Creval

Creval Tablets are indicated:

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

Creval was withdrawn from the U.S. market in 2005.

Creval is in a class of drugs called nonsteroidal anti-inflammatory drugs (NSAIDs). Creval works by reducing substances in the body that cause inflammation, pain, and fever.

Creval is used to reduce pain, inflammation, and stiffness caused by osteoarthritis and adult rheumatoid arthritis. Creval is also used to treat painful menstruation.

Creval may also be used for purposes other than those listed in this medication guide.

Applies to the following strengths: 10 mg; 20 mg

Usual Adult Dose for:

• Osteoarthritis
• Rheumatoid Arthritis
• Dysmenorrhea
• Pain

Additional dosage information:

• Renal Dose Adjustments
• Liver Dose Adjustments
• Dose Adjustments
• Precautions
• Dialysis
• Other Comments

Usual Adult Dose for Osteoarthritis

Creval was voluntarily withdrawn from the market in April, 2005 by the manufacturer following an FDA Public Health Advisory announcing that the overall risk versus benefit profile for Creval is unfavorable, based on the following: reports of serious and potentially life-threatening skin reactions, including deaths, in patients taking Creval. The risk of these reactions have occurred in patients with and without a prior history of sulfa allergy, and after both short- and long-term use. The lack of adequate data on the cardiovascular safety of long-term use of Creval, along with the increased risk of adverse CV events in short-term coronary artery bypass surgery (CABG) trial that FDA believes may be relevant to chronic use, and lack of any demonstrated advantages for Creval compared with other NSAIDs. The following dosage information applies to when the drug was available in the USA.

Initial dose: 10 mg once daily

Usual Adult Dose for Rheumatoid Arthritis

Creval was voluntarily withdrawn from the market in April, 2005 by the manufacturer following an FDA Public Health Advisory announcing that the overall risk versus benefit profile for Creval is unfavorable, based on the following: reports of serious and potentially life-threatening skin reactions, including deaths, in patients taking Creval. The risk of these reactions have occurred in patients with and without a prior history of sulfa allergy, and after both short- and long-term use. The lack of adequate data on the cardiovascular safety of long-term use of Creval, along with the increased risk of adverse CV events in short-term coronary artery bypass surgery (CABG) trial that FDA believes may be relevant to chronic use, and lack of any demonstrated advantages for Creval compared with other NSAIDs. The following dosage information applies to when the drug was available in the USA.

Initial dose: 10 mg once daily

Usual Adult Dose for Dysmenorrhea

Creval was voluntarily withdrawn from the market in April, 2005 by the manufacturer following an FDA Public Health Advisory announcing that the overall risk versus benefit profile for Creval is unfavorable, based on the following: reports of serious and potentially life-threatening skin reactions, including deaths, in patients taking Creval. The risk of these reactions have occurred in patients with and without a prior history of sulfa allergy, and after both short- and long-term use. The lack of adequate data on the cardiovascular safety of long-term use of Creval, along with the increased risk of adverse CV events in short-term coronary artery bypass surgery (CABG) trial that FDA believes may be relevant to chronic use, and lack of any demonstrated advantages for Creval compared with other NSAIDs. The following dosage information applies to when the drug was available in the USA.

Initial dose: 20 mg twice daily

Usual Adult Dose for Pain

Creval was voluntarily withdrawn from the market in April, 2005 by the manufacturer following an FDA Public Health Advisory announcing that the overall risk versus benefit profile for Creval is unfavorable, based on the following: reports of serious and potentially life-threatening skin reactions, including deaths, in patients taking Creval. The risk of these reactions have occurred in patients with and without a prior history of sulfa allergy, and after both short- and long-term use. The lack of adequate data on the cardiovascular safety of long-term use of Creval, along with the increased risk of adverse CV events in short-term coronary artery bypass surgery (CABG) trial that FDA believes may be relevant to chronic use, and lack of any demonstrated advantages for Creval compared with other NSAIDs. The following dosage information applies to when the drug was available in the USA.

Study (n=507) -

Oral or Bunionectomy Surgery: 20 or 40 mg single oral dose given 60 to 75 minutes before surgery.

Renal Dose Adjustments

Creval use in advanced renal disease is not recommended.

Liver Dose Adjustments

Creval use in patients with severe hepatic impairment (Child-Pugh Class C) is not recommended.

Initiate Creval treatment with caution in patients with mild or moderate (Child-Pugh Class B) hepatic impairment and fluid retention.

Dose Adjustments

No dosage adjustment is necessary due to age or gender differences.

Precautions

Creval is contraindicated for the treatment of postoperative pain immediately following coronary artery bypass graft (CABG) surgery and should not be used in this setting.

Creval should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other nonsteroidal anti-inflammatories. Severe, rarely fatal, anaphylactic-like reactions to nonsteroidal anti-inflammatories have been reported in such patients.

An FDA Public Health Advisory on the use of Nonsteroidal anti-inflammatory Drug Products (NSAIDs) issued as a result of recent reports of controlled clinical trials showing that COX-2 selective agents 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) states that physicians prescribing Creval should consider this emerging information when weighing the benefits against risks for individual patients. Patients who are at a high risk of gastrointestinal bleeding, have a history of intolerance to nonselective NSAIDs, or are not doing well on nonselective 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.

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 patient taking nonsteroidal anti-inflammatory drugs (NSAIDs). Creval should be used with extreme caution in patients with a prior history of ulcer disease or gastrointestinal bleeding. 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 of developing a GI bleed than patients with neither of these risk factors.

Creval should be used with caution in patients with comorbid conditions, or co-therapies that may increase the risk of gastrointestinal bleeding, such as treatment with corticosteroids, anticoagulants, prolonged use of NSAIDs, smoking, alcoholism, older age, and poor general health status.

Creval should be used with caution in patients with considerable dehydration. The manufacturer recommends that patients be rehydrated first before the drug is used.

Dialysis

Creval use in advanced renal disease is not recommended.

Other Comments

Creval may be taken with or without food. Administration with a high-fat meal may delay the time to peak plasma concentration by 1 to 2 hours.

Creval may be taken with an antacid (aluminum/magnesium hydroxide).

Creval should be monitored closely in patients on long therapy with Creval because of reports of anemia, renal injury, and elevations of one or more liver tests.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

Medical Disclaimer

More about Creval

• Creval Side Effects
• During Pregnancy or Breastfeeding
• Drug Interactions
• 12 Reviews
• Drug class: cox-2 inhibitors

Consumer resources

• Creval (Advanced Reading)

Other brands: Creval

Professional resources

Related treatment guides

• Osteoarthritis
• Pain
• Period Pain
• Rheumatoid Arthritis

See also:
What is the most important information I should know about Creval?

Creval should not be given to patients who have demonstrated allergic-type reactions to sulfonamides.

Creval Tablets are contraindicated in patients with known hypersensitivity to Creval. Creval 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.

Creval 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..

Creval is used in adults to treat pain and inflammation caused due to osteoarthritis (pain, swelling, and reduced motion in joints) and rheumatoid arthritis (inflammatory disorder that typically affects the small joints in hands and feet). It is also used to treat menstrual pain.

See also:
What other drugs will affect Creval?

The drug interaction studies with Creval were performed both with Creval and a rapidly hydrolyzed intravenous prodrug form. The results from trials using the intravenous prodrug are reported in this section as they relate to the role of Creval in drug interactions.

General

In humans, Creval metabolism is predominantly mediated via CYP 3A4 and 2C9 with glucuronidation being a further (20%) route of metabolism. In vitro studies indicate that Creval is a moderate inhibitor of CYP 2C19 (IC50 = 6 μg/mL or 19 μM) and 2C9 (IC50 = 13 μg/mL or 41 μM), and a weak inhibitor of CYP 2D6 (IC50 = 31 μg/mL or 100 μM) and 3A4 (IC50 = 44 μg/mL or 141 μM).

Aspirin

Concomitant administration of aspirin with Creval may result in an increased risk of GI ulceration and complications compared to Creval alone. Because of its lack of anti-platelet effect Creval is not a substitute for aspirin for cardiovascular prophylaxis.

In a parallel group drug interaction study comparing the intravenous prodrug form of Creval at 40 mg BID (n=10) vs placebo (n=9), Creval had no effect on in vitro aspirin-mediated inhibition of arachidonate- or collagen-stimulated platelet aggregation.

Methotrexate

Creval 10 mg BID 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 Creval concomitantly with ACEinhibitors.

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 Creval (40 mg BID 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 Creval should be closely monitored for loss of symptom control with phenytoin coadministration. Creval 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 Creval 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 Creval (40 mg BID for 7 days) resulted in a significant increase in dextromethorphan plasma levels suggesting that, at these doses, Creval is a weak inhibitor of 2D6. Even so, dextromethorphan plasma concentrations in the presence of high doses of Creval were almost 5- fold lower than those seen in CYP 2D6 poor metabolizers suggesting that dose adjustment is not necessary.

Lithium

Creval 40 mg BID 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 Creval in patients receiving lithium. Lithium carbonate (450 mg BID for 7 days) had no effect on Creval pharmacokinetics.

Warfarin

The effect of Creval on the anticoagulant effect of warfarin (1–8 mg/day) was studied in healthy subjects by coadministration of Creval 40 mg BID for 7 days. Creval 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 Creval, 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 Creval 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 Creval 20 mg with multiple doses of ketoconazole and fluconazole produced a significant increase in exposure of Creval. Plasma exposure (AUC) to Creval was increased 62% when coadministered with fluconazole and 38% when coadministered with ketoconazole.

Glyburide

Glyburide is a CYP 2C9 substrate. Coadministration of Creval (10 mg BID for 7 days) with glyburide (5 mg QD or 10 mg BID) did not affect the pharmacokinetics (exposure) of glyburide. Coadministration of Creval (40 mg BID (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 Creval (40 mg BID (day 1) and 40 mg QD (days 2– 7)) with glyburide (10 mg glyburide BID) 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 Creval 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 BID) with Creval coadministration (up to 40 mg QD) is not indicated. Coadministration of glyburide with doses higher than 40 mg Creval (e.g., 40 mg BID) has not been studied.

Omeprazole

Omeprazole is a CYP 3A4 substrate and CYP 2C19 substrate and inhibitor. Creval steady state plasma concentrations (40 mg BID) were not affected significantly with multiple doses of omeprazole (40 mg QD). Coadministration with Creval increased exposure of omeprazole (AUC) by 46%. Drugs whose absorption is sensitive to pH may be negatively impacted by concomitant administration of omeprazole and Creval. 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 Creval with doses higher than 40 mg QD omeprazole has not been studied.

Oral Contraceptives

Creval (40 mg BID) did not induce the metabolism of the combination oral contraceptive norethindrone/ethinyl estradiol (1 mg/0.035 mg combination, Ortho-Novum 1/35) is a CYP 3A4 and CYP 2C19 substrate. Plasma exposure of diazepam (10 mg BID) was increased by 28% following administration of Creval (40 mg BID) for 12 days, while plasma exposure of Creval (40 mg BID) was not substantially increased following administration of diazepam (10 mg BID) for 12 days. Although the magnitude of changes in diazepam plasma exposure when coadministered with Creval 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.

See also:
What are the possible side effects of Creval?

Applies to Creval: oral tablet

In addition to its needed effects, some unwanted effects may be caused by Creval (the active ingredient contained in Creval). In the event that any of these side effects do occur, they may require medical attention.

Major Side Effects

You should check with your doctor immediately if any of these side effects occur when taking Creval:

Less common:

• Bloating or swelling of face, arms, hands, lower legs, feet
• blood in urine
• bloody, black, or sticky stools
• blurred vision
• chills
• decreased or painful urination
• dizziness
• fever
• muscle aches and pains
• nausea
• nervousness
• pale skin
• pounding in the ears
• rapid weight gain
• severe stomach pain
• tingling of the hands or feet
• trouble breathing with exertion
• unusual bleeding or bruising
• unusual tiredness or weakness
• vomiting of blood or material that looks like coffee grounds
• yellow eyes or skin

• Blistering, peeling, loosening of skin
• constipation
• cracks in the skin
• darkened urine
• difficulty swallowing
• fast heartbeat
• hives
• indigestion
• itching
• itching, puffiness, or swelling of the eyelids or around the eyes, face, lips, or tongue
• joint or muscle pain
• large, hive-like swelling on face, eyelids, lips, tongue, throat, hands, legs, feet, sex organs
• loss of appetite
• loss of heat from the body
• nausea
• pains in stomach, side, or abdomen, possibly radiating to the back
• red skin lesions, often with a purple center
• red, irritated eyes
• red, swollen skin
• scaly skin
• shortness of breath
• skin rash
• sores, ulcers, or white spots in mouth or on lips
• tightness in chest
• vomiting
• wheezing
• yellow eyes or skin

If any of the following symptoms of overdose occur while taking Creval, get emergency help immediately:

• Bloody or black tarry stools
• continuing thirst
• dizziness
• drowsiness
• headache, severe or continuing
• nausea and/or vomiting
• shortness of breath
• stomach pain
• sudden decrease in the amount of urine
• swelling of face, fingers, and/or lower legs
• tightness in chest and/or wheezing
• troubled breathing
• unusual tiredness or weakness
• vomiting of blood or material that looks like coffee grounds
• weight gain

Minor Side Effects

Some of the side effects that can occur with Creval may not need medical attention. As your body adjusts to the medicine during treatment these side effects may go away. Your health care professional may also be able to tell you about ways to reduce or prevent some of these side effects. If any of the following side effects continue, are bothersome or if you have any questions about them, check with your health care professional:

More common:

• Acid or sour stomach
• belching
• cough
• diarrhea
• ear congestion
• headache
• heartburn
• indigestion
• sore throat

• Abdominal fullness
• accidental injury
• back pain
• bloating in the abdomen
• excess gas
• rash
• stuffy or runny nose

Creval is a prescription drug used in the treatment of osteoarthritis, rheumatoid arthritis, and painful menstruation and menstrual symptoms. It is classified as a nonsteroidal anti-inflammatory drug, or NSAID, and should not be taken by anyone allergic to these types of medications.

Creval was manufactured and marketed under the brand name Creval by G. D. Searle & Company. It was approved by the United States Food and Drug Administration on November 20, 2001, and was available by prescription in tablet form until 2005, when it was removed from the market due to concerns about possible increased risk of heart attack and stroke.