Naproben Plus

Approved Indications:

• Osteoarthritis: Relief of signs and symptoms in adults who require NSAID therapy with protection against NSAID-induced gastric ulceration.
• Rheumatoid Arthritis: Management of joint inflammation and pain in adults, especially those at risk for gastrointestinal complications from NSAIDs.
• Ankylosing Spondylitis: Treatment of spinal and peripheral joint symptoms in adults requiring long-term NSAID therapy with GI protection.
• Chronic NSAID Therapy: For patients requiring prolonged NSAID use with elevated risk of developing NSAID-associated gastric or duodenal ulcers.

Clinically Accepted Off-label Uses:

• Chronic Low Back Pain or Musculoskeletal Pain: In patients at high risk for NSAID-induced gastric irritation.
• Gout Flares: In patients needing NSAID therapy who are also at risk for gastrointestinal ulceration.

Adults:

• Standard Dose: Naproxen Sodium 500 mg + Esomeprazole Magnesium 20 mg orally once daily, taken 30 to 60 minutes before meals.
• Alternative Dose (if prescribed): Naproxen Sodium 500 mg + Esomeprazole Magnesium 20 mg twice daily in patients with higher pain intensity, under physician supervision.

Elderly (≥65 years):

• Same dosing as adults, but monitor closely for renal function and gastrointestinal bleeding. Use the lowest effective dose for the shortest duration.

Pediatric Population:

• Not recommended. Safety and efficacy in individuals below 18 years of age have not been established.

Renal Impairment:

• Mild to Moderate (CrCl 30–80 mL/min): Use with caution; monitor renal function.
• Severe Impairment (CrCl <30 mL/min): Use not recommended due to accumulation of naproxen and risk of toxicity.

Hepatic Impairment:

• Mild to Moderate: No dose adjustment needed; use with caution and monitor liver function.
• Severe: Not recommended due to reduced esomeprazole clearance.

Route of Administration: Oral
Frequency: Once or twice daily depending on clinical need
Administration Advice: Swallow tablets whole. Do not crush, chew, or split. Take with water before meals.

This combination includes two pharmacologically active components:

• Naproxen Sodium is a non-selective NSAID that inhibits both COX-1 and COX-2 enzymes. This reduces the synthesis of prostaglandins, leading to decreased inflammation, pain, and fever. However, inhibition of COX-1 also reduces gastric mucosal protection, increasing ulcer risk.
• Esomeprazole Magnesium is a proton pump inhibitor that blocks the final step of acid production in the stomach by irreversibly inhibiting the H⁺/K⁺ ATPase enzyme system in parietal cells. This action reduces gastric acid secretion, helping to prevent NSAID-induced gastric mucosal injury and ulcers.

Together, they provide effective anti-inflammatory pain relief with simultaneous protection of the gastric mucosa.

Naproxen Sodium:

• Absorption: Rapid and nearly complete; peak plasma levels reached within 1–2 hours.
• Bioavailability: Approximately 95%.
• Protein Binding: >99%.
• Metabolism: Hepatic metabolism to inactive metabolites.
• Elimination: Primarily via kidneys; ~95% excreted in urine.
• Half-life: 12–17 hours.

Esomeprazole Magnesium:

• Absorption: Delayed-release formulation; peak plasma concentration in 1.5 hours.
• Bioavailability: 64% (single dose); increases with repeated dosing.
• Protein Binding: ~97%.
• Metabolism: Liver (CYP2C19 and CYP3A4 pathways).
• Elimination: Renal and fecal.
• Half-life: 1–1.5 hours.

Pregnancy:

• FDA Pregnancy Category: Not classified under new labeling.
• Naproxen: Use should be avoided especially in the third trimester due to the risk of premature closure of the ductus arteriosus and potential fetal renal dysfunction.
• Esomeprazole: Use only if clearly needed; limited human data available.

Lactation:

• Naproxen: Present in breast milk in small amounts; may affect neonatal renal and GI function with prolonged use.
• Esomeprazole: Unclear if it passes into human milk; caution advised.
• Recommendation: Use with caution in breastfeeding mothers. Avoid long-term use.

• Primary Class: Nonsteroidal Anti-inflammatory Drug (NSAID) + Proton Pump Inhibitor (PPI)
• Subclasses:
• Naproxen: Non-selective COX inhibitor (NSAID)
• Esomeprazole: Substituted benzimidazole (PPI)
• Combination Role: NSAID with gastroprotection

• Hypersensitivity to naproxen, esomeprazole, or any component of the formulation
• History of asthma, urticaria, or allergic-type reactions to NSAIDs
• Active gastrointestinal bleeding or peptic ulcer
• Severe renal or hepatic impairment
• Pregnancy (third trimester)
• Use in pediatric patients (<18 years)
• Concurrent therapy with other NSAIDs or PPIs (unless directed by physician)

• Cardiovascular Events: NSAIDs may increase risk of heart attack and stroke; use with caution in patients with cardiovascular disease.
• Gastrointestinal Risk: Even with PPI co-administration, risk of ulceration, bleeding, and perforation persists, particularly in elderly or high-risk patients.
• Renal Effects: Risk of nephrotoxicity, especially in dehydrated patients or those with pre-existing renal impairment.
• Hepatic Effects: Liver enzyme elevation may occur; monitor in patients with liver disease.
• Hematologic Effects: Long-term NSAID use may cause anemia; periodic hemoglobin monitoring advised.
• Electrolyte Imbalance: Long-term PPI use may cause hypomagnesemia; monitor magnesium levels in prolonged therapy.
• Clostridium difficile Infection: Prolonged acid suppression increases risk.
• Bone Fracture Risk: Chronic PPI use may increase risk of osteoporosis-related fractures.

Common Side Effects:

• Gastrointestinal: Nausea, dyspepsia, abdominal pain, constipation, diarrhea, flatulence
• Neurological: Headache, dizziness, drowsiness
• Skin: Rash, pruritus
• General: Fatigue

Serious/Rare Side Effects:

• Gastrointestinal bleeding or ulcer perforation
• Anaphylaxis, angioedema
• Hepatitis, liver function abnormalities
• Renal impairment or acute renal failure
• Severe cutaneous reactions (e.g., Stevens-Johnson syndrome)
• Hypomagnesemia, seizures (with long-term PPI use)
• Clostridium difficile-associated diarrhea

Onset: Mild side effects may occur within the first few days. Serious effects often occur with prolonged use.

Major Interactions:

• Anticoagulants (e.g., warfarin): Increased bleeding risk
• Antiplatelets (e.g., clopidogrel): Esomeprazole may reduce clopidogrel efficacy (CYP2C19 inhibition)
• ACE inhibitors/ARBs/Diuretics: Increased risk of renal dysfunction with NSAIDs
• Methotrexate (high-dose): Reduced clearance due to naproxen
• SSRIs/SNRIs: Enhanced GI bleeding risk
• CYP2C19 substrates (e.g., diazepam): Increased plasma levels due to esomeprazole
• Lithium: May increase lithium toxicity with concurrent NSAID use

Food Interactions:

• Food may delay esomeprazole absorption. Administer on an empty stomach for best effect.

Alcohol Interaction:

• May increase risk of GI irritation and bleeding; avoid or limit alcohol.

Metabolism Enzymes:

• Naproxen: Not significantly via CYP450
• Esomeprazole: Metabolized by CYP2C19 and CYP3A4; also inhibits CYP2C19

• FDA (2023–2024): Reinforced boxed warnings for NSAIDs regarding cardiovascular and gastrointestinal risks.
• EMA Guidance: Continued recommendation of PPI co-therapy in long-term NSAID users at high GI risk.
• WHO Guidance: Recognizes naproxen as an essential NSAID, with attention to ulcer prophylaxis when used long-term.
• Clinical Practice Update: Preference for fixed-dose combinations like naproxen + esomeprazole in high-GI-risk arthritis patients.

• Temperature: Store below 25°C (77°F)
• Humidity: Store in a dry place; avoid exposure to moisture
• Light: Keep in original blister packaging to protect from light
• Handling: Do not split or crush tablets; swallow whole
• Reconstitution/Refrigeration: Not applicable