In accordance with paragraph 8 of Section IV of the Procedure for Expert Evaluation, the applicant must amend the instructions for medical use of the medicinal product upon receipt of new data, including bringing the instructions for medical use into line with the approved instructions for medical use of the original (reference) medicinal product, and ensure that the information on the medicinal product corresponds to current scientific knowledge.
Paracetamol (paracetamol) (single-ingredient and combination medicinal products) – High anion gap metabolic acidosis (HAGMA) as a consequence of pyroglutamic acidosis
Having reviewed all available evidence, including EudraVigilance data and literature sources, the PRAC agreed that the package leaflets of all medicinal products containing paracetamol (single-ingredient and combination medicinal products) should be amended to provide additional information on the risk of high anion gap metabolic acidosis (HAGMA) as a consequence of pyroglutamic acidosis. The PRAC considered the comments on the proposed amendment to the package leaflets of paracetamol (single-ingredient and combination medicinal products) submitted by the marketing authorization holders (MAHs): Haleon; Upsa SAS; Opella Healthcare; Teva; Zentiva; Laboratoires SMB; GlaxoSmithKline; Angelini Pharma; Stada and Johnson & Johnson.
PRAC decided that the holders of all medicinal products containing paracetamol (single-component and combination medicinal products), including the MAHs mentioned in the above-mentioned paragraph, must submit amendments to the package leaflets as described below (new text underlined and in bold, deleted text struck through). Taking into account the wording already existing in some authorized medicinal products, MAHs will need to adapt the text to the specific medicinal products.
- “Special precautions for use” section
Cases of high anion gap metabolic acidosis (HAGMA) as a result of pyroglutamic acidosis have been reported Caution is recommended when paracetamol is used concomitantly with flucloxacillin because of the increased risk of high anion gap metabolic acidosis (HAGMA), in particular in patients with severe illnesses such as severe renal impairment and sepsis, or in patients with malnutrition or other sources of glutathione deficiency (for example, chronic alcoholism), who were treated with paracetamol at a therapeutic dose for a long period or with a combination of paracetamol and flucloxacillin. as well as those who use the maximum daily doses of paracetamol. If HAGMA as a result of pyroglutamic acidosis is suspected, it is recommended to discontinue paracetamol immediately and to carry out careful monitoring, including determination of the urinary 5-oxoproline level. Measurement of the urinary 5-oxoproline level may be useful for identifying pyroglutamic acidosis as the underlying cause of HAGMA in patients with multiple risk factors.
- Section "Interaction with other medicinal products and other forms of interaction"
Paracetamol should be used with caution concomitantly with flucloxacillin, since concomitant use has been associated with high anion gap metabolic acidosis as a result of pyroglutamic acidosis, especially in patients with risk factors (see the section “Special precautions for use”).
- “Adverse reactions” section
Subdivision “Metabolism and nutrition disorders”
High anion gap metabolic acidosis with frequency “not known” (cannot be estimated from the available data)
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 who used paracetamol (see the section “Special warnings and precautions for use”). Pyroglutamic acidosis may occur as a result of low glutathione levels in these patients.
List of medicinal products containing paracetamol (single-component and combination medicinal products) authorized for medical use in Ukraine (according to the State Register of Medicinal Products as of 24.12.2024).
TO ANALYZE THE PUBLISHED INFORMATION AND SUBMIT THE CORRESPONDING APPLICATION FOR AMENDMENTS TO THE REGISTRATION MATERIALS, THE APPLICANT MUST USE THE ORIGINAL TEXT POSTED AT THE LINKS:
