FLULAVAL 2012/2013- influenza a virus a/california/7/2009 x-179a (h1n1) antigen (uv, formaldehyde inactivated), influenza a virus a/victoria/361/2011 ivr-165 (h3n2) antigen (uv, formaldehyde inactivated) and influenza b virus b/hubei-wujiagang/158/2009 bx-39 antigen (uv, formaldehyde inactivated) suspension
FLULAVAL 2013/2014- influenza a virus a/california/7/2009 x-179a (h1n1) antigen (uv, formaldehyde inactivated), influenza a virus a/texas/50/2012 x-223a (h3n2) antigen (uv, formaldehyde inactivated) and influenza b virus b/massachusetts/2/2012 bx-51b antigen (uv, formaldehyde inactivated) suspension
ID Biomedical Corporation of Quebec
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HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use FLULAVAL safely and effectively. See full prescribing information for FLULAVAL.
FLULAVAL (Influenza Virus Vaccine) Suspension for Intramuscular Injection 2013-2014 Formula Initial U.S. Approval: 2006 INDICATIONS AND USAGE
DOSAGE AND ADMINISTRATIONA single 0.5-mL intramuscular injection. (2.2) DOSAGE FORMS AND STRENGTHSSuspension for injection in 5-mL multi-dose vials containing 10 doses (each dose is 0.5 mL). (3) CONTRAINDICATIONSWARNINGS AND PRECAUTIONS
ADVERSE REACTIONS
To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or VAERS at 1-800-822-7967 or www.vaers.hhs.gov. USE IN SPECIFIC POPULATIONS
See 17 for PATIENT COUNSELING INFORMATION. Revised: 05/2013 |
FLULAVAL® is indicated for active immunization against influenza disease caused by influenza A subtype viruses and type B virus contained in the vaccine [see Description (11)]. FLULAVAL is approved for use in persons 18 years of age and older.
This indication is based on immune response elicited by FLULAVAL, and there have been no controlled trials adequately demonstrating a decrease in influenza disease after vaccination with FLULAVAL [see Clinical Studies (14)].
Shake the multi-dose vial vigorously each time before withdrawing a dose of vaccine. 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.
Use a sterile needle and sterile syringe to withdraw the 0.5‑mL 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. Changing needles between drawing vaccine from a vial and injecting it into a recipient is not necessary unless the needle has been damaged or contaminated. 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 individual.
Do not administer this product intravenously, intradermally, or subcutaneously.
Between uses, return the multi-dose vial to the recommended storage conditions, between 2º and 8ºC (36º and 46ºF). 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.
FLULAVAL is a suspension for injection available in 5-mL multi-dose vials containing 10 doses (each dose is 0.5 mL).
Do not administer FLULAVAL 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 administration of any influenza vaccine [see Description (11)].
If Guillain-Barré syndrome (GBS) has occurred within 6 weeks of receipt of a prior influenza vaccine, the decision to give FLULAVAL should be based on careful consideration of the potential benefits and risks.
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 inconclusive. If influenza vaccine does pose a risk, it is probably slightly more than one additional case/one million persons vaccinated.
Syncope (fainting) can occur in association with administration of injectable vaccines, including FLULAVAL. 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.
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.
If FLULAVAL is administered to immunosuppressed persons, including individuals receiving immunosuppressive therapy, the immune response may be lower than in immunocompetent persons.
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. As with any vaccine, there is the possibility that broad use of FLULAVAL could reveal adverse events not observed in clinical trials.
In the largest clinical trial, the most common (≥10%) solicited injection site reactions were pain (51%), redness (13%), and/or swelling (11%); the most common solicited systemic adverse events were fatigue (20%), headache (18%), and myalgia/arthralgia (18%).
Safety data has been obtained from 3 randomized, controlled trials, one of which was a placebo-controlled efficacy study. In these trials, 9,836 subjects were randomized to receive either FLULAVAL (5,114 subjects in the safety analysis), FLUZONE, a US‑licensed trivalent, inactivated influenza virus vaccine, manufactured by Sanofi Pasteur SA (894 subjects in the safety analysis), or placebo (3,828 subjects in the safety analysis), intramuscularly. In these studies, solicited events were collected for 4 days (i.e., 30 minutes post-vaccination through the next 3 days) using diary cards. Unsolicited adverse events that occurred within 22 days of vaccination (day 0‑21) were recorded based on spontaneous reports or in response to queries about changes in health status.
Study 1 (Immunogenicity): Safety information was collected in a randomized, controlled US study. This study included 1,000 adults 18 to 64 years of age who were randomized to receive FLULAVAL (N = 721) or a US‑licensed trivalent, inactivated influenza virus vaccine (N = 279). Among recipients of FLULAVAL, 57% were female; 91% of subjects were white and 9% were of other racial/ethnic groups. The mean age of subjects was 38 years; 80% were 18 to 49 years of age and 20% were 50 to 64 years of age.
Study 2 (Immunogenicity Non-Inferiority): Safety information was collected in a randomized, double-blind, active-controlled US study. The study included 1,225 adults ≥50 years of age randomized to receive FLULAVAL (N = 610) or a US‑licensed trivalent, inactivated influenza virus vaccine (N = 615). In the total population, 57% were female; 95% of subjects were white and 5% were of other racial/ethnic groups. The mean age of subjects was 66 years (46% were 50 to 64 years of age, 41% were 65 to 79 years of age, and 13% were ≥80 years of age).
Study 3 (Efficacy): Safety information was collected in a double-blind, placebo-controlled US study. The study included 7,658 adults 18 to 49 years of age randomized to receive FLULAVAL (N = 3,807) or placebo (N = 3,851). In the total population, 61% were female; 84% of subjects were white, 10% black, 2% Asian, and 4% were of other racial/ethnic groups. The mean age of subjects was 33 years.
Solicited Adverse Events: Solicited local adverse reactions and systemic adverse events collected for 4 days (day of vaccination and the next 3 days) are presented in Table 1.
Incidence of Subjects Reporting Eventb |
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Study 1c (18 to 64 years of age) |
Study 2c (50 years of age and older) |
Study 3c (18 to 49 years of age) |
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FLULAVAL |
Comparator |
FLULAVAL |
Comparator |
FLULAVAL |
Placebo |
|
N = 721 |
N = 279 |
N = 610 |
N = 615 |
N = 3,783 |
N = 3,828 |
|
Local |
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|
24 |
31 |
25 |
32 |
51 |
14 |
|
11 |
10 |
10 |
11 |
13 |
6 |
|
10 |
10 |
7 |
9 |
11 |
3 |
Systemic |
||||||
|
18 |
17 |
11 |
12 |
18 |
19 |
|
17 |
15 |
12 |
13 |
20 |
18 |
|
13 |
16 |
11 |
10 |
18 |
10 |
|
11 |
10 |
1 |
1 |
3 |
1 |
|
10 |
10 |
6 |
7 |
9 |
6 |
|
9 |
9 |
5 |
6 |
9 |
9 |
|
6 |
5 |
4 |
7 |
7 |
6 |
|
6 |
7 |
5 |
6 |
8 |
7 |
|
5 |
2 |
3 |
6 |
4 |
4 |
|
3 |
1 |
2 |
2 |
3 |
3 |
|
1 |
1 |
1 |
2 |
1 |
1 |
Unsolicited Adverse Events: The incidence of unsolicited adverse events in the 21 days post-vaccination was comparable for FLULAVAL and the active comparator in Study 1 (16% and 15%, respectively) and in Study 2 (18% and 21%, respectively). In Study 3, the incidence of unsolicited adverse events was comparable for the groups (21% for FLULAVAL and 19% for placebo).
Unsolicited adverse events defined as reported with FLULAVAL in >1.0% of subjects are described as follows: Study 1: Cough, headache, and pharyngolaryngeal pain; Study 2: Diarrhea, headache, and nasopharyngitis; and Study 3: Pharyngolaryngeal pain, headache, fatigue, cough, injection site pain, upper respiratory tract infection, musculoskeletal pain, nasopharyngitis, injection site erythema and discomfort.
Serious Adverse Events (SAEs): In Study 1, no SAEs were reported. In Study 2, 3% of subjects receiving FLULAVAL and 3% of subjects receiving the active comparator reported SAEs. In Study 3, 1% of subjects receiving FLULAVAL and 1% of subjects receiving placebo reported SAEs. In the 3 clinical trials, the rates of SAEs were comparable between groups and none of the SAEs were considered related to vaccination.
In addition to reports in clinical trials, the following adverse events have been identified during postapproval use of FLULAVAL. 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 described here are included because: a) they represent reactions which are known to occur following immunizations generally or influenza immunizations specifically; b) they are potentially serious; or c) the frequency of reporting.
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 edema of the mouth, anaphylaxis, allergic edema of the throat.
Infections and Infestations: Rhinitis, laryngitis, cellulitis.
Musculoskeletal and Connective Tissue Disorders: Muscle weakness, arthritis.
Nervous System Disorders: Dizziness, paresthesia, hypoesthesia, hypokinesia, tremor, somnolence, syncope, Guillain-Barré syndrome, convulsions/seizures, facial or cranial nerve paralysis, encephalopathy, limb paralysis.
Psychiatric Disorders: Insomnia.
Respiratory, Thoracic, and Mediastinal Disorders: Dyspnea, dysphonia, bronchospasm, throat tightness.
Skin and Subcutaneous Tissue Disorders: Urticaria, localized or generalized rash, pruritus, sweating.
Vascular Disorders: Flushing, pallor.
Anaphylaxis has been reported after administration of FLULAVAL. Although FLULAVAL contains only a limited quantity of egg protein, this protein can induce immediate hypersensitivity reactions among persons who have severe egg allergy. Allergic reactions include hives, angioedema, allergic asthma, and systemic anaphylaxis [see Contraindications (4)].
Neurological disorders temporally associated with influenza vaccination such as encephalopathy, optic neuritis/neuropathy, partial facial paralysis, and brachial plexus neuropathy have been reported.
Microscopic polyangitis (vasculitis) has been reported temporally associated with influenza vaccination.
FLULAVAL 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 with other vaccines. When concomitant administration of other vaccines is required, the vaccines should be administered at different injection sites.
Pregnancy Category B
A reproductive and developmental toxicity study has been performed in female rats at a dose approximately 56 times the human dose (on a mg/kg basis) and revealed no evidence of impaired female fertility or harm to the fetus due to FLULAVAL. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, FLULAVAL should be given to a pregnant woman only if clearly needed.
In a reproductive and developmental toxicity study, the effect of FLULAVAL on embryo-fetal and pre-weaning development was evaluated in pregnant rats. Animals were administered FLULAVAL by intramuscular injection once prior to gestation, and during the period of organogenesis (gestation days 6, 8, 11, and 15), 0.1 mL/rat/occasion (approximately 56-fold excess relative to the projected human dose on a body weight basis). No adverse effects on mating, female fertility, pregnancy, parturition, lactation parameters, and embryo-fetal or pre-weaning development were observed. There were no vaccine-related fetal malformations or other evidence of teratogenesis.
Pregnancy Registry: GlaxoSmithKline maintains a surveillance registry to collect data on pregnancy outcomes and newborn health status outcomes following vaccination with FLULAVAL during pregnancy. Women who receive FLULAVAL during pregnancy should be encouraged to contact GlaxoSmithKline directly or their healthcare provider should contact GlaxoSmithKline by calling 1-888-452-9622.
It is not known whether FLULAVAL is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when FLULAVAL is administered to a nursing woman.
Safety and effectiveness of FLULAVAL in pediatric patients have not been established.
In clinical trials, there were 330 subjects who were ≥65 years of age and received FLULAVAL; 142 of these subjects were ≥75 years of age. Hemagglutination-inhibiting (HI) antibody responses were lower in geriatric subjects than younger subjects after administration of FLULAVAL. [See Clinical Studies (14.2).] Solicited adverse events were similar in frequency to those reported in younger subjects [see Adverse Reactions (6.1)].
FLULAVAL, Influenza Virus Vaccine, for intramuscular injection, is a trivalent, split-virion, inactivated influenza virus vaccine prepared from virus propagated in the allantoic cavity of embryonated hens’ eggs. Each of the influenza virus strains 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 is a sterile, translucent to whitish opalescent suspension in a phosphate-buffered saline solution that may sediment slightly. The sediment resuspends upon shaking to form a homogeneous suspension. FLULAVAL has been standardized according to USPHS requirements for the 2013‑2014 influenza season and is formulated to contain 45 mcg hemagglutinin (HA) per 0.5-mL dose in the recommended ratio of 15 mcg HA of each of the following 3 strains: A/California/7/2009 NYMC X‑179A (H1N1), A/Texas/50/2012 NYMC X-223A (H3N2) (an A/Victoria/361/2011-like virus), and B/Massachusetts/2/2012 NYMC BX-51B.
Thimerosal, a mercury derivative, is added as a preservative. Each 0.5-mL dose contains 50 mcg thimerosal (<25 mcg mercury). Each 0.5-mL dose may also contain residual amounts of ovalbumin (≤0.3 mcg), formaldehyde (≤25 mcg), and sodium deoxycholate (≤50 mcg) from the manufacturing process. Antibiotics are not used in the manufacture of this vaccine.
The vial stoppers are not made with natural rubber latex.
Influenza illness and its complications follow infection with influenza viruses. Global surveillance of influenza identifies yearly antigenic variants. For example, since 1977, antigenic variants of influenza A (H1N1 and H3N2) viruses and influenza B viruses have been in global circulation. Specific levels of 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. Therefore, inactivated influenza vaccines are standardized to contain the hemagglutinins of strains (i.e., typically 2 type A and 1 type B), representing the influenza viruses likely to circulate in the United States in the upcoming winter.
Annual revaccination with the current vaccine is recommended because immunity declines during the year after vaccination, and because circulating strains of influenza virus change from year to year.3
The efficacy of FLULAVAL was evaluated in a randomized, double-blind, placebo-controlled study conducted in the United States during the 2005-2006 and 2006-2007 influenza seasons (Study 3). Efficacy of FLULAVAL was defined as the prevention of culture-confirmed influenza A and/or B cases, for vaccine antigenically matched strains, compared with placebo. Healthy subjects 18 to 49 years of age were randomized (1:1); a total of 3,783 subjects received FLULAVAL and 3,828 subjects received placebo [see Adverse Reactions (6.1)]. Subjects were monitored for influenza-like illnesses (ILI) starting 2 weeks post-vaccination and for duration of approximately 7 months thereafter. Culture-confirmed influenza was assessed by active and passive surveillance of ILI. Influenza-like illness was defined as illness sufficiently severe to limit daily activity and including cough, and at least one of the following: Fever >99.9°F, nasal congestion or runny nose, sore throat, myalgia or arthralgia, headache, feverishness or chills. After an episode of ILI, nose and throat swab samples were collected for analysis; attack rates and vaccine efficacy were calculated using the per protocol cohort (Table 2).
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CI = Confidence Interval.
Study 1 (Immunogenicity): In a randomized, active-controlled trial of FLULAVAL, immune responses, specifically HI antibody titers to each virus strain in the vaccine, were evaluated in sera obtained 21 days after administration of FLULAVAL.
A 1,000-subject randomized, blinded, and controlled US study was performed in 18- to 64-year-old healthy adults. A total of 721 subjects received FLULAVAL, and 279 received a US‑licensed trivalent, inactivated influenza virus vaccine, FLUZONE (manufactured by Sanofi Pasteur SA), intramuscularly; 959 subjects had complete serological data and no major protocol deviations [see Adverse Reactions (6.1)].
Analyses of immunogenicity (Table 3) were performed for each hemagglutinin (HA) antigen contained in the vaccine: 1) assessment of the lower bounds of 2‑sided 95% confidence intervals for the proportion of subjects with HI antibody titers of ≥1:40 after vaccination, and 2) assessment of the lower bounds of 2-sided 95% confidence intervals for rates of seroconversion (defined as a 4‑fold increase in post-vaccination HI antibody titer from pre-vaccination titer ≥1:10, or an increase in titer from <1:10 to ≥1:40). The pre-specified success criteria for HI titer ≥1:40 was 70% and for seroconversion rate was 40%. The lower limit of the 2-sided 95% CI for the percentage of subjects who achieved an HI titer of ≥1:40 exceeded the pre-defined criteria for the A strains. The lower limit of the 2-sided 95% CI for the percentage of subjects who achieved seroconversion exceeded the pre-defined criteria for all 3 strains.
FLULAVAL N = 692 % of Subjects (95% CI) |
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|
Pre‑vaccination |
Post‑vaccination |
|
24.6 |
96.5 (94.9, 97.8) |
|
58.7 |
98.7 (97.6, 99.4) |
|
5.4 |
62.9 (59.1, 66.5) |
| ||
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85.6 (82.7, 88.1) |
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79.3 (76.1, 82.3) |
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58.4 (54.6, 62.1) |
CI = Confidence Interval.
Study 2 (Immunogenicity Non-Inferiority): In a randomized, double-blind, active-controlled US study, immunological non-inferiority of FLULAVAL was compared with a US‑licensed trivalent, inactivated influenza virus vaccine, FLUZONE, manufactured by Sanofi Pasteur SA. A total of 1,225 adults ≥50 years of age in stable health were randomized to receive FLULAVAL or the comparator vaccine intramuscularly [see Adverse Reactions (6.1)]. Immune responses, specifically HI antibody titers to each virus strain in the vaccine, were evaluated in sera obtained 21 days after administration of FLULAVAL or the comparator vaccine.
Analyses of immunogenicity were performed for each HA antigen contained in the vaccines: 1) assessment of the lower bounds of 2‑sided 95% confidence intervals for the geometric mean antibody titer (GMT) ratio (FLULAVAL/comparator), and 2) assessment of the lower bounds of 2‑sided 95% confidence intervals for seroconversion rates (defined as a 4‑fold increase in post-vaccination HI antibody titer from pre-vaccination titer ≥1:10, or an increase in titer from <1:10 to ≥1:40). Non-inferiority of FLULAVAL to the comparator vaccine was established for all 6 co-primary endpoints (Table 4). Within each age stratum, immunogenicity results were similar between the groups.
Table 4. Serum Hemagglutination-Inhibiting (HI) Antibody Responses to FLULAVAL Versus Comparator Influenza Vaccinea (Per Protocol Cohortb)
FLULAVAL N = 592 |
Active Comparatorc N = 595 | ||
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GMT |
GMT |
GMT Ratiod |
(95% CI) |
(95% CI) |
(95% CI) |
|
|
113.4 |
110.2 |
1.03 |
(104.7, 122.8) |
(101.8, 119.3) |
(0.92, 1.15) |
|
|
223.9 |
214.6 |
1.04 |
(199.5, 251.3) |
(191.3, 240.7) |
(0.89, 1.23) |
|
|
82.3 |
97.1 |
0.85 |
(74.7, 90.6) |
(88.2, 106.8) |
(0.74, 0.97) |
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|
% of Subjects (95% CI) |
% of Subjects (95% CI) |
Difference in SeroconversionRatesf (95% CI) |
|
34 |
32 |
2 |
(30.0, 37.6) |
(28.3, 35.9) |
(-3.7, 7.0) |
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|
83 |
82 |
1 |
(80.3, 86.3) |
(78.4, 84.6) |
(-2.6, 6.1) |
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|
53 |
56 |
-3 |
(49.0, 57.1) |
(51.6, 59.6) |
(-8.3, 3.1) |
CI = Confidence Interval; GMT = geometric mean antibody titer.
FLULAVAL is supplied in a 5-mL multi-dose vial containing ten 0.5-mL doses. Once entered, the multi-dose vial should be discarded after 28 days.
NDC 19515-890-02 Vial (containing 10 doses) in Package of 1: NDC 19515-890-07
Store refrigerated between 2º and 8ºC (36º and 46ºF). Do not freeze. Discard if the vaccine has been frozen. Store in the original package to protect from light.
Provide the following information to the vaccine recipient or guardian:
FLULAVAL is a registered trademark of ID Biomedical Corporation of Quebec. FLUZONE is a registered trademark of Sanofi Pasteur Limited.
Manufactured by ID Biomedical Corporation of Quebec
Quebec City, QC, Canada, US License 1739
Distributed by GlaxoSmithKline
Research Triangle Park, NC 27709
©2013, GlaxoSmithKline. All rights reserved.
FLV:11PI
FLULAVAL
2012/2013
influenza virus vaccine suspension |
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FLULAVAL
2013/2014
influenza virus vaccine suspension |
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Labeler - ID Biomedical Corporation of Quebec (243368284) |