Cervarix suspension for injection 1 dose syringe 0.5 ml No. 1

Instructions Cervarix suspension for injection 1 dose syringe 0.5 ml No. 1

Composition

A 0.5 ml dose of vaccine contains:

active ingredients: 20 mcg of human papillomavirus type 16 L1 protein; 20 mcg of human papillomavirus type 18 L1 protein;

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

Dosage form

Suspension for injection.

Main physicochemical properties: CERVARIX™, a vaccine for the prevention of diseases caused by the human papillomavirus (HPV), manufactured using recombinant DNA technology, AS04 adjuvant, adsorbed.

Pharmacotherapeutic group

Antiviral vaccines. Vaccine for the prevention of diseases caused by the human papillomavirus (types 16, 18).

ATX code J07BM02.

Pharmacological properties

Immunological and biological properties

Mechanism of action

It has been proven that the persistence of oncogenic HPV types is the cause of virtually all cases of cervical cancer in all regions of the world.

CERVARIX™ is a recombinant vaccine made from highly purified non-infectious virus-like particles (VLPs) of the L1 core protein of HPV types 16 and 18. The VLPs do not contain viral DNA, so they cannot infect cells or cause cancer of this location. Animal studies have shown that the VLPs of the L1 core protein of the vaccine are responsible for the development of a humoral immune response and the formation of cellular immune memory.

CERVARIX™ contains the adjuvant AS04, which has been demonstrated in clinical studies to induce a higher and longer-lasting immune response compared to a vaccine containing the same antigens with aluminum hydroxide (Al(OH)3) as an adjuvant.

Invasive cervical cancer includes squamous cell carcinoma (84%) and adenocarcinoma (16%, up to 20% in developed countries according to mass screening programs).

HPV-16 and HPV-18 are responsible for approximately 70% of cervical cancers, 90% of anal cancers, 70% of HPV-related vulvar intraepithelial neoplasia (VIN 2/3) and vaginal intraepithelial neoplasia (VaIN 2/3), and 78% of HPV-related anal (AIN 2/3) high-grade intraepithelial neoplasia in all regions of the world. Other oncogenic HPV types (HPV-31, -33, -35, -39, -45, -51, -52, -56, -58, -59, -66, -68) can also cause anogenital cancers. HPV-16, -18, -45, and -31 are the 4 most common types found in squamous cell cervical carcinoma (approximately 76%) and adenocarcinoma (approximately 91%).

Clinical trial data

Evidence of anamnestic response (immune memory)

Administration of a booster dose at a median of 6.8 years after the first vaccination induced an anamnestic immune response to HPV-16 and HPV-18 (as determined by ELISA and pseudovirion neutralization assay) on day 7. At 1 month after the challenge dose, the geometric mean titer exceeded that observed one month after the primary vaccination course.

An anamnestic response was also obtained for the concomitant HPV-31 and HPV-45 types (by ELISA method).

Preventive effectiveness

Clinical efficacy in women aged 15 to 25 years

The efficacy of CERVARIX™ was evaluated in 2 controlled, double-blind, randomized clinical trials (HPV-001/007 and HPV-008) involving a total of 19,778 females aged 15 to 25 years.

The HPV-001/007 clinical trials were conducted in North and Latin America. HPV-023 enrolled patients from the Brazilian cohort of studies 001/007. Inclusion criteria were: absence of DNA from oncogenic HPV types (HPV-16, -18, -31, -33, -35, -39, -45, -51, -52, -56, -58, -59, -66 and -68) in cervical specimens, seronegative for antibodies to HPV-16 and HPV-18, and normal cytology. These characteristics were present in a population not infected with oncogenic HPV types prior to vaccination.

Clinical trials of HPV-008 were conducted in North America, Latin America, Europe, Asia-Pacific, and Australia. Prevaccination samples were tested for the presence of DNA of oncogenic HPVs (HPV-16, -18, -31, -33, -35, -39, -45, -51, -52, -56, -58, -59, -66, and -68), and serological testing for antibodies to HPV-16 and HPV-18 was also performed. Women were vaccinated regardless of baseline cytology, HPV, and DNA status. These characteristics were present in a population that included women with confirmed HPV infection in the past and/or present.

As in any preventive efficacy study, individuals initially infected with a specific HPV type were not included in the evaluation of the efficacy of that type.

Cervical intraepithelial neoplasia (CIN) grades 2 and 3 (CIN2+) have been used in studies as surrogate markers for cervical cancer. Persistent infection lasting at least 6 months has also been considered a surrogate marker for cervical cancer. Although cervical intraepithelial neoplasia (CIN) grade 1 is not a surrogate marker for cervical cancer, it does warrant medical attention.

Efficacy results for histological endpoints related to HPV-16 and/or HPV-18 (HPV-16/18) observed in study HPV-001/007 (in the total cohort, i.e., women who received at least one dose of vaccine) are presented in Table 1.

Table 1

Vaccine efficacy in preventing CIN2+ and CIN1+ cases associated with HPV types 16 and 18

(1) Cervical intraepithelial neoplasia grade 2 and above.

(2) Cervical intraepithelial neoplasia grade 1 and above.

The efficacy against HPV-16/18-related cytological abnormalities was 96.7% (95% CI: 87.3; 99.6). The efficacy against persistent HPV-16/18 infection was 98.2% (95% CI: 89.5; 100) and 96.9% (95% CI: 81.4; 99.9) at 6 and 12 months, respectively.

In study HPV-023, subjects (N = 437) were followed for 9.4 years (approximately 113 months) after the first dose. There were no new cases of infection or histopathological diseases associated with HPV-16/18 in the vaccinated group. There were 4 cases of 6-month persistent infection, 1 case of 12-month persistent infection, and 1 case of CIN1+ associated with HPV-16/18 in the placebo group.

In a descriptive factorial analysis of studies HPV-001/007/023, the efficacy against HPV-16/18 infection and 6-month persistent infection was 91.0% (95% CI: 80.3, 96.5) and 96.8% (95% CI: 80.4, 99.9), respectively. Despite evidence that women continued to be exposed to HPV infection, as observed in the control group, there was no evidence of reduced protection in vaccinated women.

Vaccine efficacy in women with proven past and/or current HPV infection (HPV-008 study)

Prophylactic efficacy against HPV-16/18 in women not infected with HPV-16 and/or HPV-18

In study HPV-008, the primary efficacy analysis was conducted in the per-protocol (PRP) cohort (PRP cohort: includes women who received 3 doses of vaccine and were not infected with the relevant HPV type at months 0 and 6) and the total vaccine cohort-1 (TVAC-1) (TVAC-1 cohort: includes women who received at least one dose of vaccine and were not infected with the relevant HPV type at month 0). Both cohorts included women with normal or low-level cytology at baseline, and only women with high-level cytology (0.5%) were excluded.

In addition, efficacy analyses were conducted on a larger total vaccinated cohort (TVC) and a total vaccinated uninfected cohort (TVC-N).

In the HPV-008 trial, approximately 26% of women had proven HPV-16/18 infection in the past and/or present, and less than 1% of women were HPV DNA positive at baseline for HPV-16 and HPV-18.

The final analysis of the HPV-008 trial was event-triggered, i.e., performed when at least 36 cases of HPV-16/18-associated CIN2+ had accumulated in the CRC cohort. The median follow-up period was 39 months after the first dose.

The analysis of the trial was performed at the end of the 4-year follow-up period (i.e., 48 months after the first dose) and included all individuals from the total vaccinated cohort (TCC).

In a protocol-defined analysis, vaccine efficacy against HPV-16/18-associated CIN1+ and CIN2+ was statistically significant in the CZP and ZKV-1 cohorts.

Further investigation revealed that several cases of CIN3+, CIN1+, and CIN2+ had different oncogenic HPV types. To distinguish the HPV type(s) most likely responsible for the disease from the HPV type(s) temporally associated, HPV type selection (research assay) was used. HPV type selection is the detection of HPV types by polymerase chain reaction (PCR) in at least one of the two submitted cytology specimens, other than the types found in the disease. Based on HPV type selection, the assay excludes cases (in the vaccine and control groups) that are not considered causally associated with HPV-16 or HPV-18 infections acquired during the study. The results observed in both assays (i.e., protocol-defined assay and HPV type selection) are shown in Table 2.

Table 2

Vaccine efficacy against CIN1+, CIN2+, CIN3+ associated with HPV-16/18

94.5%

(86.2; 98.4)

Additionally, the final analysis of the study demonstrated statistically significant vaccine efficacy against CIN2+ associated with HPV-16 and HPV-18 in both cohorts and at each analysis in some cases.

Vaccine efficacy against persistence of infection at 6 and 12 months and cytopathology (≥ presence of atypical squamous cells of undetermined significance (ASCUS cells)) associated with HPV-16/18 was also assessed. Vaccine efficacy against each endpoint was statistically significant in both cohorts.

Final analysis of the study:

6-month persistence of infection: 94.3% (91.5; 96.3) in the CZP cohort and 90.2% (87.3; 92.6) in the ZKV-1 cohort;

12-month persistence of infection: 91.4% (86.1; 95.0) in the CZP cohort and 85.3% (79.9; 89.4) in the ZKV-1 cohort;

cytological abnormalities (≥ presence of ASCUS cells): 89.0% (84.9; 92.1) in the CZP cohort and 86.7% (82.8; 89.8) in the ZKV-1 cohort.

Analysis at the final stage of the study:

6-month persistence of infection: 94.3% (92.0; 96.1) in the CZP cohort and 91.0% (88.5; 93.0) in the ZKV-1 cohort;

12-month persistence of infection: 92.9% (89.4; 95.4) in the CZP cohort and 88.2% (84.5; 91.2) in the ZKV-1 cohort;

cytological abnormalities (≥ presence of ASCUS cells): 90.7% (87.8; 93.1) in the CZP cohort and 88.6% (85.6; 91.0) in the ZKV-1 cohort.

At the final analysis, statistically significant vaccine efficacy was observed in both cohorts against VIN1+ (vulvar intraepithelial neoplasia grade 1 and higher) or VaIN1+ (vaginal intraepithelial neoplasia grade 1 and higher) associated with HPV-16/18: 80.0% (96.1% CI: 0.3; 98.1) in the CZP cohort and 83.2% (96.1% CI: 20.2; 98.4) in the ZKV-1 cohort. In the final analysis, vaccine efficacy against HPV-16/18-associated VIN1+ or VaIN1+ was 75.1% (95% CI: 22.9; 94.0) in the CZV cohort and 77.7% (95% CI: 32.4; 94.5) in the ZKV-1 cohort.

There were 2 cases of VIN2+ or VaIN2+ associated with HPV-16 or HPV-18 in the vaccination group and 7 cases in the control group in the CRC cohort. The study was not designed to demonstrate a difference between the vaccine and control groups for these endpoints.

There is no evidence of protection against disease caused by HPV types for which individuals were HPV DNA positive at study entry. However, individuals who were already infected with one of the HPV types included in the vaccine prior to vaccination were protected against clinical disease caused by another HPV type.

Overall effect of the vaccine on the severity of HPV-related diseases

Overall vaccine efficacy, regardless of HPV DNA type in lesions and stratified by baseline HPV DNA status and serostatus, was assessed in study HPV-008.

In the ZKV and ZKV-N cohorts, which included all vaccinated women, the vaccine was shown to be effective against CIN3+, CIN2+ and CIN1+ (Table 3). In these cohorts, the effect of CERVARIX™ on reducing the number of cases of local therapy on the cervix (loop electroexcision procedure, knife or laser conization) was also shown (Table 3).

The ZKV-N cohort is a subgroup of the ZKV cohort that included women with normal cytology who were HPV DNA-negative for 14 oncogenic HPV types (HPV-16, -18, -31, -33, -35, -39, -45, -51, -52, -56, -58, -59, -66, -68) and seronegative for HPV-16 and HPV-18 at baseline.

Table 3

Vaccine efficacy regardless of HPV DNA type in the disease, regardless of initial serostatus

Prophylactic efficacy against infection with oncogenic HPV types other than HPV-16 and HPV-18

In study HPV-008, vaccine efficacy against 12 oncogenic HPV types not contained in the vaccine (HPV-31, -33, -35, -39, -45, -51, -52, -56, -58, -59, -66, -68) was evaluated in the CZP and ZKV-1 cohorts.

In the final analysis of the study, statistically significant vaccine efficacy against CIN2+ was demonstrated for all HPV types combined (HPV-31, -33, -35, -39, -45, -51, -52, -56, -58, -59, -66, -68), except for HPV types-16 and -18, which was 54.0% (CI 96.1%: 34.0; 68.4) in the CZP cohort and 46.0% (CI 96.1%: 27.0; 60.3) in the ZKV-1 cohort. In the end-stage analysis of the study, the vaccine efficacy against CIN2+ for all HPV types combined, excluding HPV types 16 and 18, was 46.8% (95% CI: 30.7; 59.4) in the CZP cohort and 40.8% (95% CI: 25.5; 53.1) in the ZKV-1 cohort.

In the final analysis of the study, statistically significant vaccine efficacy against 6-month persistence of infection and against CIN2+ was observed for the following individual HPV types:

6-month persistent infection: types 31, 33, 45 in the CZP cohort; types 31, 33, 45, 51 in the ZKV-1 cohort.

CIN2+: types 31, 51, 58 in the CZP cohort; types 31, 33, 35, 51 in the ZKV-1 cohort.

In the final analysis, a higher number of cases and a lower 95% CI above zero were observed for types 31, 33, 45, and 51 for 6-month persistence of infection and CIN2+ in the CZP and ZKV-1 cohorts. For CIN2+, a lower 95% CI above zero was also observed for HPV-39 in the CZP cohort and HPV-66 in the ZKV-1 cohort.

Clinical efficacy in women aged 26 years and older

The efficacy of CERVARIX™ was evaluated in a randomized, double-blind, Phase III clinical trial (HPV-015) involving a total of 5,778 women aged 26 to 72 years (median age 37 years). This trial was conducted in North America, Latin America, Asia Pacific, and Europe. The final analysis was conducted at study completion 7 years after the first dose of CERVARIX™.

The primary endpoint was a composite of virologic and histopathologic endpoints: 6-month persistent infection and/or CIN1+ associated with HPV-16/18. Primary efficacy analyses were performed on the CRP cohort to determine efficacy and SVR, which included a subpopulation of up to 15% of women with a history of HPV-related infection or disease. Vaccine efficacy at study completion is shown in Table 4.

Table 4

Vaccine efficacy after completion of the HPV-015 study

Clinical efficacy against anal prevalent infection in women aged 18-25 years

Efficacy study against anal prevalent infection with a visit at year 4. The efficacy of the vaccine against HPV-16/18 and against non-vaccine types HPV-31/33/45 is presented in Table 5. Cervical infection in the same women was assessed for comparison.

Table 5.

Efficacy against anal and cervical prevalent infection with HPV-16/18 and HPV-31/33/45 in study HPV-009.

Vaccine-induced immunogenicity

Humoral immune responses to HPV-16 and HPV-18 were measured using type-specific enzyme-linked immunosorbent assays (ELISAs) and correlated with neutralization assays (including the pseudovirion neutralization assay developed by the National Cancer Institute). Transudation of antibodies from serum to cervical mucosa has been demonstrated in clinical studies.

The immunogenicity induced by three doses of CERVARIX™ vaccine was evaluated in 5,000 females aged 9 to 55 years and in over 800 males aged 10 to 18 years.

In clinical trials, 99.9% of initially seronegative individuals seroconverted to both HPV-16 and -18 one month after the third dose. The geometric mean titer (GMT) of post-vaccination immunoglobulin was much higher than that observed in women who were previously infected but cleared of HPV infection (natural infection). Previously seropositive and seronegative individuals achieved similar titers after vaccination.

Immunogenicity in females aged 15 to 25 years

In the HPV 001/007 clinical study, the immune response against HPV-16 and HPV-18 was studied for 76 months after the first dose of the vaccine in females aged 15-25 years at the time of vaccination. In the HPV-023 study, the immune response was studied in a subgroup of the population from the HPV-001/007 study for up to 9.4 years after the first dose.

Postvaccination immunoglobulin geometric mean titers (GMTs) against HPV-16 and HPV-18 peaked at month 7 and declined to a plateau from month 18 and, with little variation, until the end of the follow-up period (113 months). At month 113, geometric mean titers for both HPV-16 and HPV-18 were still 10-fold higher than those observed in women who had previously been infected but cleared HPV (natural infection), and 100% of women were seropositive for both antigens.

In study HPV-008, immunogenicity through month 48 was similar to the immune response observed in study HPV-001/007. A similar kinetic profile was observed with neutralizing antibodies.

Comparison of CERVARIX™ vaccine efficacy data demonstrated in females aged 15 to 25 years and other age groups

According to the pooled analysis (HPV-029, -030 and -048), 99.7% and 100% of 9-year-old girls seroconverted to HPV types 16 and 18, respectively, after the third dose (at month 7), and geometric mean titers were 1.4 and 2.4 times higher compared to the female age groups 10 to 14 years and 15 to 25 years, respectively.

In two clinical studies (HPV-012; HPV-013) conducted in girls and adolescents aged 10 to 14 years, all subjects seroconverted to both HPV-16 and HPV-18 after the third dose (at month 7), and geometric mean titers were at least twice as high compared to females aged 15 to 25 years.

In a clinical study (HPV-070) conducted in girls aged 9 to 14 years who followed the 2-dose schedule (0, 6 months or 0, 12 months), all individuals were seropositive for both HPV types 16 and 18 one month after the second dose. The immune response after 2 doses in girls aged 9 to 14 years was non-inferior to the immune response after 3 doses in women aged 15 to 25 years.

Based on immunogenicity data, a conclusion was drawn about the efficacy of CERVARIX™ in girls aged 9 to 14 years.

Duration of immune response in women aged 26 years and older

In a phase III study (HPV-015) involving women aged 26 years and older, seroconversion occurred in all patients one month after the third dose. At a follow-up period of 84 months, namely 78 months after completion of the full vaccination course, 99.3% and 95.9% of initially seronegative women remained seropositive for HPV-16 and HPV-18, respectively. Antibody titers peaked at 7 months, then gradually declined until 18 months and stabilized by 84 months.

In another clinical study (HPV-014) conducted in women aged 15 to 55 years (229 aged 15-25 years, 226 aged 26-45 years and 211 aged 46-55 years), all women were seropositive for both HPV-16 and HPV-18 after the third dose (at month 7). However, antibody titers were lower in the 26-55 year group compared to women aged 15 to 25 years. Patients (142 aged 15-25 years, 172 aged 26-45 years and 156 aged 46-55 years) who completed study HPV-014 and received the 3-dose vaccination schedule were followed for 10 years in the extension study HPV-060. Ten years after the first dose, 100% of patients in the 15-25 age group, 99.2% of patients in the 26-45 age group, and 96.3% of patients in the 46-55 age group were still seropositive for HPV-16, and 99.2%, 93.7%, and 83.8% were seropositive for HPV-18, respectively. In all age groups, antibody titers remained 5- to 32-fold higher for HPV-16 and 3- to 14-fold higher for HPV-18 than in women who had cleared HPV infection (natural infection).

Comparison of the immunogenicity of CERVARIX™ vaccine and vaccines for the prevention of diseases caused by HPV types 6, 11, 16, 18

In girls aged 9 to 14 years.

A comparative study using CERVARIX™ vaccine in a 2-dose regimen at 0 and 6 months of administration and a vaccine for the prevention of diseases caused by HPV types 6, 11, 16, 18 in a 2-dose regimen at 0 and 6 months and in a standard 3-dose regimen at 0, 2 and 6 months (study HPV-010) among females aged 9 to 14 years demonstrated, by ELISA, a greater efficacy of the immune response induced by CERVARIX™ vaccine for neutralizing antibodies to both HPV types 16 and 18 (Table 6).

Table 6

Evaluation of the greater effectiveness of the immune response against HPV-16 and HPV-18 types using the CERVARIX™ vaccine (2-dose regimen at 0 and 6 months) compared to the vaccine for the prevention of diseases caused by HPV types 6, 11, 16, 18 (2-dose regimen at 0 and 6 months and 3-dose regimen at 0, 2, and 6 months) 1 and 6 months after the last dose (total vaccinated group).

In women aged 18 to 45 years.

A comparative non-inferiority study using a commercial vaccine for the prevention of diseases caused by HPV types 6, 11, 16, 18 (study HPV-010) among women aged 18 to 45 years demonstrated non-inferiority of the immune response elicited by CERVARIX™ vaccine for neutralizing antibodies to both HPV-16 and HPV-18 in all age groups for a maximum of three years after the first vaccination (Table 7).

Table 7

Non-inferiority* in terms of neutralizing antibody titers between CERVARIX™ and HPV-16 and HPV-18 vaccines at Month 7 and Month 60 (PIT) in Study HPV-010

			CERVARIX™		Vaccine for the prevention of diseases caused by HPV types 6, 11, 16, 18		GMT coefficient CERVARIX™/vaccine for the prevention of diseases caused by HPV types 6, 11, 16, 18 97.6% CI at month 7 95% CI at month 60
		Age (years)	N	GMT (ED50)	N	GMT (ED50)
Month 7	HPV-16	18-26	104	36792	103	10053	3.7 (2.6; 5.2)
		27-35	90	23908	85	4958	4.8 (3.3; 7.1)
		36-45	96	17301	83	7634	2.3 (1.5; 3.4)
	HPV-18	18-26	118	16487	131	2258	7.3 (5.1; 10.4)
		27-35	102	9502	101	1043	9.1 (6.0; 13.9)
		36-45	110	9845	91	1439	6.8 (4.6; 10.2)
Month 60	HPV-16	18-26	35	4118	40	530	7.8 (4.3; 14.0)
		27-35	43	1925	29	346	5.6 (3.0; 10.2)
		36-45	46	1784	47	765	2.3 (1.3; 4.3)
	HPV-18	18-26	39	1523	52	126	12.1 (6.6; 22.1)
		27-35	54	967	36	74	13.0 (7.6; 22.2)
		36-45	55	817	51	105	7.8 (4.5; 13.3)
ED50 = expected dose = dilution of serum that produces a 50% reduction in signal compared to the serum-free control GMT = Geom. Mean Time Specifications Characteristics ATC code J ANTIMIBIOTICS FOR SYSTEMIC USE; J07 VACCINES; J07B VIRAL VACCINES; J07B M Human papillomavirus vaccines; J07B M02 Human papillomavirus vaccines (types 16, 18) Cold chain Medicines that require a "cold chain" during transportation and storage Country of manufacture Belgium Form Pre-filled syringes Method of application Injections Producer GlaxoSmithKline Pharmaceuticals SA Quantity per package 1 syringe Trade name Ceraxon Vacation conditions By prescription Reviews There are no reviews for this product. + Add review Write a review Cervarix suspension for injection 1 dose syringe 0.5 ml No. 1 My mark: Continue There are no reviews for this product, be the first to leave your review. Answers & questions Add your question and we will answer as soon as possible. + Ask a question Ask a question Add your question and we will answer as soon as possible. * Your question Continue No questions about this product, be the first and ask your question. You are watched new Hit Belladonna extract rectal suppositories No. 10 In stock 0 181.94 грн. Add to Cart new Hit Gensulin P solution for injection 100 units/ml bottle 10 ml No. 1 In stock 0 644.00 грн. Add to Cart new Hit Vincristine-Teva solution for injection 1 mg/ml vial 2 ml No. 1 In stock 0 749.10 грн. Add to Cart new Hit Trailers grass 1.5 g filter bag No. 20 In stock 0 150.22 грн. Add to Cart