ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Dynastat 20 mg powder for solution for injection
2.
20 mg vial: Each vial contains 20 mg parecoxib (present as 21.18 mg parecoxib sodium) for
reconstitution. After reconstitution, the final concentration of parecoxib is 20 mg/ml.
When reconstituted in sodium chloride 9 mg/ml (0.9%) solution, Dynastat contains approximately
0.22 mEq of sodium per vial.
For a full list of excipients, see section 6.1.
3.
Powder for solution for injection
White to off-white powder.
4.
For the short-term treatment of postoperative pain
.
The decision to prescribe a selective COX-2 inhibitor should be based on an assessment of the
individual patient's overall risks (see sections 4.3 and 4.4).
The recommended dose is 40 mg administered intravenously (IV) or intramuscularly (IM), followed
every 6 to 12 hours by 20 mg or 40 mg as required, not to exceed 80 mg/day. The IV bolus injection
may be given rapidly and directly into a vein or into an existing IV line. The IM injection should be
given slowly and deeply into the muscle (see section 6.6 for instructions for reconstitution).
Concomitant Use with Opioid Analgesics:
Opioid analgesics can be used concurrently with
parecoxib, dosing as described in the paragraph above. In all clinical assessments parecoxib was
administered at a fixed time interval whereas the opioids were administered on as needed basis
(PRN).
As the cardiovascular risk of cyclooxygenase-2 (COX-2) specific inhibitors may increase with dose
and duration of exposure, the shortest duration possible and the lowest effective daily dose should be
used.
Precipitation may occur when Dynastat is combined in solution with other medicinal products and
therefore Dynastat must not be mixed with any other drug, either during reconstitution or injection.
In
those patients where the same IV line is to be used to inject another medicinal product, the line must
be adequately flushed prior to and after Dynastat injection with a solution of known compatibility.
IV line solution compatibility
After reconstitution with acceptable solvents, Dynastat may
only
be injected IV or IM, or into IV
lines delivering:
sodium chloride 9 mg/ml (0.9%) solution
2
glucose 50 g/l (5%) solution for infusion
sodium chloride 4.5 mg/ml (0.45%) and glucose 50 g/l (5%) solution for injection
Ringer-Lactate solution for injection
Injection into an IV line delivering glucose 50 g/l (5%) in Ringer-Lactate solution for injection, or
other IV fluids not listed above, is
not
recommended as this may cause precipitation from solution.
Elderly:
No dosage adjustment is generally necessary in elderly patients (≥ 65 years). However, for
elderly patients weighing less than 50 kg, initiate treatment with half the usual recommended dose of
Dynastat and reduce the maximum daily dose to 40 mg (see section 5.2).
Hepatic Impairment:
No dosage adjustment is generally necessary in patients with mild hepatic
impairment (Child-Pugh score 5-6). Introduce Dynastat with caution and at half the usual
recommended dose in patients with moderate hepatic impairment (Child-Pugh score 7-9) and reduce
the maximum daily dose to 40 mg. There is no clinical experience in patients with severe hepatic
impairment (Child-Pugh score ≥10), therefore its use is contraindicated in these patients (see sections
4.3 and 5.2).
Renal Impairment:
On the basis of pharmacokinetics, no dosage adjustment is necessary in patients
with mild to moderate renal impairment (creatinine clearance of 30-80 ml/min.). In patients with
severe renal impairment (creatinine clearance < 30 ml/min.) or patients who may be predisposed to
fluid retention parecoxib should be initiated at the lowest recommended dose and the patient’s kidney
function closely monitored (see sections 4.4 and 5.2).
Children and adolescents:
There is no experience in children and adolescents. Therefore, its use is not
recommended in these patients.
Hypersensitivity to the active substance or to any of the excipients (see section 6.1).
History of previous serious allergic drug reaction of any type, especially cutaneous reactions such as
Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme.or patients with known
hypersensitivity to sulphonamides (see sections 4.4 and 4.8).
Active peptic ulceration or gastrointestinal (GI) bleeding.
Patients who have experienced bronchospasm, acute rhinitis, nasal polyps, angioneurotic oedema,
urticaria or other allergic-type reactions after taking acetylsalicylic acid or NSAIDs including COX-2
(cyclooxygenase-2) inhibitors.
The third trimester of pregnancy and breast-feeding (see sections 4.6 and 5.3).
Severe hepatic dysfunction (serum albumin <25 g/l or Child-Pugh score ≥ 10).
Inflammatory bowel disease.
Congestive heart failure (NYHA II-IV).
Treatment of post-operative pain following coronary artery bypass graft (CABG) surgery (see sections
4.8 and 5.1).
Established ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease.
3
There is limited clinical experience with Dynastat treatment beyond three days.
Because of the possibility for increased adverse reactions at higher doses parecoxib, other COX-2
inhibitors and NSAIDs, patients treated with parecoxib should be reviewed following dose increase
and, in the absence of an increase in efficacy, other therapeutic options should be considered (see
section 4.2).
COX-2 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.
Patients with significant risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia,
diabetes mellitus, smoking) should only be treated with parecoxib sodium after careful consideration
(see section 5.1).
Appropriate measures should be taken and discontinuation of parecoxib therapy should be considered
if there is clinical evidence of deterioration in the condition of specific clinical symptoms in these
patients (see section 5.1). Dynastat has not been studied in cardiovascular revascularization
procedures other than coronary artery bypass graft procedures. Studies in other surgeries than CABG
procedures included patients with ASA (American Society of Anaesthesiology) Physical Status Class
I-III only.
COX-2 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).
Upper gastrointestinal complications [perforations, ulcers or bleedings (PUBs)], some of them
resulting in fatal outcome, have occurred in patients treated with parecoxib. Caution is advised in the
treatment of patients most at risk of developing a gastrointestinal complication with NSAIDs; the
elderly, patients using any other NSAID or acetylsalicylic acid concomitantly 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 (gastrointestinal ulceration or other gastrointestinal
complications), when parecoxib sodium is taken concomitantly with acetylsalicylic acid (even at low
doses).
Dynastat has been studied in dental, orthopaedic, gynaecologic (principally hysterectomy) and
coronary artery bypass graft surgery. There is little experience in other types of surgery, for example
gastrointestinal or urological surgery.
Serious skin reactions, including erythema multiforme, exfoliative dermatitis and Stevens-Johnson
syndrome (some of them fatal) have been reported through post-marketing surveillance in patients
receiving parecoxib. Additionally, fatal reports of toxic epidermal necrolysis have been reported
through postmarketing surveillance in patients receiving valdecoxib (the active metabolite of
parecoxib) and cannot be ruled out for parecoxib (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.
Appropriate measures should be taken by physicians to monitor for any serious skin reactions with
therapy, e.g. additional patient consultations. Patients should be advised to immediately report any
emergent skin condition to their physician.
Parecoxib should be discontinued at the first appearance of skin rash, mucosal lesions, or any other
sign of hypersensitivity. Serious skin reactions are known to occur with NSAIDs including COX-2
selective inhibitors as well as other medications. However, the reported rate of serious skin events
appears to be greater for valdecoxib (the active metabolite of parecoxib) as compared to other COX-2
4
selective inhibitors. Patients with a history of sulphonamide allergy may be at greater risk of skin
reactions (see section 4.3). Patients without a history of sulphonamide allergy may also be at risk for
serious skin reactions.
Hypersensitivity reactions (anaphylaxis and angioedema) have been reported in post-marketing
experience with valdecoxib and parecoxib (see section 4.8). Some of these reactions have occurred in
patients with a history of allergic-type reactions to sulphonamides (see section 4.3). Parecoxib should
be discontinued at the first sign of hypersensitivity.
Acute renal failure has been reported through post-marketing surveillance in patients receiving
parecoxib (see section 4.8). Since prostaglandin synthesis inhibition may result in deterioration of
renal function and fluid retention, caution should be observed when administering Dynastat in
patients with impaired renal function (see section 4.2) or hypertension, or in patients with
compromised cardiac or hepatic function or other conditions predisposing to fluid retention.
Caution should be used when initiating treatment with Dynastat in patients with dehydration. In this
case, it is advisable to rehydrate patients first and then start therapy with Dynastat.
Fluid Retention and Oedema
As with other drugs known to inhibit prostaglandin synthesis, fluid retention and oedema have been
observed in some patients taking parecoxib. Therefore, parecoxib should be used with caution in
patients with compromised cardiac function, preexisting oedema, or other conditions predisposing to,
or worsened by, fluid retention including those taking diuretic treatment or otherwise at risk of
hypovolemia. If there is clinical evidence of deterioration in the condition of these patients,
appropriate measures including discontinuation of parecoxib should be taken.
Hypertension
As with all NSAIDs, parecoxib 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.
NSAIDs, including parecoxib, should be used with caution in patients with hypertension. Blood
pressure should be monitored closely during the initiation of therapy with parecoxib and throughout
the course of therapy. If blood pressure rises significantly, alternative treatment should be considered.
Dynastat should be used with caution in patients with moderate hepatic dysfunction (Child-Pugh score
7-9) (see section 4.2).
If during treatment, patients deteriorate in any of the organ system functions
described above,
appropriate measures should be taken and discontinuation of parecoxib sodium therapy should be
considered.
Dynastat may mask fever and other signs of inflammation (see section 5.1). In isolated cases, an
aggravation of soft tissue infections has been described in connection with the use of NSAIDs and in
nonclinical studies with Dynastat (see section 5.3). Caution should be exercised with respect to
monitoring the incision for signs of infection in surgical patients receiving Dynastat.
Caution should be exercised when co-administering Dynastat with warfarin and other oral
anticoagulants (see section 4.5).
The concomitant use of parecoxib with other non-aspirin NSAIDs should be avoided.
The use of Dynastat, as with any medicinal product known to inhibit cyclooxygenase/prostaglandin
synthesis, is not recommended in women attempting to conceive (see sections 4.6 and 5.1).
Interaction studies have only been performed in adults.
5
Pharmacodynamic interactions
Anticoagulant therapy should be monitored, particularly during the first few days after initiating
Dynastat therapy in patients receiving warfarin or other anticoagulants, since these patients have an
increased risk of bleeding complications. Therefore, patients receiving oral anticoagulants should be
closely monitored for their prothrombin time INR, particularly in the first few days when therapy with
parecoxib is initiated or the dose of parecoxib is changed (see section 4.4).
Dynastat had no effect on acetylsalicylic acid-mediated inhibition of platelet aggregation or bleeding
times. Clinical trials indicate that Dynastat can be given with low dose acetylsalicylic acid
(≤ 325 mg). In the submitted studies, as with other NSAIDs, an increased risk of gastrointestinal
ulceration or other gastrointestinal complications compared to use of parecoxib alone was shown for
concomitant administration of low-dose acetylsalicylic acid (see section 5.1).
Co-administration of parecoxib sodium and heparin did not affect the pharmacodynamics of heparin
(activated partial thromboplastin time) compared to heparin alone.
NSAIDs may reduce the effect of diuretics and antihypertensive medicinal products. As for NSAIDs,
the risk of acute renal insufficiency may be increased when ACE inhibitors or diuretics are co-
administered with parecoxib sodium.
Co-administration of NSAIDs and cyclosporin or tacrolimus has been suggested to increase the
nephrotoxic effect of cyclosporin and tacrolimus. Renal function should be monitored when parecoxib
sodium and any of these medicinal products are co-administered.
Dynastat may be co-administered with opioid analgesics. In clinical trials, the daily requirement for
PRN opioids was significantly reduced when coadministered with parecoxib.
Effects of other medicinal products on the pharmacokinetics of parecoxib (or its active metabolite
valdecoxib)
Parecoxib is rapidly hydrolysed to the active metabolite valdecoxib. In humans, studies demonstrated
that valdecoxib metabolism is predominantly mediated via CYP3A4 and 2C9 isozymes.
Plasma exposure (AUC and C
max
) to valdecoxib was increased (62% and 19%, respectively) when co-
administered with fluconazole (predominantly a CYP2C9 inhibitor), indicating that the dose of
parecoxib sodium should be reduced in those patients who are receiving fluconazole therapy.
Plasma exposure (AUC and C
max
) to valdecoxib was increased (38% and 24%, respectively) when co-
administered with ketoconazole (CYP3A4 inhibitor), however, a dosage adjustment should not
generally be necessary for patients receiving ketoconazole.
The effect of enzyme induction has not been studied. The metabolism of valdecoxib may increase
when co-administered with enzyme inducers such as rifampicin, phenytoin, carbamazepine or
dexamethasone.
Effect of parecoxib (or its active metabolite valdecoxib) on the pharmacokinetics of other medicinal
products
Treatment with valdecoxib (40 mg twice daily for 7 days) produced a 3-fold increase in plasma
concentrations of dextromethorphan (CYP2D6 substrate). Therefore, caution should be observed
when co-administering Dynastat and medicinal products that are predominantly metabolised by
CYP2D6 and which have narrow therapeutic margins (e.g. flecainide, propafenone, metoprolol).
Plasma exposure of omeprazole (CYP 2C19 substrate) 40 mg once daily was increased by 46%
following administration of valdecoxib 40 mg twice daily for 7 days, while the plasma exposure to
valdecoxib was unaffected. These results indicate that although valdecoxib is not metabolised by
CYP2C19, it may be an inhibitor of this isoenzyme. Therefore, caution should be observed when
6
administering Dynastat with medicinal products known to be substrates of CYP2C19 (e.g. phenytoin,
diazepam, or imipramine).
In interaction studies in rheumatoid arthritis patients receiving weekly methotrexate intramuscularly,
orally administered valdecoxib (40 mg twice daily) did not have a clinically significant effect on the
plasma concentrations of methotrexate. However, adequate monitoring of methotrexate-related
toxicity should be considered when co-administering these two medicinal products.
Co-administration of valdecoxib and lithium produced significant decreases in lithium serum
clearance (25%) and renal clearance (30%) with a 34% higher serum exposure compared to lithium
alone. Lithium serum concentration should be monitored closely when initiating or changing
parecoxib sodium therapy in patients receiving lithium.
Co-administration of valdecoxib with glibenclamide (CYP3A4 substrate) did not affect either the
pharmacokinetics (exposure) or the pharmacodynamics (blood glucose and insulin levels) of
glibenclamide.
Injectable anaesthetics
:
Coadministration of IV parecoxib sodium 40 mg with propofol (CYP2C9
substrate) or midazolam (CYP3A4 substrate) did not affect either the pharmacokinetics (metabolism
and exposure) or the pharmacodynamics (EEG effects, psychomotor tests and waking from sedation)
of IV propofol or IV midazolam. Additionally, coadministration of valdecoxib had no clinically
significant effect on the hepatic or intestinal CYP 3A4-mediated metabolism of orally administered
midazolam. Administration of IV parecoxib sodium 40 mg had no significant effect on the
pharmacokinetics of either IV fentanyl or IV alfentanil (CYP3A4 substrates).
Inhalation anaesthetics:
No formal interaction studies have been done. In surgery studies in which
parecoxib sodium was administered pre-operatively, no evidence of pharmacodynamic interaction was
observed in patients receiving parecoxib sodium and the inhalation anaesthetic agents nitrous oxide
and isoflurane (see section 5.1).
Pregnancy:
Parecoxib sodium is suspected to cause serious birth defects when administered during the last
trimester of pregnancy, because as with other medicinal products known to inhibit prostaglandin
synthesis, it may cause premature closure of the ductus arteriosus or uterine inertia (see sections 4.3,
5.1 and 5.3).
Dynastat is contraindicated (see section 4.3) in the last trimester of pregnancy.
Like other medicinal products that inhibit COX-2, Dynastat is not recommended in women attempting
to conceive (see sections 4.4, 5.1 and 5.3).
There are no adequate data from the use of parecoxib sodium in pregnant women or during labour.
Studies in animals have shown reproductive toxicity (see sections 5.1 and 5.3). The potential risk for
humans is unknown. Dynastat should not be used during the first two trimesters of pregnancy unless
clearly necessary (i.e. the potential benefit to the patient outweighs the potential risk to the foetus).
Lactation:
Parecoxib, valdecoxib (its active metabolite) and a valdecoxib active metabolite are excreted in the
milk of rats. It is not known whether valdecoxib is excreted in human milk. Dynastat should not be
administered to women who breast-feed (see sections 4.3 and 5.3).
7
No studies on the effect of Dynastat on the ability to drive or use machines have been performed.
However, patients who experience dizziness, vertigo or somnolence after receiving Dynastat should
refrain from driving or operating machines.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
The following adverse reactions were reported in patients who received parecoxib (N=5,402) in
28 placebo-controlled clinical trials.
[Very Common (≥1/10), Common (≥1/100, <1/10) Uncommon (≥1/1000, <1/100) Rare (≥1/10,000,
<1/1000) Very rare (<1/10,000) not known (cannot be estimated from the available data)]
Infections and infestations
Common: pharyngitis, alveolar osteitis (dry socket)
Uncommon: abnormal sternal serous wound drainage, wound infection
Blood and lymphatic system disorders
Common: anaemia postoperative
Uncommon: thrombocytopenia
Immune System Disorders
Rare: anaphylactoid reaction
Metabolism and nutrition disorders
Common: hypokalaemia
Uncommon: anorexia, hyperglycaemia
Pyschiatric disorders:
Common: agitation, insomnia
Nervous system disorders
Common: hypoaesthesia, dizziness
Uncommon: cerebrovascular disorder
Ear and labyrinth disorders
Uncommon: ear pain
Cardiac disorders
Uncommon: myocardial infarction, bradycardia
Vascular disorders
Common: hypertension, hypotension
Uncommon: hypertension (aggravated), orthostatic hypotension
Respiratory, thoracic and mediastinal disorders
Common: respiratory insufficiency
Uncommon: pulmonary embolism
Gastrointestinal disorders
Very common: nausea
Common: abdominal pain, vomiting, constipation, dyspepsia, flatulence
8
Uncommon: gastroduodenal ulceration, gastrooesophageal reflux disease, dry mouth, gastrointestinal
sounds abnormal
Rare: pancreatitis, oesophagitis, oedema mouth (perioral swelling)
Skin and subcutaneous tissue disorders
Common: pruritus, hyperhidrosis
Uncommon: ecchymosis, rash, urticaria
Musculoskeletal and connective tissue disorders
Common: back pain
Uncommon: arthralgia
Renal and urinary disorders
Common: oliguria
Rare: renal failure acute
General disorders and administration site conditions
Common: oedema peripheral
Uncommon: asthenia, injection site pain, injection site reaction
Investigations
Common: blood creatinine increased
Uncommon: blood creatine phosphokinase increased, blood lactate dehydrogenase increased, SGOT
increased, SGPT increased, blood urea nitrogen increased.
Injury, poisoning and procedural complaint
Uncommon: post procedural complication (skin)
The following rare, serious adverse events have been reported in association with the use of NSAIDs
and cannot be ruled out for Dynastat: bronchospasm and hepatitis.
Following coronary artery bypass graft surgery, patients administered Dynastat have a higher risk of
adverse events, such as cardiovascular/ thromboembolic events, deep surgical infections and sternal
wound healing complications. Cardiovascular/thromboembolic events include myocardial infarction,
stroke/TIA, pulmonary embolus and deep vein thrombosis (see section 4.3 and 5.1).
In post-marketing experience, the following reactions have been reported in association with the use
of parecoxib:
Rare: renal failure, congestive heart failure, dyspnoea, tachycardia and Stevens-Johnson syndrome.
Very rare: erythema multiforme, exfoliative dermatitis and hypersensitivity reactions including
anaphylaxis and angioedema (see section 4.4).
In post marketing experience, the following reaction has been reported in association with the use of
valdecoxib, and cannot be ruled out for parecoxib: toxic epidermal necrolysis (see section 4.4).
Reporting of overdose with parecoxib has been associated with adverse events which have also been
described with recommended doses of parecoxib.
In case of overdose, patients should be managed by symptomatic and supportive care. Valdecoxib is
not removed by haemodialysis. Diuresis or alkalisation of urine may not be useful due to high protein
binding of valdecoxib.
9
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Coxib, ATC code: M01AH04
Parecoxib is a prodrug of valdecoxib. Valdecoxib is a selective cyclooxygenase-2 (COX-2) inhibitor
within the clinical dose range. 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 man 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. The clinical relevance of these observations has not been
established.
The efficacy of Dynastat was established in studies of dental, gynaecologic (hysterectomy),
orthopaedic (knee and hip replacement), and coronary artery bypass graft surgical pain. The first
perceptible analgesic effect occurred in 7 -13 minutes, with clinically meaningful analgesia
demonstrated in 23-39 minutes and a peak effect within 2 hours following administration of single
doses of 40 mg IV or IM Dynastat. The magnitude of analgesic effect of the 40 mg dose was
comparable with that of ketorolac 60 mg IM or ketorolac 30 mg IV. After a single dose, the duration
of analgesia was dose and clinical pain model dependent, and ranged from 6 to greater than 12 hours.
Opioid-sparing Effects:
In a placebo-controlled, orthopedic and general surgery study (n =1050),
patients received Dynastat at an initial parenteral dose of 40 mg IV followed by 20 mg twice daily for
a minimum of 72 hours in addition to receiving standard care including supplemental patient
controlled opioids. The reduction in opioid use with Dynastat treatment on Days 2 and 3 was 7.2 mg
and 2.8 mg (37% and 28% respectively).This reduction in opioid use was accompanied by significant
reductions in patient-reported opioid symptom distress. Added pain relief compared to opioids alone
was shown. Additional studies in other surgical settings provided similar observations.There are no
data indicating less overall adverse events associated with the use of parecoxib compared to placebo
when used in conjunction with opioids.
Gastrointestinal studies
:
In short-term studies (7 days), the incidence of endoscopically observed
gastroduodenal ulcers or erosions in healthy young and elderly (≥ 65 years) subjects administered
Dynastat (5-21%), although higher than placebo (5-12%), was statistically significantly lower than the
incidence observed with NSAIDs (66-90%).
CABG post-operative Safety Studies:
In addition to routine adverse event reporting, pre-specified
event categories, adjudicated by an independent expert committee, were examined in two placebo-
controlled safety studies in which patients received parecoxib sodium for at least 3 days and then
were transitioned to oral valdecoxib for a total duration of 10-14 days. All patients received standard
of care analgesia during treatment
Patients received low-dose acetylsalicylic acid prior to randomization and throughout the two CABG
surgery studies.
The first CABG surgery study evaluated patients treated with IV parecoxib sodium 40 mg bid for a
minimum of 3 days, followed by treatment with valdecoxib 40 mg bid (parecoxib sodium/valdecoxib
group) (n=311) or placebo/placebo (n=151) in a 14-day, double-blind placebo-controlled study. Nine
10
pre-specified adverse event categories were evaluated (cardiovascular thromboembolic events,
pericarditis, new onset or exacerbation of congestive heart failure, renal failure/dysfunction, upper GI
ulcer complications, major non-GI bleeds, infections, non-infectious pulmonary complications, and
death). There was a significantly (p<0.05) greater incidence of cardiovascular/thromboembolic events
(myocardial infarction, ischemia, cerebrovascular accident, deep vein thrombosis and pulmonary
embolism) detected in the parecoxib/valdecoxib treatment group compared to the placebo/placebo
treatment group for the IV dosing period (2.2% and 0.0% respectively) and over the entire study
period (4.8% and 1.3% respectively). Surgical wound complications (most involving the sternal
wound) were observed at an increased rate with parecoxib/valdecoxib treatment.
In the second CABG surgery study, four pre-specified event categories were evaluated
(cardiovascular/thromboembolic; renal dysfunction/renal failure; upper GI ulcer/bleeding; surgical
wound complication). Patients were randomized within 24-hours post-CABG surgery to: parecoxib
initial dose of 40 mg IV, then 20 mg IV Q12H for a minimum of 3 days followed by valdecoxib PO
(20 mg Q12H) (n=544) for the remainder of a 10 day treatment period; placebo IV followed by
valdecoxib PO (n=544); or placebo IV followed by placebo PO (n=548). A significantly (p=0.033)
greater incidence of events in the cardiovascular/thromboembolic category was detected in the
parecoxib /valdecoxib treatment group (2.0%) compared to the placebo/placebo treatment group
(0.5%). Placebo/valdecoxib treatment was also associated with a higher incidence of CV
thromboembolic events versus placebo treatment, but this difference did not reach statistical
significance. Three of the six cardiovascular thromboembolic events in the placebo/valdecoxib
treatment group occurred during the placebo treatment period; these patients did not receive
valdecoxib. Pre-specified events that occurred with the highest incidence in all three treatment groups
involved the category of surgical wound complications, including deep surgical infections and sternal
wound healing events.
There were no significant differences between active treatments and placebo for any of the other pre-
specified event categories (renal dysfunction/failure, upper GI ulcer complications or surgical wound
complications).
General Surgery:
In a large (N=1050) major orthopedic/general surgery trial, patients received an
initial dose of parecoxib 40 mg IV, then 20 mg IV Q12H for a minimum of 3 days followed by
valdecoxib PO (20 mg Q12H) (n=525) for the remainder of a 10 day treatment period, or placebo IV
followed by placebo PO (n=525). There were no significant differences in the overall safety profile,
including the four pre-specified event categories described above for the second CABG surgery study,
for parecoxib sodium/valdecoxib compared to placebo treatment in these post-surgical patients.
Platelet studies:
In a series of small, multiple dose studies in healthy young and elderly subjects,
Dynastat 20 mg or 40 mg twice daily had no effect on platelet aggregation or bleeding compared to
placebo. In young subjects, Dynastat 40 mg twice daily had no clinically significant effect on
acetylsalicylic acid -mediated inhibition of platelet function (see section 4.5).
5.2 Pharmacokinetic properties
Following IV or IM injection, parecoxib is rapidly converted to valdecoxib, the pharmacologically
active substance, by enzymatic hydrolysis in the liver.
Absorption
Exposure of valdecoxib following single doses of Dynastat, as measured by both the area under the
plasma concentration vs. time curve (AUC) and peak concentration (C
max
), is approximately linear in
the range of clinical doses. AUC and C
max
following twice daily administration is linear up to 50 mg
IV and 20 mg IM. Steady state plasma concentrations of valdecoxib were reached within 4 days with
twice daily dosing.
Following single IV and IM doses of parecoxib sodium 20 mg, C
max
of valdecoxib is achieved in
approximately 30 minutes and approximately 1 hour, respectively. Exposure to valdecoxib was
similar in terms of AUC and C
max
following IV and IM administration. Exposure to parecoxib was
11
similar after IV or IM administration in terms of AUC. Average C
max
of parecoxib after IM dosing
was lower compared to bolus IV dosing, which is attributed to slower extravascular absorption after
IM administration. These decreases were not considered clinically important since C
max
of valdecoxib
is comparable after IM and IV parecoxib sodium administration.
Distribution
The volume of distribution of valdecoxib after its IV administration is approximately 55 litres. Plasma
protein binding is approximately 98% over the concentration range achieved with the highest
recommended dose, 80 mg/day. Valdecoxib, but not parecoxib, is extensively partitioned into
erythrocytes.
Metabolism
Parecoxib is rapidly and almost completely converted to valdecoxib and propionic acid in vivo with a
plasma half-life of approximately 22 minutes. Elimination of valdecoxib is by extensive hepatic
metabolism involving multiple pathways, including cytochrome P 450 (CYP) 3A4 and CYP2C9
isoenzymes and glucuronidation (about 20%) of the sulphonamide moiety. A hydroxylated metabolite
of valdecoxib (via the CYP pathway) has been identified in human plasma that is active as a COX-2
inhibitor. It represents approximately 10% of the concentration of valdecoxib; because of this
metabolite’s low concentration, it is not expected to contribute a significant clinical effect after
administration of therapeutic doses of parecoxib sodium.
Elimination
Valdecoxib is eliminated via hepatic metabolism with less than 5% unchanged valdecoxib recovered
in the urine. No unchanged parecoxib is detected in urine and only trace amounts in the faeces. About
70% of the dose is excreted in the urine as inactive metabolites. Plasma clearance (CL
p
) for
valdecoxib is about 6 l/hr. After IV or IM dosing of parecoxib sodium, the elimination half-life (t
1/2
)
of valdecoxib is about 8 hours.
Elderly Subjects:
Dynastat has been administered to 335 elderly patients (65-96 years of age) in
pharmacokinetic and therapeutic trials. In healthy elderly subjects, the apparent oral clearance of
valdecoxib was reduced, resulting in an approximately 40% higher plasma exposure of valdecoxib
compared to healthy young subjects. When adjusted for body weight, steady state plasma exposure of
valdecoxib was 16% higher in elderly females compared to elderly males (see section 4.2).
Renal Impairment:
In patients with varying degrees of renal impairment administered 20 mg IV
Dynastat, parecoxib was rapidly cleared from plasma. Because renal elimination of valdecoxib is not
important to its disposition, no changes in valdecoxib clearance were found even in patients with
severe renal impairment or in patients undergoing dialysis (see section 4.2).
Hepatic Impairment:
Moderate hepatic impairment did not result in a reduced rate or extent of
parecoxib conversion to valdecoxib. In patients with moderate hepatic impairment (Child-Pugh score
7-9), treatment should be initiated with half the usual recommended dose of Dynastat and the
maximum daily dose should be reduced to 40 mg since valdecoxib exposures were more than doubled
(130%) in these patients. Patients with severe hepatic impairment have not been studied and therefore
the use of Dynastat in patients with severe hepatic impairment is not recommended (see sections 4.2
and 4.3).
5.3
Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology or repeated dose toxicity at 2-fold the maximum human exposure to parecoxib.
However, in the repeated dose toxicity studies in dogs and rats, the systemic exposures to valdecoxib
(the active metabolite of parecoxib) were approximately 0.8-fold the systemic exposure in elderly
human subjects at the maximum recommended therapeutic dose of 80 mg daily. Higher doses were
associated with aggravation and delayed healing of skin infections, an effect probably associated with
COX-2 inhibition.
12
In reproduction toxicity tests, the incidence of post-implantation losses, resorptions and foetal body
weight retardation occurred at doses not producing maternal toxicity in the rabbit studies. No effects
of parecoxib on male or female fertilities were found in rats.
The effects of parecoxib have not been evaluated in late pregnancy or in the pre- and postnatal period.
Parecoxib sodium administered intravenously to lactating rats as a single dose showed concentrations
of parecoxib, valdecoxib and a valdecoxib active metabolite in milk similar to that of maternal
plasma.
The carcinogenic potential of parecoxib sodium has not been evaluated.
6.
6.1 List of excipients
Powder
Disodium hydrogen phosphate
Phosphoric acid and/or sodium hydroxide (for pH adjustment).
6.2 Incompatibilities
This medicinal product must
not
be mixed with other medicinal products except for those mentioned
in section 6.6.
Dynastat and opioids should not be administered together in the same syringe.
Use of Ringer-Lactate solution for injection or glucose 50 g/l (5%) in Ringer Lactate solution for
injection for reconstitution will cause the parecoxib to precipitate from solution and therefore is
not
recommended.
Use of Sterile Water for Injection is
not
recommended, as the resulting solution is not isotonic.
Do not inject Dynastat into an IV line delivering any other drug. The IV line must be adequately
flushed prior to and after Dynastat injection with a solution of known compatibility (see section 6.6).
Injection into an IV line delivering glucose 50 g/l (5%) in Ringer-Lactate solution for injection, or
other IV fluids not listed in 6.6, is
not
recommended as this may cause precipitation from solution
.
6.3 Shelf life
3 years.
Chemical and physical in-use stability of the reconstituted solution has been demonstrated for
24 hours at 25°C. From a microbiological point of view, the aseptically prepared product should be
used immediately. If not used immediately, in-use storage times and conditions prior to use are the
responsibility of the user and would not normally be longer than 12 hours at 25°C, unless
reconstitution has taken place in controlled and validated aseptic conditions.
6.4 Special precautions for storage
This medicinal product does not require special storing conditions prior to reconstitution.
Do not refrigerate or freeze reconstituted solutions.
For storage conditions of the recosntituted medicinal product see section 6.3.
13
6.5 Nature and contents of container
Parecoxib sodium vials
20 mg vials: Type I colourless glass vials (2 ml) with a laminated stopper, sealed with a yellow flip-
off cap on the aluminium overseal.
Dynastat is available in packs containing 10 vials.
6.6 Special precautions for disposal and other handling
Dynastat must be reconstituted before use. Dynastat is preservative free. Aseptic technique is required
for its preparation.
Reconstitution solvents
Acceptable solvents for reconstitution of Dynastat are:
sodium chloride 9 mg/ml (0.9%) solution
glucose 50 g/l (5%) solution for infusion
sodium chloride 4.5 mg/ml (0.45%) and glucose 50 g/l (5%) solution for injection
Reconstitution process
Use aseptic technique to reconstitute lyophilised parecoxib (as parecoxib sodium).
Remove the yellow flip-off cap to expose the central portion of the rubber stopper of the 20 mg
parecoxib vial. Withdraw, with a sterile needle and syringe, 1 ml of an acceptable solvent and insert
the needle through the central portion of the rubber stopper transferring the solvent into the 20 mg
vial. Dissolve the powder completely using a gentle swirling motion and inspect the reconstituted
product before use. The entire contents of the vial should be withdrawn for a single administration.
After reconstitution, Dynastat should be inspected visually for particulate matter and discoloration
prior to administration. The solution should not be used if discolored or cloudy, or if particulate
matter is observed. Dynastat should be administered within 24 hours of reconstitution (see section
6.3), or discarded.
The reconstituted product is isotonic.
IV line solution compatibility
After reconstitution with acceptable solvents, Dynastat may
only
be injected IV or IM, or into IV
lines delivering:
sodium chloride 9 mg/ml (0.9%) solution
glucose 50 g/l (5%) solution for infusion
sodium chloride 4.5 mg/ml (0.45%) and glucose 50 g/l (5%) solution for injection
Ringer-Lactate solution for injection
For single use only. Any unusedproduct or waste material should be disposed of in accordance with
local requirements.
7.
Pfizer Limited
Sandwich
Kent CT13 9NJ
United Kingdom
14
8.
EU/1/02/209/001
9.
Date of first authorisation: 22 March 2002
Date of first renewal: 22 March 2007
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu
15
1.
Dynastat 20 mg powder and solvent for solution for injection
2.
20 mg vial: Each vial contains 20 mg parecoxib (present as 21.18 mg parecoxib sodium) for
reconstitution. After reconstitution, the final concentration of parecoxib is 20 mg/ml.
When reconstituted in sodium chloride 9 mg/ml (0.9%) solution, Dynastat contains approximately
0.22 mEq of sodium per vial.
For a full list of excipients, see section 6.1.
3.
Powder and solvent for solution for injection
White to off-white powder.
Solvent: clear, colourless solution.
4.
For the short-term treatment of postoperative pain.
The decision to prescribe a selective COX-2 inhibitor should be based on an assessment of the
individual patient's overall risks (see sections 4.3 and 4.4).
The recommended dose is 40 mg administered intravenously (IV) or intramuscularly (IM), followed
every 6 to 12 hours by 20 mg or 40 mg as required, not to exceed 80 mg/day. The IV bolus injection
may be given rapidly and directly into a vein or into an existing IV line. The IM injection should be
given slowly and deeply into the muscle (see section 6.6 for instructions for reconstitution).
Concomitant Use with Opioid Analgesics:
Opioid analgesics can be used concurrently with
parecoxib, dosing as described in the paragraph above. In all clinical assessments parecoxib was
administered at a fixed time interval whereas the opioids were administered on as needed basis
(PRN).
As the cardiovascular risk of cyclooxygenase-2 (COX-2) specific inhibitors may increase with dose
and duration of exposure, the shortest duration possible and the lowest effective daily dose should be
used.
Precipitation may occur when Dynastat is combined in solution with other medicinal products and
therefore Dynastat must not be mixed with any other drug, either during reconstitution or injection.
In
those patients where the same IV line is to be used to inject another medicinal product, the line must
be adequately flushed prior to and after Dynastat injection with a solution of known compatibility.
16
IV line solution compatibility
After reconstitution with acceptable solvents, Dynastat may
only
be injected IV or IM, or into IV
lines delivering:
sodium chloride 9 mg/ml (0.9%) solution
glucose 50 g/l (5%) solution for infusion
sodium chloride 4.5 mg/ml (0.45%) and glucose 50 g/l (5%) solution for injection
Ringer-Lactate solution for injection
Injection into an IV line delivering glucose 50 g/l (5%) in Ringer-Lactate solution for injection, or
other IV fluids not listed above, is
not
recommended as this may cause precipitation from solution
.
Elderly:
No dosage adjustment is generally necessary in elderly patients (≥ 65 years). However, for
elderly patients weighing less than 50 kg, initiate treatment with half the usual recommended dose of
Dynastat and reduce the maximum daily dose to 40 mg (see section 5.2).
Hepatic Impairment:
No dosage adjustment is generally necessary in patients with mild hepatic
impairment (Child-Pugh score 5-6). Introduce Dynastat with caution and at half the usual
recommended dose in patients with moderate hepatic impairment (Child-Pugh score 7-9) and reduce
the maximum daily dose to 40 mg. There is no clinical experience in patients with severe hepatic
impairment (Child-Pugh score ≥10), therefore its use is contraindicated in these patients (see sections
4.3 and 5.2).
Renal Impairment:
On the basis of pharmacokinetics, no dosage adjustment is necessary in patients
with mild to moderate renal impairment (creatinine clearance of 30-80 ml/min.). In patients with
severe renal impairment (creatinine clearance < 30 ml/min.) or patients who may be predisposed to
fluid retention parecoxib should be initiated at the lowest recommended dose and the patient's kidney
function closely monitored (see sections 4.4 and 5.2).
Children and adolescents:
There is no experience in children and adolescents. Therefore, its use is not
recommended in these patients.
Hypersensitivity to the active substance or to any of the excipients (see section 6.1).
History of previous serious allergic drug reaction of any type, especially cutaneous reactions such as
Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme.or patients with known
hypersensitivity to sulphonamides (see sections 4.4 and 4.8).
Active peptic ulceration or gastrointestinal (GI) bleeding.
Patients who have experienced bronchospasm, acute rhinitis, nasal polyps, angioneurotic oedema,
urticaria or other allergic-type reactions after taking acetylsalicylic acid or NSAIDs including COX-2
(cyclooxygenase-2) inhibitors.
The third trimester of pregnancy and breast-feeding (see sections 4.6 and 5.3).
Severe hepatic dysfunction (serum albumin <25 g/l or Child-Pugh score ≥ 10).
Inflammatory bowel disease.
Congestive heart failure (NYHA II-IV).
Treatment of post-operative pain following coronary artery bypass graft (CABG) surgery (see sections
4.8 and 5.1).
17
Established ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease.
There is limited clinical experience with Dynastat treatment beyond three days.
Because of the possibility for increased adverse reactions at higher doses of parecoxib, other COX-2
inhibitors and NSAIDs, patients treated with parecoxib should be reviewed following dose increase
and, in the absence of an increase in efficacy, other therapeutic options should be considered (see
section 4.2).
COX-2 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.
Patients with significant risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia,
diabetes mellitus, smoking) should only be treated with parecoxib sodium after careful consideration
(see section 5.1).
Appropriate measures should be taken and discontinuation of parecoxib therapy should be considered
if there is clinical evidence of deterioration in the condition of specific clinical symptoms in these
patients (see section 5.1). Dynastat has not been studied in cardiovascular revascularization
procedures other than coronary artery bypass graft procedures. Studies in other surgeries than CABG
procedures included patients with ASA (American Society of Anaesthesiology) Physical Status Class
I-III only.
COX-2 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).
Upper gastrointestinal complications [perforations, ulcers or bleedings (PUBs)], some of them
resulting in fatal outcome, have occurred in patients treated with parecoxib. Caution is advised in the
treatment of patients most at risk of developing a gastrointestinal complication with NSAIDs; the
elderly, patients using any other NSAID or acetylsalicylic acid concomitantly 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 (gastrointestinal ulceration or other gastrointestinal
complications), when parecoxib sodium is taken concomitantly with acetylsalicylic acid (even at low
doses).
Dynastat has been studied in dental, orthopaedic, gynaecologic (principally hysterectomy) and
coronary artery bypass graft surgery. There is little experience in other types of surgery, for example
gastrointestinal or urological surgery.
Serious skin reactions, including erythema multiforme, exfoliative dermatitis and Stevens-Johnson
syndrome (some of them fatal) have been reported through post-marketing surveillance in patients
receiving parecoxib. Additionally, fatal reports of toxic epidermal necrolysis have been reported
through postmarketing surveillance in patients receiving valdecoxib (the active metabolite of
parecoxib) and cannot be ruled out for parecoxib (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.
Appropriate measures should be taken by physicians to monitor for any serious skin reactions with
therapy, e.g. additional patient consultations. Patients should be advised to immediately report any
emergent skin condition to their physician.
18
Parecoxib should be discontinued at the first appearance of skin rash, mucosal lesions, or any other
sign of hypersensitivity. Serious skin reactions are known to occur with NSAIDs including COX-2
selective inhibitors as well as other medications. However, the reported rate of serious skin events
appears to be greater for valdecoxib (the active metabolite of parecoxib) as compared to other COX-2
selective inhibitors. Patients with a history of sulphonamide allergy may be at greater risk of skin
reactions (see section 4.3). Patients without a history of sulphonamide allergy may also be at risk for
serious skin reactions.
Hypersensitivity reactions (anaphylaxis and angioedema) have been reported in post-marketing
experience with valdecoxib and parecoxib (see section 4.8). Some of these reactions have occurred in
patients with a history of allergic-type reactions to sulphonamides (see section 4.3). Parecoxib should
be discontinued at the first sign of hypersensitivity.
Acute renal failure has been reported through post-marketing surveillance in patients receiving
parecoxib (see section 4.8). Since prostaglandin synthesis inhibition may result in deterioration of
renal function and fluid retention, caution should be observed when administering Dynastat in
patients with impaired renal function (see section 4.2) or hypertension, or in patients with
compromised cardiac or hepatic function or other conditions predisposing to fluid retention.
Caution should be used when initiating treatment with Dynastat in patients with dehydration. In this
case, it is advisable to rehydrate patients first and then start therapy with Dynastat.
Fluid Retention and Oedema
As with other drugs known to inhibit prostaglandin synthesis, fluid retention and oedema have been
observed in some patients taking parecoxib. Therefore, parecoxib should be used with caution in
patients with compromised cardiac function, preexisting oedema, or other conditions predisposing to,
or worsened by, fluid retention including those taking diuretic treatment or otherwise at risk of
hypovolemia. If there is clinical evidence of deterioration in the condition of these patients,
appropriate measures including discontinuation of parecoxib should be taken.
Hypertension
As with all NSAIDs, parecoxib 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.
NSAIDs, including parecoxib, should be used with caution in patients with hypertension. Blood
pressure should be monitored closely during the initiation of therapy with parecoxib and throughout
the course of therapy. If blood pressure rises significantly, alternative treatment should be considered.
Dynastat should be used with caution in patients with moderate hepatic dysfunction (Child-Pugh score
7-9) (see section 4.2).
If during treatment, patients deteriorate in any of the organ system functions described above,
appropriate measures should be taken and discontinuation of parecoxib sodium therapy should be
considered.
Dynastat may mask fever and other signs of inflammation (see section 5.1). In isolated cases, an
aggravation of soft tissue infections has been described in connection with the use of NSAIDs and in
nonclinical studies with Dynastat (see section 5.3). Caution should be exercised with respect to
monitoring the incision for signs of infection in surgical patients receiving Dynastat.
Caution should be exercised when co-administering Dynastat with warfarin and other oral
anticoagulants (see section 4.5).
The concomitant use of parecoxib with other non-aspirin NSAIDs should be avoided.
The use of Dynastat, as with any medicinal product known to inhibit cyclooxygenase/prostaglandin
synthesis, is not recommended in women attempting to conceive (see sections 4.6 and 5.1).
19
Interaction studies have only been performed in adults.
Pharmacodynamic interactions
Anticoagulant therapy should be monitored, particularly during the first few days after initiating
Dynastat therapy in patients receiving warfarin or other anticoagulants, since these patients have an
increased risk of bleeding complications. Therefore, patients receiving oral anticoagulants should be
closely monitored for their prothrombin time INR, particularly in the first few days when therapy with
parecoxib is initiated or the dose of parecoxib is changed (see section 4.4).
Dynastat had no effect on acetylsalicylic acid-mediated inhibition of platelet aggregation or bleeding
times. Clinical trials indicate that Dynastat can be given with low dose acetylsalicylic acid
(≤ 325 mg). In the submitted studies, as with other NSAIDs, an increased risk of gastrointestinal
ulceration or other gastrointestinal complications compared to use of parecoxib alone was shown for
concomitant administration of low-dose acetylsalicylic acid (see section 5.1).
Co-administration of parecoxib sodium and heparin did not affect the pharmacodynamics of heparin
(activated partial thromboplastin time) compared to heparin alone.
NSAIDs may reduce the effect of diuretics and antihypertensive medicinal products. As for NSAIDs,
the risk of acute renal insufficiency may be increased when ACE inhibitors or diuretics are co-
administered with parecoxib sodium.
Co-administration of NSAIDs and cyclosporin or tacrolimus has been suggested to increase the
nephrotoxic effect of cyclosporin and tacrolimus. Renal function should be monitored when parecoxib
sodium and any of these medicinal products are co-administered.
Dynastat may be co-administered with opioid analgesics. In clinical trials, the daily requirement for
PRN opioids was significantly reduced when coadministered with parecoxib.
Effects of other medicinal products on the pharmacokinetics of parecoxib (or its active metabolite
valdecoxib)
Parecoxib is rapidly hydrolysed to the active metabolite valdecoxib. In humans, studies demonstrated
that valdecoxib metabolism is predominantly mediated via CYP3A4 and 2C9 isozymes.
Plasma exposure (AUC and C
max
) to valdecoxib was increased (62% and 19%, respectively) when co-
administered with fluconazole (predominantly a CYP2C9 inhibitor), indicating that the dose of
parecoxib sodium should be reduced in those patients who are receiving fluconazole therapy.
Plasma exposure (AUC and C
max
) to valdecoxib was increased (38% and 24%, respectively) when co-
administered with ketoconazole (CYP3A4 inhibitor), however, a dosage adjustment should not
generally be necessary for patients receiving ketoconazole.
The effect of enzyme induction has not been studied. The metabolism of valdecoxib may
increase when co-administered with enzyme inducers such as rifampicin, phenytoin, carbamazepine or
dexamethasone.
Effect of parecoxib (or its active metabolite valdecoxib) on the pharmacokinetics of other medicinal
products
Treatment with valdecoxib (40 mg twice daily for 7 days) produced a 3-fold increase in plasma
concentrations of dextromethorphan (CYP2D6 substrate). Therefore, caution should be observed
when co-administering Dynastat and medicinal products that are predominantly metabolised by
CYP2D6 and which have narrow therapeutic margins (e.g. flecainide, propafenone, metoprolol).
20
Plasma exposure of omeprazole (CYP 2C19 substrate) 40 mg once daily was increased by 46%
following administration of valdecoxib 40 mg twice daily for 7 days, while the plasma exposure to
valdecoxib was unaffected. These results indicate that although valdecoxib is not metabolised by
CYP2C19, it may be an inhibitor of this isoenzyme. Therefore, caution should be observed when
administering Dynastat with medicinal products known to be substrates of CYP2C19 (e.g. phenytoin,
diazepam, or imipramine).
In interaction studies in rheumatoid arthritis patients receiving weekly methotrexate intramuscularly,
orally administered valdecoxib (40 mg twice daily) did not have a clinically significant effect on the
plasma concentrations of methotrexate. However, adequate monitoring of methotrexate-related
toxicity should be considered when co-administering these two medicinal products.
Co-administration of valdecoxib and lithium produced significant decreases in lithium serum
clearance (25%) and renal clearance (30%) with a 34% higher serum exposure compared to lithium
alone. Lithium serum concentration should be monitored closely when initiating or changing
parecoxib sodium therapy in patients receiving lithium.
Co-administration of valdecoxib with glibenclamide (CYP3A4 substrate) did not affect either the
pharmacokinetics (exposure) or the pharmacodynamics (blood glucose and insulin levels) of
glibenclamide.
Injectable anaesthetics
:
Coadministration of IV parecoxib sodium 40 mg with propofol (CYP2C9
substrate) or midazolam (CYP3A4 substrate) did not affect either the pharmacokinetics (metabolism
and exposure) or the pharmacodynamics (EEG effects, psychomotor tests and waking from sedation)
of IV propofol or IV midazolam. Additionally, coadministration of valdecoxib had no clinically
significant effect on the hepatic or intestinal CYP 3A4-mediated metabolism of orally administered
midazolam. Administration of IV parecoxib sodium 40 mg had no significant effect on the
pharmacokinetics of either IV fentanyl or IV alfentanil (CYP3A4 substrates).
Inhalation anaesthetics:
No formal interaction studies have been done. In surgery studies in which
parecoxib sodium was administered pre-operatively, no evidence of pharmacodynamic interaction was
observed in patients receiving parecoxib sodium and the inhalation anaesthetic agents nitrous oxide
and isoflurane (see section 5.1).
Pregnancy:
Parecoxib sodium is suspected to cause serious birth defects when administered during the last
trimester of pregnancy because as with other medicinal products known to inhibit prostaglandin
synthesis, it may cause premature closure of the ductus arteriosus or uterine inertia (see sections 4.3,
5.1 and 5.3).
Dynastat is contraindicated (see section 4.3) in the last trimester of pregnancy.
Like other medicinal products that inhibit COX-2, Dynastat is not recommended in women attempting
to conceive (see sections 4.4, 5.1 and 5.3).
There are no adequate data from the use of parecoxib sodium in pregnant women or during labour.
Studies in animals have shown reproductive toxicity (see sections 5.1 and 5.3). The potential risk for
humans is unknown. Dynastat should not be used during the first two trimesters of pregnancy unless
clearly necessary (i.e. the potential benefit to the patient outweighs the potential risk to the foetus).
Lactation:
Parecoxib, valdecoxib (its active metabolite) and a valdecoxib active metabolite are excreted in the
milk of rats. It is not known whether valdecoxib is excreted in human milk. Dynastat should not be
administered to women who breast-feed (see sections 4.3 and 5.3).
21
No studies on the effect of Dynastat on the ability to drive or use machines have been performed.
However, patients who experience dizziness, vertigo or somnolence after receiving Dynastat should
refrain from driving or operating machines.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
The following adverse reactions were reported in patients who received parecoxib (N=5,402) in
28 placebo-controlled clinical trials.
[Very Common (≥1/10), Common (≥1/100, <1/10) Uncommon (≥1/1000, <1/100) Rare (≥1/10,000,
<1/1000) Very rare (<1/10,000), not known (cannot be estimated from the available data)]
Infections and infestations
Common: pharyngitis, alveolar osteitis (dry socket)
Uncommon: abnormal sternal serous wound drainage, wound infection
Blood and lymphatic system disorders
Common: anaemia postoperative
Uncommon: thrombocytopenia
Immune System Disorders
Rare: anaphylactoid reaction
Metabolism and nutrition disorders
Common: hypokalaemia
Uncommon: anorexia, hyperglycaemia
Pyschiatric disorders:
Common: agitation, insomnia
Nervous system disorders
Common: hypoaesthesia, dizziness
Uncommon: cerebrovascular disorder
Ear and labyrinth disorders
Uncommon: ear pain
Cardiac disorders
Uncommon: myocardial infarction, bradycardia
Vascular disorders
Common: hypertension, hypotension
Uncommon: hypertension (aggravated), orthostatic hypotension
Respiratory, thoracic and mediastinal disorders
Common: respiratory insufficiency
Uncommon: pulmonary embolism
Gastrointestinal disorders
Very common: nausea
Common: abdominal pain, vomiting, constipation, dyspepsia, flatulence
22
Uncommon: gastroduodenal ulceration, gastrooesophageal reflux disease, dry mouth, gastrointestinal
sounds abnormal
Rare: pancreatitis, oesophagitis, oedema mouth (perioral swelling)
Skin and subcutaneous tissue disorders
Common: pruritus, hyperhidrosis
Uncommon: ecchymosis, rash, urticaria
Musculoskeletal and connective tissue disorders
Common: back pain
Uncommon: arthralgia
Renal and urinary disorders
Common: oliguria
Rare: renal failure acute
General disorders and administration site conditions
Common: oedema peripheral
Uncommon: asthenia, injection site pain, injection site reaction
Investigations
Common: blood creatinine increased
Uncommon: blood creatine phosphokinase increased, blood lactate dehydrogenase increased, SGOT
increased, SGPT increased, blood urea nitrogen increased.
Injury, poisoning and procedural complaint
Uncommon: post procedural complication (skin)
The following rare, serious adverse events have been reported in association with the use of NSAIDs
and cannot be ruled out for Dynastat: bronchospasm and hepatitis.
Following coronary artery bypass graft surgery, patients administered Dynastat have a higher risk of
adverse events, such as cardiovascular/ thromboembolic events, deep surgical infections and
sternal
wound healing complications. Cardiovascular/thromboembolic events include myocardial infarction,
stroke/TIA, pulmonary embolus and deep vein thrombosis (see section 4.3 and 5.1).
In post-marketing experience, the following reactions have been reported in association with the use
of parecoxib:
Rare: renal failure, congestive heart failure, dyspnoea, tachycardia and Stevens-Johnson syndrome.
Very rare: erythema multiforme, exfoliative dermatitis and hypersensitivity reactions including
anaphylaxis and angioedema (see section 4.4).
In post marketing experience, the following reaction has been reported in association with the use of
valdecoxib, and cannot be ruled out for parecoxib: toxic epidermal necrolysis (see section 4.4).
Reporting of overdose with parecoxib has been associated with adverse events which have also been
described with recommended doses of parecoxib.
In case of overdose, patients should be managed by symptomatic and supportive care. Valdecoxib is
not removed by haemodialysis. Diuresis or alkalisation of urine may not be useful due to high protein
binding of valdecoxib.
23
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Coxib, ATC code: M01AH04
Parecoxib is a prodrug of valdecoxib. Valdecoxib is a selective cyclooxygenase-2 (COX-2) inhibitor
within the clinical dose range. 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 man 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. The clinical relevance of these observations has not been
established.
The efficacy of Dynastat was established in studies of dental, gynaecologic (hysterectomy),
orthopaedic (knee and hip replacement), and coronary artery bypass graft surgical pain. The first
perceptible analgesic effect occurred in 7 -13 minutes, with clinically meaningful analgesia
demonstrated in 23-39 minutes and a peak effect within 2 hours following administration of single
doses of 40 mg IV or IM Dynastat. The magnitude of analgesic effect of the 40 mg dose was
comparable with that of ketorolac 60 mg IM or ketorolac 30 mg IV. After a single dose, the duration
of analgesia was dose and clinical pain model dependent, and ranged from 6 to greater than 12 hours.
Opioid-sparing Effects:
In a placebo-controlled, orthopedic and general surgery study (n =1050),
patients received Dynastat at an initial parenteral dose of 40 mg IV followed by 20 mg twice daily for
a minimum of 72 hours in addition to receiving standard care including supplemental patient
controlled opioids. The reduction in opioid use with Dynastat treatment on Days 2 and 3 was 7.2 mg
and 2.8 mg (37% and 28% respectively).This reduction in opioid use was accompanied by significant
reductions in patient-reported opioid symptom distress. Added pain relief compared to opioids alone
was shown. Additional studies in other surgical settings provided similar observations. There are no
data indicating less overall adverse events associated with the use of parecoxib compared to placebo
when used in conjunction with opioids.
Gastrointestinal studies
:
In short-term studies (7 days), the incidence of endoscopically observed
gastroduodenal ulcers or erosions in healthy young and elderly (≥ 65 years) subjects administered
Dynastat (5-21%), although higher than placebo (5-12%), was statistically significantly lower than the
incidence observed with NSAIDs (66-90%).
CABG post-operative Safety Studies:
In addition to routine adverse event reporting, pre-specified
event categories, adjudicated by an independent expert committee, were examined in two placebo-
controlled safety studies in which patients received parecoxib sodium for at least 3 days and then
were transitioned to oral valdecoxib for a total duration of 10-14 days. All patients received standard
of care analgesia during treatment.
Patients received low-dose acetylsalicylic acid prior to randomization and throughout the two CABG
surgery studies.
The first CABG surgery study evaluated patients treated with IV parecoxib sodium 40 mg bid for a
minimum of 3 days, followed by treatment with valdecoxib 40 mg bid (parecoxib sodium/valdecoxib
group) (n=311) or placebo/placebo (n=151) in a 14-day, double-blind placebo-controlled study. Nine
24
pre-specified adverse event categories were evaluated (cardiovascular thromboembolic events,
pericarditis, new onset or exacerbation of congestive heart failure, renal failure/dysfunction, upper GI
ulcer complications, major non-GI bleeds, infections, non-infectious pulmonary complications, and
death). There was a significantly (p<0.05) greater incidence of cardiovascular/thromboembolic events
(myocardial infarction, ischemia, cerebrovascular accident, deep vein thrombosis and pulmonary
embolism) detected in the parecoxib/valdecoxib treatment group compared to the placebo/placebo
treatment group for the IV dosing period (2.2% and 0.0% respectively) and over the entire study
period (4.8% and 1.3% respectively). Surgical wound complications (most involving the sternal
wound) were observed at an increased rate with parecoxib/valdecoxib treatment.
In the second CABG surgery study, four pre-specified event categories were evaluated
(cardiovascular/thromboembolic; renal dysfunction/renal failure; upper GI ulcer/bleeding; surgical
wound complication). Patients were randomized within 24-hours post-CABG surgery to: parecoxib
initial dose of 40 mg IV, then 20 mg IV Q12H for a minimum of 3 days followed by valdecoxib PO
(20 mg Q12H) (n=544) for the remainder of a 10 day treatment period; placebo IV followed by
valdecoxib PO (n=544); or placebo IV followed by placebo PO (n=548). A significantly (p=0.033)
greater incidence of events in the cardiovascular/thromboembolic category was detected in the
parecoxib /valdecoxib treatment group (2.0%) compared to the placebo/placebo treatment group
(0.5%). Placebo/valdecoxib treatment was also associated with a higher incidence of CV
thromboembolic events versus placebo treatment, but this difference did not reach statistical
significance. Three of the six cardiovascular thromboembolic events in the placebo/valdecoxib
treatment group occurred during the placebo treatment period; these patients did not receive
valdecoxib. Pre-specified events that occurred with the highest incidence in all three treatment groups
involved the category of surgical wound complications, including deep surgical infections and sternal
wound healing events.
There were no significant differences between active treatments and placebo for any of the other pre-
specified event categories (renal dysfunction/failure, upper GI ulcer complications or surgical wound
complications).
General Surgery:
In a large (N=1050) major orthopedic/general surgery trial, patients received an
initial dose of parecoxib 40 mg IV, then 20 mg IV Q12H for a minimum of 3 days followed by
valdecoxib PO (20 mg Q12H) (n=525) for the remainder of a 10 day treatment period, or placebo IV
followed by placebo PO (n=525). There were no significant differences in the overall safety profile,
including the four pre-specified event categories described above for the second CABG surgery study,
for parecoxib sodium/valdecoxib compared to placebo treatment in these post-surgical patients.
Platelet studies:
In a series of small, multiple dose studies in healthy young and elderly subjects,
Dynastat 20 mg or 40 mg twice daily had no effect on platelet aggregation or bleeding compared to
placebo. In young subjects, Dynastat 40 mg twice daily had no clinically significant effect on
acetylsalicylic acid -mediated inhibition of platelet function (see section 4.5).
5.2 Pharmacokinetic properties
Following IV or IM injection, parecoxib is rapidly converted to valdecoxib, the pharmacologically
active substance, by enzymatic hydrolysis in the liver.
Absorption
Exposure of valdecoxib following single doses of Dynastat, as measured by both the area under the
plasma concentration vs. time curve (AUC) and peak concentration (C
max
), is approximately linear in
the range of clinical doses. AUC and C
max
following twice daily administration is linear up to 50 mg
IV and 20 mg IM. Steady state plasma concentrations of valdecoxib were reached within 4 days with
twice daily dosing.
Following single IV and IM doses of parecoxib sodium 20 mg, C
max
of valdecoxib is achieved in
approximately 30 minutes and approximately 1 hour, respectively. Exposure to valdecoxib was
similar in terms of AUC and C
max
following IV and IM administration. Exposure to parecoxib was
25
similar after IV or IM administration in terms of AUC. Average C
max
of parecoxib after IM dosing
was lower compared to bolus IV dosing, which is attributed to slower extravascular absorption after
IM administration. These decreases were not considered clinically important since C
max
of valdecoxib
is comparable after IM and IV parecoxib sodium administration.
Distribution
The volume of distribution of valdecoxib after its IV administration is approximately 55 litres. Plasma
protein binding is approximately 98% over the concentration range achieved with the highest
recommended dose, 80 mg/day. Valdecoxib, but not parecoxib, is extensively partitioned into
erythrocytes.
Metabolism
Parecoxib is rapidly and almost completely converted to valdecoxib and propionic acid in vivo with a
plasma half-life of approximately 22 minutes. Elimination of valdecoxib is by extensive hepatic
metabolism involving multiple pathways, including cytochrome P 450 (CYP) 3A4 and CYP2C9
isoenzymes and glucuronidation (about 20%) of the sulphonamide moiety. A hydroxylated metabolite
of valdecoxib (via the CYP pathway) has been identified in human plasma that is active as a COX-2
inhibitor. It represents approximately 10% of the concentration of valdecoxib; because of this
metabolite’s low concentration, it is not expected to contribute a significant clinical effect after
administration of therapeutic doses of parecoxib sodium.
Elimination
Valdecoxib is eliminated via hepatic metabolism with less than 5% unchanged valdecoxib recovered
in the urine. No unchanged parecoxib is detected in urine and only trace amounts in the faeces. About
70% of the dose is excreted in the urine as inactive metabolites. Plasma clearance (CL
p
) for
valdecoxib is about 6 l/hr. After IV or IM dosing of parecoxib sodium, the elimination half-life (t
1/2
)
of valdecoxib is about 8 hours.
Elderly Subjects:
Dynastat has been administered to 335 elderly patients (65-96 years of age) in
pharmacokinetic and therapeutic trials. In healthy elderly subjects, the apparent oral clearance of
valdecoxib was reduced, resulting in an approximately 40% higher plasma exposure of valdecoxib
compared to healthy young subjects. When adjusted for body weight, steady state plasma exposure of
valdecoxib was 16% higher in elderly females compared to elderly males (see section 4.2).
Renal Impairment:
In patients with varying degrees of renal impairment administered 20 mg
IVDynastat, parecoxib was rapidly cleared from plasma. Because renal elimination of valdecoxib is
not important to its disposition, no changes in valdecoxib clearance were found even in patients with
severe renal impairment or in patients undergoing dialysis (see section 4.2).
Hepatic Impairment:
Moderate hepatic impairment did not result in a reduced rate or extent of
parecoxib conversion to valdecoxib. In patients with moderate hepatic impairment (Child-Pugh score
7-9), treatment should be initiated with half the usual recommended dose of Dynastat and the
maximum daily dose should be reduced to 40 mg since valdecoxib exposures were more than doubled
(130%) in these patients. Patients with severe hepatic impairment have not been studied and therefore
the use of Dynastat in patients with severe hepatic impairment is not recommended (see sections 4.2
and 4.3).
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology or repeated dose toxicity at 2-fold the maximum human exposure to parecoxib.
However, in the repeated dose toxicity studies in dogs and rats, the systemic exposures to valdecoxib
(the active metabolite of parecoxib) were approximately 0.8-fold the systemic exposure in elderly
human subjects at the maximum recommended therapeutic dose of 80 mg daily. Higher doses were
associated with aggravation and delayed healing of skin infections, an effect probably associated with
COX-2 inhibition.
26
In reproduction toxicity tests, the incidence of post-implantation losses, resorptions and foetal body
weight retardation occurred at doses not producing maternal toxicity in the rabbit studies. No effects
of parecoxib on male or female fertilities were found in rats.
The effects of parecoxib have not been evaluated in late pregnancy or in the pre- and postnatal period.
Parecoxib sodium administered intravenously to lactating rats as a single dose showed concentrations
of parecoxib, valdecoxib and a valdecoxib active metabolite in milk similar to that of maternal
plasma.
The carcinogenic potential of parecoxib sodium has not been evaluated.
6.
6.1 List of excipients
Powder
Disodium hydrogen phosphate
Phosphoric acid and/or sodium hydroxide (for pH adjustment).
Solvent
Sodium chloride
Hydrochloric acid or sodium hydroxide (for pH adjustment)
Water for injections.
6.2 Incompatibilities
This medicinal product must
not
be mixed with other medicinal products except for those mentioned
in section 6.6.
Dynastat and opioids should not be administered together in the same syringe.
Use of Ringer-Lactate solution for injection or glucose 50 g/l (5%) in Ringer Lactate solution for
injection for reconstitution will cause the parecoxib to precipitate from solution and therefore is
not
recommended.
Use of Sterile Water for Injection is
not
recommended, as the resulting solution is not isotonic.
Do not inject Dynastat into an IV line delivering any other drug. The IV line must be adequately
flushed prior to and after Dynastat injection with a solution of known compatibility (see section 6.6).
Injection into an IV line delivering glucose 50 g/l (5%) in Ringer-Lactate solution for injection, or
other IV fluids not listed in 6.6, is
not
recommended as this may cause precipitation from solution.
6.3 Shelf life
3 years.
Chemical and physical in-use stability of the reconstituted solution has been demonstrated for
24 hours at 25°C. From a microbiological point of view, the aseptically prepared product should be
used immediately. If not used immediately, in-use storage times and conditions prior to use are the
responsibility of the user and would not normally be longer than 12 hours at 25°C, unless
reconstitution has taken place in controlled and validated aseptic conditions.
27
6.4 Special precautions for storage
This medicinal product does not require special storing conditions prior to reconstitution.
Do not refrigerate or freeze reconstituted solutions.
For storage conditions of the reconstituted medicinal product see section 6.3.
6.5 Nature and contents of container
Parecoxib sodium vials
20 mg vials: Type I colourless glass vials (2 ml) with a laminated stopper, sealed with a yellow flip-
off cap on the aluminium overseal.
Solvent ampoules
2 ml ampoule: colourless neutral glass, Type I.
Dynastat is supplied as a sterile, single unit-of-use vial that is packaged with a 2 ml ampoule with a
fill volume of 1 ml sodium chloride 9 mg/ml (0.9%) solution (see below for various pack sizes and
configurations).
Pack sizes
1 x 1 pack: contains 1 vial with parecoxib 20 mg and 1 ampoule with 1 ml sodium chloride 9 mg/ml
(0.9%) solution.
3 x 3 pack: contains 3 vials of parecoxib 20 mg and 3 ampoule with 1 ml sodium chloride 9 mg/ml
(0.9%) solution.
5 x 5 pack: contains 5 vials of parecoxib 20 mg and 5 ampoule with 1 ml sodium chloride 9 mg/ml
(0.9%) solution.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Dynastat must be reconstituted before use. Dynastat is preservative free. Aseptic technique is required
for its preparation.
Reconstitution solvents
Reconstitute Dynastat 20 mg with 1 ml sodium chloride 9 mg/ml (0.9%) solution.
The
only
other acceptable solvents for reconstitution are:
glucose 50 g/l (5%) solution for infusion
sodium chloride 4.5 mg/ml (0.45%) and glucose 50 g/l (5%) solution for injection
Reconstitution process
Use aseptic technique to reconstitute lyophilised parecoxib (as parecoxib sodium).
Remove the yellow flip-off cap to expose the central portion of the rubber stopper of the 20 mg
parecoxib vial. Withdraw, with a sterile needle and syringe, 1 ml of an acceptable solvent and insert
the needle through the central portion of the rubber stopper transferring the solvent into the 20 mg
vial. Dissolve the powder completely using a gentle swirling motion and inspect the reconstituted
product before use. The entire contents of the vial should be withdrawn for a single administration.
After reconstitution, Dynastat should be inspected visually for particulate matter and discoloration
prior to administration. The solution should not be used if discolored or cloudy, or if particulate
matter is observed. Dynastat should be administered within 24 hours of reconstitution (see section
6.3), or discarded
28
The reconstituted product is isotonic.
IV line solution compatibility
After reconstitution with acceptable solvents, Dynastat may
only
be injected IV or IM, or into IV
lines delivering:
sodium chloride 9 mg/ml (0.9%) solution
glucose 50 g/l (5%) solution for infusion
sodium chloride 4.5 mg/ml (0.45%) and glucose 50 g/l (5%) solution for injection
Ringer-Lactate solution for injection
For single use only. Any unused product or waste material should be disposed of in accordance with
local requirements.
7.
Pfizer Limited
Sandwich
Kent CT13 9NJ
United Kingdom
8.
EU/1/02/209/002-004
9.
Date of first authorisation: 22 March 2002
Date of first renewal: 22 March 2007
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu.
29
1.
Dynastat 40 mg powder for solution for injection
2.
40 mg vial: Each vial contains 40 mg parecoxib (present as 42.36 mg parecoxib sodium) for
reconstitution. After reconstitution, the final concentration of parecoxib is 20 mg/ml.
When reconstituted in sodium chloride 9 mg/ml (0.9%) solution, Dynastat contains approximately
0.44 mEq of sodium per vial.
For a full list of excipients, see section 6.1.
3.
Powder for solution for injection
White to off-white powder.
4.
For the short-term treatment of postoperative pain.
The decision to prescribe a selective COX-2 inhibitor should be based on an assessment of the
individual patient's overall risks (see sections 4.3 and 4.4).
The recommended dose is 40 mg administered intravenously (IV) or intramuscularly (IM), followed
every 6 to 12 hours by 20 mg or 40 mg as required, not to exceed 80 mg/day. The IV bolus injection
may be given rapidly and directly into a vein or into an existing IV line. The IM injection should be
given slowly and deeply into the muscle (see section 6.6 for instructions for reconstitution).
Concomitant Use with Opioid Analgesics:
Opioid analgesics can be used concurrently with
parecoxib, dosing as described in the paragraph above. In all clinical assessments parecoxib was
administered at a fixed time interval whereas the opioids were administered on as needed basis
(PRN).
As the cardiovascular risk of cyclooxygenase-2 (COX-2) specific inhibitors may increase with dose
and duration of exposure, the shortest duration possible and the lowest effective daily dose should be
used.
Precipitation may occur when Dynastat is combined in solution with other medicinal products and
therefore Dynastat must not be mixed with any other drug, either during reconstitution or injection.
In
those patients where the same IV line is to be used to inject another medicinal product, the line must
be adequately flushed prior to and after Dynastat injection with a solution of known compatibility.
IV line solution compatibility
After reconstitution with acceptable solvents, Dynastat may
only
be injected IV or IM, or into IV
lines delivering:
sodium chloride 9 mg/ml (0.9%) solution
30
glucose 50 g/l (5%) solution for infusion
sodium chloride 4.5 mg/ml (0.45%) and glucose 50 g/l (5%) solution for injection
Ringer-Lactate solution for injection
Injection into an IV line delivering glucose 50 g/l (5%) in Ringer-Lactate solution for injection, or
other IV fluids not listed above, is
not
recommended as this may cause precipitation from solution.
Elderly:
No dosage adjustment is generally necessary in elderly patients (≥ 65 years). However, for
elderly patients weighing less than 50 kg, initiate treatment with half the usual recommended dose of
Dynastat and reduce the maximum daily dose to 40 mg (see section 5.2).
Hepatic Impairment:
No dosage adjustment is generally necessary in patients with mild hepatic
impairment (Child-Pugh score 5-6). Introduce Dynastat with caution and at half the usual
recommended dose in patients with moderate hepatic impairment (Child-Pugh score 7-9) and reduce
the maximum daily dose to 40 mg. There is no clinical experience in patients with severe hepatic
impairment (Child-Pugh score ≥10), therefore its use is contraindicated in these patients (see sections
4.3 and 5.2).
Renal Impairment:
On the basis of pharmacokinetics, no dosage adjustment is necessary in patients
with mild to moderate renal impairment (creatinine clearance of 30-80 ml/min.). In patients with
severe renal impairment (creatinine clearance < 30 ml/min.) or patients who may be predisposed to
fluid retention parecoxib should be initiated at the lowest recommended dose and the patient's kidney
function closely monitored (see sections 4.4 and 5.2).
Children and adolescents:
There is no experience in children and adolescents. Therefore, its use is not
recommended in these patients.
Hypersensitivity to the active substance or to any of the excipients (see section 6.1).
History of previous serious allergic drug reaction of any type, especially cutaneous reactions such as
Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme or patients with known
hypersensitivity to sulphonamides (see sections 4.4 and 4.8).
Active peptic ulceration or (GI) gastrointestinal bleeding.
Patients who have experienced bronchospasm, acute rhinitis, nasal polyps, angioneurotic oedema,
urticaria or other allergic-type reactions after taking acetylsalicylic acid or NSAIDs including COX-2
(cyclooxygenase-2) inhibitors.
The third trimester of pregnancy and breast-feeding (see sections 4.6 and 5.3).
Severe hepatic dysfunction (serum albumin <25 g/l or Child-Pugh score ≥ 10).
Inflammatory bowel disease.
Congestive heart failure (NYHA II-IV).
Treatment of post-operative pain following coronary artery bypass graft (CABG) surgery (see sections
4.8 and 5.1).
Established ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease.
31
There is limited clinical experience with Dynastat treatment beyond three days.
Because of the possibility for increased adverse reactions at higher doses of parecoxib, other COX-2
inhibitors and NSAIDs, patients treated with parecoxib should be reviewed following dose increase
and, in the absence of an increase in efficacy, other therapeutic options should be considered (see
section 4.2).
COX-2 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.
Patients with significant risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia,
diabetes mellitus, smoking) should only be treated with parecoxib sodium after careful consideration
(see section 5.1).
Appropriate measures should be taken and discontinuation of parecoxib therapy should be considered
if there is clinical evidence of deterioration in the condition of specific clinical symptoms in these
patients (see section 5.1). Dynastat has not been studied in cardiovascular revascularization
procedures other than coronary artery bypass graft procedures. Studies in other surgeries than CABG
procedures included patients with ASA (American Society of Anaesthesiology) Physical Status Class
I-III only.
COX-2 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).
Upper gastrointestinal complications [perforations, ulcers or bleedings (PUBs)], some of them
resulting in fatal outcome, have occurred in patients treated with parecoxib. Caution is advised in the
treatment of patients most at risk of developing a gastrointestinal complication with NSAIDs; the
elderly, patients using any other NSAID or acetylsalicylic acid concomitantly 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 (gastrointestinal ulceration or other gastrointestinal
complications), when parecoxib sodium is taken concomitantly with acetylsalicylic acid (even at low
doses).
Dynastat has been studied in dental, orthopaedic, gynaecologic (principally hysterectomy) and
coronary artery bypass graft surgery. There is little experience in other types of surgery, for example
gastrointestinal or urological surgery.
Serious skin reactions, including erythema multiforme, exfoliative dermatitis and Stevens-Johnson
syndrome (some of them fatal) have been reported through post-marketing surveillance in patients
receiving parecoxib. Additionally, fatal reports of toxic epidermal necrolysis have been reported
through postmarketing surveillance in patients receiving valdecoxib (the active metabolite of
parecoxib) and cannot be ruled out for parecoxib (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.
Appropriate measures should be taken by physicians to monitor for any serious skin reactions with
therapy, e.g. additional patient consultations. Patients should be advised to immediately report any
emergent skin condition to their physician.
Parecoxib should be discontinued at the first appearance of skin rash, mucosal lesions, or any other
sign of hypersensitivity. Serious skin reactions are known to occur with NSAIDs including COX-2
selective inhibitors as well as other medications. However, the reported rate of serious skin events
32
appears to be greater for valdecoxib (the active metabolite of parecoxib) as compared to other COX-2
selective inhibitors. Patients with a history of sulphonamide allergy may be at greater risk of skin
reactions (see section 4.3). Patients without a history of sulphonamide allergy may also be at risk for
serious skin reactions.
Hypersensitivity reactions (anaphylaxis and angioedema) have been reported in post-marketing
experience with valdecoxib and parecoxib (see section 4.8). Some of these reactions have occurred in
patients with a history of allergic-type reactions to sulphonamides (see section 4.3). Parecoxib should
be discontinued at the first sign of hypersensitivity.
Acute renal failure has been reported through post-marketing surveillance in patients receiving
parecoxib (see section 4.8). Since prostaglandin synthesis inhibition may result in deterioration of
renal function and fluid retention, caution should be observed when administering Dynastat in
patients with impaired renal function (see section 4.2) or hypertension, or in patients with
compromised cardiac or hepatic function or other conditions predisposing to fluid retention.
Caution should be used when initiating treatment with Dynastat in patients with dehydration. In this
case, it is advisable to rehydrate patients first and then start therapy with Dynastat.
Fluid Retention and Oedema
As with other drugs known to inhibit prostaglandin synthesis, fluid retention and oedema have been
observed in some patients taking parecoxib. Therefore, parecoxib should be used with caution in
patients with compromised cardiac function, preexisting oedema, or other conditions predisposing to,
or worsened by, fluid retention including those taking diuretic treatment or otherwise at risk of
hypovolemia. If there is clinical evidence of deterioration in the condition of these patients,
appropriate measures including discontinuation of parecoxib should be taken.
Hypertension
As with all NSAIDs, parecoxib 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.
NSAIDs, including parecoxib, should be used with caution in patients with hypertension. Blood
pressure should be monitored closely during the initiation of therapy with parecoxib and throughout
the course of therapy. If blood pressure rises significantly, alternative treatment should be considered.
Dynastat should be used with caution in patients with moderate hepatic dysfunction (Child-Pugh score
7-9) (see section 4.2).
If during treatment, patients deteriorate in any of the organ system functions described above,
appropriate measures should be taken and discontinuation of parecoxib sodium therapy should be
considered.
Dynastat may mask fever and other signs of inflammation (see section 5.1). In isolated cases, an
aggravation of soft tissue infections has been described in connection with the use of NSAIDs and in
nonclinical studies with Dynastat (see section 5.3). Caution should be exercised with respect to
monitoring the incision for signs of infection in surgical patients receiving Dynastat.
Caution should be exercised when co-administering Dynastat with warfarin and other oral
anticoagulants (see section 4.5).
The concomitant use of parecoxib with other non-aspirin NSAIDs should be avoided.
The use of Dynastat, as with any medicinal product known to inhibit cyclooxygenase/prostaglandin
synthesis, is not recommended in women attempting to conceive (see sections 4.6 and 5.1).
33
Interaction studies have only been performed in adults.
Pharmacodynamic interactions
Anticoagulant therapy should be monitored, particularly during the first few days after initiating
Dynastat therapy in patients receiving warfarin or other anticoagulants, since these patients have an
increased risk of bleeding complications. Therefore, patients receiving oral anticoagulants should be
closely monitored for their prothrombin time INR, particularly in the first few days when therapy with
parecoxib is initiated or the dose of parecoxib is changed (see section 4.4).
Dynastat had no effect on acetylsalicylic acid-mediated inhibition of platelet aggregation or bleeding
times. Clinical trials indicate that Dynastat can be given with low dose acetylsalicylic acid
(≤ 325 mg). In the submitted studies, as with other NSAIDs, an increased risk of gastrointestinal
ulceration or other gastrointestinal complications compared to use of parecoxib alone was shown for
concomitant administration of low-dose acetylsalicylic acid (see section 5.1).
Co-administration of parecoxib sodium and heparin did not affect the pharmacodynamics of heparin
(activated partial thromboplastin time) compared to heparin alone.
NSAIDs may reduce the effect of diuretics and antihypertensive medicinal products. As for NSAIDs,
the risk of acute renal insufficiency may be increased when ACE inhibitors or diuretics are co-
administered with parecoxib sodium.
Co-administration of NSAIDs and cyclosporin or tacrolimus has been suggested to increase the
nephrotoxic effect of cyclosporin and tacrolimus. Renal function should be monitored when parecoxib
sodium and any of these medicinal products are co-administered.
Dynastat may be co-administered with opioid analgesics. In clinical trials, the daily requirement for
PRN opioids was significantly reduced when coadministered with parecoxib.
Effects of other medicinal products on the pharmacokinetics of parecoxib (or its active metabolite
valdecoxib)
Parecoxib is rapidly hydrolysed to the active metabolite valdecoxib. In humans, studies demonstrated
that valdecoxib metabolism is predominantly mediated via CYP3A4 and 2C9 isozymes.
Plasma exposure (AUC and C
max
) to valdecoxib was increased (62% and 19%, respectively) when co-
administered with fluconazole (predominantly a CYP2C9 inhibitor), indicating that the dose of
parecoxib sodium should be reduced in those patients who are receiving fluconazole therapy.
Plasma exposure (AUC and C
max
) to valdecoxib was increased (38% and 24%, respectively) when co-
administered with ketoconazole (CYP3A4 inhibitor), however, a dosage adjustment should not
generally be necessary for patients receiving ketoconazole.
The effect of enzyme induction has not been studied. The metabolism of valdecoxib may
increase when co-administered with enzyme inducers such as rifampicin, phenytoin, carbamazepine or
dexamethasone.
Effect of parecoxib (or its active metabolite valdecoxib) on the pharmacokinetics of other medicinal
products
Treatment with valdecoxib (40 mg twice daily for 7 days) produced a 3-fold increase in plasma
concentrations of dextromethorphan (CYP2D6 substrate). Therefore, caution should be observed
when co-administering Dynastat and medicinal products that are predominantly metabolised by
CYP2D6 and which have narrow therapeutic margins (e.g. flecainide, propafenone, metoprolol).
34
Plasma exposure of omeprazole (CYP 2C19 substrate) 40 mg once daily was increased by 46%
following administration of valdecoxib 40 mg twice daily for 7 days, while the plasma exposure to
valdecoxib was unaffected. These results indicate that although valdecoxib is not metabolised by
CYP2C19, it may be an inhibitor of this isoenzyme. Therefore, caution should be observed when
administering Dynastat with medicinal products known to be substrates of CYP2C19 (e.g. phenytoin,
diazepam, or imipramine).
In interaction studies in rheumatoid arthritis patients receiving weekly methotrexate intramuscularly,
orally administered valdecoxib (40 mg twice daily) did not have a clinically significant effect on the
plasma concentrations of methotrexate. However, adequate monitoring of methotrexate-related
toxicity should be considered when co-administering these two medicinal products.
Co-administration of valdecoxib and lithium produced significant decreases in lithium serum
clearance (25%) and renal clearance (30%) with a 34% higher serum exposure compared to lithium
alone. Lithium serum concentration should be monitored closely when initiating or changing
parecoxib sodium therapy in patients receiving lithium.
Co-administration of valdecoxib with glibenclamide (CYP3A4 substrate) did not affect either the
pharmacokinetics (exposure) or the pharmacodynamics (blood glucose and insulin levels) of
glibenclamide.
Injectable anaesthetics
:
Coadministration of IV parecoxib sodium 40 mg with propofol (CYP2C9
substrate) or midazolam (CYP3A4 substrate) did not affect either the pharmacokinetics (metabolism
and exposure) or the pharmacodynamics (EEG effects, psychomotor tests and waking from sedation)
of IV propofol or IV midazolam. Additionally, coadministration of valdecoxib had no clinically
significant effect on the hepatic or intestinal CYP 3A4-mediated metabolism of orally administered
midazolam. Administration of IV parecoxib sodium 40 mg had no significant effect on the
pharmacokinetics of either IV fentanyl or IV alfentanil (CYP3A4 substrates).
Inhalation anaesthetics:
No formal interaction studies have been done. In surgery studies in which
parecoxib sodium was administered pre-operatively, no evidence of pharmacodynamic interaction was
observed in patients receiving parecoxib sodium and the inhalation anaesthetic agents nitrous oxide
and isoflurane (see section 5.1).
Pregnancy:
Parecoxib sodium is suspected to cause serious birth defects when administered during the last
trimester of pregnancy because as with other medicinal products known to inhibit prostaglandin
synthesis, it may cause premature closure of the ductus arteriosus oruterine inertia (see sections
4.3, 5.1 and 5.3).
Dynastat is contraindicated (see section 4.3) in the last trimester of pregnancy.
Like other medicinal products that inhibit COX-2, Dynastat is not recommended in women attempting
to conceive (see sections 4.4, 5.1 and 5.3).
There are no adequate data from the use of parecoxib sodium in pregnant women or during labour.
Studies in animals have shown reproductive toxicity (see sections 5.1 and 5.3). The potential risk for
humans is unknown. Dynastat should not be used during the first two trimesters of pregnancy unless
clearly necessary (i.e. the potential benefit to the patient outweighs the potential risk to the foetus).
Lactation:
Parecoxib, valdecoxib (its active metabolite) and a valdecoxib active metabolite are excreted in the
milk of rats. It is not known whether valdecoxib is excreted in human milk. Dynastat should not be
administered to women who breast-feed (see sections 4.3 and 5.3).
35
No studies on the effect of Dynastat on the ability to drive or use machines have been performed.
However, patients who experience dizziness, vertigo or somnolence after receiving Dynastat should
refrain from driving or operating machines.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
The following adverse reactions were reported in patients who received parecoxib (N=5,402) in
28 placebo-controlled clinical trials.
[Very Common (≥1/10), Common (≥1/100, <1/10) Uncommon (≥1/1000, <1/100) Rare (≥1/10,000,
<1/1000) Very rare (<1/10,000), not known (cannot be estimated from the available data)]
Infections and infestations
Common: pharyngitis, alveolar osteitis (dry socket)
Uncommon: abnormal sternal serous wound drainage, wound infection
Blood and lymphatic system disorders
Common: anaemia postoperative
Uncommon: thrombocytopenia
Immune System Disorders
Rare: anaphylactoid reaction
Metabolism and nutrition disorders
Common: hypokalaemia
Uncommon: anorexia, hyperglycaemia
Pyschiatric disorders:
Common: agitation, insomnia
Nervous system disorders
Common: hypoaesthesia, dizziness
Uncommon: cerebrovascular disorder
Ear and labyrinth disorders
Uncommon: ear pain
Cardiac disorders
Uncommon: myocardial infarction, bradycardia
Vascular disorders
Common: hypertension, hypotension
Uncommon: hypertension (aggravated), orthostatic hypotension
Respiratory, thoracic and mediastinal disorders
Common: respiratory insufficiency
Uncommon: pulmonary embolism
Gastrointestinal disorders
Very common: nausea
Common: abdominal pain, vomiting, constipation, dyspepsia, flatulence
36
Uncommon: gastroduodenal ulceration, gastrooesophageal reflux disease, dry mouth, gastrointestinal
sounds abnormal
Rare: pancreatitis, oesophagitis, oedema mouth (perioral swelling)
Skin and subcutaneous tissue disorders
Common: pruritus, hyperhidrosis
Uncommon: ecchymosis, rash, urticaria
Musculoskeletal and connective tissue disorders
Common: back pain
Uncommon: arthralgia
Renal and urinary disorders
Common: oliguria
Rare: renal failure acute
General disorders and administration site conditions
Common: oedema peripheral
Uncommon: asthenia, injection site pain, injection site reaction
Investigations
Common: blood creatinine increased
Uncommon: blood creatine phosphokinase increased, blood lactate dehydrogenase increased, SGOT
increased, SGPT increased, blood urea nitrogen increased.
Injury, poisoning and procedural complaint
Uncommon: post procedural complication (skin)
The following rare, serious adverse events have been reported in association with the use of NSAIDs
and cannot be ruled out for Dynastat: bronchospasm and hepatitis.
Following coronary artery bypass graft surgery, patients administered Dynastat have a higher risk of
adverse events, such as cardiovascular/ thromboembolic events, deep surgical infections
and sternal
wound healing complications. Cardiovascular/thromboembolic events include myocardial infarction,
stroke/TIA, pulmonary embolus and deep vein thrombosis (see section 4.3 and 5.1).
In post-marketing experience, the following reactions have been reported in association with the use
of parecoxib:
Rare: renal failure, congestive heart failure, dyspnoea, tachycardia and Stevens-Johnson syndrome.
Very rare: erythema multiforme, exfoliative dermatitis and hypersensitivity reactions including
anaphylaxis and angioedema (see section 4.4).
In post marketing experience, the following reaction has been reported in association with the use of
valdecoxib, and cannot be ruled out for parecoxib: toxic epidermal necrolysis (see section 4.4).
Reporting of overdose with parecoxib has been associated with adverse events which have also been
described with recommended doses of parecoxib.
In case of overdose, patients should be managed by symptomatic and supportive care. Valdecoxib is
not removed by haemodialysis. Diuresis or alkalisation of urine may not be useful due to high protein
binding of valdecoxib.
37
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Coxib, ATC code: M01AH04
Parecoxib is a prodrug of valdecoxib. Valdecoxib is a selective cyclooxygenase-2 (COX-2) inhibitor
within the clinical dose range. 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 man 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. The clinical relevance of these observations has not been
established.
The efficacy of Dynastat was established in studies of dental, gynaecologic (hysterectomy),
orthopaedic (knee and hip replacement), and coronary artery bypass graft surgical pain. The first
perceptible analgesic effect occurred in 7 -13 minutes, with clinically meaningful analgesia
demonstrated in 23-39 minutes and a peak effect within 2 hours following administration of single
doses of 40 mg IV or IM Dynastat. The magnitude of analgesic effect of the 40 mg dose was
comparable with that of ketorolac 60 mg IM or ketorolac 30 mg IV. After a single dose, the duration
of analgesia was dose and clinical pain model dependent, and ranged from 6 to greater than 12 hours.
Opioid-sparing Effects:
In a placebo-controlled, orthopedic and general surgery study (n =1050),
patients received Dynastat at an initial parenteral dose of 40 mg IV followed by 20 mg twice daily for
a minimum of 72 hours in addition to receiving standard care including supplemental patient
controlled opioids. The reduction in opioid use with Dynastat treatment on Days 2 and 3 was 7.2 mg
and 2.8 mg (37% and 28% respectively).This reduction in opioid use was accompanied by significant
reductions in patient-reported opioid symptom distress. Added pain relief compared to opioids alone
was shown. Additional studies in other surgical settings provided similar observations. There are no
data indicating less overall adverse events associated with the use of parecoxib compared to placebo
when used in conjunction with opioids.
Gastrointestinal studies
:
In short-term studies (7 days), the incidence of endoscopically observed
gastroduodenal ulcers or erosions in healthy young and elderly (≥ 65 years) subjects administered
Dynastat (5-21%), although higher than placebo (5-12%), was statistically significantly lower than the
incidence observed with NSAIDs (66-90%).
CABG post-operative Safety Studies:
In addition to routine adverse event reporting, pre-specified
event categories, adjudicated by an independent expert committee, were examined in two placebo-
controlled safety studies in which patients received parecoxib sodium for at least 3 days and then
were transitioned to oral valdecoxib for a total duration of 10-14 days. All patients received standard
of care analgesia during treatment
Patients received low-dose acetylsalicylic acid prior to randomization and throughout the two CABG
surgery studies.
The first CABG surgery study evaluated patients treated with IV parecoxib sodium 40 mg bid for a
minimum of 3 days, followed by treatment with valdecoxib 40 mg bid (parecoxib sodium/valdecoxib
group) (n=311) or placebo/placebo (n=151) in a 14-day, double-blind placebo-controlled study. Nine
38
pre-specified adverse event categories were evaluated (cardiovascular thromboembolic events,
pericarditis, new onset or exacerbation of congestive heart failure, renal failure/dysfunction, upper GI
ulcer complications, major non-GI bleeds, infections, non-infectious pulmonary complications, and
death). There was a significantly (p<0.05) greater incidence of cardiovascular/thromboembolic events
(myocardial infarction, ischemia, cerebrovascular accident, deep vein thrombosis and pulmonary
embolism) detected in the parecoxib/valdecoxib treatment group compared to the placebo/placebo
treatment group for the IV dosing period (2.2% and 0.0% respectively) and over the entire study
period (4.8% and 1.3% respectively). Surgical wound complications (most involving the sternal
wound) were observed at an increased rate with parecoxib/valdecoxib treatment.
In the second CABG surgery study, four pre-specified event categories were evaluated
(cardiovascular/thromboembolic; renal dysfunction/renal failure; upper GI ulcer/bleeding; surgical
wound complication). Patients were randomized within 24-hours post-CABG surgery to: parecoxib
initial dose of 40 mg IV, then 20 mg IV Q12H for a minimum of 3 days followed by valdecoxib PO
(20 mg Q12H) (n=544) for the remainder of a 10 day treatment period; placebo IV followed by
valdecoxib PO (n=544); or placebo IV followed by placebo PO (n=548). A significantly (p=0.033)
greater incidence of events in the cardiovascular/thromboembolic category was detected in the
parecoxib /valdecoxib treatment group (2.0%) compared to the placebo/placebo treatment group
(0.5%). Placebo/valdecoxib treatment was also associated with a higher incidence of CV
thromboembolic events versus placebo treatment, but this difference did not reach statistical
significance. Three of the six cardiovascular thromboembolic events in the placebo/valdecoxib
treatment group occurred during the placebo treatment period; these patients did not receive
valdecoxib. Pre-specified events that occurred with the highest incidence in all three treatment groups
involved the category of surgical wound complications, including deep surgical infections and sternal
wound healing events.
There were no significant differences between active treatments and placebo for any of the other pre-
specified event categories (renal dysfunction/failure, upper GI ulcer complications or surgical wound
complications
).
General Surgery:
In a large (N=1050) major orthopedic/general surgery trial, patients received an
initial dose of parecoxib 40 mg IV, then 20 mg IV Q12H for a minimum of 3 days followed by
valdecoxib PO (20 mg Q12H) (n=525) for the remainder of a 10 day treatment period, or placebo IV
followed by placebo PO (n=525). There were no significant differences in the overall safety profile,
including the four pre-specified event categories described above for the second CABG surgery study,
for parecoxib sodium/valdecoxib compared to placebo treatment in these post-surgical patients.
Platelet studies:
In a series of small, multiple dose studies in healthy young and elderly subjects,
Dynastat 20 mg or 40 mg twice daily had no effect on platelet aggregation or bleeding compared to
placebo. In young subjects, Dynastat 40 mg twice daily had no clinically significant effect on
acetylsalicylic acid -mediated inhibition of platelet function (see section 4.5).
5.2 Pharmacokinetic properties
Following IV or IM injection, parecoxib is rapidly converted to valdecoxib, the pharmacologically
active substance, by enzymatic hydrolysis in the liver.
Absorption
Exposure of valdecoxib following single doses of Dynastat, as measured by both the area under the
plasma concentration vs. time curve (AUC) and peak concentration (C
max
), is approximately linear in
the range of clinical doses. AUC and C
max
following twice daily administration is linear up to 50 mg
IV and 20 mg IM. Steady state plasma concentrations of valdecoxib were reached within 4 days with
twice daily dosing.
Following single IV and IM doses of parecoxib sodium 20 mg, C
max
of valdecoxib is achieved in
approximately 30 minutes and approximately 1 hour, respectively. Exposure to valdecoxib was
similar in terms of AUC and C
max
following IV and IM administration. Exposure to parecoxib was
39
similar after IV or IM administration in terms of AUC. Average C
max
of parecoxib after IM dosing
was lower compared to bolus IV dosing, which is attributed to slower extravascular absorption after
IM administration. These decreases were not considered clinically important since C
max
of valdecoxib
is comparable after IM and IV parecoxib sodium administration.
Distribution
The volume of distribution of valdecoxib after its IV administration is approximately 55 litres. Plasma
protein binding is approximately 98% over the concentration range achieved with the highest
recommended dose, 80 mg/day. Valdecoxib, but not parecoxib, is extensively partitioned into
erythrocytes.
Metabolism
Parecoxib is rapidly and almost completely converted to valdecoxib and propionic acid in vivo with a
plasma half-life of approximately 22 minutes. Elimination of valdecoxib is by extensive hepatic
metabolism involving multiple pathways, including cytochrome P 450 (CYP) 3A4 and CYP2C9
isoenzymes and glucuronidation (about 20%) of the sulphonamide moiety. A hydroxylated metabolite
of valdecoxib (via the CYP pathway) has been identified in human plasma that is active as a COX-2
inhibitor. It represents approximately 10% of the concentration of valdecoxib; because of this
metabolite’s low concentration, it is not expected to contribute a significant clinical effect after
administration of therapeutic doses of parecoxib sodium.
Elimination
Valdecoxib is eliminated via hepatic metabolism with less than 5% unchanged valdecoxib recovered
in the urine. No unchanged parecoxib is detected in urine and only trace amounts in the faeces. About
70% of the dose is excreted in the urine as inactive metabolites. Plasma clearance (CL
p
) for
valdecoxib is about 6 l/hr. After IV or IM dosing of parecoxib sodium, the elimination half-life (t
1/2
)
of valdecoxib is about 8 hours.
Elderly Subjects
Dynastat has been administered to 335 elderly patients (65-96 years of age) in
pharmacokinetic and therapeutic trials. In healthy elderly subjects, the apparent oral clearance of
valdecoxib was reduced, resulting in an approximately 40% higher plasma exposure of valdecoxib
compared to healthy young subjects. When adjusted for body weight, steady state plasma exposure of
valdecoxib was 16% higher in elderly females compared to elderly males (see section 4.2).
Renal Impairment:
In patients with varying degrees of renal impairment administered 20 mg
IVDynastat, parecoxib was rapidly cleared from plasma. Because renal elimination of valdecoxib is
not important to its disposition, no changes in valdecoxib clearance were found even in patients with
severe renal impairment or in patients undergoing dialysis (see section 4.2).
Hepatic Impairment:
Moderate hepatic impairment did not result in a reduced rate or extent of
parecoxib conversion to valdecoxib. In patients with moderate hepatic impairment (Child-Pugh score
7-9), treatment should be initiated with half the usual recommended dose of Dynastat and the
maximum daily dose should be reduced to 40 mg since valdecoxib exposures were more than doubled
(130%) in these patients. Patients with severe hepatic impairment have not been studied and therefore
the use of Dynastat in patients with severe hepatic impairment is not recommended (see sections 4.2
and 4.3).
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology or repeated dose toxicity at 2-fold the maximum human exposure to parecoxib.
However, in the repeated dose toxicity studies in dogs and rats, the systemic exposures to valdecoxib
(the active metabolite of parecoxib) were approximately 0.8-fold the systemic exposure in elderly
human subjects at the maximum recommended therapeutic dose of 80 mg daily. Higher doses were
associated with aggravation and delayed healing of skin infections, an effect probably associated with
COX-2 inhibition.
40
In reproduction toxicity tests, the incidence of post-implantation losses, resorptions and foetal body
weight retardation occurred at doses not producing maternal toxicity in the rabbit studies. No effects
of parecoxib on male or female fertilities were found in rats.
The effects of parecoxib have not been evaluated in late pregnancy or in the pre- and postnatal period.
Parecoxib sodium administered intravenously to lactating rats as a single dose showed concentrations
of parecoxib, valdecoxib and a valdecoxib active metabolite in milk similar to that of maternal
plasma.
The carcinogenic potential of parecoxib sodium has not been evaluated.
6.
6.1 List of excipients
Powder
Disodium hydrogen phosphate
Phosphoric acid and/or sodium hydroxide (for pH adjustment).
6.2 Incompatibilities
This medicinal product must
not
be mixed with other medicinal products except for those mentioned
in section 6.6.
Dynastat and opioids should not be administered together in the same syringe.
Use of Ringer-Lactate solution for injection or glucose 50 g/l (5%) in Ringer Lactate solution for
injection for reconstitution will cause the parecoxib to precipitate from solution and therefore is
not
recommended.
Use of Sterile Water for Injection is
not
recommended, as the resulting solution is not isotonic.
Do not inject Dynastat into an IV line delivering any other drug. The IV line must be adequately
flushed prior to and after Dynastat injection with a solution of known compatibility (see section 6.6).
Injection into an IV line delivering glucose 50 g/l (5%) in Ringer-Lactate solution for injection, or
other IV fluids not listed in 6.6, is
not
recommended as this may cause precipitation from solution.
6.3 Shelf life
3 years.
Chemical and physical in-use stability of the reconstituted solution has been demonstrated for
24 hours at 25°C. From a microbiological point of view, the aseptically prepared product should be
used immediately. If not used immediately, in-use storage times and conditions prior to use are the
responsibility of the user and would not normally be longer than 12 hours at 25°C, unless
reconstitution has taken place in controlled and validated aseptic conditions.
6.4 Special precautions for storage
This medicinal nproduct does not require special storing conditions prior to reconstitution.
Do not refrigerate or freeze reconstituted solutions.
For storage conditions of the reconstituted medicinal product see section 6.3.
41
6.5 Nature and contents of container
Parecoxib sodium vials
40 mg vials: Type I colourless glass vials (5 ml) with a laminated stopper, sealed with a purple flip-off
cap on the aluminium overseal.
Dynastat is available in packs containing 10 vials.
6.6 Special precautions for disposal and other handling.
Dynastat must be reconstituted before use. Dynastat is preservative free. Aseptic technique is required
for its preparation.
Reconstitution solvents
Acceptable solvents for reconstitution of Dynastat are:
sodium chloride 9 mg/ml (0.9%) solution
glucose 50 g/l (5%) solution for infusion
sodium chloride 4.5 mg/ml (0.45%) and glucose 50 g/l (5%) solution for injection
Reconstitution Process
Use aseptic technique to reconstitute lyophilised parecoxib (as parecoxib sodium).
Remove the purple flip-off cap to expose the central portion of the rubber stopper of the 40 mg
parecoxib vial. Withdraw, with a sterile needle and syringe, 2 ml of an acceptable solvent and insert
the needle through the central portion of the rubber stopper transferring the solvent into the 40 mg
vial. Dissolve the powder completely using a gentle swirling motion and inspect the reconstituted
product before use. The entire contents of the vial should be withdrawn for a single administration.
After reconstitution, Dynastat should be inspected visually for particulate matter and discoloration
prior to administration. The solution should not be used if discolored or cloudy, or if particulate
matter is observed. Dynastat should be administered within 24 hours of reconstitution (see section
6.3), or discarded.
The reconstituted product is isotonic.
IV line solution compatibility
After reconstitution with acceptable solvents, Dynastat may
only
be injected IV or IM, or into IV
lines delivering:
sodium chloride 9 mg/ml (0.9%) solution
glucose 50 g/l (5%) solution for infusion
sodium chloride 4.5 mg/ml (0.45%) and glucose 50 g/l (5%) solution for injection
Ringer-Lactate solution for injection
For single use only. Any unused product or waste material should be disposed of in accordance with
local requirements.
7.
Pfizer Limited
Sandwich
Kent CT13 9NJ
United Kingdom
42
8.
EU/1/02/209/005
9.
Date of first authorisation: 22 March 2002
Date of first renewal: 22 March 2007
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu.
43
1.
FURTHER INFORMATION
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder.
What Dynastat contains
-
The active substance is parecoxib (as parecoxib sodium). Each vial contains 40 mg parecoxib, as
42.36 mg parecoxib sodium. When reconstituted with 2 ml solvent, provides 20 mg/ml of
parecoxib. When reconstituted in sodium chloride 9 mg/ml (0.9%) solution, Dynastat contains
approximately 0.44 mEq of sodium per vial.
-
The other ingredients are:
Powder
Disodium hydrogen phosphate
Phosphoric acid and/or sodium hydroxide (for pH adjustment).
Solvent
Sodium chloride
Hydrochloric acid or sodium hydroxide (for pH adjustment)
Water for injections.
111
What Dynastat looks like and contents of the pack
Dynastat is available as a white to off-white powder.
The powder is contained in colourless glass vials (5 ml) with a laminated stopper, sealed with a purple
flip-off cap on the aluminium overseal.
The solvent is contained in colourless neutral glass ampoules (2 ml).
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder: Pfizer Limited, Sandwich, Kent CT13 9NJ United Kingdom
Manufacturer:
Piramal Healthcare UK Limited, Whalton Road, Morpeth, Northumberland NE613YA United
Kingdom
Pfizer Manufacturing Belgium NV, Rijksweg 12, 2870 Puurs, Belgium
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder.
België /Belgique / Belgien
Pfizer S.A./ N.V.
Tél/Tel: +32 (0)2 554 62 11
Luxembourg/Luxemburg
Pfizer S.A.
Tél/Tel: +32 (0)2 554 62 11
България
Пфайзер Люксембург САРЛ, Клон България
Тел.: +359 2 970 4333
Magyarország
Pfizer Kft.
Tel.: + 36 1 488 37 00
Česká republika
Pfizer s.r.o.
Tel: +420-283-004-111
Malta
V.J. Salomone Pharma Ltd.
Tel: +356 21 22 01 74
Danmark
Pfizer ApS
Tlf: +45 44 20 11 00
Nederland
Pfizer bv
Tel: +31 (0)10 406 4301
Deutschland
Pfizer Pharma GmbH
Tel:+ 49 (0)30 550055 51000
Norge
Pfizer AS
Tlf: +47 67 52 61 00
Eesti
Pfizer Luxembourg SARL Eesti filiaal
Tel: +372 6 405 328
Österreich
Pfizer Corporation Austria Ges.m.b.H.
Tel: +43 (0)1 521 15-0
Ελλάδα
Pfizer Hellas A.E.
Τηλ: +30 210 6785800
Polska
Pfizer Polska Sp. z o.o.,
Tel.: +48 22 335 61 00
España
Pfizer S.A.
Tel: +34 91 490 99 00
Portugal
Laboratórios Pfizer, Lda.
Tel:+351 21 423 5500
France
Pfizer
Tél: +33 (0)1 58 07 34 40
România
Pfizer Rom
â
nia S.R.L.
Tel: +40 (0)21 207 28 00
112
Ireland
Pfizer Healthcare Ireland
Tel: 1800 633 363 (toll free)
+44 (0)1304 616161
Slovenija
Pfizer Luxembourg SARL
Pfizer, podružnica za svetovanje s področja
farmacevtske dejavnosti, Ljubljana
Tel: + 386 (0)152 11 400
Ísland
Icepharma hf.
Sími: + 354 540 8000
Slovenská republika
Pfizer Luxembourg SARL, organizačná zložka
Tel: +421–2–3355 5500
Italia
Pfizer Italia S.r.l.
Tel: +39 06 33 18 21
Suomi/Finland
Pfizer Oy
Puh/Tel: +358(0)9 43 00 40
Κύπρος
Geo. Pavlides & Araouzos Ltd,
Τηλ: +35722818087
Sverige
Pfizer AB
Tel: +46 (0)8 550 520 00
Latvija
Pfizer Luxembourg SARL filiāle Latvijā
Tel: +371 670 35 775
United Kingdom
Pfizer Limited
Tel: +44 (0)1304 616161
Lietuva
Pfizer Luxembourg SARL filialas Lietuvoje.
Tel. +3705 2514000
This leaflet was last approved on {date}
<------------------------------------------------------------------------------------------------------------------
Detailed information on this medicine is available on the European Medicines Agency website:
http://www.ema.europa.eu
.
113
The following information is intended for medical or healthcare professionals only
Administration is by intramuscular (IM) or intravenous (IV) injection
. The IM injection is to be
given slowly and deeply into the muscle and the IV bolus injection may be given rapidly and directly
into a vein or into an existing IV line.
Reconstitution solvents
This medicinal product must not be mixed
with other medicinal products and is to be reconstituted
only with:
• sodium chloride 9 mg/ml (0.9%) solution
• glucose 50 g/l (5%) solution for infusion
• sodium chloride 4.5 mg/ml (0.45%) and glucose 50 g/l (5%) solution for injection
Use of Ringer-Lactate solution for injection or glucose 50 g/l (5%) in Ringer-Lactate solution for
injection for reconstitution will cause the parecoxib to precipitate from solution and therefore is
not
recommended.
Use of Sterile Water for Injection for reconsitution is not recommended, as the resulting solution is
not
isotonic.
Reconstitution process
Use aseptic technique to reconstitute lyophilised parecoxib (as parecoxib sodium).
40 mg vial
: Remove the purple flip-off cap to expose the central portion of the rubber stopper of the
parecoxib 40 mg vial. Withdraw with a sterile needle and syringe, 2 ml of an acceptable solvent and
insert the needle through the central portion of the rubber stopper transferring the solvent into the
parecoxib 40 mg vial.
Dissolve the powder completely
using a gentle swirling motion and inspect the reconstituted product
before use.
The reconstituted solution must not be used
if discoloured or cloudy or if particulate matter is
observed
The entire contents of the vial should be withdrawn for a single administration.
IV line solution compatibility
Precipitation may occur when Dynastat is combined in solution with other medicinal products and
therefore Dynastat must not be mixed with any other drug, either during reconstitution or injection. In
those patients where the same IV line is to be used to inject another medicinal product, the line must
be adequately flushed prior to and after Dynastat injection with a solution of known compatibility
After reconstitution
with acceptable solvents, Dynastat may only be injected into IV lines delivering:
• sodium chloride 9 mg/ml (0.9%) solution
• glucose 50 g/l (5%) solution for infusion
• sodium chloride 4.5 mg/ml (0.45%) and glucose 50 g/l (5%) solution for injection
• Ringer-Lactate solution for injection
Injection into an IV line delivering glucose 50 g/l (5%) in Ringer-Lactate solution for injection, or
other IV fluids not listed in this section, is
not
recommended as this may cause precipitation from
solution
.
The solution is for single use only and must not be stored in a refrigerator or freezer.
114
Source: European Medicines Agency
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