Vaccine Information: Trumenba (Page 2 of 3)

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Trumenba. Because these reactions are reported voluntarily froma 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 to <18 years of age and with MCV4 and Tdap in adolescents 10 to <13 years of age [see Clinical Studies (14.0) and Adverse Reactions (6.0)].

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. 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].

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

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.

8.5 Geriatric Use

Safety and effectiveness of Trumenba in adults older than 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 following the three-dose schedule (0, 2, and 6 months) was evaluated in individuals 10 to 25 years of age in the U.S., Canada, and Europe (Studies 1 and 2) and following the two-dose (0 and 6 months) and three-dose schedules (0, 1–2, and 6 months) in individuals 11 to 18 years of age in Europe (Study 3). 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) and, when taken together, are representative 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) or 1:16 (one strain). To assess the effectiveness of the three-dose schedule of Trumenba against diverse meningococcal serogroup B strains, the proportion of subjects achieving a defined hSBA titer post-dose 3 was evaluated against a panel of 10 additional strains, each expressing a different fHBP variant.

14.1 Immunogenicity

The hSBA responses to each of the primary strains observed in U.S. subjects after the third dose of Trumenba are presented for Study 1 and Study 2 in Table 5.

Table 5: Percentages of U.S. Individuals 10 to 25 Years of Age With ≥4-fold rise in hSBA Titer and Composite Response Following Administration of Trumenba on a 0-, 2-, and 6-Month Schedule for Four Primary Strains (Studies 1 and 2)*, , , §
Study 1 Study 2
(10 to 18 Years of Age) (18 to 25 Years of Age)
n %(95% CI) n %(95% CI)
Subfamily/Subgroup fHBP Variant #, Þ
Abbreviations: CI=confidence interval; fHBP=factor H binding protein; hSBA=serum bactericidal assay using human complement; LLOQ=lower limit of quantitation; LOD=limit of detection.
Note: LLOQ = 1:16 for A22; 1:8 for A56, B24, and B44.
Note: The 4-fold increase is defined as follows: (1) For subjects with a baseline hSBA titer <1:4, a response is defined as an hSBA titer ≥1:16. (2) For subjects with a baseline hSBA titer ≥1:4, a response is defined as an hSBA titer ≥4 times the LLOQ or ≥4 times the baseline titer, whichever was higher.
Note: Pre-specified criteria for assessment of hSBA responses (4-fold rise in titer to each primary test strain, and titer above LLOQ for all four primary test strains) among U.S. subjects were met in these studies.
*
Evaluable immunogenicity population.
Study 1 = NCT01830855 and Study 2 = NCT01352845.
Study 1: Group 1 (0, 2, and 6 months).
§
Study 2: Group 1 (0, 2, and 6 months).
Exact 2-sided confidence interval (Clopper-Pearson method) based upon the observed proportion of subjects.
#
The strains expressing variants A22, A56, B24, and B44 correspond to strains PMB80, PMB2001, PMB2948, and PMB2707, respectively.
Þ
For the third dose, serum was obtained approximately 1 month after vaccination.
ß
Composite response = hSBA ≥ LLOQ for all 4 primary meningococcal B strains.
≥4-Fold Increase
PMB80 (A22) Dose 3 587 86.2(83.1, 88.9) 644 81.1(77.8, 84.0)
PMB2001 (A56) Dose 3 526 92.0(89.4, 94.2) 621 90.7(88.1, 92.8)
PMB2948 (B24) Dose 3 585 81.9(78.5, 84.9) 634 83.9(80.8, 86.7)
PMB2707 (B44) Dose 3 555 88.3(85.3, 90.8) 643 79.3(76.0, 82.4)
Composite hSBA response ß
Before Dose 1 507 0.6(0.1, 1.7) 610 3.3(2.0, 5.0)
Dose 3 537 85.7(82.4, 88.5) 625 82.4(79.2, 85.3)

The hSBA responses against a panel of 10 additional strains observed in U.S. subjects after the third dose of Trumenba are presented for Study 1 and Study 2 in Table 6.

Table 6. Percentages of U.S. Individuals 10 to 25 Years of Age With a hSBA Titer ≥ LLOQ Against 10 Additional Strains Following Administration of Trumenba on a 0-, 2-, and 6-Month Schedule (Study 1 and Study 2)- *,
Study 1 Study 2
(10 to 18 Years of Age) (18 to 25 Years of Age)
n %(95% CI) n %(95% CI)
Subfamily/Subgroup fHBP Variant §,
Abbreviations: CI=confidence interval; fHBP=factor H binding protein; hSBA=serum bactericidal assay using human complement; LLOQ=lower limit of quantitation.
Note: LLOQ = 1:16 for A06, A12, and A19; 1:8 for A07, A15, A29, B03, B09, B15, and B16.
*
The evaluable immunogenicity population was used for the analysis.
Study 1 = NCT01830855 and Study 2 = NCT01352845.
Exact 2-sided confidence interval (Clopper and Pearson) based upon the observed proportion of subjects.
§
The strains expressing variants A06, A12, A19, A07, A15, A29, B03, B09, B15, and B16 correspond to strains PMB3010, PMB824, PMB1989, PMB3040, PMB1672, PMB3175, PMB1256, PMB866, PMB431, and PMB648, respectively.
For the third dose, serum was obtained approximately 1 month after vaccination.
A/N1C1 PMB3175 (A29) Before Dose 1 169 11.2(6.9, 17.0) 160 23.8(17.4, 31.1)
Dose 3 176 98.9(96.0, 99.9) 162 98.8(95.6, 99.9)
A/N1C2 PMB3010 (A06) Before Dose 1 178 7.9(4.4, 12.8) 166 10.8(6.6, 16.6)
Dose 3 179 97.8(94.4, 99.4) 164 89.0(83.2, 93.4)
A/N2C1 PMB3040 (A07) Before Dose 1 170 37.6(30.3, 45.4) 165 55.8(47.8, 63.5)
Dose 3 178 96.1(92.1, 98.4) 165 95.2(90.7, 97.9)
PMB824 (A12) Before Dose 1 180 5.0(2.3, 9.3) 166 4.8(2.1, 9.3)
Dose 3 180 76.1(69.2, 82.1) 165 66.7(58.9, 73.8)
PMB1672 (A15) Before Dose 1 170 15.9(10.7, 22.3) 159 30.2(23.2, 38.0)
Dose 3 166 86.7(80.6, 91.5) 159 89.9(84.2, 94.1)
A/N2C2 PMB1989 (A19) Before Dose 1 174 5.7(2.8, 10.3) 158 23.4(17.1, 30.8)
Dose 3 173 91.9(86.8, 95.5) 163 94.5(89.8, 97.4)
B/N6 PMB1256 (B03) Before Dose 1 183 2.2(0.6, 5.5) 164 5.5(2.5, 10.2)
Dose 3 181 92.3(87.4, 95.7) 161 84.5(77.9, 89.7)
PMB866 (B09) Before Dose 1 180 12.2(7.8, 17.9) 165 13.9(9.0, 20.2)
Dose 3 182 85.7(79.8, 90.5) 162 72.2(64.7, 79.0)
PMB431 (B15) Before Dose 1 180 27.8(21.4, 34.9) 163 33.1(26.0, 40.9)
Dose 3 183 97.3(93.7, 99.1) 163 95.7(91.4, 98.3)
PMB648 (B16) Before Dose 1 180 6.7(3.5, 11.4) 161 11.8(7.3, 17.8)
Dose 3 180 83.9(77.7, 88.9) 159 72.3(64.7, 79.1)

In Study 3, 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 7.

Table 7: Percentages of European Individuals 11 to 18 Years of Age With a ≥4-Fold Increase in hSBA Titer and Composite Response *,
Group 1 Group 2 Group 3
3-Dose Schedule(0, 1, and 6 Months) 3-Dose Schedule(0, 2, and 6 Months)§ 2-Dose Schedule(0 and 6 Months)
fHBP Variant #, Þ %(95% CI)ß %(95% CI)ß %(95% CI)ß
Abbreviations: CI=confidence interval; fHBP=factor H binding protein; hSBA=serum bactericidal assay using human complement; LLOQ=lower limit of quantitation; NA=not applicable.
Note: LLOQ = 1:16 for PMB80 (A22) and 1:8 for PMB2001 (A56), PMB2948 (B24), and PMB2707 (B44).
Note: The ≥4-fold increase is defined as follows: (1) For subjects with a baseline hSBA titer <1:4, a ≥4-fold increase was defined as an hSBA titer ≥1:16. (2) For subjects with a baseline hSBA titer ≥1:4, a ≥4-fold increase was defined as an hSBA titer ≥4 times the LLOQ or ≥4 times the baseline titer, whichever was higher.
*
Per-schedule Evaluable populations. Dose 2 data include subjects who received two doses, irrespective of whether they received the third dose.
Study 3: NCT01299480.
Group 1 (0, 1, and 6 months). The denominators ranged from 173 to 187 after Dose 2 and 178 to 188 after Dose 3, depending on the strain.
§
Group 2 (0, 2, and 6 months). The denominators ranged from 229 to 240 after Dose 2 and 159 to 162 after Dose 3, depending on the strain.
Group 3 (0 and 6 months). The denominators ranged from 188 to 203 after Dose 2, depending on the strain.
#
The strains expressing variant A22, A56, B24, and B44 correspond to strains PMB80, PMB2001, PMB2948, and PMB2707, respectively.
Þ
For the second and third doses, serum was obtained approximately 1 month after vaccination.
ß
Exact 2-sided confidence interval (Clopper and Pearson) based upon the observed proportion of subjects.
à
Composite response = hSBA ≥LLOQ for all 4 primary meningococcal B strains.
≥4-Fold Increase
PMB80 (A22)
Dose 2 58.8(51.4, 66.0) 72.5(66.4, 78.0) 82.3(76.3, 87.3)
Dose 3 77.6(70.9, 83.4) 87.7(81.6, 92.3) NA
PMB2001 (A56)
Dose 2 87.8(82.2, 92.2) 90.7(86.2, 94.1) 90.1(85.1, 93.8)
Dose 3 91.2(86.1, 94.9) 93.8(88.8, 97.0) NA
PMB2948 (B24)
Dose 2 51.1(43.6, 58.5) 54.2(47.7, 60.7) 64.5(57.4, 71.1)
Dose 3 74.1(67.1, 80.2) 78.3(71.1, 84.4) NA
PMB2707 (B44)
Dose 2 48.1(40.7, 55.6) 53.4(46.8, 59.9) 66.0(58.9, 72.6)
Dose 3 80.9(74.5, 86.2) 78.6(71.4, 84.7) NA
Composite Response Þ , à
Before Dose 1 4.6(2.0, 8.8) 2.2(0.7, 5.0) 1.5(0.3, 4.4)
Dose 2 52.0(44.3, 59.7) 52.0(45.3, 58.6) 72.9(65.9, 79.1)
Dose 3 80.3(73.7, 85.9) 81.8(74.9, 87.4) NA

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