European Medicines Agency’s Review Concludes Evidence Does Not Support That HPV Vaccines Cause Complex Regional Pain Syndrome and Postural Orthostatic Tachycardia Syndrome

Reports of these two syndromes after HPV vaccination are consistent with what would be expected in this age group

On 5 November 2015, the European Medicines Agency announced that its Pharmacovigilance Risk Assessment Committee (PRAC) has completed a detailed scientific review of the evidence surrounding reports of two syndromes, complex regional pain syndrome (CRPS) and postural orthostatic tachycardia syndrome (POTS) in young women given human papillomavirus (HPV) vaccines. These vaccines are given to protect them from cervical cancer and other HPV-related cancers and pre-cancerous conditions. This review concluded that the evidence does not support a causal link between the vaccines (Cervarix, Gardasil/Silgard and Gardasil-9) and development of CRPS or POTS. Therefore, there is no reason to change the way the vaccines are used or amend the current product information.

CRPS is a chronic pain syndrome affecting a limb, while POTS is a condition where the heart rate increases abnormally on sitting or standing up, together with symptoms such as dizziness, fainting and weakness, as well as headache, aches and pains, nausea and fatigue. In some patients they can severely affect the quality of life. The syndromes are recognised to occur in the general population, including adolescents, regardless of vaccination.

PRAC thoroughly reviewed the published research, data from clinical trials and reports of suspected side effects from patients and healthcare professionals, as well as data supplied by Member States. It also consulted a group of leading experts in the field, and took into account detailed information received from a number of patient groups that also highlighted the impact these syndromes can have on patients and families.

Symptoms of CRPS and POTS may overlap with other conditions, making diagnosis difficult in both the general population and vaccinated individuals. However, available estimates suggest that in the general population around 150 girls and young women per million aged 10 to 19 years may develop CRPS each year, and at least 150 girls and young women per million may develop POTS each year. The review found no evidence that the overall rates of these syndromes in vaccinated girls were different from expected rates in these age groups, even taking into account possible underreporting. The PRAC noted that some symptoms of CRPS and POTS may overlap with chronic fatigue syndrome (CFS, also known as myalgic encephalomyelitis or ME). Many of the reports considered in the review have features of CFS and some patients had diagnoses of both POTS and CFS. Results of a large published study that showed no link between HPV vaccine and CFS were therefore particularly relevant.

The PRAC concluded that the available evidence does not support that CRPS and POTS are caused by HPV vaccines. Therefore there is no reason to change the way the vaccines are used or amend the current product information.

The review recognised that more than 80 million girls and women worldwide have now received these vaccines, and in some European countries they have been given to 90% of the age group recommended for vaccination. Use of these vaccines is expected to prevent many cases of cervical cancer and various other cancers and conditions caused by HPV. The benefits of HPV vaccines therefore continue to outweigh their risks.  The safety of these vaccines, as with all medicines, will continue to be carefully monitored.

The PRAC’s recommendations will now be passed to the Committee for Medicinal Products for Human Use (CHMP) for adoption of the Agency’s final position. The evidence supporting the PRAC review will be published in an assessment report following the CHMP opinion.

HPV vaccines are available in the European Union under the names Gardasil/Silgard, Gardasil 9, and Cervarix. Gardasil has been authorised since September 2006, and is approved for use in males and females for preventing precancerous growths and cancer in the cervix and anus, and genital warts. It protects against 4 types of HPV (types 6, 11, 16 and 18). Gardasil 9 (approved in June 2015) is used similarly but protects against 9 types of the virus (types 6, 11, 16, 18, 31, 33, 45, 52 and 58). Cervarix has been approved since September 2007 for use in women and girls to protect against precancerous growths and cancer in the cervix and genital area. It is active against types 16 and 18 of the virus. Following their approval, the vaccines have been introduced in national immunisation programmes in many countries. It is estimated that more than 63 million girls and women worldwide have been vaccinated with Gardasil/Silgard and more than 19 million with Cervarix.

The review of HPV vaccines was initiated on 9 July 2015 by the European Commission at the request of Denmark, under Article 20 of Regulation (EC) No 726/2004.

The review has been carried out by the PRAC, the Committee responsible for the evaluation of safety issues for human medicines, which has made a set of recommendations. These PRAC recommendations will now be sent to the CHMP, responsible for questions concerning medicines for human use, which will adopt the Agency’s final opinion. The final stage of the review procedure is the adoption by the European Commission of a legally binding decision applicable in all EU Member States.

19 October 2015 - EMA Commences Review to Further Clarify Safety Profile of HPV Vaccines

The review will focus on rare reports of complex regional pain syndrome and postural orthostatic tachycardia syndrome

The European Medicines Agency (EMA) has started a review of human papillomavirus (HPV) vaccines to further clarify aspects of their safety profile. These vaccines have been used in around 72 million people worldwide and their use is expected to prevent many cases of cervical cancer and various other cancers and conditions caused by HPV. The review does not question that the benefits of HPV vaccines outweigh their risks.

Cervical cancer is the 4th most common cause of cancer death in women worldwide, with tens of thousands of deaths in Europe each year despite the existence of screening programmes to identify the cancer early.

As for all licensed medicines the safety of these vaccines is monitored by the Agency’s Pharmacovigilance Risk Assessment Committee (PRAC). The current review will look at available data with a focus on rare reports of two conditions: complex regional pain syndrome (CRPS, a chronic pain condition affecting the limbs) and postural orthostatic tachycardia syndrome (POTS, a condition where the heart rate increases abnormally after sitting or standing up, causing symptoms such as dizziness and fainting, as well as headache, chest pain and weakness).

Reports of these conditions in young women who have received an HPV vaccine have been previously considered during routine safety monitoring by the PRAC but a causal link between them and the vaccines was not established. Both conditions can occur in non-vaccinated individuals and it is considered important to further review if the number of cases reported with HPV vaccine is greater than would be expected.

In its review the PRAC will consider the latest scientific knowledge, including any research that could help clarify the frequency of CRPS and POTS following vaccination or identify any causal link. Based on this review, the Committee will decide whether to recommend any changes to product information to better inform patients and healthcare professionals.

While the review is ongoing there is no change in recommendations for the use of the vaccine.