Interactions : אינטראקציות

4.5. Interaction with other medicinal products and other forms of interaction

Risk related to hyperkalemia:
Certain medicinal products or therapeutic groups may promote hyperkalemia: potassium salts, potassium-sparing diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, non-steroidal anti-inflammatory drugs, heparins (low-molecular-weight or unfractionated), immunosuppressants such as cyclosporin or tacrolimus, trimethoprim.

This risk is potentiated when the above-mentioned drugs are used concomittantly with ketoprofen. It is particularly high with potassium-sparing diuretics, especially when more than one are used together or when they are co-administered with potassium salts, whereas co- administration of an ACE inhibitor and NSAID, for instance, presents a lesser risk as long as the recommended precautions are implemented.

In order to identify the risks and restrictions specific to hyperkalemic agents, the interactions specific to each substance should be referred to.

However, for certain substances, such as trimethoprim, no specific interactions have been described in terms of this risk. Nevertheless, these substances may act as promoting factors when combined with other medicinal products such as those mentioned above.
Patients require strict clinical and laboratory monitoring when the following agents are co- administered with ketoprofen:

Inadvisable combinations

+ Other NSAIDs (including high-dose aspirin)
Increased risk of gastrointestinal ulcers and bleeding (additive effects).
At anti-inflammatory doses of aspirin (≥ 1 g per dose and/or ≥ 3 g daily), or at analgesic or antipyretic doses (≥ 500 mg per dose and/or < 3 g daily).
+ Oral anticoagulants
Increased risk of bleeding related to the oral anticoagulant (damage to the gastroduodenal mucosa by NSAIDs). NSAIDs are liable to increase the effects of anticoagulants, such as warfarin (see Section 4.4).
If the combination cannot be avoided, close clinical and laboratory monitoring should be carried out.
+ Unfractionated or low-molecular-weight heparins and related substances (at curative doses and/or in elderly subjects)
Increased risk of bleeding (inhibition of platelet function and damage to the gastroduodenal mucosa by NSAIDs).
If the combination cannot be avoided, close clinical monitoring should be carried out.
+ Lithium
Increased blood lithium possibly reaching toxic levels (reduced renal excretion of lithium).
If the combination cannot be avoided, blood lithium levels should be closely monitored, and lithium dosage adjusted during co-administration and after discontinuation of the NSAID.
+ Methotrexate used at doses higher than 15 mg/week
Increased hematological toxicity of methotrexate (reduced renal clearance of methotrexate due to anti-inflammatory drugs).
An interval of at least 12 hours should be allowed between discontinuing or starting treatment with ketoprofen and administration of methotrexate.
+ Pemetrexed (in patients with mild to moderate renal function impairment, creatinine clearance between 45 ml/min and 80 ml/min)
Risk of increased pemetrexed toxicity (reduced renal clearance of pemetrexed due to NSAIDs).
Combinations requiring precautions for use
+ Diuretics, ACE inhibitors, angiotensin II receptor antagonists
Acute renal failure in patients at risk (elderly subjects and/or dehydrated patients) due to decreased glomerular filtration (inhibition of vasodilatory prostaglandins by NSAIDs).
In addition, decrease in the antihypertensive effect.
Patients should be hydrated and renal function monitored at the start of treatment.
+ Methotrexate used at low doses (≤ 15 mg/week)
Increased hematological toxicity of methotrexate (reduced renal clearance of methotrexate).
Weekly blood count monitoring during the first few weeks of the combination.


Monitoring should be increased if there is even minor impairment of renal function, and in elderly subjects.
+ Pemetrexed (in patients with normal renal function)
Risk of increased pemetrexed toxicity (reduced renal clearance of pemetrexed due to NSAIDs).
Laboratory monitoring of renal function should be carried out.
+ Cyclosporin, tacrolimus
Risk of additive nephrotoxic effects, particularly in elderly subjects.
Renal function should be monitored at the start of treatment.
+ Corticosteroids : increased risk of gastrointestinal ulceration and bleeding.
+ Pentoxifylline: There is an increased risk of bleeding. More frequent clinical monitoring and monitoring of bleeding time is required.
+ Mifepristone – NSAIDs should not be used for 8-12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.


Combinations to be taken into account
+ Acetylsalicylic acid used at antiplatelet doses (50 to 375 mg per day as one or more doses)
Increased risk of gastrointestinal ulcers and bleeding.
+ Glucocorticoids (except hydrocortisone as a replacement therapy)
Increased risk of gastrointestinal ulcers and bleeding (see Section 4.4).
+ Platelet aggregation inhibitors and selective serotonin reuptake inhibitors (SSRIs) Increased risk of gastrointestinal bleeding (see Section 4.4).
+ Unfractionated and low-molecular-weight heparins (at preventive doses) Increased risk of bleeding.
+ Deferasirox
Increased risk of gastrointestinal ulcers and bleeding.
+ Beta-blockers (except esmolol)
Reduced antihypertensive effect (inhibition of vasodilatory prostaglandins by NSAIDs and water and sodium retention with pyrazole NSAIDs).

+ other antiplatelet agents (ticlopidine,clopidogrel, tirofiban, eptifibatide and abciximab, iloprost), heparin at prophylactic doses: increased risk of hemorrhage.

+ other drugs inducing hyperkalemia: potassium salts, potassium-containing diuretics, angiotensin-converting enzyme inhibitors, angiotensin II inhibitors, other non-steroidal anti- inflammatory drugs, low molecular weight or unfractionated heparin, cyclosporin, tacrolimus and trimethoprim: risk of hyperkalemia.

+ Quinolone antibiotics: Animal data indicate that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may have an increased risk of developing convulsions.
+ Thrombolytics: Increased risk of bleeding.


+ Probenecid: Concomitant administration of probenecid may markedly reduce the plasma clearance of ketoprofen