Vaccine Information: Hiberix

HIBERIX- haemophilus b conjugate vaccine (tetanus toxoid conjugate)
GlaxoSmithKline Biologicals SA

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 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 Vaccination^a (at 2, 4, and 6 Months of Age) with HIBERIX^b , Control PRP-T^b , or DTaP-IPV/Hib^c , Total Vaccinated Cohort^d

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 Vaccination^a (Dose 4 at 15 through 18 Months of Age) with HIBERIX^b , Control PRP-T^b , or DTaP-IPV/Hib, Total Vaccinated Cohort^c

Adverse Reactions	HIBERIX %		Control PRP-T %		DTaP-IPV/Hib%
	Any	Grade 3d	Any	Grade 3d	Any	Grade 3d
Local e	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 Vaccination^a (Dose 4) with HIBERIX^b Coadministered with DTaP-HBV-IPV^c , 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.