Importer / Manufacturer: Wyeth (Thailand) Ltd./ Wyeth Pharmaceutical Division of Wyeth Holdings Corporation, Pearl River, NY 10965, USA

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1 Registration No. 1C 13/46 (N) Importer / Manufacturer: Wyeth (Thailand) Ltd./ Wyeth Pharmaceutical Division of Wyeth Holdings Corporation, Pearl River, NY 10965, USA SUMMARY OF PRODUCT CHARACTERISTICS 1. NAME OF THE MEDICAL PRODUCT PREVNAR 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Prevnar is a sterile solution of saccharides of the capsular antigen of Streptococcus pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F individually conjugated to diphtheria CRM 197 protein. Each 0.5 ml dose is formulated to contain 2 µg of saccharide for serotypes 4, 9V, 14, 18C, 19F, and 23F, and 4 µg of serotype 6B (16 µg total saccharide) and approximately 20 µg of CRM 197 carrier protein and mg of aluminium as aluminium phosphate adjuvant. Other ingredients include sodium chloride and water-for-injection. Latex is present in the syringe plunger stopper and the syringe tip cap for the pre-filled syringe presentation. After shaking, the vaccine is a homogenous, white suspension. 3. PHARMACEUTICAL FORM Suspension for injection. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Prevnar is indicated for active immunization of infants and children from 6 weeks until 9 years of age against invasive disease, pneumonia and otitis media caused by Streptococcus pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F and 23F. 4.2 Posology and method of administration Prevnar is for intramuscular use only. 1

2 The dose is 0.5 ml given intramuscularly, with care to avoid injection into or near nerves and blood vessels. The preferred sites are the anterolateral aspect of the thigh in infants or the deltoid muscle of the upper arm in older children. The vaccine should not be injected in the gluteal area. The vaccine should not be injected intradermally, subcutaneously or intravenously since the safety and immunogenicity of these routes have not been evaluated. Parenteral products should be inspected visually for particulate matter or discoloration prior to use. See also Instructions for use and handling, and disposal. Vaccination Schedule Primary Immunization For infants, the immunization series of Prevnar consists of four doses of 0.5 ml each. The customary age for the first dose is 2 months of age, but it can be given as young as 6 weeks of age. The recommended dosing interval is 4 to 8 weeks. The fourth dose should be administered at approximately months of age, and at least 2 months after the third dose. Vaccination schedule for infants and toddlers Dose: Dose 1* Dose 2 Dose 3 Dose 4 l Age at Dose: 2 months 4 months 6 months months * Dose 1 may be given as early as 6 weeks of age. The recommended dosing interval is 4 to 8 weeks. l The fourth dose should be administered at approximately months of age, and at least 2 months after the third dose. For Previously Unvaccinated Older Children For previously unvaccinated older infants and children who are beyond the age of routine infant schedule, the following schedule applies: Vaccine schedule for previously unvaccinated children 7 months of age Age at First Dose Total Number of 0.5 ml Doses 7-11 months of age 3* months of age 2 24 months through 9 years of age 1 2

3 * 2 doses at least 4 weeks apart; third dose after the one-year birthday, separated from the second dose by at least 2 months. 2 doses at least 2 months apart. 4.3 Contraindication Hypersensitivity to any component of the vaccine, including diphtheria toxoid. 4.4 Special warnings and precautions for use Special Warnings Prevnar will not protect against other Streptococcus pneumoniae serogroups other than those included in the vaccine or other micro-organisms that cause invasive disease, pneumonia or otitis media. Prevnar, as with any intramuscular injection, should be given with caution to infants or children with thrombocytopenia or any coagulation disorder or to those receiving anticoagulant therapy. As with all injectable pediatric vaccines, the potential risk of apnea should be considered when administering the primary immunization series to premature infants. The need for monitoring for at least 48 hours after vaccination should be considered for very premature infants (born 30 weeks of gestation), who remain hospitalized at the time of the recommended administration. As the benefit of vaccination is high in this group of infants, vaccination should not be withheld or delayed. The syringe plunger stopper and the syringe tip cap contain dry natural rubber that may cause hypersensitivity reactions when handled by or when the product is injected into persons with known or possible latex sensitivity. Precautions Minor illnesses, such as mild respiratory infection with or without low-grade fever, are not generally contraindications to vaccination. The decision to administer or delay vaccination because of a current or recent febrile illness depends largely on the severity of the symptoms and their etiology. The administration of Prevnar should be postponed in subjects suffering from acute severe febrile illness. As with all injectable vaccines, appropriate medical treatment and supervision must always be readily available in case of a rare anaphylactic event following the administration of the vaccine. 3

4 (see ADVERSE REACTIONS) Although some antibody response to diphtheria toxin occurs, immunization with Prevnar does not substitute for routine diphtheria immunization. The use of pneumococcal conjugate vaccine does not replace use of 23-valent pneumococcal polysaccharide vaccine in children greater than or equal to 24 months of age with conditions such as sickle cell disease, asplenia, HIV infection, chronic illness, or who are immunocompromised, placing them at higher risk for invasive disease due to S. pneumoniae. Children with impaired immune responsiveness whether due to the use of immunosuppressive therapy (including irradiation, corticosteroids, antimetabolites, alkylating agents and cytotoxic agents), a genetic defect, HIV infection, or other causes may have a reduced antibody response to active immunization. Prophylactic antipyretic medication is recommended for all children receiving Prevnar simultaneously with vaccines containing whole cell pertussis. Prophylactic antipyretic medication should be considered in children at higher risk for seizures than the general population. As with any vaccine, Prevnar may not protect 100% of individuals receiving the vaccine. 4.5 Interaction with other medical products and forms of interaction Prevnar can be administered simultaneously with other paediatric vaccines in accordance with the recommended immunization schedules. Different injectable vaccines should always be given at different injection sites. During clinical studies, Prevnar was administered simultatneously with diphtheria tetanus pertussis vaccine (DTP) or diphtheria tetanus acellular pertussis vaccine (DTaP), Haemophilus influenzae type b vaccine (Hib), oral polio vaccine (OPV) or inactivated polio vaccine (IPV), hepatitis B vaccines, measles-mumps-rubella vaccine (MMR), and varicella vaccine. Thus, the safety experience with Prevnar reflects the use of this product as part of the routine immunization schedule. In some studies, differences in antibody response to some of the antigen have been inconsistently found, however, it is not anticipated to be of any clinical relevance. There are no clinical trial data available on the safety and immunogenicity of Prevnar when administered concomitantly with any meningococcal serogroup C conjugate vaccine (see Pharmacodynamic properties for data from clinical studies with an investigational combination vaccine). Data on concomitant administration of Prevnar with Infanrix hexa (DTaP/Hib(PRP- T)/IPV/HepB vaccine) have shown no clinically relevant interference in the antibody 4

5 response to each of the individual antigens when given as a 3 dose primary vaccination. Sufficient data regarding interference on the concomitant administration of other hexavalent vaccines with Prevnar are currently not available. When Prevnar is co-administered with hexavalent vaccines (DTaP/Hib(PRP-T)/IPV/HepB), the rate of febrile reactions was higher compared to that occurring following the administration of hexavalent vaccines alone. These reactions were mostly moderate (less than or equal to 39 C) and transient. Concurrent administration of Prevnar with DTaP-IPV/PRP-T vaccine (Sanofi-aventis) and hepatitis B virus vaccine (Merck), at 2, 4 and 6 months of age, (concurrent administration) was compared to the sequential administration of DTaP-IPV/PRP-T vaccine and hepatitis B virus vaccine at 2, 4 and 6 months of age and Prevnar at 3, 5 and 7 months of age (sequential administration). There were no differences in the antibody response to any Prevnar serotype in either the concurrent or the sequential group. A lower percentage of responders to hepatitis B (seroprotective level, 10 miu/ml, measured at 8 weeks post third dose) was noted in the concurrent group, 87.2% (95% CI: %), compared to that seen in the sequential group, 96.7% (95% CI: %). The clinical significance of these data is unknown. 4.6 Pregnancy and lactation Pregnacy This vaccine is NOT recommended for use in adults. Safety during pregnancy has not been established. Lactation This vaccine is NOT recommended for use in adults. Safety during lactation has not been established. 4.7 Effects on the ability to drive and use machines Not applicable 4.8 Undesirable effects Adverse reactions are listed in the Table in CIOMS frequency categories: Very common : 10% Common : 1% and < 10% Uncommon : 0.1% and < 1% 5

6 Rare : 0.01% and < 0.1% Very rare : < 0.01% Adverse Reactions from Clinical Trials These data are from clinical trials in which Prevnar was administered simultaneously with other routine childhood vaccines. Body System Adverse Reaction Administration site conditions Very Common Injection site erythema, induration/swelling, pain/tenderness Common Injection site induration/swelling or erythema greater than 2.4 cm; pain tenderness interfering with movement Gastrointestinal disorders Very Common General disorders Very Common Common Diarrhea, vomiting Fever Fever greater than 39 o C Metabolic and nutrition disorders Very Common Decreased appetite Nervous system disorders Very Common Rare Psychiatric disorders Very Common Drowsiness; restless sleep Seizures (including febrile seizures); hypotonichyporesponsive-episode Irritability Skin and subcutaneous tissue disorders Uncommon Rash; urticaria or urticaria-like rash Additional Adverse Reactions from Postmarketing Experience These frequencies are based on spontaneous reporting rates and have been calculated using number of reports and number of doses distributed. Body System Adverse Reaction Administration site conditions Very Rare Injection site dermatitis, injection site urticaria, injection site 6

7 pruritus Blood and lymphatic disorders Very Rare Lymphadenopathy localized to the region of the injection site Immune system disorders Very Rare Hypersensitivity reaction including face edema, dyspnea, bronchospasm; anaphylactic / anaphylactoid reaction including shock Skin and subcutaneous tissue disorders Very Rare Angioneurotic edema, erythema multiforme Psychiatric disorders Very Common Crying 4.9 Overdose There have been reports of overdose with Prevnar, including cases of administration of a higher than recommended dose and cases of subsequent doses administered closer than recommended to the previous dose. Most individuals were asymptomatic. In general, adverse events reported with overdose have also been reported with recommended single doses of Prevnar. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Immunogenicity In all studies in which the immune responses to Prevnar were contrasted to control, a significant antibody response was seen to all vaccine serotypes following three or four doses, although geometric mean concentration varied among serotypes. Prevnar induces functional antibodies to all vaccine serotypes, as measured by opsonophagocytosis following three doses. Table 1 presents the geometric mean concentration (GMC) of pneumococcal antibodies following the third and fourth doses of Prevnar or the control vaccine when administered with DTP-HbOC vaccine in the efficacy study. 7

8 TABLE 1 Geometric Mean Concentrations (µg/ml) of Pneumococcal Antibodies Following the Third and Fourth Doses of Prevnar or Control* When Administered Concurrently With DTP-HbOC in the Efficacy Study Serotype Post dose 3 GMC (95% CI for Prevnar) Post dose 4 GMC (95% CI for Prevnar) (1.19, 1.78) 6B 4.70 (3.59, 6.14) 9V 1.99 (1.64, 2.42) (3.70, 5.74) 18C 2.16 (1.73, 2.69) 19F 1.39 (1.16, 1.68) 23F 1.85 (1.46, 2.34) Prevnar Control* Prevnar Control* N=88 N=92 N=68 N= (1.88, 3.03) (11.17, 18.69) (2.75, 4.48) (5.18, 8.21) (2.70, 4.37) (1.66, 2.57) (2.85, 5.11) * Control was investigational meningococcal group C conjugate vaccine (MnCC). Mean age of Prevnar group was 7.8 months and of control group was 7.7 months. N is slightly less for some serotypes in each group. Mean age of Prevnar group was 14.2 months and of control group was 14.4 months. N is slightly less for some serotypes in each group. p<0.001 when Prevnar compared to control for each serotype using a Wilcoxon s test. Study Number: D118-P Table 2 presents the immune responses to pneumococcal polysaccharides observed in the Manufacturing Bridging Study and in the subset of subjects from the efficacy study that received concomitant DTaP and HbOC vaccines. 8

9 TABLE 2 Geometric Mean Concentrations (µg/ml) of Pneumococcal Antibodies Following the Third Dose of Prevnar or Control* When Administered Concurrently With DTaP and HbOC in the Efficacy Study and Manufacturing Bridging Study Serotype Efficacy Study Post dose 3 GMC (95% CI for Prevnar) Manufacturing Bridging Study Post dose 3 GMC (95% CI for Prevnar) Prevnar ll Control* Prevnar ll Control* N=32 N=32 N=159 N= (1.08, 2.02) (1.75, 2.37) 6B (1.20, 3.96) (2.43, 3.65) 9V (1.04, 2.22) (1.01, 1.39) (3.32, 7.70) (3.80, 5.66) C 0.04 (1.65, 3.02) (1.66, 2.30) F 0.10 (1.09, 2.17) (1.63, 2.25) 23F (0.97, 2.25) (1.44, 2.05) * Control in efficacy study was investigational meningococcal group C conjugate vaccine (MnCC) and in Manufacturing Bridging Study was concomitant vaccines only. Sufficient data are not available to reliably assess GMCs following 4 doses of Prevnar when administered with DTaP in the NCKP efficacy study. Mean age of the Prevnar group was 7.4 months and of the control group was 7.6 months. N is slightly less for some serotypes in each group. Mean age of the Prevnar group and the control group was 7.2 months. ll p<0.001 when Prevnar compared to control for each serotype using a Wilcoxon s test in the efficacy study and two-sample t-test in the Manufacturing Bridging Study. Study Number: D118-P8, D118-P Vaccine induced antibodies to capsular polysaccharide, specific for each serotype, are considered protective against invasive disease. Although the minimum protective antibody concentration against invasive disease has not been determined for any serotype, the WHO recommends an antibody concentration 0.35 µg/ml for all pneumococcal serotypes as predictive of vaccine effectiveness against invasive pneumococcal disease. To determine an appropriate schedule for children 7 months of age or older at the time of the first immunization with Prevnar, 483 children in 4 ancillary studies received Prevnar at various schedules and were evaluated for immunogenicity. GMCs attained using the various schedules among older infants and children were comparable to immune responses of children, who received concomitant DTaP, in the Northern California Kaiser Permanente (NCKP) efficacy 9

10 study (D118-P8) after 3 doses for most serotypes, as shown in Table 3. TABLE 3 Geometric Mean Concentrations (µg/ml) of Pneumococcal Antibodies Following Immunization of Children From 7 Months Through 9 Years of Age With Prevnar Age group, Study Sample 4 6B 9V 14 18C 19F 23F Vaccinations Size(s) 7-11 mo. 3 doses mo. 2 doses * mo. 2 doses * mo. 1 dose mo. 1 dose yrs. 1 dose , DTaP Post dose Bold = GMC not inferior to 118-8, DTaP post dose 3 (one-sided lower limit of the 95% CI of GMC ratio >0.50). * Study in Navajo and Apache populations. Numbers vary with serotype. Study: Integrated Summary on Catch-Up The immunogenicity of Prevnar has been investigated in an open label, multicenter study in 49 infants with sickle cell disease. Children were vaccinated with Prevnar (3 doses one month apart from the age of 2 months) and 46 of these children also received a 23-valent pneumococcal polysaccharide vaccine at the age of months. After primary immunisation, 95.6% of the subjects had antibody levels of at least 0.35 µg/ml for all seven serotypes found in Prevnar. A significant increase was seen in the concentrations of antibodies against the seven serotypes after the polysaccharide vaccination, suggesting that immunological memory was well established. The immunogenicity of an alternative schedule (two-dose infant series plus a booster at about one year of age) has been documented in several studies. They include: two randomized, controlled studies comparing the immunogenicity of a threedose and a two-dose infant series, three open studies comparing immunogenicity after the second dose and the third dose of a three-dose infant series (self controlled), and four open, uncontrolled studies. Lower GMC values were generally noted for most serotypes after a two-dose series than after a three-dose series and were significantly reduced for serotypes 6B and 23F. In all studies except the uncontrolled UK studies, a smaller proportion of infants achieved an antibody concentration 10

11 0.35 µg/ml against serotypes 6B and 23F after a two-series (see Table 4). TABLE 4 Percentage of infants with antibody concentration 0.35 µg/ml* for serotypes 6B and 23F, after a 2- or 3-dose primary series Study site N (post 2 / post 3) Serotype 6B response rate Serotype 23F response rate Post 2 Post 3 % difference Post 2 Post 3 % difference Randomized Controlled Study Israel 133 / % 87% 26%** 70% 83% 13%** Iceland 108 / % 86% 24% 82% 90% 8% Self-controlled Study USA 87 / 90 33% 77% 44% 53% 86% 33% Finland (P6) 51 / 51 32% 91% 59% 81% 100% 19% Finland (P809) 55 / 54 53% 85% 32% 64% 94% 30% Uncontrolled Study Sweden 75 / -- 40% % Italy 46 / -- 83% % UK (Hertfordshire) 82 / -- 89% % UK (Gloucestershire) -- / % % -- The statistical analysis of the difference in percentage responders was only performed for the two randomised, controlled trials. * WHO recommended antibody concentration for all pneumococcal serotypes as predictive of vaccine effectiveness against invasive pneumococcal disease ** p<0.05 Statistically significant difference based on the 90%CI of the difference in percentages of infants with antibody concentration 0.35 µg/ml After the booster dose, the percentage of infants with an antibody concentration 0.35 µg/ml was comparable for all serotypes following a two- or three-dose infant series. Data are available from clinical studies in which an investigational 9-valent pneumococcal- CRM 197 protein conjugate - meningococcal serogroup C-CRM 197 protein conjugate combination vaccine (9vPnCMnCC) was administered. This investigational vaccine contained the same seven conjugated serotypes as Prevnar plus two additional pneumococcal conjugated serotypes, combined with meningococcal serogroup C conjugate vaccine (the active component in Meningitec). There was no interference with the response to the pneumococcal serotypes. Two of these studies directly compared the administration of Meningitec given alone with 9vPnC-MnCC. The geometric mean titre (GMT) values of meningococcal serogroup C serum bactericidal antibody (SBA) after the primary series were significantly lower in the 9vPnC- 11

12 MnCC vaccine group compared to the Meningitec group. However, the proportions of patients in these two studies reaching SBA titres of at least 1:8 were 94.4 to 100%. A bactericidal titre of 1:8 is considered a correlate of short-term protection based on effectiveness estimated from postmarketing surveillance. Across nine studies with the 9vPnCMnCC vaccine, the median proportion of patients reaching meningococcal serogroup C SBA titres of at least 1:8 was 98% (range = 85 to 100%). The clinical implications of these observations with an investigational vaccine are unknown (see INTERACTIONS). Efficacy Efficacy was assessed in a randomized, double-blinded clinical trial in a multiethnic population at Northern California Kaiser Permanente (NCKP) beginning in October 1995, in which 37,816 infants were randomized to receive either Prevnar or a control vaccine (an investigational meningococcal group C conjugate vaccine [MnCC]) at 2, 4, 6, and months of age. Prevnar was administered to 18,906 children and the control vaccine to 18,910 children. Routinely recommended vaccines were also administered which changed during the trial to reflect changing American Academy of Pediatrics (AAP) and Advisory Committee on Immunization Practices (ACIP) recommendations. A planned interim analysis was performed upon accrual of 17 cases of invasive disease due to vaccine-type S. pneumoniae (August 1998). Ancillary endpoints for evaluation of efficacy against pneumococcal disease were also assessed in this trial. Efficacy against invasive disease Invasive disease was defined as isolation and identification of S. pneumoniae from normally sterile body sites in children presenting with an acute illness consistent with pneumococcal disease. Weekly surveillance of listings of cultures from the NCKP Regional Microbiology database was conducted to assure ascertainment of all cases. The primary endpoint was efficacy against invasive pneumococcal disease due to vaccine serotypes. The per protocol analysis of the primary endpoint included cases which occurred 14 days after the third dose. The intent-totreat (ITT) analysis included all cases of invasive pneumococcal disease due to vaccine serotypes in children who received at least one dose of vaccine. Secondary analyses of efficacy against all invasive pneumococcal disease, regardless of serotype, were also performed according to these same per protocol and ITT definitions. Results of these analyses for the interim analysis (August 1998) and through an extended follow-up period (April 1999) are presented in Tables 5a and 5b. 12

13 TABLE 5a Efficacy of Prevnar against Invasive Disease Due to S. pneumoniae in Cases Accrued from October 15, 1995 Through August 20, 1998 Prevnar Number of Cases Control* Number of Cases Efficacy 95% CI Vaccine serotypes Per protocol % 75.4, 100 Intent-to-treat % 81.7, 100 All pneumococcal serotypes Per protocol % 58.3, 98.9 Intent-to-treat % 63.8, 97.9 * Investigational meningococcal group C conjugate vaccine (MnCC). Includes one case in an immunocompromised subject. Study Number: D118-P8 TABLE 5b Efficacy of Prevnar against Invasive Disease Due to S. pneumoniae in Cases Accrued from October 15, 1995 Through April 20, 1999 # Prevnar Number of Cases Control* Number of Cases Efficacy 95% CI Vaccine serotypes Per protocol % 84.8, 99.9 Intent-to-treat % 81.0, 98.8 All pneumococcal serotypes Per protocol % 77.6, 98.6 Intent-to-treat % 74.7, 96.2 # Extended follow-up * Investigational meningococcal group C conjugate vaccine (MnCC). Includes one case in an immunocompromised subject. Study Number: D118-P8 Efficacy against otitis media (OM) The efficacy of Prevnar against otitis media was assessed in two clinical trials, in Northern California and in Finland. 13

14 In the NCKP efficacy study, physician visits for otitis media were identified by physician coding of outpatient encounter forms. Because visits may have included both acute and follow-up care, a new visit or episode was defined as a visit that was at least 21 days following a previous Acute Otitis Media (AOM) visit (at least 42 days, if the visit appointment was made > 3 days in advance). Data on placement of ear tubes were collected from automated databases. No routine tympanocentesis was performed. Table 6 presents the per protocol results of the AOM analyses. TABLE 6 Efficacy of Prevnar against Otitis Media Due to S. pneumoniae in the NCKP Trial Per Protocol N=23,746* % Reduction 95% CI All AOM Episodes 7.0 (4.1, 9.7) All AOM Visits 8.9 (5.8, 11.8) Frequent AOM 3 episodes/6mo or 4/yr 9.5 (3.2, 15.3) 4 episodes/6mo or 5/yr 11.9 (1.6, 21.1) 5 episodes/6mo or 6/yr 22.8 (6.7, 36.2) EAR TUBE PLACEMENT 20.3 (1.8, 35.4) * Number of subjects included in the Per protocol analysis. In this study, a total of 12 episodes of otitis media were prevented per 100 child-years. Study Number: D118-P8 The trial in Finland was a randomized, double-blind trial in which 1,662 infants were randomized to receive either Prevnar or a control vaccine (hepatitis B vaccine) at 2, 4, 6, and months of age. Parents of study participants were asked to bring their children to the study clinics for respiratory infections or symptoms suggesting AOM. If AOM was diagnosed, tympanocentesis was performed, and the middle ear fluid cultured. A new visit or episode of AOM was defined as a visit that was at least 30 days following a previous AOM visit. Table 7 presents the results for the per-protocol study endpoints. 14

15 TABLE 7 Efficacy of Prevnar against Otitis Media Due to S. pneumoniae in the Finnish Trial Acute Otitis Media Outcome Vaccine Efficacy Estimate Per-Protocol N=1632* 95% Confidence Interval Vaccine-serotype AOM episode 57% (44, 67) All pneumococcal culture-confirmed AOM episodes 34% (21, 45) All AOM episodes regardless of etiology 6% (-4, 16) Recurrent AOM (3 episodes in 6 months or 4 episodes in 12 months) 16% (-6, 35) * Number of subjects included in the Per protocol analysis. Study Number: D118-P809 Efficacy against pneumonia In the NCKP study efficacy against pneumonia was assessed and a total of 11,849 children in the Prevnar group have been included in the per protocol analysis. The estimated risk reduction for clinical pneumonia with abnormal X-ray was 35% (4, 56-95% CI) and for clinical pneumonia with consolidation was 63% (95% CI: 8, 87). The intent-to-treat analysis included 17,070 children in the Prevnar group and the estimated risk reduction for clinical pneumonia with abnormal X-ray was 33% (95% CI: 6, 52) and for clinical pneumonia with consolidation was 73% (95% CI: 36, 90). Table 8 presents the results of the pneumonia analysis through April Consolidation on X-ray was defined as an area of opacity 2.5 cm in the greatest dimension, with clear borders. TABLE 8 Summary of Vaccine Effect on Pneumonia Per Protocol Analysis Intent-to-Treat Analysis Pneumonia Outcome Cases in 7VPnC/MnCC % Reduction in Disease (95% Confidence Interval) P- value* Cases in 7VPnC/MnCC % Reduction in Disease (95% Confidence Interval) P- value* Clinical Pneumonia 500/566 11% (0.8, 21.1) /694 10% (0.1, 19.8)

16 Per Protocol Analysis Intent-to-Treat Analysis Pneumonia Outcome Cases in 7VPnC/MnCC % Reduction in Disease (95% Confidence Interval) P- value* Cases in 7VPnC/MnCC % Reduction in Disease (95% Confidence Interval) P- value* Clinical Pneumonia with X-ray Taken 323/372 12% (2.2, 24.7) /456 13% (0.2, 24.1).035 Clinical Pneumonia with Abnormal X-ray 45/70 35% (4.2, 56.4) /91 33% (6.2, 52.3).033 Clinical Pneumonia with Consolidation 7/19 63% (8, 87).03 7/26 73% (36, 90).001 * P-value calculated using the Exact binomial test (u= for per protocol and for intent-to-treat) Study Number: D118-P8 Addendum These data were reanalyzed through an extended follow-up period (August 1999), and used different definitions. In this reanalysis, a positive X-ray was defined as one with infiltrates beyond the perihilar area, or with consolidation or empyema. In the per protocol analysis (16,901 subjects in the Prevnar group), effectiveness against clinical pneumonia with a positive X-ray was estimated to be 20.5% (95% CI: 4.4, 34.0). In the intent-to-treat analysis (18,926 subjects in the Prevnar group), effectiveness against clinical pneumonia with a positive X-ray was estimated to be 17.7% (95% CI: 4.8, 28.9). Effectiveness Effectiveness of a two or three dose infant series has been evaluated in three universal immunization programs (USA, Canada and England & Wales). The estimates of effectiveness of an immunization programme reflect both direct (vaccine-induced) and indirect (populationrelated or herd) protection during routine use. In U.S. children, vaccine effectiveness against IPD caused by vaccine serotypes was 96% (95% CI 93-98); effectiveness point estimates were similar for meningitis (96% [95% CI 83-99]), bacteraemia (95% [95% CI 89-98]) and bacteraemic pneumonia (98% [95% CI 89-99]). When compared with no vaccine, point estimates for the effectiveness of 2-, 3-, or 4-dose schedules 16

17 were similar. Direct comparison of a 3+0 versus a 3+1 scheduled favored the 3+1 schedule (p=0.03); direct comparisons between other schedules of 2, 3 or 4 doses were restricted due to small data sets. In the USA, there was a 62% reduction in vaccine type IPD in individuals over 5 years of age after the universal introduction of Prevnar using a four dose series in infants and a catch-up programme for children up to 5 years of age. This indirect or herd effect is due to a reduction in transmission of vaccine serotypes from immunized young children to the rest of the population and coincides with decreased carriage of vaccine serotypes. In Quebec, Canada, three doses were administered to more than 90% of infants at 2, 4 and 12 months of age. At the start of the program, catch-up immunization was administered to over 70% of children up to 5 years of age according to the posology. (see section 4.2) An effectiveness of 93% (95%CI, 75% to 98%) was observed for infants who received a two-dose series and of 100% (95% CI, 91% to 100%) for infants who completed the immunization schedule. In England and Wales, three doses were administered to more than 90% of infants at 2, 4 and 13 months of age; children aged 13 to 23 months were given one dose instead of the recommended two-dose series. Effectiveness of 88% (95%CI, 54 to 97%) was observed for infants who received the two-dose primary series during the first nine months of the program increasing to 96% (95%CI, 63 to 99%) when serotype 6B cases were excluded from the analysis. These data may reflect the impact of a reduced response to serotype 6B after a two-dose infant series. The clinical effectiveness of a two-dose primary series against acute otitis media or pneumonia has not been established. Additional data Prevnar has been demonstrated to reduce carriage of vaccine serotypes after a three dose primary series followed by a booster dose. A randomised, controlled trial in 66 healthy, Israeli infants assessed the effect of a two-dose (4 and 6 months) or a three-dose (2, 4, and 6 months) primary series of Prevnar on nasopharyngeal colonization compared to controls. A statistically significant reduction in new serotype 6B acquisition between the age of 7 and 12 months was observed for infants receiving three doses of vaccine only, suggesting that lower post-dose 2 antibody response to serotype 6B may be medically significant between dose 2 and the age of 12 months when a booster dose is given. 17

18 5.2 Pharmacokinetic properties Evaluation of pharmacokinetic properties is not applicable for vaccines. 5.3 Preclinical safety data A repeated dose toxicity study of pneumococcal conjugate vaccine in rabbits revealed no evidence of any significant local or systemic toxic effects. Repeated dose subcutaneous toxicity studies of Prevnar in rats and monkeys revealed no evidence of any significant local or systemic toxic effects. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Sodium chloride Water for injections 6.2 Incompatibilities Prevnar is not be mixed with any other vaccines / products in the same syringe. 6.3 Shelf life 36 months. 6.4 Special precautions for storage Store refrigerated at 2 o C - 8 o C. (36 o F- 46 o F) Do not freeze. Discard if the vaccine has been frozen. Store in original package. 6.5 Nature and contents of container 0.5 ml suspension for injection in vial pack size of 1, 5, 10 and 12 vials 0.5 ml suspension for injection in pre-filled syringe (Type I glass) with a plunger rod (polypropylene) - pack size of 1, 5, 10 and 12 pre-filled syringes Not all pack sizes may be marketed. 18

19 6.6 Special precautions for disposal and other handling Upon storage, a white deposit and clear supernatant can be observed. Prevnar is a suspension containing an adjuvant. Therefore, shake vigorously immediately prior to use to obtain uniform suspension in the vaccine container. The vaccine must not be used if it cannot be uniformly suspended. Parenteral products should be inspected visually for particulate matter or discoloration prior to use. See also Posology and Method of Administration. 7. MARKETING AUTHORISATION HOLDER Wyeth (Thailand) Ltd. Bangkok Thailand 8. MARKETING AUTHORISATION NUMBER(S) 2C 13/46 (N) 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 08-Sep DATE OF REVISION OF THE TEXT 04-Apr-2008 CDS