Prevnar

• Tell all of your child's health care providers that your child is taking this medicine. This includes your child's doctors, nurses, pharmacists, and dentists.
• This medicine may not protect all people who use it. Talk with the doctor.
• If your child was born premature, talk with the doctor. Trouble breathing has happened in these children after getting some vaccines.
• Other drugs may be given before Prevnar to help avoid side effects.
• This medicine is not approved for use in children older than 10 years of age or in adults. Talk with the doctor.

If your child is pregnant or breast-feeding a baby:

• Talk with the doctor if your child is pregnant, becomes pregnant, or is breast-feeding a baby. You will need to talk about the benefits and risks of using this medicine.

Rx only

For Intramuscular Injection Only

Hypersensitivity to any component of the vaccine, including diphtheria toxoid, is a contraindication to use of this vaccine.

THIS VACCINE WILL NOT PROTECT AGAINST S. PNEUMONIAE DISEASE CAUSED BY SEROTYPES UNRELATED TO THOSE IN THE VACCINE, NOR WILL IT PROTECT AGAINST OTHER MICROORGANISMS THAT CAUSE INVASIVE INFECTIONS SUCH AS BACTEREMIA AND MENINGITIS OR NON-INVASIVE INFECTIONS SUCH AS OTITIS MEDIA.

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.

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. (See also Postmarketing Experience.)

In Table 6 the rate of local reactions at the Prevnar® injection site is compared at each dose to the DTaP injection site in the same children.

TABLE 6 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 Age20,21

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§
>2.4 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§
>2.4 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 7 presents the rates of local reactions in previously unvaccinated older infants and children.

TABLE 7 Percentage of Subjects Reporting Local Reactions Within 3 Days of Immunization With Prevnar® in Infants and Children from 7 Months Through 9 Years of Age31

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.

Table 8 presents the rate of systemic events observed in the efficacy study when Prevnar® was administered concomitantly with DTaP.

TABLE 8 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 Age20,21

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. § p<0.05 when Prevnar® compared to control group using a Chi-Square test.

Table 9 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 9 Percentage of Subjects* Reporting Systemic Reactions Within 3 Days Following Immunization With Prevnar®, DTaP, HbOC, Hep B, and IPV vs. Control† In Manufacturing Bridging Study25

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 Fisher's 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 2nd dose.

Table 10 presents the frequencies of systemic reactions in previously unvaccinated older infants and children.

TABLE 10 Percentage of Subjects Reporting Systemic Reactions Within 3 Days of Immunization With Prevnar® in Infants and Children from 7 Months Through 9 Years of Age31

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).20,21

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.27,30

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.20,21 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.28 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.20,21,25 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 11.

TABLE 11 Age and Season-Adjusted Comparison of SIDS Rates in the NCKP Efficacy Trial With the Expected Rate from the California State Data for 1995‑199720,21

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 12 and 13 summarize systemic reactogenicity data within 2 or 3 days across 4,748 subjects in US studies (3,848 infant doses and 997 toddler doses) for whom these data were collected and according to the pertussis vaccine administered concurrently.

TABLE 12 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 Age20,21,25,27,28,29

Systemic Event	Prevnar® Concurrently With DTaP and HbOC (3,848 Doses)†	DTaP and HbOC Control (538 Doses)‡
Fever
≥38.0°C	21.1	14.2
>39.0°C	1.8	0.4
Irritability	52.5	45.2
Drowsiness	32.9	27.7
Restless Sleep	20.6	22.3
Decreased Appetite	18.1	13.6
Vomiting	13.4	9.8
Diarrhea	9.8	4.4
Urticaria-like Rash	0.6	0.3
† 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 13 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 Age20,21,27

Systemic Event	Prevnar® Concurrently With DTaP and HbOC (270 Doses)†	Prevnar® Only No Concurrent Vaccines (727 Doses) ‡
Fever
≥38.0°C	19.6	13.4
>39.0°C	1.5	1.2
Irritability	45.9	45.8
Drowsiness	17.5	15.9
Restless Sleep	21.2	21.2
Decreased Appetite	21.1	18.3
Vomiting	5.6	6.3
Diarrhea	13.7	12.8
Urticaria-like Rash	0.7	1.2
† 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), 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.40

Postmarketing Experience

In addition to reports in clinical trials, the following adverse events have been reported since market introduction of Prevnar® worldwide. 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 strength of causal association, severity, or frequency of reporting for Prevnar®.

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

Psychiatric disorders: crying

Skin and subcutaneous tissue disorders: angioneurotic edema, erythema multiforme

Respiratory: apnea

Postmarketing Observational Safety Surveillance Study

Safety outcomes were evaluated in an observational study that included 65,927 infants. Primary safety outcomes analyses included an evaluation of pre-defined adverse events occurring in temporal relationship to immunization. Rates of adverse events occurring within various time periods post-vaccination (e.g., 0-2, 0-7, 0-14, 0-30 days) were compared to the rates of those events occurring within a control time window (i.e., 31-60 days). Secondary safety outcomes analyses included comparisons to a historical control population of infants (1995-1996, N=40,223) prior to the introduction of Prevnar®. In addition, the study included extended follow-up of subjects originally enrolled in the NCKP efficacy trial (N=37,866).

The primary safety outcomes analyses did not demonstrate a consistently elevated risk of healthcare utilization for croup, gastroenteritis, allergic reactions, seizures, wheezing diagnoses, or breath-holding across doses, health care settings, or multiple time windows. As in pre-licensure trials, fever was associated with Prevnar® administration. In analyses of secondary safety outcomes, the adjusted relative risk of hospitalization for reactive airways disease was 1.23 (95% CI: 1.11, 1.35). Potential confounders, such as differences in concomitantly administered vaccines, yearly variation in respiratory infections, or secular trends in reactive airways disease incidence, could not be controlled. Extended follow-up of subjects originally enrolled in the NCKP efficacy trial revealed no increased risk of reactive airways disease among Prevnar® recipients. In general, the study results support the previously described safety profile of Prevnar®.41,42

There have been reports of overdose with Prevnar®, including cases of administration of a higher than recommended dose and cases of subsequent doses administered closer than recommended to the previous dose. Most individuals were asymptomatic. In general, adverse events reported with overdose have also been reported with recommended single doses of Prevnar®.

Syringe, 1 Dose (10 per package) - NDC 0005-1970-50

CPT Code 90669

STORAGE

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

An overdose of Prevnar is unlikely to occur.

Your child should not receive a booster vaccine if he or she had a life-threatening allergic reaction after the first shot. Keep track of any and all side effects your child has after receiving Prevnar. When the child receives a booster dose, you will need to tell the doctor if the previous shots caused any side effects. Get emergency medical help if your child has any of these signs of an allergic reaction to Prevnar: hives; difficulty breathing; swelling of the face, lips, tongue, or throat.

Call your doctor at once if you or your child has a serious side effect such as:

• high fever (103 degrees or higher);

• seizure (convulsions);

• wheezing, trouble breathing;

• easy bruising or bleeding; or

• severe pain, itching, irritation, or skin changes where the shot was given.

Less serious Prevnar side effects may include:

• mild redness, swelling, tenderness, or a hard lump where the shot was given;

• weakness, tired feeling;

• crying, fussiness;

• drowsiness, restless sleep;

• low fever (102 degrees or less);

• vomiting, diarrhea, loss of appetite; or

• mild skin rash.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report vaccine side effects to the US Department of Health and Human Services at 1-800-822-7967.

Before receiving Prevnar, tell the doctor about all other vaccines your child has recently received.

Also tell the doctor if your child has recently received drugs or treatments that can weaken the immune system, including:

• an oral, nasal, inhaled, or injectable steroid medicine;

• chemotherapy or radiation;

• medications to treat psoriasis, rheumatoid arthritis, or other autoimmune disorders, such as azathioprine (Imuran), etanercept (Enbrel), leflunomide (Arava), and others; or

• medicines to treat or prevent organ transplant rejection, such as basiliximab (Simulect), cyclosporine (Sandimmune, Neoral, Gengraf), muromonab-CD3 (Orthoclone), mycophenolate mofetil (CellCept), sirolimus (Rapamune), or tacrolimus (Prograf).

If your child is using any of these medications, he or she may not be able to receive the vaccine, or may need to wait until the other treatments are finished.

This list is not complete and other drugs may interact with Prevnar. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.