CAPVAXIVE solution for injection in pre-filled syringe

CAPVAXIVE is indicated for 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.

The use of CAPVAXIVE should be in accordance with official recommendations.

Posology

Individuals 18 years of age and older

1 dose (0.5 mL).

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

Paediatric population

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

Method of administration

CAPVAXIVE should be administered by intramuscular injection only. This vaccine should be administered preferably in the deltoid muscle of the upper arm in adults, 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 including diphtheria toxoid, or to any of the excipients listed in section 6.1.

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.

Anaphylaxis

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

Concurrent illness

Vaccination should be postponed in individuals suffering from acute severe febrile illness or acute infection. The presence of a minor infection and/or low-grade fever should not delay vaccination.

Thrombocytopenia and coagulation disorders

As with other intramuscular injections, the vaccine should be given with caution in individuals receiving anticoagulant therapy or those with thrombocytopenia or any coagulation disorder (such as haemophilia) because bleeding or bruising may occur following an intramuscular administration in these individuals.

Anxiety-related reactions

Anxiety-related reactions, including vasovagal reactions (syncope), hyperventilation or stress‐related reactions may occur in association with vaccination as a response to the needle injection. Stress‑related reactions are temporary and resolve on their own. It is important that precautions are in place to avoid injury from fainting.

Immunocompromised individuals

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

Based on experience with pneumococcal vaccines, immunocompromised individuals, including those receiving immunosuppressive therapy, may have a reduced immune response to CAPVAXIVE.

Protection

As with any vaccine, vaccination with CAPVAXIVE may not protect all vaccine recipients. This vaccine will only protect against Streptococcus pneumoniae serotypes included in the vaccine and to the cross-reactive serotype 15B (see sections 2 and 5.1).

Sodium

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

Polysorbate 20

This medicinal product contains 0.5 mg of polysorbate 20 in each dose. Polysorbates may cause allergic reactions.

Different injectable vaccines should always be administered at different injection sites.

CAPVAXIVE can be administered concomitantly with quadrivalent influenza vaccine (split virion, inactivated). There are no data on the concomitant administration of CAPVAXIVE with vaccines other than influenza vaccines.

Pregnancy

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

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryo/foetal development, parturition or post-natal development (see section 5.3).

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

Breast-feeding

It is unknown whether CAPVAXIVE is excreted in human milk.

Fertility

No human data on the effect of CAPVAXIVE on fertility are available. Animal studies in female rats do not indicate harmful effects (see section 5.3).

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

Summary of the safety profile

The most frequently reported adverse reactions following vaccination with CAPVAXIVE in individuals 18 years of age and older were solicited. Overall, the most frequently reported adverse reactions were injection-site pain (52.9%), fatigue (25.3%), headache (17.7%), and myalgia (10.4%).

The majority of local and systemic adverse reactions for individuals who received CAPVAXIVE were mild or moderate (based on intensity or size) and of short duration (≤ 3 days); severe reactions (defined as an event that prevents normal daily activity or size ˃ 10 cm) occurred in ≤ 1.0% of adults (see Table 1).

Tabulated list of adverse reactions

Unless otherwise stated the frequency categories are based on the safety of CAPVAXIVE assessed in 6 clinical studies, conducted across the Americas, Europe, Asia Pacific and Africa which included 4 914 individuals ≥ 18 years of age; with or without stable underlying medical conditions.

Adverse reactions reported for all age groups are listed in this section per 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 the available data).

Table 1: Tabulated list of adverse reactions

* very common in individuals 18 to 49 years of age

Other special populations

Safety in individuals 65 years of age and older

A lower frequency of local injection-site reactions was observed in participants 75 years of age and older compared to participants 65 to 74 years of age. There were no clinically meaningful differences for other adverse events in participants 65 to 74 years of age and 75 years of age and older who received CAPVAXIVE.

Safety in adults living with HIV

The safety profile of CAPVAXIVE in adults living with HIV was generally comparable to the safety profile of pneumococcal 15-valent conjugate vaccine (PCV15) followed by pneumococcal 23-valent polysaccharide vaccine (PPSV23, see section 5.1).

Safety in adults with increased risk for pneumococcal disease

An additional study, Protocol 008, was conducted to evaluate CAPVAXIVE in pneumococcal vaccine‑naïve adults 18 to 64 years of age with one or more prespecified chronic medical conditions known to increase the risk of pneumococcal disease (see section 5.1). The safety profile of CAPVAXIVE was generally comparable to PCV15 followed by PPSV23 and generally similar to the profile observed in the pivotal studies.

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 CAPVAXIVE is unlikely due to its presentation as a pre-filled syringe.

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

Mechanism of action

CAPVAXIVE contains 21 pneumococcal capsular polysaccharides from Streptococcus pneumoniae (3, 6A, 7F, 8, 9N, 10A, 11A, 12F, 15A, deOAc15B, 16F, 17F, 19A, 20A, 22F, 23A, 23B, 24F, 31, 33F, and 35B), which are known to contribute to the pathogenicity of pneumococci in adults. Each serotype of activated polysaccharide is individually conjugated to a carrier protein (CRM₁₉₇), and elicits antibodies that enhance opsonisation, phagocytosis, and killing of pneumococci to protect against pneumococcal disease. CAPVAXIVE elicits a T-cell dependent immune response. Carrier protein-specific helper T-cells support specificity, functionality, and maturation of serotype-specific B-cells.

Immune responses following natural exposure to Streptococcus pneumoniae or following pneumococcal vaccination can be determined through the assessments of opsonophagocytic activity (OPA) responses, to assess functional antibodies capable of opsonizing pneumococcal capsular polysaccharides for presentation to phagocytic cells for engulfment and subsequent killing. OPA responses are considered an important immunologic surrogate measure of protection against pneumococcal disease in adults. Specific threshold values that correlate with protection in adults have not been defined. There is a positive correlation between OPA responses and anti-capsular Immunoglobulin G (IgG) responses.

Serotype‑specific immune responses (OPA and IgG) for the 21 serotypes contained in CAPVAXIVE and the cross-reactive serotype 15B were measured using a validated multiplexed opsonophagocytic assay (MOPA) and pneumococcal electrochemiluminescence (Pn ECL) assay. Serotype 15C represents the immune response to the deOAc15B polysaccharide as the molecular structure for deOAc15B and 15C are similar.

Clinical efficacy and safety

Clinical trials experience in individuals 18 years of age and older

Six Phase 3, clinical studies (Protocol 003, Protocol 004, Protocol 005, Protocol 006, Protocol 007, and Protocol 010) conducted across the Americas, Europe, Asia Pacific and Africa evaluated the immunogenicity of CAPVAXIVE in 8 369 individuals 18 years of age and older, of whom 5 450 received CAPVAXIVE. Participants enrolled in the Phase 3 studies included adults across different age groups; approximately 32% were 18 to 49 years of age, 32% were 50 to 64 years of age, 29% were 65 to 74 years of age, and 8% were 75 years of age and older. Of those vaccinated, 14% had received other prior pneumococcal vaccines, 33% had risk factors for pneumococcal disease (e.g., alcoholism, chronic heart disease, chronic liver disease, chronic lung disease including asthma, diabetes, renal disorders, smoking) and approximately 4% were adults living with HIV, which is associated with high risk of pneumococcal disease.

In each study, immunogenicity was assessed by serotype‑specific OPA and IgG responses at 1-month postvaccination.

Clinical trials conducted in pneumococcal vaccine‑naïve adults

CAPVAXIVE effectiveness in adults against invasive pneumococcal disease and pneumonia was assessed based on comparative immunogenicity to a licensed pneumococcal vaccine (pneumococcal 20-valent conjugate vaccine (PCV20) and PPSV23).

Protocol 003

In a double-blind study, 2 362 pneumococcal vaccine-naïve individuals 50 years of age and older were randomised to receive either CAPVAXIVE or PCV20. The immune response as assessed by the geometric mean titre (GMT) ratio (CAPVAXIVE/PCV20) is presented in Table 2.

CAPVAXIVE met the pre-defined statistical noninferiority criterion compared to PCV20 for the 10 serotypes included in both vaccines as assessed by the geometric mean titre (GMT) ratio (CAPVAXIVE/PCV20) where the noninferiority criterion was met if the lower bound of the 2-sided 95% Confidence Interval (CI) were ˃ 0.5. CAPVAXIVE met the predefined superiority criterion compared to PCV20 for all but one (15C) of the 11 additional serotypes to CAPVAXIVE as assessed by the GMT ratio (CAPVAXIVE/PCV20) where the statistical superiority criterion was met if the lower bound of the 2 sided 95% CI were ˃ 2.0 (see Table 2).

Table 2: Serotype‑specific OPA GMTs in pneumococcal vaccine‑naïve individuals ≥ 50 years of age (Protocol 003)

* GMTs, GMT ratio, and 95% CI were estimated from a constrained Longitudinal Data Analysis model.

^† The noninferiority criterion was met if the lower bound of the 2-sided 95% CI for the estimated GMT ratio (CAPVAXIVE/PCV20) was > 0.5.

^‡ The superiority criterion was met if the lower bound of the 2-sided 95% CI for the estimated GMT ratio (CAPVAXIVE/PCV20) was > 2.0.

N=Number of individuals randomised and vaccinated; n=Number of individuals contributing to the analysis.

CAPVAXIVE met the superiority criterion compared to PCV20 for 10 of additional 11 serotypes (except 15C) in CAPVAXIVE as assessed by the proportion of individuals who achieved a ≥ 4-fold rise from prevaccination to 1-month postvaccination for OPA responses. The superiority criterion was defined as the difference between CAPVAXIVE and PCV20 being ˃ 10 percentage points.

Immunobridging in pneumococcal vaccine-naïve individuals 18 to 49 years of age

In a double-blind study pneumococcal vaccine-naïve individuals 18 to 49 years of age were randomised in a 2:1 ratio to receive CAPVAXIVE (N=200) or PCV20 (N=100). The 18 to 49 year old group who received CAPVAXIVE (N=200) was compared to the 50 to 64 year old group (N=589) which also had received CAPVAXIVE to evaluate the OPA responses.

CAPVAXIVE successfully immunobridged serotype-specific immune responses to each of the 21 vaccine serotypes in individuals 18 to 49 years of age to individuals 50 to 64 years of age, as the lower bound of the 2-sided 95% CI for the GMT ratio for each serotype was > 0.5 (see Table 3).

Table 3: Comparison of serotype‑specific OPA GMTs in pneumococcal vaccine‑naïve individuals 18-49 years of age to 50-64 years of age who received CAPVAXIVE (Protocol 003)

* GMTs, GMT ratio, and 95% CI were estimated from a Longitudinal Data Analysis model.

^† A conclusion of immunobridging was based on the lower bound of the 95% CI for the estimated GMT ratio (18‑49 years / 50‑64 years) being > 0.5.

N=Number of individuals randomised and vaccinated; n=Number of individuals contributing to the analysis.

Protocol 010

In a double-blind study, 1 484 pneumococcal vaccine-naïve individuals 50 years of age and older were randomised to receive either CAPVAXIVE or PPSV23; 46% of participants were 50 to 64 years of age, 54% were 65 years of age and older, and 10% were 75 years of age and older. The immune response as assessed by the GMT ratio (CAPVAXIVE/PPSV23) is presented in Table 4.

CAPVAXIVE met the pre-defined statistical noninferiority criterion compared to PPSV23 for the 12 serotypes included in both vaccines as assessed by the GMT ratio (CAPVAXIVE/PPSV23) where the noninferiority criterion was met if the lower bound of the 2-sided 95% Confidence Interval (CI) were ˃ 0.5. CAPVAXIVE met the predefined superiority criterion compared to PPSV23 for the 9 additional serotypes to CAPVAXIVE as assessed by the GMT ratio (CAPVAXIVE/PPSV23) where the statistical superiority criterion was met if the lower bound of the 2 sided 95% CI were ˃ 2.0 (see Table 4).

Table 4: Serotype specific OPA GMTs in pneumococcal vaccine-naïve individuals ≥ 50 years of age (Protocol 010)

* GMTs, GMT ratio, and 95% CI were estimated from a constrained Longitudinal Data Analysis model.

^† The noninferiority criterion was met if the lower bound of the 2-sided 95% CI for the estimated GMT ratio (CAPVAXIVE/PPSV23) was > 0.5.

^‡ The superiority criterion was met if the lower bound of the 2-sided 95% CI for the estimated GMT ratio (CAPVAXIVE/PPSV23) was > 2.0.

N=Number of individuals randomised and vaccinated; n=Number of individuals contributing to the analysis.

CAPVAXIVE met the superiority criterion compared to PPSV23 for 8 of 9 additional serotypes (except 15C) in CAPVAXIVE as assessed by the proportion of individuals who achieved a ≥ 4-fold rise from prevaccination to 1-month postvaccination for OPA responses. The superiority criterion was defined as the difference between CAPVAXIVE and PPSV23 being ˃ 10 percentage points.

Clinical trials conducted in adults with prior pneumococcal vaccination

Protocol 006

A descriptive Phase 3 study, enrolled individuals ≥ 50 years of age who were previously vaccinated with other pneumococcal vaccines at least 1 year prior to study entry. Subjects were randomised to receive CAPVAXIVE or another pneumococcal vaccine.

Across all 3 cohorts, CAPVAXIVE was immunogenic for all 21 serotypes contained in the vaccine as assessed by serotype-specific OPA GMTs. OPA GMTs were generally comparable between the two vaccination groups for the shared serotypes and higher in the CAPVAXIVE group for the additional serotypes included only in CAPVAXIVE.

Special populations

Adults living with HIV

Protocol 007

In a double-blind study, 313 adults living with HIV, with or without a history of prior pneumococcal vaccination, were randomised in a 1:1 ratio to receive either CAPVAXIVE followed by placebo 8 weeks later, or PCV15 followed by PPSV23 (PCV15+PPSV23) 8 weeks later. At screening, of the participants vaccinated 6.7% had a CD4+ T-cell counts ≥ 50 to < 350 cells/µL, 18.6% had CD4+ T‑cell counts ≥ 350 to < 500 cells/µL and 74.7% had a CD4+ T-cell counts ≥ 500 cells/µL; 83% had an undetectable HIV viral load (< 20 copies/mL).

CAPVAXIVE was immunogenic for all 21 serotypes contained in the vaccine, as assessed by serotype specific OPA GMTs at 1-month postvaccination with CAPVAXIVE. CAPVAXIVE elicited immune responses that were generally comparable to PCV15+PPSV23 for the 13 common serotypes and higher for the 8 serotypes additional to CAPVAXIVE as assessed by OPA GMTs at 1-month postvaccination with CAPVAXIVE and 1-month postvaccination with PCV15+PPSV23.

Adults with increased risk for pneumococcal disease

Protocol 008

In a double-blind study, 518 individuals 18 to 64 years of age with one or more prespecified chronic medical conditions known to increase the risk of pneumococcal disease (diabetes mellitus, chronic heart disease, chronic kidney disease, chronic liver disease, or chronic lung disease) were randomised in a 3:1 ratio to receive either CAPVAXIVE followed by placebo 8 weeks later, or PCV15 followed by PPSV23 (PCV15+PPSV23) 8 weeks later. The study participants had not previously received any pneumococcal vaccines other than routine childhood PCVs.

CAPVAXIVE was immunogenic for all 21 serotypes contained in the vaccine, as assessed by serotype specific OPA GMTs at 1‑month postvaccination with CAPVAXIVE. CAPVAXIVE elicited immune responses that were generally comparable to PCV15+PPSV23 for the 13 common serotypes and higher for the 8 serotypes unique to CAPVAXIVE as assessed by OPA GMTs at 1‑month postvaccination with CAPVAXIVE and 1‑month postvaccination with PCV15+PPSV23.

Paediatric population

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

Not applicable.

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

Sodium chloride (NaCl)

Histidine

Polysorbate 20 (E432)

Hydrochloric acid (HCl; for pH adjustment)

Water for injections

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

3 years

Store in a refrigerator (2° C – 8° C).

Do not freeze.

Keep the pre-filled syringe in the outer carton in order to protect from light.

CAPVAXIVE should be administered as soon as possible after being removed from the refrigerator.

Stability data indicate that CAPVAXIVE is stable at temperatures up to 25° C for 96 hours. At the end of this time period CAPVAXIVE should be used or discarded. These data are intended to guide healthcare professionals in case of temporary temperature excursions only.

0.5 mL solution in a single-dose pre-filled syringe (Type I glass) with a plunger stopper (bromobutyl rubber) and a tip cap (styrene butadiene or isoprene bromobutyl rubber).

Pack sizes of 1 or 10 pre-filled syringes, either without needles, with 1 separate needle, or with 2 separate needles per pre-filled syringe.

Not all pack sizes may be marketed.

• The vaccine should be used as supplied.

• Inspect the solution visually for particulate matter and discolouration prior to administration. Discard the vaccine if particulates are present and/or if it appears discoloured.

• Attach a needle with Luer lock connection by twisting in a clockwise direction until the needle fits securely on the syringe.

• CAPVAXIVE should be administered by intramuscular injection only. This vaccine should be administered preferably in the deltoid muscle of the upper arm in adults, with care to avoid injection into or near nerves and blood vessels.

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