PREVNAR-20 8 Adverse Reactions

8.1 Adverse Reaction Overview

Adults 18 Years of Age and Older

The safety profile is based on the analysis of three Phase 3 clinical trials (see 14 CLINICAL TRIALS). There were 4,263 adult participants who received PREVNAR 20, which included 3,639 adults that were naïve to pneumococcal vaccines, 253 that had previously received the 23-valent pneumococcal polysaccharide vaccine, (Pneumovax® 23 [PPSV23]) only, 246 that had previously received PREVNAR 13 only, and 125 that had previously received both PPSV23 and PREVNAR 13. The most commonly reported solicited adverse reactions (>10%) were vaccination-site pain/tenderness, muscle pain, fatigue, headache and joint pain. Overall, the serious adverse events (SAEs) reported were consistent with diseases and conditions observed in adults of different age groups, and none were considered to be related to the study vaccine. In all three Phase 3 trials, PREVNAR 20 demonstrated a tolerability and safety profile similar to that of PREVNAR 13.

Infants, Children and Adolescents 6 Weeks Through 17 Years of Age

The safety of PREVNAR 20 was evaluated in 5,987 participants 6 weeks through 17 years of age in four randomized, double-blind, active-controlled clinical trials and one single-arm clinical trial (one Phase 2 and four Phase 3 trials); 3,664 participants received at least 1 dose of PREVNAR 20, and 2,323 participants received PREVNAR 13 (control vaccine). Across all 5 trials, there were similar percentages of male and female participants among the PREVNAR 20 recipients and the PREVNAR 13 recipients. Overall, 83.5% of PREVNAR 20 recipients were White, 7.9% Black, 1.6% Asian, and 24.0% Hispanic, with similar distribution among PREVNAR 13 recipients.

Infants and Children 6 Weeks to <15 Months of Age

Clinical trials were conducted in healthy infants and children 6 weeks to <15 months of age using a 3-dose series (Phase 3 Study 1012) or a 4-dose series (Phase 3 Studies 1011 and 1013 and Phase 2 Study 1003). In these 4 infant trials 5,156 participants received at least 1 dose of vaccine: 2,833 received PREVNAR 20 and 2,323 received PREVNAR 13. Overall, approximately 90% of participants in each group received all doses through the study-specified toddler dose. In all studies, local reactions and systemic events were collected after each dose, and adverse events were collected from the first dose through 1 month after the last infant vaccination and from the toddler dose through 1 month after the toddler dose in all studies. Serious adverse events were evaluated through 1 month after the last dose in Study 1012 and 6 months after the last dose in Studies 1011, 1013, and 1003.

PREVNAR 20 was well tolerated when administered on a 3-dose and a 4-dose series in the infant study populations, with low rates of severe local reactions and systemic events, and most reactions resolving within 1 to 3 days. The percentages of participants with reactogenicity events after PREVNAR 20 were generally similar to those after PREVNAR 13. Based on the infant data, the most frequently reported local reactions and systemic events after any dose of PREVNAR 20 were irritability, drowsiness, and pain at injection site. In these studies, PREVNAR 13 was co-administered or permitted to be administered with certain routine pediatric vaccines (see 14.2.3 Concomitant Vaccine Administration).

Study 1012 was a double-blind, active-controlled Phase 3 trial, in which 601 healthy infants, 2 months (≥42 to ≤112 days) of age and born at >36 weeks of gestation received PREVNAR 20 in a 3-dose series. The most frequently reported adverse reactions (>10%) after any dose of PREVNAR 20 were irritability (71.0% to 71.9%), drowsiness/increased sleep (50.9% to 61.2%), pain at injection site (22.8% to 42.4%), decreased appetite (24.7% to 39.3%), redness at injection site (25.3% to 36.9%), swelling at injection site (21.4% to 29.8%) and fever of ≥38.0°C (8.9% to 24.3%). Most adverse reactions occurred within 1 to 2 days following vaccination and were mild to moderate in severity and of short duration (1 to 2 days).

Studies 1011, 1013 and 1003 were double-blind, randomized, active-controlled trials that included 2,232 healthy infants vaccinated with PREVNAR 20 in a 4-dose series. The most frequently reported adverse reactions (>10%) observed after any dose of PREVNAR 20 in infants were irritability (58.5% to 70.6%), drowsiness/increased sleep (37.7% to 66.2%), pain at injection site (32.8% to 45.5%), decreased appetite (23.0% to 26.4%), redness at injection site (22.6% to 24.5%) and swelling at injection site (15.1% to 17.6%). Most adverse reactions were mild or moderate following vaccination and severe reactions were reported infrequently. In Study 1013, the local reactions and systemic events in the preterm subgroup (111 infants born at 34 to <37 weeks of gestation) were similar to or lower than the term infants in the study. In the preterm subgroup the frequency of any reported local reaction (31.7% to 55.3% in the PREVNAR 20 group and 37.9% to 47.1% in the PREVNAR 13 group) and systemic event (65.0% to 85.5% in the PREVNAR 20 group and 59.4% to 77.4% in the PREVNAR 13 group) were similar after PREVNAR 20 and PREVNAR 13. Most adverse reactions occurred within 1 to 2 days following vaccination and were mild to moderate in severity and of short duration (1 to 3 days).

The frequency and severity of the adverse reactions in all infant clinical trials were generally similar in the PREVNAR 20 and PREVNAR 13 groups.

Children and Adolescents 15 Months through 17 Years of Age

In Phase 3 Study 1014, 831 participants 15 months through 17 years of age received a single dose of PREVNAR 20 in four age groups (209 participants 15 to <24 months of age; 216 participants 2 years to <5 years of age; 201 participants 5 years to <10 years age; and 205 participants 10 years to <18 years of age). The participants <5 years of age had received at least 3 prior doses of PREVNAR 13.

The most frequently reported adverse reactions (>10%) observed after any dose of PREVNAR 20 in participants <2 years of age were irritability (61.8%), pain at injection site (52.5%), drowsiness/ increased sleep (41.7%), redness at injection site (37.7%), decreased appetite (25.0%), swelling at injection site (22.1%) and fever ≥38.0°C (11.8%). In participants aged 2 years and older, the most frequently reported adverse reactions were pain at injection site (66.0% to 82.9%), muscle pain (26.5% to 48.3%), redness at injection site (15.1% to 39.1%), fatigue (27.8% to 37.2%), headache (5.6% to 29.3%), and swelling at injection site (15.6% to 27.1%). Most adverse reactions occurred within 1 to 2 days following vaccination and were mild to moderate in severity and of short duration (1 to 3 days).

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials, therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

Adults 18 Years of Age and Older

Solicited Adverse Reactions

The frequency of solicited adverse reactions in adults <65 years of age naïve to pneumococcal vaccination and in adults ≥65 years of age by prior pneumococcal vaccination status are shown in Table 2 and Table 3, respectively. Local adverse reactions (redness, swelling, and pain at the injection site) were prompted daily for 10 consecutive days after vaccination. Systemic adverse events (fever, fatigue, headache, muscle pain, and joint pain) were prompted daily for 7 days after vaccination.

In general, the median onset day for local reactions was between Day 1 (day of vaccination) to Day 2.5, and they resolved with a median duration of 1 to 2 days. The median onset day for most systemic events was generally between Day 1 to Day 3.5, and they resolved with a median duration of 1 to 2 days.

8.2.1 Clinical Trial Adverse Reactions - Pediatrics 

Children 6 Weeks Through 17 Years of Age

Infants and Toddlers Receiving a Routine Vaccination Schedule

The percentages of infants and toddlers with solicited local reactions and systemic events that occurred within 7 days after each dose of PREVNAR 20 or PREVNAR 13 following a 3-dose or 4-dose series are shown in Tables 4 and 5, respectively.

Study 1012 (Table 4) evaluated a 3-dose series of either PREVNAR 20 or PREVNAR 13 with a first dose given at 42 to 112 days of age, a second dose approximately 2 months later, and the third dose at 11 to 12 months of age. Participants received concomitant vaccines at these visits (see 14.2.3 Concomitant Vaccine Administration).

Studies 1003, 1011 and 1013 evaluated a 4-dose series of either PREVNAR 20 or PREVNAR 13 given at approximately 2, 4, 6, and 12 to 15 months of age (12 months of age for Study 1003). Participants received concomitant vaccines at these visits (see 14.2.3 Concomitant Vaccine Administration). Table 5 presents pooled data from these 3 studies.

1. N = number of participants with any e-diary data reported after vaccination. This value is the denominator for percentage calculations.
2. Any: >0.0 cm; Moderate: >2.0 to 7.0 cm; severe: >7.0 cm.
3. Any: any pain at injection site; Moderate: hurts if gently touched with crying; Severe: causes limitation of arm movement.

1. N = number of participants with any e-diary data reported after vaccination. This value is the denominator for percentage calculations.
2. Any: >0.0 cm; Moderate: >2.0 to 7.0 cm; severe: >7.0 cm.
3. Any: any pain at injection site; Moderate: hurts if gently touched with crying; Severe: causes limitation of arm movement

Safety with Concomitant Vaccine Administration in Infants and Toddlers

The safety profile of PREVNAR 20 was acceptable, and similar to PREVNAR 13 when administered concomitantly with routine pediatric vaccines containing diphtheria, tetanus, acellular pertussis, hepatitis B virus, poliovirus, and Haemophilus influenzae type b antigens; measles, mumps, and rubella antigens; and varicella antigens.

Children 15 Months Through 17 Years of Age

Study 1014 evaluated the safety of a single dose of PREVNAR 20 in children 15 months through 17 years of age. The percentages of children (by age group) with solicited local reactions and systemic events that occurred within 7 days after a dose of PREVNAR 20 or PREVNAR 13 are shown in Table 6. The types of solicited systemic events collected in the participants 15 months to <2 years of age were consistent with those collected in infants, while the solicited systemic events in children ≥2 years of age required verbal communication by the participant. 

1. N = number of participants with any e-diary data reported after vaccination. This value is the denominator for percentage calculations.
2. Any: >0.0 cm; Moderate: >2.0 to 7.0 cm; severe: >7.0 cm.
3. For participants 15 months to <24 months of age: Any: any pain at injection site; Moderate: hurts if gently touched with crying; Severe: causes limitation of arm movement. For participants 2 years to <18 years of age: Any: any pain at injection site; Moderate: interferes with activity; Severe: prevents daily activity.
4. For participants 15 months to <24 months of age, solicited systemic events were fever, decreased appetite, drowsiness/increased sleep and irritability. For participants 2 years to <18 years of age, solicited systemic events were fever, fatigue, headache, muscle pain and joint pain.

8.2.2 Additional Information in Immunocompromised Patients in Studies with PREVNAR 13

Children and adolescents 6 through 17 years of age with SCD, HIV infection or HSCT who received PREVNAR 13 had similar frequencies of adverse reactions as children and adolescents 2 through 17 years of age who received PREVNAR 13, except vaccination-site pain causing limitation of limb movement, joint pain, fever, headache, vomiting, diarrhea, fatigue and muscle pain had a frequency category of very common (≥1/10).

Adults 18 years and older with HIV infection who received PREVNAR 13 had similar frequencies of adverse reactions as adults 18 years of age and older who received PREVNAR 13, except that fever and vomiting had a frequency category of Very Common (≥1/10) and nausea had a frequency category of Common (≥1/100 to <1/10).

Adults 18 years and older with a HSCT who received PREVNAR 13 had similar frequencies of adverse reactions as adults 18 years and older who received PREVNAR 13, except that fever, diarrhea and vomiting had a frequency category of Very Common (≥1/10).

8.3 Less Common Clinical Trial Adverse Reactions

Adults 18 Years of Age and Older

Listed below are the less common adverse reactions reported in adult clinical trials with PREVNAR 20 (Uncommon frequency ≥1/1,000 to <1/100).

Immune system disorders: Hypersensitivity reaction, including face edema, dyspnea, bronchospasm

Gastrointestinal disorders: Diarrhea, nausea, vomiting

Skin and subcutaneous tissue disorders: Rash, angioedema

General disorders and administration site conditions: Vaccination-site pruritus, lymphadenopathy, vaccination-site urticaria, chills

8.3.1 Less Common Clinical Trial Adverse Reactions - Pediatrics

Less common adverse reactions reported in children 6 weeks to <5 years of age in PREVNAR 20 pediatric clinical trials included vomiting (1.4%), diarrhea (1.0%), rash (1.0%), urticaria or urticaria-like rash (0.5%), seizures (including febrile seizures) (0.4%) and vaccination site hypersensitivity (<0.1%).

Less common adverse reactions reported in the PREVNAR 20 pediatric clinical in children 5 to <18 years of age included urticaria or urticaria-like rash (0.5%).

Additionally, as PREVNAR 20 contains the same 13 serotype-specific capsular polysaccharide conjugates and the same vaccine excipients as PREVNAR 13, the adverse reactions already identified and listed below for PREVNAR 13 have been adopted for PREVNAR 20. In clinical trials, the safety profile of PREVNAR 20 was similar to that of PREVNAR 13. The frequencies below are defined as follows: very common (≥10%), common (≥1% to <10%), uncommon (≥0.1% to <1%), and rare (≥0.01% to <0.1%). For the following adverse reactions reported only for PREVNAR 13 in clinical trials, but not also reported in PREVNAR 20 clinical trials, the frequency is unknown for PREVNAR 20.

Adverse reactions reported for infants and children 6 weeks to <5 years of age in PREVNAR 13 clinical trials:

Immune system disorders: Hypersensitivity reaction, including face edema, dyspnea, bronchospasm (rare)

Nervous system disorders: Hypotonic-hyporesponsive episode (rare), restless sleep/decreased sleep (very common)

Psychiatric disorders: Crying (uncommon)

Adverse reactions reported for children and adolescents 5 years to <18 years of age in PREVNAR 13 clinical trials:

Gastrointestinal disorders: Diarrhea (common), vomiting (common)

Metabolism and nutrition disorders: Decreased appetite (very common)

Nervous system disorders: Drowsiness/increased sleep (very common), restless sleep/decreased sleep (very common)

Psychiatric disorders: Irritability (very common)

Skin and subcutaneous tissue disorders: Rash (common)

8.5 Post-Market Adverse Reactions

Post-marketing Experience with PREVNAR 13

The following adverse reactions have been reported since market introduction of PREVNAR 13, and 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. These adverse reactions reported in the post-marketing experience of PREVNAR 13 in pediatric and adult populations may also be seen in post-marketing experience with PREVNAR 20 as the components of PREVNAR 13 are also contained in PREVNAR 20.