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Logo RAYZON 40 MG IV/IM
SCHEDULING STATUS:
S3

PROPRIETARY NAME
(and dosage form):

RAYZON 40 MG IV/IM
Powder and Solvent for Solution for Injection

COMPOSITION:
Each 5 mL vial contains 40 mg parecoxib (present as 42.36 mg lyophilised parecoxib sodium) for reconstitution. After reconstitution with 2 mL Sodium Chloride Intravenous Infusion (0.9% w/v) BP, the final concentration of parecoxib is 20 mg/mL.
When reconstituted in sodium chloride solution (0.9% w/v), RAYZON Injection contains approximately 0.44 mEq of sodium per 40 mg vial.

PHARMACOLOGICAL CLASSIFICATION:
A 2.9 Other Analgesics

PHARMACOLOGICAL ACTION:
Pharmacodynamic properties
Parecoxib sodium is an inactive prodrug for valdecoxib. Following injection, parecoxib is rapidly hydrolyzed to valdecoxib, which is active in animal models of prostaglandin-dependent pain, inflammation and fever.
The mechanism of action of valdecoxib is predominantly by inhibition of COX-2-mediated prostaglandin synthesis.
At therapeutic doses, valdecoxib is a specific COX-2 inhibitor and does not inhibit COX-1.
In animal models, the analgesic activity of valdecoxib is not reversible by naloxone.
Pharmacokinetic properties
Following IV or IM injection, parecoxib is rapidly converted to valdecoxib, the pharmacological moiety, by enzymatic hydrolysis in the liver.
Absorption
Exposure of valdecoxib following single doses of parecoxib injection, as measured by both the area under the plasma concentration vs. time curve (AUC) and peak concentration (Cmax), is approximately linear in the range of clinical doses. AUC and Cmax following twice a day (BID) administration is linear up to 50 mg IV and 20 mg IM. Steady state plasma concentrations of valdecoxib were reached within 4 days with BID dosing.
Following single IV and IM doses of parecoxib sodium 20 mg, Cmax of valdecoxib is achieved approximately 30 minutes and approximately 1 hour, respectively. Exposure to valdecoxib was similar in terms of AUC and Cmax following IV and IM administration.
Distribution
The volume of distribution of valdecoxib after its IV administration is approximately 55 L (greater than total body water). 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 in vivo with a plasma half-life of approximately 22 minutes. Elimination of valdecoxib is by extensive hepatic metabolism involving multiple pathways, including cytochrome P450CYP3A4 and CYP2C9 isoenzymes and CYP-independent glucuronidation 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; but 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. The valdecoxib metabolite undergoes extensive metabolism, with less than 5% of the dose excreted in urine and faeces.
Elimination
Valdecoxib is eliminated via hepatic metabolism with less than 5% unchanged drug 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 6 L/hr. After IV or IM dosing of parecoxib sodium, the elimination half-life (T½) of valdecoxib is about 8 hours.
Elderly Subjects
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. 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 parecoxib injection.
Renal Impairment
In patients with varying degrees of renal impairment administered 20 mg IV parecoxib injection as a single dose, 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 renal impairment. Therefore, on the basis of pharmacokinetics, dosing adjustment in patients with impaired renal function is not necessary. However, caution should be observed in patients with severe renal impairment (creatinine clearance < 30 mL/min) or those patients that may be predisposed to fluid retention.
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 scale 7-9), treatment should be initiated with half the usual recommended dose of parecoxib injection 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 parecoxib injection in patients with severe hepatic impairment is not recommended.

INDICATIONS:
For the management of post operative pain.

CONTRA-INDICATIONS:
Hypersensitivity to the active substance or to any other ingredient of the product.
Patients who have experienced bronchospasm, acute rhinitis, nasal polyps, angioneurotic oedema, urticaria or allergic-type reactions after taking acetylsalicylic acid or NSAIDs or other cyclooxygenase-2 (COX-2) specific inhibitors.
Severe impairment of hepatic or renal function.
Pregnancy and lactation.
Children younger than 18 years.

DOSAGE AND DIRECTIONS FOR USE:
The usual recommended dose is a single or initial 40 mg administered intravenously (IV) or intramuscularly (IM), followed every 6 to 12 hours by 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.
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.
Elderly: No dosage adjustment is generally necessary. However, for elderly female patients weighing less than 50 kg, initiate treatment with half the usual recommended dose of RAYZON Injection 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 RAYZON Injection 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 Contra-Indications).
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 severe renal impairment or patients who may be predisposed to fluid retention.
Children: RAYZON Injection has not been studied in patients under 18 years old. Therefore, its use is not recommended in these patients.

INSTRUCTIONS FOR USE/HANDLING:
Reconstitute RAYZON Injection with 2 mL Sodium Chloride solution (0.9% w/v) using aseptic technique. The only other acceptable solvents for reconstitution are 5% Glucose Intravenous Infusion, 0.45% Sodium Chloride and 5% Glucose Injection.
Use of Sterile Water for Injection is not recommended, as the resulting solution is not isotonic. Use of Lactated Ringer’s or 5% Glucose in Lactated Ringers for reconstitution will cause the drug to precipitate from solution and therefore is not recommended.
After reconstitution, RAYZON Injection should be inspected visually for particulate matter and discolouration prior to administration. The solution should not be used if discoloured or cloudy or if particulate matter is observed.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
SIDE-EFFECTS
The following common adverse events were reported in controlled clinical trials
Autonomic Nervous System Disorders: hypertension, hypotension.
Body as a Whole - General Disorders: back pain, peripheral oedema.
Central and Peripheral Nervous System Disorders: hypoaesthesia.
Gastro-intestinal System Disorders: alveolar osteitis, dyspepsia, flatulence.
Metabolic and Nutritional Disorders: creatinine increase, hypokalaemia.
Psychiatric Disorders: agitation, insomnia.
Red Blood Cell Disorders: post-operative anaemia.
Respiratory Disorders: pharyngitis, respiratory insufficiency.
Skin and Appendages Disorders: pruritis.
Urinary System Disorders: oliguria.
Less frequent adverse events reported
Autonomic Nervous System Disorders: aggravated hypertension.
Body as a Whole - General Disorders: abnormal sternal serous wound drainage, wound infection.
Heart Rate and Rhythm Disorders: bradycardia.
Liver and Biliary System Disorders: AST increased, ALT increased.
Metabolic and Nutritional Disorders: BUN increased.
Platelet, Bleeding and Clotting disorders: ecchymosis, thrombocytopenia.
Vascular (Extracardiac) Disorders: cerebrovascular disorder.

PRECAUTIONS
RAYZON Injection should be used with caution in patients with severe renal impairment (creatinine clearance <30 mL/min.) or moderate hepatic impairment (Child-Pugh scale 7-9). There is no clinical experience in patients with severe hepatic impairment (Child-Pugh scale >9), therefore, RAYZON Injection is not recommended for use in these patients.
Since prostaglandin inhibition may result in deterioration of renal function and fluid retention, caution should be observed when administering RAYZON Injection in patients with compromised renal, cardiac or hepatic function or other conditions predisposing to fluid retention.
Caution should be used when initiating treatment with RAYZON Injection in patients with considerable dehydration. It is advisable to rehydrate patients first and then start therapy with RAYZON Injection.
High-risk patients, such as those with a history of cerebrovascular disease, may have a higher risk of adverse events with RAYZON Injection.
RAYZON Injection may mask fever. In addition, caution should be exercised with respect to monitoring the incision for signs of infection in patients receiving RAYZON Injection.
Safety and efficacy of RAYZON Injection have not been established for periods of use exceeding 96 hours.
Interaction with other medicinal products and other forms of interaction
In vitro studies with human hepatic microsomal systems showed no significant inhibitory effects on CYP3A4, 2D6, 2E1, and 1A2 isoforms by parecoxib or valdecoxib. Weak inhibitory activity was found for 2C9 and 2C19 isozymes.
Parecoxib sodium is rapidly hydrolyzed to the active substance valdecoxib. In humans, studies demonstrated that valdecoxib metabolism is predominantly mediated via cytochrome P450CYP3A4 and 2C9 isozymes. Glucuronidation is a further route of metabolism. The alternate CYP-mediated and non-CYP-mediated metabolic pathways may reduce the likelihood of individuals with genetic polymorphisms having substantially higher drug plasma concentrations due to impaired metabolism.
Plasma exposure (AUC and Cmax) to valdecoxib was increased (62% and 19%, respectively) when coadministered with fluconazole, indicating that the dose of RAYZON Injection should be reduced in those patients who are receiving fluconazole therapy.
Plasma exposure (AUC and Cmax) to valdecoxib was increased (38% and 24%, respectively) when coadministered with ketoconazole, however, a dosage adjustment should not generally be necessary for patients receiving ketoconazole.
RAYZON Injection had no effect on aspirin-mediated inhibition of platelet aggregation or bleeding times. Clinical trials indicate that RAYZON Injection can be given with low dose aspirin (<325 mg). Because of its lack of platelet effects, RAYZON Injection is not a substitute for aspirin for cardiovascular prophylaxis.
Valdecoxib did not produce clinically relevant inhibition of the CYP2D6-mediated pathway involved in the conversion of dextromethorphan to dextrorphan.
Anticoagulant therapy should be monitored, particularly during the first few days after initiating RAYZON Injection therapy in patients receiving warfarin or similar agents, since these patients have an increased risk of bleeding complications.
NSAIDs may reduce the effect of diuretics and antihypertensive drugs. As for NSAIDs, the risk of acute renal insufficiency may be increased when ACE inhibitors are coadministered with RAYZON Injection.
Coadministration of NSAIDs and cyclosporin or tacrolimus have been suggested to increase the nephrotoxic effect of cyclosporin and tacrolimus. Renal function should be monitored when RAYZON Injection and any of these drugs are coadministered.
Coadministration of valdecoxib with glibenclamide (CYP3A4 substrate) did not affect either the pharmacokinetics (exposure) or the pharmacodynamics (blood glucose and insulin levels) of glibenclamide.
In interaction studies in rheumatoid arthritis patients receiving weekly methotrexate, valdecoxib did not have a clinically significant effect on the plasma exposure to methotrexate.
Valdecoxib 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 RAYZON Injection therapy in patients receiving lithium.
Injectable anaesthetics: Coadministration of IV RAYZON Injection with propofol CYP2C9 substrate) or midazolam (CYP3A4 substrate) did not affect either the pharmacokinetics (metabolism and exposure) or the pharmacodynamics of IV propofol or IV midazolam. Additionally, coadministration with IV RAYZON Injection had no significant effect on the pharmacokinetics of either IV fentanyl or IV alfentanil (CYP3A4 substrates).
Inhalation anaesthetics: In a post-orthopaedic surgery study in which RAYZON Injection was administered preoperatively, no evidence of drug interaction was observed in patients receiving RAYZON Injection and the inhalation anaesthetic agents nitrous oxide and isoflurane.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
No symptoms of overdose have been observed with single IV doses of up to 200 mg of RAYZON Injection in healthy subjects. RAYZON Injection doses of 50 mg BID IV for 7 days did not result in any signs of toxicity.
In case of overdose, patients should be managed by symptomatic and supportive care.

IDENTIFICATION:
Powder for Solution for Injection: White to off-white lyophilized powder in a stoppered 5 mL clear glass vial.
Solvent for Solution for Injection: 2 mL solvent ampoules containing 2 mL Sodium Chloride Intravenous Infusion (0.9% w/v) BP.
Reconstituted solution is clear and colourless.

PRESENTATION:
RAYZON Injection is supplied as a sterile, single unit-of-use vial, sealed with a purple flip-off cap on the aluminium overseal, that is packaged with a 2 mL ampoule containing Sodium Chloride Intravenous Infusion (0.9% w/v) BP.
Pack size available: Sets of 5 vials containing parecoxib 40 mg (as parecoxib sodium), together with 2 mL ampoules containing Sodium Chloride Intravenous Infusion (0.9% w/v) BP, packed into an outer carton.

STORAGE INSTRUCTIONS:
Store below 30°C in the outer container in order to protect from light.
Keep out of reach of children.
Reconstituted solution should be used within 24 hours and should not be stored in a refrigerator or freezer.

REGISTRATION NUMBERS:
RAYZON 40 mg IV/IM: 36/2.9/0120
RAYZON 2 ML SOLVENT: 36/34/0122

NAME AND BUSINESS ADDRESS OF THE APPLICANT:
Pharmacia South Africa (Pty) Ltd
Alphen G West
George Street
Midrand

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
April 2003

New addition to this site: February 2005
Source: Pharmaceutical Industry

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