Vaccine Information: VAXNEUVANCE (Page 2 of 3)

7 DRUG INTERACTIONS

7.1 Immunosuppressive Therapies

Immunosuppressive therapies may reduce the immune response to this vaccine [see Warnings and Precautions (5.1)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. 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 VAXNEUVANCE in pregnant women. Available data on VAXNEUVANCE administered to pregnant women are insufficient to inform vaccine-associated risks in pregnancy.

Developmental toxicity studies have been performed in female rats administered a human dose of VAXNEUVANCE on four occasions; twice prior to mating, once during gestation and once during lactation. These studies revealed no evidence of harm to the fetus due to VAXNEUVANCE [see Animal Data below].

Data

Animal Data

Developmental toxicity studies have been performed in female rats. In these studies, female rats received a human dose of VAXNEUVANCE by intramuscular injection on day 28 and day 7 prior to mating, and on gestation day 6 and on lactation day 7. No vaccine related fetal malformations or variations were observed. No adverse effect on pup weight up to post-natal day 21 was noted.

8.2 Lactation

Risk Summary

Human data are not available to assess the impact of VAXNEUVANCE on milk production, its presence in breast milk, or its effects on the breastfed child. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for VAXNEUVANCE and any potential adverse effects on the breastfed child from VAXNEUVANCE or from the underlying maternal condition. For preventive vaccines, the underlying condition is susceptibility to disease prevented by the vaccine.

8.4 Pediatric Use

The safety and effectiveness of VAXNEUVANCE in individuals younger than 18 years of age have not been established.

8.5 Geriatric Use

Of the 4,389 individuals aged 50 years and older who received VAXNEUVANCE, 2,478 (56.5%) were 65 years and older, and 479 (10.9%) were 75 years and older [see Adverse Reactions (6.1) and Clinical Studies (14.1)]. Overall, there were no clinically meaningful differences in the safety profile or immune responses observed in older individuals (65 to 74 years and 75 years of age and older) when compared to younger individuals.

8.6 Individuals at Increased Risk for Pneumococcal Disease

Adults with HIV Infection

In a double-blind, descriptive study (Study 7), the safety and immunogenicity of VAXNEUVANCE were evaluated in pneumococcal vaccine-naïve HIV-infected adults 18 years of age and older, with CD4+ T-cell count ≥50 cells per microliter and plasma HIV RNA value <50,000 copies/mL. Participants were randomized to receive VAXNEUVANCE (N=152) or Prevnar 13 (N=150), followed by PNEUMOVAX 23 two months later [see Adverse Reactions (6.1)]. Anti-pneumococcal opsonophagocytic activity (OPA) geometric mean antibody titers (GMTs) were higher after administration of VAXNEUVANCE, compared to pre-vaccination, for the 15 serotypes contained in VAXNEUVANCE. After sequential administration with PNEUMOVAX 23, OPA GMTs observed at 30 days after PNEUMOVAX 23 vaccination were numerically similar between the two vaccination groups for all 15 serotypes contained in VAXNEUVANCE. The safety profile of VAXNEUVANCE was similar between the two vaccination groups. The effectiveness of VAXNEUVANCE in HIV-infected individuals has not been evaluated.

11 DESCRIPTION

VAXNEUVANCE (Pneumococcal 15-valent Conjugate Vaccine) is a sterile suspension of purified capsular polysaccharides from S. pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 33F individually conjugated to CRM197 . Each pneumococcal capsular polysaccharide is activated via sodium metaperiodate oxidation and then individually conjugated to CRM197 carrier protein via reductive amination. CRM197 is a non-toxic variant of diphtheria toxin (originating from Corynebacterium diphtheriae C7) expressed recombinantly in Pseudomonas fluorescens.

Each of the fifteen serotypes is manufactured independently using the same manufacturing steps with slight variations to accommodate for differences in strains, polysaccharides and process stream properties. Each S. pneumoniae serotype is grown in media containing yeast extract, dextrose, salts and soy peptone. Each polysaccharide is purified by a series of chemical and physical methods. Then each polysaccharide is chemically activated and conjugated to the carrier protein CRM197 to form each glycoconjugate. CRM197 is isolated from cultures grown in a glycerol-based, chemically-defined, salt medium and purified by chromatography and ultrafiltration. The final vaccine is prepared by blending the fifteen glycoconjugates with aluminum phosphate adjuvant in a final buffer containing histidine, polysorbate 20 and sodium chloride.

Each 0.5 mL dose contains 2.0 mcg each of S. pneumoniae polysaccharide serotypes 1, 3, 4, 5, 6A, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 33F, and 4.0 mcg of polysaccharide serotype 6B, 30 mcg of CRM197 carrier protein, 1.55 mg L-histidine, 1 mg of polysorbate 20, 4.50 mg sodium chloride, and 125 mcg of aluminum as aluminum phosphate adjuvant. VAXNEUVANCE does not contain any preservatives.

The tip cap and plunger stopper of the prefilled syringe are not made with natural rubber latex.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Protection against invasive disease is conferred mainly by opsonophagocytic killing of S. pneumoniae. VAXNEUVANCE induces opsonophagocytic activity against the serotypes contained in the vaccine.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

VAXNEUVANCE has not been evaluated for carcinogenic or mutagenic potential or for impairment of male fertility in animals. VAXNEUVANCE administered to female rats had no effect on fertility [see Use in Specific Populations (8.1)] .

14 CLINICAL STUDIES

Immune responses elicited by VAXNEUVANCE and Prevnar 13 were measured by a multiplexed opsonophagocytic antibody assay (MOPA) for the 15 pneumococcal serotypes contained in VAXNEUVANCE pre- and post- vaccination.

14.1 Clinical Trials in Pneumococcal Vaccine-Naïve Adults

Study 1

Study 1 assessed serotype-specific opsonophagocytic activity (OPA) responses for each of the 15 serotypes contained in VAXNEUVANCE at 30 days postvaccination in a double-blind, active comparator-controlled study that enrolled pneumococcal vaccine-naïve participants 50 years of age and older. Participants were randomized to receive either VAXNEUVANCE (N=604) or Prevnar 13 (N=601) at sites in USA, Canada, Spain, Taiwan, and Japan. The mean age of participants was 66 years and 57.3% were female. The racial distribution was as follows: 67.7% were White, 25.1% were Asian, 6.1% were Black or African American and 22.0% were of Hispanic or Latino ethnicity.

Table 4 summarizes the OPA geometric mean antibody titers (GMTs) at 30 days postvaccination for the 15 serotypes contained in VAXNEUVANCE. The study demonstrated that VAXNEUVANCE is noninferior to Prevnar 13 for the 13 shared serotypes and induces statistically significantly greater OPA GMTs compared to Prevnar 13 for shared serotype 3 and for the 2 unique serotypes (22F, 33F).

Table 4: Serotype-Specific OPA GMTs in Pneumococcal Vaccine-Naïve Adults 50 Years of Age and Older (Study 1)
PneumococcalSerotype VAXNEUVANCE(N = 602) Prevnar 13(N = 600) GMT Ratio *(VAXNEUVANCE/Prevnar 13)(95% CI)*
n GMT * n GMT *
N=Number of participants randomized and vaccinated; n=Number of participants contributing to the analysis that had at least one pre-dose OPA measurement (VAXNEUVANCE, n=537-597; Prevnar 13, n=545-595) or post-dose OPA measurement (VAXNEUVANCE, n=568-580; Prevnar 13, n=528-574).CI=confidence interval; cLDA=constrained longitudinal data analysis; GMT=geometric mean titer; OPA=opsonophagocytic activity
*
GMTs, GMT ratio, and 95% CI are estimated from a cLDA model.
Non-inferiority for the 13 shared serotypes was met if the lower bound of the 95% CI for the GMT ratio (VAXNEUVANCE/Prevnar 13) was > 0.5.
Statistically significantly greater OPA GMT for serotype 3 was based on the lower bound of the 95% CI for the estimated GMT ratio (VAXNEUVANCE/Prevnar 13) > 1.2.
§
Statistically significantly greater OPA GMTs for serotypes 22F and 33F was based on the lower bound of the 95% CI for the estimated GMT ratio (VAXNEUVANCE/Prevnar 13) > 2.0.
Serotype
1 598 257 598 321 0.80 (0.66, 0.97)
3 598 215 598 133 1.62 (1.40, 1.87)
4 598 1109 598 1633 0.68 (0.57, 0.80)
5 598 445 598 560 0.79 (0.64, 0.98)
6A 596 5371 596 5276 1.02 (0.85, 1.22)
6B 598 3984 598 3179 1.25 (1.04, 1.51)
7F 596 4575 596 5830 0.78 (0.68, 0.90)
9V 598 1809 597 2193 0.83 (0.71, 0.96)
14 598 1976 598 2619 0.75 (0.64, 0.89)
18C 598 2749 598 2552 1.08 (0.91, 1.27)
19A 598 3177 597 3921 0.81 (0.70, 0.94)
19F 598 1688 598 1884 0.90 (0.77, 1.04)
23F 598 2029 598 1723 1.18 (0.96, 1.44)
Additional Serotypes §
22F 594 2381 585 73 32.52 (25.87, 40.88)
33F 598 8010 597 1114 7.19 (6.13, 8.43)

Study 3

In a double-blind, active comparator-controlled, descriptive study (Study 3), pneumococcal vaccine-naïve adults 50 years of age and older were randomized to receive either VAXNEUVANCE (N=327) or Prevnar 13 (N=325), followed by PNEUMOVAX 23 one year later.

Following vaccination with PNEUMOVAX 23, OPA GMTs were numerically similar between the two vaccination groups for the 15 serotypes in VAXNEUVANCE.

Study 4

In a double-blind, descriptive study (Study 4), adults 18 through 49 years of age, including individuals with increased risk of developing pneumococcal disease, were randomized to receive VAXNEUVANCE (N=1,135) or Prevnar 13 (N=380), followed by PNEUMOVAX 23 six months later [see Adverse Reactions (6.1)]. Among those who received VAXNEUVANCE, 620 participants had one risk factor and 228 participants had two or more risk factors for pneumococcal disease.

Table 5 presents OPA GMTs in the overall study population for each of the 15 serotypes 30 days following vaccination with VAXNEUVANCE or Prevnar 13.

Table 5: Serotype-Specific OPA GMTs in Pneumococcal Vaccine-Naïve Adults 18 through 49 Years of Age With or Without Risk Factors for Pneumococcal Disease (Study 4)
PneumococcalSerotype VAXNEUVANCE(N = 1,133) Prevnar 13(N = 379)
n Observed GMT 95% CI * n Observed GMT 95% CI *
N=Number of participants randomized and vaccinated; n=Number of participants contributing to the analysis. CI=confidence interval; GMT=geometric mean titer; OPA=opsonophagocytic activity.
*
The within-group 95% CIs are obtained by exponentiating the CIs of the mean of the natural log values based on the t-distribution.
Serotype
1 1004 267 (242, 295) 337 267 (220, 324)
3 990 198 (184, 214) 336 150 (129, 173)
4 1001 1401 (1294, 1517) 338 2568 (2268, 2908)
5 1003 560 (508, 618) 339 731 (613, 873)
6A 994 12763 (11772, 13838) 333 11313 (9739, 13141)
6B 999 10164 (9486, 10891) 338 6958 (5987, 8086)
7F 1004 5725 (5382, 6090) 338 7583 (6762, 8503)
9V 1000 3353 (3132, 3590) 339 3969 (3541, 4449)
14 1001 5245 (4860, 5660) 339 5863 (5191, 6623)
18C 999 5695 (5314, 6103) 339 3050 (2685, 3465)
19A 1001 5335 (4985, 5710) 339 5884 (5221, 6632)
19F 1003 3253 (3051, 3468) 339 3272 (2949, 3631)
23F 1001 4828 (4443, 5247) 337 3876 (3323, 4521)
Additional Serotypes
22F 991 3939 (3654, 4246) 317 291 (221, 383)
33F 999 11734 (10917, 12612) 334 2181 (1826, 2606)

Following vaccination with PNEUMOVAX 23, the OPA GMTs for the 15 serotypes in VAXNEUVANCE were numerically similar among subjects who had received VAXNEUVANCE or Prevnar 13 for the first vaccination.

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