Naproxen

1. Drug Name

• Generic Name: Naproxen

• Brand Names: Aleve, Naprosyn, Anaprox, Flanax, Naprelan

2. Drug Classification

• Class: Nonsteroidal Anti-Inflammatory Drug (NSAID)

• Subclass: Propionic acid derivative

3. Mechanism of Action

• Naproxen works by inhibiting cyclooxygenase (COX) enzymes—both COX-1 and COX-2—resulting in decreased formation of prostaglandins, which are mediators of pain, inflammation, and fever.

• COX-1 inhibition is linked with adverse effects such as gastrointestinal irritation, while COX-2 inhibition provides the desired anti-inflammatory and analgesic effects.

• Naproxen’s anti-inflammatory properties make it effective for both acute and chronic inflammatory conditions, with a longer duration of action compared to other NSAIDs due to its half-life.

4. Pharmacokinetics

• Absorption: Approximately 95% absorbed orally, with peak plasma concentration reached in 2-4 hours.

• Distribution: Volume of distribution (Vd) is around 0.16 L/kg, with about 99% bound to plasma proteins, primarily albumin.

• Metabolism: Metabolized mainly in the liver via CYP1A2 and CYP2C9 pathways to inactive metabolites.

• Excretion: Half-life (t½) is approximately 12-17 hours, allowing for twice-daily dosing in adults; excreted primarily via the urine.

• Special Considerations: The half-life may be prolonged in elderly patients, requiring dose adjustment or monitoring.

5. Indications

• Primary Indications:

  • Management of pain and inflammation associated with conditions such as osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, gout, and dysmenorrhea.

• Off-Label Uses:

  • Pain relief in soft tissue injuries and postoperative pain (not commonly used as first-line therapy due to GI risks).

• Specific Populations: Suitable for adults and adolescents aged 12 years and older, but dosing and duration of use must be carefully managed.

6. Dosage and Administration

• Adults:

  • Typical dose ranges from 250-500 mg twice daily (for mild pain and inflammation).

  • Maximum daily dose is generally 1000 mg for most conditions, with up to 1500 mg for a limited duration in acute pain.

• Pediatric:

  • For children 12 years and older: Dosing varies by condition; generally 5-7 mg/kg per dose.

• Route: Oral or rectal; extended-release forms available for once-daily dosing.

• Dosing Adjustments:

  • Renal impairment: Dosage adjustment may be necessary for creatinine clearance (CrCl) below 30 mL/min.

  • Hepatic impairment: Use with caution in mild to moderate liver disease; avoid in severe liver impairment.

• Maximum Safe Dose: Typically limited to 1000-1500 mg per day.

7. Contraindications

• Absolute Contraindications:

  • Known hypersensitivity to naproxen or any NSAID.

  • History of asthma, urticaria, or allergic reactions triggered by NSAIDs.

  • Active peptic ulcer disease or recent GI bleeding.

  • Severe renal or hepatic impairment.

• Relative Contraindications:

  • Cardiovascular disease, as NSAIDs can elevate the risk of cardiovascular events.

8. Warnings and Precautions

• Black Box Warnings:

  • Increased risk of cardiovascular thrombotic events, including myocardial infarction (MI) and stroke, especially with prolonged use.

  • Increased risk of gastrointestinal bleeding, ulceration, and perforation.

• Special Warnings:

  • Use with caution in patients with pre-existing hypertension or fluid retention.

  • Use during pregnancy, especially in the third trimester, is not recommended due to risk of fetal ductus arteriosus closure.

• Monitoring Parameters:

  • Periodic liver and renal function tests, blood pressure, and CBC (complete blood count), especially with prolonged use.

9. Adverse Effects

• Common Adverse Effects (≥10%): Dyspepsia, nausea, headache, dizziness.

• Less Common but Clinically Significant: Edema, GI ulceration, rash.

• Rare/Serious Adverse Reactions:

  • Gastrointestinal bleeding, perforation.

  • Hepatotoxicity, renal toxicity, anaphylaxis.

  • Serious cardiovascular events (myocardial infarction, stroke).

10. Drug Interactions

• Major Drug Interactions:

  • Anticoagulants (e.g., warfarin): Increased risk of bleeding.

  • ACE inhibitors/ARBs: May reduce antihypertensive effect and increase risk of renal impairment.

  • Methotrexate: Reduced clearance of methotrexate, increasing toxicity risk.

• Food-Drug Interactions: Food may delay absorption slightly but does not affect the extent of absorption.

• Interactions with Lab Tests: May interfere with liver function tests and increase serum creatinine levels.

11. Clinical Pharmacology

• Naproxen’s pharmacodynamics involve COX enzyme inhibition, providing anti-inflammatory, analgesic, and antipyretic effects.

• It has a longer half-life compared to many other NSAIDs, making it suitable for twice-daily dosing in chronic pain management.

12. Special Populations

• Pregnancy: Avoid, particularly in the third trimester, due to potential fetal harm.

• Lactation: Excreted in breast milk in small amounts; generally considered safe with short-term use, but long-term use is discouraged.

• Geriatrics: Higher risk of adverse effects, particularly gastrointestinal and renal; use with caution and at the lowest effective dose.

• Renal/Hepatic Dysfunction: Dose adjustment is recommended in renal impairment, and use should be avoided in severe hepatic impairment.

13. Therapeutic Uses

• First-Line Therapy: Effective for mild to moderate pain and inflammatory conditions, such as arthritis and dysmenorrhea.

• Second-Line or Adjunctive Therapy: Can be used in combination with other analgesics or disease-modifying agents in inflammatory conditions.

14. Monitoring and Follow-Up

• Recommended Lab Tests: Periodic liver and renal function tests, particularly with long-term use.

• Patient-Reported Symptom Checklists: Monitoring for signs of GI bleeding (e.g., black stools) and cardiovascular symptoms.

• Monitoring of Therapeutic and Toxic Levels: Clinical monitoring for symptoms of toxicity or adverse effects.

15. Overdose Management

• Symptoms of Overdose: Nausea, vomiting, epigastric pain, dizziness, drowsiness; in severe cases, renal failure, hypotension, and metabolic acidosis.

• Treatment Protocols:

  • Activated charcoal if overdose occurred within 1 hour.

  • Supportive care including IV fluids, close monitoring, and symptomatic treatment.

  • Hemodialysis may be useful in severe cases, as naproxen is moderately dialyzable.

16. Patient Counseling Information

• Advise patients on the importance of adhering to recommended dosages and avoiding other NSAIDs concurrently.

• Inform patients about the risks of GI bleeding and cardiovascular effects; counsel on recognizing symptoms of serious adverse effects (e.g., black stools, chest pain).

• Advise patients to avoid alcohol, as it can increase the risk of gastrointestinal irritation and bleeding.