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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