CELEBREX PACKAGE INSERT

SCHEDULING STATUS:  S3

PROPRIETARY NAME (and dosage form):

CELEBREX 100 Capsules
CELEBREX 200 Capsules

composition:

Each 100 mg capsule contains 100 mg celecoxib
Each 200 mg capsule contains 200 mg celecoxib

PHARMACOLOGICAL CLASSIFICATION:

a 3.1 Antirheumatics (anti-inflammatory agents)

PHARMACOLOGICAL ACTION:

Pharmacodynamic properties
Celecoxib is a specific cyclooxygenase-2 inhibitor (SCI). Cyclooxygenase-2 (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, oedema and pain. Celecoxib acts as an anti-inflammatory, analgesic and anti-pyretic agent by blocking the production of inflammatory prostanoids via COX-2 inhibition.

In-vivo and ex-vivo studies show that celecoxib has a very low affinity for the constitutively expressed cyclooxygenase 1 enzyme (COX-1).

Pharmacokinetic properties
When given under fasting conditions celecoxib is absorbed reaching peak plasma concentrations after approximately 2-3 hours. Celecoxib exhibits linear and dose proportional pharmacokinetics over the therapeutic dose range. Plasma protein binding, which is concentration independent, is about 97% at therapeutic plasma concentrations and the drug is not preferentially bound to erythrocytes in the blood. Dosing with food (high fat meal) delays absorption resulting in a Tmax of about 4 hours and increases bioavailability by about 20%.

In the population > 65 years there is a two-fold increase in mean Cmax and AUC for celecoxib.  This is a predominantly weight-related rather than age-related change, celecoxib levels being higher in lower weight individuals and consequently higher in the elderly population who are generally of lower mean weight than the younger population.  Therefore elderly females tend to have slightly higher drug plasma concentrations than elderly males.

Celecoxib is metabolised in the liver by hydroxylation, oxidation and some glucuronidation and in vitro and in vivo studies indicate that metabolism is mainly by cytochrome P450 CYP2C9.  Pharmacological activity resides in the parent drug. The main metabolites found in the circulation have no detectable COX-1 or COX-2 inhibitory activity.

Elimination of celecoxib is mostly by hepatic metabolism with less than 1 % of the dose excreted unchanged in urine. After multiple dosing elimination half life is 8-12 hours and the rate of clearance is about 500ml/min. With multiple dosing steady state plasma concentrations are reached before day 5. The intersubject variability on the main pharmacokinetic parameters (AUC, Cmax, elimination half-life) is about 30%. The mean steady state volume of distribution is about 500L/70kg in young healthy adults after a single 200mg dose indicating wide distribution of celecoxib into the tissues.  Pre-clinical studies indicate that the drug crosses the blood/brain barrier.

Hepatic impairment:  Plasma concentrations of celecoxib in patients with mild hepatic impairment are not significantly different from those of age and sex matched controls.  In patients with moderate hepatic impairment celecoxib plasma concentrations are about twice those of matched controls.  Patients with severe hepatic impairment have not been studied but can be expected to show accumulation of parent drug as the main route of metabolism is via the liver.

Renal impairment:  In elderly volunteers with age related reductions in glomerular filtration rate (GFR) (mean GFR>65ml/min 1.73m2) and in patients with chronic stable renal insufficiency (GFR 35-60ml/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.

Renal Effects:
At the present time the relative roles of COX-1 and COX-2 in renal physiology is incompletely understood.  CELEBREX reduces the urinary excretion of PGE2 and 6-keto-PGF1 (a prostacyclin metabolite) but leaves serum thromboxane B2 (TXB2) and urinary excretion of 11-dehydro-TXB2, a thromboxane metabolite (both COX-1 products) unaffected. Specific studies have shown CELEBREX produces no decreases in GFR in the elderly or those with chronic renal insufficiency. These studies have also shown transient reductions in fractional excretion of sodium.

indications:

Symptomatic treatment of inflammation and pain in osteoarthritis and rheumatoid arthritis.
Treatment of pain post dental surgery.

CONTRA-INDICATIONS:

Hypersensitivity to any ingredient of the product; known sulphonamide hypersensitivity.
Severe impairment of hepatic function.
Severe impairment of renal function.
Asthma, urticaria or allergic-type reactions precipitated by aspirin or non-steroidal anti-inflammatory agents.
Pregnancy and lactation, as safety has not been demonstrated.

DOSAGE AND DIRECTIONS FOR USE:

Osteoarthritis and Rheumatoid arthritis: The recommended daily dose is 200-400 mg taken in two divided doses.  200 mg once a day can also be used in osteoarthritis.
Pain post dental surgery: The recommended dose is 100 mg to 200 mg up to a maximum daily dose of 400 mg.  Dosing intervals should not be less than 4 hours.

Elderly:
No dosage adjustment is necessary.
Hepatic impairment: No dosage adjustment is necessary in patients with mild or moderate hepatic impairment. There is no clinical experience in patients with severe hepatic impairment.  (See Contra-Indications).
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 Contra-Indications).
Children:  CELEBREX has not been studied in subjects under 18 years old.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:

Side-Effects
 Adverse events reported in controlled clinical trials:
Central Nervous System:  Headache, dizziness
Gastrointestinal: Constipation, nausea, abdominal pain, diarrhoea, dyspepsia, flatulence, vomiting.  Serious clinically significant upper gastro-intestinal bleeding has been observed in patients receiving CELEBREX, although infrequently.
Respiratory:  Bronchitis, coughing, pharyngitis, rhinitis, sinusitis, upper respiratory tract infection
Other:  Arthralgia, back pain, insomnia, myalgia, pain, peripheral pain, pruritus, tooth disorder, accidental injury, allergy aggravated, ‘flu-like symptoms, peripheral oedema, rash, urinary tract infection

Warnings and special precautions
Celecoxib contains a sulphonamide moiety. In clinical trials CELEBREX did not induce bronchospasm in patients with asthma. However CELEBREX  has not been evaluated in patients in whom attacks of asthma, urticaria or acute rhinitis have been precipitated by aspirin or nonsteroidal anti-inflammatory agents. Use in such patients should be avoided until further information is available.

Safety and efficacy of CELEBREX have not been established for treatment exceeding 12 weeks in osteoarthritis and 24 weeks in rheumatoid arthritis.

Interaction with other medicinal products and other forms of interaction
General
:  Celecoxib metabolism is predominantly mediated via cytochrome P450 CYP2C9 in the liver.  Co-administration of celecoxib with drugs that are known to inhibit CYP2C9 should be done with caution.

In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of cytochrome P450 CYP2D6.  Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolised by P450 CYP2D6.

ACE-inhibitors:  Reports suggest that NSAIDs may diminish the antihypertensive effect of Angiotensin Converting Enzyme (ACE) inhibitors.  This interaction should be given consideration in patients taking CELEBREX concomitantly with ACE-inhibitors.

Furosemide:  Clinical studies, as well as post marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients.  This response has been attributed to inhibition of renal prostaglandin synthesis.

Aspirin:  CELEBREX can be used with low dose aspirin.  However, concomitant administration of aspirin with CELEBREX may result in an increased rate of GI ulceration or other complications, compared to use of CELEBREX alone.  Because of its lack of platelet effects, CELEBREX is not a substitute for aspirin for cardiovascular prophylaxis.

Fluconazole:  Concomitant administration of fluconazole at 200mg qd resulted in a two-fold increase in celecoxib plasma concentration.  This increase is due to the inhibition of celecoxib metabolism via P450 CYP2C9 by fluconazole.

Lithium:  In a study conducted in healthy subjects, mean steady-state lithium plasma levels increased approximately 17% in subjects receiving lithium 450 mg bid with CELEBREX 200 mg bid as compared to subjects receiving lithium alone.  Patients on lithium treatment should be closely monitored when CELEBREX is introduced or withdrawn.

Methotrexate:  In an interaction study of rheumatoid arthritis patients taking methotrexate, CELEBREX did not have a significant effect on the pharmacokinetics of methotrexate.

In specific studies in healthy volunteers with other agents metabolised by CYP2C9 CELEBREX was found to produce no clinically significant pharmacokinetic interaction with phenytoin or tolbutamide.

Warfarin:  Anticoagulant activity should be monitored in patients taking warfarin or similar agents, particularly in the first few days after initiating or changing celecoxib therapy. Although in an in vivo interaction study in healthy volunteers celecoxib did not affect the pharmacokinetics of warfarin or the anticoagulant effect as determined by prothrombin time.  Bleeding events in association with increases in prothrombin time have been reported, predominantly in the elderly, in patients receiving CELEBREX concurrently with warfarin.

Effects on ability to drive and use machines
The effect of CELEBREX 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.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:

There is no clinical experience of overdose. Single doses up to 1200mg and multiple doses up to 600mg twice daily have been administered to healthy subjects without clinically significant adverse effects. In the event of suspected overdose, appropriate supportive medical care should be provided. Dialysis is unlikely to be an efficient method of drug removal.

iDENTIFICATION:
CELEBREX 100:
Opaque, white to off-white, hard gelatin capsule with a blue band marked 7767 and 100, containing a white to off-white granulation.
CELEBREX 200: Opaque, white to off-white, hard gelatin capsule with a gold band marked 7767 and 200, containing a white to off-white granulation.

PRESENTATION:
Blister packs of 10,
20, 30 and 60 capsules

STORAGE INSTRUCTIONS:
Store at or below 25 ºC
Keep out of reach of children

REGISTRATION NUMBERs:
CELEBREX 100:  33/3.1/0332
CELEBREX 200:  33/3.1/0333

NAME AND BUSINESS ADDRESS OF THE APPLICANT:
Searle, Division of Monsanto (South Africa) (Pty) Ltd
7 Harrowdene Office Park
Western Services Road
Woodmead X20
Sandton

DATE OF PUBLICATION of this package insert:
23 July 1999

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The package insert above is the official package insert enclosed with Celebrex medication as registered in South Africa. 

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