Parecoxib Sodium
Pharmaceutical Form
Powder for solution for injection. White to off-white powder.
Pharmacological Properties
Pharmacodynamic properties
Pharmacotherapeutic group : Coxib. Parecoxib is a prodrug of valdecoxib. The mechanism of action of valdecoxib is by inhibition of cycloxygenase-2 (COX-2) β medicated prostaglandin synthesis. 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 proinflammatory stimuli and has been postulated to be primarily responsible for the synthesis of prostanoid mediators of pain, inflammation, and fever. At therapeutic doses, valdecoxib is a COX-2 selective inhibitor of both peripheral and central prostaglandins and does not inhibit COX-1, thereby sparing COX-1, dependent physiological processes in tissues, particularly the stomach, intestine and platelets, COX-2, is also thought to be involved in ovulation, implantation and closure of the ductus arteriosus, and central nervous system functions (fever induction, pain perception and cognitive function). The efficacy of Valus-P 40 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 dose of 40 mg IV or IM Valus-P 40 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.
Gastrointestinal studies : In short-term studies (7 days), the incidence of endoscopially observed gastroduodenal ulcers or erosions in healthy young and elderly (>65 years) subjects administered Valus-P 40 (5-21%) although higher than placebo (5-12%) was statistically significantly lower than the incidence observed with NSAIDs (66-90%).
Platelet studies : In a series of small, multiple dose studies in healthy young and elderly subjects, Valus-P 40 twice daily had no effect on platelet aggregation or bleeding compared to placebo. In young subjects, Valus-P 40 twice daily had no clinically significant effect on aspirin-mediated inhibition of platelet function.
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 Valus-P 40, as measured by both the area under the plasma concentration vs time curve (AUC) and peak concentration (Cmax), is appropriately linear in the range of clinical doses. AUC and Cmax following tiwce 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 dose of parexoxib sodium 20 mg. Cmax of valdecoxib is achieved in approximately 30 minutes and approximately 1 hour, respectively. Exposure to valdecoxib was similar in terms of AUC and Cmax following IV and IM administration. Exposure to parecoxib was similar after IV or IM administration in terms of AUC. Average Cmax 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 Cmax 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 externally 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 P450 (CYP3A4 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 is 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 (CLp) for valdecoxib is about 61/hr. After IV or IM dosing of parecoxib sodium, the elimination half-life (t 1/00) of valdecoxib is about 8 hours.
Therapeutic indication
For the short-term treatment of prostoperative pain.
Posology and method of administration
The recommended dose is 40 mg administered intravenously (IV) or intramusculary (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.
Elderly : No dosage adjustment is generally necessary in elderly patient (<65 years). However, for elderly patients weighing less than 50 kg, initiate treatment with hald the usual recommended dose of Valus-P 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 Valus-P 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 impariment (Child-Pugh scale >9), therefore its use is not recommended in these patients.
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.) or severe (creatinine clearance <30 ml/min.) renal impairment. However, caution should be observed in patients with renal impairment or patients who may be predisposed to fluid retention.
Children and adolescents : Valus-P 40 has not been studied in patients under 18 years. Therefore, its use is not recommended in these patients.
Tolerability
1962 patients with post-surgical pain were treated with parecoxib in various clinical trials. The following undesirable effects had a rate greater than placebo and have been reported among 1543 patients administered parecoxib 20 or 40 mg as a single or multiple dose (up to 80 mg/day) in 12 placebo controlled studies, including dental, gynaecological, orthopaedic surgery or coronary artery bypass graft surgery as well as pre-operative administration in dental and orthopaedic surgeries. The discontinuation rate due to adverse events in these studies was 5.0% for patients receiving parecoxib and 4.3% for patients receiving placebo.
The commonly reported adverse events in these studies included hypertension/hypotension, peripheral oedema, back pain, headache, dizziness, nausea, abdominal pain, alveolar osteitis (patients undergoing dental surgery), vomiting tachycardia, insomnia/somnolence, pharyngitis, fever and pruritis. Owing to its COX-1 sparing effect, parecoxib demonstrates an incidence of gastroduodenal ulceration that significantly lower than that observed with conventional NSAIDs such as ketorolac and comparable with placebo. Parecoxib demonstrates platelet aggregation responses and bleeding times that are not significantly different from placebo in elderly and non elderly patients. The following rare. Serious adverse events have been reported in associated with the use of NSAIDs and cannot bot ruled out for parecoxib : acute renal failure, congestive heart failure, anaphylactic shock, bronchospasm, hepatitis.
Contraindications
Previous hypersensitivity to parecoxib or valdecoxib
Acute peptic ulcer disease or gastrointestinal bleeding.
Patients with a history of bronchospasm with rhinoconjunctivitis or urticaria / angioedema associated with aspirin or other nonsteroidal anti-inflammatory agents.
Third trimester of pregnancy and lactation
Severe hepatic impairment (Child-Pugh Scale >9)
Inflammatory bowel disease.
Severe congestive cardiac failure.
Precaution
General Precaution for the use of NSAIDs and COX-2 inhibitors need to be followed for the use of parecoxib. Patient with renal impairment, bleeding disorders, and those who have undergone coronary artery bypass graft surgery need to be monitored carefully. There is limited clinical experience with parecoxib treatment beyond two day. Parecoxib 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.
Pregnancy and Lactation
Pregnancy :
The use of parecoxib is contraindicated in the last trimester of pregnancy because as with other medicinal products known to inhibit prostaglandin synthesis, it may cause premature closure to the ductus arteriosus or uterine inertia. Like other medicinal products that inhibit COX-2, parecoxib is not recommended in women attempting to conceive. There are no adequate date from the use of parexoxib sodium in pregnant women or during labour. Parecoxib should not be used during the first two trimesters of pregnancy or labour unless the potential benefit to the patients outweighs the potential risk to the foetus.
Lactation :
Parecoxib, valdecoxib and valdecoxib active metabolite are excreted in the mild of rats. It is not known whether valdecoxib is excreted in human milk Parecoxib should not be administered to women who breast-feed.
Drug Interactions
1. Parecoxib may be co-administered with opioid analgesics. When parecib was co-administered with morphine but not with same syringe, a smaller dose (reduction by 28-36%) of morphine could be used to achieve the same clinical level of analgesia.
2. Parecoxib had no effect on acetylsalicylic acid (<325 mg).
3. Co-administration of parecoxib sodium and heparin did not affect the pharmacodynamics of heparin (activated partial thromboplastin time) compared to heparin alone.
4. Since valdecoxib (active metabolite of parecoxib) is primarily metabolised by the cytochrome P450 (CYP3A4 and 2C9), isoenzymes, dose of parecoxib requires to be adjusted in patients receiving drugs that are substrates for or inhibitors / inducers of these enzymes. However, co-administration of parecoxibwith glibenclamide (CYP3A4 substrate ) did not affect either the pharmacokinetics (exposure) or the pahrmacodynamics (blood glucose and insulin levels) of glibenclamide. Further, coadministration of IV parecoxib sodium 40 mg with injectable anaesthetics such as propofol (CYP2C9 substrate) or midazolam (CYP3A4 substrate) did not affect either the pharmacokinetics or the pharmacodynamics of IV propofol of IV midazolam. Administration of IV parecoxib sodium 40 mg had no significant effect on the pharmacokinetics of either IV fentanyl or IV altentanil (CYP3A4 substrates).
5. inhalational anaesthetics : No formal interation studies have been done. In surgery studies in which parecoxib sodium was administered pre-operatively, no evidence of pharmacodynamic interation was observed in patients receiving parecoxib sodium and the inhalational anaesthetic agents, nitrous oxide and isoflurane.
6. Patients receiving ACE inhibitors, diuretics, oral anticoagulants, and lithum should be monitored closely during parecoxib therapy.
Overdose
No case of parecoxib overdose has been reported. In case of overdose, patients should be managed by symptomatic and supportive care. Valdecoxib is not removed by haemodialysis. Diuresis or alkalinization of urine may not be useful due to high protein binding of valdecoxib.
Pharmaceutical Particulars
Incompatibilities
This medicinal product must not be mixed with other medicinal products other than those mentioned.
Valus-P 40 and opiods should not be administered together in the same syringe.
Use of Ringer-Lactate solution for injection or glucose 50 g/1 (5%) in ringer Lactate solution for injection for reconstitution will cause the parecoxib to precipiate from solution and therefore is not recommended.
Use of Sterile Water for injection is not recommended, as the resulting solution is not isotonic.
Shelf life
2 years
Chemical and physical in-use stability of the reconstituted solution has been demonstrated for 24 hours at 25 C. From a microbiolocial 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.
Special precautions for storage
Store in a cool, dry place
Reconstituted injection is to be used within 12 hours
Store Reconstituted injection at 25 C. Do not freeze.
Instructions for use and handling and disposal
Accepatable solvent for reconstitution of Valus-P 40 is :
Sodium Chloride Injection IP 0.9% w/v. Use aseptic technique to reconstitute lyophilsed parecoxib (as parecoxib sodium). Remove the 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 Sodium Chloride Injection IP 0.9% w/v (provided in this pack) 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. The reconstituted solution is clear and colourless. It should be inspected visually for particulate matter and discoloration prior to administration. The solution should not be used if discoloured or cloudy or if particulate matter is observed. The reconstituted product is isotonic.
After reconstitution with Sodium Chloride Injection IP 0.9% w/v (provided in this pack), Valus-P may only be injected
V or IM or into IV lines delivering
Sodium chloride Injection IP 0.9% w/v
Glucose 50 g/1 (5%) solution for infusion
Sodium Chloride 4.5 mg/ml (0.45%) and Glucose 50 g/1 (5%) solution for injection.
For single use only. Any unused solution, solvent or wast material should be disposed.
Presentation One vial of Valus-P 40 Injection and Sodium Chloride Injection IP 0.9% w/v packed in a carton.