Cervarix^® (Suspension) Instructions for Use

Marketing Authorization Holder

GlaxoSmithKline Trading, JSC (Russia)

Manufactured By

GlaxoSmithKline Biologicals, S.A. (Belgium)

ATC Code

J07BM02 (Papillomavirus (human types 16 and 18))

Active Substance

Human papillomavirus bivalent vaccine, recombinant (FDA U.S. Food and Drug Administration)

Dosage Forms

	Cervarix®	Suspension for intramuscular administration 40 mcg/0.5 ml (1 dose): syringes 1 or 10 pcs.
		Suspension for intramuscular administration 40 mcg/0.5 ml (1 dose): fl. 1, 10 or 100 pcs.

Dosage Form, Packaging, and Composition

Suspension for intramuscular administration homogeneous, opaque, white in color, free from foreign particles, which separates into 2 layers upon standing: the upper layer is a clear colorless liquid, the lower layer is a white precipitate.

Excipients: 3-O-desacyl-4′-monophosphoryl lipid A, aluminum hydroxide, sodium chloride, sodium dihydrogen phosphate dihydrate, water for injections.

0.5 ml – vials (1) – polyethylene blisters (1) – cardboard packs.
0.5 ml – vials (5) – polyethylene blisters (2) – cardboard packs.
0.5 ml – vials (10) – polyethylene blisters (1) – cardboard packs.
0.5 ml – vials (100) – cardboard packs.
0.5 ml – syringes (1) supplied with 1 or 2 needles or without needles – polyethylene blisters (1) – cardboard packs.
0.5 ml – syringes (5) supplied with 1 or 2 needles or without needles – polyethylene blisters (2) – cardboard packs.
0.5 ml – syringes (10) supplied with 1 or 2 needles or without needles – polyethylene blisters (1) – cardboard packs.
0.5 ml – syringes (10) supplied with 1 or 2 needles or without needles – cardboard packs.

Clinical-Pharmacological Group

Vaccine for the prevention of diseases caused by human papillomavirus

Pharmacotherapeutic Group

Vaccines; viral vaccines; human papillomavirus vaccines

Pharmacological Action

Recombinant adsorbed vaccine for the prevention of diseases caused by human papillomaviruses (HPV), containing the AS04 adjuvant. It is a mixture of virus-like particles of recombinant surface proteins of HPV types 16 and 18, the action of which is enhanced by the AS04 adjuvant system.

HPV-16 and HPV-18 L1 proteins are obtained using recombinant HPV-16 and HPV-18 baculoviruses in a culture of Trichoplusia ni cells (Hi-5 Rix4446). AS04 consists of aluminum hydroxide and 3-O-desacyl-4′-monophosphoryl lipid A (MPL).

According to epidemiological data, the majority of cervical cancer cases are caused by oncogenic human papillomaviruses. HPV-16 and HPV-18 are responsible for more than 70% of cervical cancer cases, as well as approximately 50% of all cases of cervical intraepithelial lesions worldwide.

Clinical efficacy

The efficacy of Cervarix^® against HPV-16 and HPV-18 and the consequences associated with infection has been confirmed by clinical studies involving 1113 subjects aged 15-25 years. A combined analysis of the study results and subsequent 4-year follow-up showed

• 94.7% efficacy in preventing infection (95% CI: 83.5; 98.9);
• 96.0% efficacy against cervical infection persisting for at least 6 months (95% CI: 75.2; 99.9);
• 100% efficacy against cervical infection persisting for at least 12 months (95% CI: 52.2);
• 95.7% efficacy against HPV infection detected at the stage of cytological abnormalities* (95% CI: 83.5; 99.5);
• 100% protection against the development of HPV infection, detected histologically, at the stage of CIN1+** (95% CI: 42.4; 100);
• 100% protection against the development of HPV infection, detected histologically, at the stage of CIN2+*** (95% CI: -7.7; 100).

* – abnormalities detected cytologically include atypical squamous cells of undetermined significance (ASC-US), low-grade squamous intraepithelial lesion (LSIL), high-grade squamous intraepithelial lesion (HSIL), and the presence of atypical squamous cells where HSIL cannot be excluded (ASC-H).

** CIN1+ – cervical intraepithelial neoplasia grade 1 and above.

*** CIN2+ – cervical intraepithelial neoplasia grade 2 and above

The vaccine provides cross-protection in 40.6% of vaccinated individuals against any manifestations of HPV infection, detected cytologically, caused by other oncogenic HPV types (95% CI: 14.9; 58.8). The vaccine is effective against the development of any CIN2 lesions (regardless of HPV DNA type) in 73.3% of subjects (95% CI: -1.0; 95.2).

Immunogenicity of the vaccine

A full course of vaccination (according to the 0-1-6 month schedule) leads to the production of specific antibodies against HPV-16 and HPV-18, which were detected in 100% of vaccinated individuals 18 months after the administration of the last vaccine dose in age groups from 10 to 25 years.

The maximum immune response was observed immediately after the completion of the vaccination course (7th month). Antibodies persisted for 4 years of subsequent follow-up after the administration of the first dose.

Additionally, the neutralizing ability of the produced antibodies has been proven.

All initially seronegative women, including the age group 46-55 years, became seropositive upon completion of the vaccination course (7th month), the antibody level at 7 months was at least 3-4 times higher than that observed in efficacy studies at 18 months after vaccination. The protective antibody level was observed at 18 months and remained at the same level during the four-year follow-up period, without subsequent decline.

In women initially seropositive for HPV-16 and/or HPV-18, Cervarix^® induced the production of the same antibody level as in initially seronegative women, while the antibody titer was significantly higher than that produced after a past infection.

The AS04 adjuvant system induces a longer immune response, superior to that when using aluminum salts as an adjuvant. The antibody titer when using AS04 was at least twice as high over 4 years after the first dose administration, and the number of memory B-cells was approximately twice as high over 2 years after the first dose administration.

Indications

• Prevention of cervical cancer in women aged 10 to 25 years;
• Prevention of acute and chronic infections caused by HPV, cellular abnormalities, including the development of atypical squamous cells of undetermined significance (ASC-US), cervical intraepithelial neoplasias (CIN), precancerous lesions (CIN2+), caused by oncogenic human papillomaviruses (HPV) in women aged 10 to 25 years.

ICD codes

Dosage Regimen

Cervarix^® is administered intramuscularly into the deltoid muscle region. Cervarix^® must never be administered intravenously or intradermally under any circumstances.

Before use, the vaccine must be visually inspected for the absence of foreign particles and the syringe or vial must be shaken well to obtain an opaque whitish suspension. If the vaccine does not match the description provided or contains foreign particles, it must be destroyed.

Vaccination schedules

The recommended single dose for girls over 10 years of age and women is 0.5 ml.

The primary immunization schedule includes the administration of three doses of the vaccine according to the 0-1-6 month schedule.

The need for revaccination has not been established to date.

Adverse Reactions

In controlled studies of the Cervarix^® vaccine, pain at the injection site was the most frequently reported event.

The adverse reactions listed below are grouped by organ system and frequency of occurrence: very common (≥10%), common (≥1%, but <10%), uncommon (≥0.1%, but <1%), rare (≥0.01%, but <0.1%), very rare (<0.01%), including isolated reports.

From the central nervous system very common – headache; uncommon – dizziness.

From the digestive system: common – nausea, vomiting, diarrhea, abdominal pain.

From the skin and its appendages: common – pruritus, rash, urticaria.

From the musculoskeletal system and connective tissue very common – myalgia; common – arthralgia; rare — muscle weakness.

Infectious complications: uncommon – upper respiratory tract infections.

From the body as a whole and related to the injection site: very common – feeling of fatigue, local reactions including pain, redness, swelling; common – fever (≥38°C (100.4°F)); uncommon – other reactions at the injection site including induration, decreased local sensitivity, itching.

Contraindications

• Hypersensitivity to any of the vaccine components;
• Hypersensitivity reactions to previous administration of Cervarix^®.

Administration of Cervarix^® should be postponed in individuals with an acute febrile condition, including exacerbation of chronic diseases.

Use in Pregnancy and Lactation

No controlled studies have been conducted on the use of the Cervarix^® vaccine during pregnancy and breastfeeding.

Experimental studies have not revealed data on the possible negative impact of the vaccine on fetal development or postnatal development. Nevertheless, vaccination with Cervarix^® during pregnancy is recommended to be postponed and carried out after childbirth.

Experimental studies in animals have shown that antibodies to vaccine antigens may be excreted in milk.

Special Precautions

Cervarix^® should be used with caution in thrombocytopenia or coagulation disorders, as bleeding may occur during intramuscular injection.

Currently, there are no data on the possibility of subcutaneous administration of Cervarix^®.

It is unlikely that Cervarix^® can cause regression of lesions or prevent the progression of disease caused by HPV-16 and/or HPV-18 that was present before the start of vaccination, therefore the use of the vaccine for this purpose is not indicated. Clinical data indicate that Cervarix^® is safe and immunogenic when administered to individuals seropositive for HPV-16 and/or HPV-18 types, who show no signs of intraepithelial lesion on cytological examination or have only atypical squamous cells of undetermined significance (ASC-US).

Vaccination does not prevent infection and diseases caused by some HPV types.

Vaccination is a method of primary prevention and does not cancel the need for regular medical examinations (secondary prevention).

Due to the possibility of anaphylactic reactions in rare cases, vaccinated individuals should be under medical supervision for 30 minutes, and procedure rooms should be equipped with anti-shock therapy means.

In patients with immunodeficiency conditions, for example, HIV infection, an adequate immune response may not be achieved.

Effect on the ability to drive vehicles and operate machinery

No specific studies have been conducted on the effect of the vaccine on the ability to drive a car or operate machinery. However, the clinical condition of the patients and the profile of adverse reactions should be taken into account.

Overdose

No cases of overdose have been reported to date.

Drug Interactions

There are no data on the interaction of Cervarix^® with other vaccines when used simultaneously.

During clinical studies, it was found that approximately 60% of women receiving the Cervarix^® vaccine used oral contraceptives. There are no data on the negative effect of contraceptives on the efficacy of the Cervarix^® vaccine.

It is assumed that in patients receiving immunosuppressants, an adequate immune response may not be achieved.

Storage Conditions

The drug should be stored and transported at a temperature from 2°C (35.6°F) to 8°C (46.4°F); do not freeze. Keep out of reach of children.

Shelf Life

Shelf life – 3 years.

Dispensing Status

Packaging containing 1 syringe or vial is dispensed by prescription.

Packaging containing 10 or 100 syringes or vials is intended for medical and preventive institutions.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.