Appendix 1-
final agreed SPC (changes for
12.5 mg tablets only are shown)
1. NAME OF THE
MEDICINAL PRODUCT
VIOXX® 12.5 mg
Tablets
2. QUALITATIVE
AND QUANTITATIVE COMPOSITION
Each tablet contains
12.5 mg of rofecoxib.
3. PHARMACEUTICAL
FORM
Tablet.
Cream/off white,
round, shallow cup tablet marked
'MSD 74' on one side and VIOXX on
the other.
4. CLINICAL
PARTICULARS
4.1 Therapeutic
indications
Symptomatic relief
in the treatment of
osteoarthritis or rheumatoid
arthritis in adults.
4.2 Posology and
method of administration
VIOXX is
administered orally.
VIOXX may be taken
with or without food.
Osteoarthritis
The recommended adult starting
dose is 12.5 mg once daily. Some
patients may receive additional
benefit by increasing the dose to
25 mg once daily. A daily dose of
25 mg should not be exceeded.
For dosing at 12.5
mg once daily, a 12.5-mg tablet
is also available. (For the 25 mg
tablet SPC only.)
For dosing at 12.5 mg once daily,
a 12.5 mg/5 mL oral suspension is
also available. (For the 25 mg/5
mL oral suspension SPC only.)
Rheumatoid
Arthritis
The recommended dose is 25 mg
once daily. In rheumatoid
arthritis (RA) patients, no
significant additional efficacy
was seen with the 50-mg once
daily dose compared to the 25-mg
once daily dose. The maximum
recommended daily dose is 25 mg.
For dosing at 25 mg
once daily, a 25-mg tablet is
also available. (For the 12.5 mg
tablet SPC only.)
For dosing at 25 mg once daily, a
25 mg/5 mL oral suspension is
also available. (For the 12.5
mg/5 mL oral suspension SPC
only.)
Elderly: care
should be exercised when
increasing the daily dose from
12.5 mg to 25 mg in the elderly.
Renal
insufficiency: no dosage
adjustment is necessary for OA
patients with creatinine
clearance 30-80 ml/min (see 4.4
`Special warnings and special
precautions for use' and 5.2
'Pharmacokinetic properties'). At
present, there are only limited
data in RA patients with
creatinine clearance 30-80
ml/min.
Hepatic
insufficiency: in patients
with mild hepatic insufficiency
(Child-Pugh score 5-6) the dose
of 12.5 mg once daily should not
be exceeded (see 4.4 `Special
warnings and special precautions
for use' and
5.2 'Pharmacokinetic
properties'). At present, there
are only limited data in RA
patients with mild hepatic
impairment, and a recommended
dose has not yet been
established.
Paediatric use: VIOXX is not indicated for
use in children.
4.3
Contra-indications
Rofecoxib is
contra-indicated in:
- patients with
known hypersensitivity to any of
the excipients of this medicinal
product
- patients with
active peptic ulceration or
gastro-intestinal (GI) bleeding
- patients with
moderate or severe hepatic
dysfunction (Child-Pugh score
C17) - patients with estimated
creatinine clearance <30
ml/min
- patients who have
developed signs of asthma, acute
rhinitis, nasal polyps,
angioneurotic oedema or urticaria
following the administration of
aspirin or other non-steroidal
antiinflammatory drugs (NSAIDs)
- third trimester of
pregnancy and lactation (see 4.6
`Pregnancy and lactation' and 5.3
'Preclinical safety data')
- patients with
inflammatory bowel disease
- patients with
severe congestive heart failure.
4.4 Special
warnings and special precautions
for use
Renal prostaglandins
may play a compensatory role in
the maintenance of renal
perfusion. Therefore, under
conditions of compromised renal
perfusion, administration of
rofecoxib may cause a reduction
in prostaglandin formation and,
secondarily, in renal blood flow,
and thereby impair renal
function. Patients at greatest
risk of this response are those
with pre-existing significantly
impaired renal function,
uncompensated heart failure, or
cirrhosis. Monitoring of renal
function in such patients should
be considered.
Caution should be
used when initiating treatment
with rofecoxib in patients with
considerable dehydration. It is
advisable to rehydrate patients
prior to starting therapy with
rofecoxib.
Fluid retention,
oedema and hypertension have been
observed in patients taking
rofecoxib. These effects appear
to be dose-related and are seen
with an increased frequency with
chronic use of rofecoxib and at
higher therapeutic doses. Because
treatment with rofecoxib may
result in fluid retention,
caution should be exercised in
patients with history of cardiac
failure, left ventricular
dysfunction, or hypertension and
in patients with pre-existing
oedema from any other reason.
Rofecoxib should be introduced at
the lowest recommended dose in
those patients. (See 4.5
`Interactions with other
medicaments and other forms of
interaction'.)
VIOXX is not a
substitute for aspirin for
cardiovascular prophylaxis
because of its lack of effect on
platelets. Because rofecoxib at
therapeutic doses does not
inhibit platelet aggregation,
antiaggregant therapies should
not be discontinued and if
indicated should be considered in
patients at risk for or with a
history of cardiovascular or
other thrombotic events.
Medically
appropriate supervision should be
maintained when using rofecoxib
in the elderly and in patients
with renal, hepatic, or cardiac
dysfunction.
In clinical studies,
some patients treated with
rofecoxib developed perforations,
ulcers or bleeds (PUBs). Patients
with a prior history of a PUB and
patients greater than 65 years of
age appeared to be at higher risk
for a PUB. Independent of PUBS,
at daily doses higher than 25 mg,
the risk of gastro-intestinal
symptoms is increased (see 4.8
`Undesirable effects').
Elevations of ALT
and/or AST (approximately three
or more times the upper limit of
normal) have been reported in
approximately 1% of patients in
clinical trials with rofecoxib.
A patient with
symptoms and/or signs suggesting
liver dysfunction, or in whom an
abnormal liver function test has
occurred, should be evaluated for
persistently abnormal liver
function tests. If persistently
abnormal liver function tests
(three times the upper limit of
normal) are detected, rofecoxib
should be discontinued.
Rofecoxib may mask
fever.
The use of
rofecoxib, as with any drug known
to inhibit COX-2, is not
recommended in women attempting
to conceive (see 4.6 `Pregnancy
and lactation' and 5.1
'Pharmacodynamic properties')
Paediatric
patients: Rofecoxib has not
been studied in children and
should only be used in adult
patients.
The quantity of
lactose in each tablet (39.95 mg
in the 12.5-mg tablet) is
probably not sufficient to induce
specific symptoms of lactose
intolerance.
4.5 Interaction
with other medicaments and other
forms of interaction
Pharmacodynamic
interactions
In subjects
stabilised on chronic warfarin
therapy, the administration of
rofecoxib 25 mg daily was
associated with an approximate 8%
increase in prothrombin time
International Normalised Ratio
(INR). There have been reports of
increases in INR, which led to
interruption of warfarin
treatment and in some cases
prompted reversal of
anticoagulation, in patients
taking rofecoxib at clinical
doses concurrently with warfarin.
Therefore, patients receiving
warfarin or similar agents should
be closely monitored for their
prothrombin time INR,
particularly in the first few
days when therapy with rofecoxib
is initiated or the dose of
rofecoxib is changed.
In patients with
mild-to-moderate hypertension,
administration of 25 mg daily of
rofecoxib with an ACE inhibitor
(benazepril, 10 mg to 40 mg
daily) for four weeks was
associated with a small
attenuation of the
antihypertensive effect (average
increase in Mean Arterial
Pressure of 2.8 mm Hg) compared
to the ACE inhibitor alone. As
for other agents which inhibit
cyclo-oxygenase, in some patients
with compromised renal function
the co-administration of an ACE
inhibitor and rofecoxib may
result in further deterioration
of renal function, which is
usually reversible. These
interactions should be given
consideration in patients taking
rofecoxib concomitantly with ACE
inhibitors.
Concomitant use of
NSAIDs may also reduce the
antihypertensive efficacy of
beta-blockers and diuretics and
the other effects of diuretics.
There are no data on the possible
interaction between rofecoxib and
either beta-blockers or
diuretics.
At steady state,
rofecoxib 50 mg once daily had no
effect on the anti-platelet
activity of low-dose (81 mg
once-daily) aspirin. Concomitant
administration of rofecoxib with
higher doses of aspirin or other
NSAIDs should be avoided.
Coadministration of
cyclosporin or tacrolimus and
NSAIDs may increase the
nephrotoxic effect of cyclosporin
or tacrolimus. Renal function
should be monitored when
rofecoxib and either of these
drugs is used in combination.
Pharmacokinetic
interactions
The effect of
rofecoxib on the pharmacokinetics
of other drugs
The plasma
concentration of lithium could be
increased by NSAIDs. In
post-marketing experience with
rofecoxib, there have been
reports of increases in plasma
lithium levels.
VIOXX 12.5, 25, and
50 mg, each dose administered
once daily for 7 days, had no
significant effect on the plasma
concentration of methotrexate as
measured by AUC0-24hr in
patients receiving single weekly
methotrexate doses of 7.5 to 20
mg for rheumatoid arthritis.
Rofecoxib 75 mg (three to six
times higher than the recommended
doses for osteoarthritis)
administered once-daily for 10
days increased plasma
methotrexate concentrations (AUC(0-24hr))
by 23% in patients with RA
receiving methotrexate 7.5 mg to
15 mg/week. Adequate monitoring
for methotrexate-related toxicity
should be considered when
rofecoxib and methotrexate are
administered concomitantly.
No interaction with
digoxin has been observed.
In vivo data
concerning rofecoxib/warfarin and
rofecoxib/theophylline
interactions suggest that
rofecoxib may produce a modest
inhibition of CYP1A2. Care should
be exercised when administering
rofecoxib concurrently with other
drugs primarily metabolised by
CYP1A2 (e.g., amitriptyline,
tacrine and zileuton). Rofecoxib
12.5, 25 and 50 mg administered
once daily for 7 days increased
plasma theophylline
concentrations (AUC(0-oo))
by 38 to 60% in healthy subjects
administered a single 300-mg dose
of theophylline. Adequate
monitoring of theophylline plasma
concentrations should be
considered when therapy with
rofecoxib is initiated or changed
in patients receiving
theophylline.
The potential for
rofecoxib to inhibit or induce
CYP3A4 activity was investigated
in human studies using the oral
midazolam test and the
intravenous erythromycin breath
test. Rofecoxib (25 mg daily for
12 days) produced a modest
induction of CYP3A4 catalysed
metabolism of midazolam, reducing
the AUC of midazolam by 30%. This
reduction is most likely due to
increased first pass metabolism
through induction of intestinal
CYP3A4 activity by rofecoxib.
Compared to placebo, rofecoxib
(75 mg daily for 14 days) did not
produce any significant effect in
erythromycin demethylation,
indicating no induction of
hepatic CYP3A4 activity.
Although rofecoxib
produces a modest induction of
intestinal CYP3A4 activity, the
pharmacokinetics of drugs that
are primarily metabolised by
CYP3A4 are not expected to be
affected to a clinically
significant extent. However, care
should be exercised when
co-prescribing substrates of
CYP3A4.
In drug-interaction
studies, rofecoxib did not have
clinically important effects on
the pharmacokinetics of
prednisone/prednisolone or oral
contraceptives (ethinyl
oestradiol/norethindrone 35/1).
Based on in vitro
studies, rofecoxib is not
expected to inhibit cytochromes
P450 2C9, 2C 19, 2D6, or 2E 1,
although in vivo data are
not available.
Effects of other
drugs on the pharmacokinetics of
rofecoxib
The main pathway of
rofecoxib metabolism is reduction
to produce cis- and
trans-dihydro rofecoxib (as
hydroxy acids). In the absence of
potent cytochrome P450 (CYP)
inducers, CYP-catalysed
metabolism is not the dominant
pathway for rofecoxib metabolism.
However,
co-administration of rofecoxib
with rifampicin, a potent inducer
of CYP enzymes, produced an
approximate 50% decrease in
rofecoxib plasma concentrations.
Therefore, the use of the 25-mg
dose of rofecoxib should be
considered when rofecoxib is
co-administered with potent
inducers of hepatic metabolism.
Administration of
ketoconazole (a potent inhibitor
of CYP3A4) did not affect
rofecoxib plasma
pharmacokinetics. Cimetidine or
antacids do not affect the
pharmacokinetics of rofecoxib to
a clinically relevant extent.
4.6 Pregnancy and
lactation
Pregnancy
The use of
rofecoxib, as with any drug known
to inhibit COX-2 is not
recommended in women attempting
to conceive (see 5.1
'Pharmacodynamic properties').
The use of rofecoxib
is contraindicated in the last
trimester of pregnancy because,
as with other drugs known to
inhibit prostaglandin synthesis,
it may cause uterine inertia and
premature closure of the ductus
arteriosus (see 4.3.
`Contraindications').
The use of rofecoxib
in pregnant women has not been
studied in adequate and well
controlled clinical trials and
therefore it should not be used
during the first two trimesters
of pregnancy unless the potential
benefit to the patient justifies
the potential risk to the foetus
(see 5.3 'Preclinical safety
data').
Breast feeding
mothers
It is not known
whether rofecoxib is excreted in
human milk. Rofecoxib is excreted
in the milk of lactating rats.
Women who use rofecoxib should
not breast feed. (See 4.3
'Contraindications' and 5.3
'Preclinical safety data.')
4.7 Effects on
ability to drive and use machines
Patients who
experience dizziness, vertigo or
somnolence while taking rofecoxib
should refrain from driving or
operating machinery.
4.8 Undesirable
effects
In clinical trials,
rofecoxib was evaluated for
safety in approximately 11,600
individuals, including
approximately 1,000 patients
treated for one year or longer.
The following
drug-related adverse experiences
were reported at an incidence
greater than placebo in clinical
studies in patients treated with
rofecoxib 12.5 mg or 25 mg for up
to six months or in
post-marketing experience:
[Common (>I/100, <1/10)
Uncommon (>1/1000, <1/100)
Rare (>1/10,000, <1/1000)
Very rare (<1/10,000) and
isolated cases]
Body as a
whole/site unspecified:
Common: oedema/fluid
retention, abdominal pain,
dizziness.
Uncommon: asthenia/fatigue,
abdominal distension, chest pain.
Very rare: hypersensitivity
reactions, including angioedema,
urticaria and
anaphylactic/anaphylactoid
reactions.
Blood and the
lymphatic system disorders:
Common: haematocrit
decreased.
Uncommon: haemoglobin
decreased, erythrocytes
decreased, leukocytes decreased.
Very rare: thrombocytopenia.
Cardiovascular
system:
Common: hypertension.
Very rare: congestive
heart failure.
Isolated cases: myocardial
infarction (no causal
relationship has been
established).
Digestive
system:
Common: heartburn,
epigastric discomfort, diarrhoea,
nausea, dyspepsia.
Uncommon: constipation,
oral ulcer, vomiting, digestive
gas symptoms, acid reflux.
Rare: peptic ulcers,
gastrointestinal perforation and
bleeding (mainly in elderly
patients), gastritis.
Hepatobiliary
disorders:
Common: alanine
aminotransferase increased,
aspartate aminotransferase
increased. Uncommon: alkaline
phosphatase increased.
Isolated cases: hepatotoxicity
including hepatitis and jaundice.
Eyes, ears,
nose and throat: Uncommon:
tinnitus.
Very rare: blurred vision.
Metabolism and
nutrition: Uncommon: weight
gain.
Musculoskeletal:
Uncommon: muscular
cramp.
Nervous
system:
Common: headache.
Uncommon: insomnia,
somnolence, vertigo.
Very rare: paraesthesia.
Isolated cases: aseptic
meningitis.
Psychiatric
disorder:
Uncommon: depression,
mental acuity decreased.
Very rare: confusion,
hallucinations.
Respiratory
system:
Uncommon: dyspnoea.
Very rare: bronchospasm.
Urogenital:
Uncommon: BUN
increased, serum creatinine
increased, proteinuria.
Very rare: renal
insufficiency, including renal
failure, usually reversible upon
discontinuation of therapy (see
4.4 `Special warnings and special
precautions for use').
Skin and skin
appendages:
Common: pruritus.
Uncommon: rash, atopic
dermatitis.
Very rare: alopecia.
Isolated cases: cutaneo-mucosal
adverse effects and severe skin
reactions including
Stevens-Johnson Syndrome.
In clinical studies,
the undesirable effects profile
was similar in patients treated
with rofecoxib for one year or
longer.
The following
serious undesirable effects have
been reported in association with
the use of NSAIDs and cannot be
ruled out for rofecoxib:
nephrotoxicity including
interstitial nephritis and
nephrotic syndrome and
hepatotoxicity including hepatic
failure.
4.9 Overdose
In clinical studies,
administration of single doses of
rofecoxib up to 1,000 mg and
multiple doses up to 250 mg/day
for 14 days did not result in
significant toxicity.
In the event of
overdose, it is reasonable to
employ the usual supportive
measures, e.g. remove unabsorbed
material from the GI tract,
employ clinical monitoring, and
institute supportive therapy, if
required.
Rofecoxib is not
dialysable by haemodialysis; it
is not known whether rofecoxib is
dialysable by peritoneal
dialysis.
5.
PHARMACOLOGICAL PROPERTIES
5.1
Pharmacodynamic properties
ATC Code: MO1 AH
Rofecoxib is an
orally active cyclo-oxygenase-2
(COX-2) selective inhibitor
within the clinical dose range.
Cyclo-oxygenase is responsible
for the generation of
prostaglandins. Two isoforms,
COX-1 and COX-2, have been
identified. COX-1 is
constitutively expressed in a
number of tissues, including the
stomach, intestines, kidneys, and
in platelets; whereas, COX-2 is
constitutively expressed in a
limited number of tissues,
including the brain, kidney and
reproductive tract. Evidence
suggests that COX-2 plays a role
in ovulation, implantation,
closure of the ductus arteriosus,
and central nervous system
functions (fever induction, pain
perception, cognitive function).
COX-2 may play a role in ulcer
healing in experimental animals
and although COX-2 has been
identified in tissue around
gastric ulcers in man, its
relevance to humans in ulcer
healing has not been established.
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. Statistically
significant inhibition of COX-1
has not been documented in humans
with any dose of rofecoxib. Based
on in vitro data,
inhibition of COX-1 might occur
during chronic administration of
rofecoxib at >250 mg per day.
The
anti-inflammatory effects of
rofecoxib were demonstrated in
standard animal models used to
evaluate NSAIDs.
Across clinical
pharmacology studies, as compared
to placebo, rofecoxib produced
dose-dependent inhibition of
COX-2 with daily doses of 12.5 mg
and 25 mg inhibiting COX-2 by
-70%, while rofecoxib at daily
doses of 375 mg and a single 1000
mg dose inhibited COX-2 by -95%.
There was no dose-dependent
inhibition of COX-1 compared with
placebo. Rofecoxib did not
inhibit gastric prostaglandin
synthesis and had no effect on
platelet function.
A large clinical
trial (approximately 8000
patients) in rheumatoid arthritis
patients has compared the
long-term safety of rofecoxib 50
mg once daily (twice the maximum
dose recommended) and naproxen
500 mg twice daily. The rate of
serious cardiovascular
thrombo-embolic adverse events
was significantly lower in
patients receiving naproxen than
in the rofecoxib treated
patients: 0.70 events per 100
patient-years compared with 1.67
events per 100 patient-years. 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
events.
Rofecoxib was
studied for the symptomatic
treatment of osteoarthritis (OA).
The primary assessments for
efficacy were made only on either
the hip or knee joints; however,
the study population included 33%
of patients with concomitant OA
of the inter-phalangeal joints,
21% with OA of the thumb and 35%
with OA of the spine. After one
week of therapy (the first
efficacy determination
timepoint), rofecoxib provided
significant reduction in pain in
OA patients. Timepoints earlier
than one week were not evaluated.
Therefore, consideration should
be given to the Tmax of
rofecoxib (two to four hours)
when immediate onset of action is
desired.
Rofecoxib 25 mg once
daily was studied for the
symptomatic treatment of RA. In
RA patients, rofecoxib 25 mg once
daily provided significant
improvements in disease-related
measures of response, including
assessments of pain and function.
The beneficial effects were
maintained over the 12-week
placebocontrolled periods. No
significant additional efficacy
was seen with the 50-mg once
daily dose compared to the 25-mg
once daily dose.
In a predefined,
combined analysis of two 24-week
endoscopy studies in OA patients,
the percentages of patients with
endoscopically detected
gastroduodenal ulceration were
similar between placebo, and
rofecoxib 25 mg and 50 mg daily
at 12 weeks. In each of these
studies, the cumulative incidence
of gastroduodenal ulcers was
significantly less over 12 and 24
weeks in patients treated with
rofecoxib than in patients
treated with ibuprofen 2,400 mg
daily. In a 12-week,
double-blind, placebo- and
active-controlled endoscopy study
in RA patients, the cumulative
incidence of gastroduodenal
ulcers was significantly less
over 12 weeks in patients treated
with rofecoxib 50 mg once daily
(twice the maximum dose
recommended) than in patients
treated with naproxen 500 mg
twice daily.
In a predefined,
combined analysis of eight
clinical trials, the cumulative
incidence of confirmed upper GI
PUBS in patients treated with
rofecoxib was significantly lower
than the combined cumulative
incidence observed in patients
treated with NSAID comparators
(diclofenac 50 mg three times
daily, ibuprofen 800 mg three
times daily and nabumetone 1500
mg daily). These results were
primarily influenced by the
experience with ibuprofen 800 mg
three times daily. At a dosage of
50 mg the incidence of PUBS was
numerically greater compared to
25 mg, however it remained lower
than the risk with combined data
on NSAIDs used in these studies.
Discontinuations for GI adverse
experiences over 12 months were
less with rofecoxib. Incidences
of a predefined set of
drug-related GI adverse
experiences were lower with
rofecoxib over 12 months; this
effect was greater over the first
6 months.
A similar reduction
in the incidence of PUBS was seen
in the large clinical trial
(approximately 8000 patients)
conducted in rheumatoid arthritis
patients. Patients requiring
aspirin for cardiovascular
prophylaxis were excluded from
the study. The use of rofecoxib
50 mg once daily (two times the
maximum recommended dose)
compared to naproxen 500 mg twice
daily was associated with
significant reductions in
gastrointestinal event rates:
PUBS (2.08 events per 100
patient-years versus 4.49 events
per 100 patientyears),
complicated PUBs (0.59 per 100
patient-years versus 1.37 per 100
patient-years) and upper or lower
GI bleeds (1.15 per 100
patient-years versus 3.04 per 100
patient-years).
5.2
Pharmacokinetic properties
Absorption
Orally administered rofecoxib is
well absorbed at the recommended
doses of 12.5 mg and 25 mg. The
mean oral bioavailability is
approximately 93%. Following
25-mg once-daily dosing to
steady-state, the peak plasma
concentration (geometric mean Cmax = 0.305 mcg/ml) was
observed at approximately two to
four hours (Tmax) after
administration to fasted adults.
The geometric mean area under the
curve (AUC24hr,) was 3.87
mcghr/ml. VIOXX Tablets and VIOXX
Oral Suspension are
bioequivalent.
Concomitant food
intake does not affect the
pharmacokinetics of rofecoxib.
Distribution
Rofecoxib is approximately 85%
bound to human plasma protein at
concentrations of 0.05 mcg/ml to
25 mcg/ml. The volume of
distribution (Vdss) is
approximately 100 litres
(approximately 1.55 L/kg) in
humans.
Rofecoxib crosses
the placenta in rats and rabbits,
and the blood-brain barrier in
rats.
Metabolism
Rofecoxib is extensively
metabolised with -1% of a dose
recovered in urine as the parent
drug. The main metabolic pathway
is hepatic reduction to produce cis-
and trans-dihydro rofecoxib
(as hydroxy acids), and not
oxidation by cytochrome P450
(CYP) enzymes.
Six metabolites have
been identified in man. The
principal metabolites were cis-
and trans-dihydro rofecoxib
(as hydroxy acids), which
accounted for approximately 56%
of recovered radioactivity in the
urine, and the 5-hydroxy
glucuronide metabolite, which
accounted for an additional 9%.
These principal metabolites
either demonstrated no measurable
activity as cyclo-oxygenase
inhibitors or were only weakly
active as COX-2 inhibitors.
Elimination
Following administration of a
125-mg radiolabelled oral dose of
rofecoxib to healthy subjects,
72% of radioactivity was
recovered in urine and 14% in
faeces.
Elimination of
rofecoxib occurs almost
exclusively through metabolism
followed by renal excretion.
Steady-state concentrations of
rofecoxib are reached within four
days of once-daily administration
of 25 mg, with an accumulation
ratio of approximately 1.7,
corresponding to an accumulation
half-life of -17 hours. The
plasma clearance is estimated to
be approximately 120 ml/min for a
25-mg dose.
Characteristics
inpatients
Elderly: pharmacokinetics
in the elderly (65 years of age
and older) are similar to those
in the young. The systemic
exposure is -30% greater in the
elderly than in the young (see
4.2 'Posology and method of
administration').
Gender: the
pharmacokinetics of rofecoxib are
comparable in men and women.
Hepatic
insufficiency: Cirrhotic
patients with mild hepatic
insufficiency (Child-Pugh score
5-6) administered a single 25-mg
dose of rofecoxib had a mean AUC
similar to healthy subjects given
the same dose. Patients with
moderate hepatic insufficiency
(Child-Pugh score 7-9) had an
approximately 69% higher mean AUC
than healthy subjects given the
same dose. There are no clinical
or pharmacokinetic data in
patients with severe hepatic
insufficiency (Child-Pugh score
>9). (See 4.2 `Posology and
method of administration' and 4.3
`Contraindications'.)
Renal
insufficiency: the
pharmacokinetics of a single
50-mg dose of rofecoxib in
patients with end-stage renal
disease on haemodialysis were not
significantly different from
those of healthy subjects.
Haemodialysis contributed
negligibly to elimination
(dialysis clearance -40 ml/min).
(See 4.3 `Contraindications' and
4.4 `Special warnings and special
precautions for use'.)
Paediatric
patients: the
pharmacokinetics of rofecoxib in
paediatric patients have not been
studied.
5.3 Preclinical
safety data
In preclinical
studies, rofecoxib has been
demonstrated to be neither
genotoxic, mutagenic, nor
carcinogenic.
In a chronic
toxicity study in rats, rofecoxib
caused intestinal ulcers at doses
comparable to and slightly above
the human therapeutic dose, based
on systemic exposure. At
exposures several times above the
human therapeutic level, renal
tubular basophilia, and at higher
exposures renal papillary
necrosis, were induced in the
rat. At high exposures renal and
gastro-intestinal abnormalities
were seen in the dog as well.
Reproductive
toxicity studies showed that
rofecoxib (at doses >2 times
the recommended daily human dose
based on systemic exposure)
decreased fertility and
embryo/foetal survival in the
rat. A treatment-related decrease
in the diameter of the ductus
arteriosus was also observed, a
finding known to be associated
with NSAIDs. Reproductive
toxicity studies conducted in
rats and rabbits have
demonstrated no evidence of
developmental abnormalities at
doses up to 50 mg/kg/day (in rats
this represents -29 times the
recommended daily human dose
based on systemic exposure). (See
4.3 `Contraindications' and 4.6
`Pregnancy and lactation'.) In
rabbits, however, the metabolite
profile was not determined, thus
making the clinical relevance of
the rabbit model difficult to
assess.
Data from a
cross-fostering study indicated
pup toxicity, probably due to
exposure via milk from treated
dams. (See 4.6. `Pregnancy and
lactation'.)
6. PHARMACEUTICAL
PARTICULARS
6.1 List of
excipients
lactose monohydrate,
microcrystalline cellulose,
hydroxypropyl cellulose,
croscarmellose sodium, magnesium
stearate, and yellow ferric oxide
(E172).
6.2
Incompatibilities
Not applicable.
6.3 Shelf-life
24 months.
6.4 Special
precautions for storage
No special
precautions for storage.
6.5 Nature and
contents of container
Opaque PVC/aluminium
blisters in packs containing 2,
5, 7, 10, 14, 15, 20, 28, 30, 50,
56, 60, 84, 90 or 98 tablets.
Opaque PVC/aluminium
blisters (unit doses) in packs of
50 or 500 tablets.
White, round, HDPE
bottles with a white,
polypropylene, non-child
resistant closure containing 30
or 100 tablets.
6.6 Instructions
for use/handling
Not applicable.
7. MARKETING
AUTHORISATION HOLDER
To be filled in
locally.
8. MARKETING
AUTHORISATION NUMBER
To be filled in
locally.
9. DATE OF FIRST
AUTHORISATION/RENEWAL OF
AUTHORISATION
June 4, 1999
10. DATE OF
REVISION OF THE TEXT
® denotes
registered trademark of Merck
& Co., Inc., Whitehouse
Station, NJ, USA.