Overview

Nirmatrelvir/ritonavir is a new drug combination developed for the treatment of COVID-19 infection. In Malaysia, nirmatrelvir/ritonavir is indicated for the treatment of COVID-19 in adults who do not require supplemental oxygen and who are at increased risk for progression to severe COVID-19.¹ There are currently two (2) products approved under Conditional Registration of Pharmaceutical Products during Disaster containing nirmatrelvir/ritonavir, under the brand name PAXLOVID^TM.²

Nirmatrelvir acts by blocking the activity of the SARS-CoV-2 3CL protease, an enzyme required for viral replication. As nirmatrelvir is rapidly metabolised by the P450 cytochrome enzyme CYP3A4, ritonavir which is a CYP3A4 inhibitor is combined with nirmatrelvir to slow down the metabolism of nirmatrelvir. This may result in nirmatrelvir remains active in the body for a longer period of time.^1,3

Background of the Safety Issue

In June 2022, the National Pharmaceutical Regulatory Agency (NPRA) learned from the Pharmaceutical Medical Agency (PMDA), Japan about the risk of anaphylaxis associated with nirmatrelvir/ritonavir following one (1) reported case of anaphylaxis in Japan.⁴

Following the PMDA review, it was found that in addition to the one (1) case of anaphylaxis reported in Japan, there had been three (3) anaphylaxis cases reported overseas. The causal relationship between the drug and the event was determined as reasonably possible for all these cases. However, no fatalities had been observed. Based on the consultation with expert advisors by PMDA, it was concluded that the product information (PI) needs to be updated with relevant information on this risk.⁵

On the other hand, cautionary statements with regard to the risk of hypersensitivity have been added to the PI for nirmatrelvir/ritonavir in the United States⁶, Canada⁷ and Australia.⁸ Cases of hypersensitivity reactions have also been reported with ritonavir, a component of the product.⁶

Adverse Drug Reaction (ADR) Reports⁹

As of 16^th August 2022, the NPRA had received a total of 1,001 reports with 1,714 adverse events suspected to be related to nirmatrelvir/ritonavir-containing products. Out of these reports, the most frequently reported adverse events were taste bitter (562), diarrhoea (247), dysgeusia (134), vomiting (70) and nausea (69). There have been no local cases of anaphylaxis reported to the NPRA thus far. However, there were reported cases of rash (7), pruritus (6), urticarial (4), rash pruritic (2), rash maculo-papular (1), and gum swelling (1).

Advice for Healthcare Professionals 

• Advise patients to seek immediate treatment if symptoms of anaphylaxis such as feeling light-headed, suffering breathing difficulties, or a fast heartbeat occur after receiving treatment with nirmatrelvir/ritonavir.
• Advise patients to inform their healthcare provider at the first sign of a skin rash, hives, or other skin reactions, difficulty in swallowing or breathing, angioedema or other symptoms of hypersensitivity reactions after receiving treatment with nirmatrelvir/ritonavir.
• Immediately discontinue treatment with nirmatrelvir/ritonavir if patients have developed severe hypersensitivity reactions and initiate appropriate medications and/or supportive care.
• Please report all suspected adverse events associated with nirmatrelvir/ritonavir-containing products to the NPRA.

References:

1. National Pharmaceutical Regulatory Agency (NPRA). PAXLOVID (nirmatrelvir/ritonavir) Film-Coated Tablets [Package Insert]. QUEST3+ Product Search. 2020 Sep [cited 2022 Jul 22]. Available from: http://www.npra.gov.my
2. National Pharmaceutical Regulatory Agency. QUEST3+ Product Search [Internet]. 2022 [cited 2022 Jul 14]. Available from: https://www.npra.gov.my
3. Reis S, Popp M, Kuehn R, Metzendorf M, Gagyor I, Kranke P et al. Nirmatrelvir combined with ritonavir for preventing and treating COVID-19. Cochrane Database of Systematic Reviews. 2022(4). Available from: https://doi.org/10.1002/14651858.CD015395
4. Pharmaceuticals and Medical Devices Agency (PMDA). Revision of Precautions: Nirmatrelvir/Ritonavir [Internet]. 2022 Jun 14 [cited 2022 Jul 19]. Available from: https://www.pmda.go.jp/files/000246852.pdf
5. Pharmaceuticals and Medical Devices Agency (PMDA). Summary of Investigation Results: Nirmatrelvir/Ritonavir [Internet]. 2022 Jun 14 [cited 2022 Jul 19]. Available from: https://www.pmda.go.jp/files/000246859.pdf
6. United States Food and Drug Administration (US FDA). Fact Sheet for Healthcare Providers: Emergency Use Authorization for PAXLOVID^TM [Package Insert]. 2022 [cited 2022 Jul 19]. Available from: https://www.fda.gov/media/155050/download#:~:text=Hypersensitivity%20reactions%20have%20been%20reported%20with%20PAXLOVID%20including%20urticaria%2C%20angioedema,refer%20to%20NORVIR%20prescribing%20information
7. Health Canada. Product Monograph Including Patient Medication Information: PAXLOVID^TM [Package Insert]. Drug Product Database online query. 2022 Jun 13 [cited 2022 Jul 19]. Available from: https://pdf.hres.ca/dpd_pm/00066256.PDF
8. Therapeutic Goods Administration (TGA). Australian Product Information: PAXLOVID^TM (nirmatrelvir/ritonavir tablets) [Package Insert]. 2022 [cited 19 Jul 2022]. Available from: https://www.tga.gov.au/sites/default/files/paxlovid-pi.pdf
9. National Pharmaceutical Regulatory Agency. The Malaysian National ADR Database (QUEST) [Internet]. 2022 [cited 2022 Jul 14]. Available from: https://www.npra.gov.my

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, NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.

Written by: Noor'ain Shamsuddin
Reviewed/Edited by: Choo Sim Mei, Lim Sze Gee, Dr Azuana Ramli