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.