Non-steroidal anti-inflammatory (NSAID)
Naproxen is an anti-inflammatory (NSAID) used for pain, fever and inflammation, including osteoarthritis, rheumatoid arthritis, acute gout and menstrual pain. It is effective, but increases the risk of cardiovascular events and stomach bleeding.
Also known as: Naprosyn, Aleve, naproxeno sódico, naproxen
NSAID + low-dose aspirin: may reduce aspirin cardioprotection and increase GI risk.
Combining aspirin with another NSAID (naproxen) adds up gastrointestinal toxicity (ulcer, bleeding) and renal toxicity, with no additional analgesic benefit. Regarding the antiplatelet effect, interference with the irreversible acetylation of platelet COX-1 by aspirin is well documented with ibuprofen; with naproxen the data are less consistent, but the precaution applies out of prudence in patients on low-dose aspirin. Avoid simultaneous administration: use a single NSAID, consider paracetamol for analgesia and, if antiplatelet aspirin is needed, separate naproxen administration (at least 2 hours, ideally more) or use an NSAID with less interference.
Aspirin + naproxen: additive gastrointestinal risk and possible interference of naproxen with the antiplatelet effect of aspirin. Avoid simultaneous administration.
NSAIDs may occupy the same COX active site and interfere with aspirin irreversible antiplatelet inhibition.
Periodically reassess the need for the combination and gastroprotection.
Signs of thrombotic event or GI bleeding.
Take aspirin at least 2 h before the NSAID when possible; consider paracetamol for analgesia.
DailyMed (FDA) — approved Naproxen label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=24d44eb6-921e-4150-a6b2-81f42ced32ab ; approved Aspirin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3ba0a9f2-062a-401e-82eb-54383a822366 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Two NSAIDs together: no added benefit and increased GI/renal risk.
As with other combinations of two NSAIDs, ibuprofen + naproxen does not increase analgesic efficacy but adds up the risks: gastrointestinal bleeding and ulcer, sodium retention and renal deterioration, and cardiovascular events. Both inhibit platelet and gastric COX-1, so the antiplatelet and mucosal-injury effect is additive. Use a single NSAID at the lowest effective dose, alternating with paracetamol if needed, and avoid chronic simultaneous use.
Ibuprofen + naproxen (two NSAIDs): additive risk of gastrointestinal, renal and cardiovascular toxicity, without analgesic benefit. Do not combine.
Additive effects on gastric mucosa, renal function and platelet aggregation.
Renal function and GI intolerance signs in at-risk patients.
Dyspepsia, epigastric pain, oliguria, oedema.
Do not combine NSAIDs; use a single NSAID at the lowest effective dose.
DailyMed (FDA) — approved Naproxen label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=24d44eb6-921e-4150-a6b2-81f42ced32ab ; approved Ibuprofen label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=291602fa-8ebe-4200-bba7-9798c90f8a50 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Two NSAIDs together: no benefit and increased GI/renal risk.
The naproxen label includes a boxed warning about "increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal" and "increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal". Diclofenac shares the same risks. Combining two NSAIDs does not improve analgesic efficacy (COX inhibition is shared and has a ceiling effect) but adds up the GI risks (gastric mucosal irritation and bleeding), renal risks (reduced glomerular perfusion, sodium and water retention) and cardiovascular risks (thrombosis, BP elevation). The naproxen label recommends avoiding the combination: "NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided" during pemetrexed administration — a specific restriction, but the general principle of avoiding NSAID+NSAID applies to all. Use a single NSAID at the lowest effective dose; if analgesia is insufficient, add paracetamol or a non-NSAID adjuvant.
Diclofenac + naproxen: two NSAIDs — additive GI, renal and cardiovascular toxicity. Avoid (no improvement in efficacy and increased risks).
Additive effects on gastric mucosa and renal function.
Renal function and GI symptoms.
Dyspepsia, epigastric pain, oedema.
Do not combine NSAIDs; use a single NSAID at the lowest effective dose.
DailyMed (FDA) — approved Diclofenac label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2d45648f-cbea-41a4-8e3e-007b7bb7912c ; approved Naproxen label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=24d44eb6-921e-4150-a6b2-81f42ced32ab — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
NSAID + anticoagulant: increased bleeding risk (gastrointestinal and systemic).
Naproxen, like other NSAIDs, increases the bleeding risk in warfarin patients: it inhibits platelet aggregation (prolongedly, given its long half-life), injures the gastric mucosa and can interfere with warfarin pharmacokinetics. The NSAID + anticoagulant combination is associated with a substantial risk of serious gastrointestinal bleeding. Whenever possible, use alternative analgesics; if naproxen is unavoidable, use the lowest effective dose for the shortest time, consider gastroprotection and monitor the INR and bleeding signs.
NSAID + warfarin: increased bleeding risk (GI and general). Avoid NSAIDs in anticoagulated patients; if unavoidable, lowest dose, gastroprotection and INR monitoring.
NSAIDs inhibit COX and platelet aggregation and may displace warfarin from protein binding, enhancing anticoagulation.
More frequent INR monitoring when starting the NSAID; assess full blood count and GI symptoms.
Blood in stools/melena, haematemesis, skin or mucosal bleeding.
Use the lowest NSAID dose for the shortest time; consider gastroprotection (PPI). Watch for signs of bleeding.
DailyMed (FDA) — approved Naproxen label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=24d44eb6-921e-4150-a6b2-81f42ced32ab ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
NSAID + lithium: risk of raised serum lithium and lithium toxicity.
NSAIDs, including naproxen, reduce renal lithium clearance by inhibiting renal prostaglandin synthesis: the naproxen label documents increases in the mean minimum plasma lithium concentration of about 15% and a reduction in renal clearance of approximately 20%. The rise in lithium levels can precipitate lithium toxicity (tremor, confusion, ataxia, dysarthria), especially in the elderly, with dehydration or renal impairment. Monitor lithium levels when starting, adjusting or stopping the NSAID, use the lowest effective dose and watch for signs of toxicity.
Lithium + naproxen: the NSAID reduces renal lithium clearance and raises lithium levels. Monitor levels and signs of toxicity.
NSAIDs reduce renal lithium clearance (decreased excretion), raising lithium levels.
Serum lithium and renal function during combined therapy.
Nausea, confusion, tremor, signs of neurotoxicity; arrhythmias.
Stop or reduce the NSAID with serum lithium monitoring; watch for signs of lithium toxicity.
DailyMed (FDA) — approved Naproxen label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=24d44eb6-921e-4150-a6b2-81f42ced32ab ; approved Lithium label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=582697c1-063f-366f-e063-6294a90a8d1b — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Corticosteroid + NSAID: additive gastrointestinal risk (ulcer/bleeding).
NSAIDs such as naproxen increase the risk of serious gastrointestinal events (bleeding, ulceration and perforation), with a higher risk in the elderly and in patients with a history of peptic ulcer or GI bleeding; concomitant use of oral corticosteroids is a recognised factor increasing the risk of GI bleeding in the NSAID labels. Prednisolone carries a precaution to use with caution in patients with active or latent peptic ulcer. Together, the risk of ulcer, bleeding and digestive perforation increases additively. Consider gastroprotection (proton pump inhibitor) in at-risk patients, use the lowest effective dose of each drug and monitor digestive symptoms.
Naproxen + prednisolone: additive risk of peptic ulcer and gastrointestinal bleeding. Consider gastroprotection in at-risk patients.
Both weaken gastric mucosal protection and increase the risk of GI ulcer and bleeding.
Watch for dyspepsia, abdominal pain and signs of GI bleeding.
Abdominal pain, melena, haematemesis.
Combine only if necessary; consider gastroprotection and the lowest effective dose of both.
DailyMed (FDA) — approved Naproxen label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=24d44eb6-921e-4150-a6b2-81f42ced32ab ; approved Prednisolone label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=52e6e21d-94b8-41a0-8d13-371c0e66bcee — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Food slows absorption but reduces gastric irritation.
Take with food or milk to reduce stomach discomfort.
EMC-UK (MHRA) — approved Naproxen SmPC: https://www.medicines.org.uk/emc/product/13237/smpc
Alcohol worsens gastric mucosal irritation and the bleeding risk associated with NSAIDs.
Limit or avoid alcohol during treatment.
EMC-UK (MHRA) — approved Naproxen SmPC: https://www.medicines.org.uk/emc/product/13237/smpc
NSAIDs may increase the risk of cardiovascular events and cause fluid retention.
Use with caution in cardiovascular disease; prefer the lowest dose and duration.
EMC-UK (MHRA) — approved Naproxen SmPC: https://www.medicines.org.uk/emc/product/13237/smpc
NSAIDs reduce renal blood flow and may worsen renal function.
Avoid NSAIDs in renal impairment; if unavoidable, use the lowest dose and monitor creatinine.
EMC-UK (MHRA) — approved Naproxen SmPC: https://www.medicines.org.uk/emc/product/13237/smpc
NSAIDs may precipitate bronchospasm in patients with NSAID/aspirin-sensitive asthma.
Avoid NSAIDs in asthmatics with a history of sensitivity; use with caution and rescue available.
EMC-UK (MHRA) — approved Naproxen SmPC: https://www.medicines.org.uk/emc/product/13237/smpc
NSAIDs inhibit gastroprotective prostaglandin synthesis and may worsen or perforate an active ulcer.
Contraindicated; seek an alternative analgesic (paracetamol).
EMC-UK (MHRA) — approved Naproxen SmPC: https://www.medicines.org.uk/emc/product/13237/smpc
NSAIDs should be avoided in the 3rd trimester (premature ductus arteriosus closure, oligohydramnios). Occasional use in 1st/2nd trimester with caution.
Avoid in the 3rd trimester; use the lowest dose for the shortest time in the 1st/2nd trimester.
Prefer paracetamol in pregnancy when indicated.
Milk levels are low; occasional use is compatible with infant monitoring.
EMC-UK (MHRA) — approved Naproxen SmPC: https://www.medicines.org.uk/emc/product/13237/smpc
Clinical and educational support tool. The information does not replace a medical prescription or the opinion of a qualified healthcare professional.
NSAID. In vivo bioavailability of 95%, with rapid and complete absorption from the gastrointestinal tract. Volume of distribution of 0.16 L/kg; albumin binding above 99% at therapeutic levels. Elimination half-life of 12 to 17 hours (unchanged across products); steady state in 4 to 5 days.
Inhibition of cyclo-oxygenase (COX-1 and COX-2) and of prostaglandin synthesis; the reduction of prostaglandins in peripheral tissues explains the analgesic, anti-inflammatory and antipyretic activity. Concomitant administration with low-dose aspirin interferes with the antiplatelet effect of aspirin.
Rapid and complete absorption; peak plasma levels 2 to 4 hours after dosing. Above 500 mg/day there is a less than proportional increase in plasma levels, due to saturation of protein binding (increased clearance).
Extensively metabolised in the liver to 6-O-desmethylnaproxen; both are conjugated as acylglucuronides. It does not induce metabolising enzymes. About 95% of the dose is excreted in urine (66 to 92% as conjugates; less than 1% unchanged); up to 3% in faeces. Metabolites may accumulate in renal failure.
Elimination half-life of 12 to 17 hours; half-lives of the metabolites and conjugates shorter than 12 hours. In the elderly, the free (unbound) fraction increases, although it remains below 1% of the total concentration.
Medicines from the same therapeutic group (ATC classification) or the same pharmacological class.
