CELEBREX Capsule

Indications

- Symptomatic treatment of osteoarthritis (OA) and rheumatoid arthritis (RA)

- Relief of signs and symptoms Ankylosing spondylitis (AS)

- Management of acute pain

- Treatment of primary dysmenorrhea

Dosage

at doses up to 200mg twice per day, can be taken with or without food.

As the cardiovascular risks of celecoxib may increase with dose and duration of exposure, the shortest duration possible and the lowest effective daily dose should be used.

Adults

Symptomatic Treatment of Osteoarthritis (OA): 200mg as a single dose or 100mg twice per day.

Symptomatic Treatment of Rheumatoid Arthritis (RA):100mg or 200mg twice per day.

Ankylosing Spondylitis (AS): 200mg as a single dose or 100mg twice per day. up to 400mg.

Management of Acute Pain: 400mg. Initially, followed by an additional 200mg dose, if needed on the first day. On subsequent days, 200mg twice daily, as needed.

Treatment of Primary Dysmenorrhea: 400mg, initially, followed by an additional 200mg dose, if needed on the first day. On subsequent days, 200mg twice daily, as needed.

CYP2C9 Poor Metabolizers: Consider starting treatment at half the lowest recommended dose.

Elderly: No dosage adjustment is generally necessary. However, for elderly patients weighing less than 50kg, it is advisable to initiate therapy at the lowest recommended dose.

Method of Administration

For patients who have difficulty swallowing capsules, the contents of a celecoxib capsule can be added to applesauce, rice gruel, yogurt or mashed banana. To do so, the entire capsule contents must be carefully emptied onto a level teaspoon of cool or room temperature applesauce, rice gruel, yogurt mashed banana and should be ingested immediately with water. The sprinkled capsule contents on applesauce, rice gruel or yogurt are stable for up to 6 hours under refrigerated conditions (2℃-8℃/35℉-45℉). The sprinkled capsule contents on mashed banana should not be stored under refrigerated conditions and should be ingested immediately.

Hepatic Impairment: No dosage adjustment is necessary in patients with mild hepatic impairment (Child-Pugh Class A). Introduce celecoxib at half the recommended dose in arthritis or pain patients with moderate hepatic impairment (Child-Pugh Class B).

Patients with severe hepatic impairment (Child-Pugh Class C) have not been studied.

Renal Impairment: No dosage adjustment is necessary in patients with mild or moderate renal impairment. There is no clinical experience in patients with severe renal impairment.

Co-administration with Fluconazole: Celecoxib should be introduced at half the recommended dose in patients receiving fluconazole, a CYP2C9 inhibitor. Caution is advised when co-administering celecoxib with other CYP2C9 inhibitors.

- patients with known hypersensitivity to celecoxib or any other ingredient of the product,

- patients with known sulfonamide hypersensitivity,

- patients who have experienced asthma, urticaria or allergic-type reactions after taking acetylsalicylic acid (ASA (aspirin)) or other non-steroidal anti-inflammatory drugs (NSAIDs), including other cyclooxygenase-2 (COX-2) specific inhibitors,

- Treatment of peri-operative pain in the setting of coronary aftery bypass graft (CABG) surgery.

Interactions

- General: Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Patients who are known or suspected to be poor CYP2C9 metabolizers based on previous history/experience with other CYP2C9 substrates should be administered celecoxib with caution as they may have abnormally high plasma levels due to reduced metabolic clearance. Consider starting treatment at half the lowest recommended dose.

Concomitant administration of celecoxib with inhibitors of CYP2C9 such as rifampicin, carbamazepine and barbiturates can lead to decreases in plasma concentrations of celecoxib. Therefore, a dose increase of celecoxib may be necessary when celecoxib is co-administered with CYP2C9 inducers.

Clinical pharmacokinetics study and in vitro studies indicate that celecoxib, although not a substrate is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6.

- warfarin or similar agents

- Lithium

- Aspirin

- Anti-hypertensives including Angiotensin-converting enzyme inhibitors (ACEIs), AngiotensinⅡantagonists (also known as angiotensin receptor blockers, ARBs), diuretics and beta-blockers

- Cyclosporine

- Fluconazole and ketoconazole

- Dextromethorphan and metoprolol

- Diuretics

- Methotrexate

- Oral contraceptives

- Other drugs: No clinically important interactions have been observed with celecoxib and antacids (aluminum and magnesium), omeprazole, glibenciamide (glyburide), phenytoin, tolbutamide

Pregnancy ＆ Lactation

Pregnancy

There are no studies in pregnant women. Studies in animals have shown reproductive toxicity. The relevance of these data for humans is unknown.

Celecoxib may cause uterine inertia and premature closure of the ductus arteriosus and should be avoided during the third trimester of pregnancy.

Celecoxib should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

Inhibition of prostaglandin synthesis might adversely affect pregnancy. Data from epidemiological studies suggest an increased risk of spontaneous abortion after use of prostaglandin synthesis inhibitors in early pregnancy. In animals, administration of prostaglandin synthesis inhibitors has been shown to result in increased pre- and post-implantation loss.

Lactation

Studies in rats show that celecoxib is excreted in milk at concentrations similar to those in plasma. Administration of celecoxib to lactating women has shown very los transfer of celecoxib into breast milk. Because of the potential for adverse reactions in nursing infants from celecoxib, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the expected benefit of the drug to the mother.

- Cardiovascular effects

- Gastrointestinal (GI) effects

- Renal effects

- Anaphylactoid reactions

- Serious skin reactions

- Hepatic effects

- Use with oral acticoagulants

- General

By reducing inflammation, celecoxib may diminish the utility of diagnostic signs, such as fever, in detecting infections. The concomitant use of celecoxib and a non-aspirin NSAID should be avoided.

- CYP2D6 inhibition

Mechanism of action

The mechanism of action of celecoxib is via inhibition of prostaglandin synthesis primarily by inhibition of cyclooxygenase 2 (COX-2). At therapeutic concentrations in humans celecoxib does not inhibit cyclooxygenase 1 (COX-1).COX-2 is induced in response to inflammatory stimuli. This leads to the synthesis and accumulation of inflammatory prostanoids, in particular prostaglandin E2, causing inflammation, edema and pain. Celecoxib acts as an anti-inflammatory, analgesic, and antipyretic agent in animal models by blocking the production of inflammatory prostanoids via COX-2 inhibition.　In animal colon tumor models, celecoxib reduced the incidence and multiplicity of tumors.

In vivo and ex vivo studies show that celecoxib has a very low affinity for the constitutively expressed COX-1 enzyme. Consequently at therapeutic doses celecoxib has no effect on prostanoids synthesized by activation of COX-1 thereby not interfering with normal COX-1 related physiological process in tissues, particularly the stomach, intestine and platelets.