SHINGRIX powder + suspension for injection suspension medication leaflet

Shingrix powder and suspension for suspension for injection

Herpes zoster vaccine (recombinant, adjuvanted)

After reconstitution, one dose (0.5 mL) contains:

Varicella Zoster Virus1 glycoprotein E antigen2,3 50 micrograms1 Varicella Zoster Virus = VZV2 adjuvanted with AS01B containing:

plant extract Quillaja saponaria Molina, fraction 21 (QS-21) 50 micrograms3-O-desacyl-4’-monophosphoryl lipid A (MPL) from Salmonella minnesota50 micrograms3 glycoprotein E (gE) produced in Chinese Hamster Ovary (CHO) cells by recombinant DNAtechnology

Each dose contains 0.08 milligrams of polysorbate 80 (E 433) (see section 4.4).

For the full list of excipients, see section 6.1.

Powder and suspension for suspension for injection.

The powder is white.

The suspension is an opalescent, colourless to pale brownish liquid.

Shingrix is indicated for prevention of herpes zoster (HZ) and post-herpetic neuralgia (PHN), in:

* adults 50 years of age or older;

* adults 18 years of age or older at increased risk of HZ.

The use of Shingrix should be in accordance with official recommendations.

The primary vaccination schedule consists of two doses of 0.5 mL each: an initial dose followed by asecond dose 2 months later.

If flexibility in the vaccination schedule is necessary, the second dose can be administered between 2and 6 months after the first dose (see section 5.1).

For subjects who are or might become immunodeficient or immunosuppressed due to disease or therapy,and whom would benefit from a shorter vaccination schedule, the second dose can be given 1 to 2months after the initial dose (see section 5.1).

The need for booster doses following the primary vaccination schedule has not been established (seesection 5.1).

Shingrix can be given with the same schedule in individuals previously vaccinated with live attenuated

HZ vaccine (see section 5.1).

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

The safety and efficacy of Shingrix in children and adolescents have not been established.

No data are available.

For intramuscular injection only, preferably in the deltoid muscle.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

Prior to immunisation

As with all injectable vaccines, appropriate medical treatment and supervision should always bereadily available in case of an anaphylactic event following the administration of the vaccine.

As with other vaccines, vaccination with Shingrix should be postponed in subjects suffering from anacute severe febrile illness. However, the presence of a minor infection, such as a cold, should notresult in the deferral of vaccination.

As with any vaccine, a protective immune response may not be elicited in all vaccinees.

The vaccine is for prophylactic use only and is not intended for treatment of established clinicaldisease.

Shingrix should not be administered intravascularly or intradermally.

Subcutaneous administration is not recommended.

Maladministration via the subcutaneous route may lead to an increase in transient local reactions.

Shingrix should be given with caution to individuals with thrombocytopenia or any coagulationdisorder since bleeding may occur following intramuscular administration to these subjects.

Syncope (fainting) can occur following, or even before, any vaccination as a psychogenic response tothe needle injection. This can be accompanied by several neurological signs such as transient visualdisturbance, paraesthesia and tonic-clonic limb movements during recovery. It is important thatprocedures are in place to avoid injury from faints.

In a post-marketing observational study in individuals aged 65 years or older, an increased risk of

Guillain-Barré syndrome (estimated 3 excess cases per million doses administered) was observedduring the 42 days following vaccination with Shingrix. Available information is insufficient todetermine a causal relationship with Shingrix.

There are no safety, immunogenicity or efficacy data to support replacing a dose of Shingrix with adose of another HZ vaccine.

There are limited data to support the use of Shingrix in individuals with a history of HZ (see section5.1). Healthcare professionals therefore need to weigh the benefits and risks of HZ vaccination on anindividual basis.

This medicinal product contains 0.08 mg of polysorbate 80 per dose.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially‘sodium-free’.

This medicinal product contains potassium, less than 1 mmol (39 mg) per dose, i.e. essentially‘potassium-free’.

Shingrix can be given concomitantly with unadjuvanted inactivated seasonal influenza vaccine,23-valent pneumococcal polysaccharide vaccine (PPV23), 13-valent pneumococcal conjugate vaccine(PCV13), reduced antigen diphtheria-tetanus-acellular pertussis vaccine (dTpa), or coronavirus disease2019 (COVID-19) messenger ribonucleic acid (mRNA) vaccine. The vaccines should be administeredat different injection sites.

In five phase III, controlled, open-label clinical studies, adults ≥ 50 years of age were randomised toreceive 2 doses of Shingrix 2 months apart administered either concomitantly at the first dose ornon-concomitantly with an unadjuvanted inactivated seasonal influenza vaccine (N=828; Zoster-004),a PPV23 vaccine (N=865; Zoster-035), a PCV13 vaccine (N=912; Zoster-059), a dTpa vaccineformulated with 0.3 milligrams Al3+ (N=830; Zoster-042), or a monovalent COVID-19 mRNA-127350 micrograms booster vaccine (Original SARS-CoV-2 strain) (N=539; Zoster-091). The immuneresponses of the co-administered vaccines were unaffected, with the exception of lower geometricmean concentrations (GMCs) for one of the pertussis antigens (pertactin) when Shingrix isco-administered with the dTpa vaccine. The clinical relevance of this data is not known.

The adverse reactions of fever and shivering were more frequent when PPV23 vaccine wasco-administered with Shingrix (16% and 21%, respectively) compared to when Shingrix was givenalone (7% for both adverse reactions).

In adults aged 50 years and above, systemic adverse reactions that are very commonly reported (see

Table 1; such as myalgia 32.9%, fatigue 32.2%, and headache 26.3%), and arthralgia, uncommonlyreported, following administration of Shingrix alone were reported with increased frequency when

Shingrix was co-administered with a COVID-19 mRNA vaccine (myalgia 64%, fatigue 51.7%,headache 39%, arthralgia 30.3%).

Concomitant use with other vaccines than those listed above is not recommended due to lack of data.

There are no data from the use of Shingrix in pregnant women. Animal studies do not indicate director indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition orpost-natal development (see section 5.3).

As a precautionary measure, it is preferable to avoid the use of Shingrix during pregnancy.

The effect on breast-fed infants of administration of Shingrix to their mothers has not been studied.

It is unknown whether Shingrix is excreted in human milk.

Animal studies do not indicate direct or indirect effects with respect to fertility in males or females(see section 5.3).

Shingrix may have a minor influence on the ability to drive and use machines in the 2-3 days following vaccination. Fatigue and malaise may occur following administration (see section4.8).

In adults aged 50 years and above, the most frequently reported adverse reactions were pain at theinjection site (68.1% overall/dose; 3.8% severe/dose), myalgia (32.9% overall/dose; 2.9%severe/dose), fatigue (32.2% overall/dose; 3.0% severe/dose) and headache (26.3% overall/dose; 1.9%severe/dose). Most of these reactions were not long-lasting (median duration of 2 to 3 days). Reactionsreported as severe lasted 1 to 2 days.

In adults ≥ 18 years of age who are immunodeficient or immunosuppressed due to disease or therapy(referred to as immunocompromised (IC)), the safety profile was consistent with that observed inadults 50 years and above. There are limited data in adults aged 18-49 years at increased risk of HZwho are not IC.

Overall, there was a higher incidence of some adverse reactions in younger age groups:

- studies in IC adults ≥ 18 years of age (pooled analysis): the incidence of pain at the injection site,fatigue, myalgia, headache, shivering and fever was higher in adults aged 18-49 years compared tothose aged 50 years and above.

- studies in adults ≥ 50 years of age (pooled analysis): the incidence of myalgia, fatigue, headache,shivering, fever and gastrointestinal symptoms was higher in adults aged 50-69 years compared tothose aged 70 years and above.

The safety profile presented below is based on a pooled analysis of data generated in placebo-controlled clinical studies on 5 887 adults 50-69 years of age and 8 758 adults ≥ 70 years of age. Ofthese 14 645 adults, 7 408 were included in a long-term follow-up extension study over a follow-upperiod of approximately 11 years after vaccination.

In clinical studies in IC adults ≥ 18 years of age (1 587 subjects) the safety profile is consistent withthe data presented in Table 1 below.

Adverse reactions reported during post-marketing surveillance are also tabulated below.

Adverse reactions reported are listed according to the following frequency:

Very common (≥ 1/10)

Common (≥ 1/100 to < 1/10)

Uncommon (≥ 1/1 000 to < 1/100)

Rare (≥ 1/10 000 to < 1/1 000)

Very rare (< 1/10 000)

Within each frequency grouping the adverse reactions are reported in the order of decreasingseriousness.

Table 1: Adverse Reactions

System Organ Class1 Frequency Adverse reactions

Blood and lymphatic system Uncommon lymphadenopathydisorders

Immune system disorders Rare hypersensitivity reactions includingrash, urticaria, angioedema2

Nervous system disorders Very common headache

Gastrointestinal disorders Very common gastrointestinal symptoms (includingnausea, vomiting, diarrhoea and/orabdominal pain)

Musculoskeletal and connective Very common myalgiatissue disorders

Uncommon arthralgia

General disorders and Very common injection site reactions (such as pain,administration site conditions redness, swelling), fatigue, chills, fever

Common injection site pruritus, malaise1According to MedDRA (medical dictionary for regulatory activities) terminology2Adverse reactions from spontaneous reporting

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No case of overdose has been reported.

Pharmacotherapeutic group: Vaccines, varicella zoster vaccines, ATC code: J07BK03.

By combining the VZV specific antigen (gE) with an adjuvant system (AS01B), Shingrix is designedto induce antigen-specific cellular and humoral immune responses in individuals with pre-existingimmunity against VZV.

Non-clinical data show that AS01B induces a local and transient activation of the innate immunesystem through specific molecular pathways. This facilitates the recruitment and activation of antigenpresenting cells carrying gE-derived antigens in the draining lymph node, which in turn leads to thegeneration of gE-specific CD4+ T cells and antibodies. The adjuvant effect of AS01B is the result ofinteractions between MPL and QS-21 formulated in liposomes.

Clinical efficacy of Shingrix

Efficacy against Herpes Zoster (HZ) and Post-Herpetic Neuralgia (PHN)

Two phase III, placebo-controlled, observer-blind efficacy studies of Shingrix were conducted inadults ≥ 50 years with 2 doses administered 2 months apart:

- ZOE-50 (Zoster-006): Total Vaccinated Cohort (TVC) of 15 405 adults ≥ 50 years who receivedat least one dose of either Shingrix (N=7 695) or placebo (N=7 710).

- ZOE-70 (Zoster-022): TVC of 13 900 adults ≥ 70 years who received at least one dose of either

Shingrix (N=6 950) or placebo (N=6 950).

The studies were not designed to demonstrate efficacy in subgroups of frail individuals, includingthose with multiple comorbidities, although these subjects were not excluded from the studies.

Two phase III, placebo-controlled, observer-blind studies evaluating Shingrix efficacy were conductedin IC adults ≥ 18 years with 2 doses administered 1-2 months apart:

- Zoster-002: TVC of 1 846 autologous hematopoietic stem cell transplants (aHSCT) recipientswho received at least one dose of either Shingrix (N=922) or placebo (N=924) 50-70 days post-transplant, 21.3% (Shingrix) and 20.5% (placebo) of the subjects received at least oneimmunosuppressive (IS) treatment (for a duration of at least one day) from HSCT up to 30 daysafter Dose 2 (TVC). The proportion of subjects by underlying disease was: 53.1% (Shingrix)and 53.4% (placebo) for multiple myeloma (MM) and 46.9% (Shingrix) and 46.6% (placebo)for other diagnosis.

- Zoster-039: TVC of 562 subjects with hematologic malignancies who received at least one doseof either Shingrix (N=283) or placebo (N=279) during a cancer therapy course (37%) or afterthe full cancer therapy course (63%). The proportion of subjects by underlying disease was:

70.7% (Shingrix) and 71.3% (placebo) for MM and other diseases, 14.5% (Shingrix) and 14.0%(placebo) for non-Hodgkin B-cell lymphoma (NHBCL) and 14.8% (Shingrix) and 14.7%(placebo) for chronic lymphocytic leukaemia (CLL).

These studies were not designed to assess the impact of concomitant use of IS therapy on vaccineefficacy or to assess the impact of specific IS treatments on vaccine efficacy. Most vaccine recipientswere not under IS therapy at the time of vaccination (see above). Not all types of IS therapies wereused in the populations studied.

Incidence of HZ and PHN cases as well as vaccine efficacy were evaluated in the modified Total

Vaccinated Cohort (mTVC), i.e. excluding adults who did not receive the second dose of vaccine orwho had a confirmed diagnosis of HZ within one month after the second dose.

Shingrix significantly decreased the incidence of HZ compared with placebo in:

- adults ≥ 50 years (ZOE-50): 6 vs. 210 cases;

- adults ≥ 70 years (pooled analysis of ZOE-50 and ZOE-70): 25 vs. 284 cases;

- adults ≥ 18 years with aHSCT (Zoster-002): 49 vs. 135 cases;

- adults ≥ 18 years with hematologic malignancies (Zoster-039): 2 vs. 14 cases. Vaccine efficacywas calculated post-hoc.

Vaccine efficacy results against HZ are presented in Table 2.

Table 2: Shingrix efficacy against HZ (mTVC)

Shingrix Placebo

Number Number Incidence Number Number Incidence Vaccine

Ageof of HZ rate per of of HZ rate per efficacy (%)(years)evaluable cases 1 000 evaluable cases 1 000 [95% CI]subjects person subjects personyears years

ZOE-50*97.2≥ 50 7 344 6 0.3 7 415 210 9.1[93.7; 99.0]96.650-59 3 492 3 0.3 3 525 87 7.8[89.6; 99.4]97.6≥ 60 3 852 3 0.2 3 890 123 10.2[92.7; 99.6]97.460-69 2 141 2 0.3 2 166 75 10.8[90.1; 99.7]

Pooled ZOE-50 and ZOE-70**91.3≥ 70 8 250 25 0.8 8 346 284 9.3[86.8; 94.5]91.370-79 6 468 19 0.8 6 554 216 8.9[86.0; 94.9]91.4≥ 80 1 782 6 1.0 1 792 68 11.1[80.2; 97.0]

Zoster-002*** (aHSCT recipients#)68.2≥ 18 870 49 30.0 851 135 94.3[55.5; 77.6]71.818-49 213 9 21.5 212 29 76.0[38.7; 88.3]67.3≥ 50 657 40 33.0 639 106 100.9[52.6; 77.9]

Zoster-039 (hematologic malignancy patients#)87.2****≥ 18 259 2 8.5 256 14 66.2[44.2; 98.6]

CI Confidence interval

* Over a median follow-up period of 3.1 years

** Over a median follow-up period of 4.0 years

Data in subjects ≥ 70 years of age are sourced from the pre-specified pooled analyses of ZOE-50 and

ZOE-70 (mTVC) as these analyses provide the most robust estimates for vaccine efficacy in this age group.

*** Over a median follow-up period of 21 months

**** VE calculation was performed post-hoc; median follow-up period of 11.1 months# antiviral prophylaxis in line with the local standard of care was permitted

Approximately 13 000 subjects with underlying medical conditions, including conditions associatedwith a higher risk of HZ, were enrolled in ZOE-50 and ZOE-70. Post-hoc analysis of efficacy againstconfirmed HZ undertaken in patients with common conditions (chronic kidney disease, chronicobstructive pulmonary disease, coronary artery disease, depression or diabetes mellitus), indicates thatthe vaccine efficacy is aligned with the overall HZ efficacy.

Shingrix significantly decreased the incidence of PHN compared with placebo in:

- adults ≥ 50 years (ZOE-50): 0 vs. 18 cases;

- adults ≥ 70 years (pooled analysis of ZOE-50 and ZOE-70): 4 vs. 36 cases;

- adults ≥ 18 years with aHSCT (Zoster-002): 1 vs. 9 cases.

Vaccine efficacy results against PHN are presented in Table 3.

Table 3: Shingrix efficacy against PHN (mTVC)

Shingrix Placebo

Number Number Incidence Number Number Incidence Vaccine

Ageof of PHN* rate per of of PHN* rate per efficacy (%)(years)evaluable cases 1 000 evaluable cases 1 000 [95% CI]subjects person subjects personyears years

ZOE-50**≥ 50 7 340 0 0.0 7 413 18 0.6[77.1; 100]50-59 3 491 0 0.0 3 523 8 0.6[40.8; 100]≥ 60 3 849 0 0.0 3 890 10 0.7[55.2; 100]100§60-69 2 140 0 0.0 2 166 2 0.2[< 0; 100]

Pooled ZOE-50 and ZOE-70***88.8≥ 70 8 250 4 0.1 8 346 36 1.2[68.7; 97.1]93.070-79 6 468 2 0.1 6 554 29 1.2[72.4; 99.2]71.2§≥ 80 1 782 2 0.3 1 792 7 1.1[< 0; 97.1]

Zoster-002**** (aHSCT recipients#)89.3≥ 18 870 1 0.5 851 9 4.9[22.5; 99.8]100.0§18-49 213 0 0.0 212 1 2.2[< 0; 100.0]88.0≥ 50 657 1 0.7 639 8 5.8[10.4; 99.8]

* PHN was defined as zoster-associated pain rated as ≥ 3 (on a 0-10 scale), persisting orappearing more than 90 days after onset of zoster rash using Zoster Brief Pain Inventory (ZBPI)

CI Confidence interval

** Over a median follow-up period of 4.1 years

*** Over a median follow-up period of 4.0 years

Data in subjects ≥ 70 years of age are sourced from the pre-specified pooled analyses of ZOE-50 and

ZOE-70 (mTVC) as these analyses provide the most robust estimates for vaccine efficacy in this agegroup.

**** Over a median follow-up period of 21 months§ Not statistically significant# antiviral prophylaxis in line with the local standard of care was permitted

The benefit of Shingrix in the prevention of PHN can be attributed to the effect of the vaccine on theprevention of HZ. A further reduction of PHN incidence in subjects with confirmed HZ could not bedemonstrated due to the limited number of HZ cases in the vaccine group.

In the fourth year after vaccination, the efficacy against HZ was 93.1% (95% CI: 81.2; 98.2) and87.9% (95% CI: 73.3; 95.4) in adults ≥ 50 years (ZOE-50) and adults ≥ 70 years (pooled ZOE-50 and

ZOE-70), respectively.

In Zoster-002, during a follow-up period starting 1 month post-dose 2 (i.e. corresponding toapproximately 6 months after aHSCT) until 1 year after aHSCT, when the risk for HZ is the highest,the efficacy against HZ was 76.2% (95% CI: 61.1; 86.0).

Efficacy against HZ-related complications other than PHN

The evaluated HZ-related complications (other than PHN) were: HZ vasculitis, disseminated disease,ophthalmic disease, neurologic disease including stroke, and visceral disease. In the pooled analysis of

ZOE-50 and ZOE-70, Shingrix significantly reduced these HZ-related complications by 93.7% (95%

CI: 59.5; 99.9) and 91.6% (95% CI: 43.3; 99.8) in adults ≥ 50 years (1 vs. 16 cases) and adults ≥ 70years (1 vs. 12 cases), respectively. No cases of visceral disease or stroke were reported during thesestudies.

In Zoster-002, Shingrix significantly reduced HZ-related complications by 77.8% (95% CI: 19.0; 96.0)in aHSCT recipients ≥ 18 years (3 vs 13 cases).

In addition, in Zoster-002, Shingrix significantly reduced HZ-related hospitalisations by 84.7% (95%

CI: 32.1; 96.6) (2 vs. 13 cases).

Effect of Shingrix on HZ-related pain

Overall in ZOE-50 and ZOE-70, there was a general trend towards less severe HZ-related pain insubjects vaccinated with Shingrix compared to placebo. As a consequence of the high vaccine efficacyagainst HZ, a low number of breakthrough cases were accrued, and it was therefore not possible todraw firm conclusions on these study objectives.

In subjects ≥ 70 years with at least one confirmed HZ episode (ZOE-50 and ZOE-70 pooled), Shingrixsignificantly reduced the use and the duration of HZ-related pain medication by 39.0% (95% CI: 11.9;63.3) and 50.6% (95% CI: 8.8; 73.2), respectively. The median duration of pain medication use was32.0 and 44.0 days in the Shingrix and placebo group, respectively.

In subjects with at least one confirmed HZ episode, Shingrix significantly reduced the maximumaverage pain score versus placebo over the entire HZ episode (mean = 3.9 vs. 5.5, P-value = 0.049 andmean = 4.5 vs. 5.6, P-value = 0.043, in subjects  50 years (ZOE-50) and  70 years (ZOE-50 and

ZOE-70 pooled), respectively). In addition, in subjects ≥ 70 years (ZOE-50 and ZOE-70 pooled),

Shingrix significantly reduced the maximum worst pain score versus placebo over the entire HZepisode (mean = 5.7 vs. 7.0, P-value = 0.032).

The burden-of-illness (BOI) score incorporates the incidence of HZ with the severity and duration ofacute and chronic HZ-related pain over a 6 month period following rash onset.

The efficacy in reducing BOI was 98.4% (95% CI: 92.2; 100) in subjects ≥ 50 years (ZOE-50) and92.1% (95% CI: 90.4; 93.8) in subjects ≥ 70 years (ZOE-50 and ZOE-70 pooled).

In Zoster-002, Shingrix significantly reduced the duration of severe ‘worst’ HZ-associated pain by38.5% (95% CI: 11.0; 57.6) in aHSCT recipients ≥ 18 years with at least one confirmed HZ episode.

Shingrix significantly reduced the maximum average pain score versus placebo over the entire HZepisode (mean = 4.7 vs. 5.7, P-value = 0.018) and the maximum worst pain score versus placebo overthe entire HZ episode (mean = 5.8 vs. 7.1, P-value = 0.011).

The percentage of subjects with at least one confirmed HZ episode in Zoster-002 using at least onepain medication was 65.3% and 69.6% in the Shingrix and placebo group, respectively. The medianduration of pain medication use was 21.5 and 47.5 days in the Shingrix and placebo group,respectively.

Additionally, in Zoster-002, the efficacy in reducing BOI score was 82.5% (95% CI: 73.6%, 91.4%).

Long-term efficacy against HZ, PHN and HZ-related complications other than PHN

A phase IIIb, open-label, long-term follow-up study of Shingrix (Zoster-049) was conducted in adults≥ 50 years from ZOE-50 and ZOE-70. Participants were enrolled approximately 5 years after theyreceived Shingrix in ZOE-50 or ZOE-70. Adults who became immunodeficient or immunosuppresseddue to disease or therapy were excluded at study entry. The TVC for efficacy included 7 408 subjects(i.e. 50.6% of 14 645 subjects included in the TVC for efficacy for studies ZOE-50 and ZOE-70).

Persistence of efficacy remains unknown in immunocompromised/immunosuppressed population.

Vaccine efficacy was calculated descriptively against HZ, PHN and HZ-related complications otherthan PHN in the mTVC (i.e. excluding subjects who did not receive the second dose of vaccine in theprimary studies, or who developed a confirmed case of HZ within one month after the second dose).

Since the efficacy was estimated with regard to the first or only event, individuals who experienced a

HZ, PHN, or HZ-related complication (other than PHN) during studies ZOE-50 and ZOE-70 wereexcluded from the corresponding efficacy analyses over the Zoster-049 duration. Estimates ofincidence rates in the control group to assess the vaccine efficacy during Zoster-049 study werehistorical, derived from the ZOE-50 and ZOE-70 placebo groups.

Shingrix long-term efficacy results against HZ, from approximately 5 years up to approximately 11years post-vaccination, are presented in Table 4.

Table 4: Long-term Shingrix efficacy against HZ (mTVC) from approximately 5 years up toapproximately 11 years post-vaccination

Shingrix Placebo/Historical control*

Vaccineat the time Number Number Incidence Number Number Incidenceefficacy**of of of HZ rate per of of HZ rate per(%)vaccination evaluable cases 1 000 evaluable cases 1 000[95% CI](years) subjects person subjects personyears years

Over the duration of Zoster-04979.8≥ 50 7 258 69 1.8 7 258 341 8.7[73.7; 84.6]86.750-59 2 043 12 1.0 2 043 90 7.7[75.6; 93.4]87.160-69 1 242 9 1.3 1 242 70 10.1[74.2; 94.4]73.2≥ 70 3 973 48 2.4 3 973 179 8.8[62.9; 80.9]

CI Confidence interval

* Placebo group in ZOE-50/ZOE-70 was used for Year 1 through Year 4 analysis and to form thehistorical control data for Year 6 and onwards analysis in Zoster-049

** Descriptive efficacy analysis

Zoster-049 mTVC started at a median of 5.6 years post-vaccination in ZOE-50/ZOE-70 and ended at a medianof 11.4 years post-vaccination.

In the eleventh year after vaccination, the efficacy against HZ was 82.0% (95% CI: 63.0; 92.2) insubjects ≥ 50 years (Shingrix group: N=5 849), 86.7% (95% CI: 42.7; 98.5) in subjects 50-59 years(Shingrix group: N=1 883), 100.0% (95% CI: 65.1; 100.0) in subjects 60-69 years (Shingrix group:

N=1 075) and 72.0% (95% CI: 33.4; 89.8) in subjects ≥ 70 years (Shingrix group: N=2 891).

Shingrix long-term efficacy results against PHN, from approximately 5 years up to approximately 11years post-vaccination, are presented in Table 5.

Table 5: Long-term Shingrix efficacy against PHN (mTVC) from approximately 5 years up toapproximately 11 years post-vaccination

Shingrix Placebo/Historical control*

Vaccineat the time Number Number Incidence Number Number Incidenceefficacy***of of of rate per of of rate per(%)vaccination evaluable PHN** 1 000 evaluable PHN** 1 000[95% CI](years) subjects cases person subjects cases personyears years

Over the duration of Zoster-04987.5≥ 50 7 271 4 0.1 7 271 32 0.8[64.8; 96.8]50-59 2 046 0 0.0 2 046 7 0.6[46.6; 100]50.060-69 1 243 1 0.1 1 243 2 0.3[< 0; 99.2]87.0≥ 70 3 982 3 0.1 3 982 23 1.1[56.8; 97.5]

CI Confidence interval

* Placebo group in ZOE-50/ZOE-70 was used for Year 1 through Year 4 analysis and to form thehistorical control data for Year 6 and onwards analysis in Zoster-049

** PHN was defined as zoster-associated pain rated as ≥ 3 (on a 0-10 scale), persisting or appearing morethan 90 days after onset of zoster rash using Zoster Brief Pain Inventory (ZBPI)

*** Descriptive efficacy analysis

Zoster-049 mTVC started at a median of 5.6 years post-vaccination in ZOE-50/ZOE-70 and ended at a medianof 11.4 years post-vaccination.

Shingrix efficacy against HZ-related complications other than PHN, over the duration of Zoster-049,was 91.7% (95% CI: 43.7; 99.8) and 88.9% (95% CI: 19.8; 99.8) in adults ≥ 50 years (1 vs. 12 cases)and adults ≥ 70 years (1 vs. 9 cases), respectively.

Immunogenicity of Shingrix

An immunological correlate of protection has not been established; therefore the level of immuneresponse that provides protection against HZ is unknown.

In adults ≥ 50 years, the immune responses to Shingrix, given as 2 doses 2 months apart, wereevaluated in a subset of subjects from the phase III efficacy studies ZOE-50 [humoral immunity andcell-mediated immunity (CMI)] and ZOE-70 (humoral immunity). The gE-specific immune responses(humoral and CMI) elicited by Shingrix are presented in Tables 6 and 7, respectively.

Table 6: Humoral immunogenicity of Shingrix in adults ≥ 50 years (ATP cohort for immunogenicity)

Anti-gE immune response^

Month 3* Month 38**

Median fold Median foldgroupincrease of increase of(years) GMC GMCconcentrations concentrations

N (mIU/mL) N (mIU/mL)vs. vs.(95% CI) (95% CI)pre-vaccination pre-vaccination(Q1; Q3) (Q1; Q3)

ZOE-5052 376.6 11 919.641.9 9.3≥ 50 1 070 (50 264.1; 967 (11 345.6;(20.8; 86.9) (4.9; 19.5)54 577.9) 12 522.7)

Pooled ZOE-50 and ZOE-7049 691.5 10 507.734.3 7.2≥ 70 742 (47 250.8; 648 (9 899.2;(16.7; 68.5) (3.5; 14.5)52 258.2) 11 153.6)

ATP According-To-Protocol^ Anti-gE immune response = anti-gE antibody levels, measured by anti-gE enzyme-linked immunosorbentassay (gE ELISA)

* Month 3 = 1 month post-dose 2

** Month 38 = 3 years post-dose 2

N Number of evaluable subjects at the specified time point (for the GMC)

CI Confidence interval

GMC Geometric Mean Concentration

Q1; Q3 First and third quartiles

Table 7: Cell-mediated immunogenicity of Shingrix in adults ≥ 50 years (ATP cohort forimmunogenicity)gE-specific CD4[2+] T cell response^

Month 3* Month 38**

Age Median fold Median fold

Mediangroup increase of Median increase offrequency(years) N frequency vs. N frequency frequency vs.(Q1; Q3)pre-vaccination (Q1; Q3) pre-vaccination(Q1; Q3) (Q1; Q3)

ZOE-501 844.1 738.924.6 7.9≥ 50 164 (1 253.6; 152 (355.7;(9.9; 744.2) (2.7; 31.6)2 932.3) 1 206.5)1,494.6 480.2≥ 70** 33.2 7.352 (922.9; 46 (196.1;

* (10.0; 1 052.0) (1.7; 31.6)2 067.1) 972.4)

ATP According-To-Protocol^ gE-specific CD4[2+] T cell response = gE-specific CD4+ T cell activity, measured by intracellularcytokine staining (ICS) assay (CD4[2+] T cells = CD4+ T cells expressing at least 2 of 4 selected immunemarkers)

* Month 3 = 1 month post-dose 2

** Month 38 = 3 years post-dose 2

N Number of evaluable subjects at the specified time point for the median frequency

Q1; Q3 First and third quartiles

*** The gE-specific CD4[2+] data in the ≥ 70 years of age group were only generated in ZOE-50 because

CD4+ T cell activity was not assessed in ZOE-70

In IC adults ≥ 18 years, the humoral and CMI responses to Shingrix, given as 2 doses 1-2 monthsapart, were evaluated in:

- one phase I/II study: Zoster-015 (HIV infected subjects, the majority (76.42%) being stable onantiretroviral therapy (for at least one year) with a CD4 T-cell count ≥ 200 /mm3);

- one phase II/III study: Zoster-028 (patients with solid tumours undergoing chemotherapy);

- three phase III studies: Zoster-002 (aHSCT recipients vaccinated post-transplant), Zoster-039(patients with hematologic malignancies vaccinated during a cancer therapy course or after thefull cancer therapy course) and Zoster-041 (renal transplant recipients on chronicimmunosuppressive treatment at the time of vaccination).

The gE-specific immune responses (humoral and CMI) elicited by Shingrix in all IC populationsstudied are presented in Tables 8 and 9, respectively.

Table 8: Humoral immunogenicity of Shingrix in IC adults ≥ 18 years (ATP cohort forimmunogenicity)

Anti-gE immune response^

Month 3 Month 13/18/25

Median fold Median foldincrease of increase of

GMCconcentrations GMC (mIU/mL) concentrations

N (mIU/mL) Nvs (95% CI) vs(95% CI)pre-vaccination pre-vaccination(Q1; Q3) (Q1; Q3)

Zoster-002 (aHSCT recipients)

Month 13: Month 13:

54 3 183.8 2.712 753.214.1 (1 869.8; 5 421.2) (1.0; 24.0)82 (7 973.0;(1.7; 137.0)20 399.4) Month 25: Month 25:

39 2 819.0 1.3(1 387.1; 5 729.1) (0.6; 44.7)

Zoster-028 (solid tumour patients)18 291.7 Month 13: Month 13:21.587 (14 432.1; 68 4 477.3 4.1(7.0; 45.2)23 183.5) (3 482.4; 5 756.3) (2.1; 7.9)

Zoster-039 (hematologic malignancy patients)13 445.6 Month 13: Month 13:17.2217 (10 158.9; 167 5 202.7 5.1(1.4; 87.4)17 795.6) (4 074.8; 6 642.8) (1.1; 17.0)

Zoster-041 (renal transplant recipients)19 163.8 Month 13: Month 13:15.1121 (15 041.5; 111 8 545.1 6.5(6.1; 35.0)24 416.0) (6 753.7; 10 811.5) (3.1; 13.3)

Zoster-015 (HIV infected subjects)42 723.6 Month 18: Month 18:40.953 (31 233.0; 49 25 242.2 24.0(18.8; 93.0)58 441.6) (19 618.9; 32 477.3) (9.8; 39.7)

ATP According-To-Protocol^ Anti-gE immune response = anti-gE antibody levels, measured by anti-gE enzyme-linked immunosorbentassay (gE ELISA)

N Number of evaluable subjects at the specified time point (for the GMC)

CI Confidence interval

GMC Geometric Mean Concentration

Q1; Q3 First and third quartiles

In Zoster-028, GMC 1-month post Dose 2 were 22 974.3 (19 080.0; 27 663.5) in the group thatreceived the first dose of Shingrix at least 10 days prior to a chemotherapy cycle (PreChemo group)and 9 328.0 (4 492.5; 19 368.2) in the group that received the first dose of Shingrix simultaneouslywith chemotherapy cycle (OnChemo group). In Zoster-039, GMC 1-month post Dose 2 were 19 934.7(14 674.1; 27 081.2) in the group that received the first dose of Shingrix after the full cancer therapycourse and 5 777.4 (3 342.5; 9 985.9) in the group that received the first dose of Shingrix during acancer therapy course. The clinical relevance in terms of impact on efficacy, on the short and longterm, is unknown.

Table 9: Cell-mediated immunogenicity of Shingrix in IC adults ≥ 18 years (ATP cohort forimmunogenicity)gE-specific CD4[2+] T cell response^

Month 3 Month 13/18/25

Median fold Median fold

Median increase of increase of

Median frequency

N frequency frequency vs. N frequency vs.(Q1; Q3)(Q1; Q3) pre-vaccination pre-vaccination(Q1; Q3) (Q1; Q3)

Zoster-002 (aHSCT recipients)

Month 13: Month 13:

1,706.4 43.66 644.9 (591.4; 5 207.0) (13.1; 977.8)51 109.0(1 438.3;(34.4; 2 716.4)13 298.6) Month 25: Month 25:

30 2 294.4 50.9(455.2; 3 633.2) (15.3; 515.2)

Zoster-028* (solid tumour patients)778.8 Month 13: Month 13:4.922 (393.1; 18 332.9 2.0(1.7; 33.0)1 098.2) (114.9; 604.6) (1.3; 5.2)

Zoster-039 (hematologic malignancy patients)53 3 081.9 45.9 Month 13: Month 13:

(1 766.2; (16.4; 2 221.9) 44 1 006.7 21.47 413.6) (416.0; 3 284.5) (7.5; 351.4)

Zoster-041 (renal transplant recipients)32 2 149.0 47.7 Month 13: Month 13:

(569.4; (14.7; 439.6) 33 1 066.3 16.93 695.1) (424.8; 1 481.5) (5.9; 211.4)

Zoster-015 (HIV infected subjects)41 2 809.7 23.4 Month 18: Month 18:

(1 554.5; (8.5; 604.1) 49 1 533.0 12.04 663.7) (770.0; 2 643.1) (5.7; 507.0)

ATP According-To-Protocol^ gE-specific CD4[2+] T cell response = gE-specific CD4+ T cell activity, measured by intracellularcytokine staining (ICS) assay (CD4[2+] T cells = CD4+ T cells expressing at least 2 of 4 selected immunemarkers)

N Number of evaluable subjects at the specified time point for the median frequency

Q1; Q3 First and third quartiles

* Blood for CMI was only collected from the group of subjects that received the first dose of Shingrix 8-30days before the start of a chemotherapy cycle (i.e. largest group of the study)

Immunogenicity in subjects receiving 2 doses of Shingrix 6 months apart

Efficacy has not been assessed for the 0, 6-month schedule.

In a phase III, open-label clinical study (Zoster-026) where 238 adults ≥ 50 years of age were equallyrandomised to receive 2 doses of Shingrix 2 or 6 months apart, the humoral immune responsefollowing the 0, 6-month schedule was demonstrated to be non-inferior to the response with the 0,2-month schedule. The anti-gE GMC at 1 month after the last vaccine dose was 38 153.7 mIU/mL(95% CI: 34 205.8; 42 557.3) and 44 376.3 mIU/mL (95% CI: 39 697.0; 49 607.2) following the 0, 6-month schedule and the 0, 2-month schedule, respectively.

Subjects with a history of HZ prior to vaccination

Subjects with a history of HZ were excluded from ZOE-50 and ZOE-70. In a phase III, uncontrolled,open-label clinical study (Zoster-033), 96 adults ≥ 50 years of age with a physician-documentedhistory of HZ received 2 doses of Shingrix 2 months apart. Laboratory confirmation of HZ cases wasnot part of the study procedures. The anti-gE GMC at 1 month after the last vaccine dose was47 758.7 mIU/mL (95% CI: 42 258.8; 53 974.4).

There were 9 reports of suspected HZ in 6 subjects over a one-year follow up period. This is a higherrecurrence rate than generally reported in observational studies in unvaccinated individuals with ahistory of HZ. (See section 4.4)

Immunogenicity in individuals previously vaccinated with live attenuated herpes zoster (HZ) vaccine

In a phase III, open-label, multicentre clinical study (Zoster-048), a 2 dose schedule of Shingrix 2months apart was assessed in 215 adults ≥ 65 years of age with a previous history of vaccination withlive attenuated HZ vaccine ≥ 5 years earlier compared to 215 matched subjects who had neverreceived live attenuated HZ vaccine. The immune response to Shingrix was unaffected by priorvaccination with live attenuated HZ vaccine.

Persistence of immunogenicity

Persistence of immunogenicity was evaluated in a subset of subjects in a phase IIIb, open-label, long-term follow-up study (Zoster-049) in adults ≥ 50 years from ZOE-50 and ZOE-70. At Year 12 post-vaccination, the anti-gE antibody concentration in 435 evaluable subjects was 5.8-fold (95% CI: 5.2;6.4) above pre-vaccination level (Mean Geometric Increase). Median frequency of gE specific

CD4[2+] T cells at Year 12 post-vaccination in 73 evaluable subjects remained above pre-vaccinationlevel.

The European Medicines Agency has deferred the obligation to submit the results of studies with

Shingrix in one or more subsets of the paediatric population in prevention of Varicella Zoster Virusreactivation (see section 4.2 for information on paediatric use).

Not applicable.

Non-clinical data reveal no special hazard for humans based on conventional studies of acute andrepeated dose toxicity, local tolerance, cardiovascular/respiratory safety pharmacology and toxicity toreproduction and development.

Powder (gE antigen)

Sucrose

Polysorbate 80 (E 433)

Sodium dihydrogen phosphate dihydrate (E 339)

Dipotassium phosphate (E 340)

Suspension (AS01B Adjuvant System)

Dioleoyl phosphatidylcholine (E 322)

Cholesterol

Sodium chloride

Disodium phosphate anhydrous (E 339)

Potassium dihydrogen phosphate (E 340)

Water for injections

For adjuvant see also section 2.

This medicinal product must not be mixed with other medicinal products.

3 years

Chemical and physical in-use stability has been demonstrated for 24 hours at 30 °C.

From a microbiological point of view, the vaccine should be used immediately. If not usedimmediately, in-use storage times and conditions prior to use are the responsibility of the user andwould normally not be longer than 6 hours at 2 °C to 8 °C.

Store in a refrigerator (2 °C - 8 °C).

Do not freeze.

Store in the original package in order to protect from light.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

* Powder for 1 dose in a vial (type I glass) with a stopper (butyl rubber)

* Suspension for 1 dose in a vial (type I glass) with a stopper (butyl rubber).

Shingrix is available in a pack size of 1 vial of powder and 1 vial of suspension or in a pack size of 10vials of powder and 10 vials of suspension.

Not all pack sizes may be marketed

Shingrix is presented as a vial with a brown flip-off cap containing the powder (antigen) and a vialwith a blue-green flip-off cap containing the suspension (adjuvant).

The powder and the suspension must be reconstituted prior to administration.

Antigen Adjuvant

Powder Suspension1 dose (0.5 mL)

The powder and suspension should be inspected visually for any foreign particulate matter and/orvariation of appearance. If either is observed, do not reconstitute the vaccine.

How to prepare Shingrix

Shingrix must be reconstituted prior to administration.

1. Withdraw the entire contents of the vial containing the suspension into a syringe with a suitableneedle (21G to 25G).

2. Add the entire contents of the syringe into the vial containing the powder.

3. Shake gently until the powder is completely dissolved.

The reconstituted vaccine is an opalescent, colourless to pale brownish liquid.

The reconstituted vaccine should be inspected visually for any foreign particulate matter and/orvariation of appearance. If either is observed, do not administer the vaccine.

After reconstitution, the vaccine should be used promptly; if this is not possible, the vaccine should bestored in a refrigerator (2 °C - 8 °C). If not used within 6 hours it should be discarded.

Before administration1. Withdraw the entire contents of the vial containing the reconstituted vaccine into the syringe.

2. Change the needle so that you are using a new needle to administer the vaccine.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

GlaxoSmithKline Biologicals S.A.

Rue de l’Institut 89

B-1330 Rixensart

Belgium

EU/1/18/1272/001

EU/1/18/1272/002

Date of first authorisation: 21 March 2018

Date of latest renewal: 05 December 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.