Cervarix - Safety Analysis 08 October 2009

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Suspected Adverse Reaction Analysis

CERVARIX Human papillomavirus (HPV) vaccine08 October 2009

This report summarises the adverse reactions suspected to have been caused by Cervarix humanpapillomavirus (HPV) vaccine in the UK. This includes reports received between 14 April 2008 and 07October 2009. These reports have been voluntarily submitted to the MHRA by healthcare professionalsand members of the public via the Yellow Card Scheme (visit www.yellowcard.gov.uk) and by themanufacturers of the vaccine as part of their legal requirements.

It is essential to bear in mind that reports to the MHRA relate only to adverse medical events which thereporter considered could have been caused by the vaccine (i.e. if there was merely a suspicion ofcausality). Therefore, cases may be true side-effects or they may have been purely coincidental events

due to underlying or undiagnosed illness that would have occurred anyway in the absence ofvaccination. Events may also have been psychogenic1 in origin. This report therefore cannot beconsidered to represent a list of known side-effects of the vaccine. These data also cannot be used todetermine the frequency, or incidence, of known side-effects because they are often under-reported.The known side-effects, and their frequencies (based on clinical trial data), are available in the productinformation (see http://emc.medicines.org.uk/).

The reactions in this report have been broken down into 5 categories based on scientific assessment ofindividual cases by MHRA assessors: injection-site reactions; allergic reactions; psychogenic events;other recognised reactions; and suspected adverse reactions not currently recognised (reactions inthis latter category are divided into the high-level classification of System Organ Class)

2. The same

event term may appear in more than one category (e.g. rash may be associated with injection site,allergic or unrecognised suspected reactions and psychogenic events). However, an event from asingle report will appear in only one category.

A single report may contain more than one reaction, more than one sign or symptom of a singlereaction or different reactions in more than one of the above categories. Therefore the total number oflisted reactions is greater than the total number of reports and total reports in each of the 5 tablesshould not be added together.

Headline summary:

To date, the vast majority of suspected adverse reactions reported to MHRA in association withCervarix vaccine have related either to the signs and symptoms of recognised side effects listedin the product information or were due to the injection process and not the vaccine itself (i.e.psychogenic in nature).

For the isolated cases of other medical conditions reported, the available evidence does notsuggest that the vaccine caused the condition and these may have been coincidental events.

Following administration of more than 1.4 million doses across the UK since lastSeptember, the balance of risks and benefits of Cervarix remains positive.

1For this analysis, defined as non-allergic events which occurred within minutes of, or soon after, vaccination and were

most likely a psychogenic response to, or anticipation of, the injection. These are not side effects to the vaccine as suchand can occur with any needle injection procedure.2Using MedDRA terminology
http://www.yellowcard.gov.uk/http://emc.medicines.org.uk/http://emc.medicines.org.uk/http://www.yellowcard.gov.uk/


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SUMMARY OF UK SAFETY EXPERIENCE

Total number of reports received: 2,207

Total number of suspected reactions: 4,863Estimated number of doses administered across the UK: at least 1.4 million doses3

A. Injection-site reactions

Injection-site reactions including redness, pain and swelling are recognised side-effects of Cervarixvaccine and are listed in the product information. These may occur at a frequency

4of more than 1 in 10

persons vaccinated. The reported cases of Pain in extremity mainly relate to a sore arm.

The cases reported to the MHRA during use of the vaccine in the UK do not indicate any change in theseverity or nature of injection-site reactions.

Reported event (Preferred Term

2

) Number of cases

Pain in extremity 225Injection site swelling 75Injection site pain 53Hypoaesthesia 52Limb discomfort 52Injection site erythema 51Oedema peripheral 40Erythema 25Injection site rash 17Skin discolouration 16Injection site reaction 15

Local reaction 13Pain 12Injection site mass 11Musculoskeletal stiffness 11Injection site warmth 10Injection site inflammation 8Local swelling 8Paraesthesia 8Peripheral coldness 8Contusion 7Injection site pruritus 7Rash macular 7

Injection site induration 6Asthenia 4Myalgia 4Sensation of heaviness 4Sensory disturbance 4Feeling cold 3Injection site anaesthesia 3Injection site discharge 3Injection site haematoma 3Injection site infection 3Injection site urticaria 3

3

Based on UK-wide vaccine uptake data to July 2009. As the Yellow Card data are up to the present date, the availableuptake data should not be used to derive adverse reaction reporting rates (as this will result in an over-estimation)4

Based on clinical trial data

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Limb immobilisation 3Muscular weakness 3Poor peripheral circulation 3

Feeling hot 2Grip strength decreased 2Inflammation 2Injection site irritation 2Injection site vesicles 2Pallor 2Pruritus 2Sensory loss 2Swelling 2Cyanosis 1Immobile 1Injection site cellulitis 1

Injection site discolouration 1Injection site haemorrhage 1Injection site joint pain 1Injection site movement impairment 1Injection site papule 1Injection site paraesthesia 1Livedo reticularis 1Muscle spasms 1Musculoskeletal pain 1Neck pain 1Pain of skin 1Rash 1Rash maculo-papular 1

Rash pruritic 1Scab 1Sensation of pressure 1Tenderness 1Tremor 1Urticaria 1

Total reactions 820

Total reports 585

B. Allergic reactions (including skin reactions not directly related to an injection-sitereaction)

Allergic reactions are recognised side-effect of Cervarix vaccine and are listed in the productinformation. These may occur at a frequency4 between 1 in 10 persons (for non-serious types of allergicreaction such as rash and itching) to less than 1 in 10,000 persons vaccinated. Severe allergicreactions are very rare.

The cases reported to the MHRA during use of the vaccine in the UK do not indicate any change in theseverity or nature of allergic reactions.

Reported event (Preferred Term2) Number of cases

Rash 66

Urticaria 43Pruritus 28

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Swelling face 23Oedema peripheral 20Rash pruritic 19

Lip swelling 16Erythema 15Rash macular 15Anaphylactic reaction 14Dyspnoea 13Hypersensitivity 12Rash generalised 12Eye swelling 11Paraesthesia oral 10Dizziness 7Flushing 5Pallor 5

Pharyngeal oedema 5Pruritus generalised 5Rash erythematous 5Throat tightness 5Malaise 4Paraesthesia 4Wheezing 4Angioedema 3Swollen tongue 3Anaphylactic shock 2Blister 2Chest discomfort 2Dysphagia 2

Eyelid oedema 2Eye pruritus 2Feeling hot 2Heart rate increased 2Hyperhidrosis 2Hyperventilation 2Hypoaesthesia 2Nasopharyngitis 2Nausea 2Ocular hyperaemia 2Peripheral coldness 2Purpura 2

Rash maculo-papular 2Skin irritation 2Syncope 2Throat irritation 2Vomiting 2Asthenia 1Body temperature increased 1Cold sweat 1Conjunctival hyperaemia 1Convulsion 1Dermatitis 1Dermatitis allergic 1Dermatitis contact 1Eczema 1

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Eyes sunken 1Face oedema 1Fatigue 1

Feeling abnormal 1Generalised erythema 1Gingival swelling 1Hypersomnia 1Hypertension 1Laryngeal oedema 1Limb discomfort 1Local swelling 1Musculoskeletal stiffness 1Neck pain 1Oral pain 1Pain 1

Pain in extremity 1Periorbital oedema 1Petechiae 1Pyrexia 1Respiratory rate increased 1Skin disorder 1Skin reaction 1Sneezing 1Speech disorder 1Swelling 1Tachycardia 1Thirst 1Tremor 1

Type I hypersensitivity 1

Total reactions 452Total reports 257

C. Psychogenic events

Psychogenic events including vasovagal syncope, faints and panic attacks can occur with any injectionprocedure, not just vaccination, and can be common in adolescents. These are due to fear and/oranticipation of the needle injection and are not side-effects of Cervarix vaccine as such. Such eventscan be associated with a wide range of temporary signs and symptoms including loss of consciousness,

vision disturbance, injury, limb jerking (often misinterpreted as a seizure/convulsion), limb numbness ortingling, difficulty in breathing, hyperventilation etc.

The events in the list below were considered psychogenic in nature based on MHRA assessment ofthe individual case details reported. The reported cases which do not refer specifically to vasovagalsyncope, faint or panic attack (e.g. convulsion, transient blindness which refers to temporary loss ofvision at the start of a faint) were concurrently reported as signs or symptom of the psychogenic event;i.e. these also were not side-effects of the vaccine itself.


Syncope 185

Dizziness 172Nausea 88

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Headache 73Pallor 64Malaise 45

Vomiting 39Tremor 34Flushing 28Feeling hot 25Vision blurred 25Cold sweat 23Hyperhidrosis 15Presyncope 15Loss of consciousness 14Paraesthesia 13Convulsion 11Rash 10

Dyspnoea 9Pyrexia 9Unresponsive to stimuli 9Asthenia 8Chills 8Eye rolling 8Heart rate increased 8Hyperventilation 8Muscle twitching 8Panic attack 8Dyskinesia 7Fatigue 7Hypoaesthesia 7

Somnolence 7Tearfulness 7Erythema 6Feeling of body temperature change 6Muscle rigidity 6Rash macular 6Tachycardia 6Visual impairment 6Abdominal pain upper 5Chest discomfort 5Dysgeusia 5Feeling cold 5

Lethargy 5Nervousness 5Throat tightness 5Abdominal pain 4Blindness transient 4Confusional state 4Fall 4Feeling abnormal 4Muscular weakness 4Mydriasis 4Peripheral coldness 4Anorexia 3Body temperature increased 3Deafness 3

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Feeling drunk 3Hypotension 3Muscle spasms 3

Musculoskeletal stiffness 3Nasopharyngitis 3Pain 3Pulse abnormal 3Skin discolouration 3Urticaria 3Abasia 2Abdominal discomfort 2Amnesia 2Anxiety 2Bradycardia 2Chest pain 2

Diplopia 2Disorientation 2Disturbance in attention 2Dizziness postural 2Dysarthria 2Dysphagia 2Heart rate irregular 2Hot flush 2Hypertension 2Myalgia 2Neck pain 2Pain in extremity 2Photophobia 2

Pruritus 2Respiratory rate increased 2Retching 2Salivary hypersecretion 2Sensory loss 2Shock 2Throat irritation 2Tinnitus 2Agitation 1Altered state of consciousness 1Balance disorder 1Blood pressure decreased 1

Blood pressure increased 1Blood pressure systolic decreased 1Bruxism 1Burning sensation 1Consciousness fluctuating 1Cough 1Cyanosis 1Deafness transitory 1Depressed level of consciousness 1Discomfort 1Dry mouth 1Dry throat 1Dysstasia 1Ear discomfort 1

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Ear pain 1Eyelid oedema 1Face injury 1

Facial spasm 1Fear 1Feeling of despair 1Foaming at mouth 1Grand mal convulsion 1Head discomfort 1Hearing impaired 1Heart rate decreased 1Hypersomnia 1Hypoacusis 1Hypokinesia 1Lip swelling 1

Livedo reticularis 1Migraine 1Myoclonus 1Nervous system disorder 1Oropharyngeal pain 1Palpitations 1Panic reaction 1Poor peripheral circulation 1Procedural dizziness 1Psychomotor hyperactivity 1Pupil fixed 1Rash generalised 1Respiratory arrest 1

Respiratory rate decreased 1Road traffic accident 1Seizure anoxic 1Sensation of heaviness 1Sinus tachycardia 1Sleep attacks 1Urinary incontinence 1Vertigo 1


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D. Other recognised reactions

This section includes other events recognised to be side-effects of Cervarix vaccine and not already

included in sections A and B above. This also includes signs and symptoms of recognised side effects.The frequencies, where known, are listed in the product information.

The cases reported to the MHRA during use of the vaccine in the UK so far do not indicate any changein the severity or nature of these reactions.


Headache 323Nausea 308Dizziness 275Vomiting 131

Malaise 98Fatigue 97Pyrexia 94Abdominal pain 43Abdominal pain upper 32Myalgia 31Diarrhoea 26Arthralgia 22Feeling hot 21Body temperature increased 20Lethargy 17Pain 16Paraesthesia 13

Chills 11Oropharyngeal pain 11Somnolence 11Pallor 10Abdominal discomfort 8Asthenia 7Pruritus 7Influenza like illness 6Musculoskeletal stiffness 6Pain in extremity 6Neck pain 4Back pain 3

Flushing 3Hypoaesthesia 3Tremor 3Anorexia 2Cough 2Feeling cold 2Head discomfort 2Joint swelling 2Listless 2Photophobia 2Rash 2Skin warm 2

Abdominal pain lower 1Body temperature fluctuation 1

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Erythema 1Feeling of body temperature change 1Gait disturbance 1

Hot flush 1Hyperhidrosis 1Ill-defined disorder 1Induration 1Insomnia 1Local swelling 1Loss of consciousness 1Lower respiratory tract infection 1Migraine 1Muscle spasms 1Muscle twitching 1Muscular weakness 1

Musculoskeletal chest pain 1Musculoskeletal pain 1Nasal congestion 1Nervousness 1Peripheral coldness 1Pharyngitis 1Pruritus generalised 1Psoriasis 1Respiratory disorder 1Restlessness 1Thirst 1Upper respiratory tract infection 1Urticaria 1


E. Suspected adverse reactions not currently recognised

This section includes reports which, based on MHRA assessment of the case details provided, do not fitinto one of the above 4 categories.

These suspected ADRs are not currently recognised as side effects of Cervarix vaccine and theavailable evidence does not suggest a causal link with the vaccine. These are isolated medical events

which may have been coincidental with vaccination. These reports are continually assessed by theMHRA.

Guillain Barre Syndrome (GBS) naturally occurs in the population and is usually thought to be causedby a preceding infectious illness. Several hundred thousand doses of Cervarix have been given to girlsand there is no evidence that the vaccine has increased the frequency of GBS above that expected tooccur naturally in the population.

Chronic fatigue syndrome (CFS) is not an uncommon condition amongst adolescents and ratesare greater in females than in males. Given that more than 1 million doses of Cervarix have nowbeen given in the UK, it is inevitable that conditions such as CFS will occur not long aftervaccination regardless of any causal association with the vaccine.

MHRA has conducted an analysis of reported cases of CFS compared to the normal backgroundfrequency. This analysis shows that amongst the population of 12-13 yr old girls immunised so far

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in the UK, we would have expected to observe more than 70 new cases of CFS already,regardless of vaccination. We would also expect to have seen many more cases of chronicfatigue-like syndrome that have not necessarily met the diagnostic criteria for CFS amongst this

population.

The Government's independent expert advisory Committee on vaccines and medicines safety, theCommission on Human Medicines (CHM), recently reviewed the cases of CFS, post-viral fatiguesyndrome and cases that could possibly represent a chronic fatigue-like syndrome. They advisedthat the available evidence does not support a causal association between Cervarix vaccine andCFS, and the balance of risks and benefits of Cervarix remains positive. Cases of possible CFSwill remain under close and continual review by the MHRA.

System Organ Class Reported event(Preferred Term2)

Number of cases

Anaemia 1Eosinophilia 1

Blood and lymphaticsystem disorders

Lymphadenopathy 12Cyanosis 1Palpitations 3Sinus tachycardia 1

Cardiac disorders

Tachycardia 1Congenital, familial andgenetic disorders

Arteriovenousmalformation

1

Deafness 1Deafness bilateral 1Ear pain 6

Ear and labyrinthdisorders

Tinnitus 1Diplopia 1Dry eye 1Excessive eye blinking 1Eye pain 1Eye swelling 1Mydriasis 1Myodesopsia 1Photophobia 1Vision blurred 6

Eye disorders

Visual impairment 3Abdominal pain 2Abdominal pain lower 1

Abdominal pain upper 1Abnormal faeces 1Colitis ulcerative 1Constipation 1Diarrhoea 4Flatulence 1Frequent bowelmovements

1

Gastrointestinal disorder 1Hypoaesthesia oral 1Lip swelling 1Mouth ulceration 2

Nausea 14

Gastrointestinal disorders

Vomiting 8

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Abasia 3Asthenia 2Axillary pain 1

Chest discomfort 4Chest pain 9Chills 3Chronic fatigue syndrome 2Condition aggravated 1Fatigue 8Feeling abnormal 2Feeling cold 4Feeling hot 1Gait disturbance 2Inflammation 1Influenza like illness 25

Injection site reaction 1Local swelling 1Malaise 8Oedema peripheral 3Pain 9Pyrexia 5Sensation of foreign body 1Sensation of pressure 1Swelling 1

General disorders andadministration siteconditions

Thirst 1Abscess 1Acarodermatitis 1Application site pustules 1

Folliculitis 1Furuncle 1Herpes zoster 1Impetigo 1Infectious mononucleosis 1Influenza 2Kidney infection 1Lower respiratory tractinfection

3

Nasopharyngitis 4Pharyngitis 1Pneumonia viral 1

Post viral fatiguesyndrome

4

Staphylococcal infection 1Streptococcal sepsis 1Tonsillitis 1Urinary tract infection 2Varicella 1

Infections andinfestations

Viral infection 2Contusion 4Drug exposure duringpregnancy

3

Injury, poisoning andprocedural complications

Wrong technique in drugusage process

1

Investigations Blood glucose increased 3

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Blood pressure abnormal 1Blood pressure increased 1Body temperature

increased1

Cell marker increased 1Heart rate decreased 1Neutrophil countdecreased

1

Respiratory rateincreased

1

Weight decreased 2Weight increased 2Anorexia 2Decreased appetite 2Dehydration 1Diabetes mellitusinadequate control 1

Diabetic ketoacidosis 1Hypoglycaemia 1Increased appetite 1

Metabolism and nutritiondisorders

Type 1 diabetes mellitus 1Arthralgia 10Arthritis 1Arthritis reactive 1Back pain 3Bone pain 1Flank pain 1Groin pain 1

Muscle spasms 2Muscle twitching 2Muscular weakness 9Musculoskeletal chestpain

1

Musculoskeletal pain 1Musculoskeletal stiffness 4Myalgia 4Neck pain 4Pain in extremity 17Palindromic rheumatism 1Rheumatoid arthritis 1

Sensation of heaviness 1

Musculoskeletal andconnective tissuedisorders

Weight bearing difficulty 1

Benign hydatidiform mole 1Neoplasms benign,malignant andunspecified (incl cystsand polyps)

Neoplasm malignant 1

Ataxia 1Complex regional painsyndrome

1

Convulsion 14Coordination abnormal 1Crying 2Diplegia 2

Nervous systemdisorders

Disturbance in attention 1

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Dizziness 14Dizziness postural 1Dysarthria 2

Dysgeusia 1Dysstasia 3Encephalitis 1Epilepsy 3Facial palsy 1Grand mal convulsion 5Guillain-Barre syndrome 1Headache 23Hypoaesthesia 9Lethargy 6Loss of consciousness 6Meningism 1

Migraine 10Migraine with aura 1Monoplegia 1Myoclonic epilepsy 1Optic neuritis 1Paraesthesia 7Paralysis 1Psychomotor hyperactivity 1Sensory disturbance 3Sensory loss 1Somnolence 10Status epilepticus 1Syncope 13

Tremor 5Unresponsive to stimuli 1Visual field defect 3

Pregnancy, puerperiumand perinatal conditions

Abortion spontaneous 6

Abnormal behaviour 1Acute psychosis 1Aggression 1Anxiety 2Confusional state 2Depression 1Dysphemia 1

Eating disorder 1Emotional disorder 2Fear 1Hallucination 4Hallucination, visual 1Insomnia 5Screaming 1Sleep disorder 2Somatisation disorder 1

Psychiatric disorders

Tearfulness 1Renal and urinarydisorders

Urinary incontinence 1

Amenorrhoea 3Reproductive system andbreast disorders Breast pain 1

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Breast swelling 1Breast tenderness 1Cervix inflammation 1

Menorrhagia 2Menstrual disorder 1Menstruation irregular 1Metrorrhagia 1Vaginal discharge 1Vaginal haemorrhage 4Vulval ulceration 1Asthma 4Cough 3Dyspnoea 16Epistaxis 5Haemoptysis 2

Hypoventilation 1Increased upper airwaysecretion

1

Nasal congestion 1Oropharyngeal blistering 1Oropharyngeal pain 7Rhinorrhoea 1

Respiratory, thoracic andmediastinal disorders

Wheezing 3Acne 1Alopecia 4Alopecia areata 2Blister 3Dermatitis allergic 1

Eczema 4Erythema 2Erythema multiforme 4Guttate psoriasis 1Hyperhidrosis 1Hypoaesthesia facial 3Rash 3Rash generalised 1Rash maculo-papular 1Rash vesicular 1Skin discolouration 3Skin exfoliation 2

Skin hypertrophy 1Skin lesion 1Stevens-Johnsonsyndrome

1

Trichorrhexis 1

Skin and subcutaneoustissue disorders

Urticaria 2Circulatory collapse 1Deep vein thrombosis 1Flushing 1Haemorrhage 1Hot flush 1Hypotension 3Pallor 2

Vascular disorders

Peripheral coldness 5

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Total reactions 633

Total reports 352

In relation to safety in pregnancy, during pre-licensing studies of Cervarix it was found that almost870 women became pregnant before or after receiving the vaccine. The overall rates ofspontaneous abortion in these clinical trials were no greater than the background rates in thegeneral population (i.e. regardless of vaccination). There is currently no evidence to suggest thatCervarix vaccine carries any risks during pregnancy. Nonetheless, Cervarix is not recommendedfor use in pregnancy.

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Documents

Cervarix - Safety Analysis 08 October 2009