Penmenvy

Description for Penmenvy

PENMENVY (Meningococcal Groups A, B, C, W, and Y Vaccine) is a sterile injectable suspension for intramuscular use. The vaccine is supplied as one vial of Lyophilized MenACWY Component which is reconstituted at the time of use with the accompanying prefilled syringe of MenB Component.

The Lyophilized MenACWY Component contains N. meningitidis serogroups A, C, W, and Y oligosaccharides conjugated individually to Corynebacterium diphtheriae CRM₁₉₇ protein. The polysaccharides are produced by bacterial fermentation of N. meningitidis serogroups A, C, W, or Y. N. meningitidis serogroup A, C, W, and Y strains are each cultured and grown on Franz Complete medium and treated with formaldehyde. MenA, MenW, and MenY polysaccharides are purified by several steps, including extraction, filtration, and precipitation. MenC polysaccharide is purified by a combination of extraction, chromatography, and precipitation steps.

The protein carrier (CRM₁₉₇) is produced by bacterial fermentation and is purified by a series of chromatography and ultrafiltration steps. The C. diphtheriae is cultured and grown on CY medium containing yeast extracts and amino acids.

The oligosaccharides are prepared for conjugation from the purified polysaccharides which are processed by hydrolysis, sizing, and reductive amination. After activation, each oligosaccharide is covalently linked to the CRM₁₉₇ protein. The resulting glycoconjugates are purified to yield the four drug substances, which are formulated with sucrose and phosphate and lyophilized to form the Lyophilized MenACWY Component. The Lyophilized MenACWY Component is a white to off-white lyophilized cake.

The MenB Component contains recombinant N. meningitidis proteins Neisseria adhesin A (NadA), Neisserial Heparin Binding Antigen (NHBA), and factor H binding protein (fHbp), and Outer Membrane Vesicles (OMV). The NadA component is a fragment of the full-length protein derived from N. meningitidis strain 2996 (peptide 8 variant 2/3).² The NHBA component is a recombinant fusion protein comprised of NHBA (peptide 2)² and accessory protein 953 derived from N. meningitidis strains NZ98/254 and 2996, respectively. The fHbp component is a recombinant fusion protein comprised of fHbp (variant 1.1)² and the accessory protein 936 derived from N. meningitidis strains MC58 and 2996, respectively. These 3 recombinant proteins are individually produced in Escherichia coli and purified through a series of column chromatography steps. The OMV antigenic component is produced by fermentation of N. meningitidis strain NZ98/254 (expressing outer membrane protein Porin A [PorA] serosubtype P1.4),³ followed by inactivation of the bacteria by deoxycholate, which also mediates vesicle formation. The antigens are adsorbed onto aluminum hydroxide. The MenB Component is a white opalescent suspension.

After reconstitution, each approximately 0.5-mL dose contains 10 mcg MenA oligosaccharide; 5 mcg of each of MenC, MenW, and MenY oligosaccharides; 25.9 to 64.1 mcg CRM197 protein; 50 mcg each of recombinant proteins NadA, NHBA, and fHbp; and 25 mcg of OMV. Each dose also contains 1.5 mg aluminum hydroxide (0.5 mg of Al³⁺), 3.125 mg sodium chloride, 0.776 mg histidine, 22.5 mg sucrose, and ≤0.7 mg potassium phosphate salts. Each dose contains less than 0.01 mcg kanamycin (by calculation). Residual formaldehyde per dose is estimated to be not more than 0.30 mcg. After reconstitution, PENMENVY is a white opalescent suspension.

The tip cap and rubber plunger of the prefilled syringe and the stopper of the vial are not made with natural rubber latex.

PENMENVY does not contain preservatives.

ADVERSE REACTIONS

The most commonly reported (≥10%) solicited adverse reactions after Dose 1 and Dose 2, respectively, in Study 1 in participants aged 10 through 25 years (87% of whom were MenACWY conjugate vaccine-naïve) were pain at the injection site (92% and 88%), fatigue (51% and 42%), headache (42% and 36%), myalgia (15% and 12%), nausea (15% and 10%), erythema (13% and 12%), and swelling (13% and 12%).

The most commonly reported (≥10%) solicited adverse reactions after Dose 1 and Dose 2, respectively, in Study 2 in MenACWY conjugate vaccine-experienced participants aged 15 through 25 years were pain at the injection site (80% and 74%), headache (41% and 33%), fatigue (40% and 33%), myalgia (15% and 13%), and nausea (15% and 12%).

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.

The safety of PENMENVY was evaluated in 12 clinical studies¹ in which a total of 3,718 participants received at least one dose of PENMENVY. Participants in Study 1 (aged 10 through 25 years) and Study 2 (aged 15 through 25 years) were scheduled to receive PENMENVY according to the approved dosing schedule (2 doses administered 6 months apart). Participants in the other studies may have received PENMENVY according to unapproved dosing schedules. Across the 12 studies, 2,969 participants received at least 1 dose of BEXSERO (Meningococcal Group B Vaccine) and 361 participants received a single dose of MENVEO [Meningococcal (Groups A, C, Y, and W-135) Oligosaccharide Diphtheria CRM197 Conjugate Vaccine]. Across the studies, the median age was 16 years, males comprised 46%, and 86% of participants were White, 6% were Black, 4% were Asian, and 4% were of other racial groups. In these studies, 13% of participants were Hispanic. Approximately 35% of participants were from the U.S. Nine of the 12 studies (including Study 1 and Study 2) collected non-serious unsolicited adverse events through 30 days after each vaccination, and the other 3 studies collected these events through 7 days after each vaccination. All studies collected serious adverse events through at least 1 month following the last vaccination. Study 1 and Study 2 collected serious adverse events through 12 months following the first vaccination and at least 5 months following the last vaccination.

Study 1 (NCT04502693) was a randomized, controlled, observer-blind study conducted in 7 countries (U.S., Australia, Canada, Czech Republic, Estonia, Finland, and Turkey). In this study, 1,657 participants aged 10 through 25 years received at least 1 dose of PENMENVY. Participants were scheduled to receive 2 doses of PENMENVY 6 months apart. Separate groups received BEXSERO either as a 0-, 2-, 6-month schedule or 0-, 6-month schedule. A single dose of MENVEO was administered 1 month after the third dose in the 0-, 2-, 6-month group and 2 months after the first dose of BEXSERO in the 0-, 6-month group (these participants received saline placebo at month 7). A separate group received a single dose of MENVEO at month 0, a saline placebo dose at month 2, and doses of BEXSERO at months 6 and 7 (an unapproved BEXSERO dosing regimen). All participants were MenB vaccine-naïve. Both MenACWY conjugate vaccine-naïve (87%) and MenACWY conjugate vaccine-experienced (13%, vaccinated at least 4 years prior to study enrollment) participants were part of the study. The median age was 16 years, males comprised 47%, and 89% of participants were White, 5% were Asian, 4% were Black, and 2% were of other racial groups. Among study participants, 5% were Hispanic. Approximately 30% of participants were from the U.S.

Study 2 (NCT04707391) was a randomized, controlled, observer-blind study conducted in 4 countries (U.S., Australia, Canada, and Argentina). In this study, 626 participants aged 15 through 25 years received at least 1 dose of PENMENVY. All participants were MenACWY conjugate vaccine-experienced (vaccinated at least 4 years prior to study enrollment). A separate group received a single dose of MENVEO followed 6 months later by 2 doses of BEXSERO administered 1 month apart (an unapproved BEXSERO dosing regimen). In this study, the median age was 16 years, males comprised 47%, and 75% of participants were White, 14% were Black, 6% were of other racial groups, and 4% were Asian. Among study participants, 30% were Hispanic.

Approximately 59% of participants were from the U.S.

Solicited Adverse Reactions

In Study 1, solicited local and systemic adverse reactions were collected for 7 days after study vaccination using electronic diaries. The rates of local and systemic adverse reactions reported in Study 1 among participants aged 10 through 25 years following each dose of PENMENVY administered 6 months apart, each dose of BEXSERO administered 6 months apart, or a single dose of MENVEO are presented in Table 1.

Table 1. Percentage of Participants Aged 10 Through 25 Years Reporting Solicited Local and Systemic Adverse Reactions Within 7 Days of PENMENVY, BEXSERO, or MENVEO, by Dose in Study 1

		PENMENVY %		BEXSERO %		MENVEO %
Solicited Reactiona		Dose 1	Dose 2	Dose 1	Dose 2	Dose 1
		N = 1,638	N = 1,428	N = 894	N = 759	N = 178
Local Adverse Reactions
Pain	Any	92	88	92	89	38
	Severe	6	7	6	8	0
Erythema	Any	13	12	10	12	6
	Severe	1	2	1	1	1
Swelling	Any	13	12	10	11	6
	Severe	2	2	1	2	1
Induration	Any	9	8	7	8	4
	Severe	1	1	2	1	0
Systemic Adverse Reactions
Fatigue	Any	51	42	46	45	44
	Severe	3	3	1	3	2
Nausea	Any	15	10	12	11	15
	Severe	0.3	0.3	1	0.4	1
Myalgia	Any	15	12	12	14	7
	Severe	1	1	1	0.4	0
Arthralgia	Any	8	7	8	7	10
	Severe	1	0.4	0.3	0	0
Headache	Any	42	36	37	37	39
	Severe	2	1	1	1	2
Fever	Any	3	2	2	3	2
	Severe	0.1	0.1	0.1	0	1

Study 1: NCT04502693.

N = Number of participants in Solicited Safety Set (participants who received at least 1 dose of study vaccine who reported solicited safety data).

^a Erythema, swelling, and induration: Any (≥25 mm); Severe (>100 mm). Pain, fatigue, nausea, myalgia, arthralgia, headache: Any includes Mild (transient with no limitation in normal daily activity), Moderate (some limitation in normal daily activity), and Severe (unable to perform normal daily activity). Fever: Any (≥38.0°C/100.4°F); Severe (≥40.0°C/104.0°F).

In Study 2, solicited local and systemic adverse reactions were collected for 7 days after study vaccination using electronic diaries. The rates of local and systemic adverse reactions reported in Study 2 among participants aged

15 through 25 years following each dose of PENMENVY administered 6 months apart or a single dose of MENVEO are presented in Table 2.

Table 2. Percentage of Participants Aged 15 Through 25 Years Reporting Solicited Local and Systemic Adverse Reactions Within 7 Days of PENMENVY or MENVEO, by Dose in Study 2

		PENMENVY %		MENVEO %
Solicited Reactiona		Dose 1	Dose 2	Dose 1
		N = 608	N = 505-507	N = 600-601
Local Adverse Reactions
Pain	Any	80	74	32
	Severe	3	3	0.3
Erythema	Any	5	6	2
	Severe	0.5	0.6	0
Swelling	Any	4	6	2
	Severe	0.3	0.6	0.3
Induration	Any	4	5	2
	Severe	2	0.6	0.2
Systemic Adverse Reactions
Fatigue	Any	40	33	37
	Severe	1	2	0.5
Nausea	Any	15	12	13
	Severe	0.5	1	0.7
Myalgia	Any	15	13	11
	Severe	0.2	0.4	0.3
Arthralgia	Any	7	6	8
	Severe	0	0.2	0
Headache	Any	41	33	35
	Severe	1	1	0.7
Fever	Any	2	2	1
	Severe	0.2	0.4	0.2

Study 2: NCT04707391.

N = Number of participants in Solicited Safety Set (participants who received at least 1 dose of study vaccine who reported solicited safety data).

^a Erythema, swelling, and induration: Any (≥25 mm); Severe (>100 mm). Pain, fatigue, nausea, myalgia, arthralgia, headache: Any includes Mild (transient with no limitation in normal daily activity), Moderate (some limitation in normal daily activity), and Severe (unable to perform normal daily activity). Fever: Any (≥38.0°C/100.4°F); Severe (≥40.0°C/104.0°F).

Unsolicited Adverse Events

In an analysis across the 12 studies, unsolicited adverse events that were reported in participants who received PENMENVY (N = 3,718) and were determined to be causally related included syncope, dizziness, and pre-syncope (0.9%); lymphadenopathy (0.2%); and hypersensitivity (0.1%). The onset of syncope, dizziness, pre-syncope, and lymphadenopathy ranged from 1 to 30 days and the onset of hypersensitivity ranged from 9 to 27 days.

Serious Adverse Events

In Study 1, serious adverse events that occurred through 12 months following the first vaccination and at least 5 months following the last vaccination were reported by 1.5% of participants in the PENMENVY group (N = 1,648), 2.4% of participants in the group who received BEXSERO as a 0-, 6-month schedule with a dose of MENVEO at month 2 (N = 900), and 2.8% of participants in the group who received MENVEO at month 0 and BEXSERO at months 6 and 7 (N = 178).

In Study 2, serious adverse events that occurred through 12 months following the first vaccination and at least 5 months following the last vaccination were reported by 2.9% of participants in the PENMENVY group (N = 626) and 1.1% of participants in the group who received MENVEO at month 0 and BEXSERO at months 6 and 7 (N = 621).

Across the 12 clinical studies, serious adverse events were reported within 30 days after any dose by 0.6% of participants who received PENMENVY (N = 3,718), 0.4% of participants who received BEXSERO (N = 2,969), and 0.3% of participants who received MENVEO (N = 361). Two serious adverse events reported following administration of PENMENVY were assessed as vaccine-related and are described below.

In Study 3,¹ connective tissue disorder was reported in an adolescent participant who developed 3 episodes of petechiae (7 days after PENMENVY Dose 1, 18 days after PENMENVY Dose 2 [given 1 month after Dose 1], and 17 days after HAVRIX [Hepatitis A Vaccine]) and was diagnosed with a connective tissue disorder 44 days after PENMENVY Dose 2.

In Study 3,¹ seizures were reported in an adult participant with onset 9 hours after PENMENVY Dose 1.

Postmarketing Experience

The following adverse reactions have been reported during postapproval use of BEXSERO or MENVEO. The postmarketing safety experience with BEXSERO and MENVEO is relevant because PENMENVY contains the same group A, C, W, and Y CRM197-conjugated oligosaccharide components and MenB recombinant protein components. Because these reactions were 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 exposure.

Blood and Lymphatic System Disorders

Lymphadenopathy.^a,b

Ear and Labyrinth Disorders

Hearing impaired,^b ear pain,^b vertigo,^b vestibular disorder.^b

Eye Disorders

Eyelid ptosis.^b

General Disorders and Administration Site Conditions

Injection site reactions (including injection site pruritus,^b pain,^b erythema,^b inflammation,^b swelling,^b extensive swelling of the vaccinated limb,^a,b blisters at or around the injection site,^a and injection site nodule which may persist for more than 1 month^a), fatigue,^b malaise,^b pyrexia.^b

Immune System Disorders

Allergic reactions,^a anaphylactic reactions,^a eye swelling,^a rash,^a hypersensitivity reactions,^b anaphylaxis.^b

Infections and Infestations

Vaccination site cellulitis.^b

Injury, Poisoning, and Procedural Complications

Fall,^b head injury.^b

Investigation

Alanine aminotransferase increased,^b body temperature increased.^b

Musculoskeletal and Connective Tissue Disorders

Arthralgia,^b bone pain.^b

Nervous System Disorders

Dizziness,^b syncope,^a,b tonic convulsion,^b headache,^b facial paresis,^b balance disorder,^b vasovagal responses to injection.^a

Respiratory, Thoracic, and Mediastinal Disorders

Oropharyngeal pain.^b

Skin and Subcutaneous Tissue Disorders

Skin exfoliation.^b

^a Observed with BEXSERO.
^b Observed with MENVEO.

Postmarketing Observational Safety Study

In a postmarketing observational safety study conducted in a U.S. health maintenance organization, data from electronic health records of 48,899 persons aged 11 through 21 years were used to evaluate pre-specified events of interest following vaccination with MENVEO. Using a self-controlled case series method, Bell’s palsy showed a statistically significant increased risk in the period 1 to 84 days post vaccination compared with the control period, with an overall adjusted relative incidence of 2.9 (95% CI: 1.1-7.5). Among the 8 reported cases of Bell’s palsy, 6 cases occurred in persons who received MENVEO concomitantly with one or more of the following vaccines: Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed (Tdap), a human papillomavirus vaccine, and Influenza Vaccine. All reported Bell’s palsy cases resolved.

Drug Interactions for Penmenvy

No information provided

P

Warnings for Penmenvy

Included as part of the PRECAUTIONS section.

Precautions for Penmenvy

Management of Allergic Reactions

Appropriate medical treatment must be immediately available to manage potential anaphylactic reactions following administration of PENMENVY.

Syncope

Syncope (fainting) has occurred in association with administration of PENMENVY. Procedures should be in place to avoid injury from fainting.

Limitation of Vaccine Effectiveness

Vaccination with PENMENVY may not protect all vaccine recipients. PENMENVY may not provide protection against all meningococcal serogroup B strains [see Clinical Pharmacology (12.1)].

Altered Immunocompetence

Reduced Immune Response

Immunocompromised persons, including those receiving immunosuppressive therapy, may have reduced immune responses to PENMENVY.

Complement Deficiency

Persons with certain complement deficiencies and persons receiving treatment that inhibits terminal complement activation are at increased risk for invasive disease caused by N. meningitidis, including disease caused by serogroups A, B, C, W, and Y, even if they develop antibodies following vaccination with PENMENVY [see Clinical Pharmacology (12.1)].

Guillain-Barré Syndrome

Guillain-Barré syndrome (GBS) has been reported in temporal relationship following administration of a U.S.-licensed meningococcal quadrivalent polysaccharide conjugate vaccine. The decision by the healthcare professional to administer PENMENVY to persons with a history of GBS should take into account the expected benefits and potential risks.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

PENMENVY has not been evaluated for carcinogenic or mutagenic potential or impairment of male fertility in animals.

OVERDOSAGE

No information provided

Contraindications for Penmenvy

Do not administer PENMENVY to individuals with a severe allergic reaction (e.g., anaphylaxis) to a previous dose of PENMENVY, to any component of this vaccine, or to any other diphtheria toxoid-containing vaccine [see Description (11)].

Clinical Pharmacology for Penmenvy

Mechanism of Action

Protection against invasive meningococcal disease is conferred mainly by complement-mediated antibody-dependent killing of N. meningitidis strains.⁴ Immunization with PENMENVY is intended to stimulate the production of antibodies with bactericidal activity specific to the capsular polysaccharides of N. meningitidis serogroups A, C, W, and Y and to the protein antigens NHBA, NadA, fHbp and OMV expressed by serogroup B meningococcal strains.

NHBA, NadA, and fHbp are proteins found on the surface of meningococci and contribute to the ability of the bacterium to cause disease. OMV derived from the bacterial outer membrane contains PorA and other surface proteins. The susceptibility of serogroup B meningococci to complement-mediated antibody-dependent killing following vaccination with PENMENVY is dependent on both the antigenic similarity of the bacterial and vaccine antigens, as well as the amount of antigen expressed on the surface of the invading meningococci.

OVERDOSAGE

No information provided

Contraindications for Penmenvy

Do not administer PENMENVY to individuals with a severe allergic reaction (e.g., anaphylaxis) to a previous dose of PENMENVY, to any component of this vaccine, or to any other diphtheria toxoid-containing vaccine [see Description (11)].