Gardasil 9 0,5 mL Injection

GARDASIL 9 is a vaccine indicated in girls and women from 9 years of age onwards for the prevention of cervical, vulvar, vaginal and anal cancer, pre-cancerous or dysplastic lesions, genital warts and persistent infections caused by the Human Papillomavirus (HPV).

GARDASIL 9 is indicated to prevent the following diseases:

• Cervical, vulvar, vaginal and anal cancer caused by HPV types 16, 18, 31, 33, 45, 52 and 58
• Genital warts (condyloma acuminata) caused by HPV types 6 and 11.
• And persistent infections and the following pre-cancerous or dysplastic lesions caused by HPV types 6, 11, 16,18, 31, 33, 45, 52 and 58:
• Cervical intraepithelial neoplasia (CIN) grade 2/3 and Cervical adenocarcinoma in situ (AIS)
• Cervical intraepithelial neoplasia (CIN) grade 1
• Vulvar intraepithelial neoplasia (VIN) grade 2 and grade 3
• Vaginal intraepithelial neoplasia (VaIN) grade 2 and grade 3
• VIN grade 1 and VaIN grade 1
• Anal intraepithelial neoplasia (AIN) grades 1, 2 and 3.

GARDASIL 9 is indicated in boys and men from 9 years of age onward for the prevention of anal cancer, anal pre-cancerous or dysplastic lesions; external genital lesions (including genital warts) and persistent infections caused by HPV.

GARDASIL 9 is indicated to prevent the following diseases:

• Anal cancer caused by HPV types 16, 18, 31, 33, 45, 52 and 58
• Genital warts (condyloma acuminata) caused by HPV types 6 and 11.
• And persistent infections and the following pre-cancerous or dysplastic lesions caused by HPV types 6, 11, 16, and 18, 31, 33, 45, 52 and 58:
• Anal intraepithelial neoplasia (AIN) grades 1, 2 and 3.

GARDASIL 9 should be administered as soon as possible after being removed from refrigeration. GARDASIL 9 should be administered intramuscularly as 3 separate 0,5 mL doses according to the following schedule:

• First dose: at elected date.
• Second dose: 2 months after the first dose.
• Third dose: 6 months after the first dose.

Individuals are encouraged to adhere to the 0-, 2- and 6-months vaccination schedule. However in clinical studies, efficacy has been demonstrated in individuals who have received all 3 doses within a 1-year period. The second dose should be administered at least 1 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.

Alternatively in individuals 9 through 14 years of age, GARDASIL 9 can be administered according to a 2-dose schedule; 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.

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. The need for a booster dose has not been established.

Administration of GARDASIL 9 in Individuals who have been Previously Vaccinated with GARDASIL

It is recommended that individuals who receive a first dose of GARDASIL 9 complete the vaccination course with GARDASIL 9 (see section 4.4). Studies using a mixed regimen (interchangeability) of HPV vaccines were not performed for GARDASIL 9. If the decision is made to administer GARDASIL 9 after receiving 3 doses of GARDASIL, there should be an interval of at least 12 months between completion of vaccination with GARDASIL and the start of vaccination with GARDASIL 9.

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

GARDASIL 9 should be administered intramuscularly in the deltoid region of the upper arm or in the higher anterolateral area of the thigh.

GARDASIL 9 must not be injected intravascularly. Neither subcutaneous nor intradermal administration has been studied. These methods of administration are not recommended.

The pre-filled syringe is for single use only and should not be used for more than one individual. For single-use vials a separate sterile syringe and needle must be used for each individual. The vaccine should be used as supplied; no dilution or reconstitution is necessary. The full recommended dose of the vaccine should be used. Shake well before use. Thorough agitation immediately before administration is necessary to maintain suspension of the vaccine. After thorough agitation, GARDASIL 9 is a white, cloudy liquid. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Discard the product if particulates are present or if it appears discoloured.

Single-dose Vial Use

Withdraw the 0,5 mL dose of vaccine from the single-dose vial using a sterile needle and syringe free of preservatives, antiseptics and detergents. Once the single-dose vial has been penetrated, the withdrawn vaccine should be used promptly, and the vial must be discarded.

Pre-filled Syringe Use

Inject the entire contents of the syringe.

GARDASIL 9 is contraindicated in patients with hypersensitivity to either GARDASIL 9 or GARDASIL or any of the inactive ingredients in either vaccine. Individuals who develop symptoms indicative of hypersensitivity after receiving a dose of GARDASIL 9 or GARDASIL should not receive further doses of GARDASIL 9.

This vaccine should not be used interchangeably with other Human Papillomavirus (HPV) vaccines (as such use has not been studied). This vaccine should be given with caution to individuals with either thrombocytopenia or any coagulation disorder because bleeding may occur following an intramuscular administration in these individuals. Appropriate medical treatment should always be readily available in case of anaphylactic reactions following the administration of GARDASIL 9.

General

Vaccination with GARDASIL 9 may not result in protection in all vaccine recipients. This vaccine is not intended to be used for treatment of active external genital lesions; cervical, vulvar, vaginal or anal cancers; CIN, VIN, VaIN or AIN. GARDASIL 9 will not protect against diseases that are not caused by HPV.

Syncope (fainting) may follow any vaccination, especially in adolescents and young adults. Syncope, sometimes associated with falling, has occurred after vaccination with GARDASIL. Therefore, vaccinees should be carefully observed for approximately 15 minutes after administration of GARDASIL 9 (See section 4.8).

The decision to administer or delay vaccination, because of a current or recent febrile illness depends largely on the severity of the symptoms and their aetiology. Low-grade fever itself and mild upper respiratory infection are not generally contraindications to vaccination.

Individuals with impaired immune responsiveness, whether due to the use of immunosuppressive therapy, a genetic defect, Human Immunodeficiency Virus (HIV) infection or other causes, may have reduced antibody response to active immunisation (see section 4.5).

Paediatric Use

The safety and efficacy of GARDASIL 9 have not been evaluated in children younger than 9 years.

Use in Elderly

The safety and efficacy of GARDASIL 9 have not been evaluated in individuals aged 65 years and over.

Use in Other Special Populations

The safety, immunogenicity, and efficacy of GARDASIL 9 have not been fully evaluated in HIV-infected individuals.

The immunologic response to GARDASIL 9 may be diminished in immunocompromised individuals (see section 4.5)

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially u2018sodium - freeu2019.

Use with Other Vaccines

Results from clinical studies indicate that GARDASIL 9 may be administered concomitantly (at a separate injection site) with Menactra [Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine], Adacel [Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed (Tdap)], and Repevax [Diphtheria, Tetanus, Pertussis (acellular, component) and Poliomyelitis (inactivated) Vaccine, (adsorbed, reduced antigen(s) content)] (dTap-IPV).

No studies have been performed with OMZYTA (Measles, Mumps and Rubella) and yellow fever vaccines.

Use with Hormonal Contraceptives

In 7 269 women (16 through 26 years of age, from Protocols 001 and 002), 60,2 % 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.

Use with Steroids

Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs and corticosteroids (used in greater than physiologic doses), may reduce the immune responses to vaccines (see section 4.4).

Safety in pregnancy and lactation has not been established in well-controlled clinical studies.

Pregnancy

Studies in Female Rats

Reproduction studies have been performed in female rats at a dose approximately 240 times the human dose (mg/kg basis) and have revealed no evidence of impaired female fertility or harm to the foetus due to GARDASIL 9. An evaluation of the effect of GARDASIL 9 on embryo-foetal, pre- and post-weaning development was conducted in studies using rats. No adverse effects on mating, fertility, pregnancy, parturition, lactation, embryo-foetal or pre- and post-weaning development were observed. There were no vaccine-related foetal malformations or other evidence of teratogenesis noted. In addition, there were no treatment-related effects on developmental signs, behaviour, reproductive performance or fertility of the offspring. GARDASIL 9 induced a specific antibody response against HPV types 6, 11, 16, 18, 31, 33, 45, 52 and 58 in pregnant rats following one or multiple intramuscular injections. Antibodies against all 9 HPV types were transferred to the offspring during the period of gestation and lactation.

Clinical Studies in Humans

There are no adequate and well-controlled studies in pregnant women. Data from more than 1 000 pregnancy exposures to GARDASIL 9 in clinical studies and post-marketing experience do not demonstrate vaccine-associated increase in risk of major birth defects and miscarriages when GARDASIL 9 is administered during pregnancy. These pregnancies occurred in women who were pregnant at time of vaccination or became pregnant during the follow-up period in clinical studies. As a precautionary measure, the administration of GARDASIL 9 during pregnancy should be avoided. Women who become or plan to become pregnant during the vaccination series should be advised to interrupt or post-pone the vaccination regimen until completion of pregnancy.

In clinical studies, women underwent serum or urine pregnancy testing prior to administration of GARDASIL 9. Women who were found to be pregnant before completion of a 3-dose regimen of GARDASIL 9 were instructed to defer completion of their vaccination regimen until resolution of the pregnancy.

The overall proportion of pregnancies occurring at any time during the studies that resulted in an adverse outcome defined as the combined numbers of spontaneous abortion, late foetal death and congenital anomaly cases out of the total number of pregnancy outcomes for which an outcome was known (and excluding elective terminations), was 12,9 % (174/1 353) in women who received GARDASIL 9 and 14,4 % (187/1 303) in women who received GARDASIL. The proportions of adverse outcomes observed were consistent with pregnancy outcomes observed in the general population.

Further sub-analyses were conducted to evaluate pregnancies with estimated onset within 30 days or more than 30 days from administration of a dose of GARDASIL 9 or GARDASIL. For pregnancies with estimated onset within 30 days of vaccination, no cases of congenital anomaly were observed in women who have received GARDASIL 9 or GARDASIL. In pregnancies with onset more than 30 days following vaccination, 30 and 24 cases of congenital anomaly were observed in women who have received GARDASIL 9 and GARDASIL, respectively. The types of anomalies observed were consistent (regardless of when pregnancy occurred in relation to vaccination) with those generally observed in pregnancies in the general population.

A six-year pregnancy registry for GARDASIL 9 enrolled 185 women who were inadvertently exposed to GARDASIL 9 within one month prior to the last menstrual period (LMP) or at any time during pregnancy, 180 of whom were prospectively followed. After excluding elective terminations (n=1), ectopic pregnancies (n=0) and those lost to follow-up (n=110), 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 of the assessed outcomes in the prospective population were consistent with estimated background frequencies.

Data for adverse pregnancy outcomes for GARDASIL are included below as they are relevant to GARDASIL 9 since the vaccines are similar in composition and contain HPV L1 proteins of 4 of the same HPV types.

A five-year pregnancy registry for GARDASIL enrolled 2 942 women who were inadvertently exposed to GARDASIL within one month prior to the LMP or at any time during pregnancy, 2 566 of whom were prospectively followed. After excluding elective terminations (n=107), ectopic pregnancies (n=5) and those lost to follow-up (n=814), there were 1 640 pregnancies with known outcomes. Frequencies of miscarriage and major birth defects were 6,8 % of pregnancies (111/1,640) and 2,4 % of live born infants (37/1,527), respectively. These frequencies of the assessed outcomes in the prospective population were consistent with estimated background frequencies.

In two post-marketing studies of GARDASIL (one conducted in the U.S., and the other in Nordic countries), pregnancy outcomes among subjects who received GARDASIL within one month prior to the LMP or at any time during pregnancy were evaluated retrospectively. In the U.S. study database, 2 678 pregnancies were assessed for adverse pregnancy outcomes. Among GARDASIL exposed pregnancies with known outcomes (n=1 740), the estimated frequency of confirmed miscarriages was no greater than 8 %. The frequency of major birth defects was 3,6 % of live born infants (24/665). In the Nordic registry study, 499 live born infants were assessed for major birth defects. The frequency of major birth defects was 5,4 % (27/499). In both studies, frequencies of the assessed outcomes did not suggest an increased risk with the administration of GARDASIL within one month prior to the LMP or at any time during pregnancy. Thus, there is no evidence to suggest that administration of GARDASIL adversely affects fertility, pregnancy or infant outcomes.

Breastfeeding

It is not known whether vaccine antigens or antibodies induced by the vaccine are excreted in human milk. Because many pharmaceutical products are excreted in human milk, caution should be exercised when GARDASIL 9, is administered to a nursing woman. GARDASIL 9 may be administered to lactating women. A total of 92 women were breast feeding during the vaccination period of the clinical studies for GARDASIL 9. In these studies, vaccine immunogenicity was comparable between nursing women and women who did not nurse. In addition, the adverse experience profile for nursing 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 nursing during the vaccination period.

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 u201cUndesirable effectsu201d may temporarily affect the ability to drive or use machines.

The safety of GARDASIL 9 was evaluated in 7 clinical studies (Protocols 001, 002, 003, 005, 006, 007, 009) that included 15 776 individuals who received at least one dose of GARDASIL 9 and had safety follow-up. Protocol 001 and Protocol 009 included 7 378 individuals who received at least one dose of GARDASIL and had safety follow-up. The vaccines were administered on the day of enrolment and the subsequent doses administered 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 or GARDASIL. The individuals who were monitored using VRC-aided surveillance included 9 102 girls and women 16 through 26 years of age, 1 394 boys and men 16 through 26 years of age and 5 280 girls and boys 9 through 15 years of age (3 481 girls and 1 799 boys) at enrolment who received GARDASIL 9; and 7 078 girls and women 16 through 26 years of age and 300 girls 9 through 15 years of age at enrolment who received GARDASIL.

The vaccine-related adverse experiences that were observed among recipients of GARDASIL 9 at a frequency of at least 1,0 % are listed according to frequency and system organ class. The frequency classifications are as follows: Very Common (u2265 1/10); Common (u2265 1/100, < 1/10); Uncommon (u2265 1/1 000, < 1/100); Rare (u2265 1/10 000, < 1/1 000); Very Rare (< 1/10 000)

Most injection site reactions were mild to moderate.

Nervous system disorders

Very common: Headache

Common: Dizziness

Gastrointestinal disorders

Common: Nausea

Musculoskeletal and connective tissue disorders

Common: Pain in extremity

General disorders and administration site conditions

Common: Pyrexia, fatigue

Injection site reactions

Most injection site reactions were mild to moderate.

Very common: Erythema, pain and swelling

Common: Pruritus and haematoma

Few individuals (GARDASIL 9 = 0,1 % vs. GARDASIL < 0,1 %) discontinued due to adverse experiences after receiving either vaccine. The safety profile was similar between GARDASIL 9 and GARDASIL in women, men and girls and boys.

Clinical Trials Experience for Concomitant Administration of GARDASIL 9 with Other Vaccines

The safety of GARDASIL 9 when administered concomitantly with other vaccines was evaluated in clinical studies. There was an increase in injection-site swelling reported at the injection site for GARDASIL 9 when GARDASIL 9 was administered concomitantly with Diphtheria, Tetanus, Pertussis (acellular, component) and Poliomyelitis (inactivated) Vaccine, (adsorbed, reduced antigen(s) content) (dTap-IPV) or Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed (Tdap) and Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine as compared to non-concomitant vaccination. The majority of injection-site swelling seen with concomitant administration with other vaccines was reported as being mild to moderate in intensity.

Post-Marketing Reports

The post-marketing adverse experiences were reported voluntarily from a population of uncertain size, therefore, it is not possible to reliably estimate their frequency or to establish a causal relationship to vaccine exposure. The safety profile of GARDASIL 9 and GARDASIL are similar. The post-marketing adverse experience with GARDASIL is relevant to GARDASIL 9 since the vaccines are similar in composition and contain HPV L1 proteins of 4 of the same HPV types.

In addition to the adverse reactions reported in the clinical studies, the following adverse experiences have been spontaneously reported during post-approval use of GARDASIL 9:

System organ class Adverse reactions

Nervous system disorders

Syncope sometimes accompanied by tonic-clonic movements

Gastrointestinal disorders

Vomiting

General disorders and administration site conditions

Injection-site nodule

GARDASIL

Additionally, the following post-marketing adverse experiences have been spontaneously reported for GARDASIL:

System organ class Adverse reactions

Infections and infestations

Cellulitis

Blood and lymphatic system disorders

Idiopathic thrombocytopenic purpura, lymphadenopathy

Nervous system disorders

Acute disseminated encephalomyelitis, dizziness, Guillain - Barru00c8 syndrome

Musculoskeletal and connective tissue disorders

Arthralgia, myalgia

General disorders and administration site conditions

Asthenia, chills, fatigue, malaise

Immune system disorders

Hypersensitivity reactions including anaphylactic/anaphylactoid reactions, bronchospasm and urticaria

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are requested to report any suspected adverse drug reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website.

There have been no reports of administration of higher than recommended doses of GARDASIL 9.