Published: 7 March 2019

Publications

Modified-release paracetamol – Unpredictable in overdose

Prescriber Update 40(1): 7–8
March 2019

The Medicines Adverse Reaction Committee (MARC) reviewed the safety of modified-release paracetamol at the 172^nd meeting on 7 December 2017, following the suspension of these medicines in Europe¹.

Modified-release paracetamol formulation

Modified-release paracetamol tablets are marketed in New Zealand in a formulation containing 665 mg of paracetamol, which is taken up to three times a day^2–4.

The modified-release tablets contain both immediate-release paracetamol (31%) and slow-release paracetamol (69%).

Paracetamol overdose

Products formulated as modified-release paracetamol have acceptable quality, safety and efficacy when taken at the recommended dose.

Paracetamol overdose, whether intentional or accidental, has the potential to cause liver failure. Treatment with N-acetyl cysteine when given early enough can prevent these effects. However, when an overdose involves modified-release paracetamol treatment can be more difficult.

Overdose with modified-release paracetamol results in a prolonged and unpredictable pattern of paracetamol absorption. Serum paracetamol concentration may peak as late as 24 hours after ingestion of modified-release paracetamol. With very large overdoses, the modified-release tablets may form a clump (called a pharmacobezoar) in the gut, which can further delay absorption due to altered disintegration and dissolution properties of the clumped tablets⁵.

Standard treatment guidelines for overdose of immediate-release paracetamol are not designed for these extended periods of absorption. The slow absorption and unpredictable pharmacokinetics of modified-release paracetamol following overdose may lead to a delayed peak in serum paracetamol concentration above the nomogram line⁵. The MARC noted that the current paracetamol poisoning guidelines could be improved to deal with overdoses of modified-release paracetamol¹.

In situations where an overdose involving modified-release paracetamol is suspected, call the National Poisons Centre on 0800 POISON (0800 764 766) for advice.

Modified-release paracetamol is now a Restricted (Pharmacist Only) Medicine

The Medicines Classification Committee (MCC) reviewed the classification of modified-release paracetamol at the 60^th meeting in April 2018⁶ and at the 61^st meeting in November 2018⁷. The MCC recommended that modified-release paracetamol should be reclassified from Pharmacy Only to Restricted (Pharmacist Only) Medicine. The reclassification notice was published in February 2019 (https://gazette.govt.nz/notice/id/2019-go841).

The Restricted Medicine classification maintains over-the-counter access to the medicine while ensuring that consumers receive information from a pharmacist about how to take the medicine correctly, and not taking other paracetamol-containing medicines at the same time.

References

1. Medsafe. 2017. Minutes of the 172^nd Medicines Adverse Reactions Committee Meeting 20 December 2017. URL: www.medsafe.govt.nz/profs/adverse/Minutes172.htm (accessed 5 February 2019).
2. Chiew AL, Fountain JS, Graudins A, et al. 2015. Summary statement: New guidelines for the management of paracetamol poisoning in Australia and New Zealand. Medical Journal of Australia 203(5): 215–18. DOI: 10.5694/mja15.00614 (accessed 17 January 2019).
3. Tan C, Graudins A. 2006. Comparative pharmacokinetics of Panadol Extend and immediate-release paracetamol in a simulated overdose model. Emergency Medicine Australasia 18(4): 398–403. DOI: 10.1111/j.1742-6723.2006.00873.x (accessed 17 January 2019).
4. GlaxoSmithKline Consumer Healthcare. 2018. Panadol Osteo 665 mg modified-release tablets New Zealand Data Sheet 13 March 2018. URL: www.medsafe.govt.nz/profs/Datasheet/p/panadolOsteocaplets.pdf (accessed 17 January 2019).
5. Salmonsen H, Sjöberg G, Brogren J. 2018. The standard treatment protocol for paracetamol poisoning may be inadequate following overdose with modified release formulation: a pharmacokinetic and clinical analysis of 53 cases. Clinical Toxicology 56(1): 63–8. DOI: 10.1080/15563650.2017.1339887 (accessed 17 January 2019).
6. Medsafe. 2018. Minutes of the 60th meeting of the Medicines Classification Committee held in Wellington on 26 April 2018 at 9:30 am. URL: www.medsafe.govt.nz/profs/class/Minutes/2016-2020/mccMin26April2018.htm (accessed 17 January 2019).
7. Medsafe. 2018. Minutes of the 61st meeting of the Medicines Classification Committee held in Wellington on 2 November 2018 at 9:30 am. URL: www.medsafe.govt.nz/profs/class/Minutes/2016-2020/mccMin2Nov2018.htm (accessed 17 January 2019).