sunnuntai 11. marraskuuta 2018

How to Use Facebook Ads in the Search for a Missing Person

How to Use Facebook Ads in the Search for a Missing Person
We have had a missing person case in the family recently. It’s nuts. It’s mostly the uncertainty of what happened to them, that gets to you. If you look into it a little, you’ll find out that the amount of people reported missing each day, is nuts as well. Almost 2'000 reports a day in the US alone.
If your family is impacted, instead of going crazy, I guess, it’s important to try to stay as calm as possible and try to help the search as much as possible. There’s good step by step guides on the net of what to do in a missing person case (such as here or here), first and foremost of them: contacting the police.
Coming from an entrepreneurial, online marketing background, we also decided to run Facebook ads with the missing person search alert in the area our missing relative was suspected to be in. Searching the net a little, there wasn’t really much info on doing that — even though it seemed very reasonable to us — kind of ‘the missing person poster of the digital age.’ Many people already use Facebook posts to raise awareness, but the effect here is that they mostly get shared within their own circles and not necessarily in the location, where it makes sense. With Facebook ads your able to target exactly the people in the search area and ask them to not only keep an eye out for your missing loved one, but also to spread the word. Essentially, you are paying Facebook to show the post to the right people in a timely way.
That’s why we decided to do this write-up of how to go about creating and running Facebook ads to help in the search for a missing person. On top, we decided to offer doing exactly that for other people as a service on missingperson.io — for non-technical people or people who don’t want to go through all the steps themselves, uncertain of doing it right.
Maybe another hint in advance: the whole process should probably be done as timely as possible, as the first hours and days are the most critical in a missing person case.
So, here’s a quick overview of the steps involved:
  1. Create a Facebook ads account
  2. Gather all the information you need
  3. Create the ad campaign
  4. Run the ad campaign
  5. Cancel the ad campaign when your missing loved one is found

Let’s go about them one by one:
  1. Create a Facebook ads account
It turns out every Facebook account already comes with the ability to run ads. You’ll need to setup billing and familiarize yourself with the ads system. Here’s some resources to do exactly that:
If you have a family member or friend who knows Facebook ads, that would probably be the way to go: just ask them to help you with this.
2. Gather all the information you need
We suggest to have the following info ready for setting up the ad in the next step:
  • Missing person’s name, height, age, look.
  • Description of the circumstances, place and time under which they went missing.
  • Picture of the missing person, preferably two.
  • Location where a search makes sense; where they can reasonably excepted to be, considering means of transport and such.
  • Police contact and telephone number that can be published — where people are expected to call, when they see your missing loved one.
  • Links to media articles about the case (if they exist).
3. Create the ad campaign
The links in step 1 cover how to create an actual ad campaign as well. Have a look at them and we will discuss what is important for our purposes in the following.
We’d recommend to do a campaign optimized for reach, which means your missing person alert will be shown to a maximum number of people — under your budget constraint. Awareness could also be chosen, the difference being that here just the impressions count, not necessarily the amount of people reached.
You will have to chose a page your ad will be associated with, in the next step. The Facebook ad manager allows you to create a page right in the ad creation process. We would suggest you either name the page something like “Missing Person in [area]: [name of the person]” or just something generic like “Missing Person Alert.” It’s important to try to draw peoples’ attention. Mentioning the place of the search area, such as a city or region, seems beneficial, as people will recognize it as being their area.
Next comes one of the most important steps: targeting the area/region you want to show your missing person ad in. In the audience selection you can choose any geographic region or place, like a city or town, and then give a radius around that place to be included. It will look something like this:
Location targeting in the Facebook ads creation process

You can add multiple places or greater regions (counties, states, etc.) as well. On the right hand side of the picture you can see the potential reach and the estimated daily reach, which are important measures to gauge your campaign with. The estimated daily reach will depend on the budget you choose for your campaign — which brings us to the next point:
You will have to decide how much you want to spend on the ads. It will certainly depend on your budget. We would suggest around 50–200 USD daily, but it’s tough to give general advice here.
Age and gender targeting we would keep as broad as possible. Let’s get to the actual design of the ad now:
You want to draw attention to your ad. You can start your ad out with something like: “Have you seen this person?” or “Missing person in [area]” Then you should go on to describe what is important for the general public to know — some of the info we have gathered in the previous step: name, age, height, look, what they were wearing, circumstances, the area they might be in, and also info such as if they have mental problems and who to call (probably police incl. a (emergency) number) if they see them. You also want to ad a call to action like: “Please share in the [area]”
It probably makes sense to add two pictures to your ad — maybe one portrait and one full body shot, if you have. If media already reported about the case, it might make sense to link to it in the ad, as people are more engaged with media stories and hopefully can find more info on the media link about the case.
Here’s how such a post could look like:
Sample image of how a missing person search ad could look like.
Your ad is then good to go, and you should publish it as timely as possible. One last suggestion here, you might want to use a more traditional missing person poster layout (big red “MISSING” on top) for your picture that gives a bunch of information about the person in the poster, including their pictures. It is not clear weather this should be done, as Facebook usually penalizes ads with text in the picture. They might be more lenient in a missing person case though, if you request a manual approval for the picture.
4. Run the ad campaign
OK, most of the work — creating the ad — is done now. Running the campaign, it’s important to keep an eye on the costs — depending on what you want to spend. Secondly, it’s important to keep an eye on the ad itself. You can ask friends and family to do so as well by sending them a link to it and asking them to turn on notifications for it like so:
Turning on notifications for the post, to stay informed on comments.
Keeping an eye on the ad is important as people might comment valuable information. If they do, it’s often important to try to establish contact to them. Since they are already on Facebook, it’s worth trying it right there: either through replying to their comments or by trying to directly message them (maybe it’s necessary to send a friend request on Facebook first). Don’t forget to pass on new information to the officials (police, search parties).
A last remark here: it might become necessary to adjust the campaign as new information arrives — such as possible sightings, where you might want to focus the ad delivery to new or more specified areas.
5. Cancel the ad campaign when your missing loved one is found
This is the last and hopefully quick-to-come step. Don’t forget: most missing person cases are resolved within the first week and and an even greater percentage within the first month. Don’t give up hope and do what you can to help the search.

For anyone, for whom all the above is too complicated, e.g. if you aren’t that tech savvy or just want to get it done as quickly and professionally as you can, we decided to offer creating and running missing person search campaigns on social media ourselves. We’ve thrown up a quick landing page here: missingperson.io. Feel free to contact us for any help. We are still experimenting with the exact processes and design, and we will keep this post updated with new insights and best practices for missing person cases.


High exposure to radio frequency radiation associated with cancer in male rats

High exposure to radio frequency radiation associated with cancer in male rats

Reports on rat and mouse studies of radio frequency radiation like that used in 2G and 3G cell phone technologies

Date:
November 1, 2018
Source:
NIH/National Institute of Environmental Health Sciences
Summary:
The National Toxicology Program (NTP) concluded there is clear evidence that male rats exposed to high levels of radio frequency radiation (RFR) like that used in 2G and 3G cell phones developed cancerous heart tumors, according to final reports released today.


The National Toxicology Program (NTP) concluded there is clear evidence that male rats exposed to high levels of radio frequency radiation (RFR) like that used in 2G and 3G cell phones developed cancerous heart tumors, according to final reports released today. There was also some evidence of tumors in the brain and adrenal gland of exposed male rats. For female rats, and male and female mice, the evidence was equivocal as to whether cancers observed were associated with exposure to RFR. The final reports represent the consensus of NTP and a panel of external scientific experts who reviewed the studies in March after draft reports were issued in February.
"The exposures used in the studies cannot be compared directly to the exposure that humans experience when using a cell phone," said John Bucher, Ph.D., NTP senior scientist. "In our studies, rats and mice received radio frequency radiation across their whole bodies. By contrast, people are mostly exposed in specific local tissues close to where they hold the phone. In addition, the exposure levels and durations in our studies were greater than what people experience."
The lowest exposure level used in the studies was equal to the maximum local tissue exposure currently allowed for cell phone users. This power level rarely occurs with typical cell phone use. The highest exposure level in the studies was four times higher than the maximum power level permitted.
"We believe that the link between radio frequency radiation and tumors in male rats is real, and the external experts agreed," said Bucher.
The $30 million NTP studies took more than 10 years to complete and are the most comprehensive assessment, to date, of health effects in animals exposed to RFR with modulations used in 2G and 3G cell phones. 2G and 3G networks were standard when the studies were designed and are still used for phone calls and texting.
"A major strength of our studies is that we were able to control exactly how much radio frequency radiation the animals received -- something that's not possible when studying human cell phone use, which has often relied on questionnaires," said Michael Wyde, Ph.D., lead toxicologist on the studies.
He also noted the unexpected finding of longer lifespans among the exposed male rats. "This may be explained by an observed decrease in chronic kidney problems that are often the cause of death in older rats," Wyde said.
The animals were housed in chambers specifically designed and built for these studies. Exposure to RFR began in the womb for rats and at 5 to 6 weeks old for mice, and continued for up to two years, or most of their natural lifetime. The RFR exposure was intermittent, 10 minutes on and 10 minutes off, totaling about nine hours each day. RFR levels ranged from 1.5-6 watts per kilogram in rats, and 2.5-10 watts per kilogram in mice.
These studies did not investigate the types of RFR used for Wi-Fi or 5G networks.
"5G is an emerging technology that hasn't really been defined yet. From what we currently understand, it likely differs dramatically from what we studied," said Wyde.
For future studies, NTP is building smaller RFR exposure chambers that will make it easier to evaluate newer telecommunications technologies in weeks or months, rather than years. These studies will focus on developing measurable physical indicators, or biomarkers, of potential effects from RFR. These may include changes in metrics like DNA damage in exposed tissues, which can be detected much sooner than cancer.
The U.S. Food and Drug Administration nominated cell phone RFR for study by NTP because of widespread public use of cell phones and limited knowledge about potential health effects from long-term exposure. NTP will provide the results of these studies to FDA and the Federal Communications Commission, who will review the information as they continue to monitor new research on the potential effects of RFR.
NTP uses four categories to summarize the evidence that a substance may cause cancer:
  • Clear evidence (highest)
  • Some evidence
  • Equivocal evidence
  • No evidence (lowest)
More information on the categories is available at https://ntp.niehs.nih.gov/results/pubs/longterm/defs/index.html.
Editor's Note: In response to the National Toxicology Program's news release, the U.S. Food and Drug Administration (FDA) has issued a statement from Jeffrey Shuren, M.D., J.D., Director of the FDA's Center for Devices and Radiological Health on the National Toxicology Program's report on radiofrequency energy exposure (https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm624809.htm). The statement reads, in part:
"We reviewed the recently finalized research conducted by our colleagues at the National Toxicology Program (NTP), part of the National Institute of Environmental Health Sciences within the National Institutes of Health, on radiofrequency energy exposure. After reviewing the study, we disagree, however, with the conclusions of their final report regarding 'clear evidence' of carcinogenic activity in rodents exposed to radiofrequency energy.
"In the NTP study, researchers looked at the effects of exposing rodents to extremely high levels of radiofrequency throughout the entire body. This is commonly done in these types of hazard identification studies and means that the study tested levels of radiofrequency energy exposures considerably above the current whole body safety limits for cell phones. Doing this was intended to help contribute to what we already understand about the effects of radiofrequency energy on animal tissue. In fact, we only begin to observe effects to animal tissue at exposures that are 50 times higher than the current whole body safety limits set by the FCC for radiofrequency energy exposure.
"Our colleagues at NTP echoed this point in a statement earlier this year about their draft final report, including the important note that 'these findings should not be directly extrapolated to human cell phone usage.'
"We agree that these findings should not be applied to human cell phone usage."
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torstai 8. marraskuuta 2018

Flu Vaccine Contains 25,000 Times More Mercury Than Is Legally Allowed In Drinking Water

Flu Vaccine Contains 25,000 Times More Mercury Than Is Legally Allowed In Drinking Water


By October 10, 2016Health


In general, I cannot think of anything pleasant to say about vaccines, but to each his own. We are not here to sugar coat the obvious, we are here to tell you the facts and let you make decisions on your own.



Recent lab tests conducted at the Natural News Forensic Food Lab found that seasonal flu vaccines, which are pushed on the masses, including pregnant women and babies, contain outrageous amounts of neurotoxic mercury.
Vials of batch flu vaccine produced by British pharmaceutical giant GlaxoSmithKilne were found to contain upwards of 51 parts per million of mercury, or 25,000 times the legal maximum for drinking water established by the EPA.
According to Natural News,” This shocking discovery was made using advanced mass spectrometry technology with incredible accuracy, filling the gap left by the nation’s regulatory agencies that have failed to conduct this type of safety testing themselves. Millions of people are injected with flu vaccines annually, and most of them are completely unaware that one of the most toxic metals known to man is being implanted directly into their muscle tissue unabated.
“Mercury is one of the most poisonous substances known to mankind,” explained Dr. David Brownstein, a board-certified family physician and holistic medicine specialist, on his blog. “For over twenty years, I have been testing nearly every patient seen in my office for heavy metal contamination. … I have found that over 80% of my patients, both healthy and sick, have mercury toxicity.”
When you present this type of data, it often times provokes pro-vaxxers who insist that mercury is completely safe. Either that or I have even heard some people say that mercury is no longer added to the vaccines, which is a completely false statement.
The following is taken directly from RxList.com, “Thimerosal, a mercury derivative, is added as a preservative. Each 0.5-mL dose contains 50 mcg [micrograms] thimerosal ([less than] 25 mcg mercury). Each 0.5-mL dose may also contain residual amounts of ovalbumin ([less than or equal to] 0.3 mcg), formaldehyde ([less than or equal to] 25 mcg), and sodium deoxycholate ([less than] 50 mcg) from the manufacturing process.”
And even with these added contaminants, pregnant women, elderly people, and even children are told repeatedly that they need to get vaccinated by heath authorities. Never mind the fact that each of these ingredients is a known neurotoxin, not to mention the fact that formaldehyde is a known cause of cancer, please just line right up and get your flu shots!


Drug Description
FLULAVAL QUADRIVALENT
(influenza vaccine) Injection

DESCRIPTION

FLULAVAL QUADRIVALENT, Influenza Vaccine, for intramuscular injection, is a quadrivalent, split-virion, inactivated influenza virus vaccine prepared from virus propagated in the allantoic cavity of embryonated hens' eggs. Each of the influenza viruses is produced and purified separately. The virus is inactivated with ultraviolet light treatment followed by formaldehyde treatment, purified by centrifugation, and disrupted with sodium deoxycholate.
FLULAVAL QUADRIVALENT is a sterile, opalescent, translucent to off-white suspension in a phosphate-buffered saline solution that may sediment slightly. The sediment resuspends upon shaking to form a homogeneous suspension.
FLULAVAL QUADRIVALENT has been standardized according to USPHS requirements for the 2018-2019 influenza season and is formulated to contain 60 micrograms (mcg) hemagglutinin (HA) per 0.5-mL dose in the recommended ratio of 15 mcg HA of each of the following 4 viruses (2 A strains and 2 B strains): A/Singapore/GP1908/2015 (H1N1) IVR-180 (an A/Michigan/45/2015 [H1N1] pdm09-like virus), A/Singapore/INFIMH-16-0019/2016 (H3N2) IVR-186, B/Maryland/15/2016 NYMC BX-69A, (a B/Colorado/06/2017-like virus), and B/Phuket/3073/2013.
The prefilled syringe is formulated without preservatives and does not contain thimerosal. Each 0.5-mL dose from the multi-dose vial contains 50 mcg thimerosal (<25 mcg mercury); thimerosal, a mercury derivative, is added as a preservative.
Each 0.5-mL dose of either presentation may also contain residual amounts of ovalbumin (≤0.3 mcg), formaldehyde (≤25 mcg), sodium deoxycholate (≤50 mcg), α-tocopheryl hydrogen succinate (≤320 mcg), and polysorbate 80 (≤887 mcg) from the manufacturing process. Antibiotics are not used in the manufacture of this vaccine.
The tip caps and plungers of the prefilled syringes are not made with natural rubber latex. The vial stoppers are not made with natural rubber latex.

Indications & Dosage

INDICATIONS

FLULAVAL® QUADRIVALENT is indicated for active immunization for the prevention of disease caused by influenza A subtype viruses and type B viruses contained in the vaccine. FLULAVAL QUADRIVALENT is approved for use in persons aged 6 months and older.

DOSAGE AND ADMINISTRATION

For intramuscular injection only.

Dosage And Schedule

The dose and schedule for FLULAVAL QUADRIVALENT are presented in Table 1.
Table 1: FLULAVAL QUADRIVALENT: Dosing
AgeVaccination StatusDose and Schedule
6 months through 8 yearsNot previously vaccinated with influenza vaccineTwo doses (0.5mL each) at least 4 weeks apart
Vaccinated with influenza vaccine in a previous seasonOne or 2 dosesa (0.5mL each)
9 years and olderNot applicableOne 0.5mL dose
aOne dose or 2 doses (0.5mL each) depending on vaccination history as per the annual Advisory Committee on Immunization Practices (ACIP) recommendation on prevention and control of influenza with vaccines. If 2 doses, administer each 0.5mL dose at least 4 weeks apart.

Administration Instructions

Shake well before administration. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If either of these conditions exists, the vaccine should not be administered.
Attach a sterile needle to the prefilled syringe and administer intramuscularly.
For the multi-dose vial, use a sterile needle and sterile syringe to withdraw the 0.5mL dose from the multi-dose vial and administer intramuscularly. A sterile syringe with a needle bore no larger than 23 gauge is recommended for administration. It is recommended that small syringes (0.5 mL or 1 mL) be used to minimize any product loss. Use a separate sterile needle and syringe for each dose withdrawn from the multi-dose vial.
Between uses, return the multi-dose vial to the recommended storage conditions, between 2° and 8°C (36° and 46°F). Do not freeze. Discard if the vaccine has been frozen. Once entered, a multi-dose vial, and any residual contents, should be discarded after 28 days.
The preferred sites for intramuscular injection are the anterolateral thigh for children aged 6 through 11 months and the deltoid muscle of the upper arm for persons aged 12 months and older. Do not inject in the gluteal area or areas where there may be a major nerve trunk.
Do not administer this product intravenously, intradermally, or subcutaneously.

HOW SUPPLIED

Dosage Forms And Strengths

FLULAVAL QUADRIVALENT is a suspension for injection available in 0.5-mL prefilled TIPLOK syringes and 5mL multi-dose vials containing 10 doses (each dose is 0.5 mL).

Storage And Handling

FLULAVAL QUADRIVALENT is available in 0.5-mL single-dose disposable prefilled TIP-LOK syringes (packaged without needles) and in 5-mL multi-dose vials containing 10 doses (0.5 mL each).
NDC 19515-912-41 Syringe in Package of 10: NDC 19515-912-52
NDC 19515-896-01 Multi-Dose Vial (containing 10 doses) in Package of 1: NDC 19515-896-11
Store refrigerated between 2° and 8°C (36° and 46°F). Do not freeze. Discard if the vaccine has been frozen. Store in the original package to protect from light. Once entered, a multi-dose vial should be discarded after 28 days.
Manufactured by ID Biomedical Corporation of Quebec, Quebec City, QC, Canada, U.S. License 1739. Distributed by GlaxoSmithKline, Research Triangle Park, NC 27709. Revised: Jul 2017

Side Effects

SIDE EFFECTS

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared with rates in the clinical trials of another vaccine, and may not reflect the rates observed in practice. There is the possibility that broad use of FLULAVAL QUADRIVALENT could reveal adverse reactions not observed in clinical trials.
In adults who received FLULAVAL QUADRIVALENT, the most common (≥10%) solicited local adverse reaction was pain (60%); the most common (≥10%) solicited systemic adverse events were muscle aches (26%), headache (22%), fatigue (22%), and arthralgia (15%).
In children aged 6 through 35 months who received FLULAVAL QUADRIVALENT, the most common (≥10%) solicited local adverse reaction was pain (40%); the most common (≥10%) solicited systemic adverse events were irritability (49%), drowsiness (37%), and loss of appetite (29%).
In children aged 3 through 17 years who received FLULAVAL QUADRIVALENT, the most common (≥10%) solicited local adverse reaction was pain (65%). In children aged 3 through 4 years, the most common (≥10%) solicited systemic adverse events were irritability (26%), drowsiness (21%), and loss of appetite (17%). In children aged 5 through 17 years, the most common (≥10%) systemic adverse events were muscle aches (29%), fatigue (22%), headache (22%), arthralgia (13%), and gastrointestinal symptoms (10%).
FLULAVAL QUADRIVALENT has been administered in 8 clinical trials to 1,384 adults aged 18 years and older, 1,965 children aged 6 through 35 months, and 3,516 children aged 3 through 17 years.
FLULAVAL QUADRIVALENT In Adults
Trial 1 (NCT01196975) was a randomized, double-blind, active-controlled, safety and immunogenicity trial. In this trial, subjects received FLULAVAL QUADRIVALENT (n = 1,272), or one of 2 formulations of a comparator trivalent influenza vaccine (FLULAVAL, TIV-1, n = 213 or TIV-2, n = 218), each containing an influenza type B virus that corresponded to one of the 2 B viruses in FLULAVAL QUADRIVALENT (a type B virus of the Victoria lineage or a type B virus of the Yamagata lineage). The population was aged 18 years and older (mean age: 50 years) and 61% were female; 61% of subjects were white, 3% were black, 1% were Asian, and 35% were of other racial/ethnic groups. Solicited adverse events were collected for 7 days (day of vaccination and the next 6 days). The incidence of local adverse reactions and systemic adverse events occurring within 7 days of vaccination in adults are shown in Table 2.
Table 2: FLULAVAL QUADRIVALENT: Incidence of Solicited Local Adverse Reactions and Systemic Adverse Events within 7 Daysa of Vaccination in Adults Aged 18 Years and Olderb (Total Vaccinated Cohort)
FLULAVAL QUADRIVALENTc
n = 1,260 %
Trivalent Influenza Vaccine (TIV)
TIV-1 (B Victoria)
n = 208 %
TIV-2 (B Yamagata)e
n = 216 %
AnyGrade 3fAnyGrade 3fAnyGrade 3f
Local Adverse Reactions
Pain59.51.744.71.041.21.4
Swelling2.50.01.40.03.70.0
Redness1.70.02.90.01.40.0
Systemic Adverse Events
Muscle aches26.30.825.00.518.51.4
Headache21.50.919.70.522.70.0
Fatigue21.50.821.61.017.11.9
Arthralgia14.80.816.71.014.62.9
Gastrointestinal symptomsg9.30.810.11.96.90.5
Shivering8.80.67.70.56.00.9
Feverh1.30.40.50.01.40.5
Total vaccinated cohort for safety included all vaccinated subjects for whom safety data were available. n = number of subjects with diary card completed.
a7 days included day of vaccination and the subsequent 6 days.
bTrial 1: NCT01196975.
cContained 2 A strains and 2 B strains, one of Victoria lineage and one of Yamagata lineage.
dContained the same 2 A strains as FLULAVAL QUADRIVALENT and a B strain of Victoria lineage.
eContained the same 2 A strains as FLULAVAL QUADRIVALENT and a B strain of Yamagata lineage.
fGrade 3 pain: Defined as significant pain at rest; prevented normal everyday activities.
Grade 3 swelling, redness: Defined as >100 mm.
Grade 3 muscle aches, headache, fatigue, arthralgia, gastrointestinal symptoms, shivering: Defined as prevented normal activity.
Grade 3 (or higher) fever: Defined as ≥102.2°F (39.0°C).
gGastrointestinal symptoms included nausea, vomiting, diarrhea, and/or abdominal pain.
hFever: Defined as ≥100.4°F (38.0°C)

Unsolicited adverse events occurring within 21 days of vaccination were reported in 19%, 23%, and 23% of subjects who received FLULAVAL QUADRIVALENT (n = 1,272), TIV-1 (B Victoria) (n = 213), or TIV-2 (B Yamagata) (n = 218), respectively. The unsolicited adverse events that occurred most frequently (≥1% for FLULAVAL QUADRIVALENT) included nasopharyngitis, upper respiratory tract infection, headache, cough, and oropharyngeal pain. Serious adverse events occurring within 21 days of vaccination were reported in 0.4%, 0%, and 0% of subjects who received FLULAVAL QUADRIVALENT, TIV-1 (B Victoria), or TIV-2 (B Yamagata), respectively.
FLULAVAL QUADRIVALENT In Children
Trial 4 (NCT02242643) was a randomized, observer-blind, active-controlled immunogenicity and safety trial. The trial included subjects aged 6 through 35 months who received FLULAVAL QUADRIVALENT (n = 1,207) or FLUZONE QUADRIVALENT, a U.S.-licensed inactivated influenza vaccine (n = 1,217) used as comparator, manufactured by Sanofi Pasteur Inc. Children with no history of influenza vaccination received 2 doses of FLULAVAL QUADRIVALENT or the comparator vaccine approximately 28 days apart. Children with a history of influenza vaccination received one dose of FLULAVAL QUADRIVALENT or the comparator vaccine. In the overall population, 53% were male; 64% were white, 16% were black, 3% were Asian, and 17% were of other racial/ethnic groups. The mean age of subjects was 20 months. Subjects were followed for safety for 6 months; solicited local adverse reactions and systemic adverse events were collected for 7 days (day of vaccination and the next 6 days) postvaccination. The incidence of local adverse reactions and systemic adverse events occurring within 7 days of vaccination in children are shown in Table 3.
Table 3: FLULAVAL QUADRIVALENT: Incidence of Solicited Local Adverse Reactions and Systemic Adverse Events within 7 Daysa of Firs t Vaccination in Children Aged 6 through 35 Monthsb (Total Vaccinated Cohort)
FLULAVAL QUADRIVALENT %Active Comparatorc %
AnyGrade 3dAnyGrade 3d
Local Adverse Reactionsn = 1,151n= 1,146
Pain40.32.437.41.4
Swelling1.00.00.40.0
Redness1.30.01.30.0
Systemic Adverse Eventsn = 1,155n = 1,148
Irritability49.43.845.93.0
Drowsiness36.72.736.92.6
Loss of appetite28.91.628.61.3
Fever e5.61.45.81.0
Total vaccinated cohort for safety included all vaccinated subjects for whom safety data were available (i.e., diary card completed for solicited symptoms). n = number of subjects with diary card completed.
a7 days included day of vaccination and the subsequent 6 days.
bTrial 4: NCT02242643.
cU.S.-licensed quadrivalent, inactivated influenza vaccine (manufactured by Sanofi Pasteur Inc).
Grade 3 pain: Defined as cried when limb was moved/spontaneously painful.
Grade 3 swelling, redness: Defined as >100 mm.
Grade 3 irritability: Defined as crying that could not be comforted/prevented normal activity.
Grade 3 drowsiness: Defined as prevented normal activity.
Grade 3 loss of appetite: Defined as not eating at all.
Grade 3 (or higher) fever: Defined as >102.2°F (39.0°C).
eFever: Defined as ≥100.4°F (38.0°C).

In children who received a second dose of FLULAVAL QUADRIVALENT or the comparator vaccine, the incidences of solicited adverse events following the second dose were generally similar or lower than those observed after the first dose.
Unsolicited adverse events occurring within 28 days of vaccination were reported in 46% and 44% of subjects who received FLULAVAL QUADRIVALENT (n = 1,207) and the comparator vaccine (n = 1,217), respectively. The unsolicited adverse reactions that occurred most frequently (≥1%) for FLULAVAL QUADRIVALENT included upper respiratory tract infection, cough, diarrhea, pyrexia, vomiting, and rash. Serious adverse events occurring during the study period (approximately 6 months) were reported in 2% of subjects who received FLULAVAL QUADRIVALENT and in 2% of subjects who received the comparator vaccine. There were no deaths reported during the study period.
Trial 2 (NCT01198756) was a randomized, double-blind, active-controlled trial. In this trial, subjects received FLULAVAL QUADRIVALENT (n = 932) or one of 2 formulations of a comparator trivalent influenza vaccine [FLUARIX (Influenza Vaccine), TIV-1 (B Victoria), n = 929 or TIV-2 (B Yamagata), n = 932], each containing an influenza type B virus that corresponded to one of the 2 B viruses in FLULAVAL QUADRIVALENT (a type B virus of the Victoria lineage or a type B virus of the Yamagata lineage). The population was aged 3 through 17 years (mean age: 9 years) and 53% were male; 65% were white, 13% were Asian, 9% were black, and 13% were of other racial/ethnic groups. Children aged 3 through 8 years with no history of influenza vaccination received 2 doses approximately 28 days apart. Children aged 3 through 8 years with a history of influenza vaccination and children aged 9 years and older received one dose. Solicited local adverse reactions and systemic adverse events were collected for 7 days (day of vaccination and the next 6 days). The incidence of local adverse reactions and systemic adverse events occurring within 7 days of vaccination in children are shown in Table 4.
Table 4: FLULAVAL QUADRIVALENT: Incidence of Solicited Local Adverse Reactions and Systemic Adverse Events within 7 Daysa of Firs t Vaccination in Children Aged 3 through 17 Yearsb (Total Vaccinated Cohort)
FLULAVAL QUADRIVALENTc %Trivalent Influenza Vaccine (TIV)
TIV-1 (B Victoria)%TIV-2 (B Yamagata)e %
AnyGrade 3fAnyGrade 3fAnyGrade 3f
Aged 3 through 17 Years
Local Adverse Reactionsn = 913n = 911n = 915
Pain65.43.254.61.855.72.4
Swelling6.20.13.30.03.80.0
Redness5.30.13.20.03.50.0
Aged 3 through 4 Years
Systemic Adverse Eventsn = 185n = 187n = 189
Irritability25.90.516.60.021.71.6
Drowsiness21.10.019.81.623.30.5
Loss of appetite17.30.016.01.613.21.1
Feverg4.90.55.91.13.71.6
Aged 5 through 17 Years
Systemic Adverse Eventsn = 727n = 724n = 725
Muscle aches28.50.724.90.624.71.0
Fatigue22.10.723.61.823.01.0
Headache22.01.022.11.020.11.2
Arthralgia12.90.411.90.610.50.1
Gastrointestinal symptomsh9.61.09.71.09.00.7
Shivering7.00.46.91.26.90.6
Feverg1.90.63.61.12.50.3
Total vaccinated cohort for safety included all vaccinated subjects for whom safety data were available. n = number of subjects with diary card completed.
7 days included day of vaccination and the subsequent 6 days.
aTrial 2: NCT01198756.
bContained 2 A strains and 2 B strains, one of Victoria lineage and one of Yamagata lineage.
cContained the same 2 A strains as FLULAVAL QUADRIVALENT and a B strain of Victoria lineage.
dContained the same 2 A strains as FLULAVAL QUADRIVALENT and a B strain of Yamagata lineage.
eGrade 3 pain: Defined as cried when limb was moved/spontaneously painful (children 5 years), or significant pain at rest, prevented normal everyday activities (children ≥5 years).
Grade 3 swelling, redness: Defined as >100 mm.
Grade 3 irritability: Defined as crying that could not be comforted/prevented normal activity.
Grade 3 drowsiness: Defined as prevented normal activity.
Grade 3 loss of appetite: Defined as not eating at all.
Grade 3 (or higher) fever: Defined as ≥102.2°F (39.0°C).
Grade 3 muscle aches, fatigue, headache, arthralgia, gastrointestinal symptoms, shivering: Defined as prevented normal activity.
gFever: Defined as ≥100.4°F (38.0°C).
hGastrointestinal symptoms included nausea, vomiting, diarrhea, and/or abdominal pain.

In children who received a second dose of FLULAVAL QUADRIVALENT, FLUARIX TIV-1 (B Victoria), or TIV-2 (B Yamagata), the incidences of adverse events following the second dose were generally lower than those observed after the first dose.
Unsolicited adverse events occurring within 28 days of vaccination were reported in 30%, 31%, and 30% of subjects who received FLULAVAL QUADRIVALENT (n = 932), FLUARIX TIV-1 (B Victoria) (n = 929), or TIV-2 (B Yamagata) (n = 932), respectively. The unsolicited adverse events that occurred most frequently (≥1% for FLULAVAL QUADRIVALENT) included vomiting, pyrexia, bronchitis, nasopharyngitis, pharyngitis, upper respiratory tract infection, headache, cough, oropharyngeal pain, and rhinorrhea. Serious adverse events occurring within 28 days of any vaccination were reported in 0.1%, 0.2%, and 0.2% of subjects who received FLULAVAL QUADRIVALENT, FLUARIX TIV-1 (B Victoria), or TIV-2 (B Yamagata), respectively.
Trial 3 (NCT01218308) was a randomized, observer-blind, non-influenza vaccine-controlled trial evaluating the efficacy of FLULAVAL QUADRIVALENT. The trial included subjects aged 3 through 8 years who received FLULAVAL QUADRIVALENT (n = 2,584) or HAVRIX (Hepatitis A Vaccine) (n = 2,584) as a control vaccine. Children with no history of influenza vaccination received 2 doses of FLULAVAL QUADRIVALENT or HAVRIX approximately 28 days apart (this dosing regimen for HAVRIX is not a U.S.-licensed schedule). Children with a history of influenza vaccination received one dose of FLULAVAL QUADRIVALENT or HAVRIX. In the overall population, 52% were male; 60% were Asian, 5% were white, and 35% were of other racial/ethnic groups. The mean age of subjects was 5 years. Solicited local adverse reactions and systemic adverse events were collected for 7 days (day of vaccination and the next 6 days). The incidence of local adverse reactions and systemic adverse events occurring within 7 days of vaccination in children are shown in Table 5.
Table 5: FLULAVAL QUADRIVALENT: Incidence of Solicited Local Adverse Reactions and Systemic Adverse Events within 7 Daysa of Firs t Vaccination in Children Aged 3 through 8 Yearsb (Total Vaccinated Cohort)
FLULAVAL QUADRIVALENT %HAVRIX%
AnyGrade 3dAnyGrade 3d
Aged 3 through 8 Years
Local Adverse Reactionsn = 2,546n = 2,551
Pain39.40.927.80.7
Swelling1.00.00.30.0
Redness0.40.00.20.0
Aged 3 through 4 Years
Systemic Adverse Eventsn = 898n = 895
Loss of appetite9.00.38.20.4
Irritability8.10.47.50.1
Drowsiness7.70.47.30.0
Fevere3.81.24.41.3
Aged 5 through 8 Years
Systemic Adverse Eventsn = 1,648n = 1,654
Muscle aches12.00.19.70.2
Headache10.50.410.60.8
Fatigue8.40.17.10.3
Arthralgia6.30.14.50.1
Gastrointestinal symptomsf5.50.25.90.3
Shivering3.00.12.50.1
Fevere2.70.62.70.7
Total vaccinated cohort for safety included all vaccinated subjects for whom safety data were available. n = number of subjects with diary card completed.
a7 days included day of vaccination and the subsequent 6 days.
bTrial 3: NCT01218308.
cHepatitis A Vaccine used as a control vaccine.
dGrade 3 pain: Defined as cried when limb was moved/spontaneously painful (children 5 years), or significant pain at rest, prevented normal everyday activities (children ≥5 years).
Grade 3 swelling, redness: Defined as >100 mm.
Grade 3 loss of appetite: Defined as not eating at all.
Grade 3 irritability: Defined as crying that could not be comforted/prevented normal activity.
Grade 3 drowsiness: Defined as prevented normal activity.
Grade 3 (or higher) fever: Defined as ≥102.2°F (39.0°C).
Grade 3 muscle aches, headache, fatigue, arthralgia, gastrointestinal symptoms, shivering: Defined as prevented normal activity.
eFever: Defined as ≥100.4°F (38.0°C).
fGastrointestinal symptoms included nausea, vomiting, diarrhea, and/or abdominal pain.

In children who received a second dose of FLULAVAL QUADRIVALENT or HAVRIX, the incidences of adverse events following the second dose were generally lower than those observed after the first dose.
The frequency of unsolicited adverse events occurring within 28 days of vaccination was similar in both groups (33% for both FLULAVAL QUADRIVALENT and HAVRIX). The unsolicited adverse events that occurred most frequently (≥1% for FLULAVAL QUADRIVALENT) included diarrhea, pyrexia,gastroenteritis, nasopharyngitis, upper respiratory tract infection, varicella, cough, and rhinorrhea. Serious adverse events occurring within 28 days of any vaccination were reported in 0.7% of subjects who received FLULAVAL QUADRIVALENT and in 0.2% of subjects who received HAVRIX.

Postmarketing Experience

The following adverse events have been spontaneously reported during postapproval use of FLULAVAL QUADRIVALENT or FLULAVAL (trivalent influenza vaccine). Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their incidence rate or establish a causal relationship to the vaccine. Adverse events were included based on one or more of the following factors: severity, frequency of reporting, or strength of evidence for a causal relationship to FLULAVAL QUADRIVALENT or FLULAVAL.
Blood And Lymphatic System Disorders
Lymphadenopathy.
Eye Disorders
Eye pain, photophobia.
Gastrointestinal Disorders
Dysphagia, vomiting.
General Disorders And Administration Site Conditions
Chest pain, injection site inflammation, asthenia, injection site rash, influenza-like symptoms, abnormal gait, injection site bruising, injection site sterile abscess.
Immune System Disorders
Allergic reactions including anaphylaxisangioedema.
Infections And Infestations
Rhinitislaryngitiscellulitis.
Musculoskeletal And Connective Tissue Disorders
Muscle weakness, arthritis.
Nervous System Disorders
Dizziness, paresthesia, hypoesthesia, hypokinesia, tremorsomnolencesyncope, Guillain-Barré syndrome, convulsions/seizures, facial or cranial nerve paralysisencephalopathy, limb paralysis.
Psychiatric Disorders
Insomnia.
Respiratory, Thoracic, And Mediastinal Disorders
Dyspneadysphonia, bronchospasm, throat tightness.
Skin And Subcutaneous Tissue Disorders
Urticaria, localized or generalized rash, pruritus, sweating.
Vascular Disorders
Flushing, pallor.

Drug Interactions

DRUG INTERACTIONS

Concomitant Administration With Other Vaccines

FLULAVAL QUADRIVALENT should not be mixed with any other vaccine in the same syringe or vial.
There are insufficient data to assess the concomitant administration of FLULAVAL QUADRIVALENT with other vaccines. When concomitant administration of other vaccines is required, the vaccines should be administered at different injection sites.

Immunosuppressive Therapies

Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxicdrugs, and corticosteroids (used in greater than physiologic doses) may reduce the immune responseto FLULAVAL QUADRIVALENT.

Warnings & Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Guillain-Barré Syndrome

If Guillain-Barré syndrome (GBS) has occurred within 6 weeks of receipt of a prior influenza vaccine, the decision to give FLULAVAL QUADRIVALENT should be based on careful consideration of the potential benefits and risks.
The 1976 swine influenza vaccine was associated with an elevated risk of GBS. Evidence for a causal relation of GBS with other influenza vaccines is inconclusive; if an excess risk exists, it is probably slightly more than one additional case/one million persons vaccinated.

Syncope

Syncope (fainting) can occur in association with administration of injectable vaccines, including FLULAVAL QUADRIVALENT. 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.

Preventing And Managing Allergic Vaccine Reactions

Prior to administration, the healthcare provider should review the immunization history for possible vaccine sensitivity and previous vaccination-related adverse reactions. Appropriate medical treatment and supervision must be available to manage possible anaphylactic reactions following administration of FLULAVAL QUADRIVALENT.

Altered Immunocompetence

If FLULAVAL QUADRIVALENT is administered to immunosuppressed persons, including individuals receiving immunosuppressive therapy, the immune response may be lower than in immunocompetentpersons.

Limitations Of Vaccine Effectiveness

Vaccination with FLULAVAL QUADRIVALENT may not protect all susceptible individuals.

Persons At Risk Of Bleeding

As with other intramuscular injections, FLULAVAL QUADRIVALENT should be given with caution in individuals with bleeding disorders such as hemophilia or on anticoagulant therapy to avoid the risk ofhematoma following the injection.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

FLULAVAL QUADRIVALENT has not been evaluated for carcinogenic, mutagenic potential, or male infertility in animals. Vaccination of female rats with FLULAVAL QUADRIVALENT had no effect on fertility [see Use In Specific Populations].

Use In Specific Populations

Pregnancy

Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to FLULAVAL QUADRIVALENT during pregnancy. Healthcare providers are encouraged to register women by calling 1-888-452-9622.
Risk Summary
All pregnancies have a risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
There are insufficient data on FLULAVAL QUADRIVALENT in pregnant women to inform vaccineassociated risks.
A developmental toxicity study was performed in female rats administered FLULAVAL QUADRIVALENT prior to mating and during gestation and lactation periods. The total dose was 0.2 mL at each occasion (a single human dose is 0.5 mL). This study revealed no adverse effects on fetal or pre-weaning development due to FLULAVAL QUADRIVALENT [see Data].
Clinical Considerations
Disease-Associated Maternal And/Or Embryo/Fetal Risk
Pregnant women infected with seasonal influenza are at increased risk of severe illness associated with influenza infection compared with non-pregnant women. Pregnant women with influenza may be at increased risk for adverse pregnancy outcomes, including preterm labor and delivery.
Data
Animal Data
In a developmental toxicity study, female rats were administered FLULAVAL QUADRIVALENT by intramuscular injection 4 and 2 weeks prior to mating, on gestation Days 3, 8, 11, and 15, and on lactation Day 7. The total dose was 0.2 mL at each occasion (a single human dose is 0.5 mL). No adverse effects on pre-weaning development up to post-natal Day 25 were observed. There were no vaccine-related fetal malformations or variations.

Lactation

Risk Summary
It is not known whether FLULAVAL QUADRIVALENT is excreted in human milk. Data are not available to assess the effects of FLULAVAL QUADRIVALENT on the breastfed infant or on milk production/excretion. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for FLULAVAL QUADRIVALENT and any potential adverse effects on the breastfed child from FLULAVAL QUADRIVALENT or from the underlying maternal condition. For preventive vaccines, the underlying maternal condition is susceptibility to disease prevented by the vaccine.

Pediatric Use

Safety and effectiveness of FLULAVAL QUADRIVALENT in children younger than 6 months have not been established.

Geriatric Use

In a randomized, double-blind, active-controlled trial, immunogenicity and safety were evaluated in a cohort of subjects aged 65 years and older who received FLULAVAL QUADRIVALENT (n = 397); approximately one-third of these subjects were aged 75 years and older. In subjects aged 65 years and older, the geometric mean antibody titers (GMTs) post-vaccination and seroconversion rates were lower than in younger subjects (aged 18 to 64 years) and the frequencies of solicited and unsolicited adverse events were generally lower than in younger subjects [see ADVERSE REACTIONSClinical Studies].

Overdosage & Contraindications

OVERDOSE

No information provided.

CONTRAINDICATIONS

Do not administer FLULAVAL QUADRIVALENT to anyone with a history of severe allergic reactions (e.g., anaphylaxis) to any component of the vaccine, including egg protein, or following a previous dose of any influenza vaccine [see DESCRIPTION].

Clinical Pharmacology

CLINICAL PHARMACOLOGY

Mechanism Of Action

Influenza illness and its complications follow infection with influenza viruses. Global surveillance of influenza identifies yearly antigenic variants. Since 1977, antigenic variants of influenza A (H1N1 and H3N2) viruses and influenza B viruses have been in global circulation.
Public health authorities recommend influenza vaccine strains annually. Inactivated influenza vaccinesare standardized to contain the hemagglutinins of strains representing the influenza viruses likely to circulate in the United States during the influenza season.
Specific levels of hemagglutination inhibition (HI) antibody titer post-vaccination with inactivated influenza virus vaccines have not been correlated with protection from influenza illness but the antibody titers have been used as a measure of vaccine activity. In some human challenge studies, antibody titers of ≥1:40 have been associated with protection from influenza illness in up to 50% of subjects.1,2 Antibody against one influenza virus type or subtype confers little or no protection against another virus. Furthermore, antibody to one antigenic variant of influenza virus might not protect against a new antigenic variant of the same type or subtype. Frequent development of antigenic variants through antigenic drift is the virological basis for seasonal epidemics and the reason for the usual change of one or more new strains in each year's influenza vaccine.
Annual revaccination is recommended because immunity declines during the year after vaccination and because circulating strains of influenza virus change from year to year.

Clinical Studies

Efficacy Against Influenza

The efficacy of FLULAVAL QUADRIVALENT was evaluated in Trial 3, a randomized, observerblind, non-influenza vaccine-controlled trial conducted in 3 countries in Asia, 3 in Latin America, and 2 in the Middle East/Europe during the 2010-2011 influenza season. Healthy subjects aged 3 through 8 years were randomized (1:1) to receive FLULAVAL QUADRIVALENT (n = 2,584), containing A/California/7/2009 (H1N1), A/Victoria/210/2009 (H3N2), B/Brisbane/60/2008 (Victoria lineage), and B/Florida/4/2006 (Yamagata lineage) influenza strains, or HAVRIX (n = 2,584), as a control vaccine. Children with no history of influenza vaccination received 2 doses of FLULAVAL QUADRIVALENT or HAVRIX approximately 28 days apart. Children with a history of influenza vaccination received one dose of FLULAVAL QUADRIVALENT or HAVRIX [see ADVERSE REACTIONS]. In the overall population, 52% were male; 60% were Asian, 5% were white, and 35% were of other racial/ethnic groups. The mean age of subjects was 5 years.
Efficacy of FLULAVAL QUADRIVALENT was assessed for the prevention of reverse transcriptasepolymerase chain reaction (RT-PCR)-positive influenza A and/or B disease presenting as influenza-like illness (ILI). ILI was defined as a temperature ≥100°F in the presence of at least one of the following symptoms on the same day: cough, sore throatrunny nose, or nasal congestion. Subjects with ILI (monitored by passive and active surveillance for approximately 6 months) had nasal and throat swabs collected and tested for influenza A and/or B by RT-PCR. All RT-PCR-positive specimens were further tested in cell culture. Vaccine efficacy was calculated based on the ATP cohort for efficacy (Table 6).
Table 6: FLULAVAL QUADRIVALENT: Influenza Attack Rates and Vaccine Efficacy against Influenza A and/or B in Children Aged 3 through 8 Yearsa (According-to-Protocol Cohort for Efficacy)
NbncInfluenza Attack Rate % (n/N)Vaccine Efficacy % (CI)
All RT-PCR-Positive Influenza
FLULAVAL QUADRIVALENT2,379582.455.4d (95% CI: 39.1, 67.3)
HAVRIXe2,3981285.3
All Culture-Confirmed Influenzaf
FLULAVAL QUADRIVALENT2,379502.155.9 (97.5% CI: 35.4, 69.9)
HAVRIXe2,3981124.7
Antigenically Matched Culture-Confirmed Influenza
FLULAVAL QUADRIVALENT2,379311.345.1(97.5% CI: 9.3, 66.8)
HAVRIXe2,398562.3
CI = Confidence Interval; RT-PCR = Reverse transcriptase polymerase chain reaction.
aTrial 3: NCT01218308.
bAccording-to-protocol cohort for efficacy included subjects who met all eligibility criteria, were successfully contacted at least once post-vaccination, and complied with the protocol-specified efficacy criteria.
cNumber of influenza cases.
dVaccine efficacy for FLULAVAL QUADRIVALENT met the pre-defined criterion of >30% for the lower limit of the 2-sided 95% CI.
eHepatitis A Vaccine used as a control vaccine.
fOf 162 culture-confirmed influenza cases, 108 (67%) were antigenically typed (87 matched; 21 unmatched); 54 (33%) could not be antigenically typed [but were typed by RT-PCR and nucleic acid sequence analysis: 5 cases A (H1N1) (5 with HAVRIX), 47 cases A (H3N2) (10 with FLULAVAL QUADRIVALENT; 37 with HAVRIX), and 2 cases B Victoria (2 with HAVRIX)].
gSince only 67% of cases could be typed, the clinical significance of this result is unknown.



In an exploratory analysis by age, vaccine efficacy against RT-PCR-positive influenza A and/or B disease presenting as ILI was evaluated in subjects aged 3 through 4 years and 5 through 8 years; vaccine efficacy was 35.3% (95% CI: 1.3, 58.6) and 67.7% (95% CI: 49.7, 79.2), respectively. As the trial lacked statistical power to evaluate efficacy within age subgroups, the clinical significance of these results is unknown.
As a secondary objective in the trial, subjects with RT-PCR-positive influenza A and/or B were prospectively classified based on the presence of adverse outcomes that have been associated with influenza infection (defined as fever >102.2°F/39.0°C, physician-verified shortness of breath, pneumoniawheezingbronchitisbronchiolitis, pulmonary congestion, croup, and/or acute otitis media, and/or physician-diagnosed serious extra-pulmonary complications, including myositisencephalitisseizure and/or myocarditis).
The risk reduction of fever >102.2°F/39.0°C associated with RT-PCR-positive influenza was 71.0% (95% CI: 44.8, 84.8) based on the ATP cohort for efficacy [FLULAVAL QUADRIVALENT (n = 12/2,379); HAVRIX (n = 41/2,398)]. The other pre-specified adverse outcomes had too few cases to calculate a risk reduction. The incidence of these adverse outcomes is presented in Table 7.
Table 7: FLULAVAL QUADRIVALENT: Incidence of Advers e Outcomes As s ociated with RTPCR- Pos itive Influenza in Children Aged 3 through 8 Yearsa (Total Vaccinated Cohort)b


Adverse OutcomedFLULAVAL QUADRIVALENT
n = 2,584
HAVRIX
n = 2,584
Number of EventsNumber of Subjectse%Number of EventsNumber of Subjectse%
Fever >102.2°F/ 39.0°C16f150.651f501.9
Shortness of breath000550.2
Pneumonia000330.1
Wheezing110110
Bronchitis110110
Pulmonary congestion000110
Acute otitis media000110
Bronchiolitis000000
Croup000000
Encephalitis000000
Myocarditis000000
Myositis000000
Seizure000000
aTrial 3: NCT01218308.
bTotal vaccinated cohort included all vaccinated subjects for whom data were available.
cHepatitis A Vaccine used as a control vaccine.
dIn subjects who presented with more than one adverse outcome, each outcome was counted in the respective category.
eNumber of subjects presenting with at least one event in each group.
fOne subject in each group had sequential influenza due to influenza type A and type B viruses.

Immunological Evaluation

Adults
Trial 1 was a randomized, double-blind, active-controlled, safety and immunogenicity trial conducted in subjects aged 18 years and older. In this trial, subjects received FLULAVAL QUADRIVALENT (n = 1,246) or one of 2 formulations of a comparator trivalent influenza vaccine (FLULAVAL, TIV-1, n = 204 or TIV-2, n = 211), each containing an influenza type B virus that corresponded to one of the 2 B viruses in FLULAVAL QUADRIVALENT (a type B virus of the Victoria lineage or a type B virus of the Yamagata lineage) [see ADVERSE REACTIONS].
Immune responses, specifically hemagglutination inhibition (HI) antibody titers to each virus strain in the vaccine, were evaluated in sera obtained 21 days after administration of FLULAVAL QUADRIVALENT or the comparators. The immunogenicity endpoint was GMTs adjusted for baseline, performed on the According-to-Protocol (ATP) cohort for whom immunogenicity assay results were available after vaccination. FLULAVAL QUADRIVALENT was noninferior to both TIVs based on adjusted GMTs (Table 8). The antibody response to influenza B strains contained in FLULAVAL QUADRIVALENT was higher than the antibody response after vaccination with a TIV containing an influenza B strain from a different lineage. There was no evidence that the addition of the second B strain resulted in immune interference to other strains included in the vaccine (Table 8).
Table 8: Non-inferiority of FLULAVAL QUADRIVALENT Relative to Trivalent Influenza Vaccine (TIV) 21 Days Pos t-vaccination in Adults Aged 18 Years and Oldera (According-to- Protocol Cohort for Immunogenicity)b



FLULAVAL QUADRIVALENTcTIV-1 (B Victoria)dTIV-2 (B Yamagata)e
Geometric Mean Titers Againstn = 1,245-1,246 (95% CI)n = 204 (95% CI)n = 210-211 (95% CI)
A/California/7/2009 (H1N1)204.6f (190.4, 219.9)176.0 (149.1, 207.7)149.0 (122.9, 180.7)
A/Victoria/210/2009 (H3N2)125.4f (117.4, 133.9)147.5 (124.1, 175.2)141.0 (118.1, 168.3)
B/Brisbane/60/2008 (Victoria lineage)177.7(167.8, 188.1)135.9 (118.1, 156.5)71.9 (61.3, 84.2)
B/Florida/4/2006 (Yamagata lineage)399.7f (378.1, 422.6)176.9 (153.8, 203.5)306.6 (266.2, 353.3)
CI = Confidence Interval.
aTrial 1: NCT01196975.
bAccording-to-protocol cohort for immunogenicity included all evaluable subjects for whom assay results were available after vaccination for at least one trial vaccine antigen.
cContaining A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), B/Florida/04/2006 (Yamagata lineage), and B/Brisbane/60/2008 (Victoria lineage).
dContaining A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Brisbane/60/2008 (Victoria lineage).
eContaining A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Florida/04/2006 (Yamagata lineage).
fNoninferior to both TIVs based on adjusted GMTs [upper limit of the 2sided 95% CI for the GMT ratio (TIV/FLULAVAL QUADRIVALENT) ≤1.5]; superior to TIV-1 (B Victoria) with respect to the B strain of Yamagata lineage and to TIV-2 (B Yamagata) with respect to the B strain of Victoria lineage based on adjusted GMTs [lower limit of the 2sided 95% CI for the GMT ratio (FLULAVAL QUADRIVALENT/TIV) >1.5].

Children
Trial 4 was a randomized, observer-blind, active-controlled trial in children aged 6 through 35 months which was conducted in the United States and Mexico. In this trial, subjects received 0.5 mL of FLULAVAL QUADRIVALENT containing 15 mcg HA of each of the 4 influenza strains included in the vaccine (n = 1,207); or 0.25 mL of control vaccine FLUZONE QUADRIVALENT (Influenza Vaccine) containing 7.5 mcg HA of each of the 4 influenza strains included in the vaccine (n = 1,217) [ see ADVERSE REACTIONS].
Immune responses, specifically HI antibody titers to each virus strain in the vaccine, were evaluated in sera obtained 28 days following completion of vaccination regimen. Previously vaccinated children received one dose and previously unvaccinated children (i.e., unprimed individuals) received 2 doses 4 weeks apart of FLULAVAL QUADRIVALENT or the comparator. The immunogenicity endpoints were GMTs adjusted for baseline, and the percentage of subjects who achieved seroconversion, defined as a pre-vaccination HI titer of <1:10 with a post-vaccination titer ≥1:40 or at least a 4fold increase in serum HI titer over baseline to ≥1:40, following vaccination, performed on the ATP cohort. FLULAVAL QUADRIVALENT was non-inferior to the comparator for all 4 vaccine strains based on adjusted GMTs and seroconversion rates (Table 9).
Table 9: Non-inferiority of FLULAVAL QUADRIVALENT Relative to Comparator Quadrivalent Influenza Vaccine at 28 Days Post-vaccination in Children Aged 6 through 35 Monthsa (According-to-Protocol Cohort for Immunogenicity)b



Adjusted Geometric Mean Titers AgainstFLULAVAL QUADRIVALENTcActive Comparatord
n= 972-974n= 980
A/California/07/2009 (H1N1)99.6e85.1
A/Texas/50/2012 (H3N2)99.8e84.6
B/Massachusetts/02/2012 (Yamagata lineage)258.1e167.3
B/Brisbane/60/2008 (Victoria lineage)54.5e33.7
Seroconversionf to:n= 972-974 % (95% CI)n= 980 % (95% CI)
A/California/07/2009 (H1N1)73.7(70.8, 76.4)67.3 (64.3, 70.3)
A/Texas/50/2012 (H3N2)76.1e (73.3, 78.8)69.4 (66.4, 72.3)
B/Massachusetts/02/2012 (Yamagata lineage)85.5e (83.2, 87.7)73.8 (70.9, 76.5)
B/Brisbane/60/2008 (Victoria lineage)64.9(61.8, 67.9)48.5 (45.3, 51.6)
CI = Confidence Interval
Trial 4: NCT02242643.
bAccording-to-protocol cohort for immunogenicity included all evaluable subjects for whom assay results were available after vaccination for at least one trial vaccine antigen.
cA 0.5-mL dose containing 15 mcg each of A/California/07/2009 (H1N1), A/Texas/50/2012 (H3N2), B/Massachusetts/02/2012 (Yamagata lineage), and B/Brisbane/60/2008 (Victoria lineage).
dA 0.25-mL dose of U.S.-licensed quadrivalent, inactivated influenza vaccine (manufactured by Sanofi Pasteur Inc.) containing 7.5 mcg each of A/California/07/2009 (H1N1), A/Texas/50/2012 (H3N2),
eB/Massachusetts/02/2012 (Yamagata lineage), and B/Brisbane/60/2008 (Victoria lineage). Noninferior to the comparator vaccine based on adjusted GMTs [upper limit of the 2-sided 95% CI for the GMT ratio (comparator/FLULAVAL QUADRIVALENT) ≤1.5] and seroconversion rates (upper limit of the 2sided 95% CI on difference of comparator vaccine minus FLULAVAL QUADRIVALENT ≤10%).
fSeroconversion defined as a 4fold increase in post-vaccination antibody titer from pre-vaccination titer ≥1:10, or an increase in titer from <1:10 to ≥1:40.

Trial 2 was a randomized, double-blind, active-controlled trial conducted in children aged 3 through 17 years. In this trial, subjects received FLULAVAL QUADRIVALENT (n = 878), or one of 2 formulations of a comparator trivalent influenza vaccine (FLUARIX, TIV-1, n = 871 or TIV-2 n = 878), each containing an influenza type B virus that corresponded to one of the 2 B viruses in FLULAVAL QUADRIVALENT (a type B virus of the Victoria lineage or a type B virus of the Yamagata lineage) [see ADVERSE REACTIONS].
Immune responses, specifically HI antibody titers to each virus strain in the vaccine, were evaluated in sera obtained 28 days following one or 2 doses of FLULAVAL QUADRIVALENT or the comparators. The immunogenicity endpoints were GMTs adjusted for baseline, and the percentage of subjects who achieved seroconversion, defined as at least a 4fold increase in serum HI titer over baseline to ≥1:40, following vaccination, performed on the ATP cohort. FLULAVAL QUADRIVALENT was non-inferior to both TIVs based on adjusted GMTs and seroconversion rates (Table 10). The antibody response to influenza B strains contained in FLULAVAL QUADRIVALENT was higher than the antibody response after vaccination with a TIV containing an influenza B strain from a different lineage. There was no evidence that the addition of the second B strain resulted in immune interference to other strains included in the vaccine (Table 10).
Table 10: Non-inferiority of FLULAVAL QUADRIVALENT Relative to Trivalent Influenza Vaccine (TIV) at 28 Days Post-vaccination in Children Aged 3 through 17 Yearsa (According-to- Protocol Cohort for Immunogenicity)b



Geometric Mean Titers AgainstFLULAVAL QUADRIVALENTcTIV-1 (B Victoria)dTIV-2 (B Yamagata)e
n= 878 (95% CI)n= 871 (95% CI)n= 877-878 (95% CI)
A/California/7/2009 (H1N1)362.7f (335.3, 392.3)429.1 (396.5, 464.3)420.2 (388.8, 454.0)
A/Victoria/210/2009 (H3N2)143.7f (134.2, 153.9)139.6 (130.5, 149.3)151.0 (141.0, 161.6)
B/Brisbane/60/2008 (Victoria lineage)250.5f (230.8, 272.0)245.4 (226.9, 265.4)68.1 (61.9, 74.9)
B/Florida/4/2006 (Yamagata lineage)512.5f (477.6, 549.9)197.0 (180.7, 214.8)579.0 (541.2, 619.3)
Seroconversiong to:n= 876 % (95% CI)n= 870 % (95% CI)n= 876-877 % (95% CI)
A/California/7/2009 (H1N1)84.4f (81.8, 86.7)86.8 (84.3, 89.0)85.5 (83.0, 87.8)
A/Victoria/210/2009 (H3N2)70.1(66.9, 73.1)67.8 (64.6, 70.9)69.6 (66.5, 72.7)
B/Brisbane/60/2008 (Victoria lineage)74.5(71.5, 77.4)71.5 (68.4, 74.5)29.9 (26.9, 33.1)
B/Florida/4/2006 (Yamagata lineage)75.2(72.2, 78.1)41.3 (38.0, 44.6)73.4 (70.4, 76.3)
CI = Confidence Interval.
aTrial 2: NCT01198756.
bAccording-to-protocol cohort for immunogenicity included all evaluable subjects for whom assay results were available after vaccination for at least one trial vaccine antigen.
cContaining A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), B/Florida/04/2006 (Yamagata lineage), and B/Brisbane/60/2008 (Victoria lineage).
dContaining A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Brisbane/60/2008 (Victoria lineage).
eContaining A/California/07/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Florida/04/2006 (Yamagata lineage).
fNoninferior to both TIVs based on adjusted GMTs [upper limit of the 2-sided 95% CI for the GMT ratio (TIV/FLULAVAL QUADRIVALENT) ≤1.5] and seroconversion rates (upper limit of the 2sided 95% CI on difference of the TIV minus FLULAVAL QUADRIVALENT ≤10%); superior to TIV-1 (B Victoria) with respect to the B strain of Yamagata lineage and to TIV-2 (B Yamagata) with respect to the B strain of Victoria lineage based on adjusted GMTs [lower limit of the 2sided 95% CI for the GMT ratio (FLULAVAL QUADRIVALENT/TIV) >1.5] and seroconversion rates (lower limit of the 2sided 95% CI on difference of FLULAVAL QUADRIVALENT minus the TIV >10%).
gSeroconversion defined as a 4fold increase in post-vaccination antibody titer from pre-vaccination titer ≥1:10, or an increase in titer from <1:10 to ≥1:40.

REFERENCES
1 Hannoun C, Megas F, Piercy J. Immunogenicity and protective efficacy of influenza vaccination. Virus Res 2004;103:133-138.
2. Hobson D, Curry RL, Beare AS, et al. The role of serum haemagglutination-inhibiting antibody in protection against challenge infection with influenza A2 and B viruses. J Hyg Camb 1972;70:767- 777.

Medication Guide

PATIENT INFORMATION

Provide the following information to the vaccine recipient or guardian:
  • Inform of the potential benefits and risks of immunization with FLULAVAL QUADRIVALENT.
  • Educate regarding potential side effects, emphasizing that (1) FLULAVAL QUADRIVALENT contains non-infectious killed viruses and cannot cause influenza, and (2) FLULAVAL QUADRIVALENT is intended to provide protection against illness due to influenza viruses only, and cannot provide protection against all respiratory illness.
  • Encourage women exposed to FLULAVAL QUADRIVALENT during pregnancy to enroll in the pregnancy registry [see Use In Specific Populations].
  • Give the Vaccine Information Statements, which are required by the National Childhood Vaccine Injury Act of 1986 prior to each immunization. These materials are available free of charge at the Centers for Disease Control and Prevention (CDC) website (www.cdc.gov/vaccines).
  • Instruct that annual revaccination is recommended.
FLUARIX, FLULAVAL, HAVRIX, and TIP-LOK are registered trademarks of the GSK group of companies. The other brand listed is a trademark of the respective owner and is not a trademark of the GSK group of companies. The maker of this brand is not affiliated with and does not endorse the GSK group of companies or its products.


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