Consumer medicine information

Parecoxib Sandoz

Parecoxib

BRAND INFORMATION

Brand name

Parecoxib Sandoz

Active ingredient

Parecoxib

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Parecoxib Sandoz.

SUMMARY CMI

Parecoxib Sandoz® Powder for Solution for Injection

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using Parecoxib Sandoz?

Parecoxib Sandoz contains the active ingredient parecoxib. Parecoxib Sandoz is used for the prevention and treatment of pain. It can be used to relieve pain and reduce inflammation (swelling and soreness) which may occur after surgery.

For more information, see Section 1. Why am I using Parecoxib Sandoz? in the full CMI.

2. What should I know before I use Parecoxib Sandoz?

Do not use Parecoxib Sandoz if you have ever had an allergic reaction to parecoxib or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding. You must not be given Parecoxib Sandoz if you have had an attack of asthma, hives, itching, skin rash or a runny nose after taking aspirin or Non-Steroidal Anti-Inflammatory Drugs (NSAIDs, medicines used to treat pain and inflammation), including other Coxib medicines.

For more information, see Section 2. What should I know before I use Parecoxib Sandoz? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Parecoxib Sandoz and affect how it works.

Your doctor and nurse need to know if you are taking any medicines used to treat high blood pressure or other heart problems. These include ACE inhibitors, angiotensin receptor antagonists, beta blockers and diuretics (also called fluid or water tablets).

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Parecoxib Sandoz?

  • Your doctor will decide how much Parecoxib Sandoz you need. The usual recommended dose is a single 40 mg injection.
  • Your doctor may adjust the dosage you are given depending on your condition.

More information can be found in Section 4. How do I use Parecoxib Sandoz? in the full CMI.

5. What should I know while using Parecoxib Sandoz?

Things you should not do
  • Do not take any other medication unless your doctor is aware of it.
  • You must not be given Parecoxib Sandoz if you are in the third trimester of your pregnancy or are breastfeeding.
Driving or using machines
  • This medicine may cause dizziness or light-headedness in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.
Drinking alcohol
  • Tell your doctor and nurse if you drink alcohol.

For more information, see Section 5. What should I know while using Parecoxib Sandoz? in the full CMI.

6. Are there any side effects?

Common side effects: changes in blood pressure, dizziness or light-headedness due to low blood pressure, back pain, ear ache, feeling numb, stomach upset.

Serious side effects: skin rash, blistering and bleeding in the lips, eyes, mouth, nose and genitals, a slow heartbeat, a severe or persistent headache, fever, stick neck, sensitivity to light and vomiting.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

Parecoxib Sandoz® Powder for Solution for Injection

Active ingredient(s): parecoxib

Consumer Medicine Information (CMI)

This leaflet provides important information about using Parecoxib Sandoz. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Parecoxib Sandoz.

Where to find information in this leaflet:

1. Why am I using Parecoxib Sandoz?
2. What should I know before I use Parecoxib Sandoz?
3. What if I am taking other medicines?
4. How do I use Parecoxib Sandoz?
5. What should I know while using Parecoxib Sandoz?
6. Are there any side effects?
7. Product details

1. Why am I using Parecoxib Sandoz?

Parecoxib Sandoz contains the active ingredient parecoxib. Parecoxib Sandoz belongs to a group of medicines called Coxibs. These medicines work by relieving pain and inflammation.

Parecoxib Sandoz is used for the prevention and treatment of pain. It can be used to relieve pain and reduce inflammation (swelling and soreness) which may occur after surgery.

Although Parecoxib Sandoz can relieve the symptoms of pain and inflammation, it will not cure your condition.

Parecoxib Sandoz is an injection. Only a doctor or nurse can give the injection.

This medicine is not addictive.

2. What should I know before I use Parecoxib Sandoz?

Warnings

Do not use Parecoxib Sandoz if you have an allergy to:

  • parecoxib sodium or valdecoxib
  • any of the ingredients listed at the end of this leaflet
  • sulphonamides, a group of medicines which include, for example, certain antibiotics (if you are not sure whether you are taking one of these medicines ask your doctor or nurse).

Some of the symptoms of an allergic reaction to Parecoxib Sandoz may include:

  • asthma, wheezing or shortness of breath
  • swelling of the face, lips or tongue which may cause difficulty in swallowing or breathing
  • hives, itching or skin rash
  • swelling, blistering or peeling of the skin.

These symptoms may be severe if you are allergic to sulphonamides or to any of the ingredients listed at the end of this leaflet and you are given Parecoxib Sandoz.

Ask your doctor or nurse if any of this applies to you.

You must not be given Parecoxib Sandoz if you have had an attack of asthma, hives, itching, skin rash or a runny nose after taking aspirin or Non-Steroidal Anti-Inflammatory Drugs (NSAIDs, medicines used to treat pain and inflammation), including other Coxib medicines.

Many medicines used to treat headache, period pain and other aches and pains contain aspirin or an NSAID.

If you are not sure if you are taking any of these medicines, ask your doctor or nurse.

If you are allergic to aspirin or NSAIDs, including other Coxib medicines and use Parecoxib Sandoz, these symptoms may be severe.

You must not be given Parecoxib Sandoz if you are about to undergo heart or blood vessel surgery.

You should not be given Parecoxib Sandoz if you have had any of the following medical conditions. Your doctor or nurse need to know if you have ever had:

  • heart disease
  • a heart attack
  • a stroke
  • severe liver problems.

You must not be given Parecoxib Sandoz if you are in the third trimester of your pregnancy or are breastfeeding.

If you are not sure whether you should be given this medicine, talk to your doctor.

Check with your doctor and nurse if you have any allergies to:

  • any other medicines including aspirin or other NSAID medicines, including other Coxib medicines
  • any other substances, such as foods, preservatives or dyes.

Your doctor and nurse need to know about all your medical conditions, especially if you have ever had any of the following:

  • kidney or liver problems
  • heart problems, heart surgery, heart failure, heart attack or other blood vessel disease
  • stroke
  • diabetes
  • high cholesterol levels
  • high blood pressure
  • fluid retention or if you are receiving diuretic treatment
  • dehydration
  • asthma or other allergic conditions
  • skin problems such as swelling, blistering, peeling, itching or redness that can occur with fever, chills, headache, joint pain or generally feeling unwell
  • peptic ulcer i.e. stomach or duodenal ulcer.

Your doctor and nurse need to know if you currently have an infection.

If you are given Parecoxib Sandoz while you have an infection, it may hide some of the signs of an infection.

Your doctor and nurse need to know if you are a smoke or drink alcohol.

If you have not told your doctor and nurse about any of the above, tell them before you are given Parecoxib Sandoz.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor or nurse if you are pregnant or intend to become pregnant.

You should not be treated with Parecoxib Sandoz if you are in the third trimester of your pregnancy.

Treatment with Parecoxib Sandoz during the first two trimesters of your pregnancy is not recommended as it may affect your developing baby. It may also affect your labour. Your doctor will discuss with you the benefits and risks of treatment with Parecoxib Sandoz.

Related medicines, NSAIDs, have been associated with reversible infertility in some women.

Use of NSAIDs in early pregnancy can increase the risk of spontaneous abortion and may affect your developing baby.

Treatment with NSAIDs in the second or third trimester of your pregnancy may cause kidney problems in your developing baby.

Your doctor will discuss with you the benefits and risks of using it.

Talk to your doctor or nurse if you are breastfeeding or intend to breastfeed.

You should not be given Parecoxib Sandoz if you are breastfeeding.

Parecoxib Sandoz passes into breast milk, therefore, breastfeeding should be discontinued during treatment with Parecoxib Sandoz.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Your doctor and nurse need to know if you are taking any medicines used to treat high blood pressure or other heart problems. These include ACE inhibitors, angiotensin receptor antagonists, beta blockers and diuretics (also called fluid or water tablets).

These medicines can cause kidney problems if taken at the same time as you receive Parecoxib Sandoz.

Your doctor and nurse need to know if you are taking any of the following:

  • aspirin, salicylates or other NSAID medicines used to treat pain, inflammation or swelling
  • corticosteroids, medicines used to suppress the immune system or reduce inflammation
  • selective serotonin reuptake inhibitors, medicines used for depression
  • warfarin or similar medicines including Eliquis (apixaban), Xarelto (rivaroxaban), Pradaxa (dabigatran) or antiplatelet medicines that are used to prevent or stop blood clots from forming
  • lithium, a medicine used to treat some types of depression
  • some medicines used to treat diabetes
  • methotrexate, a medicine used to treat arthritis and some cancers
  • ciclosporin, a medicine used to suppress the immune system
  • fluconazole and ketoconazole used to treat fungal infections.

Your doctor and nurse have more information on medicines to be careful with or avoid while using Parecoxib Sandoz.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Parecoxib Sandoz.

4. How do I use Parecoxib Sandoz?

How much is given

  • Your doctor will decide how much Parecoxib Sandoz you need. The usual recommended dose is a single 40 mg injection. Your doctor may adjust the dosage you are given depending on your condition.
  • Parecoxib Sandoz will be given to you by your doctor. It is diluted and given by injection into a vein through an intravenous line or into a muscle.

Ask your doctor if you want more information about the dose of Parecoxib Sandoz and how it is given.

When to take Parecoxib Sandoz

  • Your doctor will decide when you will need Parecoxib Sandoz.

If you receive too much Parecoxib Sandoz

As your doctor will supervise how much Parecoxib Sandoz you are given, you are unlikely to have an overdose.

If you are given too much Parecoxib Sandoz, you may feel tired, drowsy or sick, or you may be sick, have stomach pains or other abdominal problems.

If you think that you have been given too much Parecoxib Sandoz:

You should immediately:

  • Tell your doctor or nurse immediately, or
  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • go to the Emergency Department at your nearest hospital.

5. What should I know while using Parecoxib Sandoz?

Things you should not do

  • Do not take any other medication unless your doctor is aware of it.

Driving or using machines

Be careful driving or operating machinery after your surgery in case Parecoxib Sandoz has affected you.

This medicine may cause dizziness or light-headedness in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Drinking alcohol

Tell your doctor and nurse if you drink alcohol.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
Heart-related:
  • changes in blood pressure
  • dizziness or light-headedness due to low blood pressure
Mouth and gum-related:
  • sore throat
  • swollen and sore gums
  • inflammation and pain after a tooth extraction
Gut-related:
  • stomach upset including nausea (feeling sick), vomiting, heartburn, indigestion, cramps
  • constipation, diarrhoea, pain in the stomach, wind, bloating
Skin-related:
  • feeling numb (your skin may lose sensitivity to pain and touch)
  • increased sweating
Mental or emotional-related:
  • Trouble sleeping
  • Irritability, agitation
Others:
  • back pain
  • ear ache
  • dizziness
  • passing less urine than normal
Speak to your doctor or nurse if you have any of these less serious side effects and they worry you.
They are generally mild and do not cause patients to stop taking Parecoxib Sandoz.

Serious side effects

Serious side effectsWhat to do
Allergy-related:
  • a skin rash, including hives, raised red, itchy spots
  • blistering and bleeding in the lips, eyes, mouth, nose and genitals
  • swelling, blistering or peeling of the skin, which may be accompanied by fever, chills, headache, sore throat, diarrhoea, aching joints and muscles
  • swollen glands e.g. under armpit or neck
  • any other signs of allergic reaction such as wheezing, swelling of the face, lips, mouth, tongue or throat which may cause difficulty in swallowing or breathing
  • swelling of lips and tongue
Heart-related:
  • a slow heart beat
  • have irregular heartbeat, chest pain or discomfort, swollen or sore leg veins.
Head and neurology-related:
  • a severe or persistent headache, fever, stiff neck, sensitivity to light and vomiting
  • a dry mouth, feeling of thirst and needing to urinate more often
  • feeling faint or collapse, have shortness of breath, feel tired
Blood-related:
  • bleeding or bruising more easily than normal, reddish or purplish blotches under the skin
  • any signs of anaemia, such as tiredness, being short of breath, and looking pale
Gut-related:
  • an unusual weight gain or loss of appetite
  • unusual stomach sounds
  • severe stomach or throat pain
  • you are vomiting blood or having black sticky bowel motions
Musculoskeletal-related:
  • joint pain, muscle weakness
Skin-related:
  • any infection of, or discharge from, any wounds
  • complications with skin healing after operations
  • injection site pain or reaction
  • yellowing of the skin or eyes (jaundice).
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What Parecoxib Sandoz contains

Active ingredient
(main ingredient)		parecoxib (as parecoxib sodium)
Other ingredients
(inactive ingredients)
  • Disodium hydrogen phosphate heptahydrate
  • Phosphoric acid
  • Sodium hydroxide

Do not take this medicine if you are allergic to any of these ingredients.

What Parecoxib Sandoz looks like

Parecoxib Sandoz is supplied to the hospital in single-use glass vials, and requires dilution with normal saline before use.

Parecoxib Sandoz parecoxib (as sodium) 40 mg powder for injection vial (AUST R 380863)

10 vials per pack

Who distributes Parecoxib Sandoz

Sandoz Pty Ltd
100 Pacific Highway
North Sydney, NSW 2060
Australia
Tel 1800 726 369

This leaflet was prepared in January 2024.

® Registered Trade Mark. The trade marks mentioned in this material are the property of their respective owners.

Published by MIMS March 2025

BRAND INFORMATION

Brand name

Parecoxib Sandoz

Active ingredient

Parecoxib

Schedule

S4

 

1 Name of Medicine

Parecoxib (as sodium).

2 Qualitative and Quantitative Composition

Each vial of Parecoxib Sandoz injection contains 42.36 mg parecoxib sodium corresponding to 40 mg parecoxib.

Excipient with known effect.

When reconstituted in sodium chloride (0.9% w/v), Parecoxib Sandoz injection contains approximately 0.44 mEq of sodium per 40 mg vial.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Powder for injection.
Parecoxib Sandoz injection is a white to off-white lyophilised cake or powder in a single-use vial.
When reconstituted with 0.9% NaCl, solution is clear and colourless.

4 Clinical Particulars

4.1 Therapeutic Indications

For a single peri-operative dose for the management of post-operative pain.

4.2 Dose and Method of Administration

The usual recommended dose is a single 40 mg dose 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 intravenous (IV) or intramuscular (IM) administration, Parecoxib Sandoz injection should be reconstituted with 2 mL sodium chloride solution (0.9% w/v), or a suitable alternative.
Reconstitute Parecoxib Sandoz injection with 2 mL sodium chloride solution (0.9% w/v) using aseptic technique. The only other acceptable diluents for reconstitution are:
5% glucose intravenous infusion;
0.45% sodium chloride and 5% glucose injection.
Use of sterile water for Injections is not recommended, as the resulting solution is not isotonic. Use of lactated Ringer's or 5% glucose in lactated Ringer's for reconstitution will cause the medicine to precipitate from solution and therefore is not recommended.
After reconstitution, Parecoxib Sandoz 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.
To reduce microbiological hazard, use as soon as practicable after reconstitution. The reconstituted product should not be stored in a refrigerator or freezer.
After reconstitution with acceptable diluents, Parecoxib Sandoz injection may only be injected IV or IM, or into IV lines delivering:
sodium chloride solution (0.9% w/v);
5% glucose intravenous infusion;
0.45% sodium chloride and 5% glucose injection;
lactated Ringer's.
Injection into IV lines delivering 5% glucose in lactated Ringer's, or other IV diluents not listed here, is not recommended as this may cause precipitation from solution (see Section 6.2 Incompatibilities).
For use in pregnancy and lactation, see Section 4.3 Contraindications; Section 4.6 Fertility, Pregnancy and Lactation.

Dosage adjustment.

Elderly.

No dosage adjustment is generally necessary. However, for elderly female patients weighing less than 50 kg, the recommended dose of Parecoxib Sandoz injection is 20 mg (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties, Special populations, Elderly (> 65 years)).

Hepatic impairment.

No dosage adjustment is generally necessary in patients with mild hepatic impairment (Child-Pugh score 5-6). Introduce Parecoxib Sandoz injection with caution and at half the usual recommended dose in patients with moderate hepatic impairment (Child-Pugh score 7-9). There is no clinical experience in patients with severe hepatic impairment (Child-Pugh score ≥ 10); therefore, the use of Parecoxib Sandoz injection is contraindicated in these patients (see Section 4.3 Contraindications; Section 5.2 Pharmacokinetic Properties, Hepatic impairment).

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 (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties, Renal impairment).

Children.

Parecoxib Sandoz injection has not been studied in patients under 18 years old. Therefore, its use is not recommended in these patients.

4.3 Contraindications

Parecoxib Sandoz injection is contraindicated in patients:
undergoing CABG or other major vascular surgery;
with unstable or significant established ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease;
with known hypersensitivity to parecoxib sodium, valdecoxib or to any other ingredient of the product;
who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin, NSAIDs or other COX-2 specific inhibitors. Severe, rarely fatal, anaphylactoid-like reactions to Parecoxib Sandoz injection are possible in such patients (see Section 4.4 Special Warnings and Precautions for Use, Anaphylactoid reactions and Pre-existing asthma);
who have demonstrated allergic-type reactions to sulfonamides (see Section 4.4 Special Warnings and Precautions for Use, Serious skin reactions and Anaphylactoid reactions);
with severe hepatic impairment (Child-Pugh score ≥ 10; see Section 5.2 Pharmacokinetic Properties, Special populations, Hepatic impairment; Section 4.2 Dose and Method of Administration, Dosage adjustment, Hepatic impairment);
in the third trimester of pregnancy or breastfeeding (see Section 4.6 Fertility, Pregnancy and Lactation).

4.4 Special Warnings and Precautions for Use

The decision to prescribe a selective COX-2 inhibitor should be based on an assessment of the individual patient's overall risks (see Section 4.3 Contraindications).

General.

Parecoxib injection may mask fever. The concomitant use of parecoxib with other non-specific NSAIDs should be avoided.
In addition, caution should be exercised with respect to monitoring the incision for signs of infection in patients receiving parecoxib injection. When used in post-CABG patients at a dose of 80 mg/day over 14 days, no increase in overall infection rate was seen. However, sternal wound infections occurred at a somewhat higher rate in patients receiving parecoxib compared to placebo (parecoxib 2.6%, placebo 2.0%, p=NS).
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.

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.

Use in hepatic impairment.

Borderline elevations of one or more liver function tests were observed in 3.4% of surgical patients receiving parecoxib injection and 5.8% of placebo patients. Notable elevations (greater than three or more times the upper limit of normal) were seen in 0.7% of patients treated with parecoxib injection and 0.8% of placebo patients.
Rare cases of severe hepatic reactions, including jaundice, fatal fulminant hepatitis, liver necrosis, hepatic failure (some with fatal outcome), and liver transplant have been reported with NSAIDs. In post-marketing experience, rare cases of jaundice, hepatomegaly, and hepatic failure have been reported with parecoxib injection (see Section 4.8 Adverse Effects (Undesirable Effects), Post-marketing experience).
A patient with symptoms and/or signs suggesting hepatic dysfunction, or in whom an abnormal liver function test has occurred, should be evaluated for evidence of the development of a hepatic reaction while on therapy with parecoxib injection. If clinical signs and symptoms consistent with hepatic disease develop, or if systemic manifestations occur (e.g. eosinophilia, rash, etc.), parecoxib injection should be discontinued.

Use in renal impairment.

Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a non-steroidal anti-inflammatory drug may cause a dose-dependent reduction in renal prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics, ACE inhibitors, or angiotensin receptor antagonists, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pre-treatment state. Clinical trials with valdecoxib have shown renal effects similar to those observed with comparator NSAIDs.
Caution should be used when initiating treatment with parecoxib injection in patients with considerable dehydration. It is advisable to rehydrate patients first and then start therapy with parecoxib injection.
Caution is also recommended in patients with pre-existing renal disease. Even though, pharmacokinetically, there was no difference in excretion, in patients with severe renal disease treatment with parecoxib injection should be initiated with caution. Close monitoring of the patient's renal function is advisable.
Acute renal failure has been reported through post-marketing surveillance in patients receiving parecoxib (see Section 4.8 Adverse Effects (Undesirable Effects)).

Use in the elderly.

Of the total number of patients who received parecoxib injection in clinical trials, more than 250 were 65-74 years of age, while approximately 70 additional patients were 75 years and over. No overall differences in safety and effectiveness between these patients and younger patients have been identified, but greater sensitivity of some older individuals cannot be ruled out.

Paediatric use.

Safety and effectiveness in paediatric patients below the age of 18 have not been evaluated.

Effects on laboratory tests.

Isolated laboratory abnormalities following surgery were seen in patients taking parecoxib injection, placebo and comparators. No particular testing, other than appropriate post-operative laboratory monitoring, is indicated in patients receiving parecoxib injection.

Cardiovascular adverse effects.

All NSAIDs, including 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.
Patients treated with parecoxib for pain immediately following CABG surgery have a higher risk for CV/thromboembolic events, deep surgical infections or sternal wound healing complications. This was seen more often in elderly patients (> 65 years old) or patients with a history of peripheral vascular or cerebrovascular disease or poor post-surgical renal function (see Section 5.1 Pharmacodynamic Properties, Clinical trials, Special studies, CABG post-operative safety studies).
Parecoxib is therefore contraindicated for the treatment of post-operative pain following CABG surgery (see Section 4.3 Contraindications). Parecoxib has not been studied in other cardiovascular surgical procedures.
In an analysis of non-cardiac surgery controlled trials, patients treated with parecoxib did not experience an increased risk of CV adverse events compared with placebo.
However, patients with significant and multiple risk factors for CV events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking) should only be treated with parecoxib sodium after careful consideration (see Section 5.1 Pharmacodynamic Properties, Clinical trials, Special studies, General surgery).
All patients should receive the lowest dose effective in relieving symptoms. The dose should not exceed 40 mg.

Serious skin reactions.

Serious skin reactions, including erythema multiforme and Stevens-Johnson syndrome, have been reported through post-marketing surveillance in patients receiving parecoxib. In addition to erythema multiforme and Stevens-Johnson syndrome, exfoliative dermatitis and toxic epidermal necrolysis have been reported through post-marketing surveillance in patients receiving valdecoxib.
Fatalities due to Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported with valdecoxib and the potential cannot be ruled out for parecoxib (the prodrug of valdecoxib) (see Section 4.8 Adverse Effects (Undesirable Effects), Post-marketing experience). Some NSAIDs and selective COX-2 inhibitors have been associated with an increased risk of generalised bullous fixed drug eruption (GBFDE). Drug reaction with eosinophilia and systemic symptoms syndrome (DRESS) syndrome (see Drug reaction with eosinophilia and systemic symptoms (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 in the first two weeks of treatment. Parecoxib injection 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.
Valdecoxib, the active moiety of parecoxib, contains a sulfonamide moiety. Patients with a history of sulfonamide allergy may be at a greater risk for skin reactions, however, patients without a history of sulfonamide allergy may also be at risk.

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome.

DRESS syndrome has been reported in patients taking NSAIDs. Some of these events have been fatal or life-threatening. DRESS syndrome 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 syndrome may resemble an acute viral infection. Eosinophilia 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 the NSAID and evaluate the patient immediately.

Anaphylactoid reactions.

Anaphylactoid reactions were not reported in patients receiving parecoxib injection in clinical trials. However, as with NSAIDs in general, anaphylactoid reactions may occur in patients without known prior exposure to parecoxib injection. Parecoxib injection should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use, Pre-existing asthma). Emergency help should be sought in cases where an anaphylactoid reaction occurs.
Hypersensitivity reactions (anaphylactic reactions and angioedema) have been reported in post-marketing experience with valdecoxib and parecoxib (see Section 4.8 Adverse Effects (Undesirable Effects), Post-marketing experience). These reactions have occurred in patients with and without a history of allergic-type reactions to sulfonamides (see Section 4.3 Contraindications). Parecoxib should be discontinued at the first sign of hypersensitivity.

Gastrointestinal effects - risk of GI ulceration, bleeding, and perforation.

It is unclear, at the present time, how the rates of serious GI toxicity associated with NSAIDs that inhibit both COX-1 and COX-2, apply to parecoxib injection. Parecoxib injection, a COX-2 specific inhibitor, does not affect COX-1 function as demonstrated by relevant clinical results.
Serious GI toxicity such as bleeding, ulceration, and perforation of the stomach, small intestine or large intestine, can occur at any time, with or without warning symptoms, in patients treated with non-steroidal anti-inflammatory drugs (NSAIDs), including parecoxib injection. Minor upper GI problems, such as dyspepsia, are common and may also occur at any time during NSAID therapy. Therefore, physicians and patients should remain alert for ulceration and bleeding, even in the absence of previous GI tract symptoms. Patients should be informed about the signs and/or symptoms of serious GI toxicity and the steps to take if they occur. The utility of periodic laboratory monitoring has not been demonstrated, nor has it been adequately assessed. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. It has been demonstrated that upper GI ulcers, gross bleeding or perforation, caused by NSAIDs, appear to occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. These trends continue thus, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk.
The ulcerogenic effects of parecoxib injection and oral valdecoxib on the upper GI tract were examined in short-term (7 day) studies in young and elderly healthy subjects, and a 12-week study in OA patients, respectively. Significantly fewer endoscopically detected ulcers were seen with parecoxib injection compared to ketorolac and naproxen, and with valdecoxib compared to ibuprofen and naproxen (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
Patients most at risk of developing GI complications with NSAIDs are elderly patients; patients with cardiovascular disease; patients using concomitant aspirin, corticosteroids, selective serotonin reuptake inhibitors (SSRIs), other antiplatelet drugs, or other NSAIDs; patients ingesting alcohol; and patients with a history of, or active, GI disease (such as ulceration, bleeding or inflammatory conditions). In addition, pharmacoepidemiological studies have identified several other co-therapies or co-morbid conditions that may increase the risk for GI bleeding such as: treatment with anticoagulants, longer duration of NSAID therapy, smoking, alcoholism, and poor general health status. Parecoxib injection should be prescribed with caution in these patients. Physicians and patients should remain alert for ulceration and bleeding even in the absence of symptoms.
Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore special care should be taken in treating this population. To minimise the potential risk for an adverse GI event, the lowest effective dose should be used for the shortest possible duration. For high-risk patients, alternative therapies that do not involve NSAIDs should be considered. Studies have shown that patients with a prior history of peptic ulcer disease and/or GI bleeding and who use NSAIDs, have a greater than 10-fold higher risk for developing a GI bleed than patients with neither of these risk factors.

Hypertension.

As with all NSAIDs, parecoxib can lead to the onset of new hypertension or worsening of preexisting 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.

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.

Fluid retention and oedema.

Fluid retention and oedema have been observed in < 1.0% of patients undergoing general surgery who received parecoxib injection, similar to placebo. Parecoxib injection should be used with caution in patients with compromised cardiac function, pre-existing oedema, or other conditions predisposing to, or worsened by, fluid retention including those taking diuretic treatment or otherwise at risk of hypovolaemia.

Pre-existing asthma.

Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm, which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other non-steroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, parecoxib should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with pre-existing asthma (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use, Anaphylactoid reactions).

Concomitant use of ACE inhibitors or angiotensin receptor antagonists and anti-inflammatory drugs and thiazide diuretics.

The use of an ACE inhibiting medicine (ACE inhibitor or angiotensin receptor antagonist), and an anti-inflammatory drug (NSAID or COX-2 inhibitor) and a thiazide diuretic at the same time, increases the risk of renal impairment. This includes use in fixed-combination products containing more than one class of medicine. Concomitant use of all three classes of these medications should be accompanied by increased monitoring of serum creatinine, particularly at the institution of the treatment. The concomitant use of medicines from these three classes should be used with caution particularly in elderly patients or those with pre-existing renal impairment (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Anti-hypertensives including ACE inhibitors, angiotensin receptor antagonists, beta blockers and diuretics).

Concomitant use of oral anticoagulants.

The concomitant use of NSAIDs with oral anticoagulants increases the risk of bleeding (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Anticoagulants). Oral anticoagulants include warfarin/coumarin-type and novel oral anticoagulants (e.g. apixaban, dabigatran, and rivaroxaban).

4.5 Interactions with Other Medicines and Other Forms of Interactions

General.

In vitro studies with human hepatic microsomal systems showed no significant inhibitory effects on CYP3A4, 2D6, 2E1, and 1A2 isoforms by parecoxib and valdecoxib. Weak inhibitory activity was found for 2C9 and 2C19 isozymes.
In humans, studies have demonstrated that valdecoxib metabolism is predominantly mediated via CYP450 3A4 and 2C9 isozymes. Glucuronidation is a further route of metabolism. Due to CYP450-mediated and non-CYP450-mediated metabolic pathways, genetic polymorphisms leading to substantially higher plasma concentrations resulting from impaired metabolism are not expected.

Aspirin.

Parecoxib injection had no effect on aspirin-mediated inhibition of platelet aggregation or bleeding times. Clinical trials indicate that parecoxib injection can be given with low dose aspirin. Because of its lack of platelet effects, parecoxib injection is not a substitute for aspirin for cardiovascular prophylaxis.

Methotrexate.

In interaction studies in rheumatoid arthritis patients receiving weekly methotrexate (5-20 mg IM), valdecoxib (10 mg BD and 40 mg BD) did not have a clinically significant effect on the plasma exposure to methotrexate. However, caution is advised when methotrexate is administered concurrently with NSAIDs, because NSAID administration may result in increased plasma levels of methotrexate.

Anti-hypertensives including ACE inhibitors, angiotensin receptor antagonists, beta blockers and diuretics.

Reports suggest that NSAIDs may diminish the antihypertensive effects of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor antagonists, beta blockers and diuretics. It is unclear, at the present time, how this may apply to parecoxib injection. This potential interaction should be given consideration in patients taking parecoxib injection concomitantly with ACE inhibitors, angiotensin receptor 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 and/or angiotensin receptor antagonists, may result in deterioration of renal function, including possible acute renal failure.
Therefore, the concomitant administration of these drugs 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.

Ciclosporin.

Because of their effect on renal prostaglandins, NSAIDs may increase the risk of nephrotoxicity with ciclosporin.

Injectable anaesthetics.

Propofol is metabolised by CYP2C9. Coadministration of parecoxib sodium with propofol did not affect either the pharmacokinetics (metabolism and exposure) or the pharmacodynamics of IV propofol.
Midazolam is metabolised primarily by CYP3A4. Coadministration of parecoxib sodium IV, or valdecoxib orally, with IV midazolam did not affect the pharmacokinetics (metabolism and exposure) or the pharmacodynamics of midazolam.
Fentanyl and alfentanil are extensively metabolised by CYP3A4. Coadministration with parecoxib sodium had no significant effect on the pharmacokinetics of either IV fentanyl or IV alfentanil.

Inhalation anaesthetics.

No formal interaction studies have been conducted. In the general surgery studies, no evidence of pharmacodynamic medicine interaction was observed between parecoxib sodium administered preoperatively and the inhalation anaesthetic agents; nitrous oxide and isoflurane.

Glibenclamide.

Glibenclamide is a CYP3A4 substrate. Coadministration of valdecoxib (10 mg BD for 7 days) with glibenclamide (5 mg or 10 mg OD) did not affect the pharmacokinetics (exposure) or the pharmacodynamics (blood glucose and insulin levels) of glibenclamide.

Anticonvulsants.

Potential interactions with phenytoin (2C9/19 substrate) and carbamazepine (3A4 substrate) have not been studied. However, as mentioned (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, General), no interactions were noted using prototype 3A4 and 2C9 substrates of these isozymes.

Ketoconazole and fluconazole.

AUC and Cmax of valdecoxib was increased (62%) when coadministered with fluconazole, indicating that the dose of parecoxib sodium should be reduced in those patients who are receiving fluconazole therapy. AUC and Cmax of valdecoxib was increased (38%) when coadministered with ketoconazole.

Dextromethorphan.

Valdecoxib 40 mg BD for 7 days did not produce clinically relevant inhibition in the metabolism by the CYP 2D6-mediated pathway involved in the conversion of dextromethorphan to dextrorphan.

Lithium.

Valdecoxib 40 mg BD for 7 days produced significant decreases in lithium serum clearance (25%) and renal clearance (30%) with a 34% higher serum exposure compared to lithium alone. Lithium serum concentrations should be monitored closely when initiating or changing parecoxib sodium therapy in patients receiving lithium.

Anticoagulants.

The effect of valdecoxib on the anticoagulant effect of warfarin (1 - 8 mg/day) was studied in healthy subjects by IV coadministration of 10 mg parecoxib sodium BD for 7 days. There was a slight increase in the plasma concentration of R-warfarin, but not S-warfarin, as a result of parecoxib sodium coadministration. The effect of oral valdecoxib (40 mg BD) on the anticoagulant effect of warfarin (1 - 8 mg/day) was studied in healthy subjects by coadminstration for 7 days. Valdecoxib caused a statistically significant increase in plasma exposure of R-warfarin and S-warfarin (12% and 15% respectively), and in the pharmacodynamic effects (prothrombin time, measured as INR of warfarin). While mean INR values were only slightly increased (≤ 8%) with coadministration of valdecoxib, the day-to-day variability in individual INR values was increased.
Anticoagulant therapy should be monitored, particularly during the first few days, after initiating parecoxib injection therapy in patients receiving warfarin or similar agents, since these patients are at increased risk of bleeding complications.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Parecoxib sodium did not impair rat fertility at intravenous doses of 25 mg/kg/day (males) or 12.5 mg/kg/day (females). These doses resulted in systemic exposures (plasma AUC) that were 1.4-fold human exposure for valdecoxib, at the maximum recommended therapeutic dose (40 mg BD).
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 parecoxib, should be considered.
(Category C)
Parecoxib Sandoz is contraindicated in the third trimester of pregnancy.
Parecoxib Sandoz should not be used during the first two trimesters of pregnancy unless the expected benefits to the mother outweigh the risks to the fetus. If there is a compelling need for NSAID treatment during the first or second trimester, limit use to the lowest effective dose and shortest duration possible.
Data from epidemiological studies suggest an increased risk of miscarriage and congenital malformation associated with NSAID use in early pregnancy.

Teratogenic effects.

Embryo-fetal development studies conducted with intravenous parecoxib sodium in rats and rabbits have not shown any evidence of developmental malformations. Doses used (respectively up to 25 and 40 mg/kg/day) resulted in systemic exposures (plasma AUC) to valdecoxib that were 4.3-fold and 2.2-fold human exposure at the maximum recommended therapeutic dose, respectively. Animal reproduction studies are not always predictive of human responses, and there are no adequate and well-controlled studies in pregnant women. Use of Parecoxib Sandoz injection is contraindicated in the third trimester of pregnancy.

Non-teratogenic effects.

Parecoxib sodium increased post-implantation losses in rats and rabbits at doses that resulted in systemic exposures (plasma AUC) to valdecoxib that were similar to the human exposure at the maximum recommended therapeutic dose. This effect is thought to be a consequence of the inhibition of prostaglandin synthesis, and has been reported to occur with other NSAIDs. No studies have been conducted to evaluate the effect of valdecoxib on the closure of the ductus arteriosus in humans or animals. The use of NSAIDs, including cyclooxygenase inhibitors may result in premature closure of the fetal ductus arteriosus, fetal renal impairment, inhibition of platelet aggregation, uterine inertia and may delay labour and birth. Therefore, the use of Parecoxib Sandoz injection is contraindicated in the third trimester of pregnancy.
Inhibition of prostaglandin synthesis might adversely affect pregnancy. Epidemiological studies suggest an increased risk of spontaneous abortion after use of prostaglandin synthesis inhibitors in early pregnancy. In animals, administration of prostaglandin synthesis inhibitors has been shown to result in increased pre- and post-implantation loss.

Oligohydramnios and neonatal renal impairment.

Use of NSAIDs in the second or the third trimester may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some post-marketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. Consider ultrasound monitoring of amniotic fluid if treatment extends beyond 48 hours. Discontinue treatment with NSAIDs if oligohydramnios occurs.

Labour and delivery.

Parecoxib sodium has not been studied in late pregnancy and parturition in either animals or humans. In animal studies, both COX-1 and COX-2 have been shown to be present in the ductus arteriosus of fetal lambs and to contribute to the maintenance of patency and the fetal ductus arteriosus was constricted significantly in near-term rats.
 Parecoxib, valdecoxib and an active metabolite of valdecoxib, are excreted in the milk of lactating rats. Parecoxib and valdecoxib are also reported to be transferred into the breast milk of lactating women. 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.
Parecoxib Sandoz must not be administered to women who breastfeed (see Section 4.3 Contraindications).

4.7 Effects on Ability to Drive and Use Machines

The effect of Parecoxib Sandoz injection on ability to drive or use machinery has not been studied. However, patients who experience dizziness, vertigo or somnolence after receiving Parecoxib Sandoz injection should refrain from driving or operating machinery.

4.8 Adverse Effects (Undesirable Effects)

Clinical trial experience.

The following adverse reactions were reported in patients who received parecoxib (N=5,402) in 28 placebo-controlled clinical trials.
Events occurring ≥ 10%.

Gastrointestinal disorders.

Nausea.
Events occurring ≥ 1% and < 10%.

Blood and lymphatic system disorders.

Post-operative anaemia.

Gastrointestinal disorders.

Abdominal pain, constipation, dyspepsia, vomiting.

General disorders and administration site conditions.

Oedema peripheral.

Infections and infestations.

Alveolar osteitis (dry socket).

Metabolism and nutrition disorders.

Hypokalaemia.

Nervous system disorders.

Dizziness, hypoaesthesia.

Psychiatric disorders.

Insomnia.

Renal and urinary disorders.

Oliguria.

Respiratory, thoracic and mediastinal disorders.

Respiratory insufficiency.

Skin and subcutaneous tissue disorders.

Sweating increased, pruritus.

Vascular disorders.

Hypotension.
Events occurring ≥ 0.1% and < 1%.

Blood and lymphatic system disorders.

Thrombocytopenia.

Cardiac disorders.

Bradycardia, myocardial infarction.

Ear and labyrinth disorders.

Earache.

Gastrointestinal disorders.

Mouth dry, flatulence, oesophagitis, gastroesophageal reflux, hypoactive bowel sounds, gastroduodenal ulceration.

General disorders and administration site conditions.

Injection site pain, injection site reaction, asthenia.

Infections and infestations.

Pharyngitis, abnormal sternal serous wound drainage, wound infection.

Injury, poisoning and procedural complications.

Skin post-operative complications.

Investigations.

BUN increased, creatine phosphokinase increased, creatinine increase, LDH increased, AST increased, ALT increased.

Metabolism and nutrition disorders.

Anorexia, hyperglycaemia.

Musculoskeletal and connective tissue disorders.

Back pain, arthralgia.

Nervous system disorders.

Cerebrovascular disorder.

Psychiatric disorders.

Agitation.

Respiratory, thoracic and mediastinal disorders.

Embolism pulmonary.

Skin and subcutaneous tissue disorders.

Rash, ecchymosis, urticaria.

Vascular disorders.

Hypertension, hypertension aggravated, hypotension postural.
Events occurring ≥ 0.01% and < 0.1%.

Gastrointestinal disorders.

Oesophagitis, pancreatitis, perioral swelling.

Immune system disorders.

Anaphylactoid reaction.

Renal and urinary disorders.

Renal failure acute.
Immediately following CABG surgery, patients administered parecoxib have a higher risk of adverse events, such as cardiovascular/thromboembolic events (e.g. myocardial infarction and cerebrovascular accident), renal dysfunction, deep surgical infections or sternal wound healing complications (see Section 4.3 Contraindications).

Post-marketing experience.

In post-marketing experience, the following rare, serious adverse events have been reported in association with the use of parecoxib:
Renal failure, acute renal failure, aseptic meningitis, congestive heart failure, circulatory collapse, erythema multiforme, hepatic failure, hepatomegaly, jaundice, Stevens-Johnson syndrome and hypersensitivity reactions including anaphylaxis and angioedema (see Section 4.4 Special Warnings and Precautions for Use).
In post-marketing experience, in addition to the severe cutaneous adverse reaction erythema multiforme and Stevens-Johnson syndrome, the following events have been reported in association with the use of valdecoxib and cannot be ruled out for parecoxib injection:
Myocardial infarction (very rare), exfoliative dermatitis, drug reaction with eosinophilia and systemic symptoms syndrome and toxic epidermal necrolysis (see Section 4.4 Special Warnings and Precautions for Use). The reported rate of serious skin events appears to be greater for valdecoxib as compared to other COX-2 selective inhibitors.
In post-marketing experience, the following adverse effects have with NSAID use that cannot be excluded as a class-effect:

Pregnancy, puerperium and perinatal conditions.

Oligohydramnios, neonatal renal impairment, ductus arteriosus premature closure, prolonged labour and prolonged pregnancy.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

Clinical experience of overdose is limited and a minimum human toxic dose has not been established. No symptoms of overdose have been observed with single IV doses of up to 200 mg of parecoxib sodium or oral doses up to 400 mg of valdecoxib in healthy subjects. Parecoxib sodium doses of 50 mg BD IV for 7 days did not result in any signs of toxicity.
Symptoms following acute NSAID overdoses are usually limited to lethargy, drowsiness, nausea, vomiting, epigastric pain, and other gastrointestinal effects, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose.

Treatment of overdosage.

There are no specific antidotes. Patients should be managed by symptomatic and supportive care following an overdose. Monitor patients for signs and symptoms of gastrointestinal ulceration and/or haemorrhage. Monitor serum electrolytes, renal function and urinalysis after significant overdose.
Valdecoxib is not removed by haemodialysis. Forced diuresis or alkalinisation of urine may not be useful due to high protein binding of valdecoxib.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Following injection, parecoxib sodium is rapidly converted to valdecoxib: the in vivo pharmacology of parecoxib is therefore that of valdecoxib. The mechanism of action of valdecoxib is by inhibition of cyclooxygenase-2 (COX-2)-mediated prostaglandin synthesis. At therapeutic plasma concentrations in humans, valdecoxib does not inhibit cyclooxygenase-1 (COX-1). In animal models, valdecoxib is anti-inflammatory, analgesic, and antipyretic.
By inhibition of both peripheral and central COX-2, valdecoxib reduces the production of prostaglandins that are important mediators of pain and inflammation. In animal models, the analgesic activity of valdecoxib is not reversible by naloxone. Therefore, parecoxib injection is not expected to exhibit the potential for dependence, sedation or respiratory depression seen with opioid analgesic agents.
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 6 to greater than 24 hours.

Clinical trials.

The analgesic efficacy and broad clinical utility of valdecoxib (delivered parenterally as the parecoxib sodium prodrug, parecoxib injection) have been demonstrated in multiple clinical models of pain. The analgesic efficacy of parecoxib injection was determined by various standard, primary and secondary measures, including absolute and differential pain relief scales and patient global evaluation. Comparisons were made to ketorolac (15 mg IV, 30 mg IV; 60 mg IM) and morphine (4 mg IV). Doses of parecoxib sodium are expressed in terms of parecoxib, not the sodium salt.
Analgesic response to parecoxib injection was found to be independent of age, gender or severity of pain.

Management of pain.

The peri-operative efficacy of parecoxib injection was established in studies of oral, gynaecologic, orthopaedic, and coronary artery bypass graft (CABG) surgical pain.
Post-oral surgery. In single-dose post-oral surgery (extraction of ≥ 2 third molar teeth with bone removal) pain studies, patients were randomised to receive parecoxib sodium (1 to 100 mg), placebo, or an active control. The effective analgesic dose range for parecoxib injection was 20 to 40 mg. Doses higher than 40 mg provided no additional analgesic efficacy. Onset of analgesia, following a single 20 or 40 mg dose of parecoxib injection, was 11-14 minutes; magnitude of analgesic effect of the 40 mg dose was comparable with that of ketorolac 60 mg IM (see Table 1 for a representative study). In addition, the median duration of analgesia for the 40 mg dose was 15-22 hours, providing statistically significantly superior sustained pain relief over the 20 mg dose and comparators.
Analgesic effectiveness of single and multiple doses of parecoxib injection for post-surgical pain was evaluated in 819 patients following gynaecologic (abdominal hysterectomy) or orthopaedic (hip or knee joint replacement) surgery.
Post-gynaecologic surgery. Parecoxib injection was evaluated in single and multiple dose regimens in women with moderate to severe pain following abdominal hysterectomy. Single doses of parecoxib injection 20 and 40 mg IV were compared to placebo, morphine 4 mg IV, and ketorolac 30 mg IV. Onset of analgesia, following a single dose of 40 mg of parecoxib injection, was 7-14 minutes and the magnitude of the analgesic effect was comparable to that of ketorolac (Table 2). Overall, a single dose of parecoxib injection 40 mg was more efficacious than parecoxib injection 20 mg. In the multiple dose treatment phase of the second study, 40 mg BD/PRN was comparable to 20 mg QID/PRN and both dose regimens were similar in effectiveness to ketorolac 30 mg QID/PRN.
Post-orthopaedic surgery. Two double-blind, parallel group studies were conducted in adults with moderate to severe pain following knee or hip replacement surgery. Both studies included a single-dose phase comparing parecoxib injection 20 and 40 mg IV to placebo, morphine 4 mg IV and ketorolac 30 mg IV (knee replacement study) or ketorolac 15 mg IV (hip replacement study). Onset of analgesia, following a single dose of 40 mg of parecoxib injection, was 10-11 minutes (Table 3). Overall, a single dose of parecoxib injection 40 mg was more efficacious than 20 mg. In the hip replacement study, 20 mg QID/PRN was comparable to 40 mg BD/PRN, and both dose regimens were similar in effectiveness to ketorolac 15 mg IV, QID/PRN.
Patients who required any rescue medication in the gynaecologic and orthopaedic efficacy trials were withdrawn from the study (Table 4). As a result, experience is limited with parecoxib treatment for more than 2 days.
Pre-operative administration. Two clinical studies evaluating the pre-operative administration (i.e. pre-emptive dosing) of parecoxib injection have demonstrated efficacy in reducing post-operative pain. Compared to placebo, administration of single doses of parecoxib injection 30 to 45 minutes prior to surgery significantly delayed development of post-operative pain (as measured by the proportion of patients not requiring supplemental pain medication at 6, 12 and 24 hours post-surgery) in patients undergoing oral surgery, and orthopaedic (bunionectomy and total hip arthroplasty) surgery (Figure 1). The safety profile of parecoxib injection administered pre-operatively was not different from that seen with post-operative administration.
Special studies.

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 randomisation and throughout the two CABG surgery studies.
The first CABG surgery study evaluated patients treated with IV parecoxib sodium 40 mg BD for a minimum of 3 days, followed by treatment with valdecoxib 40 mg BD (parecoxib sodium/valdecoxib group) (n=311) or placebo/placebo (n=151) in a 14-day, double-blind placebo-controlled study. Nine pre-specified adverse event categories were evaluated (cardiovascular (CV) thromboembolic events, pericarditis, new onset or exacerbation of congestive heart failure, renal failure/dysfunction, upper gastrointestinal (GI) ulcer complications, major non-GI bleeds, infections, non-infectious pulmonary complications, and death). There was a significantly (p < 0.05) greater incidence of CV/thromboembolic events (myocardial infarction, ischaemia, 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) (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use, Cardiovascular adverse effects). 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 randomised 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=1,050) major orthopaedic/general surgery trial, patients received an initial dose of parecoxib 40 mg by IV, then 20 mg IV Q12H for a minimum of 3 days followed by valdecoxib PO (20 mg Q12H) (n=512) 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 an analysis of non-cardiac surgery controlled trials in which the majority of patients were treated for 2 days, patients treated with parecoxib did not experience an increased risk of CV adverse events compared to placebo. This included patients with none, one or two CV risk factors. This analysis was powered to detect a doubling in the background rate of CV adverse events in patients treated with parecoxib (see Section 4.4 Special Warnings and Precautions for Use, Cardiovascular adverse effects).

Gastrointestinal.

Endoscopy studies were conducted to evaluate the ulcerogenic effects of parecoxib injection on the upper gastrointestinal (GI) mucosa. In short-term (7 day) studies involving healthy young or elderly subjects (≥ 65 years), parecoxib injection treatment resulted in significantly fewer ulcers than either ketorolac or naproxen (Table 5).
In a 12-week placebo-controlled study, scheduled endoscopies were conducted in 1150 patients with osteoarthritis. The gastroduodenal ulcer incidence rates with oral valdecoxib (active moiety of parecoxib injection), diclofenac sodium, and ibuprofen were compared (Figure 2). Valdecoxib was associated with a statistically significantly lower incidence of endoscopic ulcers compared to ibuprofen and diclofenac over the study period. There was no difference in the incidence of ulcers between placebo and either of the two doses of valdecoxib.

Platelets.

In clinical trials studying young and elderly (≥ 65 years) adult subjects, single and multiple doses up to 7 days of parecoxib injection 20 mg and 40 mg BD, had no effect on platelet aggregation or bleeding time. By comparison, ketorolac 15 mg and 30 mg as a single dose, or after 5 days treatment, significantly reduced platelet aggregation and significantly increased bleeding time (Figure 3). Full therapeutic doses of parecoxib injection had no clinically significant effect on aspirin-mediated inhibition of platelet function compared to placebo (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Aspirin).

5.2 Pharmacokinetic Properties

The pharmacokinetics of the prodrug parecoxib sodium and its active moiety valdecoxib, have been evaluated in more than 1600 individuals, including patients with acute pain, hepatic disease, renal disease, and young and elderly healthy subjects.

Absorption.

Following IV or IM injection, parecoxib sodium is rapidly and essentially completely converted to valdecoxib. Exposure [plasma concentration vs. time curve (AUC) and peak concentration (Cmax)] of valdecoxib following injection of parecoxib sodium is approximately linear in the dosage range of 1 mg to 100 mg IV and 1 mg to 40 mg IM given as a single dose, or 5 to 50 mg IV and 5 to 20 mg IM given repeatedly twice a day (BD). Steady state was reached within 4 days with BD dosing.
The pharmacokinetics of parecoxib and valdecoxib following single IV and IM doses of parecoxib sodium are shown in Table 6.

Distribution.

The volume of distribution of valdecoxib after its IV administration is approximately 55 L. Plasma protein binding is about 98% over the concentration range (0.21 - 2.38 microgram/mL) achieved with the highest recommended dose. Valdecoxib, but not parecoxib, is extensively partitioned into erythrocytes with an RBC to plasma concentration ratio of about 4:1 and a blood to plasma ratio of about 2.5:1. This ratio remains approximately constant with time and therapeutic blood concentrations, and therefore measurement of plasma concentrations of valdecoxib in pharmacokinetics studies is appropriate.

Metabolism.

Parecoxib is rapidly and almost completely converted to valdecoxib in vivo with a plasma half-life of < 60 minutes. The rate of conversion of parecoxib to valdecoxib is not affected in patients with mild to moderate hepatic impairment. Elimination of valdecoxib is by extensive hepatic metabolism involving multiple pathways. The cytochrome P-450 (CYP-450) dependent pathway involves predominantly 3A4 and 2C9 isozymes while the CYP-450 independent pathway leads to glucuronide conjugates of the sulfonamide moiety.
One active minor metabolite (a hydroxylated form via the CYP-450 pathway) of valdecoxib has been identified in human plasma at approximately 10% the concentration of valdecoxib. It also undergoes extensive metabolism, with < 5% of the dose excreted in the urine and faeces.
Because of its minor presence, this metabolite is not expected to contribute a significant clinical effect after administration of therapeutic doses of parecoxib sodium.

Excretion.

Following conversion from parecoxib, valdecoxib is eliminated via hepatic metabolism with < 5% of the dose excreted unchanged in the urine. No unchanged parecoxib is detected in urine and only a trace amount in faeces. About 70% of the dose is excreted in the urine as inactive metabolites. The elimination half-life (T1/2) of valdecoxib after IV or IM dosing of parecoxib sodium is about 8 hours. Plasma clearance (CLp) for valdecoxib is about 6 L/hr. In patients undergoing haemodialysis the CLp of valdecoxib was similar to the CLp found in healthy subjects.

Special populations.

Elderly (> 65 years).

Parecoxib injection has been administered to 335 elderly patients (65-96 years of age) in pharmacokinetic and therapeutic trials. Valdecoxib steady state plasma exposures in elderly female subjects, when adjusted for body weight, are about 40% higher than those in young male subjects. Dose adjustment in the elderly is not generally necessary; however for elderly female patients weighing < 50 kg, initiate treatment with half the usual recommended dose of parecoxib injection (see Section 4.2 Dose and Method of Administration).

Children and adolescents.

Parecoxib Sandoz injection has not been investigated in paediatric patients under 18 years of age.

Race.

Pharmacokinetic differences due to race have not been identified in clinical and pharmacokinetic studies conducted to date.

Renal impairment.

Valdecoxib pharmacokinetics has been studied in patients with varying degrees of renal impairment. 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 renal dialysis (see Section 4.2 Dose and Method of Administration, Dosage adjustment, Renal impairment).

Hepatic impairment.

In patients with moderate (Child-Pugh score 7-9) hepatic impairment, treatment should be initiated with half the usual recommended dose of parecoxib injection since valdecoxib exposures were more than doubled (130%) in these patients. However, moderate hepatic impairment did not result in reduced rate or extent of parecoxib conversion to valdecoxib. There is no clinical experience in patients with severe hepatic impairment (Child-Pugh score ≥ 10); therefore, the use of parecoxib injection is contraindicated in these patients (see Section 4.3 Contraindications; Section 4.2 Dose and Method of Administration, Dosage adjustment, Hepatic impairment).

5.3 Preclinical Safety Data

Genotoxicity.

Parecoxib sodium was not mutagenic in bacterial cells and the hypoxanthine-guanine phosphoribosyl transferase (HGPRT) mutation assay in Chinese hamster ovary (CHO) cells. Parecoxib increased the incidence of chromosomal aberrations in an in vitro CHO cell assay, however, it was negative in an in vivo micronucleus and chromosomal aberration test in rat bone marrow. Valdecoxib was negative in assays for gene mutations and clastogenicity.

Carcinogenicity.

Long-term animal studies to evaluate the carcinogenic potential of parecoxib sodium have not been conducted.

6 Pharmaceutical Particulars

6.1 List of Excipients

Powder for injection.

Dibasic sodium phosphate heptahydrate, phosphoric acid, sodium hydroxide.

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products and should be reconstituted only with sodium chloride solution (0.9% w/v) or the diluents mentioned in Section 4.2 Dose and Method of Administration.
Use of lactated Ringer's or 5% glucose in lactated Ringer's for reconstitution will cause the medicine to precipitate from solution and therefore is not recommended.
Use of sterile water for injections is not recommended, as the resulting solution is not isotonic.
Injection into an IV line delivering 5% glucose in lactated Ringer's, or other IV fluids not listed in Section 4.2 Dose and Method of Administration, is not recommended as this may cause precipitation from solution.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C. Protect from light.

Reconstituted product.

The reconstituted product should not be stored in a refrigerator or freezer.

6.5 Nature and Contents of Container

Parecoxib Sandoz parecoxib (as sodium) 40 mg power for injection is packaged in a 5 mL type I glass vial, closed with a dark grey bromobutyl stopper, and sealed with a flip-off cap.
Supplied in packs of 10 sterile, single-use vials.

6.6 Special Precautions for Disposal

This product contains no antimicrobial agent. Parecoxib Sandoz injection is for single use in one patient only. Discard any residue. Any unused product, diluent or waste material should be disposed of according to local requirements.

6.7 Physicochemical Properties

Chemical structure.


Chemical name: N-[[4-(5-methyl-3-phenyl-4 isoxazolyl) phenyl]sulfonyl]propanamide, sodium salt.
Molecular formula: C19H17N2O4SNa.
Molecular weight: 392.41.
Parecoxib sodium is a white to off-white solid that is very soluble in water. The formulated drug product is soluble in normal (0.9%) saline at > 50 mg/mL.

CAS number.

198470-85-8.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes