Vaccine Information: Prevnar 20 (Page 3 of 6)

6.2 Postmarketing Experience With Prevnar 13

The postmarketing safety experience with Prevnar 13 in individuals 6 weeks of age and older is relevant to Prevnar 20 since the vaccines are manufactured and formulated similarly and contain 13 of the same polysaccharide conjugates. These adverse reactions are included based on one or more of the following factors: severity, frequency of reporting, or strength of evidence for a causal relationship to Prevnar 13 vaccine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to product exposure. The following adverse reactions have been spontaneously reported during postapproval use of Prevnar 13 and may also be seen in postmarketing experience with Prevnar 20.

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Blood and lymphatic system disorders: Lymphadenopathy localized to the region of the injection site

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Cardiac disorders: Cyanosis (pediatric populations only)

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General Disorders and Administration Site Conditions: Vaccination-site dermatitis, vaccination-site pruritus, vaccination-site urticaria

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Immune System Disorders: Anaphylactic/anaphylactoid reaction, including shock

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Nervous system disorders: Hypotonia (pediatric populations only

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Respiratory: Apnea (pediatric populations only)

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Skin and Subcutaneous Tissue Disorders: Angioneurotic edema, Erythema multiforme

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Vascular disorders: Pallor (pediatric populations only)

7 DRUG INTERACTIONS

7.1 Prior Vaccination With PNEUMOVAX 23

In adults, receipt of PPSV23 1 to 5 years prior to Prevnar 20 resulted in diminished OPA geometric mean titers (GMTs) to Prevnar 20 compared to OPA GMTs in recipients who received Prevnar 13 at least 6 months prior to Prevnar 20, and compared to OPA GMTs in recipients who received Prevnar 13 followed by PPSV23, with the last dose of PPSV23 given at least 1 year prior to Prevnar 20 [see Clinical Studies (14.2)].

7.2 Immunosuppressive Therapies

Individuals with impaired immune responsiveness due to the use of immunosuppressive therapy (including irradiation, corticosteroids, antimetabolites, alkylating agents, and cytotoxic agents) may not respond optimally to Prevnar 20.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

All pregnancies have a risk of birth defect, loss, or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. There are no adequate and well-controlled studies of Prevnar 20 in pregnant women. Available data on Prevnar 20 administered to pregnant women are insufficient to inform vaccine-associated risks in pregnancy.

A developmental toxicity study was performed in female rabbits administered Prevnar 20 prior to mating and during gestation. The dose was 0.5 mL at each occasion (a single human dose is 0.5 mL). This study revealed no evidence of harm to the fetus due to Prevnar 20 (see Data).

Data

Animal Data

In a developmental toxicity study, female rabbits were administered Prevnar 20 by intramuscular injection twice prior to mating (17 days and 4 days prior to mating) and twice during gestation (Gestation Days 10 and 24), 0.5 mL/rabbit/occasion (a single human dose). No adverse effects on pre-weaning development were observed. There were no vaccine-related fetal malformations or variations.

8.2 Lactation

Risk Summary

It is not known whether Prevnar 20 is excreted in human milk. Data are not available to assess the effects of Prevnar 20 on the breastfed infant or on milk production/excretion. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Prevnar 20 and any potential adverse effects on the breastfed child from Prevnar 20 or from the underlying maternal condition. For preventive vaccines, the underlying maternal condition is susceptibility to disease prevented by the vaccine.

8.4 Pediatric Use

The safety of Prevnar 20 has been established in individuals 6 weeks through 17 years of age [see Adverse Reactions (6.1)].

The effectiveness of Prevnar 20 for the prevention of invasive disease caused by S. pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15B, 18C, 19A, 19F, 22F, 23F, and 33F has been established in individuals 6 weeks through 17 years of age [see Clinical Studies (14.2)].

The effectiveness of Prevnar 20 for the prevention of otitis media caused by serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F has been established in individuals 6 weeks through 5 years of age [see Clinical Studies (14.1)].

The effectiveness of Prevnar 20 in infants and children initiating vaccination at 7 months through 17 years of age and in children 15 months through 17 years of age previously vaccinated or incompletely vaccinated with a pneumococcal conjugate vaccine is supported by evidence from clinical studies in younger children who received a 4-dose series of Prevnar 20 and by evidence from clinical studies of catch-up vaccination with Prevnar 13 and Prevnar.

The effectiveness of Prevnar 20 for the prevention of pneumonia has not been established in individuals younger than 18 years of age.

The safety and effectiveness of Prevnar 20 in individuals younger than 6 weeks of age have not been established.

8.5 Geriatric Use

Of the total number of Prevnar 20 recipients 18 years of age and older evaluated for safety in the 3 main clinical trials (N=4263), 26.7% (n=1138) were 65 years of age and older and 1.7% (n=72) were 80 years of age and older [see Clinical Studies (14.2)].

Prevnar 20 recipients 70 through 79 years of age and ≥80 years of age had lower OPA GMTs for all pneumococcal serotypes compared to Prevnar 20 recipients 18 through 49 years, 50 through 59, and 60 through 64 years of age [see Clinical Studies (14.1)].

11 DESCRIPTION

Prevnar 20, Pneumococcal 20-valent Conjugate Vaccine is a sterile suspension of saccharides of the capsular antigens of S. pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15B, 18C, 19A, 19F, 22F, 23F, and 33F, individually linked to non-toxic diphtheria CRM₁₉₇ protein. Each serotype is grown in soy peptone broth. The individual polysaccharides are purified by a series of chemical and physical methods. The polysaccharides are chemically activated and then directly conjugated to the carrier protein CRM₁₉₇ , to form the glycoconjugate. CRM₁₉₇ is a non-toxic variant of diphtheria toxin isolated from cultures of Corynebacterium diphtheriae strain C7 (β197) grown in a casamino acids and yeast extract-based medium or in a chemically-defined medium. CRM₁₉₇ is purified by a series of chemical and physical methods. The individual glycoconjugates are purified by a series of chemical and physical methods and analyzed for saccharide to protein ratios, molecular size, free saccharide, and free protein.

The individual glycoconjugates are compounded to formulate Prevnar 20. Potency of the formulated vaccine is determined by quantification of each of the saccharide antigens and by the saccharide to protein ratios in the individual glycoconjugates. Each 0.5 mL dose of the vaccine is formulated to contain approximately 2.2 μg of each of S. pneumoniae serotypes 1, 3, 4, 5, 6A, 7F, 8, 9V, 10A, 11A, 12F, 14, 15B, 18C, 19A, 19F, 22F, 23F, 33F saccharides, 4.4 μg of 6B saccharides, 51 μg CRM₁₉₇ carrier protein, 100 μg polysorbate 80, 295 μg succinate buffer, 4.4 mg sodium chloride, and 125 μg aluminum as aluminum phosphate adjuvant.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Protection against pneumococcal disease is conferred mainly by antibodies (immunoglobulin G [IgG] directed against capsular polysaccharides) and OPA killing of S. pneumoniae. Prevnar 20 induces IgG antibodies and OPA against the 20 vaccine serotypes.

An opsonic antibody titer or serotype-specific IgG concentration that is predictive of protection against invasive pneumococcal disease or pneumococcal pneumonia has not been established.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Prevnar 20 has not been evaluated for the potential to cause carcinogenicity, genotoxicity, or impairment of male fertility. Vaccination of female rabbits with Prevnar 20 had no effect on female fertility [see Use in Specific Populations (8.1)].

14 CLINICAL STUDIES

14.1 Prevnar and Prevnar 13 Efficacy Data

Efficacy and effectiveness of Prevnar and Prevnar 13 are relevant to Prevnar 20, since Prevnar, Prevnar 13 and Prevnar 20 are manufactured similarly. In addition, Prevnar and Prevnar 20 contain 7 of the same polysaccharide conjugates and Prevnar 13 and Prevnar 20 contain 13 of the same polysaccharide conjugates.

Prevnar Efficacy Data in Children

Invasive Pneumococcal Disease (IPD)

Prevnar was licensed in the United States for infants and children in 2000, following a randomized, double‑blind, clinical trial in a multiethnic population at Northern California Kaiser Permanente (NCKP) from October 1995 through August 20, 1998, 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 12 through 15 months of age. In this study, the efficacy of Prevnar against invasive disease due to S. pneumoniae in cases accrued during this period was 100% in both the per-protocol and intent-to-treat analyses (95% confidence interval [CI]: 75.4%, 100% and 81.7%, 100%, respectively). Data accumulated through an extended follow-up period to April 20, 1999, resulted in similar efficacy estimates of 97.4% in the per-protocol analysis and 93.9% in the intent-to-treat analysis (95% CI: 82.7%, 99.9% and 79.6%, 98.5%, respectively).

Acute Otitis Media (AOM)

The efficacy of Prevnar against otitis media was assessed in 2 clinical trials: a trial in Finnish infants at the National Public Health Institute and the efficacy trial in US infants at NCKP.

The Finnish Otitis Media (FinOM) trial was a randomized, double-blind trial in which 1,662 infants were equally randomized to receive either Prevnar or a control vaccine Recombivax HB (Hepatitis B vaccine (Recombinant) [Hep B]) at 2, 4, 6, and 12 through 15 months of age. In this study, conducted between December 1995 and March 1999, parents of study participants were asked to bring their children to the study clinics if the child had respiratory infections or symptoms suggesting AOM. If AOM was diagnosed, tympanocentesis was performed, and the middle-ear fluid was cultured. If S. pneumoniae was isolated, serotyping was performed. The primary endpoint was efficacy against AOM episodes caused by vaccine serotypes in the per-protocol population.

The vaccine efficacy against AOM episodes due to vaccine serotypes assessed in the Finnish trial was 57% (95% CI: 44%, 67%) in the per-protocol population and 54% (95% CI: 41%, 64%) in the intent-to-treat population. The vaccine efficacy against AOM episodes due to vaccine-related serotypes (6A, 9N, 18B, 19A, 23A), also assessed in the Finnish trial, was 51% (95% CI: 27, 67) in the per-protocol population and 44% (95% CI: 20, 62) in the intent-to-treat population. There was a nonsignificant increase in AOM episodes caused by serotypes unrelated to the vaccine in the per-protocol population, compared to children who received the control vaccine, suggesting that children who received Prevnar appeared to be at increased risk of otitis media due to pneumococcal serotypes not represented in the vaccine. However, vaccination with Prevnar reduced pneumococcal otitis media episodes overall. In the NCKP trial, in which the endpoint was all otitis media episodes regardless of etiology, vaccine efficacy was 7% (95% CI: 4%, 10%) and 6% (95% CI: 4%, 9%), respectively, in the per-protocol and intent-to-treat analyses. Several other otitis media endpoints were also assessed in the 2 trials.

In the NCKP trial, the efficacy of Prevnar against otitis media was assessed from the beginning of the trial in October 1995 through April 1998. The otitis media analysis included 34,146 infants randomized to receive either Prevnar (N=17,070), or the control vaccine (N=17,076), at 2, 4, 6, and 12 through 15 months of age. In this trial, no routine tympanocentesis was performed, and no standard definition of otitis media was used by study physicians. The primary otitis media endpoint was efficacy against all otitis media episodes in the per‑protocol population. Recurrent AOM, defined as 3 episodes in 6 months or 4 episodes in 12 months, was reduced by 9% in both the per-protocol and intent-to-treat populations (95% CI: 3%, 15% in per-protocol and 95% CI: 4%, 14% in intent-to-treat) in the NCKP trial; a similar trend was observed in the Finnish trial. The NCKP trial also demonstrated a 20% reduction (95% CI: 2, 35) in the placement of tympanostomy tubes in the per-protocol population and a 21% reduction (95% CI: 4, 34) in the intent-to-treat population. Data from the NCKP trial accumulated through an extended follow-up period to April 20, 1999, in which a total of 37,866 children were included (18,925 in Prevnar group and 18,941 in MnCC control group), resulted in similar otitis media efficacy estimates for all endpoints.

Prevnar 13 Adult Efficacy Data

The efficacy of Prevnar 13 against vaccine-type (VT) pneumococcal community-acquired pneumonia (CAP) and IPD was assessed in a randomized, double-blind, placebo-controlled study (Community-Acquired Pneumonia Immunization Trial in Adults [CAPiTA]) conducted over ~4 years in the Netherlands. A total of 84,496 participants 65 years of age and older received a single dose of either Prevnar 13 or placebo in a 1:1 randomization; 42,240 participants were vaccinated with Prevnar 13 and 42,256 participants were vaccinated with placebo. Chronic medical conditions (asthma, diabetes, heart, liver, and/or lung diseases) were reported in 42.3% of study participants at baseline.

The primary objective was to demonstrate the efficacy of Prevnar 13 in the prevention of a first episode of confirmed VT-CAP (defined as presence of ≥2 specified clinical criteria, chest X-ray consistent with CAP as determined by a central committee of radiologists, and positive VT-specific urinary antigen detection assay [UAD] or isolation of VT S. pneumoniae from blood or other sterile site). The secondary objectives were to demonstrate the efficacy of Prevnar 13 in the prevention of a first episode of 1) confirmed nonbacteremic/noninvasive (NB/NI) VT-CAP (an episode of VT-CAP for which the blood culture result and any other sterile site culture results were negative for S. pneumoniae) and 2) VT-IPD (the presence of S. pneumoniae in a sterile site).

Surveillance for suspected pneumonia and IPD began immediately after vaccination and continued through identification of a prespecified number of cases. Participants who had a CAP or IPD episode with symptom onset less than 14 days after vaccination were excluded from all analyses.

The median duration of follow-up per participant was 3.93 years. Prevnar 13 demonstrated statistically significant vaccine efficacy (VE) in preventing first episodes of VT pneumococcal CAP, NB/NI VT pneumococcal CAP, and VT-IPD (see Table 8).

Table 8. Vaccine Efficacy for the Primary and Secondary Efficacy Endpoints – Per-Protocol Population

Abbreviations: CAP = community-acquired pneumonia; CI = confidence interval; NB/NI = nonbacteremic/noninvasive; IPD = invasive pneumococcal disease; VE = vaccine efficacy; VT = vaccine-type.
		Vaccine Group
		Prevnar 13	Placebo
		N=42,240	N=42,256
Efficacy Endpoint	Total Number of Episodes	n	N	VE (%)	(95.2% CI)
Primary endpoint: First case of confirmed VT pneumococcal CAP	139	49	90	45.6	(21.8, 62.5)
Secondary endpoint: First episode of confirmed NB/NI VT pneumococcal CAP	93	33	60	45	(14.2, 65.3)
Secondary endpoint: First episode of VT-IPD	35	7	28	75	(41.1, 90.9)