Interactions : אינטראקציות

4.5       Interaction with other medicinal products and other forms of interaction

This medicinal product should not be taken with other medicinal products containing paracetamol, ibuprofen, acetylsalicylic acid, salicylates or with any other anti-inflammatory drugs (NSAIDs) unless under a doctor’s instruction.

Ibuprofen:
As with other ibuprofen-containing products, the following combinations with Combodex IV should be avoided:
• The dicumarol group: NSAIDs may increase the effect of anticoagulants such as warfarin.
Experimental studies show that ibuprofen reinforces the effects of warfarin on bleeding time.
NSAIDs and the dicumarol group are metabolised by the same enzyme, CYP2C9.
• Antiplatelet agents: NSAIDs should not be combined with antiplatelet agents such as ticlopidine due to the additive inhibition of the platelet function (see below).
• Methotrexate: NSAIDs inhibit the tubular secretion of methotrexate and some metabolic interaction with reduced clearance of methotrexate may also occur as a result. The risk of a potential interaction between an NSAID and methotrexate should also be taken into account in connection with low-dose treatment with methotrexate, especially in patients with renal impairment. Whenever combination treatment is given, renal function should be monitored.
Caution should be exercised if both an NSAID and methotrexate are given within 24 hours, as the plasma levels of methotrexate can increase, resulting in increased toxicity. Accordingly, in high-dose treatment with methotrexate one should always avoid prescribing NSAIDs.
•   Acetylsalicylic acid: Concomitant administration of ibuprofen and acetylsalicylic acid is not generally recommended because of the potential of increased adverse effects. Experimental data suggest that ibuprofen may competitively inhibit the effect of low dose acetylsalicylic acid on platelet aggregation when they are dosed concomitantly. Although there are uncertainties regarding extrapolation of these data to the clinical situation, the possibility that regular, long- term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid cannot be excluded. No clinically relevant effect is considered to be likely for occasional ibuprofen use (see section 5.1).
•   Lithium: Ibuprofen reduces the renal clearance of lithium, as a result of which serum lithium levels may rise. The combination should be avoided unless frequent checks of serum lithium can be carried out and a possible reduction in the dose of lithium made.
•   Cardiac glycosides: NSAIDs can exacerbate heart failure, reduce glomerular filtration and increase plasma cardiac glycoside (e.g. digoxin) levels.
•   Mifepristone: A decrease of the efficacy of the medicinal product can theoretically occur due to the antiprostaglandin properties of non-steroidal anti-inflammatory drugs (NSAIDs) including acetylsalicylic acid. Limited evidence suggests that co-administration of NSAIDs on the day of prostaglandin administration does not adversely influence the effects of mifepristone or the prostaglandin on cervical ripening or uterine contractility and does not reduce the clinical efficacy of medical termination of pregnancy
•   ACE inhibitors and angiotensin-II antagonists: There is an increased risk of acute renal failure, usually reversible, in patients with renal impairment (e.g. dehydrated and/or elderly patients) when treatment with ACE inhibitors or angiotensin-II antagonists is given at the same time as NSAIDs, including selective cyclooxygenase-2 inhibitors. The combination should, therefore, be given with care to patients with renal impairment, especially elderly patients. Patients should be adequately hydrated and a check of renal function should be considered after the initiation of combination treatment and at regular intervals during treatment (see section 4.4).
•   Beta-blockers: NSAIDs counteract the antihypertensive effect of beta-adrenoceptor blocking drugs.
•   Sulphonylureas: There are rare reports of hypoglycaemia in patients on sulphonylurea medications receiving ibuprofen.
•   Zidovudine: There is evidence of an increased risk of haemarthroses and haematoma in HIV(+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.
•   Quinolone antibiotics: animal data indicate that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may have increased risk of developing convulsions.
•   Thiazides, thiazide-related preparations and loop diuretics: NSAIDs can counteract the diuretic effect of furosemide and bumetanide, possibly through inhibition of prostaglandin synthesis.
They can also counteract the antihypertensive effect of thiazides.
•   Potassium sparing diuretics: The concomitant use may lead to hyperkalaemia.
•   Aminoglycosides: NSAIDs may reduce the excretion of aminoglycosides.
•   Selective serotonin re-uptake inhibitors (SSRIs): SSRIs and NSAIDs each entail an increased risk of bleeding, e.g. from the gastrointestinal tract. This risk is increased by combination therapy.
The mechanism may possibly be linked to reduced uptake of serotonin in the platelets (see section        4.4).
•   Cyclosporine: The concomitant administration of NSAIDs and cyclosporine is thought to be capable of increasing the risk of nephrotoxicity due to decreased synthesis of prostacyclin in the kidney. Accordingly, in the event of combination treatment, renal function must be monitored closely.
•   Captopril: Experimental studies indicate that ibuprofen counteracts the effect of captopril on sodium excretion.
•   Tacrolimus: Concomitant administration of NSAIDs and tacrolimus is thought to be capable of increasing the risk of nephrotoxicity due to decreased synthesis of prostacyclin in the kidney.
Accordingly, in the event of combination treatment, renal function should be monitored closely.
•   Corticosteroids: Concomitant treatment gives rise to an increased risk of gastrointestinal ulceration or bleeding.
•   CYP2C9 Inhibitors: Concomitant administration of ibuprofen with CYP2C9 inhibitors may increase the exposure to ibuprofen (CYP2C9 substrate). In a study with voriconazole and fluconazole (CYP2C9 inhibitors) an increased S(+)-ibuprofen exposure by approximately 80 to 100% has been shown. Reduction of the ibuprofen dose should be considered when potent CYP2C9 inhibitors are administered concomitantly, particularly when high-dose ibuprofen is administered with either voriconazole or fluconazole.
•   Phenytoin: Plasmatic levels of phenytoin may be increased in the concomitant treatment with ibuprofen and therefore the risk of toxicity may increase.
•   Probenecid and sulfinpyrazone: Medicinal products that contain probenecid or sulfinpyrazone may delay the excretion of ibuprofen.
•   Herbal extracts: Ginkgo biloba may potentiate the risk of bleeding with NSAIDs.

Paracetamol:
• Probenecid inhibits the binding of paracetamol to glucuronic acid, thus leading to a reduction in paracetamol clearance by a factor of approximately 2. In patients concurrently taking probenecid, the paracetamol dose should be reduced.
• Enzyme-inducing drugs such as certain antiepileptics (phenytoin, phenobarbital, carbamazepine) decreased plasma AUC of paracetamol to approximately 60% in pharmacokinetic studies. Other substances with enzyme-inducing properties (i.e. rifampicin, Hypericum) could also result in decreased concentrations of paracetamol. In addition, the risk of liver damage during treatment with the maximum recommended dose of paracetamol is probably higher in patients who receive enzyme-inducing drugs.
• Zidovudine may affect paracetamol metabolism and vice versa, which may add to the toxicity of both.
• Anticoagulant drugs (warfarin) - dosage may require reduction if paracetamol and anticoagulants are taken for a prolonged period of time.
• Severe hepatotoxicity at therapeutic doses or moderate overdoses of paracetamol has been reported in patients receiving isoniazid alone or with other drugs for tuberculosis • Paracetamol may affect the pharmacokinetics of chloramphenicol. Monitoring of chloramphenicol plasma levels is recommended if combining paracetamol with chloramphenicol injection treatment.
• Ethyl alcohol potentiates paracetamol toxicity, possibly by inducing hepatic production of paracetamol-derived hepatotoxic products.
• Caution should be taken when paracetamol is used concomitantly with flucloxacillin as concurrent intake has been associated with high anion gap metabolic acidosis, especially in patients with risks factors (see section 4.4)

Effects on laboratory tests
Intake of paracetamol can affect tests for uric acid using phosphotungstic acid and blood sugar tests using glucose-oxidase-peroxidase.

Paediatric population
Interaction studies have only been performed in adults.