Adverse reactions from Gardasil® in the period 1 May – 31 August 2009

Status: Significantly fewer reports of atopic dermatitis and a relatively low number of side effects.


In the period May-August, the Danish Medicines Agency received 69 reports describing 145 suspected adverse reactions. The majority of the reports are not serious, and the majority (two thirds) of the side effects are already known and described in the summary of product characteristics. Among the unknown side effects, the number of reports of atopic dermatitis has dropped significantly. In the period from May to August, the Danish Medicines Agency only received 11 reports of atopic dermatitis, and thus the reporting is back to the level before the media publicity in February.

Only eight reports are classified as serious, i.e. the patient has been hospitalised or the like. In the opinion of the Danish Medicines Agency, there is no causal association between the symptoms and the vaccination with Gardasil®.

One of the reports describes an occurrence of hyperventilation (rapid and/or deep breathing). Hyperventilation is a well-known phenomenon after a needle prick and it is not a distinctive feature of vaccination with Gardasil®. Several other reports describe different neurological symptoms such as headache, dizziness and impairment of speech. In most cases, the symptoms were temporary.

The Danish Medicines Agency does not know the number of persons vaccinated, but in the period 1 May 2009 - 31 August 2009, the Danish State Serum Institute has dispensed 97,320 doses of Gardasil® for the Danish childhood immunisation programme.

Most suspected side effects are reported by doctors.

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

The Danish Medicines Agency will publish the next report of side effects from Gardasil® in the beginning of 2010.
You can find previous overviews via the factbox to the right.

Adverse reaction reports from 1 May 2009 to 31 August 2009
This report provides an overview of adverse reactions from the HPV vaccine Gardasil® reported in the period 1 May - 31 August 2009. Gardasil® was introduced in the Danish childhood immunisation programme on 1 January 2009 with the aim of preventing cervical cancer.

From 1 May to 31 August this year, the Danish Medicines Agency received 69 adverse reaction reports describing 145 adverse reactions. Only eight of these reports were classified as serious (see below).

Number of received adverse reaction reports

Exposure
The Danish State Serum Institute has dispensed 97,320 doses of Gardasil® to the childhood immunisation programme from 1 May 2009 to 31 August 2009. During the entire period from beginning until 31 August 2009, the State Serum Institute has dispensed 403,810 doses of Gardasil® for the childhood immunisation programme.

The adverse reactions were reported by
In the period from 1 October 2008 to 31 August 2009, which is comprised by the immunisation programme, 86 % of all reports were submitted by doctors and other healthcare professionals. 16 % of the reports were submitted by vaccinees and relatives.

Specification of the side effects
As in our previous reports, we have divided the adverse reactions into five categories: reactions at the injection site, allergic reactions, psychogenic factors, other known adverse reactions and unknown adverse reactions.

The table below lists the number of reported adverse reactions distributed into the five categories and listed under the catch-up phase (1 October 2008 - 31 December 2008), the period from 1 January - 30 April 2009 and finally the period from 1 May 2009 - 31 August 2009.

What really stands out is the significant drop in the number of allergic reactions and the number of unknown adverse reactions. The decreased number of unknown adverse reactions is especially due to a significant drop in the number of reports of atopic dermatitis. During the latest period, the Danish Medicines Agency only received 11 reports on atopic dermatitis.

As shown in the below figure, the number of reports on atopic dermatitis is back to the initial level. The large number of reports in spring is undoubtedly due to stimulated reporting caused by media publicity of actual occurrences of atopic dermatitis.

Figure 1. Number of reports of atopic dermatitis in the months January-August 2009. The first media publicity took place on 6 February 2009.

8 reports classified as serious
8 reports were classified as serious:

• one case of idiopathic thrombocytopenic purpura
• one case of hyperventilation
• one case of exercise-induced asthma
• one case of dizziness interpreted as possible vestibular neuritis
• one case of an attack of dizziness, muscle and joint pain, cramps and weakness
• one case of dizziness, marked fatigue, headache and a slight temperature increase
• one case of twitching arms and legs, trembling, impairment of speech, difficulties with fine motor control, headache
• one case of a prickling sensation in hands and feet.

Idiopathic thrombocytopenic purpura – is a rare blood disorder where the number of blood platelets (thrombocytes) is reduced, causing an increased risk of bleeding. The cause is unknown. The disorder most commonly occurs in children. In the particular case, the child concerned is a teenage girl who was hospitalised with this diagnosis 10 days after the third dose of her vaccination with Gardasil®. Now, the girl is unaffected, she is monitored as an outpatient and her platelet count is increasing toward a normal level.

An occurrence of hyperventilation, possibly accompanied by a prickling or pins and needles sensation in the face or in arms and legs, is well known in connection with vaccinations. In the previous period, we also received one report on hyperventilation. The symptoms usually disappear within a few hours.

Exercise-induced asthma was observed in a girl with no previous history of any illness of the lungs. Approximately 3 weeks after her first dose of Gardasil®, she caught a cold and developed a dry cough, which was subsequently triggered by physical exertion.

The remaining five reports mainly describe neurological symptoms:

A girl with suspected vestibular neuritis experienced dizziness, nausea and vomiting approx. 12 hours after her first vaccination with Gardasil. She is now being clinically investigated by a specialist.

A girl experienced dizziness, muscle and joint pain, cramps and weakness one week after her first dose of Gardasil®. She experienced both recovery and recurrence of her symptoms prior to the second dose. A clinical neurological examination showed marked fatigue and near paralysis of arms and legs. Apart from these severe symptoms, no other abnormal symptoms were discovered. No magnetic resonance imaging has been performed. A child psychiatry investigation revealed nothing abnormal. 2-3 weeks after her third dose of Gardasil®, the girl experienced a third attack of the same symptoms. Fortunately, she recovered within a few days. Approx. 6 weeks after her third dose of Gardasil®, she had a fourth attack, but only of dizziness and pain in her hands during physical activity.

A girl experienced dizziness, fatigue, headache and a slight temperature increase one month after her first dose of Gardasil®. After the second dose, she experienced fatigue, but none of the other symptoms. She does not wish to have the last dose of the vaccination. A detailed examination programme has been carried out, including magnetic resonance imaging. Nothing abnormal has been detected.

A month after her second dose of Gardasil, a girl experienced an attack lasting several hours of twitching arms and legs, trembling, impairment of speech (motor aphasia), difficulties with fine motor control, headache and fatigue. Examinations including magnetic resonance imaging have revealed nothing abnormal.

A girl experienced episodic occurrences of a prickling sensation in hands and feet in the month when she had her first dose of Gardasil®. Over the following months, the symptoms came and went. The second and third dose of her vaccination with Gardasil® were injected as planned. 6-7 months after the first symptoms, a magnetic resonance imaging was carried out of the brain, brain stem and spinal cord. The examination showed signs of several lesions of the brain stem.

Overall assessment of the serious reports
In the opinion of the Danish Medicines Agency, the observed pathological pictures are probably isolated cases with no clear causal relationship with the vaccinations. A causal relationship has not been established in any of the cases.

The complete list of adverse reactions from Gardasil® from 1 October 2008 to 31 August 2009 is available via the factbox.

Note!
Please note that the Danish Medicines Agency updates the database of adverse drug reactions on an ongoing basis. When we receive additional information, it may cause changes of the codes and number of adverse reactions. This entails that information from two periods are not always comparable when it comes to the number and type of adverse reactions.

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 results in the patient’s death, is life-threatening, requires hospitalisation, results in significant disability, 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 yet 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 Senior Medical Officer Torbjørn Callreus, Consumer Safety Division, tel.: +45 4488 9140.

Danish Medicines Agency, 8 October 2009