Overview

In Malaysia, there are currently eight (8) types of COVID-19 vaccines conditionally registered with the Drug Control Authority (DCA), namely Comirnaty, Vaxzevria, CoronaVac, Spikevax, Janssen, Covilo, Convidecia, and Covaxin. However, only Comirnaty, Vaxzevria, Covilo, CoronaVac, and Convidecia are being used in the National COVID-19 Immunisation Programme (PICK).¹

Tinnitus is commonly described as ringing in the ears, but it can also be presented as buzzing or hissing sound or other noises. The noise may differ in volume and can be temporary or persistent in either one or both ears. Some people with tinnitus have no difficulty in hearing, however, it is often noticeable when the background noise is low, especially at night.^2-3 The incidence of tinnitus is common in the general population with 2 in every 3 people experiencing it.⁴

 

Background of the Safety Issue

In July 2022, the National Pharmaceutical Regulatory Agency (NPRA) through its global safety signal monitoring activity learned about the uncommon risk of tinnitus following the use of Vaxzevria COVID-19 vaccine. This safety signal was identified based on the analysis of global data during post-marketing surveillance by the Australia Therapeutic Goods Administration (TGA).⁴ Around the same time, the European Medicines Agency (EMA) also published an update to the product information of Vaxzevria with the uncommon risk of tinnitus. According to the EMA’s assessment, cases of tinnitus have been reported spontaneously following the use of Vaxzevria as well as in ongoing clinical trials.⁵

Upon review, back in August 2021, the EMA Pharmacovigilance Risk Assessment Committee (PRAC) had concluded that there was a link between tinnitus and the use of Janssen COVID-19 vaccine. According to the PRAC’s review, there were six (6) cases observed in clinical trials and 108 cases identified by the company during spontaneous reports monitoring of Janssen COVID-19 vaccine. Hence, the package insert of the vaccine was recommended to be updated with tinnitus. However, the benefit-risk balance of the vaccine remains positive.⁶

On the other hand, in 2021, the EMA made a cumulative review and concluded that a causal association of tinnitus with Comirnaty exposure was not suggested and the signal was closed.⁷

Earlier this year, the Uppsala Monitoring Centre (UMC), through the publication of the World Health Organisation (WHO) Pharmaceuticals Newsletter No.1, 2022, raised a signal of COVID-19 vaccines with tinnitus. The UMC detected disproportional reporting of COVID-19 vaccines with tinnitus in the WHO global database of individual case safety reports (ICSRs), VigiBase. It was found that tinnitus has been reported for most of the COVID-19 vaccines, but with different Information Component (IC) values.² (Note: IC is a measure of the disproportionality between the observed and the expected reporting of a drug-event pair. A positive IC value indicates that a particular drug-event pair is reported more often than expected. The higher the value of the IC, the more the combination stands out from the background.)⁸

Tinnitus can be caused by many factors, including hearing loss, an ear infection, some medicines use or other underlying ear problems.⁴ Stress and anxiety may also be contributing factors to the onset of tinnitus or making it worse.^3,10 There were also reports of tinnitus in people infected with COVID-19 disease³ and the symptoms can last longer and become long-COVID.⁹

According to the UMC review, the time to onset of tinnitus ranged from several minutes to 30 days after vaccination, with nearly half recovered at the time of reporting. Tinnitus has been reported in the first and second doses of vaccination.² There were also cases of positive re-challenge for tinnitus.¹¹ 

To date, the causal associations have been confirmed for Vaxzevria and Janssen COVID-19 vaccines. Whilst, the signal of tinnitus was closed by EMA for Comirnaty COVID-19 vaccine. Information on causality links for other COVID-19 vaccines are still limited.

 

Adverse Drug Reaction Reports^12-13

Till date, the NPRA had received 35 local reports of tinnitus following the use of COVID-19 vaccines. All the reports were assigned causality ‘indeterminate’. Nineteen (19) reports were reported following the first dose, 11 reports were reported after the second dose, and three (3) reports were reported following a booster dose. This information is missing for the remaining two (2) reports.

The distribution of local reports on tinnitus according to COVID-19 vaccine brands is shown in the table below:

Vaccine Brand	No. of vaccine doses administered (as of 31st July 2022)	No. of tinnitus cases reported
Comirnaty	44,325,076	20
CoronaVac	21,524,960	5
Vaxzevria	5,704,774	7
Covilo	43,854	1
Unknown brand	--	2
TOTAL	71,843,829*	35

*Numbers may not add up to the total due to missing values.

As of 31^st July 2022, 224,408 doses of Convidecia COVID-19 vaccine have been administered but no cases of tinnitus have been reported to date.

 

Advice for Healthcare Professionals^14-15

1. Be aware of the potential causal association between tinnitus and COVID-19 vaccines, particularly for Vaxzevria and Janssen vaccines.
2. Remind anyone who received COVID-19 vaccines to get medical attention if there is a new onset or change in otologic symptoms.
3. When a patient presents with otologic symptoms, inquire about their COVID-19 vaccination history and onset of the symptoms.
4. Promptly refer vaccinated patients with new or worsening otologic symptoms for evaluation and treatment.
5. Report all suspected adverse events, including tinnitus, following the COVID-19 vaccination to the NPRA.

To report adverse events:

1. Visit www.npra.gov.my
2. Select “Reporting ADR” under Health Professionals.
   a)  Choose Online Reporting; or
   b) Download the manual form and submit the completed form via email to This email address is being protected from spambots. You need JavaScript enabled to view it. or This email address is being protected from spambots. You need JavaScript enabled to view it. (for AEFIs related to COVID-19 vaccines); alternatively, post to:

The Pharmacovigilance Section,
National Pharmaceutical Regulatory Agency (NPRA),
Ministry of Health, Malaysia.
Lot 36, Jalan Prof Diraja Ungku Aziz (Jalan Universiti),
46200 Petaling Jaya, Selangor, Malaysia.

 

The local package insert of Janssen COVID-19 vaccine in Malaysia has been updated with tinnitus. The NPRA is currently in the midst of evaluating these safety issues for other COVID-19 vaccines to view the need to update the local package inserts with the relevant safety information.  

 

References:

1. National Pharmaceutical Regulatory Agency (NPRA). QUEST3+ Product Search [Internet]. 2022 [cited on 2022 Aug 10]. Available from: https://www.npra.gov.my
2. World Health Organization (WHO). WHO Pharmaceuticals Newsletter No. 1, 2022 [Internet]. 2022 [cited on 2022]. Available from: https://apps.who.int/iris/bitstream/handle/10665/351326/9789240042452-eng.pdf?sequence=1&isAllowed=y
3. Understanding tinnitus – the basics [Internet]. 2021 Nov12 [cited on 2022 Aug 29]. Available from: https://www.webmd.com/a-to-z-guides/understanding-tinnitus-basics
4. Australia Therapeutic Goods Administration (TGA). COVID-19 vaccine safety report [Internet]. 2022 Jul 28 [cited 2022 Aug 10]. Available from: https://www.tga.gov.au/periodic/covid-19-vaccine-safety-report-28-07-2022
5. European Medicines Agency (EMA). COVID-19 vaccines safety update [Internet]. Rev. 1; 2022 Aug 3 [cited 2022 Aug 10]. Available from: https://www.ema.europa.eu/en/documents/covid-19-vaccine-safety-update/covid-19-vaccines-safety-update-14-july-2022_en.pdf
6. European Medicines Agency (EMA). Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 5 August 2021 [Internet]. 2021 Aug 6 [cited 2022 Aug 10]. Available from: https://www.ema.europa.eu/en/news/meeting-highlights-pharmacovigilance-risk-assessment-committee-prac-5-august-2021
7. European Medicines Agency (EMA). Assessment report on the annual renewal of the conditional marketing authorization [Internet]. 2021 [cited 2022 Aug 10]. Available from: https://www.ema.europa.eu/en/documents/variation-report/comirnaty-h-c-5735-r-0046-epar-assessment-report-renewal_en.pdf
8. Uppsala Monitoring Centre (UMC). The UMC measures of disproportionate reporting: A brief guide to their interpretation [Internet]. [cited on 2022 Aug 10]. Available from: https://who-umc.org/media/164041/measures-of-disproportionate-reporting_2016.pdf
9. United Kingdom’s National Health Service (NHS). Long-term effects of coronavirus (long COVID) [Internet]. 2022 Aug 9 [cited on 2022 Aug 10]. Available from: https://www.nhs.uk/conditions/coronavirus-covid-19/long-term-effects-of-coronavirus-long-covid/
10. British Tinnitus Association. Tinnitus and COVID-19 FAQs [Internet]. 2021 Jul 21 [cited on 2022 Aug 10]. Available from: https://www.tinnitus.org.uk/tinnitus-and-covid19-faq
11. Uppsala Monitoring Centre (UMC). The WHO Global ICSR Database (VigiLyze) [Internet]. 2022 [cited on 2022 Aug 10]. Available from: https://vigilyze.who-umc.org (access restricted)
12. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian National ADR Database (QUEST) [Internet]. 2022 [cited on 2022 Aug 10]. Available from: https://www.npra.gov.my (access restricted)
13. COVID-19 Immunisation Task Force (CITF). Open data on Malaysia's National Covid-19 Immunisation Programme [Internet]. 2022 [cited on 2022 Aug 4]. Available from https://github.com/CITF-Malaysia/citf-public
14. Wichova H, Miller ME, Derebery MJ. Otologic manifestations after COVID-19 vaccination: The house ear clinic experience. Otol Neurotol. 2021 Oct 1;42(9):e1213-e1218. Available from: https://doi.org/10.1097%2FMAO.0000000000003275
15. Ahmed SH, Waseem S, Shaikh TG, Qadir NA, Siddiqui SA, Ullah I, Waris A, Yousaf Z. SARS-CoV-2 vaccine-associated-tinnitus: A review. Ann Med Surg (Lond). 2022 Mar;75:103293. Available from: https://doi.org/10.1016%2Fj.amsu.2022.103293 

 

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.

 

Written by: Wang Khee Ing
Reviewed/Edited by: Choo Sim Mei, Lee Sing Chet, Lim Sze Gee, Noor'ain Shamsuddin, Dr. Azuana Ramli