Rofecoxib

Special Alerts

Rofecoxib Withdrawal Announced - September 30, 2004

Merck & Co announced today that rofecoxib (Vioxx®) has been withdrawn from the market. The withdrawal is voluntary and is based on results from a recent clinical trial designed to evaluate rofecoxib's effectiveness in preventing the recurrence of colorectal polyps. The study noted an increased relative risk for cardiovascular events and was stopped early for safety reasons. Patients taking rofecoxib chronically were noted to have twice the risk of heart attack when compared to patients taking placebo. The Food and Drug Administration (FDA) has acknowledged the withdrawal and is working with Merck to safely remove this product from the market. Patients should contact their healthcare providers for alternative therapies as Merck will no longer be providing this medication to pharmacies worldwide.

A complete copy of the press announcement can be found at: http://www.vioxx.com/

Additional information can also be found on the following websites:

http://www.fda.gov/bbs/topics/news/2004/NEW01122.html

http://www.hc-sc.gc.ca/english/protection/warnings/2004/2004_50.htm

Pronunciation

(roe fe COX ib)

U.S. Brand Names

Vioxx® [DSC]

Generic Available

Canadian Brand Names

Vioxx® [DSC]

Use

Relief of the signs and symptoms of osteoarthritis, rheumatoid arthritis, and juvenile rheumatoid arthritis (JRA); management of acute pain; treatment of primary dysmenorrhea; treatment of migraine attacks

Use - Dental

Management of acute pain in adults

Pregnancy Risk Factor

C/D (3rd trimester)

Pregnancy Implications

In late pregnancy, may cause premature closure of the ductus arteriosus. Safety and efficacy have not been established in pregnant women. Healthcare providers are encouraged to provide prenatal exposure to the pregnancy registry (800-986-8999).

Lactation

Excretion in breast milk unknown/not recommended

Contraindications

Hypersensitivity to rofecoxib or any component of the formulation, aspirin, or other NSAIDs; patients with "aspirin triad" (bronchial asthma, aspirin intolerance, rhinitis); pregnancy (3rd trimester)

Warnings/Precautions

Gastrointestinal irritation, ulceration, bleeding, and perforation may occur with NSAIDs (rofecoxib has been associated with rates of these events which are lower than naproxen, a nonselective NSAID); use the lowest effective dose for the shortest duration possible to decrease risk. Use with caution in patients with a history of GI disease (bleeding or ulcers), decreased renal function, hepatic disease, CHF, hypertension, or asthma. Edema, GI irritation, and/or hypertension occur at an increased frequency with chronic use of 50 mg/day. Use with caution in patients with ischemic heart disease; antiplatelet therapies should be considered (rofecoxib is not a substitute for antiplatelet agents). Anaphylactoid reactions may occur, even with no prior exposure to rofecoxib. Safety and efficacy in pediatric patients <2 years of age and <10 kg, and in cluster headaches have not been established.

Adverse Reactions

2% to 10%:

Cardiovascular: Peripheral edema (4%), hypertension (up to 10%)

Central nervous system: Headache (5%), dizziness (3%)

Gastrointestinal: Diarrhea (7%), nausea (5%), heartburn (4%), epigastric discomfort (4%), dyspepsia (4%), abdominal pain (3%); dry socket (post-dental extraction alveolitis 2%)

Genitourinary: Urinary tract infection (3%)

Neuromuscular & skeletal: Back pain (3%), weakness (2%)

Respiratory: Upper respiratory infection (9%), bronchitis (2%), sinusitis (3%)

Miscellaneous: Flu-like syndrome (3%)

0.1% to 2%:

Cardiovascular: Chest pain, upper extremity edema, atrial fibrillation, bradycardia, arrhythmia, palpitation, tachycardia, venous insufficiency, fluid retention

Central nervous system: Anxiety, depression, decreased mental acuity, hypesthesia, insomnia, neuropathy, migraine, paresthesia, somnolence, vertigo, fever, pain

Dermatologic: Alopecia, atopic dermatitis, basal cell carcinoma, contact dermatitis, pruritus, rash, erythema, urticaria, dry skin

Endocrine & metabolic: Weight gain, hypercholesteremia

Gastrointestinal: Reflux, abdominal distension, abdominal tenderness, constipation, dry mouth, esophagitis, flatulence, gastritis, gastroenteritis, hematochezia, hemorrhoids, oral ulceration, dental caries, aphthous stomatitis

Genitourinary: Breast mass, cystitis, dysuria, menopausal disorder, nocturia, urinary retention, vaginitis, pelvic pain

Hematologic: Hematoma

Hepatic: Transaminases increased >3 times ULN (1%)

Neuromuscular & skeletal: Muscle spasm, sciatica, arthralgia, bursitis, cartilage trauma, joint swelling, muscle cramps, muscle weakness, myalgia, tendonitis, traumatic arthropathy, fracture (wrist)

Ocular: Blurred vision, conjunctivitis

Otic: Otic pain, otitis media, tinnitus

Respiratory: Asthma, cough, dyspnea, pneumonia, respiratory infection, pulmonary congestion, rhinitis, epistaxis, laryngitis, dry throat, pharyngitis, tonsillitis, diaphragmatic hernia

Miscellaneous: Allergy, fungal infection, insect bite reaction, syncope, viral syndrome, herpes simplex, herpes zoster, increased diaphoresis

<0.1% (Limited to important or life-threatening): Acute renal failure, anaphylactoid reaction, angioedema, aseptic meningitis, breast cancer, CHF, cholecystitis, colitis, colonic neoplasm, deep venous thrombosis, duodenal ulcer, duodenal perforation, gastric perforation, gastrointestinal bleeding, hallucinations, interstitial nephritis intestinal obstruction, lymphoma, MI, pancreatitis, prostatic cancer, pulmonary embolism, transient ischemic attack, urolithiasis, stroke, unstable angina

Postmarketing and/or case reports: Agranulocytosis, aplastic anemia, hallucinations, pancytopenia, photosensitivity, reaction, Stevens-Johnson syndrome, toxic epidermal necrolysis

Overdosage/Toxicology

Symptoms may include epigastric pain, drowsiness, lethargy, nausea, and vomiting. Gastrointestinal bleeding may occur. Rare manifestations include hypertension, respiratory depression, coma, and acute renal failure. Treatment is symptomatic and supportive. Hemodialysis does not remove rofecoxib.

Drug Interactions

Substrate of CYP2C8/9 (minor); Inhibits CYP1A2 (weak); Induces CYP3A4 (weak)

ACE inhibitors: Antihypertensive effects may be reduced by rofecoxib.

Aspirin: Rofecoxib may be used with low-dose aspirin, however, rates of gastrointestinal bleeding may be increased with coadministration.

Cimetidine increases AUC of rofecoxib by 23%.

Diuretics: Thiazide diuretics, loop diuretics: Effects may be diminished by rofecoxib.

Lithium: Serum concentrations/toxicity may be increased by rofecoxib; monitor.

Methotrexate: Severe bone marrow suppression, aplastic anemia, and GI toxicity have been reported with concomitant NSAID therapy. Selective COX-2 inhibitors appear to have a lower risk of this toxicity, however, caution is warranted.

Rifampin reduces the serum concentration of rofecoxib by ~50%; consider using initial dose of 25 mg/day for osteoarthritis.

Theophylline: Serum concentrations may be increased during therapy with rofecoxib; monitor.

Warfarin: Rofecoxib may increase the INR in patients receiving warfarin and may increase the risk of bleeding complications. However, rofecoxib does not appear to inhibit platelet aggregation.

Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol (may increase gastric mucosal irritation)

Food: Time to peak concentrations are delayed when taken with a high-fat meal, however, peak concentration and AUC are unchanged.

Mechanism of Action

Inhibits prostaglandin synthesis by decreasing the activity of the enzyme, cyclooxygenase-2 (COX-2), which results in decreased formation of prostaglandin precursors. Rofecoxib does not inhibit cyclooxygenase-1 (COX-1) at therapeutic concentrations.

Pharmacodynamics/Kinetics

Onset of action: 45 minutes

Duration: Up to >24 hours

Distribution: Vdss (apparent): 86-91 L

Protein binding: 87%

Metabolism: Hepatic (99%); minor metabolism via CYP2C8/9 isoenzyme; metabolites inactive

Bioavailability: 93%

Half-life elimination: 17 hours

Time to peak: 2-3 hours

Excretion: Urine (72% as metabolites, <1% as unchanged drug); feces (14% as unchanged drug)

Dosage

Oral:

Children 2-17 years and 10 kg: JRA: 0.6 mg/kg/day (maximum: 25 mg/day)

Adults:

Osteoarthritis: 12.5 mg once daily; may be increased to a maximum of 25 mg once daily

Acute pain and management of dysmenorrhea: 50 mg once daily as needed (use for longer than 5 days has not been studied)

Migraine attack: 25 mg once daily, as needed; may be increased to a maximum of 50 mg once daily

Rheumatoid arthritis: 25 mg once daily

Dosing comment in renal impairment: Use in advanced renal disease is not recommended

Dosing adjustment in hepatic impairment: Moderate hepatic dysfunction (Child-Pugh score 7-9): Maximum dose: 12.5 mg/day

Monitoring Parameters

Signs and symptoms of gastrointestinal bleeding

Dietary Considerations

May be taken without regard to meals.

Patient Education

Do not take more than recommended dose. May be taken with food to reduce GI upset. Do not take with antacids. Avoid alcohol, aspirin, and OTC medication unless approved by prescriber. You may experience dizziness, confusion, or blurred vision (avoid driving or engaging in tasks requiring alertness until response to drug is known); or anorexia, nausea, vomiting, taste disturbance, gastric distress (small, frequent meals, frequent mouth care, sucking lozenges, or chewing gum may help). GI bleeding, ulceration, or perforation can occur with or without pain; rofecoxib has rates of these events which are lower than nonselective NSAIDs. Stop taking medication and report stomach pain or cramping, unusual bleeding or bruising, or blood in vomitus, stool, or urine immediately. Report persistent insomnia; skin rash; unusual fatigue or easy bruising or bleeding; muscle pain, tremors, or weakness; sudden weight gain; abdominal pain; itching, yellowing of skin; chest pain; changes in hearing (ringing in ears); vision changes; changes in urination pattern; or respiratory difficulty. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. This drug should not be used in the 3rd trimester of pregnancy. Breast-feeding is not recommended.

Anesthesia and Critical Care Concerns/Other Considerations

Does not inhibit platelets or prolong bleeding.

Dental Health: Effects on Dental Treatment

In models of postoperative dental pain, rofecoxib was effective against dental pain rated as moderate to severe. The analgesic efficacy of a single 50 mg dose of rofecoxib was apparently similar to 40 mg of ibuprofen or 550 mg of naproxen sodium. The onset of analgesia for postoperative dental pain with a single 50 mg dose of rofecoxib was 45 minutes.

Platelets: Bleeding time was not altered after a single dose of 500 mg or 1000 mg of rofecoxib. In addition, according to the manufacturer, multiple doses of rofecoxib 12.5 mg, 25 mg, and up to 375 mg administered daily up to 12 days, had no effect on bleeding time relative to placebo. However, according to the manufacturer, rofecoxib may increase the INR in patients receiving warfarin (see Drug Interactions).

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Dental Comment

Recent news reports have noted an association between selective COX-2 inhibitors and increased cardiovascular risk. This was prompted by the publication of a meta-analysis entitled, "Risk of Cardiovascular Events Associated With Selective COX-2 Inhibitors" in the August 22, 2001 edition of the Journal of the American Medical Association (JAMA), viewable at http://jama.ama-assn.org/issues/v286n8/rfull/jsc10193.html. The researchers reanalyzed four previously published trials, assessing cardiovascular events in patients receiving either celecoxib or rofecoxib. They found an association between the use of COX-2 inhibitors and cardiovascular events (including myocardial infarction and ischemic stroke). The annualized myocardial infarction rate was found to be significantly higher in patients receiving celecoxib or rofecoxib than in the control (placebo) group from a recent meta-analysis of primary prevention trials. Although cause and effect cannot be established (these trials were originally designed to assess GI effects, not cardiovascular effects), the authors believe the available data raise a cautionary flag concerning the risk of cardiovascular events with the use of COX-2 inhibitors. The manufacturers of these agents dispute the methods and validity of the study's conclusions.

New indications, warnings added to Vioxx® labeling - April, 2002: The FDA has approved new labeling which extends its approved indications to the symptomatic management of rheumatoid arthritis in adults and emphasized differences in the adverse event profile as compared to nonselective NSAIDs. A reduction in GI adverse events relative to a nonselective NSAID (naproxen) is noted. Precautions concerning the use in cardiovascular disease (including ischemic disease) have also been added. The potential development of edema and hypertension with rofecoxib, particularly at high dosages (50 mg/day), is emphasized. Prescribers are reminded that rofecoxib does not possess antiplatelet activity, which may influence risk of ischemic events (as compared to nonselective NSAIDs). Data concerning ischemic cardiovascular events, including myocardial infarction, are presented but it is noted that prospective studies to evaluate cardiovascular risk have not been conducted.

Mental Health: Effects on Mental Status

May cause dizziness; may rarely cause anxiety, depression, decreased mental acuity, hypesthesia, insomnia, somnolence

Mental Health: Effects on Psychiatric Treatment

May increase serum lithium levels; monitor

Dosage Forms

[DSC] = Discontinued product

Suspension, oral [DSC]: 12.5 mg/5 mL (150 mL); 25 mg/5 mL (150 mL) [strawberry flavor]

Tablet [DSC]: 12.5 mg, 25 mg, 50 mg

References

Ehrich EW, Dallob A, De Lepeleire I, et al, "Characterization of Rofecoxib as a Cyclooxygenase-2 Isoform Inhibitor and Demonstration of Analgesia in the Dental Pain Model," Clin Pharmacol Ther , 1999, 65(3):336-47.

Hawkey CJ, "COX-2 Inhibitors," Lancet , 1999, 353(9149):307-14.

International Brand Names

Algioxib® (AR); Alrof® (IN); Arofexx® (IT); Befol® (AR); Blokium Cox® (AR); Ceoxx® (ES, IE, PT); Coxiro® (AR); Coxxil® (IT, PT); Diex® (CO); Dolcoxx® (IT); Dolib® (IN); Dolostop® (IT); Doxtran® (AR); Flanax® (CO); Foldoxx® (AR); Miraxx® (IT); Rofecoxib MK® (CO); Rofetab® (IN); Rofexib® (CO); Rofiz Gel® (IN); Rofiz® (IN); Silfox® (AR); Sivoz® (CO); Toloxane® (AR); Unicalm® (AR); Versatil® (IN); Vioxx® [DSC] (CA)

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