Generic Name: Pneumococcal 13-valent Conjugate Vaccine ‘Trade Name: Prevenar 1 (CDS Effective Date: June 01, 2013 Supersedes: NIA ‘Approved by BPOM: PT. PFIZER INDONESIA. Local Product Document Generic Name: Pneumococcal 13-valent Conjugate Vaccine ‘Trade Name: Prevenar 13™ CDS Effective Date: June 01, 2013 Supersedes: N/A Prevenar 13™ Pneumococcal 13-valent Conjugate Vaccine NAME OF THE MEDICINAL PRODUCT. Prevenar 13 suspension for injection Pneumococcal polysaccharide conjugated vaccine, (13-valent, adsorbed) QUALITATIVE AND QUANTITATIVE COMPOSITION I dose (0.5 mL. contains: 2.2 1g of saccharide for serotypes 1, 3, 4,5, 6A, 7F, 9V, 14, 18C, 19A, 19F and 23F 4.4 ug of saccharide for serotype 6B Conjugated to CRM197 carrier protein and adsorbed on aluminium phosphate (0.125 mg aluminium). PHARMACEUTICAL FORM Suspension for injection, The vaccine is a homogeneous white suspension. CLINICAL PARTICULARS. Therapeutic Indications Children 6 weeks to 5 vears of age Active immunisation for the prevention of invasive disease, pneumonia and acute otitis media caused by ‘Streptococeus pneumoniae in infants and children from 6 weeks to 5 years of age (see sections Special ‘Warnings and Precautions for Use and Pharmacodynamic Properties for information on protection against specific pneumococcal serotypes). Adults 50 years of age and older Prevenar 13 is indicated for active immunization for prevention of pneumococcal disease (including pneumonia and invasive disease) in adults 50 years of age and older caused by Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, I8C, 19A, 19F and 23P. ‘This indication is based on immune responses elicited by Prevenar 13, and there have been no controlled trials in adults demonstrating a decrease in invasive pneumococcal disease or pneumococcal pneumonia after vaccination with Prevenar 13. 2018-0045724 Page 1 of 19Generic Name: Pneumocoecal 13-valent Conjugate Vaccine “Trade Name: Prevenar 13° (CDS Effective Date: Jane 01, 2013 Supersedes: N/A “Approved by BPOM: ‘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. Posology and Method of Administration Posology For intramuscular use only. ‘The dose is 0.5 mL. given intramuscularly, with care to avoid injection into near nerves and blood vessel. ‘The vaceine should not be injected in the gluteal area. Do not administer Prevenar 13 intravascularly. Children 6 weeks to 5 years of age ‘The immunisation schedules for Prevenar 13 should be based on official recommendations. Itis 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 Pharmacodynamic Properties). Unvaccinated Infants and Children =7 Months of Age 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 CRMo7. Infants and children who have begun immunisation with Prevenar may switch to Prevenar 13 at any point in the schedule. 2018-0045724 Page 2 of 19Generic Name: Pneumococcal 13-valent Conjugate Vaccine Trade Name: Prevenar 13°™ CCDS Effective Date: June 01,2013 Supersedes: NVA “Approved by BPOM: ‘Switch Vaccination Table Three-dose primary series | Booster Doses (1224 ee months) Ww Ww Ww {pv | BV “|v | 3v_ Jv 5 a =] “Two-dose primary series | Booster Doses (12-24 months) Ww W 1BV BY 7 [13 BV 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. Children aged 2 - 5 years ‘One single dose. Adults 50 Years of Age and Older Prevenar 13 is to be administered as a single dose to adults 50 years and older including those previously vaccinated with a pneumococcal polysaccharide vaccine. ‘The need for re-vaccination with a subsequent dose of Prevenar 13 has not been established. For specific guidelines, please refer to local recommendation. ‘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 young children, Contraindications Hypersensitivity to the active substances, to any of the excipients, 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 ofa minor infection, such as a cold, should not result in the deferral of vaccination. Special Warnings and Precautions for Use 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 vaceine should not be given to individuals with thrombocytopenia or any coagulation disorder that would contraindicate intramuscular injection or to those receiving anticoagulant therapy, unless the potential benefit clearly outweighs the risk of administration 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. 2018-0045724 Page 3 of 19Generic Name: Pneumococcal 13-valent Conjugate Vaccine ‘Trade Name: Prevenar 13" CDS Effective Date: June 01,2013, Supersedes: N/A ‘Approved by BPOM: 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 Pharmacodynamic Properties). The proportions of functional antibody responders (OPA titres >1:8) to serotypes 1, 3 and 5 were high. However, the OPA geometric mean titres were lower than those against each of the remaining additional vaccine serotypes; the clinical relevance of this observation for protective efficacy is unknown (see section Pharmacodynamic Properties). Individuals with impaired immune responsiveness, whether due to the use of immunosuppressive therapy, a ‘genetic defect, HIV infection, or other causes, may have reduced antibody response to active immunisation. individuals with another congenital or acquired splenic dysfunction, HIV infected, malignancy, hematopoetic stem, nephrotic syndrome). Vaccination in high-risk groups should be considered on an individual basis. Specific data are not yet available for Prevenar 13. Children younger than 2 years old should receive the appropriate-for-age Prevenar 13 vaccination series (see section Posology and Method of Administration). The use of pneumococcal conjugate vaccine does not replace the use of 23-valent pneumococcal polysaccharide vaccines( PPSV23) in children >24 months of age with conditions (such as sickle cell disease, asplenia, HIV infection, chronic illness, or those who are immunocompromised) placing them at higher risk for invasive disease due to Streptococcus pneumoniae. ‘Whenever recommended, children at risk who are >24 months of age and already primed with Prevenar 13 should receive 23-valent pneumococcal polysaccharide vaccine. The interval between the 13-valent pneumococcal conjugate vaccine (Prevenar 13) and the 23-valent pneumococcal polysaccharide vaccine should not be less than 8 weeks. There are no data available to indicate whether the administration of 23- valent pneumococcal polysaccharide vaccine to unprimed children or to children primed with Prevenar 13 might result in hyporesponsiveness to further doses of Prevenar 13. ‘The potential risk of apnoea and the need for respiratory monitoring for 48 72 h should be considered when administering the primary immunisation series to very premature infants (born <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. 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 Pharmacodynamic Properties). Antipyretic treatment should be initiated according to local treatment guidelines for children with seizure disorders or with a prior history of febrile seizures and forall children receiving Prevenar 13 simultaneously with vaccines containing whole cell pertussis. 2018-0045724 Page 4 of 19Generic Name: Pneumocogeal 13-valent Conjugate Vaccine ‘Trade Name: Prevenar 13" CDS Bifective Date: Sune 01,2013 Supersedes: A “Approved by BPOM: Use in Specific Population Pedi ic Use Safety and effectiveness of Prevenar 13 in children below the age of 6 weeks or on or after the 6* birthday have not been established. Prevenar 13 is not approved for use in children in these age groups. Immune responses elicited by Prevenar 13 among infants born prematurely have not been specifically studied. Geri Prevenar 13 has been shown to be safe and immunogenic in the geriatric population. Of the 5,667 adults enrolled in the 6 studies of the clinical development program who received Prevenar 13 alone, 31.5% were 65 to 74 years of age, while 22.3% were 75 years of age and over. No clinically significant differences in safety or immunogenicity were observed between 65 to 74 year old individuals and greater than 75 year old individuals. Interaction with Other Medicinal Products and Other Forms of Interaction Children 6 weeks to 5 vears of age 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 trials, where there was concomitant administration of Prevenar 13 and rotavirus vacci change in the safety profiles of these vaccines was observed. Different injectable vaccines should always be given at different injection sites. Adults aged 50 vears and older In adults, Prevenar 13 was administered concomitantly with TIV (Trivalent influenza vaccine). When Prevenar 13 is administered at the same time as another injectable vaccine(s), the vaccines should always be administered with different syringes and given at different injection sites. Do not mix Prevenar 13 with other vaccines/products in the same syringe. Undesirable Effects Children 6 weeks to 5 years of age ‘The safety of the vaccine was assessed in controlled clinical trials 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 Interaction with Other Medicinal Products and Other Forms of Interaction). 2018-0045724 Page 5 of 19Generic Name: Paeumococeal 13-valent Conjugate Vaccine Trade Name: Prevenar 13°" CDS Effective Date: June 01,2013 Supersedes: N/A Approved by BPOM: 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 reaction reported in clinical studies or from the post-marketing experience are listed in the following table per body system and per frequency, and this is forall age groups. Adults 50 vears of age and older ‘The safety of Prevenar 13 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 adults were aged 50 to 64 years and 3,051 adults were 65 years and older. Of the Prevenar 13 recipients 1,916 adults were previously vaccinated with PPSV23 at least 3 years prior, and 3,751 adults were PPSV23 unvaccinated. Frequencies shown below are for adults aged 50 to 64 years of age, and 65 and older. Subjects older than 65 years of age reported fewer events than younger adults, regardless of prior immunization status. Overal, the frequency categories were similar for both age groups. ‘The frequency is defined as follows: very common: >1/10, common: >1/100 and <1/10, uncommon: 21/1,000 and <1/100, rare: >1/10,000 and <1/1,000, very rare: <1/10,000. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Adverse Reactions from Clinical Trials Children 6 weeks to 5 years of age 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: Immune system disorders Rare : Hypersensitivity reaction including face oedema, dyspnoea, bronchospasm ‘Nervous system disorders Very common : Drowsiness/increased sleep; restless sleep/decreased sleep Uncommon: Seizure (including febrile convulsions) Rare : Hypotonic-hyporesponsive episode Gastrointestinal disorders Very common : Decreased appetite Common —_: Vomiting; diarrhoea ‘Skin and subcutaneous tissue disorders Common: Rash Uncommon: Urticaria or urticaria-like rash Rare Rash; urticaria or urticaria-like rash 2018-0045724 Page 6 of 19Generic Name: Pneumococcal 13-valent Conjugate Vaccine Trade Name: Prevenar 13" (CDS Effective Date: June 01, 2013, ‘Supersedes: N/A. “Approved by BPOM: idministr conditions Very common : Pyrexia; irritability; any injection-site erythema, induration/swelling or pain/tendemess; somnolence; poor quality sleep; Injection-site erythema or induration/swelling 2.5 cm 7.0 em (after the booster dose and in older children [age 2 to 5 years}) Common _: Pyrexia >39°C; injection-site pain/tendemess; interfering with movement; injection-site erythema or induration/swelling 2.5 em ~ 7.0 em (after infant series) Uncommon _: Injection-site erythema, or induration/swelling > 7.0 em; Crying Adults aged 50 years of age and older Metabolism and nutrition disorders Very common + Decrease appetite Nervous system di Very common : Headaches Gastrointestinal disorders Very common. : Diarrhea Common Vomiting Uncommon: Nausea Immune system disorders Uncommon: Hypersensi ity reaction including face edema, dyspnea, bronchospasm Skin and subcutaneous tissue Very common: Rash isorders Musculoskeletal and connective tissue disorders ‘Very common : Generalized new/aggravated joint pain; generalized new/aggravated muscle pain General disorders and administration site conditions ‘Very common : Chills; fatigue; injection-site erythema; injection-site induration/swelling; injection-site pairvtenderness; limitation of arm movement Common Fever Uncommon _: Lymphadenopathy localized to the region of injection site Overall, no significant differences in frequencies of adverse reactions were noted if Prevenar 13 was given to adults pre-vaccinated with PPSV23 adults or PPSV23 unvaccinated, Frequency categories for all adverse reactions of adults aged 50 to 60 years and adults 265 years of age were similar. Solicited Adverse Reactions in Adult Clinical Studies of Concomitant Administration of Prevenar 13 and mw The safety of concomitant administration of Prevenar 13 with TIV was assessed in 2 studies in PPSV23 unvaccinated adults. Frequencies of local Prevenar 13 was admi ictions in adults aged 50-59 years and in adults aged >65 years were similar after tered with TIV compared to Prevenar 13 administered alone. 2018-0045724 Page 7 of 19Generic Name: Pneumocoeeal 13-valent Conjugate Vaccine ‘Trade Name: Prevenar 13" CDS Effective Date: Sune 01,2013 Supersedes: NAA Approved by BPOM. Higher frequency in some solicited systemic reactions was observed when Prevenar 13 administered ‘concomitantly with TIV compared to TIV given alone (headache, chills, rash, decreased appetite, muscle and joint pain) or Prevenar 13 given alone (headache, fatigue, chills, decreased appetite, and joint pain). Adverse Reactions from Prevenar Post-marketing Experience Children 6 weeks to $ vears of age Although the following adverse drug reactions were not observed in the Prevenar 13 clinical studies, 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. Bl atic system disorders Very rare Lymphadenopathy (localised to the region of the injection site) Immune system disorders Rare + Anaphylactic/anaphylactoid reaction including shock; Angioedema ‘Skin and subcutaneous tissue disorders Very rare srythema multiforme General disorders and administration site conditions Rare Injection-site urticaria; injection-site dermatitis; injection-site pruritus; flushing, ‘Additional information in special populations: ‘Apnoea in very premature infants (<28 weeks of gestation) (see section Special War for Use). igs and Precautions Overdose Overdose with Prevenar 13 is unlikely due to its presentation as a pre-filled syringe. However, 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 schedules of Prevenar 13. PHARMACOLOGICAL PROPERTIES Pharmacodynamic Properties Pharmacotherapeutic group: pneumococcal vaccines; ATC code: JO7AL02 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, Children 6 weeks to 5 vears of age Based on serotype surveillance in Europe performed before the introduction of Prevenat, 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. 2018-0045724 Page 8 of 19Generie Name: Preumocoocal 13-valent Conjugate Vaccine ‘Trade Name: Prevenar 13" CDS Ffective Date: Sune 01,2013 Supersedes: N/A Approved by BPOM: account for 15.6% to 59.7% of invasive disease, depending on the country, the use of Prevenar. period studied, and the 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. Prevenar 13 Immunogenicity Clinical Studies ‘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 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 Followi 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 20.35 g/ml one month after the primary series and the comparison of IgG geometric mean concentrations (ELISA GMCs); in addition, functional antibody titres (OPA) between subjects receiving Prevenar 13 and Prevenar were compared. For the six additional serotypes, these values were compared with the lowest response among all of the seven common serotypes in the Prevenar recipients. ‘The non-inferiority immune response comparisons for study 006, based on the proportion of infants achieving anti-polysaccharide IgG concentrations 20.35 jg/mL, are shown in Table 1. Results for study 004 were similar. Prevenar 13 non-inferiority (lower bound of the 95% CI for the difference in percentage of responders at 0.35 jig/ml between groups was >-10%) was demonstrated for all 7 common serotypes, ‘except for serotype 6B in study 006 and serotypes 6B and 9V in study 004, which missed by a small margin. All seven common serotypes met pre-defined non-inferiority criteria for IgG ELISA GMCs. Prevenar 13 elicited comparable, although slightly lower, antibody levels than Prevenar for the 7 common serotypes. The clinical relevance of these differences is not known. Non-inferiority was met for the 6 additional serotypes based on the proportion of infants achieving antibody concentrations 20.35 ug/ml. and comparison of IgG ELISA GMCs in study 006 and was met for 5 out of the 6 serotypes, with the exception of serotype 3 for study 004. For serotype 3, the percentage of Prevenar 13 recipients with serum IgG 20.35 g/mL. were 98.2 % (study 006) and 63.5 % (study 004). Table 1: Comparison of the proportion of subjects achieving a pneumococcal anti-polysaccharide IgG antibody concentration >0.35 jsp/mL. after dose 3 of the infant series ~ study 006 Prevenar 13 “Tevalent Prevenar Serotypes % % Difference (N=282-285) (N=277-279) (05% CD, — “valent Prevenar serotypes 4 982 — 98.2 0.0 -2.5,2.6) 6B 775 87.1 6 (16.0, 3.3) OV, 98.6 96.4 2.2 (0.4, 5.2) 14 98.9 975 150.9, 4.1) isc |__97.2 98.6 =14 C42, 1.2) 2018-0045724 Page 9 of 19Generic Name: Pneumococeal 13-valent Conjugate Vaccine ‘Trade Name: Prevenae 13" (CDS Effective Date: June 01,2013, Supersedes: N/A “Approved by BPOM: Prevenar 15 T-valent Prevenar % % Serotypes | (y.-282-285) (N=277.279) 358 36.0) 0338.33) #87 5 018 (600,45) ‘Additonal serotypes in Pre 361 a1" 31 45,139) 98.2 7.1 11.2 (70, 15.8) 33.0 a7 5908, 11.1) 91.9 #71 [= 48 (03, 10.1) 8s 87.1 11.5 (74, 16.1) 19a 99.3 71 12283, 168) Th rpm even wi wn pat esis as GB in gy OG. 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 21:8. For each of the seven common serotypes, >96% and >90% of the Prevenar 13 recipients reached an OPA titre 21:8 one month after the primary series in studies 006 and 004, respectively. For each of the 6 additional serotypes, Prevenar 13 elicited OPA titres >1:8 in 91.4% to 100% of vaccines cone month after the primary series in studies 004/006. The functional antibody (OPA) geometric mean titres for serotypes 1, 3 and 5 were lower than the titres for each of the other additional serotypes; the clinical relevance of this observation for protective efficacy is unknown, Immune Responses Following a Two-Dose Primary 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 >0.35 g/mL one month after the second dose ranged from 79.6% to 98.5% across 11 of the 13 vaccine serotypes. Smaller proportions of infants achieved this antibody concentration threshold for serotype 6B (27.9% to 57.3%) and 23F (55.8% to 68.1%) for all studies using a 2, 4 month regimen, compared to 58.4% for serotype 6B and (68.6% for 23F fora study using a 3, 5 month regimen. After the booster dose, all vaccine serotypes including 6B and 23F had immune responses consistent with adequate priming with a two-dose primary series. In a UK study, the functional antibody (OPA) responses were comparable for all serotypes including, ‘6B and 23F in the Prevenar and Prevenar 13 arms after the primary series at two and four months of age and after the booster dose at 12 months of age. For Prevenar 13 recipients, the proportion of responders with an OPA titre 21:8 was at least 87% following the infant series, and at least 93% following the booster dose. ‘The OPA geometric mean titres for serotypes 1, 3 and 5 were lower than the titres for each of the other additional serotypes; the clinical relevance of this observation is unknown, -r Responses Following Two-Dose and Thr imary 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 Posology and Method of Administration) result in levels of anti-capsular polysaccharide IgG 2018-0045724 Page 10 of 19Generic Name: Pneumococcal 13-valent Conjugate Vaccine “Trade Name: Prevenar 13" CDS Bifective Date: June 01,2013 Supersedes: NAA Approved by BPOM: 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. Prevenar (7-valent vaccine) Protective Efficacy The efficacy of 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). Table 2: Summary of Efficacy of 7-valent Prevenar Test N VE [95% NCKP: Vaccine-serotype IPD” 30,258 97% | 85, 100 NCKP: Clinical pneumonia with abnormal chest X-ra 23,746 | 35% 4,56 ‘NCKP: Acute Otitis Media (AOMY 23,746 Total episodes % 4,10 | Recurrent AOM (3 episodes in 6 months, or 4 episodes in 9% 3,15 | Lyear) Recurrent AOM (5 episodes in 6 months, or 6 episodes in 23% 7,36 1 year) ‘Tympanostomy tube placement | 20%. 2,38 FinOM: AOM 1,662 Total episodes &% “4,16 Al pneumococcal AOM 34% | 21,45 ‘Vaceine-serotype AOM. 5™% | 44,67 Pe protocol 2 Vaccine efficacy oetobe 195 1 April 2, 1999 Geto 195 1 Apri 30, 1998 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 I year in the UK were 66% (-29, 919%) and 100% (25, 100%) for serotype 6B and 23F, respectively. 2018-0045724 Page 11 of 19Generic Name: Pneumocogeal 13-valent Conjugate Vaccine “Trade Name: Prevenar 13" (CDS Effective Date: une 01, 2013 Supersedes: N/A “Approved by BPOM: Table 3. Summary of effectiveness of 7-valent Prevenar for invasive pneumococcal disease ‘Country Recommended schedule | Disease reduction, % 95% CL (year of introduction) UK (England & Wales)" | 2,4, ¥ 13 months Vaccine serotype: 0, 95% (2006) Two doses under age 1 _ 85% USA @000) 246, 412-15 Children 70 years (61 1SA1-3005). One study (6115A1-3000) in PPSV23 pre- vaccinated adults collected safety data only. Two studies (6115A1-3001 and 6115A1-3008) assessed the concomitant administration of Prevenar 13 with seasonal TIV. Clinical trials conducted in adults not previously vaccinated with PPSV23 In an active-controlled modified' double-blind clinical trial (6115A1-004) of Prevenar 13 in the US, PPSV23-unvaccinated adults aged 60 to 64 years were randomly assigned (1:1) to receive Prevenar 13 or PPSV23. In addition, adults aged 50 to 59 years were enrolled and received one dose of Prevenar 13 (open- label). ‘The OPA antibody responses elicited by Prevenar 13 were non-inferior to those elicited by PPSV23 for the 12 serotypes in common to both vaccines. In addition, 8 of the serotypes in common exhibited a statistically significantly greater immune response after Prevenar 13 compared with after PPSV23. For serotype 6A, which is unique to Prevenar 13, the proportions of adults with a 4-fold increase after Prevenar 13 (88.5%) were significantly greater than after PPSV23 (39.2%) in PPSV23-unvaccinated adults aged 60-64 years. OPA GMT for serotype 6A were statistically significantly greater after Prevenar 13 compared with after PPSV23. ‘The OPA responses elicited by Prevenar 13 in adults aged 50-59 years were non-inferior to the Prevenar 13 responses in adults aged 60-64 years for all 13 serotypes. In addition, 9 of the 13 serotypes exhibited a " Modified double-blind means that the ste staff dispensing and administering the vaccine were unblinded, but all other study personnel including the principal investigator and subject were blinded 2018-0045724 Page 13 of 19Generic Name: Pneumocogeal 13-valent Conjugate Vaccine ‘Trade Name: Prevenar 13" CDS Effective Date: Sune 01,2013 Supersedes: N/A Approved by BPOM: statistically significantly greater immune response in adults aged 50-59 years compared with adults aged 60- 64 years, ‘This clinical trial demonstrated that the immune responses elicited by Prevenar 13 are non-inferior and for most serotype statistically greater than PPSV23. In addition, the immune responses in adults aged 50 ~ 59 years were non-inferior and for most serotypes statistically significantly greater than those observed in adults aged 60 — 64 years. In adults aged 60-64 years, antibody levels one year after vaccination were greater after Prevenar 13 compared to antibody levels alter PPSV23 for 7 of 12 serotypes in common. In adults aged 50-59 years, antibody levels one year after vaccination with Prevenar 13 were greater for 12 of 13 serotypes compared to vaccination with Prevenar 13 in 60-64 year olds. [Table 4: OPA GMTs in PPSV23 Unvaccinated Adults Aged 50-59 Years Given Prevenar 13; and in Adults Aged] _ 60-64 Years given Prevenar 13 or PPSV23"" Prevenar 13. Prevenar13 | _PPSV23_| —Prevenar 13, | Prevenar 13 Relative 50-59 Years (60-64 Years | 60-64 Years| 50-59 Relative to to PPSV23, __|__N=350.384 1N=359-404 | 1N=367-402 | __60-64 Years 60-64 Years Serotype GMT GMT. GMT [GMR | 5% C)_[GMR | 05% CD 1 200 146 104 14 [ (1.08, 1.73) [14 | (1.10, 1.78) 3 or 93. 85 1.0 | O81, 1.19) {1.1 | (0.90, 132) 4 2833 2062 1295 [14 | .07,1.77) | 16 | -.19, 2.13) 3 269 199 162, 14 [.01,.1.80) [1.2 | (0.93, 1.62) [6a 4328 2593 213 17 [ (30,213) | 12.1 | (8.63, 17.08) B. 3212 1984 788 16 [(.24,2.12) [2.5 | (1.82, 3.48) _F 1520 1120 405. 14 (.03,1.79) | 2.8 | (0.98,3.87) ov 1726 164 407 15_[G.11, 1.98) | 2.9 | (2.00, 4.08) 14 957 612 692 1.6 [.16,2.12) | 0.9 | (0.64, 121) 18C 1939 1726 925 11 _| 86, 1.47) [19 | (39.251) [19a 956 682 382 14 [16 1.69) | 1.9 | 56, 2.41) 19F 599 S17 539 1.2 [-(0:87, 154) | 1.0” | (0.72, 1.28) 23F 494 375 R 13 [94,184 | $2 | G.67,733) IMT, Geomets Nan Te IMR, Goometis Mean Rai, 6A iba serotype ungue to Prevenar 13 but not contained in PPSV23. ‘Non-infrrity was defined asthe lowe imi ofthe 2skded 95% C for GM geste than 0.5. Staisticallysignicanly greater responses were lefined asthe lower bound of the 2-sided 95% CI forthe GMR peste tha [Espo SA whch nic ever 3 etsy sien peer pose ws ned ath lve bond ofthe 2 95% Ct Clinical trials conducted in adults previously vaccinated with PPSV23 (pre-vaccinated) In a phase 3 active-controlled, modified? double-blind clinical trial (61151-3005) of Prevenar 13 in the US and Sweden PPSV23-prevaccinated adults aged >70 years who had received one dose of PPSV23 >S years prior were randomly assigned (1:1) to receive either Prevenar 13 or PPSV23. The OPA antibody responses elicited by Prevenar 13 were non-inferior for the 12 serotypes in common to those elicited by PPSV23 when the vaccines were administered at a minimum of 5 years after PPSV23. In addition, 10 of the serotypes in common exhibited a statistically significantly greater immune response after Prevenar 13 compared with after PPSV23. For serotype 6A, which is unique to Prevenar 13, proportions of adults with a 4-fold increase after Prevenar 13 (71.1%) was significantly greater than after PPSV23 (27.3%) in PPSV23-pre-vaccinated adults aged ? Modified double-blind means thatthe site staff dispensing and ad istering the vaccine were unblinded, but al other study personnel including the principal investigator and subject were blinded 20180045724 Page 14 of 19Generic Name: Pneumocogeal 13-valent Conjugate Vaccine ‘Trade Name: Prevenar 13"™ (CDS Effective Date: Jane 01,2013 Supersedes: N/A “Approved by BPOM: 210 years. OPA GMTs for serotype 6A were statistically significantly greater after Prevenar 13 compared with after PPSV23 “Table 5: OPA GMTs in PPSV23 previously va iated Adults Aged 270 Years Given Prevenar 13 or PPSV23"* Serotype Ntoou Rett toPESV23 our or Ratio 5% T a 3 13 17, 18) 3 3 ® [8 135) 7 205 [37 95374) 5 7 36 20 C3526) cat 905 34 ~ 96 (700, 1336) es 1261 a7 “30 G21, 413) F as 160 13 (1.07, 2:18) ov 13 30 20 136,257) 7 20 BE io O75 133) 18C 907 481 19 (142, 2.50) 19x 3 200 18 43,220) 19F 333 24 16 (1.17, 2.06) BF 158 y B 37 (2.69, 5.09) ‘GAIT, Geomete Mean Tier "6A is a serotype unique o Prevenar 13 but ot contsined in PPSV23 * Nominteriority was defined asthe lower limi ofthe 2-sided 95% Cl for GMR greater than 0.5, Statisaly significant reuter esponses defined ‘asthe lower bound af the 2sided 95% Cl or the GM greater han | ° For serespe 64, which i unique to Prevenar forthe GMR greater than2. a statistically siniticany greater response was defined asthe lower bound ofthe 2-sided 95% CL Clinical Trials to Assess Prevenar 13 Given with Seasonal TIV in Adults ‘Two randomized, double-blind clinical trials evaluated the immunogenicity of Prevenar 13 given with TIV (AJHINI, A/H3N2, and B strains) in adults who were PPSV23 unvaccinated aged 50-59 years and in adults 265 years. Bach clinical trial compared concomitant administration of Prevenar 13 and TIV (administered in opposite of 19 2018-0045724 PageGeneric Name: Pheumococeal 13-valent Conjugate Vaceine Trade Name: Prevenar 13° DS Effective Date: June 01,2013 Supersedes: NA. ‘Approved by BPOM: arms) with [1] TIV given with placebo and [2] with Prevenar 13 given alone. Group I received Prevenar 13 given with TIV, followed one month later by placebo; Group 2 received TIV given with placebo, followed ‘one month later by Prevenar 13. ‘A phase 3 randomized, double-blind clinical trial (6115A1-3001) of Prevenar 13 given with TIV in adults aged 50-59 years who were PPSV23 unvaccinated in the US assessed the immune responses of TIV when TIV was given with Prevenar 13 compared with TIV given with placebo (in the following called TIV alone). ‘A phase 3 randomized, double-blind clinical trial (61151-3008) of Prevenar 13 TIV in adults aged >65 years who were PPSV23 unvaccinated in Europe assessed the immune responses of TIV when TIV was given with Prevenar 13 compared with TIV given with placebo. Immune responses elicited by TIV were measured by haemagglutination inhibition (HAI) assays one month after TIV vaccination. The immune responses were measured as the proportion of adults achieving a >4-fold increase in HAI titer (responder) for each TIV strain | month after vaccination. The non-inferiority criterion was achieved for each vaccine antigen if the lower limit of the 95% CI for the difference in proportions of responders was >-10%, ‘The studies also assessed the immune responses of Prevenar 13 when Prevenar 13 was given with TIV compared with Prevenar 13 given alone. The immune responses elicited by Prevenar 13 were measured by ELISA IgG GMC one month after Prevenar 13 vaccination. The noninferiority criterion was achieved if the ower limit of the 2-sided, 95% Cl for the IgG GMC ratios (Prevenar 13 and TIV relative to Prevenar 13 alone) was >0.5 (2-fold criterion). TIV immune responses 50-59 years of age: The immune responses were similar after Prevenar 13 given concomitantly with TIV compared to TIV alone. Non-inferiority was met for all 3 TIV strains after Prevenar 13 given concomitantly with TIV compared to TIV alone (Table 6). TIV immune responses in >65 years of age: Non-inferiority was met for A/HINI, and B-strains but not for AJHBN2 with a lower limit of the 95% CI of -10.4% (Table 7). “Table 6: Proportion of Participants Aged 50-9 Years with a >4-fold Increase in HAI Titer after TIV with Prevenar 13 and TIV With Placebo TV TIV + Prevenar 13 TIV + Placebo Difference HAL WN _% (95% CI) nN 1% (95% CI) % (95 ‘AIMINI_| 445/530 [$4.0 (80.6, 87.0) [31/531 81.2(76,844) | 2.8(-18,7.4) ‘AIH3N2_|377/530_[ 71.1 (67.1, 75.0) | 369/531 69.5 (65.4, 73.4) 72) B 321/530 | 60.6 (563, 64.8) | 320/531 60:3 (56.0, 645) 6.2) ‘Table 7; Proportion of Participants Aged >65 Years with a >4-fold Increase in HAI Titer afler TIV with Prevenar 13 and TIV With Placebo TIV + Prevenar 13 TIV + Placebo Difference WN 9% (95% CD, nN % (95% CI) 9% (95% Cl) 440/548 [80.3 (76.7, 83.5) | 429/546 78.6 (749, 81.9) 17(3.1,63) ‘AJHBN2_| 316/545 [58.0 (53.7, 62.2) | 341/545 62.6 (58.4, 6.6) ~4.6(-10.4, 13) B 286/548 | 52.2(47.9, 56.4) | 295/546 54.0 (49.7, 583) | -1.878,4.1) Prevenar 13 immune responses in 50-59 year olds: Non-inferiority was met for all serotypes (Table 8). 2018-0045724 Page 16 of 19Generic Name: Pneut imococeal 13-valent Conjugate Vaceine ‘Trade Name: Prevenar 13™ CDS Effective Date Supersedes: N/A Approved by BPOM: Prevenar 13 imm June 01,2013 une responses in >65 year olds: Non-infer ity was met for all serotypes except serotype 19F. The lower limit of the 95% CI of the GMR for 19F was 0.49 [criterion 0.5] (Table 9).. ‘Table 8: Pneumococcal IgG GMC 1 Month After Prevenar 13 and TIV; and 1 Month After Prevenar 13 (Given 1 month After Placebo and TIV) for Participants 50-59 Years Post-dose 1 Post-dose 2 Prevenar 13+ TIV Prevenar 13* Vaccine Comparison | (N=247-294) (N=247-289) _ Serotype ‘GMC. jig/ml. GMC, ug/ml. Ratio (95% CD, 1 4.05 3.45 0.74 (0.58, 0.95) 3 115 146 0.79 (0.66, 0.93) 4 235 Bal 10.69 (0.55, 0.87) ss 6.03 718 (0.84 (0.67, 1.05) ON 5.78 670 0.86 (0.70, 1.06) OB 738 10.09 (0.75 (0.60,0.93) TF B14 10.37 0.77 (0.63, 0.95) ov 4.96 697 0.71 (0.59, 0.86) 14 10.77 14.05 0.77 (0.60, 0.98) 1sc 9.65 13.49 0.72 (0.58, 0.8) 19a 16.80 18.84 10.89 (0.74, 1.08) 19F 6.13 7.13 0.86 (0.67, 1.10) 23F 77 854 10.84 (0.66, 1.08) some man conconalon ion weeks alr Placebo and TV ‘Antibody measured by a standardized ELISA, "The non-nferiony criterion was achieved the lower imitof the sided, 95% Cl or the TG GMC ratios (Prevear 13 and TIV relative Prevenar 13 alone) was 20.5 (fold ererion, ‘Table 9: Pneumococcal IgG GMC 1 Month After Prevenar 13 and TIV; and 1 Month After Prevenar 13 (Given ‘Lmonth After Placebo and TIV) for Participants >65 Years" 7 Post-dose 1 Post-dose 2 Prevenar 13+ T1V Prevenar 13° ‘Vaccine Comparison (N-247-294) (N=247-289) [Serotype GMC, ug/ml. ‘GMC, ig/ml. Ratio (O5% CD, 1 252 320 0.79 (0.60, 1.04) 3 108 LAs 0.94 (0.78, 1.13) 4 215 324 0.66 (0:51, 0387) 5 4.74 6.90 0.69 (0.55, 0.86) [6a 461 6.10 0.76 (0.61, 0.94) CB. 624 6.43 0.97 (0.75, 1.25) TF 7.63 9.04 0.84 (0.67, 1.07) ov 497 621 0,80 (0.63, 1.02) 14 5.95 12.44 (0.72.(0.53, 097) isc 8.88 1107 0.80 (0.64, 1.01) 19A, 11.953 17.10 0.70 (0.56, 0.87) 19F 478 7:39 0.65 (0.49, 0.85) 23F 542 611 0.95 (0.71, 1.27) “GRC, geomet mean concentration. ‘Given t weeks afer Placebo and TL. Antibody measured by ‘standardized ELISA, "The nom inferiority ereion was achieved ifthe lower limit f the 2-sded, 95% Cl forthe IgG GMC ratios (Prevenar 13 and TIV relative wo Prevenar 13 alone) vas S05 (-flderterin), Prevenar 13 may be given with TIV ‘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 significance oft 2018-0045724 is unknown. Page 17 of 19Generic Name: Pneumococcal 13-valent Conjugate Vaccine “rade Name: Prevenar 13" CDS Effective Date: June 01,2013, Supersedes: WA Approved by BPOM: Pharmacokinetic Properties Evaluation of pharmacokinetic properties is not available for vaccines. Preclinical Safety Data Studies with a vaccine formulation representative of Prevenar 13 revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, juvenile toxicity and local tolerance. Incompatibilities In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. ‘The vaccine is not to be mixed with other vaccines/products in the same syringe. Shelf-life 3 years. Special Precautions for Storage Store in a reftigerator (2°C- 8°C). Do not freeze. Discard if the vaccine has been frozen. Prevenar 13 has been shown to be stable at temperatures of up to 25°C for 4 days. These data are not recommendations for shipping or storage, but may guide decisions for use in case of temporary temperature How Supplied Box, | pre-filled syringe @ 0.5 mL (Reg. No. DK11786101643A2). Box, 50 vial @ 0.5 mL (Reg. No.: DKI1786101643A1) Special Precautions for Disposal and Other Handling During storage, a white deposit and clear supernatant can be observed. ‘The vaccine should be shaken well to obtain a homogeneous white suspension prior to expelling air from the syringe, and should be inspected visually for any particulate matter and/or variation of physical aspect prior to administration. Do not use if the content appears otherwise. ‘Any unused product or waste material should be disposed of in accordance with local requirements. HARUS DENGAN RESEP DOKTER Manufactured by: Pfizer Ireland Pharmaceuticals, Grange Castle Business Park, Clondalkin, Dublin 22, Ireland Packed and Released by: 2018-0045724 Page 18 of 19Generic Name: Pneumocooeal 13-valent Conjugate Vaccine ‘Trade Name: Prevenar 13" (CDS Effective Date: June 01,2013, Supersedes: N/A ‘Approved by BPOM: Pfizer Manufacturing Belgium NV, Puurs, Belgium Imported by: PT. Pfizer Indonesia Jakarta, Indonesia Vial: Manufactured by: Pfizer Manufacturing Belgium NV, Puurs, Belgium Imported by: PT. Pfizer Indonesia Jakarta, Indonesia 2018-0045724 Page 19 of 19