Paracetamol 500mg Tablets (PL 43461/0003)

For the treatment of mild to moderate pain, including headache, neuralgia, toothache, period pains, aches and pains.

Symptomatic relief of rheumatic aches and pains.

Symptomatic relief of influenza, feverishness, feverish colds.

These tablets are for oral administration.

Adults, the elderly and children 16 years or older:

Children:

Dosage instruction:

Take every 4 to 6 hours, as required. Do not take more frequently than every 4 hours. Not more than 4 doses should be administered in any 24 hour period.

Hypersensitivity to paracetamol or any other ingredients.

If you are taking any other medicines that contain Paracetamol

Cases of high anion gap metabolic acidosis (HAGMA) due to pyroglutamic acidosis have been reported in patients with severe illness such as severe renal impairment and sepsis, or in patients with malnutrition or other sources of glutathione deficiency (e.g. chronic alcoholism) who were treated with paracetamol at therapeutic dose for a prolonged period or a combination of paracetamol and flucloxacillin. If HAGMA due to pyroglutamic acidosis is suspected, prompt discontinuation of paracetamol and close monitoring, is recommended. The measurement of urinary 5-oxoproline may be useful to identify pyroglutamic acidosis as underlying cause of HAGMA in patients with multiple risk factors.

Alcohol reduces liver capacity to deal with paracetamol.

Chronic use of paracetamol enhances effect of warfarin and other coumarins with increased risk of bleeding; occasional doses have no significant effect.

Colestyramine reduces absorption of paracetamol. Therefore, the colestyramine should not be taken within one hour if maximal analgesia is required.

Metoclopramide and Domperidone accelerate absorption of paracetamol.

However concurrent use need not be avoided.

May interact with Chloramphenicol causing increased plasma levels of Chloramphenicol.

Caution should be taken when paracetamol is used concomitantly with flucloxacillin as concurrent intake has been associated with high anion gap metabolic acidosis due to pyroglutamic acidosis, especially in patients with risks factors (see section 4.4)

Epidemiological studies in human pregnancy have shown no ill effects due to paracetamol being used in the recommended dosage, but patients should follow the advice of their doctor regarding its use. Paracetamol is excreted in breast milk but not in clinically significant quantities. Available published data do not contraindicate breast- feeding.

A large amount of data on pregnant women indicate neither malformative, nor feto/neonatal toxicity. Epidemiological studies on neurodevelopment in children exposed to paracetamol in utero show inconclusive results. If clinically needed, paracetamol can be used during pregnancy however it should be used at the lowest effective dose for the shortest possible time and at the lowest possible frequency

None known.

Adverse events of paracetamol from historical clinical trial data are both infrequent and from small patient exposure.

Accordingly, events reported from extensive postmarketing experience at therapeutic/labelled dose and considered attributable are tabulated below by system class.

Due to limited clinical trial data, the frequency of these adverse events is not known (cannot be estimated from available data), but postmarketing experience indicates that adverse reactions to paracetamol are rare and serious reactions are very rare.

Immune system disorders

Hypersensitivity including skin rash may occur.

Not known: anaphylactic shock, angioedema

Blood and lymphatic system disorders

Not known: blood dyscrasias including thrombocytopenia and agranulocytosis.

Respiratory, thoracic and mediastinal disorders

Bronchospasm*

Hepatobiliary disorders

Hepatic dysfunction

* There have been cases of bronchospasm with paracetamol, but these are more likely in asthmatics sensitive to aspirin or other NSAIDs.

Gastrointestinal

Not known: acute pancreatitis

Skin and subcutaneous disorders

Very rare cases of serious skin reactions such as Toxic Epidermal Necrolysis (TEN), Stevens-Johnson syndrome (SJS), acute generalised exanthematous pustulosis, fixed drug eruption have been reported.

Metabolism and nutrition disorders

Not known: High anion gap metabolic acidosis

Description of selected adverse reactions

High anion gap metabolic acidosis

Cases of high anion gap metabolic acidosis due to pyroglutamic acidosis have been observed in patients with risk factors using paracetamol (see section 4.4). Pyroglutamic acidosis may occur as a consequence of low glutathione levels in these patients.

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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

Liver damage is possible in adults who have taken 10 g or more of paracetamol. Ingestion of 5 g or more of paracetamol may lead to liver damage if the patient has risk factors (see below).

Risk Factors:

If the patient

a, Is on long term treatment with carbamazepine, phenobarbitone, phenytoin, primidone, rifampicin, St John's Wort or other drugs that induce liver enzymes.

Or

b, Regularly consumes ethanol in excess of recommended amounts.

Or

c, Is likely to be glutathione deplete e.g. eating disorders, cystic fibrosis, HIV infection, starvation, cachexia.

Symptoms:

Symptoms of paracetamol overdosage in the first 24 hours are pallor, nausea, vomiting, anorexia and abdominal pain. Liver damage may become apparent 12 to 48 hours after ingestion. Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, haemorrhage, hypoglycaemia, cerebral oedema, and death. Acute renal failure with acute tubular necrosis, strongly suggested by loin pain, haematuria and proteinuria, may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have been reported.

Management:

Immediate treatment is essential in the management of paracetamol overdose. Despite a lack of significant early symptoms, patients should be referred to hospital urgently for immediate medical attention. Symptoms may be limited to nausea or vomiting and may not reflect the severity of overdose or the risk of organ damage. Management should be in accordance with established treatment guidelines, see BNF overdose section.

Treatment with activated charcoal should be considered if the overdose has been taken within 1 hour. Plasma paracetamol concentration should be measured at 4 hours or later after ingestion (earlier concentrations are unreliable). Treatment with N-acetylcysteine may be used up to 24 hours after ingestion of paracetamol, however, the maximum protective effect is obtained up to 8 hours post-ingestion. The effectiveness of the antidote declines sharply after this time. If required the patient should be given intravenous N- acetylcysteine, in line with the established dosage schedule. If vomiting is not a problem, oral methionine may be a suitable alternative for remote areas, outside hospital. Management of patients who present with serious hepatic dysfunction beyond 24h from ingestion should be discussed with the NPIS or a liver unit.

It is considered that excess quantities of a toxic metabolite (usually adequately detoxified by glutathione when normal doses of paracetamol are employed) become irreversibly bound to liver tissue.

ATC code: N02BE01, Other analgesics and antipyretics

Paracetamol is an effective analgesic and antipyretic agent but has only weak antiinflammatory properties. The mechanism of action is probably similar to that of aspirin. Paracetamol may act predominantly by inhibiting prostaglandin synthesis in the central nervous system and to a lesser extent, through a peripheral action by blocking pain-impulse generation. This inhibition appears, however to be on a selective basis.

The peripheral action may also be due to inhibition of prostaglandin synthesis or to the synthesis or actions of other substances that sensitise pain receptors to mechanical or chemical stimulation.

Antipyretic- paracetamol probably produces antipyresis by acting centrally on the hypothalamic heat-regulation centre to produce peripheral vasodilation resulting in increased blood flow through the skin, sweating and heat loss.

The central action probably involves inhibition of prostaglandin synthesis in the hypothalamus.

Paracetamol is readily absorbed from the gastrointestinal tract with peak plasma concentrations occurring in 30 to 60 minutes. It is metabolised in the liver and excreted in the urine mainly as the glucuronide and sulphate conjugates. The elimination half-life varies from about 1-4 hours after therapeutic doses. Paracetamol is relatively uniformly distributed throughout most body fluids. Binding of the drug to plasma proteins is variable; 20 to 30% may be bound at the concentrations encountered during acute intoxication.

Following therapeutic doses 90 - 100% of the drug may be recovered in the urine within the first day. However, practically no paracetamol is excreted unchanged and the bulk is excreted after hepatic conjugation.

A minor hydroxylated metabolite which is usually produced in very small amounts by mixed- function oxidases in the liver and which is usually detoxified by conjugation with liver glutathione may accumulate following paracetamol overdosage and cause liver damage.

There is no pre-clinical data of relevance to a prescriber, which is additional to that already included in other sections of the SPC.

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

Pregelatinised starch (maize)

Sodium metabisulphite

Stearic acid (E570)

Magnesium stearate (E572)

None stated.

5 years.

This medicinal product does not require any special storage conditions.

Paracetamol 500mg Tablets are available in child-resistant packs (Glassine paper foil/ Aluminium or PVC I Aluminium foil) of 100 tablets.

Specification details of blister packs :

PVC/Aluminium foil

- PVC (white, rigid, opaque): 250 microns

- PVC/Aluminium foil (hard tempered): 15/20 microns

- Primer (nitrocellulose): 1.5 to 2.5 gsm

- Heat seal lacquer: 6.5 to 8.5 gsm

PVC/Glassine paper – Aluminium foil

- PVC (white, rigid, opaque): 250 microns

- Glassine paper/Aluminium foil :35±3.50/25±2.0 gsm

No special precautions required.