Package Insert and Label Information: PREVNAR 13

By Wyeth Pharmaceutical Division of Wyeth Holdings Corporation, a subsidiary of Pfizer Inc. | Last revised: 31 December 2011

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PREVNAR 13- 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 4 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 6b 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 14 capsular polysaccharide diphtheria crm197 protein conjugate antigen, streptococcus pneumoniae type 18c 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 and streptococcus pneumoniae type 23f capsular polysaccharide diphtheria crm197 protein conjugate antigen injection, suspension
Wyeth Pharmaceutical Division of Wyeth Holdings Corporation, a subsidiary of Pfizer Inc.

1 INDICATIONS AND USAGE

1.1 Children 6 Weeks Through 5 Years of Age

In children 6 weeks through 5 years of age (prior to the 6^th 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 Streptococcus 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 Adults 50 Years of Age and Older

In adults 50 years of age and older, Prevnar 13 is indicated for:

active immunization for the prevention of pneumonia and invasive disease caused by Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F. This indication is based on immune responses elicited by Prevnar 13. There have been no controlled trials in adults demonstrating a decrease in invasive pneumococcal disease or pneumococcal pneumonia after vaccination with Prevnar 13.

1.3 Limitations of Prevnar 13 Use and Effectiveness

Prevnar 13 will not protect against disease caused by Streptococcus pneumoniae serotypes that are not in the vaccine.
The effectiveness of Prevnar 13 administered less than 5 years after Pneumovax^® 23 (23 valent pneumococcal vaccine polyvalent, PPSV23) is not known [see Clinical Studies 14.3].

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. Do not inject intravenously, intradermally, or subcutaneously.

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, young 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 2†	Dose 3†	Dose 4‡
* Dose 1 may be given as early as 6 weeks of age. † The recommended dosing interval is 4 to 8 weeks. ‡ 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 of Age

For children who are beyond the age of the routine infant schedule and have not received Prevnar^® or Prevnar 13, the following catch-up schedule applies:

Table 2: Vaccination Schedule for Unvaccinated Children ≥ 7 Months of Age
Age at First Dose	Total Number of 0.5 mL Doses
* The 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. † Two doses at least 2 months apart.
7–11 months of age	3*
12–23 months of age	2†
24 months through 5 years of age (prior to the 6^th 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 to 15 months). In children 24 months through 5 years of age, the catch-up schedule may result in lower antibody concentrations 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 Previously Vaccinated With Prevnar Pneumococcal 7-valent Conjugate Vaccine (Diphtheria CRM ₁₉₇ Protein)

Children who have received one or more doses of Prevnar may complete the immunization series with Prevnar 13. Children 15 months through 5 years of age who are considered completely immunized with Prevnar may receive one dose of Prevnar 13 to elicit immune responses to the six additional serotypes. This catch-up (supplemental) dose of Prevnar 13 should be administered with an interval of at least 8 weeks after the final dose of Prevnar. The immune responses induced by this Prevnar 13 schedule may result in lower antibody concentrations for the 6 additional serotypes (types 1, 3, 5, 6A, 7F, and 19A), compared to antibody concentrations following 4 doses of Prevnar 13 (given at 2, 4, 6, and 12 to 15 months).

2.6 Vaccination Schedule for Adults 50 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.

4 CONTRAINDICATIONS

Severe allergic reaction (e.g., anaphylaxis) to any component of Prevnar 13 or any diphtheria toxoid-containing vaccine.

5 WARNINGS AND PRECAUTIONS

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

Data on the safety and effectiveness of Prevnar 13 when administered to immunocompromised individuals 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) are not available. Individuals in these groups may have reduced antibody response to active immunization due to impaired immune responsiveness.

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. As with any vaccine, there is the possibility that broad use of Prevnar 13 could reveal adverse reactions not observed in clinical trials.

6.1 Clinical Trials Experience With Prevnar 13 in Infants and Toddlers

The safety of Prevnar 13 was evaluated in 13 clinical trials in which 4,729 infants and toddlers 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 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 events 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 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 bleed approximately 1 month after the infant series; 2) 3.6% and 2.7% from the bleed after the infant series to the toddler dose; 3) 0.9% and 0.8% from the toddler dose to the bleed 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. 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 Age *
	Dose 1		Dose 2		Dose 3		Dose 4
Graded Local Reaction	Prevnar 13(N †=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)%
* Data are from three primary US safety studies (the US phase II infant study [National Clinical Trial (NCT) number NCT00205803], the US noninferiority study [NCT00373958], and the US consistency study [NCT00444457]). All infants received concomitant routine infant immunizations. Concomitant vaccines and pneumococcal conjugate vaccines were administered in different limbs. † Number of subjects reporting Yes for at least 1 day or No for all days. ‡ Diameters 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). § Statistically significant difference p < 0.05. No adjustments for multiplicity.
Redness ‡
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	13.4§
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 Age *^, †
	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)%
* Number 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 II infant study [NCT00205803], the US noninferiority study [NCT00373958], and the US consistency study [NCT00444457]). All infants received concomitant routine infant immunizations. Concomitant vaccines and pneumococcal conjugate vaccines were administered in different limbs. ‡ Fever 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 between the Prevnar 13 and Prevnar groups.
Fever ‡
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

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

In a catch-up study conducted in Poland, 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 Vaccination *
	7 through 11 months			12 through 23 months		24 months through 5 years
Graded Local Reaction	Dose 1N †=86%	Dose 2N †=86–87%	Dose 3N †=78–82%	Dose 1N †=108–110%	Dose 2N †=98–106%	Dose 1N †=147–149%
* Study conducted in Poland (NCT00452452). † Number of subjects reporting Yes for at least 1 day or No for all days. ‡ Diameters 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).
Redness ‡
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 Vaccination *
	7 through 11 months			12 through 23 months		24 months through 5 years
Systemic Reaction	Dose 1N †=86–87%	Dose 2N †=86–87%	Dose 3N †=78–81%	Dose 1N †=108%	Dose 2N †=98–100%	Dose 1N †=147–148%
* Study conducted in Poland (NCT00452452). † Number of subjects reporting Yes for at least 1 day or No for all days. ‡ Fever 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.
Fever ‡
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 study evaluated the use of Prevnar 13 in children previously immunized with Prevnar. In this open label trial, 284 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 (75.0%), 15.8% were Black or African-American, and 1.6% were Asian; 86.6% of subjects were non-Hispanic and non-Latino and 13.4% were Hispanic or Latino. Overall, 54.0% of subjects were male infants.

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 Vaccination
	15 months through 23 months *		24 months through 59 months †
Graded Local Reaction	1 dose Prevnar 133 prior Prevnar dosesN ‡=28–32%	1 dose Prevnar 134 prior Prevnar dosesN ‡=62–76%	1 dose Prevnar 133 or 4 prior Prevnar dosesN ‡=138–155%
Note – Clinical trial.gov NCT number is as follows: NCT00761631.
* Dose 2 data not shown. † 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. ‡ Number of subjects reporting Yes for at least 1 day or No for all days. § Diameters 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).
Redness §
Any	46.9	36.6	34.9
Mild	31.0	31.4	31.5
Moderate	22.6	7.9	9.9
Severe	0.0	0.0	0.0
Swelling §
Any	35.5	21.2	22.2
Mild	26.7	18.8	20.3
Moderate	13.8	7.7	5.7
Severe	0.0	0.0	0.0
Tenderness
Any	53.1	50.0	61.9
Interferes with limb movement	10.3	6.3	10.6

Table 8: Percentage of US 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 Vaccination
	15 through 23 months *		24 months through 59 months †
Systemic Reaction	1 dose Prevnar 133 prior Prevnar dosesN ‡=28–33%	1 dose Prevnar 134 prior Prevnar dosesN ‡=62–75%	1 dose Prevnar 133 or 4 prior Prevnar dosesN ‡=138–151%
Note – Clinical trial.gov NCT number is as follows: NCT00761631.
* Dose 2 data not shown. † 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. ‡ Number of subjects reporting Yes for at least 1 day or No for all days. § Fever 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.
Fever §
Mild	10.7	18.8	5.1
Moderate	7.1	3.2	0.7
Severe	0.0	0.0	0.7
Decreased appetite	56.7	36.2	24.8
Irritability	66.7	57.3	39.7
Increased sleep	30.0	33.8	15.9
Decreased sleep	22.6	22.7	14.0