PNEUMOCOCCAL POLYSACCHARIDE CONJUGATE VACCINE (15-VALENT ADSORBED), VAXNEUVANCE SUSPENSION FOR INJECTION IN PRE-FILLED SYRINGE - summary of medicine characteristics

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1 NAME OF THE MEDICINAL PRODUCT

Vaxneuvance® suspension for injection in pre-filled syringe

Pneumococcal polysaccharide conjugate vaccine (15-valent, adsorbed)

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

1 dose (0.5 mL) contains:

1Conjugated to CRM197 carrier protein. CRM197 is a nontoxic mutant of diphtheria toxin (originating from Corynebacterium diphtheriae C7) expressed recombinantly in Pseudomonas fluorescens.

2Adsorbed on aluminium phosphate adjuvant.

1 dose (0.5 mL) contains 125 micrograms aluminium (Al3+) and approximately 30 micrograms CRM197 carrier protein.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Suspension for injection (injection).

The vaccine is an opalescent suspension.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Vaxneuvance 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 Vaxneuvance should be in accordance with official recommendations.

4.2 Posology and method of administration

Posology

Individuals 18 years of age and older

1 dose (0.5 mL).

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

Paediatric population

The safety and efficacy of Vaxneuvance in children and adolescents less than 18 years of age have not been established.

Special populations

One dose of Vaxneuvance may be given to individuals who have one or more underlying conditions predisposing them to an increased risk of pneumococcal disease (e.g., adults living with human immunodeficiency virus (HIV) or immunocompetent adults 18 to 49 years of age with risk factors for pneumococcal disease; see section 5.1).

Method of administration

The vaccine should be administered by intramuscular injection. The preferred site is the deltoid muscle of the upper arm.

No data are available for administration via the subcutaneous or intradermal routes.

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

4.3 Contraindications

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

4.4 Special warnings and precautions for use

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.

Precaution related to route of administration

Vaxneuvance must not be administered intravascularly.

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 to individuals receiving anticoagulant therapy, or to those with thrombocytopenia or any coagulation disorder such as haemophilia. Bleeding or bruising may occur following an intramuscular administration in these individuals.

Immunocompromised individuals

Immunocompromised individuals, whether due to the use of immuno-suppressive therapy, a genetic defect, HIV infection, or other causes, may have reduced antibody response to active immunisation.

Safety and immunogenicity data for Vaxneuvance are available for individuals living with HIV infection (see section 5.1). Safety and immunogenicity data for Vaxneuvance are not available for individuals in other specific immunocompromised groups (e.g., haematopoietic stem cell transplant) and vaccination should be considered on an individual basis.

Protection

As with any vaccine, vaccination with Vaxneuvance may not protect all vaccine recipients. Vaxneuvance will only protect against Streptococcus pneumoniae serotypes included in the vaccine (see sections 2 and 5.1).

Sodium

This medicinal product contains less than 1 mmol sodium (23 milligrams) per dose, i.e. essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction Vaxneuvance can be administered concomitantly with seasonal quadrivalent influenza vaccine (split virion, inactivated).

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

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

Immunosuppressive therapies may reduce the immune responses to vaccines.

4.6 Fertility, pregnancy and lactation

Pregnancy

There is limited experience with the use of Vaxneuvance 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 Vaxneuvance 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 Vaxneuvance is excreted in human milk.

Fertility

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

4.7 Effects on ability to drive and use machines

Vaxneuvance 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.

4.8 Undesirable effects

Summary of the safety profile

The safety of Vaxneuvance in healthy and immunocompetent adults was assessed in 6 clinical studies in 7,136 adults > 18 years of age. An additional clinical study assessed 302 adults > 18 years of age living with HIV. Vaxneuvance was administered to 5,630 adults; 1,241 were 18 to 49 years of age, 1,911 were 50 to 64 years of age, and 2,478 were 65 years of age and older. Of those who received Vaxneuvance, 1,134 were immunocompetent adults 18 to 49 years of age who had no (n=285), 1 (n=620) or > 2 (n=229) risk factors for pneumococcal disease and 152 were adults > 18 years of age living with HIV. In addition, 5,253 adults were pneumococcal vaccine-naive and 377 adults were previously vaccinated with 23-valent pneumococcal polysaccharide vaccine (PPV23) at least 1 year prior to enrolment.

The most frequently reported adverse reactions following vaccination with Vaxneuvance were solicited. In the pooled analysis of the 7 studies, the most frequent adverse reactions were injection-site pain (64.6%), fatigue (23.4%), myalgia (20.7%), headache (17.3%), injection-site swelling (16.1%), injection-site erythema (11.3%) and arthralgia (7.9%). The majority of solicited adverse reactions were mild (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 < 1.5% of adults across the clinical program.

Older adults reported fewer adverse reactions than younger adults.

Tabulated list of adverse reactions

Local and systemic adverse reactions were solicited daily after vaccination for 5 and 14 days, respectively. Unsolicited adverse reactions were reported for 14 days after vaccination. The table presented below is based on safety data from 7 clinical studies in adults who received Vaxneuvance, of whom 4,389 were > 50 years of age and 1,241 were 18 to 49 years of age.

Frequencies are reported as:

– 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 adults 18 to 49 years of age

^common in adults 18 to 49 years of age

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.

4.9

There are no data with regard to overdose.

5.1 Pharmacodynamic properties

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

Mechanism of action

Vaxneuvance contains 15 purified pneumococcal capsular polysaccharides from Streptococcus pneumoniae (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, 33F), each conjugated to a carrier protein (CRM197). Vaxneuvance elicits a T-cell dependent immune response to induce antibodies that enhance opsonisation, phagocytosis, and killing of pneumococci to protect against pneumococcal disease.

Clinical immunogenicity in immunocompetent adults > 18 years of age

Immune responses following natural exposure to Streptococcus pneumoniae or following pneumococcal vaccination can be determined by measuring opsonophagocytic activity (OPA) and immunoglobulin G (IgG) responses. OPA represents functional antibodies capable of opsonizing pneumococcal capsular polysaccharides for presentation to phagocytic cells for engulfment and subsequent killing, and are considered an important immunologic surrogate measure of protection against pneumococcal disease in adults. OPA titres are expressed as the reciprocal of the highest serum dilution that reduces the survival of the pneumococci by at least 50%. A validated multiplex opsonophagocytic assay (MOPA) was used to measure serotype-specific OPA titres for each of the 15 serotypes in Vaxneuvance.

Five clinical studies (Protocol 007, Protocol 016, Protocol 017, Protocol 019, and Protocol 021) conducted in the Americas, Europe and Asia Pacific evaluated the immunogenicity of Vaxneuvance in healthy and immunocompetent adults across different age groups including individuals with or without previous pneumococcal vaccination. Each clinical study included adults with stable underlying medical conditions (e.g., diabetes mellitus, renal disorders, chronic heart disease, chronic liver disease, chronic lung disease including asthma) and/or behavioural risk factors (e.g., current tobacco use, increased alcohol consumption) that are known to increase the risk of pneumococcal disease.

In each study, immunogenicity was assessed by serotype-specific OPA and IgG responses at 30 days postvaccination. Study endpoints included OPA geometric mean titres (GMTs) and IgG geometric mean concentrations (GMCs). The pivotal study (Protocol 019) aimed to show noninferiority of the OPA GMTs for 12 of 13 serotypes that Vaxneuvance shares with the 13-valent pneumococcal polysaccharide conjugate vaccine, noninferiority and superiority for the shared serotype 3, and superiority for serotypes 22F and 33F, unique to Vaxneuvance. Superiority assessment of Vaxneuvance to the 13-valent pneumococcal polysaccharide conjugate vaccine was based on the between-group comparisons of OPA GMTs and the proportions of participants with a > 4-fold rise in serotype-specific OPA titres from prevaccination to 30 days postvaccination.

Pneumococcal vaccine-naïve adults

In the pivotal, double-blind, active comparator-controlled study (Protocol 019), 1,205 immunocom­petent pneumococcal vaccine-naïve subjects > 50 years of age were randomised to receive Vaxneuvance or the 13-valent pneumococcal polysaccharide conjugate vaccine. The median age of participants was 66 years (range: 50 to 92 years), with approximately 69% over 65 years of age, and approximately 12% over 75 years of age. 57.3% were female and 87% reported history of at least one underlying medical condition.

The study demonstrated that Vaxneuvance is noninferior to the 13-valent pneumococcal polysaccharide conjugate vaccine for the 13 shared serotypes and superior for the 2 unique serotypes and for the shared serotype 3. Table 2 summarises the OPA GMTs at 30 days postvaccination. IgG GMCs were generally consistent with the results observed for the OPA GMTs.

Table 2: Serotype-specific OPA GMTs at 30 days Postvaccination in Pneumococcal Vaccine-Naïve Adults > 50 Years of age (Protocol 019)

GMTs, GMT ratio, and 95% CI are estimated from a cLDA model.

^A conclusion of non-inferiority for the 13 shared serotypes is based on the lower bound of the 95% CI for the estimated GMT ratio (Vaxneuvance/13-valent PCV) being > 0.5.

A conclusion of superiority for serotype 3 is based on the lower bound of the 95% CI for the estimated GMT ratio (Vaxneuvance/13-valent PCV) being > 1.2.

§A conclusion of superiority for the 2 unique serotypes is based on the lower bound of the 95% CI for the estimated GMT ratio (Vaxneuvance/13-valent PCV) being > 2.0.

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

CI=confidence interval; cLDA=constrained longitudinal data analysis;

GMT=geometric mean titre (1/dil); OPA=opsonopha­gocytic activity; PCV=pneumococcal conjugate vaccine.

In a double-blind, descriptive study (Protocol 017), 1,515 immunocom­petent subjects 18 to 49 years of age with or without risk factors for pneumococcal disease were randomised 3:1 and received Vaxneuvance or the 13-valent pneumococcal polysaccharide conjugate vaccine, followed by PPV23 6 months later. Risk factors for pneumococcal disease included the following: diabetes mellitus, chronic heart disease including heart failure, chronic liver disease with compensated cirrhosis, chronic lung disease including persistent asthma and chronic obstructive pulmonary disease (COPD), current tobacco use, and increased alcohol consumption. Overall, of those who received Vaxneuvance, 285 (25.2%) had no risk factor, 620 (54.7%) had 1 risk factor, and 228 (20.1%) had 2 or more risk factors.

Vaxneuvance elicited immune responses to all 15 serotypes contained in the vaccine as assessed by OPA GMTs (Table 3) and IgG GMCs. OPA GMTs and IgG GMCs were generally comparable between the two vaccination groups for the 13 shared serotypes and higher in the Vaxneuvance group for the 2 unique serotypes. Following vaccination with PPV23, OPA GMTs and IgG GMCs were generally comparable between the two vaccination groups for all 15 serotypes.

In a subgroup analysis based on the number of reported risk factors, Vaxneuvance elicited immune responses to all 15 serotypes contained in the vaccine as assessed by OPA GMTs and IgG GMCs at 30 days postvaccination in adults with no, 1, or 2 or more risk factors. The results in each subgroup were generally consistent with those observed in the overall study population. Sequential administration of Vaxneuvance followed 6 months later by PPV23 was also immunogenic for all 15 serotypes contained in Vaxneuvance.

Table 3: Serotype-specific OPA GMTs at 30 days Postvaccination in

Pneumococcal Vaccine-Naive Adults 18–49 Years of Age With or Without Risk

Factors for Pneumococcal Disease (Protocol 017)

*The within-group 95% CIs are obtained by exponentiating the CIs of the mean of the natural log values based on the t-distribution.

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

CI=confidence interval; GMT=geometric mean titre (1/dil); OPA=opsonopha­gocytic activity; PCV=pneumococcal conjugate vaccine.

Sequential administration of pneumococcal vaccines in adults

The sequential administration of Vaxneuvance followed by PPV23 was assessed in Protocol 016, Protocol 017 (see section 5.1, Pneumococcal vaccine-naïve adults), and Protocol 018 (see section 5.1, Adults living with HIV).

In a double-blind, active comparator-controlled study (Protocol 016), 652 pneumococcal vaccine-naïve subjects > 50 years of age were randomised to receive Vaxneuvance or the 13-valent pneumococcal polysaccharide conjugate vaccine, followed by PPV23 one year later.

Following vaccination with PPV23, OPA GMTs and IgG GMCs were comparable between the two vaccination groups for all 15 serotypes in Vaxneuvance.

Immune responses elicited by Vaxneuvance persisted up to 12 months postvaccination as assessed by OPA GMTs and IgG GMCs. Serotype-specific OPA GMTs declined over time, as they were lower at Month 12 than Day 30, but remained above baseline levels for all the serotypes contained in either Vaxneuvance or the 13-valent pneumococcal polysaccharide conjugate vaccine. OPA GMTs and IgG GMCs were generally comparable between the intervention groups at Month 12 for the 13 shared serotypes and higher for the 2 unique serotypes among recipients of Vaxneuvance.

Adults with prior pneumococcal vaccination

In a double-blind, descriptive study (Protocol 007), 253 subjects > 65 years of age who were previously vaccinated with PPV23 at least one year prior to study entry were randomised to receive Vaxneuvance or the 13-valent pneumococcal polysaccharide conjugate vaccine.

IgG GMCs and OPA GMTs were generally comparable between the two vaccination groups for the 13 shared serotypes and higher in the Vaxneuvance group for the 2 unique serotypes.

In a clinical study, in which another PCV was administered < 1 year after PPV23, reduced immune responses were observed for the common serotypes compared to immune responses observed when PCV was given either alone or before PPV23. The clinical significance of this is unknown.

Clinical immunogenicity in special populations

Adults living with HIV

In a double-blind, descriptive study (Protocol 018), 302 pneumococcal vaccine-naïve subjects > 18 years of age living with HIV with CD4+ T-cell count > 50 cells/gL and plasma HIV ribonucleic acid (RNA) <50,000 copies/mL were randomised to receive Vaxneuvance or the 13-valent pneumococcal polysaccharide conjugate vaccine, followed by PPV23 2 months later. The majority of participants had a CD4+ T-cell count > 200 cells/gL; 4 (1.3%) had a CD4+ T-cell count > 50 to < 200 cells/gL, 152 (50.3%) had a CD4+ T-cell count > 200 to < 500 cells/gL, and 146 (48.3%) had a CD4+ T-cell count > 500 cells/gL.

Vaxneuvance elicited immune responses to all 15 serotypes contained in the vaccine as assessed by OPA GMTs and IgG GMCs at 30 days postvaccination. Immune responses seen in the HIV-infected participants were consistently lower compared to healthy participants but comparable for both vaccination groups, except for serotype 4. OPA GMT and IgG GMC for serotype 4 were lower for Vaxneuvance. After sequential administration with PPV23, OPA GMTs and IgG GMCs were generally comparable between the two vaccination groups for all 15 serotypes.

5.2 Pharmacokinetic properties

Not applicable

5.3 Preclinical safety data

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

Vaxneuvance administered to female rats had no effects on mating performance, fertility, embryonic/foetal development, or development of the offspring.

Vaxneuvance administered to pregnant female rats resulted in detectable antibodies to all 15 serotypes in offspring. This was attributable to the acquisition of maternal antibodies via placental transfer during gestation and possibly via lactation.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium chloride (NaCl)

L-histidine

Polysorbate 20

Water for injections

For adjuvant, see section 2.

6.2 Incompatibilities

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

6.3 Shelf life

2 years

6.4 Special precautions for storage

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.

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

In the event of temporary temperature excursions, stability data indicate that Vaxneuvance is stable at temperatures up to 25 °C for 48 hours.

6.5 Nature and contents of container

0.5 mL suspension in pre-filled syringe (Type I glass) with a plunger stopper (latex-free bromobutyl rubber) and a tip cap (latex-free styrene-butadiene rubber).

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

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

The vaccine should be used as supplied.

Immediately prior to use, hold the pre-filled syringe horizontally and shake vigorously to obtain an opalescent suspension. Do not use the vaccine if it cannot be resuspended.

Inspect the suspension 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.

Inject immediately using the intramuscular (IM) route, preferably in the deltoid area of the upper arm.

Exercise care to avoid harm from an accidental needle stick.

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

7 MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme (UK) Limited

120 Moorgate

London

EC2M 6UR

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PLGB 53095/0090