Adverse reactions from the HPV vaccine

Updated 23 May 2017

The Danish Medicines Agency’s monitoring of adverse reactions

Possible adverse reactions from HPV vaccines are monitored closely. We monitor the safety of HPV vaccines in close collaboration with the European Medicines Agency (EMA) and the drug regulatory authorities in the other EU countries.

Since the HPV vaccines are authorised by the European Commission, the EMA is responsible for assessing whether new or changed risks can be associated with the vaccines, including adverse reactions. The EMA’s assessment is made by two scientific committees, PRAC and CHMP, consisting of experts from the entire EU (including representatives of the Danish Medicines Agency).

Both healthcare professionals and citizens can report suspected adverse reactions directly to the Danish Medicines Agency. A suspicion is enough to submit a report. This means that you can send a report even if you only suspect that the symptoms may be caused by the vaccine – you do not have to be sure that there is a causal relationship. We register all reports of suspected adverse reactions in a database of adverse reactions. In connection with the registration, we assess whether additional information is required – it may be from the person submitting the report or the patient’s treating doctor. We also assess whether the adverse reactions are serious.

In accordance with international criteria, the Danish Medicines Agency defines an adverse reaction report as serious if the condition requires hospitalisation or prolongation of hospitalisation, results in persistent or significant disability or incapacity (or inability to attend school), birth defects, congenital anomaly, is life-threatening or results in death.

The reporting of a suspected adverse reaction does not necessarily mean that there is a documented causal relationship between the medicinal product used and the reported adverse reaction. When we assess reports of suspected adverse reactions, one of the things we look at is whether there is a greater likelihood that other diseases or circumstances can explain the symptoms.

The Danish Medicines Agency has a vaccination panel consisting of internal and external experts who make quarterly assessments of all Danish reports of suspected adverse reactions from vaccines of the Danish childhood vaccination programme, including the HPV vaccines.

We send all suspected adverse reactions concerning HPV vaccines to the common European database of adverse reactions (the EudraVigilance database). The EMA and the national drug regulatory authorities also collaborate with the WHO about pharmacovigilance. We send copies of Danish reports of suspected adverse reactions to the WHO that runs a pharmacovigilance programme and maintains a global register of reports of adverse reactions from medicinal products.

We send all reports of suspected adverse reactions from a HPV vaccine in anonymised form to the pharmaceutical company holding the marketing authorisation. The reports form part of the Periodic Safety Update Reports that are analysed by the EMA’s scientific committee to assess whether the risk/benefit balance of the vaccines has changed.

Known adverse reactions

The known adverse reactions from HPV vaccines are described in the product information of the HPV vaccines.

The summary of product characteristics describes the adverse reactions identified in clinical trials of the vaccines before they were authorised as well as adverse reactions discovered after the vaccines were marketed. As we gain more experience with the vaccine worldwide, the adverse reactions described in the product information of the vaccines may be updated.

Consequently, it is a good idea to keep updated in the product information, which is available on the website of the European Medicines Agency (EMA):

Summary of product characteristics and package leaflet for Gardasil®

Summary of product characteristics and package leaflet for Gardasil9®

Summary of product characteristics and package leaflet for Cervarix®

Status on the number of reported suspected adverse reactions

Note that the figures may have changed – these figures were published on 30 March 2017 in Danish Pharmacovigilance Update. The page showing the status on adverse reaction reports is updated on an ongoing basis.

Since HPV vaccination was implemented in the Danish childhood vaccination programme in 2009, we have received 2,320 reports of suspected adverse reactions from HPV vaccines up to and including 2016. 1,023 of the reports were classified as serious.

The number of reported adverse reactions does not necessarily mean that there is a link between the vaccine and the reported suspected adverse reaction. See the table of reported suspected adverse reactions:

Table 1

The number of sold doses and the number of adverse reaction reports from 2009 to 2016

HPV vaccine

2009

2010

2011

2012

2013

2014

2015

2016

Total

Number of reports

288

67

43

95

511

190

820

306

2,320

Number of serious reports

26

7

10

18

192

100

488

182

1,023

Number of doses sold

347,690

151,476

163,374

349,730

488,224

114,457

53,781

56,174

1,724,916

Table 1: The number of adverse reaction reports concerning HPV vaccines received from 2009 up to and including 2016 as well as the number of serious reports. The number of sold doses in Denmark is also shown. (Note that when we receive additional information, the figures may be changed. This means that there may be minor differences in the accumulated figures from previous publications and the above).

The figures in the table only cover the reported suspected adverse reactions that we have received since HPV vaccination was implemented in the Danish childhood vaccination programme in 2009. We also received reports of suspected adverse reactions from HPV vaccines before 2009. From 2006 when the first HPV vaccine was marketed and until 2009, we received a total of 83 reports about HPV vaccines – 11 of these reports were classified as serious.

Free access to overviews of all reported adverse reactions from HPV vaccines in Denmark

On this website, we regularly publish all Danish reports of suspected adverse reactions from HPV vaccines. The reports are also available under the Drug Analyses Prints (DAP), search for Human Papilloma Virus. The DAPs are updated once a month.

In our electronic newsletter Danish Pharmacovigilance Update, we publish a quarterly status of reported adverse reactions related to the Danish childhood vaccination programme as well as an assessment of all the reported suspected serious adverse reactions, including an assessment of the likelihood that there is a causal link between the suspected adverse reaction and the vaccine.

Development in the number of reports

Since the summer 2013, possible adverse reactions from the HPV vaccine have attracted great attention. As expected, the increased attention is also reflected in the overall reporting rate of the HPV vaccine, and the number of both serious and non-serious reports increased significantly in 2013 and 2015 compared to other years.

When looking at the reports in relation to when the adverse reactions occurred instead of when they were reported to the Danish Medicines Agency, it appears that we received most reports with adverse reaction onset in 2013, followed by 2012 and 2009. Most doses were also sold in these years. In 2012-13, a particularly large number of people were vaccinated because women born from 1985 to 1992 were offered vaccination free of charge in that period. See the analysis in Danish Pharmacovigilance Update, December 2015.

Suspected adverse reactions reported from HPV vaccination

Since HPV vaccination was implemented in the Danish childhood vaccination programme, the majority of the reports we have received were related to non-serious adverse reactions, like headache, redness and pain at the injection site.

The reports related to HPV vaccines that we have classified as serious include reports of fainting, neurological symptoms and a number of diffuse symptoms, such as long-term headache and stomach ache. Some of the reported suspected adverse reactions from HPV vaccines are not included in the summaries of product characteristics of the vaccines. The reason is that it is still unknown whether the adverse reactions are caused by the vaccine.

The major population surveys, including Danish studies, conducted so far suggest no causal relationship between HPV vaccination and a number of serious diseases.

Cases of Postural Orthostatic Tachycardi Syndrome (POTS) have also been reported. POTS is characterised by an abnormal increase in the heart rate after sitting or standing up and in a labile blood pressure when standing up. POTS is a relatively new diagnosis, which was also found in girls/women in the same age group before the introduction of the HPV vaccine. At the request of the Danish authorities, the EMA carried out a detailed review of HPV vaccines and their safety profile, see below.

The EMA’s review of POTS and CRPS

In November 2015, the EMA completed a review of the safety of HPV vaccines with focus on the available data for the two reported syndromes: CRPS (Complex Regional Pain Syndrome affecting the extremities) and POTS in young women given HPV vaccines.  The EMA found no evidence that the two syndromes, POTS and CRPS, occur more frequently in HPV vaccinated girls than in girls who have not been vaccinated, and concluded that the evidence does not support a causal link between the HPV vaccines and the development of CRPS or POTS.

The review is based on published research data, data from clinical trials and reports of suspected adverse reactions from patients and healthcare professionals as well as data from the member countries, including a recent review of adverse reaction reports submitted by the Danish authorities. The EMA has also consulted a group of leading experts in this field and taken into account detailed information from a number of patient groups.

Read the EMA's Assessment report - Human papillomavirus (HPV) vaccines (PDF)

POTS and CRPS must still be monitored closely in connection with future reviews of the safety of HPV vaccines, and special measures have been launched in the form of a new questionnaire that will ensure follow-up on adverse reaction reports of symptoms suggestive of POTS or CRPS.

Continued focus on the safety of HPV vaccines

The Danish Medicines Agency continues to monitor possible adverse reactions from HPV vaccines closely. For example, through our work with reports of suspected adverse reactions from HPV vaccination and by following new research and studies in this field both in Denmark and abroad.

From 1 February 2016, the HPV vaccine Cervarix® will be used in the Danish childhood vaccination programme, formerly Gardasil® was used. Since Cervarix® will be used for the first time in the Danish childhood vaccination programme, we have decided that the vaccine will be subject to stricter reporting requirements so that doctors (dentists and midwives)1 must report all suspected adverse reactions from the vaccine.

The Danish Medicines Agency encourages doctors and citizens to continue to report suspected adverse reactions from HPV vaccination. Adverse reactions can be reported electronically at www.meldenbivirkning.dk (in Danish). To be able to monitor the safety of medicines in the best possible way, it is important that the information in the report is as complete as possible.

You can claim compensation from the Patient Compensation Association, if you suffer from injury caused by a vaccine. Read more at the Patient Compensation Association

Regional screening centres

Since the summer 2015, general practitioners and hospital departments have had the opportunity to refer patients to a specialist departments in the region in which the vaccinated person lives. The doctors at these wards are responsible for the screening and any treatment of girls showing diffuse symptoms that may be caused by adverse reactions from the HPV vaccine. The departments are responsible for coordinating the patient pathway and involving the required medical skills.


1. Cervarix® has been added to the Danish Medicines Agency’s list of medicinal products with stricter reporting requirements for doctors, dentists and midwives to report adverse reactions (except for suspected adverse reactions as a result of medication errors) in humans they are treating or have treated to the Danish Medicines Agency. The doctor, dentist or midwife must report serious adverse reactions to the Danish Medicines Agency no later than 15 days after they have come to their attention. The list is available on our website.

Did you get answers to your questions?

Please tell us how we can improve our website?