1 Name of Medicine
Paracetamol.
2 Qualitative and Quantitative Composition
Each tablet contains paracetamol 500 mg.
For the full list of excipients, see Section 6.1 List of Excipients.
3 Pharmaceutical Form
White to off white, caplet shaped tablet with score notch on one side and "P" debossed on the other.
4.1 Therapeutic Indications
Temporary relief of pain associated with headache, migraine headache, neuralgia, muscular aches and pains, cold and flu symptoms, arthritis, osteoarthritis, toothache, sore throat, period pain, rheumatic pain. Reduces fever.
4.2 Dose and Method of Administration
Dosage.
Children (7-12 years).
Take half to 1 caplet every 4 to 6 hours as required, not exceeding 4 caplets per 24 hours. Take with water.
Adults and children aged 12 years and over.
Take 1 to 2 caplets every 4 to 6 hours as required, not exceeding 8 caplets per 24 hours. Take with water.
Children under 7 years.
Not recommended for children under 7 years.4.3 Contraindications
This medication is contraindicated in patients who are hypersensitive to paracetamol or to any of the excipients of this medicine. It must not be used in patients with known glucose-6-phosphate-dehydrogenase deficiency. This medicine must not be used in patients with impaired liver function.
4.4 Special Warnings and Precautions for Use
This medication may be dangerous when used in large amounts or for long periods. Hepatotoxicity may occur with paracetamol even at therapeutic doses, after short treatment duration and in patients without pre-existing liver dysfunction. Hepatotoxicity may develop following as little as 10 to 15 g of paracetamol and hepatic failure is known to occur occasionally with long-term use of paracetamol.
To avoid the risk of overdose.
Check that paracetamol is absent from the composition of other medicinal products taken concomitantly.
Patients with known analgesic intolerance or known bronchial asthma must only use this medication after having consulted a physician (hypersensitivity reactions including bronchospasm possible).
Caution is advised in patients with underlying sensitivity to aspirin and/or to non-steroidal anti-inflammatory drugs (NSAIDs).
Severe cutaneous adverse reactions (SCARs).
Life-threatening cutaneous reactions Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) have been reported with the use of paracetamol. Patients should be advised of the signs and symptoms and monitored closely for skin reactions. If symptoms or signs of SJS and TEN (e.g. progressive skin rash often with blisters or mucosal lesions) occur, patients should stop paracetamol treatment immediately and seek medical advice.
Paracetamol should be used upon medical advice in patients with:
severe renal insufficiency;
chronic alcohol use including recent cessation of alcohol intake;
low glutathione reserves;
Gilbert's syndrome.
Use in hepatic impairment.
This medication should not be administered to patients with hepatic dysfunction (see Section 4.3 Contraindications).
Use in renal impairment.
This medication should not be administered to patients with renal dysfunction (see Section 4.3 Contraindications).
Use in the elderly.
No data available.
Paediatric use.
Not recommended for children under 7 years of age.
Effects on laboratory tests.
Uric acid and blood glucose.
Intake of paracetamol may affect the laboratory determination of uric acid by phosphotungstic acid and of blood glucose by glucose oxidase-peroxidase.4.5 Interactions with Other Medicines and Other Forms of Interactions
Paracetamol may increase the risk of bleeding in patients taking warfarin and other antivitamin K. Anticoagulant dosage may require reduction and patients should be monitored for appropriate coagulation and bleeding complications.
Paracetamol absorption is increased by drugs which increase gastric emptying e.g. metoclopramide and domperidone and decreased by drugs which decrease gastric emptying e.g. propantheline, antidepressants with anticholinergic properties, narcotic analgesics.
Paracetamol may increase chloramphenicol concentrations by slowing down excretion, entailing the risk of increased toxicity. The risk of paracetamol toxicity may be increased in patients receiving other potentially hepatoxic drugs or drugs that induce liver microsomal enzymes, such as antiepileptics (such as phenobarbital, phenytoin, carbamazepine, topiramate), barbiturates, hypnotics, rifampicin and alcohol.
Paracetamol excretion may be affected and plasma concentrations altered when given probenecid.
Cholestyramine reduces the absorption of paracetamol if given within 1 hour of paracetamol. Chelating resins 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.
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.
When used concurrently with zidovudine, an increased tendency for neutropenia may develop. Combination of paracetamol and zidovudine should be avoided.
4.6 Fertility, Pregnancy and Lactation
Effects on fertility.
No data available.
(Category A)
Drugs which have been taken by a large number of pregnant women and women of childbearing age without any proven increase in the frequency of malformations or other direct or indirect harmful effects on the foetus having been observed. 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.
Paracetamol can cross the placenta; however, so teratogenic effects have been observed in rats or mice, after doses of up to 250 mg/kg.
A woman in the third trimester of pregnancy ingested 22.5 g paracetamol. Early treatment with oral acetylcysteine resulted in good outcome for both mother and foetus.
Paracetamol is excreted in breast milk. The amount available for ingestion by the infant has been reported variously as less than 0.1% of a single 500 mg dose and as 0.04 to 0.23% of a single 650 mg dose. Maternal ingestion of paracetamol in usual analgesic doses does not appear to present a risk to the nursing infant.4.7 Effects on Ability to Drive and Use Machines
The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.
4.8 Adverse Effects (Undesirable Effects)
Reports of adverse reactions are rare. Although the following reactions have been reported: dyspepsia, sweating, erythema, urticaria, anaphylactic shock, angioneurotic oedema, difficulty breathing, drop in blood pressure, nausea, allergic reactions such as skin rashes, hypersensitivity reactions and haematological reactions, including thrombocytopenia, leukopenia, neutropenia, agranulocytosis and pancytopenia. Bronchospasm may be triggered in patients having a tendency of analgesic asthma. Toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), acute generalised exanthematous pustulosis, fixed drug eruption (see Section 4.4 Special Warnings and Precautions for Use) and cytolytic hepatitis, which may lead to acute hepatic failure, have also been reported. Overdosage with paracetamol if left untreated can result in severe, sometimes fatal liver damage and rarely, acute renal tubular necrosis.
Haemolytic anaemia, particularly in patients with underlying glucose-6-phosphate-dehydrogenase deficiency has been reported. Kounis syndrome has been reported, as has pyroglutamic acidosis in patients with pre-disposing factors for glutathione depletion.
Reporting suspected adverse effects.
Reporting suspected adverse reactions after registration 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 at http://www.tga.gov.au/reporting-problems.4.9 Overdose
Elderly persons, small children, patients with liver disorders, chronic alcohol consumption or chronic malnutrition, as well as patients concomitantly treated with enzymes-inducing drugs are at an increased risk of intoxication, including fatal outcome.
Symptoms.
Toxic symptoms include vomiting, abdominal pain, hypotension and sweating. Nausea, vomiting, anorexia, pallor and abdominal pain generally appear during the first 24 hours of overdosage with paracetamol. Overdosage with paracetamol may cause hepatic cytolysis which can lead to hepatocellular insufficiency, gastrointestinal bleeding, metabolic acidosis, encephalopathy, disseminated intravascular coagulation, coma and death. Increased levels of hepatic transaminases, lactate dehydrogenase and bilirubin with a reduction in prothrombin level can appear 12 to 48 hours after acute overdosage. Overdosage can also lead to pancreatitis acute renal failure and pancytopenia. The most serious adverse effect of acute overdosage of paracetamol is a dose-dependent, potentially fatal hepatic necrosis. In adults, hepatotoxicity may occur after ingestion of a single dose of 12 g (24 tablets) of paracetamol; a dose of 25 g (50 tablets) or more is potentially fatal. Symptoms during the first 2 days of acute poisoning by paracetamol do not reflect the potential seriousness of the intoxication. Major manifestations of liver failure such as jaundice, hypoglycaemia and metabolic acidosis may take at least 3 days to develop.
Treatment.
Despite lack of significant early symptoms, patients should be referred to hospital urgently for immediate medical attention.
Determinations of the plasma concentration of paracetamol are recommended.
Plasma concentration of paracetamol should be measured at 4 hours or later after ingestion (earlier concentrations are unreliable).
Where paracetamol intoxication is suspected, intravenous administration of SH group donators such as acetylcysteine within the first 10 hours after ingestion is indicated. Although acetylcysteine is most effective if initiated within this period, it can still offer some degree of protection if given as late as 48 hours after ingestion; in this case it is taken for longer.
If the history suggests that 12 g paracetamol or more has been ingested, administer one of the following antidotes:
Acetylcysteine 20% iv.
Administer intravenously, 20% acetylcysteine immediately without waiting for positive urine test or plasma level results. For dosage instructions refer to the acetylcysteine 20% iv product information.
Oral methionine.
For dosage instructions refer to the methionine product information.
Further measures will depend on the severity, nature and course of clinical symptoms of intoxication and should follow standard intensive care protocols.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).5 Pharmacological Properties
5.1 Pharmacodynamic Properties
Mechanism of action.
Paracetamol has analgesic and antipyretic effects.
Clinical trials.
No data available.
5.2 Pharmacokinetic Properties
Absorption.
After oral administration, paracetamol is absorbed rapidly and completely from the small intestine; peak plasma levels occur 10 to 60 minutes after oral administration. Food intake delays paracetamol absorption.
Distribution.
Paracetamol is uniformly distributed throughout most body fluids; the apparent volume of distribution is 1 to 1.2 L/kg. Paracetamol can cross the placenta and is excreted in breast milk. Plasma protein binding is negligible at usual therapeutic concentrations but increases with increasing concentrations.
Metabolism.
Paracetamol is metabolised by the hepatic microsomal enzyme system. In adults at therapeutic doses, paracetamol is mainly conjugated with glucuronide (45-55%) or sulfate (20-30%). A minor proportion (less than 20%) is metabolised to catechol derivatives, and mercapturic acid compounds via oxidation. Paracetamol is metabolised differently by infants and children compared to adults, the sulfate conjugate being predominant.
Excretion.
Paracetamol is excreted in the urine mainly as the glucuronide and sulfate conjugates. Less than 5% is excreted as unchanged paracetamol. 85-90% of the administered dose is eliminated in the urine within 24 hours of ingestion. The elimination half-life is about 1 to 4 hours.
5.3 Preclinical Safety Data
Genotoxicity.
No data available.
Carcinogenicity.
No data available.6 Pharmaceutical Particulars
6.1 List of Excipients
Hypromellose, macrogol 6000, magnesium stearate, pregelatinised maize starch, propylene glycol, purified talc, titanium dioxide.
6.2 Incompatibilities
Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
6.3 Shelf Life
In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.
6.4 Special Precautions for Storage
Store below 25°C.
6.5 Nature and Contents of Container
PVC/Al blister packs of 16, 20, 24, 32, 48, 50, 100 caplets.
Not all pack sizes may be marketed.
6.6 Special Precautions for Disposal
In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.
6.7 Physicochemical Properties
Chemical structure.
Chemical name: N-acetyl-p-aminophenol.
Structural formula:
Molecular formula: C8H9NO2.
Molecular weight: 151.17.
CAS number.
103-90-2.7 Medicine Schedule (Poisons Standard)
Packs of 16 - Not scheduled.
Packs of 20, 24, 32, 48, 50 - S2, Pharmacy Medicine.
Packs of 100 - S3, Pharmacist Only Medicine.
Summary Table of Changes
