Pneumococcal 7-valent Conjugate Vaccine (Diphtheria CRM₁₉₇ Protein), Prevnar®, is a sterile solution of saccharides of the capsular antigens of Streptococcus pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F individually conjugated to 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 to the protein carrier CRM₁₉₇ to form the glycoconjugate. This is effected by reductive amination. CRM₁₉₇ is a nontoxic variant of diphtheria toxin isolated from cultures of Corynebacterium diphtheriae strain C7 (b197) grown in a casamino acids and yeast extract-based medium. CRM197 is purified through ultrafiltration, ammonium sulfate precipitation, and ion-exchange chromatography. The individual glycoconjugates are purified by ultrafiltration and column chromatography and are analyzed for saccharide to protein ratios, molecular size, free saccharide, and free protein.

The individual glycoconjugates are compounded to formulate the vaccine, Prevnar^®. 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.

Prevnar^®is manufactured as a liquid preparation. Each 0.5 mL dose is formulated to contain:

2 mg of each saccharide for serotypes 4, 9V, 14, 18C, 19F, and 23F, and 4 mg of serotype 6B per dose (16 mg total saccharide); approximately 20 mg of CRM₁₉₇ carrier protein; and 0.125 mg ^of aluminum per 0.5 mL dose as aluminum phosphate adjuvant. After shaking, the vaccine is a homogeneous, white suspension.

Prevnar^®is indicated for active immunization of infants and toddlers against invasive disease caused by S. pneumoniae due to capsular serotypes included in the vaccine (4, 6B, 9V, 14, 18C, 19F, and 23F). The routine schedule is 2, 4, 6, and 12-15 months of age.

The decision to administer Pneumococcal 7-valent Conjugate Vaccine (Diphtheria CRM₁₉₇ Protein), Prevnar^®should be based primarily on its efficacy in preventing invasive pneumococcal disease. As with any vaccine, Prevnar^®may not protect all individuals receiving the vaccine from invasive pneumococcal disease.

Prevnar^®is also indicated for active immunization of infants and toddlers against otitis media caused by serotypes included in the vaccine. However, for vaccine serotypes, protection against otitis media is expected to be substantially lower than protection against invasive disease. Additionally, because otitis media is caused by many organisms other than serotypes of S. pneumoniae represented in the vaccine, protection against all causes of otitis media is expected to be low.

(See CLINICAL PHARMACOLOGY for estimates of efficacy against invasive disease and otitis media).

For additional information on usage, see DOSAGE AND ADMINISTRATION.

This vaccine is not intended to be used for treatment of active infection.

For intramuscular injection only. Do not inject intravenously.

The dose is 0.5 mL to be given intramuscularly.

Since this product is a suspension containing an adjuvant, shake vigorously immediately prior to use to obtain a uniform suspension in the vaccine container. The vaccine should not be used if it cannot be resuspended.

After shaking, the vaccine is a homogeneous, white suspension.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration (see DESCRIPTION). This product should not be used if particulate matter or discoloration is found.

The vaccine should be injected intramuscularly. The preferred sites are the anterolateral aspect of the thigh in infants or the deltoid muscle of the upper arm in toddlers and young children. The vaccine should not be injected in the gluteal area or areas where there may be a major nerve trunk and/or blood vessel. Before injection, the skin at the injection site should be cleansed and prepared with a suitable germicide. After insertion of the needle, aspirate and wait to see if any blood appears in the syringe, which will help avoid inadvertent injection into a blood vessel. If blood appears, withdraw the needle and prepare for a new injection at another site.

Vaccine Schedule

For infants, the immunization series of Prevnar^®consists of three doses of 0.5 mL each, at approximately 2-month intervals, followed by a fourth dose of 0.5 mL at 12-15 months of age. The customary age for the first dose is 2 months of age, but it can be given as young as 6 weeks of age. The recommended dosing interval is 4 to 8 weeks. The fourth dose should be administered at least 2 months after the third dose.

Previously Unvaccinated Older Infants and Children

For previously unvaccinated older infants and children, who are beyond the age of the routine infant schedule, the following schedule applies: ³⁵

Age at First Dose	Total Number of 0.5 mL Doses
7-11 months of age	3*
12-23 months of age	2†
≥24 months through 9 years of age	1
* 2 doses at least 4 weeks apart; third dose after the one-year birthday, separated from the second dose by at least 2 months.
† 2 doses at least 2 months apart.

(See CLINICAL PHARMACOLOGY section for the limited available immunogenicity data and ADVERSE EVENTS section for limited safety data corresponding to the previously noted vaccination schedule for older children).

Safety and immunogenicity data are either limited or not available for children in specific high risk groups for invasive pneumococcal disease (eg, persons with sickle cell disease, asplenia, HIV-infected).

Vial, 1 Dose (5 per package) - NDC 0005-1970-67

CPT Code 90669

STORAGE

DO NOT FREEZE. STORE REFRIGERATED, AWAY FROM FREEZER COMPARTMENT, AT 2°C TO 8°C (36°F TO 46°F).

REFERENCES

1 Schuchat A, Robinson K, Wenger JD, et al. Bacterial meningitis in the United States in 1995. N Engl J Med. 1997; 337:970-6.

2 Zangwill KM, Vadheim CM, Vannier AM, et al. Epidemiology of invasive pneumococcal disease in Southern California: implications for the design and conduct of a pneumococcal conjugate vaccine efficacy trial. J Infect Dis. 1996; 174:752-9.

3 Pastor P, Medley F, Murphy T. Invasive pneumococcal disease in Dallas County, Texas: results from population-based surveillance in 1995. Clin Infect Dis. 1998; 26:590-5.

4 Hofmann J, Cetron MS, Farley MM, et al. The prevalence of drug-resistant Streptococcus pneumoniae in Atlanta. N Engl J Med. 1995; 333:481-515.

5 Breiman R, Spika J, Navarro V, et al. Pneumococcal bacteremia in Charleston County, South Carolina. Arch Intern Med. 1990; 150:1401-5.

6 Plouffe J, Breiman R, Facklam R. Franklin County Study Group. Bacteremia with Streptococcus pneumoniae in adults-implications for therapy and prevention. JAMA. 1996; 275:194-8.

7 Levine O, Farley M, Harrison LH, et al. Risk factors for invasive pneumococcal disease in children: a population-based case-control study in North America. Pediatrics. 1999; 103:1-5.

8 Kaplan SL, Mason EO, Barson WJ, et al. Three-year multicenter surveillance of systemic pneumococcal infections in children. Pediatrics. 1998; 102:538-44.

9 Arditi M, Mason E, Bradley J, et al. Three-year multicenter surveillance of pneumococcal meningitis in children: clinical characteristics and outcome related to penicillin susceptibility and dexamethasone use. Pediatrics. 1998; 102:1087-97.

10 Shappert SM. Ambulatory care visits to physician offices, hospital outpatient departments, and emergency departments: United States, 1997. National Center for Health Statistics. Vital Health Sat. 1999; 13(143):1-41.

11 Hall MJ, Lawrence L. Ambulatory surgery in the United States, 1996. Adv Data Vital Health Stat. 1998; 300:1-16.

12 Teele DW, Klein JO, Rosner B, et al. Epidemiology of otitis media during the first seven years of life in children in greater Boston: a prospective, cohort study. J Infect Dis. 1989; 160:83-94.

13 Shappert, SM. Office visits for otitis media: United States, 1975-1990. Adv Data Vital Health Stat. 1992; 214:1-20.

14 Bluestone CD, Stephenson BS, Martin LM. Ten-year review of otitis media pathogens. Pediatr Infect Dis J. 1992; 11:S7-S11.

15 Giebink GS. The microbiology of otitis media. Pediatr Infect Dis J. 1989; 8:S18-S20.

16 Rodriguez WJ, Schwartz RH. Streptococcus pneumoniae causes otitis media with higher fever and more redness of tympanic membrane than Haemophilus influenzae or Moraxella catarrhalis. Pediatr Infect Dis J. 1999; 18:942-4.

17 Barnett ED, Klein JO. The problem of resistant bacteria for the management of acute otitis media. Ped Clin North Am. 1995; 42:509-17.

18 Butler JC, Breiman RF, Lipman HB, et al. Serotype distribution of Streptococcus pneumoniae infections among preschool children in the United States, 1978-1994: implications for development of a conjugate vaccine. J Infect Dis. 1995; 171:885-9.

19 Paisley JW, Lauer BA, McIntosh K, et al. Pathogens associated with acute lower respiratory tract infection in young children. Pediatr Infect Dis J. 1984; 3:14-9.

20 Heiskanen-Kosma T, Korppi M, Jokinen C, et al. Etiology of childhood pneumonia: serologic results of a prospective, population-based study. Pediatr Infect Dis J. 1998; 17:986-91.

21 American Academy of Pediatrics Committee on Infectious Diseases. Therapy for children with invasive pneumococcal infections. Pediatrics. 1997; 99:289-300.

22 Hausdorff WP, Bryant J, Paradiso PR, Siber GR. Which pneumococcal serogroups cause the most invasive disease: implications for conjugate vaccine formulation and use, part I. Clin Infect Dis. 2000; 30:100-21.

23 Butler JC, Hoffman J, Cetron MS, et al. The continued emergence of drug-resistant Streptococcus pneumoniae in the United States. An Update from the Centers for Disease Control and Preventions Pneumococcal Sentinel Surveillance System. J Infect Dis. 1996; 174:986-93.

24 Lederle Laboratories, Data on File: D118-P8.

25 Black S, Shinefield H, Ray P, et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Pediatr Infect Dis J. 2000; 19:187-195.

26 Lederle Laboratories, Data on File: D118-P809.

27 Eskola J, Kilpi T, Palma A, et al. Efficacy of a pneumococcal conjugate vaccine against acute otitis media. N Engl J Med. 2001; 344:403-409.

28 Fireman B, Black S, Shinefield H, et al. The impact of the pneumococcal conjugate vaccine on otitis media. Pediatr Infect Dis J. In press.

29 Lederle Laboratories, Data on File: D118-P16.

30 Lederle Laboratories, Data on File: D118-P8 Addendum DTaP Immunogenicity.

31 Shinefield HR, Black S, Ray P. Safety and immunogenicity of heptavalent pneumococcal CRM₁₉₇ conjugate vaccine in infants and toddlers. Pediatr Infect Dis J. 1999; 18:757-63.

32 Lederle Laboratories, Data on File: D118-P12.

33 Rennels MD, Edwards KM, Keyserling HL, et al. Safety and immunogenicity of heptavalent pneumococcal vaccine conjugated to CRM₁₉₇ in United States infants. Pediatrics. 1998; 101(4):604-11.

34 Lederle Laboratories, Data on File: D118-P3.

35 Lederle Laboratories, Data on File: Integrated Summary on Catch-Up.

36 Report of the Committee on Infectious Diseases 24^th Edition. Elk Grove Village, IL: American Academy of Pediatrics. 1997; 31-3.

37 Update: Vaccine Side Effects, Adverse Reactions, Contraindications, and Precautions. MMWR. 1996; 45 (RR-12):1-35.

38 Recommendations of the Advisory Committee on Immunization Practices (ACIP): use of vaccines and immunoglobulins in persons with altered immunocompetence. MMWR. 1993; 43(RR-4):1-18.

39 Vernacchio L, Neufeld EJ, MacDonald K, et al. Combined schedule of 7-valent pneumococcal conjugate vaccine followed by 23-valent pneumococcal vaccine in children and young adults with sickle cell disease. J Pediatr. 1998; 103:275-8.

40 Immunization of children infected with human immunodeficiency virus supplementary ACIP statement. MMWR. 1988; 37(12):181-83.

41 Centers for Disease Control and Prevention. General recommendations on immunization. Recommendations of the Advisory Committee on Immunization Practices (ACIP) and the American Academy of Family Physicians (AAFP). MMWR. 2002; 51(RR-2):1-36.

42 Fawcett HA, Smith NP. Injection-site granuloma due to aluminum. Archives Dermatology. 1984; 120:1318-22.

43 Vaccines Adverse Event Reporting System United States. MMWR. 1990; 39:730-3.

Manufactured by: LEDERLE LABORATORIES, Division American Cyanamid Company Pearl River, NY 10965 USA US GOVERNMENT LICENSE NO. 17

Marketed by: Wyeth-Ayerst Laboratories Philadelphia, PA 19101, W10430C002 ET01 Rev 05/03

Pre-Licensure Clinical Trial Experience

The majority of the safety experience with Prevnar^®comes from the NCKP Efficacy Trial in which 17,066 infants received 55,352 doses of Prevnar^®, along with other routine childhood vaccines through April 1998 (see CLINICAL PHARMACOLOGY section). The number of Prevnar^®recipients in the safety analysis differs from the number included in the efficacy analysis due to the different lengths of follow-up for these study endpoints. Safety was monitored in this study using several modalities. Local reactions and systemic events occurring within 48 hours of each dose of vaccine were ascertained by scripted telephone interview on a randomly selected subset of approximately 3,000 children in each vaccine group. The rate of relatively rare events requiring medical attention was evaluated across all doses in all study participants using automated databases. Specifically, rates of hospitalizations within 3, 14, 30, and 60 days of immunization, and of emergency room visits within 3, 14, and 30 days of immunization were assessed and compared between vaccine groups for each diagnosis. Seizures within 3 and 30 days of immunization were ascertained across multiple settings (hospitalizations, emergency room or clinic visits, telephone interviews). Deaths and SIDS were ascertained through April 1999. Hospitalizations due to diabetes, autoimmune disorders, and blood disorders were ascertained through August 1999.

In Tables 8 and 9 the rate of local reactions at the Prevnar^®injection site is compared at each dose to the DTP or DTaP injection site in the same children.

TABLE 8 Percentage of Subjects Reporting Local Reactions Within 2 Days Following Immunization With Prevnar®and DTP-HbOC* Vaccines at 2, 4, 6, and 12-15 Months of Age 24,25
Reaction	Dose 1	Dose 2		Dose 3		Dose 4
	Prevnar® Site	DTP-HbOC Site	Prevnar®Site	DTP-HbOC Site†	Prevnar®Site	DTP- HbOC Site†	Prevnar®Site	DTP- HbOC Site†
	N=2890	N=2890	N=2725	N=2725	N=2538	N=2538	N=599	N=599
Erythema
Any	12.4	21.9	14.3	25.1	15.2	26.5	12.7	23.4
>2.4 cm	1.2	4.6	1.0	2.9	2.0	4.4	1.7	6.4
Induration
Any	10.9	22.4	12.3	23.0	12.8	23.3	11.4	20.5
>2.4 cm	2.6	7.2	2.4	5.6	2.9	6.7	2.8	7.2
Tenderness
Any	28.0	36.4	25.2	30.5	25.6	32.8	36.5	45.1
Interfered with limb movement	7.9	10.7	7.4	8.4	7.8	10.0	18.5	22.2
* If Hep B vaccine was administered simultaneously, it was administered into the same limb as the DTP-HbOC vaccine. If reactions occurred at either or both sites on that limb, the more severe reaction was recorded.
† p<0.05 when Prevnar®site compared to the DTP-HbOC site using the sign test.

 

TABLE 9 Percentage of Subjects Reporting Local Reactions Within 2 Days Following Immunization With Prevnar®* and DTaP Vaccines† at 2, 4, 6, and 12-15 Months of Age24,25
Reaction		Dose 1		Dose 2		Dose 3		Dose 4
		Prevnar®Site	DtaP Site	Prevnar®Site	DtaP Site	Prevnar®Site	DtaP Site	Prevnar®Site	DtaP Site†
		N=693	N=693	N=526	N=526	N=422	N=422	N=165	N=165
Erythema
	Any	10.0	6.7§	11.6	10.5	13.8	11.4	10.9	3.6§
	γ¯¾2.4 cm	1.3	0.4§	0.6	0.6	1.4	1.0	3.6	0.6
Induration
	Any	9.8	6.6§	12.0	10.5	10.4	10.4	12.1	5.5§
	γ¯¾2.4 cm	1.6	0.9	1.3	1.7	2.4	1.9	5.5	1.8
Tenderness
	Any	17.9	16.0	19.4	17.3	14.7	13.1	23.3	18.4
	Interfered with limb movement	3.1	1.8§	4.1	3.3	2.9	1.9	9.2	8.0
* HbOC was administered in the same limb as Pneumococcal 7-valent Conjugate Vaccine (Diphtheria CRM197 Protein), Prevnar®. If reactions occurred at either or both sites on that limb, the more severe reaction was recorded.
† If Hep B vaccine was administered simultaneously, it was administered into the same limb as DTaP. If reactions occurred at either or both sites on that limb, the more severe reaction was recorded.
† Subjects may have received DTP or a mixed DTP/DTaP regimen for the primary series. Thus, this is the 4th dose of a pertussis vaccine, but not a 4th dose of DTaP.
§ p<0.05 when Prevnar ®site compared to DTaP site using the sign test.

Table 10 presents the rates of local reactions in previously unvaccinated older infants and children.

TABLE 10 Percentage of Subjects Reporting Local Reactions Within 3 Days of Immunization With Prevnar® in Infants and Children from 7 Months Through 9 Years of Age 35
Age at 1st Vaccination		7 - 11 Mos.						12 - 23 Mos.			24-35 Mos.	36 - 59 Mos.	5 - 9 Yrs.
Study No.		118-12			118-16			118-9* 118-18			118-18	118-18	118-18
Dose Number		1	2	3†	1	2	3†	1	1	2	1	1	1
Number of Subjects		54	51	24	81	76	50	60	114	117	46	48	49
Reaction
Erythema
	Any	16.7	11.8	20.8	7.4	7.9	14.0	48.3	10.5	9.4	6.5	29.2	24.2
	>2.4 cm†	1.9	0.0	0.0	0.0	0.0	0.0	6.7	1.8	1.7	0.0	8.3	7.1
Induration
	Any	16.7	11.8	8.3	7.4	3.9	10.0	48.3	8.8	6.0	10.9	22.9	25.5
	>2.4 cm†	3.7	0.0	0.0	0.0	0.0	0.0	3.3	0.9	0.9	2.2	6.3	9.3
Tenderness
	Any	13.0	11.8	12.5	8.6	10.5	12.0	46.7	25.7	26.5	41.3	58.3	82.8
	Interfered with limb movement§	1.9	2.0	4.2	1.2	1.3	0.0	3.3	6.2	8.5	13.0	20.8	39.4
* For 118-9, 2 of 60 subjects were ≥24 months of age.
† For 118-12, dose 3 was administered at 15 - 18 mos. of age. For 118-16, dose 3 was administered at 12 - 15 mos. of age.
† For 118-16 and 118-18, ≥2 cm.
§ Tenderness interfering with limb movement.

Tables 11 and 12 present the rates of systemic events observed in the efficacy study when Prevnar^®was administered concomitantly with DTP or DTaP.

TABLE 11 Percentage of Subjects* Reporting Systemic Events Within 2 Days Following Immunization With Prevnar® or Control† Vaccine Concurrently With DTP-HbOC Vaccine at 2, 4, 6, and 12-15 Months of Age24,25
	Reaction	Dose 1		Dose 2		Dose 3		Dose 4
		Prevnar®	Control†	Prevnar®	Control†	Prevnar®	Control†	Prevnar®	Control†
		N=2998	N=2982	N=2788	N=2761	N=2596	N=2591	N=709	N=733
Fever
	≥38.0°C	33.4	28.7†	34.7	27.4†	40.6	32.4†	41.9	36.9
	>39.0°C	1.3	1.3	3.0	1.6†	5.3	3.4†	4.5	4.5
Irritability		71.3	67.9†	69.4	63.8†	68.9	61.6†	72.8	65.8†
Drowsiness		49.2	50.6	32.5	33.6	25.9	23.4†	21.3	22.7
Restless Sleep		18.1	17.9	27.3	24.3†	33.3	30.1†	29.9	28.0
DecreasedAppetite		24.7	23.6	22.8	20.3†	27.7	25.6	33.0	27.4†
Vomiting		17.9	14.9†	16.2	14.4	15.5	12.7†	9.6	6.8
Diarrhea		12.0	10.7	10.9	9.9	11.5	10.4	12.1	11.2
Urticaria-like Rash		0.7	0.6	0.8	0.8	1.4	1.1	1.4	0.8
* Approximately 90% of subjects received prophylactic or therapeutic antipyretics within 48 hours of each dose.
† Investigational meningococcal group C conjugate vaccine (MnCC).
† p<0.05 when Prevnar® compared to control group using a Chi-Square test.

 

TABLE 12 Percentage of Subjects* Reporting Systemic Events Within 2 Days Following Immunization With Prevnar®or Control† Vaccine Concurrently With DTaP Vaccine at 2, 4, 6, and 12-15 Months of Age 24,25
Reaction		Dose 1		Dose 2		Dose 3		Dose 4†
		Prevnar®	Control†	Prevnar®	Control†	Prevnar®	Control†	Prevnar®	Control†
		N=710	N=711	N=559	N=508	N=461	N=414	N=224	N=230
Fever
	≥38.0°C	15.1	9.4§	23.9	10.8§	19.1	11.8§	21.0	17.0
	>39.0°C	0.9	0.3	2.5	0.8§	1.7	0.7	1.3	1.7
Irritability		48.0	48.2	58.7	45.3§	51.2	44.8	44.2	42.6
Drowsiness		40.7	42.0	25.6	22.8	19.5	21.9	17.0	16.5
Restless Sleep		15.3	15.1	20.2	19.3	25.2	19.0§	20.2	19.1
Decreased Appetite		17.0	13.5	17.4	13.4	20.7	13.8§	20.5	23.1
Vomiting		14.6	14.5	16.8	14.4	10.4	11.6	4.9	4.8
Diarrhea		11.9	8.4§	10.2	9.3	8.3	9.4	11.6	9.2
Urticaria-like Rash		1.4	0.3§	1.3	1.4	0.4	0.5	0.5	1.7
* Approximately 75% of subjects received prophylactic or therapeutic antipyretics within 48 hours of each dose.
† Investigational meningococcal group C conjugate vaccine (MnCC).
† Most of these children had received DTP for the primary series. Thus, this is a 4th dose of a pertussis vaccine, but not of DTaP.
§ pγ¯Â¼0.05 when Prevnar® compared to control group using a Chi-Square test.

Table 13 presents results from a second study (Manufacturing Bridging Study) conducted at Northern California and Denver Kaiser sites, in which children were randomized to receive one of three lots of Pneumococcal 7-valent Conjugate Vaccine (Diphtheria CRM₁₉₇ Protein),

Prevnar^®, with concomitant vaccines including DTaP, or the same concomitant vaccines alone. Information was ascertained by scripted telephone interview, as described above.

TABLE 13 Percentage of Subjects* Reporting Systemic Reactions Within 3 Days Following Immunization With Prevnar® , DTaP, HbOC, Hep B, and IPV vs. Control† In Manufacturing Bridging Study 29
Reaction		Dose 1		Dose 2		Dose 3
		Prevnar®	Control†	Prevnar®	Control†	Prevnar®	Control†
		N=498	N=108	N=452	N=99	N=445	N=89
Fever
	≥38.0°C	21.9	10.2†	33.6	17.2†	28.1	23.6
	>39.0°C	0.8	0.9	3.8	0.0	2.2	0.0
Irritability		59.7	60.2	65.3	52.5†	54.2	50.6
Drowsiness		50.8	38.9†	30.3	31.3	21.2	20.2
Decreased Appetite		19.1	15.7	20.6	11.1†	20.4	9.0†
* Approximately 72% of subjects received prophylactic or therapeutic antipyretics within 48 hours of each dose.
† Control group received concomitant vaccines only in the same schedule as the Prevnar®group (DTaP, HbOC at dose 1, 2, 3; IPV at doses 1 and 2; Hep B at doses 1 and 3).
† p<0.05 when Prevnar®compared to control group using Fishers Exact test.

Fever (≥38.0°C) within 48 hours of a vaccine dose was reported by a greater proportion of subjects who received Prevnar^®, compared to control (investigational meningococcal group C conjugate vaccine [MnCC]), after each dose when administered concurrently with DTP-HbOC or DTaP in the efficacy study. In the Manufacturing Bridging Study, fever within 48-72 hours was also reported more commonly after each dose compared to infants in the control group who received only recommended vaccines. When administered concurrently with DTaP in either study, fever rates among Prevnar^®recipients ranged from 15% to 34%, and were greatest after the 2^nd dose.

Table 14 presents the frequencies of systemic reactions in previously unvaccinated older infants and children.

TABLE 14 Percentage of Subjects Reporting Systemic Reactions Within 3 Days of Immunization With Prevnar®in Infants and Children from 7 Months Through 9 Years of Age35
Age at 1st Vaccination	7 - 11 Mos.						12 - 23 Mos			24 - 35 Mos.	36 - 59 Mos.	5 - 9 Yrs.
Study No.	118-12			118-16			118-9*	118-18		118-18	118-18	118-18
Dose Number	1	2	3†	1	2	3†	1	1	2	1	1	1
Number of Subjects	54	51	24	85	80	50	60	120	117	47	52	100
Reaction
Fever
≥38.0°C	20.8	21.6	25.0	17.6	18.8	22.0	36.7	11.7	6.8	14.9	11.5	7.0
>39.0°C	1.9	5.9	0.0	1.6	3.9	2.6	0.0	4.4	0.0	4.2	2.3	1.2
Fussiness	29.6	39.2	16.7	54.1	41.3	38.0	40.0	37.5	36.8	46.8	34.6	29.3
Drowsiness	11.1	17.6	16.7	24.7	16.3	14.0	13.3	18.3	11.1	12.8	17.3	11.0
Decreased Appetite	9.3	15.7	0.0	15.3	15.0	30.0	25.0	20.8	16.2	23.4	11.5	9.0
* For 118-9, 2 of 60 subjects were ≥24 months of age.
† For 118-12, dose 3 was administered at 15 - 18 mos. of age. For 118-16, dose 3 was administered at 12 - 15 mos. of age.

Of the 17,066 subjects who received at least one dose of Prevnar^®in the efficacy trial, there were 24 hospitalizations (for 29 diagnoses) within 3 days of a dose from October 1995 through April 1998. Diagnoses were as follows: bronchiolitis (5); congenital anomaly (4); elective procedure, UTI (3 each); acute gastroenteritis, asthma, pneumonia (2 each); aspiration, breath holding, influenza, inguinal hernia repair, otitis media, febrile seizure, viral syndrome, well child/reassurance (1 each). There were 162 visits to the emergency room (for 182 diagnoses) within 3 days of a dose from October 1995 through April 1998. Diagnoses were as follows: febrile illness (20); acute gastroenteritis (19); trauma, URI (16 each); otitis media (15); well child (13); irritable child, viral syndrome (10 each); rash (8); croup, pneumonia (6 each); poisoning/ingestion (5); asthma, bronchiolitis (4 each); febrile seizure, UTI (3 each); thrush, wheezing, breath holding, choking, conjunctivitis, inguinal hernia repair, pharyngitis (2 each); colic, colitis, congestive heart failure, elective procedure, hives, influenza, ingrown toenail, local swelling, roseola, sepsis (1 each).^24,25

In the large-scale efficacy study, urticaria-like rash was reported in 0.4%-1.4% of children within 48 hours following immunization with Prevnar^®administered concurrently with other routine childhood vaccines. Urticaria-like rash was reported in 1.3%-6% of children in the period from 3 to 14 days following immunization, and was most often reported following the fourth dose when it was administered concurrently with MMR vaccine. Based on limited data, it appears that children with urticaria-like rash after a dose of Prevnar^®may be more likely to report urticaria-like rash following a subsequent dose of Prevnar^®.

One case of a hypotonic-hyporesponsive episode (HHE) was reported in the efficacy study following Prevnar^®and concurrent DTP vaccines in the study period from October 1995 through April 1998. Two additional cases of HHE were reported in four other studies and these also occurred in children who received Prevnar^®concurrently with DTP vaccine. ^31,34

In the Kaiser efficacy study in which 17,066 children received a total of 55,352 doses of Prevnar^®and 17,080 children received a total of 55,387 doses of the control vaccine

(investigational meningococcal group C conjugate vaccine [MnCC]), seizures were reported in 8 Prevnar^®recipients and 4 control vaccine recipients within 3 days of immunization from October 1995 through April 1998. Of the 8 Prevnar^®recipients, 7 received concomitant DTP-containing vaccines and one received DTaP. Of the 4 control vaccine recipients, 3 received concomitant DTP-containing vaccines and one received DTaP.^24,25 In the other 4 studies combined, in which 1,102 children were immunized with 3,347 doses of Prevnar^®and 408 children were immunized with 1,310 doses of control vaccine (either investigational meningococcal group C conjugate vaccine [MnCC] or concurrent vaccines), there was one seizure event reported within 3 days of immunization.³² This subject received Prevnar^®concurrent with DTaP vaccine.

Twelve deaths (5 SIDS and 7 with clear alternative cause) occurred among subjects receiving Prevnar^®, of which 11 (4 SIDS and 7 with clear alternative cause) occurred in the Kaiser efficacy study from October 1995 until April 20, 1999. In comparison, 21 deaths (8 SIDS, 12 with clear alternative cause and one SIDS-like death in an older child), occurred in the control vaccine group during the same time period in the efficacy study.^24,25,29 The number of SIDS deaths in the efficacy study from October 1995 until April 20, 1999 was similar to or lower than the age and season-adjusted expected rate from the California State data from 1995-1997 and are presented in Table 15.

 

TABLE 15 Age and Season-Adjusted Comparison of SIDS Rates in the NCKP Efficacy Trial With the Expected Rate from the California State Data for 1995-1997 24,25
Vaccine	<One Week After Immunization		≤Two Weeks After Immunization		≤One Month After Immunization		≤One Year After Immunization
	Exp	Obs	Exp	Obs	Exp	Obs	Exp	Obs
Prevnar®	1.06	1	2.09	2	4.28	2	8.08	4
Control*	1.06	2	2.09	3†	4.28	3†	8.08	8†
* Investigational meningococcal group C conjugate vaccine (MnCC).
† Does not include one additional case of SIDS-like death in a child older than the usual SIDS age (448 days).

In a review of all hospitalizations that occurred between October 1995 and August 1999 in the efficacy study for the specific diagnoses of aplastic anemia, autoimmune disease, autoimmune hemolytic anemia, diabetes mellitus, neutropenia, and thrombocytopenia, the numbers of such cases were equal to or less than the expected numbers based on the 1995 Kaiser Vaccine Safety Data Link (VSD) data set.

Overall, the safety of Prevnar^®was evaluated in a total of five clinical studies in the US in which 18,168 infants and children received a total of 58,699 doses of vaccine at 2, 4, 6, and 12-15 months of age. In addition, the safety of Prevnar^®was evaluated in 831 Finnish infants using the same schedule, and the overall safety profile was similar to that in US infants. The safety of Prevnar^®was also evaluated in 560 children from 4 ancillary studies in the US who started immunization at 7 months to 9 years of age. Tables 16 and 17 summarize systemic reactogenicity data within 2 or 3 days across 4,748 subjects in US studies (13,039 infant doses and 1,706 toddler doses) for whom these data were collected and according to the pertussis vaccine administered concurrently.

TABLE 16 Overall Percentage of Doses Associated With Systemic Events Within 2 or 3 Days For The US Efficacy Study and All US Ancillary Studies When Prevnar®Administered To Infants As a Primary Series at 2, 4, and 6 Months of Age24,25, 29,31,32,33
Systemic Event		Prevnar® Concurrently With DTP-HbOC(9,191 Doses)*	Prevnar® Concurrently With DTaP and HbOC(3,848 Doses)†	DTaP and HbOC Control(538 Doses)†
Fever
	≥38.0°C	35.6	21.1	14.2
	>39.0°C	3.1	1.8	0.4
Irritability		69.1	52.5	45.2
Drowsiness		36.9	32.9	27.7
Restless Sleep		25.8	20.6	22.3
Decreased Appetite		24.7	18.1	13.6
Vomiting		16.2	13.4	9.8
Diarrhea		11.4	9.8	4.4
Urticaria-like Rash		0.9	0.6	0.3
* Total from which reaction data are available varies between reactions from 8,874-9,191 doses. Data from studies 118-3, 118-7, 118-8.
† Total from which reaction data are available varies between reactions from 3,121-3,848 doses. Data from studies 118-8, 118-12, 118-16.
† Total from which reaction data are available varies between reactions from 295-538 doses. Data from studies 118-12 and 118-16.

 

TABLE 17 Overall Percentage of Doses Associated With Systemic Events Within 2 or 3 Days For The US Efficacy Study and All US Ancillary Studies When Prevnar® Administered To Toddlers as a Fourth Dose At 12 to 15 Months of Age 24,25,31
Systemic Event		Prevnar®Concurrently With DTP-HbOC (709 Doses)*	Prevnar®Concurrently With DTaP and HbOC (270 Doses) †	Prevnar®Only No Concurrent Vaccines (727 Doses)†
Fever
	≥38.0°C	41.9	19.6	13.4
	>39.0°C	4.5	1.5	1.2
Irritability		72.8	45.9	45.8
Drowsiness		21.3	17.5	15.9
Restless Sleep		29.9	21.2	21.2
Decreased Appetite		33.0	21.1	18.3
Vomiting		9.6	5.6	6.3
Diarrhea		12.1	13.7	12.8
Urticaria-like Rash		1.4	0.7	1.2
* Total from which reaction data are available varies between reactions from 706-709 doses. Data from study 118-8.
† Total from which reaction data are available varies between reactions from 269-270 doses. Data from studies 118-7 and 118-8.
† Total from which reaction data are available varies between reactions from 725-727 doses. Data from studies 118-7 and 118-8.

With vaccines in general, including Pneumococcal 7-valent Conjugate Vaccine (Diphtheria CRM₁₉₇ Protein), PrevnarÒ, it is not uncommon for patients to note within 48 to 72 hours at or around the injection site the following minor reactions: edema; pain or tenderness; redness, inflammation or skin discoloration; mass; or local hypersensitivity reaction. Such local reactions are usually self-limited and require no therapy.

As with other aluminum-containing vaccines, a nodule may occasionally be palpable at the injection site for several weeks.⁴²

Postmarketing Experience

Additional adverse reactions identified from postmarketing experience are listed below:

Administration site conditions: injection site dermatitis, injection site urticaria, injection site pruritus

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

Immune system disorders: hypersensitivity reaction including face edema, dyspnea, bronchospasm; anaphylactic/anaphylactoid reaction including shock

Skin and subcutaneous tissue disorders: angioneurotic edema, erythema multiforme

There have been spontaneous reports of apnea in temporal association with the administration of Prevnar. In most cases Prevnar was administered concomitantly with other vaccines including diphtheria tetanus pertussis vaccine (DTP), diphtheria tetanus acellular pertussis vaccine (DTaP), hepatitis B vaccines, inactivated polio vaccine (IPV), Haemophilus influenzae type b vaccine (Hib), measles-mumps-rubella vaccine (MMR), and/or varicella vaccine. In addition, in most of the reports existing medical conditions such as history of apnea, infection, prematurity, and/or seizure were present.

ADVERSE EVENT REPORTING

Any suspected adverse events following immunization should be reported by the healthcare professional to the US Department of Health and Human Services (DHHS). The National Vaccine Injury Compensation Program requires that the manufacturer and lot number of the vaccine administered be recorded by the healthcare professional in the vaccine recipients permanent medical record (or in a permanent office log or file), along with the date of administration of the vaccine and the name, address, and title of the person administering the vaccine.

The US DHHS has established the Vaccine Adverse Event Reporting System (VAERS) to accept all reports of suspected adverse events after the administration of any vaccine including, but not limited to, the reporting of events required by the National Childhood Vaccine Injury Act of 1986. The FDA web site is: http://www.fda.gov/cber/vaers/vaers.htm.

The VAERS toll-free number for VAERS forms and information is 800-822-7967.⁴³

Children receiving therapy with immunosuppressive agents (large amounts of corticosteroids, antimetabolites, alkylating agents, cytotoxic agents) may not respond optimally to active immunization.^37,38,40,41 (See PRECAUTIONS, General.)

As with other intramuscular injections, Prevnar^® should be given with caution to children on anticoagulant therapy.

Simultaneous Administration with Other Vaccines

During clinical studies, Prevnar^®was administered simultaneously with DTP-HbOC or DTaP and HbOC, OPV or IPV, Hep B vaccines, MMR, and Varicella vaccine. Thus, the safety experience with Prevnar^® reflects the use of this product as part of the routine immunization schedule.^{24,25,29,31,32,34}

The immune response to routine vaccines when administered with Prevnar^®(at separate sites) was assessed in 3 clinical studies in which there was a control group for comparison. Results for the concurrent immunizations in infants are shown in Table 6 and for toddlers in Table 7. Enhancement of antibody response to HbOC in the infant series was observed. Some suppression of Haemophilus influenzae type b (Hib) response was seen at the 4^th dose, but over 97% of children achieved titers ≥1 mg/mL. Although some inconsistent differences in response to pertussis antigens were observed, the clinical relevance is unknown. The response to 2 doses of IPV given concomitantly with Prevnar^®, assessed 3 months after the second dose, was equivalent to controls for poliovirus Types 2 and 3, but lower for Type 1. MMR and Varicella immunogenicity data from controlled clinical trials with concurrent administration of Prevnar^®are not available.

TABLE 6 Concurrent Administration of Prevnar®With Other Vaccines to Infants in Non-Efficacy Studies 29,32
Antigen*		GMC*		% Responders†		Study	Vaccine Schedule†	N
		Prevnar®	Control§	Prevnar®	Control§		(mo.)	Prevnar®	Control§
Hib		6.2	4.4	99.5, 88.3	97.0, 88.1	118-12	2, 4, 6	214	67
Diphtheria		0.9	0.8	100	97.0
Tetanus		3.5	4.1II	100	100
PT		19.1	17.8	74.0	69.7
FHA		43.8	46.7	66.4	69.7
Pertactin		40.1	50.9	65.6	77.3
Fimbriae 2		3.3	4.2	44.7	62.5ll
Hib		11.9	7.8 ll	100, 96.9	98.8, 92.8	118-16	2, 4, 6	159	83
Hep B		--	--	99.4	96.2	118-16	0, 2, 6	156	80
IPV Type 1		--	--	89.0	93.6¶	118-16	2, 4	156	80
	Type 2	--	--	94.2	93.6
	Type 3	--	--	83.8	80.8
* Hib vaccine was HibTITER®, DTaP vaccine was Acel-Imune®. Hib (mg/mL); Dip, Tet (IU/mL); Pertussis Antigens (PT, FHA, Ptn, Fim) (units/mL).
† Responders γ¯Â½γ¯Â Hib ( ≥ 0.15 mg/mL, ≥1.0 mg/mL); Dip, Tet (≥0.1 IU/mL); Pertussis Antigens (PT, FHA, Ptn, Fim) [4-fold rise]; IPV (≥1:10); Hep B ( ≥ 10 mIU/mL).
† Schedule for concurrently administered vaccines; Pneumococcal 7-valent Conjugate Vaccine (Diphtheria CRM197 Protein), Prevnar®administered at 2, 4, 6 mos.; blood for antibody assessment attained 1 month after third dose, except for IPV (3 months post-immunization).
§ Concurrent vaccines only.
ll p<0.05 when Prevnar®compared to control group using the following tests: ANCOVA for GMCs in 118-12; ANOVA for GMCs in 118-16; and Fishers Exact test for % Responders in 118-12.
¶ Lower bound of 90% CI of difference >10%.

 

TABLE 7 Concurrent Administration of Prevnar®With Other Vaccines to Toddlers in a Non-Efficacy Study 31
Antigen*	GMC*		% Responders†		Study†	Vaccine Schedule