Adult: Naproxen 375 mg and esomeprazole 20 mg modified-release tab Naproxen 500 mg and esomeprazole 20 mg modified-release tab
For patients at risk of developing NSAID-associated gastric and/or duodenal ulcers: 1 tab bid. Use the lowest effective dose for the shortest possible duration.
Oral Juvenile idiopathic arthritis
Child: For patients at risk of developing NSAID-associated gastric ulcers: Naproxen 375 mg and esomeprazole 20 mg modified-release tab ≥12 years Patient weighing 38-<50 kg: 1 tab bid. Use the lowest effective dose for the shortest possible duration.
Naproxen 375 mg and esomeprazole 20 mg modified-release tab Naproxen 500 mg and esomeprazole 20 mg modified-release tab ≥12 years Patient weighing ≥50 kg: 1 tab bid. Use the lowest effective dose for the shortest possible duration. Treatment recommendations may vary between countries and among individual products (refer to specific product guidelines).
Special Patient Group
Pharmacogenomics:
Esomeprazole
Esomeprazole is metabolised primarily by CYP2C19, a polymorphic enzyme, and to a lesser extent by CYP3A4 isoenzyme. Individuals who lack a functional CYP2C19 isoenzyme are called poor metabolisers. Approx 3% of Caucasians and 15-20% of Asians are CYP2C19 poor metabolisers. Product labelling of esomeprazole notes that these individuals possibly metabolise esomeprazole primarily by CYP3A4 isoenzyme and may have higher exposure as compared to extensive metabolisers. However, this change in exposure has no implications in the dosage of esomeprazole; no changes in esomeprazole therapy are recommended on CYP2C19 poor metabolisers.
Renal Impairment
CrCl (mL/min)
Dosage
<30
Contraindicated.
Hepatic Impairment
Mild to moderate: Dose reduction on the naproxen component may be considered. Severe: Contraindicated.
Administration
Esomeprazole + Naproxen modified-release tab: Should be taken on an empty stomach. Take at least 30 min prior to food intake. Swallow whole, do not split/chew/crush.
Contraindications
Hypersensitivity to naproxen, esomeprazole or other substituted benzimidazoles. History of asthma, urticaria, or allergic-type reactions after receiving aspirin or other NSAIDs. Active peptic ulceration; active gastrointestinal bleeding, cerebrovascular bleeding or other bleeding disorders; severe heart failure. Use in the setting of CABG surgery. Severe renal (CrCl <30 mL/min) and hepatic impairment. Pregnancy (3rd trimester). Concomitant use with rilpivirine-containing products, atazanavir and nelfinavir.
Special Precautions
Patient with mild to moderate CHF, uncontrolled hypertension, established ischaemic heart disease, risk factors for CV disease (e.g. diabetes mellitus, hyperlipidaemia, smoking), peripheral arterial disease, cerebrovascular disease; coagulation disorders; history of gastrointestinal bleeding or gastrointestinal diseases (e.g. peptic ulcer disease, ulcerative colitis, Crohn's disease); SLE, mixed connective tissue disorder; hypovolaemia, dehydration, oedema, salt depletion; pre-existing asthma (without known aspirin sensitivity); reduced body stores or risk factors for reduced vitamin B12 absorption. Not recommended for initial treatment of acute pain. May mask fever and other signs of inflammation which may lead to diminished diagnostic detection of infections. Debilitated patients or those at risk of osteoporosis. Patients receiving corticosteroids, anticoagulants, antiplatelet agents, and SSRIs. Mild to moderate renal and hepatic impairment. Children and elderly. Pregnancy (1st-2nd trimester) and lactation.
Adverse Reactions
Significant: Hypertension, hyperkalaemia; increased risk of Clostridioides difficile-associated diarrhoea or other gastrointestinal infections (e.g. Salmonella, Campylobacter); cutaneous lupus erythematosus, SLE; decreased platelet aggregation, prolonged bleeding time, anaemia; Na and fluid retention, oedema, acute tubulointerstitial nephritis, renal papillary necrosis and other renal injury (prolonged use); elevations of transaminases, vitamin B12 deficiency (long-term use); bone fractures (particularly with high doses and prolonged use); fundic gland polyps (particularly with prolonged use). Rarely, increased risk of aseptic meningitis (particularly in patients with SLE or mixed connective tissue disorders); severe blood dyscrasias (e.g. aplastic anaemia, agranulocytosis, thrombocytopenia); hypomagnesaemia (long-term use). Cardiac disorders: Palpitations. Ear and labyrinth disorders: Vertigo, tinnitus, hearing disturbances. Eye disorders: Visual disturbances. Gastrointestinal disorders: Dyspepsia, abdominal pain, diarrhoea, flatulence, oesophagitis, constipation, gastritis, nausea, vomiting, dysgeusia, diverticulitis, stomatitis. General disorders and administration site conditions: Fatigue, thirst. Musculoskeletal and connective tissue disorders: Arthralgia. Nervous system disorders: Headache, dizziness, drowsiness. Psychiatric disorders: Insomnia, depression. Renal and urinary disorders: UTI. Respiratory, thoracic and mediastinal disorders: Dsypnoea, URTI. Skin and subcutaneous tissue disorders: Rash, pruritus, ecchymoses, purpura, sweating. Potentially Fatal: Gastrointestinal inflammation, bleeding, ulceration or perforation; anaphylactic or anaphylactoid reactions, severe bronchospasm (particularly in patients with aspirin-sensitive asthma); serious CV thrombotic events (e.g. MI, stroke). Rarely, severe hepatic reactions (e.g. jaundice, fulminant hepatitis, hepatic necrosis, hepatic failure); severe cutaneous adverse reactions (e.g. exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, acute generalised exanthematous pustulosis).
This drug may cause dizziness, drowsiness or blurred vision, if affected, do not drive or operate machinery.
Monitoring Parameters
Monitor CBC, chemistry profile, and LFT (periodically); occult blood loss, blood pressure; renal function (particularly urine output, serum BUN and creatinine); serum Mg at baseline and periodically thereafter during prolonged use; serum Ca at baseline and periodically thereafter in patients with risk factors of hypocalcaemia (e.g. hypoparathyroidism). Perform ophthalmic exam periodically during prolonged treatment. Monitor for signs and symptoms of gastrointestinal ulceration or bleeding, hepatotoxicity, and serious skin reactions.
Overdosage
Symptoms: Naproxen: Dizziness, drowsiness, nausea, vomiting, abdominal discomfort, epigastric pain, indigestion, lethargy, transient alterations in liver function, hypoprothrombinaemia, metabolic acidosis, apnoea, renal dysfunction, disorientation, gastrointestinal bleeding, and anaphylactoid reactions. Rarely, hypertension, acute renal failure, respiratory depression, and coma. Management: Symptomatic and supportive treatment. If symptoms are present or in case of a large overdose, may induce emesis and/or administer activated charcoal or osmotic cathartic within 4 hours of ingestion.
Drug Interactions
May increase the serum levels and enhance the toxicity of methotrexate.
Naproxen: Increased risk of nephrotoxicity with tacrolimus and ciclosporin. May reduce the natriuretic effect of loop diuretics (e.g. furosemide) or thiazide diuretics. May diminish the antihypertensive effects of β-blockers (e.g. propranolol), ACE inhibitors and ARBs. May increase the plasma concentrations of lithium and digoxin. May potentiate the effects of oral anticoagulants (e.g. warfarin), heparin, and thrombocyte aggregation inhibitors. Increased serum levels with probenecid. Colestyramine may delay the absorption of naproxen.
Esomeprazole: May reduce the antiplatelet effect of clopidogrel. May increase the serum concentration of cilostazol or tacrolimus. May increase the trough plasma level of phenytoin. May increase the exposure of digoxin. May decrease the absorption of agents with gastric pH-dependent absorption (e.g. ketoconazole, itraconazole, posaconazole, erlotinib). Serum levels may be reduced with inducers of CYP2C19 and/or CYP3A4 (e.g. rifampicin). Increased exposure with combined CYP2C19 and CYP3A4 inhibitors (e.g. voriconazole). Potentially Fatal: Naproxen: Increased risk of gastrointestinal ulceration or bleeding with other NSAIDs, SSRIs, corticosteroids, anticoagulants (e.g. warfarin), aspirin or other antiplatelet agents.
Esomeprazole: May reduce the serum concentrations and efficacy of rilpivirine, atazanavir and nelfinavir which may lower their antiviral effects.
Food Interaction
Naproxen: Food significantly delays absorption and reduces peak plasma concentration.
Esomeprazole: Food significantly reduces the extent of absorption. Serum levels may be reduced with St. John's wort.
Lab Interference
Naproxen: May interfere with certain urinary assays of 5-hydroxyindoleacetic acid.
Esomeprazole: May increase serum chromogranin A levels which may lead to false-positive results in diagnostic assessments for neuroendocrine tumours.
Action
Description: Mechanism of Action: Naproxen, a propionic acid derivative, is an NSAID that exhibits anti-inflammatory, analgesic and antipyretic actions. It reversibly inhibits the cyclooxygenase-1 and 2 (COX-1 and 2) enzymes, thereby resulting in reduced formation of prostaglandin precursors.
Esomeprazole, the S-isomer of omeprazole, is a substituted benzimidazole proton pump inhibitor (PPI) that reduces gastric acid secretion by inhibiting the H+/K+-ATPase enzyme in the gastric parietal cells. Pharmacokinetics: Absorption: Naproxen: Readily and completely absorbed from the gastrointestinal tract. Food significantly delays absorption and reduces peak plasma concentration. Bioavailability: 95%. Time to peak plasma concentration: Approx 2-4 hours.
Esomeprazole: Rapidly absorbed. Food significantly reduces the extent of absorption. Bioavailability: Approx 68% (for 20 mg doses). Time to peak plasma concentration: Approx 1-2 hours. Distribution: Naproxen: Diffuses into synovial fluid. Crosses the placenta; enters breast milk (small amounts). Volume of distribution: 0.16 L/kg. Plasma protein binding: >99%, mainly to albumin.
Esomeprazole: Crosses the placenta and enters breast milk. Plasma protein binding: Approx 97%. Metabolism: Naproxen: Undergoes extensive metabolism in the liver by CYP2C9 and CYP1A2 into 6-O-desmethylnaproxen; naproxen and its metabolite are further metabolised into their respective acylglucuronide conjugated metabolites.
Esomeprazole: Extensively metabolised in the liver mainly by CYP2C19 into inactive hydroxy and desmethyl metabolites, and to a lesser extent by CYP3A4 into esomeprazole sulfone (main metabolite in plasma). Excretion: Naproxen: Via urine (approx 95% as unchanged drug and metabolites); faeces (<5%). Elimination half-life: Approx 9-15 hours.
Esomeprazole: Via urine (approx 80%, mainly as metabolites; <1% as unchanged drug); faeces (20%). Elimination half-life: Approx 1-1.5 hours.
Chemical Structure
Naproxen Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 156391, Naproxen. https://pubchem.ncbi.nlm.nih.gov/compound/Naproxen. Accessed June 25, 2024.
Esomeprazole Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 156391, Naproxen. https://pubchem.ncbi.nlm.nih.gov/compound/Naproxen. Accessed June 25, 2024.
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