Pericob 40 40 mg Powder for solution for injection.

For the short-term management of post-operative pain in patients who need parenteral therapy and for when a similar benefit could not be obtained from oral therapy. It is reminded that patients be transferred to alternative oral therapy as soon as clinically indicated. PERICOB 40 is also indicated for the reduction of post-operative opioid use in patients who have undergone hip replacement surgery, for up to 48 hours.

Posology
PERICOB 40 is only indicated for patients with a need for parenteral therapy and for whom a similar benefit could not be obtained from alternative oral therapy. It is recommended that patients be transitioned to alternative oral therapy as soon as clinically indicated. As the cardiovascular risk of PERICOB 40 may increase with dose and duration of exposure, the shortest duration possible and the lowest effective daily dose should be used. However, the relevance of these findings for the short-term use of PERICOB 40 in the post-operative setting has not been evaluated. Safety and efficacy of PERICOB 40 have not been established for periods of use exceeding 96 hours.

Management of post-operative pain
The usual recommended dose is a single or initial 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. When given at the recommended doses for management of acute pain, the onset of analgesia was 7 - 14 minutes and reached a peak effect within 2 hours. After a single dose, the duration of analgesia was dose and clinical pain model dependent and ranged from 7 to greater than 24 hours.

Concomitant use with opioid analgesia
Opioid analgesia can be used concurrently with PERICOB 40 dosing as described in the paragraph above, for the management of post-operative pain for up to 48 hours. In a hip replacement surgery trial, the daily requirements for opioid were significantly reduced (20 - 40 %) when co-administered with PERICOB 40. An optimal effect is achieved when PERICOB 40 is given at the end of hip replacement surgery, prior to opioid administration. In all clinical assessments PERICOB 40 was administered at a fixed time interval (i.e. 12 hourly), whereas the opioids were administered when needed (PRN basis).

Special populations
Elderly
Dosage adjustment in the elderly is not generally necessary, however, for elderly female patients weighing less than 50 kg, initiate treatment with half the usual recommended dose of PERICOB 40 and reduce the maximum daily dose to 40 mg.

Hepatic impairment
No dosage adjustment is generally necessary in patients with mild hepatic impairment (Child-Pugh scale 5 - 6). Introduce PERICOB 40 with caution and at half the usual recommended dose in patients with moderate hepatic impairment (Child-Pugh scale 7 - 9) and reduce the maximum daily dose to 40 mg. There is no clinical experience in patients with severe hepatic impairment (Child-Pugh scale > 9); therefore, its use is not recommended in these patients (see section 4.3).

Renal impairment
On the basis of pharmacokinetics, no dosage adjustment is necessary in patients with mild to moderate (creatinine clearance of 30 - 80 ml/min) renal impairment. In patients with severe (creatinine clearance < 30 ml/min) renal impairment or patients who may be predisposed to fluid retention, PERICOB 40 should not be used (see section 4.3).

Children
PERICOB 40 has not been studied in patients under 18 years old. Therefore, its use is not recommended in these patients.

Method of administration
PERICOB 40 can be administered intravenously (IV) or intramuscularly (IM). 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. For instructions on reconstitution of PERICOB 40 before administration and PERICOB 40 diluent incompatibilities, see sections 6.2 and 6.6. Modes of administration other than IV or IM (e.g. intra-articular of intrathecal) have not been studies and should not be used.

• Hypersensitivity to parecoxib or to any of the excipients (see section 6.1).
• History of previous serious allergic medicine reaction of any type, especially cutaneous reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme or patients with known hypersensitivity to sulfonamides (see sections 4.4 and 4.8).
• Active peptic ulceration or gastrointestinal (GI) bleeding.
• Patients who have experienced bronchospasm, acute rhinitis, nasal polyps, angioedema, urticaria or other allergic-type reactions after taking acetylsalicylic acid or nonsteroidal anti-inflammatory medicines (NSAIDs) including COX-2 inhibitors.
• Pregnancy and lactation (see section 4.6).
• Severe hepatic impairment (serum albumin < 25 g/l or Child-Pugh score u226510).
• Severe renal impairment.
• 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.
• Children younger than 18 years.

PERICOB 40 may predispose to cardiovascular events, cerebrovascular events, gastrointestinal events, or cutaneous reactions which may be fatal.

During pregnancy, the regular use of non-steroidal inflammatory parecoxib may result in:

First trimester
Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development. Data from epidemiological studies raise concern about an increased risk of miscarriage and of cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk for cardiovascular malformation was increased from less than 1 %, up to approximately 1,5 %. In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and post- implantation loss and embryo-foetal lethality. In addition, increased incidences of various malformations including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period.

Second and Third trimester.
During the third trimester of pregnancy, prostaglandin synthesis inhibitors, may expose the foetus to: cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension); renal dysfunction, which may progress to renal failure with oligo-hydroamniosis. At the end of pregnancy, the mother and the neonate may be exposed to: possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses; inhibition of uterine contractions resulting in delayed or prolonged labour.

Parecoxib reaction with Eosinophillia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as PERICOB 40. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, haematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophillia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue PERICOB 40 and evaluate the patient immediately.

Cardiovascular
There appears to be a higher risk for cardiovascular events with higher doses and longer duration of treatment. 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. Caution is advised when PERICOB 40 is prescribed to patients with cardiovascular risk factors e.g. hypertension, diabetes, smoking and hypercholesterolaemia (see section 5.1). Appropriate measures should be taken and discontinuation of PERICOB 40 therapy should be considered if there is clinical evidence of deterioration in the condition of specific clinical symptoms in these patients.

Acetylsalicylic acid (aspirin) and other NSAIDs
Because of its lack of platelet effects, PERICOB 40 is not a substitute for aspirin for cardiovascular prophylaxis. Therefore, antiplatelet therapies should not be discontinued (see section 5.1). Caution should be exercised when co-administering PERICOB 40 with warfarin and other oral anticoagulants (see section 4.5). The concomitant use of PERICOB 40 with other non-acetylsalicylic acid NSAIDs should be avoided.

PERICOB 40 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 PERICOB 40. Caution should be exercised with respect to monitoring the incision for signs of infection in surgical patients receiving PERICOB 40.

Gastrointestinal
Upper gastrointestinal (GI) 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, or patients with a prior history of gastrointestinal disease, such as ulceration and GI bleeding, or patients using acetylsalicylic acid concomitantly. The NSAIDs class is also associated with increased GI complications when co-administered with glucocorticoids, selective serotonin reuptake inhibitors, other antiplatelet medicines, other NSAIDs or patients ingesting alcohol. There is further increase in the risk of gastrointestinal adverse effects (gastrointestinal ulceration or other gastrointestinal complications), when parecoxib is used concomitantly with acetylsalicylic acid (even at low doses).

Skin reactions
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, as contained in PERICOB 40. Additionally, fatal reports of toxic epidermal necrolysis have been reported through post-marketing 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 doctors 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 doctor.

PERICOB 40 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. 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 sulfonamide allergy may be at greater risk of skin reactions (see section 4.3). Patients without a history of sulfonamide allergy may also be at risk for serious skin reactions.

Hypersensitivity
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 sulfonamides (see section 4.3). PERICOB 40 should be discontinued at the first sign of hypersensitivity.

Cases of severe hypotension shortly following parecoxib administration have been reported in post-marketing experience with parecoxib. Some of these cases have occurred without other signs of anaphylaxis. The doctor should be prepared to treat severe hypotension.

Fluid retention, oedema, renal
Due to inhibitors of prostaglandin synthesis, fluid retention and oedema have been observed in patients taking parecoxib, therefore PERICOB 40 should be used with caution in patients with compromised cardiac function and other conditions predisposing to, or worsened by fluid retention. Patients with pre-existing congestive heart failure or hypertension should be closely monitored. If there is clinical evidence of deterioration in the condition of these patients, appropriate measures including discontinuation of PERICOB 40 should be taken.

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 PERICOB 40 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 PERICOB 40 in patients with dehydration. In this case, it is advisable to rehydrate patients first and then start therapy with PERICOB 40.

Hypertension
PERICOB 40 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. PERICOB 40 should be used with caution in patients with hypertension. Blood pressure should be monitored closely during the initiation of therapy with PERICOB 40 and throughout the course of therapy. If blood pressure rises significantly, alternative treatment should be considered.

Hepatic impairment
PERICOB 40 should be used with caution in patients with moderate hepatic impairment (Child-Pugh score 7-9) (see section 4.2).

Use with oral anticoagulants
The concomitant use of NSAIDs, including PERICOB 40 with oral anticoagulants increases the risk of bleeding.

PERICOB 40 is not a substitute for aspirin for cardiovascular prophylaxis because of its lack of platelet effects. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious cardiovascular thrombotic events associated with PERICOB 40.

Pharmacodynamic interactions
Anticoagulant therapy should be monitored, particularly during the first few days after initiating PERICOB 40 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 PERICOB 40 is initiated or the dose of PERICOB 40 is changed (see section 4.4).

PERICOB 40 had no effect on acetylsalicylic acid-mediated inhibition of platelet aggregation or bleeding times. Clinical trials indicate that PERICOB 40 can be given with low dose acetylsalicylic acid (u2264 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 and heparin did not affect the pharmacodynamics of heparin (activated partial thromboplastin time) compared to heparin alone.

Inhibition of prostaglandins by NSAIDs, including COX-2 inhibitors, may diminish the effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin II antagonists, beta-blockers, and diuretics. This interaction should be given consideration in patients receiving PERICOB 40 concomitantly with ACE-inhibitors, angiotensin II antagonists, beta-blockers, and diuretics.

In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors or Angiotensin-II antagonists, may result in further deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Therefore, the concomitant administration of these medicines should be done with caution. Patients should be adequately hydrated and the need to monitor the renal function should be assessed at the beginning of the concomitant treatment and periodically thereafter.

Co-administration of NSAIDs and ciclosporin or tacrolimus has been suggested to increase the nephrotoxic effect of ciclosporin and tacrolimus because of NSAID effects on renal prostaglandins. Renal function should be monitored when PERICOB 40 and any of these medicines are co-administered.

PERICOB 40 may be co-administered with opioid analgesics. The daily requirement for PRN opioids is significantly reduced when co-administered with parecoxib.

Use of PERICOB 40 is contraindicated in pregnancy and lactation (see section 4.3)

Pregnancy
Parecoxib is suspected to cause serious birth defects when administered during the last trimester of pregnancy because as with other medicines known to inhibit prostaglandin, it may cause premature closure of the ductus arteriosus or uterine inertia (see sections 4.3 and 5.1).

Regular use of non-steroidal inflammatory parecoxib may result in:

First trimester
Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development. Data from epidemiological studies raise concern about an increased risk of miscarriage and of cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk for cardiovascular malformation was increased from less than 1 %, up to approximately 1,5 %. In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and post- implantation loss and embryo-foetal lethality. In addition, increased incidences of various malformations including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period.

Second and Third trimester.
During the third trimester of pregnancy, prostaglandin synthesis inhibitors, may expose the foetus to: cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension); renal dysfunction, which may progress to renal failure with oligo-hydroamniosis. At the end of pregnancy, the mother and the neonate may be exposed to: possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses; inhibition of uterine contractions resulting in delayed or prolonged labour. Pregnant women on NSAIDs should be closely monitored for amniotic fluid volume.

Breastfeeding
PERICOB 40 must not be administered to women who breastfeed (see section 4.3). Administration of a single dose of parecoxib to lactating women following caesarean section resulted in the transfer of a relatively small amount of parecoxib and its active metabolite valdecoxib into human milk, and this resulted in a low relative dose for the infant (approximately 1 % of the weight-adjusted maternal dose). PERICOB 40 must not be administered to women who breastfeed (see section 4.3).

Fertility
Because of its inhibitory effect on cyclooxygenase/prostaglandin synthesis, the use of PERICOB 40 is not recommended in women attempting to conceive (see sections 4.3 and 5.1). Based on the mechanism of action, the use of NSAIDs, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of NSAIDs, including PERICOB 40 should be considered.

Patients who experience dizziness, vertigo, or somnolence after receiving PERICOB 40 should refrain from driving or operating machines.

a. Summary of the safety profile
The most frequent adverse reaction for PERICOB 40 is nausea. The most serious reactions occur less frequently and include cardiovascular events such as myocardial infarction and severe hypotension, as well as hypersensitivity events such as anaphylaxis, angioedema, and severe skin reactions. Following coronary artery bypass graft surgery, patients administered PERICOB 40 have a higher risk of adverse reactions such as: cardiovascular/thromboembolic events (including myocardial infarction, stroke/TIA, pulmonary embolus, and deep vein thrombosis; see sections 4.3 and 5.1), deep surgical infections, and sternal wound healing complications.

b. Tabulated summary of adverse reactions
Within each frequency grouping, adverse reactions are listed using MedDRA terminology and presented in order of decreasing seriousness.

MedDRA system organ class Frequency Adverse reactions
Infections and infestations Frequent Pharyngitis, alveolar osteitis (dry socket)
Less frequent Abnormal sternal serous wound drainage, wound infection
Blood and lymphatic system disorders Frequent Anaemia postoperative
Less frequent Thrombocytopenia
Immune system disorders Less frequent Anaphylactoid reaction
Metabolism and nutrition disorders Frequent Hypokalaemia
Less frequent Hyperglycaemia, anorexia
Psychiatric disorders Frequent Agitation, insomnia
Nervous system disorders Frequent Hypoaesthesia, dizziness, somnolence
Less frequent Cerebrovascular disorder, cerebrovascular incidents (stroke)
Ear and labyrinth disorders Less frequent Ear pain, vertigo
Cardiac disorders Frequent Oedema peripheral
Less frequent Dysrhythmia, palpitations, cardiovascular thrombotic events, myocardial infarction, bradycardia, congestive heart failure, tachycardia
Frequency unknown Circulatory collapse
Vascular disorders Frequent Hypertension, hypotension
Less frequent Hypertension (aggravated), orthostatic hypotension, hypotension, flushing
Respiratory, thoracic and mediastinal disorders Frequent Respiratory insufficiency
Less frequent Pulmonary embolism
Frequency unknown Dyspnoea
Gastrointestinal disorders Frequent Nausea, abdominal pain, vomiting, constipation, dyspepsia, flatulence
Less frequent Gastroduodenal ulceration, gastro-oesophageal reflux disease, dry mouth, abnormal gastrointestinal sounds
Frequency unknown Pancreatitis, oesophagitis, oedema mouth (perioral swelling)
Skin and subcutaneous tissue disorders Frequent Pruritus, hyperhidrosis
Less frequent Ecchymosis, rash, urticarial
Frequency unknown Stevens-Johnson syndrome, erythema multiforme, exfoliative dermatitis, toxic epidermal necrolysis
Musculoskeletal and connective tissue disorders Frequent Back pain
Less frequent Arthralgia
Renal and urinary disorders Frequent Oliguria
Less frequent Renal failure acute
Frequency unknown Renal failure
General disorders and administration site conditions Less frequent Asthenia, injection site pain, injection site reaction
Frequency unknown Hypersensitivity reactions including anaphylaxis and angioedema
Investigations Frequent Increased blood creatinine
Less frequent Increased blood CPK, increased blood LDH, increased AST, increased ALT, increased BUN

Reporting of overdose with parecoxib has been associated with adverse reactions 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.