Label: HIBERIX (haemophilus b conjugate vaccine- tetanus toxoid conjugate kit

  • NDC Code(s): 58160-816-01, 58160-816-05, 58160-817-01, 58160-817-05, view more
    58160-818-11
  • Packager: GlaxoSmithKline Biologicals SA
  • Category: VACCINE LABEL
  • DEA Schedule: None
  • Marketing Status: Biologic Licensing Application

Drug Label Information

Updated May 8, 2019

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  • HIGHLIGHTS OF PRESCRIBING INFORMATION
    These highlights do not include all the information needed to use HIBERIX safely and effectively. See full prescribing information for HIBERIX.
    HIBERIX [Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate)] for injection, for intramuscular use
    Initial U.S. Approval: 2009

    INDICATIONS AND USAGE

    HIBERIX is a vaccine indicated for active immunization for the prevention of invasive disease caused by Haemophilus influenzae type b. HIBERIX is approved for use in children aged 6 weeks through 4 years (prior to fifth birthday). (1)

    DOSAGE AND ADMINISTRATION

     
    For intramuscular administration only.

    A 4-dose series (0.5-mL each) given by intramuscular injection (2.3):

    Primary series: One dose each at 2, 4, and 6 months of age. The first dose may be given as early as 6 weeks of age.
    Booster: One dose at 15 through 18 months of age.

    Do not mix HIBERIX with any other vaccine in the same syringe or vial. (2.2)

    DOSAGE FORMS AND STRENGTHS

    Solution for injection supplied as a vial of lyophilized vaccine to be reconstituted with the accompanying vial of saline diluent. A single dose, after reconstitution, is 0.5 mL. (3)

    CONTRAINDICATIONS

    Severe allergic reaction (e.g., anaphylaxis) after a previous dose of any H. influenzae type b- or tetanus toxoid-containing vaccine or any component of HIBERIX. (4)

    WARNINGS AND PRECAUTIONS

    If Guillain-Barré syndrome has occurred within 6 weeks of receipt of a prior vaccine containing tetanus toxoid, the decision to give HIBERIX should be based on potential benefits and risks. (5.1)
    Syncope (fainting) can occur in association with administration of injectable vaccines, including HIBERIX. Procedures should be in place to avoid falling injury and to restore cerebral perfusion following syncope. (5.2)
    Apnea following intramuscular vaccination has been observed in some infants born prematurely. Decisions about when to administer an intramuscular vaccine, including HIBERIX, to infants born prematurely should be based on consideration of the individual infant’s medical status, and the potential benefits and possible risks of vaccination. (5.3)

    ADVERSE REACTIONS

    Common solicited adverse reactions (≥20%) were pain and redness at the injection site, irritability, drowsiness, fever, loss of appetite, fussiness, and restlessness. (6.1)

    To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or VAERS at 1-800-822-7967 or www.vaers.hhs.gov.

    See 17 for PATIENT COUNSELING INFORMATION.

    Revised: 5/2019

  • Table of Contents
  • 1 INDICATIONS AND USAGE

    HIBERIX is indicated for active immunization for the prevention of invasive disease caused by Haemophilus influenzae(H. influenzae) type b. HIBERIX is approved for use in children aged 6 weeks through 4 years (prior to fifth birthday).

    The evaluation of effectiveness of HIBERIX was based on immune responses in children using serological endpoints that predict protection from invasive disease due to H. influenzae type b [see Clinical Pharmacology (12.1), Clinical Studies (14.1)].

  • 2 DOSAGE AND ADMINISTRATION

    2.1 Reconstitution

    HIBERIX is to be reconstituted only with the accompanying saline diluent. The reconstituted vaccine should be a clear and colorless solution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If either of these conditions exists, the vaccine should not be administered.

    Figure 1Figure 2Figure 3Figure 4

    Figure 1. Cleanse both vial stoppers. Withdraw 0.6 mL of saline diluent from accompanying vial.

    Figure 2. Transfer 0.6 mL saline diluent into lyophilized vaccine vial.

    Figure 3. Shake the vial well.

    Figure 4. After reconstitution, withdraw 0.5 mL of reconstituted vaccine and administer intramuscularly.

    Use a separate sterile needle and sterile syringe for each individual.

    After reconstitution, administer HIBERIX immediately or store refrigerated between 2° and 8°C (36° and 46°F) and administer within 24 hours. If the vaccine is not administered immediately, shake the solution well again before administration.

    2.2 Administration

    For intramuscular use only.

    HIBERIX is administered as a single dose (0.5 mL) by intramuscular injection into the anterolateral aspect of the thigh or deltoid.

    Do not administer this product intravenously, intradermally, or subcutaneously.

    If HIBERIX is administered concomitantly with other injectable vaccines, they should be given with separate syringes and at different injection sites. HIBERIX should not be mixed with any other vaccine in the same syringe or vial.

    2.3 Dose and Schedule

    HIBERIX is administered as a 4-dose series (0.5-mL each dose) given by intramuscular injection. The series consists of a primary immunization course of 3 doses administered at 2, 4, and 6 months of age, followed by a booster dose administered at 15 through 18 months of age. The first dose may be given as early as 6 weeks of age.

  • 3 DOSAGE FORMS AND STRENGTHS

    HIBERIX is a solution for injection supplied as a single-dose vial of lyophilized vaccine to be reconstituted with the accompanying vial of saline diluent. A single dose, after reconstitution, is 0.5 mL.

  • 4 CONTRAINDICATIONS

    Severe allergic reaction (e.g., anaphylaxis) after a previous dose of any H. influenzae type b- or tetanus toxoid-containing vaccine or any component of the vaccine is a contraindication to administration of HIBERIX [see Description (11)].

  • 5 WARNINGS AND PRECAUTIONS

    5.1 Guillain-Barré Syndrome

    If Guillain-Barré syndrome has occurred within 6 weeks of receipt of a prior vaccine containing tetanus toxoid, the decision to give any tetanus toxoid-containing vaccine, including HIBERIX, should be based on careful consideration of the potential benefits and possible risks.

    5.2 Syncope

    Syncope (fainting) can occur in association with administration of injectable vaccines, including HIBERIX. Syncope can be accompanied by transient neurological signs such as visual disturbance, paresthesia, and tonic-clonic limb movements. Procedures should be in place to avoid falling injury and to restore cerebral perfusion following syncope.

    5.3 Apnea in Premature Infants

    Apnea following intramuscular vaccination has been observed in some infants born prematurely. Decisions about when to administer an intramuscular vaccine, including HIBERIX, to infants born prematurely should be based on consideration of the individual infant’s medical status and the potential benefits and possible risks of vaccination.

    5.4 Preventing and Managing Allergic Vaccine Reactions

    Prior to administration, the healthcare provider should review the patient's immunization history for possible vaccine hypersensitivity. Epinephrine and other appropriate agents used for the control of immediate allergic reactions must be immediately available should an acute anaphylactic reaction occur.

    5.5 Altered Immunocompetence

    Safety and effectiveness of HIBERIX in immunosuppressed children have not been evaluated. If HIBERIX is administered to immunosuppressed children, including children receiving immunosuppressive therapy, the expected immune response may not be obtained.

    5.6 Interference with Laboratory Tests

    Urine antigen detection may not have a diagnostic value in suspected disease due to H. influenzae type b within 1 to 2 weeks after receipt of a H. influenzae type b-containing vaccine, including HIBERIX [see Drug Interactions (7.1)].

    5.7 Tetanus Immunization

    Immunization with HIBERIX does not substitute for routine tetanus immunization.

  • 6 ADVERSE REACTIONS

    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 with rates in the clinical trials of another vaccine and may not reflect the rates observed in practice. There is the possibility that broad use of HIBERIX could reveal adverse reactions not observed in clinical trials.

    Across clinical trials, common solicited adverse reactions (≥20%) were pain and redness at the injection site, irritability, drowsiness, fever, loss of appetite, fussiness, and restlessness.

    Study 1: In a randomized, controlled clinical trial conducted in the U.S., children were vaccinated with HIBERIX (n = 2,963), a U.S.-licensed monovalent Haemophilus b Conjugate Vaccine (Control PRP-T) (Sanofi Pasteur SA) (n = 520), or a U.S.-licensed combined Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Inactivated Poliovirus and Haemophilus b Conjugate Vaccine (DTaP-IPV/Hib) (Sanofi Pasteur Ltd.) (n = 520) at 2, 4, and 6 months of age. HIBERIX and Control PRP-T (Sanofi Pasteur SA) were administered concomitantly with PEDIARIX (DTaP-HBV-IPV) [Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Hepatitis B (Recombinant) and Inactivated Poliovirus Vaccine] and Pneumococcal 13-valent Conjugate Vaccine (PCV13) (Wyeth Pharmaceuticals Inc.) with Doses 1, 2, and 3 and ROTARIX [Rotavirus Vaccine, Live, Oral] with Doses 1 and 2. DTaP-IPV/Hib was administered concomitantly with PCV13 and ENGERIX-B [Hepatitis B Vaccine (Recombinant)] with Doses 1, 2, and 3 and ROTARIX with Doses 1 and 2. If a birth dose of hepatitis B vaccine was received, ENGERIX-B was given with Doses 1 and 3. In the total population, 51.2% were male; 61% were white, 8% were Asian, 9% were black, and 22% were other racial/ethnic groups.

    In Study 1, children received a booster dose of either HIBERIX (n = 2,336), a Haemophilus b Conjugate Vaccine (Control PRP-T) (Sanofi Pasteur SA) (n = 435), or a combined Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Inactivated Poliovirus and Haemophilus b Conjugate Vaccine (DTaP-IPV/Hib) (Sanofi Pasteur Ltd.) (n = 400) at 15 to 18 months of age (mean age: 15.6 months) following primary vaccination at 2, 4, and 6 months of age with the same vaccine. The booster dose of HIBERIX and Control PRP-T (Sanofi Pasteur SA) was administered concomitantly with INFANRIX (DTaP) [Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed

    In 7 additional clinical studies, 1,008 children received HIBERIX as a booster dose following primary vaccination with either HIBERIX (n = 530), Haemophilus b Conjugate Vaccine (Control PRP-T) (Sanofi Pasteur SA) (n = 235), Haemophilus b Conjugate Vaccine (Merck & Co., Inc.) (n = 26), or Haemophilus b Conjugate Vaccine (Wyeth Pharmaceuticals Inc.) (no longer licensed in the U.S., n = 217). None of the studies included a comparator group that received a booster dose with a U.S.-licensed Haemophilus b Conjugate Vaccine. Studies were conducted in Europe, Canada, and Latin America. Across these studies, the mean age of subjects at the time of booster vaccination with HIBERIX ranged from 16 to 19 months. At the time of vaccination, 172 (17.1%) subjects were aged 11 to 14 months, 642 (63.7%) subjects were aged 15 to 18 months, and 194 (19.2%) subjects were aged 19 to 25 months. Approximately half of the subjects were male. Among subjects for whom information on race/ethnicity was available, nearly all subjects were white.

    In these 7 studies, HIBERIX was administered concomitantly with non-U.S. formulations (containing 2.5 mg 2-phenoxyethanol per dose as preservative) of one of the following U.S.-licensed vaccines: INFANRIX (DTaP) [Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed], KINRIX (DTaP-IPV) [Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed and Inactivated Poliovirus Vaccine], or PEDIARIX (DTaP-HBV-IPV). In the studies, DTaP-IPV and DTaP-HBV-IPV were administered in dosing regimens not approved in the U.S. Some subjects received DTaP-HBV (GlaxoSmithKline Biologicals, not licensed in U.S.) concomitantly with HIBERIX.

    Solicited Adverse Reactions

    The reported frequencies of solicited local reactions and general adverse reactions from Study 1 after primary and booster vaccination are presented in Table 1 and Table 2, respectively.

    Table 1. Percentage of Children with Solicited Local Reactions and General Adverse Reactions within 4 Days of Primary Series Vaccinationa (at 2, 4, and 6 Months of Age) with HIBERIXb, Control PRP-Tb, or DTaP-IPV/Hibc, Total Vaccinated Cohortd

    Adverse Reactions

    HIBERIX

    %

    Control PRP-T

    %

    DTaP-IPV/Hib

    %

    Dose

    Dose

    Dose

    1

    2

    3

    1

    2

    3

    1

    2

    3

    Locale

    n

    2,828

    2,668

    2,553

    498

    481

    463

    492

    469

    443

    Pain

    49

    45

    43

    57

    53

    48

    58

    50

    49

    Pain, Grade 3f

    4

    3

    2

    9

    5

    4

    9

    3

    3

    Redness

    19

    25

    29

    24

    32

    30

    26

    31

    37

    Redness, >20 mm

    1

    1

    1

    2

    1

    0

    2

    2

    2

    Swelling

    13

    15

    19

    19

    22

    20

    20

    24

    24

    Swelling, >20 mm

    2

    1

    1

    4

    3

    1

    4

    2

    2

    General

    n

    2,830

    2,669

    2,553

    499

    480

    463

    492

    469

    443

    Irritability

    69

    70

    67

    76

    71

    67

    73

    67

    69

    Irritability, Grade 3g

    4

    6

    5

    8

    8

    5

    6

    5

    3

    Drowsiness

    60

    54

    49

    66

    56

    50

    61

    52

    50

    Drowsiness, Grade 3h

    2

    3

    2

    4

    2

    1

    4

    3

    3

    Loss of appetite

    29

    28

    28

    33

    32

    27

    34

    24

    24

    Loss of appetite, Grade 3i

    1

    2

    2

    2

    1

    0

    1

    0

    1

    Fever

    14

    19

    19

    16

    19

    16

    12

    11

    18

    Fever, Grade 3j

    0

    1

    1

    0

    0

    1

    0

    0

    1

     
    n = All subjects for whom safety data were available.
     
    a Within 4 days of vaccination defined as day of vaccination and the next 3 days.
     
    b Each dose (Doses 1, 2, and 3) of HIBERIX or Control PRP-T (Sanofi Pasteur SA) was concomitantly administered with PEDIARIX (DTaP-HBV-IPV) and PCV13. Doses 1 and 2 were concomitantly administered with ROTARIX.
     
    c Each dose (Doses 1, 2, and 3) of DTaP-IPV/Hib was concomitantly administered with PCV13 and ENGERIX-B with Doses 1, 2, and 3 and ROTARIX with Doses 1 and 2. If a birth dose of hepatitis B vaccine was received, ENGERIX-B was given with Doses 1 and 3.
     
    d Study 1: NCT01000974.
     
    e Local reactions at the injection site for HIBERIX, Control PRP-T, or DTaP-IPV/Hib.
     
    f Grade 3 pain defined as cried when limb was moved/spontaneously painful.
     
    g Grade 3 irritability defined as crying that could not be comforted/prevented normal activity.
     
    h Grade 3 drowsiness defined as prevented normal daily activity.
     
    i Grade 3 loss of appetite defined as did not eat at all.
     
    j Fever defined as ≥100.4°F (≥38.0°C) rectally; Grade 3 fever defined as >103.1°F (>39.5°C) rectally.
    Table 2. Percentage of Children with Solicited Local Reactions and General Adverse Reactions within 4 Days of Booster Vaccinationa (Dose 4 at 15 through 18 Months of Age) with HIBERIXb, Control PRP-Tb, or DTaP-IPV/Hib, Total Vaccinated Cohortc

    Adverse Reactions

    HIBERIX

    %

    Control PRP-T

    %

    DTaP-IPV/Hib%

    Any

    Grade 3d

    Any

    Grade 3d

    Any

    Grade 3d

    Locale

    n = 2,224

    n = 416

    n = 379

    Pain

    41

    1

    43

    1

    43

    2

    Redness

    30

    0

    31

    1

    30

    3

    Swelling

    18

    1

    20

    1

    20

    3

    General

    n = 2,225

    n = 416

    n = 379

    Irritability

    58

    2

    60

    5

    53

    2

    Drowsiness

    39

    1

    39

    3

    31

    0

    Loss of appetite

    28

    1

    34

    2

    22

    1

    Feverf

    15

    1

    14

    1

    18

    1

     
    n = All subjects for whom safety data were available.
     
    Subjects received primary vaccination at 2, 4, and 6 months of age with the same vaccine as the booster dose.

    a Within 4 days of vaccination defined as day of vaccination and the next 3 days.

    b The booster dose of HIBERIX and Control PRP-T (Sanofi Pasteur SA) was concomitantly administered with INFANRIX (DTaP).

    c Study 1: NCT01000974.

    d Grade 3 pain defined as cried when limb was moved/spontaneously painful.

    Grade 3 redness, swelling defined as >20 mm.

    Grade 3 irritability defined as crying that could not be comforted/prevented normal activity.

    Grade 3 drowsiness defined as prevented normal daily activity.

    Grade 3 loss of appetite defined as did not eat at all.

    Grade 3 fever defined as >102.2°F (>39.0°C) axillary.

    e Local reactions at the injection site for HIBERIX, Control PRP-T, or DTaP-IPV/Hib.

    f Fever defined as ≥99.5°F (≥37.5°C) axillary.

    In an open-label, multicenter study conducted in Germany (Study 2), 371 children received a booster dose of HIBERIX administered concomitantly with DTaP-HBV-IPV. The mean age at the time of vaccination was 16 months. Subjects in this study had previously received a primary series with either HIBERIX (n = 92), Control PRP-T (Sanofi Pasteur SA) (n = 96), or Haemophilus b Conjugate Vaccine (Wyeth Pharmaceuticals Inc.) (no longer licensed in the U.S.) (n = 183). All subjects previously received 3 doses of DTaP-HBV-IPV. The reported frequencies of solicited local reactions and general adverse reactions are presented in Table 3.

    Table 3. Percentage of Children with Solicited Local Reactions and General Adverse Reactions within 4 Days of Booster Vaccinationa (Dose 4) with HIBERIXb Coadministered with DTaP-HBV-IPVc, Intent-to-Treat Cohort (n = 371)

    %

    %

    Adverse Reactions

    Any

    Grade 3

    Locald

    Redness

    25

    2e

    Pain

    21

    1f

    Swelling

    15

    2e

    General

    Feverg

    35

    4

    Fussiness

    26

    1h

    Loss of appetite

    23

    1i

    Restlessness

    22

    1i

    Sleepiness

    20

    1i

    Diarrhea

    15

    1i

    Vomiting

    5

    1i

    n = All subjects for whom safety data were available.

    a Within 4 days of vaccination defined as day of vaccination and the next 3 days.

    b In this study, 92 subjects previously received 3 doses of HIBERIX, 96 subjects previously received 3 doses of a Control PRP-T (Sanofi Pasteur SA), and 183 subjects previously received 3 doses of a Haemophilus b Conjugate Vaccine that is no longer licensed in the U.S.

    c In this study, DTaP-HBV-IPV was given to subjects who previously received 3 doses of DTaP-HBV-IPV. In the U.S., PEDIARIX is approved for use as a 3-dose primary series; use as a fourth consecutive dose is not approved in the U.S.

    d Local reactions at the injection site for HIBERIX.

    e Grade 3 redness or swelling defined as >20 mm.

    f Grade 3 pain defined as causing crying when limb moved.

    g Fever defined as ≥100.4°F (≥38.0°C) rectally or ≥99.5°F (≥37.5°C) axillary, oral, or tympanic; Grade 3 fever defined as >103.1°F (>39.5°C) rectally or >102.2°F (>39.0°C) axillary, oral, or tympanic.

    h Grade 3 fussiness defined as persistent crying and could not be comforted.

    i Grade 3 for these symptoms defined as preventing normal daily activity.

    Serious Adverse Reactions

    In Study 1, one of 2,963 subjects who received HIBERIX and coadministered vaccines given at 2, 4, and 6 months of age experienced a serious adverse reaction which was in temporal association with vaccination and had no alternative plausible causes (convulsion on Day 14 after Dose 1). One of 2,336 subjects who received a booster dose of HIBERIX concomitantly with INFANRIX experienced a serious adverse reaction which was in temporal association with vaccination and had no alternative plausible causes (new onset febrile seizure on Day 1 after Dose 4).

    In the 7 additional studies, 2 of 1,008 subjects reported a serious adverse reaction that occurred in the 31-day period following booster immunization with HIBERIX. One subject developed bilateral pneumonia 9 days post-vaccination and one subject experienced asthenia following accidental drug ingestion 18 days post-vaccination.

    6.2 Postmarketing Experience

    In addition to reports in clinical trials for HIBERIX, the following adverse reactions have been identified during postapproval use of HIBERIX. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to vaccination.

    General Disorders and Administration Site Conditions

    Extensive swelling of the vaccinated limb, injection site induration.

    Immune System Disorders

    Allergic reactions (including anaphylactic and anaphylactoid reactions), angioedema.

    Nervous System Disorders

    Convulsions (with or without fever), hypotonic-hyporesponsive episode (i.e., sudden onset of hypotonia, hyporesponsiveness, and pallor or cyanosis), somnolence, syncope, or vasovagal responses to injection.

    Respiratory, Thoracic, and Mediastinal Disorders

    Apnea [see Warnings and Precautions (5.3)].

    Skin and Subcutaneous Tissue Disorders

    Rash, urticaria.

  • 7 DRUG INTERACTIONS

    7.1 Interference with Laboratory Tests

    Haemophilus b capsular polysaccharide derived from Haemophilus b Conjugate Vaccines has been detected in the urine of some vaccinees.1 Urine antigen detection may not have a diagnostic value in suspected disease due to H. influenzae type b within 1 to 2 weeks after receipt of a H. influenzae type b-containing vaccine, including HIBERIX [see Warnings and Precautions (5.6)].

    7.2 Concomitant Vaccine Administration

    In clinical studies, HIBERIX was administered concomitantly with routinely recommended pediatric vaccines [see Clinical Studies (14.2)].

    7.3 Immunosuppressive Therapies

    Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs, and corticosteroids (used in greater than physiologic doses), may reduce the immune response to HIBERIX.

  • 8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    HIBERIX is not approved for use in individuals aged 5 years and older. No human or animal data with HIBERIX are available to assess vaccine-associated risks in pregnancy.

    8.2 Lactation

    HIBERIX is not approved for use in individuals aged 5 years and older. No human or animal data are available to assess the impact of HIBERIX on milk production, its presence in breast milk, or its effects on the breastfed infant.

    8.4 Pediatric Use

    Safety and effectiveness of HIBERIX in children younger than 6 weeks and in children aged 5 to 16 years have not been established.

  • 11 DESCRIPTION

    HIBERIX [Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate)] is a solution for intramuscular injection, supplied as a sterile, lyophilized powder which is reconstituted at the time of use with the accompanying saline diluent. HIBERIX contains Haemophilus b capsular polysaccharide (polyribosyl-ribitol-phosphate [PRP]), a high molecular weight polymer prepared from the H. influenzae type b strain 20,752 grown in a synthetic medium that undergoes heat inactivation and purification. The tetanus toxin, prepared from Clostridium tetani grown in a semi-synthetic medium, is detoxified with formaldehyde and purified. The capsular polysaccharide is covalently bound to the tetanus toxoid. After purification, the conjugate is lyophilized in the presence of lactose as a stabilizer. The diluent for HIBERIX is a sterile saline solution (0.9% sodium chloride) supplied in vials.

    After reconstitution, each 0.5-mL dose is formulated to contain 10 mcg of purified capsular polysaccharide conjugated to approximately 25 mcg of tetanus toxoid, 12.6 mg of lactose, and ≤0.5 mcg of residual formaldehyde.

    HIBERIX does not contain a preservative.

    The lyophilized vaccine and saline diluent vial stoppers are not made with natural rubber latex.

  • 12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    H. influenzae is a gram-negative coccobacillus. Most strains of H. influenzae that cause invasive disease are type b. H. influenzae type b can cause invasive disease such as sepsis and meningitis.

    Specific levels of antibodies to polyribosyl-ribitol-phosphate (anti-PRP) have been shown to correlate with protection against invasive disease due to H. influenzae type b. Based on data from passive antibody studies2 and a clinical efficacy study with unconjugated Haemophilus b polysaccharide vaccine3, an anti-PRP concentration of 0.15 mcg/mL has been accepted as a minimal protective level. Data from an efficacy study with unconjugated Haemophilus b polysaccharide vaccine indicate that an anti-PRP concentration of ≥1.0 mcg/mL predicts protection through at least a 1-year period.4,5 These antibody levels have been used to evaluate the effectiveness of Haemophilus b Conjugate Vaccines, including HIBERIX.

  • 13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

    HIBERIX has not been evaluated for carcinogenic or mutagenic potential, or for impairment of fertility.

  • 14 CLINICAL STUDIES

    14.1 Immunological Evaluation

    Primary Series Vaccination (Doses 1, 2, and 3)

    The immunogenicity of HIBERIX was evaluated in a randomized, controlled trial (Study 1). HIBERIX or control vaccines were administered concomitantly with U.S.-licensed vaccines [see Adverse Reactions (6.1)].

    Anti-PRP geometric mean concentrations (GMCs) and seroprotection rates 1 month following Dose 3 of HIBERIX, Control PRP-T (Sanofi Pasteur SA), or DTaP-IPV/Hib are presented in Table 4.

    Table 4. Anti-PRP GMCs and Seroprotection Rates 1 Month following 3 Doses of HIBERIX, Control PRP-Ta, or DTaP-IPV/Hibb Administered at 2, 4, and 6 Months of Age, ATP Cohort for Immunogenicityc

    Vaccine

    n

    Anti-PRP GMC

    (mcg/mL)

    (95% CI)

    % Anti-PRP

    ≥0.15 mcg/mL

    (95% CI)

    % Anti-PRP

    ≥1.0 mcg/mL

    (95% CI)

    HIBERIX

    1,590

    5.19

    (4.77, 5.66)

    96.6

    (95.6, 97.4)

    81.2

    (79.2, 83.1)

    Control PRP-T

    274

    6.74

    (5.59, 8.13)

    96.7d

    (93.9, 98.5)

    89.8e

    (85.6, 93.1)

    DTaP-IPV/Hib

    253

    3.64

    (2.89, 4.58)

    92.5f

    (88.5, 95.4)

    78.3f

    (72.7, 83.2)

    a U.S.-licensed monovalent Haemophilus b Conjugate Vaccine (Control PRP-T) (Sanofi Pasteur SA).

    b U.S.-licensed DTaP-IPV/Hib Vaccine (Sanofi Pasteur Ltd.).

    c Study 1: NCT01000974.

    d HIBERIX was non-inferior to Control PRP-T for percent of subjects achieving anti-PRP ≥0.15 mcg/mL (lower limit of 95% CI on difference of HIBERIX minus Control PRP-T ≥ predefined limit of -5%).

    e The non-inferiority criterion was not met (lower limit of 95% CI for the difference in the percentages of subjects with anti-PRP ≥1.0 mcg/mL between two groups [HIBERIX minus Control PRP-T] was -12.28%, which was lower than the predefined limit of -10%).

    f Analyses of anti-PRP immune responses following DTaP-IPV/Hib vaccination were exploratory.

    Booster Vaccination (Dose 4)

    The immunogenicity of HIBERIX administered as a booster dose at 15 to 18 months of age was evaluated in a subset of children from Study 1 (n = 336) in comparison with U.S.-licensed vaccines following primary vaccination at 2, 4, and 6 months of age [see Adverse Reactions (6.1)]. The booster dose of HIBERIX and Control PRP-T (Sanofi Pasteur SA) was administered concomitantly with INFANRIX.

    Antibodies to PRP were measured in sera obtained immediately prior to and 1 month after booster vaccination with HIBERIX or the control vaccines. Anti-PRP GMCs and seroprotection rates are presented in Table 5.

    Table 5. Anti-PRP GMCs and Seroprotection Rates prior to and 1 Month following a Booster Dose (Dose 4 at 15 through 18 Months of Age) of HIBERIX, Control PRP-Ta, or DTaP-IPV/Hibb, ATP Cohort for Immunogenicityc

    Anti-PRP GMC

    % Anti-PRP

    % Anti-PRP

    (mcg/mL)

    (95% CI)

    ≥0.15 mcg/mL

    (95% CI)

    ≥1.0 mcg/mL

    (95% CI)

    Vaccine

     
    n

    Pre-

    Post-

    Pre-

    Post-

    Pre-

    Post-

    HIBERIX

    329-336

    0.50

    (0.42, 0.59)

    48.78

    (42.0, 56.66)

    75.1

    (70.0, 79.7)

    100.0

    (98.9, 100.0)

    32.2

    (27.2, 37.6)

    99.1

    (97.4, 99.8)

    Control PRP-T

    226-236

    0.47

    (0.38, 0.57)

    40.29

    (33.39, 48.63)

    76.1

    (70.0, 81.5)

    99.6

    (97.7, 100.0)

    27.0

    (21.3, 33.3)

    97.9d

    (95.1, 99.3)

    DTaP-IPV/Hib

    175-186

    0.38

    (0.30, 0.48)

    37.54

    (30.53, 46.16)

    66.3

    (58.8, 73.2)

    100.0

    (98.0, 100.0)

    25.1

    (18.9, 32.2)

    98.9e

    (96.2, 99.9)

    a U.S.-licensed monovalent Haemophilus b Conjugate Vaccine (Control PRP-T) (Sanofi Pasteur SA).

    b U.S.-licensed DTaP-IPV/Hib Vaccine (Sanofi Pasteur Ltd.).

    c Study 1: NCT01000974.

    d HIBERIX was non-inferior to Control PRP-T for percent of subjects achieving anti-PRP ≥1.0 mcg/mL (lower limit of 97.5% CI on difference of HIBERIX minus Control PRP-T ≥predefined limit of -10%) at 1 month following the booster dose.

    e Analyses of anti-PRP immune responses following DTaP-IPV/Hib vaccination were exploratory.

    In 6 additional clinical studies, the immune response to HIBERIX administered as a booster dose was evaluated in a total of 415 children aged 12 to 23 months. At the time of vaccination, 30 children were aged 12 to 14 months, 316 children were aged 15 to 18 months, and 69 children were aged 19 to 23 months. Among subjects, 43% to 60% were male. Among subjects for whom information on race/ethnicity was available, nearly all subjects were white. None of the studies included a comparator group that received a booster dose with a U.S.-licensed Haemophilus b Conjugate Vaccine. Characteristics of 3 of these studies are presented in Table 6.

    Table 6. Characteristics of 3 Open-Label Booster Immunization Studies of HIBERIX

    Study

    Country

    Per-Protocol Immunogenicity Cohort

    n

    Priming History

    Booster Vaccination with HIBERIX

    Age at Vaccination (months)

    Concomitantly Administered Vaccinea

    3

    Canada

    42

    DTaP-HBV-IPVb + Haemophilus b Conjugate Vaccinec

    at 2, 4, and 6 months of age

    16-18

    DTaP-HBV-IPVb

    4

    Canada

    64

    DTaP-IPVd + HIBERIX

    at 2, 4, and 6 months of age

    16-19

    DTaP-IPVd

    5

    Germany

    108

    DTaP-HBVe + HIBERIX

    at 3, 4, and 5 months of age

    16-23

    DTaP-HBVe

    a Administered at a separate site.

    b Non-U.S. formulation equivalent to PEDIARIX with the exception of containing 2.5 mg 2-phenoxyethanol per dose as preservative. In the U.S., PEDIARIX is approved for use as a 3-dose primary series; use as a fourth consecutive dose is not approved in the U.S.

    c U.S.-licensed Haemophilus b Conjugate Vaccine (Control PRP-T) (Sanofi Pasteur SA).

    d Non-U.S. formulation equivalent to KINRIX with the exception of containing 2.5 mg 2-phenoxyethanol per dose as preservative. In the U.S., KINRIX is approved for use as the fifth dose of DTaP and the fourth dose of IPV in children aged 4 to 6 years previously primed with approved dosing regimens of INFANRIX and/or PEDIARIX. The DTaP-IPV dosing regimen is not approved in the U.S.

    e Manufactured by GlaxoSmithKline Biologicals (not licensed in the U.S.).

    Antibodies to PRP were measured in sera obtained immediately prior to and 1 month after booster vaccination with HIBERIX. Geometric mean concentrations and anti-PRP seroprotection rates are presented in Table 7.

    Table 7. Anti-PRP GMCs and Seroprotection Rates prior to and 1 Month following a Booster Dose of HIBERIX, Per-Protocol Immunogenicity Cohort

    Anti-PRP GMC

    % Anti-PRP

    % Anti-PRP

    (mcg/mL)

    ≥0.15 mcg/mL

    ≥1.0 mcg/mL

    Study

    n

    Pre-

    Post-

    Pre-

    Post-

    Pre-

    Post-

    3a

    42

    0.46

    59.07

    76.2

    100

    35.7

    97.6

    4b

    63-64

    0.25

    47.78

    71.4

    100

    12.7

    100

    5c

    108

    0.59

    96.12

    77.8

    100

    32.4

    100

    GMC = Geometric mean antibody concentration.

    n = Number of children for whom serological results were available for the pre- and post-dose immunological evaluations.

    Studies 3, 4, and 5 correspond to Studies 3, 4, and 5, respectively in Table 6.

    a Canadian study in children aged 16 to 18 months who previously received 3 doses of DTaP-HBV-IPV and Haemophilus b Conjugate Vaccine (Control PRP-T) (Sanofi Pasteur SA). The booster dose of HIBERIX was coadministered with DTaP-HBV-IPV (a fourth consecutive dose of PEDIARIX is not approved in the U.S.). In this study, pre-vaccination sera may have been obtained up to 1 week prior to booster vaccination with HIBERIX.

    b Canadian study in children aged 16 to 19 months who previously received 3 doses of DTaP-IPV and HIBERIX. The booster dose of HIBERIX was coadministered with DTaP-IPV. The DTaP-IPV dosing regimen is not approved in the U.S.

    c German study in children aged 16 to 23 months who previously received 3 doses of DTaP-HBV (GlaxoSmithKline Biologicals, not licensed in the U.S.) and HIBERIX. The booster dose of HIBERIX was coadministered with DTaP-HBV.

    14.2 Concomitant Vaccine Administration

    Primary Series Vaccination (Doses 1, 2, and 3)

    In U.S. Study 1, subjects who received HIBERIX concomitantly with PEDIARIX (DTaP-HBV-IPV) and PCV13 at 2, 4, and 6 months of age had no evidence for reduced antibody responses relative to the response in control subjects administered Control PRP-T (Sanofi Pasteur SA) concomitantly with PEDIARIX (DTaP-HBV-IPV) and PCV13, to pertussis antigens (GMC to pertussis toxin, filamentous hemagglutinin, and pertactin), diphtheria toxoid (antibody levels ≥0.1 IU/mL), tetanus toxoid (antibody levels ≥0.1 IU/mL), poliovirus types 1, 2, and 3 (antibody levels ≥1:8 to each virus), PCV13 (antibody levels ≥0.2 mcg/mL and GMC to each serotype), or hepatitis B (anti-hepatitis B surface antigen ≥10 mIU/mL). The immune responses to PEDIARIX (DTaP-HBV-IPV) and PCV13 were evaluated 1 month following Dose 3. Subjects in both groups received ROTARIX at 2 and 4 months of age.

    Booster Vaccination (Dose 4)

    In U.S. Study 1, subjects who received a booster dose of HIBERIX concomitantly with INFANRIX at 15 to 18 months of age had no evidence for reduced antibody responses to pertussis antigens (GMC to pertussis toxin, filamentous hemagglutinin, and pertactin), diphtheria toxoid (antibody levels ≥0.1 IU/mL), and tetanus toxoid (antibody levels ≥0.1 IU/mL), relative to the responses in control subjects administered Control PRP-T (Sanofi Pasteur SA) concomitantly with INFANRIX.

    In 7 additional studies, a booster dose of HIBERIX was administered concomitantly with non-U.S. formulations of INFANRIX, KINRIX, and PEDIARIX. Non-U.S. formulations of KINRIX and PEDIARIX were administered in dosing regimens not approved in the U.S.

    Sufficient data are not available to confirm lack of interference in immune responses to vaccines other than INFANRIX administered concomitantly with a booster dose of HIBERIX.

  • 15 REFERENCES

    1.
    Rothstein EP, Madore DV, Girone JAC, et al. Comparison of antigenuria after immunization with three Haemophilus influenzae type b conjugate vaccines. Pediatr Infect Dis J. 1991;10:311-314.
    2.
    Robbins JB, Parke JC, Schneerson R, et al. Quantitative measurement of “natural” and immunization-induced Haemophilus influenzae type b capsular polysaccharide antibodies. Pediatr Res. 1973;7:103-110.
    3.
    Peltola H, Käythy H, Sivonen A, et al. Haemophilus influenzae type b capsular polysaccharide vaccine in children: A double-blind field study of 100,000 vaccinees 3 months to 5 years of age in Finland. Pediatrics. 1977;60:730-737.
    4.
    Käythy H, Peltola H, Karanko V, et al. The protective level of serum antibodies to the capsular polysaccharide of Haemophilus influenzae type b. J Infect Dis. 1983;147:1100.
    5.
    Anderson P. The protective level of serum antibodies to the capsular polysaccharide of Haemophilus influenzae type b. J Infect Dis. 1984;149:1034.
  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    HIBERIX is available in single-dose vials of lyophilized vaccine, accompanied by vials containing 0.85 mL of saline diluent (packaged without syringes or needles).

    Supplied as package of 10 doses (NDC 58160-818-11):

    NDC 58160-816-01 Vial of lyophilized vaccine in Package of 10: NDC 58160-816-05

    NDC 58160-817-01 Vial of saline diluent in Package of 10: NDC 58160-817-05

    16.1 Storage before Reconstitution

    Lyophilized vaccine vials: Store refrigerated between 2° and 8°C (36° and 46°F). Protect vials from light.

    Diluent: Store refrigerated or at controlled room temperature between 2° and 25°C (36° and 77°F). Do not freeze. Discard if the diluent has been frozen.

    16.2 Storage after Reconstitution

    Administer within 24 hours of reconstitution. After reconstitution, store refrigerated between 2° and 8°C (36° and 46°F). Discard the reconstituted vaccine if not used within 24 hours. Do not freeze. Discard if the vaccine has been frozen.

  • 17 PATIENT COUNSELING INFORMATION

    Inform parents or guardians of the potential benefits and risks of immunization with HIBERIX.
    Inform parents or guardians about the potential for adverse reactions that have been temporally associated with administration of HIBERIX or other vaccines containing similar components.
    Give parents or guardians the Vaccine Information Statements, which are required by the National Childhood Vaccine Injury Act of 1986 to be given prior to immunization. These materials are available free of charge at the Centers for Disease Control and Prevention (CDC) website (www.cdc.gov/vaccines).
  • SPL UNCLASSIFIED SECTION

    Trademarks are owned by or licensed to the GSK group of companies.

    Manufactured by GlaxoSmithKline Biologicals

    Rixensart, Belgium, U.S. License 1617, and

    Distributed by GlaxoSmithKline

    Research Triangle Park, NC 27709

    ©2019 GSK group of companies or its licensor.

    HRX:8PI

     

  • PRINCIPAL DISPLAY PANEL

    PRINCIPAL DISPLAY PANEL

    NDC 58160-818-11

    HIBERIX

    Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate)

    Hib

    Rx only

    Contents (see back panel for storage instructions):

    10 Vials of Lyophilized Vaccine

    10 Vials of Sterile Saline Diluent (for reconstitution of Lyophilized Vaccine).

    For Use from 6 weeks through 4 years of age

    Lyophilized Vaccine Made in Belgium

    ©2019 GSK group of companies or its licensor.

    Rev. 2/19

    497079

    Hiberix 10 count carton
  • INGREDIENTS AND APPEARANCE
    HIBERIX 
    haemophilus b conjugate vaccine (tetanus toxoid conjugate) kit
    Product Information
    Product TypeVACCINEItem Code (Source)NDC:58160-818
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC:58160-818-111 in 1 CARTON; Type 0: Not a Combination Product
    Quantity of Parts
    Part #Package QuantityTotal Product Quantity
    Part 110 VIAL 5 mL
    Part 210 VIAL 8.5 mL
    Part 1 of 2
    HIBERIX 
    haemophilus b conjugate vaccine (tetanus toxoid conjugate) injection, powder, for solution
    Product Information
    Item Code (Source)NDC:58160-816
    Route of AdministrationINTRAMUSCULAR
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    HAEMOPHILUS INFLUENZAE TYPE B STRAIN 20752 CAPSULAR POLYSACCHARIDE TETANUS TOXOID CONJUGATE ANTIGEN (UNII: C9R35M8XV6) (HAEMOPHILUS INFLUENZAE TYPE B STRAIN 20752 CAPSULAR POLYSACCHARIDE TETANUS TOXOID CONJUGATE ANTIGEN - UNII:C9R35M8XV6) HAEMOPHILUS INFLUENZAE TYPE B STRAIN 20752 CAPSULAR POLYSACCHARIDE TETANUS TOXOID CONJUGATE ANTIGEN10 ug  in 0.5 mL
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC:58160-816-0510 in 1 CARTON
    1NDC:58160-816-010.5 mL in 1 VIAL; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    BLABLA12534712/21/2015
    Part 2 of 2
    DILUENT 
    sterile water solution
    Product Information
    Item Code (Source)NDC:58160-817
    Route of AdministrationINTRAMUSCULAR
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    WATER (UNII: 059QF0KO0R) (WATER - UNII:059QF0KO0R) WATER1 mL  in 1 mL
    Inactive Ingredients
    Ingredient NameStrength
    SODIUM CHLORIDE (UNII: 451W47IQ8X)  
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC:58160-817-0510 in 1 PACKAGE
    1NDC:58160-817-010.85 mL in 1 VIAL; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    BLABLA12534712/21/2015
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    BLABLA12534712/21/2015
    Labeler - GlaxoSmithKline Biologicals SA (372748392)