Consumer medicine information

Celecoxib Sandoz

Celecoxib

BRAND INFORMATION

Brand name

Celecoxib Sandoz

Active ingredient

Celecoxib

Schedule

S4

 

Consumer medicine information (CMI) leaflet

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

What is in this leaflet

This leaflet answers some common questions about CELECOXIB SANDOZ. It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking CELECOXIB SANDOZ against the benefits it is expected to have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Read this leaflet carefully before you start CELECOXIB SANDOZ and keep it with the medicine. You may need to read it again.

What CELECOXIB SANDOZ is used for

CELECOXIB SANDOZ is used to relieve the symptoms of joint pain, tenderness, swelling and stiffness in:

  • osteoarthritis,
  • rheumatoid arthritis and
  • ankylosing spondylitis, a chronic inflammatory rheumatic disorder that primarily affects, but is not limited to, the spine.

CELECOXIB SANDOZ also provides short-term pain relief in conditions such as:

  • menstrual cramps or period pain
  • after surgery
  • muscle and joint injuries.

CELECOXIB SANDOZ belongs to a group of medicines called coxibs which are used to relieve pain and inflammation in a number of conditions.

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

Your doctor, however, may have prescribed CELECOXIB SANDOZ for another purpose.

Ask your doctor if you have any questions about why CELECOXIB SANDOZ has been prescribed for you.

CELECOXIB SANDOZ is not recommended for use in children or adolescents under 18 years of age.

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

Before you take CELECOXIB SANDOZ

When you must not take it

Do not take CELECOXIB SANDOZ if:

  • you suffer from chest pains or angina and they occur even when you are resting and are becoming more frequent, severe, or lasting for longer than usual
  • you have or have had problems with your blood circulation
  • your doctor has told you that you have severe heart or blood vessel disease affecting the circulation in your brain or limbs
  • you have severe liver problems
    Your doctor will decide if your condition is too severe to take this medicine.
  • you have problems with your kidney function
  • you are undergoing cardiac surgery called coronary artery bypass graft (CABG)
  • 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 allergic to aspirin, NSAIDs, or other coxib medicines and use CELECOXIB SANDOZ, these symptoms may be severe.
  • you have an allergy to:
    - CELECOXIB SANDOZ
    - any of the ingredients listed at the end of this leaflet
    - sulfonamides, a group of medicines which include, for example, certain antibiotics (if you are not sure if you are taking one of these medicines ask your Pharmacist).

Symptoms of an allergic reaction to these medicines 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
  • fainting.

If you are allergic to sulfonamides or any of the capsule ingredients and take CELECOXIB SANDOZ, these symptoms may be severe.

Ask your doctor or pharmacist if any of this applies to you. CELECOXIB SANDOZ may not be suitable for you if any of the conditions below apply to you.

  • you are already taking an NSAID
  • you have an ulcer or gastric bleeding
  • you have Irritable Bowel Disease
  • you have heart failure
  • you have had a heart attack, a "mini" stroke or stroke or blood vessel disease affecting circulation of blood to your brain or limbs, especially in the last 3 months.

Do not take CELECOXIB SANDOZ if the expiry date printed on the packaging has passed, even though the capsules may look alright. If you take this medicine after the expiry date has passed, it may not work as well.

Do not take CELECOXIB SANDOZ if the packaging is torn or shows signs of tampering.

If you are not sure if you should be taking CELECOXIB SANDOZ, talk to your doctor.

Before you start to take it

You must tell your doctor if:

  • you currently have diabetes, high blood pressure, high cholesterol levels, heart failure or have a history of heart problems or stroke, or problems with the circulation in your limbs
  • you have any allergies to:
    - any other medicines
    - any other substances such as foods, dyes or preservatives.
  • you are pregnant or intend to become pregnant
    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.
    There is no information on the use of CELECOXIB SANDOZ during pregnancy.
    CELECOXIB SANDOZ may affect your developing baby if taken during pregnancy.
    Particular caution should be exerted from the twentieth week of the pregnancy.
    CELECOXIB SANDOZ use is not recommended in pregnancy unless your doctor considers it essential. If you are taking CELECOXIB SANDOZ while pregnant, you may need to be closely monitored by your doctor. Discuss any questions you may have with your doctor.
  • you are breast-feeding or intend to breast-feed
    CELECOXIB SANDOZ passes into breast milk in small amounts, therefore, the use of CELECOXIB SANDOZ during breastfeeding should be discussed with your doctor.
  • you have any other health problems including:
    - liver or kidney problems
    - asthma, hives, itching, skin rash or a runny nose
    - high blood pressure
    - fluid retention or other medical conditions that can cause fluid retention
    - peptic ulcer (i.e. stomach or duodenal ulcer), a recent history of one, or have had peptic ulcers before
    - vomiting blood or material that looks like coffee grounds
    - bleeding from the rectum (back passage), have black sticky bowel motions (stools) or bloody diarrhoea
    - bowel problems such as ulcerative colitis.
  • you are taking CELECOXIB SANDOZ together with any medicines used to treat high blood pressure and some other heart problems such as ACE inhibitors, angiotensin receptor antagonists and diuretics (also called fluid or water tablets).
    When taken together these medicines can cause kidney problems.
  • you drink large amounts of alcohol
  • you are a smoker
  • you currently have an infection.
    If you are given CELECOXIB SANDOZ while you have an infection, it may hide some of the signs of an infection.

If you have not told your doctor or pharmacist about these things, tell them before you start taking CELECOXIB SANDOZ.

Taking other medicines

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

Some medicines and CELECOXIB SANDOZ may interfere with each other. These include

  • any medicines used to treat high blood pressure and some other heart problems such as ACE inhibitors, angiotensin receptor antagonists, beta blockers or diuretics (also called fluid or water tablets)
  • digoxin, a medicine used to treat abnormal heart beats and some other heart problems
  • fluconazole, an antifungal agent
  • lithium, a medicine used to treat some types of depression
  • warfarin or similar medicines including Eliquis (apixaban), Xarelto (rivaroxaban) or Pradaxa (dabigatran), a medicine used to stop blood clots
  • aspirin or salicylates, medicines used to treat pain
  • antacids, medicines used to treat indigestion
  • dextromethorphan, a medicine used to treat dry coughs
  • some medicines used to treat diabetes
  • methotrexate, a medicine used to treat arthritis and some cancers
  • ciclosporin, medicine used to suppress the immune system
  • corticosteroids, such as prednisolone, medicines that are used to reduce inflammation
  • certain medicines used to treat pain and inflammation called non-steroidal anti-inflammatory drugs (NSAIDs).

Your doctor may need to adjust the dosage of these medicines, or provide additional advice if you are also taking CELECOXIB SANDOZ.

How to take CELECOXIB SANDOZ

Follow all directions given to you by your doctor and pharmacist carefully. They may differ from the information in this leaflet.

If you do not understand the instructions on the label, ask your doctor or pharmacist for help.

How much to take

Osteoarthritis
200 mg once daily or 100 mg twice daily.

Rheumatoid arthritis
100 mg twice daily.

Your doctor may increase the dose to 200 mg twice daily for a short period of time if you have a flare up.

Ankylosing spondylitis
100 mg twice daily or 200 mg once daily.

Menstrual cramps or period pain
400 mg as a single dose on the first day and 200 mg twice daily on the following days. You may take CELECOXIB SANDOZ for up to 5 days.

Muscle and joint injuries or after surgery
400 mg as a first dose followed by 200 mg once or twice daily as required. You may take CELECOXIB SANDOZ for up to 5 days.

How to take it

Swallow the capsules whole with a glass of fluid. CELECOXIB SANDOZ can be taken with or without food.

When to take it

Take your medicine at about the same time each day. Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

If you need to take an antacid, take it at least 2 hours before or 2 hours after your dose of CELECOXIB SANDOZ.

How long to take it

Depending on your condition, you may need CELECOXIB SANDOZ for a few days or for longer periods.

CELECOXIB SANDOZ will not cure your condition but should help control pain, swelling and stiffness.

Keep taking CELECOXIB SANDOZ for as long as your doctor advises.

Do not exceed the dosage recommended by your doctor.

Your risk of developing heart or blood vessel disease (e.g. heart attack) may increase with dose and duration of use even if you don't have a history of heart or blood vessel disease.

If you need to take CELECOXIB SANDOZ for a long time see your doctor for regular check-ups so that he/she can monitor your condition and treatment.

If you forget to take it

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to. Otherwise, take it as soon as you remember, then go back to taking your capsules as you would normally.

Do not take a double dose to make up for the dose you missed.

If you take too much (overdose)

Immediately telephone your doctor or Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at your nearest hospital if you think you or anyone else may have taken too much CELECOXIB SANDOZ. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

If you take too much CELECOXIB SANDOZ, you may feel tired, drowsy, sick, vomit, and have stomach pain. You may also have difficulty breathing and feel faint.

While you are taking it

Things you must do

If you become pregnant while taking CELECOXIB SANDOZ, tell your doctor immediately.

If you are about to start any new medicines, tell your doctor and pharmacist that you are taking CELECOXIB SANDOZ.

Tell all doctors, dentists and pharmacists who are treating you that you are taking CELECOXIB SANDOZ.

If you develop any skin rash (e.g. hives, spots) while being treated with CELECOXIB SANDOZ, contact your doctor immediately. The onset of these events, if they occur, can occur at any time, but most often occur in the first month of treatment.

If you are about to have any blood tests, tell your doctor that you are taking this medicine.

Things you must not do

Do not give CELECOXIB SANDOZ to anyone else, even if they have the same symptoms or condition as you.

Do not use CELECOXIB SANDOZ to treat any other complaints unless your doctor tells you to.

Side effects

Check with your doctor as soon as possible if you have any problems while taking CELECOXIB SANDOZ, even if you do not think the problems are connected with the medicine or are not listed in this leaflet.

Like other medicines, CELECOXIB SANDOZ can cause some side effects. If they occur, most are likely to be minor and temporary.

Ask your doctor or pharmacist any questions you may have.

Tell your doctor if you notice any of the following:

  • stomach pain, diarrhoea, indigestion, wind
  • swollen hands, ankles and feet, unexplained weight gain
  • dizziness
  • sore throat, runny nose, sinusitis, upper respiratory tract infection.

Tell your doctor immediately or go to the Accident and Emergency at your nearest hospital if you notice any of the following:

  • 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
  • muscles weakness
  • 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
  • collapse or fainting, shortness of breath or tiredness, irregular heartbeat, chest pain, swollen or sore leg veins
  • severe stomach or throat pain, vomiting blood or black sticky bowel motions
  • bleeding or bruising more than usual, reddish or purple blotches under the skin
  • nausea, lethargy, itchiness, flu-like symptoms or yellowing of the skin or eyes (jaundice)
  • signs of anaemia such as tiredness, being short of breath and looking pale
  • loss or deterioration of hearing
  • confusion
  • redness, irritation or watering of the eye(s)
  • experience sensations with any of the senses (sight, sound, touch, taste or feel) which may not be real
  • severe or persistent headache, fever, stiff neck, sensitivity to light and vomiting
  • sudden severe headache, loss of consciousness, sudden tingling, numbness or paralysis on one side of the face, arm, leg or body, difficulty speaking, understanding, reading or writing, loss of coordination or balance.

These are serious side effects. You may need urgent medical attention.

Not all of these side effects have been reported with CELECOXIB SANDOZ but have been seen with similar medicines.

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

Do not be alarmed by this list of possible side effects. You may not get any of them.

Tell your doctor if you notice anything else that is making you feel unwell, even if it is not on this list.

After taking CELECOXIB SANDOZ

Storage

Keep your capsules where young children cannot reach them. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Keep CELECOXIB SANDOZ in a cool, dry place where the temperature stays at or below 30°C. Do not store it, or any other medicine, in the bathroom or near a sink. Do not leave it in the car or on window sills. Heat and dampness can destroy some medicines.

Keep your capsules in their blister pack until it is time to take them. If you take the capsules out of their container they may not keep well.

Disposal

If your doctor tells you to stop taking CELECOXIB SANDOZ, or the capsules have passed their expiry date, ask your pharmacist what to do with any left over.

Product description

What it looks like

  • CELECOXIB SANDOZ 100 mg - opaque, white and blue capsules.
    The 100 mg capsules come in blister packs of 60.
  • CELECOXIB SANDOZ 200 mg - opaque, white and orange capsules.
    The 200 mg capsules come in blister packs of 30.

Ingredients

Active ingredient

The active ingredient in CELECOXIB SANDOZ is celecoxib.

  • CELECOXIB SANDOZ 100 mg - 100 mg celecoxib/capsule
  • CELECOXIB SANDOZ 200 mg - 200 mg celecoxib/capsule

Other ingredients

  • lactose monohydrate
  • sodium lauryl sulfate
  • carrageenan
  • cellulose - microcrystalline
  • silica - colloidal anhydrous
  • talc - purified
  • magnesium stearate
  • gelatin
  • titanium dioxide
  • indigo carmine (100 mg capsule)
  • iron oxide red (200 mg capsule)
  • iron oxide yellow (200 mg capsule)
  • CELECOXIB SANDOZ does not contain sucrose, gluten, tartrazine or other azo dyes.

Supplier

CELECOXIB SANDOZ is supplied in Australia by:

Sandoz Pty Ltd
ABN 60 075 449 553
54 Waterloo Road
Macquarie Park NSW 2113
Tel: 1800 726 369

Australian Registration Number:

CELECOXIB SANDOZ 100 mg - AUST R 210630

CELECOXIB SANDOZ 200 mg - AUST R 210632

This document was last revised in August 2021.

Published by MIMS October 2021

BRAND INFORMATION

Brand name

Celecoxib Sandoz

Active ingredient

Celecoxib

Schedule

S4

 

1 Name of Medicine

Celecoxib.

2 Qualitative and Quantitative Composition

Each Celecoxib Sandoz 100 mg capsule contains 100 mg celecoxib.
Each Celecoxib Sandoz 200 mg capsule contains 200 mg celecoxib.
Not all strengths may be marketed in Australia.

Excipient with known effect.

Lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Celecoxib Sandoz 100 mg capsules are opaque, white capsules with blue cap containing white to slightly yellowish pellets.
Celecoxib Sandoz 200 mg capsules are opaque, white capsules with orange cap containing white to slightly yellowish pellets.

4 Clinical Particulars

4.1 Therapeutic Indications

For the symptomatic treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis.
For the treatment of primary dysmenorrhoea in adults.
For the short-term treatment of acute pain in adults following surgery or musculoskeletal and/or soft tissue injury.

4.2 Dose and Method of Administration

Dosage.

As the cardiovascular (CV) risks of celecoxib may increase with dose and duration of exposure, the shortest duration possible and the lowest effective daily dose should be used (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
Patients on long-term treatment should be reviewed regularly, such as every three months, with regards to efficacy, risk factors and ongoing need for treatment.

Adults.

Osteoarthritis.

The usual recommended daily dose is 200 mg taken once daily or in two divided doses.

Rheumatoid arthritis.

The recommended daily dose is 200 mg taken in two divided doses.
A dose of up to 400 mg daily may be used for short-term management of disease flares or exacerbations.

Ankylosing spondylitis.

The maximum recommended daily dose is 200 mg taken once daily or in two divided doses.

Primary dysmenorrhoea.

The recommended dose is 400 mg as a single dose or divided on the first day, followed by 200 mg once daily on subsequent days. Patients may be instructed to take an additional dose of 200 mg on any given day, if needed. The maximum recommended treatment duration is 5 days.

Acute pain following surgery or musculoskeletal and/or soft tissue injury.

The recommended dose is a loading dose of 400 mg then 200 mg once or twice daily as required for up to 5 days.
The effective dose in this patient population is 200 mg twice daily.

Method of administration.

To be taken orally without regard to timing of meals.

Dosage adjustment.

Renal impairment.

No dosage adjustment is necessary in patients with mild or moderate renal impairment. There is no clinical experience in patients with severe renal impairment (see Section 5.2 Pharmacokinetic Properties).

Hepatic impairment.

No dosage adjustment is necessary in patients with mild hepatic impairment.
In arthritis patients with moderate hepatic impairment, Celecoxib Sandoz should be introduced at half the recommended dose.
There is no clinical experience in patients with severe hepatic impairment. Therefore, the use of Celecoxib Sandoz in patients with severe hepatic impairment (Child-Pugh score ≥ 10) is contraindicated (see Section 4.3 Contraindications; Section 5.2 Pharmacokinetic Properties).

Elderly.

No dosage adjustment is generally necessary. However, for elderly patients with a lower than average bodyweight (< 50 kg), it is advisable to initiate therapy at the lowest recommended dose (see Section 5.2 Pharmacokinetic Properties).

Children and adolescent.

Celecoxib Sandoz is not approved for use in patients under 18 years of age.

CYP2C9 poor metabolisers.

Patients who are known, or suspected to be CYP2C9 poor metabolisers based on previous history/experience with other CYP2C9 substrates should be administered celecoxib with caution. Consider starting treatment at a reduced dose (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 5.2 Pharmacokinetic Properties).

Pregnancy.

See Section 4.6 Fertility, Pregnancy and Lactation.

4.3 Contraindications

Known hypersensitivity to celecoxib or any of the excipients contained in the Celecoxib Sandoz capsules (see Section 6.1 List of Excipients).
Demonstrated allergic type reactions to sulfonamides.
Celecoxib should not be given to patients who have experienced asthma, urticaria, or allergic type reactions after taking aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs), including other cyclooxygenase-2 (COX-2) specific inhibitors. Severe, rarely fatal, anaphylactoid reactions to NSAIDs have been reported in such patients (see Section 4.4 Special Warnings and Precautions for Use, Anaphylactoid reactions).
Celecoxib should not be used with other NSAIDs because of the absence of any evidence demonstrating synergistic benefits and the potential for additive adverse reactions.
Celecoxib is contraindicated for the perioperative treatment of pain in patients undergoing coronary artery bypass graft (CABG) surgery (see Section 4.4 Special Warnings and Precautions for Use).
Celecoxib is contraindicated in:
Patients with unstable ischaemic heart disease of thrombus aetiology, significant established ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease (see Section 4.4 Special Warnings and Precautions for Use, Cardiovascular and thrombotic events) or documented myocardial infarction or stroke within 3 months.
Patients with active peptic ulceration or gastrointestinal (GI) bleeding.
Patients with estimated creatinine clearance < 30 mL/min.
Patients with congestive heart failure (NYHA II-IV).
Patients with severe hepatic impairment (Child-Pugh# score ≥ 10; see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).
# Child-Pugh is a classification of the severity of liver disease (see Table 1).

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 and benefits of therapy (see Section 4.3 Contraindications).

Cardiovascular and thrombotic events.

COX-2 inhibitors, including celecoxib have been associated with an increased risk of serious CV thrombotic adverse events, myocardial infarction, and stroke, which can be fatal (see Section 5.1 Pharmacodynamic Properties, Clinical trials, Cardiovascular safety).
All NSAIDs, both COX-2 selective and nonselective may cause an increased risk of serious CV thrombotic events. This risk may increase with duration of use.
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 CV disease or CV risk factors may be at greater risk in terms of absolute incidence, due to their increased rate at baseline.
Celecoxib should be used with caution in patients with significant established ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease as well as patients at high risk of CV disease including those with significant and multiple risk factors (e.g. diabetes, hypertension, hypercholesterolaemia, cardiac failure and smokers) (see Section 4.3 Contraindications).
COX-2 selective inhibitors are not a substitute for acetylsalicylic acid for prophylaxis of cardiovascular thromboembolic diseases because of their lack of antiplatelet effects. Therefore, antiplatelet therapies should not be discontinued. To minimize the potential risk for an adverse CV event in patients treated with celecoxib, the lowest effective dose should be used for the shortest duration possible (see Section 4.2 Dose and Method of Administration; Section 5.1 Pharmacodynamic Properties, Clinical trials, Cardiovascular safety).
Physicians and patients should remain alert for such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV toxicity and the steps to take if they occur.

Gastrointestinal effects.

Infrequently, serious gastrointestinal (GI) toxicity such as bleeding, ulceration, and upper and lower GI perforation (including perforations of the stomach or intestine) has been observed in patients treated with celecoxib. Physicians and patients should remain alert for ulceration and bleeding, even in the absence of previous GI tract symptoms.
Celecoxib exhibited a low incidence of gastroduodenal ulceration and serious clinically significant GI events within clinical trials. The following information for NSAIDs should be borne in mind.
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 NSAIDs. Minor upper GI problems, such as dyspepsia, are common, and may also occur at any time during NSAID therapy. Therefore, physicians should remain alert for ulceration and bleeding in patients treated with NSAIDs, 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. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore special care should be taken in treating this population.
Among 5,285 patients who received celecoxib in the original arthritis trials of 1 to 6 months duration (most were 3 month studies) at a daily dose of 200 mg or more, 2 (0.04%) experienced significant upper GI bleeding, at 14 and 22 days after initiation of dosing. Approximately 40% of these 5,285 patients were in studies that required them to be free of ulcers by endoscopy at study entry. Thus it is unclear if this study population is representative of the general population.
The incidences of complicated and symptomatic ulcers for patients treated with celecoxib 400 mg twice daily (4-fold and 2-fold greater than the recommended OA and RA doses, respectively) from the prospective randomised controlled long-term outcomes trial in 8000 OA and RA patients in which low dose aspirin use was allowed was 0.68% on celecoxib alone and 1.08% on celecoxib with or without aspirin.
Patients most at risk of developing GI complications with NSAIDs are elderly patients; patients with CV disease; patients using concomitant antiplatelet drugs (such as aspirin) or corticosteroids; patients who consume alcohol; or patients with a prior history of GI disease (such as ulceration, GI bleeding or inflammatory conditions). Celecoxib should be prescribed with extreme caution in these patients. Physicians and patients should remain alert for ulceration and GI 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 of an ulcer complication, the lowest effective dose of celecoxib should be used for the shortest possible duration. For high risk patients, alternate 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.
There is no definitive evidence that the concomitant administration of histamine H2-receptor antagonists and/or antacids will either prevent the occurrence of GI side effects or allow the continuation of celecoxib when and if these adverse reactions appear.

Anaphylactoid reactions.

As with NSAIDs in general, anaphylactoid reactions have occurred in patients without known prior exposure to celecoxib. In post-marketing experience, rare cases of anaphylactoid reactions and angioedema have been reported in patients receiving celecoxib. Celecoxib 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.

Severe skin reactions.

Serious skin reactions, some of them fatal, including drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome (see Drug reaction with eosinophilia with systemic symptoms (DRESS)), exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of celecoxib. Patients appear to be at highest risk for these events early in the course of therapy: the onset of the event occurring in the majority of cases within the first month of treatment. Celecoxib should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Drug reaction with eosinophilia with systemic symptoms (DRESS).

DRESS has been reported in patients taking NSAIDs. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, haematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. 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.

Hypertension.

As with all NSAIDs, celecoxib can lead to the onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. NSAIDs, including celecoxib, should be used with caution in patients with hypertension. Blood pressure should be monitored closely during the initiation of therapy with celecoxib and throughout the course of therapy.

Renal effects.

NSAIDs, including celecoxib, may cause renal toxicity. 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 NSAID may cause a dose dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Such patients should be carefully monitored while receiving treatment with celecoxib. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors (see Section 4.4 Special Warnings and Precautions for Use, Concomitant use of ACE inhibitors or angiotensin receptor antagonists and anti-inflammatory drugs and thiazide diuretics), and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
Clinical trials with celecoxib have shown renal effects similar to those observed with comparator NSAIDs. At the present time the relative roles of COX-1 and COX-2 in renal physiology is incompletely understood. Celecoxib reduces the urinary excretion of PGE2 and 6-keto-PGF1α (a prostacyclin metabolite) but leaves serum thromboxane B2 (TXB2) and urinary excretion of 11-dehydro-TXB2, a thromboxane metabolite (both COX-1 products) unaffected.
Caution should be used when initiating treatment with celecoxib in patients with considerable dehydration. It is advisable to rehydrate patients first and then start therapy with celecoxib.
No information is available regarding the use of celecoxib in patients with advanced kidney disease. Therefore, treatment with celecoxib is not recommended in these patients. If celecoxib therapy must be initiated, close monitoring of the patient's kidney function is advisable.

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

The use of an ACE inhibiting drug (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 drug. Concomitant use of all three classes of these medications should be accompanied by increased monitoring of serum creatinine, particularly at the initiation of the treatment. The concomitant use of drugs from these three classes should be used with caution particularly in elderly patients or those with pre-existing renal impairment.

Use with oral anticoagulants.

The concomitant use of NSAIDs with oral anticoagulants increases the risk of bleeding and should be given with caution (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Oral anticoagulants).

Use with drugs metabolised by CYP2D6.

Celecoxib has shown to be a moderately potent CYP2D6 inhibitor. For drugs that are metabolised by CYP2D6, a dose reduction during initiation of celecoxib treatment or a dose increase upon termination of celecoxib treatment may be necessary (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Dextromethorphan and metoprolol).

Use with other NSAIDs.

The concomitant use of celecoxib and a nonaspirin NSAID should be avoided.

Hepatic effects.

Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs, and notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy.
Rare cases of severe hepatic reactions, including jaundice, fatal fulminant hepatitis, liver necrosis and hepatic failure (some with fatal outcome or requiring liver transplant), have been reported with NSAIDs, including celecoxib (see Section 4.8 Adverse Effects (Undesirable Effects)).
In controlled clinical trials of celecoxib, the incidence of borderline elevations of liver tests was 6% for celecoxib and 5% for placebo, and approximately 0.2% of patients taking celecoxib and 0.3% of patients taking placebo had notable elevations of ALT and AST.
Physician and patients should remain alert for hepatotoxicity. Patients should be informed about the signs and/or symptoms of hepatotoxicity. A patient with symptoms and/or signs suggesting liver dysfunction (e.g. nausea, fatigue, lethargy, pruritus, jaundice, abdominal tenderness in the right upper quadrant and "flu-like" symptoms), or in whom an abnormal liver test has occurred, should be monitored carefully for evidence of the development of a more severe hepatic reaction while on therapy with celecoxib.
If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g. eosinophilia, rash, etc.), celecoxib should be discontinued.
The incidence of elevations in ALT and/or AST may be increased in patients treated with celecoxib at doses greater than 400 mg daily.

Haematological effects.

Anaemia is sometimes seen in patients receiving celecoxib. In controlled clinical trials, the incidence of anaemia was 0.6% with celecoxib and 0.4% with placebo. Patients on long-term treatment with celecoxib should have their haemoglobin or haematocrit checked if they exhibit any signs or symptoms of anaemia or blood loss. Celecoxib does not generally affect platelet counts, prothrombin time (PT), or partial thromboplastin time (PTT), and does not appear to inhibit platelet aggregation at indicated dosages (see Section 5.1 Pharmacodynamic Properties, Clinical trials, Celecoxib long-term arthritis safety study (CLASS), Platelet function).

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 NSAIDs has been reported in such aspirin sensitive patients, celecoxib should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with pre-existing asthma.

Fluid retention and oedema.

Fluid retention and oedema have been observed in some patients taking celecoxib (see Section 4.8 Adverse Effects (Undesirable Effects)). Therefore, celecoxib should be used with caution in patients with fluid retention, hypertension, heart failure, compromised cardiac function, pre-existing edema or other conditions predisposing to, or worsened by, fluid retention including those taking diuretic treatment or otherwise at risk of hypovolaemia. Patients with pre-existing congestive heart failure or hypertension should be closely monitored.

Use in patients being treated with corticosteroids.

Abrupt discontinuation of corticosteroids may lead to exacerbation of corticosteroid responsive illness. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.

Use in patients with inflammatory bowel disease (IBD).

Short-term exposure of celecoxib to patients with ulcerative colitis (UC) in remission has not shown an exacerbation of IBD in spondyloarthropathies, but the implications of longer term exposure remain unknown. NSAIDs have been associated with an exacerbation of IBD associated with spondyloarthropathies.

Detecting infections.

By reducing inflammation, celecoxib may diminish the utility of diagnostic signs, such as fever, in detecting infections.

Use in the elderly.

Of the total number of patients who received celecoxib in clinical trials, more than 3,300 were 65-74 years of age, while approximately 1,300 additional patients were 75 years and over. While the incidence of adverse experiences tended to be higher in elderly patients, no substantial differences in safety and effectiveness were observed between these subjects and younger subjects. Other reported clinical experience including data from the Celecoxib Long-term Arthritis Safety Study have not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out (see Section 4.4 Special Warnings and Precautions for Use, Gastrointestinal effects).
In clinical studies comparing renal function as measured by the GFR, BUN (blood urea nitrogen) and creatinine, and platelet function as measured by bleeding time and platelet aggregation, the results were not different between elderly and young volunteers.

Paediatric use.

Celecoxib is not approved for use in patients under 18 years of age.

Effects on laboratory tests.

Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. In controlled clinical trials elevated BUN occurred more frequently in patients receiving celecoxib compared with patients on placebo. This abnormality was also seen in patients who received comparator NSAIDs in these studies. The clinical significance of this abnormality has not been established.

4.5 Interactions with Other Medicines and Other Forms of Interactions

General.

Celecoxib metabolism is predominantly mediated via cytochrome P450 2C9 in the liver. Patients who are known or suspected to be poor CYP2C9 metabolisers based on previous history/experience with other CYP2C9 substrates should be administered celecoxib with caution as they may have abnormally high plasma levels due to reduced metabolic clearance. Coadministration of celecoxib with drugs that are known to inhibit 2C9 should be done with caution. Consider starting treatment at a reduced dose (see Section 4.2 Dose and Method of Administration).
Concomitant administration of celecoxib with inhibitors of CYP2C9 can lead to increases in plasma concentrations of celecoxib. Therefore, a dose reduction of celecoxib may be necessary when celecoxib is coadministered with CYP2C9 inhibitors.
Concomitant administration of celecoxib with inducers of CYP2C9 (such as rifampicin, carbamazepine and barbiturates) can lead to decreases in plasma concentrations of celecoxib. Therefore, a dose increase of celecoxib may be necessary when celecoxib is coadministered with CYP2C9 inducers.
Clinical pharmacokinetics study and in vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of cytochrome P450 2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolised by P450 2D6.

Antihypertensives including angiotensin converting enzyme (ACE) inhibitors, angiotensin II antagonists, diuretics and beta-blockers.

Reports suggest that inhibition of prostaglandins may diminish the effect of antihypertensive effects including angiotensin converting enzyme (ACE) inhibitors and/or angiotensin II antagonists (also known as angiotensin receptor blockers of ARBs), diuretics and beta-blockers. This interaction should be given consideration in patients taking celecoxib concomitantly with these drugs.
In patients who are elderly, volume depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, angiotensin II antagonists or diuretics, 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 clinical need to monitor the renal function should be assessed at the beginning of the concomitant treatment and periodically thereafter.

Furosemide.

Clinical studies, as well as postmarketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis.

Aspirin.

Celecoxib can be used with low dose aspirin. However, concomitant administration of aspirin with celecoxib may result in an increased rate of GI ulceration or other complications, compared to use of celecoxib alone (see Section 5.1 Pharmacodynamic Properties, Clinical trials, Celecoxib long-term arthritis safety study (CLASS)).
In the long-term outcome study, the incidences of MI, stroke, unstable angina and deep thrombophlebitis in nonaspirin users were 0.2%, < 0.1%, < 0.1% and 0.3% respectively and in aspirin users were 1.5%, 0.6%, 0.9% and 0.3% respectively. Incidence rates with celecoxib were not different from those of the two comparators. Because of its lack of platelet effects, celecoxib is not a substitute for aspirin for cardiovascular prophylaxis.

Ciclosporin.

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

Fluconazole.

Concomitant administration of fluconazole at 200 mg once daily resulted in a twofold increase in celecoxib plasma concentration. This increase is due to the inhibition of celecoxib metabolism via P450 2C9 by fluconazole (see Section 5.2 Pharmacokinetic Properties). Celecoxib should be introduced at the lowest recommended dose in patients receiving fluconazole.

Dextromethorphan and metoprolol.

Concomitant administration of celecoxib resulted in increases in plasma concentrations of dextromethorphan and metoprolol (CYP2D6 substrates). These increases are due to celecoxib inhibition to the CYP2D6 substrate metabolism via CYP2D6. Therefore, the dose of drugs which are CYP2D6 substrate may need to be reduced when treatment with celecoxib is initiated or increased when treatment with celecoxib is terminated (see Section 4.4 Special Warnings and Precautions for Use, Use with drugs metabolised by CYP2D6).

Lithium.

In a study conducted in healthy subjects, mean steady-state lithium plasma levels increased approximately 17% in subjects receiving lithium 450 mg twice daily with celecoxib 200 mg twice daily as compared to subjects receiving lithium alone. Patients on lithium treatment should be closely monitored when celecoxib is introduced or withdrawn.

Oral hypoglycaemics.

The effect of celecoxib on the pharmacokinetics and/or pharmacodynamics of glibenclamide and tolbutamide has been studied and clinically important interactions have not been found.

Glucocorticoids.

Oral glucocorticoids should be used with caution since they increase the risk of GI side effects such as ulceration and bleeding. This is especially the case in older (> 65 years of age) individuals.

Antacids.

Coadministration of celecoxib with an aluminium and magnesium containing antacid resulted in a reduction in plasma celecoxib concentrations with a decrease of 37% in Cmax and 10% in AUC.

Methotrexate.

Celecoxib did not have a significant effect on the pharmacokinetics of methotrexate.
Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g. neutropenia, thrombocytopenia, renal dysfunction). During concomitant use of celecoxib and methotrexate, patients should be monitored for methotrexate toxicity.

Ketoconazole.

Celecoxib did not have a significant effect on the pharmacokinetics of ketoconazole.

Phenytoin.

Celecoxib did not have a significant effect on the pharmacokinetics of phenytoin.

Oral anticoagulants.

The concomitant use of NSAIDs with oral anticoagulants increases the risk of bleeding and should be given with caution. Oral anticoagulants include warfarin/coumarin-type and novel oral anticoagulants (e.g. apixaban, dabigatran, and rivaroxaban). Because increases in prothrombin time (INR) have been reported, anticoagulation/INR should be monitored, particularly in the first few days, after initiating or changing celecoxib therapy in patients receiving warfarin/coumarin-type anticoagulant, since these patients are at an increased risk of bleeding complications.
The effect of celecoxib on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of 2 mg to 5 mg of warfarin. In these subjects, celecoxib did not alter the anticoagulant effect of warfarin as determined by INR. However, in postmarketing experience, bleeding events have been reported, some of them fatal, predominantly in the elderly, in association with increases in INR in patients receiving celecoxib concurrently with warfarin or similar agents (see Section 4.4 Special Warnings and Precautions for Use, Gastrointestinal effects).

Digoxin.

Concomitant use of celecoxib with digoxin has been reported to increase serum concentration and prolong half-life of digoxin. During concomitant use of celecoxib and digoxin, serum digoxin levels should be monitored.

Other drug interactions.

No drug interaction data are available for celecoxib and the coadministration of the following products: paracetamol, aminoglycosides, bone marrow depressants, butemide, cholestyramine, colchicine, gold compounds, indapamide, insulin, nephrotoxic agents, oral contraceptives, potassium supplements, probenecid, valproic acid, and zidovudine.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Celecoxib did not affect male or female fertility in rats at oral doses up to 600 mg/kg/day (approximately 7-fold human exposure based on AUC0-24 h at 400 mg twice daily, which is twice the recommended maximum daily dose).
Based on the mechanism of action, the use of NSAIDs, including celecoxib, 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 celecoxib, should be considered.
(Category B3)
Non-steroidal anti-inflammatory (NSAIDs) agents inhibit prostaglandin synthesis and, when given during the latter part of pregnancy, may cause closure of the foetal ductus arteriosus, foetal renal impairment, inhibition of platelet aggregation, and delay labour and birth. There is no information on the use of celecoxib in pregnant women. Celecoxib use is not recommended in pregnancy unless it is considered clinically essential (see information on animal studies). No studies have been done to evaluate the effect of celecoxib on the closure of the ductus arteriosus in 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 maintenance of patency. Therefore, use of celecoxib during the third trimester of pregnancy should be avoided, and celecoxib should not be used during the first and second trimesters of pregnancy unless the potential benefit to the mother justifies the potential risk to the fetus. The effects of celecoxib on labour and delivery in pregnant women are not known.
If used during second or third trimester of pregnancy, NSAIDs may cause fetal renal dysfunction which may result in reduction of amniotic fluid volume or oligohydramnios in severe cases (see Oligohydramnios and neonatal renal impairment).
In rats, celecoxib caused early embryonic death at doses greater than 30 mg/kg/day administered before mating and during early gestation (approximately 2-fold human exposure based on AUC0-24 h at 400 mg twice daily, which is twice the recommended maximum daily dose). This effect is attributable to inhibition of prostaglandin production, and is not associated with permanent alteration of reproductive function. Celecoxib was shown to cross the placenta in rats. Teratology studies disclosed an increased incidence of wavy ribs in one study in rats dosed at 100 mg/kg/day, increased incidences of diaphragmatic hernias at 30 and 100 mg/kg/day in another rat study; and increased incidences of rib and sternebral abnormalities in rabbits at doses of 60 mg/kg/day or greater and CV abnormalities in rabbits at doses of 150 mg/kg/day or greater. At the no effect dose in rats (10 mg/kg/day), AUC0-24 h was similar to that in humans dosed at 400 mg BD. At the threshold dose of 60 mg/kg/day in rabbits, AUC0-24 h was slightly below that in humans dosed at 400 mg twice daily. Celecoxib had a marginal effect on parturition in rats, causing slight prolongation of gestation and parturition and increased incidence of still births at oral doses of 10 mg/kg/day or greater (slightly greater than human exposure based on AUC0-24 h at 400 mg twice daily).
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 postimplantation loss.

Oligohydramnios and neonatal renal impairment.

Use of NSAIDs from about 20 weeks gestation may cause foetal 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.
If, after careful consideration of alternative treatment options for pain management, NSAID treatment is necessary from about 20 weeks, limit use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if treatment extends beyond 48 hours. Discontinue treatment with NSAIDs if oligohydramnios occurs.
 Studies in rats show that celecoxib is excreted in milk at concentrations similar to those in plasma. Administration of celecoxib to lactating women has shown very low transfer of celecoxib into breast milk. Because of the potential for adverse reactions to celecoxib in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the expected benefit of the drug to the mother.

4.7 Effects on Ability to Drive and Use Machines

The effect of celecoxib on ability to drive or use machinery has not been studied, but based on its pharmacodynamic properties and overall safety profile it is unlikely to have an effect.

4.8 Adverse Effects (Undesirable Effects)

Of the celecoxib treated patients in controlled trials, approximately 4,250 were patients with OA, approximately 2,100 were patients with RA, and over 1,000 were patients with postsurgical pain. More than 8,500 patients have received a total daily dose of celecoxib of 200 mg (100 mg twice daily or 200 mg once daily) or more, including more than 400 treated at 800 mg (400 mg twice daily). Approximately 3,900 patients have received celecoxib at these doses for 6 months or more; approximately 2,300 of these have received it for 1 year or more and 124 of these have received it for 2 years or more.

Adverse events from original celecoxib arthritis trials.

Table 2 lists all adverse events, regardless of causality, occurring in ≥ 2% of patients receiving celecoxib from 12 controlled studies conducted in patients with OA or RA that included a placebo and/or an active control group.
In placebo or active controlled clinical trials, the discontinuation rate due to adverse events was 7.1% for patients receiving celecoxib and 6.1% for patients receiving placebo. Among the most common reasons for discontinuation due to adverse events in the celecoxib treatment groups were dyspepsia and abdominal pain (cited as reasons for discontinuation in 0.8% and 0.7% of celecoxib patients, respectively). Among patients receiving placebo, 0.6% discontinued due to dyspepsia and 0.6% withdrew due to abdominal pain.
The adverse event profile from the Celecoxib Long-term Arthritis Safety Study (at 4 and 2-fold the recommended doses for OA and RA, respectively) was similar to those reported in the arthritis controlled trials.
The following adverse events occurred in 0.1-1.9% of patients taking celecoxib 100-200 mg twice daily or 200 mg once daily regardless of causality.

Blood and lymphatic system disorders.

Anaemia, thrombocythaemia.

Cardiac disorders.

Aggravated hypertension, angina pectoris, coronary artery disorder, myocardial infarction, arrhythmia, palpitation, tachycardia.

Ear and labyrinth disorders.

Deafness, ear abnormality, ear ache, tinnitus, vertigo.

Eye disorders.

Vision blurred, cataract, conjunctivitis, eye pain, glaucoma.

Gastrointestinal disorders.

Constipation, diverticulitis, dysphagia, eructation, oesophagitis, gastritis, gastroenteritis, gastroesophageal reflux, haemorrhoids, hiatal hernia, melaena, dry mouth, stomatitis, tenesmus, tooth disorder, vomiting.

General disorders and administration site conditions.

Asthenia, chest pain, cyst, oedema generalised, face oedema, fatigue, pyrexia, influenza-like illness, pain, peripheral pain, injection site reaction.

Hepatobiliary disorders.

Hepatic function abnormal, AST increased, ALT increased.

Infections and infestations.

Herpes simplex, herpes zoster, infection bacterial, infection fungal, infection soft tissue, infection viral, moniliasis, moniliasis genital, otitis media, cellulitis, cystitis, urinary tract infection.

Injury, poisoning and procedural complications.

Fracture accidental.

Immune system disorders.

Hypersensitivity.

Investigations.

BUN increased, CPK increased, blood alkaline phosphatase increased, non-protein nitrogen increased, blood creatinine increased, weight increased.

Metabolism and nutritional disorders.

Diabetes mellitus, hypercholesterolaemia, hyperglycaemia, hypokalaemia.

Musculoskeletal and connective tissue disorders.

Arthralgia, arthrosis, bone disorder, myalgia, neck stiffness, synovitis, tendinitis, leg cramps.

Nervous system disorders.

Hypertonia, hypoaesthesia, migraine, neuralgia, neuropathy, paraesthesia, dysgeusia.

Neoplasms benign, malignant and unspecified (incl cysts and polyps).

Breast neoplasm.

Psychiatric disorders.

Anorexia, anxiety, appetite increased, depression, nervousness, somnolence.

Reproductive system and breast disorders.

Breast fibroadenosis, breast pain, dysmenorrhoea, menstrual disorder, vaginal haemorrhage, vaginitis, prostatic disorder.

Respiratory, thoracic and mediastinal disorders.

Bronchitis, bronchospasm, bronchospasm aggravated, cough, dyspnoea, laryngitis, pneumonia, epistaxis.

Renal and urinary system disorders.

Albuminuria, dysuria, haematuria, pollakiuria, nephrolithiasis, urinary incontinence.

Skin and subcutaneous tissue disorders.

Alopecia, dermatitis, nail disorder, photosensitivity reaction, pruritus, rash erythematous, rash maculopapular, skin disorder, skin dry, hyperhidrosis, urticaria, ecchymosis, dermatitis contact, skin mass.

Vascular disorders.

Hot flushes.

Other serious adverse events which occur rarely (0.1%), regardless of causality.

The following serious adverse events have occurred rarely in patients, taking celecoxib.

Blood and lymphatic disorders.

Thrombocytopenia.

Cardiac disorders.

Syncope, cardiac failure congestive, ventricular fibrillation.

Ear and labyrinth disorders.

Decreased hearing.

Gastrointestinal disorders.

Intestinal obstruction, intestinal perforation, gastrointestinal bleeding, colitis with bleeding, oesophageal perforation, pancreatitis, ileus, oesophageal ulcer, gastric ulcer, duodenal ulcer.

General disorders and administration site conditions.

Sepsis, sudden death.

Hepatobiliary disorders.

Cholelithiasis.

Infection and infestation.

Peripheral gangrene, meningitis aseptic.

Nervous system disorders.

Ataxia, epilepsy, cerebrovascular accident.

Psychiatric disorders.

Suicide, confusional state.

Renal and urinary disorders.

Renal failure acute.

Respiratory, thoracic, and mediastinal disorders.

Pulmonary embolism.

Vascular disorders.

Thrombophlebitis.

Adverse events from the primary dysmenorrhoea studies.

These studies had an overall incidence of adverse events of 30.5% in the placebo treatment period, 31.2% in the celecoxib treatment period, and 36.3% in the NSAID comparator (naproxen sodium) period. Overall, nausea, headache, and dizziness were the most common adverse events in the celecoxib treatment group. These adverse events can be related to primary dysmenorrhoea.

Adverse reactions from polyp prevention trials.

The following additional adverse events in Table 3 were reported at incidence rates greater than placebo in long-term polyp prevention studies of duration up to 3 years at daily doses from 400 mg up to 800 mg (see Section 5.1 Pharmacodynamic Properties, Clinical trials, Cardiovascular safety, long-term studies involving patients with sporadic adenomatous polyps). Frequencies of ADRs in Table 3 were determined based on long-term polyp prevention studies. Adverse events are listed by system organ class are ranked by frequency. Frequencies are defined as: very common (≥ 10%), common (≥ 1% and < 10%), uncommon (≥ 0.1% and < 1%).

Other adverse effects.

Intestinal anastomotic ulceration was observed in 3 of 58 patients enrolled in familial adenomatous polyposis clinical trials and who had prior intestinal surgery, one at 100 mg twice daily, and two at 400 mg twice daily.
Aggravation of gastrointestinal inflammation has been reported.

Post-marketing experience.

The following adverse reactions have been identified during post approval use of celecoxib.

Blood and lymphatic system disorders.

Agranulocytosis, aplastic anaemia, pancytopenia, leukopenia.

Eye disorders.

Retinal artery or vein occlusion.

Hepatobiliary disorders.

Hepatic necrosis, hepatitis, jaundice, hepatic failure, hepatitis fulminant, cholestasis, hepatitis cholestatic, liver transplant, hepatic enzyme increased (sometimes fatal or requiring liver transplant).

Immune system disorders.

Anaphylactic reaction.

Metabolism and nutrition disorders.

Hypoglycemia, hyponatraemia.

Musculoskeletal and connective tissue disorders.

Myositis.

Nervous system disorders.

Ageusia, anosmia, intracranial haemorrhage (including fatal intracranial haemorrhage), cerebral haemorrhage.

Pregnancy, puerperium and perinatal conditions.

Oligohydramnios, neonatal renal impairment.

Psychiatric.

Hallucination.

Renal and urinary disorders.

Tubulointerstitial nephritis, nephrotic syndrome, glomerulonephritis minimal lesion.

Respiratory, thoracic and mediastinal disorders.

Pneumonitis.

Reproductive system and breast disorders.

Menstrual disorders, infertility female (female fertility decreased).

Skin and subcutaneous tissue disorders.

Angioedema, photosensitivity reaction, erythema multiforme, dermatitis exfoliative, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalised exanthematous pustulosis (AGEP), dermatitis bullous.

Vascular disorders.

Vasculitis.

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 http://www.tga.gov.au/reporting-problems.

4.9 Overdose

Clinical experience of overdose is limited. No overdoses of celecoxib were reported during clinical trials. Doses up to 2400 mg/day for up to 10 days in 12 patients did not result in serious toxicity.

Signs and symptoms.

Symptoms following acute NSAID overdoses are usually limited to lethargy, drowsiness, nausea, vomiting, epigastric pain and other gastrointestinal adverse 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.
Consider activated charcoal in the event of a potentially toxic ingestion. Activated charcoal is most effective when administered within one or two hours of ingestion and may reduce absorption of the drug. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via a nasogastric tube, once the airway is protected.
No information is available regarding the removal of celecoxib by haemodialysis, but based on its high degree of plasma protein binding (> 97%) dialysis is unlikely to be useful in overdose. Forced diuresis, alkalinisation of urine, haemodialysis, or haemoperfusion may not be useful due to high protein binding.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Celecoxib is chemically unrelated to anti-inflammatory agents of steroidal or non-steroidal nature.
Pharmacotherapeutic group: M01AH Coxibs.

Mechanism of action.

Celecoxib is a cyclooxygenase-2 (COX-2) specific inhibitor, a member of a larger class of nonsteroidal anti-inflammatory drugs that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of celecoxib is believed to be due to inhibition of prostaglandin synthesis, primarily by inhibition of COX-2. At therapeutic concentrations in humans celecoxib does not inhibit cyclooxygenase-1 (COX-1). COX-2 is induced in response to inflammatory stimuli. This leads to the synthesis and accumulation of inflammatory prostanoids, in particular prostaglandin E2, causing inflammation, oedema and pain. In animal models, celecoxib acts as an anti-inflammatory, analgesic, and antipyretic agent by blocking the production of inflammatory prostanoids via COX-2 inhibition. In animal colon tumour models, celecoxib reduced the incidence and multiplicity of tumours.
In vivo and ex vivo studies show that celecoxib has a very low affinity for the constitutively expressed COX-1 enzyme. Consequently at therapeutic doses celecoxib has no effect on prostanoids synthesised by activation of COX-1 thereby not interfering with normal COX-1 related physiological processes in tissues, particularly the stomach, intestine and platelets.

Clinical trials.

Osteoarthritis (OA).

Celecoxib has demonstrated significant reduction in joint pain compared to placebo. Celecoxib was evaluated for treatment of the signs and the symptoms of OA of the knee and hip in approximately 4,200 patients in placebo and active controlled clinical trials of up to 12 weeks duration. In patients with OA, treatment with celecoxib 100 mg BD or 200 mg once daily resulted in improvement in WOMAC (Western Ontario and McMaster Universities) osteoarthritis index, a composite of pain, stiffness, and functional measures in OA. In three 12 week studies of pain accompanying OA flare, celecoxib doses of 100 mg BD and 200 mg BD provided significant reduction of pain within 24-48 hours of initiation of dosing. At doses of 100 mg BD or 200 mg BD the efficacy of celecoxib was shown to be similar to that of naproxen 500 mg BD. Doses of 200 mg BD provided no additional benefit above that seen with 100 mg BD. A total daily dose of 200 mg has been shown to be equally effective whether administered as 100 mg BD or 200 mg OD.

Rheumatoid arthritis (RA).

Celecoxib has demonstrated significant reduction in joint tenderness/pain and joint swelling compared to placebo. Celecoxib was evaluated for treatment of the signs and symptoms of RA in approximately 2,100 patients in placebo and active controlled clinical trials of up to 24 weeks in duration. Celecoxib was shown to be superior to placebo in these studies, using the ACR20 Responder Index, a composite of clinical, laboratory, and functional measures in RA. Celecoxib doses of 100 mg BD and 200 mg BD were similar in effectiveness and both were comparable to naproxen 500 mg BD.
Although celecoxib 100 mg BD and 200 mg BD provided similar overall effectiveness, some patients derived additional benefit from the 200 mg BD dose. Doses of 400 mg BD provided no additional benefit above that seen with 100-200 mg BD.

Ankylosing spondylitis (AS).

Celecoxib has been investigated in 896 patients in placebo and active (diclofenac, naproxen or ketoprofen) controlled clinical trials of 6 weeks (one trial) and 12 weeks (three trials) duration for the symptomatic treatment of AS. At doses of 100 mg twice daily (BD), 200 mg once daily (OD), and 400 mg once daily (OD), celecoxib was statistically superior to placebo for all measures of efficacy including global pain intensity, global disease activity and functional impairment. In two 12 week studies of celecoxib at 200 mg total daily dose and 400 mg total daily dose, noninferiority was demonstrated relative to diclofenac 150 mg total daily dose for global pain intensity.
Results for global pain intensity are presented in Table 4.

Dysmenorrhoea.

The analgesic efficacy of celecoxib 400 mg for the treatment of primary dysmenorrhoea has been established in replicate, single dose, controlled studies where the primary measures of efficacy were Summed Pain Intensity Difference for the first 8 hours (SPID8) and the sum of the pain relief scores for the first 8 hours (TOTPAR8). A secondary measure of efficacy was time to onset of analgesia. Naproxen sodium 550 mg was included in a third arm of these studies for comparison against placebo.
On the basis of the primary measures of efficacy, studies 129 and 130 show that celecoxib is significantly superior to placebo in the treatment of primary dysmenorrhoea. In study 129, the median time to onset of analgesia for celecoxib was significantly shorter than that observed for placebo. In study 130, the median time to onset of analgesia for celecoxib was shorter than that observed for placebo, but the difference was not significant. See Table 5.

Dental surgery.

The analgesic efficacy of celecoxib was demonstrated in five studies of patients with post oral surgery pain, a well validated pain model. In these studies 1,130 patients were evaluated including over 360 at single doses of 100 mg or 200 mg. These doses showed analgesic activity beginning by 45 minutes and continuing for approximately 8 hours.
In the placebo controlled comparative study with aspirin (650 mg), celecoxib 100 mg provided statistically significant pain relief and reduction in pain intensity compared to placebo. Although time to onset of pain relief was 0.6 hours for aspirin and 1.0 hour for celecoxib, a greater proportion of the celecoxib group completed the study without rescue medication.
Four further single dose studies compared celecoxib with placebo and either ibuprofen (400 mg) or naproxen sodium (550 mg). All active agents were statistically superior to placebo. Median time to onset of perceptible pain relief with celecoxib 100 mg was 45 and 39 mins; celecoxib 200 mg 38, 30, 44 and 40 mins; ibuprofen 33 and 28 mins, naproxen sodium 24 and 36 mins.

Postsurgery.

The efficacy of celecoxib for use in acute pain postsurgery has been demonstrated in three pivotal studies; all were randomised, double blind and placebo controlled trials. Two of the studies had a duration of 3 days and the third study was for 5 days postoperative. All three studies used an 11 point score for pain analysis.
The first study was conducted in 120 patients undergoing major plastic surgery, e.g. breast augmentation, abdominoplasty procedure. The patients received celecoxib either as an initial 400 mg postoperative dose, then 200 mg BD for 3 days (40 patients) or 400 mg 30-90 mins before surgery then 200 mg BD for 3 days; the remaining 40 patients received placebo. The primary variable opioid analgesia use was significantly less in the postoperative and perioperative groups compared to the placebo group for the 3 postoperative days (18 and 23 mg vs. 68 mg; 5 and 13 mg vs. 40 mg; 3 and 3 mg vs. 32 mg respectively, p < 0.05) as were the average pain scores. As a result, pain scores were relatively low with the greatest difference (approximately 1.75) being at 4 h and 24 h.
The second study was conducted in 77 patients undergoing laparoscopic surgery. The patients received either placebo (38) or 400 mg/day celecoxib (39) administered initially in the recovery room and then continued as 200 mg BD for 3 days postsurgery. The primary variable was the times to resume normal dietary (3 ± 2 vs. 2 ± 2 days), bowel (3 ± 2 vs. 2 ± 1 days) and physical activities (6 ± 3 vs. 4 ± 2 days); these latter two were significantly and clinically different. The effects on pain management were assessed by pain score and rescue analgesia requirements. The pain scores on the first, second and third days were significantly lower in the celecoxib group vs. placebo (differences at 24, 48 and 72 h = 2, 2 and 1). The corresponding percentages of patients requiring rescue analgesia were similarly significantly lower (21, 15, 12% vs. 30, 29, 27% at 24, 48 and 72 h).
The third study was conducted to evaluate the management of pain after tonsillectomy. Thirty nine patients received celecoxib 200 mg, 39 received placebo and 37 received ketoprofen 100 mg. This was initially preoperative and then BD for 5 days and then as required. The primary outcome parameter was the consumption of rescue analgesic during the first 24 h after surgery. All patients in the celecoxib group, 32 of 37 (86%) in the ketoprofen group (p = 0.024, celecoxib vs. ketoprofen) and 37 of 39 (95%) in the placebo group were provided oxycodone for rescue analgesia during the first 4 h after surgery. In the celecoxib group, the time to first dose of rescue analgesia was significantly shorter than in the ketoprofen group (p = 0.039). All patients were provided rescue analgesia during the first 24 h after surgery. The total number of oxycodone doses was 215 (mean 5 [range 2-14]) in the celecoxib group, 179 (5 [1-9]) doses in the ketoprofen group and 230 (6 [1-13]) doses in the placebo patients (p = 0.021, placebo vs. ketoprofen).

Musculoskeletal pain.

The efficacy of celecoxib was demonstrated in five studies in patients with musculoskeletal pain, including ankle sprain and low back pain. In these studies over 1,822 patients were evaluated.
Four studies in ankle sprain demonstrated celecoxib 200 mg BD to be noninferior to a variety of active comparators (naproxen, ibuprofen or diclofenac) in the treatment of acute ankle sprains in all primary measures and in most secondary measures, with one instance of inferiority to the active comparator (Physician's Global Assessment of Ankle Injury, day 4).
Finally in a further study in low back pain, the celecoxib treatment was observed to be as effective as diclofenac.

Celecoxib long-term arthritis safety study (CLASS).

Study design.

A prospective 12 month study was conducted in approximately 5,800 OA patients and 2,200 RA patients. The primary endpoint of this outcome study was the incidence of complicated ulcers (gastrointestinal bleeding, perforation or obstruction) in celecoxib treated patients compared to each comparator. Patients received celecoxib 400 mg BD (4-fold and 2-fold greater than the recommended OA and RA doses, respectively), ibuprofen 800 mg TDS (approved maintenance dose is 1600 mg daily) or diclofenac 75 mg BD (approved maintenance dose is 75-100 mg daily) for a median exposure of 9 months for celecoxib and diclofenac, and 6 months for ibuprofen. Patients were allowed to take concomitant low dose aspirin ≤ 325 mg mostly for cardiovascular prophylaxis.

Study results.

No statistically significant differences were demonstrated for the incidence of complicated ulcers among the three treatment groups in all patients. In an additional nonprotocol specified analysis, there was no difference in the incidence of complicated and symptomatic ulcers in patients on celecoxib vs. those on diclofenac, although the incidence was significantly lower for celecoxib than for ibuprofen in all patients, and in those patients not taking aspirin (ASA) (Figure 1). Approximately 22% of patients were taking low dose aspirin. Concomitant low dose aspirin use increased the risk of complicated and symptomatic ulcers on celecoxib, diclofenac and ibuprofen (see Section 5.1 Pharmacodynamic Properties, Clinical trials, Use with aspirin). The incidence rates for diclofenac may be underestimated because of a higher incidence of early withdrawals due to GI adverse events than celecoxib and ibuprofen.
Celecoxib (4-fold and 2-fold greater than the recommended OA and RA doses, respectively) was also associated with a significantly lower incidence of clinically relevant decreases in haemoglobin (> 20 g/L) or haematocrit (≥ 10 points) than ibuprofen and diclofenac regardless of aspirin use (Figure 2).
The incidence of clinically relevant decreases in haemoglobin and haematocrit in celecoxib patients taking aspirin was lower than in ibuprofen and diclofenac patients taking aspirin.
In the original registration studies, the incidence of serious upper gastrointestinal complications (bleeding, perforation, gastric outlet obstruction) with celecoxib is not significantly different from placebo and is approximately 8-fold less than with nonspecific COX inhibitors.

Endoscopic studies.

Scheduled upper GI endoscopic evaluations were performed in over 4,500 arthritis patients who were enrolled in five controlled randomised 12-24 week trials using active comparators, two of which also included placebo controls. Twelve week endoscopic ulcer data are available on approximately 1,400 patients and 24 week endoscopic ulcer data are available on 184 patients on celecoxib at doses ranging from 50-400 mg BD. In all three studies that included naproxen 500 mg BD, and in the study that included ibuprofen 800 mg TDS, celecoxib was associated with a statistically significantly lower incidence of endoscopic ulcers over the study period. Two studies compared celecoxib with diclofenac 75 mg BD; one study revealed a statistically significantly higher prevalence of endoscopic ulcers in the diclofenac group at the study endpoint (6 months on treatment), and one study revealed no statistically significant difference between cumulative endoscopic ulcer incidence rates in the diclofenac and celecoxib groups after 1, 2, and 3 months of treatment. There was no consistent relationship between the incidence of gastroduodenal ulcers and the dose of celecoxib over the range studied.
Figure 3 and Table 6 summarise the incidence of endoscopic ulcers in two 12 week studies that enrolled patients in whom baseline endoscopies revealed no ulcers.
Figure 4 and Table 7 summarise data from two 12 week studies that enrolled patients in whom baseline endoscopies revealed no ulcers. Patients underwent interval endoscopies every 4 weeks to give information on ulcer risk over time.
One randomised and double blinded 6 month study in 430 RA patients was conducted in which an endoscopic examination was performed at 6 months. The results are shown in Figure 5.
The correlation between findings of endoscopic studies, and the relative incidence of clinically serious upper GI events that may be observed with different products, has not been fully established.
Serious clinically significant upper GI bleeding has been observed in patients receiving celecoxib in controlled and open labelled trials, albeit infrequently. Patients most at risk of developing an ulcer complication were the elderly (≥ 75 years), patients in poor health or with cardiovascular disease, aspirin users and patients with a history of a GI ulcer or upper GI bleeding.

Use with aspirin.

Approximately 11% of patients (440/4,000) enrolled in 4 of the 5 endoscopic studies were taking aspirin (≤ 325 mg/day). In the celecoxib groups, the endoscopic ulcer rate appeared to be higher in aspirin users than in nonusers. However, the increased rate of ulcers in these aspirin users was less than the endoscopic ulcer rates observed in the active comparator groups, with or without aspirin.
In the Celecoxib Long-term Arthritis Safety Study, approximately 22% of patients were taking aspirin (≤ 325 mg/day). Subjects on concomitant low dose aspirin experienced 4-fold higher rates of complicated and symptomatic ulcers on celecoxib.

Platelet function.

In healthy volunteers, celecoxib, at multiple doses of 600 mg BD (three times the highest recommended therapeutic dose) had no effect on platelet aggregation and bleeding time compared to placebo. Active controls (nonspecific COX inhibitors i.e. naproxen, diclofenac, ibuprofen) all significantly reduced platelet aggregation and prolonged bleeding time (see Figures 6 and 7).
Because of its lack of platelet effects, celecoxib is not a substitute for aspirin for cardiovascular prophylaxis.

Cardiovascular safety, long-term studies involving patients with sporadic adenomatous polyps.

Two studies involving patients with sporadic adenomatous polyps were conducted with celecoxib i.e. the APC trial (Adenoma Prevention with Celecoxib) and the PreSAP trial (Prevention of Spontaneous Adenomatous Polyps). In the APC trial, there was a dose related increase in the composite endpoint of cardiovascular death, myocardial infarction, or stroke (adjudicated) with celecoxib compared to placebo over 3 years of treatment. The PreSAP trial did not demonstrate a statistically significant increased risk for the same composite endpoint.
In the APC trial, the hazard ratios compared to placebo for a composite endpoint of cardiovascular death, myocardial infarction, or stroke (adjudicated) were 3.4 (95% CI 1.4-8.5) with celecoxib 400 mg twice daily and 2.8 (95% CI 1.1-7.2) with celecoxib 200 mg twice daily (cumulative rates for this composite endpoint over 3 years were 20/671 subjects, 3.0%, and 17/685 subjects, 2.5%, respectively, compared to 6/679 subjects, 0.9%, for placebo). The increases for both celecoxib dose groups versus placebo were mainly driven by myocardial infarction.
In the PreSAP trial, the hazard ratio compared to placebo for this same composite endpoint was 1.2 (95% CI 0.6-2.4) with celecoxib 400 mg once daily (cumulative rates for this composite endpoint over 3 years were 21/933 subjects, 2.3%, compared to 12/628 subjects, 1.9%, for placebo).
When data from the APC and PreSAP trials were considered together, risk for cardiovascular thromboembolic events was greater in celecoxib treated patients with a history of atherosclerotic cardiovascular disease, than in celecoxib treated patients without such history.

Cardiovascular safety, long-term study of Alzheimer's disease anti-inflammatory prevention trial (ADAPT).

Data from a third long-term study, ADAPT (The Alzheimer's Disease Anti-inflammatory Prevention Trial), did not show a significantly increased cardiovascular risk with celecoxib 200 mg BD compared to placebo. The relative risk compared to placebo for a similar composite endpoint (CV death, MI, stroke) was 1.14 (95% CI 0.61-2.12) with celecoxib 200 mg twice daily. The incidence of myocardial infarction was 1.1% (8/717 patients) with celecoxib 200 mg twice daily and 1.2% (13/1070 patients) with placebo.

Cardiovascular safety, celecoxib long-term arthritis safety study (CLASS).

Cardiovascular safety outcomes were evaluated in CLASS (see Section 5.1 Pharmacodynamic Properties, Clinical trials for description of trial). Kaplan-Meier cumulative rates for investigator reported serious cardiovascular thromboembolic adverse events (including MI, pulmonary embolism, deep venous thrombosis, unstable angina, transient ischaemic attacks and ischaemic cerebrovascular accidents) demonstrated no differences between the celecoxib, diclofenac or ibuprofen treatment groups. The cumulative rates in all patients at nine months for celecoxib, diclofenac and ibuprofen were 1.2%, 1.4% and 1.1%, respectively. The cumulative rates in nonaspirin users at nine months in each of the three treatment groups were less than 1%. The cumulative rates for myocardial infarction in the nonaspirin users at nine months in each of the three treatment groups were less than 0.2%. There was no placebo group in the CLASS trial, which limits the ability to determine whether the three drugs tested had no increased risk of CV events or if they all increased risk to a similar degree.
Two large, controlled, clinical trials of a different COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see Section 4.3 Contraindications).

5.2 Pharmacokinetic Properties

Absorption.

When celecoxib is given under fasting conditions, peak plasma concentrations are reached after approximately 2-3 hours. Intersubject variability in the Cmax and AUC is about 30%. Under fasting conditions, both peak plasma levels (Cmax) and area under the curve (AUC) are roughly dose proportional up to 200 mg BD; at higher doses there are less than proportional increases in Cmax and AUC (see Food effects). Absolute bioavailability studies have not been conducted because of celecoxib's low solubility in aqueous media. The relative oral bioavailability of celecoxib capsules compared with a suspension is about 99%. With multiple dosing, steady state conditions are reached on or before day 5.

Food effects.

When celecoxib capsules were taken with a high fat meal, peak plasma levels were delayed for about 1 to 2 hours with an increase in total absorption (AUC) of 10% to 20%. Under fasting conditions, at doses above 200 mg, there is less than a proportional increase in Cmax and AUC, which is thought to be due to the low solubility of the drug in aqueous media. Celecoxib, at doses up to 200 mg BD can be administered without regard to the timing of meals. When multiple total daily doses of celecoxib as high as 1200 mg were given with food, an improved correlation between the dose and AUC(0-12) was observed.
Coadministration of celecoxib with an aluminium and magnesium containing antacid resulted in a reduction in plasma celecoxib concentrations with a decrease of 37% in Cmax and 10% in AUC.

Distribution.

In healthy subjects, celecoxib is highly protein bound (~ 97%) within the therapeutic dose range. In vitro studies indicate that it binds primarily to albumin, and to a lesser extent, α1 glycoprotein. The apparent volume of distribution at steady state is about 400 L in healthy young adults, suggesting extensive tissue distribution.

Metabolism.

Celecoxib is extensively metabolised in the liver. In vitro and in vivo studies indicate that metabolism is mainly by cytochrome P450 CYP 2C9 (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Three metabolites have been identified in human plasma, a primary alcohol, the corresponding carboxylic acid and its glucuronide conjugate. Pharmacological activity resides in the parent drug. The main metabolites found in human plasma have no detectable COX-1 or COX-2 inhibitory activity.
Cytochrome P450 2C9 activity is reduced in individuals with genetic polymorphisms that lead to reduced enzyme activity, such as those homozygous for the CYP 2C9*3 polymorphism.
Patients who are known or suspected to be poor P450 2C9 metabolisers based on previous history should be administered celecoxib with caution as they may have abnormally high plasma concentrations due to reduced metabolic clearance. Consider starting treatment at a reduced dose (see Section 4.2 Dose and Method of Administration; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Excretion.

Elimination of celecoxib is mostly by hepatic metabolism with less than 1% of the dose being excreted unchanged in the urine. Following a single oral dose of radiolabelled drug, approximately 57% of the dose was excreted in the faeces and 27% was excreted into the urine. The primary metabolite in both the urine and faeces was the carboxylic acid metabolite (73% of the dose) with low amounts of the glucuronide also appearing in the urine. At steady state, the elimination half-life (t1/2) was 4-15 hours and the clearance was about 500 mL/min. It appears that the low solubility of the drug prolongs absorption resulting in variable terminal half-life (t1/2) determinations.

Special populations.

Hepatic impairment.

A pharmacokinetic study in subjects with mild (Child-Pugh class I) and moderate (Child-Pugh class II) hepatic impairment has shown that steady state celecoxib AUC is increased about 40% and 180%, respectively, above that seen in healthy control subjects. Therefore, celecoxib capsules should be introduced at half the recommended dose in arthritis patients with moderate hepatic impairment.
Patients with severe hepatic impairment have not been studied. Therefore, the use of celecoxib in patients with severe hepatic impairment (Child-Pugh score ≥ 10) is contraindicated (see Section 4.3 Contraindications; Section 4.2 Dose and Method of Administration).

Renal impairment.

In elderly volunteers with age related reductions in glomerular filtration rate (GFR) (mean GFR > 65 mL/min/1.73 m2) and in patients with chronic stable renal insufficiency (GFR 35-60 mL/min/1.73 m2) celecoxib pharmacokinetics were comparable to those seen in patients with normal renal function. No significant relationship was found between serum creatinine (or creatinine clearance) and celecoxib clearance. Severe renal insufficiency would not be expected to alter clearance of celecoxib since the main route of elimination is via hepatic metabolism to inactive metabolites. There are no studies in patients with severe renal impairment.

Elderly subjects.

At steady state, subjects older than 65 years of age had a 40% higher Cmax and a 50% higher AUC than those of younger subjects. In elderly females, the Cmax and AUC were higher than those for elderly males predominantly due to the lower bodyweight of the females. No dosage adjustment in the elderly is generally necessary. However, for elderly patients with a bodyweight of less than 50 kg treatment should be initiated at the lowest recommended dose.

Children and adolescents.

Celecoxib is not approved for use in patients under 18 years of age.

Race.

Meta-analysis of pharmacokinetic studies has suggested an approximately 40% higher AUC of celecoxib in Blacks compared to Caucasians. The cause and clinical significance of this finding is unknown.

5.3 Preclinical Safety Data

Genotoxicity.

Celecoxib was not mutagenic in the Ames test and a mutation assay in Chinese hamster ovary (CHO) cells, nor clastogenic in a chromosome aberration assay in CHO cells and in vivo micronucleus test in rat bone marrow.

Carcinogenicity.

Celecoxib was not carcinogenic in 2 year studies in rats given oral doses up to 200 mg/kg/day for males and 10 mg/kg/day for females (approximately 2-4 fold the human exposure as measured by the AUC0-24 h at 400 mg BD, which is twice the recommended maximum daily dose), or in mice given dietary doses up to 25 mg/kg/day for males and 50 mg/kg/day for females (slightly less than human exposure at 400 mg BD).

6 Pharmaceutical Particulars

6.1 List of Excipients

Celecoxib Sandoz 100 mg and 200 mg capsules contain the inactive (excipients) ingredients lactose monohydrate, sodium lauryl sulfate, carrageenan, cellulose - microcrystalline, silica - colloidal anhydrous, talc - purified and magnesium stearate. The capsule shells contain gelatin, titanium dioxide and the inks contain: indigo carmine (100 mg capsule); iron oxide yellow and iron oxide red (200 mg capsule).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
For information on interactions with other medicines and other forms of interactions, see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

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.

6.5 Nature and Contents of Container

Celecoxib Sandoz 100 mg capsules are available in Al/PVC/TE/PVDC blister pack of 60 capsules.
Celecoxib Sandoz 200 mg capsules are available in Al/PVC/TE/PVDC blisters pack of 30 capsules.
Not all strengths or presentations may be available in Australia.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Celecoxib is weakly acidic with a pKa in water of 11.1 and is practically insoluble in water. Celecoxib does not contain a chiral centre. Celecoxib is white or almost white, crystalline amorphous powder.
Celecoxib is practically insoluble in water, freely soluble in anhydrous ethanol and soluble in methylene chloride.

Chemical structure.

Celecoxib is a diaryl substituted pyrazole and has the following chemical structure:
Chemical name: 4-[5-(4-methylphenyl)- 3-(trifluoromethyl)-1H-pyrazol-1-yl] benzenesulfonamide.
Molecular formula: C17H14F3N3O2S.
Molecular weight: 381.38.

CAS number.

169590-42-5.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes