DrugBuyers.Com: Vioxx

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, 25 or 50 mg of rofecoxib and the following inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, lactose, magnesium stearate, microcrystalline cellulose, and yellow 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%.

INDICATIONS

VIOXX is indicated:

For relief of the signs and symptoms of osteoarthritis. For the management of acute pain in adults (see CLINICAL STUDIES). For the treatment of primary dysmenorrhea.

DOSAGE AND ADMINISTRATION

VIOXX is administered orally. The lowest dose of VIOXX should be sought for each patient.

Osteoarthritis

The recommended starting dose of VIOXX is 12.5 mg once daily. Some patients may receive additional benefit by increasing the dose to 25 mg once daily. The maximum recommended daily dose is 25 mg.

Management of Acute Pain and Treatment of Primary Dysmenorrhea

The recommended initial dose of VIOXX is 50 mg once daily. Subsequent doses should be 50 mg once daily as needed. Use of VIOXX for more than 5 days in management of pain has not been studied (see CLINICAL STUDIES, Analgesia, including dysmenorrhea ).

VIOXX tablets may be taken with or without food.

Oral Suspension

VIOXX Oral Suspension 12.5 mg/ 5 mL or 25 mg/ 5 mL may be substituted for VIOXX Tablets 12.5 or 25 mg, respectively, in any of the above indications. Shake before using.

HOW SUPPLIED

No. 3810 - Tablets VIOXX, 12.5 mg, are cream/ off- white, round, shallow cup tablets engraved MRK 74 on one side and VIOXX on the other. They are supplied as follows:

NDC 0006- 0074- 31 unit of use bottles of 30

NDC 0006- 0074- 28 unit dose packages of 100

NDC 0006- 0074- 68 bottles of 100

NDC 0006- 0074- 82 bottles of 1000 NDC 0006- 0074- 80 bottles of 8000.

No. 3811 - Tablets VIOXX, 25 mg, are yellow, round, tablets engraved MRK 110 on one side and VIOXX on the other. They are supplied as follows:

NDC 0006- 0110- 31 unit of use bottles of 30

NDC 0006- 0110- 28 unit dose packages of 100

NDC 0006- 0110- 68 bottles of 100

NDC 0006- 0110- 82 bottles of 1000 NDC 0006- 0110- 80 bottles of 8000.

No. 3818 - Tablets VIOXX, 50 mg, are orange, round, tablets engraved MRK 114 on one side and VIOXX on the other. They are supplied as follows:

NDC 0006-0114-31 unit of use bottles of 30

NDC 0006-0114-28 unit dose packages of 100 NDC 0006-0114-68 bottles of 100

NDC 0006-0114-74 bottles of 500

NDC 0006-0114-81 bottles of 4000.

No. 3784 - Oral Suspension VIOXX, 12.5 mg/ 5 mL is an opaque, white to faint yellow suspension with a strawberry flavor that is easily resuspended upon shaking.

NDC 0006- 3784- 64 unit of use bottles containing 150 mL (12.5 mg/ 5 mL).

No. 3785 - Oral Suspension VIOXX, 25 mg/ 5 mL, is an opaque, white to faint yellow suspension with a strawberry flavor that is easily resuspended upon shaking.

NDC 0006- 3785- 64 unit of use bottles containing 150 mL (25 mg/ 5 mL).

Storage

VIOXX Tablets: Store at 25° C (77° F), excursions permitted to 15- 30° C (59- 86° F). [See USP Controlled Room Temperature.]

VIOXX Oral Suspension: Store at 25° C (77° F), excursions permitted to 15- 30° C (59- 86° F). [See USP Controlled Room Temperature.]

PATIENT INFORMATION

VIOXX can cause discomfort and rarely, more serious side effects, such as gastrointestinal bleeding, which may result in hospitalization and even fatal outcomes. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be apprised of the importance of this follow- up (see WARNINGS, Gastrointestinal (GI) Effects - Risk of GI Ulceration, Bleeding and Perforation).

Patients should promptly report signs or symptoms of gastrointestinal ulceration or bleeding, skin rash, unexplained weight gain, or edema to their physicians.

Patients should be informed of the warning signs and symptoms of hepatotoxicity (e. g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and "flu- like" symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy.

Patients should also be instructed to seek immediate emergency help in the case of an anaphylactoid reaction (see WARNINGS).
In late pregnancy VIOXX should be avoided because it may cause premature closure of the ductus arteriosus.

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 upper 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 or 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- 6 months, and in about 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
Among 3357 patients who received VIOXX in controlled clinical trials of 6 - weeks to one- year duration (most were enrolled in six - month or longer studies) at a daily dose of 12.5 mg to 50 mg, a total of four patients experienced a serious upper GI event, using protocol- derived criteria. Two patients experienced an upper GI bleed within three months (at day 62 and 87, respectively) (0. 06%). One additional patient experienced an obstruction within six months (Day 130) and the remaining patient developed an upper GI bleed within 12 months (Day 322) (0. 12%). Approximately 23% of these 3357 patients were in studies that required them to be free of ulcers at study entry. It is unclear if this study population is representative of the general population. Prospective, long - term studies required to compare the incidence of serious, clinically significant upper GI adverse events in patients taking VIOXX vs comparator NSAID products have not been performed.

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. To minimize the potential risk for an adverse GI event, the lowest effective dose should be used for the shortest possible duration. 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 p.o. general health status.

Anaphylactoid REACTIONS

Anaphylactoid reactions were not reported in patients receiving VIOXX in clinical trials. However, as with NSAIDs in general, anaphylactoid reactions may occur in patients without known prior exposure to VIOXX. VIOXX should not be given to patients with the aspirin t.i.d. 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.

Advanced Renal Disease

No safety information is available regarding the use of VIOXX in patients with advanced kidney disease. Therefore, treatment with VIOXX is not recommended in these patients. If VIOXX therapy must be initiated, close monitoring of the patient's kidney function is advisable (see

PRECAUTIONS
, Renal Effects).

Pregnancy

In late pregnancy VIOXX should be avoided because it may cause premature closure of the ductus arteriosus.

PRECAUTIONS

General

VIOXX cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to exacerbation of corticosteroid- responsive illness. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.

The pharmacological activity of VIOXX in reducing inflammation, and possibly fever, may diminish the utility of these diagnostic signs in detecting infectious 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, and 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 be 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 VIOXX, the incidence of borderline elevations of liver tests at doses of 12.5 and 25 mg daily was comparable to the incidence observed with ibuprofen and lower than that observed with diclofenac. In placebo- controlled trials, approximately 0.5% of patients taking rofecoxib (12.5 or 25 mg QD) and 0.1% of patients taking placebo had notable 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 VIOXX. Use of VIOXX is not recommended in patients with moderate or severe hepatic insufficiency (see CLINICAL PHARMACOLOGY: Pharmacokinetics, Special Populations). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e. g., eosinophilia, rash, etc.), VIOXX 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 ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. Clinical trials with VIOXX at daily doses of 12.5 and 25 mg have shown renal effects (e. g., hypertension, edema) similar to those observed with comparator NSAIDs; these occur with an increased frequency with chronic use of VIOXX at doses above the 12.5 to 25 mg range. (See ADVERSE REACTIONS.)

Caution should be used when initiating treatment with VIOXX in patients with considerable dehydration. It is advisable to rehydrate patients first and then start therapy with VIOXX. Caution is also recommended in patients with pre- existing kidney disease (see

WARNINGS
, Advanced Renal Disease).

Hematological Effects

Anemia is sometimes seen in patients receiving VIOXX. In placebo- controlled trials, there were no significant differences observed between VIOXX and placebo in clinical reports of anemia. Patients on long- term treatment with VIOXX should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia or blood loss. VIOXX does not generally affect platelet counts, prothrombin time (PT), or partial thromboplastin time (PTT), and does not inhibit platelet aggregation at indicated dosages (see CLINICAL STUDIES, Special Studies, Platelets).

Fluid Retention and Edema

Fluid retention and edema have been observed in some patients taking VIOXX (see ADVERSE REACTIONS). VIOXX should be used with caution, and should be introduced at the lowest recommended dose 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, VIOXX should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.

Information for Patients

VIOXX can cause discomfort and rarely, more serious side effects, such as gastrointestinal bleeding, which may result in hospitalization and even fatal outcomes. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be apprised of the importance of this follow- up (see

WARNINGS
, Gastrointestinal (GI) Effects - Risk of GI Ulceration, Bleeding and Perforation).

Patients should promptly report signs or symptoms of gastrointestinal ulceration or bleeding, skin rash, unexplained weight gain, or edema to their physicians.

Patients should be informed of the warning signs and symptoms of hepatotoxicity (e. g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and "flu- like" symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy.

Patients should also be instructed to seek immediate emergency help in the case of an anaphylactoid reaction (see

WARNINGS
).

In late pregnancy VIOXX should be avoided because it may cause premature closure of the ductus arteriosus.

Laboratory Tests

Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding.

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. 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 platelet aggregation and serum TXB 2 generation in clotting blood. VIOXX is not a substitute for aspirin for cardiovascular prophylaxis.

Cimetidine: Co- administration with high doses of cimetidine [800 mg twice daily] increased the C max of rofecoxib by 21%, the AUC 0- 120hr by 23% and the t 1/ 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. Thus, when VIOXX and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity.

Methotrexate: VIOXX 75 mg administered once daily for 10 days increased plasma concentrations by 23% as measured by AUC 0- 24hr in patients receiving methotrexate 7.5 to 15 mg/ week for rheumatoid arthritis. An equivalent magnitude of reduction in methotrexate renal clearance was observed. 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). The effects of the recommended doses for osteoarthritis (12.5 and 25 mg) of VIOXX on plasma methotrexate levels are unknown. 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.

Warfarin: Prothrombin time (measured as I.R. increased in both single and multiple dose cross- over studies in healthy individuals receiving both warfarin and rofecoxib. In a 21- day multiple- dose study in healthy individuals stabilized on warfarin (2 to 8.5 mg daily), administration of rofecoxib 25 mg QD was associated with mean increases in INR of approximately 8% (range of INR on warfarin alone, 1.1 to 2.2; range of INR on warfarin plus rofecoxib, 1.2 to 2.4). Somewhat greater mean increases in INR of approximately 11% (range of maximum INR on warfarin alone, 1.5 to 2.7; range of maximum INR on warfarin plus rofecoxib, 1.6 to 4.4) were also seen in a single dose PK screening study using a 30- mg dose of warfarin and 50 mg of rofecoxib. Standard monitoring of INR values should be conducted when therapy with VIOXX is initiated or changed, particularly in the first few days, in patients receiving warfarin or similar agents.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Rofecoxib was not carcinogenic in mice given oral doses up to 30 mg/ kg (male) and 60 mg/ kg (female) (approximately 5- and 2- fold the human exposure at 25 and 50 mg daily based on AUC 0- 24 ) and in male and female rats given oral doses up to 8 mg/ kg (approximately 6- and 2- fold the human exposure at 25 and 50 mg daily based on AUC 0- 24 ) for two years. Rofecoxib was not mutagenic in an Ames test or in a V- 79 mammalian cell mutagenesis assay, nor clastogenic in a chromosome aberration assay in Chinese hamster ovary (CHO) cells, in an in vitro and an in vivo alkaline elution assay, or in an in vivo chromosomal aberration test in mouse bone marrow.

Rofecoxib did not impair male fertility in rats at oral doses up to 100 mg/ kg (approximately 20- and 7- fold human exposure at 25 and 50 mg daily based on the AUC 0- 24 ) and rofecoxib had no effect on fertility in female rats at doses up to 30 mg/ kg (approximately 19- and 7- fold human exposure at 25 and 50 mg daily based on AUC 0- 24 ).

Pregnancy

Teratogenic effects: Pregnancy Category C. Rofecoxib was not teratogenic in rats at doses up to 50 mg/ kg/ day (approximately 28- and 10- fold human exposure at 25 and 50 mg daily based on AUC 0- 24 ). There was a slight, non- statistically significant increase in the overall incidence of vertebral malformations only in the rabbit at doses of 50 mg/ kg/ day (approximately 1- or
Nonteratogenic effects: Rofecoxib produced peri- implantation and post- implantation losses and reduced embryo/ fetal survival in rats and rabbits at oral doses ³ 10 and ³ 75 mg/ kg/ day, respectively (approximately 9- and 3- fold [rats] and 2- and
Labor and Delivery

Rofecoxib produced no evidence of significantly delayed labor or parturition in females at doses 15 mg/ kg in rats (approximately 10- and 3- fold human exposure as measured by the AUC 0- 24 at 25 and 50 mg). The effects of VIOXX on labor and delivery in pregnant women are unknown.

Nursing Mothers

Rofecoxib is excreted in the milk of lactating rats at concentrations similar to those in plasma. There was an increase in pup mortality and a decrease in pup body weight following exposure of pigs to milk from dams administered VIOXX during lactation. The dose tested represents an approximate 18- and 6- fold human exposure at 25 and 50 mg based on AUC 0- 24. 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 serious adverse reactions in nursing infants from VIOXX, 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.

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 18 years have not been evaluated.

Geriatric Use

Of the patients who received VIOXX in osteoarthritis clinical trials, 1455 were 65 years of age or older (this included 460 who were 75 years or older). No substantial differences in safety and effectiveness were observed between these subjects and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. Dosage adjustment in the elderly is not necessary; however, therapy with VIOXX should be initiated at the lowest recommended dose.

In one of these studies (a six- week, double- b.i.d. randomized clinical trial), VIOXX 12.5 or 25 mg once daily was administered to 174 osteoarthritis patients ³ 80 years of age. The safety profile in this elderly population was similar to that of younger patients treated with VIOXX.

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