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
Methotrexate + diclofenac: NSAIDs reduce renal methotrexate excretion, increasing its toxicity (especially at anticancer doses) (QUADRO 2).
NSAIDs, including diclofenac, inhibit the renal tubular secretion of organic acids and may reduce methotrexate clearance, in addition to reducing renal flow in susceptible patients: both mechanisms increase methotrexate exposure. QUADRO 2 of Annex 7 lists the combination of NSAIDs with methotrexate as carrying an increased risk of myelosuppression and nephrotoxicity. The interaction is more dangerous with high-dose methotrexate, renal impairment, dehydration and in the elderly. In practice, NSAIDs should be avoided during methotrexate therapy; when analgesic relief is needed, paracetamol should be preferred. If the combination is unavoidable, monitor blood count, renal function and signs of mucositis, and ensure adequate hydration.
Methotrexate + diclofenac: NSAIDs reduce methotrexate renal excretion — risk of pancytopenia and renal failure; avoid, especially at high doses.
NSAIDs inhibit prostaglandins and reduce renal methotrexate excretion — possible increased toxicity, especially at anticancer doses (QUADRO 2, NSAIDs: "Methotrexate: possible increased methotrexate toxicity (especially at anticancer doses)").
Monitor blood counts and renal function during the combination.
Pancytopenia, mucositis, renal failure in a patient on methotrexate + diclofenac.
Avoid NSAIDs in patients on methotrexate; if unavoidable, monitor closely.
Prontuário Terapêutico do INFARMED (11th ed., 2012) — Annex 7, QUADRO 2 (NSAIDs)
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)
Rivaroxaban + diclofenac: diclofenac may reduce rivaroxaban metabolism and increase bleeding risk — QUADRO 2 lists diclofenac among the drugs that increase the bleeding risk.
NSAIDs such as diclofenac inhibit cyclo-oxygenase and reduce platelet aggregation, and also damage the GI mucosa; rivaroxaban antagonises factor Xa. The effect on haemostasis and mucosa is additive, increasing the bleeding risk, particularly upper GI bleeding. QUADRO 2 of Annex 7 records this combination in the oral anticoagulants section. The risk is higher with high doses, prolonged use, advanced age, history of peptic ulcer or concomitant antiplatelet therapy. Prefer paracetamol or a short-course NSAID at the lowest effective dose; if an NSAID is unavoidable, consider gastric protection and surveillance for occult bleeding.
Rivaroxaban + diclofenac: antiplatelet/anti-inflammatory effect of NSAIDs added to anticoagulation — GI bleeding risk; avoid prolonged use.
Diclofenac (NSAID) increases the bleeding risk through platelet antiaggregant effect and potential pharmacokinetic interaction with rivaroxaban (QUADRO 2, Oral anticoagulants: "Rivaroxaban: May reduce rivaroxaban metabolism and increase bleeding risk: ... Diclofenac").
Watch for signs of bleeding (GI, urinary) during concomitant use.
GI or urinary bleeding in a patient taking rivaroxaban + NSAID.
Avoid NSAIDs in patients taking rivaroxaban; if unavoidable, use the lowest dose and shortest duration.
Prontuário Terapêutico do INFARMED (11th ed., 2012) — Annex 7, QUADRO 2 (Oral anticoagulants)
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)
Diclofenac + furosemide: NSAIDs decrease the natriuretic and antihypertensive diuretic response to furosemide (QUADRO 2).
NSAIDs (such as diclofenac) inhibit renal prostaglandins, reducing the response to loop diuretics and potentially causing sodium and water retention, blood pressure elevation and deterioration of renal function, especially in dehydrated patients or those with heart failure. QUADRO 2 of Annex 7 records this interaction in the NSAID section. The risk of acute kidney injury is higher in the elderly, hypovolaemic patients and those with pre-existing renal disease. Monitor weight, blood pressure, creatinine and diuretic response; prefer paracetamol and use the lowest NSAID dose for the shortest duration if unavoidable.
Furosemide + diclofenac: NSAIDs reduce the diuretic effect and may worsen renal function — fluid retention and nephrotoxicity risk; monitor.
The prostaglandin inhibition by NSAIDs reduces renal sodium excretion and decreases the response to furosemide (QUADRO 2, NSAIDs: "Furosemide: decreased natriuretic and antihypertensive diuretic response to furosemide").
Monitor weight, urine output and BP.
Fluid retention, worsening HF or hypertension with diclofenac + furosemide.
Watch the diuretic response and BP when combining an NSAID with a loop diuretic.
Prontuário Terapêutico do INFARMED (11th ed., 2012) — Annex 7, QUADRO 2 (NSAIDs)
Acenocoumarol + diclofenac: diclofenac increases the hypoprothrombinemic response and irritates the gastric mucosa — increased bleeding risk.
QUADRO 2 (Warfarin) records that "some agents increase the hypoprothrombinemic response (diclofenac, ibuprofen, ketorolac)". Diclofenac combines a pharmacodynamic effect on coagulation with the gastrotoxic risk of NSAIDs, potentiating the bleeding risk of coumarins.
Monitor INR and signs of gastrointestinal bleeding during co-administration.
Haematochezia, melaena, elevated INR or falling haemoglobin with concomitant use.
Prefer alternative analgesics (paracetamol at controlled dose) when possible; if diclofenac is unavoidable, use the lowest dose and shortest duration, with gastric protection.
Prontuário Terapêutico do INFARMED (11th ed., 2012) — Annex 7, Table 2 (Oral anticoagulants: Acenocoumarol — see Warfarin)
Fondaparinux + diclofenac: increased bleeding risk (NSAID) — monitor closely.
The FDA fondaparinux label explicitly includes NSAIDs among the drugs that increase bleeding risk when used concomitantly. Diclofenac inhibits COX-1 and COX-2, reduces platelet aggregation and damages the gastric mucosa, while fondaparinux inhibits factor Xa: the haemostasis mechanisms affected are complementary and the risk of gastrointestinal and other-site bleeding is additive. In anticoagulated patients requiring analgesia, alternatives with less impact on haemostasis (e.g., adequate-dose paracetamol) should be preferred whenever possible. If the NSAID is unavoidable, use the lowest dose and shortest duration, with gastric protection in at-risk patients and monitoring for signs of bleeding.
Fondaparinux + diclofenac: additive bleeding risk (NSAID) — avoid or limit the combination.
The FDA fondaparinux label documents that NSAIDs (e.g., piroxicam in studies) do not affect fondaparinux pharmacokinetics, but "Agents that may enhance the risk of hemorrhage should be discontinued prior to initiation of therapy with fondaparinux sodium unless these agents are essential" (7). NSAIDs such as diclofenac increase bleeding risk through platelet inhibition and gastrointestinal irritation.
Monitor for bleeding and gastrointestinal symptoms during the combination.
Active bleeding, melaena or abdominal pain with the combination.
Discontinue NSAIDs before starting fondaparinux unless essential; if the combination is necessary, monitor closely.
DailyMed/FDA (NIH/NLM) — approved Fondaparinux label (section 7 Drug Interactions): https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=41a37a19-1bf8-4ba0-a12d-dbb6cc8c295c ; approved Diclofenac label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=97bd5a1e-5c20-4a1b-9cd1-ccf55b1bf7ce
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 ; Prontuário Terapêutico do INFARMED (11th ed., 2012) — Annex 2, Drugs and Breastfeeding: Present in milk in very small amounts unlikely to be harmful.
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.
