Prevenar 20 suspension for injection in pre-filled syringe (formerly Apexxnar)

Active immunisation for the prevention of pneumococcal disease caused by Streptococcus pneumoniae in individuals from 6 weeks of age and older.

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

Prevenar 20 should be used in accordance with official recommendations.

Posology

It is recommended that infants who receive a first dose of Prevenar 20 complete the vaccination course with Prevenar 20.

Paediatric population

The safety and efficacy of Prevenar 20 in infants below 6 weeks of age have not been established. No data are available.

Special populations

There are no data with Prevenar 20 in special populations. The use of Prevenar 20 should be guided by official recommendations.

Experience from clinical studies with Prevenar 13 (a pneumococcal conjugate vaccine consisting of 13 polysaccharide conjugates that are also in Prevenar 20) are available in adults and children at higher risk of pneumococcal infection including immunocompromised adults and children with human immunodeficiency virus (HIV) infection or haematopoietic stem cell transplant (HSCT), and children with sickle cell disease (SCD) (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 SCD 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 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 4 weeks between doses. A booster dose was recommended 6 months after the third dose (see section 5.1).

The recommended dosing of Prevenar 13 may be considered in guiding vaccination with Prevenar 20 in higher risk populations. For immune responses to pneumococcal vaccines in immunocompromised individuals, please also refer to sections 4.4. and 5.1.

Method of administration

For intramuscular use only.

One dose (0.5 mL) of Prevenar 20 should be administered intramuscularly, preferably in the anterolateral aspect of the thigh (vastus lateralis muscle) in infants or the deltoid muscle of the upper arm in children and 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, to any of the excipients listed in section 6.1, or to diphtheria toxoid.

Do not inject Prevenar 20 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

Prevenar 20 will only protect against Streptococcus pneumoniae serotypes included in the vaccine and will not protect against other microorganisms that cause invasive disease, pneumonia or otitis media (OM). As with any vaccine, Prevenar 20 may not protect all individuals receiving the vaccine from pneumococcal invasive disease, OM 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 Prevenar 20 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 Prevenar 20.

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 immunisation. 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 Prevenar 20) are available for a limited number of individuals with HIV infection, SCD 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 opsonophagocytic activity (OPA) geometric mean titres were observed with Prevenar 20 for most of the serotypes compared to Prevenar 13 (see section 5.1). In children, numerically lower immunoglobulin G (IgG) geometric mean concentrations (GMCs) were observed for all shared serotypes compared with Prevenar 13 (see section 5.1). The clinical relevance of these observations for immunocompromised individuals is unknown.

Paediatric population

The potential risk of apnoea and the need for respiratory monitoring for 48 to 72 h should be considered when administering the primary immunisation series to very premature infants (born less than or equal to 28 weeks of gestation), and particularly for those with a previous history of respiratory immaturity. As the benefit of vaccination is high in this group of infants, vaccination should not be withheld or delayed.

Excipient

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

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

Do not mix Prevenar 20 with other vaccines/medicinal products in the same syringe.

Paediatric population

In infants and children, 6 weeks to less than 5 years of age, Prevenar 20 can be administered concomitantly with any of the following vaccine antigens, either as monovalent or combination vaccines: diphtheria, tetanus, acellular pertussis, hepatitis B, Haemophilus influenzae type b, inactivated poliomyelitis, measles, mumps, rubella, and varicella vaccines. The vaccine has been safely administered with influenza and rotavirus vaccines.

Individuals 18 years of age and older

Prevenar 20 can be administered concomitantly with seasonal influenza vaccine (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 seasonal influenza vaccine and Prevenar 20 (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 Prevenar 20 when given concomitantly with a quadrivalent seasonal influenza vaccine (surface antigen, inactivated, adjuvanted) compared to when Prevenar 20 was given alone. The clinical relevance of this finding is unknown.

Prevenar 20 can be administered concomitantly with COVID-19 mRNA vaccine (nucleoside modified).

There are no data on the concomitant administration of Prevenar 20 with other vaccines.

Pregnancy

There are no data on the use of Prevenar 20 in pregnant women.

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

Administration of Prevenar 20 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 Prevenar 20 is excreted in human milk.

Fertility

No human data on the effect of Prevenar 20 on fertility are available. Animal studies do not indicate direct or indirect harmful effects with respect to female fertility (see section 5.3).

Prevenar 20 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

Paediatric population

The safety of Prevenar 20 was evaluated in 5,987 participants 6 weeks of age to less than 18 years of age in four randomised double-blind, active-controlled, clinical trials and one single-arm clinical trial (one Phase 2 and four Phase 3); 3,664 participants received at least 1 dose of Prevenar 20, and 2,323 participants received Prevenar 13 (control vaccine).

Participants 6 weeks to less than 15 months of age

In four infant trials, 5,156 participants received at least 1 dose of vaccine: 2,833 received Prevenar 20 and 2,323 received Prevenar 13. Prevenar 20 was well tolerated when administered in a 3-dose or 4-dose series, with low rates of severe local and systemic reactions, and most reactions resolving within 1 to 3 days. The most frequently reported reactions after any dose of Prevenar 20 were irritability, drowsiness, and pain at injection site. In these studies, Prevenar 20 was co-administered or permitted to be administered with certain routine paediatric vaccines (see section 4.5).

In a 3-dose series study, 601 healthy infants, 2 months (≥ 42 to ≤ 112 days) of age and born at > 36 weeks of gestation, received Prevenar 20. The most frequently reported adverse reactions (> 10%) after any dose were irritability (71.0% to 71.9%), drowsiness/increased sleep (50.9% to 61.2%), pain at injection site (22.8% to 42.4%), decreased appetite (24.7% to 39.3%), redness at the injection site (25.3% to 36.9%), swelling at the injection site (21.4% to 29.8%), and fever ≥ 38.0° C (8.9% to 24.3%). Most adverse reactions occurred within 1 to 2 days following vaccination and were mild or moderate in severity and of short duration (1 to 2 days).

Three other studies included 2,232 healthy infants vaccinated with Prevenar 20 in a 4-dose series. The most frequently reported adverse reactions (> 10%) observed after any dose were irritability (58.5% to 70.6%), drowsiness/increased sleep (37.7% to 66.2%), pain at injection site (32.8% to 45.5%), decreased appetite (23.0% to 26.4%), redness at the injection site (22.6% to 24.5%) and swelling at the injection site (15.1% to 17.6%). Most adverse reactions were mild or moderate following vaccination and severe reactions were reported infrequently. The local and systemic reactions in a preterm subgroup (111 infants born at 34 to less than 37 weeks of gestation) were similar to or lower than in the term infants of the study.

The frequency and severity of the adverse reactions in all infant clinical trials were generally similar in the Prevenar 20 and Prevenar 13 groups.

Participants aged 15 months to less than 18 years of age

In one study, 831 participants who received a single dose of Prevenar 20 were included in four age groups: 209 participants 15 to less than 24 months of age; 216 participants 2 years to less than 5 years of age; 201 participants 5 years to less than 10 years age; and 205 participants 10 years to less than 18 years of age. The participants less than 5 years of age had received at least 3 prior doses of Prevenar 13.

The most frequently reported adverse reactions (> 10%) observed after any dose in participants less than 2 years of age were irritability (61.8%), pain at the injection site (52.5%), drowsiness/increased sleep (41.7%), redness at the injection site (37.7%), decreased appetite (25.0%), swelling at the injection site (22.1%) and fever ≥ 38.0 ° C (11.8%). In participants aged 2 years and older, the most frequently reported adverse reactions were pain at the injection site (66.0% to 82.9%), muscle pain (26.5% to 48.3%), redness at the injection site (15.1% to 39.1%), fatigue (27.8% to 37.2%), headache (5.6% to 29.3%), and swelling at the injection site (15.6% to 27.1%).

Adult population

The safety of Prevenar 20 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), with 2,496 participants in the control groups.

In the Phase 3 trials, 4,263 participants received Prevenar 20. 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). Overall, 3,639 subjects were naï ve to pneumococcal vaccines, 253 had previously received a 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).

In participants 18 to 49 years of age, 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, 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, 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.

In a study that evaluated Prevenar 20 in participants ≥ 65 years of age with varying prior pneumococcal status (prior PPSV23, prior Prevenar 13 or prior Prevenar 13 followed by PPSV23), the most frequently reported adverse reactions were similar in frequency to those described for participants ≥ 60 years of age, 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 in paediatric and adult clinical trials, and postmarketing experience are presented below.

Adverse reactions from clinical trials

As Prevenar 20 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 Prevenar 20. Table 1 presents adverse reactions reported in clinical trials based on the highest frequency reported after vaccination in a Prevenar 20 group or integrated dataset. The data from clinical trials in infants reflect Prevenar 20 administered simultaneously with other routine childhood vaccines. In the case of adverse reactions reported in clinical trials of Prevenar 13, but not reported in Prevenar 20 trials, the frequency indicated in the table is the frequency of the adverse reaction in Prevenar 13 trials.

In clinical trials, the safety profile of Prevenar 20 was similar to that of Prevenar 13 and 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 Prevenar 20 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 Prevenar 20 alone: 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 in paediatric and adult populations, which may also occur with Prevenar 20. The postmarketing safety experience with Prevenar 13 is relevant to Prevenar 20, as Prevenar 20 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.

Additional information in special populations in studies with Prevenar 13

Participants 6 to < 18 years of age with HIV infection have similar frequencies of adverse reactions in Table 1, except fever (11% to 19%), joint pain (24% to 42%), and vomiting (8% to 18%) which were very common. 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 2 to < 18 years of age with HSCT have similar frequencies of adverse reactions in Table 1, except vaccination-site pain causing limitation of limb movement (5% to 15%), vomiting (6% to 21%), diarrhoea (15% to 32%), and joint pain (25% to 32%) which were very 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.

Participants 6 to < 18 years of age with SCD have similar frequencies of adverse reactions in Table 1, except vaccination-site pain causing limitation of limb movement (11% to 16%), fever (21% to 22%), vomiting (13% to 15%), diarrhoea (13% to 25%), and joint pain (40% to 45%) 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 Prevenar 20 is unlikely due to its presentation as a pre-filled syringe.

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

Mechanism of action

Prevenar 20 contains 20 pneumococcal capsular polysaccharides all conjugated to 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 an enhanced antibody response and generation of memory B cells, allowing for an anamnestic (booster) response on re-exposure to the bacterium.

Vaccination with Prevenar 20 induces serum antibody production and immunologic memory against the serotypes contained within the vaccine. Serotype-specific immune responses that correlate with individual protection against pneumococcal disease have not been clearly defined.

Clinical efficacy

No efficacy studies have been performed with Prevenar 20. Efficacy data of Prevenar and Prevenar 13 in children are summarised at the end of this section.

Immunogenicity data

Prevenar 20 clinical trials in infants, children and adolescents

Approval of Prevenar 20 for the paediatric population is based on comparing the totality of the immune responses after receiving Prevenar 20 to the immune responses after receiving Prevenar 13. The comparison, following the World Health Organization (WHO) guideline, included the percentage of participants with predefined IgG (immunoglobulin G) concentrations and IgG geometric mean concentrations (GMCs). The predefined IgG concentration corresponding to 0.35 µ g/mL in the WHO enzyme-linked immunosorbent assay (ELISA) is only applicable at the population level and cannot be used to predict individual or serotype-specific protection against IPD. Immune responses can also be determined by measuring opsonophagocytic activity (OPA), which measures functional antibody activity.

Two Phase 3 clinical trials (Study 1012, Study 1011) and one Phase 2 clinical trial (Study 1003) evaluated the immunogenicity of Prevenar 20 in a 3-dose or a 4-dose series in infants. One Phase 3 trial (Study 1014) of children 15 months to less than 18 years of age evaluated a single dose of Prevenar 20.

Immune responses following a 3-dose vaccination series

In Study 1012, 1204 infants, 2 months old and born at >36 weeks of gestation, were randomised (1:1) to receive either Prevenar 20 or Prevenar 13. The first dose was given at 42 to 112 days of age, the second dose approximately 2 months later, and the third (booster) dose at approximately 11 to 12 months of age. Participants received concomitant vaccines at these visits.

Prevenar 20 elicited immune responses, as assessed by the percentage of participants with predefined IgG concentrations, IgG GMCs and OPA GMTs for all 20 serotypes contained in the vaccine. The observed IgG GMCs and percentages of participants with predefined IgG concentrations 1 month after the third (booster) dose of Prevenar 20 were generally comparable to the Prevenar 13 group for the 13 matched serotypes and higher for the 7 additional serotypes. Predefined IgG GMR non-inferiority criteria were met for 12 of the 13 matched serotypes (except for 6B) and for all 7 additional serotypes (Table 3). IgG GMCs and percentages of participants with a predefined IgG concentration were higher after Dose 3 than before Dose 3, and also increased relative to the levels after Dose 2, indicating that a memory response was elicited by the 2 infant doses.

One month after the 2 infant doses the observed IgG GMCs were generally comparable for most serotypes to the Prevenar 13 group but the percentages of participants with predefined IgG concentrations for the 13 matched serotypes were generally lower in the Prevenar 20 group than in the Prevenar 13 group. IgG GMR non-inferiority criteria were not met for 4 of the 13 matched serotypes (6A, 6B, 9V, and 23F) (Table 4). The immune responses to the additional 7 serotypes were higher in the Prevenar 20 group than the Prevenar 13 group and the IgG GMR non-inferiority criteria were met for all. However, two of the 7 additional serotypes (10A and 12F) failed the non-inferiority criterion for the endpoint of percentages of participants with predefined IgG concentration level.

The OPA geometric mean titres (GMTs) for the 13 matched serotypes at 1 month after Dose 2 and 1 month after Dose 3 in the Prevenar 20 group were generally similar to the observed OPA GMTs in the Prevenar 13 group for most serotypes. The observed OPA GMTs were lower for serotype 6B after Dose 2 and serotype 1 after Dose 3 in the Prevenar 20 group. OPA GMTs were higher after Dose 3 than after Dose 2 for all serotypes, indicating that a memory response was elicited by the 2 infant doses. The observed OPA GMTs for the 7 additional serotypes, including serotypes 10A and 12F, both 1 month after the second dose and 1 month after the third dose were substantially higher in the Prevenar 20 group than those in the Prevenar 13 group (Table 5).

Immune responses following a 4-dose infant vaccination series

Two randomised studies (Study 1003 and Study 1011) evaluated the immunogenicity of Prevenar 20 in infants receiving 3 infant doses at 2, 4, 6 months and a toddler dose at 12 to 15 months of age.

In Study 1011, conducted in the United States and Puerto Rico, 1,991 healthy infants, 2 months (≥ 42 to ≤ 98 days) of age at the time of consent and born at > 36 weeks of gestation, were randomised (1:1) to receive either Prevenar 20 or Prevenar 13. One month after the toddler dose, predefined IgG GMR non-inferiority criteria were met for all 13 matched serotypes and for all 7 additional serotypes. One month after the third dose, the non-inferiority criteria for the percentages of participants with predefined serotype-specific IgG concentrations were met for 8 of the 13 serotypes and missed for 5 serotypes (serotypes 1, 3, 4, 9V, and 23F). Six of the 7 additional serotypes met the non-inferiority criterion; serotype 12F missed the statistical non-inferiority criterion. At both time points, the IgG GMCs and percentages of participants with predefined IgG concentrations for all 7 additional serotypes, including serotype 12F, were significantly higher than the corresponding serotype responses in the Prevenar 13 group.

OPA GMTs for the 13 matched serotypes in the Prevenar 20 group were generally numerically similar to the OPA GMTs in the Prevenar 13 group 1 month after the third infant dose and slightly lower for most serotypes after the toddler dose. There is variability of the OPA data due to small sample sizes, while interpretation of the clinical relevance of slightly lower OPA GMTs is unknown. The observed OPA GMTs were substantially higher for the 7 additional serotypes in the Prevenar 20 group than the Prevenar 13 group. Prevenar 20 immune responses also show boosting after the toddler dose, indicating that a memory response was elicited by the 3 infant doses.

Children 15 months to less than 18 years of age

In a multicentre, single-arm trial (Study 1014), participants were enrolled into the study by age group (approximately 200 participants per group) to receive a single dose of Prevenar 20 as described below.

Children 15 months to less than 5 years of age previously vaccinated with Prevenar 13

In the 15 months to less than 5 years of age groups, participants had been previously vaccinated with 3 or 4 doses of Prevenar 13. Increases in IgG concentrations from before to 1 month after Prevenar 20 were observed for all 20 vaccine serotypes (Table 6). The observed IgG GMFRs to the 7 additional serotypes ranged from 27.9 to 1847.7 in children 15 months to less than 24 months of age and from 36.6 to 796.2 in children 24 months to less than 5 years of age.

Children and adolescents 5 years to less than 18 years of age previously unvaccinated or vaccinated with Prevenar 13 or Prevenar

Participants 5 years to less than 18 years of age could be unvaccinated or previously vaccinated with Prevenar 13. Prevenar 20 elicited robust IgG and OPA immune responses to the 20 vaccine serotypes after a single dose. Increases in OPA GMTs (Table 7) were observed for all 20 vaccine serotypes with OPA GMFRs ranging from 11.5 to 499.0 for the 7 additional serotypes.

Preterm infants

No immunogenicity data is available with Prevenar 20 in preterm infants. Based on experience with Prevenar and Prevenar 13, immune responses are elicited in preterm infants, although they may be lower than in term infants. The safety and tolerability of Prevenar 20 were evaluated in Study 1013, which included 111 late preterm infants (born at 34 to less than 37 weeks of gestational age) among the total study population. Participants were randomised to receive a 4-dose series of either Prevenar 20 (N = 77) or Prevenar 13 (N = 34).

Prevenar 20 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 Prevenar 20 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 Prevenar 20 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 Prevenar 20 to Prevenar 13 and PPSV23

In a randomised, active-controlled, double-blind, non-inferiority clinical trial (Pivotal Study 1007) of Prevenar 20 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 Prevenar 20 or control. Participants 60 years of age and older were randomised in a 1:1 ratio to receive Prevenar 20 (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 Prevenar 20 (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 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 Prevenar 20 to a control vaccine for a serotype was declared if the lower bound of the 2-sided 95% CI for the GMT ratio (Prevenar 20/Prevenar 13; Prevenar 20/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 Prevenar 20 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 Prevenar 20 in the matched serotypes compared to Prevenar 13 (Table 7), however the clinical relevance of these findings is unknown.

The immune responses induced by Prevenar 20 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 8). The clinical relevance of this observation is unknown. Supportive analyses for other serotype 8 endpoints in the Prevenar 20 group showed favourable outcomes. These include a 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 Prevenar 20 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 Prevenar 20 in the younger age group versus Prevenar 20 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 (Prevenar 20 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. Prevenar 20 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 9).

While not planned as an active control for immunogenicity evaluations in the study, a post hoc descriptive analysis showed generally numerically lower OPA GMTs 1 month after Prevenar 20 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 Prevenar 20 in adults previously vaccinated with pneumococcal vaccine

A Phase 3 randomised, open-label clinical trial (Study 1006) described immune responses to Prevenar 20 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).

Prevenar 20 elicited immune responses to all 20 vaccine serotypes in participants 65 years of age and older with prior pneumococcal vaccination (Table 10). 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 SCD, HIV, and haematopoietic stem cell transplant (HSCT) participants have not been conducted with Prevenar 20.

Limited experience from clinical studies with Prevenar 13 are available in adults and children with HIV infection and HSCT, and children with SCD.

Participants who were healthy, or with stable non-immunocompromising chronic medical conditions, in all the age groups analysed had a lower immune response with Prevenar 20 compared with Prevenar 13 in spite of meeting the predefined non-inferiority margins. The clinical relevance of this observation is unknown.

Sickle cell disease (SCD)

An open-label single-arm study with 2 doses of Prevenar 13 given 6 months apart was conducted in 158 children and adolescents ≥ 6 to < 18 years of age with SCD who were previously vaccinated with one or more doses of PPSV23 at least 6 months prior to enrolment. After the first vaccination, Prevenar 13 elicited antibody levels measured by both IgG GMCs and OPA GMTs that were statistically significantly higher when compared with levels prior to vaccination. In general, antibodies declined over the 6 months between doses 1 and 2, but remained higher than before dose 1 levels for all serotypes. After the second dose, immune responses were comparable to those after the first dose for all serotypes (Table 11).

Table 11. Pneumococcal OPA GMTs at Dose 1 and Dose 2– Evaluable Immunogenicity Population

One year after the second dose, antibody levels measured by both IgG GMCs and OPA GMTs were higher than levels prior to the first dose of Prevenar 13, except the IgG GMC for serotype 3 that was similar.

HIV infection

Children and adults not previously vaccinated with a pneumococcal vaccine

In Study 6115A1-3002 (B1851021), 151 HIV-infected participants 6 to < 18 years of age and 152 participants ≥ 18 years of age (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 128 to 133 evaluable participants 6 to < 18 years of age and in 131 to 137 evaluable participants ≥ 18 years of age approximately 1 month after each dose of the vaccine. After the first dose, 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 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 (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.

Haematopoietic stem cell transplant (HSCT)

In Study 6115A1-3003 (B1851022), 61 participants 2 to < 18 years of age and 190 participants ≥ 18 years of age 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 41 to 52 evaluable participants 2 to < 18 years of age and in 127 to 159 evaluable participants ≥ 18 years of age 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 with the exception of serotype 3 in the 2 to < 18 years age group. Overall, participants 2 to < 18 years of age had generally higher serotype-specific immune responses compared with those ≥ 18 years of age.

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.

Prevenar efficacy and Prevenar 13 effectiveness in children

Invasive pneumococcal disease (IPD)

The information captured in this section comes from published literature.

The impact of Prevenar 13 on the rates of IPD in the United States was measured using an active population-based and laboratory-based surveillance system: the Active Bacterial Core surveillance (ABCs). In 2000, Prevenar (7-valent) was introduced into the routine infant immunisation programme in the USA, with a 3 dose primary series and a booster dose in the second year of life. In 2010, Prevenar 13 replaced Prevenar.

For the 2012-2013 period, there were statistically significant declines in the incidence of IPD for the Prevenar-13 unique serotypes (i.e. “ Prevenar 13 minus Prevenar” serotypes. The disease reductions were calculated using a model of observed versus expected (if Prevenar 13 had not replaced Prevenar) IPD cases with 95% Interval Estimates (IEs) and are shown in Table 12.

In all age groups, these reductions were driven principally by declines in IPD caused by serotypes 19A and 7F. There was no significant increase in disease caused by non-Prevenar 13 serotypes among children younger than 5 years and most adult age groups, except for adults 50– 64 years old where a 26% increase (95% IE 13– 44) was detected in non-Prevenar 13 type IPD during 2012– 13 compared to expected incidence, although no non-Prevenar 13 serotype predominated. However, serotype replacement may not be expected within 2 years after introduction of Prevenar 13.

The prevalence of at least one risk factor increased among children and adults with IPD after the introduction of Prevenar 13. The proportions of cases resulting in hospital admission were also higher in the period after the introduction of Prevenar 13 in both children and adults, but case-fatality rates did not change.

After the introduction of Prevenar 13, a reduction in the incidence of antibiotic-resistant IPD (vaccine serotype or non-vaccine serotype IPD) was also identified. Penicillin-non-susceptible IPD, erythromycin-non-susceptible IPD and multiply-non-susceptible IPD decreased by 78-96% among children younger than 5 years. Among adults, reductions in the incidence of penicillin-non-susceptible IPD and multiply-non-susceptible IPD were also seen. The reductions in antibiotic non-susceptible IPD were largely attributable to reductions in IPD caused by serotype 19A, the serotype associated with increased antibiotic non-susceptibility before the introduction of Prevenar 13.

In England and Wales, PPSV23 was in use for risk subjects > 2 years of age from 1992. This vaccine was also recommended for adults ≥ 80 years, ≥ 75 years and ≥ 65years of age from 2003, 2004 and 2005, respectively. Prevenar (7-valent) was first recommended for risk children < 2 years of age in 2002 and from 2005 for “ risk children” < 5 years. From 2006, Prevenar (7-valent) was introduced into the Routine Childhood Immunisation Programme with a catch-up campaign for children up to two years of age. As of April 2010 the Prevenar (7-valent) was replaced by Prevenar 13 and it simply replaced Prevenar (7-valent) at the point in the schedule that any child had reached. There was no catch-up programme.

Four years after the introduction of Prevenar (7-valent) as a two dose primary series plus booster dose in the second year of life and with a 94% vaccine uptake, a 98% (95% CI 95; 99) reduction of disease caused by the Prevenar (7-valent) vaccine serotypes was reported in children under 2 years, in England and Wales. However, reductions were accompanied by an increase in IPD from non-vaccine serotypes, such as 7F, 19A and 22F, thus diminishing the effect of Prevenar (7-valent) on overall IPD incidence.

Subsequently, four years following the switch to Prevenar 13, the additional reduction in incidence of IPD due to the 7 serotypes in Prevenar ranged from 76% (95% CI 7; 94) in children less than 2 years of age to 91% (95% CI 33; 99) in children 5-14 years of age. The serotype specific reductions for each of the 5 additional serotypes in Prevenar 13 (no cases of serotype 5 IPD were observed) by age group are shown in Table 13 and ranged from 68% (95% CI 6; 89) (serotype 3) to 100% (95% CI 62; 100) (serotype 6A) for children less than 5 years of age. Significant incidence reductions were also observed in older age groups who had not been vaccinated with Prevenar 13 (indirect effect). Overall, the reductions observed were attenuated by the increase in non-PCV13 IPD, both in adults ≥ 65 years and in children younger < 5 years - the two groups with the highest incidence of pneumococcal-attributable disease.

Otitis media (OM)

Information captured in this section has been taken from published literature.

A study was conducted one year following the introduction of Prevenar 13 in the USA. It utilised an insurance claims database of a large, nationwide managed health care plan. Enrolled children aged 6 years or younger and those with OM visits were identified (5.51 million child-years). There was a significant drop in OM visit rates that coincided with the introduction of Prevenar 13 in 2010 and the observed OM visit rates in 2010 and 2011 were lower than the projected rates based on the 2005-2009 trend (p < 0.001).

In a multicentre surveillance study of Streptococcus pneumoniae isolates from spontaneous drainage, PE tube placement, myringotomy or mastoid surgical cultures from 8 children's hospitals in the USA were obtained. In 2011, 74 of 149 (50%) isolates were Prevenar 13 plus a related serotype; in 2012 and 2013, these serotypes accounted for 47 of 116 (40.5%) and 34 of 118 (29%) of isolates, respectively. Overall, there was a reduction in the proportion of isolates included in Prevenar 13 over the 3 years following the introduction of that vaccine, including antibiotic resistant strains. Serotype 19A was the most common serotype isolated in each year. The number of serotype 19A isolates in 2013 (n = 12, 10.2% of total) decreased 76% compared with 2011 (n = 50, 33.6% of total).

In a published study performed prospectively in Israel between 2004 and 2013, the impact on OM of introduction of a 2-dose primary series of Prevenar 13 plus booster dose in the second year of life was recorded in a population-based active-surveillance system including culture results of middle ear fluid obtained by tympanocentesis. The decision to perform tympanocentesis in the presence of OM was independent of the study protocol. Overall, 6,122 OM episodes with middle ear fluid cultures were recorded in children less than 2 years of age. Declines in incidence were recorded from 2.1 to 0.1 cases per 1,000 children (96%) for the Prevenar serotypes plus serotype 6A and a decline in incidence from 0.9 to 0.1 cases per 1,000 children (85%) for the additional serotypes 1, 3, 5, 7F, and 19A in Prevenar 13. The annual overall pneumococcal incidence of OM declined from 9.6 to 2.1 cases per 1,000 children (77%) between July 2004 (prior to the introduction of Prevenar) and June 2013 (post Prevenar 13 introduction). However, the true reduction of overall OM incidences could not be studied, as simple OM can be subclinical, subject to over- and under diagnosis and, above all, not subjected to middle ear fluid culture.

In a prospective, population-based, long-term surveillance study conducted in Israel between 2004 and 2015 following the introduction of pneumococcal 7-valent conjugate vaccine and subsequently Prevenar 13, reductions of non-pneumococcal bacteria isolated from children < 3 years of age with OM were 75% for all NTHi cases, and 81% and 62% for cases of OM due to M. catarrhalis and S. pyogenes, respectively.

Pneumonia

Information captured in this section has been taken from published literature.

The effect of Prevenar 13 on admissions to hospital in the USA 2 years after its introduction in 2010 was assessed using data from a private inpatient discharge record database covering approximately 20% of inpatients in the USA. A multiple regression model was used to estimate change in admissions to hospital for all-cause pneumonia, invasive pneumococcal disease, non-invasive pneumococcal pneumonia, and empyema, and for negative controls, urinary tract infection and hospital admission for any reason. Direct cause and effect cannot be inferred from analyses of this type.

Reduction in hospital admission for all-cause pneumonia of 21% [95% CI 14-28] was reported for children aged less than 2 years and 17% [95% CI 7-27]. for those aged 2-4 years: For empyema the reduction was 50% [95% CI 22– 68] for children age < 2 years, 46% [95% CI 21-64] for children 2-4 years, and 37% [95% CI 13-54] for those aged 5-17 years. All-cause pneumonia was reduced in adults 18-39 years (12% (95% CI 6-17) but not for other adult age groups. Non-invasive pneumococcal or lobar pneumonia fell for all age groups except toddlers aged 2-4 years.

In a multicentre observational study in France between June 2009 and May 2012 comparing the periods before and after the switch from Prevenar (7-valent) to Prevenar 13, there was 16% reduction in all community acquired pneumonia (CAP) cases in emergency departments in children 1 month to 15 years of age. Reductions were 53% (p < 0.001) for CAP cases with pleural effusion and 63% (p < 0.002) for microbiologically confirmed pneumococcal CAP cases. In the second year after the introduction of Prevenar 13 the total number of CAP cases due to the 6 additional vaccine serotypes in Prevenar 13 was reduced by 74% (27 to 7 isolates).

In an ongoing surveillance system (2002 to 2013) to document the impact of Prevenar (7-valent) and subsequently Prevenar 13 on CAP in children less than 5 years in Southern Israel using a 2 dose primary series with a booster dose in the second year of life, there was a reduction of 68% (95% CI 61; 73) in outpatient visits and 32% (95% CI 22; 39) in hospitalisations for alveolar CAP (a dense opacity that may be a fluffy consolidation of a portion, whole of a lobe or of the entire lung, often containing air bronchogram and sometimes associated with pleural effusion) following the introduction of Prevenar 13 when compared to the period before the introduction of Prevenar (7-valent) was introduced.

Carriage

The information captured in this section has been taken from published literature.

A study of nasopharyngeal carriage of Streptococcus pneumoniae in predominantly black children 6-59 months of age presenting to a children's hospital emergency department in Atlanta, USA between 1 July 2010 and 30 June 2013 showed a significant reduction in carriage of Prevenar 13 serotypes and antibiotic resistant strains after the introduction of Prevenar 13. The overall proportion of children with Streptococcus pneumoniae carriage ranged from 28% to 35.4% and did not significantly change through the study period. Carriage of Prevenar 13 serotypes decreased significantly from 29% (36/124) to 3% (3/99; p < 0.0001), primarily due to a significant decrease in serotype 19A carriage from 25.8% (32/124) to 3% (3/99; p < 0.0001). The proportion of carriage isolates with nonsusceptibility to ceftriaxone declined from 22.6% to 3% and nonsusceptibility to penicillin also declined from 24% to 3%.

The proportion of pneumococcal carriage accounted for by non-PCV13 serotypes (excluding 6C) increased from 68.4% (78/114) to 96.9% (95/98; p < 0.0001). Non-PCV13 serotypes 35B, 15B/C, 11A, 21, 23B and 15A were the most commonly carried serotypes during the last 2 study periods. Carriage of serotype 35B increased during the 6 study periods from 8.9% (11/124) to 25.3% (25/99). Serotype 35B demonstrated moderate non-susceptibility to selected antibiotics.

Reduction of Antimicrobial Resistance (AMR)

The information captured in this section has been taken from published literature.

Following the introduction of Prevenar (7-valent) and subsequently Prevenar 13, a reduction in AMR has been shown as a result of direct reduction of serotypes and clones associated with AMR from the population (including 19A), reduction of transmission (herd effects), and reduction in the use of antimicrobial agents.

A post-hoc analysis of a double– blind, randomised, controlled study enrolling 1866 subjects in Israel conducted between February 2008 and September 2009, compared Prevenar (7-valent) and Prevenar 13. The reported reduction of new acquisitions of S. pneumoniae, serotypes 19A, 19F, and 6A not susceptible to either penicillin, erythromycin, clindamycin, penicillin plus erythromycin, or multiple drugs (≥ 3 antibiotics) ranged between 34% and 62% depending on serotype and antibiotic.

Data from 10 surveillance sites of the United States Centers for Disease Control and Prevention covering 31 million individuals show that from 2009 to 2013, rates of antibiotic-nonsusceptible IPD caused by serotypes included in Prevenar 13 but not in Prevenar (7-valent) decreased from 6.5 to 0.5 per 100,000 in children aged < 5 years and from 4.4 to 1.4 per 100,000 in adults aged ≥ 65 years. Antibiotic-non-susceptible IPD caused by non-Prevenar 13 serotypes increased from 41.8% (n = 1995) to 65.0% (n = 2397) (p < 0.001). Among antibiotic-non-susceptible IPD caused by non-Prevenar 13 serotypes, increases from 2009 to 2013 among children aged < 5 years (from 2.5 to 3.1 per 100,000) and among adults aged ≥ 65 years (from 6.4 to 7.3 per 100,000) were observed. In 2013, the most frequent non-vaccine serotypes among cases with antibiotic-non-susceptible IPD were 35B (16.2%), 33F (15.5%), 22F (12.3%), and 15A (11.7%). Among multidrug-non-susceptible IPD, the most frequent non-vaccine serotypes were 35B (59.9%), 15A (17.8%), 6C (5.6%), and 15C (5.6%).

Prevenar (7-valent) protective efficacy in infants and children

The efficacy of Prevenar (7-valent) was evaluated in two major trials – the Northern California Kaiser Permanente (NCKP) trial and the Finnish Otitis Media trial (FinOM). Both trials were randomised, double-blind, active-control trials in which infants were randomised to receive either Prevenar (7-valent) or control vaccine (NCKP, meningococcal serogroup C CRM-conjugate [MnCC] vaccine; FinOM, hepatitis B vaccine) in a four-dose series at 2, 4, 6, and 12-15 months of age. The various efficacy results from these trials (for invasive pneumococcal disease, pneumonia, and acute otitis media) are presented below (Table 14).

The licensing authority has deferred the obligation to submit the results of studies with Prevenar 20 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.

2 years

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 Prevenar 20 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.