PREVNAR 13 (pneumococcal 13-valent conjugate vaccine) injection, suspension
Wyeth Pharmaceutical Division of Wyeth Holdings LLC

Wyeth Pharmaceutical Division of Wyeth Holdings LLC
Pfizer Ireland Pharmaceuticals
Wyeth BioPharma Division of Wyeth Pharmaceuticals LLC
Wyeth Pharmaceutical Division of Wyeth Holdings LLC
Pfizer Manufacturing Belgium NV
BioReliance Corporation
BioAgilytix Labs
PREVNAR 13
pneumococcal 13-valent conjugate vaccine
STREPTOCOCCUS PNEUMONIAE TYPE 1 CAPSULAR POLYSACCHARIDE DIPHTHERIA CRM197 PROTEIN CONJUGATE ANTIGEN
STREPTOCOCCUS PNEUMONIAE TYPE 1 CAPSULAR POLYSACCHARIDE DIPHTHERIA CRM197 PROTEIN CONJUGATE ANTIGEN
STREPTOCOCCUS PNEUMONIAE TYPE 3 CAPSULAR POLYSACCHARIDE DIPHTHERIA CRM197 PROTEIN CONJUGATE ANTIGEN
STREPTOCOCCUS PNEUMONIAE TYPE 3 CAPSULAR POLYSACCHARIDE DIPHTHERIA CRM197 PROTEIN CONJUGATE ANTIGEN
STREPTOCOCCUS PNEUMONIAE TYPE 4 CAPSULAR POLYSACCHARIDE DIPHTHERIA CRM197 PROTEIN CONJUGATE ANTIGEN
STREPTOCOCCUS PNEUMONIAE TYPE 4 CAPSULAR POLYSACCHARIDE DIPHTHERIA CRM197 PROTEIN CONJUGATE ANTIGEN
STREPTOCOCCUS PNEUMONIAE TYPE 5 CAPSULAR POLYSACCHARIDE DIPHTHERIA CRM197 PROTEIN CONJUGATE ANTIGEN
STREPTOCOCCUS PNEUMONIAE TYPE 5 CAPSULAR POLYSACCHARIDE DIPHTHERIA CRM197 PROTEIN CONJUGATE ANTIGEN
STREPTOCOCCUS PNEUMONIAE TYPE 6A CAPSULAR POLYSACCHARIDE DIPHTHERIA CRM197 PROTEIN CONJUGATE ANTIGEN
STREPTOCOCCUS PNEUMONIAE TYPE 6A CAPSULAR POLYSACCHARIDE DIPHTHERIA CRM197 PROTEIN CONJUGATE ANTIGEN
STREPTOCOCCUS PNEUMONIAE TYPE 6B CAPSULAR POLYSACCHARIDE DIPHTHERIA CRM197 PROTEIN CONJUGATE ANTIGEN
STREPTOCOCCUS PNEUMONIAE TYPE 6B CAPSULAR POLYSACCHARIDE DIPHTHERIA CRM197 PROTEIN CONJUGATE ANTIGEN
STREPTOCOCCUS PNEUMONIAE TYPE 7F CAPSULAR POLYSACCHARIDE DIPHTHERIA CRM197 PROTEIN CONJUGATE ANTIGEN
STREPTOCOCCUS PNEUMONIAE TYPE 7F CAPSULAR POLYSACCHARIDE DIPHTHERIA CRM197 PROTEIN CONJUGATE ANTIGEN
STREPTOCOCCUS PNEUMONIAE TYPE 9V CAPSULAR POLYSACCHARIDE DIPHTHERIA CRM197 PROTEIN CONJUGATE ANTIGEN
STREPTOCOCCUS PNEUMONIAE TYPE 9V CAPSULAR POLYSACCHARIDE DIPHTHERIA CRM197 PROTEIN CONJUGATE ANTIGEN
STREPTOCOCCUS PNEUMONIAE TYPE 14 CAPSULAR POLYSACCHARIDE DIPHTHERIA CRM197 PROTEIN CONJUGATE ANTIGEN
STREPTOCOCCUS PNEUMONIAE TYPE 14 CAPSULAR POLYSACCHARIDE DIPHTHERIA CRM197 PROTEIN CONJUGATE ANTIGEN
STREPTOCOCCUS PNEUMONIAE TYPE 18C CAPSULAR POLYSACCHARIDE DIPHTHERIA CRM197 PROTEIN CONJUGATE ANTIGEN
STREPTOCOCCUS PNEUMONIAE TYPE 18C CAPSULAR POLYSACCHARIDE DIPHTHERIA CRM197 PROTEIN CONJUGATE ANTIGEN
STREPTOCOCCUS PNEUMONIAE TYPE 23F CAPSULAR POLYSACCHARIDE DIPHTHERIA CRM197 PROTEIN CONJUGATE ANTIGEN
STREPTOCOCCUS PNEUMONIAE TYPE 23F CAPSULAR POLYSACCHARIDE DIPHTHERIA CRM197 PROTEIN CONJUGATE ANTIGEN
STREPTOCOCCUS PNEUMONIAE TYPE 19A CAPSULAR POLYSACCHARIDE DIPHTHERIA CRM197 PROTEIN CONJUGATE ANTIGEN
STREPTOCOCCUS PNEUMONIAE TYPE 19A CAPSULAR POLYSACCHARIDE DIPHTHERIA CRM197 PROTEIN CONJUGATE ANTIGEN
STREPTOCOCCUS PNEUMONIAE TYPE 19F CAPSULAR POLYSACCHARIDE DIPHTHERIA CRM197 PROTEIN CONJUGATE ANTIGEN
STREPTOCOCCUS PNEUMONIAE TYPE 19F CAPSULAR POLYSACCHARIDE DIPHTHERIA CRM197 PROTEIN CONJUGATE ANTIGEN
CORYNEBACTERIUM DIPHTHERIAE CRM197 PROTEIN
POLYSORBATE 80
ALUMINUM PHOSPHATE
SUCCINATE DIANION

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

Children 6 weeks through 5 years: The four-dose immunization series consists of a 0.5 mL intramuscular injection administered at 2, 4, 6, and 12–15 months of age. (2.3)

Children 6 through 17 years of age: a single dose. (2.5)

Adults 18 years and older: a single dose. (2.6)

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.

Table 1: Vaccination Schedule for Infants and Toddlers
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:

Table 2: Vaccination Schedule for Unvaccinated Children 7 Months of Age Through 5 Years of Age
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.

Table 3: Percentage of US Infant and Toddler Subjects Reporting Solicited Local Reactions at the Prevnar 13 or Prevnar Injection Sites Within 7 Days After Each Vaccination at 2, 4, 6, and 12–15 Months of AgeData are from three primary US safety studies (the US Phase 2 infant study [National Clinical Trial (NCT) number NCT00205803] Study 1, the US noninferiority study [NCT00373958] Study 2, and the US lot consistency study [NCT00444457] Study 3). All infants received concomitant routine infant immunizations. Concomitant vaccines and pneumococcal conjugate vaccines were administered in different limbs.
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

Table 4: Percentage of US Infant and Toddler Subjects Reporting Solicited Systemic Adverse Reactions Within 7 Days After Each Vaccination at 2, 4, 6, and 12–15 Months of AgeNumber of subjects reporting Yes for at least 1 day or No for all days.,Data are from three primary US safety studies (the US Phase 2 infant study [NCT00205803] Study 1, the US noninferiority study [NCT00373958] Study 2, and the US lot consistency study [NCT00444457] Study 3). All infants received concomitant routine infant immunizations. Concomitant vaccines and pneumococcal conjugate vaccines were administered in different limbs.
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.

Table 5: Percentage of Subjects 7 Months Through 5 Years of Age Reporting Solicited Local Reactions Within 4 Days After Each Catch-Up Prevnar 13 VaccinationStudy conducted in Poland (NCT00452452) Study 4.
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

Table 6: Percentage of Subjects 7 Months Through 5 Years of Age Reporting Solicited Systemic Adverse Reactions Within 4 Days After Each Catch-Up Prevnar 13 VaccinationStudy conducted in Poland (NCT00452452) Study 4.
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.

Table 7: Percentage of Subjects 15 Months Through 59 Months of Age, Previously Vaccinated With 3 or 4 Prior Infant Doses of Prevnar, Reporting Solicited Local Reactions Within 7 Days After One Supplemental Prevnar 13 VaccinationStudy conducted in US NCT00761631 (Study 5).
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

Table 8: Percentage of Subjects 15 Months Through 59 Months of Age, Previously Vaccinated With 3 or 4 Prior Infant Prevnar Doses, Reporting Solicited Systemic Adverse Reactions Within 7 Days After One Supplemental Prevnar 13 VaccinationStudy conducted in US NCT00761631 (Study 5).
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.

Table 9: Percentage of Subjects 5 Through 17 Years of Age, Reporting Solicited Local Reactions Within 7 Days After Prevnar 13 Vaccination Study conducted in US NCT00761631 (Study 5).
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

Table 10: Percentage of Subjects 5 Through 17 Years of Age, Reporting Solicited Systemic Adverse Reactions Within 7 Days After Prevnar 13 VaccinationStudy conducted in US NCT00761631 (Study 5).
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).

Table 11 - Percentage of Subjects With Solicited Local Adverse Reactions Within 7 or 14 Days in PPSV23 Unvaccinated AdultsStudies conducted in US NCT00427895 (Study 6) and NCT00574548 (Study 8) reported local reactions within 14 days. Study conducted in the Netherlands NCT00744263 (Study 12) reported local reactions within 7 days.
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

Table 12 - Percentage of Subjects With Solicited Local Adverse Reactions in PPSV23 Previously Vaccinated AdultsStudy conducted in US and Sweden NCT00546572 (Study 7) reported local reactions within 14 days. Study conducted in US, Sweden and Germany NCT00500266 (Study 9) reported local reactions within 14 days.
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

Table 13 - Percentage of Subjects With Solicited Systemic Events in PPSV23 Unvaccinated AdultsStudies conducted in US NCT00427895 (Study 6) and NCT00574548 (Study 8) reported systemic events within 14 days. Study conducted in the Netherlands NCT00744263 (Study 12) reported systemic events within 7 days.
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

Table 14 - Percentage of Subjects With Systemic Events in PPSV23 Previously Vaccinated AdultsStudy conducted in US and Sweden NCT00546572 (Study 7) reported systemic events within 14 days. Study conducted in US, Sweden and Germany NCT00500266 (Study 9) reported systemic events within 14 days.
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

  >40.0°C

0.0

0.0

0.0

Fatigue

34.0

43.3Statistically significant difference p <0.05. No adjustments for multiplicity.

34.4

Headache

23.7

26.0

26.1

Chills

7.9

11.2

7.5

Rash

7.3

16.4

8.4

Vomiting

1.7

1.3

0.9

Decreased appetite

10.4

11.5

11.2

Generalized new muscle pain

36.8

44.7

25.3

Generalized aggravated muscle pain

20.6

27.5

12.3

Generalized new joint pain

12.6

14.9

12.8

Generalized aggravated joint pain

11.6

16.5

9.7

Safety Results from Adult Clinical Study of Concomitant Administration of Prevnar 13 and IIV4 (Fluzone Quadrivalent) (Study 13)

The safety profile of Prevnar 13 when administered concomitantly with seasonal inactivated influenza vaccine, quadrivalent, to PPSV23 previously vaccinated adults ≥50 years of age was generally consistent with the known safety profile of Prevnar 13.

6.3 Post-marketing Experience With Prevnar 13 in Infants and Toddlers

The following adverse events have been reported through passive surveillance since market introduction of Prevnar 13. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to the vaccine. The following adverse events were included based on one or more of the following factors: severity, frequency of reporting, or strength of evidence for a causal relationship to Prevnar 13 vaccine.

Administration site conditions: Vaccination-site dermatitis, vaccination-site pruritus, vaccination-site urticaria

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

Cardiac disorders: Cyanosis

Immune system disorders: Anaphylactic/anaphylactoid reaction including shock

Nervous system disorders: Hypotonia

Skin and subcutaneous tissue disorders: Angioneurotic edema, erythema multiforme

Respiratory: Apnea

Vascular disorders: Pallor

7 DRUG INTERACTIONS

7.1 Concomitant Immunizations

In clinical trials with infants and toddlers, Prevnar 13 was administered concomitantly with the following US-licensed vaccines: Pediarix [Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Hepatitis B (Recombinant) and Inactivated Poliovirus Vaccine Combined] (DTaP-HBV-IPV) and ActHIB [Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate)] (PRP-T) for the first three doses and with PedvaxHIB [Haemophilus b Conjugate Vaccine (Meningococcal Protein Conjugate)] (PRP-OMP), M-M-R II [Measles, Mumps, Rubella Virus Vaccine Live] (MMR) and Varivax [Varicella Virus Vaccine Live], or ProQuad [Measles, Mumps, Rubella and Varicella Virus Vaccine Live] (MMRV) and VAQTA [Hepatitis A vaccine, Inactivated] (HepA) for dose 4 [see Clinical Studies (14.2) and Adverse Reactions (6.1)].

In children and adolescents, data are insufficient to assess the concomitant administration of Prevnar 13 with Human Papillomavirus Vaccine (HPV), Meningococcal Conjugate Vaccine (MCV4) and Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine, Adsorbed (Tdap).

In adults, Prevnar 13 was administered concomitantly with US-licensed inactivated influenza vaccines, trivalent and quadrivalent (Studies 10, 11 and 13)[see Clinical Studies (14.4) and Adverse Reactions (6.2)]. There are no data on the concomitant administration of Prevnar 13 with diphtheria toxoid-containing vaccines and other vaccines licensed for use in adults 50 years of age and older.

When Prevnar 13 is administered at the same time as another injectable vaccine(s), the vaccines should always be administered with different syringes and given at different injection sites.

Do not mix Prevnar 13 with other vaccines/products in the same syringe.

7.2 Immunosuppressive Therapies

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

7.3 Antipyretics

A post-marketing clinical study conducted in Poland using a non-US vaccination schedule (2, 3, 4, and 12 months of age) evaluated the impact of prophylactic oral acetaminophen on antibody responses to Prevnar 13. The data show that 3 doses of acetaminophen (the first dose administered at the time of each vaccination and the subsequent doses at 6 to 8 hour intervals) reduced the antibody response to some serotypes following the third dose of Prevnar 13, compared with responses among infants who received antipyretics only as needed for treatment. Reduced antibody responses were not observed after the fourth dose of Prevnar 13 when acetaminophen was administered prophylactically.

7.4 Prior Vaccination with PPSV23

Prior receipt of PPSV23 within 1 year results in diminished immune responses to Prevnar 13 compared to PPSV23 naïve individuals [see Clinical Studies (14.3)].

8 USE IN SPECIFIC POPULATIONS

Pediatric Use: Safety and effectiveness of Prevnar 13 in children below the age of 6 weeks have not been established. (8.4)

8.1 Pregnancy

Risk Summary

All pregnancies have a risk of birth defect, loss, or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Available data on Prevnar 13 administered to pregnant women are insufficient to inform vaccine-associated risks in pregnancy.

A developmental toxicity study has been performed in female rabbits administered Prevnar 13 prior to mating and during gestation. Each dose was approximately 20 times the human dose. This study revealed no evidence of harm to the fetus due to Prevnar 13 (see 8.1 Data).

Data

Animal

In a developmental toxicity study, female rabbits were administered Prevnar 13 by intramuscular injection twice prior to mating (17 days and 3 days prior to mating) and twice during gestation (gestation days 10 and 24), 0.5 mL/rabbit/occasion (each dose approximately 20 times the human dose). No adverse effects on pre-weaning development were observed. There were no vaccine-related fetal malformations or variations.

8.2 Lactation

Risk Summary

Data are not available to assess the effects of Prevnar 13 on the breastfed infant or on milk production/excretion. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Prevnar 13 and any potential adverse effects on the breastfed child from Prevnar 13 or from the underlying maternal condition. For preventive vaccines, the underlying maternal condition is susceptibility to disease prevented by the vaccine.

8.4 Pediatric Use

Safety and effectiveness of Prevnar 13 in children below the age of 6 weeks have not been established.

8.5 Geriatric Use

Of the total number of Prevnar 13 recipients aged 50 years and older in clinical studies (N=47,907), 94.5% (45,291 of 47,907 ) were 65 years and older and 30.3 % (14,498 of 47,907) were 75 years and older [see Clinical Studies (14.1) and (14.3)].

8.6 High Risk Populations

Individuals with the diseases or conditions listed below are at increased risk of pneumococcal disease. Immunogenicity and safety data in these populations are limited.

Infants Born Prematurely

Immune responses elicited by Prevnar 13 administered on a US schedule to preterm infants have not been studied. When preterm infants (<37 weeks gestational age, N=100) were administered 4 doses of Prevnar 13 on a non-US schedule, the serotype-specific IgG antibody responses after the third and fourth dose were lower compared to responses among term infants (≥37 weeks gestational age, N=100) for some serotypes; the effectiveness of Prevnar 13 in preterm infants cannot be established from this study.

Children with Sickle Cell Disease

In an open-label, single-arm, descriptive study, 2 doses of Prevnar 13 were administered 6 months apart to children ≥6 to <18 years of age with sickle cell disease who previously received PPSV23 at least 6 months prior to enrollment. Children with a prior history of pneumococcal conjugate vaccination were excluded. For all vaccine serotypes, anti-pneumococcal opsonophagocytic activity (OPA) geometric mean antibody titers (GMTs) were higher after the first dose compared to pre-vaccination (N=95–131); OPA GMTs following the first and second dose were comparable. The effectiveness of Prevnar 13 in this specific population has not been established.

Individuals with Hematopoietic Stem Cell Transplant

In an open-label, single-arm, descriptive study, 4 doses of Prevnar 13 were administered to subjects ≥2 years of age (range 2 to 71 years) who had received an allogeneic hematopoietic stem cell transplant 3 to 6 months prior to enrollment. All subjects had a history of stable engraftment (absolute neutrophil count>1000/µL, platelet count >50,000/µL), and did not have uncontrolled graft versus host disease. The first three doses of Prevnar 13 were administered one month apart, followed by a fourth dose of Prevnar 13 six months after the third dose. Sera were obtained approximately one month after each vaccination. Immune responses (IgG GMCs) after the first dose of Prevnar 13 were numerically higher for all serotypes compared with baseline. In addition, after each subsequent dose of Prevnar 13, IgG GMCs for all serotypes were numerically higher than responses after the previous dose. A post hoc analysis of the immune responses as measured by OPA antibody assay showed the pattern of functional antibody responses to be consistent with IgG responses for each serotype. The effectiveness of Prevnar 13 in this specific population has not been established.

Individuals with HIV Infection

In an open-label, single-arm, descriptive study, 3 doses of Prevnar 13 were administered 6 months apart to HIV-infected adults ≥18 years of age (median age 48 years), with CD4 counts ≥200 cells/µL and serum HIV RNA titer <50,000 copies/mL. All subjects had been vaccinated previously with PPSV23 at least 6 months prior to enrollment. For all vaccine serotypes anti-pneumococcal OPA GMTs were numerically higher after the first dose compared to pre-vaccination (N=227–253); OPA GMTs following the first, second and third dose were generally comparable. The effectiveness of Prevnar 13 in this specific population has not been established.

In an open-label, single-arm, descriptive study, 3 doses of Prevnar 13 were administered 1 month apart to HIV-infected subjects ≥6 years of age with CD4 counts ≥200 cells/µL, and serum HIV RNA titer <50,000 copies/mL. Subjects had not previously been vaccinated with a pneumococcal vaccine. For all vaccine serotypes anti-pneumococcal OPA GMTs were numerically higher after the first dose compared to pre-vaccination (N=197–257); OPA GMTs following the first, second and third dose were generally comparable. The effectiveness of Prevnar 13 in this specific population has not been established.

11 DESCRIPTION

Prevnar 13, Pneumococcal 13-valent Conjugate Vaccine (Diphtheria CRM197 Protein) is a sterile suspension of saccharides of the capsular antigens of Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F, individually linked to non-toxic diphtheria CRM197 protein. Each serotype is grown in soy peptone broth. The individual polysaccharides are purified through centrifugation, precipitation, ultrafiltration, and column chromatography. The polysaccharides are chemically activated to make saccharides, which are directly conjugated by reductive amination to the protein carrier CRM197, to form the glycoconjugate. CRM197 is a nontoxic variant of diphtheria toxin isolated from cultures of Corynebacterium diphtheriae strain C7 (β197) grown in a casamino acids and yeast extract-based medium or in a chemically-defined medium. CRM197 is purified through ultrafiltration, ammonium sulfate precipitation, and ion-exchange chromatography. The individual glycoconjugates are purified by ultrafiltration and column chromatography and analyzed for saccharide to protein ratios, molecular size, free saccharide, and free protein.

The individual glycoconjugates are compounded to formulate Prevnar 13. Potency of the formulated vaccine is determined by quantification of each of the saccharide antigens and by the saccharide to protein ratios in the individual glycoconjugates. Each 0.5 mL dose of the vaccine is formulated to contain approximately 2.2 µg of each of Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 7F, 9V, 14, 18C, 19A, 19F, 23F saccharides, 4.4 μg of 6B saccharides, 34 µg CRM197 carrier protein, 100 µg polysorbate 80, 295 µg succinate buffer and 125 µg aluminum as aluminum phosphate adjuvant.

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

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Prevnar 13, comprised of pneumococcal polysaccharides conjugated to a carrier protein (CRM197), elicits a T-cell dependent immune response. Protein carrier-specific T-cells provide the signals needed for maturation of the B-cell response.

Nonclinical and clinical data support opsonophagocytic activity, as measured by opsonophagocytic activity (OPA) antibody assay, as a contributor to protection against pneumococcal disease. The OPA antibody assay provides an in vitro measurement of the ability of serum antibodies to eliminate pneumococci by promoting complement-mediated phagocytosis and is believed to reflect relevant in vivo mechanisms of protection against pneumococcal disease. OPA antibody titers are expressed as the reciprocal of the highest serum dilution that reduces survival of the pneumococci by at least 50%.

In infants that have received Prevnar 13, opsonophagocytic activity correlates well with serotype specific anti-capsular polysaccharide IgG levels as measured by ELISA. A serum anti-capsular polysaccharide antibody concentration of 0.35 µg/mL as measured by ELISA one month after the third dose as a single antibody reference concentration was used to estimate the effectiveness of Prevnar 13 against invasive pneumococcal disease (IPD) in infants and children. The assa