4.1. Therapeutic indications

Gardasil 9 is indicated for active immunisation of individuals from the age of 9 years against the following HPV diseases:

• Premalignant lesions and cancers affecting the cervix, vulva, vagina and anus caused by vaccine HPV types.

• Genital warts (Condyloma acuminata) caused by specific HPV types.

See sections 4.4 and 5.1 for important information on the data that support these indications.

The use of Gardasil 9 should be in accordance with official recommendations.

4.2. Posology and method of administration

Posology

Individuals 9 to and including 14 years of age at time of first injection

Gardasil 9 can be administered according to a 2-dose (0, 6 – 12 months) schedule (see section 5.1). The second dose should be administered between 5 and 13 months after the first dose. If the second vaccine dose is administered earlier than 5 months after the first dose, a third dose should always be administered.

Gardasil 9 can be administered according to a 3-dose (0, 2, 6 months) schedule. The second dose should be administered at least one month after the first dose and the third dose should be administered at least 3 months after the second dose. All three doses should be given within a 1-year period.

Individuals 15 years of age and older at time of first injection

Gardasil 9 should be administered according to a 3-dose (0, 2, 6 months) schedule.

The second dose should be administered at least one month after the first dose and the third dose should be administered at least 3 months after the second dose. All three doses should be given within a 1-year period.

The use of Gardasil 9 should be in accordance with official recommendations.

It is recommended that individuals who receive a first dose of Gardasil 9 complete the vaccination course with Gardasil 9 (see section 4.4).

The need for a booster dose has not been established.

Studies using a mixed regimen (interchangeability) of HPV vaccines were not performed for Gardasil 9.

Subjects previously vaccinated with a 3-dose regimen of quadrivalent HPV types 6, 11, 16, and 18 vaccine (Gardasil), hereafter referred to as qHPV vaccine, may receive 3 doses of Gardasil 9 (see section 5.1). qHPV vaccine was also known as Silgard in some countries.

Paediatric population (children <9 years of age)

The safety and efficacy of Gardasil 9 in children below 9 years of age have not been established. No data are available (see section 5.1).

Method of administration

The vaccine should be administered by intramuscular injection. The preferred site is the deltoid area of the upper arm or in the higher anterolateral area of the thigh.

Gardasil 9 must not be injected intravascularly, subcutaneously or intradermally. The vaccine should not be mixed in the same syringe with any other vaccines and solution.

For instructions on the handling of the vaccine before administration, see section 6.6.

4.3. Contraindications

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

Individuals with hypersensitivity after previous administration of Gardasil 9 or Gardasil/Silgard should not receive Gardasil 9.

4.4. Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

The decision to vaccinate an individual should take into account the risk for previous HPV exposure and potential benefit from vaccination.

As with all injectable vaccines, appropriate medical treatment and supervision should always be readily available in case of rare anaphylactic reactions following the administration of the vaccine.

Syncope (fainting), sometimes associated with falling, can occur following, or even before, any vaccination, especially in adolescents as a psychogenic response to the needle injection. This can be accompanied by several neurological signs such as transient visual disturbance, paraesthesia, and tonic-clonic limb movements during recovery. Therefore, vaccinees should be observed for approximately 15 minutes after vaccination. It is important that procedures are in place to avoid injury from fainting.

Vaccination should be postponed in individuals suffering from an acute severe febrile illness. However, the presence of a minor infection, such as a mild upper respiratory tract infection or low-grade fever, is not a contraindication for immunisation.

As with any vaccine, vaccination with Gardasil 9 may not result in protection in all vaccine recipients.

The vaccine will only protect against diseases that are caused by HPV types targeted by the vaccine (see section 5.1). Therefore, appropriate precautions against sexually transmitted diseases should continue to be used.

The vaccine is for prophylactic use only and has no effect on active HPV infections or established clinical disease. The vaccine has not been shown to have a therapeutic effect. The vaccine is therefore not indicated for treatment of cervical, vulvar, vaginal and anal cancer, high-grade cervical, vulvar, vaginal and anal dysplastic lesions or genital warts. It is also not intended to prevent progression of other established HPV-related lesions.

Gardasil 9 does not prevent lesions due to a vaccine HPV type in individuals infected with that HPV type at the time of vaccination.

Vaccination is not a substitute for routine cervical screening. Since no vaccine is 100 % effective and Gardasil 9 will not provide protection against every HPV type, or against HPV infections present at the time of vaccination, routine cervical screening remains critically important and should follow local recommendations.

There are no data on the use of Gardasil 9 in individuals with impaired immune responsiveness. Safety and immunogenicity of a qHPV vaccine have been assessed in individuals aged 7 to 12 years who are known to be infected with Human Immunodeficiency Virus (HIV) (see section 5.1).

Individuals with impaired immune responsiveness, due to either the use of potent immunosuppressive therapy, a genetic defect, Human Immunodeficiency Virus (HIV) infection, or other causes, may not respond to the vaccine.

This vaccine should be given with caution to individuals with thrombocytopaenia or any coagulation disorder because bleeding may occur following an intramuscular administration in these individuals.

Long-term follow-up studies are currently ongoing to determine the duration of protection (see section 5.1).

There are no safety, immunogenicity or efficacy data to support interchangeability of Gardasil 9 with bivalent or quadrivalent HPV vaccines.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

Safety and immunogenicity in individuals who have received immunoglobulin or blood-derived products during the 3 months prior to vaccination have not been studied in clinical trials.

Use with other vaccines

Gardasil 9 may be administered concomitantly with a combined booster vaccine containing diphtheria (d) and tetanus (T) with either pertussis [acellular, component] (ap) and/or poliomyelitis [inactivated] (IPV) (dTap, dT-IPV, dTap-IPV vaccines) with no significant interference with antibody response to any of the components of either vaccine. This is based on the results from a clinical trial in which a combined dTap-IPV vaccine was administered concomitantly with the first dose of Gardasil 9 (see section 4.8).

Use with hormonal contraceptives

In clinical studies, 60.2 % of women aged 16 to 26 years who received Gardasil 9 used hormonal contraceptives during the vaccination period of the clinical studies. Use of hormonal contraceptives did not appear to affect the type-specific immune responses to Gardasil 9.

4.6. Fertility, pregnancy and lactation

Pregnancy

Post-marketing data on pregnant women indicates no malformative nor foeto/neonatal toxicity of Gardasil 9 when administered during pregnancy.

Animal studies do not indicate reproductive toxicity (see section 5.3).

A six-year pregnancy registry for Gardasil 9 prospectively followed 180 women of which there were 69 pregnancies with known outcomes. Frequencies of miscarriage and major birth defects were 4.3 % of pregnancies (3/69) and 4.5 % of live born infants (3/67), respectively. These frequencies were consistent with estimated background frequencies. These data support similar findings from a five year pregnancy registry for qHPV vaccine in which 1,640 pregnancies with known outcomes were included.

However, these data are considered insufficient to recommend use of Gardasil 9 during pregnancy. Vaccination should be postponed until completion of pregnancy (see section 5.1).

Breast-feeding

Gardasil 9 can be used during breast-feeding.

A total of 92 women were breast-feeding during the vaccination period of the clinical studies of Gardasil 9 in women aged 16 to 26 years. In the studies, vaccine immunogenicity was comparable between breast-feeding women and women who did not breast-feed. In addition, the adverse experience profile for breast-feeding women was comparable to that of the women in the overall safety population. There were no vaccine-related serious adverse experiences reported in infants who were breast-feeding during the vaccination period.

Fertility

No human data on the effect of Gardasil 9 on fertility are available. Animal studies do not indicate harmful effects on fertility (see section 5.3).

4.7. Effects on ability to drive and use machines

Gardasil 9 has no or negligible influence on the ability to drive or use machines. However, some of the effects mentioned under section 4.8 “Undesirable effects” may temporarily affect the ability to drive or use machines.

4.8. Undesirable effects

Summary of the safety profile

In 7 clinical trials, individuals were administered Gardasil 9 on the day of enrolment and approximately 2 and 6 months thereafter. Safety was evaluated using vaccination report card (VRC)-aided surveillance for 14 days after each injection of Gardasil 9. A total of 15,776 individuals (10,495 subjects aged 16 to 26 years and 5,281 adolescents aged 9 to 15 years at enrolment) received Gardasil 9. Few individuals (0.1 %) discontinued due to adverse experiences.

In one of these clinical trials which enrolled 1,053 healthy adolescents aged 11 to 15 years, administration of the first dose of Gardasil 9 concomitantly with a combined diphtheria, tetanus, pertussis [acellular, component] and poliomyelitis [inactivated] booster vaccine showed that more injection-site reactions (swelling, erythema), headache and pyrexia were reported. The differences observed were < 10 % and in the majority of subjects, the adverse events were reported as mild to moderate in intensity (see section 4.5).

In a clinical trial that included 640 individuals aged 27 to 45 years and 570 individuals aged 16 to 26 years who received Gardasil 9, the safety profile of Gardasil 9 was comparable between the two age groups.

The most common adverse reactions observed with Gardasil 9 were injection-site adverse reactions (84.8 % of vaccinees within 5 days following any vaccination visit) and headache (13.2 % of the vaccinees within 15 days following any vaccination visit). These adverse reactions usually were mild or moderate in intensity.

Tabulated summary of adverse reactions

The adverse reactions are categorised by frequency using the following convention:

- Very common (≥1/10)

- Common (≥1/100 to <1/10)

- Uncommon (≥1/1,000 to <1/100)

- Rare (≥1/10,000 to <1/1,000)

- Not known (cannot be estimated from the available data)

Clinical trials

Table 1 presents adverse reactions considered as being at least possibly related to vaccination and observed in recipients of Gardasil 9 at a frequency of at least 1.0 % from 7 clinical trials (PN 001, 002, 003, 005, 006, 007 and 009, N=15,776 individuals) (see section 5.1 for description of the clinical trials).

Post-marketing experience

Table 1 also includes adverse events which have been spontaneously reported during the post-marketing use of Gardasil 9 worldwide. Their frequencies were estimated based on relevant clinical trials.

Table 1: Adverse reactions following administration of Gardasil 9 from clinical trials and adverse events from post-marketing data

System organ class

Frequency

Adverse reactions

Blood and lymphatic system disorders

Uncommon

Lymphadenopathy*

Immune system disorders

Rare

Hypersensitivity*

Not known

Anaphylactic reactions*

Nervous system disorders

Very common

Headache

Common

Dizziness

Uncommon

Syncope sometimes accompanied by tonic-clonic movements*

Gastrointestinal disorders

Common

Nausea

Uncommon

Vomiting*

Skin and subcutaneous tissue disorders

Uncommon

Urticaria*

Musculoskeletal and connective tissue disorders

Uncommon

Arthralgia*, myalgia*

General disorders and administration site conditions

Very common

At the injection site: pain, swelling, erythema

Common

Pyrexia, fatigue,

At the injection site: pruritus, bruising

Uncommon

Asthenia*, chills*, malaise*, injection site nodule*

*Adverse events reported during post-marketing use of Gardasil 9. The frequency was estimated based on relevant clinical trials. For events not observed in clinical trials the frequency is indicated as 'Not known'.

qHPV vaccine

Table 2 includes adverse experiences that have been spontaneously reported during post-approval use of qHPV vaccine. The post-marketing safety experience with qHPV vaccine is relevant to Gardasil 9 since the vaccines contain L1 HPV proteins of 4 of the same HPV types.

Because these events were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or to establish, for all events, a causal relationship to vaccine exposure.

Table 2: Adverse reactions reported from post-marketing experience with qHPV vaccine

System organ class

Frequency

Adverse reactions

Infections and infestations

Not known

Injection-site cellulitis

Blood and lymphatic system disorders

Not known

Idiopathic thrombocytopaenic purpura

Immune system disorders

Not known

Anaphylactoid reactions, bronchospasm

Nervous system disorders

Not known

Acute disseminated encephalomyelitis, Guillain-Barré syndrome

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

No cases of overdose have been reported.