What is the recommended dosing for Celebrex (celecoxib) in pediatric patients, particularly those with juvenile rheumatoid arthritis and/or impaired renal function, liver disease, or history of gastrointestinal bleeding?

Celebrex (Celecoxib) Dosing in Pediatric Patients

Recommended Dosing for Juvenile Rheumatoid Arthritis

For pediatric patients aged 2 years and older with JRA, celecoxib dosing is weight-based: 50 mg twice daily for patients weighing 10-25 kg, and 100 mg twice daily for patients weighing >25 kg. 1

Weight-Based Dosing Algorithm

• Patients ≥10 kg to ≤25 kg: 50 mg twice daily 1
• Patients >25 kg: 100 mg twice daily 1
• Maximum dose: Not to exceed the weight-appropriate dose listed above 1

Administration Considerations

• Celecoxib can be given without regard to timing of meals 1
• For patients with difficulty swallowing capsules: Empty the entire capsule contents onto a level teaspoon of cool or room temperature applesauce and ingest immediately with water 1
• The sprinkled capsule contents on applesauce remain stable for up to 6 hours under refrigerated conditions (2°C to 8°C) 1

Special Populations Requiring Dose Adjustment

Poor CYP2C9 Metabolizers

Alternative treatments should be considered for pediatric JRA patients who are known or suspected to be poor CYP2C9 metabolizers (such as those homozygous for CYP2C9*3/*3), as these patients may experience 3- to 7-fold higher systemic drug levels. 1

• Poor metabolizers have significantly reduced enzyme activity and impaired celecoxib clearance 1
• The frequency of homozygous *3/*3 genotype is estimated at 0.3% to 1.0% in various ethnic groups 1
• If celecoxib must be used in poor metabolizers, initiate with half the lowest recommended dose, though alternative management is preferred 1

Hepatic Impairment

• Moderate hepatic impairment (Child-Pugh Class B): Reduce dose by 50% 1
• Severe hepatic impairment (Child-Pugh Class C): Celecoxib is not recommended 1
• Steady-state celecoxib AUC increases approximately 180% in moderate hepatic impairment 1

Renal Impairment

Celecoxib is not recommended in patients with severe renal insufficiency. 1

• Celecoxib AUC is approximately 40% lower in patients with chronic renal insufficiency (GFR 35-60 mL/min) 1
• Patients with severe renal insufficiency have not been studied 1
• Monitor for signs of renal dysfunction, as NSAIDs including celecoxib can cause acute renal failure 2

Critical Safety Considerations in Pediatric JRA

Systemic Onset JRA

Patients with systemic onset JRA require enhanced monitoring for coagulation abnormalities. 1

• Both celecoxib and naproxen have been associated with mild prolongation of activated partial thromboplastin time (APTT) in systemic onset JRA 1
• Monitor patients for signs and symptoms of abnormal clotting or bleeding due to risk of disseminated intravascular coagulation 1
• Patients with systemic onset JRA should have abnormal coagulation tests monitored regularly 1

Age and Weight Restrictions

• Celecoxib has not been studied in patients under 2 years of age 1
• Celecoxib has not been studied in patients with body weight less than 10 kg (22 lbs) 1
• Celecoxib has not been studied beyond 24 weeks in JRA patients 1
• Celecoxib has not been studied in patients with active systemic features of JRA 1

Gastrointestinal Risk Management

Concurrent NSAID Use

Avoid combining celecoxib with other NSAIDs, including low-dose aspirin, as this significantly increases gastrointestinal bleeding risk. 3

• Combined use of aspirin with an NSAID increases the relative risk of ulcer complications over 10-fold compared to non-users 3
• Concurrent use of more than one NSAID substantially increases risk of GI complications 3

Risk Factors for GI Complications

The most significant risk factors include 3:

• Prior peptic ulcer disease or prior ulcer complication (2-4 fold increased risk)
• Advancing age (approximately 4% increased risk per year)
• Concomitant use of corticosteroids or anticoagulants
• High doses or multiple NSAIDs

Protective Strategies

• COX-2 selective inhibitors like celecoxib have a better GI safety profile than nonselective NSAIDs 3
• In clinical trials, celecoxib was associated with significantly fewer upper GI complications than comparator NSAIDs 4
• Celecoxib had fewer symptomatic ulcers, endoscopically detected ulcers, and discontinuations for GI adverse events compared to NSAIDs 4

Concurrent Use with Methotrexate

NSAIDs including celecoxib can be given concurrently with low-dose methotrexate in children with normal renal function. 3

Monitoring Requirements

• NSAIDs can reduce renal elimination of methotrexate, leading to increased serum levels and potential toxicity 5
• COX-2 selective inhibitors like celecoxib appear to have less interaction with methotrexate than nonselective NSAIDs 5
• More frequent monitoring of liver function tests and renal function is recommended when methotrexate is used with NSAIDs 5

Practical Recommendations

• Use the lowest effective dose of celecoxib for the shortest duration possible when combined with methotrexate 5
• Patients should have a detailed medication history and review of potential interactions before starting methotrexate 5
• Elderly patients are at higher risk due to age-related decline in renal function 5

Role in JRA Treatment Algorithm

Initial Therapy

NSAIDs including celecoxib are conditionally recommended as adjunct therapy in pediatric JIA, but should not delay initiation of disease-modifying therapy. 3, 6

• For polyarticular JIA, initial therapy with a DMARD is strongly recommended over NSAID monotherapy 3, 6
• Methotrexate is the recommended first-line DMARD treatment 3, 6
• NSAID adjuvant therapy requires an adequate trial period of at least 8 weeks 3

NSAID Selection

Naproxen is the preferred NSAID over other selective COX-1 or COX-2 inhibitors due to its efficacy and safety profile in children, though celecoxib is an acceptable alternative. 3

• No evidence of superiority in efficacy or safety has been found between naproxen and other NSAIDs 3
• If naproxen is contraindicated or unavailable, alternative NSAIDs including celecoxib can be used based on FDA or EMA approval for pediatric use 3
• Celecoxib is FDA-approved for JRA in patients aged 2 years and older 1

Pharmacokinetic Considerations

Dose Rationale

The recommended weight-based dosing achieves plasma concentrations similar to those that demonstrated non-inferiority to naproxen 7.5 mg/kg twice daily in clinical trials. 1, 7

• Oral clearance of celecoxib increases less than proportionally to increasing weight 1, 7
• Patients weighing 10 kg and 25 kg have approximately 40% and 24% lower clearance, respectively, compared to a 70 kg adult 1, 7
• The effective half-life is approximately 11 hours under fasted conditions 1

Bioavailability

• Systemic exposures (AUC) are similar for the suspension, capsule sprinkles, and intact capsule formulations 1, 7
• The low solubility of celecoxib prolongs the absorption process 1
• Celecoxib is eliminated predominantly by hepatic metabolism with less than 3% unchanged drug recovered in urine and feces 1