Special Warning : אזהרת שימוש

4.4.       Special warnings and precautions for use

Warnings:
-    In adults and adolescents 14 years and older. The maximum dose of 8 tablets of Zaldiar should not be exceeded. In order to avoid inadvertent overdose, patients should be advised not to exceed the recommended dose and not to use any other paracetamol (including over the counter) or tramadol hydrochloride containing products concurrently without the advice of a physician.
-     In severe renal insufficiency (creatinine clearance <10 ml/mm), Zaldiar is not recommended.
-     In patients with severe hepatic impairment Zaldiar should not be used ( See Section 4.3). The hazards of paracetamol overdose are greater in patients with non- cirrhotic alcoholic liver disease. In moderate cases prolongation of dosage interval should be carefully considered.
-     In severe respiratory insufficiency, Zaldiar is not recommended.
-     Tramadol is not suitable as a substitute in opioid-dependent patients. Although it is an opioid agonist, tramadol cannot suppress morphine withdrawal symptoms.
-     Convulsions have been reported in tramadol-treated patients susceptible to seizures or taking other medications that lower the seizure threshold, especially selective serotonin re-uptake inhibitors, tricyclic antidepressants, antipsychotics, centrally acting analgesics or local anaesthesia. Epileptic patients controlled by a treatment or patients susceptible to seizures should be treated with Zaldiar only if there are compelling circumstances. Convulsions have been reported in patients receiving tramadol at the recommended dose levels. The risk may be increased when doses of tramadol exceed the recommended upper dose limit -    Concomitant use of opioid agonists-antagonists (nalbuphine, buprenorphine, pentazocine) is not recommended (see section 4.5).


Sleep-related breathing disorders
Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep- related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.

Serotonin syndrome

Serotonin syndrome, a potentially life-threatening condition, has been reported in patients receiving tramadol in combination with other serotonergic agents or tramadol alone (see sections 4.5, 4.8 and 4.9).

If concomitant treatment with other serotonergic agents is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose escalations.

Symptoms of serotonin syndrome may include mental status changes, autonomic instability, neuromuscular abnormalities and/or gastrointestinal symptoms.

If serotonin syndrome is suspected, a dose reduction or discontinuation of therapy should be considered depending on the severity of the symptoms. Withdrawal of the serotonergic drugs usually brings about a rapid improvement.

CYP2D6 metabolism

Tramadol is metabolised by the liver enzyme CYP2D6. If a patient has a deficiency or is completely lacking this enzyme an adequate analgesic effect may not be obtained. Estimates indicate that up to 7% of the Caucasian population may have this deficiency. However, if the patient is an ultra-rapid metaboliser there is a risk of developing side effects of opioid toxicity even at commonly prescribed doses.

General symptoms of opioid toxicity include confusion, somnolence, shallow breathing, small pupils, nausea, vomiting, constipation and lack of appetite. In severe cases this may include symptoms of 
circulatory and respiratory depression, which may be life threatening and very rarely fatal. Estimates of prevalence of ultra-rapid metabolisers in different populations are summarised below: 

Population                Prevalence %

African/Ethiopian         29%

African American          3.4% to 6.5%
Asian                     1.2% to 2%

Caucasian                 3.6% to 6.5%

Greek                     6.0%
Hungarian                 1.9%

Northern European         1% to 2%

Post-operative use in children
There have been reports in the published literature that tramadol given post-operatively in children after tonsillectomy and/or adenoidectomy for obstructive sleep apnoea, led to rare, but life threatening adverse events. Extreme caution should be exercised when tramadol is administered to children for post-operative pain relief and should be accompanied by close monitoring for symptoms of opioid toxicity including respiratory depression.


Children with compromised respiratory function

Tramadol is not recommended for use in children in whom respiratory function might be compromised including neuromuscular disorders, severe cardiac or respiratory conditions, upper respiratory or lung infections, multiple trauma or extensive surgical procedures. These factors may worsen symptoms of opioid toxicity.


Adrenal insufficiency

Opioid analgesics may occasionally cause reversible adrenal insufficiency requiring monitoring and glucocorticoid replacement therapy. Symptoms of acute or chronic adrenal insufficiency may include e.g. severe abdominal pain, nausea and vomiting, low blood pressure, extreme fatigue, decreased appetite, and weight loss.

Precautions for use
Risk from concomitant use of sedative medicines such as benzodiazepines or related drugs Concomitant use of Tramadol hydrochloride/Paracetamol and sedative medicines such as benzodiazepines or related drugs may result in sedation, respiratory depression, coma and death.
Because of these risks, concomitant prescribing with these sedative drugs should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe Tramadol hydrochloride/Paracetamol concomitantly with sedative medicines, the lowest effective dose should be used, and the duration of the concomitant treatment should be as short as possible.


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.



The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their caregivers to be aware of these symptoms (see section 4.5).


Tolerance, psychic and physical dependence may develop, even at therapeutic doses and especially after long-term use. The clinical need for analgesic treatment should be reviewed regularly (see section 4.2). In opioid-dependent patients and patients with a history of drug abuse or dependence, treatment should only be for short period and under medical supervision. Zaldiar should be used with caution in patients with cranial trauma, in patients prone to convulsive disorder, biliary tract disorders, in a state of shock, in an altered state of consciousness for unknown reasons, with problems affecting the respiratory center or the respiratory function, or with an increased intracranial pressure.

Paracetamol in overdosage may cause hepatic toxicity in some patients.

Symptoms of withdrawal reaction, similar to those occurring during opiate withdrawal, may occur even at therapeutic doses and for short term treatment (see section 4.8). When a patient no longer requires therapy with Zaldiar, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal, especially after long treatment periods. Rarely, cases of dependence and abuse have been reported (see section 4.8).


In one study, use of tramadol during general anaesthesia with enflurane and nitrous oxide was reported to enhance intra-operative recall. Until further information is available, use of tramadol during light planes of anaesthesia should be avoided.

Zaldiar tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium- free'.

Effects on Driving

4.7     Effects on ability to drive and use machines
Tramadol may cause drowsiness or dizziness, which may be enhanced by alcohol or other CNS depressants. If affected, the patient should not drive or operate machinery.

This medicine can impair cognitive function and can affect a patient’s ability to drive safely.
When prescribing this medicine, patients should be told:
•   The medicine is likely to affect your ability to drive
•   Do not drive until you know how the medicine affects you
•   It is an offence to drive while under the influence of this medicine •   However, you would not be committing an offence (called ‘statutory defence’) if: o      The medicine has been prescribed to treat a medical or dental problem and o      You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and o      It was not affecting your ability to drive safely