Adverse reactions : תופעות לוואי

Adverse Reactions
Adverse Reactions in Connection with Acetylsalicylic Acid
Gastric irritation may occur.
Some patients may exhibit notable sensitivity to acetylsalicylic acid which may provoke various reactions including urticaria and other skin eruptions, angioneurotic edema, rhinitis, severe paroxysmal bronchospasm, dyspnea and tinnitus.
Acetylsalicylic acid increases bleeding time, decreases platelet adhesiveness and modifies fibrinolysis. In large doses, it may cause hypoprothrombinemia.

Adverse Reactions in Connection with Paracetamol
Adverse reactions of paracetamol are usually mild, though hematological reactions have been reported in rare cases.
Skin eruptions may occur as an allergic reaction.
Long term use and/or high dosage may cause liver and kidney damage.

Adverse Reactions in Connection with Caffeine
Caffeine may cause nausea, abdominal pain, diarrhea, insomnia, restlessness, nervousness, tinnitus, muscular tremor and palpitations.

Precautions
For Acetylsalicylic Acid
Acetylsalicylic acid should be used with great caution in patients prone to dyspepsia or known to have a lesion of the gastric mucosa.
Acetylsalicylic acid should be used with caution in the following situations:
• in dehydrated patients, particularly children
• in patients with coagulation or platelet function disorders.
• in patients with gout (see Drug Interactions and Diagnostic Interference) 
For Paracetamol
If a sensitivity reaction occurs, discontinue use.

For Acetylsalicylic Acid and Paracetamol
Paracetamol and aspirin may cause liver damage (additive effect with alcohol) and stomach bleeding

Drug Interactions
For Acetylsalicylic acid
Acetylsalicylic Acid/Alcohol/Anti-inflammatory Agents: The ulcerogenic effects may be increased when used concurrently.
Acetylsalicylic Acid/Paracetamol: Prolonged use in high dosage of a combination of these two drugs, with or without other non-steroidal anti-inflammatory drugs, increases the risk of nephropathy.
Acetylsalicylic Acid/Corticosteroids: Corticosteroids increase salicylate clearance, thus reducing serum salicylate levels.
Acetylsalicylic Acid/Phenothiazines: Concurrent use may mask the symptoms of salicylate-induced ototoxicity, such as dizziness, vertigo and tinnitus.
Acetylsalicylic Acid/Oral Anticoagulants: Concurrent use may cause possible potentiation of the hypoprothrombinemic effects.

Acetylsalicylic Acid, Paracetamol & Caffeine Caplets       14. 2. 2005, RH   Page 3 of 6 Acetylsalicylic Acid/Oral Hypoglycemics/Insulin: The hypoglycemic effect may be increased when these drugs are used concurrently.
Acetylsalicylic Acid/Methotrexate: Drug displacement from binding sites leading to toxic plasma concentration of methotrexate may occur when these drugs are used concurrently.
Acetylsalicylic Acid/Probenecid/Sulfinpyrazone: The uricosuric effects of these agents may be affected when used concurrently with salicylates (see Diagnostic Interference).
Acetylsalicylic Acid/Urinary Alkalinizers: Alkalinized urine leads to decreased plasma levels of acetylsalicylic acid because of increased excretion. Withdrawal of these medications from a patient stabilized on a salicylate may increase the plasma levels of acetylsalicylic acid to a toxic level.
Acetylsalicylic Acid/Urinary Acidifiers: Acidified urine leads to increased plasma levels of acetylsalicylic acid because of decreased excretion. Addition of these medications to patients stabilized on acetylsalicylic acid may lead to toxic acetylsalicylic acid levels.
Acetylsalicylic Acid/Diuretic Drugs: acetylsalicylic acid may inhibit or minimize the diuretic effects of spironolactone and furosemide.

For Paracetamol
Paracetamol/Oral Anticoagulants: Regular administration of paracetamol may enhance the activity of coumarin anticoagulants when given concurrently. Occasional doses have no significant effect.
Paracetamol/       Hepatic Enzyme-Inducing Agents/Hepatotoxic Medications/ Alcohol: Concurrent administration of enzyme inducers and paracetamol may decrease the therapeutic effect of paracetamol, probably because of increased metabolism resulting from induction of hepatic microsomal enzyme activity.
The risk of hepatotoxicity with single toxic doses or prolonged use of high doses of paracetamol may be increased in alcoholics or in patients taking other hepatotoxic medications
Paracetamol/       Salicylates/     Other Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): Chronic high-dose administration of paracetamol with salicylates and/or other non- steroidal anti-inflammatory drugs increases the risk of analgesic nephropathy.
Paracetamol/ Zidovudine: Paracetamol      may competitively inhibit the hepatic glucuronidation and decrease the clearance of zidovudine. Zidovudine may also inhibit the hepatic glucuronidation of paracetamol. Concurrent use should be avoided, because the toxicity of either or both medications may be potentiated.

For Caffeine
Caffeine/Bronchodilators/Caffeine Containing Beverages: Concomitant administration may result in additive CNS stimulation. Too much caffeine may cause nervousness, irritability, sleeplessness, and, occasionally, rapid heart beat.

Diagnostic Interference
For Acetylsalicylic Acid
The Gerhardt test for urine acetoacetic acid may give false-positive test results, because the reaction with ferric chloride produces a reddish color that persists after boiling.
Urine 5-hydroxyindoleacetic acid (5-HIAA) determination may give false test results with acetylsalicylic acid when the fluorescent method is used
Urine vanillylmandelic acid (VMA) levels may be falsely increased or decreased, depending on the method used.
Urine phenolsulfonphthalein (PSP) concentrations may be decreased because of the competition of salicylates with PSP for renal tubular secretion.
Bleeding time may be prolonged by acetylsalicylic acid for 4-7 days because of suppressed platelet aggregation.
Acetylsalicylic Acid, Paracetamol & Caffeine Caplets       14. 2. 2005, RH   Page 4 of 6 Serum potassium concentration may be decreased because of increased potassium excretion caused by direct effect on renal tubules.
Serum uric acid concentrations may be increased or decreased, depending on salicylate dosage. Salicylate concentrations below 100-150 µg/ml increase serum uric acid concentrations, while salicylate concentrations above 100-150 µg/ml decrease uric acid concentrations.
Serum uric acid values may be falsely increased with colorimetric acid methods when plasma salicylate concentrations exceed 130 µg/ml; the uricase acid method is not affected.
Fehling’s test for urine sugar may give false-positive test results with doses of salicylates equivalent to, or exceeding 2.4 g of acetylsalicylic acid per day.

For Paracetamol
Blood Glucose Determinations: May be falsely decreased when measured by the glucose oxidase/ peroxidase method, but probably not when measured by the hexokinase/ glucose-6-phosphate dehydrogenase (G6PD) method.
Serum Uric Acid Determinations: Falsely increased values may occur when the phosphotungstate uric acid test method is used.
Urine 5-hydroxyindoleacetic Acid (5-HIAA) Determinations: Qualitative screening tests using nitrosonaphthol reagent may produce false-positive test results. The quantitative test is unaffected.
Pancreatic Function Test Using Bentiromide: Administration of paracetamol prior to the bentiromide test will invalidate the test results, because paracetamol is also metabolized to an arylamine and will therefore increase the apparent quantity of para- aminobenzoic acid (PABA) recovered. It is recommended that paracetamol be discontinued at least 3 days prior to administration of bentiromide.

For Caffeine
Caffeine may interfere with laboratory determinations of bilirubin, fasting blood glucose, uric acid in blood, and catecholamines and 5-hydroxy indoleacetic acid in urine.

Dosage and Administration
Adults and Children Over 12 Years of Age
2 caplets with a full glass of water after meal every 6 hours while symptoms persist,
not to exceed 8 caplets in 24 hours. Not to be taken for more than 48 hours for the pain of migraine.
Note: The patient should be instructed not to lie down for 15-30 minutes following drug intake in order to reduce the risk of esophageal irritation and ulceration.