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Medically reviewed by Kovalenko Svetlana Olegovna, PharmD. Last updated on 12.03.2022
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Valiflex Tablets are indicated:
- For relief of the signs and symptoms of osteoarthritis and adult rheumatoid arthritis.
- For the treatment of primary dysmenorrhea.
Osteoarthritis And Adult Rheumatoid Arthritis
The recommended dose of Valiflex Tablets for the relief of the signs and symptoms of arthritis is 10 mg once daily.
Primary Dysmenorrhea
The recommended dose of Valiflex Tablets for treatment of primary dysmenorrhea is 20 mg twice daily, as needed.
Valiflex should not be given to patients who have demonstrated allergic-type reactions to sulfonamides.
Valiflex Tablets are contraindicated in patients with known hypersensitivity to valdecoxib. Valiflex should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs are possible in such patients (see WARNINGS — Anaphylactoid Reactions, and PRECAUTIONS — Preexisting Asthma).
Valiflex is contraindicated for the treatment of post-operative pain immediately following coronary artery bypass graft (CABG) surgery and should not be used in this setting. (See Clinical Studies — Safety Studies).
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 Valiflex (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. Valiflex 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 Valiflex 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 Valiflex (see ADVERSE REACTIONS — Postmarketing Experience). These cases have occurred in patients with and without a history of allergic-type reactions to sulfonamides (see CONTRAINDICATIONS). Valiflex 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 Valiflex 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. Valiflex 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 Valiflex Tablets in patients with advanced kidney disease. Therefore, treatment with Valiflex is not recommended in these patients. If therapy with Valiflex must be initiated, close monitoring of the patient's kidney function is advisable (PRECAUTIONS — Renal Effects).
Pregnancy
In late pregnancy, Valiflex should be avoided because it may cause premature closure of the ductus arteriosus.
PRECAUTIONS
General
Valiflex 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 Valiflex. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash), Valiflex 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 Valiflex in patients with considerable dehydration. It is advisable to rehydrate patients first and then start therapy with Valiflex. Caution is also recommended in patients with preexisting kidney disease. (See WARNINGS — Advanced Renal Disease.)
Hematological Effects
Anemia is sometimes seen in patients receiving Valiflex. Patients on long-term treatment with Valiflex should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.
Valiflex 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 Valiflex (see ADVERSE REACTIONS). Therefore, Valiflex 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, Valiflex 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. Valiflex 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 Valiflex 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 Valiflex 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 Valiflex, 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 Valiflex in pediatric patients below the age of 18 years have not been evaluated.
Geriatric Use
Of the patients who received Valiflex 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.
Of the patients treated with Valiflex Tablets in controlled arthritis trials, 2665 were patients with OA, and 2684 were patients with RA. More than 4000 patients have received a chronic total daily dose of Valiflex 10 mg or more. More than 2800 patients have received Valiflex 10 mg/day, or more, for at least 6 months and 988 of these have received Valiflex for at least 1 year.
Osteoarthritis And Rheumatoid Arthritis
Table 4 lists all adverse events, regardless of causality, that occurred in ≥2.0% of patients receiving Valiflex 10 and 20 mg/day in studies of three months or longer from 7 controlled studies conducted in patients with OA or RA that included a placebo and/or a positive control group.
Table 4 Adverse Events with Incidence ≥2.0% in Valdecoxib Treatment Groups : Controlled Arthritis Trials of Three Months or Longer
(Total Daily Dose) | ||||||
Valdecoxib | Diclofenac | Ibuprofen | Naproxen | |||
Adverse Event Number Treated | Placebo 973 | 10 mg 1214 | 20 mg 1358 | 150 mg 711 | 2400 mg 207 | 1000 mg 766 |
Autonomic Nervous System Disorders | ||||||
Hypertension | 0.6 | 1.6 | 2.1 | 2.5 | 2.4 | 1.7 |
Body as a Whole | ||||||
Back pain | 1.6 | 1.6 | 2.7 | 2.8 | 1.4 | 1.0 |
Edema peripheral | 0.7 | 2.4 | 3.0 | 3.2 | 2.9 | 2.1 |
Influenza-like symptoms | 2.2 | 2.0 | 2.2 | 3.1 | 2.9 | 2.0 |
Injury accidental | 2.8 | 4.0 | 3.7 | 3.9 | 3.9 | 3.0 |
Central and Peripheral Nervous System Disorders | ||||||
Dizziness | 2.1 | 2.6 | 2.7 | 4.2 | 3.4 | 2.7 |
Headache | 7.1 | 4.8 | 8.5 | 6.6 | 4.3 | 5.5 |
Gastrointestinal System Disorders | ||||||
Abdominal fullness | 2.0 | 2.1 | 1.9 | 3.0 | 2.9 | 2.5 |
Abdominal pain | 6.3 | 7.0 | 8.2 | 17.0 | 8.2 | 10.1 |
Diarrhea | 4.2 | 5.4 | 6.0 | 10.8 | 3.9 | 4.7 |
Dyspepsia | 6.3 | 7.9 | 8.7 | 13.4 | 15.0 | 12.9 |
Flatulence | 4.1 | 2.9 | 3.5 | 3.1 | 7.7 | 5.4 |
Nausea | 5.9 | 7.0 | 6.3 | 8.4 | 7.7 | 8.7 |
Musculoskeletal System Disorders | ||||||
Myalgia | 1.6 | 2.0 | 1.9 | 2.4 | 2.4 | 1.4 |
Respiratory System Disorders | ||||||
Sinusitis | 2.2 | 2.6 | 1.8 | 1.1 | 3.4 | 3.4 |
Upper respiratory tract infection | 6.0 | 6.7 | 5.7 | 6.3 | 4.3 | 6.4 |
Skin and Appendages Disorders | ||||||
Rash | 1.0 | 1.4 | 2.1 | 1.5 | 0.5 | 1.4 |
In these placebo- and active-controlled clinical trials, the discontinuation rate due to adverse events was 7.5% for arthritis patients receiving valdecoxib 10 mg daily, 7.9% for arthritis patients receiving valdecoxib 20 mg daily and 6.0%for patients receiving placebo.
In the seven controlled OA and RA studies, the following adverse events occurred in 0.1–1.9% of patients treated with Valiflex 10–20 mg daily, regardless of causality.
Application site disorders: Cellulitis, dermatitis contact
Cardiovascular: Aggravated hypertension, aneurysm, angina pectoris, arrhythmia, cardiomyopathy, congestive heart failure, coronary artery disorder, heart murmur, hypotension
Central, peripheral nervous system: Cerebrovascular disorder, hypertonia, hypoesthesia, migraine, neuralgia, neuropathy, paresthesia, tremor, twitching, vertigo
Endocrine: Goiter
Female reproductive: Amenorrhea, dysmenorrhea, leukorrhea, mastitis, menstrual disorder, menorrhagia, menstrual bloating, vaginal hemorrhage
Gastrointestinal: Abnormal stools, constipation, diverticulosis, dry mouth, duodenal ulcer, duodenitis, eructation, esophagitis, fecal incontinence, gastric ulcer, gastritis, gastroenteritis, gastroesophageal reflux, hematemesis, hematochezia, hemorrhoids, hemorrhoids bleeding, hiatal hernia, melena, stomatitis, stool frequency increased, tenesmus, tooth disorder, vomiting
General: Allergy aggravated, allergic reaction, asthenia, chest pain, chills, cyst NOS, edema generalized, face edema, fatigue, fever, hot flushes, halitosis, malaise, pain, periorbital swelling, peripheral pain
Hearing and vestibular: Ear abnormality, earache, tinnitus
Heart rate and rhythm: Bradycardia, palpitation, tachycardia
Hemic: Anemia
Liver and biliary system: Hepatic function abnormal, hepatitis, ALT increased, AST increased
Male reproductive: Impotence, prostatic disorder
Metabolic and nutritional: Alkaline phosphatase increased, BUN increased, CPK increased, creatinine increased, diabetes mellitus, glycosuria, gout, hypercholesterolemia, hyperglycemia, hyperkalemia, hyperlipemia, hyperuricemia, hypocalcemia, hypokalemia, LDH increased, thirst increased, weight decrease, weight increase, xerophthalmia
Musculoskeletal: Arthralgia, fracture accidental, neck stiffness, osteoporosis, synovitis, tendonitis
Neoplasm: Breast neoplasm, lipoma, malignant ovarian cyst
Platelets (bleeding or clotting): Ecchymosis, epistaxis, hematoma NOS, thrombocytopenia
Psychiatric: Anorexia, anxiety, appetite increased, confusion, depression, depression aggravated, insomnia, nervousness, morbid dreaming, somnolence
Resistance mechanism disorders: Herpes simplex, herpes zoster, infection fungal, infection soft tissue, infection viral, moniliasis, moniliasis genital, otitis media
Respiratory: Abnormal breath sounds, bronchitis, bronchospasm, coughing, dyspnea, emphysema, laryngitis, pneumonia, pharyngitis, pleurisy, rhinitis
Skin and appendages: Acne, alopecia, dermatitis, dermatitis fungal, eczema, photosensitivity allergic reaction, pruritus, rash erythematous, rash maculopapular, rash psoriaform, skin dry, skin hypertrophy, skin ulceration, sweating increased, urticaria
Special senses: Taste perversion
Urinary system: Albuminuria, cystitis, dysuria, hematuria, micturition frequency increased, pyuria, urinary incontinence, urinary tract infection
Vascular: Claudication intermittent, hemangioma acquired, varicose vein
Vision: Blurred vision, cataract, conjunctival hemorrhage, conjunctivitis, eye pain, keratitis, vision abnormal
White cell and RES disorders: Eosinophilia, leukopenia, leukocytosis, lymphadenopathy, lymphangitis, lymphopenia
Other serious adverse events that were reported rarely (estimated <0.1%) in clinical trials, regardless of causality, in patients taking Valiflex:
Autonomic nervous system disorders: Hypertensive encephalopathy, vasospasm
Cardiovascular: Abnormal ECG, aortic stenosis, atrial fibrillation, carotid stenosis, coronary thrombosis, heart block, heart valve disorders, mitral insufficiency, myocardial infarction, myocardial ischemia, pericarditis, syncope, thrombophlebitis, unstable angina, ventricular fibrillation
Central, peripheral nervous system: Convulsions
Endocrine: Hyperparathyroidism
Female reproductive: Cervical dysplasia
Gastrointestinal: Appendicitis, colitis with bleeding, dysphagia, esophageal perforation, gastrointestinal bleeding, ileus, intestinal obstruction, peritonitis
Hemic: Lymphoma-like disorder, pancytopenia
Liver and biliary system: Cholelithiasis
Metabolic: Dehydration
Musculoskeletal: Pathological fracture, osteomyelitis
Neoplasm: Benign brain neoplasm, bladder carcinoma, carcinoma, gastric carcinoma, prostate carcinoma, pulmonary carcinoma
Platelets (bleeding or clotting): Embolism, pulmonary embolism, thrombosis
Psychiatric: Manic reaction, psychosis
Renal: Acute renal failure
Resistance mechanism disorders: Sepsis
Respiratory: Apnea, pleural effusion, pulmonary edema, pulmonary fibrosis, pulmonary infarction, pulmonary hemorrhage, respiratory insufficiency
Skin: Basal cell carcinoma, malignant melanoma
Urinary system: Pyelonephritis, renal calculus
Vision: Retinal detachment
Postmarketing Experience
The following reactions have been identified during postmarketing use of Valiflex. These reactions have been chosen for inclusion either due to their seriousness, reporting frequency, possible causal relationship to Valiflex, or a combination of these factors. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
General: Hypersensitivity reactions (including anaphylactic reactions and angioedema)
Gastrointestinal: Pancreatitis
Skin and appendages: Erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis
Symptoms following acute NSAID overdoses are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression and coma may occur, but are rare.
Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose.
Patients should be managed by symptomatic and supportive care following an NSAID overdose. There are no specific antidotes. Hemodialysis removed only about 2% of administered valdecoxib from the systemic circulation of 8 patients with end-stage renal disease and, based on its degree of plasma protein binding (>98%), dialysis is unlikely to be useful in overdose. Forced diuresis, alkalinization of urine, or hemoperfusion also may not be useful due to high protein binding.
Absorption
Valdecoxib achieves maximal plasma concentrations in approximately 3 hours. The absolute bioavailability of valdecoxib is 83% following oral administration of Valiflex 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
Valiflex 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 Valiflex was taken with a high fat meal. The time to peak plasma concentration (Tmax, however, was delayed by 1–2 hours. Administration of Valiflex 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 Valiflex 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 Valiflex.
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.