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1 * 2 µg 6B * 4 µg 9V * 2 µg 14 * 2 µg 18C * 2 µg 19F * 2 µg 23F * 2 µg * CRM B 9V 14 18C 19F 23F (4 6B 9V 14 18C 19F 23F) %

2 4.2 2 ~ ~ ~ ~ ( ) ~ (HIV)

3 ( HIV ) HIV /b / /B 39 C b / PRP-T /B CRM b b 4 b IPV /b /

4 /B 3 C Meningitec 7 C 3 CRM C , ,066 55, ~ cm /b / /B 38 C 15.6 ~ ~ C 0.6 ~ ,662 DTP

5 C C % 1 ~ 10 % 0.1 ~ 1 % 0.01 ~ 0.1 % < 0.01 % / / / 38 C 2.4 / 39 C - Hypotonic hyporesponsive episode / ATC J07AL code

6 pneumococcal disease IPD ~ 86 2 ~ 5 50 ~ Northern California Kaiser Permanente(NCKP) 37, ( C [MnCC]) IPD intent-to-treat; ITT CI (per protocol a CI ( ) ITT CI (per protocol analysis) CI 65 ~ 79 Kaiser S. pneumoniae CI X-ray (ITT) X-ray CI CI

7 1,662 acute otitis media AOM endpoint Northern California secondary endpoint % CI) ITT % ( CI ( % CI ) Northern California 9.5% 15 (3 95 % CI ) 20% % CI) (2 6 ( % CI ) NorthernCalifornia 7 ( % CI ) 3 ~ ~ ~ 5

8 ~ ml (polypropylene) (Type I glass) 6.6

9 7. Wyeth Pharmaceuticals Division of Wyeth Holdings Corporation 401 North Middletown Road, Pearl River, New York Baxter Pharmaceutical Solutions LLC 927 South Curry Pike, Bloomington, Indiana John Wyeth & Brother Ltd. New Lane, Havant, Hampshire, P09 2NG, U.K. ( ) (02)

10 1. NAME OF THE MEDICINAL PRODUCT Prevenar suspension for injection Pneumococcal saccharide conjugated vaccine, adsorbed 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each 0.5 ml dose contains: Pneumococcal polysaccharide serotype 4* Pneumococcal polysaccharide serotype 6B* Pneumococcal polysaccharide serotype 9V* Pneumococcal polysaccharide serotype 14* Pneumococcal oligosaccharide serotype 18C* Pneumococcal polysaccharide serotype 19F* Pneumococcal polysaccharide serotype 23F* 2 micrograms 4 micrograms 2 micrograms 2 micrograms 2 micrograms 2 micrograms 2 micrograms * Conjugated to the CRM 197 carrier protein and adsorbed on aluminium phosphate (0.5 mg) For excipients, see PHARMACEUTICAL FORM Suspension for injection. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Active immunisation against invasive disease (including sepsis, meningitis, bacteraemic pneumonia, bacteraemia) caused by Streptococcus pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F and 23F in: - infants and young children from 2 months of age to 2 years of age - previously unvaccinated children aged 2 years to 5 years (for high-risk subjects, see section 4.4). For the number of doses to be administered in the different age groups, see section 4.2. The use of Prevenar should be determined on the basis of official recommendations taking into consideration variability of serotype epidemiology in different geographical area as well as the impact of invasive disease in different age groups (see sections 4.4, 4.8 and 5.1). 4.2 Posology and method of administration The vaccine should be given by intramuscular injection. The preferred sites are anterolateral aspect of the thigh (vastus lateralis muscle) in infants or the deltoid muscle of the upper arm in young children.

11 Infants aged 2-6 months: three doses, each of 0.5 ml, the first dose usually given at 2 months of age and with an interval of at least 1 month between doses. A fourth dose is recommended in the second year of life. Previously unvaccinated older 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 months: two doses, each of 0.5 ml, with an interval of at least 2 months between doses. Children aged 24 months 5years: one single dose. The need for a booster dose after these immunisation schedules has not been established. Immunisation schedules: The immunisation schedules for Prevenar should be based on official recommendations. 4.3 Contraindications Hypersensitivity to the active substances or to any of the excipients, or to diphtheria toxoid. 4.4 Special warnings and special precautions for use As with other vaccines, the administration of Prevenar should be postponed in subjects suffering from acute moderate or severe febrile illness. 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. Prevenar will not protect against other Streptococcus pneumoniae serotypes than those included in the vaccine nor other micro-organisms that cause invasive disease or otitis media. This vaccine should not be given to infants or children with thrombocytopenia or any coagulation disorder that would contraindicate intramuscular injection unless the potential benefit clearly outweighs the risk of administration. Although some antibody response to diphtheria toxoid may occur, immunisation with this vaccine does not substitute for routine diphtheria immunisation. For children from 2 years through 5 years of age, a single dose immunization schedule was used. A higher rate of local reactions has been observed in children older than 24 months of age compared with infants (see section 4.8). Children 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. Safety and immunogenicity data are limited in children with sickle cell disease and not yet available for children in other specific high-risk groups for invasive pneumococcal disease (e.g. children with congenital and acquired splenic dysfunction, HIV-infected, malignancy, nephrotic syndrome). Vaccination in high-risk groups should be considered on an individual basis.

12 Children below 2 years old (including those at high-risk) should receive the appropriate-for-age Prevenar 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 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 Streptococcus pneumoniae. Children 24 months of age at high risk, previously immunised with Prevenar should receive 23 valent pneumococcal polysaccharide vaccine whenever recommended. Based on limited data, the interval between the pneumococcal conjugate vaccine (Prevenar) and the 23 valent pneumococcal polysaccharide vaccine should not be less than 8 weeks. Only limited data are available to inform the use of mixed schedules of pneumococcal conjugate vaccine and 23- valent pneumococcal polysaccharide vaccine in previously unimmunised high-risk children 2-5 years of age. Use of schedules may be considered on an individual basis taken into account current national recommendation. When Prevenar is co-administered with hexavalent vaccines (DTaP/Hib(PRP-T)/IPV/HepB), the physician should be aware that data from clinical studies indicate that 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 (see section 4.8). Antipyretic treatment should be initiated according to local treatment guidelines. Prophylactic antipyretic medication is recommended: - for all children receiving Prevenar simultaneously with vaccines containing whole cell pertussis because of higher rate of febrile reactions (see section 4.8). - for children with seizure disorders or with a prior history of febrile seizures. Do not administer Prevenar intravenously. 4.5 Interaction with other medicinal products and other forms of interaction Prevenar can be administered simultaneously with other paediatric vaccines in accordance with the recommended immunisation schedules. Different injectable vaccines should always be given at different injection sites. The immune response to routine paediatric vaccines co-administered with Prevenar at different injection sites was assessed in 7 controlled clinical studies. The antibody response to Hib tetanus protein conjugate (PRP-T), tetanus and Hepatitis B (HepB) vaccines was similar to controls. For CRM-based Hib conjugate vaccine, enhancement of antibody responses to Hib and diphtheria in the infant series was observed. At the booster, some suppression of Hib antibody level was observed but all children had protective levels. Inconsistent reduction in response to pertussis antigens as well as to inactivated polio vaccine (IPV) were observed. The clinical relevance of these interactions is unknown. Limited results from open label studies showed an acceptable response to MMR and varicella. Data on concomitant administration of Prevenar with Infanrix hexa (DTaP/Hib(PRP- T)/IPV/HepB vaccine) have shown no clinically relevant interference in the antibody 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 Prevenar are currently not available.

13 Data on concomitant administration with meningococcal C conjugate vaccines are not available, but data on an investigational combination vaccine containing the same 7 pneumococcal serotypes conjugated antigens of Prevenar and serogroup C meningococcal conjugated antigen of Meningitec has shown no clinically relevant interference in the antibody response to each of the individual antigens, suggesting that concomitant administration of Prevenar and CRM conjugate meningococcal C vaccines would not result in any immunologic interference when given as a 3 dose primary vaccination in the 1st year of life. 4.6 Pregnancy and lactation Prevenar is not intended for use in adults. Information on the safety of the vaccine when used during pregnancy and lactation is not available. 4.7 Effects on ability to drive and use machines Not relevant 4.8 Undesirable effects The safety of the vaccine was assessed in different controlled clinical studies in which more than 18,000 healthy infants (6 weeks to 18 months) were included. The majority of the safety experience comes from the efficacy trial in which 17,066 infants received 55,352 doses of Prevenar. Also safety in previously unvaccinated older children has been assessed. In all studies, Prevenar was administered concurrently with the recommended childhood vaccines. Amongst the most commonly reported adverse reactions were injection site reactions and fever. No consistent increased local or systemic reactions within repeated doses were seen throughout the primary series Or with the boosterdose, the exceptions being a higher rate of transient tenderness (36.5 %) and tenderness that interfered with limb movement (18.5 %) were seen with the booster dose. In older children receiving a single dose of vaccine, a higher rate of local reactions has been observed than that previously described in infancy. These reactions were primarily transient in nature. In a post licensure study involving 115 children between 2-5 years of age, tenderness was reported in up to 39.1 % of children; in 15.7 % of children the tenderness interfered with limb movement. Redness was reported in 40.0 % of children, and induration was reported in 32.2 % of subjects. Redness of induration >2cm in diameter was reported in 22.6 % and 13.9 % of children respectively. When Prevenar is co-administered with hexavalent vaccines (DTaP/Hib(PRP-T)/IPV/HepB), fever 38 C per dose was reported in 28.3 % to 48.3 % of infants in the group receiving Prevenar and the hexavalent vaccine at the same time as compared to 15.6 % to 23.4 % in the group receiving the hexavalent vaccine alone. Fever of greater than 39.5 C per dose was observed in 0.6 to 2.8 % of infants receiving Prevenar and hexavalent vaccines (see section 4.4). Reactogenicity was higher in children receiving whole cell pertussis vaccines concurrently. In a study, including 1,662 children, fever of 38 C was reported in 41.2 % of children who received Prevenar simultaneously with DTP as compared to 27.9 % in the control group. Fever of > 39 C was reported in 3.3 % of children compared to 1.2 % in the control group.

14 Undesirable effects reported in clinical trials or from the post-marketing experience are listed in the following table per body system and per frequency and this is for all age groups. The frequency is defined as follows: very common: 10 %, common: 1 % and < 10 %, uncommon: 0.1 % and < 1 %, rare: 0.01 % and < 0.1 %, very rare: < 0.01 %. Blood and lymphatic system disorders: Very rare: Lymphadenopathy localised to the region of the injection site Nervous system disorders: Rare: Seizures, including febrile seizures. Gastrointestinal disorders: Very common: Decreased appetite, vomiting, diarrhoea. Skin and subcutaneous tissue disorders: Uncommon: Rash/urticaria. Very rare: Erythema multiforme. General disorders and administration site conditions: Very common: Injection site reactions (e.g. erythema, induration/swelling, pain/tenderness); fever 38 C, irritability, drowsiness, restless sleep. Common: Injection site swelling/induration and erythema >2.4 cm, tenderness interfering with movement, fever > 39 C. Rare: Hypotonic hyporesponsive episode, injection site hypersensitivity reactions (eg., dermatitis, pruritus, urticaria). Immune system disorders: Rare: Hypersensitivity reaction including face oedema, angioneurotic oedema, dyspnoea, bronchospasm, anaphylactic/anaphylactoid reaction including shock. 4.9 Overdose There have been reports of overdose with Prevenar, including cases of administration of a higher than recommended dose and cases of subsequent doses administered closer than recommended to the previous dose. No undesirable effects were reported in the majority of individuals. In general, adverse events reported with overdose have also been reported with recommended single doses of Prevenar. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: pneumococcal vaccines, ATC code: J07AL Estimates of efficacy against invasive disease were obtained in the US population where vaccine serogroup coverage ranged from %. Epdemiological data between 1998 and 2003 indicated that in Europe coverage is lower and varies from country to country. The coverage established for children less than 2 years of age is lower in the Northern part and higher in the Southern part of Europe. Consequently, Prevenar will cover between 71 % and 86 % of isolates

15 from invasive pneumococcal disease (IPD) in European children less than 2 years of age. More than 80 % of the antimicrobial resistant strains are covered by the serotypes included in the vaccine. The vaccine serotype coverage in the pediatric population decreases with increasing age. In European children between 2 to 5 years of age, Prevenar should cover about 50 % to 75 % of the clinical isolates responsible for invasive pneumococcal disease. The decrease in the incidence of IPD seen in older children may be partly due to naturally acquired immunity. Efficacy against invasive disease Efficacy against invasive disease was assessed in a large-scale randomised double-blind clinical trial in a multiethnic population in Northern California (Kaiser Permanente trial). More than 37,816 infants were immunised with either Prevenar or a control vaccine (meningococcal conjugate group C vaccine), at 2, 4, 6 and months of age. At the time of the study, the serotypes included in the vaccine accounted for 89 % of IPD. A total of 52 cases of invasive disease caused by vaccine serotype had accumulated in a blinded follow-up period through April 20, The estimate of vaccine serotype specific efficacy was 94 % (81, % CI) in the intent-to-treat population and 97 % (85, % CI) in the per protocol (fully immunized) population (40 cases). The corresponding estimates for vaccine serogroups are 92 % (79, % CI) for the intent-to-treat population and 97 % (85, % CI) for the fully immunized population. In Europe, the estimates of effectiveness range from 65 % to 79 % when considering vaccine coverage of serogroups causing invasive disease. In the Kaiser trial, efficacy was 87 % (7, % CI) against bacteraemic pneumonia due to vaccine serotypes of S. pneumoniae. Effectiveness (no microbiological confirmation of diagnosis was performed) against pneumonia was also assessed. The estimated risk reduction for clinical pneumonia with abnormal X-ray was 33 % (6, % CI) and for clinical pneumonia with consolidation was 73 % (36, % CI) in the intent-to-treat analysis. Additional clinical data Results from clinical trials support efficacy of Prevenar against otitis media due to vaccine serotypes, but the effectiveness was lower than in invasive disease. Efficacy of Prevenar against acute otitis media (AOM) was assessed as a primary endpoint in a randomised double blind clinical trial of 1,662 Finnish infants and as a secondary endpoint in the Northern California trial. The estimate for vaccine efficacy against vaccine-serotype AOM in the Finnish trial was 57 % (44, % CI). In the intent-to-treat analysis the vaccine efficacy was 54 % (41, % CI). A 34 % increase in AOM due to non-vaccine serogroups was observed in immunised subjects. However, the overall benefit was a statistically significant reduction (34 %) in the incidence of all pneumococcal AOM. For recurrent otitis media ( 3 episodes in 6 months or 4 in 12 months), the impact of the vaccine was a statistically non-significant 16 % reduction (-6, % CI) in the Finnish trial. In the Northern California trial, the impact of the vaccine was a statistically significant 9.5 % reduction (3, % CI). In Northern California, there was also a 20 % (2, % CI) reduction in the placement of ear tubes in vaccine recipients. In the Finnish trial, the impact of the vaccine on total number of episodes of otitis media regardless of etiology was a statistically non-significant 6 % reduction (-4, 16-95% CI) while in

16 the Northern California trial the impact of the vaccine was a statistically significant 7 % reduction (4, 10-95% CI). Immunogenicity Vaccine induced antibody to capsular polysaccharide specific of each serotype are considered protective against invasive disease. The minimum protective antibody concentration against invasive disease has not been determined for any serotype. A significant antibody response was seen following three and four doses to all vaccine serotypes in infants that received Prevenar, although geometric mean concentrations varied among serotypes. For all serotypes, peak primary series responses were seen after 3 doses, with boosting following the 4 th dose. Prevenar induces functional antibodies to all vaccine serotypes, as measured by opsonophagocytosis following the primary series. Long-term persistence of antibodies after completion of immunisation has not been investigated in infants and older children (catch-up immunisation). A plain polysaccharide challenge at 13 months following the primary series with Prevenar elicited an anamnestic antibody response for the 7 serotypes included in the vaccine which is indicative for priming. A significant antibody response to all vaccine serotypes was seen after one dose of Prevenar in children aged 2 to 5 years. The vaccination with one dose of Prevenar in children aged 2 to 5 years resulted in similar immune responses to that seen following the primary series in infants and toddlers who were less than 2 years of age, in whom clinical effectiveness (protection) was demonstrated. Efficacy trials in the 2-to 5-year-old population have not been conducted. Data on the immunogenicity of Prevenar administered at 3 and 5 months with a booster dose at 12 months of age are available from an open-label, uncontrolled clinical study conducted in Sweden in 83 infants. At the age of 13 months, one month after dose 3, geometric mean concentration (GMC) of serotype-specific antibody concentrations were substantially increased, ranging from 4.59 microgram/ml (serotype 23F) to microgram/ml (serotype 14) and were comparable for all serotypes to those achieved following a fourth dose in European or U.S. infants immunized with a 4-dose series. However, at the age of 6 months, after 2 doses, GMC values for the seven vaccine serotypes were not all comparable to those seen in infants after 3 doses. For five serotypes, the GMC values ranged from 2.47 microgram/ml (serotype 18C) to 5.03 microgram/ml (serotype 19F), but for serotype 6B the GMC was 0.3 microgram/ml and for 23F the GMC was 0.88 microgram/ml. Lower antibody levels after two priming doses at 3 and 5 months of age to two serotypes (6B and 23F) as compared to a 3-dose priming schedule were observed at the 6 months time point. Responses to the third (booster) dose indicated adequate priming and resulted in comparable antibody levels to all serotypes as after the booster dose in the 3-dose priming schedule. The clinical relevance of these observations remains unknown. 5.2 Pharmacokinetic properties Evaluation of pharmacokinetic properties is not available 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.

17 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Sodium chloride Water for injections 6.2 Incompatibilities In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. 6.3 Shelf life 3 years 6.4 Special precautions for storage Store at 2 C 8 C (in a refrigerator). Do not freeze. 6.5 Nature and contents of container 0.5 ml suspension for injection in vial (Type I glass) with a grey butyl rubber stopper - pack size of 1 and 10 vials without syringe/needles. Pack size of 1 vial with syringe and 2 needles (1 for withdrawal, 1 for injection). Not all pack sizes may be marketed. 6.6 Instructions for use and handling, and disposal Upon storage, a white deposit and clear supernatant can be observed. The vaccine should be well shaken to obtain a homogeneous white suspension and be inspected visually for any particulate matter and/or variation of physical aspect prior to administration. Do not use if the content appears otherwise. 7. MARKETING AUTHORISATION HOLDER Wyeth Lederle Vaccines S.A. Rue du Bosquet, 15 B-1348 Louvain-la-Neuve Belgium 8. MARKETING AUTHORISATION NUMBER(S) EU/1/00/167/001 EU/1/00/167/002

18 EU/1/00/167/ DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 02/02/ DATE OF REVISION OF THE TEXT

864 现代药物与临床 Drugs & Clinic 第 31 卷第 6 期 2016 年 6 月 of apoptosis related factors, decrease the incidence of adverse reactions, which is of great

864 现代药物与临床 Drugs & Clinic 第 31 卷第 6 期 2016 年 6 月 of apoptosis related factors, decrease the incidence of adverse reactions, which is of great 现代药物与临床 Drugs & Clinic 第 31 卷第 6 期 2016 年 6 月 863 曲妥珠单抗联合多西紫杉醇治疗 Her-2 阳性乳腺癌的临床研究 * 周永安, 刘训碧黄石市中心医院 ( 普爱院区 ) 乳腺肿瘤外科, 湖北黄石 435000 摘要 : 目的探析注射用曲