Saturday, April 14, 2012

Vaccine Components and Safety Info

Ever wonder about vaccine ingredients? Efficacy (how effective it is)? Ever wonder about side effects? Ever wonder why your doctor never tells you these things??


AFLURIA Influenza Virus Vaccine (this package insert detail is from Nov. 2011) - This vaccine has been approved for ages 5+ - there is a different influenza vaccine for the younger crowd.
This vaccine only shows a 60% efficacy! You get this vaccine to not get the flu, right? And it is only effective 60% of the time?
6.3 Adverse Reactions Associated With Influenza Vaccination
Anaphylaxis has been reported after administration of AFLURIA. Egg protein can induce immediate
hypersensitivity reactions among persons who have severe egg allergy. Allergic reactions include hives,
angioedema, asthma, and systemic anaphylaxis (see Contraindications [4]).
The 1976 swine influenza vaccine was associated with an increased frequency of GBS. Evidence for a
causal relation of GBS with subsequent vaccines prepared from other influenza viruses is unclear. If
influenza vaccine does pose a risk, it is probably slightly more than one additional case per 1 million
persons vaccinated.
Neurological disorders temporally associated with influenza vaccination, such as encephalopathy, optic
neuritis/neuropathy, partial facial paralysis, and brachial plexus neuropathy, have been reported.
Microscopic polyangiitis (vasculitis) has been reported temporally associated with influenza vaccination.

 AFLURIA is prepared from influenza virus propagated in the allantoic fluid of embryonated
chicken eggs. Following harvest, the virus is purified in a sucrose density gradient using continuous flow
zonal centrifugation. The purified virus is inactivated with beta-propiolactone, and the virus particles are
disrupted using sodium taurodeoxycholate to produce a ″split virion″. The disrupted virus is further purified
and suspended in a phosphate buffered isotonic solution.
AFLURIA is standardized according to USPHS requirements for the 2011-2012 influenza season and is
formulated to contain 45 mcg hemagglutinin (HA) per 0.5 mL dose in the recommended ratio of 15 mcg
HA for each of the three influenza strains recommended for the 2011-2012 Northern Hemisphere influenza
season: A/California/7/2009, NYMC X-181 (H1N1), A/Victoria/210/2009, NYMC X-187 (H3N2) (an A/Perth/
16/2009-like strain), and B/Brisbane/60/2008.
Thimerosal, a mercury derivative, is not used in the manufacturing process for the single dose
presentations; therefore these products contain no preservative. The multi-dose presentation contains
thimerosal, added as a preservative; each 0.5 mL dose contains 24.5 mcg of mercury.

A single 0.5 mL dose of AFLURIA contains sodium chloride (4.1 mg), monobasic sodium phosphate (80
mcg), dibasic sodium phosphate (300 mcg), monobasic potassium phosphate (20 mcg), potassium chloride
(20 mcg), and calcium chloride (1.5 mcg). From the manufacturing process, each 0.5 mL dose may also
contain residual amounts of sodium taurodeoxycholate (≤ 10 ppm), ovalbumin (≤ 1 mcg), neomycin sulfate
(≤ 3 nanograms [ng]), polymyxin B (≤ 0.5 ng), and beta-propiolactone (≤ 2 ng).
The rubber tip cap and plunger used for the preservative-free, single-dose syringes and the rubber stoppers
used for the multi-dose vial contain no latex.
(Emphasis of bolding is mine)



CERVARIX [Human Papillomavirus Bivalent (Types 16 and 18) Vaccine, 
Recombinant] (this package insert is from Feb 2012)


CERVARIX does not provide protection against disease due to all HPV types [see
Clinical Studies (14.3)].
 CERVARIX has not been demonstrated to provide protection against disease from
vaccine and non-vaccine HPV types to which a woman has previously been exposed through
sexual activity [see Clinical Studies (14.2)].
 Females should continue to adhere to recommended cervical cancer screening procedures
[see Patient Counseling Information (17)].
 Vaccination with CERVARIX may not result in protection in all vaccine recipients. 

 CERVARIX is available in vials and 2 types of prefilled syringes. One type of prefilled
syringe has a tip cap which may contain natural rubber latex and a plunger which does not
contain latex. The other type has a tip cap and a rubber plunger which contain dry natural latex
rubber. Use of these syringes may cause allergic reactions in latex-sensitive individuals. The vial
stopper does not contain latex. [See How Supplied/Storage and Handling (16).]




...37 deaths were reported during the 7.4 years of follow-up: 20 in subjects who
received CERVARIX (0.06%, 20/33,623) and 17 in subjects who received control (0.07%,
17/23,700). Causes of death among subjects were consistent with those reported in adolescent
and adult female populations. The most common causes of death were motor vehicle accident (5
subjects who received CERVARIX; 5 subjects who received control) and suicide (2 subjects
who received CERVARIX; 5 subjects who received control), followed by neoplasm (3 subjects
who received CERVARIX; 2 subjects who received control), autoimmune disease (3 subjects
who received CERVARIX; 1 subject who received control), infectious disease (3 subjects who
received CERVARIX; 1 subject who received control), homicide (2 subjects who received
CERVARIX; 1 subject who received control), cardiovascular disorders (2 subjects who received
CERVARIX), and death of unknown cause (2 subjects who received control). Among females
10 through 25 years of age, 31 deaths were reported (0.05%, 16/29,467 of subjects who received
CERVARIX and 0.07%, 15/20,192 of subjects who received control).


Sub-analyses were conducted to describe
pregnancy outcomes in 761 women [N = 396 for CERVARIX and N = 365 pooled control, HAV
360 EL.U., HAV 720 EL.U., and 500 mcg Al(OH)3] who had their last menstrual period within
30 days prior to, or 45 days after a vaccine dose and for whom pregnancy outcome was known.
The majority of women gave birth to normal infants (65.2% and 69.3% of recipients of
CERVARIX and control, respectively). Spontaneous abortion was reported in a total of 11.7% of
subjects (13.6% of recipients of CERVARIX and 9.6% of control recipients) and elective
termination was reported in a total of 9.7% of subjects (9.9% of recipients of CERVARIX and
9.6% of control recipients). Abnormal infant other than congenital anomaly was reported in a
total of 4.9% of subjects (5.1% of recipients of CERVARIX and 4.7% of control recipients) and
premature birth was reported in a total of 2.5% of subjects (2.5% of both groups). Other
outcomes (congenital anomaly, stillbirth, ectopic pregnancy, and therapeutic abortion) were
reported in 0.3% to 1.8% of pregnancies among recipients of CERVARIX and in 0.3% to 1.4%
of pregnancies among control recipients.
 It is not known whether the observed numerical imbalance in spontaneous abortions in
pregnancies which occurred around the time of vaccination is due to a vaccine-related effect.

 GARDASIL
[Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) 
Vaccine, Recombinant] (this package insert is from April 2011)


CONTRAINDICATIONS-------------------------------
• Hypersensitivity, including severe  allergic reactions to yeast (a
vaccine component), or after a previous dose of GARDASIL. (4)

 Of the entire study population (29,323 individuals), 0.04% of the reported serious systemic adverse
reactions were judged to be vaccine related by the study investigator. The most frequently (frequency of 4
cases or greater with either GARDASIL, AAHS control, saline placebo, or the total of all three) reported
serious systemic adverse reactions, regardless of causality, were:
Headache [0.02% GARDASIL (3 cases) vs. 0.02% AAHS control (2 cases)],
Gastroenteritis [0.02% GARDASIL (3 cases) vs. 0.02% AAHS control (2 cases)],
Appendicitis [0.03% GARDASIL (5 cases) vs. 0.01% AAHS control (1 case)],
Pelvic inflammatory disease  [0.02% GARDASIL (3 cases) vs. 0.03% AAHS control (4 cases)],
Urinary tract infection [0.01% GARDASIL (2 cases) vs. 0.02% AAHS control (2 cases)],
Pneumonia [0.01% GARDASIL (2 cases) vs. 0.02% AAHS control (2 cases)],
Pyelonephritis [0.01% GARDASIL (2 cases) vs. 0.02% AAHS control (3 cases)],
Pulmonary embolism [0.01% GARDASIL (2 cases) vs. 0.02% AAHS control (2 cases)].
One case (0.006% GARDASIL; 0.0% AAHS control or saline placebo) of bronchospasm; and 2 cases
(0.01% GARDASIL; 0.0% AAHS control or saline placebo) of asthma were reported as serious systemic
adverse reactions that occurred following any vaccination visit.
In addition, there was 1 individual in the clinical trials, in the group that received GARDASIL, who
reported two injection-site serious adverse reactions (injection-site pain and injection-site joint movement
impairment).
Deaths in the Entire Study Population
Across the clinical studies, 40 deaths (GARDASIL N = 21 or 0.1%; placebo N = 19 or 0.1%) were
reported in 29,323 (GARDASIL N = 15,706; AAHS  control N = 13,023, saline placebo N = 594)
individuals (9- through 45-year-old girls and women; and 9- through 26-year-old boys and men). The
events reported were consistent with events expected in healthy adolescent and adult populations. The
most common cause of death was motor vehicle accident (5 individuals who received GARDASIL and 4
individuals who received AAHS control), followed by drug overdose/suicide (2 individuals who received
GARDASIL and 6 individuals who received AAHS control), gun shot wound (1 individual who received
GARDASIL and 3 individuals who received AAHS control), and pulmonary embolus/deep vein thrombosis
(1 individual who received GARDASIL and 1 individual who received AAHS control). In addition, there
were 2 cases of sepsis, 1 case of pancreatic cancer, 1 case of arrhythmia, 1 case of pulmonary
tuberculosis, 1 case of hyperthyroidism, 1 case of post-operative pulmonary embolism and acute renal
failure, 1 case of traumatic brain injury/cardiac arrest, 1 case of systemic lupus erythematosus, 1 case of
cerebrovascular accident, 1 case of breast cancer, and 1 case of nasopharyngeal cancer in the group
that received GARDASIL; 1 case of asphyxia, 1 case of acute lymphocytic leukemia, 1 case of chemical
poisoning, and 1 case of myocardial ischemia in the AAHS control group; and 1 case of medulloblastoma
in the saline placebo group.
Systemic Autoimmune Disorders in Girls and Women 9 Through 26 Years of Age
In the clinical studies, 9- through 26-year-old girls and women were evaluated for new medical
conditions that occurred over the course of follow-up. New medical conditions potentially indicative of a
systemic autoimmune disorder seen in the group that received GARDASIL or AAHS control or saline
placebo are shown in Table 9. This population includes all girls and women who received at least one
dose of GARDASIL or AAHS control or saline placebo, and had safety data available. GARDASIL
®
[Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Recombinant] 9883616


 7 DRUG INTERACTIONS
7.1 Use with RECOMBIVAX HB
Results from clinical studies indicate that  GARDASIL may be administered concomitantly (at a
separate injection site) with RECOMBIVAX HB [hepatitis B vaccine (recombinant)] [see Clinical Studies
(14.9)].
7.2 Use with Menactra and Adacel
Results from clinical studies indicate that  GARDASIL may be administered concomitantly (at a
separate injection site) with Menactra [Meningococcal (Groups A, C, Y and W-135) Polysaccharide
Diphtheria Toxoid Conjugate Vaccine] and Adacel  [Tetanus Toxoid, Reduced Diphtheria Toxoid and
Acellular Pertussis Vaccine Adsorbed (Tdap)] [see Clinical Studies (14.10)].
7.3 Use with Hormonal Contraceptives
In clinical studies of 16- through 26-year-old women, 13,912 (GARDASIL N = 6952; AAHS control or
saline placebo N = 6960) who had post-Month 7 follow-up used hormonal contraceptives for a total of
33,859 person-years (65.8% of the total follow-up time in the studies).
In one clinical study of 24- through 45-year-old women, 1357 (GARDASIL N = 690; AAHS control N =
667) who had post-Month 7 follow-up used hormonal contraceptives for a total of 3400 person-years
(31.5% of the total follow-up time in the study). Use of hormonal contraceptives or lack of use of hormonal
contraceptives among study participants did not impair the immune  response in the per protocol
immunogenicity (PPI) population.
7.4 Use with Systemic Immunosuppressive Medications
Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic
drugs, and corticosteroids (used in greater than physiologic doses), may reduce the immune responses
to vaccines [see Use in Specific Populations (8.6)].  GARDASIL
®
[Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Recombinant] 9883616
12
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category B:
Reproduction studies have been performed in female rats at doses equivalent to the recommended
human dose and have revealed no evidence of impaired  female fertility or harm to the fetus due to
GARDASIL. There are, however, no adequate and well-controlled studies in pregnant women. Because
animal reproduction studies are not always predictive of human responses, GARDASIL should be used
during pregnancy only if clearly needed.  
An evaluation of the effect  of GARDASIL on embryo-fetal, pre- and postweaning development was
conducted using rats. One group of rats was administered GARDASIL twice prior to gestation, during the
period of organogenesis (gestation Day 6) and on lactation Day 7. A second group of pregnant rats was
administered GARDASIL during the period of organogenesis (gestation Day 6) and on lactation Day 7
only. GARDASIL was administered at 0.5 mL/rat/occasion (120 mcg total protein which is equivalent to
the recommended human dose) by intramuscular injection. No adverse effects on mating, fertility,
pregnancy, parturition, lactation,  embryo-fetal or pre- and postweaning development were observed.
There were no vaccine-related fetal malformations or other evidence of teratogenesis noted in this study.
In addition, there were no treatment-related effects on developmental signs, behavior, reproductive
performance, or fertility of the offspring.
Clinical Studies in Humans
In clinical studies, women underwent urine pregnancy testing prior to administration of each dose of
GARDASIL. Women who were found to be pregnant  before completion of a 3-dose regimen of
GARDASIL were instructed to defer completion of  their vaccination regimen  until resolution of the
pregnancy.
GARDASIL is not indicated for women 27 years of age or older. However, safety data in women 16
through 45 years of age was collected, and 3819 women (GARDASIL N = 1894 vs. AAHS control or
saline placebo N = 1925) reported at least 1 pregnancy each.
The overall proportions of pregnancies that resulted in an adverse outcome, defined as the combined
numbers of spontaneous abortion, late fetal death, and congenital anomaly cases out of the total number
of pregnancy outcomes for which an outcome was known (and excluding elective terminations), were
22.6% (446/1973) in women who received GARDASIL and 23.1% (460/1994) in women who received
AAHS control or saline placebo.
Overall, 55 and 65 women in the group that received GARDASIL or AAHS control or saline placebo,
respectively (2.9% and 3.4% of all women who reported a pregnancy in the respective vaccination
groups), experienced a serious adverse reaction during pregnancy. The most common events reported
were conditions that can result in Caesarean section (e.g., failure of labor, malpresentation, cephalopelvic
disproportion), premature onset of labor (e.g., threatened abortions, premature rupture of membranes),
and pregnancy-related medical problems (e.g., pre-eclampsia, hyperemesis). The proportions of
pregnant women who experienced such events were comparable between the groups receiving
GARDASIL and AAHS control or saline placebo.
There were 45 cases of congenital anomaly in pregnancies that occurred in women who received
GARDASIL and 34 cases of congenital anomaly in pregnancies that occurred in women who received
AAHS control or saline placebo.
Further sub-analyses were conducted to evaluate pregnancies with estimated onset within 30 days or
more than 30 days from administration of a dose of GARDASIL or AAHS control or saline placebo. For
pregnancies with estimated onset within 30 days of vaccination, 5 cases of congenital anomaly were
observed in the group that received GARDASIL compared to 1 case of congenital anomaly in the group
that received AAHS control or saline placebo.  The congenital anomalies seen in pregnancies with
estimated onset within 30 days of vaccination included pyloric stenosis, congenital megacolon, congenital
hydronephrosis, hip dysplasia, and club foot. Conversely, in pregnancies with onset more than 30 days
following vaccination, 40 cases of congenital anomaly were observed in the group that received GARDASIL
®
[Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Recombinant] 9883616
13
GARDASIL compared with 33 cases of congenital anomaly in the group that received AAHS control or
saline placebo.
Pregnancy Registry for GARDASIL
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., maintains a Pregnancy Registry to
monitor fetal outcomes of pregnant women exposed to GARDASIL. Patients and health care providers
are encouraged to report any exposure to GARDASIL during pregnancy by calling (800) 986-8999.
8.3 Nursing Mothers
Women 16 Through 45 Years of Age
It is not known whether GARDASIL is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when GARDASIL is administered to a nursing woman.
GARDASIL or AAHS control were given to a total of 1133 women (vaccine N = 582, AAHS control N =
551) during the relevant Phase III clinical studies.
Overall, 27 and 13 infants of women who received GARDASIL or AAHS control, respectively
(representing 4.6% and 2.4% of the total number of women who were breast-feeding during the period in
which they received GARDASIL or AAHS control, respectively), experienced a serious adverse reaction.
In a post-hoc analysis of clinical studies, a higher number of breast-feeding infants (n = 7) whose
mothers received GARDASIL had acute respiratory  illnesses within 30 days post vaccination of the
mother as compared to infants (n = 2) whose mothers received AAHS control.  

Vaccination does not eliminate the necessity for women to continue to undergo recommended
cervical cancer screening. Women who receive GARDASIL should continue to undergo cervical
cancer screening per standard of care.
• Recipients of GARDASIL should not discontinue anal cancer screening if it has been
recommended by a health care provider.
• GARDASIL has not been demonstrated to provide protection against disease from vaccine and
non-vaccine HPV types to which a person has previously been exposed through sexual activity.
• Since syncope has been reported following vaccination sometimes resulting in falling with injury,
observation for 15 minutes after administration is recommended.
• Vaccine information is required to be given with each vaccination to the patient, parent, or
guardian.
• Information regarding benefits and risks associated with vaccination.
• GARDASIL is not recommended for use in pregnant women.
• Importance of completing the immunization series unless contraindicated.
 
 INFANRIX (Diphtheria and Tetanus Toxoids and Acellular Pertussis 
Vaccine Adsorbed)  (This package insert is from Nov. 2011)


5 WARNINGS AND PRECAUTIONS
5.1 Guillain-Barré Syndrome
 If Guillain-Barré syndrome occurs within 6 weeks of receipt of a prior vaccine containing
tetanus toxoid, the decision to give any tetanus toxoid-containing vaccine, including INFANRIX,
should be based on careful consideration of the potential benefits and possible risks. When a
decision is made to withhold tetanus toxoid, other available vaccines should be given, as
indicated.
5.2 Latex
 INFANRIX is available in vials and 2 types of prefilled syringes. One type of prefilled
syringe has a tip cap which may contain natural rubber latex and a plunger which does not
contain latex. The other type has a tip cap and a rubber plunger which contain dry natural latex
rubber. Use of these syringes may cause allergic reactions in latex sensitive individuals. The vial
stopper does not contain latex. [See How Supplied/Storage and Handling (16).]
5.3 Syncope
 Syncope (fainting) can occur in association with administration of injectable vaccines,
including INFANRIX. Syncope can be accompanied by transient neurological signs such as
visual disturbance, paresthesia, and tonic-clonic limb movements. Procedures should be in place
to avoid falling injury and to restore cerebral perfusion following syncope.
5.4 Adverse Events Following Prior Pertussis Vaccination
 If any of the following events occur in temporal relation to receipt of a pertussis-
3

 The diphtheria toxin is produced by growing Corynebacterium diphtheriae in Fenton
medium containing a bovine extract. Tetanus toxin is produced by growing Clostridium tetani in
a modified Latham medium derived from bovine casein. The bovine materials used in these
extracts are sourced from countries which the United States Department of Agriculture (USDA)
has determined neither have nor present an undue risk for bovine spongiform encephalopathy
(BSE). Both toxins are detoxified with formaldehyde, concentrated by ultrafiltration, and
purified by precipitation, dialysis, and sterile filtration.
 The acellular pertussis antigens (PT, FHA, and pertactin) are isolated from Bordetella
pertussis culture grown in modified Stainer-Scholte liquid medium. PT and FHA are isolated
from the fermentation broth; pertactin is extracted from the cells by heat treatment and
flocculation. The antigens are purified in successive chromatographic and precipitation steps. PT
is detoxified using glutaraldehyde and formaldehyde. FHA and pertactin are treated with
formaldehyde.
 Diphtheria and tetanus toxoids and pertussis antigens (PT, FHA, and pertactin) are
individually adsorbed onto aluminum hydroxide.
 Diphtheria and tetanus toxoid potency is determined by measuring the amount of
neutralizing antitoxin in previously immunized guinea pigs. The potency of the acellular
pertussis components (PT, FHA, and pertactin) is determined by enzyme-linked immunosorbent
assay (ELISA) on sera from previously immunized mice.
 Each 0.5-mL dose contains aluminum hydroxide as adjuvant (not more than 0.625 mg
aluminum by assay) and 4.5 mg of sodium chloride. Each dose also contains ≤100 mcg of
residual formaldehyde and ≤100 mcg of polysorbate 80 (Tween 80).
 INFANRIX is available in vials and 2 types of prefilled syringes. One type of prefilled
syringe has a tip cap which may contain natural rubber latex and a plunger which does not
contain latex. The other type has a tip cap and a rubber plunger which contain dry natural latex
rubber. The vial stopper does not contain latex. [See How Supplied/Storage and Handling (16).]
 INFANRIX is formulated without preservatives

 Efficacy of a 3-dose primary series of INFANRIX has been assessed in 2 clinical studies.
 A double-blind, randomized, active Diphtheria and Tetanus Toxoids (DT)-controlled trial
conducted in Italy assessed the absolute protective efficacy of INFANRIX when administered at
2, 4, and 6 months of age. The population used in the primary analysis of the efficacy of
INFANRIX included 4,481 infants vaccinated with INFANRIX and 1,470 DT vaccinees. The
mean length of follow-up was 17 months, beginning 30 days after the third dose of vaccine.
After 3 doses, the absolute protective efficacy of INFANRIX against WHO-defined typical
pertussis (21 days or more of paroxysmal cough with infection confirmed by culture and/or
serologic testing) was 84% (95% CI: 76, 89). When the definition of pertussis was expanded to
13include clinically milder disease with respect to type and duration of cough, with infection
confirmed by culture and/or serologic testing, the efficacy of INFANRIX was calculated to be
71% (95% CI: 60, 78) against >7 days of any cough and 73% (95% CI: 63, 80) against ≥14 days
of any cough. Vaccine efficacy after 3 doses and with no booster dose in the second year of life
was assessed in 2 subsequent follow-up periods. A follow-up period from 24 months to a mean
age of 33 months was conducted in a partially unblinded cohort (children who received DT were
offered pertussis vaccine and those who declined were retained in the study cohort). During this
period, the efficacy of INFANRIX against WHO-defined pertussis was 78% (95% CI: 62, 87).
During the third follow-up period which was conducted in an unblinded manner among children
from 3 to 6 years of age, the efficacy of INFANRIX against WHO-defined pertussis was 86%
(95% CI: 79, 91). Thus, protection against pertussis in children administered 3 doses of
INFANRIX in infancy was sustained to 6 years of age.
 A prospective efficacy trial was also conducted in Germany employing a household
contact study design. In preparation for this study, 3 doses of INFANRIX were administered at 3,
4, and 5 months of age to more than 22,000 children living in 6 areas of Germany in a safety and
immunogenicity study. Infants who did not participate in the safety and immunogenicity study
could have received a DTwP vaccine or DT vaccine. Index cases were identified by spontaneous
presentation to a physician. Households with at least one other member (i.e., besides index case)
aged 6 through 47 months were enrolled. Household contacts of index cases were monitored for
incidence of pertussis by a physician who was blinded to the vaccination status of the household.
Calculation of vaccine efficacy was based on attack rates of pertussis in household contacts
classified by vaccination status. Of the 173 household contacts who had not received a pertussis
vaccine, 96 developed WHO-defined pertussis, as compared with 7 of 112 contacts vaccinated
with INFANRIX. The protective efficacy of INFANRIX was calculated to be 89% (95% CI: 77,
95), with no indication of waning of protection up until the time of the booster vaccination. The
average age of infants vaccinated with INFANRIX at the end of follow-up in this trial was
13 months (range 6 to 25 months). When the definition of pertussis was expanded to include
clinically milder disease, with infection confirmed by culture and/or serologic testing, the
efficacy of INFANRIX against ≥7 days of any cough was 67% (95% CI: 52, 78) and against
≥7 days of paroxysmal cough was 81% (95% CI: 68, 89). The corresponding efficacy of
INFANRIX against ≥14 days of any cough or paroxysmal cough were 73% (95% CI: 59, 82) and
84% (95% CI: 71, 91), respectively. 

 FluMist®
Influenza Vaccine Live, Intranasal
Intranasal Spray
2011-2012 Formula (This package insert is from May 2011)


FluMist is a vaccine indicated for the active immunization of individuals 2-49 years of age against
influenza disease caused by influenza virus subtypes A and type B contained in the vaccine. (1)
- CONTRAINDICATIONS - - - - - - - - - - - - - - - - - - - - - - - - - - -
• Hypersensitivity to eggs, egg proteins, gentamicin, gelatin, or arginine, or life-threatening reactions
to previous influenza vaccination. (4.1)
• Concomitant aspirin therapy in children and adolescents. (4.2)
- - - - - - - - - - - - - - - - - - - - - - - - WARNINGS AND PRECAUTIONS - - - - - - - - - - - - - - - - - - - - - - - -
• Do not administer FluMist to children <24 months of age because of increased risk of hospitalization
and wheezing observed in clinical trials. (5.1)
• FluMist should not be administered to any individuals with asthma or children <5 years of age with
recurrent wheezing because of the potential for increased risk of wheezing post vaccination. (5.2)
• If Guillain-Barré syndrome has occurred with any prior influenza vaccination, the decision to give
FluMist should be based on careful consideration of the potential benefits and risks. (5.3)
• Data supporting the safety and effectiveness of FluMist administration in immunocompromised
individuals are limited. (5.4)
• Safety has not been established in individuals with underlying medical conditions predisposing them
to wild-type influenza infection complications. (5.5)
- - - - - - - - - - - - - - - - - - - - - - - - - - - - ADVERSE REACTIONS - - - - - - - - - - - - - - - - - - - - - - - - - - -
Most common adverse reactions (≥10% in FluMist and at least 5% greater than in control) are runny nose
or nasal congestion in all ages, fever >100°F in children 2-6 years of age, and sore throat in adults. (6.1)


 5 WARNINGS AND PRECAUTIONS
5.1 Risks in Children <24 Months of Age
Do not administer FluMist to children <24 months of age. In clinical trials, an increased risk of wheezing
post-vaccination was observed in FluMist recipients <24 months of age. An increase in hospitalizations
was observed in children <24 months of age after vaccination with FluMist. [See Adverse Reactions (6.1).]
5.2 Asthma/Recurrent Wheezing
FluMist should not be administered to any individuals with asthma or children <5 years of age with
recurrent wheezing because of the potential for increased risk of wheezing post vaccination unless the
potential benefit outweighs the potential risk.
Do not administer FluMist to individuals with severe asthma or active wheezing because these
individuals have not been studied in clinical trials.
5.3 Guillain-Barré Syndrome
If Guillain-Barré syndrome has occurred within 6 weeks of any prior influenza vaccination, the decision
to give FluMist should be based on careful consideration of the potential benefits and potential risks
[see also Adverse Reactions (6.2)].
5.4 Altered Immunocompetence
Data supporting the safety and effectiveness of FluMist administration in immunocompromised
individuals are limited to 174 individuals with HIV infection and 10 mild to moderately immunocompromised children and adolescents with cancer [see Clinical Studies (14.3)].
5.5 Medical Conditions Predisposing to Influenza Complications
The safety of FluMist in individuals with underlying medical conditions that may predispose them to
complications following wild-type influenza infection has not been established. FluMist should not be
administered unless the potential benefit outweighs the potential risk.
5.6 Management of Acute Allergic Reactions
Appropriate medical treatment and supervision must be available to manage possible anaphylactic
reactions following administration of the vaccine [see Contraindications (4.1)].
5.7 Limitations of Vaccine Effectiveness
FluMist may not protect all individuals receiving the vaccine.
6 ADVERSE REACTIONS
FluMist is not indicated in children <24 months of age. In a clinical trial, among children 6-23 months of
age, wheezing requiring bronchodilator therapy or with significant respiratory symptoms occurred in
5.9% of FluMist recipients compared to 3.8% of active control (injectable influenza vaccine made by
Sanofi Pasteur Inc.) recipients (Relative Risk 1.5, 95% CI: 1.2, 2.1). Wheezing was not increased in
children ≥24 months of age.
Hypersensitivity, including anaphylactic reaction, has been reported post-marketing.
[See Warnings and Precautions (5.1) and Adverse Reactions (6.1, 6.2).]
6.1 Adverse Reactions in Clinical Trials
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.
A total of 9537 children and adolescents 1-17 years of age and 3041 adults 18-64 years of age received
FluMist in randomized, placebo-controlled Studies D153-P501, AV006, D153-P526, AV019, and AV009
described below. In addition, 4179 children 6-59 months of age received FluMist in Study MI-CP111, a
randomized, active-controlled trial. Among pediatric FluMist recipients 6 months-17 years of age, 50%
were female; in the study of adults, 55% were female. In MI-CP111, AV006, D153-P526, AV019, and
AV009, subjects were White (71%), Hispanic (11%), Asian (7%), Black (6%), and Other (5%), while in
D153-P501, 99% of subjects were Asian.
Adverse Reactions in Children and Adolescents
In a placebo-controlled safety study (AV019) conducted in a large Health Maintenance Organization
(HMO) in children 1-17 years of age (n = 9689), an increase in asthma events, captured by review of
diagnostic codes, was observed in children <5 years of age (Relative Risk 3.53, 90% CI: 1.1, 15.7). This
observation was prospectively evaluated in Study MI-CP111.
In MI-CP111, an active-controlled study, increases in wheezing and hospitalization (for any cause) were
observed in children <24 months of age, as shown in Table 1.

 8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C
Animal reproduction studies have not been conducted with FluMist. It is not known whether FluMist can
cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. FluMist
should be given to a pregnant woman only if clearly needed.
The effect of the vaccine on embryo-fetal and pre-weaning development was evaluated in a developmental
toxicity study using pregnant rats receiving the frozen formulation. Groups of animals were administered
the vaccine either once (during the period of organogenesis on gestation day 6) or twice (prior to
gestation and during the period of organogenesis on gestation day 6), 250 microliter/rat/occasion
(approximately 110-140 human dose equivalents), by intranasal instillation. No adverse effects on
pregnancy, parturition, lactation, embryo-fetal or pre-weaning development were observed. There were
no vaccine-related fetal malformations or other evidence of teratogenesis noted in this study.
8.3 Nursing Mothers
It is not known whether FluMist is excreted in human milk. Therefore, as some viruses are excreted in
human milk, caution should be exercised if FluMist is administered to nursing mothers.
8.4 Pediatric Use
Safety and effectiveness of the vaccine has been demonstrated for children 2 years of age and older with
reduction in culture-confirmed influenza rates compared to active control (injectable influenza vaccine
made by Sanofi Pasteur Inc.) and placebo [see Clinical Studies (14.1)]. FluMist is not approved for use
in children <24 months of age. FluMist use in children <24 months has been associated with increased
risk of hospitalization and wheezing in clinical trials [see Warnings and Precautions (5.1) and Adverse
Reactions (6.1)].
8.5 Geriatric Use
FluMist is not approved for use in individuals ≥65 years of age. Subjects with underlying high-risk
medical conditions (n = 200) were studied for safety. Compared to controls, FluMist recipients had a
higher rate of sore throat.
8.6 Use in Individuals 50-64 Years of Age
FluMist is not approved for use in individuals 50-64 years of age. In Study AV009, effectiveness was not
demonstrated in individuals 50-64 years of age (n = 641). Solicited adverse events were similar in type
and frequency to those reported in younger adults.


 Specific pathogen-free (SPF) eggs are inoculated with each of the reassortant strains and incubated to
allow vaccine virus replication. The allantoic fluid of these eggs is harvested, pooled, and then clarified
by filtration. The virus is concentrated by ultracentrifugation and diluted with stabilizing buffer to obtain
the final sucrose and potassium phosphate concentrations. Ethylene diamine tetraacetic acid (EDTA) is
added to the dilution buffer for H3N2 strains. The viral harvests are then sterile filtered to produce the
monovalent bulks. Each lot is tested for ca, ts, and att phenotypes and is also tested extensively by in vitro
and in vivo methods to detect adventitious agents. Monovalent bulks from the three strains are
subsequently blended and diluted as required to attain the desired potency with stabilizing buffers to
produce the trivalent bulk vaccine. The bulk vaccine is then filled directly into individual sprayers for nasal
administration.
Each pre-filled refrigerated FluMist sprayer contains a single 0.2 mL dose. Each 0.2 mL dose contains
10
6.5-7.5
FFU of live attenuated influenza virus reassortants of each of the three strains: A/California/7/2009
(H1N1), A/Perth/16/2009 (H3N2), and B/Brisbane/60/2008. Each 0.2 mL dose also contains
0.188 mg/dose monosodium glutamate, 2.00 mg/dose hydrolyzed porcine gelatin, 2.42 mg/dose
arginine, 13.68 mg/dose sucrose, 2.26 mg/dose dibasic potassium phosphate, 0.96 mg/dose monobasic
potassium phosphate, and <0.015 mcg/mL gentamicin sulfate. FluMist contains no preservatives.

 14.5 Shedding Studies
FluMist contains live attenuated influenza viruses that must infect and replicate in cells lining the
nasopharynx of the recipient to induce immunity. Vaccine viruses capable of infection and replication can
be cultured from nasal secretions obtained from vaccine recipients (shedding).
Shedding of vaccine viruses within 28 days of vaccination was evaluated in 1) multi-center study
MI-CP129 which enrolled healthy individuals 6-59 months of age (N = 200); and 2) multi-center study
FM026 which enrolled healthy individuals 5-49 years of age (N = 344). In each study, nasal secretions were
obtained daily for the first 7 days and every other day through either Day 25 and on Day 28 or through
Day 28. In study MI-CP129, individuals with a positive shedding sample at Day 25 or Day 28 were to
have additional shedding samples collected every 7 days until culture negative on 2 consecutive samples.
Results of these studies are presented in Table 6.
Table 6 Characterization of Shedding in Specified Age Groups by Frequency, Amount, and Duration
Age
Number of
% Shedding
b
Peak Titer % Shedding Day of Last
Subjects (TCID50
/mL)
c
After Day 11 Positive Culture
6 - 23 months
a
99 89 < 5 log10
7.0 Day 23
d
24 - 59 months 100 69 < 5 log10
1.0 Day 25
e
5 - 8 years 102 50 < 5 log10
2.9 Day 23
f
9 - 17 years 126 29 < 4 log10
1.6 Day 28
f
18 - 49 years 115 20 < 3 log10
0.9 Day 17
f
a
FluMist is not approved for use in children <24 months of age [see Adverse Reactions (6)].
b
Proportion of subjects with detectable virus at any time point during the 28 days.
c
Peak titer at any time point during the 28 days among samples positive for a single vaccine virus.
d
A single subject who shed previously on Days 1-3; TCID50
/mL was less than 1.5 log10
on Day 23.
e
A single subject who did not shed previously; TCID50
/mL was less than 1.5 log10
.
f
A single subject who did not shed previously; TCID50
/mL was less than 1.0 log10
.
The highest proportion of subjects in each group shed one or more vaccine strains on Days 2-3 postvaccination. After Day 11 among individuals 2-49 years of age (n = 443), virus titers did not exceed
1.5 log10
TCID50
/mL.

ProQuad® 
Measles, Mumps, Rubella and Varicella Virus Vaccine Live  
Lyophilized preparation for subcutaneous injection (This package insert is from August 2011)



-CONTRAINDICATIONS-------------------------------
• History of anaphylactic reaction to neomycin or hypersensitivity to
gelatin or any other component of the vaccine. (4.1)
• Primary or acquired immunodeficiency states. (4.2)
• Family history of congenital or hereditary immunodeficiency. (4.2)
• Immunosuppressive therapy. (4.2, 7.3)
• Active untreated tuberculosis or febrile illness (>101.3°F
or >38.5°C). (4.3)
• Pregnancy. (4.4, 8.1, 17.1)
----------------------- WARNINGS AND PRECAUTIONS------------------------
• Administration of ProQuad (dose 1) to children 12 to 23 months
old who have not been previously vaccinated against measles,
mumps, rubella, or varicella, nor had a history of the wild-type
infections, is associated with higher rates of fever and febrile
seizures at 5 to 12 days after vaccination when compared to
children vaccinated with M-M-R® II and VARIVAX® administered
separately. (5.1, 6.1, 6.3)
• Use caution when administering ProQuad to children with a history
of cerebral injury or seizures or any other condition in which stress
due to fever should be avoided. (5.2)
• Use caution when administering ProQuad to children with
anaphylaxis or immediate hypersensitivity to eggs (5.3) or contact
hypersensitivity to neomycin. (5.4)

 ADVERSE REACTIONS ------------------------------
• The most frequent vaccine-related adverse events reported in
≥5% of subjects vaccinated with ProQuad were:
o injection-site reactions (pain/tenderness/soreness,
erythema, and swelling)
o fever
o irritability. (6.1)
• Systemic vaccine-related adverse events that were reported at a
significantly greater rate in recipients of ProQuad than in
recipients of the component vaccines administered concomitantly
were:
o fever
o measles-like rash. (6.1)
 
 In an open-label clinical trial, 699 healthy children 12 to 23 months of age were randomized to receive
2 doses of VAQTA® (hepatitis A vaccine, inactivated) (N=352) or 2 doses of VAQTA concomitantly with 2
doses of ProQuad (N=347) at least 6 months apart. An additional 1101 subjects received 2 doses of
VAQTA alone at least 6 months apart (non-randomized), resulting in 1453 subjects receiving 2 doses of
VAQTA alone (1101 non-randomized and 352 randomized) and 347 subjects receiving 2 doses of
VAQTA concomitantly with ProQuad (all randomized). The race distribution of the study subjects following
a dose of ProQuad was as follows: 47.3% White; 42.7% Hispanic; 5.5% other; 2.9% African-American;
and 1.7% Asian/Pacific. The gender distribution of the study subjects following a dose of ProQuad was
49.3% male and 50.7% female. Vaccine-related injection-site adverse reactions (days 1 to 5
postvaccination) and systemic adverse events (days 1 to 14 post VAQTA and days 1 to 28 post ProQuad
vaccination) observed among recipients of VAQTA and ProQuad administered concomitantly with VAQTA
at a rate of at least 1% are shown in Tables 5 and 6, respectively. In addition, among the randomized
cohort, in the 14 days after each vaccination, the rates of fever (including all vaccine- and
non-vaccine-related reports) were significantly higher in subjects who received ProQuad with VAQTA
concomitantly after dose 1 (22.0%) as compared to subjects given dose 1 of VAQTA without ProQuad
(10.8%). However, rates of fever  were not significantly higher in subjects who received ProQuad with
VAQTA concomitantly after dose 2 (12.5%) as compared to subjects given dose 2 of VAQTA without
ProQuad (9.4%). In post-hoc analyses, these rates were significantly different for dose 1 (RR 2.03 [95%
CI: 1.42, 2.94]), but not dose 2 (RR 1.32 [95% CI: 0.82, 2.13]). Rates of injection-site adverse reactions
and other systemic adverse events were lower following a second dose than following the first dose of
both vaccines given concomitantly. 

 8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C: Animal reproduction studies have not been conducted with ProQuad.
Do not administer ProQuad to pregnant females.  It is also not known whether ProQuad can cause
fetal harm when administered to a pregnant woman or can affect reproduction capacity. If vaccination of
post-pubertal females is undertaken, pregnancy should be avoided for 3 months following vaccination.
[See Contraindications (4.4).]
In counseling women who are inadvertently vaccinated when pregnant or who become pregnant within
3 months of vaccination, the healthcare provider should be aware of the following: (1) Reports have
indicated that contracting wild-type measles during pregnancy enhances fetal risk. Increased rates of
spontaneous abortion, stillbirth, congenital defects, and prematurity have been observed subsequent to
wild-type measles during pregnancy. There are no adequate studies of the attenuated (vaccine) strain of
measles virus in pregnancy. However, it would be prudent to assume that the vaccine strain of virus is
also capable of inducing adverse fetal effects; (2) Mumps infection during the first trimester of pregnancy
may increase the rate of spontaneous abortion. Although mumps vaccine virus has been shown to infect
the placenta and fetus, there is no evidence that it causes congenital malformations in humans;
5
 (3) In a
10-year survey involving over 700 pregnant women who received rubella vaccine within 3 months before
or after conception (of whom 189 received the Wistar RA 27/3 strain), none of the newborns had
abnormalities compatible with congenital rubella syndrome;
6
and (4) Wild-type varicella can sometimes
cause congenital varicella infection.
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., maintains a Pregnancy Registry to
monitor fetal outcomes of pregnant women exposed to varicella-containing vaccine (Oka/Merck). In the
first 9 years of the Pregnancy Registry for varicella vaccine (Oka/Merck), of 129 seronegative women and
423 women of unknown serostatus who received varicella vaccine during pregnancy or within 3 months
before pregnancy, none had newborns with abnormalities compatible with congenital varicella syndrome.
Patients and health care providers are encouraged to report any exposure to varicella-containing
vaccine (Oka/Merck) during pregnancy by calling 1-800-986-8999.
8.3 Nursing Mothers
Do not administer ProQuad to nursing women. It is not known whether ProQuad is excreted in human
milk. Because many drugs are excreted in human milk, caution should be exercised when ProQuad is
administered to a nursing woman. The secretion of measles and mumps viruses in human milk has not
been studied; however, studies have shown that lactating postpartum women vaccinated with live rubella
vaccine may secrete the virus in breast milk and transmit it to breast-fed infants. Limited evidence in the
literature suggests that virus, viral DNA, or viral antigen could not be detected in the breast milk of women
who were vaccinated postpartum with the vaccine strain of varicella virus.
7,8
[See Warnings and
Precautions (5.8).]
8.4 Pediatric Use
Do not administer ProQuad to infants younger than 12 months of age or to children 13 years and
older. Safety and effectiveness of ProQuad in infants younger than 12 months of age and in children 13
years and older have not been studied. ProQuad is not approved for use in persons in these age groups.
[See Adverse Reactions (6) and Clinical Studies (14).]
8.5 Geriatric Use
ProQuad is not indicated for use in the geriatric population (≥age 65)

 ProQuad (Measles, Mumps, Rubella and Varicella Virus Vaccine Live) is a combined, attenuated, live
virus vaccine containing measles, mumps, rubella, and varicella viruses. ProQuad is a sterile lyophilized
preparation of (1) the components of M-M-R II (Measles, Mumps, and Rubella Virus Vaccine Live):
Measles Virus Vaccine Live, a more attenuated line of measles virus, derived from Enders' attenuated
Edmonston strain and propagated in chick embryo cell culture; Mumps Virus Vaccine Live, the Jeryl
Lynn™ (B level) strain of mumps virus propagated in chick embryo cell culture; Rubella Virus Vaccine
Live, the Wistar RA 27/3 strain of live attenuated rubella virus propagated in WI-38 human diploid lung ProQuad®
Measles, Mumps, Rubella and Varicella Virus Vaccine Live 9950905
16
fibroblasts; and (2) Varicella Virus Vaccine Live (Oka/Merck), the Oka/Merck strain of varicella-zoster
virus propagated in MRC-5 cells. The cells, virus  pools, bovine serum, and human albumin used in
manufacturing are all tested to provide assurance that the final product is free of potential adventitious
agents.
ProQuad, when reconstituted as directed, is a sterile suspension for subcutaneous administration.
Each 0.5-mL dose contains not less than 3.00 log10 TCID50 of measles virus; 4.30 log10 TCID50
of mumps
virus; 3.00 log10 TCID50 of rubella virus; and a minimum of 3.99 log10 PFU of Oka/Merck varicella virus.
Each 0.5-mL dose of the vaccine contains no more than 21 mg of sucrose, 11 mg of hydrolyzed
gelatin, 2.4 mg of sodium chloride, 1.8 mg of sorbitol, 0.40 mg of monosodium L-glutamate, 0.34 mg of
sodium phosphate dibasic, 0.31 mg of human albumin, 0.17 mg of sodium bicarbonate, 72 mcg of
potassium phosphate monobasic, 60 mcg of potassium chloride; 36 mcg of potassium phosphate dibasic;
residual components of MRC-5 cells including DNA and protein; <16 mcg of neomycin, bovine calf serum
(0.5 mcg), and other buffer and media ingredients. The product contains no preservative.