Special Warning : אזהרת שימוש

4.4     Special warnings and precautions for use

A doctor should be consulted if the symptoms persist or worsen or if the product is required for more than 3 days.

Hepatic Impairment
The use of paracetamol at higher than recommended doses can lead to hepatotoxicity and even hepatic failure and death. Also, patients with impaired liver function or a history of liver disease, or who are on long term ibuprofen therapy or paracetamol treatment should have hepatic function monitored at regular intervals, as ibuprofen has been reported to have a minor and transient effect on liver enzymes.
Severe hepatic reactions, including jaundice and cases of fatal hepatitis, though rare, have been reported with ibuprofen as with other NSAIDs. If abnormal liver tests persist or worsen, or if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g. eosinophilia, rash, etc.), ibuprofen should be discontinued. Both active drugs have been reported to cause hepatotoxicity and even hepatic failure, especially paracetamol.
Patients who regularly consume alcohol in excess of recommended amounts should not take this medicine.
Dose reduction is recommended in patients showing signs of worsening hepatic function. Treatment should be stopped in those patients who develop severe liver failure (see section 4.3).


Renal Impairment
Paracetamol can be used in patients with chronic renal disease without dosage adjustment. There is minimal risk of paracetamol toxicity in patients with moderate to severe renal failure. However, for the ibuprofen component of this product - caution should be used when initiating treatment with ibuprofen in patients with dehydration. The two major metabolites of ibuprofen are excreted mainly in the urine and impairment of renal function may result in their accumulation. The significance of this is unknown.
NSAIDs have been reported to cause nephrotoxicity in various forms: interstitial nephritis, nephritic syndrome and renal failure. Renal impairment from ibuprofen use is usually reversible. In patients with renal, cardiac or hepatic impairment, those taking diuretics and ACE Inhibitors, and the elderly, caution is required since the use of nonsteroidal anti-inflammatory drugs may result in deterioration of renal function.
The dose should be kept as low as possible and renal function should be monitored in these patients.
Treatment should be stopped in those patients who develop severe renal failure (see section 4.3).

Combination use of ACE inhibitors or angiotensin receptor antagonists, anti-inflammatory drugs and thiazide diuretics
The use of an ACE inhibiting drug (ACE-inhibitor or angiotensin receptor antagonist), an anti- inflammatory drug (NSAID or COX-2 inhibitor) and thiazide diuretic at the same time increases the risk of renal impairment. This includes use in fixed-combination products containing more than one class of drug.
Combined use of these medications should be accompanied by increased monitoring of serum creatinine, particularly at the institution of the combination. The combination of drugs from these three classes should be used with caution particularly in elderly patients or those with pre-existing renal impairment.

Elderly
No adjustment in labelled dosage is necessary for older patients who require paracetamol therapy. Those who require therapy for longer than 3 days should consult their physician for condition monitoring; however, no reduction in recommended dosage is necessary. However, caution should be taken with regard to the use of ibuprofen as it should not be taken by adults over the age of 65 without consideration of co- morbidities and co-medications because of an increased risk of adverse effects, in particular heart failure, gastrointestinal ulceration and renal impairment.

Haematological Effects
Blood dyscrasias have been rarely reported. Patients on long-term therapy with ibuprofen should have regular haematological monitoring.

Coagulation Defects
Like other NSAIDs, ibuprofen can inhibit platelet aggregation. Ibuprofen has been shown to prolong bleeding time (but within the normal range), in normal subjects. Because this prolonged bleeding effect may be exaggerated in patients with underlying haemostatic defects, products containing ibuprofen should be used with caution in persons with intrinsic coagulation defects and those on anti-coagulation therapy.

Gastrointestinal Events
Upper gastro-intestinal ulcers, gross bleeding or perforation have been described with NSAIDs. The risks increase with dose and duration of treatment, and are more common in patients over the age of 65 years.
Some patients will experience dyspepsia, heartburn, nausea, stomach pain or diarrhoea. These risks are minimal when this product is used at the prescribed dose for a few days.
Products containing ibuprofen should be used with caution and at the lowest effective dose for the shortest duration, in patients with a history of gastrointestinal haemorrhage or ulcer since their condition may be exacerbated.
Due to the ibuprofen component should be given with care to patients with a history of GI disease (ulcerative colitis, Crohn’s disease) as well as in patients with porphyria and varicella.
This product should be discontinued if there is any evidence of gastrointestinal bleeding.
The concurrent use of acetylsalicylic acid and NSAIDs also increases the risk of serious gastrointestinal adverse events.
Cardiovascular Thrombotic Events
Clinical studies suggest that use of ibuprofen, particularly at a high dose (2400 mg/day) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke).
Overall, epidemiological studies do not suggest that low dose ibuprofen (e.g. ≤ 1200 mg/day) is associated with an increased risk of arterial thrombotic events.
Patients with uncontrolled hypertension, congestive heart failure (NYHA II-III), established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with ibuprofen after careful consideration and high doses (2400 mg/day) should be avoided.
Careful consideration should also be exercised before initiating long-term treatment of patients with risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking), particularly if high doses of ibuprofen (2400 mg/day) are required.
Patients with cardiovascular disease or cardiovascular risk factors may also be at greater risk. To minimize the potential risk of an adverse cardiovascular event in patients taking an NSAID, especially in those with cardiovascular risk factors, the lowest effective dose should be used for the shortest possible duration.
There is no consistent evidence that the concurrent use of acetylsalicylic acid mitigates the possible increased risk of serious cardiovascular thrombotic events associated with NSAIDs use.

Hypertension:
NSAIDs may lead to onset of new hypertension or worsening of pre-existing hypertension and patients taking antihypertensive medicines with NSAIDs may have an impaired anti-hypertensive response.
Caution is advised when prescribing NSAIDs to patients with hypertension. Blood pressure should be monitored closely during initiation of NSAID treatment and at regular intervals thereafter.

Heart failure
Fluid retention and oedema have been observed in some patients taking NSAIDs; therefore caution is advised in patients with fluid retention or heart failure.

Severe Skin Reactions
NSAIDs may very rarely cause serious cutaneous adverse events such as exfoliative dermatitis, toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), which can be fatal and occur without warning. These serious adverse events are idiosyncratic and are independent of dose or duration of use.
Acute generalised exanthematous pustulosis (AGEP) has been reported in relation to ibuprofen containing products. Patients should be advised of the signs and symptoms of serious skin reactions and to consult their doctor at the first appearance of a skin rash or any other sign of hypersensitivity.

Respiratory disorders
In patients suffering from, or with a history of, bronchial asthma or allergic disease, NSAIDs have been reported to precipitate bronchospasm.

Ophthalmological effects
Adverse ophthalmological effects have been observed with NSAIDs; accordingly, patients who develop visual disturbances during treatment with products containing ibuprofen should have an ophthalmological examination.

Aseptic Meningitis
For products containing ibuprofen aseptic meningitis has been reported only rarely, usually but not always in patients with systemic lupus erythematosus (SLE) or other connective tissue disorders.
Potential Laboratory Test Interferences
Using current analytical systems, paracetamol does not cause interference with laboratory assays.
However, there are certain methods with which the possibility of laboratory interference exists, as described below:

Urine Tests
Paracetamol in therapeutic doses may interfere with the determination of 5-hydroxyindoleacetic acid (5HIAA), causing false-positive results. False determinations may be eliminated by avoiding paracetamol ingestion several hours before and during the collection of the urine specimen.

Masking of symptoms of underlying Infections
Combodex can mask symptoms of infection, which may lead to delayed initiation of appropriate treatment and thereby worsening the outcome of the infection. This has been observed in bacterial community acquired pneumonia and bacterial complications to varicella. When Combodex is administered for fever or pain relief in relation to infection, monitoring of infection is advised. In non-hospital settings, the patient should consult a doctor if symptoms persist or worsen.
As with other drugs of this class containing ibuprofen, by reducing fever this may mask the usual signs of infection.

Flucloxacillin
Caution is advised if paracetamol is administered concomitantly with flucloxacillin due to increased risk of high anion gap metabolic acidosis (HAGMA), particularly in patients with severe renal impairment, sepsis, malnutrition and other sources of glutathione deficiency (e.g. chronic alcoholism), as well as those using maximum daily doses of paracetamol. Close monitoring, including measurement of urinary 5-oxoproline, is recommended.

Special Precautions
In order to avoid exacerbation of disease or adrenal insufficiency, patients who have been on prolonged corticosteroid therapy should have their therapy tapered slowly rather than discontinued abruptly when products containing ibuprofen are added to the treatment program.
There is some evidence that drugs which inhibit cyclo-oxygenase/prostaglandin synthesis may cause impairment of female fertility by an effect on ovulation. This is reversible on stopping the medicine.
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose- galactose malabsorption should not take this medicine.
This medicine contains less than 1 mmol sodium (23 mg) per caplet, that is to say essentially 'sodium-free'.

Effects on Driving

4.7     Effects on ability to drive and use machines
This product has no or negligible influence on the ability to drive and use machines.