1. CELECOXIB HISTORY
How was Celecoxib discovered?

Celecoxib was approved by the U.S. Food and Drug Administration for use in relieving the signs and symptoms of osteoarthritis and adult rheumatoid arthritis in September 2001. It is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic and antipyretic activities.

2. CELECOXIB FACTS

In clinical trials of over 13,000 patients and healthy volunteers, Celecoxib was shown to be very effective in treating arthritis pain and inflammation. The recommended therapeutic dose for use in osteoarthritis is 200 mg daily, administered as a single dose, or 100 mg administered twice daily. For use in rheumatoid arthritis, the recommended therapeutic dosage is 100 mg to 200 mg, given twice daily.

In clinical trials, Celecoxib was associated with a statistically significant reduction in the incidence of upper gastrointestinal ulcers, compared with results obtained with other drugs.

3. ABOUT CELECOXIB MEDICATION

Celecoxib is a type of medicine known as a non-steroidal anti-inflammatory drug (NSAID} prescribed for relieving the signs and symptoms of arthritis.

The NSAIDs (Non-Steroidal Anti-Inflammatory Drugs) are a large class of drugs used to treat arthritis. One of the NSAIDs is usually included in the medication regimen of an arthritis patient.

NSAIDs help combat arthritis pain by interfering with the inflammatory process.

There are now three types of NSAIDs:

1. Salicylates: The original category of NSAIDs– the salicylates includes aspirin.
2. The Traditional NSAIDs Include:
   • Flurbiprofen
   • Misoprostol
   • Diclofenac Potassium
   • Oxaprozin
   • Diflunisal
   • Piroxicam
   • Ibuprofen
   • Indomethacin
   • Ketoprofen
   • Etodolac
   • Meclofenamate Sodium
   • Meloxicam
   • Fenoprofen
   • Naproxen
   • Mefanamic Acid
   • Nabumetone
   • Tolmetin Sodium
   • Dicolfenac Sodium
     
3. The COX-2 Inhibitors Include:
   • Celecoxib
   • Rofecoxib
   • Valdecoxib
   • Traditional NSAIDs– ibuprofen, naproxen and piroxicam, to name a few-inhibit both cox-1 and cox-2 prostaglandins. Many of the undesirable side effects of using these non-selective NSAIDs result from inhibiting the cox-1 "maintenance" prostaglandins. The beneficial effects of the newer NSAIDs result from inhibiting, or limiting, only the cox-2 "inflammatory " prostaglandins. These specific NSAIDs are effective for treatment of musculoskeletal pain and are without many of the side effects associated with the traditional agents.

NSAIDs work by blocking the action of a substance in the body called cyclo-oxygenase. Cyclo-oxygenase is involved in producing prostaglandins, in response to injury or certain diseases. These prostaglandins cause pain, swelling and inflammation. Because NSAIDs block the production of these prostaglandins, they are effective at relieving pain and inflammation.

Cyclo-oxygenase does not only produce prostaglandins that cause inflammation. It also produces prostaglandins that have useful roles in the body. There are two different forms of cyclo-oxygenase, COX-1 and COX-2. COX-2 is the form that (among other things) produces prostaglandins that cause inflammation. COX-1 does not produce inflammatory prostaglandins, but does produce others that have useful effects, including some that are involved in maintaining a healthy stomach and intestinal lining.

Traditional NSAIDs, such as ibuprofen or diclofenac, block the action of both COX-1 and COX-2, and this is why they can sometimes cause side effects such as stomach irritation and peptic ulcers. Celecoxib belongs to a new generation of NSAIDs that selectively block the action of COX-2. This means that Celecoxib stops the production of inflammatory prostaglandins, without stopping the production of prostaglandins that protect the stomach and intestines. Celecoxib therefore reduces pain and inflammation, but is less likely than traditional NSAIDs to cause side effects on the stomach and intestines.

Arthritis literally means joint inflammation, and it can affect joints in any part of the body. Joints are places in the body where two bones meet.

Many people use the term arthritis to refer to rheumatic diseases; however, the different kinds of arthritis comprise just a portion of the rheumatic diseases.

Arthritis is often a chronic disease, which means that it can affect you over a long period of time. Many forms of arthritis cause swelling, redness, heat, and pain.

The two main forms of arthritis are:
Osteoarthritis
Osteoarthritis is the most common form of arthritis among older people.
Osteoarthritis occurs when cartilage, the tissue that cushions the ends of the bones within the joints, breaks down and wears away. In some cases, all of the cartilage may wear away, leaving bones that rub up against each other.

Symptoms range from stiffness and mild pain that comes and goes to severe joint pain. Osteoarthritis affects hands, low back, neck, and weight-bearing joints such as knees, hips, and feet

These are the areas of the body commonly affected by osteoarthritis.

Osteoarthritis is one of the most frequent causes of physical disability among older adults.

The disease affects both men and women. Before age 45, Osteoarthritis is more common in men than in women. After age 45, Osteoarthritis is more common in women. By age 65, more than half of the population has x-ray evidence of Osteoarthritis in at least one joint.

Osteoarthritis affects only joints, not internal organs.

Rheumatoid arthritis
Rheumatoid arthritis not only affects the joints, but may also attack tissue in the skin, lungs, eyes, and blood vessels. People with Rheumatoid arthritis may feel sick, tired, and sometimes feverish.

Rheumatoid arthritis is classified as an autoimmune disease. An autoimmune disease occurs when the immune system turns against parts of the body it is designed to protect.

Rheumatoid arthritis generally occurs in a symmetrical pattern. This means that if one knee or hand is involved, the other one is, too. It can occur at any age, but usually begins during a person's most productive years.

Rheumatoid arthritis occurs much more frequently in women than in men. About two to three times as many women as men have the disease.

Researchers suspect that osteoarthritis is caused by a combination of factors in the body and the environment. The chance of developing osteoarthritis increases with age. By age 65, half of the population has x-ray evidence of osteoarthritis in at least one joint, most often in the hips, knees, or fingers.

Causes of arthritis
Osteoarthritis often results from years of wear and tear on joints. This wear and tear mostly affects the cartilage, the tissue that cushions the ends of bones within the joint. Osteoarthritis occurs when the cartilage begins to fray, wear away, and decay.

Putting too much stress on a joint that has been previously injured, improper alignment of joints, and excess weight all may lead to the development of Osteoarthritis

Rheumatoid arthritis results from the interaction of many factors such as genes, hormones, and the environment. Research suggests that a person's genetic makeup is an important part of the picture, but not the whole story.

Some evidence shows that infectious agents, such as viruses and bacteria, may trigger Rheumatoid arthritis in people with an inherited tendency to develop the disease. However, a specific agent or agents are not yet known.

It is important to note that rheumatoid arthritis is not contagious. A person cannot catch it from someone else.

4. CELECOXIB EFFECTIVENESS

When is Celecoxib best taken?
Absorption
Peak plasma levels of Celecoxib occur approximately 3 hrs after an oral dose. Under fasting conditions, both peak plasma levels and area under the curve are roughly dose proportional up to 200 mg taken twice a day; at higher doses there are less than proportional increases in maximum concentration. Absolute bioavailability studies have not been conducted. With multiple dosing, steady state conditions are reached on or before day 5.

Summary of Single Dose (200 mg) of CELECOXIB in Healthy Subjects
C max , ng/mL	T max , hr	Effective t 1/2 , hr	V ss /F, L	CL/F, L/hr
705 (38)	2.8 (37)	11.2 (31)	429 (34)	27.7 (28)
Subjects under fasting conditions (n=36, 19-52 yrs.)

Food Effects
When Celecoxib capsules were taken with a high fat meal, peak plasma levels were delayed for about 1 to 2 hours with an increase in total absorption of 10% to 20%. Under fasting conditions, at doses above 200 mg, there is less than a proportional increase in maximum concentration, which is thought to be due to the low solubility of the drug in aqueous media. Co administration of Celecoxib with an aluminum and magnesium containing antacid resulted in a reduction in plasma Celecoxib concentrations with a decrease of 37% in maximum concentration. Celecoxib, at doses up to 200 mg twice a day can be administered without regard to the timing of meals. Higher doses (400 mg twice a day) should be administered with food to improve absorption.

Distribution
In healthy subjects, Celecoxib is highly protein bound within the clinical dose range. In vitro studies indicate that Celecoxib binds primarily to albumin and, to a lesser extent, (alpha) 1 -acid glycoprotein. The apparent volume of distribution at steady state is approximately 400 L, suggesting extensive distribution into the tissues. Celecoxib is not preferentially bound to red blood cells.

Metabolism
Celecoxib metabolism is primarily mediated via cytochrome P450 2C9. Three metabolites, a primary alcohol, the corresponding carboxylic acid and its glucuronide conjugate, have been identified in human plasma. These metabolites are inactive as COX-1 or COX-2 inhibitors. Patients who are known or suspected to be P450 2C9 poor metabolizers based on a previous history should be administered Celecoxib with caution as they may have abnormally high plasma levels due to reduced metabolic clearance.

Excretion
Celecoxib is eliminated predominantly by hepatic metabolism with little (<3%) unchanged drug recovered in the urine and feces. Following a single oral dose of radio labeled drug, approximately 57% of the dose was excreted in the feces and 27% was excreted into the urine. The primary metabolite in both urine and feces was the carboxylic acid metabolite (73% of dose) with low amounts of the glucuronide also appearing in the urine. It appears that the low solubility of the drug prolongs the absorption process making terminal half-life (t 1/2 ) determinations more variable. The effective half-life is approximately 11 hours under fasted conditions. The apparent plasma clearance (CL/F) is about 500 mL/min.

5. CELECOXIB EFFECTS ON SPECIAL POPULATION

How do different people react to Celecoxib?
Geriatric : At steady state, elderly subjects (over 65 years old) had a 40% higher Cmax and a 50% higher AUC compared to the young subjects. In elderly females, Celecoxib Cmax and AUC are higher than those for elderly males, but these increases are predominantly due to lower body weight in elderly females. Dose adjustment in the elderly is not generally necessary. However, for patients of less than 50 kg in body weight, initiate therapy at the lowest recommended dose.

Pediatric : Celecoxib capsules have not been investigated in pediatric patients below 18 years of age.

Race : Meta-analysis of pharmacokinetic studies has suggested an approximately 40% higher AUC of Celecoxib in Blacks compared to Caucasians. The cause and clinical significance of this finding is unknown.

Hepatic Insufficiency : A pharmacokinetic study in subjects with mild and moderate hepatic impairment has shown that steady-state Celecoxib AUC is increased about 40% and 180%, respectively, above that seen in healthy control subjects. Therefore, the daily-recommended dose of Celecoxib capsules should be reduced by approximately 50% in patients with moderate hepatic impairment. Patients with severe hepatic impairment have not been studied. The use of Celecoxib in patients with severe hepatic impairment is not recommended.

Renal Insufficiency : In a cross-study comparison, Celecoxib AUC was approximately 40% lower in patients with chronic renal insufficiency than that seen in subjects with normal renal function. No significant relationship was found between GFR and Celecoxib clearance. Patients with severe renal insufficiency have not been studied. Similar to other NSAIDs, Celecoxib is not recommended in patients with severe renal insufficiency.

6. CELECOXIB EFFECTS ON MEDICAL CONDITIONS

How does Celecoxib affect your existing condition/ailment?
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 NSAID, 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.

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 NSAID 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 poor general health status.

Anaphylactoid Reactions
As with NSAIDs in general, anaphylactoid reactions have occurred in patients without known prior exposure to Celecoxib. In post-marketing experience, Celecoxib. Celecoxib should not be given to patients with the aspirin triad. 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. Emergency help should be sought in cases where an anaphylactoid reaction occurs.

Advanced Renal Disease
No information is available from controlled clinical studies regarding the use of Celecoxib in patients with advanced kidney disease. Therefore, treatment with Celecoxib is not recommended in these patients with advanced kidney disease. If Celecoxib therapy must be initiated, close monitoring of the patient's kidney function is advisable.

7. OTHER/ALTERNATE USES OF CELECOXIB

What else does Celecoxib treat?
Celecoxib is also used to decrease growths found in the intestines (colon polyps) of persons with a family history of this condition.

8. ADVERSE/SIDE EFFECTS of CELECOXIB

What are the side effects of Celecoxib?
Of the Celecoxib treated patients in the premarketing controlled clinical trials, approximately 4,250 were patients with OA, approximately 2,100 were patients with RA, and approximately 1,050 were patients with post-surgical pain. More than 8,500 patients have received a total daily dose of Celecoxib of 200 mg (100 mg BID or 200 mg QD) or more, including more than 400 treated at 800 mg (400 mg BID). Approximately 3,900 patients have received Celecoxib at these doses for 6 months or more; approximately 2,300 of these have received it for 1 year or more and 124 of these have received it for 2 years or more.

Adverse events from Celebrex premarketing controlled arthritis trials: The table below lists all adverse events, regardless of causality, occurring in >/=2% of patients receiving Celecoxib from 12 controlled studies conducted in patients with OA or RA that included a placebo and/or a positive control group.

Adverse Events Occurring in >/=2% of Celecoxib Patients From Celecoxib Premarketing Controlled Arthritis Trials
	Celecoxib (100-200 mg BID or 200 mg QD)	Placebo	Naproxen 500 mg BID	Diclofenac 75 mg BID	Ibuprofen 800 mg TID
	(n=4146)	(n=1864)	(n=1366)	(n=387)	(n=345)
Gastrointestinal
Abdominal Pain	4.1%	2.8%	7.7%	9.0%	9.0%
Diarrhea	5.6%	3.8%	5.3%	9.3%	5.8%
Dyspepsia	8.8%	6.2%	12.2%	10.9%	12.8%
Flatulence	2.2%	1.0%	3.6%	4.1%	3.5%
Nausea	3.5%	4.2%	6.0%	3.4%	6.7%
Body as a whole
Back Pain	2.8%	3.6%	2.2%	2.6%	0.9%
Peripheral edema	2.1%	1.1%	2.1%	1.0%	3.5%
Injury-accidental	2.9%	2.3%	3.0%	2.6%	3.2%
Central and peripheral nervous system
Dizziness	2.0%	1.7%	2.6%	1.3%	2.3%
Headache	15.8%	20.2%	14.5%	15.5%	15.4%
Psychiatric
Insomnia	2.3%	2.3%	2.9%	1.3%	1.4%
Respiratory
Pharyngitis	2.3%	1.1%	1.7%	1.6%	2.6%
Rhinitis	2.0%	1.3%	2.4%	2.3%	0.6%
Sinusitis	5.0%	4.3%	4.0%	5.4%	5.8%
Upper respiratory    tract infection	8.1%	6.7%	9.9%	9.8%	9.9%
Skin
Rash	2.2%	2.1%	2.1%	1.3%	1.2%

In placebo or active-controlled clinical trials, the discontinuation rate due to adverse events was 7.1% for patients receiving Celecoxib and 6.1% for patients receiving placebo. Among the most common reasons for discontinuation due to adverse events in the Celecoxib treatment groups were dyspepsia and abdominal pain (cited as reasons for discontinuation in 0.8% and 0.7% of Celecoxib patients, respectively). Among patients receiving placebo, 0.6% discontinued due to dyspepsia and 0.6% withdrew due to abdominal pain.

The following adverse events occurred in 0.1-1.9% of patients regardless of causality.

Celecoxib (100-200 mg twice a day or 200 mg four times a day)

Gastrointestinal:	Constipation, diverticulitis, dysphagia, eructation, esophagitis, gastritis, gastroenteritis, gastroesophageal reflux, hemorrhoids, hiatal hernia, melena, dry mouth, stomatitis, tenesmus, tooth disorder, vomiting
Cardiovascular:	Aggravated hypertension, angina pectoris, coronary artery disorder, myocardial infarction
General:	Allergy aggravated, allergic reaction, asthenia, chest pain, cyst NOS, edema generalized, face edema, fatigue, fever, hot flushes, influenza-like symptoms, pain, peripheral pain
Resistance mechanism disorders:	Herpes simplex, herpes zoster, infection bacterial, infection fungal, infection soft tissue, infection viral, monoliasis, monoliasis genital, otitis media
Central, peripheral nervous system:	Leg cramps, hypertonia, hypoesthesia, migraine, neuralgia, neuropathy, paresthesia, vertigo
Female reproductive:	Breast fibroadenosis, breast neoplasm, breast pain, dysmenorrhea, menstrual disorder, vaginal hemorrhage, vaginitis
Male reproductive:	Prostatic disorder
Hearing and vestibular:	Deafness, ear abnormality, earache, tinnitus
Heart rate and rhythm:	Palpitation, tachycardia
Liver and biliary system:	Hepatic function abnormal, SGOT increased, SGPT increased
Metabolic and nutritional:	BUN increased, CPK increased, diabetes mellitus, hypercholesterolemia, hyperglycemia, hypokalemia, NPN increase, creatinine increased, alkaline phosphatase increased, weight increase
Musculoskeletal:	Arthralgia, arthrosis, bone disorder, fracture accidental, myalgia, neck stiffness, synovitis, tendinitis
Platelets (bleeding or clotting):	Ecchymosis, epistaxis, thrombocythemia
Psychiatric:	Anorexia, anxiety, appetite increased, depression, nervousness, somnolence
Hemic:	Anemia
Respiratory:	Bronchitis, bronchospasm, bronchospasm aggravated, coughing, dyspnea, laryngitis, pneumonia
Skin and appendages:	Alopecia, dermatitis, nail disorder, photosensitivity reaction, pruritus, rash erythematous, rash maculopapular, skin disorder, skin dry, sweating increased, urticaria
Application site disorders:	Cellulitis, dermatitis contact, injection site reaction, skin nodule
Special senses:	Taste perversion
Urinary system:	Albuminuria, cystitis, dysuria, hematuria, micturition frequency, renal calculus, urinary incontinence, urinary tract infection
Vision:	Blurred vision, cataract, conjunctivitis, eye pain, glaucoma

Other serious adverse reactions which occur rarely (estimated <0.1%), regardless of causality: The following serious adverse events have occurred rarely in patients taking Celecoxib. Cases reported only in the post-marketing experience are indicated in italics.

Cardiovascular:	Syncope, congestive heart failure, ventricular fibrillation, pulmonary embolism, cerebrovascular accident, peripheral gangrene, thrombophlebitis , vasculitis
Gastrointestinal:	Intestinal obstruction, intestinal perforation, gastrointestinal bleeding, colitis with bleeding, esophageal perforation, pancreatitis, ileus
Liver and biliary system:	hepatitis, jaundice, liver failure
Hemic and lymphatic:	Thrombocytopenia, agranulocytosis, aplastic anemia, pancytopenia, leukopenia
Metabolic:	Hypoglycemia, hyponatremia
Nervous system:	Aseptic meningitis, ataxia, suicide
Renal:	Acute renal failure, interstitial nephritis
Skin:	Erythema, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis
General:	Sepsis, sudden death, angioedema

Suggested Links

http://nihseniorhealth.gov/arthritis/arthritisdefined/01.html

http://www.medicinenet.com/celecoxib-oral/article.htm