PREVNAR 13 (pneumococcal 13-valent conjugate vaccine) injection, suspension
Wyeth Pharmaceutical Division of Wyeth Holdings LLC
1 INDICATIONS AND USAGE
In children 6 weeks through 5 years of age (prior to the 6th birthday), Prevnar 13 is indicated for:
- active immunization for the prevention of invasive disease caused by Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F. (1.1)
- active immunization for the prevention of otitis media caused by S. pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F. No otitis media efficacy data are available for serotypes 1, 3, 5, 6A, 7F, and 19A. (1.1)
In children 6 years through 17 years of age (prior to the 18th birthday), Prevnar 13 is indicated for:
- active immunization for the prevention of invasive disease caused by S. pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F. (1.2)
In adults 18 years of age and older, Prevnar 13 is indicated for:
- active immunization for the prevention of pneumonia and invasive disease caused by S. pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F. (1.3)
Limitations of Prevnar 13 Use and Effectiveness
- Prevnar 13 does not protect against disease caused by S. pneumoniae serotypes that are not in the vaccine. (1.4)
1.1 Children 6 Weeks Through 5 Years of Age
In children 6 weeks through 5 years of age (prior to the 6th birthday), Prevnar 13® is indicated for:
- active immunization for the prevention of invasive disease caused by Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F.
- active immunization for the prevention of otitis media caused by S. pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F. No otitis media efficacy data are available for serotypes 1, 3, 5, 6A, 7F, and 19A.
1.2 Children 6 Years Through 17 Years of Age
In children 6 years through 17 years of age (prior to the 18th birthday), Prevnar 13 is indicated for:
- active immunization for the prevention of invasive disease caused by S. pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F.
1.3 Adults 18 Years of Age and Older
- In adults 18 years of age and older, Prevnar 13 is indicated for:
- active immunization for the prevention of pneumonia and invasive disease caused by S. pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F.
1.4 Limitations of Prevnar 13 Use and Effectiveness
- Prevnar 13 does not protect against disease caused by S. pneumoniae serotypes that are not in the vaccine.
2 DOSAGE AND ADMINISTRATION
2.1 Preparation for Administration
Since this product is a suspension containing an adjuvant, shake vigorously immediately prior to use to obtain a homogenous, white suspension in the vaccine container. Do not use the vaccine if it cannot be resuspended. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration [see Description (11)]. This product should not be used if particulate matter or discoloration is found.
Do not mix Prevnar 13 with other vaccines/products in the same syringe.
2.2 Administration Information
For intramuscular injection only.
Each 0.5 mL dose is to be injected intramuscularly using a sterile needle attached to the supplied prefilled syringe. The preferred sites for injection are the anterolateral aspect of the thigh in infants and the deltoid muscle of the upper arm in toddlers, children and adults. The vaccine should not be injected in the gluteal area or areas where there may be a major nerve trunk and/or blood vessel.
2.3 Vaccination Schedule for Infants and Toddlers
Prevnar 13 is to be administered as a four-dose series at 2, 4, 6, and 12–15 months of age.
Dose | Dose 1 Dose 1 may be given as early as 6 weeks of age. , The recommended dosing interval is 4 to 8 weeks. | Dose 2 | Dose 3 | Dose 4 The fourth dose should be administered at approximately 12–15 months of age, and at least 2 months after the third dose. |
---|---|---|---|---|
Age at Dose |
2 months |
4 months |
6 months |
12–15 months |
2.4 Vaccination Schedule for Unvaccinated Children 7 Months Through 5 Years of Age
For children 7 months through 5 years of age who have not received Prevnar® or Prevnar 13, the catch-up schedule in Table 2 applies:
Age at First Dose | Total Number of 0.5 mL Doses |
---|---|
7–11 months of age |
3The first 2 doses at least 4 weeks apart; third dose after the one-year birthday, separated from the second dose by at least 2 months. |
12–23 months of age |
2Two doses at least 2 months apart. |
24 months through 5 years of age (prior to the 6th birthday) |
1 |
The immune responses induced by this catch-up schedule may result in lower antibody concentrations for some serotypes, compared to antibody concentrations following 4 doses of Prevnar 13 (given at 2, 4, 6, and 12–15 months). In children 24 months through 5 years of age, lower antibody concentrations were observed for some serotypes, compared to antibody concentrations following 3 doses of Prevnar 13 (given at 2, 4, and 6 months).
2.5 Vaccination Schedule for Children 6 Years Through 17 Years of Age
In children 6 years through 17 years of age, Prevnar 13 is administered as single dose. If Prevnar was previously administered, then at least 8 weeks should elapse before receiving Prevnar 13.
2.6 Vaccination Schedule for Adults 18 Years of Age and Older
- Prevnar 13 is administered as a single dose.
3 DOSAGE FORMS AND STRENGTHS
Prevnar 13 is a suspension for intramuscular injection available in 0.5 mL single-dose prefilled syringes.
0.5 mL suspension for intramuscular injection, supplied in a single-dose prefilled syringe. (3)
4 CONTRAINDICATIONS
- Severe allergic reaction (e.g., anaphylaxis) to any component of Prevnar 13 or any diphtheria toxoid-containing vaccine [see Description (11)].
Severe allergic reaction (e.g., anaphylaxis) to any component of Prevnar 13 or any diphtheria toxoid-containing vaccine. (4)
5 WARNINGS AND PRECAUTIONS
Apnea following intramuscular vaccination has been observed in some infants born prematurely. Decisions about when to administer an intramuscular vaccine, including Prevnar 13, to infants born prematurely should be based on consideration of the individual infant's medical status, and the potential benefits and possible risks of vaccination. (5.3)
5.1 Management of Allergic Reactions
Epinephrine and other appropriate agents used to manage immediate allergic reactions must be immediately available should an acute anaphylactic reaction occur following administration of Prevnar 13.
5.2 Altered Immunocompetence
Individuals with altered immunocompetence, including those at higher risk for invasive pneumococcal disease (e.g., individuals with congenital or acquired splenic dysfunction, HIV infection, malignancy, hematopoietic stem cell transplant, nephrotic syndrome), may have reduced antibody responses to immunization with Prevnar 13 [see Use in Specific Populations (8.6)].
5.3 Apnea in Premature Infants
Apnea following intramuscular vaccination has been observed in some infants born prematurely. Decisions about when to administer an intramuscular vaccine, including Prevnar 13, to infants born prematurely should be based on consideration of the individual infant's medical status and the potential benefits and possible risks of vaccination.
6 ADVERSE REACTIONS
Because clinical trials are conducted under widely varying conditions, adverse-reaction rates observed in the clinical trials of a vaccine cannot be directly compared to rates in the clinical trials of another vaccine and may not reflect the rates observed in practice.
- In infants and toddlers vaccinated at 2, 4, 6, and 12–15 months of age in US clinical trials, the most commonly reported solicited adverse reactions (>5%) were irritability (>70%), injection site tenderness (>50%), decreased appetite (>40%), decreased sleep (>40%), increased sleep (>40%), fever (>20%), injection site redness (>20%), and injection site swelling (>20%). (6.1)
- In children aged 5 through 17 years, the most commonly reported solicited adverse reactions (>5%) were injection site tenderness (>80%), injection site redness (>30%), injection site swelling (>30%), irritability (>20%), decreased appetite (>20%), increased sleep (>20%), fever (>5%), and decreased sleep (>5%). (6.1)
- In adults aged 18 years and older, the most commonly reported solicited adverse reactions (>5%) were pain at the injection site (>50%), fatigue (>30%), headache (>20%), muscle pain (>20%), joint pain (>10%), decreased appetite (>10%), injection site redness (>10%), injection site swelling (>10%), limitation of arm movement (>10%), vomiting (>5%), fever (>5%), chills (>5%), and rash (>5%). (6.2)
To report SUSPECTED ADVERSE REACTIONS, contact Wyeth Pharmaceuticals LLC. at 1-800-438-1985 or VAERS at 1-800-822-7967 or http://vaers.hhs.gov.
6.1 Clinical Trials Experience With Prevnar 13 in Children 6 Weeks Through 17 Years of Age
The safety of Prevnar 13 was evaluated in 13 clinical trials in which 4,729 infants (6 weeks through 11 months of age) and toddlers (12 months through 15 months of age) received at least one dose of Prevnar 13 and 2,760 infants and toddlers received at least one dose of Prevnar active control. Safety data for the first three doses are available for all 13 infant studies; dose 4 data are available for 10 studies; and data for the 6-month follow-up are available for 7 studies. The vaccination schedule and concomitant vaccinations used in these infant trials were consistent with country-specific recommendations and local clinical practice. There were no substantive differences in demographic characteristics between the vaccine groups. By race, 84.0% of subjects were White, 6.0% were Black or African-American, 5.8% were Asian and 3.8% were of 'Other' race (most of these being biracial). Overall, 52.3% of subjects were male infants.
Three studies in the US (Studies 1, 2 and 3)1,2,3 evaluated the safety of Prevnar 13 when administered concomitantly with routine US pediatric vaccinations at 2, 4, 6, and 12–15 months of age. Solicited local and systemic adverse reactions were recorded daily by parents/guardians using an electronic diary for 7 consecutive days following each vaccination. For unsolicited adverse events, study subjects were monitored from administration of the first dose until one month after the infant series, and for one month after the administration of the toddler dose. Information regarding unsolicited and serious adverse events, newly diagnosed chronic medical conditions, and hospitalizations since the last visit were collected during the clinic visit for the fourth-study dose and during a scripted telephone interview 6 months after the fourth-study dose. Serious adverse events were also collected throughout the study period. Overall, the safety data show a similar proportion of Prevnar 13 and Prevnar subjects reporting serious adverse events. Among US study subjects, a similar proportion of Prevnar 13 and Prevnar recipients reported solicited local and systemic adverse reactions as well as unsolicited adverse events.
Serious Adverse Events in All Infant and Toddler Clinical Studies
Serious adverse events were collected throughout the study period for all 13 clinical trials. This reporting period is longer than the 30-day post-vaccination period used in some vaccine trials. The longer reporting period may have resulted in serious adverse events being reported in a higher percentage of subjects than for other vaccines. Serious adverse events reported following vaccination in infants and toddlers occurred in 8.2% among Prevnar 13 recipients and 7.2% among Prevnar recipients. Serious adverse events observed during different study periods for Prevnar 13 and Prevnar respectively were: 1) 3.7% and 3.5% from dose 1 to the blood draw approximately 1 month after the infant series; 2) 3.6% and 2.7% from the blood draw after the infant series to the toddler dose; 3) 0.9% and 0.8% from the toddler dose to the blood draw approximately 1 month after the toddler dose and 4) 2.5% and 2.8% during the 6 month follow-up period after the last dose.
The most commonly reported serious adverse events were in the 'Infections and infestations' system organ class including bronchiolitis (0.9%, 1.1%), gastroenteritis, (0.9%, 0.9%), and pneumonia (0.9%, 0.5%) for Prevnar 13 and Prevnar respectively.
There were 3 (0.063%) deaths among Prevnar 13 recipients, and 1 (0.036%) death in Prevnar recipients, all as a result of sudden infant death syndrome (SIDS). These SIDS rates are consistent with published age specific background rates of SIDS from the year 2000.
Among 6,839 subjects who received at least 1 dose of Prevnar 13 in clinical trials conducted globally, there was 1 hypotonic-hyporesponsive episode adverse reaction reported (0.015%). Among 4,204 subjects who received at least 1 dose of Prevnar in clinical trials conducted globally, there were 3 hypotonic-hyporesponsive episode adverse reactions reported (0.071%). All 4 events occurred in a single clinical trial in Brazil in which subjects received whole cell pertussis vaccine at the same time as Prevnar 13 or Prevnar.
Solicited Adverse Reactions in the Three US Infant and Toddler Studies
A total of 1,907 subjects received at least 1 dose of Prevnar 13 and 701 subjects received at least 1 dose of Prevnar in the three US studies (Studies 1, 2 and 3)1,2,3. Most subjects were White (77.3%), 14.2% were Black or African-American, and 1.7% were Asian; 79.1% of subjects were non-Hispanic and non-Latino and 14.6% were Hispanic or Latino. Overall, 53.6% of subjects were male infants.
The incidence and severity of solicited adverse reactions that occurred within 7 days following each dose of Prevnar 13 or Prevnar administered to US infants and toddlers are shown in Tables 3 and 4.
Dose 1 | Dose 2 | Dose 3 | Dose 4 | |||||
---|---|---|---|---|---|---|---|---|
Graded Local Reaction |
Prevnar 13
(N Number of subjects reporting Yes for at least 1 day or No for all days. =1375–1612) % |
Prevnar
(N =516–606) % |
Prevnar 13
(N =1069–1331) % |
Prevnar
(N =405–510) % |
Prevnar 13
(N =998–1206) % |
Prevnar
(N =348–446) % |
Prevnar 13
(N =874–1060) % |
Prevnar
(N =283–379) % |
RednessDiameters were measured in caliper units of whole numbers from 1 to 14 or 14+. One caliper unit = 0.5 cm. Measurements were rounded up to the nearest whole number. Intensity of induration and erythema were then characterized as Mild (0.5–2.0 cm), Moderate (2.5–7.0 cm), or Severe (>7.0 cm). |
||||||||
Any |
24.3 |
26.0 |
33.3 |
29.7 |
37.1 |
36.6 |
42.3 |
45.5 |
Mild |
23.1 |
25.2 |
31.9 |
28.7 |
35.3 |
35.3 |
39.5 |
42.7 |
Moderate |
2.2 |
1.5 |
2.7 |
2.2 |
4.6 |
5.1 |
9.6 |
13.4Statistically significant difference p <0.05. No adjustments for multiplicity. |
Severe |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Swelling |
||||||||
Any |
20.1 |
20.7 |
25.2 |
22.5 |
26.8 |
28.4 |
31.6 |
36.0 |
Mild |
17.2 |
18.7 |
23.8 |
20.5 |
25.2 |
27.5 |
29.4 |
33.8 |
Moderate |
4.9 |
3.9 |
3.7 |
4.9 |
3.8 |
5.8 |
8.3 |
11.2 |
Severe |
0 |
0 |
0.1 |
0 |
0 |
0 |
0 |
0 |
Tenderness |
||||||||
Any |
62.5 |
64.5 |
64.7 |
62.9 |
59.2 |
60.8 |
57.8 |
62.5 |
Interferes with limb movement |
10.4 |
9.6 |
9.0 |
10.5 |
8.4 |
9.0 |
6.9 |
5.7 |
Dose 1 | Dose 2 | Dose 3 | Dose 4 | |||||
---|---|---|---|---|---|---|---|---|
Graded Systemic Events |
Prevnar 13
(N =1360 – 1707) % |
Prevnar
(N =497–640) % |
Prevnar 13
(N =1084–1469) % |
Prevnar
(N =409–555) % |
Prevnar 13
(N =997–1361) % |
Prevnar
(N =354–521) % |
Prevnar 13
(N =850–1227) % |
Prevnar
(N =278–436) % |
FeverFever gradings: Mild (≥38°C but ≤39°C), Moderate (>39°C but ≤40°C), and Severe (>40°C). No other systemic event other than fever was graded. Parents reported the use of antipyretic medication to treat or prevent symptoms in 62 to 75% of subjects after any of the 4 doses. There were no statistical differences in frequencies of adverse reactions reported between the Prevnar 13 and Prevnar groups. |
||||||||
Any |
24.3 |
22.1 |
36.5 |
32.8 |
30.3 |
31.6 |
31.9 |
30.6 |
Mild |
23.6 |
21.7 |
34.9 |
31.6 |
29.1 |
30.2 |
30.3 |
30.0 |
Moderate |
1.1 |
0.6 |
3.4 |
2.8 |
4.2 |
3.3 |
4.4 |
4.6 |
Severe |
0.1 |
0.2 |
0.1 |
0.3 |
0.1 |
0.7 |
1.0 |
0 |
Decreased appetite |
48.3 |
43.6 |
47.8 |
43.6 |
47.6 |
47.6 |
51.0 |
49.4 |
Irritability |
85.6 |
83.6 |
84.8 |
80.4 |
79.8 |
80.8 |
80.4 |
77.8 |
Increased sleep |
71.5 |
71.5 |
66.6 |
63.4 |
57.7 |
55.2 |
48.7 |
55.1 |
Decreased sleep |
42.5 |
40.6 |
45.6 |
43.7 |
46.5 |
47.7 |
45.3 |
40.3 |
The incidence rates of any fever (≥38.0°C) were similar on days 1 and 2 following each dose of Prevnar 13 compared to after each dose of Prevnar administered to US infants and toddlers (day 1 = day of vaccination). After dose 1, fever was reported in 11.0–12.7% on day 1 and 6.4–6.8% on day 2. After dose 2, fever was reported in 12.3–13.1% on day 1 and 12.5–12.8% on day 2. After dose 3, fever was reported in 8.0–9.6% on day 1 and 9.1–10.5% on day 2. And after dose 4, fever was reported in 6.3–6.4% on day 1 and 7.3–9.7% on day 2.
Unsolicited Adverse Reactions in the Three US Infant and Toddler Safety Studies
The following were determined to be adverse drug reactions based on experience with Prevnar 13 in clinical trials.
Reactions occurring in greater than 1% of infants and toddlers: diarrhea, vomiting, and rash.
Reactions occurring in less than 1% of infants and toddlers: crying, hypersensitivity reaction (including face edema, dyspnea, and bronchospasm), seizures (including febrile seizures), and urticaria or urticaria-like rash.
Safety Assessments in the Catch-Up Studies in Infants and Children Through 5 Years of Age
In a catch-up study4 conducted in Poland (Study 4), 354 children (7 months through 5 years of age) receiving at least one dose of Prevnar 13 were also monitored for safety. All subjects in this study were White and non-Hispanic. Overall, 49.6% of subjects were male infants. The incidence and severity of solicited adverse reactions that occurred within 4 days following each dose of Prevnar 13 administered to pneumococcal-vaccine naïve children 7 months through 5 years of age are shown in Tables 5 and 6.
7 through 11 months | 12 through 23 months | 24 months through 5 years | ||||
---|---|---|---|---|---|---|
Graded Local Reaction |
Dose 1
N Number of subjects reporting Yes for at least 1 day or No for all days. =86 % |
Dose 2
N =86–87 % |
Dose 3
N =78–82 % |
Dose 1
N =108–110 % |
Dose 2
N =98–106 % |
Dose 1
N =147–149 % |
RednessDiameters were measured in caliper units of whole numbers from 1 to 14 or 14+. One caliper unit = 0.5 cm. Measurements were rounded up to the nearest whole number. Intensity of redness and swelling were then characterized as Mild (0.5–2.0 cm), Moderate (2.5–7.0 cm), or Severe (>7.0 cm). |
||||||
Any |
48.8 |
46.0 |
37.8 |
70.0 |
54.7 |
50.0 |
Mild |
41.9 |
40.2 |
31.3 |
55.5 |
44.7 |
37.4 |
Moderate |
16.3 |
9.3 |
12.5 |
38.2 |
25.5 |
25.7 |
Severe |
0.0 |
0.0 |
0.0 |
0.0 |
0.0 |
0.0 |
Swelling |
||||||
Any |
36.0 |
32.2 |
25.0 |
44.5 |
41.0 |
36.9 |
Mild |
32.6 |
28.7 |
20.5 |
36.7 |
36.2 |
28.2 |
Moderate |
11.6 |
14.0 |
11.3 |
24.8 |
12.1 |
20.3 |
Severe |
0.0 |
0.0 |
0.0 |
0.0 |
0.0 |
0.0 |
Tenderness |
||||||
Any |
15.1 |
15.1 |
15.2 |
33.3 |
43.7 |
42.3 |
Interferes with limb movement |
1.2 |
3.5 |
6.4 |
0.0 |
4.1 |
4.1 |
7 through 11 months | 12 through 23 months | 24 months through 5 years | ||||
---|---|---|---|---|---|---|
Systemic Reaction |
Dose 1
N Number of subjects reporting Yes for at least 1 day or No for all days. =86–87 % |
Dose 2
N =86–87 % |
Dose 3
N =78–81 % |
Dose 1
N =108 % |
Dose 2
N =98–100 % |
Dose 1
N =147–148 % |
FeverFever gradings: Mild (≥38°C but ≤39°C), Moderate (>39°C but ≤40°C), and Severe (>40°C). No other systemic event other than fever was graded. |
||||||
Mild |
3.4 |
8.1 |
5.1 |
3.7 |
5.1 |
0.7 |
Moderate |
1.2 |
2.3 |
1.3 |
0.9 |
0.0 |
0.7 |
Severe |
0.0 |
0.0 |
0.0 |
0.0 |
0.0 |
0.0 |
Decreased appetite |
19.5 |
17.2 |
17.5 |
22.2 |
25.5 |
16.3 |
Irritability |
24.1 |
34.5 |
24.7 |
30.6 |
34.0 |
14.3 |
Increased sleep |
9.2 |
9.3 |
2.6 |
13.0 |
10.1 |
11.6 |
Decreased sleep |
24.1 |
18.4 |
15.0 |
19.4 |
20.4 |
6.8 |
A US study5 (Study 5) evaluated the use of Prevnar 13 in children previously immunized with Prevnar. In this open label trial, 596 healthy children 15 through 59 months of age previously vaccinated with at least 3 doses of Prevnar, received 1 or 2 doses of Prevnar 13. Children 15 months through 23 months of age (group 1) received 2 doses, and children 24 months through 59 months of age (group 2) received one dose. Most subjects were White (74.3%), 14.9% were Black or African-American, and 1.2% were Asian; 89.3% of subjects were non-Hispanic and non-Latino and 10.7% were Hispanic or Latino. Overall, 52.2% of subjects were male.
The incidence and severity of solicited adverse reactions that occurred within 7 days following one dose of Prevnar 13 administered to children 15 months through 59 months of age are shown in Tables 7 and 8.
15 months through 23 months Dose 2 data not shown. | 24 months through 59 months The data for this age group are only represented as a single result as 95% of children received 4 doses of Prevnar prior to enrollment. | ||
---|---|---|---|
Graded Local Reaction |
1 dose Prevnar 13
3 prior Prevnar doses N Number of subjects reporting Yes for at least 1 day or No for all days. =67–72 % |
1 dose Prevnar 13
4 prior Prevnar doses N =154–184 % |
1 dose Prevnar 13
3 or 4 prior Prevnar doses N =209–238 % |
RednessDiameters were measured in caliper units of whole numbers from 1 to 14 or 14+. One caliper unit = 0.5 cm. Measurements were rounded up to the nearest whole number. Intensity of redness and swelling were then characterized as Mild (0.5–2.0 cm), Moderate (2.5–7.0 cm), or Severe (>7.0 cm). |
|||
Any |
26.4 |
28.2 |
35.4 |
Mild |
18.8 |
24.3 |
31.1 |
Moderate |
11.4 |
7.5 |
12.1 |
Severe |
1.5 |
0.0 |
0.0 |
Swelling |
|||
Any |
23.9 |
19.6 |
20.7 |
Mild |
18.6 |
16.4 |
17.2 |
Moderate |
8.8 |
8.1 |
7.5 |
Severe |
0.0 |
0.0 |
0.0 |
Tenderness |
|||
Any |
48.6 |
47.3 |
62.6 |
Interferes with limb movement |
5.9 |
6.4 |
10.7 |
15 through 23 months Dose 2 data not shown. | 24 months through 59 months The data for this age group are only represented as a single result as 95% of children received 4 doses of Prevnar prior to enrollment. | ||
---|---|---|---|
Systemic Reaction |
1 dose Prevnar 13
3 prior Prevnar doses N Number of subjects reporting Yes for at least 1 day or No for all days. =66–75 % |
1 dose Prevnar 13
4 prior Prevnar doses N =154–189 % |
1 dose Prevnar 13
3 or 4 prior Prevnar doses N =209–236 % |
FeverFever gradings: Mild (≥38°C but ≤39°C), Moderate (>39°C but ≤40°C), and Severe (>40°C). No other systemic event other than fever was graded. |
|||
Any |
19.1 |
19.9 |
8.1 |
Mild |
16.2 |
17.4 |
7.6 |
Moderate |
6.1 |
3.9 |
1.9 |
Severe |
0.0 |
0.0 |
0.5 |
Decreased appetite |
44.4 |
39.3 |
28.1 |
Irritability |
73.3 |
65.1 |
45.8 |
Increased sleep |
35.2 |
35.3 |
18.8 |
Decreased sleep |
25.0 |
29.7 |
14.8 |
Clinical Trials Experience With Prevnar 13 in Children 5 Through 17 Years of Age
In a US study5 (Study 5), the safety of Prevnar 13 was evaluated in children 5 through 9 years of age previously immunized with at least one dose of Prevnar, and in children 10 through 17 years of age with no prior pneumococcal vaccination. In this open label trial, 592 children, including those with asthma, received a single dose of Prevnar 13. The percentage of children 5 through 9 years of age who received 3 and 4 prior doses of Prevnar was 29.1% and 54.5% respectively.
Most subjects were White (72.8%), 21.8% were Black or African-American, and 1.5% were Asian; 91.4% of subjects were non-Hispanic and non-Latino and 8.6% were Hispanic or Latino. Overall, 51.2% of subjects were male.
The incidence and severity of solicited adverse reactions that occurred within 7 days following one dose of Prevnar 13 administered to children 5 through 17 years of age are shown in Tables 9 and 10.
Vaccine Group (as Administered) | ||||||
---|---|---|---|---|---|---|
Prevnar 13
(5 Through 9 Years) |
Prevnar 13
(10 Through 17 Years) |
|||||
Local Reaction | N N = number of subjects reporting Yes for at least 1 day or No for all days. | n n = Number of subjects reporting the specific characteristic. | % | N | n | % |
Redness |
||||||
Any |
233 |
100 |
42.9 |
232 |
70 |
30.2 |
MildMild, 0.5 – 2.0 cm; moderate, 2.5 – 7.0 cm; severe, >7.0 cm. |
226 |
63 |
27.9 |
226 |
48 |
21.2 |
Moderate |
218 |
48 |
22.0 |
221 |
31 |
14.0 |
Severe |
212 |
7 |
3.3 |
213 |
4 |
1.9 |
Swelling |
||||||
Any |
226 |
85 |
37.6 |
233 |
86 |
36.9 |
Mild |
220 |
48 |
21.8 |
221 |
50 |
22.6 |
Moderate |
219 |
48 |
21.9 |
226 |
48 |
21.2 |
Severe |
211 |
7 |
3.3 |
214 |
4 |
1.9 |
Tenderness |
||||||
Any |
265 |
230 |
86.8 |
283 |
252 |
89.0 |
SignificantSignificant = present and interfered with limb movement. |
221 |
43 |
19.5 |
242 |
106 |
43.8 |
Vaccine Group (as Administered) | ||||||
---|---|---|---|---|---|---|
Prevnar 13
(5 Through 9 Years) |
Prevnar 13
(10 Through 17 Years) |
|||||
Systemic Event | N N = number of subjects reporting Yes for at least 1 day or No for all days. | n n = Number of subjects reporting the event. | % | N | n | % |
Any fever ≥38°C |
214 |
13 |
6.1 |
214 |
12 |
5.6 |
MildFever gradings: Mild (≥38°C but ≤39°C), Moderate (>39°C but ≤40°C), and Severe (>40°C). No other systemic event other than fever was graded. Parents reported the use of antipyretic medication to treat or prevent symptoms in 45.1% and 33.1% of subjects 5 through 9 years of age and 10 through 17 years of age, respectively. |
212 |
9 |
4.2 |
214 |
11 |
5.1 |
Moderate |
212 |
5 |
2.4 |
212 |
1 |
0.5 |
Severe |
210 |
1 |
0.5 |
212 |
1 |
0.5 |
Decreased appetite |
227 |
52 |
22.9 |
223 |
51 |
22.9 |
Irritability |
234 |
73 |
31.2 |
234 |
59 |
25.2 |
Increased sleep |
226 |
48 |
21.2 |
229 |
61 |
26.6 |
Decreased sleep |
212 |
12 |
5.7 |
224 |
42 |
18.8 |
Hives (urticaria) |
213 |
4 |
1.9 |
214 |
3 |
1.4 |
6.2 Clinical Trials Experience With Prevnar 13 in Adults ≥18 Years of Age
The safety of Prevnar 13 was assessed in 7 clinical studies (Studies 6–12) 6–12 conducted in the US and Europe which included 91,593 adults (48,806 received Prevnar 13) ranging in age from 18 through 101 years.
The 48,806 Prevnar 13 recipients included 899 adults who were aged 18 through 49 years, 2,616 adults who were aged 50 through 64 years, 45,291 adults aged 65 years and older. Of the 48,806 Prevnar 13 recipients, 46,890 adults had not previously received Pneumovax® 23 (pneumococcal polysaccharide vaccine [23-valent], PPSV23) ("PPSV23 unvaccinated") and 1,916 adults were previously vaccinated ("PPSV23 previously vaccinated") with PPSV23 at least 3 years prior to enrollment.
Safety and Immunogenicity Studies
Safety and immunogenicity of Prevnar 13 is supported by 6 clinical studies. Study 66 evaluated the safety and immunogenicity of Prevnar 13 in adults 18 through 64 years of age who had not received a previous dose of pneumococcal vaccine. Adults 18 through 59 years of age received a single dose of Prevnar 13, and adults 60 through 64 years of age received a single dose of Prevnar 13 or PPSV23.
Study 7 was randomized and compared the safety and immunogenicity of Prevnar 13 with PPSV23 as a single dose in adults ≥70 years vaccinated with PPSV23 (≥5 years prior to enrollment).7 Study 8 was randomized and evaluated the safety and immunogenicity of Prevnar 13 and PPSV23 in different sequential order in PPSV23 naive adults aged 60 through 64 years8.
One clinical safety study9 (Study 9) of Prevnar 13, conducted in PPSV23 previously vaccinated (≥3 years prior to enrollment) adults aged ≥68 years was a single arm study. Two studies, one in the US10 (Study 10) in adults aged 50 through 59 years and the other in Europe11 (Study 11) in adults aged ≥65 years, evaluated the concomitant administration of Prevnar 13 with inactivated influenza vaccine, trivalent (Fluarix ® , A/H1N1, A/H3N2, and B, Fall 2007/Spring 2008: IIV3) in these two age groups in PPSV23 unvaccinated adults.
The total safety population in the 6 safety and immunogenicity studies was 7,097. In 5 of the 6 safety and immunogenicity studies, more females than males were enrolled (50.2% – 61.8%). Across the 6 studies the racial distribution included: >85% White; 0.2%–10.7% Black or African American; 0%–1.7% Asian; <1% Native Hawaiian or other Pacific Islander; ≤1%, American Indian or Alaskan Native. Ethnicity data were not collected in Study 11; in the 5 other studies 0.6%–4.8% were Hispanic or Latino.
In five studies,6–8,10,11 subjects with pre-existing underlying diseases were enrolled if the medical condition was stable (did not require a change in therapy or hospitalization for worsening disease for 12 weeks before receipt of study vaccine) except in Study 9 where subjects were enrolled if the medical condition was stable for 6 or more weeks before receipt of study vaccine.
In the 6 safety and immunogenicity studies,6–11 subjects were excluded from study participation due to prior receipt of diphtheria toxoid-containing vaccines within 6 months of study vaccine. However, the time of prior receipt of a diphtheria toxoid-containing vaccine was not recorded.
Solicited adverse reactions for Prevnar 13 in the safety and immunogenicity studies were monitored by subjects recording local adverse reactions and systemic reactions daily using an electronic diary for 14 consecutive days following vaccination. Unsolicited serious and non-serious adverse events were collected for one month after each vaccination. In addition, serious adverse events were collected for an additional 5 months after each vaccination (at the 6-month follow-up phone contact) in all studies except Study 11.
Following licensure of Prevnar 13 in adults ≥50 years of age, a randomized, double-blind, placebo-controlled US study (Study 13) was conducted to evaluate concomitant administration of Prevnar 13 with inactivated influenza vaccine, quadrivalent (Fluzone ® Quadrivalent, A/H1N1, A/H3N2, B/Brisbane, and B/Massachusetts, Fall 2014/Spring 2015: IIV4) in PPSV23 previously vaccinated adults ≥50 years of age. Unsolicited serious and non-serious adverse events were collected as described above for Studies 6–10.
Efficacy Study
Study 1212 was a randomized double-blind placebo-controlled study conducted in the Netherlands in community-dwelling adults aged 65 years and older with no prior pneumococcal vaccination history. A total of 84,496 subjects received either a single dose of Prevnar 13 (42,240) or placebo (42,256) in a 1:1 randomization. Among the 84,496 subjects, 58,072 (68.7%) were ≥65 to <75 years of age, 23,481 (27.8%) were ≥75 and <85 years of age, and 2,943 (3.5%) were ≥85 years of age. In the total safety population, more males (55.9%) were enrolled than females. The racial distribution was 98.5% White, 0.3% Black, 0.7% Asian, 0.5% Other, with <0.1% having missing data.
Adults with immunocompromising conditions or receiving immunosuppressive therapy and adults residing in a long-term care facility or requiring semiskilled nursing care were excluded. Adults with pre-existing medical conditions, as well as subjects with a history of smoking were eligible for enrollment. In the safety population, 42.3% of subjects had pre-existing medical conditions including heart disease (25.4%), lung disease or asthma (15.1%) and type 1 and type 2 diabetes mellitus (12.5%). Smoking was reported at baseline by 12.3% of the subjects.
For a subset of 2,011 subjects (1,006 Prevnar 13 recipients and 1,005 placebo recipients), solicited adverse reactions were monitored by recording local and systemic events using electronic diaries for 7 days after vaccination; unsolicited adverse events were collected for 28 days after vaccination, and serious adverse events were collected for 6 months after vaccination. For the remaining 41,231 Prevnar 13 and 41,250 placebo vaccinated subjects, serious adverse events were collected for 28 days after vaccination.
Serious Adverse Events in Adult Clinical Studies
Safety and Immunogenicity Studies
Across the 6 safety and immunogenicity studies,6–11 serious adverse events within 1 month of vaccination were reported after an initial study dose in 0.2%–1.4% of 5,057 subjects vaccinated with Prevnar 13, and in 0.4%–1.7% of 1,124 subjects vaccinated after an initial study dose of PPSV23. From 1 month to 6 months after an initial study dose, serious adverse events were reported in 0.2%–5.8% of subjects vaccinated during the studies with Prevnar 13 and in 2.4%–5.5% of subjects vaccinated with PPSV23. One case of erythema multiforme occurred 34 days after receipt of a second dose of Prevnar 13.
Twelve of 5,667 (0.21%) Prevnar 13 recipients and 4 of 1,391 (0.29 %) PPSV23 recipients died. Deaths occurred between Day 3 and Day 309 after study vaccination with Prevnar 13 or PPSV23. Two of 12 deaths occurred within 30 days of vaccination and both deaths were in subjects >65 years of age. One death due to cardiac failure occurred 3 days after receiving placebo. This subject had received Prevnar 13 and IIV3 one month earlier. The other death was due to peritonitis 20 days after receiving Prevnar 13. The reported causes of the 10 remaining deaths occurring greater than 30 days after receiving Prevnar 13 were cardiac disorders (4), neoplasms (4), Mycobacterium avium complex pulmonary infection (1) and septic shock (1).
Efficacy Study
In Study 1212 (subjects 65 years and older), serious adverse events within 1 month of vaccination were reported in 327 of 42,237 (0.8%) Prevnar 13 recipients (352 events) and in 314 of 42,225 (0.7%) placebo recipients (337 events). In the subset of subjects where serious adverse events were monitored for 6 months, 70 of 1,006 (7%) Prevnar 13 vaccinated subjects (90 events) and 60 of 1,005 (6%) placebo vaccinated subjects (69 events) reported serious adverse events.
During the follow-up period (average of 4 years) for case accumulation there were 3,006 deaths (7.1%) in the Prevnar 13 group and 3,005 deaths (7.1%) in the placebo group. There were 10 deaths (<0.1%) in the Prevnar 13 group and 10 deaths (<0.1%) in the placebo group within 28 days of vaccination. There were 161 deaths (0.4%) in the Prevnar 13 group and 144 deaths (0.3%) in the placebo group within 29 days – 6 months following vaccination. These data do not provide evidence for a causal relationship between deaths and vaccination with Prevnar 13.
Solicited Adverse Reactions in Adult Clinical Studies
The incidence and severity of solicited adverse reactions that occurred within 7 or 14 days following each dose of Prevnar 13, PPSV23, or placebo administered to adults in 5 studies are shown in Tables 11, 12, 13, and 14.
The commonly reported local adverse reactions after Prevnar 13 vaccination in PPSV23 unvaccinated and PPSV23 previously vaccinated adults were redness, swelling and pain at the injection site, or limitation of arm movement (Tables 11 and 12). The commonly reported systemic adverse reactions in PPSV23 unvaccinated and PPSV23 previously vaccinated adults were fatigue, headache, chills, rash, decreased appetite, or muscle pain and joint pain (Tables 13 and 14).
Study 6 | Study 8 | Study 12 | ||||||
---|---|---|---|---|---|---|---|---|
Age in Years | 18–49 | 50–59 | 60–64 | 60–64 | ≥65 | |||
Local Reaction |
Prevnar 13
Open label administration of Prevnar 13.
N Number of subjects with known values (number of subjects reporting yes for at least one day or no for all days). =266–787 % |
Prevnar 13
N =152–322 % |
Prevnar 13
N =193–331 % |
PPSV23
N =190–301 % |
Prevnar 13
N =270–370 % |
PPSV23
N =134–175 % |
Prevnar 13
N =886–914 % |
Placebo
N =859–865 % |
RednessDiameters were measured in caliper units of whole numbers from 1 to 21 or 21+. One caliper unit = 0.5 cm. Measurements were rounded up to the nearest whole number. Intensity of redness and swelling were then characterized as Mild = 2.5 to 5.0 cm, Moderate = 5.1 to 10.0 cm, and Severe is >10.0 cm. |
||||||||
Any |
30.5 |
15.8 |
20.2 |
14.2 |
12.2 |
11.2 |
4.9Statistically significant difference p <0.05. No adjustments for multiplicity. |
1.2 |
Mild |
26.4 |
15.2 |
15.9 |
11.2 |
8.3 |
9.7 |
3.7 |
0.8 |
Moderate |
11.9 |
5.0 |
8.6 |
4.9 |
6.4 |
3.9 |
1.7 |
0.3 |
Severe |
2.8 |
0.7 |
1.7 |
0.0 |
1.2 |
0.8 |
0.5 |
0.1 |
Swelling |
||||||||
Any |
39.4 |
21.7 |
19.3 |
13.1 |
10.0 |
10.4 |
6.8 |
1.2 |
Mild |
37.2 |
20.6 |
15.6 |
10.1 |
8.2 |
6.1 |
5.5 |
0.7 |
Moderate |
15.1 |
4.3 |
8.2 |
4.4 |
3.8 |
7.6 |
2.6 |
0.6 |
Severe |
1.4 |
0.0 |
0.6 |
1.1 |
0.0 |
0.0 |
0.1 |
0.1 |
PainMild = awareness of symptom but easily tolerated, Moderate = discomfort enough to cause interference with usual activity, Severe = incapacitating with inability to do usual activity. |
||||||||
Any |
96.7 |
88.8 |
80.1 |
73.4 |
69.2 |
58.3 |
36.1 |
6.1 |
Mild |
93.2 |
85.9 |
78.6 |
68.6 |
66.1 |
52.9 |
32.9 |
5.6 |
Moderate |
77.1 |
39.5 |
23.3 |
30.0 |
20.1 |
21.7 |
7.7 |
0.6 |
Severe |
16.0 |
3.6 |
1.7 |
8.6 |
2.3 |
0.8 |
0.3 |
0.1 |
Limitation of arm movementMild = some limitation of arm movement, Moderate = unable to move arm above head but able to move arm above shoulder, and Severe = unable to move arm above shoulder. |
||||||||
Any |
75.2 |
40.7 |
28.5 |
30.8 |
23.5 |
28.2 |
14.1 |
3.2 |
Mild |
71.5 |
38.6 |
26.9 |
29.3 |
22.7 |
26.1 |
12.4 |
2.5 |
Moderate |
18.5 |
2.9 |
2.2 |
3.8 |
1.2 |
3.1 |
1.7 |
0.5 |
Severe |
15.6 |
2.9 |
1.7 |
4.3 |
1.1 |
2.3 |
1.2 |
0.7 |
Study 7 | Study 9 | ||
---|---|---|---|
Age in Years | ≥70 | ≥68 | |
Local Reaction |
Prevnar 13
N Number of subjects with known values. =306–362 % |
PPSV23
N =324–383 % |
Prevnar 13
Open label administration of Prevnar 13.
N =664–777 % |
RednessDiameters were measured in caliper units of whole numbers from 1 to 21 or 21+. One caliper unit = 0.5 cm. Measurements were rounded up to the nearest whole number. Intensity of redness and swelling were then characterized as Mild = 2.5 to 5.0 cm, Moderate = 5.1 to 10.0 cm, and Severe is >10.0 cm. |
|||
Any |
10.8 |
22.2Statistically significant difference p <0.05. No adjustments for multiplicity. |
14.3 |
Mild |
9.5 |
13.5 |
12.6 |
Moderate |
4.7 |
11.5 |
6.5 |
Severe |
1.7 |
4.8 |
1.1 |
Swelling |
|||
Any |
10.4 |
23.1 |
12.8 |
Mild |
8.9 |
14.0 |
10.9 |
Moderate |
4.0 |
13.6 |
5.5 |
Severe |
0.0 |
4.8 |
0.6 |
PainMild = awareness of symptom but easily tolerated, Moderate = discomfort enough to cause interference with usual activity, Severe = incapacitating with inability to do usual activity. |
|||
Any |
51.7 |
58.5 |
51.0 |
Mild |
50.1 |
54.1 |
49.4 |
Moderate |
7.5 |
23.6 |
9.0 |
Severe |
1.3 |
2.3 |
0.2 |
Limitation of arm movementMild = some limitation of arm movement, Moderate = unable to move arm above head but able to move arm above shoulder, and Severe = unable to move arm above shoulder. |
|||
Any |
10.5 |
27.6 |
16.2 |
Mild |
10.3 |
25.2 |
14.8 |
Moderate |
0.3 |
2.6 |
1.6 |
Severe |
0.7 |
3.0 |
1.6 |
Study 6 | Study 8 | Study 12 | ||||||
---|---|---|---|---|---|---|---|---|
Age in Years | 18–49 | 50–59 | 60–64 | 60–64 | ≥65 | |||
Prevnar 13
Open label administration of Prevnar 13.
N Number of subjects with known values (number of subjects reporting yes for at least one day or no for all days). =221–561 % |
Prevnar 13
N =137–248 % |
Prevnar 13
N =174–277 % |
PPSV23
N =176–273 % |
Prevnar 13
N =261–328 % |
PPSV23
N =127–173 % |
Prevnar 13
N =881–896 % |
Placebo
N =860–878 % |
|
Systemic Event |
||||||||
Fever |
||||||||
≥38.0°C |
7.2 |
1.5 |
4.0 |
1.1 |
4.2 |
1.6 |
2.9Statistically significant difference p <0.05. No adjustments for multiplicity. |
1.3 |
38.0°C to 38.4°C |
4.2 |
1.5 |
4.0 |
1.1 |
3.8 |
0.8 |
1.1 |
0.6 |
38.5°C to 38.9°C |
1.9 |
0.0 |
0.6 |
0.0 |
0.8 |
0.0 |
0.6 |
0.2 |
39.0°C to 40.0°C |
1.4 |
0.0 |
0.0 |
0.0 |
0.4 |
0.8 |
0.7 |
0.2 |
>40.0°CFevers >40.0°C were confirmed to be data entry errors and remain in the table for the following: 1 case in the 18- to 49- year-old cohort (Study 6), and 7 cases in the Prevnar 13 group and 3 cases in placebo group (Study 12). For the other cohorts in Study 6 and for Study 8, data entry errors were removed. |
0.5 |
0.0 |
0.0 |
0.0 |
0.0 |
0.0 |
0.8 |
0.3 |
Fatigue |
80.5 |
63.3 |
63.2 |
61.5 |
50.5 |
49.1 |
18.8 |
14.8 |
Headache |
81.4 |
65.9 |
54.0 |
54.4 |
49.7 |
46.1 |
15.9 |
14.8 |
Chills |
38.1 |
19.6 |
23.5 |
24.1 |
19.9 |
26.9 |
9.4 |
8.4 |
Rash |
21.3 |
14.2 |
16.5 |
13.0 |
8.6 |
13.4 |
3.3 |
0.8 |
Vomiting |
15.0 |
6.9 |
3.9 |
5.4 |
3.1 |
3.1 |
0.3 |
0.9 |
Decreased appetite |
55.6 |
25.3 |
21.3 |
21.7 |
14.7 |
23.0 |
5.3 |
3.7 |
Generalized new muscle pain |
82.0 |
61.8 |
56.2 |
57.8 |
46.9 |
51.5 |
18.4 |
8.4 |
Generalized aggravated muscle pain |
55.9 |
39.9 |
32.6 |
37.3 |
22.0 |
32.5 |
9.1 |
4.4 |
Generalized new joint pain |
41.7 |
31.5 |
24.4 |
30.1 |
15.5 |
23.8 |
7.4 |
5.4 |
Generalized aggravated joint pain |
28.6 |
25.6 |
24.9 |
21.4 |
14.0 |
21.1 |
5.2 |
4.2 |
Study 7 | Study 9 | ||
---|---|---|---|
Age in Years | ≥70 | ≥68 | |
Prevnar 13
N Number of subjects with known values. =299–350 % |
PPSV23
N =303–367 % |
Prevnar 13
Open label administration of Prevnar 13.
N =635–733 % |
|
Systemic Event |
|||
Fever |
|||
≥38.0°C |
1.0 |
2.3 |
1.1 |
38.0°C to 38.4°C |
1.0 |
2.0 |
0.8 |
38.5°C to 38.9°C |
0.0 |
0.0 |
0.0 |
39.0°C to 40.0°C |
0.0 |
0.3 |
0.3 |