Valdecoxib

Valdecoxib is a Cyclooxygenase-2 (COX-2) inhibitor / non-steroidal anti-inflammatory drugs (NSAIDs) belonging to Analgesic class.

Valdecoxib is a COX-2 inhibitor / NSAID used for the treatment of osteoarthritis and dysmenorrhea.

The oral bioavailability of Valdecoxib is 83%. Time taken to reach Peak plasma concentrations is after approximately 2.25-3 hrs (oral). 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 Extensively metabolized via hepatic route ,Mainly excreted via Urine (as metabolites).

Valdecoxib shows side effects like Blurred vision, Chills, Decreased or painful urination, Dizziness, Nausea, Nervousness, Rapid weight gain, unusual tiredness, or weakness, Tingling of hands and feet, Abdominal and stomach pain, Cough, Yellow colored eyes or skin, Stevens-Johnson Syndrome (A rare, serious disorder of the skin and mucous membranes).

Valdecoxib is available in the form of an Oral tablet.

Valdecoxib is an Analgesic a belonging to the class Cyclooxygenase-2 (COX-2) inhibitor / non-steroidal anti-inflammatory drugs (NSAIDs).

Valdecoxib selectively inhibits the cyclooxygenase-2 (COX-2) enzyme, important for the mediation of inflammation and pain.

The Tmax of Valdecoxib is about 2.25-3 hours.

Valdecoxib is available in the form of an Oral tablet.

Valdecoxib tablet is taken orally, usually once or twice a day.

Valdecoxib is used to relieve pain and swelling in conditions such as arthritis and dysmenorrhea. Patients are advised to drink an adequate amount of water during treatment with this medicine to minimize stomach irritation. Valdecoxib is not recommended for use in patients under 18 years of age.

Valdecoxib is a Cyclooxygenase-2 (COX-2) inhibitor belonging to non-steroidal anti-inflammatory drugs (NSAIDs).

Valdecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, is classified as a nonsteroidal anti-inflammatory drug (NSAID). Valdecoxib is used for its anti-inflammatory, analgesic, and antipyretic activities in the management of osteoarthritis (OA) and for the treatment of dysmenorrhea or acute pain.

Valdecoxib is approved for use in the following clinical indications

• For relief of the signs and symptoms of osteoarthritis and adult rheumatoid arthritis. ·
• For the treatment of primary dysmenorrhea.

• Osteoarthritis, Rheumatoid arthritis

Adult dose: 10 mg once daily.

• Dysmenorrhoea

Adult dose: 20 mg twice a day.

Valdecoxib is available in various strengths as 10mg and 20mg.

Valdecoxib is available in the form of an Oral tablet.

• Dosage Adjustment in Kidney Patient

CrCl <30: Initiate with caution.

• Dosage Adjustment in Hepatic impairment Patient

Child-Pugh scale 7-9: Initiate with caution.

Child-Pugh scale >10: Avoid.

Valdecoxib is contraindicated in patients with

• Valdecoxib should not be given to patients who have demonstrated allergic-type reactions to sulfonamides.
• Valdecoxib Tablets are contraindicated in patients with known hypersensitivity to valdecoxib. Valdecoxib 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.
• Valdecoxib 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.

• 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 Valdecoxib. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash), Valdecoxib 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 Valdecoxib in patients with considerable dehydration. It is advisable to rehydrate patients first and then start therapy with Valdecoxib. Caution is also recommended in patients with preexisting kidney disease.

• Hematological Effects

Anemia is sometimes seen in patients receiving Valdecoxib. Patients on long-term treatment with Valdecoxib should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia. Valdecoxib 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.

• Fluid Retention and Edema

Fluid retention and edema have been observed in some patients taking Valdecoxib, Therefore, Valdecoxib 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 aspirin sensitive 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, Valdecoxib should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.

• 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-mortwice a day 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.

• 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 Valdecoxib. Fatalities due to Stevens-Johnson syndrome and toxic epidermal necrolysis 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. Valdecoxib 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 Valdecoxib as compared to other COX-2 agents.

• Anaphylactoid Reactions

In postmarketing experience, cases of hypersensitivity reactions (anaphylactic reactions and angioedema) have been reported in patients receiving Valdecoxib. These cases have occurred in patients with and without a history of allergic type reactions to sulfonamides. Valdecoxib 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.

• Coronary Artery Bypass

Graft Surgery Patients treated with Valdecoxib for pain following coronary artery bypass graft surgery have a higher risk for cardiovascular/thromboembolic events, deep surgical infections or sternal wound complications. Valdecoxib is therefore contraindicated for the treatment of postoperative pain following CABG surgery.

• Advanced Renal Disease

No information is available regarding the safe use of Valdecoxib Tablets in patients with advanced kidney disease. Therefore, treatment with Valdecoxib is not recommended in these patients. If therapy with Valdecoxib must be initiated, close monitoring of the patient’s kidney function is advisable. Pregnancy In late pregnancy, Valdecoxib should be avoided because it may cause premature closure of the ductus arteriosus.

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 Valdecoxib, 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.

Teratogenic Effects

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. Valdecoxib should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Common

Hypertension, back pain, myalgia, peripheral oedema, influenza-like symptoms, dizziness, headache, abdominal fullness, abdominal pain, diarrhea, dyspepsia, flatulence, nausea, myalgia, sinusitis, Toxic epidermal necrolysis, exfoliative dermatitis.

• Aspirin

Concomitant administration of aspirin with valdecoxib may result in an increased risk of GI ulceration and complications compared to valdecoxib alone. Because of its lack of anti-platelet effect valdecoxib is not a substitute for aspirin for cardiovascular prophylaxis. In a parallel group drug interaction study comparing the intravenous prodrug form of valdecoxib at 40 mg TWICE A DAY (n=10) vs placebo (n=9), valdecoxib had no effect on in vitro aspirin-mediated inhibition of arachidonate- or collagen-stimulated platelet aggregation.

• Methotrexate

Valdecoxib 10 mg twice a day did not show a significant effect on the plasma exposure or renal clearance of methotrexate.

• ACE-Inhibitors

Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking VALDECOXIB concomitantly with ACE inhibitors.

• Furosemide

Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis.

• Anticonvulsants (Phenytoin)

Steady state plasma exposure (AUC) of valdecoxib (40 mg TWICE A DAY for 12 days) was decreased by 27% when coadministered with multiple doses (300 mg QD for 12 days) of phenytoin (a CYP 3A4 inducer). Patients already stabilized on valdecoxib should be closely monitored for loss of symptom control with phenytoin coadministration. Valdecoxib did not have a statistically significant effect on the pharmacokinetics of phenytoin (a CYP 2C9 and CYP 2C19 substrate). Drug interaction studies with other anticonvulsants have not been conducted. Routine monitoring should be performed when therapy with VALDECOXIB is either initiated or discontinued in patients on anticonvulsant therapy.

• Dextromethorphan

Dextromethorphan is primarily metabolized by CYP 2D6 and to a lesser extent by 3A4. Coadministration with valdecoxib (40 mg TWICE A DAY for 7 days) resulted in a significant increase in dextromethorphan plasma levels suggesting that, at these doses, valdecoxib is a weak inhibitor of 2D6. Even so, dextromethorphan plasma concentrations in the presence of high doses of valdecoxib were almost 5- fold lower than those seen in CYP 2D6 poor metabolizers suggesting that dose adjustment is not necessary.

• Lithium

Valdecoxib 40 mg twice a day for 7 days produced significant decreases in lithium serum clearance (25%) and renal clearance (30%) with a 34% higher serum exposure compared to lithium alone. Lithium serum concentrations should be monitored closely when initiating or changing therapy with valdecoxib in patients receiving lithium. Lithium carbonate (450 mg twice a day for 7 days) had no effect on valdecoxib pharmacokinetics.

• Warfarin

The effect of valdecoxib on the anticoagulant effect of warfarin (1–8 mg/day) was studied in healthy subjects by coadministration of valdecoxib 40 mg twice a day for 7 days. Valdecoxib caused a statistically significant increase in plasma exposures of R-warfarin and S-warfarin (12% and 15%, respectively), and in the pharmacodynamic effects (prothrombin time, measured as INR) of warfarin. While mean INR values were only slightly increased with coadministration of valdecoxib, the day-to-day variability in individual INR values was increased. Anticoagulant therapy should be monitored, particularly during the first few weeks, after initiating therapy with valdecoxib in patients receiving warfarin or similar agents.

• Fluconazole And Ketoconazole

Ketoconazole and fluconazole are predominantly CYP 3A4 and 2C9 inhibitors, respectively. Concomitant single dose administration of valdecoxib 20 mg with multiple doses of ketoconazole and fluconazole produced a significant increase in exposure of valdecoxib. Plasma exposure (AUC) to valdecoxib was increased 62% when coadministered with fluconazole and 38% when coadministered with ketoconazole.

• Glyburide

Glyburide is a CYP 2C9 substrate. Coadministration of valdecoxib (10 mg twice a day for 7 days) with glyburide (5 mg QD or 10 mg twice a day) did not affect the pharmacokinetics (exposure) of glyburide. Coadministration of valdecoxib (40 mg twice a day (day 1) and 40 mg QD (days 2–7)) with glyburide (5 mg QD) did not affect either the pharmacokinetics (exposure) or the pharmacodynamics (blood glucose and insulin levels) of glyburide. Coadministration of valdecoxib (40 mg twice a day (day 1) and 40 mg QD (days 2– 7)) with glyburide (10 mg glyburide twice a day) resulted in 21% increase in glyburide AUC(0–12hr) and a 16% increase in glyburide Cmax leading to a 16%decrease in glucose AUC(0–24hr). Insulin parameters were not affected. Because changes in glucose concentrations with valdecoxib coadministration were within the normal variability and individual glucose concentrations were above or near 70 mg/dL, dose adjustment for glyburide (5 mg QD and 10 mg twice a day) with valdecoxib coadministration (up to 40 mg QD) is not indicated. Coadministration of glyburide with doses higher than 40 mg valdecoxib (e.g., 40 mg twice a day) has not been studied.

• Omeprazole

Omeprazole is a CYP 3A4 substrate and CYP 2C19 substrate and inhibitor. Valdecoxib steady state plasma concentrations (40 mg twice a day) were not affected significantly with multiple doses of omeprazole (40 mg QD). Coadministration with valdecoxib increased exposure of omeprazole (AUC) by 46%. Drugs whose absorption is sensitive to pH may be negatively impacted by concomitant administration of omeprazole and valdecoxib. However, because higher doses (up to 360 mg QD) of omeprazole are tolerated in Zollinger-Ellison (ZE) patients, no dose adjustment for omeprazole is recommended at current doses. Coadministration of valdecoxib with doses higher than 40 mg QD omeprazole has not been studied.

• Oral Contraceptives

Valdecoxib (40 mg twice a day) did not induce the metabolism of the combination oral contraceptive norethindrone/ethinyl estradiol (1 mg/0.035 mg combination, Ortho-Novum 1/35^®). Coadministration of valdecoxib and Ortho-Novum 1/35^® increased the exposure of norethindrone and ethinyl estradiol by 20% and 34%, respectively. Although there is little risk for loss of contraceptive efficacy, the clinical significance of these increased exposures in terms of safety is not known. These increased exposures of norethindrone and ethinyl estradiol should be taken into consideration when selecting an oral contraceptive for women taking valdecoxib.

• Diazepam

Diazepam is a CYP 3A4 and CYP 2C19 substrate. Plasma exposure of diazepam (10 mg twice a day) was increased by 28% following administration of valdecoxib (40 mg twice a day) for 12 days, while plasma exposure of valdecoxib (40 mg twice a day) was not substantially increased following administration of diazepam (10 mg twice a day) for 12 days. Although the magnitude of changes in diazepam plasma exposure when coadministered with valdecoxib were not sufficient to warrant dosage adjustments, patients may experience enhanced sedative side effects caused by increased exposure of diazepam under this circumstance. Patients should be cautioned against engaging in hazardous activities requiring complete mental alertness such as operating machinery or driving a motor vehicle.

The common side effects of Valdecoxib include the following

• Common side effects

Blurred vision, Chills, Decreased or painful urination, Dizziness, Nausea, Nervousness, Rapid weight gain, unusual tiredness, or weakness, Tingling of hands and feet, Abdominal and stomach pain, Cough.

• Rare side effects

Yellow colored eyes or skin, Stevens-Johnson Syndrome (A rare, serious disorder of the skin and mucous membranes).

• Pregnancy

Pregnancy Category C

Teratogenic Effects

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. Valdecoxib should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

• 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 Valdecoxib, 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 Valdecoxib in pediatric patients below the age of 18 years have not been evaluated.

• Geriatric Use

Of the patients who received Valdecoxib 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.

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.

Management: 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.

• Pharmacodynamic

Valdecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, is classified as a nonsteroidal anti-inflammatory drug (NSAID). Valdecoxib is used for its anti-inflammatory, analgesic, and antipyretic activities in the management of osteoarthritis (OA) and for the treatment of dysmenorrhea or acute pain.

• Pharmacokinetics

Absorption

The oral bioavailability of Valdecoxib is 83%. Time taken to reach Peak plasma concentrations is after approximately 2.25-3 hours (oral).

Distribution

Valdecoxib has volume of distribution of 86 L. Its Protein-binding is approximately 98%

Metabolism and Excretion

Valdecoxib Extensively metabolized via hepatic route, mainly excreted via Urine (as metabolites).

• https://go.drugbank.com/drugs/DB00580
• https://www.accessdata.fda.gov/drugsatfda_docs/label/2004/21341lbl.pdf
• https://www.drugs.com/dosage/valdecoxib.html
• https://www.rxlist.com/Valdecoxib-drug.htm#contraindications
• https://go.drugbank.com/drugs/DB00580