Paracetamol Other names: Acetaminophen

Co-administration of paracetamol with barbiturates, anticholinesterases, alcohol results in a reduced ability to metabolize large doses of paracetamol and increase the half-life of paracetamol in plasma.

Care is advised in the administration of paracetamol to patients with severe hepatic impairment. The hazards of overdose are greater in those with non-cirrhotic alcoholic liver disease.

In patients with chronic or compensated active hepatic disease, hepatocellular insufficiency or Gilbert’s syndrome the maximum daily dose must not exceed 3 g.

Care is advised in the administration of paracetamol to patients with severe renal impairment.

In patients with renal impairment, the minimum interval between each IV administration should be modified according to the following schedule:

Alcohol may increase the hepatotoxicity of paracetamol during overdose.

Paracetamol should be used with caution in cases of chronic alcoholism.

The anticoagulant effect of warfarin and other coumarins may be enhanced by prolonged regular use of paracetamol with increased risk of bleeding; occasional doses have no significant effect.

Chronic administration of antiepileptics or oral steroidal contraceptives affect hepatic enzymes and may prevent therapeutic plasma levels of paracetamol by increasing its first pass metabolism or elimination.

Co-administration of paracetamol with non-steroidal anti-inflammatory drugs and interferons increases the risk of liver damage.

Paracetamol antinociceptive effectiveness is not influenced by N-Acetylcysteine. The effect of paracetamol at therapeutic dosage on glutathione may be counteracted by N-Acetylcysteine (https://pubmed.ncbi.nlm.nih.gov/30471141/).

In coadministration of paracetamol with chloramphenicol, there is increased plasma concentration of chloramphenicol.

The speed of absorption of paracetamol is reduced by cholestyramine. Therefore, the cholestyramine should not be taken within one hour if maximal analgesia is required.

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

Paracetamol reduces the bioavailability of lamotrigine without its clinical significance being clear.

The absorption of paracetamol is increased by metoclopramide and domperidone. However, concurrent use need not be avoided.

Co-administration of drugs that induce liver enzymes (eg phenobarbital, isoniazid, carbamazepine, rifampicin, etc.) increase the risk of liver damage.

Proesenidine may reduce renal excretion and increase plasma paracetamol levels.

Salicylamide may prolong the elimination t_1/2 of paracetamol.

In patients suffering from a genetically caused G-6-PD deficiency (favism) the occurrence of a haemolytic anaemia is possible due to the reduced allocation of glutathione following the administration of paracetamol.

Paracetamol should be used with caution in cases of dehydration.

Clinical experience of intravenous administration of paracetamol is limited.

Reproductive studies with the intravenous form of paracetamol have not been performed in animals.

However, a large amount of data for oral use in 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.

After oral administration, paracetamol is excreted into breast milk in small quantities. No undesirable effects on nursing infants have been reported. Consequently, paracetamol may be used in breast-feeding women.

None known.

Adverse events of paracetamol from historical clinical trial data are both infrequent and from small patient exposure. Accordingly, events reported from extensive post-marketing experience at therapeutic/labelled dose and considered attributable are tabulated below by system class and frequency.

The following convention has been utilised for the classification of the undesirable effects: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000) and very rare (<1/10,000), not known (cannot be estimated from available data).

Adverse event frequencies have been estimated from spontaneous reports received through post-marketing data.

Blood and lymphatic system disorders

Very rare: Thrombocytopenia, Agranulocytosis

Immune system disorders

Very rare: Anaphylaxis,Cutaneous hypersensitivity reactions including, among others, skin rashes and angioedema. Very rare cases of serious skin reactions have been reported

Respiratory, thoracic and mediastinal disorders

Very rare: Bronchospasm^*

Hepatobiliary disorders

Very rare: Hepatic dysfunction

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

IV administration

As all paracetamol products, adverse drug reactions are rare (>1/10000, <1/1000) or very rare (<1/10000), they are described below:

Frequent adverse reactions at injection site have been reported during clinical trials (pain and burning sensation).

Very rare cases of hypersensitivity reactions ranging from simple skin rash or urticaria to anaphylactic shock have been reported and require discontinuation of treatment.

Cases of erythema, flushing, pruritus and tachycardia have been reported.

Very rare cases of serious skin reactions have been reported.