section 4.6

Life-threatening adverse events or neonatal death may occur even at therapeutic doses.

Paracetamol

A large amount of data on the use of paracetamol in pregnancy indicate neither malformative, nor feto/neonatal toxicity.  Epidemiological studies on neurodevelopment in children exposed to paracetamol in utero show inconclusive results.

Section 5.3

5.3       Preclinical Safety Data

Paracetamol

Conventional studies using the currently accepted standards for the evaluation of toxicity to reproduction and development are not available.

4.2       Posology and Method of Administration

Adults

Two tablets not to be taken more frequently than every six hours up to a maximum of eight tablets in any 24 hour period.

Adults (18 years and over):

Two tablets every 4‐6 hours to a maximum of four doses in any 24 hours.

Do not exceed eight tablets in 24 hours.

Paediatric Population

                Children aged 12 years to 18 years:

The recommended Solpadol dose for children 12 years and older should be one to two tablets not to be taken more frequently than every six hours up to a maximum of eight tablets in any 24 hour period

Children aged 16 to 18 years:

One to two tablets every 6 hours to a maximum of four doses in any 24 hours.

Do not exceed 8 tablets in 24 hours.

Children (12‐15 years):

One tablet every 6 hours to a maximum of four doses in any 24 hours.

Do not exceed 4 tablets in 24 hours.

                Children aged less than 12 years:

Solpadol should not be used in children below the age of 12 years because of the risk of opioid toxicity due to the variable and unpredictable metabolism of codeine to morphine (see sections 4.3 and 4.4).

In patients with renal failure (creatinine clearance lower than 10 ml/min), the interval between two doses should be at least 8 hours.

Renal impairment:

It is recommended, when giving paracetamol to patients with renal impairment, to reduce the dose and to increase the minimum interval between each administration to at least 6 hours unless directed otherwise by a physician.  See Table below:

Hepatic Impairment:

In the event of impending childbirth or in case of risk of premature birth (see section 4.6).

4.4       Special Warnings and Precautions for Use

Paracetaol should be administered with caution under the following circumstances (see     section 4.2 where relevant):

• Hepatic impairment
• Chronic alcoholism
• Renal impairment (GFR≤50ml/min)
• Gilbert’s Syndrome (familial non-haemolytic jaundice)
• Concomitant treatment with medicinal products affecting hepatic function
• Glucose-6-phosphate dehydrogenase deficiency
• Haemolytic anaemia
• Glutathione deficiency
• Dehydration
• Chronic malnutrition
• Weight less than 50kg
• Elderly
  Solpadol should be used after careful risk-benefit assessment in case of:

• Opioid dependence
• Chronic constipation
• Impaired consciousness
• Compromised respiratory function and chronic obstructive airway disease

Estimates of prevalence of ultra-rapid metabolisers in different populations are summarized below:

Children with compromised respiratory function

Solpadol Codeine is not recommended for use in children in whom respiratory function might be compromised including neuromuscular disorders, severe cardiac or respiratory conditions,

Solpadol should be administered with caution in certain patients, such as those who present impaired cardiac, hepatic or renal function, and in cases of benign prostatic hyperplasia, urethral stenosis, adrenal insufficiency (Addison’s disease), hypothyroidism, multiple sclerosis, chronic colitis ulcerative, gall bladder conditions and diseases that present with reduced respiratory capacity such as emphysema, kyphoscoliosis and severe obesity.

Extensive use of analgesics to relieve headaches or migraines, especially at high doses, may induce headaches that must not be treated with increased doses of the drug.  In such cases the analgesic should not continue to be taken without medical advice.

            Use with caution in patients with convulsive disorders.

Codeine has a primary potential for dependence.  Tolerance, psychological and physical dependence (addiction) develop with prolonged use of high doses with withdrawal symptoms, such as restlessness and irritability, after sudden discontinuation of the drug.  Cross-tolerance with other opioids exists.  Rapid relapses can be expected in patients with pre-existing opiate dependence (including those in remission).  Administration must be discontinued gradually after prolonged treatments.

Tolerance and dependence can occur, especially with prolonged high dosage of codeine.

There have been reports of drug abuse with codeine, including cases in children and adolescents.  Caution is particularly recommended for use in children, adolescents, young adults and in patients with a history of drug and/or alcohol abuse.

The risk-benefit of continued use should be assessed regularly by the prescriber. 

Prolonged regular use, except under medical supervision, may lead to physical and psychological dependence (addiction) and result in withdrawal symptoms such as restlessness and irritability, once the drug is stopped (see Section 4.8).

Each effervescent tablet contains 388mg sodium (16.87 mEq).  This medicinal product contains 388mg sodium per effervescent tablet, equivalent to 19 % of the WHO recommended maximum daily intake of 2g sodium for an adult.  This sodium content should be taken into account when prescribing for patients in whom sodium restriction is indicated.

Patients with rare hereditary problems of fructose intolerance should not take this medicine.

Monitoring after prolonged use should include blood count, liver function and renal function.

In patients with intracranial hypertension, codeine may increase the severity of this hypertension.  Solpadol is contraindicated for use in these patients.  Section 4.3.

In patients who have had a cholecystectomy, codeine may induce acute biliary or pancreatic abdominal pain, which usually occurs with abnormal laboratory results, suggesting a spasm of the sphincter of Oddi. Solpadol is contraindicated for use in these patients.  Section 4.3.

If the patient has a productive cough, codeine may impede expectoration.

Elderly patients may be more sensitive to the effects of this medicinal product, especially respiratory depression; they are also more prone to suffering hypertrophy, prostatic obstruction and age-related kidney impairment and they have a higher likelihood of undesirable effects due to opioid-induced urinary retention.

Elderly patients: the initial dosage should be reduced to half the recommended dosage; this may be later increased based on patient tolerance and needs.  See section 4.2.

In ultra-rapid opiate/codeine metabolisers, there is an increased risk of developing opioid toxicity even at low doses. Symptoms of opioid toxicity include nausea, vomiting, constipation, lack of appetite and somnolence. In severe cases this may include symptoms of circulatory and respiratory depression.

Chelating resin can decrease the intestinal absorption of paracetamol and potentially decrease its efficacy if taken simultaneously.  In general, there must be an interval of more than 2 hours between taking the resin and taking paracetamol, if possible.

Tricyclic antidepressants

A codeine-induced respiratory depression can be potentiated by tricyclic antidepressants.

Mono Amine Oxidase Inhibitors (MAOI’s)

Concomitant administration of MAOI can potentiate the central nervous effects and other side effects of unpredictable severity.  Solpadol should not be used in patients currently receiving or within 14 days of stopping monoamine oxidase inhibitor therapy.  See section 4.3

Antiperistaltic antidiarrhoeal drugs

Concomitant use of codeine with antiperistaltic antidiarrhoeal drugs can increase the risk of severe constipation and CNS depression.

4.8       Undesirable Effects

The following CIOMS frequency rating is used, when applicable:

Very common ≥ 10%; Common ≥ 1 and < 10%; Uncommon ≥ 0.1 and <1%;

Rare ≥ 0.01 and < 0.1%; Very rare < 0.01%; Not known (cannot be estimated from available data)

Paracetamol

Immune system disorders: Hypersensitivity, anaphylactic shock, angioedema.

Blood and lymphatic system disorders:  thrombocytopenia, agranulocytosis, leukopenia, neutropenia, haemolytic anaemia in patients with underlying glucose 6-phosphate-deshydrogenase deficiency.

Other reactions may occur:

Skin and subcutaneous disorders: erythema, urticarial, rash. Very rare cases of serious skin reactions such as Toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), acute generalized exanthematous pustulosis, and fixed drug eruption(see section 4.4) have been reporte

Cardiac disorders: Kounis syndrome.

Respiratory, thoracic and mediastinal disorders:  bronchospasm (See section 4.5).

Hepatobiliary disorders: cytolytic hepatitis, which may lead to acute hepatic failure

Codeine:

At therapeutic doses, the adverse effects of Codeine can produce typical opioid effects but they are less frequent and more moderate including:

• sedation, euphoria, dysphoria,
• constipation, nausea, vomiting,
• dizziness, light-headedness, confusion, drowsiness
• hypersensitivity reactions (pruritus, urticaria and rash)
• myosis, urinary retention. 
• bronchospasm, respiratory depression (see Section 4.3),
• acute biliary or pancreatic abdominal pain, suggesting a spasm of the sphincter of Oddi and occurring mainly in patients who have had a cholecystectomy,
• pancreatitis: very rare cases have been reported.
   
  At supratherapeutic doses: there is a risk of dependence and withdrawal syndrome if treatment is suddenly discontinued. This may occur both in the patient and in the neonates of mothers with codeine intoxication.
   
  Reporting of suspected adverse reactions
  Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971;  Fax: +353 1 6762517. Website: www.hpra.ie; e-mail: medsafety@hpra.ie.
   
  4.9       Overdose
   
  Paracetamol:
   
  There is a risk of poisoning with paracetamol particularly in elderly subjects, young children,  patients with liver disease, cases of chronic alcoholism and in patients with chronic malnutrition. Overdosing may be fatal in these cases.
  Symptoms generally appear within the first 24 hours and may comprise: nausea, vomiting, anorexia, pallor, and abdominal pain, or patients may be asymptomatic.
  Overdose of paracetamol in a single administration in adults or in children can cause liver cell necrosis likely to induce complete and irreversible necrosis, resulting in hepatocellular insufficiency, gastrointestinal bleeding, metabolic acidosis and encephalopathy which may lead to coma and death. Simultaneously, increased levels of hepatic transaminases (AST, ALT), lactate dehydrogenase and bilirubin are observed together with increased prothrombin levels that may appear 12 to 48 hours after administration.
  Liver damage is likely in adults who have taken more than the recommended amounts of paracetamol. It is considered that excess quantities of toxic metabolite (usually adequately detoxified by glutathione when normal doses of paracetamol are ingested), become irreversibly bound to liver tissue.
  Some patients may be at increased risk of liver damage from paracetamol toxicity.
  Risk Factors include: If the patient;

• Is on long-term treatment with carbamazepine, phenobarbitone, phenytoin, primidone, rifampicin, St John’s Wort or other drugs that induce liver enzymes.
• Regularly consumes ethanol in excess of recommended amounts
• Is likely to be glutathione depleted e.g. eating disorders, cystic fibrosis, HIV infection, starvation, cachexia
   
  Emergency Procedure:
  Immediate transfer to hospital.
  Blood sampling to determine initial paracetamol plasma concentration. In the case of a single acute overdose, paracetamol plasma concentration should be measured 4 hours post ingestion.  Administration of activated charcoal should be considered if >150mg/kg paracetamol has been taken within 1 hour.
  The antidote N-acetylcysteine, should be administered as soon as possible in accordance with National treatment guidelines
  Symptomatic treatment should be implemented.
  Paracetamol
  Paracetamol overdose can result in liver damage which may be fatal.
   
  Symptoms generally appear within the first 24 hours and may comprise: nausea, vomiting, anorexia, pallor, and abdominal pain, or patients may be asymptomatic.
  Overdose of paracetamol can cause liver cell necrosis likely to induce complete and irreversible necrosis, resulting in hepatocellular insufficiency, metabolic acidosis and encephalopathy which may lead to coma and death. Simultaneously, increased levels of hepatic transaminases (AST, ALT), lactate dehydrogenase and bilirubin are observed together with increased prothrombin levels that may appear 12 to 48 hours after administration.
  Liver damage is likely in patients who have taken more than the recommended amounts of paracetamol. It is considered that excess quantities of toxic metabolite become irreversibly bound to liver tissue.
  Some patients may be at increased risk of liver damage from paracetamol toxicity:
   
  Risk factors include:

• Patients with liver disease
• Elderly patients
• Young children
• Patients receiving long-term treatment with carbamazepine, phenobarbitone, phenytoin, primidone, rifampicin, St John’s Wort or other drugs that induce liver enzymes.
• Patients who regularly consume ethanol in excess of recommended amounts
• Patients with glutathione depletion  e.g. eating disorders, cystic fibrosis, HIV infection, starvation, cachexia
  Acute renal failure with acute tubular necrosis may also develop.
  Cardiac arrhythmias and pancreatitis have also been reported.
   
  Emergency Procedure:
  Immediate transfer to hospital.
  Blood sampling to determine initial paracetamol plasma concentration. In the case of a single acute overdose, paracetamol plasma concentration should be measured 4 hours post ingestion.  Administration of activated charcoal should be considered if the overdose of paracetamol has been ingested within the previous hour.
   
  The antidote N-acetylcysteine, should be administered as soon as possible in accordance with national treatment guidelines.
   
  Symptomatic treatment should be implemented.
   
  Codeine
  The effects in overdosage will be potentiated by simultaneous ingestion of alcohol and psychotropic drugs.
   
  Symptoms:
  Central nervous system depression, including respiratory depression, may develop but is unlikely to be severe unless other sedative agents have been co-ingested, including alcohol, or the overdose is very large. The pupils may be pin-point in size; nausea and vomiting are common. Hypotension and tachycardia are possible but unlikely. Drowsiness, ,rash, pruritis, ataxia, pulmonary edema (more rare) are possible.
   
  The ingestion of very high doses can cause initial excitation, anxiety, insomnia followed by drowsiness in certain cases, areflexia progressing to stupor or coma, headache, miosis, alterations in blood pressure, arrhythmias, dry mouth, hypersensitivity reactions, cold clammy skin, bradycardia, tachycardia, convulsions, gastrointestinal disorders, nausea, vomiting and respiratory depression.
   
  Severe intoxication can lead to apnoea, circulatory collapse, cardiac arrest and death.

Type II.C.1.4 variation to update Section 4.4 of the SmPC with regard to the possibility of SCARS (severe cutaneous adverse reactions) such as SJS and TEN following a Global Labelling Update for paracetamol. 

Type IB.C.I.3.a variation to update the Summary of Product Characteristics and Patient Leaflet following the PRAC (Pharmacovigilance Risk Assessment Committee) recommendation and the CMDh position for Codeine containing products.