Special Warning : אזהרת שימוש

4.4. Special warnings and precautions for use

The efficacy and safety of Cod Acamol tablets in children below the age of 12 years has not been established, and use in such children is contraindicated.
Cod Acamol must be used with caution in patients with increased intracranial pressure, acute abdominal conditions, the elderly, the debilitated, impaired hepatic or renal function, hypothyroidism, Addison's disease, prostatic hypertrophy, and urethral stricture. (See also “Contraindications”. Note particularly that Cod Acamol is contraindicated in patients with severe renal or hepatic impairment.) 
Zapain tablets must be used with caution in patients with increases intracranial pressure, debilitated, impaired hepatic or renal function, , and urethral stricture. (See also “Contraindications”. Note particularly that Zapain is contraindicated in patients with severe renal or hepatic impairment.) 
Care should be observed in administering the product to any patient, whose condition may be exacerbated by opioids, including the elderly, who may be sensitive to their central and gastro-intestinal effects, those on concurrent CNS depressant drugs, those with prostatic hypertrophy, hypothyroidism and those with acute abdominal conditions like inflammatory or obstructive bowel disorders, Addison's disease or myasthenia gravis. Care should also be observed if prolonged therapy is contemplated.


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Caution is advised if paracetamol is administered concomitantly with flucloxacillin due to increased risk of high anion gap metabolic acidosis (HAGM A), 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.


Drug dependence, tolerance and potential for abuse
For all patients, prolonged use of opioids causes drug dependence (addiction), even at therapeutic doses. The risks are increased in individuals with current or past history of substance misuse disorder (including alcohol misuse) or mental health disorder (e.g., major depression).
Additional support and monitoring may be necessary when prescribing for patients at risk of opioid misuse.
A comprehensive patient history should be taken to document concomitant medications, including over- the-counter medicines and medicines obtained online, and past and present medical and psychiatric conditions.
Patients may find that treatment is less effective with chronic use and express a need to increase the dose to obtain the same level of pain control as initially experienced. Patients may also supplement their treatment with additional pain relievers. These could be signs that the patient is developing tolerance.
The risks of developing tolerance should be explained to the patient.
Overuse or misuse may result in overdose and/or death. It is important that patients only use medicines that are prescribed for them at the dose they have been prescribed and do not give this medicine to anyone else.
Patients should be closely monitored for signs of misuse, abuse, or addiction.
The clinical need for analgesic treatment should be reviewed regularly.


Drug withdrawal syndrome
Prior to starting treatment with any opioids, a discussion should be held with patients to put in place a withdrawal strategy for ending treatment with codeine.
Drug withdrawal syndrome may occur upon abrupt cessation of therapy or dose reduction. When a patient no longer requires therapy, it is advisable to taper the dose gradually to minimise symptoms of withdrawal. Tapering from a high dose may take weeks to months.
The opioid drug withdrawal syndrome is characterised by some or all of the following: restlessness, lacrimation, rhinorrhoea, yawning, perspiration, chills, myalgia, mydriasis and palpitations. Other symptoms may also develop including irritability, agitation, anxiety, hyperkinesia, tremor, weakness, insomnia, anorexia, abdominal cramps, nausea, vomiting, diarrhoea, increased blood pressure, increased respiratory rate or heart rate.
If women take this drug during pregnancy, there is a risk that their newborn infants will experience neonatal withdrawal syndrome.


Hyperalgesia
Hyperalgesia may be diagnosed if the patient on long-term opioid therapy presents with increased pain.
This might be qualitatively and anatomically distinct from pain related to disease progression or to breakthrough pain resulting from development of opioid tolerance. Pain associated with hyperalgesia tends to be more diffuse than the pre-existing pain and less defined in quality. Symptoms of hyperalgesia may resolve with a reduction of opioid dose.
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Risk from concomitant use of sedative medicines such as benzodiazepines or related drugs: Concomitant use of Cod Acamol 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 medicines should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe Cod Acamol concomitantly with sedative medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible.
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).
CYP2D6 metabolism
Codeine is metabolized by the liver enzyme CYP2D6 into morphine, its active metabolite. If a patient has a deficiency or is completely lacking this enzyme an adequate analgesic effect will not be obtained.
Estimates indicate that up to 7% of the Caucasian population may have this deficiency. However, if the patient is an extensive or ultra-rapid metabolizer there is an increased risk of developing side effects of opioid toxicity even at commonly prescribed doses. These patients convert codeine into morphine rapidly resulting in higher than expected serum morphine levels.
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 metabolizer in different populations are summarized 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%-2%


Post-operative use in children
There have been reports in the published literature that codeine given postoperatively in children after tonsillectomy and/or adenoidectomy for obstructive sleep apnoea, led to rare, but life-threatening adverse events including death (see also section 4.3). All children received doses of codeine that were within the appropriate dose range; however there was evidence that these children were either ultrarapid or extensive metabolisers in their ability to metabolise codeine to morphine.

Children with compromised respiratory function
Codeine 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 
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infections, multiple trauma or extensive surgical procedures. These factors may worsen symptoms of morphine toxicity.
Overdosage in patients with non-cirrhotic alcoholic liver disease can be hazardous. The hazard of paracetamol overdose is greater in those with alcoholic liver disease.

Codeine at high doses has the same disadvantages as morphine, including respiratory depression. Drug dependence of the morphine type can be produced by the Codeine, and the potential for drug abuse with codeine must be considered. Codeine may impair mental or physical abilities required in the performance of potentially hazardous tasks.

Patients must be advised not to exceed the recommended doses.
Patients must be advised not to take other products containing paracetamol or opiate derivatives when taking Cod Acamol, and to consult their doctor if symptoms persist.
The cough suppressant effect of codeine may be undesirable in patients with some respiratory conditions.
Children
Codeine-containing medicines should only be used to treat acute (short lived) moderate pain in children above 12 years of age, and only if it cannot be relieved by other painkillers such as paracetamol or ibuprofen, because of the risk of respiratory depression associated with codeine use.2 Codeine should not be used at all in children (aged below 18 years) who undergo surgery for the removal of the tonsils or adenoids to treat obstructive sleep apnoea, as these patients are more susceptible to respiratory problems.
Children and adolescents (aged below 18 years) with conditions associated with breathing problems must not use codeine (see Contraindications).
Children with obstructive sleep apnea who are treated with codeine for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to the respiratory depressant effects of codeine that has been rapidly metabolized to morphine. Codeine is contraindicated for post-operative pain management in all pediatric patients undergoing tonsillectomy and/or adenoidectomy (see Contraindications).

Rare but serious skin reactions
Paracetamol has been associated with a risk of rare but serious skin reactions. These skin reactions, known as Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP), can be fatal.
Reddening of the skin, rash, blisters, and detachment of the upper surface of the skin can occur with the use of drug products that contain paracetamol. These reactions can occur with first-time use of paracetamol or at any time while it is being taken.
Anyone who develops a skin rash or reaction while using paracetamol should stop the drug and seek medical attention right away. Anyone who has experienced a serious skin reaction with paracetamol should not take the drug again and should contact their health care professional to discuss alternative pain relievers/fever reducers.
Health care professionals should be aware of this rare risk and consider paracetamol along with other drugs already known to have such an association, when assessing patients with potentially drug induced skin reactions.


Cod Acamol contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.


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

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