Vaccine Information: Shingrix (Page 2 of 5)

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of SHINGRIX. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to the vaccine.

General Disorders and Administration Site Conditions

Decreased mobility of the injected arm which may persist for 1 or more weeks.

Immune System Disorders

Hypersensitivity reactions, including angioedema, rash, and urticaria.

Nervous System Disorders

Guillain-Barré syndrome.

Postmarketing Observational Study of the Risk of Guillain-Barré Syndrome following Vaccination with SHINGRIX

The association between vaccination with SHINGRIX and GBS was evaluated among Medicare beneficiaries aged 65 years or older. Using Medicare claims data, from October 2017 through February 2020, vaccinations with SHINGRIX among beneficiaries were identified through National Drug Codes, and potential cases of hospitalized GBS among recipients of SHINGRIX were identified through International Classification of Diseases codes.

The risk of GBS following vaccination with SHINGRIX was assessed in self-controlled case series analyses using a risk window of 1 to 42 days post-vaccination and a control window of 43 to 183 days post-vaccination. The primary analysis (claims-based, all doses) found an increased risk of GBS during the 42 days following vaccination with SHINGRIX, with an estimated 3 excess cases of GBS per million doses administered to adults aged 65 years or older. In secondary analyses, an increased risk of GBS was observed during the 42 days following the first dose of SHINGRIX, with an estimated 6 excess cases of GBS per million doses administered to adults aged 65 years or older, and no increased risk of GBS was observed following the second dose of SHINGRIX. These analyses of GBS diagnoses in claims data were supported by analyses of GBS cases confirmed by medical record review. While the results of this observational study suggest a causal association of GBS with SHINGRIX, available evidence is insufficient to establish a causal relationship.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

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. The data are insufficient to establish if there is vaccine-associated risk with SHINGRIX in pregnant women.

A developmental toxicity study was performed in female rats administered SHINGRIX or the AS01B adjuvant alone prior to mating, during gestation, and during lactation. The total dose was 0.2 mL on each occasion (a single human dose of SHINGRIX is 0.5 mL). This study revealed no adverse effects on fetal or pre-weaning development due to SHINGRIX (see Data).

Data

Animal Data: In a developmental toxicity study, female rats were administered SHINGRIX or the AS01B adjuvant alone by intramuscular injection 28 and 14 days prior to mating, on gestation Days 3, 8, 11, and 15, and on lactation Day 7. The total dose was 0.2 mL on each occasion (a single human dose of SHINGRIX 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.

8.2 Lactation

Risk Summary

It is not known whether SHINGRIX is excreted in human milk. Data are not available to assess the effects of SHINGRIX 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 SHINGRIX and any potential adverse effects on the breastfed child from SHINGRIX or from the underlying maternal condition. For preventive vaccines, the underlying maternal condition is susceptibility to disease prevented by the vaccine.

8.4 Pediatric Use

Safety and effectiveness in individuals younger than 18 years have not been established. SHINGRIX is not indicated for prevention of primary varicella infection (chickenpox).

8.5 Geriatric Use

Adults Aged 60 Years and Older

Of the total number of subjects who received at least 1 dose of SHINGRIX in Studies 1 and 2 (n = 14,645), 2,243 (15%) were aged 60 to 69 years, 6,837 (47%) were aged 70 to 79 years, and 1,921 (13%) were 80 years and older. There were no clinically meaningful differences in efficacy across the age groups [See Clinical Studies (14.1, 14.2, 14.3).]

The frequencies of solicited local and general adverse reactions in subjects aged 70 years and older were lower than in younger adults (aged 50 through 69 years). [See Adverse Reactions (6.1).]

Immunocompromised Adults Aged 65 Years and Older

Of the total number of subjects who received at least 1 dose of SHINGRIX in the auHSCT study (n = 922), 172 (18.7%) were aged 65 years and older [see Clinical Studies (14.6)]. There were no clinically meaningful differences in efficacy between these subjects and younger adults (aged 18 through 64 years).

Of the total number of subjects who received at least 1 dose of SHINGRIX across the 6 studies in immunocompromised subjects (n = 1,587), 337 (21.2%) were aged 65 years and older. The frequencies of solicited local and general adverse reactions in subjects aged 65 years and older were generally similar to or lower than those reported by younger adults (aged 18 through 64 years).

11 DESCRIPTION

SHINGRIX (Zoster Vaccine Recombinant, Adjuvanted) is a sterile suspension for intramuscular injection. The vaccine is supplied as a vial of lyophilized recombinant varicella zoster virus surface glycoprotein E (gE) antigen component, which must be reconstituted at the time of use with the accompanying vial of AS01B adjuvant suspension component. The lyophilized gE antigen component is presented in the form of a sterile white powder. The AS01B adjuvant suspension component is an opalescent, colorless to pale brownish liquid supplied in vials.

The gE antigen is obtained by culturing genetically engineered Chinese Hamster Ovary cells, which carry a truncated gE gene, in media containing amino acids, with no albumin, antibiotics, or animal-derived proteins. The gE protein is purified by several chromatographic steps, formulated with excipients, filled into vials, and lyophilized.

The adjuvant suspension component is AS01B which is composed of 3-O -desacyl-4’-monophosphoryl lipid A (MPL) from Salmonella minnesota and QS-21, a saponin purified from plant extract Quillaja saponaria Molina, combined in a liposomal formulation. The liposomes are composed of dioleoyl phosphatidylcholine (DOPC) and cholesterol in phosphate-buffered saline solution containing disodium phosphate anhydrous, potassium dihydrogen phosphate, sodium chloride, and water for injection.

After reconstitution, each 0.5‑mL dose is formulated to contain 50 mcg of the recombinant gE antigen, 50 mcg of MPL, and 50 mcg of QS-21. Each dose also contains 20 mg of sucrose (as stabilizer), 4.385 mg of sodium chloride, 1 mg of DOPC, 0.54 mg of potassium dihydrogen phosphate, 0.25 mg of cholesterol, 0.160 mg of sodium dihydrogen phosphate dihydrate, 0.15 mg of disodium phosphate anhydrous, 0.116 mg of dipotassium phosphate, and 0.08 mg of polysorbate 80. After reconstitution, SHINGRIX is a sterile, opalescent, colorless to pale brownish liquid.

SHINGRIX does not contain preservatives. Each dose may also contain residual amounts of host cell proteins (≤3.0%) and DNA (≤2.1 picograms) from the manufacturing process.

The vial stoppers are not made with natural rubber latex.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The risk of developing HZ, which increases with age and with immunosuppression due to disease and/or therapy, appears to be related to a decline in varicella zoster virus (VZV)-specific immunity. SHINGRIX was shown to boost VZV-specific immune response, which is thought to be the mechanism by which it protects against zoster disease [see Clinical Studies (14)].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

SHINGRIX has not been evaluated for its carcinogenic or mutagenic potential. Vaccination of female rats with SHINGRIX had no effect on fertility [see Use in Specific Populations (8.1)]. In a male fertility study, rats were vaccinated with 0.1 mL of SHINGRIX (a single human dose is 0.5 mL) on 42, 28, and 14 days prior to mating. There were no effects on male fertility.

14 CLINICAL STUDIES

14.1 Efficacy in Subjects Aged 50 Years and Older

Study 1 was a randomized, placebo-controlled, observer-blind clinical study conducted in 18 countries. Randomization was stratified (8:5:3:1) by age: 50 to 59 years, 60 to 69 years, 70 to 79 years, and ≥80 years. The study excluded, among others, subjects who were immunocompromised, had a history of previous HZ, were vaccinated against varicella or HZ, and patients whose survival was not expected to be at least 4 years or with conditions that might interfere with study evaluations. Subjects were followed for the development of HZ and postherpetic neuralgia (PHN) for a median of 3.1 years (range: 0 to 3.7 years). Suspected HZ cases were followed prospectively for the development of PHN, an HZ-related complication defined as HZ-associated pain (rated as 3 or greater on a 0- to 10-point scale by the study subject) occurring or persisting at least 90 days following the onset of rash in confirmed cases of HZ.

The primary efficacy analysis population (referred to as the modified Total Vaccinated Cohort [mTVC]) included 14,759 subjects aged 50 years and older who received 2 doses (0 and 2 months) of either SHINGRIX (n = 7,344) or placebo (n = 7,415) and did not develop a confirmed case of HZ within 1 month after the second dose. In the mTVC population, 61% were female; 72% were White, 19% were Asian, 1.7% were Black, and 7% were of other racial/ethnic groups. The mean age of subjects was 62.3 years.

Confirmed HZ cases were determined by either Polymerase Chain Reaction (PCR) (89.4%) or by a Clinical Evaluation Committee (10.6%).

Efficacy against Herpes Zoster

Compared with placebo, SHINGRIX significantly reduced the risk of developing HZ by 97.2% (95% CI: 93.7, 99.0) in subjects aged 50 years and older (Table 4).

Table 4. Efficacy of SHINGRIX on Incidence of Herpes Zoster Compared with Placebo in Study 1a (mTVCb)
N = Number of subjects included in each group; n = Number of subjects having at least 1 confirmed HZ episode; HZ = Herpes zoster; CI = Confidence Interval.a Study 1: NCT01165177.b mTVC = Modified Total Vaccinated Cohort defined as subjects who received 2 doses (0 and 2 months) of either SHINGRIX or placebo and did not develop a confirmed case of HZ within 1 month after the second dose.c Primary study endpoint was based on confirmed HZ cases in subjects aged 50 years and older.

Age Group

(Years)

SHINGRIX

Placebo

% Efficacy (95% CI)

N

n

Incidence Rate of HZ per 1,000 Person-Years

N

n

Incidence Rate of HZ per 1,000 Person-Years

Overall (≥50)c

7,344

6

0.3

7,415

210

9.1

97.2

(93.7, 99.0)

50-59

3,492

3

0.3

3,525

87

7.8

96.6

(89.6, 99.3)

60-69

2,141

2

0.3

2,166

75

10.8

97.4

(90.1, 99.7)

≥70

1,711

1

0.2

1,724

48

9.4

97.9

(87.9, 100.0)

In a descriptive analysis, vaccine efficacy against HZ in subjects aged 50 years and older was 93.1% (95% CI: 81.3, 98.2) in the fourth year post-vaccination.

Occurrence of Postherpetic Neuralgia

Among all subjects aged 50 years or older in the mTVC, no cases of PHN were reported in the vaccine group compared with 18 cases reported in the placebo group.

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