chapter
Non-steroidal anti-inflammatory drugs (NSAIDs)
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Additive effect; both drugs lower the seizure threshold

Avoid co-administration

NEFOPAM MAOIs Risk of arrhythmias Additive effect; both drugs have sympathomimetic effects

Avoid co-administration

NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs)

NSAIDs ANALGESICS

NSAIDs ANTACIDS 1. Magnesium hydroxide ≠ absorption of ibuprofen, flurbiprofen, mefenamic acid and tolfenamic acid 2. Aluminium-containing antacids ↓ absorption of these NSAIDs

Uncertain These effects are ↓ by taking these drugs with food

NSAIDs NSAIDs ≠ risk of gastrointestinal bleeding Additive effect. Avoid co-administration

PARECOXIB ANTIARRHYTHMICS – FLECAINIDE, PROPAFENONE

Possible ≠ flecainide or propafenone levels

Parecoxib weakly inhibits CYP2D6 Monitor PR and BP closely. If possible, use only short courses of NSAID

NSAIDs ANTIBIOTICS

INDOMETACIN AMINOGLYCOSIDES ≠ amikacin, gentamicin, and vancomycin levels in neonates

Uncertain; indometacin possibly ↓ renal clearance of these aminoglycosides

Halve the dose of antibiotic. Uncertain whether this applies to adults but suggest check levels. Otherwise use an alternative NSAID

INDOMETACIN CEPHALOSPORINS Indometacin ≠ ceftazidime levels in neonates

Indometacin ↓ clearance of ceftazidime

↓ dose of ceftazidime

NSAIDs QUINOLONES Reports of convulsions when NSAIDs are added to quinolones in epileptic patients

Unknown Take care in co-administering epileptics and NSAIDs in epileptic patients

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ANALGESICS NON-STEROIDAL ANTI-INFLAMMATORY DRUGS

Rifampicin ≠ CYP2C9-mediated metabolism of these NSAIDs

Monitor analgesic effects; consider using alternative NSAIDs

NSAIDs CYTOTOXICS 1. ≠ risk of bleeding with erlotinib 2. ≠ plasma concentrations of celecoxib, diclofenac and piroxicam, with risk of toxic effects when co-administered with imatinib 3. ≠ risk of photosensitivity reactions when porfimer is co-administered with celecoxib, ibuprofen, ketoprofen or naproxen

1. Additive effect 2. Imatinib is a potent inhibitor of CYP2C9, which metabolizes celecoxib, diclofenac and piroxicam 3. Attributed to additive effects

1. Avoid co-administration 2. Monitor for toxic effects of celecoxib (flatulence, insomnia, pharyngitis, stomatitis, palpitations, paraesthesia), diclofenac (nausea, diarrhoea, gastrointestinal bleeding, rashes, angioedema, renal damage) and piroxicam (e.g. gastrointestinal effects). It is necessary to monitor effects 2 weeks after initiating treatment with piroxicam, and the use of a gastroprotective agent is advised by CSM 3. Avoid exposure of skin and eyes to direct sunlight for 30 days after porfimer therapy

NSAIDs CICLOPSORIN 1. ≠ risk of renal failure with NSAIDs 2. Diclofenac levels ≠ by ciclosporin 3. Rofecoxib ↓ plasma concentrations of ciclosporin, with risk of transplant rejection

1. Additive effect; both can cause renal insufficiency 2. Uncertain 3. Rofecoxib is a mild inducer of CYP3A4 and not a substrate of CYP3A4

1. Monitor renal function closely 2. Halve the dose of diclofenac 3. Be aware. May not be clinically significant

NSAIDs CORTICOSTEROIDS 1. ≠ risk of gastrointestinal ulceration and bleeding 2. Parecoxib levels may be ↓ by dexamethasone

1. Additive effect 2. Dexamethasone induces CYP3A4-mediated metabolism of parecoxib

1. Watch for early signs of gastrointestinal upset; remember that corticosteroids may mask these features 2. Watch for poor response to parecoxib

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Mechanism Precautions

indometacin and possibly diclofenac, flurbiprofen, ketoprofen, meloxicam and naproxen

Uncertain; postulated that an NSAID-induced ↓ in renal perfusion may have an effect

Consider using an alternative NSAID

NSAIDs MYCOPHENOLATE, PENICILLAMINE, SIROLIMUS, TACROLIMUS

≠ risk of nephrotoxicity Additive effect Monitor renal function closely

NSAIDs ANTICOAGULANTS

NSAIDs ANTICOAGULANTS – ORAL 1. Risk of gastrointestinal bleeding with all NSAIDs 2. Possible ≠ anticoagulant effect with celecoxib, etoricoxib, flurbiprofen, piroxicam and sulindac

1. NSAIDs irritate the gastric mucosa and can cause bleeding, which is exacerbated by anticoagulants 2. Uncertain but possibly a combination of impaired hepatic metabolism and displacement of anticoagulants from their plasma proteins

1. Extreme caution when co-administering; monitor patients closely 2. Monitor INR closely

NSAIDs ANTICOAGULANTS – PARENTERAL

1. Risk of prolonged bleeding when ketorolac is co-administered with dalteparin (but not enoxaparin), and intravenous diclofenac is given with heparins 2. ≠ risk of hyperkalaemia when ketorolac is given with heparin

1. Uncertain 2. Heparin inhibits aldosterone secretion, causing hyperkalaemia

1. Avoid co-administration 2. Monitor potassium levels closely

NSAIDs ANTIDEPRESSANTS

NSAIDs LITHIUM NSAIDs may ≠ lithium levels; cases of toxicity have been reported

Uncertain; possibly NSAIDs ↓ renal clearance of lithium

Monitor lithium levels closely

NSAIDs SSRIs, VENLAFAXINE Slight ≠ risk of bleeding Unknown Warn patients to watch for early signs of bleeding

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ANALGESICS NON-STEROIDAL ANTI-INFLAMMATORY DRUGS

impairment due to NSAIDs. Phenylbutazone is likely to ↓ renal elimination of metformin and ≠ plasma levels

These drugs are often used in the long term. NSAIDs can cause renal dysfunction. As metformin is not protein-bound, as are the sulphonylureas, displacement from such binding sites is unlikely

Do not use metformin if serum creatinine is 1.5 mg/dL in males and1.4 mg/dL in females, or creatinine clearance is 30 mL/min. Use with caution in patients who have a creatinine clearance of 30-60 mL/min. Warn patients about hypoglycaemia ➣ For signs and symptoms of hypoglycaemia, see Clinical Features of Some Adverse Drug Interactions, Hypoglycaemia

NSAIDs SULPHONYLUREAS Enhanced hypoglycaemic effect of sulphonylureas with most NSAIDs, which are highly protein bound. There have been reports of hyperglycaemia and hypoglycaemia (e.g. with diclofenac)

Attributed to displacement of sulphonylureas from proteinbinding sites, thus increasing the plasma concentration. Some NSAIDs may impair the renal elimination of sulphonylureas, particularly chlorpropamide

Be aware. Conflicting reports. Suggestions that sulindac and Arthrotec may interact minimally

NSAIDs ANTIEMETICS 1. Metoclopramide speeds up the onset of action of tolfenamic acid 2. Metoclopramide ↓ efficacy of ketoprofen

Metoclopramide promotes gastric emptying 1. Tolfenamic acid reaches its main site of absorption in the small intestine more rapidly 2. Ketoprofen has low solubility and has less time to dissolve in the stomach; therefore less ketoprofen is absorbed

1. This interaction can be used beneficially to hasten the onset of analgesia 2. Take ketoprofen at least 2 hours before metoclopramide

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Mechanism Precautions

2. Report of ≠ phenytoin levels when celecoxib added

1. Carbamazepine and phenytoin induce CYP3A4-mediated metabolism of parecoxib 2. Uncertain; possibly competitive inhibition of CYP2C9-mediated metabolism of phenytoin

1. Watch for poor response to parecoxib 2. Monitor phenytoin levels

NSAIDs ANTIFUNGALS – FLUCONAZOLE

Fluconazole ≠ celecoxib and possibly parecoxib levels

Fluconazole inhibits CYP2C9mediated metabolism of celecoxib and parecoxib

Halve the dose of celecoxib and start parecoxib at the lowest dose

NSAIDs ANTIGOUT DRUGS – PROBENECID

≠ levels of indometacin, ketorolac and possibly dexketoprofen, ketoprofen, naproxen, tenoxicam and tiaprofenic acid

Probenecid competitively inhibits renal metabolism of these NSAIDs

Watch for signs of toxicity of these NSAIDs. Consider using an alternative NSAID. The manufacturers of ketorolac advise avoiding co-administration of ketorolac and probenecid

NSAIDs ANTIHYPERTENSIVES AND HEART FAILURE DRUGS

NSAIDs ANTIHYPERTENSIVES AND HEART FAILURE DRUGS

↓ hypotensive effect, especially with indometacin. The effect is variable among different ACE inhibitors and NSAIDs, but is most notable between captopril and indometacin

NSAIDs cause sodium and water retention and raise BP by inhibiting vasodilating renal prostaglandins. ACE inhibitors metabolize tissue kinins (e.g. bradykinin), and this may be the basis for indometacin attenuating the hypotensive effect of captopril

Monitor BP at least weekly until stable. Avoid co-administering indometacin with captopril

NSAIDs ACE INHIBITORS, ANGIOTENSIN II RECEPTOR ANTAGONISTS

1. ≠ risk of renal impairment with NSAIDs and ACE inhibitors 2. ≠ risk of hyperkalaemia with ketorolac

1. Additive effect 2. Ketorolac causes hyperkalaemia, and ACE inhibitors can ↓ renal function

1. Monitor renal function and BP closely. Benefits often outweigh risks for short-term NSAID use 2. Ketorolac is licensed only for shortterm control of perioperative pain. Monitor serum potassium daily

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ANALGESICS NON-STEROIDAL ANTI-INFLAMMATORY DRUGS

Etoricoxib inhibits sulphotransferase activity

Monitor BP closely

SIBUTRAMINE

Additive effect Avoid co-administration

NSAIDs ANTIPLATELET AGENTS

NSAIDs ASPIRIN 1. Risk of gastrointestinal bleeding when aspirin, even low dose, is co-administered with NSAIDs 2. Ibuprofen ↓ antiplatelet effect of aspirin

1. Additive effect 2. Ibuprofen competitively inhibits binding of aspirin to platelets

1. Avoid co-administration 2. Avoid co-administration

NSAIDs CLOPIDOGREL 1. Risk of gastrointestinal bleeding when clopidogrel is co-administered with NSAIDs 2. Case report of intracerebral haemorrhage when clopidogrel is given with celecoxib

1. NSAIDs may cause gastric mucosal irritation/ulceration; clopidogrel inhibits platelet aggregation 2. Uncertain; possible that celecoxib inhibits CYP2D6-mediated metabolism of clopidogrel

1. Warn patients to report immediately any gastrointestinal symptoms; use NSAIDs for as short a course as possible 2. Avoid co-ingestion of clopidogrel and celecoxib

NSAIDs ANTIPSYCHOTICS 1. Reports of ≠ sedation when indometacin was added to haloperidol 2. Risk of agranulocytosis when azaproprazone is given with clozapine

1. Unknown 2. Unknown 1. Avoid co-administration 2. Avoid co-administration

NSAIDs ANTIVIRALS

NSAIDs NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS

Risk of haematological effects of zidovudine with NSAIDs

Unknown Avoid co-administration

NSAIDs PROTEASE INHIBITORS Ritonavir ≠ piroxicam levels Uncertain; ritonavir is known to inhibit CYP2C9, for which NSAIDs are substrates

Avoid co-administration

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Mechanism Precautions

blockers with indometacin, piroxicam, and possibly ibuprofen and naproxen. Other NSAIDs do not seem to show this effect

Additive toxic effects on kidney, salt and water retention by NSAIDs. NSAIDs can raise BP by inhibiting the renal synthesis of vasodilating prostaglandins. Uncertain why this effect is specific to these NSAIDs

Watch for ↓ response to beta-blockers with indometacin, piroxicam, ibuprofen and naproxen

PARECOXIB METOPROLOL Risk of ≠ hypotensive efficacy of metoprolol

Metoprolol is metabolized by CYP2D6, which is inhibited by valdecoxib

Monitor BP at least weekly until stable. Warn patients to report symptoms of hypotension (light-headedness, dizziness on standing, etc.)

NSAIDs BISPHOSPHONATES – ALENDRONATE

Risk of oesophagitis/peptic ulceration

Additive effect Avoid co-administration

NSAIDs BRONCHODILATORS – BETA-2 AGONISTS

Etoricoxib may ≠ oral salbutamol levels

Etoricoxib inhibits sulphotransferase activity

Monitor PR and BP closely

NSAIDs CALCIUM CHANNEL BLOCKERS

↓ antihypertensive effect of calcium channel blockers

NSAIDs cause salt retention and vasoconstriction at possibly both renal and endothelial sites

Monitor BP at least weekly until stable

NSAIDs CARDIAC GLYCOSIDES Diclofenac, indometacin and possibly fenbufen, ibuprofen and tiaprofenic ≠ plasma concentrations of digoxin and ≠ risk of precipitating cardiac failure and renal dysfunction

Uncertain. Postulated that NSAIDinduced renal impairment plays a role; however, since all NSAIDs have this effect, it is not understood why only certain NSAIDs actually influence digoxin levels

Monitor renal function closely; watch for digoxin toxicity and check levels if necessary

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ANALGESICS NON-STEROIDAL ANTI-INFLAMMATORY DRUGS

bolic pathway and the alternative pathways are either genetically deficient or affected

Modafinil is a moderate inhibitor of CYP2C9

Be aware

NAPROXEN MODAFINIL May cause ↓ naproxen levels if CYP1A2 is the predominant metabolic pathway and alternative metabolic pathways are either genetically deficient or affected

Modafinil is moderate inducer of CYP1A2 in a concentrationdependent manner

Be aware

NSAIDs DESMOPRESSIN ≠ efficacy of desmopressin with indometacin

Uncertain Monitor U&Es and BP closely

NSAIDs DIURETICS – POTASSIUMSPARING AND ALDOSTERONE ANTAGONISTS

Risk of hyperkalaemia with NSAIDs Renal insufficiency caused by NSAIDs can exacerbate potassium retention by these diuretics

Monitor renal function and potassium closely

NSAIDs – CELECOXIB DRUG DEPENDENCE THERAPIES – BUPROPION

≠ plasma concentrations of these substrates, with risk of toxic effects

Bupropion and its metabolite hydroxybupropion inhibit CYP2D6

Initiate therapy of these drugs at the lowest effective dose

NSAIDs LIPID-LOWERING DRUGS Colestyramine ↓ absorption of some NSAIDs

Colestyramine binds NSAIDs in the intestine, reducing their absorption; it also binds those NSAIDs with a significant enterohepatic recirculation (meloxicam, piroxicam, sulindac. tenoxicam)

Give NSAID 1 hour before or 4-6 hours after colestyramine; however, meloxicam, piroxicam, sulindac or tenoxicam should not be given with colestyramine