Indications:
Symptomatic treatment of osteoarthritis (OA) and rheumatoid arthritis (RA).
Relief of signs and symptoms of juvenile idiopathic arthritis (JIA) in patients 2 years of age and older weighing at least 10 kg.
Relief of signs and symptoms of ankylosing spondylitis (AS).
Management of acute pain.
For the treatment of primary dysmenorrhea.
Dosage and administration:
Dosage:
Celecoxib capsules, at doses up to 200 mg twice daily, can be taken with or without food.
As the cardiovascular (CV) risks of celecoxib may increase with dose and duration of exposure, the shortest duration possible and the lowest effective daily dose should be used.
Adult:
Symptomatic treatment of osteoarthritis (OA): The recommended dose of celecoxib is 200 mg administered as a single dose or as 100 mg twice daily.
Symptomatic treatment of rheumatoid arthritis (RA): The recommended dose of celecoxib is 100 mg or 200 mg twice daily.
Ankylosing spondylitis (AS): The recommended dose of celecoxib is 200 mg administered as a single dose or as 100 mg twice daily. Some patients may benefit from a total daily dose of 400 mg.
Management of acute pain: The recommended dose of celecoxib is 400 mg, initially, followed by an additional 200 mg dose, if needed on the first day. On subsequent days, the recommended dose is 200 mg twice daily, as needed.
Treatment of primary dysmenorrhea: The recommended dose of celecoxib is 400 mg, initially, followed by an additional 200 mg dose, if needed on the first day. On subsequent days, the recommended dose is 200 mg twice daily, as needed.
CYP2C9 poor metabolizers: Patients who are known, or suspected to be CYP2C9 poor metabolizers based on previous history/experience with other CYP2C9 substrates should be administered celecoxib with caution. Consider starting treatment at half the lowest recommended dose (see Interactions and Metabolism).
Elderly:
No dosage adjustment is generally necessary. However, for elderly patients weighing less than 50 kg, it is advisable to initiate therapy at the lowest recommended dose.
Children:
Juvenile idiopathic arthritis (JIA)
| Paediatric population (2 years of age and older) | Dosage |
| ≥ 10 kg to ≤ 25 kg | 50 mg twice daily |
| > 25 kg | 100 mg twice daily |
Celecoxib has been studied in patients with juvenile idiopathic arthritis 2 to 17 years of age.
The safety and efficacy of celecoxib in children have not been studied beyond six months or weighing less than 10 kg (22 lbs) or patients with manifestations of systemic disease.
Administration:
For patients who have difficulty swallowing capsules, the contents of a celecoxib in 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 or 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°C/35-45°F). 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 (see Hepatic effects).
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 (see Renal effects).
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 (see Interactions).
Some special attention on the handling of the medicine before and after use:
There are no special requirements for handling this medicine after use.
Contraindications:
Celecoxib is contraindicated in:
- Patients with known hypersensitivity to celecoxib and other ingredient
- 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 artery bypass graft (CABG) surgery (see Warnings and precautions for use).
Warnings and precautions for use:
Cardiovascular effects
Cardiovascular thrombosis: Celecoxib may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs may have a similar risk. This risk may increase with with dose, duration of use and risk factors for cardiovascular (CV) disease. Patients with a history of cardiovascular disease may be at higher risk. To minimise the potential risk for an adverse CV event in patients treated with celecoxib, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and symptoms of serious CV toxicity and the steps to take if they occur (see Pharmacodynamic properties).
Two large, controlled clinical trials showed an increased incidence of myocardial infarction and stroke when using a different COX-2 selective NSAID for the treatment of pain in the first 10–14 days following coronary artery bypass graft (CABG) surgery (see Contraindications).
Celecoxib is not a substitute for acetylsalicylic acid for prophylaxis of cardiovascular thromboembolic diseases due to lack of effect on platelet function. Because celecoxib dose not inhibit platelet aggregation, antiplatelet therapies should not be discontinued (e.g., acetylsalicylic acid).
Hypertension: As with all NSAIDs, celecoxib can lead to the onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. NSAIDs, including celecoxib should be used with caution in patients with hypertension. Blood pressure should be monitored closely during the initiation of therapy with celecoxib and throughout the course of therapy.
Fluid retention and edema: As with other drugs known to inhibit prostaglandin synthesis, fluid retention and edema have been observed in some patients taking celecoxib. Therefore, patients with pre-existing congestive heart failure (CHF) or hypertension should be closely monitored. Celecoxib should be used with caution in patients with compromised cardiac function, pre-existing edema or other conditions predisposing to, or worsened by, fluid retention including those taking diuretic treatment or otherwise at risk of hypovolemia.
Gastrointestinal (GI) effects
Upper and lower GI perforations, ulcers or bleeds have occurred in patients treated with celecoxib. Patients most at risk of developing these types of GI complications with NSAIDs are the elderly, patients with CV disease, patients using aspirin, glucocorticoids, or other NSAIDs, patients using alcohol or patients with a prior history of, or active, GI disease, such as ulceration, GI bleeding or inflammatory conditions. Most spontaneous reports of fatal GI events have been in elderly or debilitated patients.
Renal effects
NSAIDs including celecoxib may cause renal toxicity. Clinical trials with celecoxib have shown renal effects similar to those observed with comparator NSAIDs. Patients at greatest risk for renal toxicity are those with impaired renal function, heart failure, liver dysfunction, and the elderly. Such patients should be carefully monitored while receiving treatment with celecoxib.
Caution should be used when initiating treatment in patients with dehydration. It is advisable to rehydrate patients first and then start therapy with celecoxib.
Advanced renal disease
Renal function should be closely monitored in patients with advanced renal disease who are administered celecoxib (see Dosage and administration).
Anaphylactoid reactions
As with NSAIDs in general, anaphylactoid reactions have occurred in patients exposed to Celecoxib (see Contraindications).
Serious skin reactions
Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of celecoxib. Patients appear to be at highest risk for these events early in the course of therapy, the onset of the event occurring in the majority of cases within the first month of treatment. Celecoxib should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.
Hepatic effects:
Patients with severe hepatic impairment (Child-Pugh Class C) have not been studied. The use of celecoxib in patients with severe hepatic impairment is not recommended. Celecoxib should be used with caution when treating patients with moderate hepatic impairment (Child-Pugh Class B), and initiated at half the recommended dose (see Dosage and administration).
Rare cases of severe hepatic reactions, including fulminant hepatitis (some with fatal outcome), liver necrosis, and hepatic failure (some with fatal outcome or requiring liver transplant), have been reported with celecoxib.
A patient with symptoms and/or signs of liver failure, or in whom an abnormal liver function test has occurred, should be monitored carefully for evidence of the development of a more severe hepatic reaction while on therapy with celecoxib.
Use with oral anticoagulants
The concomitant use of NSAIDs with oral anticoagulants increases the risk of bleeding and should be given with caution. Oral anticoagulants include warfarin/coumarin-type and novel oral anticoagulants (such as apixaban, dabigatran, and rivaroxaban). In patients on concurrent therapy with warfarin or similar agents, serious bleeding events, some of them fatal, have been reported. Because increases in prothrombin time (INR) have been reported, anticoagulation/INR should be monitored in patients taking a warfarin/coumarin-type anticoagulant after initiating treatment with celecoxib or changing the dose (see Interaction with other medicinal products and other forms of interaction).
Systemic-onset juvenile idiopathic arthritis (JIA)
Caution should be exercised when administering NSAIDs including celecoxib in patients with systemic-onset juvenile idiopathic arthritis, due to the risk of disseminated intravascular coagulation. Patients with systemic-onset JIA should be monitored for the development of abnormal coagulation tests when celecoxib is used.
General
With anti-inflammatory effects, celecoxib may diminish the utility of diagnostic signs, such as fever symptom in detecting infections.
The concomitant use of celecoxib and a non-aspirin NSAID should be avoided.
CYP2D6 inhibition
Celecoxib is a moderately CYP2D6 inhibitor. For drugs that are metabolized by CYP2D6, a dose reduction during initiation of celecoxib treatment or a dose increase upon termination of celecoxib treatment may be necessary (see Interaction with other medicinal products and other forms of interaction).
This medicine contains lactose: Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Fertility, pregnancy and lactation:
Fertility:
Based on the mechanism of action, the use of NSAIDs, including celecoxib, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of NSAIDs, including celecoxib, should be considered.
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, as with other drugs inhibiting prostaglandin synthesis, may cause uterine inertia and premature closure of the ductus arteriosus, celecoxib 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 low 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.
Effects on ability to drive and use machines:
The effect of celecoxib on ability to drive or use machinery has not been studied, but based on its pharmacodynamic properties and overall safety profile it is unlikely to have an effect.
Interactions, incompatibilities of medicine:
Interaction with other medicinal products and other forms of interaction:
General
Celecoxib is mainly metabolized via cytocrom P450 (CYP) 2C9 in the liver. Caution should be exercised when celecoxib is used in patients who have or are suspected of poor metabolism via CYP2C9 based on a history of other CYP2C9 substrates because these patients may have abnormally high plasma celecoxib concentrations due to reduced metabolic clearance. Treatment should be started at half the lowest recommended dose (see Dosage and administration and Metabolism).
Concomitant administration of celecoxib with inhibitors of CYP2C9 can lead to increases in plasma concentrations of celecoxib. Therefore, a dose reduction of celecoxib may be necessary when celecoxib is co-administered with CYP2C9 inhibitors.
Concomitant administration of celecoxib with inducers of CYP2C9 such as rifampicin, carbamazepine and barbiturates decrease 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 are a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6.
Drug-specific
Interaction of celecoxib with warfarin or similar agents: (see Use with oral anticoagulants).
Lithium: In healthy subjects, lithium plasma levels increased approximately 17% in subjects receiving lithium together with celecoxib. Patients on lithium treatment should be closely monitored when celecoxib is introduced or withdrawn.
Aspirin: Celecoxib does not interfere with the anti-platelet effect of low-dose aspirin (see Gastrointestinal (GI) effects). Because of its lack of platelet effects, Celecoxib is not a substitute for aspirin in the prophylactic treatment of CV disease.
Anti-hypertensives including angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II antagonists (also known as angiotensin receptor blockers [ARBs]), diuretics and beta-blockers: Inhibition of prostaglandins may diminish the effect of anti-hypertensives including ACEIs and/or ARBs, diuretics and beta-blockers. This interaction should be given consideration in patients taking celecoxib concomitantly with ACEIs and/or ARBs, diuretics and beta-blockers.
In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs including selective COX-2 inhibitors with ACE inhibitors, angiotensin II antagonists or diuretics, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Therefore, the concomitant administration of these drugs should be done with caution. Patients should be adequately hydrated and the clinical need to monitor the renal function should be assessed at the beginning of the concomitant treatment and periodically thereafter.
Results from lisinopril study: In a 28-day clinical study in patients with lisinopril-controlled Stage I and II hypertension, administration of celecoxib 200 mg twice daily resulted in no clinically significant increases, when compared to placebo treatment, in mean daily systolic or diastolic blood pressure as determined using 24-hour ambulatory blood pressure monitoring. Among patients co-administered with celecoxib 200 mg twice daily, 48% were considered unresponsive to lisinopril at the final clinic visit (defined as either cuff diastolic blood pressure > 90 mmHg or cuff diastolic blood pressure increased >10% compared to baseline), compared to 27% of patients co-administered with placebo; this difference was statistically significant.
Cyclosporine: Because of their effect on renal prostaglandins, NSAIDs may increase the risk of nephrotoxicity with cyclosporine.
Fluconazole and ketoconazole: Concomitant administration of fluconazole at 200 mg once daily resulted in a two-fold increase in celecoxib plasma concentration. This increase is due to the inhibition of celecoxib metabolism via CYP P450 2C9 by fluconazole. Celecoxib should be introduced at half the recommended dose in patients receiving the CYP2C9 inhibitor fluconazole (see Dosage and administration). Ketoconazole, a CYP3A4 inhibitor, showed no clinically relevant inhibition in the metabolism of celecoxib.
Dextromethorphan and metoprolol: Concomitant administration of celecoxib 200 mg twice daily resulted in a 2.6-fold and a 1.5-fold increases in plasma concentrations of dextromethorphan and metoprolol (CYP2D6 substrates), respectively. These increases are due to celecoxib inhibition to the CYP2D6 substrate metabolism via CYP2D6. Therefore, the dose of drugs as CYP2D6 substrate may need to be reduced when treatment with celecoxib is initiated or increased when treatment with celecoxib is terminated (see Use with oral anticoagulants).
Diuretics: Clinical studies have shown that NSAIDs, in some patients, can reduce the natriuretic effect of furosemide and thiazides by inhibition of renal prostaglandin synthesis.
Methotrexate: No clinically interactions and important pharmacokinetic have been observed in a clinical study between celecoxib and methotrexate.
Oral contraceptives: In an interaction study, celecoxib had no clinically relevant effects on the pharmacokinetics of a prototype combination oral contraceptive (1 mg norethindrone/0.035 mg ethinyl estradiol).
Other drugs: No clinically important interactions have been observed with celecoxib and antacids (aluminum and magnesium), omeprazole, glibenclamide (glyburide), phenytoin, or tolbutamide.
Incompatibilities:
Because there are no studies of drug incompatibility, do not mix this drug with other drugs.
Undesirable effects:
Clinical trials experience
The following adverse drug reactions (ADRs) in table 1 were identified with incidence rates greater than 0.01% in celecoxib group and greater than those reported in placebo group, during 12 placebo- and/or active-controlled clinical trials of treatment duration up to 12 weeks at daily doses from 100 mg up to 800 mg in adults. The frequencies on the ADRs in table 1 are updated based on a more recent pooling of 89 randomized, controlled clinical trials data representing clinical exposure in 38,102 patients taking celecoxib ADR frequencies are defined as: Very common (≥10%), common (≥ 1% and < 10%), uncommon (≥ 0.1% and < 1%), rare (≥ 0.01% and < 0.1%), very rare (< 0.01%). The ADRs in table 1 are listed by system organ class and ranked by frequency in descending order.
| Table 1. Adverse drug reactions (adrs) in 12 placebo- and/or active-controlled clinical trials and adr frequency from 89 pain and inflammation randomized, controlled clinical trials with daily doses of 25 mg to 800 mg in adult populations. | |
| System Organ Class
Frequency |
Adverse drug reaction |
| Infections and infestations | |
| Common | Bronchitis, sinu
itis, upper respiratory tract infection, urinary tract infection |
| Uncommon | Pharyngitis, rhinitis |
| Blood and lymphatic system disorders | |
| Uncommon | Anemia |
| Rare | Thrombocytopenia |
| Immune system disorders | |
| Uncommon | Hypersensitivity |
| Psychiatric disorders | |
| Common | Insomnia |
| Uncommon | Anxiety |
| Rare | Confusional state |
| Nervous system disorders | |
| Common | Dizziness |
| Uncommon | Hypertonia, somnolence |
| Eye disorders | |
| Uncommon | Vision blurred |
| Ear and labyrinth disorders | |
| Uncommon | Tinnitus |
| Cardiac disorders | |
| Uncommon | Palpitations |
| Rare | Cardiac failure congestive, arrhythmia, |
| Vascular disorders | |
| Common | Hypertension (including aggra
ated hypertension) |
| Rare | Flushing |
| Respiratory, thoracic and mediastinal disorders | |
| Common | Cough |
| Gastrointestinal disorders | |
| Common | Vomiting, abdominal pain, diarrhea, dyspepsia, flatulence |
| Uncommon | Gastric ulcer, dental problems |
| Rare | Duodenal ulce
, esophageal ulcer |
| Very rare | Intestinal perforation, pancreatitis |
| Hepatobiliary disorders | |
| Uncommon | Hepatic enzyme increase
(includes alanine aminotransferase increased and aspartate aminotransferase increased) |
| Skin and subcutaneous tissue disorders | |
| Common | Pruritus (includes pruritus generalized), rash |
| Uncommon | Urticaria, ecchymosis |
| Rare | Angioedema, alopecia |
| Very rare | Dermatitis bullous |
| General disorders and administration site conditions | |
| Common | Edema peripheral |
| Uncommon | Face edema, influenza like illness |
| Injury, poisoning and procedural conditions | |
| Uncommon | Injury |
The following additional adverse drug reactions in table 2 were identified with incidence rates greater than placebo in long-term polyp prevention studies of duration up to 3 years at daily doses from 400 mg up to 800 mg. (See Cardiovascular Safety – Long term studies involving patients with sporadic adenomatous polyps under actions).
Frequencies of ADRs in Table 2 were determined based on these long-term polyp prevention studies and defined as: very common (≥ 10%), common (≥ 1% and < 10%), uncommon (≥ 0.1% and < 1%). The ADRs in table 2 are listed by system organ class and ranked by frequency in descending order.
| Table 2: Adverse reactions from polyp prevention studies of duration up to 3 years and daily doses of 400 mg – 800 mg | |
| System organ class | Adverse drug reaction |
| Frequency | |
| Infections and infestations | |
| Common | Ear infection, fungal infection** |
| Uncommon | Helicobacter infection, Herpes zoster, erysipelas, wound infection, gingivitis, labyrinthitis, bacterial infection |
| Neoplasms benign, malignant, and unspecified | |
| Uncommon | Lipoma |
| Psychiatric disorders | |
| Uncommon | Sleep disorder |
| Nervous system disorders | |
| Uncommon | Cerebral infarction |
| Eye disorders | |
| Uncommon | Conjunctival hemorrhage, vitreous floaters |
| Ear and labyrinth disorders | |
| Uncommon | Hypoacusis |
| Cardiac disorders | |
| Common | Myocardial infarction, angina pectoris |
| Uncommon | Angina unstable, aortic valve incompetence, arteriosclerosis coronary artery, sinus bradycardia, ventricular hypertrophy |
| Vascular disorders | |
| Very common | Hypertension* |
| Uncommon | Deep vein thrombosis, hematoma |
| Respiratory, thoracic and mediastinal disorders | |
| Common | Dyspnea |
| Uncommon | Dysphonia |
| Gastrointestinal disorders | |
| Very common | Diarrhea* |
| Common | Vomiting*, dysphagia, irritable bowel syndrome, gastroesophageal reflux disease, nausea, diverticulum |
| Uncommon | Hemorrhoidal hemorrhage, f
equent bowel movements, mouth ulceration, stomatitis |
| Hepatobiliary disorders | |
| Rare | Hepatic enzyme increased (includes alanine aminotransferase increased and aspartate aminotransferase increased)* |
| Skin and subcutaneous tissue disorders | |
| Uncommon | Dermatitis allergic |
| Musculoskeletal and connective tissue disorders | |
| Common | Muscle spasms |
| Uncommon | Synovial cyst |
| Renal and urinary disorders | |
| Common | Nephrolithiasis |
| Uncommon | Nocturia |
| Reproductive system and breast disorders | |
| Common | Vaginal hemorrhage, prostatitis, benign prostatic hyperplasia |
| Uncommon | Ovarian cyst, menopausal symptoms, breast tenderness, dysmenorrhea |
| General disorders and administration site conditions | |
| Uncommon | Edema |
| Investigations | |
| Common | Blood creatinine increased, prostatic specific antigen increased, weight increased |
| Uncommon | Blood potassium increased, blood sodium increased, blood testosterone decreased, hematocrit decreased, hemoglobin increased |
| Injury, poisoning and procedural complications | |
| Uncommon | Foot fracture, lower limb fracture, fracture, epicondylitis, tendon rupture |
*Hypertension, vomiting, diarrhea, and hepatic enzymes increased are included in table 2 because these events were reported more frequently in these studies, which were of 3-year duration, compared to table 10, which includes adverse reactions from studies of 12-week duration.
** Fungal infections were primarily non-systemic.
Pediatric
Generally, undesirable effects observed in the pivotal studies in children are similar to those encountered in studying the reaction arthritis in adults (see Table 1 and Juvenile idiopathic arthritis). In addition, the following are the undesirable effects that are not listed in Table 1 as observed by researchers and may be related to celecoxib: Headache (11.3%, very common), hematuria (0.6%, uncommon) and asthma attack (0.6%, uncommon). Compared with naproxen, celecoxib at doses of 3 and 6 mg/kg twice daily had no observable deleterious effect on growth and development during the course of the 12-week double-blind study.
Post-marketing experience
Adverse reactions identified from post-marketing experience are provided as follows. Even though these were identified as reactions from post-marketing reports, trial data was consulted to estimate frequency. As previously mentioned, frequencies are based on a pooling of trials representing exposure in 38,102 patients. Frequencies are defined as: Very common (≥ 10%), common (≥ 1% and < 10%), uncommon (≥ 0.1% and < 1%), rare (≥ 0.01% and < 0.1%), very rare (< 0.01%), not known (cannot be estimated from the available data).
Immune system disorders:
Very rare: Anaphylactic reactions.
Psychiatric disorders:
Rare: Hallucination
Nervous system disorders:
Very rare: Cerebral hemorrhage, meningitis aseptic, ageusia, anosmia.
Eye disorders:
Uncommon: Conjunctivitis.
Vascular disorders:
Very rare: Vasculitis.
Respiratory, thoracic and mediastinal disorders:
Rare: Pulmonary embolism, pneumonitis
Gastrointestinal disorders:
Rare: Gastrointestinal hemorrhage.
Hepatobiliary disorders:
Rare: Hepatitis.
Very rare: Hepatic failure, hepatitis fulminant, hepatic necrosis (see Hepatic effect), cholestasis, hepatitis cholestatic, jaundice.
Skin and subcutaneous tissue disorders:
Rare: Photosensitivity reaction
Very rare: Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS or or hypersensitivity syndrome), acute generalized exanthematous pustulosis (AGEP), dermatitis exfoliative.
Renal and urinary disorders:
Rare: Renal failure acute (see Renal effects) hyponatremia.
Very rare: Tubulointerstitial nephritis, nephrotic syndrome, glomerulonephritis minimal lesion.
Reproductive system and breast disorders:
Rare: Menstrual disorder
Not known: Fertility disorder in women (see Fertility, pregnancy and lactation).
General disorders and administration site conditions:
Uncommon: Chest pain.
Women intending to become pregnant are excluded from all trials, thus consultation of the trial database for the frequency of this event was not reasonable.
Overdosage and management:
Clinical experience with overdose is limited. Single dose of 1200 mg or multiple dose (twice daily) with a total dose of 1200 mg in healthy subjects did not show any adverse effects of clinical significance. In the event of a suspected overdose, appropriate medical assistance should be taken. Dialysis is unlikely to be an efficient method of medicinal product removal due to high protein binding.
Pharmacodynamic properties:
Pharmacotherapeutic group: Coxibs.
ATC code: M01AH01
The mechanism of action of celecoxib is inhibition of prostaglandin synthesis, primarily via inhibition of cyclooxygenase-2 (COX-2). At therapeutic concentrations in humans celecoxib does not inhibit the enzyme cyclooxygenase-1 (COX-1). COX-2 is induced in response to inflammatory agent. This leads to the synthesis and accumulation of inflammatory prostanoids, in particular prostaglandin E2, causing inflammation, oedema and pain. In animal models, celecoxib acts as an anti-inflammatory, analgesic and antipyretic agent by blocking the production of inflammatory prostanoids via COX-2 inhibition. In animal colon tumour models, celecoxib reduced the incidence and multiplicity of tumours.
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 synthesised by activation of COX-1 thereby not interfering with normal COX-1 related physiological processes in tissues, particularly the stomach, intestine and platelets.
Pharmacokinetic properties:
Absorption
The pharmacokinetics of celecoxib have been evaluated in approximately 1500 individuals. When celecoxib is given under fasting conditions, peak plasma concentrations are reached after approximately 2-3 hours. The relative oral bioavailability of capsules compared with a suspension is about 99% (available optimal oral form). Under fasting conditions, both peak plasma levels (Cmax) and area under the curve (AUC) are roughly dose proportional up to 200 mg twice daily; at higher doses there are less than proportional increases in Cmax and AUC.
Distribution
Plasma protein binding is about 97 % at therapeutic plasma concentrations and the medicinal product is not preferentially bound to erythrocytes.
Metabolism
Celecoxib metabolism is primarily mediated via cytochrome P450 2C9. Three metabolites, inactive as COX-1 or COX-2 inhibitors, have been identified in human plasma i.e., a primary alcohol, the corresponding carboxylic acid and its glucuronide conjugate.
Cytochrome P450 2C9 activity is reduced in individuals with genetic polymorphisms that lead to reduced enzyme activity, such as those homozygous for the CYP 2C9*3 polymorphism.
In a pharmacokinetic study of celecoxib 200 mg administered once daily in healthy volunteers, genotyped as either CYP2C9*1/*1, CYP2C9*1/*3, or CYP2C9*3/*3, the median Cmax and AUC0-24 of celecoxib on day 7 were approximately 4-fold and 7-fold, respectively, in subjects genotyped as CYP2C9*3/*3 compared to other genotypes. In three separate single dose studies, involving a total of 5 subjects genotyped as CYP2C9*3/*3, single-dose AUC0-24 increased by approximately 3-fold compared to normal metabolisers. It is estimated that the frequency of the homozygous *3/*3 genotype is 0.3-1.0 % among different ethnic groups.
Patients who are known, or suspected to be CYP2C9 poor metabolisers based on previous history/experience with other CYP2C9 substrates should be administered celecoxib with caution. Consideration should be given to initiating therapy with a lower starting dose (see Dosage and administration and Interactions with other medicines).
Elimination
Elimination of celecoxib is mostly by hepatic metabolism with less than 1% of the dose being excreted unchanged in the urine. After using a multi-dose, the half-life is 8 – 12 hours and the clearance rate is about 500 ml/min. With multiple dose, steady state plasma concentrations are reached within 5 days of treatment. Intersubject variability in the Cmax and AUC is about 30%. The apparent volume of distribution at steady state is about 500 L/70 kg in healthy young adults, suggesting extensive tissue distribution. Preclinical studies have determined that the drug crosses the blood-brain barrier.
Food effects
Dosing with food (high fat meal) delays absorption of celecoxib by about 1 hour resulting in a Tmax of about 4 hours and increases bioavailability by about 20%. (Dosage and administration).
In healthy adult volunteers, the overall systemic exposure (AUC) of celecoxib was equivalent when celecoxib was administered as intact capsule or capsule contents sprinkled on applesauce. There were no significant alterations in Cmax, Tmax or T1/2 after administration of capsule contents on applesauce.
Special Populations
Elderly
In people over 65 years of age, the Cmax and AUC of celecoxib increases by 1.5 – 2 times. This is primarily related to weight, not change age, celecoxib levels are higher in patients with lower body weight and therefore elderly people with low average weight have higher celecoxib concentrations than younger people. Thus, elderly females have plasma drug concentrations are higher than those for elderly males. No dosage adjustment is generally necessary. However, for elderly patients with a body weight of less than 50 kg treatment should be initiated at the lowest recommended dose.
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 impairment
Celecoxib plasma concentrations in patients with mild hepatic impairment (Child-Pugh Class A) no significant difference compared with the levels in the control group of the same age and gender. In patients with moderate hepatic impairment (Child-Pugh Class B) serum celecoxib concentrations are approximately 2 times that of the corresponding control group (see Dosage and administration).
Renal impairment
In elderly volunteers with age related reductions in glomerular filtration rate (GFR) (mean GFR > 65 mL/min/1.73m2) and in patients with chronic stable renal insufficiency (GFR 35 – 60 mL/min/1.73m2) celecoxib pharmacokinetics were comparable to those seen in patients with normal renal function. No significant relationship was found between serum creatinine (or creatinine clearance) and celecoxib clearance. Severe renal insufficiency would not be expected to alter clearance of celecoxib since the main route of elimination is via hepatic metabolism to inactive metabolites.
Renal effects
The relative roles of COX-1 and COX-2 in rena physiology is incompletely understood. Celecoxib reduces the urinary excretion of PGE2 and 6-keto-PGF1α (a prostacyclin metabolite) but leaves serum thromboxane B2 (TXB2) and urinary excretion of 11-dehydro-TXB2, a thromboxane metabolite (both COX-1 products) unaffected. Separate studies have shown that celecoxib did not reduce the GFR in elderly patients or patients with chronic renal failure. These studies also showed a slight decrease in sodium excretion. In studies in patients with arthritis, the incidence of peripheral angioedema was observed to be comparable to that in patients on non specific COX inhibitors (which also had COX-2 inhibitor effects). This is most noticeable in the patients receiving combination therapy with diuretics. However, there was no increase in the incidence of hypertension and heart failure; Peripheral angioedema is usually mild and resolves.
Storage conditions, shelf – life, quality specification of the medicine:
Storage conditions: Protect from humidity and light, below 300C.
Shelf – life: 36 months from the manufacture date.
Quality specification: In house specification.
A1203007303
