Vaccine Information: Shingrix

SHINGRIX- zoster vaccine recombinant, adjuvanted
GlaxoSmithKline Biologicals SA

1 INDICATIONS AND USAGE

SHINGRIX is a vaccine indicated for prevention of herpes zoster (HZ) (shingles):

• in adults aged 50 years and older.

• in adults aged 18 years and older who are or will be at increased risk of HZ due to immunodeficiency or immunosuppression caused by known disease or therapy.

Limitations of Use:

SHINGRIX is not indicated for prevention of primary varicella infection (chickenpox).

2 DOSAGE AND ADMINISTRATION

For intramuscular injection only.

2.1 Reconstitution

SHINGRIX is supplied in 2 vials that must be combined prior to administration. Prepare SHINGRIX by reconstituting the lyophilized varicella zoster virus glycoprotein E (gE) antigen component (powder) with the accompanying AS01B adjuvant suspension component (liquid). Use only the supplied adjuvant suspension component (liquid) for reconstitution. The reconstituted vaccine should be an opalescent, colorless to pale brownish liquid. 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.

Figure 1
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Figure 2bFigure 3
Figure 4
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Figure 1. Cleanse both vial stoppers. Using a sterile needle and sterile syringe, withdraw the entire contents of the vial containing the adjuvant suspension component (liquid) by slightly tilting the vial. Vial 1 of 2.

Figure 2. Slowly transfer entire contents of syringe into the lyophilized gE antigen component vial (powder). Vial 2 of 2.

Figure 3. Gently swirl the vial until powder is completely dissolved. Do not shake vigorously.

Figure 4. After reconstitution, withdraw 0.5 mL from the vial containing the reconstituted vaccine and administer intramuscularly.

2.2 Administration Instructions

For intramuscular injection only.

After reconstitution, administer SHINGRIX immediately or store refrigerated between 2° and 8°C (36° and 46°F) and use within 6 hours. Discard reconstituted vaccine if not used within 6 hours.

Use a separate sterile needle and sterile syringe for each individual. The preferred site for intramuscular injection is the deltoid region of the upper arm.

2.3 Dose and Schedule

Two doses (0.5 mL each) administered intramuscularly according to the following schedules:

• A first dose at Month 0 followed by a second dose administered 2 to 6 months later.

• For individuals who are or will be immunodeficient or immunosuppressed and who would benefit from a shorter vaccination schedule: A first dose at Month 0 followed by a second dose administered 1 to 2 months later.

3 DOSAGE FORMS AND STRENGTHS

SHINGRIX is a suspension for injection supplied as a single-dose vial of lyophilized gE antigen component to be reconstituted with the accompanying vial of AS01B adjuvant suspension component. A single dose after reconstitution is 0.5 mL.

4 CONTRAINDICATIONS

Do not administer SHINGRIX to anyone with a history of a severe allergic reaction (e.g., anaphylaxis) to any component of the vaccine or after a previous dose of SHINGRIX [see Description (11)].

5 WARNINGS AND PRECAUTIONS

5.1 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 SHINGRIX.

5.2 Guillain-Barré Syndrome (GBS)

In a postmarketing observational study, an increased risk of GBS was observed during the 42 days following vaccination with SHINGRIX [see Adverse Reactions (6.2)].

5.3 Syncope

Syncope (fainting) can be associated with the administration of injectable vaccines, including SHINGRIX. 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.

6 ADVERSE REACTIONS

6.1 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 SHINGRIX could reveal adverse reactions not observed in clinical trials.

Adults Aged 50 Years and Older

Overall, 17,041 adults aged 50 years and older received at least 1 dose of SHINGRIX in 17 clinical studies.

The safety of SHINGRIX was evaluated by pooling data from 2 placebo-controlled clinical studies (Studies 1 and 2) involving 29,305 subjects aged 50 years and older who received at least 1 dose of SHINGRIX (n = 14,645) or saline placebo (n = 14,660) administered according to a 0- and 2-month schedule. At the time of vaccination, the mean age of the population was 69 years; 7,286 (25%) subjects were aged 50 to 59 years, 4,488 (15%) subjects were aged 60 to 69 years, and 17,531 (60%) subjects were aged 70 years and older. Both studies were conducted in North America, Latin America, Europe, Asia, and Australia. In the overall population, the majority of subjects were White (74%), followed by Asian (18%), Black (1.4%), and other racial/ethnic groups (6%); 58% were female.

Solicited Adverse Reactions: In Studies 1 and 2, data on solicited local and general adverse reactions were collected using standardized diary cards for 7 days following each vaccine dose or placebo (i.e., day of vaccination and the next 6 days) in a subset of subjects (n = 4,886 receiving SHINGRIX, n = 4,881 receiving placebo with at least 1 documented dose). Across both studies, the percentages of subjects aged 50 years and older reporting each solicited local and general adverse reaction following administration of SHINGRIX (both doses combined) were pain (78%), redness (38%), and swelling (26%); and myalgia (45%), fatigue (45%), headache (38%), shivering (27%), fever (21%), and gastrointestinal symptoms (17%).

The reported frequencies of specific solicited local adverse reactions and general adverse reactions (overall per subject), by age group, from the 2 studies are presented in Table 1.

Table 1. Percentage of Subjects with Solicited Local and General Adverse Reactions within 7 Daysa of Vaccination in Adults Aged 50 to 59 Years, 60 to 69 Years, and 70 Years and Olderb (Total Vaccinated Cohort with 7-Day Diary Card)
Total vaccinated cohort for safety included all subjects with at least 1 documented dose (n).a 7 days included day of vaccination and the subsequent 6 days.b Data for subjects aged 50 to 59 years and 60 to 69 years are based on Study 1. Data for subjects 70 years and older are based on pooled data from Study 1: NCT01165177 and Study 2: NCT01165229.c Placebo was a saline solution.d Grade 3 pain: Defined as significant pain at rest; prevents normal everyday activities.e Grade 3 myalgia, fatigue, headache, shivering, and GI: Defined as preventing normal activity.f Fever defined as ≥37.5°C/99.5°F for oral, axillary, or tympanic route, or ≥38°C/100.4°F for rectal route; Grade 3 fever defined as >39.0°C/102.2°F.g GI = Gastrointestinal symptoms including nausea, vomiting, diarrhea, and/or abdominal pain.

Adverse Reactions

Aged 50-59 Years

Aged 60-69 Years

Aged ≥70 Years

SHINGRIX

Placebo c

SHINGRIX

Placebo c

SHINGRIX

Placebo c

Local Adverse Reactions

n = 1,315

%

n = 1,312

%

n = 1,311

%

n = 1,305

%

n = 2,258

%

n = 2,263

%

Pain

88

14

83

11

69

9

Pain, Grade 3d

10

1

7

1

4

0.2

Redness

39

1

38

2

38

1

Redness, >100 mm

3

0

3

0

3

0

Swelling

31

1

27

1

23

1

Swelling, >100 mm

1

0

1

0

1

0

General Adverse Reactions

n = 1,315

%

n = 1,312

%

n = 1,309

%

n = 1,305

%

n =2,252

%

n = 2,264

%

Myalgia

57

15

49

11

35

10

Myalgia, Grade 3e

9

1

5

1

3

0.4

Fatigue

57

20

46

17

37

14

Fatigue, Grade 3e

9

2

5

1

4

1

Headache

51

22

40

16

29

12

Headache, Grade 3e

6

2

4

0.2

2

0.4

Shivering

36

7

30

6

20

5

Shivering, Grade 3e

7

0.2

5

0.3

2

0.3

Fever

28

3

24

3

14

3

Fever, Grade 3f

0.4

0.2

1

0.2

0.1

0.1

GIg

24

11

17

9

14

8

GI, Grade 3e

2

1

1

1

1

0.4

The incidence of solicited local and general reactions was lower in subjects aged 70 years and older compared with those aged 50 to 69 years.

The local and general adverse reactions seen with SHINGRIX had a median duration of 2 to 3 days.

There were no differences in the proportions of subjects reporting any or Grade 3 solicited local reactions between Dose 1 and Dose 2. Headache and shivering were reported more frequently by subjects after Dose 2 (28% and 21%, respectively) compared with Dose 1 (24% and 14%, respectively). Grade 3 solicited general adverse reactions (headache, shivering, myalgia, and fatigue) were reported more frequently by subjects after Dose 2 (2.3%, 3%, 4%, and 4%, respectively) compared with Dose 1 (1.4%, 1.4%, 2.3%, and 2.4%, respectively).

Unsolicited Adverse Events: Unsolicited adverse events that occurred within 30 days following each vaccination (Day 0 to 29) were recorded on a diary card by all subjects. In the 2 studies, unsolicited adverse events occurring within 30 days of vaccination were reported in 51% and 32% of subjects who received SHINGRIX (n = 14,645) or placebo (n = 14,660), respectively (Total Vaccinated Cohort). Unsolicited adverse events that occurred in ≥1% of recipients of SHINGRIX and at a rate at least 1.5-fold higher than placebo included chills (4% versus 0.2%), injection site pruritus (2.2% versus 0.2%), malaise (1.7% versus 0.3%), arthralgia (1.7% versus 1.2%), nausea (1.4% versus 0.5%), and dizziness (1.2% versus 0.8%).

Gout (including gouty arthritis) was reported by 0.18% (n = 27) versus 0.05% (n = 8) of subjects who received SHINGRIX or placebo, respectively, within 30 days of vaccination; available information is insufficient to determine a causal relationship with SHINGRIX.

Serious Adverse Events (SAEs): In the 2 studies, SAEs were reported at similar rates in subjects who received SHINGRIX (2.3%) or placebo (2.2%) from the first administered dose up to 30 days post-last vaccination. SAEs were reported for 10.1% of subjects who received SHINGRIX and for 10.4% of subjects who received placebo from the first administered dose up to 1 year post-last vaccination. One subject (<0.01%) reported lymphadenitis and 1 subject (<0.01%) reported fever greater than 39°C; there was a basis for a causal relationship with SHINGRIX.

Optic ischemic neuropathy was reported in 3 subjects (0.02%) who received SHINGRIX (all within 50 days after vaccination) and 0 subjects who received placebo; available information is insufficient to determine a causal relationship with SHINGRIX.

Deaths: From the first administered dose up to 30 days post-last vaccination, deaths were reported for 0.04% of subjects who received SHINGRIX and 0.05% of subjects who received placebo in the 2 studies. From the first administered dose up to 1 year post-last vaccination, deaths were reported for 0.8% of subjects who received SHINGRIX and for 0.9% of subjects who received placebo. Causes of death among subjects were consistent with those generally reported in adult and elderly populations.

Potential Immune-Mediated Diseases: In the 2 studies, new onset potential immune-mediated diseases (pIMDs) or exacerbation of existing pIMDs were reported for 0.6% of subjects who received SHINGRIX and 0.7% of subjects who received placebo from the first administered dose up to 1 year post-last vaccination. The most frequently reported pIMDs occurred with comparable frequencies in the group receiving SHINGRIX and the placebo group.

Dosing Schedule: In an open-label clinical study, 238 subjects 50 years and older received SHINGRIX as a 0- and 2-month or 0- and 6-month schedule. The safety profile of SHINGRIX was similar when administered according to a 0- and 2-month or 0- and 6-month schedule and was consistent with that observed in Studies 1 and 2.

Immunocompromised Adults Aged 18 Years and Older

The safety of SHINGRIX was evaluated in 6 placebo-controlled clinical studies that enrolled 3,116 subjects aged 18 years and older from 5 different immunodeficient or immunosuppressed (referred to as immunocompromised) populations, in which a total of 1,587 received SHINGRIX. In all studies, subjects received Doses 1 and 2 of SHINGRIX 1 to 2 months apart. Safety monitoring for these studies was similar to Studies 1 and 2. In addition, subjects were monitored for events relevant to their specific disease or condition.

At the time of receipt of SHINGRIX or placebo, the mean age of the population was 55 years; 28% subjects were aged 18 to 49 years and 72% subjects were aged 50 years and older. Each of the studies was conducted in one or more of the following regions: North America, Latin America, Europe, Asia, Africa and Australia/New Zealand. The majority of subjects were White (77%), followed by Asian (17%), Black (2%), and other racial groups (3%); 4% were of American Hispanic or Latino ethnicity; 37% were female.

Table 2. Clinical Studies with SHINGRIX in Immunocompromised Adults Aged ≥18 Years
a The first dose was administered within 50 to 70 days after autologous hematopoietic stem cell transplantation.b Safety follow-up was driven by HZ case accrual and ranged from a minimum of 12 months post last vaccination to 4 years at subject level.c For subjects who were vaccinated during a cancer therapy course, each dose was administered with at least 10 days between vaccination and cancer therapy cycles.d For subjects who received the vaccination after a full cancer therapy course, the first dose was administered from 10 days to 6 months after cancer therapy had ended.e The first dose was administered between 4 to 18 months after renal transplantation.f In the PreChemo group (TVC: SHINGRIX [n = 90], placebo [n = 91]), the first dose was administered a maximum of 1 month to a minimum of 10 days before the start of a chemotherapy cycle, and the second dose was administered on the first day of a chemotherapy cycle.g In the OnChemo group (TVC: SHINGRIX [n = 27], placebo [n = 24]), each dose was administered on the first day of a chemotherapy cycle.

Clinical Studies

Number of Subjects Vaccinated

Study Population

Safety Follow-up Period

SHINGRIX

Placebo

auHSCT (NCT01610414)

922

924

Autologous hematopoietic stem cell transplant recipientsa

29 months median safety follow-upb

Hematologic Malignancies (NCT01767467)

283

279

Hematologic malignanciesc,d

12 months post last vaccination

Renal Transplant

(NCT02058589)

132

132

Renal transplant recipientse

12 months post last vaccination

Solid MalignantTumors (NCT01798056)

117

115

Solid tumors receiving chemotherapyf,g

12 months post last vaccination

HIV (NCT01165203)

74

49

HIV-infected subjects

12 months post last vaccination

auHSCT (NCT00920218)

59

30

Autologous hematopoietic stem cell transplant recipientsa

12 months post last vaccination

In the auHSCT study (NCT01610414), at the time of receipt of SHINGRIX or placebo, the mean age of the population was 55 years; 25% of subjects were aged 18 to 49 years and 75% subjects were aged 50 years and older. The majority of subjects were White (78%), followed by Asian (16%), Black (2%), and other racial groups (3%); 3% were of American Hispanic or Latino ethnicity; 37% were female.

Solicited Adverse Reactions: Solicited local adverse reactions reported within 7 days following administration of SHINGRIX (both doses combined) in auHSCT recipients (aged 18 to 49 and ≥50 years of age) were pain (88% and 83%), redness (30% and 35%), and swelling (21% and 18%). Solicited general adverse reactions reported within 7 days following administration of SHINGRIX (both doses combined) in auHSCT recipients (aged 18 to 49 and ≥50 years of age) were fatigue (64% and 54%), myalgia (58% and 52%), headache (44% and 30%), gastrointestinal symptoms (21% and 28%), shivering (31% and 25%), and fever (28% and 18%). The percentages of subjects aged 18 years and older reporting each solicited local and general adverse reaction following administration of each dose of SHINGRIX or placebo in the auHSCT study (NCT01610414) are presented in Table 3.

Table 3. Adult auHSCT Recipients (NCT01610414): Percentage of Subjects with Solicited Local and General Adverse Reactions within 7 Daysa of Vaccination in Adults Aged 18 to 49 Years and 50 Years and Older by Dose (Total Vaccinated Cohort)
Total vaccinated cohort (TVC) for safety included all subjects with at least 1 documented dose (n).% = Percentage of subjects reporting the symptom at least once.a 7 days included day of vaccination and the subsequent 6 days.b Placebo was sucrose reconstituted with saline solution.c Grade 3 pain: defined as significant pain at rest preventing normal everyday activities.d Grade 3 myalgia, fatigue, headache, shivering, and GI: defined as preventing normal activity.e GI = Gastrointestinal symptoms including nausea, vomiting, diarrhea, and/or abdominal pain.

Adverse Reactions

Aged 18-49 Years

Aged ≥50 Years

SHINGRIX

Placebob

SHINGRIX

Placebob

Dose 1

Dose 2

Dose 1

Dose 2

Dose 1

Dose 2

Dose 1

Dose 2

Local Adverse Reactions

n = 223%

n = 205%

n = 217%

n = 207%

n = 673%

n = 635%

n = 673%

n = 627%

Pain

81

82

8

6

75

74

6

5

Pain, Grade 3c

11

11

1

0

5

7

0.3

0

Redness

20

25

0

0

21

28

1

1

Redness, >100 mm

1

2

0

0

1

3

0

0

Swelling

14

17

0

0

10

15

1

1

Swelling, >100 mm

0

2

0

0

0.1

1

0

0

General Adverse Reactions

n = 222 %

n = 203

%

n = 218 %

n = 207 %

n = 674 %

n = 633 %

n = 674 %

n = 628 %

Myalgia

41

51

22

21

37

43

18

17

Myalgia, Grade 3d

4

8

2

2

2

4

1

1

Fatigue

49

51

34

25

37

46

31

26

Fatigue, Grade 3d

6

10

1

2

3

4

2

3

Headache

23

38

17

17

15

25

13

8

Headache, Grade 3d

1

5

0

2

0.1

2

0.4

1

Shivering

20

26

12

6

11

21

7

7

Shivering, Grade 3d

1

6

0

0

0.4

3

1

0.2

Fever, ≥37.5°C/99.5°F

9

28

4

2

6

15

3

4

Fever, Grade 3 >39.5°C/103.1°F

0

1

0

0

0.1

0.2

0

0.2

GIe

14

13

13

12

18

18

16

12

GI, Grade 3d

1

1

0

1

1

2

1

2

In general, the reported frequencies of solicited local and general adverse reactions in the other studies in immunocompromised populations were similar to that in the auHSCT study (NCT01610414). The local and general adverse reactions seen with SHINGRIX had a median duration of 1 to 3 days across all studies enrolling immunocompromised subjects.

Unsolicited Adverse Events: Across all 6 studies enrolling immunocompromised subjects, unsolicited adverse events, including both serious and non-serious events, occurring within 30 days following each vaccination were reported in 46% and 44% of subjects who received SHINGRIX or placebo. Adverse events of arthralgia, infective pneumonia, and influenza-like illness occurred in ≥1% of recipients of SHINGRIX and at a rate at least 1.5-fold higher than placebo (1.5% versus 1.0%, 1.5% versus 0.9%, and 1.3% versus 0.6%, respectively).

Serious Adverse Events: Across all 6 studies enrolling immunocompromised subjects, SAEs were reported at similar rates in subjects who received SHINGRIX (7%) or placebo (8%) from the first administered dose up to 30 days post-last vaccination. SAEs were reported for 26% of subjects who received SHINGRIX and for 27% of subjects who received placebo from the first administered dose up to 1 year post-last vaccination. SAEs of infective pneumonia were reported for 21 subjects (1.3%) who received SHINGRIX and for 11 subjects (0.7%) who received placebo up to 30 days post-last vaccination. Available information is insufficient to determine a causal relationship to vaccination.

Deaths: Across all 6 studies enrolling immunocompromised subjects, from the first administered dose up to 30 days post-last vaccination, deaths were reported for 2 subjects (0.1%) who received SHINGRIX and 7 subjects (0.5%) who received placebo. From the first administered dose up to 1 year post-last vaccination, deaths were reported for 6% of subjects who received SHINGRIX and for 6% of subjects who received placebo. Causes of death among subjects were consistent with those expected in the populations evaluated.

Potential Immune-Mediated Diseases: Across all 6 studies enrolling immunocompromised subjects, new onset pIMDs or exacerbation of existing pIMDs were reported for 1.3% of subjects who received SHINGRIX and 1.0% of subjects who received placebo from the first administered dose up to 1 year post-last vaccination. There were no notable imbalances in specific pIMDs between treatment groups.

Other Medically Relevant Events: In the auHSCT study (NCT01610414), relapse or progression was reported by 315 of 922 subjects (34%) who received at least one dose of SHINGRIX and 331 of 924 subjects (36%) who received placebo from the first vaccination to study end.

In the auHSCT study (NCT00920218), relapse or progression was reported by 17 of 59 subjects (29%) who received at least one dose of SHINGRIX and 8 of 30 subjects (27%) who received placebo from the first vaccination to study end.

In the hematologic malignancy study, relapse or progression was reported by 45 of 283 subjects (16%) who received at least one dose of SHINGRIX and 58 of 279 subjects (21%) who received placebo from the first vaccination to study end.

In the renal transplant study, biopsy-confirmed allograft rejection was reported by 4 of 132 (3%) of subjects who received SHINGRIX and by 7 of 132 (5%) of subjects who received placebo from the first vaccination to study end (approximately 13 months later). Creatinine as a measure of graft function and changes in alloimmunity post-vaccination were not systematically evaluated.

In the HIV study, at least 1 event of worsening HIV condition was reported by 9 of 74 (12%) of subjects who received SHINGRIX and by 5 of 49 (10%) of subjects who received placebo from the first vaccination to study end.

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