1. Name Of The Medicinal Product
Prevenar 13 suspension for injection
Pneumococcal polysaccharide conjugate vaccine (13-valent, adsorbed)
2. Qualitative And Quantitative Composition
1 dose (0.5 ml) contains:
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1Conjugated to CRM197 carrier protein and adsorbed on aluminium phosphate (0.125 mg aluminium).
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Suspension for injection.
The vaccine is a homogeneous white suspension.
4. Clinical Particulars
4.1 Therapeutic Indications
Active immunisation for the prevention of invasive disease, pneumonia and acute otitis media caused by Streptococcus pneumoniae in infants and children from 6 weeks to 5 years of age.
Active immunisation for the prevention of invasive disease caused by Streptococcus pneumoniae in adults aged 50 years and older.
See sections 4.4 and 5.1 for information on protection against specific pneumococcal serotypes.
The use of Prevenar 13 should be determined on the basis of official recommendations taking into consideration the impact of invasive disease in different age groups as well as the variability of serotype epidemiology in different geographical areas.
4.2 Posology And Method Of Administration
The immunisation schedules for Prevenar 13 should be based on official recommendations.
Posology
Infants and children aged 6 weeks to 5 years
It is recommended that infants who receive a first dose of Prevenar 13 complete the vaccination course with Prevenar 13.
Infants aged 6 weeks-6 months
Three-dose primary series
The recommended immunisation series consists of four doses, each of 0.5 ml. The primary infant series consists of three doses, with the first dose usually given at 2 months of age and with an interval of at least 1 month between doses. The first dose may be given as early as six weeks of age. The fourth (booster) dose is recommended between 11 and 15 months of age.
Two-dose primary series
Alternatively, when Prevenar 13 is given as part of a routine infant immunisation programme, a series consisting of three doses, each of 0.5 ml, may be given. The first dose may be administered from the age of 2 months, with a second dose 2 months later. The third (booster) dose is recommended between 11 and 15 months of age (see section 5.1).
Unvaccinated infants and children
Infants aged 7-11 months
Two doses, each of 0.5 ml, with an interval of at least 1 month between doses. A third dose is recommended in the second year of life.
Children aged 12-23 months
Two doses, each of 0.5 ml, with an interval of at least 2 months between doses.
Children aged 2-5 years
One single dose of 0.5 ml.
Prevenar 13 vaccine schedule for infants and children previously vaccinated with Prevenar (7-valent) (Streptococcus pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F)
Prevenar 13 contains the same 7 serotypes included in Prevenar, using the same carrier protein CRM197. Infants and children who have begun immunisation with Prevenar may switch to Prevenar 13 at any point in the schedule.
Children aged 12-23 months
Children who have not received two doses of Prevenar 13 during the infant series should receive two doses of the vaccine (with an interval of at least 2 months between doses) to complete the immunisation series for the six additional serotypes. Alternatively, complete the immunisation series according to official recommendations.
Children aged 2-5 years
One single dose.
Adults aged 50 years and older
One single dose.
The need for revaccination with a subsequent dose of Prevenar 13 has not been established.
Regardless of prior pneumococcal vaccination status, if the use of 23-valent polysaccharide vaccine is considered appropriate, Prevenar 13 should be given first (see sections 4.5 and 5.1).
Method of administration
The vaccine should be given by intramuscular injection. The preferred sites are the anterolateral aspect of the thigh (vastus lateralis muscle) in infants or the deltoid muscle of the upper arm in children and adults.
4.3 Contraindications
Hypersensitivity to the active substances, to any of the excipients (see section 6.1), or to diphtheria toxoid.
As with other vaccines, the administration of Prevenar 13 should be postponed in subjects 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.
4.4 Special Warnings And Precautions For Use
Prevenar 13 must not be administered intravascularly.
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.
This vaccine should not be given as an intramuscular injection to individuals with thrombocytopaenia or any coagulation disorder that would contraindicate intramuscular injection, but may be given subcutaneously if the potential benefit clearly outweighs the risks (see section 5.1).
Prevenar 13 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. As with any vaccine, Prevenar 13 may not protect all individuals receiving the vaccine from pneumococcal disease.
Individuals with impaired immune responsiveness, whether due to the use of immuno-suppressive therapy, a genetic defect, human immunodeficiency virus (HIV) infection, or other causes, may have reduced antibody response to active immunization.
Safety and immunogenicity data for Prevenar 13 are not available for individuals in specific immuno-compromised groups (e.g., congenital or acquired splenic dysfunction, HIV infected, malignancy, haematopoietic stem cell transplant, nephrotic syndrome) and vaccination should be considered on an individual basis.
Infants and children aged 6 weeks to 5 years
In clinical studies, Prevenar 13 elicited an immune response to all thirteen serotypes included in the vaccine. The immune response for serotype 3 following the booster dose was not increased above the levels seen after the infant vaccination series; the clinical relevance of this observation regarding the induction of serotype 3 immune memory is unknown (see section 5.1).
The proportions of functional antibody responders (OPA titres
Limited data have demonstrated that Prevenar 7 valent (three-dose primary series) induces an acceptable immune response in infants with sickle cell disease with a safety profile similar to that observed in non-high-risk groups (see section 5.1).
Children younger than 2 years old should receive the appropriate-for-age Prevenar 13 vaccination series (see section 4.2). The use of pneumococcal conjugate vaccine does not replace the use of 23-valent pneumococcal polysaccharide vaccines in children Streptococcus pneumoniae. Whenever recommended, children at risk who are
The potential risk of apnoea and the need for respiratory monitoring for 48-72h should be considered when administering the primary immunisation series to very premature infants (born
For vaccine serotypes, protection against otitis media is expected to be lower than protection against invasive disease. As otitis media is caused by many organisms other than pneumococcal serotypes represented in the vaccine, protection against all otitis media is expected to be low (see section 5.1).
Antipyretic treatment should be initiated according to local treatment guidelines for children with seizure disorders or with a prior history of febrile seizures and for all children receiving Prevenar 13 simultaneously with vaccines containing whole cell pertussis.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Infants and children aged 6 weeks to 5 years
Prevenar 13 can be given with any of the following vaccine antigens, either as monovalent or combination vaccines: diphtheria, tetanus, acellular or whole cell pertussis, Haemophilus influenzae type b, inactivated poliomyelitis, hepatitis B, meningococcal serogroup C, measles, mumps, rubella and varicella. Clinical studies demonstrated that the immune responses and the safety profiles of the administered vaccines were unaffected.
In clinical studies, where there was concomitant administration of Prevenar 13 and rotavirus vaccine, no change in the safety profiles of these vaccines was observed.
Adults aged 50 years and older
Prevenar 13 may be administered concomitantly with the seasonal trivalent inactivated influenza vaccine (TIV).
In two studies conducted in adults aged 50-59 and 65 years and older, it was demonstrated that Prevenar 13 may be given concomitantly with trivalent inactivated influenza vaccine (TIV). The responses to all three TIV antigens were comparable when TIV was given alone or concomitantly with Prevenar 13.
When Prevenar 13 was given concomitantly with TIV, the immune responses to Prevenar 13 were lower compared to when Prevenar 13 was given alone. The clinical significance of this is unknown.
Concomitant use with other vaccines has not been investigated.
Different injectable vaccines should always be given at different injection sites.
Concomitant administration of Prevenar 13 and 23-valent polysaccharide vaccine has not been studied. In clinical studies when Prevenar 13 was given 1 year after 23-valent polysaccharide vaccine the immune responses were lower for all serotypes compared to when Prevenar 13 was given to subjects not previously immunized with 23-valent polysaccharide vaccine. The clinical significance of this is unknown.
4.6 Pregnancy And Lactation
Fertility and pregnancy
There are no data from the use of pneumococcal 13-valent conjugate in pregnant women.
Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).
Lactation
It is unknown whether pneumococcal 13-valent conjugate is excreted in human milk.
4.7 Effects On Ability To Drive And Use Machines
Not relevant.
4.8 Undesirable Effects
Adverse reactions reported in clinical studies or from the post-marketing experience 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 (
Infants and children aged 6 weeks to 5 years
The safety of the vaccine was assessed in controlled clinical studies where 14,267 doses were given to 4,429 healthy infants from 6 weeks of age at first vaccination and 11-16 months of age at booster dose. In all infant studies, Prevenar 13 was co-administered with routine paediatric vaccines (see section 4.5).
Safety in 354 previously unvaccinated children (7 months to 5 years of age) was also assessed.
The most commonly reported adverse reactions were injection-site reactions, fever, irritability, decreased appetite, and increased and/or decreased sleep.
An increase in injection site reactions was reported in children older than 12 months compared to rates observed in infants during the primary series with Prevenar 13.
Adverse reactions from clinical studies
In clinical studies, the safety profile of Prevenar 13 was similar to Prevenar. The following frequencies are based on adverse reactions assessed as related to vaccination in Prevenar 13 clinical studies:
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Adverse reactions from Prevenar postmarketing experience
Although the following adverse drug reactions were not observed in the Prevenar 13 clinical studies in infants and children, the following are considered adverse drug reactions for Prevenar and are considered adverse drug reactions for Prevenar 13 as well. These frequencies are based on spontaneous reporting rates for Prevenar.
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Additional information in special populations:
Apnoea in very premature infants (
Adults aged 50 years and older
Safety was assessed in 6 clinical studies including 6,198 adults ranging in age from 50 to 95 years. Prevenar 13 was administered to 5,667 adults; 2,616 (46.2 %) aged 50 to 64 years, and 3,051 (53.8 %) aged 65 years and older. Of the Prevenar 13 recipients 1,916 adults were previously vaccinated with the 23-valent pneumococcal polysaccharide vaccine at least 3 years prior to study vaccination, and 3,751 were 23-valent polysaccharide vaccine unvaccinated. Subjects older than 65 years of age reported fewer adverse reactions than younger adults, regardless of prior pneumococcal vaccination status. Overall, the frequency categories were similar for both age groups.
Adverse reactions from clinical studies
Local reactions and systemic events were solicited daily for 14 days after each vaccination in all the clinical studies. The following frequencies are based on adverse reactions assessed as related to vaccination with Prevenar 13 in adults:
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Overall, no significant differences in frequencies of adverse reactions were seen when Prevenar 13 was given to adults previously vaccinated with the pneumococcal polysaccharide vaccine.
Higher frequency in some solicited systemic reactions was observed when Prevenar 13 was administered concomitantly with trivalent inactivated influenza vaccine (TIV) compared to TIV given alone (headache, chills, rash, decreased appetite, arthralgia, and myalgia) or Prevenar 13 given alone (headache, fatigue, chills, decreased appetite, and arthralgia).
4.9 Overdose
Overdose with Prevenar 13 is unlikely due to its presentation as a pre-filled syringe. However, in infants and children there have been reports of overdose with Prevenar 13 defined as subsequent doses administered closer than recommended to the previous dose. In general, adverse events reported with overdose are consistent with those that have been reported with doses given in the recommended paediatric schedules of Prevenar 13.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: vaccines, pneumococcal vaccines; ATC code: J07AL02
Mechanism of action
Prevenar 13 contains the 7 pneumococcal capsular polysaccharides that are in Prevenar (4, 6B, 9V, 14, 18C, 19F, 23F) plus 6 additional polysaccharides (1, 3, 5, 6A, 7F, 19A) all conjugated to CRM197 carrier protein.
Burden of disease in infants and children aged 6 weeks to 5 years
Based on serotype surveillance in Europe performed before the introduction of Prevenar, Prevenar 13 is estimated to cover 73-100 % (depending on the country) of serotypes causing invasive pneumococcal disease (IPD) in children less than 5 years of age. In this age group, serotypes 1, 3, 5, 6A, 7F, and 19A account for 15.6 % to 59.7 % of invasive disease, depending on the country, the time period studied, and the use of Prevenar.
Acute otitis media (AOM) is a common childhood disease with different aetiologies. Bacteria can be responsible for 60-70 % of clinical episodes of AOM. S. pneumoniae is one of the most common causes of bacterial AOM worldwide.
Prevenar 13 is estimated to cover over 90 % of serotypes causing antibiotic-resistant IPD.
Burden of disease in adults aged 50 years and older
The incidence of invasive pneumococcal disease (IPD) in adults increases with age from 50 years, risk factors (smoking status or alcohol use), and underlying co-morbidities (chronic cardiovascular disease, chronic pulmonary disease including asthma, renal disorders, diabetes mellitus, and chronic liver disease including alcoholic liver disease). Bacteraemic pneumonia, bacteraemia without a focus, and meningitis are the most common manifestations of IPD in adults aged 50 years or older. Based on surveillance data, the pneumococcal serotypes in Prevenar 13 may be responsible for at least 50 – 76% (depending on country) of IPD in adults aged over 50 years. Approximately 80% of IPD in adults is bacteraemic pneumonia.
Prevenar 13 immunogenicity clinical studies in infants and children
The protective efficacy of Prevenar 13 against IPD has not been studied. As recommended by the World Health Organization (WHO) the assessment of potential efficacy against IPD in infants and young children has been based on a comparison of immune responses to the seven common serotypes shared between Prevenar 13 and Prevenar, for which protective efficacy has been proven. Immune responses to the additional 6 serotypes were also measured.
Immune responses following a three-dose primary infant series
Clinical studies have been conducted in a number of European countries and the US using a range of vaccination schedules, including two randomised non-inferiority studies (Germany using a 2, 3, 4 month primary series [006] and US using a 2, 4, 6 month primary series [004]). In these two studies pneumococcal immune responses were compared using a set of non-inferiority criteria including the percentage of subjects with serum anti-polysaccharide serotype specific IgG
The non-inferiority immune response comparisons for study 006, based on the proportion of infants achieving anti-polysaccharide IgG concentrations
Non-inferiority was met for the 6 additional serotypes based on the proportion of infants achieving antibody concentrations
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Prevenar 13 elicited functional antibodies to all 13 vaccine serotypes in studies 004 and 006. For the 7 common serotypes there were no differences between groups in the proportion of subjects with OPA titres
For each of the 6 additional serotypes, Prevenar 13 elicited OPA titres
Immune responses following a two-dose primary infant series
The immunogenicity after two doses in infants has been documented in four studies. The proportion of infants achieving a pneumococcal anti-capsular polysaccharide IgG concentration
Booster responses following two-dose and three-dose primary infant series
Following the booster dose, antibody concentrations increased from the pre-booster level for all 13 serotypes. Post-booster antibody concentrations were higher for 12 serotypes than those achieved after the infant primary series. These observations are consistent with adequate priming (the induction of immunologic memory). The immune response for serotype 3 following the booster dose was not increased above the levels seen after the infant vaccination series; the clinical relevance of this observation regarding the induction of serotype 3 immune memory is unknown.
Antibody responses to booster doses following two-dose or three-dose infant primary series were comparable for all 13 vaccine serotypes.
For children aged from 7 months to 5 years, age appropriate catch-up immunisation schedules (as described in section 4.2) result in levels of anti-capsular polysaccharide IgG antibody responses to each of the 13 serotypes that are at least comparable to those of a three-dose primary series in infants.
Long-term persistence of antibodies has not been investigated after administration of Prevenar 13 as either a primary series in infants plus booster or after administration of a single priming dose in older children. Since the introduction of 7-valent Prevenar in 2000, pneumococcal disease surveillance data have not shown that the immunity elicited by Prevenar in infancy have waned over time.
Immune responses after subcutaneous administration
Subcutaneous administration of Prevenar 13 was evaluated in a non-comparative study in 185 healthy Japanese infants and children who received 4 doses at 2, 4, 6 and 12-15 months of age. The study demonstrated that safety and immunogenicity were generally comparable with observations made in studies of intramuscular administration.
The European Medicines Agency has deferred the obligation to submit the results of studies with Prevenar 13 in one or more subsets of the paediatric population in Pneumococcal disease (see section 4.2 for information on paediatric use).
Prevenar (7-valent vaccine) protective efficacy in infants and children
The efficacy of 7-valent Prevenar was evaluated in two major studies – the Northern California Kaiser Permanente (NCKP) study and the Finnish Otitis Media (FinOM) study. Both studies were randomised, double-blind, active-control studies in which infants were randomised to receive either Prevenar 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 efficacy results from these studies (for invasive pneumococcal disease, pneumonia, and acute otitis media) are presented below (Table 2).
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Prevenar (7-valent) effectiveness
The effectiveness (both direct and indirect effect) of 7-valent Prevenar against pneumococcal disease has been evaluated in both three-dose and two-dose primary infant series immunisation programmes, each with booster doses (Table 3). Following the widespread use of Prevenar, the incidence of IPD has been consistently and substantially reduced. An increase in the incidence of IPD cases caused by serotypes not contained in Prevenar, such as 1, 7F and 19A, has been reported in some countries. Surveillance will continue with Prevenar 13, and as countries update their surveillance data, information in this table may change.
Using the screening method, serotype specific effectiveness estimates for 2 doses under the age of 1 year in the UK were 66 % (-29, 91 %) and 100 % (25, 100 %) for serotype 6B and 23F, respectively.
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