CAPVAXIVE - Merck Sharp & Dohme LLC

Administer a single 0.5 mL dose.

CAPVAXIVE is a colorless, clear to opalescent solution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if particulate matter or discoloration is observed. Administer intramuscularly.

Appropriate medical treatment must be immediately available to manage potential anaphylactic reactions following administration of CAPVAXIVE.

Syncope (fainting) may occur in association with administration of injectable vaccines. Procedures should be in place to avoid injury from fainting.

Individuals with altered immunocompetence, including those receiving immunosuppressive therapy, may have a reduced immune response to CAPVAXIVE.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared with rates in the clinical trials of another vaccine and may not reflect the rates observed in practice.

The most commonly reported (>10%) solicited adverse reactions in individuals 18 through 49 years of age who received CAPVAXIVE were: injection-site pain (73.1%), fatigue (36.0%), headache (27.5%), myalgia (16.4%), injection-site erythema (13.8%), and injection-site swelling (13.3%).

The most commonly reported (>10%) solicited adverse reactions in individuals 50 years of age and older who received CAPVAXIVE were: injection-site pain (41.2%), fatigue (19.7%), and headache (11.0%).

The most commonly reported (>10%) solicited adverse reactions in individuals 2 through 17 years of age who are at increased risk for pneumococcal disease were injection-site pain (67.7%), injection-site erythema (24.3%), fatigue (20.1%), injection-site swelling (18.8%), headache (17.1%), malaise (13.3%), and irritability (11.6%).

Safety Assessment in Clinical Studies

In all studies, safety was monitored using an electronic Vaccination Report Card for 30 days postvaccination. Injection-site adverse reactions, systemic adverse reactions, and body temperature were solicited Day 1 through Day 5 postvaccination. At subsequent visits, approximately 7 to 30 days postvaccination, individuals or parents/guardians reviewed vaccination report cards with study investigators and, when necessary, made corrections or clarifications. Unsolicited adverse events were reported Day 1 through Day 30 postvaccination. Serious adverse events (SAEs) were reported through 6 months postvaccination in all studies.

Demographics of Individuals in Clinical Studies

Across Studies 1-4, the mean age of the individuals who were randomized and vaccinated was 53.5 years, and 57.2% were female. The racial distribution was as follows: 76.0% were White, 10.2% were Black or African American, 9.9% were Asian, and 0.5% were American Indian or Alaska Native; 20.6% were of Hispanic or Latino ethnicity. Approximately 34% of vaccinated individuals had one or more prespecified chronic medical conditions known to increase the risk of pneumococcal disease (i.e., diabetes, renal disorders, chronic heart disease, chronic liver disease, chronic lung disease including asthma, smoking, alcoholism).

In Study 6, in individuals with one or more prespecified medical conditions, the mean age of those who were randomized and vaccinated was 52.6 years and 45.2% were female. The racial distribution was as follows: 76.6% were White, 3.5% were Black or African American, 14.3% were Asian, and 0.2% were American Indian or Alaska Native; 26.4% were of Hispanic or Latino ethnicity.

In Study 7, in individuals 2 through 17 years of age with one or more prespecified chronic medical conditions known to increase the risk of pneumococcal disease and who have previously completed a primary pneumococcal vaccine regimen, the mean age of those who were randomized and vaccinated was 8.0 years and 41.1% were female. The racial distribution was as follows: 59.6% were White, 5.7% were Black or African American, 9.6% were Asian, and 10.4% were American Indian or Alaska Native; 44.4% were of Hispanic or Latino ethnicity.

Pneumococcal Vaccine-Naïve Individuals 18 years of Age and Older

In a double-blind study, Study 1, individuals 18 years of age and older who had not previously received a pneumococcal vaccine were enrolled and randomized to receive a single dose of CAPVAXIVE or Prevnar 20. The percentage of individuals 18 through 49 years of age and 50 years of age and older who reported solicited adverse reactions that occurred within 5 days postvaccination of CAPVAXIVE or Prevnar 20 is shown in Table 2. Solicited adverse reactions following administration of CAPVAXIVE lasted a median of 2 days with 81.3% of reactions lasting ≤3 days for individuals 18 through 49 years of age and a median of 1 day with 86.5% of reactions lasting ≤3 days for individuals 50 years of age and older.

In Study 2, individuals 18 through 49 years of age who had not previously received a pneumococcal vaccine were enrolled and randomized to receive a single dose of CAPVAXIVE or PNEUMOVAX 23. The percentage of individuals 18 through 49 years of age with solicited adverse reactions that occurred within 5 days postvaccination of CAPVAXIVE or PNEUMOVAX 23 is shown in Table 3.

Individuals 50 years of Age and Older Who Previously Received Pneumococcal Vaccines

Study 3 enrolled individuals 50 years of age and older who had previously received a pneumococcal vaccine at least 1 year prior to enrollment. Participants were enrolled into 1 of 3 cohorts based on their pneumococcal vaccination history (cohort 1: PNEUMOVAX 23, cohort 2: Prevnar 13, or cohort 3: PNEUMOVAX 23 followed by or preceded by Prevnar 13, PNEUMOVAX 23 preceded by VAXNEUVANCE, or VAXNEUVANCE alone). Participants in cohort 1 were randomized to receive CAPVAXIVE or VAXNEUVANCE, participants in cohort 2 were randomized to receive CAPVAXIVE or PNEUMOVAX 23, and participants in cohort 3 received CAPVAXIVE. The percentage of individuals with solicited adverse reactions that occurred within 5 days postvaccination of CAPVAXIVE or active comparator is shown in Table 4.

Safety with Concomitant Influenza Vaccine Administration

In Study 4, individuals 50 years of age and older with or without a history of prior pneumococcal vaccination were enrolled and randomized to receive either CAPVAXIVE and quadrivalent influenza vaccine [Fluzone Quadrivalent, (QIV)] concomitantly followed by placebo 30 days later (concomitant group), or QIV and placebo concomitantly followed by CAPVAXIVE 30 days later (sequential group).

In Study 4, the rates and severity of solicited systemic adverse reactions and solicited local adverse reactions at the CAPVAXIVE injection-site were similar when CAPVAXIVE was administered with or without inactivated QIV.

Serious Adverse Events in Individuals 18 years of Age and Older

Across studies 1-4, the proportion of individuals reporting 1 or more SAEs within 1-month postvaccination was 0.3% in individuals vaccinated with CAPVAXIVE (n=14) and 0.3% in individuals vaccinated with an active comparator (n=7). The proportion of individuals reporting 1 or more SAEs within 6 months postvaccination was 1.4% in individuals vaccinated with CAPVAXIVE (n=56) and 2.0% in individuals vaccinated with an active comparator (n=40). There were no notable patterns or imbalances between vaccine groups for SAEs. Two individuals who received CAPVAXIVE had SAEs considered related to vaccination. One individual experienced an acute allergic reaction of bronchospasm (Grade 3, required medical intervention) which occurred within 30 minutes postvaccination; one individual experienced injection-site cellulitis (Grade 4, required hospitalization) on Day 6 postvaccination.

In Study 6, no SAEs were considered to be related to CAPVAXIVE.

Individuals 2 through 17 years of Age at Increased Risk for Pneumococcal Disease

In Study 7, individuals 2 through 17 years of age with one or more prespecified medical conditions known to increase the risk of pneumococcal disease and who have previously completed a primary pneumococcal vaccination regimen at least 8 weeks prior to enrollment were randomized to receive a single dose of CAPVAXIVE or PNEUMOVAX 23. The percentage of individuals with solicited adverse reactions that occurred within 5 days postvaccination of CAPVAXIVE or PNEUMOVAX 23 is shown in Table 5. Injection-site pain was reported in 67.7% of participants in the CAPVAXIVE group and 54.5% in the PNEUMOVAX 23 group, and injection-site erythema was reported in 24.3% and 16.4% of participants, respectively. Solicited adverse reactions following administration of CAPVAXIVE lasted a median of 2 days (range of 1 to 12 days) with 88.1% of reactions lasting ≤3 days, and 98.2% of reactions lasting ≤5 days.

Serious Adverse Events in Individuals 2 through 17 years of Age at Increased Risk for Pneumococcal Disease

In Study 7, the proportion of individuals reporting 1 or more SAEs within 6 months postvaccination was 5.5% (n=29) in individuals vaccinated with CAPVAXIVE and 7.2% (n=25) in individuals vaccinated with PNEUMOVAX 23. There were no notable patterns or imbalances between vaccine groups for SAEs. A 5 year old individual (0.2%) who received CAPVAXIVE was hospitalized for syncope, which occurred approximately 3 minutes postvaccination and was considered related to vaccination.

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 CAPVAXIVE in pregnant individuals. Data on CAPVAXIVE administered to pregnant individuals are insufficient to inform vaccine-associated risks in pregnancy.

A developmental toxicity study has been performed in female rats administered 0.25 mL of a conjugated polysaccharide vaccine formulation on four occasions: twice prior to mating, once during gestation, and once during lactation. This study revealed no adverse effects on fetal or preweaning development [see Animal Data below].

Data

Animal Data

In a developmental toxicity study, female rats were administered 0.25 mL of a conjugated polysaccharide vaccine formulation containing the same conjugated polysaccharides as in CAPVAXIVE. Animals received 42 mcg polysaccharide per dose (a full human dose of CAPVAXIVE contains 84 mcg polysaccharide/dose) by intramuscular injection on four occasions: 28 and 7 days prior to mating, on gestation day 6, and on lactation day 7. There were no embryofetal deaths or fetal malformations, and no adverse effects on female fertility and preweaning development were observed.

Risk Summary

Human data are not available to assess the impact of CAPVAXIVE 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 CAPVAXIVE and any potential adverse effects on the breastfed child from CAPVAXIVE or from the underlying maternal condition. For preventive vaccines, the underlying condition is susceptibility to disease prevented by the vaccine.

The safety and effectiveness of CAPVAXIVE in individuals younger than 2 years of age have not been established.

Across studies 1-4, of the 4,556 individuals who received CAPVAXIVE, 1,487 individuals (32.6%) were 65 years of age and older, and 339 individuals (7.4%) were 75 years of age and older. In Study 1, of the 1,379 individuals who received CAPVAXIVE, 590 individuals (42.8%) were 65 years of age and older, and 126 individuals (9.1%) were 75 years of age and older. No clinically meaningful differences in safety of CAPVAXIVE were observed between these individuals and individuals less than 65 years of age. The opsonophagocytic activity (OPA) responses in individuals 65 years of age and older were generally lower than those observed in individuals less than 65 years of age.

In a double-blind descriptive study, Study 5, 313 individuals 18 years of age and older living with HIV, with CD4+ Tcells/μL ≥50 and plasma HIV ribonucleic acid (RNA) <50,000 copies/mL, with or without a history of prior pneumococcal vaccination, were randomized in a 1:1 ratio to receive either CAPVAXIVE followed by placebo 8 weeks later, or VAXNEUVANCE followed by PNEUMOVAX 23 (VAXNEUVANCE + PNEUMOVAX 23) 8 weeks later. At screening, of the participants vaccinated, 6.7% had a CD4+ T-cell counts ≥50 to <350 cells/μL, 18.6% had CD4+ Tcell counts ≥350 to <500 cells/μL, and 74.7% had CD4+ Tcell counts ≥500 cells/μL; 83% had an undetectable HIV viral load (<20 copies/mL).

The mean age of those who were randomized and vaccinated was 45.3 years and 29.2% were female. The racial distribution was as follows: 47.8% were White, 39.7% were Black or African American, 10.6% were Asian, and 0.6% were American Indian or Alaska Native; 24.4% were of Hispanic or Latino ethnicity.

Following vaccination with CAPVAXIVE, the most frequently reported (>10%) solicited adverse reactions were: injection-site pain (48.4%), fatigue (21.3%), and headache (16.8%). No SAEs were considered to be related to CAPVAXIVE.

OPA geometric mean titers (GMTs) at 1-month postvaccination in participants who received CAPVAXIVE were numerically similar to those in participants who received VAXNEUVANCE + PNEUMOVAX 23 for the 13 shared serotypes. CAPVAXIVE OPA GMTs at 1-month postvaccination were numerically higher for the 8 serotypes unique to CAPVAXIVE compared with VAXNEUVANCE + PNEUMOVAX 23. The effectiveness of CAPVAXIVE in individuals with HIV has not been established.

Protection against invasive pneumococcal disease is conferred mainly by opsonophagocytic killing of S. pneumoniae. CAPVAXIVE induces OPA against 22 S. pneumoniae serotypes. The de-O-acetylated polysaccharide from serotype 15B has a molecular structure similar to the polysaccharide from serotype 15C and induces OPA to serotype 15C. The deOAc15B also induces cross-reactive OPA against serotype 15B. An OPA titer that is predictive of protection against invasive pneumococcal disease or pneumococcal pneumonia has not been established.

CAPVAXIVE has not been evaluated for carcinogenic or mutagenic potential or for impairment of male fertility in animals.

The effectiveness of CAPVAXIVE in individuals 18 years of age and older for the prevention of invasive disease caused by S. pneumoniae serotypes 3, 6A, 7F, 8, 9N, 10A, 11A, 12F, 15A, 15B, 15C, 16F, 17F, 19A, 20A, 22F, 23A, 23B, 24F, 31, 33F and 35B and for the prevention of pneumonia caused by S. pneumoniae serotypes 3, 6A, 7F, 8, 9N, 10A, 11A, 12F, 15A, 15C, 16F, 17F, 19A, 20A, 22F, 23A, 23B, 24F, 31, 33F, and 35B was demonstrated based on comparative immunogenicity to a licensed pneumococcal vaccine (Prevnar 20).

Pneumococcal Vaccine-Naïve Individuals 50 years of Age and Older

In Study 1, 2,362 pneumococcal vaccine-naïve individuals 50 years of age and older were randomized to receive either CAPVAXIVE or Prevnar 20. [see Adverse Reactions (6.1)].

Table 6 summarizes the 21 serotype-specific OPA geometric mean antibody titers (GMTs) at 30 days postvaccination. The study demonstrated that CAPVAXIVE is noninferior to Prevnar 20 for the 10 shared serotype polysaccharides and induces statistically significantly greater OPA GMTs compared with Prevnar 20 for 10 of 11 serotype polysaccharides unique to CAPVAXIVE. Serotype 15C did not meet the criterion for statistical significance.

Table 7 summarizes the proportion of individuals who achieved a ≥4-fold rise from prevaccination to 1-month postvaccination for OPA responses. For 10 of 11 serotype polysaccharides unique to CAPVAXIVE, CAPVAXIVE induced statistically significantly greater OPA responses compared with Prevnar 20. Serotype 15C did not meet the criterion for statistical significance.

In Study 1, 64.7% of individuals 50 years of age and older, who received CAPVAXIVE, had ≥4-fold rise in cross-reactive OPA titers for serotype 15B, which met the prespecified success criterion (lower bound of the 2-sided 95% CI of the proportion of individuals with a ≥4-fold rise in OPA responses is >50%). In a descriptive analysis, the S. pneumoniae serotype 15B OPA GMT was 4,400.6 following administration of CAPVAXIVE, and 4,640.0 following administration of Prevnar 20, with a GMT ratio of 0.95 (95% CI: 0.84, 1.07).

Pneumococcal Vaccine-Naïve Individuals 18 through 49 years of Age

In Study 1, pneumococcal vaccine-naïve individuals 18 through 49 years of age were randomized in a 2:1 ratio to receive CAPVAXIVE or Prevnar 20. [see Adverse Reactions (6.1)].

Effectiveness of CAPVAXIVE in individuals 18 through 49 years of age was assessed by a comparison of the OPA responses induced by CAPVAXIVE in this age group to the OPA responses of individuals 50 through 64 years of age. The OPA responses of individuals 18 through 49 years of age to each of 22 S. pneumoniae serotypes met the criteria for immunobridging as the lower bound of the 2-sided 95% CI for the GMT ratio for each serotype was >0.5 (see Table 8). The S. pneumoniae serotype 15B cross-reactive OPA GMT was 10,976.7 following administration of CAPVAXIVE in individuals 18 through 49 years of age and 5,438.9 following administration of CAPVAXIVE in individuals 50 through 64 years of age, with a GMT ratio of 2.02 (95% CI: 1.57, 2.60).

Individuals 50 years of Age and Older with Prior Pneumococcal Vaccination

Study 3, a descriptive Phase 3 study, enrolled individuals 50 years of age and older who were previously vaccinated with other pneumococcal vaccines at least 1 year prior to study entry. Participants were enrolled into 1 of 3 cohorts based on their pneumococcal vaccination history (cohort 1: PNEUMOVAX 23, cohort 2: Prevnar 13, or cohort 3: PNEUMOVAX 23 followed by or preceded by Prevnar 13, PNEUMOVAX 23 preceded by VAXNEUVANCE, or VAXNEUVANCE alone).

Participants in cohort 1 were randomized to receive CAPVAXIVE (n=231) or VAXNEUVANCE (n=119), participants in cohort 2 were randomized to receive CAPVAXIVE (n=176) or PNEUMOVAX 23 (n=85), and participants in cohort 3 were allocated to receive CAPVAXIVE (n=106).

In each of the 3 cohorts, serotype-specific OPA GMTs and the proportion of individuals with ≥4-fold rise in OPA responses from baseline to 1-month postvaccination were assessed. In Cohort 1, CAPVAXIVE elicited OPA responses that were comparable to VAXNEUVANCE for the 6 shared serotypes, and higher for the 15 unique serotypes and serotype 15B. In Cohort 2, CAPVAXIVE elicited OPA responses comparable to PNEUMOVAX 23 for the 12 shared serotypes and serotype 15B, and higher for the 9 unique serotypes. OPA responses to CAPVAXIVE were similar across the 3 cohorts of participants who previously received one or more pneumococcal vaccines.

Individuals 18 through 64 years of Age at Increased Risk of Pneumococcal Disease due to Certain Medical Conditions

In a double-blind descriptive study, Study 6, 518 pneumococcal vaccine-naïve individuals 18 years through 64 years of age at increased risk of pneumococcal disease due to one or more prespecified medical conditions were randomized in a 3:1 ratio to receive either CAPVAXIVE followed by placebo 8 weeks later, or VAXNEUVANCE followed by PNEUMOVAX 23 (VAXNEUVANCE + PNEUMOVAX 23) 8 weeks later. Among the vaccinated participants with one condition increasing the risk of pneumococcal disease, 194 (37.6%) had diabetes mellitus, 99 (19.2%) had chronic lung disease, 84 (16.3%) had chronic heart disease, 34 (6.6%) had chronic liver disease, and 23 (4.5%) had chronic kidney disease. 82 (15.9%) participants had ≥2 increased risk conditions.

OPA GMTs at 1-month postvaccination in participants who received CAPVAXIVE were numerically similar to those in participants who received VAXNEUVANCE + PNEUMOVAX 23 for the 13 shared serotypes. CAPVAXIVE OPA GMTs at 1-month postvaccination were numerically higher for the 8 serotypes unique to CAPVAXIVE compared with VAXNEUVANCE + PNEUMOVAX 23.

In a double-blind study (Study 7), 882 individuals 2 through 17 years of age, with one or more prespecified medical conditions known to increase the risk of pneumococcal disease who completed a primary pneumococcal vaccination regimen at least 8 weeks prior to enrollment, were randomized in a 3:2 ratio to receive either CAPVAXIVE or PNEUMOVAX 23. Among the vaccinated participants, 499 (57.1%) had chronic lung disease, 143 (16.4%) had chronic heart disease, 135 (15.4%) had diabetes mellitus, 76 (8.7%) had chronic kidney disease, 60 (6.9%) had chronic liver disease, and 36 (4.1%) had ≥2 increased risk conditions.

The study demonstrated that CAPVAXIVE was noninferior to PNEUMOVAX 23 for the 12 shared serotypes and induced statistically significantly greater OPA GMTs compared to PNEUMOVAX 23 for the 9 serotypes unique to CAPVAXIVE (Table 9).

CAPVAXIVE also elicited immune responses to serotype 15B (cross-reactive to serotype 15C). In Study 7, 86.1% of individuals 2 through 17 years of age who received CAPVAXIVE had ≥4-fold rise in cross-reactive OPA titers for serotype 15B. In a post hoc analysis, the S. pneumoniae serotype 15B OPA GMT was 18,395.6 following administration of CAPVAXIVE, and 4,863.4 following administration of PNEUMOVAX 23, with a GMT ratio of 3.78 (95% CI: 3.03, 4.73). Utilizing the same pre-specified non-inferiority criterion that was used for the shared serotypes, CAPVAXIVE was non-inferior to PNEUMOVAX 23 for serotype 15B.

In a double-blind study (Study 4), 1,080 individuals 50 years of age and older, with or without a history of prior pneumococcal vaccination, were randomized in a 1:1 ratio. One vaccination group received CAPVAXIVE and QIV concomitantly, followed by placebo 30 days later (concomitant group). A second vaccination group received QIV and placebo concomitantly, followed by CAPVAXIVE 30 days later (sequential group). Antibody responses were assessed 1-month postvaccination.

The OPA responses to CAPVAXIVE administered concomitantly with QIV were non-inferior to the OPA responses to CAPVAXIVE administered sequentially after QIV for 20 of 21 serotypes [lower bound of the 2-sided 95% CI of the GMT ratio (concomitant group/sequential group) was >0.5]; the non-inferiority was not met for serotype 23B [lower bound of the 2-sided 95% CI of the GMT ratio (concomitant group/sequential group) was 0.44]. The OPA response to serotype 15B was not assessed for non-inferiority. In a descriptive analysis, the OPA GMT in the concomitant group was 3,438.7 and in the sequential group was 4,440.5, with a GMT ratio of 0.77 (95% CI: 0.64, 0.94). The influenza strain-specific hemagglutination inhibition (HAI) responses to QIV administered concomitantly with CAPVAXIVE were non-inferior to the HAI responses to QIV administered alone for 3 of 4 influenza strains [lower bound of the 2-sided 95% CIs for HAI GMT ratios (concomitant group/sequential group) was >0.67 (non-inferiority margin); the lower bound was 0.67 for the A/H3N2 influenza strain].

Store refrigerated at 2°C to 8°C (36°F to 46°F).

Do not freeze. Protect from light.

The tip cap and plunger stopper are not made with natural rubber latex.