Apexxnar suspension for injection in pre-filled syringe

Active immunisation for the prevention of invasive disease and pneumonia caused by Streptococcus pneumoniae in individuals 18 years of age and older.

See sections 4.4 and 5.1 for information on protection against specific pneumococcal serotypes.

Apexxnar should be used in accordance with official recommendations.

Posology

Individuals 18 years of age and older

Apexxnar is to be administered as a single dose to individuals 18 years of age and older.

The need for revaccination with a subsequent dose of Apexxnar has not been established.

No data on sequential vaccination with other pneumococcal vaccines or a booster dose are available for Apexxnar. Based on the clinical experience with Prevenar 13 (a pneumococcal conjugate vaccine consisting of 13 polysaccharide conjugates that are also in Apexxnar), if the use of 23-valent pneumococcal polysaccharide vaccine (Pneumovax 23 [PPSV23]) is considered appropriate, Apexxnar should be given first (see section 5.1).

Paediatric population

The safety and efficacy of Apexxnar in children and adolescents younger than 18 years of age have not been established. No data are available.

Special populations

There are no data with Apexxnar in special populations.

Limited experience from clinical studies with Prevenar 13 (a pneumococcal conjugate vaccine consisting of 13 polysaccharide conjugates that are also in Apexxnar) are available in adults at higher risk of pneumococcal infection either immunocompromised individuals or following bone marrow transplantation (see sections 4.4 and 5.1).

Based on these data the following posology was recommended for Prevenar 13:

- Individuals at higher risk of pneumococcal infection (e.g., individuals with sickle cell disease or HIV infection), including those previously vaccinated with 1 or more doses of PPSV23, were recommended to receive at least 1 dose of Prevenar 13.

- In individuals with a hematopoietic stem cell transplant (HSCT), the recommended immunisation series with Prevenar 13 consisted of 4 doses of 0.5 mL each. The primary series consisted of 3 doses, with the first dose given 3 to 6 months after HSCT and with an interval of at least 1 month between doses. A booster dose was recommended 6 months after the third dose (see section 5.1).

Please also refer to sections 4.4. and 5.1.

Method of administration

For intramuscular use only.

One dose (0.5 mL) of Apexxnar should be administered intramuscularly, preferably in the deltoid muscle, with care to avoid injection into or near nerves and blood vessels.

For instructions on the handling of the vaccine before administration, see section 6.6.

Hypersensitivity to the active substances, to any of the excipients listed in section 6.1, or to diphtheria toxoid.

Do not inject Apexxnar intravascularly.

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Hypersensitivity

As with all injectable vaccines, appropriate medical treatment and supervision must always be readily available in case of a rare anaphylactic reaction following the administration of the vaccine.

Concurrent illness

Vaccination should be postponed in individuals suffering from acute severe febrile illness. However, the presence of a minor infection, such as a cold, should not result in the deferral of vaccination.

Thrombocytopenia and coagulation disorders

The vaccine must be administered with caution to individuals with thrombocytopenia or a bleeding disorder since bleeding may occur following an intramuscular administration.

The risk of bleeding in patients with coagulation disorders needs to be carefully evaluated before intramuscular administration of any vaccine, and subcutaneous administration should be considered if the potential benefit clearly outweighs the risks.

Protection against pneumococcal disease

Apexxnar will only protect against Streptococcus pneumoniae serotypes included in the vaccine, and will not protect against other microorganisms that cause invasive disease or pneumonia. As with any vaccine, Apexxnar may not protect all individuals receiving the vaccine from pneumococcal invasive disease or pneumonia. For the most recent epidemiological information in your country, you should consult with the relevant national organisation.

Immunocompromised individuals

Safety and immunogenicity data on Apexxnar are not available for individuals in immunocompromised groups. Vaccination should be considered on an individual basis.

Based on experience with pneumococcal vaccines, some individuals with altered immunocompetence may have reduced immune responses to Apexxnar.

Individuals with impaired immune response, whether due to the use of immunosuppressive therapy, a genetic defect, HIV infection, or other causes, may have reduced antibody response to active immunization. The clinical relevance of this is unknown.

Safety and immunogenicity data with Prevenar 13 (a pneumococcal conjugate vaccine consisting of 13 polysaccharide conjugates that are also in Apexxnar) are available for a limited number of individuals with HIV infection, or with a HSCT (see sections 4.8 and 5.1).

In adults across all studied age groups, formal non-inferiority criteria were met although numerically lower geometric mean titres were observed with Apexxnar for most of the serotypes compared to Prevenar 13 (see section 5.1), however the clinical relevance of this observation for immunocompromised individuals is unknown.

Excipient

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

Apexxnar may be administered concomitantly with seasonal influenza vaccine (QIV; surface antigen, inactivated, adjuvanted). In subjects with underlying conditions associated with a high risk of developing life-threatening pneumococcal disease, consideration may be given to separating administrations of QIV and Apexxnar (e.g., by approximately 4 weeks). In a double-blind, randomised study (B7471004) in adults 65 years of age and older, the immune response was formally non-inferior, however numerically lower titres were observed for all pneumococcal serotypes included in Apexxnar when given concomitantly with seasonal influenza vaccine (QIV, surface antigen, inactivated, adjuvanted) compared to when Apexxnar was given alone. The clinical relevance of this finding is unknown.

Apexxnar can be administered concomitantly with COVID-19 mRNA vaccine (nucleoside modified).

There are no data on the concomitant administration of Apexxnar with other vaccines.

Different injectable vaccines should always be given at different vaccination sites.

Do not mix Apexxnar with other vaccines/medicinal products in the same syringe.

Pregnancy

There are no data on the use of Apexxnar in pregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity.

Administration of Apexxnar in pregnancy should only be considered when the potential benefits outweigh any potential risks for the mother and foetus.

Breast-feeding

It is unknown whether Apexxnar is excreted in human milk.

Fertility

No human data on the effect of Apexxnar on fertility are available. Animal studies do not indicate direct or indirect harmful effects with respect to female fertility (see section 5.3).

Apexxnar has no or negligible influence on the ability to drive and use machines. However, some of the effects mentioned under section 4.8 may temporarily affect the ability to drive or use machines.

Summary of the safety profile

Participants 18 years of age and older

The safety of Apexxnar was evaluated in 4,552 participants 18 years of age and older in six clinical trials (two Phase 1, one Phase 2, and three Phase 3), and 2,496 participants in the control groups.

In the Phase 3 trials, 4,263 participants received Apexxnar. This included 1,798 participants 18 through 49 years of age, 334 participants 50 through 59 years of age, and 2,131 participants 60 years of age and older (1,138 were 65 years of age and older). Of the participants who received Apexxnar in the Phase 3 trials, 3,639 were naï ve to pneumococcal vaccines, 253 had previously received Pneumovax 23 (pneumococcal polysaccharide vaccine [23-valent]; PPSV23) (≥ 1 to ≤ 5 years prior to enrolment), 246 had previously received Prevenar 13 only (≥ 6 months prior to enrolment), and 125 had previously received Prevenar 13 followed by PPSV23 (the dose of PPSV23 ≥ 1 year prior to enrolment).

Participants in the Phase 3 trial B7471007 (Pivotal Study 1007) were evaluated for adverse events for 1 month after vaccination, and serious adverse events through 6 months after vaccination. This study included 447 participants 18 to 49 years of age, 445 participants 50 to 59 years of age, 1,985 participants 60 to 64 years of age, 624 participants 65 to 69 years of age, 319 participants 70 to 79 years of age, and 69 participants ≥ 80 years of age.

In participants 18 to 49 years of age in Studies 1007 and a Phase 3 trial B7471008 (Lot Consistency Study 1008), the most frequently reported adverse reactions were pain at injection site (79.2%), muscle pain (62.9%), fatigue (46.7%), headache (36.7%), and joint pain (16.2%). In participants 50 to 59 years of age in Study 1007, the most frequently reported adverse reactions were pain at injection site (72.5%), muscle pain (49.8%), fatigue (39.3%), headache (32.3%), and joint pain (15.4%). In participants ≥ 60 years of age in Study 1007, the most frequently reported adverse reactions were pain at injection site (55.4%), muscle pain (39.1%), fatigue (30.2%), headache (21.5%), and joint pain (12.6%). These were usually mild or moderate in intensity and resolved within a few days after vaccination.

Phase 3 Study B7471006 (Study 1006) evaluated Apexxnar in participants ≥ 65 years of age with varying prior pneumococcal status (prior PPSV23, prior Prevenar 13 or prior Prevenar 13 followed by PPSV23). In this study, the most frequently reported adverse reactions for participants were similar in frequency to those described for participants ≥ 60 years of age in Study 1007, with slightly higher injection site pain (61.2%) in participants with prior Prevenar 13, and joint pain (16.8%) in participants with prior Prevenar 13 followed by PPSV23.

Tabulated list of adverse reactions

Tabulated lists of adverse reactions from the Phase 3 clinical trials and postmarketing experience are presented below.

Adverse reactions from clinical trials

As Apexxnar contains the same 13 serotype-specific capsular polysaccharide conjugates and the same vaccine excipients as Prevenar 13, the adverse reactions already identified for Prevenar 13 have been adopted for Apexxnar. Table 1 presents adverse reactions reported in Phase 3 trials of Apexxnar, based on the highest frequency among adverse reactions, local reactions, or systemic events after vaccination in any Apexxnar group. In clinical trials, the safety profile of Apexxnar was similar to that of Prevenar 13. No new adverse reactions were identified as compared to Prevenar 13.

Adverse reactions are listed by system organ class in decreasing order of frequency and seriousness. The frequency is defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from available data).

Safety with concomitant vaccine administration in adults

When Apexxnar was administered to adults aged ≥ 65 years together with the third (booster) dose of a COVID-19 mRNA vaccine (nucleoside modified), the tolerability profile generally resembled that of the COVID-19 mRNA vaccine (nucleoside modified) administered alone. There were a few differences in the safety profile when compared to administration of Apexxnar alone. In the phase 3 trial B7471026 (Study 1026), pyrexia (13.0%) and chills (26.5%) were reported as “ very common” with co administration. There was also one report of dizziness (0.5%) in the co-administration group.

Adverse reactions from postmarketing experience

Table 2 includes adverse experiences that have been spontaneously reported during the postmarketing use of Prevenar 13, which may also occur with Apexxnar. The postmarketing safety experience with Prevenar 13 is relevant to Apexxnar, as Apexxnar contains all components (polysaccharide conjugates and excipients) of Prevenar 13. These events were reported voluntarily from a population of uncertain size. Therefore, it is not possible to reliably estimate their frequency or to establish, for all events, a causal relationship to vaccine exposure.

Events reported spontaneously in Prevenar 13 postmarketing experience; therefore, the frequencies could not be estimated from the available data and are considered as not known.

Additional information in special populations in studies with Prevenar 13

Participants ≥ 18 years of age with HIV infection have similar frequencies of adverse reactions in Table 1, except for pyrexia (5% to 18%) and vomiting (8% to 12%) which were very common and nausea (< 1% to 3%) which was common.

Participants ≥ 18 years of age with an HSCT have similar frequencies of adverse reactions in Table 1, except for pyrexia (4% to 15%), vomiting (6% to 21%), and diarrhoea (25% to 36%) which were very common.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Overdose with Apexxnar is unlikely due to its presentation as a pre-filled syringe.

Pharmacotherapeutic group: vaccines, pneumococcal vaccines; ATC code: J07AL02

Mechanism of action

Apexxnar contains 20 pneumococcal capsular polysaccharides all conjugated to a CRM₁₉₇ carrier protein, which modifies the immune response to the polysaccharide from a T-cell independent response to a T-cell dependent response. The T-cell dependent response leads to both an enhanced antibody response and generation of memory B-cells, allowing for an anamnestic (booster) response on re-exposure to the bacterium.

Vaccination with Apexxnar induces serum antibody production and immunologic memory against the serotypes contained within the vaccine. In adults, the levels of circulating antibodies that correlate with protection against pneumococcal disease have not been clearly defined.

Clinical efficacy

No efficacy studies have been performed with Apexxnar.

Immunogenicity data

Apexxnar clinical trials in adults

Three Phase 3 clinical trials, B7471006, B7471007 and B7471008 (Study 1006, Study 1007, and Study 1008), were conducted in the United States and Sweden evaluating the immunogenicity of Apexxnar in different adult age groups, and in participants who were either pneumococcal vaccine-naï ve, or previously vaccinated with Prevenar 13, PPSV23, or both.

Each study included participants who were healthy or immunocompetent with stable underlying conditions, including chronic cardiovascular disease, chronic pulmonary disease, renal disorders, diabetes mellitus, chronic liver disease, and medical risk conditions and behaviours (e.g., smoking) that are known to increase the risk of serious pneumococcal pneumonia and IPD. In the pivotal study (Study 1007), these risk factors were identified in 34%, 32%, and 26% of participants 60 years of age and over, 50 to 59 years of age, and 18 to 49 years of age, respectively. A stable medical condition was defined as a medical condition not requiring significant change in therapy in the previous 6 weeks (i.e., change to new therapy category due to worsening disease), or any hospitalization for worsening disease within 12 weeks before receiving the study vaccine.

In each study, immune responses elicited by Apexxnar and the control pneumococcal vaccines were measured by an opsonophagocytic activity (OPA) assay. OPA assays measure functional antibodies to S. pneumoniae.

Comparison of immune responses of Apexxnar to Prevenar 13 and PPSV23

In a randomised, active-controlled, double-blind, non-inferiority clinical trial (Pivotal Study 1007) of Apexxnar in the United States and Sweden, pneumococcal vaccine-naï ve participants 18 years of age and older were enrolled into 1 of 3 cohorts based on their age at enrolment (18 to 49, 50 to 59, and ≥ 60 years of age), and randomised to receive Apexxnar or control. Participants 60 years of age and older were randomised in a 1:1 ratio to receive Apexxnar (n = 1,507) followed 1 month later with the administration of saline placebo or Prevenar 13 (n = 1,490), and with the administration of PPSV23 1 month later. Participants 18 to 49 years of age and 50 to 59 years of age were randomly assigned (3:1 ratio); they received a dose of Apexxnar (18 to 49 years of age: n = 335; 50 to 59 years of age: n = 334) or Prevenar 13 (18 to 49 years of age: n = 112; 50 to 59 years of age: n = 111).

Serotype-specific OPA geometric mean titres (GMTs) were measured before the first vaccination and 1 month after each vaccination. Non-inferiority of immune responses, OPA GMTs 1 month after vaccination, with Apexxnar to a control vaccine for a serotype was declared if the lower bound of the 2-sided 95% confidence interval (CI) for the GMT ratio (Apexxnar/Prevenar 13; Apexxnar/PPSV23) for that serotype was greater than 0.5.

In participants 60 years of age and older, the immune responses to all 13 matched serotypes elicited by Apexxnar were non-inferior to those elicited by Prevenar 13 for the same serotypes 1 month after vaccination. In general, numerically lower geometric mean titres were observed with Apexxnar in the matched serotypes compared to Prevenar 13 (Table 3), however the clinical relevance of these findings is unknown.

The immune responses induced by Apexxnar to 6/7 additional serotypes were non-inferior to those induced by PPSV23 to the same serotypes 1 month after vaccination. The response to serotype 8 missed the pre-specified statistical non-inferiority criterion (the lower bound of the 2-sided 95% CI for the GMT ratio is 0.49 instead of > 0.50) (Table 3). The clinical relevance of this observation is unknown. Supportive analyses for other serotype 8 endpoints in the Apexxnar group showed favourable outcomes. These include a geometric mean fold rise (GMFR) of 22.1 from before vaccination to 1 month post-vaccination, 77.8% of participants achieved a ≥ 4-fold rise in OPA titres from before vaccination to 1 month after vaccination, and 92.9% of participants achieved OPA titres ≥ LLOQ 1 month after vaccination.

Immunogenicity in participants 18 through 59 years of age

In Study 1007, participants 50 through 59 years of age and participants 18 through 49 years of age were randomly assigned (3:1 ratio) to receive 1 vaccination with Apexxnar or Prevenar 13. Serotype-specific OPA GMTs were measured before vaccination and 1 month after vaccination. With both vaccines, higher immune responses were observed in younger participants compared with older participants. A non-inferiority analysis of Apexxnar in the younger age group versus Apexxnar in participants 60 through 64 years of age per serotype was performed to support the indication in adults 18 through 49 years of age and 50 through 59 years of age. Non-inferiority was declared if the lower bound of the 2-sided 95% CI for the GMT ratio (Apexxnar in participants 18 through 49 years of age / 60 through 64 years of age and in 50 through 59 years of age / 60 through 64 years of age) for each of the 20 serotypes was > 0.5. Apexxnar elicited immune responses to all 20 vaccine serotypes in the two of the younger age groups that were non-inferior to responses in participants 60 through 64 years of age 1 month after vaccination (Table 4).

While not planned as an active control for immunogenicity evaluations in the study, a post hoc descriptive analysis showed generally numerically lower OPA geometric mean titres 1 month after Apexxnar for the matched serotypes compared to Prevenar 13 in participants 18 through 59 years of age, however the clinical relevance of these findings is unknown.

As noted above, individuals with risk factors were included in this study. Across all the age groups studied, in general, a numerically lower immune response was observed in participants with risk factors compared to participants without risk factors. The clinical relevance of this observation is unknown.

Immunogenicity of Apexxnar in adults previously vaccinated with pneumococcal vaccine

A Phase 3 randomised, open-label clinical trial (Study 1006) described immune responses to Apexxnar in participants 65 years of age and older previously vaccinated with PPSV23, with Prevenar 13, or with Prevenar 13 followed by PPSV23. Participants previously vaccinated with Prevenar 13 (Prevenar 13 only or followed by PPSV23) were enrolled at sites in the United States, whereas participants previously vaccinated with PPSV23 only were also enrolled from Swedish sites (35.5% in that category).

Apexxnar elicited immune responses to all 20 vaccine serotypes in participants 65 years of age and older with prior pneumococcal vaccination (Table 5). Immune responses were lower in participants in both groups who received prior PPSV23 vaccinations.

Immune responses in special populations

Individuals with the conditions described below have an increased risk of pneumococcal disease.

Studies in HIV and bone marrow transplant participants have not been conducted with Apexxnar.

Limited experience from clinical studies with Prevenar 13 (a pneumococcal conjugate vaccine consisting of 13 polysaccharide conjugates that are also in Apexxnar) are available in adults with HIV infection, and adults following a bone marrow transplant.

Participants who were healthy, or with stable non-immunocompromising chronic medical conditions, in all the age groups analysed had a lower immune response with Apexxnar compared with Prevenar 13 in spite of meeting the predefined non-inferiority margins. The clinical relevance of this observation is unknown.

HIV infection

Adults not previously vaccinated with a pneumococcal vaccine

In Study 6115A1-3002 (B1851021), 152 HIV-infected participants 18 years of age and older (CD4 ≥ 200 cells/µ L, viral load < 50,000 copies/mL and free of active acquired immunodeficiency syndrome [AIDS]-related illness) not previously vaccinated with a pneumococcal vaccine were enrolled to receive 3 doses of Prevenar 13. As per the general recommendations, a single dose of PPSV23 was subsequently administered. The vaccines were administered at 1-month intervals. Immune responses were assessed in 131 to 137 evaluable participants approximately 1 month after each dose of the vaccine. After the first dose, Prevenar 13 elicited antibody levels, measured by immunoglobulin G (IgG) geometric mean concentrations (GMCs) and OPA GMTs, that were statistically significantly higher compared with levels prior to vaccination. After the second and third dose of Prevenar 13, immune responses were similar to or higher than those after the first dose.

Adults previously vaccinated with PPSV23

In Study 6115A1-3017 (B1851028), immune responses were assessed in 329 HIV-infected participants 18 years of age and older (CD4+ T-cell count ≥ 200 cells/µ L and viral load < 50,000 copies/mL) previously vaccinated with PPSV23 administered at least 6 months prior to enrolment. Participants received 3 doses of Prevenar 13: at enrolment, 6 months, and 12 months after the first dose of Prevenar 13. After the first vaccination, Prevenar 13 elicited antibody levels measured by IgG GMCs and OPA GMTs that were statistically significantly higher compared with levels prior to vaccination. After the second and third dose of Prevenar 13, immune responses were comparable to or higher than those after the first dose. Participants who received previously 2 or more doses of PPSV23 showed a similar immune response compared to participants who previously received a single dose.

Hematopoietic stem cell transplant (HSCT)

In Study 6115A1-3003 (B1851022), 190 participants 18 years of age and older with an allogeneic HSCT were enrolled to receive 3 doses of Prevenar 13 with an interval of at least 1 month between doses. The first dose was administered at 3 to 6 months after HSCT. A fourth (booster) dose of Prevenar 13 was administered 6 months after the third dose. As per the general recommendations, a single dose of PPSV23 was administered 1 month after the fourth dose of Prevenar 13. Immune responses as measured by IgG GMCs were assessed in 130 to 159 evaluable participants approximately 1 month after vaccination. Prevenar 13 elicited increased antibody levels after each dose. Immune responses after the fourth dose of Prevenar 13 were significantly increased for all serotypes compared with those after the third dose.

This study demonstrated that 4 doses of Prevenar 13 elicited serum IgG concentrations similar to those induced by a single dose in healthy participants of the same age group.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Apexxnar in one or more subsets of the paediatric population for the condition of prevention of disease caused by Streptococcus pneumoniae (see section 4.2 for information on paediatric use).

Not applicable.

Non-clinical data revealed no special hazard for humans based on conventional studies of repeated-dose toxicity and reproduction and developmental toxicity.

Sodium chloride

Succinic acid

Polysorbate 80

Water for injections

For adjuvant, see section 2.

In the absence of compatibility studies, this vaccine must not be mixed with other medicinal products.

24 months

Store in a refrigerator (2 ° C to 8 ° C). Pre-filled syringes should be stored in the refrigerator horizontally to minimise the resuspension time.

Do not freeze. Discard if the vaccine has been frozen.

From a microbiological point of view, once removed from the refrigerator, the vaccine should be used immediately.

Stability data indicate that the vaccine is stable for 96 hours when stored at temperatures from 8 ° C to 25 ° C, or 72 hours when stored at temperatures from 0 ° C to 2 ° C. At the end of these time periods Apexxnar should be used or discarded. These data are intended to guide healthcare professionals in case of temporary temperature excursion only.

0.5 mL suspension for injection in pre-filled syringe (Type I glass) with a tip cap (synthetic isoprene/bromobutyl blend rubber) and a plunger stopper (chlorobutyl rubber).

Pack sizes of 1, 10, and 50 pre-filled syringes, with or without needle.

Not all pack sizes may be marketed.

During storage, a white deposit and clear supernatant may be observed in the pre-filled syringe containing the suspension. Pre-filled syringes should be stored horizontally to minimise the resuspension time.

Preparation for administration

Any unused product or waste material should be disposed of in accordance with local requirements.