Ibuprofen

Mechanism

Ketorolac and ibuprofen are both NSAIDs. Additive risk of gastrointestinal bleeding, acute kidney injury, and blood pressure dysregulation. FDA Toradol Section 4.3 specifically lists other NSAIDs as contraindications.

Symptoms

Black or tarry stools (melena), vomiting blood or coffee-ground material, epigastric pain. Acute kidney injury and a rise in blood pressure are also possible. Risk of bleeding multiplies in patients over 65 and with prior peptic ulcer disease.

Management

The combination is not prescribed. One NSAID at a time. Ketorolac courses are limited to 5 days. If analgesia from one NSAID is insufficient, add paracetamol or a short opioid – not a second NSAID.

Mechanism

Ibuprofen reversibly binds platelet COX-1 and blocks aspirin's access to its irreversible acetylation site. Aspirin's antiplatelet effect is lost – cardiovascular event risk.

Symptoms

No symptoms – risk is loss of cardioprotection.

Management

If ibuprofen needed – take 8 hours BEFORE or 30 minutes AFTER aspirin. Alternative in cardiovascular risk – paracetamol.

Mechanism

Apixaban inhibits factor Xa; ibuprofen (NSAID) injures the gastric mucosa and transiently inhibits platelet aggregation. The GI bleeding risk is additive.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, blood in urine or stool, menorrhagia. Severe cases include gastrointestinal or intracranial haemorrhage. Risk rises in patients over 65 and with prior peptic ulcer disease.

Management

Avoid where possible. If a short ibuprofen course is needed, use the minimum effective dose for no more than 5–7 days under pantoprazole cover. For chronic analgesia, choose paracetamol, a selective COX-2 inhibitor (celecoxib), or topical NSAIDs.

Mechanism

SSRI + NSAID – GI bleeding.

Symptoms

GI bleeding.

Management

PPI or paracetamol.

Mechanism

Dabigatran inhibits thrombin while ibuprofen damages gastric mucosa and blocks platelet aggregation, so two bleeding pathways add up. The label separates two scenarios: short-term NSAID analgesia was not linked to more bleeding, whereas with chronic use in the RE-LY study NSAIDs raised bleeding risk by about 50 % with both dabigatran and warfarin.

Symptoms

Black stools, coffee-ground vomit, gum or nose bleeding that is slow to stop, large bruises without trauma, pink urine. Fatigue and pallor point to anaemia from slow bleeding. Impaired renal function multiplies the risk, since dabigatran is cleared by the kidneys.

Management

For occasional pain, paracetamol replaces ibuprofen without touching coagulation. If an NSAID is needed, use the shortest course with gastric protection, watching stools and haemoglobin. Continuous ibuprofen alongside dabigatran should be reconsidered: that is exactly the scenario with the extra 50 % risk.

Mechanism

The dexketoprofen label lists other NSAIDs among the combinations that are not recommended and explains why: giving several NSAIDs together potentiates the risk of gastrointestinal ulcers and bleeding through a synergistic effect. Dexketoprofen acts fast and ibuprofen covers the hours that follow, leaving the mucosa without protective prostaglandins for most of the day.

Symptoms

Epigastric pain, nausea, black stools, vomiting blood. Reduced urine output, oedema and high blood pressure if the kidney was already compromised or the patient takes diuretics or ACE inhibitors. Pain may not improve despite the double dose, because the target is already saturated.

Management

Pick one of the two. Dexketoprofen is reserved for short courses of severe acute pain, and ibuprofen is withdrawn during that time, including self-medication for headache or period pain. To reinforce analgesia, add paracetamol, which does not share the mechanism.

Mechanism

The diclofenac label notes that giving it with other NSAIDs or corticosteroids can increase gastrointestinal adverse effects, and the ibuprofen label asks to avoid simultaneous use with other NSAIDs. On top of the digestive risk comes the cardiovascular one, highest in the group for diclofenac at high doses and long courses.

Symptoms

Epigastric pain, dyspepsia, black stools, anaemia from slow bleeding. Fluid retention, rising blood pressure and worse hypertension control. In ischaemic heart disease the thrombotic risk of diclofenac outweighs any analgesic gain.

Management

Keep a single NSAID, and in cardiovascular patients avoid choosing diclofenac. Topical diclofenac gels and patches contribute little systemically, but over large areas or under occlusive dressing absorption rises and they count as another dose. Extra analgesia comes from paracetamol.

Mechanism

Ibuprofen (NSAID) suppresses prostaglandin synthesis maintaining glomerular perfusion at lower blood pressure. On enalapril, which dilates efferent arterioles, the combination raises acute kidney injury risk (the 'triple whammy' with a diuretic is more dangerous still).

Symptoms

Reduced urine output, rising creatinine and potassium. Blood pressure rise and oedema. Symptoms appear earlier in older patients and chronic kidney disease.

Management

Avoid chronic ibuprofen on enalapril. If a short course is needed, use the minimum effective dose for 5–7 days with pantoprazole cover. For chronic analgesia: paracetamol, celecoxib, or topical NSAIDs.

Mechanism

SSRI + NSAID – increased GI bleeding risk.

Symptoms

GI bleeding in at-risk patients.

Management

PPI gastroprotection or paracetamol alternative.

Mechanism

Ibuprofen reduces lithium renal clearance by inhibiting prostaglandin synthesis in the proximal tubule. Lithium plasma concentration rises 25–60%, leading to intoxication. Lithium has a narrow therapeutic index (target 0.6–1.0 mmol/L, toxic above 1.5).

Symptoms

Within 5–10 days: nausea, vomiting, diarrhea, tremor, confusion, drowsiness. Severe toxicity: seizures, coma, renal injury, arrhythmia.

Management

In bipolar disorder, paracetamol is the first-line analgesic. If an NSAID is needed, use a short course (up to 5 days); check lithium level 4–7 days after NSAID start and 4–7 days after stop. Reduce lithium by 50% and titrate to level.

Mechanism

NSAIDs reduce renal blood flow via prostaglandin blockade. The ARB (losartan) lowers glomerular pressure. The combination causes acute kidney injury, especially in older patients, chronic kidney disease, and dehydration.

Symptoms

Reduced urine output, rising creatinine and potassium, oedema. Symptoms appear earlier in older patients and in chronic kidney disease.

Management

Avoid prolonged combination. If ibuprofen is needed for a short course, use the minimum effective dose for 5–7 days with pantoprazole cover and creatinine monitoring. For chronic analgesia: paracetamol or celecoxib.

Mechanism

Ibuprofen reduces methotrexate renal elimination by inhibiting proximal tubular secretion. With high-dose methotrexate (oncology, high-dose psoriasis) concentration rises 2–3 fold causing severe myelosuppression and mucositis. With low-dose weekly methotrexate (rheumatoid arthritis 7.5–25 mg/week) risk is lower but not absent.

Symptoms

Within 7–14 days: mouth ulcers, fever, infections, bruising, gum bleeding. CBC: leukopenia, thrombocytopenia; rising creatinine.

Management

With high-dose methotrexate, contraindicated: stop NSAID 48 h before infusion, resume no sooner than 2–3 days after. With low-dose weekly methotrexate, choose paracetamol as first-line analgesic. If an NSAID is needed, check CBC, creatinine and transaminases every 2 weeks for the first 2 months.

Mechanism

Both are NSAIDs blocking the same enzyme, so analgesia does not add up the way harm does. The ibuprofen label is blunt: simultaneous use with other NSAIDs should be avoided, since it can increase the risk of gastrointestinal ulcer and bleeding. Naproxen's long half-life keeps inhibition running for hours after the last dose, so the overlap is real even with spaced dosing.

Symptoms

Black or tarry stools, coffee-ground vomit, epigastric pain that food does not settle. Ankle oedema, reduced urine output, rising blood pressure and creatinine follow. Over 65, with prior ulcer, anticoagulants or corticosteroids, bleeding may be the first sign.

Management

Keep a single NSAID. If naproxen is not enough, reinforce with paracetamol or metamizole rather than adding ibuprofen. If both have already been taken, stop one and keep gastric protection where risk factors exist; black stools or coffee-ground vomit call for urgent assessment.

Mechanism

Additive gastroesophageal ulcer and bleeding risk. Glucocorticoids reduce GI mucosal repair; NSAIDs block protective prostaglandins.

Symptoms

Black or tarry stools (melena), vomiting blood or coffee-ground material, epigastric pain. Risk multiplies in older patients and with prior peptic ulcer disease.

Management

Avoid prolonged combination. If ibuprofen is needed for a short course on prednisolone, use the minimum effective dose for 5–7 days with mandatory pantoprazole cover. For chronic analgesia: paracetamol or celecoxib.

Mechanism

Additive GI bleeding risk: anticoagulant (rivaroxaban) + ulcerogenic NSAID with antiplatelet effect (ibuprofen).

Symptoms

Black or tarry stools (melena), vomiting blood or coffee-ground material, epigastric pain. Risk multiplies in older patients and with prior peptic ulcer disease.

Management

Avoid prolonged combination. If ibuprofen is needed for a short course, use the minimum effective dose for 5–7 days under pantoprazole cover. For chronic analgesia: paracetamol, celecoxib, or topical NSAIDs.

Mechanism

SSRIs reduce platelet serotonin uptake – impaired aggregation. With NSAIDs (antiplatelet + GI mucosal damage) – significant GI bleeding risk increase.

Symptoms

GI bleeding, especially in patients over 60 with prior peptic ulcer disease.

Management

In high-risk patients – PPI gastroprotection. Alternative analgesic – paracetamol.

Mechanism

Ibuprofen reduces renal blood flow via PGE2 inhibition. Tacrolimus is nephrotoxic in its own right. Additive acute kidney injury risk in transplant patients.

Symptoms

Reduced urine output, rising creatinine and potassium, oedema. The risk is higher in older patients, in kidney disease, heart failure or liver dysfunction, and with diuretics or angiotensin-converting enzyme inhibitors.

Management

Avoid using tacrolimus with drugs known to harm the kidneys; the list names non-steroidal anti-inflammatory drugs (NSAIDs) and ibuprofen specifically (tacrolimus SmPC). If ibuprofen cannot be avoided, monitor renal function and other adverse effects and adjust the tacrolimus dose if needed (tacrolimus SmPC); monitor renal function closely (ibuprofen SmPC). The US Food and Drug Administration (FDA) also advises monitoring renal function and tacrolimus blood concentrations when tacrolimus is used with nephrotoxic drugs (US tacrolimus label). NSAIDs are highly bound to plasma proteins, so check tacrolimus trough blood concentrations and adjust the dose if needed (tacrolimus SmPC). Use ibuprofen at the lowest dose for the shortest time; it is contraindicated in severe renal impairment (glomerular filtration rate below 30 mL/min) (ibuprofen SmPC).

Mechanism

Similar to losartan + ibuprofen. NSAIDs reduce renal blood flow; the ARB (telmisartan) lowers glomerular pressure. The combination causes acute kidney injury.

Symptoms

Reduced urine output, rising creatinine and potassium, oedema. Symptoms appear earlier in older patients and in chronic kidney disease.

Management

Avoid prolonged combination. If ibuprofen is needed for a short course, use the minimum effective dose for 5–7 days with pantoprazole cover and creatinine monitoring. For chronic analgesia: paracetamol or celecoxib.

Mechanism

Ibuprofen and warfarin compete for plasma protein (albumin) binding. The free warfarin fraction rises and its anticoagulant effect intensifies. In parallel, ibuprofen reversibly inhibits platelet aggregation and damages the gastric mucosa – two additional bleeding mechanisms. INR may rise modestly, but gastrointestinal bleeding risk increases independently of INR.

Symptoms

Black or tarry stools (melena), vomiting blood or coffee-ground material, epigastric pain. Less severe presentations: gum bleeding, epistaxis, bruising. Risk multiplies in patients with a history of peptic ulcer disease.

Management

For analgesia in a warfarinised patient, paracetamol is preferred (up to 2 g/day, short courses). If chronic NSAID therapy is needed, switch to a selective COX-2 inhibitor (celecoxib) with proton pump inhibitor cover and frequent INR monitoring. Topical NSAIDs (gels, creams) deliver minimal systemic absorption and are acceptable.

Mechanism

NSAIDs weaken amlodipine's antihypertensive effect via renal prostaglandin suppression. Additive acute kidney injury risk in dehydration.

Symptoms

Gradual blood pressure rise 1–2 weeks after starting the NSAID. In chronic kidney disease: risk of fluid retention and oedema.

Management

For short ibuprofen courses (5–7 days), monitor blood pressure. For chronic analgesia: switch to paracetamol, celecoxib (with PPI cover), or topical NSAIDs.

Mechanism

Similar to bisoprolol + ketorolac. Ibuprofen weakens the antihypertensive effect of the beta-blocker via renal prostaglandin blockade.

Symptoms

Gradual blood pressure rise 1–2 weeks after starting the NSAID. In chronic kidney disease: risk of fluid retention and oedema.

Management

For short ibuprofen courses (5–7 days), monitor blood pressure. For chronic analgesia: switch to paracetamol, celecoxib (with PPI cover), or topical NSAIDs.

Mechanism

Additive GI ulcer and bleeding risk with systemic budesonide. Inhaled budesonide does not clinically affect risk.

Symptoms

Epigastric pain, heartburn, black or tarry stools, blood in vomit, bruising. Higher risk in older patients, prior peptic ulcer, and concurrent anticoagulants.

Management

On systemic budesonide, limit ibuprofen to short courses (no more than 5–7 days) with pantoprazole 20 mg/day. For long-term analgesia: paracetamol up to 2 g/day. Inhaled budesonide with ibuprofen is safe. In older patients and prior peptic ulcer, risk outweighs benefit — consider paracetamol or topical NSAIDs.

Mechanism

Ibuprofen, like other non-steroidal anti-inflammatory drugs (NSAIDs), can inhibit platelet aggregation and prolong bleeding time (ibuprofen SmPC); clopidogrel also prolongs bleeding time (clopidogrel SmPC). Ibuprofen itself can cause ulcers and gastrointestinal bleeding, and antiplatelet drugs raise the risk of such bleeding (ibuprofen SmPC). The US Food and Drug Administration (FDA) states that clopidogrel with NSAIDs increases the risk of gastrointestinal bleeding (clopidogrel FDA label). In patients who also take low-dose aspirin, ibuprofen may competitively reduce its effect on platelets; with occasional ibuprofen use a clinically relevant effect is unlikely (ibuprofen SmPC).

Symptoms

Bleeding gums, nosebleeds, bruising without injury, black tarry stools, blood in the urine, vomiting blood or coffee-ground material, abdominal pain. The risk of gastrointestinal bleeding is higher in older people, after a previous ulcer, especially one complicated by bleeding or perforation, and with higher ibuprofen doses (ibuprofen SmPC).

Management

Clopidogrel is used with caution with non-steroidal anti-inflammatory drugs (NSAIDs) (clopidogrel SmPC), and ibuprofen with special caution with antiplatelet drugs (ibuprofen SmPC). Use ibuprofen at the lowest effective dose for the shortest time needed to relieve symptoms (ibuprofen SmPC). For patients who need drugs that raise gastrointestinal risk, the ibuprofen SmPC advises considering gastroprotection with misoprostol or a proton pump inhibitor; for older patients and those with a history of ulcer it recommends such protection and a start at the lowest dose (ibuprofen SmPC). Warn the patient that bleeding may last longer on clopidogrel and ask them to report any unusual bleeding or abdominal symptoms at once (clopidogrel and ibuprofen SmPCs). Stop ibuprofen at once if gastrointestinal bleeding or an ulcer occurs (ibuprofen SmPC).

Mechanism

Additive nephrotoxicity. NSAIDs reduce renal blood flow by suppressing vasodilatory prostaglandin synthesis; contrast adds tubular osmotic load. Contrast-induced AKI risk rises.

Symptoms

Decreased urine output, rising creatinine, oedema, nausea. Symptoms develop 24–72 hours after contrast.

Management

Stop ibuprofen 24–48 hours before elective contrast imaging; restart 48 hours after the study once creatinine normalises. With creatinine clearance below 60 mL/min, give IV isotonic hydration 6–12 hours before and after imaging. Alternative: paracetamol up to 3 g/day.

Mechanism

Metamizole is a pyrazolone with central analgesic and spasmolytic action, not a classic NSAID, so the ban on stacking NSAIDs does not apply and direct gastric damage is lower. What it does bring is a risk of its own: the European review summarised by AEMPS confirmed agranulocytosis as a rare, unpredictable reaction and recommended short courses at the lowest dose. The pair is not metabolically neutral either, since metamizole induces CYP2B6 and CYP3A4.

Symptoms

The signal not to miss belongs to metamizole: returning fever, sore throat, mouth ulcers, an infection that will not clear. Any of these during treatment means stopping it and checking a full blood count. From ibuprofen, the digestive and renal risks continue unchanged by the pairing.

Management

They can be alternated in severe acute pain when one alone is not enough, over a few days. Metamizole is not continued unmonitored and is stopped at any new fever or infection. In patients on bupropion, methadone, valproate, ciclosporin, tacrolimus or sertraline, metamizole lowers their levels and another analgesic is the better choice.

Mechanism

There is no direct pharmacokinetic interaction: in the FDA label, ibuprofen 400 mg did not change the concentration of metformin 850 mg, and metformin did not change ibuprofen. The risk runs through the kidney. Ibuprofen, like other non-steroidal anti-inflammatory drugs (NSAIDs), inhibits the synthesis of prostaglandins that maintain renal blood flow. In vulnerable patients it causes fluid retention and an acute drop in kidney function. The kidney clears metformin, so when the glomerular filtration rate (GFR) falls the drug accumulates. Metformin accumulation is the main risk factor for lactic acidosis. The metformin label names NSAIDs directly among drugs that can acutely impair kidney function and raise the risk of lactic acidosis.

Symptoms

The first signal is worsening kidney function: rising creatinine and falling glomerular filtration rate (GFR), less urine, oedema from fluid retention. Elderly patients and those with dehydration, heart failure or diuretic treatment are most at risk. Lactic acidosis starts quietly: acidotic dyspnoea, abdominal pain, muscle cramps, weakness and hypothermia, then reduced consciousness up to coma. Laboratory findings: blood pH below 7.35, lactate above 5 mmol/L, a widened anion gap.

Management

The combination is acceptable under kidney monitoring. Ibuprofen is started with caution in a patient on metformin (metformin label, 4.4), and kidney function is followed closely while both are used (metformin label, 4.5). Glomerular filtration rate (GFR) is measured before metformin is started and then regularly: at least once a year, and every 3–6 months in the elderly and in patients at risk of progressive kidney disease (metformin label, 4.2 and 4.4). At GFR below 30 mL/min both drugs are contraindicated (metformin and ibuprofen labels, 4.3). Ibuprofen is given at the lowest dose for the shortest time, with monitoring, especially in heart, liver or kidney disease, on diuretics and in the elderly (ibuprofen label, 4.4; FDA ibuprofen label, Renal Effects). With dehydration from diarrhoea, vomiting, fever or low fluid intake, metformin is paused (metformin label, 4.4). Ibuprofen is contraindicated in severe dehydration (ibuprofen label, 4.3). No pharmacokinetic dose change is needed: ibuprofen 400 mg does not change metformin 850 mg exposure and vice versa (FDA metformin label, 12.3). If lactic acidosis is suspected (acidotic dyspnoea, abdominal pain, muscle cramps, weakness, hypothermia), metformin is stopped and the patient needs immediate medical care (metformin label, 4.4).

Mechanism

Ibuprofen blocks prostaglandin synthesis in the kidney, which weakens the diuretic, natriuretic and blood-pressure-lowering effect of spironolactone (spironolactone labels). Spironolactone blocks aldosterone, so the kidneys keep potassium; nonsteroidal anti-inflammatory drugs (NSAIDs) given with potassium-sparing diuretics raise the risk of hyperkalaemia (both SmPCs). NSAIDs reduce renal blood flow, and taken with a diuretic they raise the risk of kidney damage, especially in older or dehydrated patients and in those with heart, kidney or liver disease (ibuprofen SmPC).

Symptoms

Hyperkalaemia often causes no symptoms and shows only in blood tests. At higher potassium levels, the patient may have tingling and numbness, muscle weakness and cramps, flaccid paralysis and heart rhythm disturbances (spironolactone SmPC). Worsening kidney function shows as rising creatinine and urea and reduced urine output. If the diuretic effect weakens, oedema increases and weight and blood pressure go up.

Management

Use the combination with caution and check serum potassium while the patient takes both drugs (ibuprofen SmPC). Check potassium within 1 week of starting or increasing spironolactone and regularly after that (spironolactone label, US Food and Drug Administration, FDA). With nonsteroidal anti-inflammatory drugs, more frequent checks may be needed (spironolactone FDA label). Keep the patient well hydrated and check renal function, volume status and the diuretic effect of spironolactone after starting the combination and periodically (ibuprofen SmPC, spironolactone labels). In patients with heart, liver or kidney disease, keep the ibuprofen dose as low and the course as short as possible (ibuprofen SmPC). If hyperkalaemia occurs, reduce the spironolactone dose or stop it (spironolactone FDA label). In severe heart failure, interrupt spironolactone if potassium is above 5 mmol/L or creatinine above 4 mg/dL (spironolactone SmPC). Ibuprofen is contraindicated when the glomerular filtration rate is below 30 mL/min and in New York Heart Association class IV heart failure, and spironolactone in hyperkalaemia or acute renal failure (both SmPCs).

Mechanism

Omeprazole blocks the parietal cell proton pump and lowers the acidity against which ibuprofen leaves the mucosa unprotected by inhibiting prostaglandins. The ibuprofen label recommends exactly this: protective agents, misoprostol or proton pump inhibitors, in patients at risk. They neither compete for metabolism nor cancel each other out.

Symptoms

The pair is meant to prevent symptoms, not cause them. Worth knowing what it does not cover: omeprazole protects neither the kidney nor blood pressure nor the cardiovascular risk of the NSAID, and it does not prevent bleeding from the lower gut. Long PPI courses bring hypomagnesaemia and falling vitamin B12.

Management

The PPI is added with a history of ulcer or bleeding, older age, corticosteroids, anticoagulants or low-dose aspirin alongside. Protection does not extend the NSAID course: ibuprofen stays at the lowest effective dose for the shortest time, and omeprazole is stopped when the NSAID ends unless another indication exists.

Mechanism

Ibuprofen inhibits cyclooxygenase in peripheral tissues, while paracetamol acts mainly centrally and has no appreciable effect on gastric mucosa or platelet aggregation. With different targets, the analgesia adds up: the Cochrane review of single doses in acute postoperative pain found greater relief from the combination than from either drug alone. Paracetamol is not an NSAID, so the ibuprofen label warning against combining several NSAIDs does not apply to it.

Symptoms

The combination adds no symptoms of its own. What shows up after several days belongs to each drug separately: epigastric discomfort, nausea or dark stools from ibuprofen, and liver injury if paracetamol exceeds the 4 g per 24 hours set by the label. That ceiling drops with low body weight, prolonged fasting, regular alcohol use or existing liver disease.

Management

Adults can take them together, or alternate them every 3-4 hours when pain is severe. Daily doses are counted separately for each: paracetamol stays within 4 g per 24 hours, ibuprofen at the lowest effective dose for the shortest time. In children under five with fever, NICE states not to give both at once and to consider alternating only if distress returns before the next dose is due.