Naproxen

Dosage for naproxen is highly individualized based on the condition being treated and the patient's response. Healthcare providers generally aim for the lowest effective dose for the shortest duration possible to minimize the risk of adverse effects.

• Rheumatoid Arthritis, Osteoarthritis, and Ankylosing Spondylitis: The typical starting dose is 250 mg, 375 mg, or 500 mg taken twice daily (morning and evening). During acute flares, the dose may be increased up to 1,500 mg per day for limited periods under medical supervision.
• Acute Gout: A common regimen involves a loading dose of 750 mg, followed by 250 mg every 8 hours until the attack subsides.
• Acute Pain, Dysmenorrhea, and Tendonitis: The initial dose is usually 500 mg, followed by 250 mg every 6 to 8 hours as needed. The total daily dose should generally not exceed 1,250 mg on the first day and 1,000 mg on subsequent days.
• Over-the-Counter (OTC) Use: For minor aches and pains, the standard dose is 220 mg (naproxen sodium) every 8 to 12 hours. Users should not exceed 2 tablets in an 8-to-12-hour period or 3 tablets in a 24-hour period unless directed by a doctor.

Naproxen is approved for use in children aged 2 years and older for the treatment of Juvenile Rheumatoid Arthritis (JRA).

• JRA Dosing: The recommended total daily dose is approximately 10 mg/kg, divided into two doses (5 mg/kg twice daily).
• Safety Note: Naproxen is not generally recommended for other uses in children under 12 years of age unless specifically directed by a pediatrician. Clinical data for use in infants under 2 years of age is limited, and safety has not been established.

Renal Impairment

Since naproxen is primarily eliminated by the kidneys, patients with impaired renal function require careful monitoring. Naproxen is not recommended for use in patients with moderate-to-severe renal impairment (creatinine clearance < 30 mL/min). In patients with mild impairment, a dose reduction may be necessary to prevent drug accumulation.

Hepatic Impairment

Patients with chronic alcoholic liver disease or other forms of cirrhosis may have higher levels of unbound naproxen in their blood. Healthcare providers may prescribe the lowest effective dose for these individuals.

Elderly Patients

Older adults (65+) are at a significantly higher risk for serious GI bleeding and renal complications. Clinical guidelines suggest starting at the lower end of the dosing range and monitoring frequently for signs of toxicity.

• With Food: To reduce the risk of stomach upset, heartburn, or ulcers, it is highly recommended to take naproxen with food, milk, or an antacid.
• Hydration: Drink a full glass of water (8 ounces) with each dose to facilitate absorption and protect renal function.
• Swallow Whole: Enteric-coated (EC) or extended-release (XR) tablets must be swallowed whole. Do not crush, chew, or break them, as this destroys the specialized coating and increases the risk of stomach irritation or alters the drug's release profile.
• Storage: Store at room temperature (68°F to 77°F) away from moisture, heat, and direct light. Keep the container tightly closed.

If you miss a dose, take it as soon as you remember. However, if it is almost time for your next scheduled dose, skip the missed dose and resume your regular schedule. Do not double the dose to catch up, as this increases the risk of gastrointestinal and cardiovascular side effects.

Signs of a naproxen overdose may include lethargy, drowsiness, epigastric pain (upper stomach pain), nausea, vomiting, and GI bleeding. In severe cases, hypertension, acute renal failure, respiratory depression, and coma may occur. If an overdose is suspected, contact a poison control center or seek emergency medical attention immediately.

> Important: Follow your healthcare provider's dosing instructions exactly. Do not adjust your dose or stop taking the medication without medical guidance, especially if treating a chronic inflammatory condition.

Like all NSAIDs, naproxen is associated with a range of side effects, most commonly affecting the gastrointestinal and central nervous systems. Common side effects include:

• Gastrointestinal Distress: This is the most frequent complaint and includes dyspepsia (indigestion), heartburn, nausea, and abdominal pain. These symptoms typically occur shortly after taking the medication.
• Central Nervous System Effects: Headache and dizziness are common. Some patients report a feeling of 'lightheadedness' or drowsiness.
• Dermatologic Issues: Pruritus (itching) and minor skin rashes or ecchymosis (bruising) may occur.

• Tinnitus: A ringing or buzzing sensation in the ears.
• Edema: Swelling of the hands, feet, or ankles due to fluid retention.
• Constipation or Diarrhea: Changes in bowel habits are frequently reported with ongoing use.
• Visual Disturbances: Blurred vision or other changes in sight.
• Vertigo: A sensation of spinning or loss of balance.

• Aseptic Meningitis: Particularly in patients with existing autoimmune disorders like systemic lupus erythematosus (SLE).
• Hematologic Changes: Anemia, leukopenia (low white blood cell count), or thrombocytopenia (low platelets).
• Hepatotoxicity: Jaundice or hepatitis (inflammation of the liver).
• Photosensitivity: Increased sensitivity to sunlight, leading to easier sunburn or skin blistering.

> Warning: Stop taking Naproxen and call your doctor immediately if you experience any of these serious symptoms.

1. 1Gastrointestinal Bleeding: Signs include black, tarry, or bloody stools; coughing up blood; or vomit that looks like coffee grounds. This can occur without warning and may be fatal.
2. 2Cardiovascular Events: Chest pain, shortness of breath, sudden weakness on one side of the body, or slurred speech (signs of heart attack or stroke).
3. 3Anaphylaxis: Severe allergic reactions involving swelling of the face or throat, hives, and difficulty breathing.
4. 4Renal Failure: Sudden decrease in urine output, swelling in the legs, and fatigue.
5. 5Severe Skin Reactions: Stevens-Johnson Syndrome (SJS) or Toxic Epidermal Necrolysis (TEN), characterized by fever, sore throat, and a painful red or purplish rash that spreads and causes blistering.
6. 6Liver Dysfunction: Upper right-sided abdominal pain, fatigue, dark urine, and yellowing of the eyes or skin.

Prolonged use of naproxen increases the cumulative risk of several chronic conditions:

• Chronic Kidney Disease: Long-term NSAID use can lead to renal papillary necrosis and other forms of permanent kidney damage.
• Peptic Ulcer Disease: Continuous inhibition of protective prostaglandins in the stomach can lead to chronic ulceration and perforation.
• Cardiovascular Risk: The risk of thrombotic events (blood clots) increases with the duration of use and the presence of underlying heart disease.

The FDA has issued a Black Box Warning for naproxen, the highest level of alert for medications. This warning highlights two critical risks:

1. 1Cardiovascular Thrombotic Events: NSAIDs, including naproxen, cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction (heart attack) and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use. Naproxen is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery.
2. 2Gastrointestinal Bleeding, Ulceration, and Perforation: NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events.

Report any unusual symptoms or side effects to your healthcare provider promptly to ensure safe and effective treatment.

Naproxen is a powerful medication that requires careful management. Patients should be aware that taking more than the recommended dose or combining it with other NSAIDs (like ibuprofen or aspirin) significantly increases the risk of life-threatening complications. It is vital to disclose your full medical history, particularly any history of heart disease, high blood pressure, or stomach ulcers, to your healthcare provider before starting naproxen.

Cardiovascular Risk: Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use. Naproxen is contraindicated in the setting of coronary artery bypass graft (CABG) surgery.

Gastrointestinal Risk: NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events.

• Allergic Reactions: Patients with the 'aspirin triad' (asthma, nasal polyps, and aspirin sensitivity) should not take naproxen, as it can trigger severe bronchospasm (tightening of the airways).
• Hepatotoxicity: Borderline elevations of liver tests may occur. Rare but severe hepatic reactions, including jaundice and fatal fulminant hepatitis, have been reported. If clinical signs of liver disease develop, the drug should be discontinued.
• Hypertension: Naproxen can lead to the onset of new hypertension or the worsening of pre-existing high blood pressure, both of which contribute to increased cardiovascular risk. Blood pressure should be monitored closely during the initiation and throughout the course of therapy.
• Heart Failure and Edema: Fluid retention and edema have been observed in some patients taking NSAIDs. Naproxen should be used with caution in patients with fluid retention or heart failure.
• Renal Toxicity: Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Patients at greatest risk include those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly.

Patients on long-term naproxen therapy should undergo periodic laboratory monitoring, including:

• Complete Blood Count (CBC): To check for anemia or other blood cell abnormalities.
• Liver Function Tests (LFTs): To monitor for signs of hepatic injury.
• Renal Function Tests: Including serum creatinine and glomerular filtration rate (GFR) to ensure the kidneys are processing the drug safely.
• Fecal Occult Blood Test: To screen for asymptomatic GI bleeding.

Naproxen may cause drowsiness, dizziness, or visual disturbances in some patients. If you experience these effects, avoid driving or operating heavy machinery until you know how the medication affects you.

Consuming alcohol while taking naproxen significantly increases the risk of gastrointestinal bleeding and stomach ulcers. It is generally advised to avoid or strictly limit alcohol consumption during treatment.

While naproxen does not typically require a tapering schedule for short-term use, patients using it for chronic conditions should consult their doctor before stopping. Abruptly stopping may cause a return of inflammatory symptoms. There is no known withdrawal syndrome associated with naproxen.

> Important: Discuss all your medical conditions, including any history of asthma or heart disease, with your healthcare provider before starting Naproxen.

• Other NSAIDs (e.g., Ibuprofen, Celecoxib, Ketorolac): Combining naproxen with other NSAIDs increases the risk of gastrointestinal bleeding and renal failure without providing additional therapeutic benefit. Ketorolac, in particular, should never be used with naproxen due to the extreme risk of severe GI toxicity.
• Cidofovir: NSAIDs can increase the plasma levels of cidofovir, leading to severe nephrotoxicity (kidney damage).

• Anticoagulants (e.g., Warfarin, Rivaroxaban): Naproxen can inhibit platelet function and damage the gastric mucosa, which significantly increases the risk of life-threatening bleeding when combined with blood thinners. Prothrombin time (PT/INR) must be monitored closely.
• Antiplatelet Agents (e.g., Aspirin, Clopidogrel): Concurrent use increases the risk of GI ulceration and bleeding. Furthermore, naproxen may interfere with the low-dose aspirin's ability to provide cardioprotection by competing for the COX-1 binding site.
• Lithium: Naproxen reduces the renal clearance of lithium, leading to increased lithium plasma levels and potential toxicity (tremors, confusion, seizures). Lithium levels must be monitored frequently.
• Methotrexate: NSAIDs can reduce the tubular secretion of methotrexate, leading to dangerously high levels and bone marrow suppression or kidney failure.

• ACE Inhibitors and Angiotensin II Receptor Blockers (ARBs): Naproxen may diminish the antihypertensive effect of these drugs. In elderly or volume-depleted patients, the combination may lead to acute renal failure.
• Diuretics (e.g., Furosemide, Hydrochlorothiazide): Naproxen can reduce the natriuretic (salt-excreting) effect of diuretics, leading to fluid retention and decreased blood pressure control.
• SSRIs and SNRIs (e.g., Sertraline, Venlafaxine): These antidepressants can increase the risk of upper gastrointestinal bleeding when taken with NSAIDs.
• Corticosteroids (e.g., Prednisone): Concurrent use increases the risk of gastrointestinal ulceration.

• Alcohol: As previously noted, alcohol increases the risk of GI bleeding.
• High-Fat Meals: While food does not affect the total absorption (AUC), a high-fat meal can delay the time to peak concentration (Tmax), which may delay pain relief in acute settings.

• Ginkgo Biloba, Garlic, Ginger, and Ginseng: These supplements possess mild antiplatelet properties and may increase the risk of bleeding when combined with naproxen.
• St. John’s Wort: May increase the risk of GI side effects.
• Glucosamine/Chondroitin: Generally safe, but patients should monitor for increased bruising.

• Urinary 5-Hydroxyindoleacetic Acid (5-HIAA): Naproxen may interfere with some urinary assays for 5-HIAA, leading to false-positive results.
• Adrenal Function Tests: Naproxen should be discontinued 48 hours before adrenal function tests (e.g., Porter-Silber test) because it may interfere with the measurement of 17-ketogenic steroids.

For each major interaction, the primary management strategy is either avoidance, dose adjustment, or increased clinical and laboratory monitoring.

> Important: Tell your doctor about ALL medications, supplements, and herbal products you are taking to prevent dangerous drug-drug interactions.

Naproxen must NEVER be used in the following circumstances:

• Hypersensitivity: Patients with a known allergy to naproxen or any component of the formulation.
• Aspirin-Sensitive Asthma: Patients who have experienced asthma, urticaria (hives), or allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic-like reactions have been reported in such patients.
• CABG Surgery: Naproxen is strictly contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery due to the high risk of myocardial infarction and stroke.
• Active Peptic Ulcer or GI Bleeding: Use in patients with active bleeding or ulceration can lead to perforation and fatal hemorrhage.
• Severe Renal Impairment: Patients with a creatinine clearance of less than 30 mL/min should not use naproxen as it can cause further deterioration of kidney function.

Conditions requiring a careful risk-benefit analysis and close medical supervision include:

• Congestive Heart Failure (CHF): Due to the risk of fluid retention and worsening of heart function.
• Hypertension: Especially if poorly controlled, as NSAIDs can raise blood pressure.
• Coagulation Disorders: Such as hemophilia or von Willebrand disease, due to the antiplatelet effects of naproxen.
• Mild to Moderate Renal Insufficiency: Requires lower doses and frequent monitoring.
• Hepatic Cirrhosis: Increased risk of renal failure and GI bleeding.

There is a high degree of cross-sensitivity between naproxen and other NSAIDs, including ibuprofen, diclofenac, and indomethacin. If a patient has had a severe reaction to one NSAID, they are likely to react to naproxen. However, there is no cross-sensitivity with acetaminophen (Tylenol), which may be an alternative for pain relief in such patients.

> Important: Your healthcare provider will evaluate your complete medical history, including any previous reactions to pain medications, before prescribing Naproxen.

• First and Second Trimester: Naproxen is generally classified as Pregnancy Category C. Use should be avoided unless the potential benefit justifies the potential risk to the fetus. Some studies suggest an increased risk of miscarriage and congenital malformations with early NSAID use.
• Third Trimester (Starting at 20-30 weeks): Naproxen is Pregnancy Category D. Use after 20 weeks of gestation may cause fetal renal dysfunction leading to oligohydramnios (low amniotic fluid). Use after 30 weeks is strictly contraindicated because it can cause premature closure of the ductus arteriosus (a vital fetal blood vessel), which can lead to fetal heart failure or pulmonary hypertension.

Naproxen is excreted in human milk in very small amounts (less than 1% of the maternal dose). While the American Academy of Pediatrics considers naproxen generally compatible with breastfeeding, the long half-life of the drug suggests that caution should be exercised. Short-acting alternatives like ibuprofen are often preferred for nursing mothers. Monitor the infant for signs of GI upset or bruising.

Naproxen is approved for the treatment of Juvenile Rheumatoid Arthritis (JRA) in children 2 years of age and older. It has not been established as safe or effective for other uses in children under 12. Pediatric patients should be monitored for growth and any signs of gastrointestinal or renal toxicity during long-term therapy.

Elderly patients (65+) are at the highest risk for adverse effects from naproxen. They are more likely to experience asymptomatic GI ulceration and are more sensitive to the drug's effects on the kidneys. Clinical guidelines recommend using the lowest effective dose and performing regular blood work to monitor renal function and hemoglobin levels.

Naproxen is not recommended for patients with moderate-to-severe renal impairment (creatinine clearance < 30 mL/min). In patients with milder impairment, the drug can cause a further reduction in renal blood flow by inhibiting vasodilatory prostaglandins. Dose reduction and frequent monitoring of serum creatinine are required.

In patients with severe hepatic impairment (Child-Pugh Class C), the levels of free (unbound) naproxen may be significantly increased due to low albumin levels. These patients require lower doses and careful monitoring for signs of toxicity.

> Important: Special populations require individualized medical assessment and frequent monitoring to ensure the safe use of Naproxen.

Naproxen is a non-selective inhibitor of the cyclooxygenase enzymes, COX-1 and COX-2. By binding to the active site of these enzymes, naproxen prevents the conversion of arachidonic acid into prostaglandin G2 (PGG2) and subsequently into various other prostaglandins (PGE2, PGI2) and thromboxanes (TXA2). Prostaglandin E2 is a primary mediator of inflammation and pain sensitization; by reducing its concentration, naproxen exerts its therapeutic effects. The inhibition of TXA2 in platelets leads to a temporary reduction in platelet aggregation, though this effect is less sustained than that of aspirin.

• Onset of Action: Analgesic effects typically begin within 30 to 60 minutes for naproxen sodium and 1 to 2 hours for naproxen base. Anti-inflammatory effects may take up to 2 weeks of consistent dosing to reach peak efficacy.
• Duration of Effect: Due to its long half-life, the effects of a single dose last approximately 8 to 12 hours.
• Tolerance: There is no evidence of pharmacological tolerance; however, the underlying disease progression may require dosage adjustments over time.

| Parameter | Value |

|---|---|

| Bioavailability | 95% |

| Protein Binding | >99% (primarily to albumin) |

| Half-life | 12 - 17 hours |

| Tmax | 1 - 4 hours (formulation dependent) |

| Metabolism | Hepatic (CYP1A2, CYP2C9) |

| Excretion | Renal (95%), Fecal (<5%) |

• Molecular Formula: C14H14O3
• Molecular Weight: 230.26 g/mol
• Solubility: Practically insoluble in water at low pH; freely soluble in water at high pH.
• Structure: A white to off-white crystalline powder; a derivative of 2-naphthylpropionic acid.

Naproxen is classified as a nonsteroidal anti-inflammatory drug (NSAID) and a propionic acid derivative. It is in the same therapeutic class as ibuprofen, ketoprofen, and flurbiprofen, but differs significantly in its longer duration of action.