Celecoxib

Mechanism

Ketorolac outweighs other NSAIDs in antiplatelet and ulcerogenic effect. Its label places treatment with aspirin or other NSAIDs, selective COX-2 inhibitors included, among the contraindications, and the interactions section states it must not be used with other NSAIDs because of the increased rate of serious class adverse effects: gastrointestinal bleeding and perforation, renal injury, and bleeding from platelet inhibition. Analgesia does not improve when the second drug is added, since the target is the same enzyme family – cyclooxygenase.

Symptoms

Black or tarry stools, coffee-ground vomit, epigastric pain, sudden weakness and pallor from anaemia. Falling urine output and swelling as a sign of renal injury. In older people and those with a history of ulcer the picture may begin with the bleed itself, without preceding pain.

Management

The combination is taken apart: one NSAID remains. For severe pain that is usually ketorolac in a short course within the label limit, with the rest of the analgesia covered by paracetamol, metamizole or an opioid. Gastroprotection with a proton pump inhibitor does not lift the contraindication. After a ketorolac dose, another NSAID is not added until its action ends, not merely until the next scheduled dose.

Mechanism

NSAIDs reduce renal blood flow via prostaglandin blockade. The ACE-I (enalapril) dilates glomerular efferent arterioles. 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

For prolonged celecoxib therapy, check creatinine 2–4 weeks after start, then every 3 months. In older patients and chronic kidney disease, paracetamol is preferable.

Mechanism

Contrast (iopromide) and an NSAID (celecoxib) are both nephrotoxic. NSAID-induced reduction in renal blood flow amplifies contrast-induced nephropathy risk, especially in chronic kidney disease.

Symptoms

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

Management

Stop celecoxib 48 hours before planned contrast and resume 48 hours after with stable renal function. Provide contrast nephroprotection with adequate saline hydration.

Mechanism

NSAIDs (including selective COX-2 inhibitors like celecoxib) reduce renal lithium clearance. Lithium plasma levels rise.

Symptoms

Tremor, muscle twitching, nausea, vomiting, diarrhoea, poor coordination and confusion; severe cases progress to seizures and coma. Toxicity is expected at serum lithium concentrations of about 1.5 mmol/L and above, but some patients develop it at lower levels, including within the therapeutic range.

Management

The UK National Institute for Health and Care Excellence (NICE) advises avoiding non-steroidal anti-inflammatory drugs (NSAIDs) in people on lithium if possible and warning them not to take over-the-counter NSAIDs (NICE CG185). If celecoxib is needed, prescribe it for regular use rather than as needed, and check lithium levels monthly until stable, then every 3 months (NICE CG185). When celecoxib is started or stopped, monitor the patient carefully (celecoxib SmPC), measure lithium more often, moving to weekly checks (lithium SmPC), and reduce the lithium dose according to levels and clinical response if needed (lithium SmPC; US lithium label, FDA). Take the lithium sample 12 hours after the last dose (lithium SmPC). Warn the patient about signs of lithium toxicity: diarrhoea, vomiting, coarse tremor, poor coordination, confusion and seizures (NICE NG222).

Mechanism

Similar to enalapril + celecoxib. NSAIDs reduce renal blood flow; the ARB (losartan) 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

For prolonged celecoxib therapy, check creatinine 2–4 weeks after start, then every 3 months. In older patients and chronic kidney disease, paracetamol is preferable.

Mechanism

NSAIDs can slow renal excretion of methotrexate and increase its blood, gastrointestinal and kidney toxicity (methotrexate SmPCs). For celecoxib itself, no significant effect on methotrexate pharmacokinetics was found at rheumatological doses (celecoxib SmPC). The US celecoxib label (FDA) also states that celecoxib does not change methotrexate pharmacokinetics, but warns that combining NSAIDs with methotrexate may raise the risk of methotrexate toxicity: neutropenia, thrombocytopenia, renal dysfunction.

Symptoms

Mouth ulcers (mucositis), nausea, diarrhoea, hair loss. Blood counts fall: leukocytes, platelets, erythrocytes. Severe cases: fatal pancytopenia, nephrotoxicity.

Management

With high oncological methotrexate doses, NSAIDs are not given before or together with methotrexate (methotrexate 100 mg/ml SmPC). With low rheumatological doses, NSAIDs may continue only under strict medical supervision, and with any kidney impairment, even mild, the combination is not recommended (methotrexate 2.5 mg SmPC). Take care if the NSAID and methotrexate are given within 24 hours of each other, since methotrexate levels can rise (methotrexate 2.5 mg SmPC). While an NSAID is taken, check full blood count and kidney function more often than the usual methotrexate schedule (methotrexate 2.5 mg SmPC). Both celecoxib labels, Spanish and US (FDA), ask for monitoring of methotrexate toxicity, and the US methotrexate label advises close monitoring for methotrexate adverse reactions if the combination cannot be avoided.

Mechanism

Celecoxib (a selective COX-2 inhibitor) reduces renal blood flow via prostaglandin suppression. Tacrolimus is nephrotoxic in its own right. Additive acute kidney injury risk, especially with borderline renal function.

Symptoms

Reduced urine output, rising creatinine and potassium, fluid retention, raised blood pressure. The risk is higher in older patients, in impaired renal or liver function or heart failure, and with diuretics, angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers.

Management

Avoid using tacrolimus with drugs known to harm the kidneys, including non-steroidal anti-inflammatory drugs (NSAIDs) such as celecoxib (tacrolimus SmPC). If celecoxib cannot be avoided, monitor renal function and other adverse effects and adjust the tacrolimus dose if needed (tacrolimus SmPC); renal function must be monitored with this combination (celecoxib 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 concentrations and adjust the dose if needed (tacrolimus SmPC). Measure blood pressure at the start of celecoxib and during treatment (celecoxib SmPC).

Mechanism

Celecoxib and warfarin together have a synergistic effect on bleeding (US celecoxib label, FDA). With the combination, increases in prothrombin time (international normalised ratio, INR) and serious, sometimes fatal, bleeding have been reported, mostly in older patients (celecoxib SmPC). Like other non-steroidal anti-inflammatory drugs (NSAIDs), celecoxib can itself cause ulcers, perforation and bleeding in the stomach and gut (celecoxib SmPC).

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

High doses of non-steroidal anti-inflammatory drugs (NSAIDs) are contraindicated with warfarin (warfarin SmPC). At usual doses, celecoxib is combined with warfarin with caution (celecoxib SmPC). Monitor prothrombin time (international normalised ratio, INR) carefully, especially in the first days after starting celecoxib and after any dose change (celecoxib SmPC), and watch for signs of bleeding (US celecoxib label, FDA). The risk of gastrointestinal bleeding is higher in older patients, in those with a history of ulcer or bleeding, with concomitant aspirin, other NSAIDs or glucocorticoids, and with alcohol use (celecoxib SmPC). Celecoxib is contraindicated in active peptic ulcer or gastrointestinal bleeding (celecoxib SmPC).

Mechanism

Celecoxib is a selective COX-2 inhibitor and does not displace aspirin from COX-1 (unlike ibuprofen/naproxen). Aspirin's antiplatelet effect is preserved. Additive GI bleeding risk persists.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, black or tarry stools. Severe cases: GI bleeding.

Management

The combination is acceptable. Aspirin's cardioprotective effect is preserved. PPI cover with pantoprazole is mandatory in chronic celecoxib therapy. Check blood pressure and creatinine every 3 months.

Mechanism

Celecoxib is a CYP2C9 substrate. Amiodarone weakly inhibits CYP2C9, so celecoxib AUC may rise moderately. Clinically significant amplification of celecoxib side effects is unlikely.

Symptoms

Possible typical celecoxib side effects: dyspepsia, peripheral oedema, BP rise. GI bleeding is rare.

Management

No dose adjustment needed. On long-term celecoxib, check BP and renal function every 3 months. Alternatives for rheumatologic pain: topical NSAIDs, paracetamol up to 2 g/day.

Mechanism

Additive anticholinergic effect (amitriptyline pronounced, celecoxib mild). In older patients, side-effect severity intensifies.

Symptoms

Dry mouth, constipation, urinary retention, accommodation disturbance, tachycardia. In older patients: delirium and confusion risk.

Management

On the combination, reassess the celecoxib benefit — for osteoarthritis, alternatives: topical NSAIDs or paracetamol up to 2 g/day. Avoid the combination in older patients. If unavoidable, cap amitriptyline at 25 mg/day. For constipation: fibre and adequate fluid intake (1.5 L/day).

Mechanism

Apixaban is a direct factor Xa inhibitor, and NSAIDs, including celecoxib, usually increase bleeding risk (apixaban SmPC). Celecoxib has no antiplatelet effect of its own, but it can cause upper gastrointestinal ulcers and bleeding, sometimes fatal (celecoxib SmPC). With an anticoagulant the risks add up.

Symptoms

Gum bleeding, nosebleeds, bruising without injury, black or tarry stools, blood in the urine. Gastrointestinal complications are more likely in older patients, with a history of ulcer or gastrointestinal bleeding, with alcohol use and with glucocorticoids (celecoxib SmPC).

Management

The combination is allowed with caution: both the apixaban SmPC (EMA) and the Spanish celecoxib SmPC, which names apixaban directly, require it (apixaban SmPC, EMA; celecoxib SmPC). Give celecoxib at the lowest effective daily dose for the shortest possible time and review the need for it regularly (celecoxib SmPC). Take particular care in older patients, in those with a history of ulcer or gastrointestinal bleeding, and in those who drink alcohol or take glucocorticoids or antiplatelet drugs (celecoxib SmPC). The US apixaban label asks doctors to explain the signs of blood loss and to tell patients to report them at once; apixaban is stopped in active pathological bleeding (US apixaban label).

Mechanism

Glucocorticoid plus NSAID — additive GI ulcer risk with systemic budesonide. Celecoxib (selective COX-2 inhibitor) gives lower gastric risk than non-selective NSAIDs, but the effect persists.

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 and celecoxib, in older patients, prior peptic ulcer, or long-term therapy: pantoprazole 20 mg/day. Alternatives in osteoarthritis: topical NSAIDs, paracetamol up to 2 g/day. Inhaled budesonide with celecoxib is safe.