Indications:¹

For the management of acute pain in adults and for the treatment of primary dysmenorrhea. Relief of the acute and chronic pain and inflammation of rheumatoid arthritis and osteoarthritis. Relief of signs and symptoms of ankylosing spondylitis. For the management of low back pain (100 mg and 200 mg only).

• Osteoarthritis
• Rheumatoid Arthritis
• Low Back Pain
• Primary Dysmenorrhea
• Ankylosing spondylitis
• Management of acute and chronic pain

Powerful control of pain and inflammation across many indications.^1,6,11

More favourable GI safety vs. numerous ns-NSAIDs.^2-4

Similar CV safety compared to naproxen or ibuprofen.⁵

GI: Gastrointestinal; CV: Cardiovascular; ns-NSAIDs: Non-Selective Non-Steroidal Anti-Inflammatory Drugs

Throughout 12 weeks of continuous use, CELEBREX^® demonstrated significant improvement in OA pain, physical function and joint stiffness, similar to naproxen⁶

 

Adapted from Bensen, et al.

P≤0.05 for CELEBREX ^® and naproxen vs. placebo at weeks 2 and 12.

To minimize the potential risk for an adverse GI or CV event in patients treated with NSAIDs, including CELEBREX^® , the lowest effective dose should be used for the shortest duration consistent with individual patient treatment goals.^1,10

CELEBREX^® also demonstrated powerful control of pain and inflammation in:^1,11

• Rheumatoid arthritis
• Ankylosing spondylitis
• Low back pain
• Acute pain

Consider CELEBREX^® to control pain and inflammation.¹

CV: Cardiovascular; GI: Gastrointestinal; NSAIDs: Non-Steroidal Anti-Inflammatory Drugs; OA: Osteoarthritis; WOMAC: Western Ontario and McMaster Universities

CELEBREX^® has a significant GI advantage:

Demonstrated reduced risk of GI events throughout the upper and lower GI tracts^2,3 vs. diclofenac + omeprazole^2*

CELEBREX^® is recommended by international guidelines

Consider CELEBREX^® for your arthritis patients at increased GI risk.^10,12-14

BID: Bis in Die (twice daily); QD: Quaque Die (once daily); EULAR: European League Against Rheumatism; GI: Gastrointestinal; ns-NSAIDs: Non-Selective Non-Steroidal Anti-Inflammatory Drugs; OA: Osteoarthritis; OARSI: Osteoarthritis Research Society International; COX-1: Cyclooxygenase-1; GI-REASONS: Gastrointestinal - Randomized Event and Safety Open-Label Nonsteroidal Anti-inflammatory Drug Study; SR: Sustained release.

* A double-blind, triple-dummy, parallel-group randomized trial.

† The most commonly prescribed ns-NSAIDs in GI-REASONS were meloxicam, naproxen, nabumetone, diclofenac, ibuprofen and etodolac.

‡ A prospective, randomized, open-label, blinded endpoint (PROBE).

§ Clinically significant anemia was defined in the protocol as a decrease in hemoglobin of 2 g/dL or more, or a decrease in hematocrit of at least 10 percentage points.

In the large PRECISION study, CELEBREX^®  demonstrated a similar incidence of CV events compared to naproxen or ibuprofen.^5* 

 

PRECISION TRIAL INTEGRITY

• PRECISION was governed by an independent executive committee composed of multidisciplinary specialists.¹⁵
• Members agreed to not accept honoraria, consulting fees, or other compensation related to NSAIDs during the course of the trial.¹⁵
• All safety endpoints have been independently reviewed and adjudicated in a prospective manner.¹⁵

APTC: Antiplatelet Trialists Collaboration; BID: Bid in Die (twice daily); CI: Confidence Interval; CV: Cardiovascular; HR: Hazard Ratio; NI: Non-Inferiority; NSAID: Non-Steroidal Anti-Inflammatory Drug; TID: Ter in Die (three times daily); PRECISION: Prospective Randomized Evaluation of Celecoxib Integrated Safety vs. Ibuprofen Or Naproxen

Disclaimer: ''Viatris does not promote the use of Celebrex in patients with established CVD. We believe the study results will enable physicians to make better informed decisions based on validated scientific research about treatment options for patients who require long term pain management''

Celecoxib capsules can be taken with or without food.

Acute pain and Primary dysmenorrhea: The recommended dose of Celecoxib is 400 mg, initially, followed by an additional 200 mg dose, if needed on the first day. On subsequent days, the recommended dose is 200 mg twice daily, as needed.

Ankylosing Spondylitis: 200 mg to 400 mg daily.

Osteoarthritis (OA): 200 mg once daily.

Rheumatoid arthritis (RA): 200 mg twice daily.

Low Back Pain (LBP): Usual dosage for adults is 200 mg of Celecoxib orally once daily.

Elderly: No dosage adjustment is necessary. However, for elderly patients with a lower-than-average body weight (<50kg), it is advisable to initiate therapy at the lowest recommended dose.

Hepatic impairment: Patients with severe hepatic impairment have not been studied (Child-Pugh Class C).

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.

• Patients with known hypersensitivity to celecoxib or any other ingredient of the product.
• Patients with known sulfonamide hypersensitivity.
• Patients who have experienced asthma, urticaria or allergic-type reactions after taking acetylsalicylic acid (ASA [aspirin]) or other nonsteroidal anti-inflammatory drugs (NSAIDs), including other cyclooxygenase-2 (COX-2) specific inhibitors.
• Treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (please refer next tab - Special warnings and precautions).
• Patients who have established CV disease (ischaemic heart disease and stroke).

ASA: Acetylsalicylic Acid; CABG: Coronary Artery Bypass Graft; NSAIDs: Non-steroidal Anti-Inflammatory Drug; COX-2: Cyclooxygenase-2

Cardiovascular effect: May increase risk of serious cardiovascular thrombotic events, myocardial infarction and stroke. The lowest effective dose should be used for the shortest duration possible. May lead to the onset of new hypertension or worsening of pre-existing hypertension and should be used with caution in patients with hypertension and monitor BP closely. Use with caution in patients with 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 hypovolemia.¹

Gastrointestinal effect: Upper and lower GI perforations, ulcers or bleeds have occurred in patients treated with celecoxib. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with Celecoxib. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, antiplatelet drugs (such as aspirin), anticoagulants; or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. The lowest effective dose should be used for the shortest duration possible.¹

Renal: Caution should be used in dehydrated patients. It is advisable to rehydrate patients before starting Celecoxib. Renal function should be closely monitored in patients with advanced renal disease who are administered Celecoxib.¹

Anaphylactoid Reactions: Refer to contraindication. Celecoxib should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.¹

Hepatic: Celecoxib should be used with caution when treating patients with moderate hepatic impairment (Child-Pugh Class B) and initiated at half the recommended dose. Patients with severe hepatic impairment (Child-Pugh Class C) have not been studied and Celecoxib is not recommended. Patient with symptoms and/or signs of liver dysfunction, or in whom an abnormal liver function test has occurred, should be monitored carefully for evidence of the development of a more severe hepatic reaction while on therapy with Celecoxib. Anticoagulation/INR should be monitored in patients taking a warfarin/ coumarin-type anticoagulant after initiating treatment with Celecoxib or changing the dose. The concomitant use of Celecoxib and a non-aspirin NSAID should be avoided. Serious skin reactions, some of them fatal, including drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), 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.¹

BP: Blood Pressure; GI: Gastrointestinal; INR: International Normalized Ratio; NSAID: Non-steroidal Anti-Inflammatory Drug

Bronchitis, sinusitis, upper respiratory tract infection, urinary tract infection, ear and fungal infection, insomnia, dizziness, hypertension (including aggravated hypertension), cough, vomiting, abdominal pain, diarrhoea, dysphagia, irritable bowel syndrome, GERD, nausea, diverticulum, dyspepsia, flatulence, pruritus (includes pruritus generalized), rash, oedema, peripheral edema, myocardial infarction, angina pectoris, dyspnoea, hepatic enzyme increased, muscle spasms, nephrolithiasis, vaginal haemorrhage, prostatitis, benign prostatic hyperplasia, blood creatinine increased, prostatic specific antigen increased, weight increased.¹

GERD: Gastroesophageal Reflux Disease

 

Prospective Randomized Evaluation of Celecoxib Integrated Safety vs Ibuprofen Or Naproxen

Study design:

A randomized, double-blind, parallel-group study evaluating the cardiovascular safety of CELEBREX^® vs. prescription strength naproxen and ibuprofen in 24,081 subjects with osteoarthritis or rheumatoid arthritis at high risk for, or with, established CVD who required daily NSAID treatment to maintain their quality of life.^1,2

Minimum follow-up

18 months¹

CV preventive management

At baseline approximately 46% of patients were taking low-dose aspirin (≤325 mg/day) for cardioprotection¹

Gastroprotection

All patients received open-label treatment with the proton pump inhibitor esomeprazole¹

CV safety:

Primary end Point

• First occurrence of the Antiplatelet Trialists Collaboration (ATPC) endpoint,
  which is a composite of :¹
• Death from cardiovascular causes, including hemorrhagic death
• Nonfatal myocardial infarction
• Nonfatal stroke

Celebrex ^® showed similar incidence of CV events compared to Naproxen and Ibuprofen¹

Gastrointestinal (GI) safety: Composite of secondary + tertiary endpoints

Occurrence of clinically significant GI events, which is composite of clinically significant iron deficiency anemia of GI origin and clinically significant GI events, which includes¹:

• Symptomatic gastric or duodenal ulcer
• Gastroduodenal, small-bowel or large-bowel perforation or hemorrhage
• Gastric outlet obstruction
• Acute GI hemorrhage of unknown origin

Celebrex ^® showed a significantly lower incidence of serious GI events vs. naproxen and ibuprofen.¹

Adapted from Nissen SE, et al.

Renal safety:

Tertiary endpoint

Occurrence of serious renal events, defined as development of any of the following:¹

• Verified serum creatinine level of ≥2.0 mg/dL and an increase of verified serum creatinine level of ≥0.7 mg/dL from baseline
• Hospitalization for acute renal failure
• Initiation of hemodialysis or peritoneal dialysis

Celebrex ^® showed a significantly lower incidence of renal events vs. ibuprofen and a similar incidence to naproxen.¹

Adapted from Nissen SE, et.al.

A landmark randomized controlled trial to prospectively examine the CV safety of Celebrex ^® in arthritis patients with, or at increased risk of CV disease.¹

Independent executive committee

PRECISION was governed by an executive committee composed of cardiology, gastroenterology, and rheumatology specialists.²

Measures to ensure academic integrity

Members of the executive committee agreed not to accept honoraria, consulting fees, or other compensation related to NSAIDs during the course of the trail.

All safety end points have been independently adjudicated.²

8 years in the making

PRECISION broadens our understanding of the risks associated with the use of three commonly prescribed NSAIDs in arthritis patients with or at increased risk for CV disease.^1,2

NSAID: Non-Steroidal Anti-Inflammatory Drug; BID: Bis in Die (twice daily); TID: Ter in Die (three times a day); CV: Cardiovascular; HR: Hazard ratio; CI: Confidence Interval; COX-2: Cyclooxygenase-2

Celebrex^® showed a significantly lower incidence of renal events vs. ibuprofen and naproxen.³

Time to event analysis for the primary composite outcome of cardiorenal events in intention-to-treat population.

A summary of the practice advisory on the appropriate use of NSAIDs in primary care:

Background

Cyclo-oxygenase (COX)-2 selective and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) are an important bridge between paracetamol and opioids, in the treatment of chronic pain secondary to inflammation. COX-2 selective NSAIDs were introduced with the aim of reducing gastrointestinal (GI) side effects associated with the use of nonselective NSAIDs. However, the market withdrawal of the COX-2 NSAID, rofecoxib due to cardiovascular (CV) safety issues, sparked concerns and triggered an attempt to determine if CV risk were indeed a class effect of coxibs.

Data has shown that COX-2 selective NSAIDs are not inferior to nonselective NSAIDs in terms of CV risk. In fact, in certain instances, nonselective NSAIDs have been associated with elevated CV risk compared with COX-2 selective NSAIDs. Recent data from the PRECISION trial have shown that the COX-2 selective NSAID, celecoxib, is noninferior to ibuprofen and naproxen in terms of CV safety; in addition to ibuprofen and naproxen being associated with greater GI and renal toxicity.

Aim of the practice advisory

To summarize current evidence on the use of NSAIDs, and provide updated guidance to primary care practitioners (PCPs) on prescription of oral NSAIDs, with an emphasis on CV, GI, and renal toxicity.

Methodology

A multidisciplinary group of clinicians came up with proposals for ten clinically relevant consensus statements to represent their clinical practice recommendations on NSAID use for Asian PCPs. The consensus process was conducted via a modified Delphi method, whereby agreement with a statement by 75% of total voting members was defined a priori as consensus.

Current evidence

Gastrointestinal risk

• The reduced impact of COX-2 selective NSAIDs on GI toxicity can be explained by the absence of dual COX inhibition rather than any COX-1 sparing effects.
• GI risk is increased with concomitant use of antiplatelet therapy, corticosteroids and selective serotonin reuptake inhibitors (SSRIs).
• Celecoxib reduced the incidence of GI adverse events among elderly arthritis patients compared with naproxen, ibuprofen or diclofenac.
• Celecoxib was associated with significantly lower risk of all clinically significant GI events throughout the entire GI tract.
• MEDAL program: Etoricoxib was associated with significantly fewer upper GI events than diclofenac. The difference was due to a reduction in uncomplicated events in the etoricoxib arm.
• CLASS study: Risk of upper GI ulceration was higher for standard doses of ibuprofen or diclofenac compared with celecoxib administered at doses greater than those indicated clinically.
• CONDOR trial: The risk of a clinically significant upper or lower GI event was lower in patients treated with a COX-2 selective NSAID compared with a nonselective NSAID plus PPI.
• H. Pylori eradication is equivalent to the administration of PPIs in the prevention of GI complications and may even be inferior.
• Appropriate assessment and regular monitoring are crucial in mitigating the risk of GI toxicity with NSAID use.

Cardiovascular risk

• Different COX-2 selective inhibitors and nonselective NSAIDs have different safety profiles.
• MEDAL program: Etoricoxib was associated with a similar risk of thrombotic events to diclofenac; at moderate doses, celecoxib exhibited similar CV safety to ibuprofen and naproxen.
• SCOT study: Switching to celecoxib resulted in a similar rate of CV events as continuing on prescribed nonselective NSAIDs in elderly patients (≥60 years of age) with osteoarthritis or rheumatoid arthritis without established CV disease and on chronic nonselective NSAIDs.
• PRECISION study: Overall CV risk was similar for ibuprofen, naproxen and celecoxib. Naproxen and ibuprofen had a significantly higher risk of a major toxicity in patients with symptomatic arthritis who had at least a moderate CV risk.
• Celecoxib may be associated with increased CV risk at dosages higher than recommended.

Renal risk

• Renal risk factors include older age, renal impairment, heart failure, liver disease, diabetes mellitus, and concurrent prescription of antihypertensive drugs (e.g., diuretics, renin angiotensin system inhibitors).
• MEDAL program: Etoricoxib had a greater risk of reno-vascular adverse events than diclofenac.
• PRECISION study: Risk of renal events were significantly lower with celecoxib compared with ibuprofen.
• A meta-analysis reported that NSAIDs with high COX-2 selectivity had a lower association with acute kidney injury (AKI) compared to NSAIDs with low COX-2 selectivity.
• NSAIDs have a low but tangible renal risk. Their role in progressive kidney disease is associated only with long-term use in high cumulative doses.
• Preventive strategies should be in place for patients with risk factors for renal impairment; such as, lowest effective NSAID dose for the shortest possible time, as well as monitoring of renal function, fluid retention and electrolyte abnormalities.

Practice advisory statement:

Screening for CV, GI, and renal risk factors prior to initiating NSAID therapy

Statement 1:

Prior to initiating NSAID therapy for a patient, the following factors must be taken into consideration. (Level of agreement: strongly agree, 86%; agree, 14%; consensus, 100%).

• Age, associated medical comorbidities, previous medical or surgical history, concomitant use of medications (particularly antiplatelet medications, anticoagulants, corticosteroids, angiotensin-converting enzyme (ACE) inhibitors, and SSRIs), H. Pylori infection, and blood pressure (BP) monitoring.

Statement 2:

Consider taking a baseline complete blood count and renal function test (if not previously available) in the following patients. (Level of agreement: strongly agree, 64%; agree, 36%; consensus, 100%).

• Patients with a history of renal impairment, congestive heart failure, elevated BP and/or type 2 diabetes mellitus, or the presence of unexplained anaemia.

Statement 3:

Use NSAIDs with caution in the following high-risk patients. (Level of agreement: strongly agree, 79%; agree, 21%; consensus, 100%).

• Patients at high GI risk:

  • More than 65 years of age, use of high-dose NSAIDs, history of peptic ulcer and related complications, and concurrent use of aspirin, anti-platelet therapy or anticoagulant therapy (especially those receiving double antiplatelet therapy).

• Patients at high CV risk:

  • History of acute coronary syndrome or percutaneous/surgical coronary revascularization, stable angina and angiographic evidence of significant coronary artery stenosis, a history of stroke/transient ischaemic attack, documented significant carotid artery stenosis, or congestive heart failure.

• Patients at high renal risk:

  • More than 75 years of age, impaired renal function based on estimated glomerular filtration rate <60 mL/min, and concomitant administration of an antihypertensive from any of the diuretic, ACE inhibitor, or angiotensin receptor blocker (ARB) classes.

  • If the risks of NSAID treatment outweigh its potential benefits, analgesics such as paracetamol, tramadol or codeine may be used in its place (upon consideration of efficacy, availability and potential adverse effects).

Choice of NSAIDs

Statement 4:

The choice of NSAID should depend on patient risk profile, pathophysiology of the pain condition, duration of therapy, and efficacy/side effects of the drug. (Level of agreement: strongly agree, 93%; agree, 7%; consensus, 100%).

Statement 5:

The lowest effective dose and for the shortest duration, consistent with treatment goals, remains the guiding principle. (Level of agreement: strongly agree, 100%; consensus, 100%).

Statement 6:

Current GI protective therapies are generally adequate for protection of the upper GI tract of NSAID users. (Level of agreement: strongly agree, 21%; agree, 57%; consensus, 78%).

• GI protective therapies (e.g., PPIs) benefit patients with moderate to high risk for upper GI complications.

Statement 7:

COX-2 selective NSAIDs are superior to nonselective NSAIDs for preventing both upper and lower GI tract adverse events. (Level of agreement: strongly agree, 43%; agree, 57%; consensus, 100%).

• Data from the CONDOR trial, the SUCCESS trial, and the MEDAL program reported that COX-2 selective NSAIDs are superior to nonselective NSAIDs in the prevention of GI adverse events.

Statement 8:

Both nonselective NSAIDs and COX-2 selective NSAIDs may increase renal adverse effects. (Level of agreement: strongly agree, 36%; agree, 64%; consensus, 100%).

• According to a meta-analysis, NSAIDs with high COX-2 selectivity (≥5-fold) had a lower association with AKI compared with those with lower COX-2 selectivity (<5-fold).
• Findings from PRECISION concluded a lower risk of renal events with celecoxib compared with ibuprofen.

Figure 1. Treatment algorithm for choice of NSAID in patients with different risk profiles.

Statement 9:

The treatment algorithm should consider the renal function, GI risk, and CV risk profile of the patient. (Level of agreement: strongly agree, 79%; agree, 21%; consensus, 100%).

• An updated treatment algorithm which supports recommended NSAID prescribing practices based on GI, CV and renal risk factors is shown in Figure 1.

Statement 10:

Regularly monitor for drug adverse events, including high blood pressure, and signs of GI bleeding. (Level of agreement: strongly agree, 79%; agree, 21%; consensus, 100%).

• BP to be measured at each visit, and laboratory tests should be conducted at least once yearly.

Conclusion

• This practice advisory serves to update previously published guidelines and offer PCPs a simplified approach to choosing an appropriate NSAID for pain management based on recent evidence and according to the risk profile of patients.
• Individual effects of each NSAID need to be considered for appropriate risk management, as the assignment of GI and CV risk according to COX-1 and COX-2 selectivity is too simplistic.
• There is an ongoing need for patient monitoring and risk assessment upon selection of an appropriate NSAID. 

MEDAL: Multinational Etoricoxib and Diclofenac Arthritis Long-Term Program; CLASS: Celecoxib Long-term Arthritis Safety Study; CONDOR: Celecoxib versus Omeprazole and Diclofenac in Patients with Osteoarthritis and Rheumatoid Arthritis; SCOT: The Standard Care versus Celecoxib Outcome Trial; PRECISION: Prospective Randomized Evaluation of Celecoxib Integrated Safety vs. Ibuprofen Or Naproxen; H. pylori: Helicobacter pylori; PPI: Proton-Pump Inhibitor