PedvaxHIB (Haemophilus b Conjugate)

PedvaxHIB®

MSD

Haemophilus b Conjugate Vaccine (Meningococcal Protein Conjugate)

Vaccine

Action And Clinical Pharmacology: Disease Epidemiology: Prior to the introduction of Haemophilus b conjugate vaccines, H. influenzae type b (Haemophilus b) was the most frequent cause of bacterial meningitis and a leading cause of serious systemic bacterial disease in young children worldwide.

Haemophilus b disease occurred primarily in children under 5 years of age in the United States prior to the initiation of a vaccine program and was estimated to account for nearly 20 000 cases of invasive infections annually, approximately 12 000 of which were meningitis. The mortality rate from Haemophilus b meningitis is about 5%. In addition, up to 35% of survivors develop neurological sequelae including convulsions, deafness, and mental retardation. Other invasive diseases caused by this bacterium include cellulitis, epiglottitis, sepsis, pneumonia, septic arthritis, osteomyelitis and pericarditis. Since the introduction and widespread use of Haemophilus b conjugate vaccines in the United States, the incidence of invasive Haemophilus b disease has declined 95% among children aged less than 5 years.

Prior to the introduction of the vaccine, it was estimated that 17% of all cases of Haemophilus b disease occurred in infants less than 6 months of age. The peak incidence of Haemophilus b meningitis occurs between 6 and 11 months of age. Forty-seven percent of all cases occur by 1 year of age with the remaining 53% of cases occurring over the next 4 years.

Among children under 5 years of age, the risk of invasive Haemophilus b disease is further increased in certain populations including the following: day-care attendees, lower socio-economic groups, blacks (especially those who lack the Km(1) immunoglobulin allotype), caucasians who lack the G2m(n or 23) immunoglobulin allotype, native americans, household contacts of cases, individuals with asplenia, sickle cell disease, or antibody deficiency syndromes.

Immunology of Haemophilus B Disease: An important virulence factor of the Haemophilus b bacterium is its polysaccharide capsule (PRP). Antibody to PRP (anti-PRP) has been shown to correlate with protection against Haemophilus b disease. While the anti-PRP level associated with protection using conjugated vaccines has not yet been determined, the level of anti-PRP associated with protection in studies using bacterial polysaccharide immune globulin or nonconjugated PRP vaccines ranged from ³0.15 to ³1.0 µg/mL.

PedvaxHIB and Liquid PedvaxHIB are PRP-conjugate vaccines that overcome the deficiencies of nonconjugated PRP vaccines in infants and young children. Conjugation of a carbohydrate to a protein carrier enhances antibody responses to the carbohydrate, a process that is thought to convert the T-independent antigen (PRP alone) into a T-dependent antigen which results in both an enhanced antibody response and immunologic memory.

The protective efficacy, safety, and antibody responses to PedvaxHIB were evaluated in 3 486 Native American (Navajo) infants who completed the primary two-dose regimen in a randomized, double-blind, placebo-controlled study (The Protective Efficacy Study). This population has a much higher incidence of Haemophilus b disease than the United States population as a whole and also has a lower antibody response to Haemophilus b conjugate vaccines, including PedvaxHIB.

Each infant in this study received two doses of either placebo or PedvaxHIB with the first dose administered at a mean of 8 weeks of age and the second administered approximately two months later; DTP and OPV were administered concomitantly. Antibody levels were measured in a subset of each group

In this study, 22 cases of invasive Haemophilus b disease occurred in the placebo group (8 cases after the first dose and 14 cases after the second dose) and only 1 case in the vaccine group (none after the first dose and 1 after the second dose). Following the recommended two-dose regimen, the protective efficacy of PedvaxHIB was calculated to be 93% with a 95% confidence interval of 57 to 98% (p=0.001, two-tailed). In the 2 months between the first and second doses, the difference in number of cases of disease between placebo and vaccine recipients (8 vs 0 cases, respectively) was statistically significant (p=0.008, two-tailed); however, a primary two-dose regimen is required for infants 2 to 14 months of age. A subset of 1 368 infants from this study was followed to 15 months of age with no additional cases of invasive Haemophilus b disease occurring after the primary two-dose regimen of PedvaxHIB (see Dosage, including Booster Dose).

Since protective efficacy with PedvaxHIB was demonstrated in such a high risk population, it would be expected to be predictive of efficacy in other populations.

Clinical Evaluation: The safety and immunogenicity of PedvaxHIB were evaluated in infants and children in other clinical studies that were conducted in various locations throughout the United States. PedvaxHIB was highly immunogenic in all age groups studied.

These data were derived by evaluating the sera in one laboratory using a radioimmunoassay which correlated with both the Finnish National Public Health Institute assay and that recommended by the Center for Biologics Evaluation and Research of the FDA.

PedvaxHIB induced antibody levels greater than 1.0 µg/mL in children who were poor responders to nonconjugated PRP vaccines. In a study involving such a subpopulation, children ranging in age from 27 to 61 months who developed invasive Haemophilus b disease despite previous vaccination with nonconjugated PRP vaccines were assigned randomly to 2 groups. One group (n=14) was immunized with PedvaxHIB and the other group (n=20) with a nonconjugated PRP vaccine at a mean interval of approximately 12 months after recovery from disease. All 14 children immunized with PedvaxHIB but only 6 of 20 children re-immunized with a nonconjugated PRP vaccine achieved an antibody level of >1.0 µg/mL. The 14 children who had not responded to revaccination with the nonconjugated PRP vaccine were then immunized with a single dose of PedvaxHIB and following this vaccination, all achieved antibody levels of >1.0 µg/mL.

In addition, PedvaxHIB has been studied in children 2 to 17 months of age at high risk of Haemophilus b disease because of genetically related deficiencies (Blacks who were Km (1) allotype negative and Caucasians who were G2m (23) allotype negative) and are considered hyporesponsive to nonconjugated PRP vaccines on this basis. The hyporesponsive children had anti-PRP responses comparable to those of allotype positive children of similar age range when vaccinated with PedvaxHIB. All children achieved anti-PRP levels of >1.0 µg/mL.

Antibody Persistence: Persistence of antibody at 36 months of age was studied in 35 children following 3 doses of PedvaxHIB and in 134 children following 3 doses of Liquid PedvaxHIB (last dose [booster] given when 12 to 15 months old). Similar results were observed in children who received either PedvaxHIB or Liquid PedvaxHIB. In those children who received PedvaxHIB or Liquid PedvaxHIB, respectively, 91% and 98% had antibody titres >0.15 µg/mL, and 37% and 58% had antibody titres >1.0 µg/mL. Anti-PRP geometric mean titres (GMTs) in the children who received either PedvaxHIB or Liquid PedvaxHIB, were 0.8 µg/mL and 1.5 µg/mL, respectively.

Postmarket Effectiveness Data: Two post-licensure effectiveness studies using PedvaxHIB were performed: one in the United States with Navajo infants and children, and one in Israel. Both studies demonstrated 95% effectiveness against invasive Hib disease.

Interchangeability of PedvaxHIB and Liquid PedvaxHIB: The immunogenicity of PedvaxHIB (15 µg PRP) and Liquid PedvaxHIB (7.5 µg PRP) in infants and children was compared in a multicenter clinical study and was similar. It is expected that the immune response would be comparable if the two formulations were used interchangeably.

Indications And Clinical Uses: For routine vaccination against invasive disease caused by H. influenzae type b in infants and children 2 to 59 months of age.

As with other vaccines, several days following administration of PedvaxHIB or Liquid PedvaxHIB are required for protective levels of antibody to be achieved.

PedvaxHIB and Liquid PedvaxHIB will not protect against H. influenzae other than type b or against other microorganisms that cause meningitis or sepsis.

Revaccination: Infants completing the primary two-dose regimen before 12 months of age should receive a booster dose (see Dosage).

Use with Other Vaccines: Studies have been conducted in which PedvaxHIB and Liquid PedvaxHIB have been administered concomitantly with the primary vaccination series and/or booster doses of DTP and OPV, or concomitantly with M-M-R II (using separate sites and syringes). No impairment of immune response to individual tested antigens was demonstrated. The type, frequency and severity of adverse experiences observed in these studies were similar to those seen when the individual vaccines were given alone.

Note: The National Advisory Committee on Immunization (NACI) recommends administration on a single day of all vaccines (i.e., DTP, IPV (or OPV), M-M-R II and H. influenzae type b conjugate vaccine), appropriate to the patient’s age and previous vaccination status, if the patient is unlikely to return for further vaccination. If this is done, separate sites and syringes should be used for the injectable vaccines: PedvaxHIB or Liquid PedvaxHIB, M-M-R II, DTP, IPV and DTP-IPV.

Contra-Indications: Hypersensitivity to any component of the vaccine or the diluent.

Manufacturers’ Warnings In Clinical States: Use only the aluminum hydroxide diluent supplied to reconstitute the lyophilized vaccine.

The expected immune response may not be obtained when PedvaxHIB or Liquid PedvaxHIB is used in persons with malignancies or those receiving immunosuppressive therapy or who are otherwise immunocompromised.

Precautions: General: Adequate treatment provisions, including epinephrine, should be available for immediate use should an anaphylactoid reaction occur.

As with any vaccine, vaccination with PedvaxHIB or Liquid PedvaxHIB b conjugate vaccine may not result in a protective antibody response in 100% of susceptible persons given the vaccine.

As reported with Haemophilus b polysaccharide vaccine and another Haemophilus b conjugate vaccine, cases of Haemophilus b disease may occur in the week after vaccination, prior to the onset of the protective effects of the vaccines.

There is insufficient evidence showing that PedvaxHIB or Liquid PedvaxHIB given immediately after exposure to natural H. influenzae type b will prevent illness.

Any acute infection or febrile illness is reason for delaying use of PedvaxHIB or Liquid PedvaxHIB except when, in the opinion of the physician, withholding the vaccine entails a greater risk.

An immunogenic response to the carrier protein (N. meningitidis) has been demonstrated but its clinical benefit has not been established.

Pregnancy: Animal reproduction studies have not been conducted with PedvaxHIB or Liquid PedvaxHIB. These products are not recommended for use in individuals 6 years of age or older.

Children: Safety and effectiveness in infants below the age of 2 months and in children 6 years of age and older have not been established.

Carcinogenesis, Mutagenesis, and Impairment of Fertility: PedvaxHIB and Liquid PedvaxHIB have not been evaluated for their carcinogenic or mutagenic potential, or its potential to impair fertility.

Laboratory Tests: Sensitive tests, e.g., Latex Agglutination Kits, may detect PRP derived from the vaccine in the urine of some vaccinees for at least 30 days following vaccination with PedvaxHIB. In clinical studies with PedvaxHIB, children with this antigenuria demonstrated a normal immune response to the vaccine.

Adverse Reactions: PedvaxHIB: In clinical studies involving the administration of 8 086 doses of PedvaxHIB alone to 5 027 healthy infants and children 2 months of age to 71 months of age, PedvaxHIB was generally well tolerated. No serious adverse reactions were reported.

In a subset of these infants and children, during a two-day period following vaccination with PedvaxHIB, the most frequently reported adverse reactions, excluding those shown in Table VI, in decreasing order of frequency included irritability, sleepiness, respiratory infection/symptoms, and ear infection/otitis media. Urticaria was reported in 2 children. Thrombocytopenia was seen in one child. A cause and effect relationship between these side effects and the vaccination has not been established.

Summarized in Table VI from early clinical studies are selected objective observations reported by parents over a 48-hour period in infants and children 2 to 71 months of age following primary vaccination with PedvaxHIB.

In later clinical studies with PedvaxHIB, one additional serious adverse reaction (tracheitis, possibly related to the vaccine) was reported.

As with any vaccine, there is the possibility that broad use of PedvaxHIB could reveal adverse reactions not observed in clinical trials. The following additional adverse reactions have been reported with use of the marketed vaccine:

Hemic and Lymphatic System: lymphadenopathy.

Hypersensitivity: rarely, angioedema.

Nervous System: seizures (including febrile seizures).

Skin: sterile injection site abscess; pain at the injection site.

Liquid PedvaxHIB: The type and frequency of adverse reactions reported with Liquid PedvaxHIB were similar to those seen with PedvaxHIB.

In a multicenter clinical study (n=903) comparing the effects of Liquid PedvaxHIB with those of PedvaxHIB, 1 699 doses of Liquid PedvaxHIB were administered to 678 healthy infants 2 to 6 months of age from the general U.S. population. DTP and OPV were administered concomitantly to most subjects. Both PedvaxHIB and Liquid PedvaxHIB were generally well tolerated and no serious vaccine-related adverse reactions were reported.

During a three-day period following primary vaccination with Liquid PedvaxHIB in these infants, the most frequently reported (>1%) adverse reactions, without regard to causality, excluding those shown in Table VII, in decreasing order of frequency, were: irritability, sleepiness, injection site pain/soreness, injection site erythema, injection site swelling/induration unusual high-pitched crying, prolonged crying (>4 hours), diarrhea, vomiting, crying, pain, otitis media, rash, and upper respiratory infection.

Adverse reactions reported during a three-day period following primary vaccination were generally similar in type and frequency to those seen following administration of the booster dose.

As with any vaccine, there is the possibility that broad use of Liquid PedvaxHIB could reveal adverse reactions not observed in clinical trials.

Potential Side Effects: The use of Haemophilius b Polysaccharide Vaccines and another Haemophilus b Conjugate Vaccine has been associated with the following additional adverse effects: convulsions, early onset Haemophilus b disease, Guillain Barr© syndrome. A cause and effect relationship between these side effects and the vaccination was not established.

Dosage And Administration: For i.m. administration. Do not inject i.v. or intradermally.

PedvaxHIB: To reconstitute PedvaxHIB use only the aluminum hydroxide diluent supplied.

First, agitate the diluent vial, then, using sterile technique, withdraw the entire volume of aluminum hydroxide diluent into the syringe to be used for reconstitution. Inject all the aluminum hydroxide diluent in the syringe into the vial of lyophilized vaccine, and agitate to mix thoroughly.

Withdraw the entire contents into a syringe and inject the total volume (about 0.5 mL) of reconstituted vaccine i.m., preferably into the anterolateral thigh or the outer aspect of the upper arm.

It is recommended that the lyophilized vaccine be used as soon as possible after reconstitution. Store reconstituted vaccine in the vaccine vial at 2 to 8°C and discard if not used within 24 hours. Agitate prior to injection.

Liquid PedvaxHIB: The vaccine should be used as supplied; no reconstitution is necessary.

Shake well before withdrawal and use. Thorough agitation is necessary to maintain suspension of the vaccine.

Inject 0.5 mL i.m., preferably into the anterolateral thigh or the outer aspect of the upper arm.

Parenteral drug products should be inspected visually for extraneous particulate matter and discoloration prior to administration. PedvaxHIB (when reconstituted as directed), the aluminum hydroxide diluent and Liquid PedvaxHIB are all slightly opaque white suspensions.

Special care should be taken to ensure that the injection does not enter a blood vessel.

It is important to use a separate sterile syringe and needle for each patient to prevent transmission of hepatitis B or other infectious agents from one person to another.

Children: 2 to 6 months: Infants beginning immunization at 2 to 6 months of age should receive 2 doses of vaccine (0.5 mL/dose) 2 months apart with a booster dose at 12 months of age.

7 to 11 months: Unvaccinated children 7 to 11 months of age should receive 2 doses (0.5 mL/dose) 2 months apart with a booster dose at 15 to 18 months of age (or as soon as possible thereafter) and not less than 2 months after the second dose.

12 to 17 months: Unvaccinated children 12 to 17 months of age should receive a single dose (0.5 mL) of vaccine as soon as possible and an additional dose at, or after 18 months of age, and at least 2 months after the first dose.

18 to 59 months: Children 18 to 59 months of age who have not previously received the vaccine should receive a single dose (0.5 mL) of vaccine.

Availability And Storage: Liquid: Each 0.5 mL dose contains: Haemophilus b PRP 7.5 µg and N. meningitidis OMPC 125 µg. Nonmedicinal ingredients: aluminum as aluminum hydroxide, sodium borate and sodium chloride. Single dose vials of 0.5 mL. Store between 2 and 8°C. Do not freeze.

Powder: Each 0.5 mL dose, when reconstituted as directed contains: Haemophilus b PRP 15 µg and N. meningitidis OMPC 250 µg. Nonmedicinal ingredients: aluminum as aluminum hydroxide, lactose, sodium borate, sodium chloride and thimerosal (a mercury derivative) as preservative. Diluent: The aluminum hydroxide diluent is required for the reconstitution of the lyophilized formulation. Boxes of 5 single dose vials (0.5 mL) of lyophilized vaccine and 5 vials (0.7 mL) of aluminum hydroxide as diluent. Before reconstitution, store the lyophilized vaccine and the aluminum hydroxide diluent between 2 and 8°C. Store reconstituted vaccine in the vaccine vial between 2 and 8°C and discard if not used within 24 hours. Do not freeze the aluminum hydroxide diluent or the reconstituted vaccine.

The vaccines must be maintained between 2 and 8°C during shipment to ensure that there is no loss of potency.

PedvaxHIB® MSD Haemophilus b Conjugate Vaccine (Meningococcal Protein Conjugate) Vaccine

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