4.1 Hypersensitivity

Severe allergic reaction (e.g., anaphylaxis) to any ingredient of Quadracel [see Description (11)] or following any diphtheria toxoid, tetanus toxoid, pertussis-containing vaccine, or inactivated poliovirus vaccine, is a contraindication to administration of Quadracel.

4.2 Encephalopathy

Encephalopathy (e.g., coma, decreased level of consciousness, prolonged seizures) within 7 days 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 Quadracel.

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 Quadracel. 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 Management of Acute Allergic Reactions

Epinephrine hydrochloride solution (1:1,000) and other appropriate agents and equipment must be available for immediate use in case an anaphylactic or acute hypersensitivity reaction occurs.

5.2 Adverse Reactions Following Prior Pertussis Vaccination

If any of the following events have occurred within the specified period after administration of a pertussis vaccine, the decision to administer Quadracel should be based on careful consideration of benefits and risks.

• Temperature of ≥40.5°C (≥105°F) within 48 hours, not attributable to another identifiable cause.
• Collapse or shock-like state (hypotonic-hyporesponsive episode [HHE]) within 48 hours.
• Persistent, inconsolable crying lasting ≥3 hours within 48 hours.
• Seizures with or without fever within 3 days.

5.3 Guillain-Barré Syndrome

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

5.4 Limitations of Vaccine Effectiveness

Vaccination with Quadracel may not protect all individuals.

5.5 Altered Immunocompetence

If Quadracel is administered to immunocompromised persons, including persons receiving immunosuppressive therapy, the expected immune response may not be obtained [see Drug Interactions (7.2)].

5.6 Syncope

Syncope (fainting) may occur in association with administration of injectable vaccines including Quadracel. Procedures should be in place to avoid injury from fainting.

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 to rates in the clinical trials of another vaccine and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to vaccine use and for approximating rates of those events. The poliovirus component (poliovirus types 1, 2, and 3) of this formulation of Quadracel is grown in Vero cells [see Description (11)]. The clinical study data in this section were accrued with a Quadracel formulation in which poliovirus component was grown in MRC-5 cells.

In a randomized, controlled, multicenter study conducted in the US and Puerto Rico (Study M5I02; ClinicalTrials.gov Identifier: NCT01346293), 3,372 children, 4 to 6 years of age, who had received 4 doses of DAPTACEL and/or Pentacel vaccine(s) received Quadracel, or DAPTACEL + IPOL (Poliovirus Vaccine Inactivated) vaccines administered concomitantly but at separate sites. Subjects also received Measles, Mumps, and Rubella Virus Vaccine Live (MMR) (Merck & Co., Inc.) and Varicella Virus Vaccine Live (Varicella vaccine) (Merck & Co., Inc.) administered concomitantly at separate sites. Safety was evaluated in 2,733 subjects who received Quadracel and 621 subjects who received DAPTACEL + IPOL vaccines.

Among these subjects, 51.5% were male, 48.5% were female, 75.7% were Caucasian, 8.6% were Black, 7.9% were Hispanic, 0.9% were Asian, and 7.8% were of other racial/ethnic groups. The mean age for both groups was 4.4 years and the ratio of male to female subjects and ethnicity were balanced between both groups.

Solicited injection site reactions and systemic reactions were collected daily for 7 days following vaccination, via diary cards. Participants were monitored for unsolicited adverse events for 28 days and serious adverse events (SAEs) for 6 months after vaccination.

6.2 Postmarketing Experience

The following adverse events have been spontaneously reported, during the post-marketing use of Quadracel outside the US, in infants and children from 2 months through 6 years of age. Because these events are reported voluntarily from a population of uncertain size, it is not possible to estimate their frequency reliably or establish a causal relationship to vaccine exposure. This list includes adverse events based on one or more of the following factors: severity, frequency of reporting, or strength of evidence for a causal relationship to Quadracel.

• Immune system disorders
  Anaphylactic reaction, hypersensitivity and allergic reactions (such as rash, urticaria, dyspnea)
• Psychiatric disorders
  Screaming
• Nervous system disorders
  Somnolence, convulsion, febrile convulsion, HHE, hypotonia
• Cardiac disorders
  Cyanosis
• Vascular disorders
  Pallor
• General disorders and administration site conditions
  Listlessness
  Injection site reactions (including inflammation, mass, sterile abscess, and edema)
  Large injection site reactions (>50 mm), including limb swelling which may extend from the injection site beyond one or both joints
• Infections and Infestations
  Injection site cellulitis, injection site abscess

7.1 Concomitant Administration with Other Vaccines

In the US clinical trial, Study M5I02, Quadracel was administered concomitantly with one or more of the following US-licensed vaccines: MMR vaccine and varicella vaccine [see Adverse Reactions (6.1)].

When Quadracel is given at the same time as another injectable vaccine(s), the vaccines should be administered with different syringes and at different injection sites.

7.2 Immunosuppressive Treatments

Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs and corticosteroids (used in greater than physiologic doses), may reduce the immune response to Quadracel [see Warnings and Precautions (5.5)].

8.4 Pediatric Use

The safety and effectiveness of Quadracel has not been established in children less than 4 years of age or children 7 through 16 years of age and is not approved for use in these age groups.

12.1 Mechanism of Action

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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

14.1 Immunogenicity

In Study M5I02, children 4 through 6 years of age received Quadracel or DAPTACEL + IPOL as the fifth dose in the diphtheria, tetanus, and pertussis vaccination series and the fourth or fifth dose in the inactivated poliovirus vaccination series. Subjects also received their second dose of MMR and Varicella vaccines, concomitantly. The immunogenicity subset comprised 263 subjects in the Quadracel group and 253 subjects in the DAPTACEL + IPOL vaccines group [see Clinical Trials Experience (6.1)].

Antibody levels to diphtheria, tetanus, pertussis (PT, FHA, PRN and FIM) and poliovirus antigens were measured in sera obtained immediately prior to vaccination and 28 days after vaccination. The co-primary endpoints were booster response rates and antibody geometric mean concentrations/titers (GMCs/GMTs) to diphtheria, tetanus, pertussis and poliovirus antigens elicited after vaccination. Booster response rates and antibody GMCs/GMTs following Quadracel vaccination were compared to those after DAPTACEL + IPOL vaccination.

Quadracel was non-inferior to DAPTACEL + IPOL vaccines administered concomitantly at separate sites, as demonstrated by comparison of the post-vaccination antibody booster response rates and GMCs/GMTs to diphtheria and tetanus (Table 2), to all pertussis antigens (Table 3) and to poliovirus 1, 2 and 3 (Table 4).

16.1 How Supplied

The vial stopper, syringe plunger stopper, and syringe tip cap are not made with natural rubber latex.

Single-dose vial (NDC No. 49281-564-58) in packages of 10 vials (NDC No. 49281-564-10).

Single-dose, prefilled syringe, without needle, (NDC No. 49281-564-88). Supplied as package of 10 (NDC No. 49281-564-15).

16.2 Storage and Handling

Quadracel should be stored at 2° to 8°C (35° to 46°F). Do not freeze. Product which has been exposed to freezing should not be used. Do not use after expiration date shown on the label.