Vaccine Information: Flublok Quadrivalent Northern Hemisphere

FLUBLOK QUADRIVALENT NORTHERN HEMISPHERE- influenza a virus a/wisconsin/588/2019 (h1n1) recombinant hemagglutinin antigen, influenza a virus a/darwin/6/2021 (h3n2) recombinant hemagglutinin antigen, influenza b virus b/austria/1359417/2021 recombinant hemagglutinin antigen and influenza b virus b/phuket/3073/2013 recombinant hemagglutinin antigen injection
Sanofi Pasteur Inc.

1 INDICATIONS AND USAGE

Flublok Quadrivalent is a vaccine indicated for active immunization against disease caused by influenza A subtype viruses and type B viruses contained in the vaccine. Flublok Quadrivalent is approved for use in persons 18 years of age and older [see Clinical Studies (14)].

2 DOSAGE AND ADMINISTRATION

For intramuscular injection only.

2.1 Dosage

Administer Flublok Quadrivalent as a single 0.5 mL dose.

2.2 Administration

Invert the prefilled syringe containing Flublok Quadrivalent gently prior to affixing the appropriate size needle for intramuscular 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.

The preferred site for injection is the deltoid muscle. Flublok Quadrivalent should not be mixed in the same syringe with any other vaccine.

3 DOSAGE FORMS AND STRENGTHS

Flublok Quadrivalent is a sterile solution supplied in prefilled, single-dose syringes, 0.5 mL.

4 CONTRAINDICATIONS

Flublok Quadrivalent is contraindicated in individuals with known severe allergic reactions (e.g., anaphylaxis) to any component of the vaccine [see Postmarketing Experience (6.2) and Description (11)].

5 WARNINGS AND PRECAUTIONS

5.1 Managing Allergic Reactions

Appropriate medical treatment and supervision must be available to manage possible anaphylactic reactions following administration of the vaccine.

5.2 Guillain Barré Syndrome

The 1976 swine influenza vaccine was associated with an increased frequency of Guillain Barré Syndrome (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 per 1 million persons vaccinated. If GBS has occurred within 6 weeks of receipt of a prior influenza vaccine, the decision to give Flublok should be based on careful consideration of the potential benefits and risks.

5.3 Altered Immunocompetence

If Flublok Quadrivalent is administered to immunocompromised individuals, including persons receiving immunosuppressive therapy, the immune response may be diminished.

5.4 Limitations of Vaccine Effectiveness

Vaccination with Flublok Quadrivalent may not protect all vaccine recipients.

6 ADVERSE REACTIONS

In adults 18 through 49 years of age, the most common (≥10%) injection-site reactions were tenderness (48%) and pain (37%); the most common (≥10%) solicited systemic adverse reactions were headache (20%), fatigue (17%), myalgia (13%), and arthralgia (10%) [see Clinical Trials Experience (6.1)].

In adults 50 years of age and older, the most common (≥10%) injection site reactions were tenderness (34%) and pain (19%); the most common (≥10%) solicited systemic adverse reactions were headache (13%) and fatigue (12%) [see Clinical Trials Experience (6.1)].

6.1 Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a vaccine cannot be directly compared to rates in the clinical studies of another vaccine and may not reflect the rates observed in clinical practice.

Flublok Quadrivalent

Flublok Quadrivalent has been administered to and safety data collected from 998 adults 18-49 years of age (Study 1) and 4328 adults 50 years of age and older (Study 2).

In Studies 1 and 2, local (injection site) and systemic adverse reactions were solicited with the use of a memory aid for 7 days following vaccination, unsolicited adverse events were collected for ~28 days post-vaccination, and serious adverse events (SAEs) were collected for 6 months post-vaccination via clinic visit or remote contact.

Study 1 included 1330 subjects 18 through 49 years of age for safety analysis, randomized to receive Flublok Quadrivalent (n=998) or a comparator inactivated influenza vaccine (Fluarix^® Quadrivalent, manufactured by GlaxoSmithKline) (n=332) [see Clinical Studies (14)]. The mean age of participants was 33.5 years. Overall, 65% of subjects were female, 59% white/Caucasian, 37% black/African American, 1.0% Native Hawaiian/Pacific Islander, 0.8% American Indian/Alaskan Native, 0.5% Asian, 1.4% other racial groups, and 16% of Hispanic/Latino ethnicity. Table 1 summarizes the incidence of solicited local and systemic adverse reactions reported within seven days of vaccination with Flublok Quadrivalent or the comparator vaccine.

Table 1: Frequency of Solicited Local Injection Site Reactions and Systemic Adverse Reactions within 7 Days of Administration of Flublok Quadrivalent or Comparator * in Adults 18-49 Years of Age, Study 1 (Reactogenicity Populations)*^, †

ReactogenicityTerm	Flublok QuadrivalentN=996%			ComparatorN=332%
	Any Grade ‡	Grade 3	Grade 4	Any Grade ‡	Grade 3	Grade 4
NOTE: Data based on the most severe response reported by subjects. Results ≥1% reported to nearest whole percent; results >0 but <1% reported as <1%.
* Comparator = U.S.-licensed comparator quadrivalent inactivated influenza vaccine manufactured by GlaxoSmithKline. † Study 1 is registered as NCT02290509 under the National Clinical Trials registry. ‡ Denominators for fever: Flublok Quadrivalent n = 990, Comparator n = 327. § Reactogenicity Populations were defined as all randomized subjects who received study vaccine according to the treatment actually received and who had at least one non-missing data point for injection site, systemic or body temperature reactogenicity categories. For local pain, tenderness and systemic reactions: Grade 1 = No interference with activities. Grade 2 = Prevented some activities, and headache may have required non-narcotic pain reliever. Grade 3 = Prevented most or all normal activities or required prescription medications. Grade 4 = Required visit to ER or hospitalization. For injection site redness and firmness/swelling: Grade 1=25 to ≤50 mm (small). Grade 2=51 to ≤100 mm (medium). Grade 3=>100 mm (large). Grade 4=necrosis or exfoliative dermatitis. ¶ Denominators for injection site reactions: Flublok Quadrivalent n = 996, Comparator n =332. # Denominators for systemic reactions: Flublok Quadrivalent n = 994, Comparator n = 332. Þ Fever defined as ≥100.4°F (38°C). Grade 1 (≥100.4°F to ≤101.1°F); Grade 2 (101.2°F to ≤102.0°F); Grade 3 (102.1°F to ≤104°F). Grade 4 >104°F.
Subjects with ≥1 injection site reaction §, ¶	51	1	0	52	2	0
Local Tenderness	48	1	0	47	1	0
Local Pain	37	1	0	36	1	0
Firmness / Swelling	5	0	0	3	0	0
Redness	4	0	0	1	0	0
Subjects with ≥1 systemic reaction §, #	34	2	<1	36	3	<1
Headache	20	1	0	21	2	<1
Fatigue	17	1	0	17	1	0
Muscle Pain	13	1	0	12	1	0
Joint Pain	10	1	0	10	1	0
Nausea	9	1	<1	9	1	0
Shivering / Chills	7	1	0	6	1	0
Fever ‡, Þ	2	<1	0	1	<1	0

Study 2 included 8672 subjects 50 years of age and older for safety analysis, randomized to receive Flublok Quadrivalent (n=4328) or Comparator (Fluarix Quadrivalent, manufactured by GlaxoSmithKline) as an active control (n=4344) [see Clinical Studies (14)]. The mean age of participants was 62.7 years. Overall, 58% of subjects were female, 80% white/Caucasian, 18% black/African American, 0.9% American Indian/Alaskan Native, 0.4% Asian, 0.2% Native Hawaiian/Pacific Islander, 0.7% other racial groups, and 5% of Hispanic/Latino ethnicity. Table 2 summarizes the incidence of solicited local and systemic adverse reactions reported within seven days of vaccination with Flublok Quadrivalent or Comparator.

Table 2: Frequency of Solicited Local Injection Site Reactions and Systemic Adverse Reactions within 7 Days of Administration of Flublok Quadrivalent or Comparator * in Adults 50 Years of Age and Older, Study 2 (Reactogenicity Populations)†^, ‡

Reactogenicity Term	Flublok QuadrivalentN=4312%			ComparatorN=4327%
	Any Grade	Grade 3	Grade 4	Any Grade	Grade 3	Grade 4
NOTE: Data based on the most severe response reported by subjects. Results ≥1% reported to nearest whole percent; results >0 but <1% reported as <1%.
* Comparator = U.S.-licensed comparator quadrivalent inactivated influenza vaccine, Fluarix Quadrivalent, manufactured by GlaxoSmithKline. † Study 2 is registered as NCT02285998 under the National Clinical Trials registry. ‡ Reactogenicity Populations were defined as all randomized subjects who received study vaccine according to the treatment actually received and who had at least one non-missing data point for injection site, systemic or body temperature reactogenicity categories. For local pain, tenderness, and systemic reactions: Grade 1=No interference with activity. Grade 2=Some interference with activity. Grade 3=Prevents daily activity. Grade 4=Required ER visit or hospitalization. For injection site redness and firmness/swelling: Grade 1=25 to ≤50 mm (small). Grade 2=51 to ≤100 mm (medium). Grade 3=>100 mm (large). Grade 4=necrosis or exfoliative dermatitis. § Denominators for injection site reactions: Flublok Quadrivalent n = 4307, Comparator n = 4319. ¶ Denominators for systemic reactions: Flublok Quadrivalent n = 4306, Comparator n = 4318. # Denominators for fever: Flublok Quadrivalent n = 4262, Comparator n = 4282. Þ Fever defined as ≥100.4°F (38°C). Grade 1 (≥100.4°F to ≤101.1°F); Grade 2 (101.2°F to ≤102.0°F); Grade 3 (102.1°F to ≤104°F). Grade 4 >104°F.
Subjects with ≥1 injection site reaction ‡, §	38	<1	<1	40	<1	<1
Local Tenderness	34	<1	<1	37	<1	<1
Local Pain	19	<1	0	22	<1	<1
Firmness / Swelling	3	<1	0	3	<1	0
Redness	3	<1	0	2	<1	0
Subjects with ≥1 systemic reactogenicity event ‡, ¶	25	1	<1	26	1	<1
Headache	13	<1	<1	14	1	<1
Fatigue	12	<1	0	12	<1	<1
Muscle Pain	9	<1	<1	9	<1	<1
Joint Pain	8	<1	0	8	<1	<1
Nausea	5	<1	0	5	<1	<1
Shivering / Chills	5	<1	0	4	<1	<1
Fever #, Þ	<1	<1	0	1	<1	0

Among adults 18-49 years of age (Study 1), through 6 months post-vaccination, no deaths were reported. SAEs were reported by 12 subjects, 10 (1%) Flublok Quadrivalent recipients and 2 (0.6%) Comparator recipients. No SAEs were considered related to study vaccine.

Among adults 50 years of age and older (Study 2), 20 deaths occurred in the 6 months post-vaccination, including 8 Flublok Quadrivalent and 12 Comparator recipients. No deaths were considered related to study vaccine. SAEs were reported by 145 (3.4%) Flublok Quadrivalent recipients and 132 (3%) Comparator recipients. No SAEs were considered related to study vaccine.

In the 28 days following vaccination, one or more unsolicited treatment emergent adverse events occurred in 10.3% of Flublok Quadrivalent and 10.5% of Comparator recipients in Study 1 (adults 18-49 years of age) and in 13.9% of Flublok Quadrivalent and 14.1% of Comparator recipients in Study 2 (adults ≥50 years of age). In both studies, rates of individual events were similar between treatment groups, and most events were mild to moderate in severity.

Flublok (Trivalent Formulation)

The safety experience with Flublok is relevant to Flublok Quadrivalent because both vaccines are manufactured using the same process and have overlapping compositions [see Description (11)].

Flublok (trivalent formulation) has been administered to and safety data collected from a total of 4547 subjects in five clinical trials (Studies 3-7): 2497 adults 18 through 49 years, 972 adults 50 through 64 years, and 1078 adults 65 years and older. In Studies 3 — 5 and 7, SAEs were collected for 6 months post-vaccination. Study 6 collected SAEs through 30 days following receipt of vaccine. Study 6 also actively solicited pre-specified common hypersensitivity-type reactions through 30 days following receipt of vaccine as a primary endpoint.

Study 3 included 4648 subjects 18 through 49 years of age for safety analysis, randomized to receive Flublok (n=2344) or placebo (n=2304) [see Clinical Studies (14)].

Study 4 included 602 subjects 50 through 64 years of age for safety analysis, randomized to receive Flublok (n=300) or another U.S.-licensed trivalent influenza vaccine (Fluzone^® , manufactured by Sanofi Pasteur, Inc.) as an active control (n=302).

Study 5 included 869 subjects aged 65 years and older for safety analysis, randomized to receive Flublok (n=436) or another U.S.-licensed trivalent influenza vaccine (Fluzone) as an active control (n=433).

Study 6 included 2627 subjects aged 50 years and older for safety analysis, randomized to receive Flublok (n=1314) or another U.S.-licensed trivalent influenza vaccine (Afluria, manufactured by Seqirus Pty Ltd.) as an active control (n=1313). Among subjects 50 through 64 years of age, 672 received Flublok and 665 received Afluria. Among subjects aged 65 years and older, 642 received Flublok and 648 received Afluria.

Study 7 was a Phase 2 dose-finding trial conducted in adults 18 through 49 years of age, 153 of whom received Flublok 135 mcg, the licensed trivalent formulation.

Serious Adverse Events

Among 2497 adults 18-49 years of age (Studies 3 and 7 pooled), through 6 months post-vaccination, two deaths were reported, one in a Flublok recipient and one in a placebo recipient. Both deaths occurred more than 28 days following vaccination and neither was considered vaccine-related. SAEs were reported by 32 Flublok recipients and 35 placebo recipients. One SAE (pleuropericarditis) in a Flublok recipient was assessed as possibly related to the vaccine.

Among 972 adults 50-64 years of age (Studies 4 and 6 pooled), through up to 6 months post-vaccination, no deaths occurred, and SAEs were reported by 10 subjects, 6 Flublok recipients and 4 Comparator recipients. One of the SAEs, vasovagal syncope following injection of Flublok, was considered related to administration of study vaccine.

Among 1078 adults 65 years of age and older (Studies 5 and 6 pooled), through up to 6 months post-vaccination, 4 deaths occurred, 2 in Flublok recipients and 2 in Comparator recipients. None were considered related to the study vaccines. SAEs were reported by 80 subjects (37 Flublok recipients, 43 Comparator recipients). None were considered related to the study vaccines.

Among 1314 adults 50 years of age and older (Study 7) for whom the incidence of rash, urticaria, swelling, non-pitting edema, or other potential hypersensitivity reactions were actively solicited for 30 days following vaccination, a total of 2.4% of Flublok recipients and 1.6% of Comparator recipients reported such events over the 30 day follow-up period. A total of 1.9% and 0.9% of Flublok and Comparator recipients, respectively, reported these events in the 7 days following vaccination. Of these solicited events, rash was most frequently reported (Flublok 1.3%, Comparator 0.8%) over the 30 day follow-up period.