Nonsteroidal anti-inflammatory drug (NSAID)
Diclofenac is an anti-inflammatory (NSAID) used for pain and inflammation in osteoarthritis, rheumatoid arthritis and ankylosing spondylitis. It is effective, but increases the risk of cardiovascular events and stomach bleeding — use the lowest effective dose for the shortest time.
Also known as: Voltaren
Increased gastrointestinal bleeding risk when a corticosteroid (Prednisolone) is combined with an NSAID.
NSAIDs such as diclofenac increase the risk of serious gastrointestinal events (bleeding, ulceration and perforation), and the diclofenac label identifies concomitant use of oral corticosteroids as a factor that increases the risk of GI bleeding. Prednisolone, in turn, 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, especially in the elderly, with a history of ulcer/bleeding or in prolonged treatment. Consider gastroprotection (proton pump inhibitor) in at-risk patients, use the lowest effective dose of each drug and monitor digestive symptoms.
Diclofenac + prednisolone: additive risk of peptic ulcer and gastrointestinal bleeding. Consider gastroprotection in at-risk patients.
Additive gastric mucosal injury (reduced protective prostaglandins).
Watch for dyspepsia and occult blood in stool.
Severe abdominal pain, melaena, haematemesis.
Consider gastric protection (PPIs) if unavoidable; use the lowest effective doses for the shortest time.
DailyMed/FDA (NIH/NLM) — approved Diclofenac label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ddd2278b-70be-41ca-8a84-e3fe0f1a1561 ; approved Prednisolone label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=52e6e21d-94b8-41a0-8d13-371c0e66bcee
Additive nephrotoxicity risk between Streptomycin and Diclofenac (an NSAID).
NSAIDs (including diclofenac) inhibit renal prostaglandin synthesis, reducing renal blood flow and glomerular filtration rate — which increases aminoglycoside exposure and nephrotoxicity. The streptomycin label warns that "the concurrent or sequential use of other neurotoxic and/or nephrotoxic drugs... should be avoided" and that "nephrotoxicity does occur, although rarely, streptomycin being the least nephrotoxic of the aminoglycosides". In elderly, hypovolaemic, diabetic or pre-existing renal impairment patients, combining an NSAID with an aminoglycoside can precipitate acute kidney injury. Whenever possible, avoid; if unavoidable (e.g. tuberculosis with inflammatory pain), use the lowest NSAID dose for the shortest time, ensure hydration and monitor creatinine and urine output.
Diclofenac + streptomycin: the NSAID reduces renal perfusion and increases the nephrotoxic risk of the aminoglycoside. Monitor renal function; avoid if possible.
Same NSAID and aminoglycoside mechanism.
Creatinine and urine output.
Acute renal failure (oliguria, fatigue, oedema).
Avoid NSAIDs; hydrate; monitor renal function.
DailyMed/FDA (NIH/NLM) — approved Streptomycin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=abd1f64e-4283-4370-aae8-3666316aa36e ; approved Diclofenac label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b0931350-28a9-4f00-9254-1d72e31f04c3
Not recommended to use two NSAIDs at once: increases the risk of bleeding, ulceration and renal injury without adding efficacy.
Combining two non-selective NSAIDs does not improve analgesia and adds up the adverse effects: gastrointestinal injury (dyspepsia, ulcer, bleeding), sodium retention and renal injury (especially in the elderly, in hypovolaemic patients or in those with pre-existing renal disease) and cardiovascular risk. Both inhibit COX-1, so the antiplatelet and gastric effect is additive. A single NSAID should be used at the lowest effective dose, preferring non-pharmacological alternatives or paracetamol when appropriate. Chronic combination should be avoided.
Diclofenac + ibuprofen (two NSAIDs): no analgesic benefit and increased risk of gastrointestinal, renal and cardiovascular toxicity. Do not combine.
Additive COX inhibition and reduced protective gastric and renal prostaglandins.
Gastrointestinal signs (dyspepsia, melaena) and renal function in prolonged use.
Abdominal pain, melaena, haematemesis, oedema, rising blood pressure.
Avoid the combination; use only one NSAID at the lowest effective dose, with gastric protection if unavoidable.
DailyMed/FDA (NIH/NLM) — approved Ibuprofen label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=14515409-736f-4119-b6a0-cb19ee2e948e ; approved Diclofenac label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ddd2278b-70be-41ca-8a84-e3fe0f1a1561
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.
Diclofenac, like other NSAIDs, increases the bleeding risk in warfarin patients through three pathways: reversible platelet aggregation inhibition, gastric mucosal injury (ulcer and GI bleeding risk) and possible interference with warfarin pharmacokinetics. The risk of serious gastrointestinal bleeding with the NSAID + anticoagulant combination is substantial and well documented. Whenever possible, use alternative analgesics (paracetamol at controlled doses); if diclofenac is unavoidable, use the lowest effective dose for the shortest time, consider gastroprotection (PPI) and monitor the INR and bleeding signs.
NSAID + warfarin: increased bleeding risk (GI and general). Avoid NSAIDs in anticoagulated patients; if unavoidable, use the lowest dose, gastroprotection and INR monitoring.
Diclofenac inhibits COX and platelet aggregation and may interact with warfarin, enhancing anticoagulation.
INR and GI symptoms.
Melena, haematemesis, ecchymosis.
Use the lowest NSAID dose; consider gastroprotection and watch for bleeding.
DailyMed (FDA) — approved Diclofenac label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2d45648f-cbea-41a4-8e3e-007b7bb7912c ; 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)
Combining Lithium with Diclofenac increases serum Lithium concentrations, with a risk of toxicity.
NSAIDs, including diclofenac, reduce renal lithium clearance by inhibiting renal prostaglandin synthesis: the diclofenac 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.
Diclofenac + lithium: the NSAID reduces renal lithium clearance and raises lithium levels. Monitor levels and signs of toxicity.
NSAIDs such as Diclofenac decrease the renal excretion of Lithium, raising its serum levels.
Watch for signs of Lithium toxicity after starting Diclofenac.
Signs of Lithium toxicity (confusion, tremor, vomiting, seizures) require urgent evaluation.
Avoid the combination; if needed, use the lowest Diclofenac dose and monitor Lithium levels.
DailyMed/FDA (NIH/NLM) — approved Lithium label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0e6b0a2d-b79c-44d8-b785-5267df9e8f72 ; approved Diclofenac label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b0931350-28a9-4f00-9254-1d72e31f04c3 — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Alcohol increases the risk of gastric irritation and bleeding.
Avoid alcohol during treatment.
EMC-UK (MHRA) — approved Diclofenac SmPC: https://www.medicines.org.uk/emc/product/4333/smpc
NSAIDs may increase cardiovascular risk.
Use with caution in cardiovascular disease.
EMC-UK (MHRA) — approved Diclofenac SmPC: https://www.medicines.org.uk/emc/product/4333/smpc
NSAIDs may worsen renal function.
Avoid or use the lowest dose with creatinine monitoring.
EMC-UK (MHRA) — approved Diclofenac SmPC: https://www.medicines.org.uk/emc/product/4333/smpc
Risk of bronchospasm in NSAID-sensitive patients.
Avoid in aspirin-sensitive asthma.
EMC-UK (MHRA) — approved Diclofenac SmPC: https://www.medicines.org.uk/emc/product/4333/smpc
NSAIDs may worsen or perforate an active ulcer.
Contraindicated; seek an alternative.
EMC-UK (MHRA) — approved Diclofenac SmPC: https://www.medicines.org.uk/emc/product/4333/smpc
Avoid in the 3rd trimester; limited data in early pregnancy.
Avoid in the 3rd trimester; use the lowest dose possible.
Limited data; occasional use probably compatible.
Use paracetamol where possible; no specific contraception.
EMC-UK (MHRA) — approved Diclofenac SmPC: https://www.medicines.org.uk/emc/product/4333/smpc
Clinical and educational support tool. The information does not replace a medical prescription or the opinion of a qualified healthcare professional.
NSAID. Complete oral absorption (100% vs intravenous, by urine recovery), but only about 50% of the dose is systemically available due to first-pass metabolism. Apparent volume of distribution of 1.4 L/kg; serum protein binding above 99% (albumin). Terminal half-life of about 2 hours.
Inhibition of cyclo-oxygenase (COX-1 and COX-2) and of prostaglandin synthesis; since prostaglandins sensitise afferent nerves and mediate inflammation, the reduction of their synthesis explains the analgesic, anti-inflammatory and antipyretic effect.
Complete oral absorption, but only about 50% systemic bioavailability (first pass); Tmax of about 2.3 hours. Food delays the onset of absorption (1 to 4.5 hours) without reducing the extent; absorption is higher while fasting.
Metabolised in the liver: 5 metabolites identified; the main one, 4-hydroxy-diclofenac (very weak activity), is formed by CYP2C9, with participation of CYP2C8 and CYP3A4; glucuronidation (UGT2B7) and sulfation follow, with biliary excretion. About 65% of the dose is excreted in urine and 35% in bile, as conjugates; less than 1% unchanged in urine.
Terminal half-life of about 2 hours; diclofenac diffuses into synovial fluid, where levels become higher than plasma after the distribution phase. No adjustment is needed in mild to moderate renal impairment; in hepatic disease a dose reduction may be needed.
Medicines from the same therapeutic group (ATC classification) or the same pharmacological class.
