Vioxx side effects

This drug was removed from the US Market 9/'04


SIDE EFFECTS

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.
Clinical Adverse Experiences occurring in ≥ 2.0% of Patients Treated with VIOXX in OA Clinical Trials


Placebo
VIOXX 12.5 or 25 mg daily
Ibuprofen 2400 mg daily
Diclofenac 150 mg daily

(N = 783)
(N = 2829)
(N = 847)
(N = 498)

Body As A Whole/Site Unspecified

Abdominal Pain
4.1
3.4
4.6
5.8

Asthenia/Fatigue
1.0
2.2
2.0
2.6

Dizziness
2.2
3.0
2.7
3.4

Influenza-Like Disease
3.1
2.9
1.5
3.2

Lower Extremity Edema
1.1
3.7
3.8
3.4

Upper Respiratory Infection
7.8
8.5
5.8
8.2

Cardiovascular System

Hypertension
1.3
3.5
3.0
1.6

Digestive System

Diarrhea
6.8
6.5
7.1
10.6

Dyspepsia
2.7
3.5
4.7
4.0

Epigastric Discomfort
2.8
3.8
9.2
5.4

Heartburn
3.6
4.2
5.2
4.6

Nausea
2.9
5.2
7.1
7.4

Eyes, Ears, Nose, And Throat

Sinusitis
2.0
2.7
1.8
2.4

Musculoskeletal System

Back Pain
1.9
2.5
1.4
2.8

Nervous System

Headache
7.5
4.7
6.1
8.0

Respiratory System

Bronchitis
0.8
2.0
1.4
3.2

Urogenital System

Urinary Tract Infection
2.7
2.8
2.5
3.6


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 reactions, severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis.

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 (see DOSAGE AND ADMINISTRATION).

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. (See CLINICAL STUDIES, Special Studies, Upper Endoscopy in Patients with Osteoarthritis and Rheumatoid Arthritis.)

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.