Human Papillomavirus Bivalent is indicated for women aged 9-45 years. It is used for preventing the following diseases caused by oncogenic human papillomavirus (HPV) types 16 and/or 18:

• Cervical cancer
• Cervical intraepithelial neoplasia Grade 2 or 3 (CIN2/3) and adenocarcinoma in-situ (AIS)
• Cervical intraepithelial neoplasia Grade 1 (CIN1) and persistent infections of HPV types 16 and/or 18

The risk of exposure to HPV increases with age, especially with sexual debut. Therefore, it is recommended to vaccinate as early as possible. It would be more beneficial to receive the vaccine at the earlier time between ages 9-45 years.

Human papillomavirus bivalent is a suspension for injection in a prefilled syringe. Upon storage, a fine white deposit with a clear colorless supernatant can be observed. This would be a suspension after thorough agitation. This does not contain any preservative.

Excipients: Aluminum hydroxide, Sodium dihydrogen phosphate, Disodium hydrogen phosphate, Sodium chloride, Polysorbate 80 & Water for injection.

Each 0.5 ml contains Human Papillomavirus Vaccine (rDNA) BP consisting of:

• Recombinant human papillomavirus type 16 L1 protein 40 µg
• Recombinant human papillomavirus type 18 L1 protein 20 µg

This is a mixture of two aluminum hydroxide adjuvant-absorbed recombinant L1 capsid proteins of human papillomavirus (HPV) type-16 and type-18, each self-assembled into virus-like particles (VLPs). The HPV-16 and HPV-18 L1 antigens are expressed in Escherichia coli by recombinant DNA technology.

It is recommended to receive 3 doses of 0.5-ml each, by intramuscular injection according to the following schedule: 0, 1, and 6 months. If flexibility in the vaccination schedule is necessary, the second dose can be administered between 1 month and 2 months after the first dose and third dose between 5 and 8 months after the first dose. On the basis of the clinical trial results and refer to the recommendations in Human Papillomavirus Vaccines: WHO Position Paper (2017), females aged 9-14 years can also choose a vaccination schedule of two doses at 0 month and 6 months (0.5-ml per dose, with an interval of not less than 5 months). At present, it has not been determined whether the booster vaccination is required.

• Immunization consists of 3 doses of 0.5-ml each, by intramuscular injection according to the following schedule: 0, 1, and 6 months. The preferred site of administration is the deltoid region of the upper arm.
• There has been no data on subcutaneous injection. Intravascular or intradermal injection is prohibited.
• The content of the pre-filled syringe should be inspected visually both before and after shaking for any foreign particulate matter and/or abnormal physical appearance prior to administration. In the event of either being observed, discard the vaccine.
• The vaccine should be shaken well before use, and it should be a white homogeneous suspension after shaking.
• It should be vaccinated as soon as possible after removal from the refrigeration container.
• The full recommended dose of the vaccine should be used.
• Any pre-filled syringe with crack, label unclear or invalid and vaccine with abnormal appearance should not be used.

Administration

Co-administration:

• There are no data to assess the concomitant use of HPV vaccine with other vaccines. Do not mix it with any other vaccine in the same syringe or vial.
• Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs, and corticosteroids (used in greater than physiologic doses), may reduce the immune response to Human papillomavirus bivalent (Types 16 and 18) vaccine.
• The use of immunoglobulin or blood products should be avoided within 3 months prior to the vaccination of HPV vaccine.
• There has been no clinical evidence available to demonstrate whether the use of hormonal contraceptives will affect the preventive effect of HPV vaccine.
• Like other vaccines, vaccination of HPV vaccine in immunocompromised people may not induce adequate immune response. Concomitant use with immunosuppressive agents may not induce an optimal active immune response.
• At present, there has been no clinical data available to support the interchangeable use among HPV vaccines.
• The injection of HPV vaccine combined with other medicinal products is prohibited.

Immunosuppressive therapies e.g., irradiation, cytotoxic drugs and corticosteroids may reduce a patient's immune response to the vaccine.

Hypersensitivity to the active substances or to any component of the excipients of the vaccine. Individuals who develop symptoms indicative of hypersensitivity after receiving a dose of this vaccine.

Human papillomavirus bivalent (Types 16 and 18) vaccine is generally well tolerated. The most common local adverse reactions were pain, redness, and swelling at the injection site. The most common general adverse events were fatigue, headache, myalgia, gastrointestinal symptoms, and arthralgia.

Systemic Adverse Reactions:

• Very common: Fever (≥37.1°C)
• Common: Headache, fatigue, cough, muscle pain, nausea, diarrhea, dizziness and vomiting
• Occasional: Hypersensitivity, allergic dermatitis, rash, dizziness and pruritus

Local Adverse Reactions:

• Very common: Pain at the injection site
• Common: Pruritus, induration, swelling and erythema at injection site
• Occasional: Rash and discomfort at injection site

Most of the above adverse reactions are mild to moderate.

Pregnancy: At present, there has been no independent study conducted to systematically evaluate the effect on pregnant women. The very limited data from the clinical trial showed that accidental vaccination during pregnancy does not cause abnormal pregnancy outcomes and neonatal health conditions, and no adverse effects on pregnancy rate, pregnancy outcomes and neonatal health conditions were observed after vaccination with HPV vaccine. However, the data are not sufficient to determine whether pregnant women are at risk of adverse pregnancy (including spontaneous abortion) after vaccination. In animal experiments, no direct or indirect adverse effects on reproduction, pregnancy, embryo/fetus development, parturition or postnatal development are observed after vaccination. Vaccination should be avoided during pregnancy. If a woman is pregnant or preparing for pregnancy, it is recommended to postpone or interrupt the vaccination procedure, and vaccination can be conducted after the end of pregnancy.

Lactation: There have been no relevant study data on HPV vaccine. As many drugs can be secreted in breast milk, HPV vaccine should be used with caution in lactating women.

Vaccination cannot replace routine cervical cancer screening or other measures to prevent HPV infection and sexually transmitted diseases. Therefore, routine cervical cancer screening remains extremely important as recommended by the relevant health administrative departments.

Prior to vaccination, medical personnel should inquire and review the vaccinee's medical history (especially prior vaccination history and any prior adverse reaction related to vaccination), and conduct clinical examination to evaluate the benefits and risks of vaccination.

It is not recommended for populations other than those described in the package insert.

Like other vaccines for injection, appropriate medical emergency measures and monitoring methods should be prepared to ensure that those who develop allergic reactions after the injection receive proper care.

Syncope (fainting) may occur after any dose of vaccine, leading to falls and injuries, especially in adolescents and young adults. Therefore, it is recommended that observation on site be conducted for at least 30 minutes after each injection as required in the vaccination procedures.

It has been reported that syncope associated with tonic-clonic seizures and other epileptiform seizures may occur after vaccination with similar products overseas. Syncope associated with tonic-clonic seizures is usually transient, and it can be resolved spontaneously when the vaccinee is placed in a supine or head-down position and cerebral perfusion is restored. Some vaccinees may experience psychogenic reactions before/after vaccination, and measures should be taken to avoid injury from syncope.

Like other vaccines, vaccination should be postponed in vaccinees with acute serious febrile illness. In case of current or recent fever symptoms, whether to postpone vaccination depends mainly on the severity of the symptoms and their etiology. Low-grade fever and mild upper respiratory tract infection are not absolute contraindications to vaccination.

The vaccine should be used with caution in vaccinees with thrombocytopenia or any coagulation disorder.

Like any other vaccine, vaccination with HPV vaccine may not ensure the protective effect for all vaccinees.

It is only used for preventive purposes, but not indicated for the treatment of existing HPV-related lesions or preventing the progression of lesions.

It cannot prevent lesions caused by all high-risk types of HPV infections. It has not been proved that it can prevent lesions caused by infection with non-vaccine types of HPV as well as diseases not caused by HPV infection.

There have been no data on the use of HPV vaccine in vaccinees with impaired immune system (such as receiving immunosuppressive agents). Like other vaccines, vaccination in immunocompromised people may not induce adequate immune response.

Keep out of the reach and sight of children. Store at +2°C to +8°C. Transportation should also be at +2°C to +8°C. Do not freeze. Discard vaccine if frozen. Protect from light.