Vioxx



by Nathan Wei, MD, FACP, FACR

Nathan Wei is a nationally known board-certified rheumatologist and author of the Second Opinion Arthritis Treatment Kit. It's available exclusively at this website... not available in stores.

Click here: Second Opinion Arthritis Treatment Kit


Information from Merck

Vioxx was a COX 2 selective anti-inflammatory drug that was voluntarily removed by its manufacturer, Merck, in September 2004.

VIOXX* (rofecoxib) is described chemically as 4-[4-(methylsulfonyl)phenyl]-3-phenyl-2(5H)-furanone.

Rofecoxib is a white to off-white to light yellow powder. It is sparingly soluble in acetone, slightly soluble in methanol and isopropyl acetate, very slightly soluble in ethanol, practically insoluble in octanol, and insoluble in water. The empirical formula for rofecoxib is C17H14O4S, and the molecular weight is 314.36.

Each tablet of VIOXX for oral administration contains either 12.5 mg, 25 mg, or 50 mg of rofecoxib and the following inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, lactose, magnesium stearate, microcrystalline cellulose, and yellow ferric oxide. The 50 mg tablets also contain red ferric oxide.

Each 5 mL of the oral suspension contains either 12.5 or 25 mg of rofecoxib and the following inactive ingredients: citric acid (monohydrate), sodium citrate (dihydrate), sorbitol solution, strawberry flavor, xanthan gum, and purified water. Added as preservatives are sodium methylparaben 0.13% and sodium propylparaben 0.02%.



Osteoarthritis

Approximately 3600 patients with osteoarthritis were treated with VIOXX; approximately 1400 patients received VIOXX for 6 months or longer and approximately 800 patients for one year or longer. The following table of adverse experiences lists all adverse events, regardless of causality, occurring in at least 2% of patients receiving VIOXX in nine controlled studies of 6-week to 6-month duration conducted in patients with OA at the therapeutically recommended doses (12.5 and 25 mg), which included a placebo and/or positive control group.

In the OA studies, the following spontaneous adverse events occurred in >0.1% to 1.9% of patients treated with VIOXX regardless of causality:

Body as a Whole: abdominal distension, abdominal tenderness, abscess, chest pain, chills, contusion, cyst, diaphragmatic hernia, fever, fluid retention, flushing, fungal infection, infection, laceration, pain, pelvic pain, peripheral edema, postoperative pain, syncope, trauma, upper extremity edema, viral syndrome.

Cardiovascular System: angina pectoris, atrial fibrillation, bradycardia, hematoma, irregular heartbeat, palpitation, premature ventricular contraction, tachycardia, venous insufficiency.

Digestive System: acid reflux, aphthous stomatitis, constipation, dental caries, dental pain, digestive gas symptoms, dry mouth, duodenal disorder, dysgeusia, esophagitis, flatulence, gastric disorder, gastritis, gastroenteritis, hematochezia, hemorrhoids, infectious gastroenteritis, oral infection, oral lesion, oral ulcer, vomiting.

Eyes, Ears, Nose, and Throat: allergic rhinitis, blurred vision, cerumen impaction, conjunctivitis, dry throat, epistaxis, laryngitis, nasal congestion, nasal secretion, ophthalmic injection, otic pain, otitis, otitis media, pharyngitis, tinnitus, tonsillitis.

Immune System: allergy, hypersensitivity, insect bite reaction.

Metabolism and Nutrition: appetite change, hypercholesterolemia, weight gain.

Musculoskeletal System: ankle sprain, arm pain, arthralgia, back strain, bursitis, cartilage trauma, joint swelling, muscular cramp, muscular disorder, muscular weakness, musculoskeletal pain, musculoskeletal stiffness, myalgia, osteoarthritis, tendinitis, traumatic arthropathy, wrist fracture.

Nervous System: hypesthesia, insomnia, median nerve neuropathy, migraine, muscular spasm, paresthesia, sciatica, somnolence, vertigo.

Psychiatric: anxiety, depression, mental acuity decreased.

Respiratory System: asthma, cough, dyspnea, pneumonia, pulmonary congestion, respiratory infection.

Skin and Skin Appendages: abrasion, alopecia, atopic dermatitis, basal cell carcinoma, blister, cellulitis, contact dermatitis, herpes simplex, herpes zoster, nail unit disorder, perspiration, pruritus, rash, skin erythema, urticaria, xerosis.

Urogenital System: breast mass, cystitis, dysuria, menopausal symptoms, menstrual disorder, nocturia, urinary retention, vaginitis.

The following serious adverse events have been reported rarely (estimated <0.1%) in patients taking VIOXX, regardless of causality. Cases reported only in the post-marketing experience are indicated in italics.

Cardiovascular: cerebrovascular accident, congestive heart failure, deep venous thrombosis, hypertensive crisis, myocardial infarction, pulmonary edema, pulmonary embolism, transient ischemic attack, unstable angina.

Gastrointestinal: cholecystitis, colitis, colonic malignant neoplasm, duodenal perforation, duodenal ulcer, esophageal ulcer, gastric perforation, gastric ulcer, gastrointestinal bleeding, hepatic failure, hepatitis, intestinal obstruction, jaundice, pancreatitis.

Hemic and lymphatic: agranulocytosis, aplastic anemia, leukopenia, lymphoma, pancytopenia, thrombocytopenia.

Immune System: anaphylactic/anaphylactoid reaction, angioedema, bronchospasm, hypersensitivity vasculitis.

Metabolism and nutrition: hyponatremia.

Nervous System: aseptic meningitis, epilepsy aggravated.

Psychiatric: confusion, hallucinations.

Skin and Skin Appendages: photosensitivity

Urogenital System: acute renal failure, breast malignant neoplasm, hyperkalemia, interstitial nephritis, prostatic malignant neoplasm, urolithiasis, worsening chronic renal failure.

In 1-year controlled clinical trials and in extension studies for up to 86 weeks (approximately 800 patients treated with VIOXX for one year or longer), the adverse experience profile was qualitatively similar to that observed in studies of shorter duration.



Rheumatoid Arthritis

Approximately 1,100 patients were treated with VIOXX in the Phase III rheumatoid arthritis efficacy studies. These studies included extensions of up to 1 year. The adverse experience profile was generally similar to that reported in the osteoarthritis studies. In studies of at least three months, the incidence of hypertension in RA patients receiving the 25 mg once daily dose of VIOXX was 10.0% and the incidence of hypertension in patients receiving naproxen 500 mg twice daily was 4.7%.



Analgesia, including primary dysmenorrhea

Approximately one thousand patients were treated with VIOXX in analgesia studies. All patients in post-dental surgery pain studies received only a single dose of study medication. Patients in primary dysmenorrhea studies may have taken up to 3 daily doses of VIOXX, and those in the post-orthopedic surgery pain study were prescribed 5 daily doses of VIOXX.

The adverse experience profile in the analgesia studies was generally similar to those reported in the osteoarthritis studies. The following additional adverse experience, which occurred at an incidence of at least 2% of patients treated with VIOXX, was observed in the post-dental pain surgery studies: post-dental extraction alveolitis (dry socket).

Migraine with or without aura

Approximately 750 patients were treated with a single dose of VIOXX 25 mg or 50 mg in two single-attack migraine studies. Approximately 460 patients in the 3-month extension phase of one study treated up to 8 (average 3) migraine attacks per month. In single attack studies, the following adverse events were more frequent in the VIOXX treatment groups (25 mg and 50 mg) compared to the placebo group, and occurred at an incidence of at least 2% of patients treated: dizziness, nausea, somnolence and dyspepsia. In the 3-month extension phase of one study, the following adverse events occurred at an incidence of at least 2% of patients treated in the VIOXX treatment groups (25 mg and 50 mg): dizziness, dry mouth, nausea, and vomiting.



Clinical Studies in OA and RA with VIOXX 50 mg (Twice the highest dose recommended for chronic use)

In OA and RA clinical trials which contained VIOXX 12.5 or 25 mg as well as VIOXX 50 mg, VIOXX 50 mg QD was associated with a higher incidence of gastrointestinal symptoms (abdominal pain, epigastric pain, heartburn, nausea and vomiting), lower extremity edema, hypertension, serious* adverse experiences and discontinuation due to clinical adverse experiences compared to the recommended chronic doses of 12.5 and 25 mg.

Pauciarticular and Polyarticular Course Juvenile Rheumatoid Arthritis

In a 12-week study, 209 JRA patients,  2 years to  17 years of age, were treated with rofecoxib; 109 and 100 patients were treated with lower-dose rofecoxib and higher-dose rofecoxib, respectively. In a 52-week open-label extension, 160 JRA patients,  2 years to  17 years of age, were treated with higher-dose rofecoxib for up to 15 months. No new adverse experiences were identified other than a single case of pseudoporphyria (a photo-induced blistering reaction), an adverse event that has been seen in patients with JRA treated with non-selective NSAIDs. In this 12-week study, the most common adverse experiences (at 0.6 mg/kg dose) were upper abdominal pain, nasopharyngitis, diarrhea, upper respiratory tract infection, abdominal pain, headache and rhinitis. Rash was also reported.

*adverse experience that resulted in death, permanent or substantial disability, hospitalization, congenital anomaly, or cancer, was immediately life threatening, was due to an overdose, or was thought by the investigator to require intervention to prevent one of the above outcomes

DRUG INTERACTIONS

ACE inhibitors: Reports suggest that NSAIDs may diminish the antihypertensive effect of Angiotensin Converting Enzyme (ACE) inhibitors. In patients with mild to moderate hypertension, administration of 25 mg daily of VIOXX with the ACE inhibitor benazepril, 10 to 40 mg for 4 weeks, was associated with an average increase in mean arterial pressure of about 3 mm Hg compared to ACE inhibitor alone. This interaction should be given consideration in patients taking VIOXX concomitantly with ACE inhibitors.

Aspirin

Concomitant administration of low-dose aspirin with VIOXX may result in an increased rate of GI ulceration or other complications, compared to use of VIOXX alone. In a 12-week endoscopy study conducted in OA patients there was no difference in the cumulative incidence of endoscopic gastroduodenal ulcers in patients taking low-dose (81 mg) enteric coated aspirin plus VIOXX 25 mg daily, as compared to those taking ibuprofen 2400 mg daily alone. Patients taking low-dose aspirin plus ibuprofen were not studied.

At steady state, VIOXX 50 mg once daily had no effect on the anti-platelet activity of low-dose (81 mg once daily) aspirin, as assessed by ex vivo platelet aggregation and serum TXB2 generation in clotting blood. Because of its lack of platelet effects, VIOXX is not a substitute for aspirin for cardiovascular prophylaxis. Therefore, in patients taking VIOXX, antiplatelet therapies should not be discontinued and should be considered in patients with an indication for cardiovascular prophylaxis. (See CLINICAL STUDIES, Special Studies, Platelets and PRECAUTIONS, Cardiovascular Effects.) Prospective, long-term studies on concomitant administration of VIOXX and aspirin have not been conducted.

Cimetidine
Co-administration with high doses of cimetidine [800 mg twice daily] increased the Cmax of rofecoxib by 21%, the AUC0-120hr by 23% and the t1/2 by 15%. These small changes are not clinically significant and no dose adjustment is necessary.

Digoxin
Rofecoxib 75 mg once daily for 11 days does not alter the plasma concentration profile or renal elimination of digoxin after a single 0.5 mg oral dose.

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.

Ketoconazole
Ketoconazole 400 mg daily did not have any clinically important effect on the pharmacokinetics of rofecoxib.

Lithium
NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In post-marketing experience there have been reports of increases in plasma lithium levels. Thus, when VIOXX and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity.

Methotrexate
VIOXX 12.5, 25, and 50 mg, each dose administered once daily for 7 days, had no effect on the plasma concentration of methotrexate as measured by AUC0-24hr in patients receiving single weekly methotrexate doses of 7.5 to 20 mg for rheumatoid arthritis. At higher than recommended doses, VIOXX 75 mg administered once daily for 10 days increased plasma concentrations by 23% as measured by AUC0-24hr in patients receiving methotrexate 7.5 to 15 mg/week for rheumatoid arthritis. At 24 hours postdose, a similar proportion of patients treated with methotrexate alone (94%) and subsequently treated with methotrexate co-administered with 75 mg of rofecoxib (88%) had methotrexate plasma concentrations below the measurable limit (5 ng/mL). Standard monitoring of methotrexate-related toxicity should be continued if VIOXX and methotrexate are administered concomitantly.

Oral Contraceptives
Rofecoxib did not have any clinically important effect on the pharmacokinetics of ethinyl estradiol and norethindrone.

Prednisone/prednisolone
Rofecoxib did not have any clinically important effect on the pharmacokinetics of prednisolone or prednisone.

Rifampin
Co-administration of VIOXX with rifampin 600 mg daily, a potent inducer of hepatic metabolism, produced an approximate 50% decrease in rofecoxib plasma concentrations. Therefore, a starting daily dose of 25 mg of VIOXX should be considered for the treatment of osteoarthritis when VIOXX is co-administered with potent inducers of hepatic metabolism.

Theophylline

VIOXX 12.5, 25, and 50 mg administered once daily for 7 days increased plasma theophylline concentrations (AUC(0-)) by 38 to 60% in healthy subjects administered a single 300-mg dose of theophylline. Adequate monitoring of theophylline plasma concentrations should be considered when therapy with VIOXX is initiated or changed in patients receiving theophylline. These data suggest that rofecoxib may produce a modest inhibition of cytochrome P450 (CYP) 1A2. Therefore, there is a potential for an interaction with other drugs that are metabolized by CYP 1A2 (e.g., amitriptyline, tacrine, and zileuton).

Warfarin
Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing VIOXX therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding complications. In single and multiple dose studies in healthy subjects receiving both warfarin and rofecoxib, prothrombin time (measured as INR) was increased by approximately 8% to 11%. In post-marketing experience, bleeding events have been reported, predominantly in the elderly, in association with increases in prothrombin time in patients receiving VIOXX concurrently with warfarin.



Public Health Advisory
Non-Steroidal Anti-Inflammatory Drug Products (NSAIDS)
The FDA is issuing a public health advisory concerning use of non-steroidal anti-inflammatory drug products (NSAIDS) including those known as COX-2 selective agents.

Recently released data from controlled clinical trials showing that the COX-2 selective agents (Vioxx, Celebrex, and Bextra) may be associated with an increased risk of serious cardiovascular events (heart attack and stroke) especially when they are used for long periods of time or in very high risk settings (immediately after heart surgery).

Preliminary results from a long-term clinical trial (up to three years) suggest that long term use of a non-selective NSAID, naproxen (sold as Aleve, Naprosyn and other trade name and generic products), may be associated with an increased cardiovascular (CV) risk compared to placebo.

While the results of these studies are preliminary and conflict with other study data on the same drugs, FDA is providing this advisory as an interim measure, pending further review of data that continue to be collected. Specifically:

• Physicians prescribing Celebrex (celecoxib) or Bextra (valdecoxib), should consider this emerging information when weighing the benefits against risks for individual patients. Patients who are at a high risk of gastrointestinal (GI) bleeding, have a history of intolerance to non-selective NSAIDs, or are not doing well on non-selective NSAIDs may be appropriate candidates for COX-2 selective agents.
• Individual patient risk for cardiovascular events and other risks commonly associated with NSAIDs should be taken into account for each prescribing situation.
• Consumers are advised that all over-the-counter (OTC) pain medications, including NSAIDs, should be used in strict accordance with the label directions. If use of an OTC NSAID is needed for longer than ten days, a physician should be consulted.


Non-selective NSAIDs are widely used in both over-the-counter (OTC) and prescription settings. As prescription drugs, many are approved for short-term use in the treatment of pain and primary dysmenorrhea (menstrual discomfort), and for longer-term use to treat the signs and symptoms of osteoarthritis and rheumatoid arthritis. FDA has previously posted extensive NSAID medication information at http://www.fda.gov/cder/drug/analgesics/default.htm.

FDA will be analyzing all available information from the new studies of Vioxx, Celebrex, Bextra, and naproxen, and other data for non-selective NSAIDs and COX-2 selective products to determine whether additional regulatory action is needed. An advisory committee meeting is planned for February 2005 which will provide for a full discussion of these issues.

Personally, my feeling is this... All drugs have potential side effects. The current atmosphere of litigation is such that we will all pay the price for frivolous actions. We will pay through higher prescription costs, less access to medication because of the dampening effect on new research, and the continuing atmosphere engendered by “ambulance chasers.”

As a practicing rheumatologist, I am angered by the actions of attorneys who attempt to gain profit from this situation.

Just recently, a patient’s spouse “earned” a multi-million dollar settlement for a purported side-effect. The side effect was a cardiac arrhythmia occurring in a patient who had been on Vioxx for approximately nine months. The cardiovascular events reported in the clinical trials occurred in patients treated longer than 18 months. And arrhythmias are not the type of event that was reported. What was reported was a slightly increased incidence of heart attacks and strokes.

From the side effect profile described above it is clear that Vioxx, like any other medicine, had potential side-effects.

People need to begin to accept responsibility for what they put into their bodies. Nobody is forcing anyone to take medicine. If you don’t have enough of a problem to warrant taking a medicine, don’t take it.

Now a disclaimer. Don’t follow my advice if it offends you or if you would like to take a medication. In fact, don’t listen to a word I have to say if it offends you. Forget you ever came to this page. I take no responsibility for actions anyone might take as a result of reading these pages. The information and advice on this page should not be construed as offering medical advice or medical information.




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