Adults: Two tablets should be taken at the first warning of a migraine attack.  This dosage may be repeated to a maximum of 6 tablets in a 24 hour period.

The maximum daily dose should not exceed 60mg/kg/day of paracetamol (up to a maximum of 4 tablets per day) in the following situations, unless directed by a physician:

• Weight less than 50kg
• Chronic alcoholism
• Dehydration
• Chronic malnutrition

Elderly patients:

Experience has indicated that normal adult dosage is usually appropriate. However in frail, immobile, elderly subjects or in elderly patients with renal or hepatic impairment, a reduction in the amount or frequency of dosing may be appropriate.

In elderly patients a dose reduction should be considered, based on renal and hepatic function and overall frailty.

Young adults (18-20 years) : At the first warning of a migraine attack 1 to 2  tablets should be taken.  Do not exceed 5 tablets in a 24 hour period.

Children Paediatric population including adolescents:

Use in children less than 1 year of age is contraindicated (see Section 4.3).

Use in children and adolescents between the ages of 1 and 18 years is not recommended.

A presentation of Paramax suitable for the treatment of children under 18 years of age is not available.

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:

Adults:

Glomerular filtration rate	Dose
10-50 ml/min	1  tablet every 6 hours
<10ml/min	1  tablet  every 8 hours

In patients with severe renal impairment (Creatinine clearance < 15 ml/min, the daily dose should be reduced by 75%.

In patients with moderate to severe renal impairment (Creatinine clearance 15-60 ml/min), the dose should be reduced by 50%.

Hepatic impairment:

Severe hepatic impairment:  In patients with severe hepatic impairment the dose should be reduced by 50%.

In patients with hepatic impairment or Gilbert’s Syndrome, the dose should be reduced or the dosing interval prolonged.

The daily dose should not exceed 4 tablets per day unless directed by a physician.

4.3       Contraindications

 

 

4.4       Special warnings and precautions for use

Paramax should be used with caution and upon medical advice in patients with:

• Hepatic impairment
• Renal impairment (GFR≤50ml/min)
• Chronic alcoholism including recent withdrawal
• Glutathione deficiency
• Glucose 6 phosphate dehydrogenase deficiency
• Gilberts syndrome(familial non-haemolytic jaundice)
• Concomitant treatment with medicinal products affecting hepatic function
• Haemolytic anaemia
• Dehydration
• Chronic malnutrition
• Weight less than 50kg
• Elderly
  Patients should be advised not to exceed the recommended dose and not to take other paracetamol containing products concurrently. 
   In general, medicinal products containing paracetamol should be taken for only a few days without the advice of a physician or dentist and not at high doses.
  If high fever or signs of secondary infection occur or if symptoms persist for longer than 3 days, a physician should be consulted.
  Prolonged or frequent use is discouraged.  Patients should be advised not to take other paracetamol containing products concurrently. Taking multiple daily doses in one administration can severely damage the liver; in such case medical assistance should be sought immediately.
  In general, it is advised that treatment with metoclopramide should not exceed 3 months due to the risk of tardive dyskinesia associated with its use.

Co-administration of flucloxacillin with paracetamol may lead to metabolic acidosis, particularly in patients presenting risk factors of glutathione depletion, such as sepsis, malnutrition or chronic alcoholism.

Colestyramine can decrease the intestinal absorption of paracetamol and potentially decrease its efficacy if taken simultaneously. 

Since extrapyramidal symptoms may occur with both metoclopramide and phenothiazines, care should be exercised in the event of both drugs being prescribed concurrently.

Combination to be avoided:

Levodopa: Levodopa or dopaminergic agonists and metoclopramide have a mutual antagonism, concomitant use is therefore contraindicated.

Alcohol: Alcohol potentiates the sedative effect of metoclopramide. Paracetamol may potentiate the effects of alcohol.  Therefore, the risk of sedation and the effects of alcohol may be increased when Paramax is taken with alcohol.

Due to the prokinetic effect of metoclopramide, the absorption of certain drugs may be modified.

Serotoninergic drugs:

The use of metoclopramide with serotonergic drugs such as selective serotonin reuptake inhibitors (SSRIs) may increase the risk or serotonin syndrome.

Digoxin:

Metoclopramide decreases digoxin bioavailability. Careful monitoring of digoxin plasma concentration is required.

4.8       Undesirable effects

Frequencies are defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10);   uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to <1/1,000); and very rare (< 1/10,000)      or not known (cannot be estimated from available data).

Paracetamol:

General disorders and administration site conditions

Common: asthenia

Uncommon: hypersensitivity

Not known: anaphylactic reaction (including anaphylactic shock)

Immune system disorders:

Uncommon: hypersensitivity

Not known: anaphylactic reaction (including anaphylactic shock)

Vascular disorders

Not known: QT prolongation and torsade de pointes (see section 4.4) atrioventricular block,  

Central nervous system and psychiatric disorders

The following reactions, sometimes associated, occur more frequently when high doses are used:

           

• Extrapyramidal symptoms may occur. Acute dystonia and dyskinesia, parkinsonian syndrome, akathisia may increase, even following administration of a single dose, particularly in young adults (see section 4.4). The incidence of extrapyramidal symptoms in young adults may increase if the metoclopramide dosage exceeds 0.5mg/kg body weight/day.
  Although rare, tardive dyskineisa may be irreversible.
  Reactions include spasm of the facial muscles, trismus, rhythmic protrusion of the tongue, a bulbar type of speech, spasm of extra-ocular muscles including oculogyric crises, unnatural positioning of the head and shoulders and opisthotonos.  There may be a generalised increase in muscle tone.  The majority of reactions occur within 36 hours of starting treatment and the effects usually disappear within 24 hours of withdrawal of the drug.  Should treatment of a dystonic reaction be required, a benzodiazepine or an anticholinergic anti-parkinsonian drug may be used. 
• Drowsiness, decreased level of consciousness, restlessness, anxiety, confusion, suicidal ideation.
  Other reactions may occur:
• Tardive dyskinesia can occur during use or after prolonged use, particularly in elderly patients (see section 4.4).
• Restlessness, anxiety and dizziness.
• Depression.
• Seizures
• Neuroleptic malignant syndrome.
  Gastro-intestinal disorders

• Diarrhoea
  Haematological disorders
• Very rare (less than 0.01%) cases of methaemoglobinaemia which could be related to NADH cytochrome b5 reductase deficiency have been reported, particularly in neonates. (see section 4.4).
• Sulfhaemoglobinaemia, mainly with concomitant administration of high doses of sulphur-releasing drugs.
• Blood dyscrasias including thrombocytopenia and agranulocytosis.
• Haemolytic anaemia in patients with underlying glucose 6-phosphate-deshydrogenase deficiency.
  Endocrine disorders

• Hyperprolactinaemia with (amenorrhea, galactorrhea, gynaecomastia).

Body as a whole

• Very rarely hypersensitivity, including anaphylaxis has been reported.
• Asthenia.
• Skin rash.
  Cardiovascular disorders

• Hypotension especially with intravenous formulation.
• Blood pressure increase in patients with or without phaeochromocytoma (see section 4.3).
• QT prolongation and torsade de pointes (see section 4.4).
• Very rarely (less than 0.01%) cases of bradycardia and atrioventricular block have been reported with metoclopramide, particularly with the intravenous formulation.
• Not known:  Kounis syndrome.
• Not known:  Transient increase in blood pressure.
  Respiratory, thoracic and mediastinal disorders
  Not known: bronchospasm (see section 4.5).
  Immune system disorders
• Anaphylactic shock, angioedema.
  Skin and subcutaneous disorders
• 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 reported.
  Hepatobiliary disorders
• cytolytic hepatitis, which may lead to acute hepatic failure
  Since extrapyramidal symptoms may occur with both metoclopramide and phenothiazines, care should be exercised in the event of both drugs being prescribed concurrently

Overdose
   Paracetamol overdose
            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
            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.
  It can also lead to pancytopenia.
              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/kgthe            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.

 

PSUSA updates to the SmPC and PL with regard to transient increase in blood pressure – implementation of PSUSA/00002036/201510. 

4.6=

Paracetamol: A large amount of data on pregnant women indicate neither malformative, nor feto/neonatal toxicity. Paracetamol can be used during pregnancy if clinically needed however it should be used at the lowest effective dose for the shortest possible time and at the lowest possible frequency.


4.9=

 

Overdosage with paracetamol may cause hepatic cytolysis which can lead to hepatocellular insufficiency, gastrointestinal bleeding, metabolic acidosis, encephalopathy, coma and death. Increased levels of hepatic transaminases, lactate deshydrogenase and bilirubin with a reduction in prothrombin level can appear 12 to 48 hours after acute overdosage. It can also lead to pancreatitis, acute renal failure and pancytopenia.

 

 

Section 4.2: Elderly patients, renal impairment and severe hepatic impairment updated.
Section 4.3: updated to include severe hypertension episodes, dopaminergic agonists, parkinsons disease and known history of methemoglobinemia.
Section 4.4: new paragraph re: SCARs and TEN, risk factors and concomitant use updated.
Section 4.5: dopaminergic agonists and information on CYP2D6 included.
Section 4.6: metoclopramide dministration before delivery, extrapyramidal disorders in newborns cannot be excluded.
Section 4.8: suicidal ideation included.  Cardiovascular disorders updated

Type IAIN variation to register the new Marketing Authorisation Holder for the product in line with registered company details.  The address and PA number remain unchanged

Sections 4.1-4.5 & 4.8 have been updated in line with the Company Core Safety Data Sheet versions 6 & 7 for Metoclopramide.  The proposed changes consist of mainly the rewording of the above sections along with the revision of Section 4.9 to reflect improved management of overdose.

Update section 4.4 and 4.8 of SPC

Update section 1 - product name