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Administration other than IV or IM: Modes of administration other than IV or IM (e.g., intra-articular, intrathecal) have not been studied and should not be used.
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. There is limited clinical experience with Dynastat treatment beyond three days.
If, during treatment, patients deteriorate in any of the organ system functions described as follows, appropriate measures should be taken and discontinuation of parecoxib therapy should be considered.
Cardiovascular Effects: COX-2 inhibitors, of which parecoxib is one, have been associated with an increased risk of cardiovascular and thrombotic adverse events when taken long term. The relative increase of this risk appears to be similar in those with or without known CV disease or CV risk factors. However, patients with known cardiovascular disease or CV risk factors may be at greater risk in terms of absolute incidence, due to their increased rate at baseline. 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 after careful consideration.
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. Dynastat has not been studied in cardiovascular revascularization procedures other than CABG procedures.
Two separate studies in coronary artery bypass graft (CABG) surgery showed that patients receiving parecoxib for a minimum of 3 days followed by oral valdecoxib (the active metabolite of parecoxib) for 7 to 14 days, had increased incidence of cardiovascular/thromboembolic events (e.g., myocardial infarction and cerebrovascular accident) compared to those receiving placebo (see Pharmacology: Pharmacodynamics under Actions). Parecoxib is therefore contraindicated for the treatment of post-operative pain immediately following CABG surgery.
Gastrointestinal (GI) Effects: Upper gastrointestinal (GI) perforations, ulcers, or bleeds, some of them resulting in fatal outcome, have occurred in patients treated with parecoxib. Patients most at risk of developing these types of GI complications with NSAIDs are the elderly, patients with cardiovascular disease, or patients with a history of, or active, GI disease, such as ulceration, bleeding, or inflammatory conditions; or patients using concomitant aspirin. The NSAIDs class is also associated with increased GI complications when co-administered with corticosteroids, selective serotonin reuptake inhibitors, other antiplatelet drugs, other NSAIDs or patients ingesting alcohol, however, there are currently no specific parecoxib clinical data.
Skin Effects: Valdecoxib, the active moiety of parecoxib, contains a sulphonamide moiety and patients with a known history of a sulphonamide allergy may be at a greater risk of skin reactions. Patients without a history of sulphonamide allergy may also be at risk for serious 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. In addition to erythema multiforme and Stevens-Johnson syndrome, fatal reports of toxic epidermal necrolysis have been reported through post-marketing surveillance in patients receiving valdecoxib and the potential cannot be ruled out for parecoxib. Generalised bullous fixed drug eruption (GBFDE) may occur with parecoxib exposure based on a reaction with etoricoxib exposure.
Drug reaction with eosinophilia and systemic symptoms syndrome (DRESS syndrome) may occur with parecoxib exposure based on other serious skin reactions reported with celecoxib and valdecoxib exposure.
Patients appear to be at highest risk for these events early in the course of therapy, with the onset of the event occurring in the majority of cases within the first two weeks 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 have been reported with other COX-2 inhibitors during post-marketing experience. The reported rate of these events appears to be greater for valdecoxib as compared to other COX-2 agents.
Anaphylactoid Reactions: Hypersensitivity reactions (anaphylactic reactions and angioedema) have been reported in post-marketing experience with valdecoxib and parecoxib (see Adverse Reactions). These reactions have occurred in patients with and without a history of allergic-type reactions to sulphonamides (see Contraindications). Parecoxib should be discontinued at the first sign of hypersensitivity.
Severe Hypotension: 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 practitioner should be prepared to treat severe hypotension.
Use with Oral Anticoagulants: The concomitant use of NSAIDs with oral anticoagulants increases the risk of bleeding. Oral anticoagulants include warfarin/coumarin-type and novel oral anticoagulants (e.g., apixaban, dabigatran, and rivaroxaban).
Co-administration of parecoxib with warfarin caused a small increase in the AUC of warfarin, and also in the prothrombin time (measured by International Normalised Ratio [INR]). While mean INR values were only slightly increased with co-administration of parecoxib, the day-to-day variability in individual INR values was increased. Anticoagulant activity should be monitored, particularly during the first few days after initiating parecoxib, in patients receiving warfarin or similar agents, since these patients may be at increased risk of bleeding complications.
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.
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, pre-existing oedema, or other conditions pre-disposing 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.
Renal Effects: Acute renal failure has been reported through post-marketing surveillance in patients receiving parecoxib (see Adverse Reactions). 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 or hypertension, or in patients with compromised cardiac or hepatic function or other conditions pre-disposing to fluid retention. Renal function should be closely monitored in patients with advanced renal disease who are administered parecoxib (see Dosage & Administration).
Caution should be used when initiating treatment in patients with dehydration. It is advisable to rehydrate patients first and then start therapy with parecoxib.
Hepatic Effects: Patients with severe hepatic impairment (Child-Pugh Class C) have not been studied. The use of parecoxib in patients with severe hepatic impairment is contraindicated. Parecoxib should be used with caution when treating patients with moderate hepatic impairment (Child-Pugh Class B), and initiated at the lowest recommended dose (see Dosage & Administration).
A patient with symptoms and/or signs of liver dysfunction, or in whom an abnormal liver function test has occurred, should be monitored carefully for evidence of the development of a more severe hepatic reaction while on therapy with parecoxib.
General: By reducing inflammation, parecoxib may diminish the utility of diagnostic signs, such as fever, in detecting infections. The concomitant use of parecoxib with other non-specific NSAIDs should be avoided.
Effects on ability to drive and use machines: Patients who experience dizziness, vertigo or somnolence after receiving Dynastat should refrain from driving or operating machines.
