Drug Criteria & Outcomes-COX-2 inhibitors: A review of prostaglandin pathway
By Christine Petraglia, RPh
Nancy Jordan, PharmD, BCPS
Neal Kelly, MD
Holyoke (MA) Hospital
Department of Pharmacy
Introduction
The first of the COX-2 (cyclooxygenase) inhibi tors arrived this year with a flurry of media promotion. Touted as super-aspirin, prescriptions for celecoxib (Celebrex), topped 2.5 million in its first three months on the market.
The second COX-2 inhibitor, rofecoxib (Vioxx), with an in vitro selectivity 1,000 times that of celecoxib, was approved this spring. To understand the excitement generated by this new class of nonsteroidal anti-inflammatory drugs (NSAIDs) a review of prostaglandin pathway is warranted.
Prostaglandins are synthesized from arachidonic acid catalyzed by the enzyme cyclooxygenase. It had been believed that only one form of cyclooxygenase existed until Simmons and cowork ers discovered an isoenzyme. COX-1 is present in most cells and tissues catalyzing the production of prostaglandins necessary for normal homeostatic functions (e.g. PGE2 for gastrointestinal mucosa protection; thromboxane for platelet function and regulation of blood flow; and PGI2 for platelet function, kidney function, regulation of blood flow, and gastrointestinal protection).
On the other hand, COX-2 is not present in most resting tissues with the exception of the brain, reproductive organs, and kidneys but is rapidly induced at sites of inflammation and is responsible for the production of prostaglandins involved in the inflammatory response.
Inhibition of COX-2 should not affect the everyday prostaglandins that are involved in homeostasis. Therapeutic doses of celecoxib and rofecoxib appear to inhibit only COX-2. The potential advantage of these products is lack of GI bleeding and lack of inhibition of platelet aggregation as compared to salicylates or traditional NSAIDs.
Pharmacology and administration
Celecoxib is approved for use in osteoarthritis (OA) and rheumatoid arthritis (RA). For OA, the approved dose is 200 mg daily or 100 mg BID. Doses of 100 mg to 200 mg BID are recommended for RA. The capsules may be administered without regard to timing of meals. The medication appears to be as effective as older NSAIDs for these conditions but may be less effective for acute pain and hence is not approved for that condition.
Rofecoxib has indications that include OA, acute pain in adults (such as dental pain and post-orthopedic surgical pain), and primary dysmenorrhea. Rofecoxib does not have an indication for RA. For OA, 12.5 mg and 25 mg once daily without regard to meals was shown to decrease joint stiffness upon morning awakening. Fifty mg once daily was effective for reducing moderate to severe pain and for dysmenorrhea (for a maximum of five days). The product is available in 12.5 and 25 mg tablets and as an oral suspension.
The most frequent adverse reactions associated with celecoxib were dyspepsia (8.8%) and diarrhea (2%); whereas, the most prevalent ones with rofecoxib were upper respiratory infection (8.5%), diarrhea (6.5%), nausea (5.2%), headache (4.7%), heartburn (4.2%), epigastric discomfort (3.8%), and dyspepsia (3.5%).
The incidence of endoscopically proven gas troduodenal ulcers over a twelve-week period was 7% (placebo 4%) with celecoxib and 5.9% (placebo 5%) with rofecoxib. That compared with 10% to 35% for other NSAIDs such as diclofenac, ibuprofen, and naproxen.
The renal effects of COX-2 inhibitors are similar to those of older NSAIDs, and subsequently, the drugs should be used with caution in those prone to renal dysfunction and avoided in those with advanced kidney disease. The incidence of liver function test evaluations was similar to that of placebo, but both products emphasize warning patients to be on the lookout for signs/symptoms of hepatotoxicity. COX-2 inhibitors do not inhibit platelet aggregation. Anemia may be seen in patients on this medication, and hemoglobin and hematocrit should be followed if patients exhibit any signs or symptoms of blood loss. Fluid retention and edema have been reported with both drugs.
Expected drug interactions include diminished antihypertensive effect with ACE inhibitors and diminished natriuretic effect with furosemide. Lithium levels are increased by 17%, necessitating close monitoring of levels with the addition or deletion of celecoxib therapy, and a similar response can be expected with rofecoxib.
Celecoxib is metabolized via the CYP2C9 isoenzyme in the liver and is an inhibitor of CYP2D6 isoenzyme. Fluconazole, through its inhibition of the CYP isoenzyme, increases celecoxib levels by 200%. Lovastatin, another 2C9 inhibitor commonly used in the elderly for hyperlipidemias, may be expected to have a similar effect, although no studies or reports establishing an interaction are known to date.
Similarly, since celecoxib inhibits the CYP2D6 isoenzyme, caution should be used with drugs such as tricyclic antidepressants, phenothiazines, metoprolol, propranolol, risperidone, venlafaxine, haloperidol, paroxetine and sertraline.
CYP450 plays a minor role in rofecoxib metab ol ism, but use of a nonspecific drug inducer such as rifampin resulted in a 50% decrease in rofecoxib levels. Other potentially significant drug interactions with rofecoxib include methotrexate (increased methotrexate levels) and warfarin (increased INR). The U.S. Food and Drug Admin istration recently mandated changes to celecoxib labeling indicating the post-marketing surveillance has shown that bleeding events particularly in the elderly associated with increased INRs occurred during concomitant celecoxib and warfarin therapy. Both drugs are contraindicated in patients with aspirin allergies.
Summary
Will COX-2 inhibitors be everything they promise to be? Even with the in vitro specificity, serious bleeding events have occurred. Since serious GI damage can occur anytime during therapy and often occurs without symptoms, monitoring for those events and proper patient selection cannot be overlooked. The constitutive presence of COX-2 in the kidney probably negates the potential of decreasing the renally associated side effects of NSAIDs. Initially, it was thought it might be advantageous to use COX-2 inhibitors in patients on warfarin to decrease the risk of bleeding because they do not increase bleeding time, but both medications have shown to increase the INR, and clinically significant bleeding has occurred in elderly patients.
Acetaminophen is currently the drug of choice for osteoarthritis, recommended by groups such as the American Geriatric Association because of the risks associated with NSAIDs. Switching all patients to COX-2 inhibitors at this time would not seem warranted until post-marketing surveillance confirms that the incidence of GI bleeding is truly decreased.
Converting patients at risk for GI bleeding to COX-2 inhibitors does not negate the need for continual monitoring and patient education regarding the signs and symptoms of serious GI effects. Using the lowest dose for the shortest amount of time will aid in reducing the chance of developing GI problems. Cost, as always, is a consideration, and these drugs have been priced competitively to compete with other newly marketed NSAIDs. Older NSAIDs and generic versions still remain less expensive.
Error alert for celecoxib
Fifty-four instances of medication errors resulting from name confusion with Celebrex were reported to the FDA within the first few months of marketing. This spring, co-marketers Searle and Pfizer sent out a fax to all pharmacists notifying them of confusion with look-alike/sound-alike drugs.
Celebrex; Celexa (citalopram), a new SSRI for depression; and Cerebyx (fosphenytoin) were the focus of the memo and are summarized in the table. (See p. 4.)
| A COX-2 Overview | ||||
| Brand Name | Celebrex | Celexa | Cerebyx | |
| Generic name | celecoxib | citalopram hydrobromide | fosphenytoin sodium | |
| Strength and form | 100 mg, 200 mg capsules | 20 mg, 40 mg tablets | 50 mg PE*/ml - 2ml and 10 ml vials | |
| Pronunciation | sell´-uh-brecks | sell-eks´-uh | ser´-uh-bicks | |
| Manufacturer | Searle | Forest Labs | Parke-Davis | |
| Indication | Osteoarthritis and adult RA | major depression | seizure prevention and treatment | |
| Dosage and Administration | OA: 200 mg daily or 100 mg bid | 20-40 mg daily (oral) | status epilepticus: 15-20 mg/PE/kg | |
| RA: 100-200 mg bid (oral) | maintenance dose: 4-6 mg PE/kg/day (intravenous) | |||
| *PE = phenytoin equivalent | ||||
When ordering any drug, it is imperative to neatly write or print and correctly spell the drug name. Include the dosage, form, strength, number, and indication for the prescription. Remember, the pharmacist at the local drug store may not know the patient's diagnosis, so including indication for use can aid in interpreting unclear orders.
[Editor's note: For more information, contact the authors at Holyoke Hospital, 575 Beech St., Holyoke, MA 01040. Telephone: (413) 534-2500.]
You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content