For Intramuscular Injection Only
Prevnar, Pneumococcal 7-valent Conjugate Vaccine (Diphtheria CRM 197 Protein), 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 CRM 197 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 CRM 197 to form the glycoconjugate. This is effected by reductive amination. CRM 197 is a nontoxic variant of diphtheria toxin isolated from cultures of Corynebacterium diphtheriae strain C7 ((beta)197) grown in a casamino acids and yeast extract-based medium. CRM 197 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 µg of each saccharide for serotypes 4, 9V, 14, 18C, 19F, and 23F, and 4 µg of serotype 6B per dose (16 µg total saccharide); approximately 20 µg of CRM 197 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.
S. pneumoniae is an important cause of morbidity and mortality in persons of all ages worldwide. The organism causes invasive infections, such as bacteremia and meningitis, as well as pneumonia and upper respiratory tract infections including otitis media and sinusitis. In children older than 1 month, S. pneumoniae is the most common cause of invasive disease. 1 Data from community-based studies performed between 1986 and 1995, indicate that the overall annual incidence of invasive pneumococcal disease in the United States is an estimated 10 to 30 cases per 100,000 persons, with the highest risk in children aged less than or equal to 2 years of age (140 to 160 cases per 100,000 persons). 2,3,4,5,6 Children in group child care can have an increased risk for invasive pneumococcal disease. 7,8
Immunocompromised individuals with neutropenia, asplenia, sickle cell disease, disorders of complement and humoral immunity, human immunodeficiency virus (HIV) infections or chronic underlying disease are also at risk for invasive pneumococcal disease. 8 S. pneumoniae is the most common cause of bacterial meningitis in the United States. 1 The annual incidence of pneumococcal meningitis in children between 1 to 23 months of age is approximately 7 cases per 100,000 persons. 1 Pneumococcal meningitis in childhood has been associated with 8% mortality and may result in neurological sequelae (25%) and hearing loss (32%) in survivors. 9
S. pneumoniae is an important cause of acute otitis media, identified in 20 to 40% of middle ear fluid cultures. 10,11 The seven serotypes account for approximately 60% of acute otitis media due to S. pneumoniae (12-24% of all acute otitis media). 12 The exact contribution of S. pneumoniae to childhood pneumonia is unknown, as it is often not possible to identify the causative organisms. In studies of children less than 5 years of age with community-acquired pneumonia, where diagnosis was attempted using serological methods, antigen testing, or culture data, 30% of cases were classified as bacterial pneumonia, and 70% of these (21% of total community-acquired pneumonia) were found to be due to S. pneumoniae . 13,14
In the past decade the proportion of S. pneumoniae isolates resistant to antibiotics has been on the rise in the United States and worldwide. In a multi-center US surveillance study, the prevalence of penicillin and cephalosporin-nonsusceptible (intermediate or high level resistance) invasive disease isolates from children was 21% (range < 5% to 38% among centers), and 9.3% (range 0-18%), respectively. Over the 3-year surveillance period (1993-1996), there was a 50% increase in penicillin-nonsusceptible S. pneumoniae (PNSP) strains and a three-fold rise in cephalosporin-nonsusceptible strains. 8 Although generally less common than PNSP, pneumococci resistant to macrolides and trimethoprin-sulfazoxole have also been observed. 4 Day care attendance, a history of ear infection, and a recent history of antibiotic exposure, have also been associated with invasive infections with PNSP in children 2 months to 59 months of age. 7,8 There has been no difference in mortality associated with PNSP strains. 8,9 However, the American Academy of Pediatrics (AAP) revised the antibiotic treatment guidelines in 1997 in response to the increased prevalence of antibiotic-resistant pneumococci. 15
Approximately 90 serotypes of S. pneumoniae have been identified based on antigenic differences in their capsular polysaccharides. The distribution of serotypes responsible for disease differ with age and geographic location. 16
Serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F have been responsible for approximately 80% of invasive pneumococcal disease in children < 6 years of age in the United States. 12 These 7 serotypes also accounted for 74% of PNSP and 100% of pneumococci with high level penicillin resistance isolated from children < 6 years with invasive disease during a 1993-1994 surveillance by the Centers for Disease Control
Efficacy was assessed in a randomized, double-blind clinical trial in a multiethnic population at Northern California Kaiser Permanente (NCKP), beginning in October 1995, in which 37,816 infants were randomized to receive either Prevnar or a control vaccine (an investigational meningococcal group C conjugate vaccine [MnCC]) at 2, 4, 6, and 12-15 months of age. Prevnar was administered to 18,906 children and the control vaccine to 18,910 children. Routinely recommended vaccines were also administered which changed during the trial to reflect changing AAP and Advisory Committee on Immunization Practices (ACIP) recommendations. A planned interim analysis was performed upon accrual of 17 cases of invasive disease due to vaccine-type S. pneumoniae (August 1998). Ancillary endpoints for evaluation of efficacy against pneumococcal disease were also assessed in this trial.
Efficacy against invasive disease: Invasive disease was defined as isolation and identification of S. pneumoniae from normally sterile body sites in children presenting with an acute illness consistent with pneumococcal disease. Weekly surveillance of listings of cultures from the NCKP Regional Microbiology database was conducted to assure ascertainment of all cases. The primary endpoint was efficacy against invasive pneumococcal disease due to vaccine serotypes. The per protocol analysis of the primary endpoint included cases which occurred >/= 14 days after the third dose. The intent-to-treat (ITT) analysis included all cases of invasive pneumococcal disease due to vaccine serotypes in children who received at least one dose of vaccine. Secondary analyses of efficacy against all invasive pneumococcal disease, regardless of serotype, were also performed according to these same per protocol and ITT definitions. Results of these analyses are presented in Table 1.
All 22 cases of invasive disease due to vaccine serotype strains in the ITT population were bacteremic. In addition, the following diagnoses were also reported: meningitis (2), pneumonia (2), and cellulitis (1).
Preliminary efficacy data through an extended follow-up period to April 20, 1999, resulted in a similar efficacy estimate (Per protocol: 1 case in Prevnar group, 39 cases in control group; ITT: 3 cases in Prevnar group, 49 cases in the control group).
Subjects from a subset of selected study sites in the NCKP efficacy study were approached for participation in the immunogenicity portion of the study on a volunteer basis. Immune responses following three or four doses of Prevnar or the control vaccine were evaluated in children who received either concurrent Diphtheria and Tetanus Toxoids and Pertussis Vaccine Adsorbed and Haemophilus b Conjugate Vaccine (Diphtheria CRM 197 Protein Conjugate), (DTP-HbOC), or Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed (DTaP), and Haemophilus b Conjugate Vaccine (Diphtheria CRM 197 Protein Conjugate), (HbOC) vaccines at 2, 4, and 6 months of age. The use of Hepatitis B (Hep B), Oral Polio Vaccine (OPV), Inactivated Polio Vaccine (IPV), Measles-Mumps-Rubella (MMR), and Varicella vaccines were permitted according to the AAP and ACIP recommendations.
Table 2 presents the geometric mean concentrations (GMC) of pneumococcal antibodies following the third and fourth doses of Prevnar or the control vaccine when administered concurrently with DTP-HbOC vaccine in the efficacy study.
In another randomized study (Manufacturing Bridging Study, 118-16), immune responses were evaluated following three doses of Prevnar administered concomitantly with DTaP and HbOC vaccines at 2, 4, and 6 months of age, IPV at 2 and 4 months of age, and Hep B at 2 and 6 months of age. The control group received concomitant vaccines only. Table 3 presents the immune responses to pneumococcal polysaccharides observed in both this study and in the subset of subjects from the efficacy study that received concomitant DTaP and HbOC vaccines.
In all studies in which the immune responses to Prevnar were contrasted to control, a significant antibody response was seen to all vaccine serotypes following three or four doses, although geometric mean concentrations of antibody varied among serotypes. 18,19,20,21,22,23,24,25 The minimum serum antibody concentration necessary for protection against invasive pneumococcal disease has not been determined for any serotype.
Prevnar induces functional antibodies to all vaccine serotypes, as measured by opsonophagocytosis following three doses. 25
To determine an appropriate schedule for children 7 months of age or older at the time of the first immunization with Prevnar, 483 children in 4 ancillary studies received Prevnar at various schedules. GMCs attained using the various schedules among older infants and children were comparable to immune responses of children, who received concomitant DTaP, in the NCKP efficacy study (118-8) after 3 doses for most serotypes, as shown in Table 4. These data support the schedule for previously unvaccinated older infants and children who are beyond the age of the infant schedule. For usage in older infants and children see DOSAGE AND ADMINISTRATION .
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. For additional information on usage, see DOSAGE AND ADMINISTRATION .
This vaccine is not intended to be used for treatment of active infection.
As with any vaccine, Prevnar may not protect 100% of individuals receiving the vaccine.
Hypersensitivity to any component of the vaccine, including diphtheria toxoid, is a contraindication to use of this vaccine.
The decision to administer or delay vaccination because of a current or recent febrile illess depends largely on the severity of the symptoms and their etiology. Although a severe or even a moderate febrile illness is sufficient reason to postpone vaccinations, minor illnesses, such as a mild upper respiratory infection with or without low-grade fever, are not generally contraindications. 27,28
THIS VACCINE WILL NOT PROTECT AGAINST S. PNEUMONIAE DISEASE OTHER THAN THAT CAUSED BY THE SEVEN SEROTYPES INCLUDED IN THE VACCINE, NOR WILL IT PROTECT AGAINST OTHER MICROORGANISMS THAT CAUSE INVASIVE INFECTION SUCH AS BACTEREMIA AND MENINGITIS.
This vaccine should not be given to infants or children with thrombocytopenia or any coagulation disorder that would contraindicate intramuscular injection unless the potential benefit clearly outweighs the risk of administration. If the decision is made to administer this vaccine to children with coagulation disorders, it should be given with caution. (See DRUG INTERACTIONS. )
Immunization with Prevnar does not substitute for routine diphtheria immunization.
Healthcare professionals should prescribe and/or administer this product with caution to patients with a possible history of latex sensitivity since the packaging contains dry natural rubber.
Prevnar is for intramuscular use only. Prevnar SHOULD UNDER NO CIRCUMSTANCES BE ADMINISTERED INTRAVENOUSLY. The safety and immunogenicity for other routes of administration (e.g. subcutaneous) have not been evaluated.
CARE IS TO BE TAKEN BY THE HEALTHCARE PROFESSIONAL FOR THE SAFE AND EFFECTIVE USE OF THIS PRODUCT.
Prior to administration of this vaccine, the healthcare professional should inform the parent, guardian, or other responsible adult of the potential benefits and risks to the patient (see ADVERSE REACTIONS and sections), and the importance of completing the immunization series unless contraindicated. Parents or guardians should be instructed to report any suspected adverse reactions to their healthcare professional. The healthcare professional should provide vaccine information statements prior to each vaccination.
Children receiving therapy with immunosuppressive agents (large amounts of corticosteroids, antimetabolites, alkylating agents, cytotoxic agents) may not respond optimally to active immunization. 28,29,31,32 (See PRECAUTIONS , General .)
As with other intramuscular injections, Prevnar should be given with caution to children on anticoagulant therapy.
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. 19,20,22,23,25
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 5 and for toddlers in Table 6. 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 4th dose, but over 97% of children achieved titers >/= 1 µg/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.
Prevnar has not been evaluated for any carcinogenic or mutagenic potential, or impairment of fertility.
Animal reproductive studies have not been conducted with this product. It is not known whether Prevnar can cause fetal harm when administered to a pregnant woman or whether it can affect reproductive capacity. This vaccine is not recommended for use in pregnant women.
It is not known whether vaccine antigens or antibodies are excreted in human milk. This vaccine is not recommended for use in a nursing mother.
Prevnar has been shown to be usually well-tolerated and immunogenic in infants. The safety and effectiveness of Prevnar in children below the age of 6 weeks have not been established. Immune responses elicited by Prevnar among infants born prematurely have not been studied. See DOSAGE AND ADMINISTRATION for the rcommended pediatric dosage.
This vaccine is NOT recommended for use in adult populations. It is not to be used as a substitute for the pneumococcal polysaccharide vaccine, in geriatric populations.
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 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 7 and 8, 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 9 presents the rates of local reactions in previously unvaccinated older infants and children.
Tables 10 and 11 present the rates of systemic events observed in the efficacy study when Prevnar was administered concomitantly with DTP or DTaP.
Table 12 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 Prevnar with concomitant vaccines including DTaP, or the same concomitant vaccines alone. Information was ascertained by scripted telephone interview, as described below.
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 2nd dose.
Table 13 presents the frequencies of systemic reactions in previously unvaccinated older infants and children.
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). 19
One case of 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. 22,25
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. 19 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. 23 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. 19,20 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 14.
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 either 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 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 560 children from 4 ancillary studies who started immunization at 7 months to 9 years of age. Tables 15 and 16 summarize systemic reactogenicity data within 2 or 3 days across 4,748 subjects (13,039 infant doses and 1,706 toddler doses) for whom these data were collected and according to the pertussis vaccine administered concurrently.
With vaccines in general, including Prevnar, 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. 33
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 by recorded by the healthcare professional in the vaccine recipient' 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:
The VAERS toll-free number for VAERS forms and information is 800-822-7967. 34
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 ). This product should not be used if particulate matter of 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.
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.
For previously unvaccinated older infants and children, who are beyond the age of the routine infant schedule, the following schedule applies: 26
(See 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 (e.g. persons with sickle cell disease, asplenia, HIV-infected).
Vial, 1 Dose (5 per package)--NDC 0005-1970-67
CPT Code 90669
DO NOT FREEZE. STORE REFRIGERATED, AWAY FROM FREEZER COMPARTMENT, AT 2°C TO 8°C (36°F TO 46°F).
Division American Cyanamid Company
Pearl River, NY 10965 USA
US GOVT. LICENSE NO. 17
Philadelphia, PA 19101
CI 6044-1 Issued February 16, 2000