In adults for the symptomatic relief in the treatment of:

-                  osteoarthritis

-                  rheumatoid arthritis

-                  ankylosing spondylitis

 

The decision to prescribe a selective cyclooxygenase-2 (COX-2) inhibitor should be based on an assessment of the individual patient’s overall risks (see sections 4.3 and 4.4).

Posology

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. The patient’s need for symptomatic relief and response to therapy should be re-evaluated periodically, especially in patients with osteoarthritis (see sections 4.3, 4.4, 4.8 and 5.1).

 

Osteoarthritis

The usual recommended daily dose is 200 mg taken once daily or in two divided doses. In some patients, with insufficient relief from symptoms, an increased dose of 200 mg twice daily may increase efficacy. In the absence of an increase in therapeutic benefit after two weeks, other therapeutic options should be considered.

 

Rheumatoid arthritis

The initial recommended daily dose is 200 mg taken in two divided doses. The dose may, if needed, later be increased to 200 mg twice daily. In the absence of an increase in therapeutic benefit after two weeks, other therapeutic options should be considered.

 

Ankylosing spondylitis

The recommended daily dose is 200 mg taken once daily or in two divided doses. In a few patients, with insufficient relief from symptoms, an increased dose of 400 mg once daily or in two divided doses may increase efficacy. In the absence of an increase in therapeutic benefit after two weeks, other therapeutic options should be considered.

The maximum recommended daily dose is 400 mg for all indications. Special populations

Elderly (>65 years)

As in younger adults, 200 mg per day should be used initially. The dose may, if needed, later be increased to 200 mg twice daily. Particular caution should be exercised in elderly with a body weight less than 50 kg (see sections 4.4 and 5.2).

 

Paediatric population

Celecoxib is not indicated for use in children.

 

CYP2C9 poor metabolisers

Patients who are known, or suspected to be CYP2C9 poor metabolisers based on genotyping or previous history/experience with other CYP2C9 substrates should be administered celecoxib with caution as the risk of dose-dependent adverse effects is increased. Consider reducing the dose to half the lowest recommended dose (see section 5.2).

 

Hepatic impairment

Treatment should be initiated at half the recommended dose in patients with established moderate liver

 

impairment with a serum albumin of 25-35 g/l. Experience in such patients is limited to cirrhotic patients (see sections 4.3, 4.4 and 5.2).

 

Renal impairment

Experience with celecoxib in patients with mild or moderate renal impairment is limited, therefore such patients should be treated with caution (see sections 4.3, 4.4 and 5.2).

 

Method of administration Oral use

 

Revcox may be taken with or without food.

 

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 or mashed banana and should be ingested immediately with a glass of water.

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. - Known hypersensitivity to sulfonamides. - Active peptic ulceration or gastrointestinal (GI) bleeding. - Patients who have experienced asthma, acute rhinitis, nasal polyps, angioneurotic oedema, urticaria or other allergic-type reactions after taking acetylsalicylic acid or other non-steroidal anti- inflammatory drugs (NSAIDs) including cyclooxygenase-2 (COX-2) inhibitors. - In pregnancy and in women of childbearing potential unless using an effective method of contraception (see section 4.6). Celecoxib has been shown to cause malformations in the two animal species studied (see sections 4.6 and 5.3). The potential for human risk in pregnancy is unknown, but cannot be excluded. - Breast-feeding (see sections 4.6 and 5.3). - Severe hepatic dysfunction (serum albumin <25 g/l or Child-Pugh score ≥10). - Patients with estimated creatinine clearance <30 ml/min. - Inflammatory bowel disease. - Congestive heart failure (NYHA II-IV). - Established ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease.

Gastrointestinal (GI) effects

Upper and lower gastrointestinal complications (perforations, ulcers or bleedings [PUBs]), some of them resulting in fatal outcome, have occurred in patients treated with celecoxib. Caution is advised with treatment of patients most at risk of developing a gastrointestinal complication with NSAIDs; the elderly, patients using any other NSAID or antiplatelet medicinal products (such as acetylsalicylic acid) or glucocorticoids concomitantly, patients using alcohol, or patients with a prior history of gastrointestinal disease, such as ulceration and GI bleeding.

 

There is further increase in the risk of gastrointestinal adverse effects for celecoxib (gastrointestinal ulceration or other gastrointestinal complications), when celecoxib is taken concomitantly with acetylsalicylic acid (even at low doses).

 

A significant difference in GI safety between selective COX-2 inhibitors plus acetylsalicylic acid vs. NSAIDs plus acetylsalicylic acid has not been demonstrated in long-term clinical trials (see section 5.1).

 

Concomitant NSAID use

The concomitant use of celecoxib and a non-acetylsalicylic acid NSAID should be avoided.

 

Cardiovascular effects

Increased number of serious cardiovascular events, mainly myocardial infarction, has been found in a long-term placebo-controlled study in subjects with sporadic adenomatous polyps treated with celecoxib at doses of 200 mg twice daily and 400 mg twice daily compared to placebo (see section 5.1).

 

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. NSAIDs, including COX-2 selective inhibitors, have been associated with increased risk of cardiovascular and thrombotic adverse events when taken long term. The exact magnitude of the risk associated with a single dose has not been determined, nor has the exact duration of therapy associated with increased risk. The patient’s need for symptomatic relief and response to therapy should be re-evaluated periodically, especially in patients with osteoarthritis (see sections 4.2, 4.3, 4.8 and 5.1).

 

Patients with significant risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking) should only be treated with celecoxib after careful consideration (see section 5.1).

 

COX-2 selective inhibitors are not a substitute for acetylsalicylic acid for prophylaxis of cardiovascular thrombo-embolic diseases because of their lack of antiplatelet effects. Therefore, antiplatelet therapies should not be discontinued (see section 5.1).

 

Fluid retention and oedema

As with other active substances known to inhibit prostaglandin synthesis fluid retention and oedema have been observed in patients taking celecoxib. Therefore, celecoxib should be used with caution in

 

patients with history of cardiac failure, left ventricular dysfunction or hypertension, and in patients with pre-existing oedema from any other reason, since prostaglandin inhibition may result in deterioration of renal function and fluid retention. Caution is also required in patients taking diuretic treatment or otherwise at risk of hypovolaemia.

 

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 cardiovascular events. Therefore, blood pressure should be monitored closely during the initiation of therapy with celecoxib and throughout the course of therapy.

 

Hepatic and renal effects

Compromised renal or hepatic function and especially cardiac dysfunction are more likely in the elderly and therefore medically appropriate supervision should be maintained.

 

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, those taking diuretics, angiotensin converting enzyme (ACE)-inhibitors, angiotensin II receptor antagonists, and the elderly (see section 4.5). Such patients should be carefully monitored while receiving treatment with celecoxib.

 

Some 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. Among the cases that reported time to onset, most of the severe adverse hepatic events developed within one month after initiation of celecoxib treatment (see section 4.8).

 

If during treatment, patients deteriorate in any of the organ system functions described above, appropriate measures should be taken and discontinuation of celecoxib therapy should be considered.

 

CYP2D6 inhibition

Celecoxib inhibits CYP2D6. Although it is not a strong inhibitor of this enzyme, a dose reduction may be necessary for individually dose-titrated medicinal products that are metabolised by CYP2D6 (see section 4.5).

 

CYP2C9 poor metabolisers

Patients known to be CYP2C9 poor metabolisers should be treated with caution (see section 5.2).

 

Skin and systemic hypersensitivity 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 (see section 4.8). Patients appear to be at highest risk for these reactions early in the course of therapy: the onset of the reaction occurring in the majority of cases within the first month of treatment. Serious hypersensitivity reactions (including anaphylaxis, angioedema and drug rash with eosinophilia and systemic symptoms [DRESS, or hypersensitivity syndrome]) have been reported in patients receiving celecoxib (see section 4.8). Patients with a history of sulfonamide allergy or any medicinal product allergy may be at greater risk of serious skin reactions or hypersensitivity reactions (see section 4.3). Celecoxib should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

 

General

Celecoxib may mask fever and other signs of inflammation.

 

Use with oral anticoagulants

In patients on concurrent therapy with warfarin, serious bleeding events, some of them fatal, have been reported. Increased prothrombin time (INR) with concurrent therapy has been reported.

Therefore, this should be closely monitored in patients receiving warfarin/coumarin-type oral anticoagulants, particularly when therapy with celecoxib is initiated or celecoxib dose is changed

 

(see section 4.5). Concomitant use of anticoagulants with NSAIDs may increase the risk of bleeding. Caution should be exercised when combining celecoxib with warfarin or other oral anticoagulants, including novel anticoagulants (e.g. apixaban, dabigatran and rivaroxaban).

 

Excipients

Revcox 100 mg and 200 mg capsules contain lactose (see section 2). Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

 

This medicinal product contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially ‘sodium-free’.

Pharmacotherapeutic group: Antiinflammatory and antirheumatic products, Coxibs, ATC code: M01AH01

 

Mechanism of action

Celecoxib is an oral, selective, cyclooxygenase-2 (COX-2) inhibitor within the clinical dose range (200-400 mg daily). No statistically significant inhibition of COX-1 (assessed as ex vivo inhibition of thromboxane B2 [TxB2] formation) was observed in this dose range in healthy volunteers.

 

Pharmacodynamic effects

Cyclooxygenase is responsible for generation of prostaglandins. Two isoforms, COX-1 and COX-2, have been identified. COX-2 is the isoform of the enzyme that has been shown to be induced by pro- inflammatory stimuli and has been postulated to be primarily responsible for the synthesis of prostanoid mediators of pain, inflammation, and fever. COX-2 is also involved in ovulation, implantation and closure of the ductus arteriosus, regulation of renal function, and central nervous system functions (fever induction, pain perception and cognitive function). It may also play a role in ulcer healing. COX-2 has been identified in tissue around gastric ulcers in humans but its relevance to ulcer healing has not been established.

 

The difference in antiplatelet activity between some COX-1 inhibiting NSAIDs and COX-2 selective inhibitors may be of clinical significance in patients at risk of thrombo-embolic reactions. COX-2 selective inhibitors reduce the formation of systemic (and therefore possibly endothelial) prostacyclin without affecting platelet thromboxane.

 

Celecoxib is a diaryl-substituted pyrazole, chemically similar to other non-arylamine sulfonamides (e.g. thiazides, furosemide) but differs from arylamine sulfonamides (e.g. sulfamethoxazole and other sulfonamide antibiotics).

 

A dose dependent effect on TxB2 formation has been observed after high doses of celecoxib. However, in healthy subjects, in small multiple dose studies with 600 mg twice daily (three times the

 

highest recommended dose) celecoxib had no effect on platelet aggregation and bleeding time compared to placebo.

 

Clinical efficacy and safety

Several clinical studies have been performed confirming efficacy and safety in osteoarthritis, rheumatoid arthritis and ankylosing spondylitis. Celecoxib was evaluated for the treatment of the inflammation and pain of osteoarthritis of the knee and hip in approximately 4,200 patients in placebo and active controlled trials of up to 12 weeks duration. It was also evaluated for treatment of the inflammation and pain of rheumatoid arthritis in approximately 2,100 patients in placebo and active controlled trials of up to 24 weeks duration. Celecoxib at daily doses of 200 mg - 400 mg provided pain relief within 24 hours of dosing. Celecoxib was evaluated for the symptomatic treatment of ankylosing spondylitis in 896 patients in placebo and active controlled trials of up to 12 weeks duration. Celecoxib at doses of 100 mg twice daily, 200 mg once daily, 200 mg twice daily and 400 mg once daily in these studies demonstrated significant improvement in pain, global disease activity and function in ankylosing spondylitis.

 

Five randomised double-blind controlled studies have been conducted including scheduled upper gastrointestinal endoscopy in approximately 4,500 patients free from initial ulceration (celecoxib doses from 50 mg - 400 mg twice daily). In twelve week endoscopy studies celecoxib (100 - 800 mg per day) was associated with a significantly lower risk of gastroduodenal ulcers compared with naproxen (1,000 mg per day) and ibuprofen (2,400 mg per day). The data were inconsistent in comparison with diclofenac (150 mg per day). In two of the 12-week studies the percentage of patients with endoscopic gastroduodenal ulceration was not significantly different between placebo and celecoxib 200 mg twice daily and 400 mg twice daily.

 

In a prospective long-term safety outcome study (6 to 15 month duration, CLASS study),

5,800 osteoarthritis and 2, 200 rheumatoid arthritis patients received celecoxib 400 mg twice daily (4-fold and 2-fold the recommended osteoarthritis and rheumatoid arthritis doses, respectively), ibuprofen 800 mg three times daily or diclofenac 75 mg twice daily (both at therapeutic doses).

Twenty-two percent of enrolled patients took concomitant low-dose acetylsalicylic acid (≤325 mg/day), primarily for cardiovascular prophylaxis. For the primary endpoint complicated ulcers (defined as gastrointestinal bleeding, perforation or obstruction) celecoxib was not significantly different than either ibuprofen or diclofenac individually. Also for the combined NSAID group there was no statistically significant difference for complicated ulcers (relative risk 0.77, 95 % CI 0.41- 1.46, based on entire study duration). For the combined endpoint, complicated and symptomatic ulcers, the incidence was significantly lower in the celecoxib group compared to the NSAID group, relative risk 0.66, 95% CI 0.45-0.97, but not between celecoxib and diclofenac. Those patients on celecoxib and concomitant low-dose acetylsalicylic acid experienced 4-fold higher rates of complicated ulcers as compared to those on celecoxib alone. The incidence of clinically significant decreases in haemoglobin (>2 g/dl), confirmed by repeat testing, was significantly lower in patients on celecoxib compared to the NSAID group, relative risk 0.29, 95% CI 0.17- 0.48. The significantly lower incidence of this event with celecoxib was maintained with or without acetylsalicylic acid use.

 

In a prospective randomised 24 week safety study in patients who were aged ≥60 years or had a history of gastroduodenal ulcers (users of ASA excluded), the percentages of patients with decreases in haemoglobin (≥2 g/dl) and/or haematocrit (≥10%) of defined or presumed GI origin were lower in patients treated with celecoxib 200 mg twice daily (N=2,238) compared to patients treated with diclofenac sustained release 75 mg twice daily plus omeprazole 20 mg once daily (N=2,246) (0.2 % vs. 1.1 % for defined GI origin, p= 0.004; 0.4 % vs. 2.4 % for presumed GI origin, p = 0.0001). The rates of clinically manifest GI complications such as perforation, obstruction or haemorrhage were very low with no differences between the treatment groups (4-5 per group).

 

Cardiovascular safety – long-term studies involving subjects with sporadic adenomatous polyps Two studies involving subjects with sporadic adenomatous polyps were conducted with celecoxib i.e., the APC trial (Adenoma Prevention with Celecoxib) and the PreSAP trial (Prevention of Spontaneous Adenomatous Polyps). In the APC trial, there was a dose-related increase in the composite endpoint of cardiovascular death, myocardial infarction, or stroke (adjudicated) with

 

celecoxib compared to placebo over 3 years of treatment. The PreSAP trial did not demonstrate a statistically significant increased risk for the same composite endpoint.

 

In the APC trial, the relative risks compared to placebo for a composite endpoint (adjudicated) of cardiovascular death, myocardial infarction, or stroke were 3.4 (95% CI 1.4 - 8.5) with celecoxib 400 mg twice daily and 2.8 (95% CI 1.1- 7.2) with celecoxib 200 mg twice daily. Cumulative rates for this composite endpoint over 3 years were 3.0% (20/671 subjects) and 2.5% (17/685 subjects) respectively, compared to 0.9% (6/679 subjects) for placebo. The increases for both celecoxib dose groups versus placebo were mainly due to an increased incidence of myocardial infarction.

 

In the PreSAP trial, the relative risk compared to placebo for this same composite endpoint (adjudicated) was 1.2 (95% CI 0.6 - 2.4) with celecoxib 400 mg once daily compared to placebo. Cumulative rates for this composite endpoint over 3 years were 2.3% (21/933 subjects) and 1.9% (12/628 subjects), respectively. The incidence of myocardial infarction (adjudicated) was 1.0% (9/933 subjects) with celecoxib 400 mg once daily and 0.6% (4/628 subjects) with placebo.

 

Data from a third long-term study, ADAPT (The Alzheimer’s Disease Anti-inflammatory Prevention Trial), did not show a significantly increased cardiovascular risk with celecoxib 200 mg twice daily compared to placebo. The relative risk compared to placebo for a similar composite endpoint (cardiovascular death, myocardial infarction, stroke) was 1.14 (95% CI 0.61 - 2.12) with celecoxib 200 mg twice daily. The incidence of myocardial infarction was 1.1% (8/717 patients) with celecoxib 200 mg twice daily and 1.2% (13/1070 patients) with placebo.

 

Prospective Randomised Evaluation of Celecoxib Integrated Safety vs. Ibuprofen Or Naproxen (PRECISION)

The PRECISION study was a double-blind study of cardiovascular safety in OA or RA patients with or at high risk for cardiovascular disease comparing celecoxib (200-400 mg daily) with naproxen (750-1000 mg daily) and ibuprofen (1800-2400 mg daily). The primary endpoint, Antiplatelet Trialists Collaboration (APTC), was an independently adjudicated composite of cardiovascular death (including hemorrhagic death), non-fatal myocardial infarction or non-fatal stroke. The study was planned with 80% power to evaluate non-inferiority. All patients were prescribed open-label esomeprazole (20-40 mg) for gastro protection. Patients who were taking low-dose acetylsalicylic acid were permitted to continue therapy, at baseline nearly half of the subjects were on acetylsalicylic acid. Secondary and tertiary endpoints included cardiovascular, gastrointestinal and renal outcomes. The average dose dispensed was 209±37 mg/day for celecoxib, 2045±246 for ibuprofen and 852±103 for naproxen.

 

Regarding the primary endpoint, celecoxib, as compared with either naproxen or ibuprofen, met all four pre-specified non-inferiority requirements, see Table 2.

 

Other independently adjudicated secondary and tertiary endpoints included cardiovascular, gastrointestinal and renal outcomes. Additionally, there was a 4-month substudy focusing on the effects of the three active substances on blood pressure as measured by ambulatory monitoring (ABPM).

 

Table 2. Primary analysis of the Adjudicated APTC Composite Endpoint

 

Intent-To-Treat analysis (ITT, through month 30)
	Celecoxib 100-200 mg bid	Ibuprofen 600-800 mg tid	Naproxen 375-500 mg bid
N	8,072	8,040	7,969
Subjects with events	188 (2.3%)	218 (2.7%)	201 (2.5%)
Pairwise comparison	Celecoxib vs. naproxen	Celecoxib vs. ibuprofen	Ibuprofen vs. naproxen
HR (95% CI)	0.93 (0.76, 1.13)	0.86 (0.70, 1.04)	1.08 (0.89, 1.31)
Modified Intent-To-Treat analysis (mITT, on treatment through month 43)
	Celecoxib 100-200 mg bid	Ibuprofen 600-800 mg tid	Naproxen 375-500 mg bid

 

N	8,030	7,990	7,933
Subjects with events	134 (1.7%)	155 (1.9%)	144 (1.8%)
Pairwise comparison	Celecoxib vs. naproxen	Celecoxib vs. ibuprofen	Ibuprofen vs. naproxen
HR (95% CI)	0.90 (0.72, 1.14)	0.81 (0.64, 1.02)	1.12 (0.889, 1.40)

 

The results were overall numerically similar in the celecoxib and comparator groups for the secondary and tertiary endpoints and there were overall no unexpected safety findings.

 

Taken together the PRECISION study indicates that celecoxib at the lowest approved dose of 100 mg twice daily is non-inferior to ibuprofen dosed in the range of 600 mg-800 mg three times daily or naproxen dosed in the range of 375 mg-500 mg twice daily with respect to cardiovascular adverse effects. The cardiovascular risks of the NSAID class, including coxibs, are dose-dependent, therefore, the results for celecoxib 200 mg daily on the composite cardiovascular endpoint cannot be extrapolated to dosing regimens using the higher doses of celecoxib.

Pregnancy

Studies in animals (rats and rabbits) have shown reproductive toxicity, including malformations (see sections 4.3 and 5.3). 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. The potential for human risk in pregnancy is unknown, but cannot be excluded. Celecoxib, as with other active substances inhibiting prostaglandin synthesis, may cause uterine inertia and premature closure of the ductus arteriosus during the last trimester.

 

During the second or third trimester of pregnancy, NSAIDs including celecoxib may cause fetal renal dysfunction which may result in reduction of amniotic fluid volume or oligohydramnios in severe cases. Such effects may occur shortly after treatment initiation and are usually reversible.

 

Celecoxib is contraindicated in pregnancy and in women who can become pregnant (see section 4.3). If a woman becomes pregnant during treatment, celecoxib should be discontinued.

 

Breast-feeding

Celecoxib is excreted in the milk of lactating rats at concentrations similar to those in plasma. Administration of celecoxib to a limited number of lactating women has shown a very low transfer of celecoxib into breast milk. Celecoxib is contraindicated during breast-feeding (see section 4.3).

 

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.

Patients who experience dizziness, vertigo or somnolence while taking celecoxib should refrain from driving or operating machinery.

Adverse reactions are listed by system organ class and ranked by frequency in Table 1, reflecting data from the following sources:

-                  Adverse reactions reported in osteoarthritis patients and rheumatoid arthritis patients at incidence rates greater than 0.01% and greater than those reported for placebo during

12 placebo- and/or active-controlled clinical trials of duration up to 12 weeks at celecoxib daily doses from 100 mg up to 800 mg. In additional studies using non-selective NSAID comparators, approximately 7400 arthritis patients have been treated with celecoxib at daily doses up to

800 mg, including approximately 2300 patients treated for 1 year or longer. The adverse reactions observed with celecoxib in these additional studies were consistent with those for osteoarthritis and rheumatoid arthritis patients listed in Table 1.

-                  Adverse reactions reported at incidence rates greater than placebo for subjects treated with celecoxib 400 mg daily in long-term polyp prevention trials of duration up to 3 years (the Adenoma Prevention with Celecoxib (APC) and Prevention of Colorectal Sporadic Adenomatous Polyps (PreSAP) trials; see section 5.1 “Cardiovascular safety – long-term studies involving patients with sporadic adenomatouspolyps”).

-                  Adverse drug reactions from post-marketing surveillance as spontaneously reported during a period in which an estimated >70 million patients were treated with celecoxib (various doses, durations, and indications). Even though these were identified as reactions from post-marketing reports, trial data were consulted to estimate frequency. Frequencies are based on a cumulative meta-analysis with pooling of trials representing exposure in 38,102 patients.

 

Table 1. Adverse Drug Reactions in Celecoxib Clinical Trials and Surveillance Experience (MedDRA Preferred Terms)1,2

 

System	Very	Common	Uncommon	Rare	Very rare	Frequency
Organ Class	common	(≥1/100 to	(≥1/1,000 to	(≥1/10,000 to	(<1/10,000)	not known
	(≥1/10)	<1/10)	<1/100)	<1/1,000)		(cannot be
						estimated
						from the
						available
						data)
Infections		Sinusitis,
and		upper
infestations		respiratory
		tract
		infection,
		pharyngitis
		urinary
		tract
		infection
Blood and lymphatic			Anaemia	Leukopenia, thrombocyto-	Pancytopenia 4
system				penia
disorders
Immune system		Hyper- sensitivity			Anaphylactic shock4,
disorders					anaphylactic reaction4
Metabolism and nutrition disorders			Hyperkalaemia
Psychiatric disorders		Insomnia	Anxiety, depression, fatigue	Confusional state, hallucinations4

 

System Organ Class	Very common (≥1/10)	Common (≥1/100 to <1/10)	Uncommon (≥1/1,000 to <1/100)	Rare (≥1/10,000 to <1/1,000)	Very rare (<1/10,000)	Frequency not known (cannot be estimated from the available data)
Nervous system disorders		Dizziness, hypertonia, headache4	Cerebral infarction1, paraesthesia,	Ataxia, dysgeusia	Haemorrhage intracranial (including
			somnolence		fatal
					intracranial
					haemorrhage
					)4,
					meningitis
					aseptic4,
					epilepsy
					(including
					aggravated
					epilepsy)4,
					ageusia4,
					anosmia4
Eye disorders			Vision blurred, conjunctivitis4	Eye haemorrhage4	Retinal artery occlusion4,
					retinal vein
					occlusion4
Ear and labyrinth disorders			Tinnitus, hypoacusis1
Cardiac disorders		Myocardial infarction1	Cardiac failure, palpitations, tachycardia	Arrhythmia4
Vascular disorders	Hyper- tension1 (includin			Pulmonary embolism4, flushing4	Vasculitis4
	g
	aggravat
	ed
	hyper-
	tension)

 

System Organ Class	Very common (≥1/10)	Common (≥1/100 to <1/10)	Uncommon (≥1/1,000 to <1/100)	Rare (≥1/10,000 to <1/1,000)	Very rare (<1/10,000)	Frequency not known (cannot be estimated from the available data)
Respiratory , thoracic and mediastinal disorders		Rhinitis, cough, dyspnoea1	Bronchospasm4	Pneumonitis4
Gastro-		Nausea4,	Constipation,	Gastro-
intestinal disorders		abdominal pain,	gastritis, stomatitis,	intestinal haemorrhage4,
		diarrhoea,	gastrointestinal	duodenal
		dyspepsia,	inflammation	ulcer,
		flatulence, vomiting1, dysphagia1	(including aggravation of gastrointestinal	gastric ulcer, oesophageal ulcer,
			inflammation),	intestinal and
			eructation	large intestinal
				ulcer,
				intestinal
				perforation,
				oesophagitis,
				melaena,
				pancreatitis,
				colitis4

 

System Organ Class	Very common (≥1/10)	Common (≥1/100 to <1/10)	Uncommon (≥1/1,000 to <1/100)	Rare (≥1/10,000 to <1/1,000)	Very rare (<1/10,000)	Frequency not known (cannot be estimated from the available data)
Hepato- biliary			Hepatic function abnormal,	Hepatitis4	Hepatic failure4
disorders			hepatic enzymes		(sometimes
			increased		fatal or
			(including		requiring
			increased SGOT		liver
			and SGPT)		transplant),
					hepatitis
					fulminant4
					(some with
					fatal
					outcome),
					hepatic
					necrosis4,
					cholestasis4,
					hepatitis
					cholestatic4,
					jaundice4

 

System Organ Class	Very common (≥1/10)	Common (≥1/100 to <1/10)	Uncommon (≥1/1,000 to <1/100)	Rare (≥1/10,000 to <1/1,000)	Very rare (<1/10,000)	Frequency not known (cannot be estimated from the available data)
Skin and subcuta-		Rash, pruritus	Urticaria, ecchymosis4	Angioedema4, alopecia,	Dermatitis exfoliative4,
neous tissue disorders		(includes pruritus		photosensi- tivity	erythema multiforme4,
		generalised)			Stevens-
					Johnson
					syndrome4,
					toxic
					epidermal
					necrolysis4,
					drug reaction
					with
					eosinophilia
					and systemic
					symptoms
					(DRESS)4,
					acute
					generalised
					exanthemato
					us pustulosis
					(AGEP)4,
					dermatitis
					bullous4
Musculoske		Arthralgia4	Muscle spasms		Myositis4
letal and			(leg cramps)
connective
tissue
disorders
Renal and urinary disorders			Blood creatinine increased, blood urea increased	Renal failure acute4, hypo- natraemia4	Tubulointerst itial nephritis4, nephrotic syndrome4,
					glomerulone
					phritis
					minimal
					lesion4

 

System Organ Class	Very common (≥1/10)	Common (≥1/100 to <1/10)	Uncommon (≥1/1,000 to <1/100)	Rare (≥1/10,000 to <1/1,000)	Very rare (<1/10,000)	Frequency not known (cannot be estimated from the available data)
Reproduc- tive system and breast disorders				Menstrual disorder4		Infertility female (female fertility decreased)3
General disorders and administra- tion site conditions		Influenza- like illness, oedema peripheral/f luid retention	Face oedema, chest pain4
Injury, poisoning and procedural complicatio ns		Injury (accidental injury)
	1 Adverse drug reactions that occurred in polyp prevention trials, representing subjects treated with celecoxib 400 mg daily in 2 clinical trials of duration up to 3 years (the APC and PreSAP trials). The adverse drug reactions listed above for the polyp prevention trials are only those that have been previously recognized in the post- marketing surveillance experience, or have occurred more frequently than in the arthritis trials. 2 Furthermore, the following previously unknown adverse reactions occurred in polyp prevention trials, representing subjects treated with celecoxib 400 mg daily in 2 clinical trials of duration up to 3 years (the APC and PreSAP trials): Common: angina pectoris, irritable bowel syndrome, nephrolithiasis, blood creatinine increased, benign prostatic hyperplasia, weight increased. Uncommon: helicobacter infection, herpes zoster, erysipelas, bronchopneumonia, labyrinthitis, gingival infection, lipoma, vitreous floaters, conjunctival haemorrhage, deep vein thrombosis, dysphonia, haemorrhoidal haemorrhage, frequent bowel movements, mouth ulceration, allergic dermatitis, ganglion, nocturia, vaginal haemorrhage, breast tenderness, lower limb fracture, blood sodium increased. 3 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. 4 Frequencies are based on cumulative meta-analysis with pooling of trials representing exposure in 38,102 patients.

 

In final data (adjudicated) from the APC and PreSAP trials in patients treated with celecoxib 400 mg daily for up to 3 years (pooled data from both trials; see section 5.1 for results from individual trials), the excess rate over placebo for myocardial infarction was 7.6 events per 1,000 patients (uncommon) and there was no excess rate for stroke (types not differentiated) over placebo.

 

To report any side effect(s):

•                      Saudi Arabia:

 

 

•                      Other GCC states:

-           Please contact the relevant competent authority.

There is no clinical experience of overdose. Single doses up to 1,200 mg and multiple doses up to 1,200 mg twice daily have been administered to healthy subjects for nine days without clinically significant adverse effects. In the event of suspected overdose, appropriate supportive medical care should be provided e.g. by eliminating the gastric contents, clinical supervision and, if necessary, the institution of symptomatic treatment. Dialysis is unlikely to be an efficient method of active substance removal due to high protein binding.

Pharmacotherapeutic group: Antiinflammatory and antirheumatic products, Coxibs, ATC code: M01AH01

 

Mechanism of action

Celecoxib is an oral, selective, cyclooxygenase-2 (COX-2) inhibitor within the clinical dose range (200-400 mg daily). No statistically significant inhibition of COX-1 (assessed as ex vivo inhibition of thromboxane B2 [TxB2] formation) was observed in this dose range in healthy volunteers.

 

Pharmacodynamic effects

Cyclooxygenase is responsible for generation of prostaglandins. Two isoforms, COX-1 and COX-2, have been identified. COX-2 is the isoform of the enzyme that has been shown to be induced by pro- inflammatory stimuli and has been postulated to be primarily responsible for the synthesis of prostanoid mediators of pain, inflammation, and fever. COX-2 is also involved in ovulation, implantation and closure of the ductus arteriosus, regulation of renal function, and central nervous system functions (fever induction, pain perception and cognitive function). It may also play a role in ulcer healing. COX-2 has been identified in tissue around gastric ulcers in humans but its relevance to ulcer healing has not been established.

 

The difference in antiplatelet activity between some COX-1 inhibiting NSAIDs and COX-2 selective inhibitors may be of clinical significance in patients at risk of thrombo-embolic reactions. COX-2

 

selective inhibitors reduce the formation of systemic (and therefore possibly endothelial) prostacyclin without affecting platelet thromboxane.

 

Celecoxib is a diaryl-substituted pyrazole, chemically similar to other non-arylamine sulfonamides (e.g. thiazides, furosemide) but differs from arylamine sulfonamides (e.g. sulfamethoxazole and other sulfonamide antibiotics).

 

A dose dependent effect on TxB2 formation has been observed after high doses of celecoxib. However, in healthy subjects, in small multiple dose studies with 600 mg twice daily (three times the highest recommended dose) celecoxib had no effect on platelet aggregation and bleeding time compared to placebo.

 

Clinical efficacy and safety

Several clinical studies have been performed confirming efficacy and safety in osteoarthritis, rheumatoid arthritis and ankylosing spondylitis. Celecoxib was evaluated for the treatment of the inflammation and pain of osteoarthritis of the knee and hip in approximately 4,200 patients in placebo and active controlled trials of up to 12 weeks duration. It was also evaluated for treatment of the inflammation and pain of rheumatoid arthritis in approximately 2,100 patients in placebo and active controlled trials of up to 24 weeks duration. Celecoxib at daily doses of 200 mg - 400 mg provided pain relief within 24 hours of dosing. Celecoxib was evaluated for the symptomatic treatment of ankylosing spondylitis in 896 patients in placebo and active controlled trials of up to 12 weeks duration. Celecoxib at doses of 100 mg twice daily, 200 mg once daily, 200 mg twice daily and

400 mg once daily in these studies demonstrated significant improvement in pain, global disease activity and function in ankylosing spondylitis.

 

Five randomised double-blind controlled studies have been conducted including scheduled upper gastrointestinal endoscopy in approximately 4,500 patients free from initial ulceration (celecoxib doses from 50 mg - 400 mg twice daily). In twelve week endoscopy studies celecoxib (100 - 800 mg per day) was associated with a significantly lower risk of gastroduodenal ulcers compared with naproxen (1,000 mg per day) and ibuprofen (2,400 mg per day). The data were inconsistent in comparison with diclofenac (150 mg per day). In two of the 12-week studies the percentage of patients with endoscopic gastroduodenal ulceration was not significantly different between placebo and celecoxib 200 mg twice daily and 400 mg twice daily.

 

In a prospective long-term safety outcome study (6 to 15 month duration, CLASS study),

5,800 osteoarthritis and 2, 200 rheumatoid arthritis patients received celecoxib 400 mg twice daily (4- fold and 2-fold the recommended osteoarthritis and rheumatoid arthritis doses, respectively), ibuprofen 800 mg three times daily or diclofenac 75 mg twice daily (both at therapeutic doses).

Twenty-two percent of enrolled patients took concomitant low-dose acetylsalicylic acid (≤325 mg/day), primarily for cardiovascular prophylaxis. For the primary endpoint complicated ulcers (defined as gastrointestinal bleeding, perforation or obstruction) celecoxib was not significantly different than either ibuprofen or diclofenac individually. Also for the combined NSAID group there was no statistically significant difference for complicated ulcers (relative risk 0.77, 95 % CI 0.41-1.46, based on entire study duration). For the combined endpoint, complicated and symptomatic ulcers, the incidence was significantly lower in the celecoxib group compared to the NSAID group, relative risk

 

0.66, 95% CI 0.45-0.97, but not between celecoxib and diclofenac. Those patients on celecoxib and concomitant low-dose acetylsalicylic acid experienced 4-fold higher rates of complicated ulcers as compared to those on celecoxib alone. The incidence of clinically significant decreases in haemoglobin (>2 g/dl), confirmed by repeat testing, was significantly lower in patients on celecoxib compared to the NSAID group, relative risk 0.29, 95% CI 0.17- 0.48. The significantly lower incidence of this event with celecoxib was maintained with or without acetylsalicylic acid use.

 

In a prospective randomised 24 week safety study in patients who were aged ≥60 years or had a history of gastroduodenal ulcers (users of ASA excluded), the percentages of patients with decreases in haemoglobin (≥2 g/dl) and/or haematocrit (≥10%) of defined or presumed GI origin were lower in patients treated with celecoxib 200 mg twice daily (N=2,238) compared to patients treated with diclofenac sustained release 75 mg twice daily plus omeprazole 20 mg once daily (N=2,246) (0.2 % vs. 1.1 % for defined GI origin, p= 0.004; 0.4 % vs. 2.4 % for presumed GI origin, p = 0.0001). The rates of clinically manifest GI complications such as perforation, obstruction or haemorrhage were very low with no differences between the treatment groups (4-5 per group).

 

Cardiovascular safety – long-term studies involving subjects with sporadic adenomatous polyps

Two studies involving subjects with sporadic adenomatous polyps were conducted with celecoxib i.e., the APC trial (Adenoma Prevention with Celecoxib) and the PreSAP trial (Prevention of Spontaneous Adenomatous Polyps). In the APC trial, there was a dose-related increase in the composite endpoint of cardiovascular death, myocardial infarction, or stroke (adjudicated) with celecoxib compared to placebo over 3 years of treatment. The PreSAP trial did not demonstrate a statistically significant increased risk for the same composite endpoint.

 

In the APC trial, the relative risks compared to placebo for a composite endpoint (adjudicated) of cardiovascular death, myocardial infarction, or stroke were 3.4 (95% CI 1.4 - 8.5) with celecoxib

400 mg twice daily and 2.8 (95% CI 1.1- 7.2) with celecoxib 200 mg twice daily. Cumulative rates for this composite endpoint over 3 years were 3.0% (20/671 subjects) and 2.5% (17/685 subjects) respectively, compared to 0.9% (6/679 subjects) for placebo. The increases for both celecoxib dose groups versus placebo were mainly due to an increased incidence of myocardial infarction.

 

In the PreSAP trial, the relative risk compared to placebo for this same composite endpoint (adjudicated) was 1.2 (95% CI 0.6 - 2.4) with celecoxib 400 mg once daily compared to placebo. Cumulative rates for this composite endpoint over 3 years were 2.3% (21/933 subjects) and 1.9% (12/628 subjects), respectively. The incidence of myocardial infarction (adjudicated) was 1.0% (9/933 subjects) with celecoxib 400 mg once daily and 0.6% (4/628 subjects) with placebo.

 

Data from a third long-term study, ADAPT (The Alzheimer’s Disease Anti-inflammatory Prevention Trial), did not show a significantly increased cardiovascular risk with celecoxib 200 mg twice daily compared to placebo. The relative risk compared to placebo for a similar composite endpoint (cardiovascular death, myocardial infarction, stroke) was 1.14 (95% CI 0.61 - 2.12) with celecoxib 200 mg twice daily. The incidence of myocardial infarction was 1.1% (8/717 patients) with celecoxib 200 mg twice daily and 1.2% (13/1070 patients) with placebo.

Absorption

Celecoxib is well absorbed reaching peak plasma concentrations after approximately 2-3 hours. 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%.

 

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.

 

Distribution

Plasma protein binding is about 97% at therapeutic plasma concentrations and the active substance is not preferentially bound to erythrocytes.

 

Biotransformation

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 CYP2C9*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 (see section 4.2).

 

No clinically significant differences were found in PK parameters of celecoxib between elderly African-Americans and Caucasians.

 

The plasma concentration of celecoxib is approximately 100% increased in elderly women (>65 years).

 

Compared to subjects with normal hepatic function, patients with mild hepatic impairment had a mean increase in Cmax of 53% and in AUC of 26% of celecoxib. The corresponding values in patients with moderate hepatic impairment were 41% and 146%, respectively. The metabolic capacity in patients with mild to moderate impairment was best correlated to their albumin values. Treatment should be initiated at half the recommended dose in patients with moderate liver impairment (with serum albumin 25-35 g/l). Patients with severe hepatic impairment (serum albumin <25 g/l) have not been studied and celecoxib is contraindicated in this patient group.

 

There is little experience of celecoxib in renal impairment. The pharmacokinetics of celecoxib has not been studied in patients with renal impairment but is unlikely to be markedly changed in these patients. Thus caution is advised when treating patients with renal impairment. Use of celecoxib in patients with severe renal impairment is contraindicated.

 

Elimination

Celecoxib is mainly eliminated by metabolism. Less than 1% of the dose is excreted unchanged in urine. The inter-subject variability in the exposure of celecoxib is about 10-fold. Celecoxib exhibits dose- and time-independent pharmacokinetics in the therapeutic dose range. Elimination half-life is 8- 12 hours. Steady state plasma concentrations are reached within 5 days of treatment.

Non-clinical safety data revealed no special hazard for humans based on conventional studies of repeated dose toxicity, mutagenicity or carcinogenicity beyond those addressed in section 4.4, 4.6 and

5.1 of the SmPC.

 

Celecoxib at oral doses ³150 mg/kg/day (approximately 2-fold human exposure at 200 mg twice daily as measured by AUC0-24), caused an increased incidence of ventricular septal defects, a rare event, and fetal alterations, such as ribs fused, sternebrae fused and sternebrae misshapen when rabbits were treated throughout organogenesis. A dose-dependent increase in diaphragmatic hernias was observed when rats were given celecoxib at oral doses ³30 mg/kg/day (approximately 6-fold human exposure based on the AUC0-24 at 200 mg twice daily) throughout organogenesis. These effects are expected following inhibition of prostaglandin synthesis. In rats, exposure to celecoxib during early embryonic development resulted in pre-implantation and post-implantation losses, and reduced embryo/fetal survival.

 

Celecoxib was excreted in rat milk. In a peri-post natal study in rats, pup toxicity was observed.

In a 2-year toxicity study an increase in nonadrenal thrombosis was observed in male rat at high doses.

Capsules, content: Carrageenan (E407), Sodium laurilsulphate, Lactose monohydrate,

Microcrystalline cellulose (E460), Magnesium stearate (E470b), Silica, colloidal, anhydrous (E551), Talc (E553b).

 

Capsule shell:

body:

Gelatin (E441),

Titanium dioxide (E171).

 

cap Revcox 100 mg capsules, hard: Gelatin (E441),

Titanium dioxide (E171), Indigo carmine (E132).

cap Revcox 200 mg capsules, hard: Gelatin (E441),

Titanium dioxide (E171), Iron oxide, red (E172), Iron oxide, yellow (E172).

Not applicable.

2 years

Do not store above 30°C.

1.1          PVC/TE/PVDC/Alu foil blister containing 10 hard capsules. Pack sizes: 10, 20, 30, 50, 60, 90 or 100 hard capsules

Not all pack sizes may be marketed.

 

No special requirements for disposal.