audição e vestibular: Anormalidade no ouvido, dor de ouvido, zumbido
Frequência cardíaca e ritmo: Bradicardia, palpitações, taquicardia
Hêmico: Anemia
Fígado e sistema biliar: Função hepática anormal, hepatite, ALT aumentada, AST aumentada
Reprodutivo masculino: Impotência, distúrbio prostático
Metabólico e nutricional: A fosfatase alcalina aumentou, o BUN aumentou, o CPK aumentou, a creatinina aumentou, diabetes mellitus, glicosúria, gota, hipercolesterolemia, hiperglicemia, hipercalemia, hipercalcemia, hipocalcemia, LDH aumentou, sede aumentada, diminuição de peso, aumento de peso, xeroftalmia
Musculoesquelético: Artralgia, fratura acidental, rigidez do pescoço, osteoporose, sinovite, tendinite
Neoplasia: Neoplasia mamária, lipoma, cisto ovariano maligno
Plaquetas (sangramento ou coagulação): Equimose, epistaxe, hematoma NOS, trombocitopenia
Psiquiátrico: Anorexia, ansiedade, apetite aumentado, confusão, depressão, depressão agravada, insônia, nervosismo, sonho mórbido, sonolência
Distúrbios do mecanismo de resistência: Herpes simplex, herpes zoster, infecção fúngica, infecção de tecidos moles, infecção viral, monilíase, monilíase genital, otite média
Respiratório: Sons anormais da respiração, bronquite, broncoespasmo, tosse, dispnéia, enfisema, laringite, pneumonia, faringite, pleurisia, rinite
Pele e anexos: Acne, alopecia, dermatite, dermatite fúngica, eczema, reação alérgica à fotosensibilidade, prurido, erupção cutânea eritematosa, erupção cutânea maculopapular, erupção cutânea psoriaform, pele seca, hipertrofia da pele, ulceração da pele, sudorese aumentada, urticária
Sentidos especiais: Proversão de sabor
Sistema urinário: Albuminúria, cistite, disúria, hematúria, frequência de micção aumentada, piuria, incontinência urinária, infecção do trato urinário
Vascular: Claudicação intermitente, hemangioma adquirido, varizes
Visão: Visão turva, catarata, hemorragia conjuntival, conjuntivite, dor ocular, ceratite, visão anormal
Distúrbios das células brancas e das FER: Eosinofilia, leucopenia, leucocitose, linfadenopatia, linfangite, linfopenia
Outros eventos adversos graves que foram relatados raramente (estimados <0,1%) em ensaios clínicos, independentemente da causalidade, em pacientes que tomaram Valdex :
Distúrbios autonômicos do sistema nervoso: Encefalopatia hipertensiva, vasoespasmo
Cardiovascular: ECG anormal, estenose aórtica, fibrilação atrial, estenose carotídea, trombose coronariana, bloqueio cardíaco, distúrbios das válvulas cardíacas, insuficiência mitral, infarto do miocárdio, isquemia miocárdica, pericardite, síncope, tromboflebite, angina instável, fibrilação ventricular
Sistema nervoso central e periférico: Convulsões
Endócrino: Hiperparatireoidismo
Reprodutivo feminino: Displasia cervical
Gastrointestinal: Apendicite, colite com sangramento, disfagia, perfuração esofágica, sangramento gastrointestinal, íleo, obstrução intestinal, peritonite
Hêmico: Distúrbio semelhante ao linfoma, pancitopenia
Fígado e sistema biliar: Colelitíase
Metabólico: Desidratação
Musculoesquelético: Fratura patológica, osteomielite
Neoplasia: Neoplasia cerebral benigna, carcinoma da bexiga, carcinoma, carcinoma gástrico, carcinoma da próstata, carcinoma pulmonar
Plaquetas (sangramento ou coagulação): Embolia, embolia pulmonar, trombose
Psiquiátrico: Reação maníaca, psicose
Renal: Insuficiência renal aguda
Distúrbios do mecanismo de resistência: Sepse
Respiratório: Apnéia, derrame pleural, edema pulmonar, fibrose pulmonar, infarto pulmonar, hemorragia pulmonar, insuficiência respiratória
Pele: Carcinoma basocelular, melanoma maligno
Sistema urinário: Pielonefrite, cálculo renal
Visão: Destacamento da retina
Experiência pós-comercialização
As seguintes reações foram identificadas durante o uso pós-comercialização do Valdex. Essas reações foram escolhidas para inclusão devido à sua gravidade, frequência de notificação, possível relação causal com Valdex ou uma combinação desses fatores. Como essas reações foram relatadas voluntariamente de uma população de tamanho incerto, não é possível estimar com segurança sua frequência ou estabelecer uma relação causal com a exposição a medicamentos.
Geral: Reações de hipersensibilidade (incluindo reações anafiláticas e angioedema)
Gastrointestinal: Pancreatite
Pele e anexos: Eritema multiforme, dermatite esfoliativa, síndrome de Stevens-Johnson, necrólise epidérmica tóxica
Os sintomas após overdoses agudas de AINEs geralmente são limitados à letargia, sonolência, náusea, vômito e dor epigástrica, que geralmente são reversíveis com o cuidado de suporte. Pode ocorrer sangramento gastrointestinal. Hipertensão, insuficiência renal aguda, depressão respiratória e coma podem ocorrer, mas são raras.
Foram relatadas reações anafilactóides com ingestão terapêutica de AINEs e podem ocorrer após uma overdose.
Os pacientes devem ser tratados com cuidados sintomáticos e de suporte após uma overdose de AINE. Não há antídotos específicos. A hemodiálise removeu apenas cerca de 2% do valdecoxibe administrado da circulação sistêmica de 8 pacientes com doença renal em estágio terminal e, com base no seu grau de ligação às proteínas plasmáticas (> 98%), é improvável que a diálise seja útil em overdose. Diurese forçada, alcalinização da urina ou hemoperfusão também podem não ser úteis devido à alta ligação às proteínas.
Absorption
Valdecoxib achieves maximal plasma concentrations in approximately 3 hours. The absolute bioavailability of valdecoxib is 83% following oral administration of Valdex compared to intravenous infusion of valdecoxib.
Dose proportionality was demonstrated after single doses (1–400 mg) of valdecoxib. With multiple doses (up to 100 mg/day for 14 days), valdecoxib exposure as measured by the AUC, increases in a more than proportional manner at doses above 10 mg BID. Steady state plasma concentrations of valdecoxib are achieved by day 4.
The steady state pharmacokinetic parameters of valdecoxib in healthy male subjects are shown in Table 1.
Table 1 Mean (SD) Steady State Pharmacokinetic Parameters
Steady State Pharmacokinetic Parameters after Valdecoxib 10 mg Once Daily for 14 Days | Healthy Male Subjects (n=8, 20 to 42 yr.) |
AUC(0–24hr) (hr·ng/mL) | 1479.0 (291.9) |
Cmax (ng/mL) | 161.1 (48.1) |
Tmax (hr) | 2.25 (0.71) |
Cmin (ng/mL) | 21.9 (7.68) |
Elimination Half-life (hr) | 8.11 (1.32) |
No clinically significant age or gender differences were seen in pharmacokinetic parameters that would require dosage adjustments.
Effect Of Food And Antacid
Valdex can be taken with or without food. Food had no significant effect on either the peak plasma concentration (Cmax ) or extent of absorption (AUC) of valdecoxib when Valdex was taken with a high fat meal. The time to peak plasma concentration (Tmax, however, was delayed by 1–2 hours. Administration of Valdex with antacid (aluminum/magnesium hydroxide) had no significant effect on either the rate or extent of absorption of valdecoxib.
Distribution
Plasma protein binding for valdecoxib is about 98% over the concentration range (21–2384 ng/mL). Steady state apparent volume of distribution (Vss/F) of valdecoxib is approximately 86 L after oral administration. Valdecoxib and its active metabolite preferentially partition into erythrocytes with a blood to plasma concentration ratio of about 2.5:1. This ratio remains approximately constant with time and therapeutic blood concentrations.
Metabolism
In humans, valdecoxib undergoes extensive hepatic metabolism involving both P450 isoenzymes (3A4 and 2C9) and non-P450 dependent pathways (i.e., glucuronidation). Concomitant administration of Valdex with known CYP 3A4 and 2C9 inhibitors (e.g., fluconazole and ketoconazole) can result in increased plasma exposure of valdecoxib (see DRUG INTERACTIONS).
One active metabolite of valdecoxib has been identified in human plasma at approximately 10% the concentration of valdecoxib. This metabolite, which is a less potent COX-2 specific inhibitor than the parent, also undergoes extensive metabolism and constitutes less than 2% of the valdecoxib dose excreted in the urine and feces. Due to its low concentration in the systemic circulation, it is not likely to contribute significantly to the efficacy profile of Valdex.
Excretion
Valdecoxib is eliminated predominantly via hepatic metabolism with less than 5% of the dose excreted unchanged in the urine and feces. About 70% of the dose is excreted in the urine as metabolites, and about 20% as valdecoxib N-glucuronide. The apparent oral clearance (CL/F) of valdecoxib is about 6 L/hr. The mean elimination half-life (T1/2) ranges from 8–11 hours, and increases with age.