2.1 Preparation for Administration

Shake vigorously to obtain a homogeneous, turbid, white suspension. Do not use if resuspension does not occur with vigorous shaking. 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.

Attach a sterile needle and administer intramuscularly.

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

2.2 Recommended Dose and Schedule

KINRIX is to be administered as a 0.5-mL dose by intramuscular injection. The preferred site of administration is the deltoid muscle of the upper arm.

KINRIX may be used for the fifth dose in the DTaP immunization series and the fourth dose in the IPV immunization series in children aged 4 through 6 years (prior to the seventh birthday) whose previous DTaP vaccine doses have been with INFANRIX and/or PEDIARIX for the first 3 doses and INFANRIX for the fourth dose [see Indications and Usage (1)].

4.1 Hypersensitivity

Severe allergic reaction (e.g., anaphylaxis) after a previous dose of any diphtheria toxoid-, tetanus toxoid-, pertussis- or poliovirus-containing vaccine, or to any component of KINRIX, including neomycin and polymyxin B, is a contraindication to administration of KINRIX [see Description (11)]. Because of the uncertainty as to which component of the vaccine might be responsible, no further vaccination with any of these components should be given. Alternatively, such individuals may be referred to an allergist for evaluation if immunization with any of these components is considered.

4.2 Encephalopathy

Encephalopathy (e.g., coma, decreased level of consciousness, prolonged seizures) within 7 days of administration of a previous dose of a pertussis-containing vaccine that is not attributable to another identifiable cause is a contraindication to administration of any pertussis-containing vaccine, including KINRIX.

4.3 Progressive Neurologic Disorder

Progressive neurologic disorder, including infantile spasms, uncontrolled epilepsy, or progressive encephalopathy, is a contraindication to administration of any pertussis-containing vaccine, including KINRIX. Pertussis vaccine should not be administered to individuals with such conditions until a treatment regimen has been established and the condition has stabilized.

5.1 Guillain-Barré Syndrome

If Guillain-Barré syndrome occurs within 6 weeks of receipt of a prior vaccine containing tetanus toxoid, the decision to give any tetanus toxoid-containing vaccine, including KINRIX, should be based on careful consideration of the potential benefits and possible risks. When a decision is made to withhold tetanus toxoid, other available vaccines should be given, as indicated.

5.2 Latex

The tip caps of the prefilled syringes contain natural rubber latex which may cause allergic reactions.

5.3 Syncope

Syncope (fainting) can occur in association with administration of injectable vaccines, including KINRIX. 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.

5.4 Adverse Reactions following Prior Pertussis Vaccination

If any of the following reactions occur in temporal relation to receipt of a pertussis-containing vaccine, the decision to give any pertussis-containing vaccine, including KINRIX, should be based on careful consideration of the potential benefits and possible risks:

•

Temperature of ≥40.5oC (105oF) within 48 hours not due to another identifiable cause;

•

Collapse or shock-like state (hypotonic-hyporesponsive episode) within 48 hours;

•

Persistent, inconsolable crying lasting ≥3 hours, occurring within 48 hours;

•

Seizures with or without fever occurring within 3 days.

When a decision is made to withhold pertussis vaccination, other available vaccines should be given, as indicated.

5.5 Children at Risk for Seizures

For children at higher risk for seizures than the general population, an appropriate antipyretic may be administered at the time of vaccination with a pertussis-containing vaccine, including KINRIX, and for the ensuing 24 hours to reduce the possibility of post-vaccination fever.

5.6 Preventing and Managing Allergic Vaccine Reactions

Prior to administration, the healthcare provider should review the patient’s immunization history for possible vaccine sensitivity and previous vaccination-related adverse reactions to allow an assessment of benefits and risks. Epinephrine and other appropriate agents used for the control of immediate allergic reactions must be immediately available should an acute anaphylactic reaction occur.

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.

A total of 4,013 children were vaccinated with a single dose of KINRIX in 4 clinical trials. Of these, 381 children received a non-U.S. formulation of KINRIX (containing ≤2.5 mg 2‑phenoxyethanol per dose as preservative).

The primary study (Study 048), conducted in the United States, was a randomized, controlled clinical trial in which children aged 4 to 6 years were vaccinated with KINRIX (n = 3,156) or control vaccines (INFANRIX and IPOL vaccine [IPV, Sanofi Pasteur SA]; n = 1,053) as a fifth DTaP vaccine dose following 4 doses of INFANRIX and as a fourth IPV dose following 3 doses of IPOL. Subjects also received the second dose of U.S.‑licensed measles, mumps, and rubella (MMR) vaccine (Merck & Co., Inc.) administered concomitantly, at separate sites.

Data on adverse events were collected by parents/guardians using standardized forms for 4 consecutive days following vaccination with KINRIX or control vaccines (i.e., day of vaccination and the next 3 days). The reported frequencies of solicited local reactions and general adverse reactions in Study 048 are presented in Table 1.

In 3 studies (Studies 046, 047, and 048), children were monitored for unsolicited adverse events, including serious adverse events that occurred in the 31-day period following vaccination, and in 2 studies (Studies 047 and 048), parents/guardians were actively queried about changes in the child’s health status, including the occurrence of serious adverse events, through 6 months post-vaccination.

In Study 048, KINRIX was non-inferior to INFANRIX with regard to swelling that involved >50% of the injected upper arm length and that was associated with a >30 mm increase in mid-upper arm circumference within 4 days following vaccination (upper limit of 2-sided 95% Confidence Interval for difference in percentage of KINRIX [0.6%, n = 20] minus INFANRIX [1.0%, n = 11] ≤2%).

Serious Adverse Events

Within the 31-day period following study vaccination in 3 studies (Studies 046, 047, and 048) in which all subjects received concomitant MMR vaccine (U.S.‑licensed MMR vaccine [Merck & Co., Inc.] in Studies 047 and 048, non—U.S.-licensed MMR vaccine in Study 046), 3 subjects (0.1% [3/3,537]) who received KINRIX reported serious adverse events (dehydration and hypernatremia; cerebrovascular accident; dehydration and gastroenteritis) and 4 subjects (0.3% [4/1,434]) who received INFANRIX and inactivated poliovirus vaccine (Sanofi Pasteur SA) reported serious adverse events (cellulitis, constipation, foreign body trauma, fever without identified etiology).

6.2 Postmarketing Experience

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

General Disorders and Administration Site Conditions

Injection site vesicles.

Nervous System Disorders

Syncope.

Skin and Subcutaneous Tissue Disorders

Pruritus.

Additional adverse reactions reported following postmarketing use of INFANRIX, for which a causal relationship to vaccination is plausible, are: Allergic reactions, including anaphylactoid reactions, anaphylaxis, angioedema, and urticaria; apnea; collapse or shock-like state (hypotonic-hyporesponsive episode); convulsions (with or without fever); lymphadenopathy; and thrombocytopenia.

7.1 Concomitant Vaccine Administration

In U.S. clinical trials, KINRIX was administered concomitantly with the second dose of MMR vaccine (Merck & Co., Inc.); in one of these trials (Study 055), KINRIX was also administered concomitantly with varicella vaccine (Merck & Co., Inc.) [see Clinical Studies (14.2)].

When KINRIX is administered concomitantly with other injectable vaccines, they should be given with separate syringes. KINRIX should not be mixed with any other vaccine in the same syringe.

7.2 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 KINRIX.

8.4 Pediatric Use

Safety and effectiveness of KINRIX in children younger than 4 years and children aged 7 to 16 years have not been evaluated. KINRIX is not approved for use in persons in these age groups.

12.1 Mechanism of Action

Diphtheria

Diphtheria is an acute toxin-mediated infectious disease caused by toxigenic strains of C. diphtheriae. Protection against disease is due to the development of neutralizing antibodies to the diphtheria toxin. A serum diphtheria antitoxin level of 0.01 IU/mL is the lowest level giving some degree of protection; a level of 0.1 IU/mL is regarded as protective.1

Tetanus

Tetanus is an acute toxin-mediated disease caused by a potent exotoxin released by C. tetani. Protection against disease is due to the development of neutralizing antibodies to the tetanus toxin. A serum tetanus antitoxin level of at least 0.01 IU/mL, measured by neutralization assays, is considered the minimum protective level.2,3 A level of ≥0.1 IU/mL is considered protective.4

Pertussis

Pertussis (whooping cough) is a disease of the respiratory tract caused by B. pertussis. The role of the different components produced by B. pertussis in either the pathogenesis of, or the immunity to, pertussis is not well understood. There is no well-established serological correlate of protection for pertussis. The efficacy of the pertussis component of KINRIX was determined in clinical trials of INFANRIX administered as a 3-dose series in infants (see INFANRIX prescribing information).

Poliomyelitis

Poliovirus is an enterovirus that belongs to the picornavirus family. Three serotypes of poliovirus have been identified (Types 1, 2, and 3). Neutralizing antibodies against the 3 poliovirus serotypes are recognized as conferring protection against poliomyelitis disease.5

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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

14.1 Immunological Evaluation

In a U.S. multicenter study (Study 048), 4,209 children were randomized in a 3:1 ratio to receive either KINRIX or INFANRIX and IPV (Sanofi Pasteur SA) administered concomitantly at separate sites. Subjects also received MMR vaccine (Merck & Co., Inc.) administered concomitantly at a separate site. Subjects were children aged 4 through 6 years who previously received 4 doses of INFANRIX, 3 doses of IPV, and 1 dose of MMR vaccine. Among subjects in both vaccine groups combined, 49.6% were female; 45.6% of subjects were White, 18.8% Hispanic, 13.6% Asian, 7.0% Black, and 15.0% were of other racial/ethnic groups.

Levels of antibodies to the diphtheria, tetanus, pertussis (PT, FHA, and pertactin), and poliovirus antigens were measured in sera obtained immediately prior to vaccination and 1 month (range: 31 to 48 days) after vaccination (Table 2). The co-primary immunogenicity endpoints were anti-diphtheria toxoid, anti-tetanus toxoid, anti-PT, anti-FHA, and anti-pertactin booster responses, and anti-poliovirus Type 1, Type 2, and Type 3 geometric mean antibody titers (GMTs) 1 month after vaccination. KINRIX was shown to be non-inferior to INFANRIX and IPV administered separately, in terms of booster responses to DTaP antigens and post-vaccination GMTs for anti-poliovirus antibodies (Table 2).

14.2 Concomitant Vaccine Administration

In a U.S. study (Study 055) that enrolled children aged 4 to 6 years, KINRIX was administered concomitantly at separate sites with MMR vaccine (Merck & Co., Inc.) (n = 237) or with MMR vaccine and varicella vaccine (Merck & Co., Inc.) (n = 239). Immune responses to the antigens contained in KINRIX were measured approximately 1 month (28 to 48 days) after vaccination. Booster responses to diphtheria, tetanus, and pertussis antigens and GMTs for poliovirus (Type 1, 2, and 3) after the receipt of KINRIX administered concomitantly with MMR vaccine and varicella vaccine were non-inferior to immune responses following concomitant administration of KINRIX administered with MMR vaccine.