Overview

Carbocisteine and acetylcysteine (also known as N-acetylcysteine or NAC) are cysteine derivatives indicated for use as mucolytic agents. They are assumed to reduce mucus viscosity by breaking the disulfide bonds, and thus promoting expectoration. In addition, acetylcysteine is well-established as a specific antidote in paracetamol overdose. Acetylcysteine is also commonly used off-label as a nephroprotective agent in prevention of radiocontrast-induced nephropathy.

In Malaysia, carbocisteine and acetylcysteine are registered as controlled medicines or over-the-counter medicines (OTC), available in either single-ingredient or combination products¹. Given its antioxidant properties, acetylcysteine is also found in some health supplements.

Background of Safety Issue^1,2,3,4,5

The National Pharmaceutical Regulatory Agency (NPRA) initiated a safety review on the potential risk of anaphylactic/anaphylactoid reactions and severe cutaneous adverse reactions (SCARs) with the use of carbocisteine. This safety review was triggered through the submission of new safety information by the product registration holder of carbocisteine. NPRA subsequently extended the review to include another cysteine derivative, acetylcysteine.

Based on the safety findings, it was suggested that both carbocisteine and acetylcysteine are associated with anaphylactic/anaphylactoid reactions. Further to the review, the occurrence of serious skin reactions such as erythema multiforme, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with the use of carbocisteine and acetylcysteine. In most of these reported cases of SCAR, at least one other drug was concurrently administered, which may have contributed to the described mucocutaneous effects.

Having considered the current available evidence from local and global post-marketing case reports, scientific literature, input of local clinical experts, as well as action taken by foreign regulatory authorities, NPRA concluded that an update of the labels and package inserts of carbocisteine- and acetylcysteine-containing products is warranted to reflect the possibly life-threatening risks discussed above.

Adverse Drug Reaction Reports²

• The NPRA has received four (4) ADR reports with 12 adverse events suspected to be related to carbocisteine. These include urticaria, pruritus, angioedema, rash, and peripheral oedema.  NPRA has not received any reports of anaphylactic/anaphylactoid reactions or SCARs associated with carbocisteine use.
• NPRA has received 154 ADR reports with 370 adverse events suspected of being linked to acetylcysteine use. Of these:

• Four (4) reports of anaphylactic/anaphylactoid reactions were associated with intravenous acetylcysteine use. In two of these cases, the initial intravenous infusions were reported to be completed within 15 minutes (instead of the current recommended duration of 60-minutes).
• One report of erythema multiforme was suspected of being possibly linked to oral acetylcysteine (as mucolytic agent) and another two co-suspected drugs (sodium valproate and ceftriaxone).

Advice for Healthcare Professionals

Carbocisteine and Acetylcysteine (for indications other than paracetamol overdose)

• Inform patients about the initial signs and symptoms of serious hypersensitivity reactions, such as nausea, vomiting, flushing, skin rash, pruritus and urticaria.
• Advise patients to stop taking the product and seek medical attention immediately if they develop any of these initial signs and symptoms.
• In the event of a serious hypersensitivity reaction, instruct patient to avoid repeated exposure to the offending active ingredient.

Acetylcysteine for Paracetamol Overdose^5,6

• Anaphylactic/anaphylactoid reactions occur particularly during the administration of the initial loading dose of intravenous acetylcysteine. These risks appear to be concentration and rate-dependent, which can be reduced by slow initial infusion over 60 minutes. [Refer to local and professional guidelines in relation to acetylcysteine administration in paracetamol overdose management⁶].
• Management of hypersensitivity reactions should be based upon the severity of the reaction. These include temporary interruption or slowing of acetylcysteine infusion, and/or administration of antihistamines.
• In light of the life-saving role of acetylcysteine for paracetamol overdose, specialist advice should be sought on the management of patients with previous or developed severe hypersensitivity reactions (including SCARs) to acetylcysteine.
• Please report all suspected adverse drug reactions to NPRA.

A directive [Ruj. Kami: (14) dlm. BPFK/PPP/07/25 Jld. 2] has been issued by NPRA for updates to the local product packaging insert and consumer medication information leaflet (Risalah Maklumat Ubat untuk Pengguna) related to this safety issue. Please refer to the directive for more information.

References:

1. The NPRA QUEST 3+ database, [Accessed: 16 November 2017]
2. The Malaysian National ADR Database, NPRA [Accessed: 16 November 2017]
3. The WHO VigiLyze Database, Uppsala Monitoring Centre (UMC) [Accessed: 27 November 2017]
4. Yavuz H & Emiroglu M (2011). Toxic epidermal necrolysis treated with N-acetylcysteine. Pediatrics International, 56, e52–e54.
5. Medicines & Healthcare Products Regulatory Agency (MHRA) (2012). Paracetamol overdose: Simplification of the use of intravenous acetylcysteine. Safety Warnings and Messages for Medicines. United Kingdom.
6. Pharmaceutical Services Division (2015). Clinical Pharmacokinetics Pharmacy Handbook. Ministry of Health Malaysia.

DISCLAIMER

This publication is aimed at health professionals. The information is meant to provide updates on medication safety issues, and not as a substitute for clinical judgement. While reasonable care has been taken to verify the accuracy of the information at the time of publication, the NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.