Medicines Safety Update is the medicines safety bulletin of the Therapeutic Goods Administration (TGA)
In this issue:
- Accidental paracetamol poisoning
- Strontium ranelate and venous thromboembolism and serious skin reactions
- Better information on medicine labels – have your say
Accidental paracetamol poisoning
The hepatotoxic effects of paracetamol when taken as an intentional overdose are well-known. However, paracetamol hepatotoxicity can also occur in other situations, including accidental overdose and use at normal doses.
Paracetamol-induced hepatotoxicity at therapeutic doses
"In a study of 662 patients with acute liver failure, 275 were cases of severe paracetamol-induced hepatotoxicity. 131 (48%) of these 275 cases were the result of an unintentional overdose and 19 (7%) of the 275 patients had not exceeded the recommended maximum daily dose of 4g."
The correct reference for this paragraph is:
Larson AM, Polson J, Fontana RF, Davern TJ, Lalani E, Hynan LS, et al. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology 2005;42:1364-72.
In many patients with hepatotoxicity, the paracetamol was taken for therapeutic purposes only. In a study of 662 patients with severe paracetamol-induced hepatotoxicity, 48% had not exceeded the recommended maximum daily dose of 4g.1
A 45-year-old woman suffered fatal paracetamol-induced liver failure after receiving paracetamol at a therapeutic dose. She had been hospitalised for subacute bowel obstruction and treated with paracetamol 1g ‘qid’ for 8 days while remaining nil by mouth.1
Risk factors for paracetamol hepatotoxicity include fasting, regular excessive alcohol use, and concomitant use of drugs that induce cytochrome P450 (CYP) 2E1 (e.g. ethanol). Paracetamol is normally metabolised through conjugation in the liver and excreted in urine. A small proportion of paracetamol is converted by CYP enzymes 2E1 and 3A4 to the hepatotoxic compound N -acetyl- p -benzoquinone imine (NAPQI), which is then conjugated with glutathione and excreted. Prolonged fasting depletes the substrates necessary for conjugation, including glutathione, leading to a build-up of NAPQI.1,2.
A three-year-old chronically malnourished boy with a history of gastric dysmotility syndrome was hospitalised with fever and vomiting. Being intolerant of oral medication, he was prescribed the intravenous formulation of paracetamol, Perfalgan 150 mg (15 mL). Due to confusion between mg and mL he was given a single dose of 150 mL (1500 mg).3 He experienced transient hepatotoxicity, which responded to treatment with N-acetylcysteine. To avoid this type of dosing error, specify the dose volume in mL when prescribing, particularly in neonates and infants.4
Concomitant administration of oral and intravenous paracetamol is another cause of hepatotoxicity. When administering paracetamol, it is advisable to check no other sources of paracetamol have been given.
Information for health professionals
Australian guidelines for the management of paracetamol overdose include an updated treatment nomogram, and recommended investigations and N -acetylcysteine dosing regimens.2
Strontium ranelate and venous thromboembolism and serious skin reactions
Health professionals are advised of additional contraindications and precautions for strontium ranelate (Protos), to help manage the risk of venous thromboembolism (VTE) and serious skin hypersensitivity reactions.
Strontium ranelate, marketed as Protos, is indicated for the treatment of postmenopausal osteoporosis to reduce the risk of fracture, and for the treatment of osteoporosis in men at increased risk of fracture.
The European Medicines Agency (EMA) recently completed a review of Protos.5 It concluded that while Protos remains an important treatment for osteoporosis, changes were required to the information provided to health professionals to better manage the associated risks.
Risk of VTE
The risk of VTE was found to be higher in patients with a previous history of VTE, and in patients who are temporarily or permanently immobilised. A higher rate of VTE was also identified in elderly patients aged >80 years receiving Protos, compared to placebo.
Risk of serious skin hypersensitivity reactions
Post-marketing surveillance has identified cases of severe skin reactions, such as drug rash with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), in patients prescribed Protos. However, the overall occurrence of serious skin reactions was low. Since these conditions are best managed with early diagnosis and immediate discontinuation of any suspect medicines, it is important that health professionals are aware of the time-to-onset, signs and symptoms of these conditions.
Changes to the Product information
The Australian Product Information has been updated to include strengthened advice for managing the risk of VTE and serious skin hypersensitivity reactions (see below).
|New contraindications and precautions for strontium ranelate (Protos)*|
|* For full prescribing information, see the Protos Product Information available on the TGA website|
Better information on medicine labels - have your say
Health professionals are invited to submit comments on the TGA’s consultation paper for the Medicine Labelling and Packaging Review. In particular, the TGA is interested in comments from health professionals on the relevance and impact of the proposed changes on the quality use of medicines and consumer safety.
The objective of the review is to develop appropriate regulatory solutions that effectively address the consumer safety risks posed by the following issues:
- active ingredients prominence
- look-alike medicine branding, also known as brand extension or trade name extension
- look-alike and sound-alike medicine names
- look-alike medicine packaging
- standardised formats for information included on medicines labels and packaging
- mandatory space for dispensing stickers
- information provided on blister strips
- information included on small containers
- information provided in pack inserts.
The aim of the proposed changes is to reduce the risk of errors by health professionals and facilitate consumer access to the information they need to:
- make informed choices where they are self-managing minor conditions, such as a headache or a cold
- safely use a medicine that they have been prescribed by a health practitioner for the treatment of a more serious condition.
Full details of the process and the consultation paper can be found on the TGA website:www.tga.gov.au/newsroom/consult-labelling-packaging-review-120524.htm
|What to report? You don't need to be certain, just suspicious!|
|The TGA encourages the reporting of allsuspected adverse reactions to medicines, including vaccines, over-the-counter medicines, herbal, traditional or alternative remedies. We particularly request reports of:||Reports may be submitted:|
Medicines Safety Update is aimed at health professionals. It is intended to provide practical information to health professionals on medicine safety, including emerging safety issues. The information in Medicines Safety Update is necessarily general and is not intended to be a substitute for a health professional's judgment in each case, taking into account the individual circumstances of their patients. Reasonable care has been taken to ensure that the information is accurate and complete at the time of publication. The Australian Government gives no warranty that the information in this document is accurate or complete, and shall not be liable for any loss whatsoever due to negligence or otherwise arising from the use of or reliance on this document.
© Commonwealth of Australia 2016.
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- Lubel JS, Angus PW, Gow PJ. Accidental paracetamol poisoning. Med J Aust 2007;186:371–2 .
- Daly FF, Fountain JS, Murray L, Graudins A, Buckley NA; Panel of Australian and New Zealand clinical toxicologists. Guidelines for the management of paracetamol poisoning in Australia and New Zealand. Med J Aust 2008;188:296-301.
- Berling I, Anscombe M, Isbister GK. Intravenous paracetamol toxicity in a malnourished child. Clin Toxicol (Phila) 2012;50:74-6.
- Dear Healthcare Professional Letter. Bristol-Myers Squibb Australia Pty Ltd. 2012 May.
- European Medicines Agency confirms positive benefit-risk balance of Protelos/Osseor, but recommends new contraindications and revised warnings [press release]. European Medicines Agency. 2012 Mar .