Vaccine Information: VAXELIS (Page 2 of 4)

6.2 Data from Postmarketing Experience

The following adverse events have been reported during post-marketing use of other vaccines containing the antigens of VAXELIS. These adverse events are included based on a suspected causal connection to components of DAPTACEL, IPOL® (Poliovirus Vaccine Inactivated), COMVAX® [Haemophilus b Conjugate (Meningococcal Protein Conjugate) and Hepatitis B (Recombinant) Vaccine] and use of VAXELIS outside of the US. Because these events 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.

  • Immune System Disorders
    Hypersensitivity (such as rash, urticaria, dyspnea, erythema multiforme), anaphylactic reaction (such as urticaria, angioedema, edema, face edema, shock).
  • General Disorders and Administration Site Conditions
    Extensive swelling of injected limb (including swelling that involves adjacent joints).
  • Nervous System Seizure, febrile seizure.

7 DRUG INTERACTIONS

7.1 Interference with Laboratory Tests

Sensitive tests (e.g., Latex Agglutination kits) have detected vaccine-derived polyribosylribitol phosphate (PRP) in the urine of vaccinees for at least 30 days following vaccination with PedvaxHIB [Haemophilus b Conjugate Vaccine (Meningococcal Protein Conjugate)]. (2) Therefore, urine antigen detection may not have definite diagnostic value in suspected H. influenzae type b disease following vaccination with VAXELIS. [See WARNINGS AND PRECAUTIONS (5.7).]

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

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

8.2 Lactation

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

8.4 Pediatric Use

The safety of VAXELIS has been established in the age group 6 weeks through 15 months, and the effectiveness of VAXELIS was established in the age group 6 weeks through 6 months on the basis of clinical studies. [See ADVERSE REACTIONS (6.1) AND CLINICAL STUDIES (14).]

The safety and effectiveness of VAXELIS in older children through 4 years of age are supported by evidence in younger children. The safety and effectiveness of VAXELIS in infants less than 6 weeks of age and in children and adolescents 5 through 17 years of age have not been established.

11 DESCRIPTION

VAXELIS (Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Inactivated Poliovirus, Haemophilus b Conjugate [Meningococcal Protein Conjugate] and Hepatitis B [Recombinant] Vaccine) is a sterile suspension for intramuscular injection.

Each 0.5 mL dose is formulated to contain 15 Lf diphtheria toxoid, 5 Lf tetanus toxoid, acellular pertussis antigens [20 mcg detoxified pertussis toxin (PT), 20 mcg filamentous hemagglutinin (FHA), 3 mcg pertactin (PRN), 5 mcg fimbriae types 2 and 3 (FIM)], inactivated polioviruses [29 D-antigen units (DU) Type 1 (Mahoney), 7 DU Type 2 (MEF-1), 26 DU Type 3 (Saukett)], 3 mcg polyribosylribitol phosphate (PRP) of H. influenzae type b covalently bound to 50 mcg of the outer membrane protein complex (OMPC) of Neisseria meningitidis serogroup B, and 10 mcg hepatitis B surface antigen (HBsAg). Each 0.5 mL dose contains 319 mcg aluminum from aluminum salts used as adjuvants.

Other ingredients per 0.5 mL dose include <0.0056% polysorbate 80 and the following residuals from the manufacturing process: ≤14 mcg formaldehyde, ≤50 ng glutaraldehyde, ≤50 ng bovine serum albumin, <5 ng of neomycin, <200 ng streptomycin sulfate, <25 ng polymyxin B sulfate, ≤0.125 μg ammonium thiocyanate and ≤0.1 mcg yeast protein (maximum 1% relative to HBsAg protein).

Corynebacterium diphtheriae is grown in modified Mueller’s growth medium. (3) After purification by ammonium sulfate fractionation, the diphtheria toxin is detoxified with formaldehyde and diafiltered.

Clostridium tetani is grown in modified Mueller-Miller casamino acid medium without beef heart infusion. (4) Tetanus toxin is detoxified with formaldehyde and purified by ammonium sulfate fractionation and diafiltration. Diphtheria and tetanus toxoids are individually adsorbed onto aluminum phosphate.

The acellular pertussis vaccine antigens are produced from Bordetella pertussis cultures grown in Stainer-Scholte medium (5) modified by the addition of casamino acids and dimethyl-beta-cyclodextrin. PT, FHA and PRN are isolated separately from the supernatant culture medium. FIM are extracted and copurified from the bacterial cells. The pertussis antigens are purified by sequential filtration, salt-precipitation, ultrafiltration and chromatography. PT is detoxified with glutaraldehyde. FHA is treated with formaldehyde and the residual aldehydes are removed by ultrafiltration. The individual antigens are adsorbed separately onto aluminum phosphate.

The Type 1, Type 2, and Type 3 polioviruses are individually grown in Vero cells. The viral harvests are concentrated and purified, then inactivated with formaldehyde to produce monovalent suspensions of each serotype. Specified quantities of monovalent suspensions of each serotype are mixed to produce the trivalent poliovirus concentrate.

The HBsAg antigen is harvested and purified from fermentation cultures of a recombinant strain of the yeast Saccharomyces cerevisiae containing the gene for the adw subtype of HBsAg. The recombinant Saccharomyces cerevisiae is grown in a fermentation medium which consists of an extract of yeast, soy peptone, dextrose, amino acids, and mineral salts. The HBsAg protein is released from the yeast cells by cell disruption and purified by a series of physical and chemical methods which includes ion and hydrophobic chromatography, and diafiltration. The purified protein is treated in phosphate buffer with formaldehyde and then co-precipitated with alum (potassium aluminum sulfate) to form bulk vaccine adjuvanted with amorphous aluminum hydroxyphosphate sulfate.

The purified PRP of H. influenzae type b (Haemophilus b, Ross strain) is conjugated to an OMPC of the B11 strain of N. meningitidis serogroup B. H. influenzae type b is grown in a fermentation medium which includes an extract of yeast, nicotinamide adenine dinucleotide, hemin chloride, soy peptone, dextrose, and mineral salts. The PRP is purified from the culture broth by purification procedures which include ethanol fractionation, enzyme digestion, phenol extraction and diafiltration. N. meningitidis serogroup B is grown in a fermentation medium which includes an extract of yeast, amino acids and mineral salts. The OMPC is purified by detergent extraction, ultracentrifugation, diafiltration and sterile filtration. PRP is conjugated to OMPC by chemical coupling and the PRP-OMPC is then adsorbed onto an amorphous aluminum hydroxyphosphate sulfate adjuvant.

The adsorbed diphtheria, tetanus, and acellular pertussis antigens are combined with aluminum phosphate (as adjuvant) and water for injection into an intermediate concentrate. The individual HBsAg and PRP-OMPC adjuvanted bulks are added followed by the trivalent poliovirus concentrate, to produce VAXELIS.

Both diphtheria and tetanus toxoids induce at least 2 neutralizing units per mL of serum in the guinea pig potency test. The potency of the acellular pertussis antigens is evaluated by the antibody response of immunized mice to detoxified PT, FHA, PRN and FIM as measured by enzyme-linked immunosorbent assay (ELISA). The immunogenicity of the inactivated polioviruses is evaluated by the antibody response in rats measured by virus neutralization. The potency of the HBsAg component is measured relative to a standard by an in vitro immunoassay. The potency of the PRP-OMPC component is measured by quantitating the polysaccharide concentration using an HPLC method.

VAXELIS does not contain a preservative. The vial stopper is not made with natural rubber latex.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Diphtheria

Diphtheria is an acute toxin-mediated disease caused by toxigenic strains of C. diphtheriae. Protection against disease is due to the development of neutralizing antibodies to diphtheria toxin. A serum diphtheria antitoxin level of 0.01 IU/mL is the lowest level giving some degree of protection. Antitoxin levels of ≥0.1 IU/mL are generally regarded as protective. (6) Levels of 1.0 IU/mL have been associated with long-term protection. (7)

Tetanus

Tetanus is an acute disease caused by an extremely potent neurotoxin produced by C. tetani. Protection against disease is due to the development of neutralizing antibodies to tetanus toxin. A serum tetanus antitoxin level of ≥0.01 IU/mL, measured by neutralization assay is considered the minimum protective level. (6) (8) A tetanus antitoxoid level ≥0.1 IU/mL as measured by the ELISA used in clinical studies of VAXELIS is considered protective.

Pertussis

Pertussis (whooping cough) is a respiratory disease caused by B. pertussis. This Gram-negative coccobacillus produces a variety of biologically active components, though their role in either the pathogenesis of, or immunity to, pertussis has not been clearly defined.

Poliomyelitis

Polioviruses, of which there are 3 serotypes (Types 1, 2, and 3), are enteroviruses. The presence of poliovirus type-specific neutralizing antibodies has been correlated with protection against poliomyelitis. (9)

Hepatitis B

Hepatitis B virus is one of several hepatitis viruses that cause systemic infection, with major pathology in the liver. Antibody concentrations of ≥10 mIU/mL against HBsAg correlate with protection against hepatitis B virus infection.

Haemophilus influenzae type b Invasive Disease

H. influenzae type b can cause invasive disease such as meningitis and sepsis. Anti-PRP antibody has been shown to correlate with protection against invasive disease due to H. influenzae type b.

Based on data from passive antibody studies (10) and an efficacy study with H. influenzae type b polysaccharide vaccine in Finland, (11) a post-vaccination anti-PRP level of ≥0.15 mcg/mL is considered a minimal protective level. Data from an efficacy study with H. influenzae type b polysaccharide vaccine in Finland indicate that an anti-PRP level of ≥1.0 mcg/mL 3 weeks after vaccination predicts protection through a subsequent 1-year period. (11) (12) These levels have been used to evaluate the effectiveness of H. influenzae type b conjugate vaccines, including the PRP-OMPC component of VAXELIS.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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

14 CLINICAL STUDIES

14.1 Effectiveness of VAXELIS

The effectiveness of VAXELIS is based on the immunogenicity of the individual antigens compared to US licensed vaccines. Serological correlates of protection exist for diphtheria, tetanus, hepatitis B, poliomyelitis, and invasive disease due to H. influenzae type b. The effectiveness against pertussis is based upon the pertussis immune responses following 3 doses of VAXELIS compared to 3 doses of Pentacel, as well as the pertussis immune responses following a subsequent dose of DAPTACEL in the same 2 groups of children. VAXELIS, Pentacel and DAPTACEL contain the same pertussis antigens, manufactured by the same processes.

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