QUADRACEL- diphtheria and tetanus toxoids and acellular pertussis adsorbed and inactivated poliovirus vaccine injection, suspension
Sanofi Pasteur Inc.
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use Quadracel safely and effectively. See full prescribing information for Quadracel.
Quadracel (Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed and Inactivated Poliovirus Vaccine)
Suspension for Intramuscular Injection
Initial U.S. Approval: 2015
INDICATIONS AND USAGE
Quadracel is a vaccine indicated for active immunization against diphtheria, tetanus, pertussis and poliomyelitis. A single dose of Quadracel is approved for use in children 4 through 6 years of age as a fifth dose in the diphtheria, tetanus, pertussis vaccination (DTaP) series, and as a fourth or fifth dose in the inactivated poliovirus vaccination (IPV) series, in children who have received 4 doses of Pentacel and/or DAPTACEL vaccine. (1)
DOSAGE AND ADMINISTRATION
A single intramuscular injection of 0.5 mL. (2)
DOSAGE FORMS AND STRENGTHS
Suspension for injection, supplied in single dose (0.5 mL) vials. (3)
WARNINGS AND PRECAUTIONS
In a clinical study, the most common solicited injection site reactions were pain (>75%), increase in arm circumference (>65%), erythema (>55%), and swelling (>40%). Common solicited systemic reactions were myalgia (>50%), malaise (>35%), and headache (>15%). (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Pharmacovigilance Department, Sanofi Pasteur Inc., Discovery Drive, Swiftwater, PA 18370 at 1-800-822-2463 (1-800-VACCINE) or VAERS at 1-800-822-7967 or http://vaers.hhs.gov
See 17 for PATIENT COUNSELING INFORMATION.
FULL PRESCRIBING INFORMATION: CONTENTS*
Quadracel® is a vaccine indicated for active immunization against diphtheria, tetanus, pertussis and poliomyelitis. A single dose of Quadracel is approved for use in children 4 through 6 years of age as a fifth dose in the diphtheria, tetanus, pertussis vaccination (DTaP) series, and as a fourth or fifth dose in the inactivated poliovirus vaccination (IPV) series, in children who have received 4 doses of Pentacel® [Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed, Inactivated Poliovirus and Haemophilus b conjugate (Tetanus Toxoid Conjugate) Vaccine] and/or DAPTACEL® (Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed).
For intramuscular use only.
Just before use, shake the vial well, until a uniform, white, cloudy suspension results. 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 exist, the product should not be administered.
Using a sterile needle and syringe and aseptic technique, withdraw and administer a 0.5 mL dose of Quadracel vaccine intramuscularly into the deltoid muscle of the upper arm. Discard unused portion.
Quadracel should not be combined through reconstitution or mixed with any other vaccine.
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.
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.
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.
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.
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.
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.
Vaccination with Quadracel may not protect all individuals.
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).]
In a clinical study, the most common solicited injection site reactions were pain (>75%), increase in arm circumference (>65%), erythema (>55%), and swelling (>40%). Common solicited systemic reactions were myalgia (>50%), malaise (>35%), and headache (>15%).
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.
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.
Solicited Adverse Reactions
The incidence and severity of solicited injection site and systemic adverse reactions that occurred within 7 days after vaccination in each study group are shown in Table 1.
(N† = 2,500-2,689)
|DAPTACEL + IPOL
(N† = 598-603)
|Injection Site Reactions||Quadracel site||DAPTACEL or IPOL site|
|Change in limb circumference§||Any||68.1||65.1|
|>0 to <25 mm||31.6||31.8|
|≥25 to <50 mm||9.5||9.6|
|>0 to <25 mm||23.5||23.1|
|≥25 to <50 mm||8.1||6.1|
|Extensive limb swelling¶||Any||1.5||1.3|
|≥38.0°C to ≤38.4°C||2.6||3.0|
|≥38.5°C to ≤38.9°C||2.1||1.8|
Serious Adverse Events
In Study M5I02, within 28 days following vaccination with Quadracel, or DAPTACEL + IPOL vaccines, and concomitant MMR and varicella vaccines, 0.1% of subjects (3/2,733) in the Quadracel group experienced a serious adverse event. During the same time period, 0.2% subjects (1/621) in the DAPTACEL + IPOL group experienced a SAE. Within the 6-month follow-up period after vaccination, SAEs were reported in 0.8% of subjects (21/2,733) who received Quadracel and 0.5% of subjects (3/621) who received DAPTACEL + IPOL vaccines, none of which were assessed as related to vaccination.
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
Nervous system disorders
General disorders and administration site conditions
Infections and Infestations
Injection site cellulitis, injection site abscess
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.
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).]
Quadracel (Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed and Inactivated Poliovirus 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)], and inactivated polioviruses [40 D-antigen units (DU) Type 1 (Mahoney), 8 DU Type 2 (MEF-1), 32 DU Type 3 (Saukett)].
Corynebacterium diphtheriae is grown in modified Mueller's growth medium. (1) 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. (2) 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 (3) 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.
Poliovirus Type 1, Type 2 and Type 3 are each grown in separate cultures of MRC-5 cells, a line of normal human diploid cells, by the microcarrier method. (4) (5) The cells are grown in CMRL (Connaught Medical Research Laboratories) 1969 medium, supplemented with calf serum. For viral growth, the culture medium is replaced by Medium 199, without calf serum. After clarification and filtration, the viral suspensions are concentrated by ultrafiltration, and purified by liquid chromatography steps. The monovalent viral suspensions are inactivated with formaldehyde. Monovalent concentrates of each inactivated poliovirus are combined to produce a trivalent poliovirus concentrate.
The adsorbed diphtheria, tetanus and acellular pertussis antigens are combined with aluminum phosphate, 2-phenoxyethanol (not as a preservative) and water for injection, into an intermediate concentrate. The trivalent poliovirus concentrate is added and the vaccine is diluted to its final concentration.
Each 0.5 mL dose contains 1.5 mg aluminum phosphate (0.33 mg aluminum) as the adjuvant, polysorbate 80 (approximately 10 ppm by calculation), <2 mcg residual formaldehyde, <50 ng residual glutaraldehyde, ≤50 ng residual bovine serum albumin, 3.3 mg (0.6% v/v) 2-phenoxyethanol (not as a preservative), <4 pg of neomycin and <4 pg polymyxin B sulfate.
Quadracel does not contain a preservative.
Both diphtheria and tetanus toxoids induce at least 2 neutralizing units per mL 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 potency of the inactivated poliovirus antigens is determined by measuring antibody-mediated neutralization of poliovirus in sera from immunized rats.
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 at least 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 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 at least 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 Quadracel is considered protective.
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.
There is no well-established serological correlate of protection for pertussis. Because DAPTACEL contains the same pertussis antigens manufactured by the same process as those in Quadracel, the effectiveness of Quadracel against pertussis was based on a comparison of pertussis immune responses following Quadracel to those following DAPTACEL (Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed). [See Clinical Studies (14)]. The efficacy of the pertussis component of DAPTACEL was determined in clinical trials of DAPTACEL administered to infants (see DAPTACEL prescribing information). Quadracel contains twice as much detoxified PT and four times as much FHA as DAPTACEL.
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 study description in Adverse Reactions (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).
|DAPTACEL + IPOL
|% Booster Response‡||97.3§||99.2|
|Pre-vaccination % ≥0.1 IU/mL¶||90.7||83.1|
|Post-vaccination % ≥0.1 IU/mL¶||100.0||99.6|
|Post-vaccination % ≥1.0 IU/mL¶||99.6||99.6|
|Post-vaccination GMC (IU/mL)||18.6#||15.5|
|% Booster Response‡||84.2§||84.3|
|Pre-vaccination % ≥0.1 IU/mL¶||91.7||89.1|
|Post-vaccination % ≥0.1 IU/mL¶||100.0||99.2|
|Post-vaccination % ≥1.0 IU/mL¶||98.9||96.8|
|Post-vaccination GMC (IU/mL)||6.4#||5.5|
|DAPTACEL + IPOL
|% Booster Response‡||95.2§||89.9|
|Post-vaccination GMC (EU/mL)||120.7¶||61.3|
|% Booster Response‡||94.9§||87.5|
|Post-vaccination GMC (EU/mL)||123.5¶||79.0|
|% Booster Response‡||96.9§||93.1|
|Post-vaccination GMC (EU/mL)||282.6¶||187.5|
|% Booster Response‡||97.2§||92.4|
|Post-vaccination GMC (EU/mL)||505.8¶||378.9|
|DAPTACEL + IPOL
|% Booster Response‡||85.9§||82.3|
|Pre-vaccination % ≥1:8 dilution||98.4||98.8|
|Post-vaccination % ≥1:8 dilution||100.0||99.6|
|% Booster Response‡||78.3§||79.0|
|Pre-vaccination % ≥1:8 dilution||99.6||99.6|
|Post-vaccination % ≥1:8 dilution||100.0||100.0|
|% Booster Response‡||85.0§||84.7|
|Pre-vaccination % ≥1:8 dilution||96.8||93.1|
|Post-vaccination % ≥1:8 dilution||100.0||100.0|
The vial stopper for this product is not made with natural latex rubber.
Quadracel is supplied in a single-dose vial (NDC No. 49281-562-58) in packages of 10 vials (NDC No. 49281-562-10).
Inform the parent or guardian of the following:
Provide the Vaccine Information Statements (VIS), which are required by the National Childhood Vaccine Injury Act of 1986.
Sanofi Pasteur Limited
Toronto Ontario Canada
Sanofi Pasteur Inc.
Swiftwater PA 18370 USA
Quadracel® is a registered trademark of Sanofi Pasteur Limited.
4 yrs - 6 yrs
Diphtheria and Tetanus
Toxoids and Acellular
Pertussis Adsorbed and
Single-dose (0.5 mL)
Sanofi Pasteur Limited
diphtheria and tetanus toxoids and acellular pertussis adsorbed and inactivated poliovirus vaccine injection, suspension
|Labeler - Sanofi Pasteur Inc. (086723285)|
|Sanofi Pasteur Limited||208206623||MANUFACTURE|