Interactions : אינטראקציות

4.5 Interaction with other medicinal products and other forms of interaction
Medicinal product interactions with other substances that might be caused by each individual ingredient are well-known and there is no indication that those might change through combined use. There are no safety-relevant interactions between acetylsalicylic acid and paracetamol.

Table 4-1 Acetylsalicylic acid (ASA)                  Possible outcome: Combination of Acetylsalicylic acid with:
There is an increased risk of GI ulcers and
Other Non-Steroidal Anti- Inflammatory Drugs        haemorrhages due to synergic effects. If (NSAIDs)                                            concurrent use is necessary, where appropriate, the use of gastroprotection may be considered for prophylaxis of NSAID- induced GI damage. Thus, concomitant use is not recommended (see section 4.4).
There is an increased risk of GI ulceration or
Corticosteroids                                     bleeding due to synergic effects. It may be advisable to consider the use of gastroprotection in patients taking ASA and corticosteroids, especially if they are elderly.
Thus, concomitant use is not recommended
(see section 4.4).
ASA can increase the anticoagulant effect.
Oral anticoagulants (e.g. coumarin derivatives)     Clinical and laboratory monitoring of the bleeding time and prothrombin time should be performed. Concomitant use is therefore not recommended (see section 4.4).
There is an increased risk of bleeding.
Thrombolytics                               Particularly, treatment with ASA should not be initiated within the first 24 hours after treatment with alteplase in acute stroke patients. Concomitant use is therefore not recommended (see section 4.4).
Heparin & Platelet aggregation inhibitors           There is an increased risk of bleeding. Clinical (ticlopidine, clopidogrel, cilostazol)              and laboratory monitoring of the bleeding time should be performed. Concomitant use is therefore not recommended (see section 4.4).
They could affect coagulation or platelet
Selective Serotonin Reuptake Inhibitors (SSRIs)     function when concomitantly taken with ASA, leading to increased occurrence of bleeding in general, and in particular GI bleeding.
Therefore, concomitant use should be avoided.

Phenytoin                                           ASA increases its serum levels; serum phenytoin should be well monitored.



Valproate                    ASA inhibits its metabolism and hence could increase its toxicity; valproate levels should be wellmonitored.
Aldosterone antagonists      ASA may reduce their activity due to inhibition of urinary sodium excretion; (spironolactone,             blood pressure should be wellmonitored.
canrenoate)
Loop diuretics (e.g.         ASA may reduce their activity due to competition and inhibition of urinary furosemide)                  prostaglandins. NSAIDs can cause acute kidney failure, especiallyin dehydrated patients. If a diuretic is administered simultaneously with ASA, it is necessary to ensure adequate hydration of the patient and to monitor the kidney function and blood pressure, particularly when starting diuretic treatment.

Antihypertensives (ACE-      ASA may reduce their activity due to competition and inhibition of urinary inhibitors, angiotensin II   prostaglandins. This combination could lead to acute kidney failure in elderly or receptor antagonists,        dehydrated patients. It is recommended that blood pressure and renal function calcium-channel blockers)    should be well monitored when starting treatment andthe patient should be regularly hydrated. In case of association with verapamil the bleeding time should be also monitored.
Uricosurics (e.g.            ASA may reduce their activity due to inhibition of tubular resorption, probenecid,                  leading to high plasma levels of ASA.
sulfinpyrazone)
Methotrexate                 ASA, like all NSAIDs, reduces the tubular secretion ofmethotrexate, increasing ≤ 15 mg/week                 its plasma concentrations and thereby also its toxicity.The concomitant use of NSAIDs is therefore not recommended in patients treated with high doses of methotrexate (see section 4.3). The risk of interactions between methotrexate and NSAIDs must also beconsidered for patients who take low doses of methotrexate, especially thosewith altered kidney function. If combined treatment is necessary, the complete blood count, liver and renal functions should be monitored, especially during the first days of treatment.

Sulphonylureas and insulin   ASA increases their hypoglycaemic effect, thus some downward readjustment of the dosage of the antidiabetic may be appropriate if large doses of salicylates are used. Increased blood glucose controls are recommended.

Alcohol                      There is an increased risk of GI bleeding; this combination shouldbe avoided
Table 4-2 Paracetamol

Combination of              Possible outcome: paracetamol with:
Liver enzyme inducers or potentially hepatotoxic     Increased toxicity of paracetamol that could lead to liver damage even with substances (eg., alcohol,   otherwise harmless doses of paracetamol; therefore, liver function should rifampicin, isoniazide,     be monitored (see section 4.4). Concomitant use is not recommended.
hypnotics and antiepileptics including phenobarbital, phenytoin and carbamazepine)
Chloramphenicol             Paracetamol may increase the risk of elevated plasma concentrations of chloramphenicol. Concomitant use is not recommended.
Zidovudine                  Paracetamol could increase the tendency to develop neutropenia; therefore, the hematological blood monitoring should be performed.
Concomitant use is not recommended unless monitored by a doctor.
Probenecid                  It reduces paracetamol clearance, thus paracetamol doses should be decreased when combined with these agents. Concomitant use is not


 recommended.
Oral anticoagulants         The repeated use of paracetamol for more than one week increases anticoagulant effects. Sporadic doses of paracetamol do not have a significant effect.
Propantheline or other      These agents delay paracetamol absorption; rapid pain relief may be agents that lead to slowing delayed and reduced.
of gastric emptying

Metoclopramide or other These active substances accelerate the paracetamol absorption with agents that lead to     increase of the effectiveness and onset of analgesia.
acceleration of gastric emptying
Cholestyramin           It reduces paracetamol absorption; therefore cholestyramin should not be given within 1 hour of paracetamol if maximal analgesia is to be achieved.

Table 4-3 Caffeine

Combination of              Possible outcome: caffeine with:
Hypnotic agents            Concomitant use can reduce the hypnotic effect, or antagonize the (eg., benzodiazepines,    anticonvulsive effects of barbiturates. Concomitant use is therefore not barbiturates,     recommended. If needed, the combination may possibly be more useful in antihistamines, etc)      the morning.
Lithium                    Caffeine withdrawal increases serum lithium since renal clearance of lithium can be increased by caffeine, therefore when caffeine is withdrawn, it may be necessary to reduce the dose of lithium. Concomitant use is therefore not recommended.
Disulfiram                 Alcoholic patients who are recovering using treatment with disulfiram must be warned to avoid the use of caffeine in order to avoid the risk of alcohol abstinence syndrome worsening due to caffeine-induced cardiovascular and cerebral excitation.
Substances of the          Their combination could have an increased dependency potential.
ephedrine type            Concomitant use is therefore not recommended.
Sympathomimetics           Their combination could have an enhanced tachycardic effect due or levothyroxine          to synergic effects. Concomitant use is therefore not recommended.
Theophylline               Concomitant use could reduce the excretion of theophylline.
Antibacterials of            Increased caffeine half-life due to inhibition of the hepatic the quinolone type            cytochrome P - 450 pathway; therefore, patients with hepatic disorders, (ciprofloxacin, enoxacin,     cardiac arrhythmias or latent epilepsy should avoid taking caffeine.
and pipemidic acid),
terbinafine, cimetidine,
fluvoxamine and oral contraceptives
Nicotine,                    They decrease the elimination half-life of caffeine.
phenytoin and phenylpropanolamine
Clozapine                     Caffeine increases the serum levels of clozapine due to the probable interaction through both pharmacokinetic and pharmacodynamic mechanisms. Clozapine serum levels should be monitored. Concomitant use is therefore not recommended.

Interaction with laboratory testing
•     High doses of ASA can affect the results of several clinical-chemical laboratory tests.

•     Paracetamol intake can affect the results of uric acid when using the phosphotungstic acid method and for glycaemia when using the glucose oxidase/peroxidase method.

•     Caffeine can inverse the effects of dipyridamole and adenosine on myocardial blood flow, thereby interfering with the results of myocardial imaging tests. It is recommended that the ingestion of caffeine be suspended at least 24 hours prior to the test.