Adverse reactions from Gardasil® in the period 1 January – 30 April 2009

The number of adverse reactions remains low

The HPV vaccine Gardasil® has been introduced in the Danish childhood immunisation programme with the aim of preventing cervical cancer. For the first four months after the introduction of Gardasil®, the Danish Medicines Agency received 191 adverse reaction reports describing 280 adverse reactions.  The majority of the reports do not describe any serious adverse reactions, and most of the reports were submitted by doctors. We do not know how many girls that have been vaccinated, but in the same period, vaccine was delivered in a quantity sufficient to vaccinate approximately 50,000 girls.

As many as 52 of the 191 reports describe atopic dermatitis (infantile eczema) as an adverse reaction. The large number of reports is unquestionably the result of the media focus in February this year. Unfortunately, many of the reports lack vital information, such as details about the time elapsed from the vaccination to the onset of the atopic dermatitis. It is therefore necessary to retrieve further information in order to complete the assessment. However, international experience does not suggest that vaccination with Gardasil® leads to an increased occurrence of atopic dermatitis.

In February this year, the Danish Medicines Agency published the first review of adverse reactions from Gardasil®. This review also contains some background information on cervical cancer and the vaccine. The review covered the period from the marketing was initiated in September 2006 until September 2008, as well as the period from 1 October - 31 December 2008, the so-called start-up phase for girls born in 1993, 1994 and 1995. You can find a link to the review from February in the factbox to the right.

The Danish Medicines Agency advises doctors and patients/relatives to report it to the Danish Medicines Agency if they suspect any side effects.

The next routine statement of side effects from Gardasil® will be published in the fall 2009.

Adverse reaction reports from 1 January 2009 to 30 April 2009

This message contains an overview of the reported adverse reactions from the HPV vaccine Gardasil® which we received in the period 1 January - 30 April 2009. Gardasil® was introduced in the Danish childhood immunisation programme on 1 January 2009 with the aim of preventing cervical cancer.

From 1 January to 30 April this year, the Danish Medicines Agency received 191 adverse reaction reports describing 280 adverse reactions. Only nine of these reports were classified as serious (see below).

Number of received adverse reaction reports

Consumption

In the same period, the Danish State Serum Institute delivered 148,480 doses of vaccine, which corresponds to approximately 49,500 vaccinated girls. 164,240 doses were delivered in the start-up phase. However, the exact number of vaccinated girls is not known yet.

The adverse reactions were reported by

In the period from 1 October 2008 to 30 April 2009, which is comprised by the immunisation programme, 84 % of the reports were submitted by doctors and other healthcare professionals and 16 % of the reports were submitted by medicine users and relatives.

Specification of the side effects

As in the first review, we have divided the adverse reactions into five categories: reactions at the injection site, allergic reactions, psychogenic factors, other known adverse reactions, unknown adverse reactions.

The table below lists the number of reported adverse reactions distributed into the five categories and listed under the start-up phase and the period from 1 January - 30 April 2009, respectively.

What really stands out is the number of allergic reactions and the number of unknown adverse reactions.

9 reports classified as serious

9 of the reports were classified as serious, they describe:

• one case of Henoch-Schönlein purpura
• one case of rhabdomyosarcoma
• one case of meningitis
• one case of Guillain-Barré syndrome
• one case of anaphylactic shock
• one case of swollen lymph nodes (lymphadenopathy)
• one case of fainting
• Finally, there are two reports describing several simultaneous adverse reactions:
• hyperventilation/nausea/presyncope/fever, and
• fainting/dizziness/nausea/fever

The first three adverse reactions on the list are described below under the category unknown adverse reactions.As you can read below, the Danish Medicines Agency does not find that there is a connection with the vaccination with Gardasil®.

The Guillain-Barré syndrome is a neurological disorder, which leads to limb paralysis. The relation between this disease and vaccination with Gardasil® is not documented, but the summary of product characteristics mentions some reports on this.

See the complete list of adverse reactions from Gardasil from 1 October 2008 to 30 April 2009 (Word document).

Atopic dermatitis

In February 2009, the Danish media thoroughly emphasised the suspicion that a Gardasil® vaccination could increase the risk of atopic dermatitis (infantile eczema). Therefore, it is not surprising that we have received many reports describing atopic dermatitis as a side effect. We have received all reports but one after 6 February, where the media publicity began.

8 reports were submitted by relatives to vaccinated girls, and 44 reports were submitted by doctors. 39 of these reports state that it is an exacerbation of previously diagnosed atopic dermatitis. With regard to the remaining 13 reports, it is not – based on the submitted information – possible to assess whether the atopic dermatitis has occurred for the first time or if it is an exacerbation of a previously diagnosed condition.

When we assess whether there is a causal relationship between a medicinal product and an adverse reaction, it is of the utmost importance that we know when the suspected adverse reaction first occurred in relation to the time when the medicinal product was administered. Unfortunately, this information is not present in 15 of the 52 reports. For the 37 reports that do contain this information, the distribution is as follows:

In 38 reports it is stated, after which vaccination (of the 3 planned vaccinations) the atopic dermatitis broke out:

Among the many other reports on adverse reactions that are manifested in the skin, there may possibly be several cases that meet the diagnostic criteria for atopic dermatitis. For example, nine reports state that the vaccinated girl has previously had atopic dermatitis, but the report does not specifically mention that the actual skin condition is suspected to be atopic dermatitis.

As previously described, atopic dermatitis is a relatively common disorder, and it is also a disorder that frequently flares up. Therefore, it is not surprising to see a number of instances of coincidence between vaccination and debut or flare-up of atopic dermatitis. The Danish Medicines Agency will compare the Danish experience with the international experience. Moreover, it is necessary to gather additional information in many instances. Thus, it is not possible to make any final conclusions at the moment. But at present there is no reason to consider the many reports as anything but an expression for the well-known phenomenon stimulated reporting, which is caused by the media publicity.

Interesting unknown adverse reactions:

Rhabdomyosarcoma – cancer in the connective tissues. An adverse reaction report describes a rapidly growing cancer tumour in the abdominal cavity of a patient who was well before and who gets the first symptoms two days after the vaccination with Gardasil®. The Danish Medicines Agency assesses that the relation is a coincidence and that there is no reason to suspect a connection with the vaccination with Gardasil®.

Facial paralysis. A report describes a temporary occurrence of left-sided facial paralysis. The paralysis occurred approximately 14 days after the vaccination with Gardasil®. This is the second report of facial paralysis. In both instances, the paralysis disappeared completely. The Danish Medicines Agency assesses that the occurrence is coincidental.

Meningitis – inflammation of the membranes of the brain or spinal cord. A report describes a case of meningitis diagnosed three weeks after the vaccination with Gardasil® in a patient who was well before. The course was uncomplicated. The Danish Medicines Agency assesses that the occurrence is coincidental.

Henoch-Schönlein purpura – a disease characterised by vasculitis, accumulation of blood in the skin, joint pain and abdominal pain. The disease occurs more often in children than in adults. One report describes an occurrence of the disease in a girl who was well before. The disease occurred after the first vaccination, but it is not stated how long it took from the vaccination until the debut of the disease. The Danish Medicines Agency waits for additional information from the doctor who reported the adverse reaction.

General information about adverse reaction data

An adverse reaction report contained in the pharmacovigilance database does not necessarily mean that there is a correlation (causality) between the medicinal product and the adverse reaction.

• The Danish Medicines Agency registers information about an adverse reaction in the database even if it is only suspected that there might be a correlation between the medicinal product and the adverse reaction. Therefore, the information in the database may include actual adverse reactions from a medicinal product as well as random incidences due to e.g. a disease in the patient or another medicinal product which has been administered to the patient at the same time.
• The Danish Medicines Agency is only notified of a small proportion of all adverse reactions. Therefore, the information in the pharmacovigilance database cannot indicate the frequency of the adverse reactions.
• A single adverse reaction report may contain more than one adverse reaction. Therefore, the number of registered adverse reactions is usually higher than the number of adverse reaction reports.
• An adverse reaction is considered to be serious if it leads to the patient’s death, disability, hospitalisation, or if the patient is unable to work or go to school.
• The Danish Medicines Agency sends information about all serious adverse reactions to the marketing authorisation holder, to the European pharmacovigilance database and to the WHO.
• All reports must form part of the periodic safety update reports which the marketing authorisation holder must regularly send to the Danish Medicines Agency. A periodic safety update report describes all reported adverse reactions from all countries in which the medicinal product is marketed. The periodic safety update reports thus provide a good overview, and they form an important basis for continuous updates of the summary of product characteristics and the package leaflet.
• An unknown adverse reaction is an adverse reaction that is not listed in the summary of product characteristics. If it appears that it is a new, as yet unacknowledged adverse reaction, the adverse reaction will be added to the summary of product characteristics.

For further information, please contact Chief Medical Officer Doris I. Stenver, Consumer Safety Division, tel.: +45 4488 9247.

Danish Medicines Agency, 9 July 2009