These highlights do not include all the information needed to use TRUMENBA safely and effectively. See full prescribing information for TRUMENBA.TRUMENBA® (Meningococcal Group B Vaccine)Suspension for intramuscular injectionInitial U.S. Approval: 2014

1 INDICATIONS AND USAGE

Trumenba is indicated for active immunization to prevent invasive disease caused by Neisseria meningitidis serogroup B. Trumenba is approved for use in individuals 10 through 25 years of age.

2 DOSAGE AND ADMINISTRATION

For intramuscular use only.

2.1 Dose and Schedule

SPL UNCLASSIFIED SECTION

Two-dose schedule: Administer a dose (0.5 mL) at 0 and 6 months. If the second dose is administered earlier than 6 months after the first dose, a third dose should be administered at least 4 months after the second dose.

SPL UNCLASSIFIED SECTION

Three-dose schedule: Administer a dose (0.5 mL) at 0, 1–2, and 6 months.

The choice of dosing schedule may depend on the risk of exposure and the patient's susceptibility to meningococcal serogroup B disease.

2.2 Administration

Shake syringe vigorously to ensure that a homogenous white suspension of Trumenba is obtained. Do not use the vaccine if it cannot be re-suspended. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if particulate matter or discoloration is found.

Inject each 0.5 mL dose intramuscularly, using a sterile needle attached to the supplied prefilled syringe. The preferred site for injection is the deltoid muscle of the upper arm. Do not mix Trumenba with any other vaccine in the same syringe.

2.3 Use of Trumenba with other Meningococcal Group B Vaccines

Data are not available on the safety and effectiveness of using Trumenba and other meningococcal group B vaccines interchangeably to complete the vaccination series.

3 DOSAGE FORMS AND STRENGTHS

Trumenba is a suspension for intramuscular injection in 0.5 mL single-dose prefilled syringe.

4 CONTRAINDICATIONS

Severe allergic reaction (e.g. anaphylaxis) to any component of Trumenba [see Description (11)].

5 WARNINGS AND PRECAUTIONS

5.1 Management of Allergic Reactions

Epinephrine and other appropriate agents used to manage immediate allergic reactions must be immediately available should an acute anaphylactic reaction occur following administration of Trumenba.

5.2 Altered Immunocompetence

SPL UNCLASSIFIED SECTION

Reduced Immune Response

Some individuals with altered immunocompetence may have reduced immune responses to Trumenba.

SPL UNCLASSIFIED SECTION

Complement Deficiency

Persons with certain complement deficiencies and persons receiving treatment that inhibits terminal complement activation (for example, eculizumab) are at increased risk for invasive disease caused by N. meningitidis serogroup B even if they develop antibodies following vaccination with Trumenba [see Clinical Pharmacology (12)].

5.3 Limitation of Vaccine Effectiveness

Vaccination with Trumenba may not protect all vaccine recipients against N. meningitidis serogroup B infections.

5.4 Syncope

Syncope (fainting) can occur in association with administration of injectable vaccines, including Trumenba. Procedures should be in place to avoid injury from fainting.

6 ADVERSE REACTIONS

In clinical studies, the most common solicited adverse reactions in adolescents and young adults were pain at the injection site (≥85%), fatigue (≥60%), headache (≥55%), and muscle pain (≥35%).

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 to rates in the clinical trials of another vaccine and may not reflect the rates observed in clinical practice.

The safety of Trumenba was evaluated in 16,284 subjects 10 through 25 years of age in 12 clinical studies (9 randomized controlled and 3 supportive non-controlled studies) conducted in the U.S., Europe, Canada, Chile, and Australia. A total of 11,991 subjects 10 through 18 years of age, and 4,293 subjects 19 through 25 years of age received at least one dose of Trumenba. A total of 5,501 subjects 10 through 25 years of age in the control groups received saline placebo and/or one of the following vaccine(s): Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Recombinant (HPV4) (Merck & Co., Inc.); Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed (Tdap) (Sanofi Pasteur Ltd.); Meningococcal (Serogroups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine (MenACWY) (Sanofi Pasteur Inc.); a non-U.S. licensed reduced diphtheria toxoid, tetanus toxoid, acellular pertussis and inactivated polio virus vaccine (dTaP-IPV) (Sanofi Pasteur, Inc.); Hepatitis A Vaccine (HAV) (GlaxoSmithKline Biologicals).

The safety evaluation in the clinical studies included an assessment of: (1) solicited local and systemic reactions, and use of antipyretic medication after each vaccination in an electronic diary maintained by the subject or the subject's parent/legal guardian and (2) spontaneous reports of adverse events (AEs), including serious adverse events (SAEs), throughout the study (day of vaccination through 1 month or 6 months after the last vaccination, depending on the study and safety parameter).

In controlled studies, demographic characteristics were generally similar with regard to gender, race, and ethnicity among subjects who received Trumenba and those who received control. Among participants in clinical trials B1971009 (Study 1009), B1971016 (Study 1016), and B1971057 (Study 1057), 41.3% to 51.5% were male, 76.1% to 87.3% were White, 8.1% to 20.8% were Black or African-American, <2% were Asian, and 5.8% to 17.1% were Hispanic/Latino.

SPL UNCLASSIFIED SECTION

Solicited Local and Systemic Adverse Reactions

Study 1057 was a randomized, observer-blinded, multicenter trial in the U.S. and Europe. In this study, 1057 subjects 10 through 25 years of age received at least 1 dose of Trumenba on a 0- and 6-month schedule. Trumenba was co-administered with Meningococcal (Groups A, C, Y, W-135) Oligosaccharide Diphtheria CRM197 Conjugate Vaccine (MenACWY) (GSK Vaccines, SRL) for the first dose.

Study 1009 was a randomized, active-controlled, observer-blinded, multicenter trial in the U.S., Canada, and Europe in which 2,693 subjects 10 through 18 years of age received at least 1 dose of Trumenba on a 0-, 2-, and 6- month schedule. A control group (n=897) received HAV at 0 and 6 months, and saline at 2 months.

Study 1016 was a randomized, placebo-controlled, observer-blinded, multicenter trial in the U.S., Canada, and Europe in which 2,471 subjects 18 through 25 years of age received at least 1 dose of Trumenba and 822 subjects received saline on a 0-, 2,- and 6- month schedule.

Local adverse reactions at the injection site were assessed in the three studies.

Tables 1, 2, and 3 present the percentage and severity of reported local adverse reactions within 7 days following each dose of Trumenba for Study 1057 and following each dose of Trumenba or control (HAV/saline or saline) for Study 1009 and Study 1016, respectively.

In Studies 1009 and 1016, local adverse reactions were reported more frequently following Trumenba compared to control (see Tables 2 and 3, respectively).

In Study 1057, among Trumenba recipients, mean duration of pain was 2.7 days (range 1–17 days) after the first vaccination and 2.7 days (range 1–12 days) after the second vaccination; redness was 2.2 days (range 1–9 days) and 2.4 days (1–11 days), respectively; and swelling was 2.2 days (range 1–17 days) and 2.5 days (range 1–27 days), respectively.

In Study 1009, mean duration of pain was 2.4 to 2.6 days (range 1–17 days), redness was 2.0 to 2.2 days (range 1–12 days) and swelling was 2.0 to 2.1 days (range 1–21 days) for the three-dose series in the Trumenba groups. In Study 1016, mean duration of pain was 2.6 to 2.8 days (range 1–67 days), redness was 2.2 to 2.5 days (range 1–13 days) and swelling was 2.1 to 2.6 days (range 1–70 days) in the Trumenba group.

Tables 4, 5, and 6 present the percentage and severity of reported solicited systemic adverse reactions within 7 days of each dose of Trumenba for Study 1057 and within 7 days of each dose of Trumenba or control (HAV/saline or saline) for Study 1009 and Study 1016, respectively.

In three early phase studies in which it was solicited, nausea was reported in up to 24% of adolescents.

The frequencies of adverse reactions were highest after the first dose regardless of the schedule. After subsequent doses, the frequencies of adverse reactions were similar regardless of dose number and schedule.

SPL UNCLASSIFIED SECTION

Serious Adverse Events

Among the 8 controlled studies investigating the three-dose (0, 1–2, and 6 months) schedule (Trumenba N=13,275, control N=5,501), SAEs were reported by 213 (1.6%) subjects and by 106 (1.9%) subjects who received at least one dose of Trumenba or control, respectively.

SPL UNCLASSIFIED SECTION

Non-serious Adverse Events

Among the 8 controlled studies investigating the three-dose (0, 1–2, and 6 months) schedule (Trumenba N=13,275, control N=5,501), AEs that occurred within 30 days of vaccination were reported in 4,056 (30.6%) subjects who received at least one dose of Trumenba and 1,539 (28.0%) subjects in the control group who received at least one dose. AEs that occurred at a frequency of at least 2% and were more frequently observed in subjects who received Trumenba than subjects in the control group were injection site pain, fever, and headache.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Trumenba. 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 product exposure.

Immune System Disorders: Hypersensitivity reactions, including anaphylactic reactions.

Nervous system disorder: Syncope (fainting).

7 DRUG INTERACTIONS

In clinical trials, Trumenba was administered concomitantly with HPV4 in adolescents 11 through 17 years of age and with MenACWY and Tdap in adolescents 10 through 12 years of age [see Clinical Studies (14) and Adverse Reactions (6)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

SPL UNCLASSIFIED SECTION

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. There are no adequate and well-controlled studies of Trumenba in pregnant women. Available human data on Trumenba administered to pregnant women are insufficient to inform vaccine-associated risks in pregnancy.

Two developmental toxicity studies were performed in female rabbits administered Trumenba prior to mating and during gestation. The dose was 0.5 mL at each occasion (a single human dose is 0.5 mL). These studies revealed no evidence of harm to the fetus or offspring (until weaning) due to Trumenba [see Animal Data].

SPL UNCLASSIFIED SECTION

Animal Data

Two developmental toxicity studies were performed in female rabbits. Animals were administered Trumenba by intramuscular injection 17 days and 4 days prior to mating and on gestation Days 10 and 24. The dose was 0.5 mL at each occasion (a single human dose is 0.5 mL). No adverse effects on pre-weaning development up to post-natal day 21 were observed. There were no fetal malformations or variations observed due to the vaccine.

8.2 Lactation

SPL UNCLASSIFIED SECTION

Risk Summary

Available data are not sufficient to assess the effects of Trumenba 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 Trumenba and any potential adverse effects on the breastfed child from Trumenba 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 have not been established in children <10 years of age. In a clinical study, 90% of infants <12 months of age who were vaccinated with a reduced dosage formulation had fever. Clinical data strongly suggest that a two-dose regimen of Trumenba would be ineffective in children 1 to <10 years of age.

8.5 Geriatric Use

Safety and effectiveness of Trumenba in adults >65 years of age have not been established.

11 DESCRIPTION

Trumenba is a sterile suspension composed of two recombinant lipidated factor H binding protein (fHbp) variants from N. meningitidis serogroup B, one from fHbp subfamily A and one from subfamily B (A05 and B01, respectively).1 The proteins are individually produced in E. coli. Production strains are grown in defined fermentation growth media to a specific density. The recombinant proteins are extracted from the production strains and purified through a series of column chromatography steps. Polysorbate 80 (PS80) is added to the drug substances and is present in the final drug product.

Each 0.5 mL dose contains 60 micrograms of each fHbp variant (total of 120 micrograms of protein), 0.018 mg of PS80 and 0.25 mg of Al3+ as AlPO4 in 10 mM histidine buffered saline at pH 6.0.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Protection against invasive meningococcal disease is conferred mainly by complement-mediated antibody-dependent killing of N. meningitidis. The effectiveness of Trumenba was assessed by measuring serum bactericidal activity using human complement (hSBA).

fHbp is one of many proteins found on the surface of meningococci and contributes to the ability of the bacterium to avoid host defenses. fHbps can be categorized into two immunologically distinct subfamilies, A and B.1 The susceptibility of serogroup B meningococci to complement-mediated antibody-dependent killing following vaccination with Trumenba is dependent on both the antigenic similarity of the bacterial and vaccine fHbps, as well as the amount of fHbp expressed on the surface of the invading meningococci.

13 NONCLINICAL TOXICOLOGY

Trumenba has not been evaluated for carcinogenic or mutagenic potential or impairment of fertility in males. Vaccination of female rabbits with Trumenba had no effect on fertility [see Pregnancy (8.1)].

14 CLINICAL STUDIES

The immunogenicity of Trumenba described in this section is based on results from four clinical studies:

Serum bactericidal antibodies were measured with hSBA assays that used each of four meningococcal serogroup B strains. These four primary test strains express fHbp variants representing the two subfamilies (A and B) of meningococcal serogroup B strains causing invasive disease in the U.S. and Europe. The studies assessed the proportions of subjects with a 4-fold or greater increase in hSBA titer for each of the four primary strains. The studies also assessed the composite response to the four primary strains combined (proportion of subjects who achieved a hSBA titer greater than or equal to 1:8 [three strains] and 1:16 [one strain]). To assess the effectiveness of the two- and three-dose schedules of Trumenba against diverse meningococcal serogroup B strains, the proportion of subjects achieving a defined hSBA titer (≥LLOQ) following completion of the two- or three-dose series was evaluated against a panel of 10 additional strains, each expressing a different fHbp variant.

• •Following the two-dose schedule (0 and 6 months) in subjects 10 through 25 years of age in the U.S. and Europe (Study 1057);
• •Following the three-dose schedule (0, 2, and 6 months) in subjects 10 through 25 years of age in the U.S., Canada, and Europe (Studies 1009 and 1016); and
• •Following the two-dose (0 and 6 months) and three-dose schedules (0, 1–2, and 6 months) in subjects 11 through 18 years of age in Europe (Study 1012).

14.1 Immunogenicity

The hSBA responses to each of the primary strains observed after the second dose of Trumenba in Study 1057 are presented in Table 7.

The hSBA responses after the second dose of Trumenba in Study 1057 against a panel of 10 additional strains representing the diversity of meningococcal fHbp types prevalent among strains circulating in the US are presented in Table 8.

The hSBA responses to each of the primary strains observed in U.S. subjects after the third dose of Trumenba are presented for Study 1009 and Study 1016 in Table 9.

The hSBA responses after the third dose of Trumenba against a panel of 10 additional strains representing the diversity of meningococcal fHbp types prevalent among strains circulating in the U.S. are presented for Study 1009, and Study 1016 in Table10.

In Study 1012, Trumenba was administered according to different schedules, including Group 1 (0, 1, and 6 months), Group 2 (0, 2, and 6 months) and Group 3 (0 and 6 months). The hSBA responses observed after the second dose in Groups 1, 2, and 3 and completion of the three-dose series in Group 1 and 2 are presented in Table 11.

14.2 Concomitant Vaccine Administration

Study B1971011 (Study 1011) evaluated the immunogenicity of concomitantly administered Trumenba and Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Recombinant (HPV4) (Merck & Co, Inc.). U.S. subjects 11 through 17 years of age were randomized into three groups: Group 1 received Trumenba and HPV4 (N=992), Group 2 received Trumenba and saline (N=990), and Group 3 received saline and HPV4 (N=501). All vaccines were administered according to a 0-, 2- and 6-month schedule. Immune responses were evaluated by comparisons of geometric mean titer [GMT] for each HPV type at 1 month after the third HPV4 vaccination (Group 1 vs. Group 3), and hSBA GMTs using two meningococcal serogroup B strains [variants A22 and B24] 1 month after the third Trumenba vaccination (Group 1 vs. Group 2). The noninferiority criteria for the comparisons of GMTs [lower limit of the 2-sided 95% confidence interval (CI) of the GMT ratio (Group 1/Group 3 for HPV and Group 1/Group 2 for meningococcal serogroup B strains) >0.67] were met for three HPV types (6, 11 and 16) and for the meningococcal serogroup B strains tested. For HPV-18, the lower bound of the 95% CI for the GMT ratio was 0.62 at 1 month after the third HPV4 vaccination

Study B1971015 (Study 1015) evaluated the immunogenicity of concomitantly administered Trumenba and Meningococcal (Serogroups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine (MenACWY) (Sanofi Pasteur Inc.) and Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed (Tdap) (Sanofi Pasteur Ltd.) vaccines. U.S. subjects 10 through 12 years of age were randomized into three groups: Group 1 received Trumenba at 0, 2, and 6 months, and MenACWY and Tdap were coadministered with the first Trumenba dose (N=883). Group 2 received saline at 0, 2 and 6 months, and MenACWY and Tdap were coadministered with the first saline injection (N=870). Group 3 received Trumenba at 0, 2 and 6 months, and saline was coadministered with the first Trumenba dose (N=875). Immune responses were evaluated by comparisons of GMTs for each of the MenACWY and Tdap antigens 1 month after the first Trumenba vaccination, and hSBA GMTs using two meningococcal serogroup B strains [variants A22 and B24] 1 month after the third Trumenba vaccination. The noninferiority criteria for the comparisons of GMTs [lower limit of the 2-sided 95% CI of the GMT ratio (Group 1/Group 3 for meningococcal serogroup B strains and Group 1/Group 2 for MenACWY and Tdap) >0.67] were met for all antigens.

15 REFERENCES

• 1.Wang X, et al. Prevalence and genetic diversity of candidate vaccine antigens among invasive Neisseria meningitidis isolates in the U.S. Vaccine 2011; 29:4739–4744.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Trumenba is supplied in the following strengths and package configurations:

Prefilled Syringe, 1 Dose (10 per package) – NDC 0005-0100-10.

Prefilled Syringe, 1 Dose (5 per package) – NDC 0005-0100-05.

Prefilled Syringe, 1 Dose (1 per package) – NDC 0005-0100-02 (This Package Not for Sale).

After shipping, Trumenba may arrive at temperatures between 2°C to 25°C (36°F to 77°F).

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

16.2 Storage and Handling

Upon receipt, store refrigerated at 2°C to 8°C (36°F to 46°F).

Store syringes in the refrigerator horizontally (laying flat on the shelf) to minimize the re-dispersion time.

Do not freeze. Discard if the vaccine has been frozen.

17 PATIENT COUNSELING INFORMATION

Prior to administration of this vaccine, the healthcare professional should inform the individual, parent, guardian, or other responsible adult of the following:

Provide the Vaccine Information Statements, which are available free of charge at the Centers for Disease Control and Prevention (CDC) website (www.cdc.gov/vaccines).

U.S. Govt. License No. 3

LAB-0722-11.0

• •The importance of completing the immunization series.
• •Report any suspected adverse reactions to a healthcare professional.