Celecoxib (Celebrex): Drug Whys

Celecoxib, often sold as Celebrex, is used for relief of osteoarthritis and rheumatoid arthritis symptoms, management of acute pain, and to treat other conditions


By Mike McEvoy

Generic Name: Celecoxib (no generic available – U.S. patent expires November 2013)
Common Brand Name: Celebrex (Pharmacia/Pfizer – U.S.)
Popularity: 35th most commonly prescribed drug between 2002 – 2008 (U.S.)
Class: nonsteroidal anti-inflammatory drug (NSAID), COX-2 inhibitor

Treatment Uses – For relief of osteoarthritis and rheumatoid arthritis symptoms. Management of acute pain. Treatment of primary dysmenorrhea (painful menstrual cramps). To reduce the number of colon and rectal polyps in patients with familial adenomatous polyposis (FAP). Reduces pain and disability from ankylosing spondylitis and has been used with good results for head pain. In conjunction with risperidone, celecoxib has hastened improvement in schizophrenia. May be useful in management of systemic lupus erythematosis (SLE) symptoms. COX-2 inhibitors are used in cancer patients for pain management and antitumor effects. Studies of COX-2 inhibitors in cancer prevention have been inconclusive.

COX-2 inhibitors exploded onto the market in 1999 as a new class of wonder drugs for arthritis sufferers. Previously, NSAIDs were used for treatment of arthritis. NSAIDs attacked COX-2 enzymes responsible for causing pain and inflammation but also attacked COX-1 enzymes responsible for protecting the stomach lining and kidneys.

This new COX-2 inhibitor drug class promised more selectivity for COX-2 enzymes, supposedly leaving the kidneys and stomach lining alone. Many NSAID users, unable to tolerate the gastrointestinal (GI) side effects of their older medications were thrilled with the COX-2 inhibitors. Interestingly, studies (even those to date) have failed to show clear differences. An even less impressive discovery about COX-2 inhibitors was their inability to reduce production of thromboxane A2 (TXA2), a chemical that activates platelets and promotes clotting.

Aspirin reduces TXA2 production, lessening risks for adverse clotting events such as heart attack and stroke; other NSAIDs also reduce TXA2 production to varying degrees. It now appears that all NSAIDs, including COX-2 inhibitors, can potentially block the cardioprotective effects of aspirin, increasing risk of cardiovascular (CV) events.
Interestingly, celecoxib does not appear to block aspirin's protective effects with any measurable significance.

In 2004, Merck pulled its COX-2 inhibitor (Vioxx) off the market after cancer prevention studies seemed to suggest the drug increased CV event risks. Researchers found that 18 months after patients began taking Vioxx, they developed an increased risk of stroke and heart attack, compared to patients who took placebo (dummy pills). The resulting hullabaloo led to reviews of all COX-2 inhibitors ending with the U.S. Food and Drug Administration (FDA) ordering revised labeling. Today, prescribers and users remain confused about the relative safety of all NSAIDs.

Based on currently available data, the FDA decided that effective October 2005, all NSAIDs (both prescription and over the counter agents) including celecoxib but excluding aspirin, must bear a Black Box warning (the FDA's highest level safety warning) highlighting an increased CV event risk and the serious risk of potentially life threatening gastrointestinal bleeding. The FDA also requested that accompanying NSAID package inserts include a contraindication for patients immediately post operative from coronary artery bypass (CABG) surgery since this group has more serious risk than the general population.

How the FDA guidelines and currently available data influence prescribers is very confusing, but can be synthesized into a few basic guidelines. Considering that all NSAIDs excluding celecoxib have potential to block the cardioprotective effects of aspirin, patients taking aspirin for CV protection (heart disease, stroke, clotting abnormalities, etc.) should avoid all NSAIDs and use celecoxib if an NSAID is absolutely necessary.

With the exception of aspirin, no NSAID should be used by patients immediately post-op from CABG, during acute coronary syndromes, and during or after undergoing percutaneous coronary interventions (roto-rooter work on the vessels of the heart).

For patients with high risk features for cardiovascular disease (males over 45, females over 55, family history, smokers, hypertensive, obese, high cholesterol, etc.), naproxen should be the only NSAID (besides aspirin) used. All NSAIDs should be used in the smallest effective dose and for the shortest duration necessary.

The American College of Rheumatology considers naproxen and celecoxib the safest choices, compared to other NSAIDs. The risk of adverse CV events with NSAIDs appears increased with higher doses and long durations of therapy. The available data do not show increased risk of serious CV events for the short-term, low dose use of NSAIDs available over the counter.

Dosing and Administration – For adults with acute pain or primary dysmenorrhea, the initial dose is 400 milligrams orally followed by an additional 200 milligram dose if needed on the first day. Afterwards, 200 milligrams twice daily as needed is recommended. For FAP, 400 milligrams orally twice daily is recommended for adults.

Osteoarthritis dosing is 100 milligrams twice daily or 200 milligrams once a day. Rheumatoid arthritis dosing is 100 to 200 milligrams twice a day. Celecoxib is approved for relief of symptoms of Juvenile Rheumatoid Arthritis (JRA) in children 2 years of age and older. Safety in children under 6 months of age has not been studied. Also unknown is whether children may be susceptible to the same long term NSIAD risks as adults.

Celecoxib oral doses up to 200 milligrams can be taken without regard to meals. Higher doses should be administered with food to improve absorption. For patients with difficulty swallowing celecoxib capsules, the contents may be added to 1 level teaspoon of cool or room temperature applesauce and ingested immediately with water. The sprinkled capsule contents on applesauce mixture remains stable for up to six hours when refrigerated.

A 50 percent dose reduction is recommended in patients with moderate liver dysfunction. Use of celecoxib is not recommended in patients with severe liver impairment or advanced kidney disease. Dose adjustment is not usually needed in geriatric patients, except that patients who weigh less than 50 kilograms should have therapy initiated at the lowest recommended dose.

Doses of up to 2400 milligrams daily for 10 days in 12 patients did not produce significant toxic effects. Other NSAID overdoses typically produce lethargy, nausea, vomiting, and epigastric pain. There are no specific antidotes; symptoms should be managed with supportive care. Symptomatic patients seen within four hours of ingesting a large overdose may benefit from emesis and/or activated charcoal and/or an osmotic cathartic. Celecoxib is probably not removed by hemodialysis.

Pharmacology/Pharmacokinetics/Stability – Celecoxib is rapidly absorbed following oral administration; initial response is seen within one hour and drug action lasts an average of 11 hours. Peak concentrations appear in the bloodstream in three hours. Maximal response in arthritis takes one to two weeks and FAP up to 6 months. The liver is responsible for most metabolism of celecoxib, hence the need for dosage adjustment in patients with liver disease.

Up to 27 percent of celecoxib is excreted in the urine, and most of the remainder in feces. There are insufficient human studies of celecoxib use during pregnancy to reliably predict fetal effects. Animal studies have shown increased occurrence of fetal damage but significance of these studies to humans is uncertain.

While there may be fetal risks, benefits may outweigh these in some cases; prescribers and patients are advised to consider both. Risks may be greatest during the third trimester and the manufacturer recommends against use of celecoxib during this period. Celecoxib is excreted in breast milk at low levels. Safe use by nursing mothers has not been determined but the low levels excreted appear clinically insignificant to breastfeeding infants and no studies to date have shown any adverse effects.

Celecoxib is believed to work in the body by inhibiting COX-2 synthesis, resulting in anti-inflammatory, analgesic, and antipyretic (anti-fever) activity.

Celecoxib comes in 100, 200, and 400 milligram capsules. Celecoxib (Celebrex) 100 milligram capsules are white with a reverse printed blue band on both the body and the cap and the markings 7767 on the cap and 100 on the body. 200 milligram capsules are white, reverse printed gold bands with the markings 7767 on the cap and 200 on the body. 400 milligram capsules are white, reverse printed green bands with the markings 7767 on the cap and 400 on the body. Capsules should be stored at room temperature between 59-86F.

Cautions and Warnings – Celecoxib should not be taken by patients with sulfonamide (sulfa) allergies or allergic type reactions (including asthma or rash) to aspirin or other NSAIDs. Patients with the “aspirin triad” (aspirin allergy, nasal polyps, and asthma) should not take celecoxib. Celecoxib should be used with caution in patients with heart failure or conditions aggravated by fluid retention and edema, history of GI bleeding, ulcers, or other bleeding problems, asthma, dehydration, or (previously mentioned) liver or kidney dysfunction.

Important Side Effects and Interactions – Headache is the most frequently reported adverse reaction from celecoxib, occurring in 15.8 percent of users. GI symptoms are also common, typically occurring as stomach upset (8.8 percent), abdominal pain (4.1 percent), diarrhea (5.6 percent), nausea (3.5 percent), and flatulence (2.2 percent). Back pain (2.8 percent), peripheral edema (2.1 percent), dizziness (2 percent), insomnia (2.3 percent), and skin rash are also common. Upper respiratory infections (8.1 percent), runny nose (2 percent), sinus infections (5 percent), and throat infections (2.3 percent) also occur.

Serious adverse reactions, although rare, have been reported including GI bleeding (<0.1 percent), allergic reactions and liver function test abnormalities (both <2 percent), and renal failure and congestive heart failure (both <0.1 percent).

There are clear connections between side effects and long term use, higher doses, and preexisting conditions that predispose patients to increased risk of adverse reactions.

Seventy four drugs and drug classes are reported to interact with celecoxib, of which eight have good documentation. Combinations of celecoxib with aspirin or selective serotonin reuptake inhibitors (SSRIs) have resulted in increased bleeding risks, particularly GI bleeding. Low-dose aspirin appears safe for use with celecoxib, but prescribers are encouraged to use enteric coated aspirin and closely monitor any patients who receive more than low-dose aspirin.

Concomitant use of celecoxib and warfarin may increase risk of bleeding in elderly patients; no significant effects were found in a study involving healthy subjects. The antifungal antibiotic fluconazole seems to double plasma levels of celecoxib; prescribers should use the lowest recommended celecoxib dosing in these patients. NSAIDs, including celecoxib are known to reduce the diuretic and antihypertensive effects of both loop and thiazide diuretics.

They also interfere with the vasodilator effects of angiotensin converting enzyme inhibitors (ACEI) and with blood pressure lowering effects of diltiazem. Although not many patients take lithium these days, NSAIDs including celecoxib have increased blood lithium levels and led to lithium toxicity (weakness, tremors, excessive thirst, and confusion).

There are no foods specifically noted to interact with celecoxib, but it would stand to reason that heavy alcohol consumption would dramatically increase GI irritation when combined with celecoxib.

Average Costs – U.S.
• 200 mg capsules (brand name Celebrex)*
Patient cost: $ 5.00 each
Large Hospital cost: $3.47 each
*(Wal Mart® and Target don't include this med in their $4/month programs)

References:

  • MICROMEDEX® Healthcare Series: Thomson Micromedex, Greenwood Village, Colorado (accessed March, 2010).
  • Albany Medical Center Pharmacy, Albany, New York.

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