Human Papillomavirus 9-valent Vaccine, Recombinant

Registered South African indications:

• Prevention of cervical, vulvar, vaginal and anal cancer, pre-cancerous or dysplastic lesions, genital warts and persistent infections caused by the Human Papillomavirus (HPV) in females
• Prevention of anal cancer, anal pre-cancerous or dysplastic lesions; external genital lesions (including genital warts) and persistent infections caused by HPV in males

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Hypersensitivity to human papillomavirus vaccine [Types 6, 11, 16, 18] (recombinant, adsorbed)
• Individuals who develop symptoms indicative of hypersensitivity after receiving a dose of human papillomavirus 9-valent vaccine, recombinant or human papillomavirus vaccine [Types 6, 11, 16, 18] (recombinant, adsorbed) should not receive further doses of human papillomavirus 9-valent vaccine, recombinant

Contraindications registered in other jurisdictions

• Hypersensitivity to the active ingredient or any of its excipients
• Individuals with hypersensitivity after previous administration of human papillomavirus 9-valent vaccine or human papillomavirus vaccine [Types 6, 11, 16, 18] (recombinant, adsorbed)

South African recommendations

Caution in the following patient groups

• Pregnancy
• Breastfeeding
• Renal impairment
• Hepatic impairment
• Elderly

Use with other human papillomavirus vaccine (HPV)

• Human papillomavirus 9-valent vaccine should not be used interchangeably with other HPV vaccines due to lack of studies on such use

Patients with thrombocytopenia or any coagulation disorder

• Administer with caution to individuals with thrombocytopenia or any coagulation disorder, as intramuscular administration may lead to bleeding in these individuals

Anaphylactic reactions

• Ensure that appropriate medical treatment is readily available to manage any anaphylactic reactions following the administration of human papillomavirus 9-valent vaccine

Vaccination precautions

• Vaccination with HPV vaccine may not guarantee protection for all recipients
• Human papillomavirus 9-valent vaccine is not intended to be used for treatment of active external genital lesions or cancers (such as cervical, vulvar, vaginal, or anal cancers) and conditions like CIN, VIN, VaIN, or AIN
• This vaccine does not offer protection against diseases not caused by human papillomavirus (HPV)
• Syncope (fainting) can occur following vaccination, particularly in adolescents and young adults. It's advisable to monitor vaccine recipients for about 15 minutes post-vaccination
• The decision to proceed with or postpone vaccination due to recent or current febrile illness depends largely on the severity of the symptoms and their aetiology. Minor illnesses like a low-grade fever or mild respiratory infection typically do not warrant delaying vaccination

Compromised immune systems

• Individuals with compromised immune systems, whether from immunosuppressive therapy, genetic conditions, HIV infection, or other causes, may exhibit a diminished antibody response to the vaccine

HIV infected individuals

• The safety, immunogenicity, and efficacy of human papillomavirus 9-valent vaccine have not been fully evaluated in HIV-infected individuals. The immunologic response to human papillomavirus 9-valent vaccine may be diminished in immunocompromised individuals

Recommendations in other jurisdictions

Caution in the following patient groups

• Pregnancy
• Renal impairment
• Hepatic impairment
• Elderly

Traceability

• The name and batch number of the vaccine should be recorded to enhance traceability of biological medicinal products

Vaccination decision

• Consider the risk of prior HPV exposure and the potential benefits of vaccination

Anaphylactic reactions

• Ensure readiness for medical intervention in case of rare anaphylactic reactions post-vaccination

Syncope (fainting)

• Observation for about 15 minutes post-vaccination is advised due to possible syncope, which may include neurological signs like transient visual disturbances and tonic-clonic limb movements

Acute severe febrile illness

• Postpone vaccination in the presence of acute severe febrile illness. Minor infections, such as a mild upper respiratory tract infection or low-grade fever, is not a contraindication for immunisation

Vaccine efficacy

• Vaccination may not protect all recipients and only guards against diseases caused by HPV types included in the vaccine. Continue using precautions against sexually transmitted diseases

Prophylactic use

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

Routine screening

• Human papillomavirus 9-valent vaccine does not replace cervical screening. Routine screening remains essential  and should follow local recommendations

Use in immunocompromised individuals

• The response to human papillomavirus 9-valent vaccine in individuals with impaired immune responsiveness may be diminished

Coagulation disorders

• Administer with caution to individuals with thrombocytopenia or any coagulation disorder due to the risk of bleeding from intramuscular administration

Duration of protection

• Long-term protection duration is under study

Interchangeability

• There are no data supporting the interchangeability of human papillomavirus 9-valent vaccine with other HPV vaccines

Sodium content

• The vaccine is essentially sodium-free, containing less than 1mmol sodium (23mg) per dose

Ability to drive and use machines

• Human papillomavirus 9-valent vaccine has no or negligible influence on the ability to drive or use machines. However, some of the adverse effects may temporarily affect the ability to drive or use machines

Forms avail. in SA and covered in this monograph: inj

South African registered indications and dosages

Prevention of cervical, vulvar, vaginal and anal cancer, pre-cancerous or dysplastic lesions, genital warts and persistent infections caused by the Human Papillomavirus (HPV) in females
- 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
Prevention of anal cancer, anal pre-cancerous or dysplastic lesions; external genital lesions (including genital warts) and persistent infections caused by HPV in males
- Anal cancer 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

• IM: First dose: 0.5ml, at elected date; Second dose: 0.5ml, 2 months after first dose; Third dose: 0.5ml, 6 months after first dose

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Human papillomavirus 9-valent vaccine (recombinant) should be administered as soon as possible after being removed from refrigeration

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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

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The use of human papillomavirus 9-valent vaccine, recombinant should be in accordance with official recommendations

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It is recommended that individuals who receive a first dose of human papillomavirus 9-valent vaccine, recombinant complete the vaccination course with human papillomavirus 9-valent vaccine, recombinant. The need for a booster dose has not been established

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See Additional Prescribing Points for admin. of human papillomavirus 9-valent vaccine, recombinant in individuals who have been previously vaccinated with human papillomavirus vaccine [Types 6, 11, 16, 18] (Recombinant, adsorbed)

Paed. forms avail. in SA and covered in this monograph: inj

South African registered indications and dosages

Prevention of cervical, vulvar, vaginal and anal cancer, pre-cancerous or dysplastic lesions, genital warts and persistent infections caused by the Human Papillomavirus (HPV) in females
- 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
Prevention of anal cancer, anal pre-cancerous or dysplastic lesions; external genital lesions (including genital warts) and persistent infections caused by HPV in males
- 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

• Younger than 9 years: Not established for use
• Between 9-14 years: IM: See adult dosage OR 2 dose schedule: First dose: 0.5ml, at elected date; Second dose: 0.5ml, between 5-13 months after the 1st dose; If the second vaccine dose is administered earlier than 5 months after the first dose, a third dose should always be administered
• Older than 14 years: See adult dosage

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Human papillomavirus 9-valent vaccine (recombinant) should be administered as soon as possible after being removed from refrigeration

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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

---

The use of human papillomavirus 9-valent vaccine, recombinant should be in accordance with official recommendations

---

It is recommended that individuals who receive a first dose of human papillomavirus 9-valent vaccine, recombinant complete the vaccination course with human papillomavirus 9-valent vaccine, recombinant. The need for a booster dose has not been established

---

See Additional Prescribing Points for admin. of human papillomavirus 9-valent vaccine, recombinant in individuals who have been previously vaccinated with human papillomavirus vaccine [Types 6, 11, 16, 18] (Recombinant, adsorbed)

Pregnancy

South African recommendations

• Caution
• Safety in pregnancy has not been established in well-controlled clinical studies
• Reproduction studies in female rats at a dose approximately 240 times the human dose showed no evidence of impaired fertility or harm to the foetus from human papillomavirus 9-valent vaccine
• Studies found no adverse effects on mating, fertility, pregnancy, parturition, lactation, embryo-foetal, or pre- and post-weaning development
• There were no vaccine-related foetal malformations or evidence of teratogenesis
• No treatment-related effects on developmental signs, behaviour, reproductive performance, or fertility of the offspring were observed
• Human papillomavirus 9-valent vaccine induced a specific antibody response against HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58 in pregnant rats after one or multiple intramuscular injections
• Antibodies against all 9 HPV types were transferred to the offspring during gestation and lactation
• No adequate and well-controlled studies in pregnant women for human papillomavirus 9-valent vaccine; pregnancy should be avoided during vaccination regimen
• Clinical studies included serum or urine pregnancy testing before administering human papillomavirus 9-valent vaccine
• Pregnant women in the studies were advised to defer completion of their 3-dose regimen until after pregnancy resolution
• The rate of adverse pregnancy outcomes (spontaneous abortion, late foetal death, congenital anomaly) was 12.9% (174/1,353) for human papillomavirus 9-valent vaccine recipients and 14.4% (187/1,303) for human papillomavirus vaccine [Types 6, 11, 16, 18] (recombinant, adsorbed) recipients, consistent with general population outcomes
• Sub-analyses showed no congenital anomalies in pregnancies with onset within 30 days of vaccination for both human papillomavirus 9-valent vaccine and human papillomavirus vaccine [Types 6, 11, 16, 18] (recombinant, adsorbed)
• For pregnancies with onset more than 30 days post-vaccination, 30 cases of congenital anomaly were observed in human papillomavirus 9-valent vaccine recipients, and 23 cases in human papillomavirus vaccine [Types 6, 11, 16, 18] (recombinant, adsorbed) recipients, with types of anomalies consistent with those observed in the general population
• No evidence suggests that human papillomavirus vaccine [Types 6, 11, 16, 18] (recombinant, adsorbed) administration adversely affects, pregnancy, or infant outcomes

Recommendations in other jurisdictions

• Caution
• Post-marketing data shows no malformative nor foeto/neonatal toxicity of human papillomavirus 9-valent vaccine when administered during pregnancy
• Animal studies reveal no reproductive toxicity
• A six-year pregnancy registry for human papillomavirus 9-valent vaccine followed 180 women, documenting 69 pregnancies with known outcomes. Miscarriage occurred in 4.3% of these pregnancies (3/69), and major birth defects in 4.5% of live-born infants (3/67), both rates consistent with background frequencies
• Similar findings came from a five-year pregnancy registry for the quadrivalent HPV vaccine (qHPV), which included 1,640 pregnancies with known outcomes
• Despite these findings, the data are deemed insufficient to recommend human papillomavirus 9-valent vaccine use during pregnancy. Vaccination is advised to be postponed until after pregnancy

Breastfeeding

South African recommendations

• Caution
• Safety in lactation has not been established in well-controlled clinical studies
• The excretion of vaccine antigens or antibodies induced by human papillomavirus 9-valent vaccine in human milk is unknown
• Caution is advised when administering human papillomavirus 9-valent vaccine to nursing women due to the general excretion of pharmaceuticals in human milk
• Human papillomavirus 9-valent vaccine may be given to lactating women
• In clinical studies, 92 women were breastfeeding during the vaccination period
• Immunogenicity of the vaccine was comparable between nursing women and those who were not nursing
• The adverse experience profile in nursing women was similar to that of the overall safety population
• No vaccine-related serious adverse experiences were reported in infants breastfed during the vaccination period

Recommendations in other jurisdictions

• Safe
• Human papillomavirus 9-valent vaccine can be used during breastfeeding
• Clinical studies involved 92 breastfeeding women receiving human papillomavirus 9-valent vaccine, aged 16-26 years
• The vaccine's immunogenicity was similar between breastfeeding women and those who were not breastfeeding
• The adverse experience profile for breastfeeding women matched that of the overall safety population in the studies
• No vaccine-related serious adverse experiences were reported in infants who were breastfeeding during the vaccination period

Fertility

South African recommendations

• No evidence suggests that human papillomavirus vaccine [Types 6, 11, 16, 18] (recombinant, adsorbed) administration adversely affects fertility

Recommendations in other jurisdictions

• No human data on the effect of human papillomavirus 9-valent vaccine on fertility are available. Animal studies do not indicate harmful effects on fertility

Recommendations below are applicable to South Africa and other jurisdictions

• Caution; no information available

Recommendations below are applicable to South Africa and other jurisdictions

• Caution; no information available

Recommendations below are applicable to South Africa and other jurisdictions

• Caution; no information available

Blood and Lymphatic System Disorders

Uncommon

• Lymphadenopathy

Immune System Disorders

Rare

• Hypersensitivity

Not known

• Anaphylatic 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

Post-Marketing Experience - Human Papillomavirus 9-valent Vaccine

Blood and Lymphatic System Disorders

Uncommon

• Lymphadenopathy

Immune System Disorders

Rare

• Hypersensitivity

Frequency unknown

• 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

Post-Marketing Experience - Human Papillomavirus Quadrivalent Vaccine

Infections and Infestations

Frequency unknown

• Injection site cellulitis

Blood and Lymphatic System Disorders

Frequency unknown

• Idiopathic thrombocytopenic purpura

Immune System Disorders

Frequency unknown

• Anaphylactoid reactions
• Bronchospasm

Nervous System Disorders

Frequency unknown

• Acute disseminated encephalomyelitis
• Guillain-Barré syndrome

• Steroids
• Immunosuppressive therapies
• Antimetabolites
• Alkylating agents
• Cytotoxic agents
• Corticosteroids (used in greater than physiologic doses)

Other interactions

• Irradiation

• Anal cancer screening
• Gynecologic screening exam (females)
• Papillomavirus test (females)
• Cervical cancer screening (females)

Additional observations

• Monitor for hypersensitivity and syncope for 15 minutes following administration (If seizure-like activity associated with syncope occurs, maintain patient in supine or Trendelenburg position to reestablish adequate cerebral perfusion)

Administration of human papillomavirus 9-valent vaccine, recombinant in individuals who have been previously vaccinated with human papillomavirus vaccine [Types 6, 11, 16, 18] (Recombinant, adsorbed)

• It is recommended that individuals who receive a first dose of human papillomavirus 9-valent vaccine, recombinant complete the vaccination course with human papillomavirus 9-valent vaccine, recombinant
• Studies using a mixed regimen (interchangeability) of HPV vaccines were not performed for human papillomavirus 9-valent vaccine, recombinant
• If the decision is made to administer human papillomavirus 9-valent vaccine, recombinant after receiving 3 doses of human papillomavirus vaccine [Types 6, 11, 16, 18] (recombinant, adsorbed), there should be an interval of at least 12 months between completion of vaccination with human papillomavirus vaccine [Types 6, 11, 16, 18] (recombinant, adsorbed) and the start of vaccination with human papillomavirus 9-valent vaccine, recombinant

Method of Administration

• Administer intramuscularly in the deltoid region of the upper arm or in the higher anterolateral area of the thigh
• The vaccine 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, human papillomavirus 9-valent vaccine, recombinant is a white, cloudy liquid
• Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration
• Discard the product if particulates are present or if it appears discoloured

Single-dose Vial Use

• Withdraw the 0.5ml 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

Human papillomavirus 9-valent vaccine is a non-infectious recombinant 9-valent vaccine prepared from the purified virus-like particles (VLPs) of the major capsid (L1) protein of HPV Types 6, 11, 16, 18, 31, 33, 45, 52 and 58. HPV only infects human beings. Animal studies with analogous animal papillomaviruses suggest that the efficacy of L1 VLP vaccines may involve the development of humoral immune responses. Human beings develop a humoral immune response to the vaccine, although the exact mechanism of protection is unknown.

Human papillomavirus Type 6/ Type 11/ Type 16/ Type 18/ Type 31/ Type 33/ Type 45/ Type 52/ Type 58 (L1 protein)

Injection (0.5ml) 30µg/40µg/60µg/40µg/20µg/20µg/20µg/20µg/20µg

• Gardasil 9 (MSD) originator