Diphtheria and Tetanus Toxoids and Pertussis Vaccine Adsorbed (Systemic)


Note: This monograph describes diphtheria and tetanus toxoids combined with either whole-cell pertussis vaccine or acellular pertussis vaccine. The acellular pertussis-containing vaccine is indicated by the term DTaP or acellular DTP. The whole-cell pertussis-containing vaccine is indicated by the term DTwP or whole-cell DTP. For general statements, the term DTP will be used.


VA CLASSIFICATION
Primary: IM900

Commonly used brand name(s): Acel-Imune; Certiva; Infanrix; Tripedia.

Other commonly used names are
acellular DTP, DTaP, DTP, DTwP, and whole-cell DTP .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Immunizing agent (active)—

Indications

General considerations
Diphtheria is a rare disease in the U.S. {01} {02} However, epidemic diphtheria has reemerged in the New Independent States (NIS) of the former Soviet Union and has resulted in more than 47,000 reported cases in 1994 and 50,000 reported cases in 1995 {03}. Although no imported cases were reported in the U.S. during those years, more than 20 cases of diphtheria were reported in Europe, and two cases occurred among U.S. citizens who resided in or were traveling in the NIS {03}. This threat of infection underscores the importance of maintaining high levels of diphtheria immunity in the U.S. population {03}.

Diphtheria is an acute infectious disease caused by toxicogenic strains of Corynebacterium diphtheriae {04}, Corynebacterium pseudotuberculosis , and Corynebacterium ulcerans {05} {06}. The usual incubation period is 2 to 5 days but occasionally it is longer {04}. Humans are the only known reservoir of C. diphtheriae {04}. Sources of infection include discharges from the nose, throat, eyes, and skin lesions of infected persons {04}. Transmission results primarily from intimate contact with a patient or a carrier {04}. Rarely, fomites can serve as vehicles of transmission, and food-borne outbreaks have occurred {07}.

Tetanus (lockjaw) is a neurologic disease characterized by severe muscular spasms {08}. It is caused by the neurotoxin produced by the anaerobic bacterium Clostridium tetani in a contaminated wound {08}. Onset is gradual, occurring over 1 to 7 days, and progresses to severe generalized muscle spasms (severe enough to cause spinal fractures), which frequently are aggravated by any external stimulus {08}. Severe spasms persist for 1 week or more and subside in a period of weeks in those who recover {08}. Neonatal tetanus, a common cause of neonatal mortality in developing countries but rare in the U.S., is caused by contamination of the umbilical stump {08}. Local tetanus is manifested by local muscle spasms in areas contiguous to a wound infected with C. tetani {08}.

Pertussis (whooping cough) is a disease of the respiratory tract caused by Bordetella pertussis {09} {10}. Pertussis is highly communicable (attack rates of more than 90% have been reported among unvaccinated household contacts), and can cause severe disease, particularly among very young children {09} {10}. Complications of pertussis include pneumonia, apnea, seizures, and death, and are more common in the very young, especially in infants younger than 6 months of age {11}. Routine vaccination with diphtheria and tetanus toxoids and whole-cell pertussis vaccine (DTwP) has significantly reduced pertussis-related morbidity and mortality {09} {10}.

Although DTwP is effective in prevention of pertussis disease, concerns about local and systemic reactions have stimulated efforts to produce less reactogenic vaccines {12} {13}. Clinical trials sponsored by the National Institutes of Health (NIH) have evaluated the safety and immunogenicity of acellular pertussis vaccines {12} {13}. In these studies, the adverse events after administration of diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP) were significantly less frequent and less severe than those associated with DTwP reference group, and the acellular pertussis vaccines were immunogenic {12}.

Accepted

Diphtheria, tetanus, and pertussis (prophylaxis)—DTwP and DTaP are indicated for immunization of infants and children from 2 months to 7 years of age against diphtheria, tetanus, and pertussis {07}. Unless otherwise contraindicated, all infants and children from 2 months to 7 years of age should be immunized against diphtheria, tetanus, and pertussis {07} {09} {10} {14} {15} {16}.

Note: The routine diphtheria, tetanus, and pertussis vaccination schedule comprises five doses of vaccine containing diphtheria, tetanus, and pertussis antigens {07}. Three (primary) doses should be administered during the first year of life, generally at 2, 4, and 6 months of age {07}. The fourth (first booster) dose is recommended for children 15 to 18 months of age {07}. The fourth dose should be administered at or after 6 months after the third dose {07}. A fifth dose is not necessary if the fourth dose in the series is administered on or after the fourth birthday {07}. In the U.S., DTaP is preferred for all doses in the immunization schedule {12}. During the transition period from the use of DTwP to DTaP, DTwP is an acceptable alternative for any of the five doses {12}.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Diphtheria and tetanus toxoids and whole-cell pertussis vaccine (DTwP) consists of a mixture of the detoxified toxins (toxoids) of diphtheria and tetanus and inactivated Bordetella pertussis that have been adsorbed onto an aluminum salt. Diphtheria and tetanus toxoids and acellular pertussis vaccines (DTaP) contain pertussis toxin (PT) and one or more of the following components of B. pertussis {07}:    • Filamentous hemagglutinin (FHA) {07} {17} {18}.
   • Fimbrial antigens (FIM) {07} {17} {18}.
   • Pertactin (PRN, formerly known as 69-kd protein) {07} {17} {18}.


Mechanism of action/Effect:

Note: Although serologic correlates of pertussis immunity are not defined, it has been determined that DTaP vaccines can stimulate immune responses that exceed those of DTwP vaccines with respect to the measured antibodies {17}. Particularly for PT, immunogenicity seems to depend on factors in addition to antigen concentration, possibly including antigen derivation and formulation {17}.


Diphtheria—Following intramuscular injection, diphtheria toxoid induces the formation of antibody to diphtheria toxin {17}.

Tetanus—Following intramuscular injection, tetanus toxoid induces the formation of antibody to tetanus toxin {17}.

Pertussis—Following intramuscular injection, acellular or whole-cell pertussis vaccine induces the formation of several antibodies thought to be clinically protective {17}. The levels of antibody necessary for protection have not been determined {17}.


Protective effect

The Multicenter Acellular Pertussis Trial, an immunogenicity and safety study conducted in six centers in the U.S. and sponsored by the National Institutes of Health (NIH), compared the antibody response of infants vaccinated at 2, 4, and 6 months of age with DTwP or with one of 13 different DTaP vaccines {07}. Antibody to pertussis antigens was measured in serum samples taken before administration of the first dose and 1 month after administration of the third dose of one of the 13 different DTaP vaccines; 99 and 86% of children had fourfold or greater increases in titers of antibody to PT and FHA, respectively {07}. More than 90% of children administered one of the 13 different DTaP vaccines and more than 90% of those administered DTwP developed diphtheria and tetanus antibody levels indicative of immunity to these diseases {07}.


Duration of protective effect

Diphtheria—Primary immunization with DTP protects more than 95% of persons for at least 10 years {19}.

Tetanus—Primary immunization with DTP protects 95% of persons for at least 10 years {19}.

Pertussis—Following primary immunization with DTP vaccine, immunity to pertussis usually persists through childhood, but is thought to decrease over time {09} {10} {14} {16} {19} {20}. Lifelong immunity probably is attained through subsequent mild pertussis infection.


Precautions to Consider

Pregnancy/Reproduction
Fertility—
Diphtheria and tetanus toxoids and whole-cell pertussis vaccine (DTwP) and diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP) have not been evaluated for their potential to impair fertility {10}.

Pregnancy—
Studies have not been done in humans {09} {10} {14}. However, DTP is not recommended for use in pregnant women {09} {10} {14}.

Studies have not been done in animals {09} {10} {14}.

FDA Pregnancy Category C {09} {10} {14}.

Breast-feeding

It is not known whether DTP passes into breast milk. However, DTP is not recommended for use in persons 7 years of age and older (see Adolescents ) {09} {10} {14} {16}.

Pediatrics

Infants and young children who previously have had seizures (whether febrile or nonfebrile) are at greater risk for seizures after receiving DTwP than are infants who do not have such a history {07}. Because these reactions may be caused by the fever induced by DTwP and because DTaP is less frequently associated with moderate to high fever, DTaP is the vaccine of choice when pertussis vaccination is considered for these children {07}.

Among infants and children with a history of seizures, it is important to delay pertussis vaccination until their neurologic status has been assessed {07}. Infants and children with a stable neurologic condition, including well-controlled seizures, may be vaccinated with DTaP {07}. Infants with evolving neurologic conditions should not be vaccinated until a treatment regimen has been established and the condition has stabilized {07}. Acetaminophen or ibuprofen may be administered to these infants and children at the time of DTaP vaccination and every 4 hours for 24 hours thereafter to reduce the risk of postvaccination fever {07}.

Data from one study indicate that infants and young children who have a parent or sibling with a history of convulsions are more likely to have seizures following DTwP vaccination than those without such histories {07}. However, seizures occur infrequently after administration of DTwP, are usually febrile in nature, and generally have a benign outcome {07}. An estimated 5 to 7% of children have parents or siblings with a history of convulsions {07}. If these children were exempted from vaccination, unvaccinated persons and the general population might face an increased risk for pertussis {07}. Therefore, a family history of convulsions or other central nervous system disorders is not a contraindication to pertussis vaccination {07}. Acetaminophen or ibuprofen may be administered to these children at the time of DTaP vaccination and every 4 hours for 24 hours thereafter to reduce the risk of postvaccination fever {07}.



Adolescents

DTwP and DTaP are licensed for use among infants and children 6 weeks to 7 years of age only {07} {09} {10} {14} {16}. In the U.S., adolescents and adults whose immunity has waned are an important reservoir for Bordetella pertussis and may infect unvaccinated young children {07}. In the future, booster doses of adult formulations of acellular pertussis vaccines may be recommended to prevent the occurrence and spread of the disease among these older persons {07}. However, acellular pertussis vaccines combined with diphtheria and tetanus toxoids will need to be reformulated for use in adults because all infant formulations contain more diphtheria toxoid than is recommended for persons 7 years of age and older {07}. Because it is very important to maintain high levels of diphtheria and tetanus immunity among adolescents and adults, tetanus and diphtheria toxoids adsorbed for adult use (Td) should be used in persons 7 years of age and older {03} {09} {10} {14} {16}.

If a dose of Td has been administered after receipt of tetanus- and diphtheria-containing vaccine at 4 to 6 years of age and before the routine Td booster at 11 to 12 years of age, the dose at 11 to 12 years of age is not indicated {03}. The next dose should follow the last dose by 10 years, unless specifically indicated because of a tetanus-prone injury {03}. Persons who sustain a tetanus-prone injury should be administered a Td booster dose immediately if more than 5 years have elapsed since their last Td booster dose {03}.


Geriatrics


No information is available on the relationship of age to the effects of DTP in geriatric patients. However, DTP is not recommended for use in persons 7 years of age and older (see Adolescents ) {09} {10} {14} {16}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Immunosuppressive agents or
Radiation therapy    (because normal defense mechanisms are suppressed, concurrent use of immunosuppressive agents or radiation therapy with diphtheria and tetanus toxoids and whole-cell pertussis vaccine (DTwP) and diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP) may decrease the patient's antibody response to DTP or may result in aberrant responses to active immunization procedures. The precaution does not apply to corticosteroids used as replacement therapy, for short-term [less than 2 weeks] systemic therapy, or by other routes of administration that do not cause immunosuppression. If immunosuppressive therapy will be discontinued shortly, immunization with DTP should be deferred until the patient has discontinued therapy for 1 month; otherwise, the patient should be immunized with DTP while still undergoing therapy {09} {10} {14} {16} {19} {20})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Anaphylactic reaction    (if an immediate anaphylactic reaction occurs after administration of DTwP or DTaP, subsequent vaccination with DTaP or DTwP should be deferred because of uncertainty as to which component of the vaccine might be responsible; because of the importance of tetanus vaccination, persons who experience anaphylactic reactions may be referred to an allergist for evaluation and [if specific allergy can be demonstrated] desensitized to tetanus toxoid {07} {09} {10} {14} {16} {19} {20})


» Encephalopathy    (encephalopathy not due to an identifiable cause, occurring within 7 days of a prior DTwP or DTaP immunization and consisting of major alterations of consciousness, unresponsiveness, generalized or focal seizures that persist for more than a few hours, and failure to recover within 24 hours should be considered a contraindication to further use; even though causation cannot be established, no subsequent doses of pertussis vaccine should be given {07} {09} {10} {14} {16} {19} {20})


» Febrile illness, acute    (immunization should be deferred during the course of an acute febrile illness; the decision about whether to administer or delay vaccination because of a current or recent febrile illness depends on the severity of symptoms and on the etiology of the disease; vaccine can be administered to persons with mild illness such as diarrhea, mild upper respiratory infection with or without low-grade fever, or other low-grade febrile illness {07} {09} {10} {14} {16} {19} {20})


Risk-benefit should be considered when the following medical problems exist
Fever of 40.5 °C (105 °F) or more, occurring within 48 hours, not attributable to another identifiable cause
Collapse or shock-like state (hypotonic-hyporesponsive episode) within 48 hours
Persistent crying lasting 3 or more hours, occurring within 48 hours
Convulsions with or without fever, occurring within 3 days    (if any of these adverse effects occurs within the specified period after administration of either DTwP or DTaP, vaccine providers and parents should evaluate the risks and benefits of administering subsequent doses of a pertussis-containing vaccine; in circumstances in which the benefits of further pertussis vaccination outweigh the possible risks [e.g., during an outbreak of pertussis], DTaP should be administered for the subsequent doses {07} {09} {10} {14} {16} {19} {20})


Sensitivity to diphtheria or tetanus toxoids or to pertussis vaccine{07}{09}{10}{14}{16}{19}{20}


Side/Adverse Effects

Note: Mild systemic reactions such as fever, drowsiness, fretfulness, and anorexia may occur after both diphtheria and tetanus toxoids and whole-cell pertussis vaccine (DTwP) and diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP) administration {07}. However, data concerning adverse reactions following the first four doses indicate that these mild reactions are less common among children who receive DTaP {07}. These reactions are self-limited and can be managed safely with symptomatic treatment {07}.
Moderate-to-severe systemic reactions (e.g., temperature of ³ 40.5 °C [³ 105 °F], febrile seizures, persistent crying lasting more than 3 hours, and hypnotic-hyporesponsive episodes) have been reported rarely after administration of DTaP, and occur less frequently among children administered DTaP than among children administered DTwP {07}.
Data from the Vaccine Adverse Events Reporting System (VAERS) were used to compare rates of fever, seizures, and hospitalizations among children who, having had three or more previous doses of DTwP, were administered either DTwP or DTaP for the fourth or fifth doses {07}. During 1991 to 1993, approximately 5 million doses of DTaP and 27 million doses of DTwP were distributed for use among children 15 months to 6 years of age. Adverse effects were reported significantly less frequently among the children who received DTaP {07}. VAERS is a passive surveillance system and these data should be interpreted with caution because the events reported may be linked to vaccine administration only by temporal coincidence {07}.
Sudden infant death syndrome (SIDS) has occurred after DTP immunization, but several studies provide evidence that DTP immunization is not associated with SIDS {15}. A large case-control study of SIDS in the U.S. demonstrated that SIDS victims were no more likely to have received DTP vaccination recently than control children who did not have SIDS {15} {21}. Because SIDS occurs most commonly at the age when DTP immunization is recommended, coincidental, temporal associations between the death and immunization by chance alone are expected {15}.
The temporal relation of DTP immunization and severe adverse effects, such as death, encephalopathy, onset of a seizure disorder, developmental delay, or learning or behavioral problems, does not establish causation by vaccination {15}. Many of the manifestations of alleged vaccine reactions have other causes, such as viral encephalitis, concurrent infections, pre-existing neurologic disorders, and metabolic and other congenital abnormalities {15}. For example, whereas infantile spasms frequently have their onset in the first 6 months of life and, in some cases, have been temporally related to the administration of pertussis vaccine, epidemiologic data demonstrate that the vaccine does not cause infantile spasms {15} {21}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent
    
Hypotonic-hyporesponsive episodes {09}{10}{14}{16}{19}{20}(collapse or shock-like state)
    
crying, persistent and inconsolable, occurring within 48 hours and lasting 3 or more hours{09}{10}{14}{16}{19}{20}


Note: Hypotonic-hyporesponsive episodes have been reported after DTwP vaccination to occur at an incidence of 1:1750 doses administered {15}. However, rates appear to vary widely, ranging from 3.5 to 291 cases per 100,000 immunizations in other observations {15}. These episodes occur less frequently following DTaP vaccination {15}. A follow-up study of a group of children who experienced hypotonic-hyporesponsive episodes following DTwP vaccination demonstrated no evidence of subsequent serious neurologic damage or intellectual impairment {15}.
Persistent, severe, inconsolable screaming or crying for 3 or more hours is sometimes observed within 48 hours of DTwP vaccination {15}. The occurrence of inconsolable crying for 3 or more hours is significantly less frequent following DTaP vaccination {15}. Distinguishing between these features and crying from pain can be difficult and requires close questioning of the child's caregiver {15}. The significance of persistent crying is unknown {15}. It has been noted after receipt of immunizations other than pertussis vaccine and is not known to be associated with sequelae {15}.

Incidence rare
    
Anaphylactic reaction {09}{10}{14}{16}{19}{20}(difficulty in breathing or swallowing; hives; itching, especially of soles or palms; reddening of skin, especially around ears; swelling of eyes, face, or inside of nose; unusual tiredness or weakness, sudden and severe)
    
convulsions, with or without fever, occurring within 3 days {09}{10}{14}{16}{19}{20}
    
encephalopathy, occurring within 7 days {09}{10}{14}{16}{19}{20}(severe alterations in consciousness, with generalized or focal neurological signs; confusion; severe or continuing headache; unusual irritability; excessive sleepiness; severe or continuing vomiting)
    
fever of 40.5 °C (105 °F) or more, occurring within 48 hours {09}{10}{14}{16}{19}{20}

Note: The rate of anaphylaxis to DTwP is estimated to be approximately two cases per 100,000 injections; the incidence of allergic reactions following DTaP vaccination is unknown {15}. Severe anaphylactic reactions and resulting deaths, if any, are extremely rare following pertussis immunization {15}. The transient urticarial rashes that occur occasionally after pertussis immunization, unless appearing immediately (i.e., within minutes), are unlikely to be anaphylactic in origin {15}. These rashes probably represent a serum sickness–type reaction caused by circulating antigen-antibody complexes due to one of the antigens in pertussis vaccine and corresponding antibody acquired either from an earlier dose or transplacentally {15}. Because formation of such complexes is dependent on a precise balance between concentrations of circulating antigen and antibody, such reactions are unlikely to recur after a subsequent dose and are not contraindications to further doses {15}.
The incidence of seizures occurring within 48 hours of administration of DTwP has been estimated to be 1:1750 doses administered {15}. In field trials of DTaP and postlicensure surveillance of adverse effects associated with DTaP, the incidence of seizures has been substantially less than that associated with DTwP {15}. Most seizures occurring after DTP immunization are brief, self-limited, and generalized, occur in febrile children, and occur after the third and fourth doses of the vaccine series {15}. These characteristics suggest that seizures associated with pertussis vaccine usually are febrile convulsions {15}. These seizures have not been demonstrated to result in the subsequent development of recurrent afebrile seizures (i.e., epilepsy) or other neurologic sequelae {15}. Predisposing factors to seizures occurring within 48 hours include underlying convulsive disorder, personal history of convulsions, and family history of convulsions {15}.




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Abscess or local reaction {09}{10}{14}{16}{19}{20}(redness, swelling, tenderness, or pain at injection site)
    
fever between 38 and 39 °C (100.4 and 102.2 °F) —usually lasting up to, but no longer than, 48 hours; may be accompanied by fretfulness, drowsiness, vomiting, and anorexia{09}{10}{14}{16}{19}{20}
    
lump at injection site —may be present for a few weeks after injection{09}{10}{14}{16}{19}{20}

Incidence less frequent
    
Fever between 39 and 40 °C (102.2 and 104 °F) —usually lasting up to, but no longer than, 48 hours; may be accompanied by fretfulness, drowsiness, vomiting, and anorexia{09}{10}{14}{16}{19}{20}

Incidence rare
    
Cervical lymphadenopathy {09}{10}{14}{16}{19}{20}(swollen glands on side of neck following DTP injections into arm)
    
fever between 40 and 40.5 °C (104 and 105 °F) —usually lasting up to, but no longer than, 48 hours; may be accompanied by fretfulness, drowsiness, vomiting, and anorexia{09}{10}{14}{16}{19}{20}
    
skin rash {09}{10}{14}{16}{19}{20}





Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Diphtheria and Tetanus Toxoids and Pertussis Vaccine Adsorbed (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before receiving this vaccine
»   Conditions affecting use, especially:
Sensitivity to diphtheria or tetanus toxoids, pertussis vaccine, or DTP
Other medical problems, especially acute febrile illness; anaphylactic reaction; or encephalopathy

Proper use of this vaccine

» Proper dosing

After receiving this vaccine
Possibly receiving acetaminophen at time of injection; possibly continuing acetaminophen every 4 hours for 24 hours following injection; checking with physician if there are questions

Notifying physician of any side effect that occurs after a dose of DTP, even though the side effect may have gone away without treatment


Side/adverse effects
Signs of potential side effects, especially hypotonic-hyporesponsive episodes; crying, persistent and inconsolable, occurring within 48 hours and lasting 3 or more hours; anaphylactic reaction; convulsions, with or without fever, occurring within 3 days; encephalopathy occurring within 7 days; fever of 40.5 °C (105 °F) or more, occurring within 48 hours


General Dosing Information
Appropriate precautions should be taken prior to vaccine injection to prevent or relieve allergic or other unwanted reactions {09} {10} {14}. Precautions should include a review of the patient's history regarding possible sensitivity and the ready availability of epinephrine 1:1000 and other appropriate agents used for control of immediate allergic reactions {09} {10} {14}. If an immediate anaphylactic reaction occurs following vaccination, further vaccination with any of the three components of diphtheria and tetanus toxoids and whole-cell pertussis vaccine (DTwP) or diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP) should be deferred because of uncertainty as to which component of the vaccine might be responsible {07}. Because of the importance of tetanus vaccination, persons who experience anaphylactic reactions may be referred to an allergist for evaluation and, if specific allergy can be demonstrated, desensitized to tetanus toxoid {07}.

The routine diphtheria, tetanus, and pertussis vaccination schedule comprises five doses of DTP {07}. Three (primary) doses should be administered during the first year of life, generally at 2, 4, and 6 months of age {07}. To maintain adequate immunity during preschool years, the fourth (first booster) dose is recommended for children 15 to 18 months of age; it should be administered at or after 6 months after the third dose {07}. If the interval between the third and fourth doses is 6 or more months and the child is not likely to return for a visit at the recommended age, the fourth dose of DTP may be administered as early as 12 months of age {07}. The fifth (second booster) dose is recommended for children 4 to 6 years of age to confer continued protection against disease during the early school years {07}. A fifth dose is not necessary if the fourth dose in the series is administered on or after the fourth birthday {07}.

The Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC) and The Committee on Infectious Diseases of the American Academy of Pediatrics (AAP) recommend the use of DTaP vaccines for all five doses in the vaccination schedule {07} {15}. DTaP vaccines are efficacious when administered to infants as the primary series (i.e., doses 1 to 3) {07}. In addition, local reactions, fever, and other systemic events occur substantially less often after DTaP administration than after administration of DTwP {07}. For children who have started the vaccination series with one, two, three, or four doses of DTwP, DTaP is recommended for all remaining doses in the schedule {07}. During the period of transition from use of DTwP to DTaP, DTwP is an acceptable alternative to DTaP for any of the five doses {07}. Also for the first four doses, DTwP combined with Haemophilus influenzae b vaccine (DTP-Hib vaccine) is an acceptable alternative to DTaP and Hib vaccine administered at separate sites {07}. Vaccines should not be mixed in the same syringe unless the specific combination is approved by the Food and Drug Administration (FDA) {15}.

Whenever feasible, the same brand of DTaP vaccine should be used for all doses of the vaccination series {07}. Data are not available regarding the safety, immunogenicity, and efficacy of using DTaP vaccines from different manufacturers for successive doses of the primary or booster vaccination series {07}. However, the vaccine provider may not know or may not have available the type of DTaP vaccine previously administered to a child {07}. These circumstances should not be barriers to administration of the vaccine and any of the licensed DTaP vaccines may be used to complete the vaccination series {07}.

The dose of DTP is 0.5 mL, administered intramuscularly {07}. It should not be administered subcutaneously {09}. The preferred injection sites are the anterolateral aspect of the thigh and the deltoid muscle of the upper arm {07}. Fractional doses (i.e., doses < 0.5 mL) should not be administered {07} {09}. The effect of fractional doses on the frequency of serious adverse effects and on efficacy has not been determined {09}.

The first dose of DTP should be administered at 2 months of age {07} {09}. However, it may be given as early as 6 weeks of age and up to 7 years of age {07} {09} {12}. Interruption of the recommended schedule with a delay between doses should not interfere with the final immunity achieved with the vaccine {09}. There is no need to start the series over again, regardless of the time between doses {09}.

The decision about whether to give DTP to infants and children with underlying neurologic disorders can be difficult and must be made on an individual basis after careful and continuing consideration of the risks and benefits {15}. In some cases these disorders may constitute a cause for deferring pertussis immunization and, based on the medical history of the child, subsequent administration of DTP {15}. Because outbreaks of pertussis continue to occur, the decision to defer immunization should be reassessed at each subsequent medical visit; and the decision to give DTP should be based on the adjudged risks and consequences of seizures after DTwP or DTaP vaccination in comparison with the risk of pertussis and its complications {15}. If pertussis immunization is continued, DTaP is recommended {15}. Children with associated neurologic deficits may be at increased risk for complications if they develop pertussis {15}. Children traveling to or residing in areas of endemic or epidemic pertussis are at increased risk for developing pertussis {15}. Efforts should be undertaken to ensure pertussis immunization of children attending child care centers, special clinics, or residential care institutions {15}.

The Committee on Infectious Diseases of the AAP offers the following recommendations for immunization of infants and children with neurological disorders:    • Deferral of pertussis immunization, often permanently, should be considered in infants and children known to have, or suspected of having, neurologic conditions, characterized by developmental delays or neurologic findings, that predispose them to seizures or neurologic deterioration {15}. Such conditions include tuberous sclerosis and certain inherited metabolic or degenerative diseases {15}. Administration of DTwP or DTaP may coincide with or hasten the recognition of inevitable manifestations of the disorder, such as infantile spasms and other epilepsies, with resulting confusion about causation {15}.
   • Infants and children with a personal history of convulsions have an increased risk of convulsions after receipt of DTwP {15}. A retrospective review of adverse events after the receipt of DTwP indicated that children with a personal history of seizures were seven times more likely to have a seizure after DTwP vaccination than children who had local or other nonneurologic, post-DTwP adverse effects {15}. No evidence indicates that these vaccine-associated seizures induce permanent brain damage, cause epilepsy, aggravate neurologic disorders, or affect the prognosis in children with underlying disorders {15}. However, because the risk of postvaccination convulsion is increased, pertussis immunization of children with recent seizures should be deferred until a progressive neurologic disorder is excluded {15}. Infants and children with well-controlled seizures or those in whom a seizure is unlikely to recur may be vaccinated {15}. DTaP is recommended because it is less frequently associated with moderate to high fever and thus, much less likely to precipitate a seizure than is DTwP {15}. Administration of acetaminophen also should be considered at the time of vaccination and every 4 hours for the ensuing 24 hours {15}.
   • Children with unstable or evolving neurologic disorders that may predispose them to seizures or neurologic deterioration should be observed for a period of time to ascertain before immunization the diagnosis and prognosis of the primary neurologic disorder and to determine which of the disorders are nonprogressive and for which symptoms may change as the child matures {15}.
   • Children in the first year of life with neurologic disorders that necessitate temporary deferment of pertussis immunization should not receive DTwP, DTaP, or DT because the risk of acquiring diphtheria or tetanus in children younger than 1 year of age in the U.S. is remote {15}. However, at or before the first birthday, the decision to give either DTaP or diphtheria and tetanus toxoids for pediatric use (DT) should be made to ensure that the child is immunized at least against diphtheria and tetanus. As children become ambulatory, their risk of incurring tetanus-prone wounds increases {15}. Children with neurologic disorders that are recognized after the first birthday frequently will have received one or more doses of pertussis-containing vaccine {15}. The physician may temporarily defer additional doses of DTP in anticipation of stabilization of the child's neurologic status {15}. If the physician determines that the child probably should not receive further pertussis immunizations, DT immunization should be completed according to the recommended schedule {15}. If pertussis immunization is continued, DTaP is recommended {15}.


Simultaneous administration of measles, mumps, and rubella virus vaccine live, DTP, and oral poliovirus vaccine (OPV) has resulted in rates of seroconversion and of side effects similar to those observed when these vaccines are administered at separate times {15}. Since simultaneous administration of common vaccines is not known to affect the efficacy or safety of any of the routinely recommended childhood vaccines, if return of a child for further immunization is doubtful, simultaneous administration of DTP, OPV or poliovirus vaccine inactivated enhanced-potency (eIPV), measles, mumps, and rubella virus vaccine live, varicella virus vaccine live, hepatitis B vaccine, and Hib vaccine appropriate for the age and previous vaccination status of the child is recommended {15}.

For treatment of adverse effects
Recommended treatment includes:

   • For mild hypersensitivity reaction—Administering antihistamines, and, if necessary, corticosteroids {22}. In mild anaphylaxis, antihistamines or subcutaneous epinephrine may be all that is necessary if the condition is progressing slowly and is not life-threatening, regardless of the organ or system affected {22}. Under these circumstances, the risks associated with intravenous epinephrine administration outweigh the benefits {22}.
   • For severe hypersensitivity or anaphylactic reaction—Administering epinephrine {22}. Antihistamines and/or corticosteroids also may be administered as required {22}. Epinephrine is the treatment of choice for severe hypersensitivity or anaphylactic reaction {22}. If the patient's condition is not stable, epinephrine should be infused {22}. Norepinephrine may be preferable if there is no bronchospasm {22}. For bronchospasm, epinephrine should be given with a corticosteroid {22}. Other bronchodilators, such as intravenous aminophylline or albuterol by nebulization, also should be considered {22}.


Parenteral Dosage Forms

DIPHTHERIA AND TETANUS TOXOIDS AND ACELLULAR PERTUSSIS VACCINE ADSORBED

Usual adult and adolescent dose
Use is not recommended (see Adolescents section) {09} {10} {14} {16} {20}.

Usual pediatric dose
Children 2 months to 7 years of age
Intramuscular, preferably into the anterolateral aspect of the thigh or the deltoid muscle of the upper arm, 0.5 mL at four- to eight-week intervals for three doses, followed by a fourth dose of 0.5 mL six to twelve months after the third dose {09} {10} {14} {16} {20}. A booster (fifth) dose of 0.5 mL usually is administered at four, five, or six years of age; however, if the fourth dose of the basic immunizing series was administered after the fourth birthday, a booster (fifth) dose is not necessary {09} {10} {14} {16} {20}.

Children 7 years of age and older
Use is not recommended (see Adolescents section) {09} {10} {14} {16} {20}.


Strength(s) usually available
U.S.—


6.7 Limit of flocculation (Lf) of diphtheria toxoid, 5 Lf of tetanus toxoid, 23.4 mcg protein of filamentous hemagglutinin (FHA), and 23.4 mcg protein of inactivated pertussis toxin (PT) (toxoid), in each 0.5-mL dose. Each 0.5-mL dose contains aluminum present as aluminum potassium sulfate (Rx) [Tripedia (thimerosal 1:10,000)]{09}


7.5 Lf of diphtheria toxoid, 5 Lf of tetanus toxoid, and 300 hemagglutinating (HA) units of acellular pertussis vaccine, in each 0.5-mL dose. The acellular pertussis vaccine component contains approximately 40 mcg of pertussis antigens (approximately 86% filamentous hemagglutinin [FHA], approximately 8% PT, also known as lymphocytosis-promoting factor [LPF], approximately 4% 69-kilodalton [69kd] outer membrane protein, and approximately 2% type 2 fimbriae [pertussis-specific agglutinogen]), in each 0.5-mL dose. Each 0.5-mL dose contains not more than 850 mcg (0.85 mg) of aluminum present as aluminum hydroxide and aluminum phosphate (Rx) [Acel-Imune (thimerosal 1:10,000)]{16}


15 Lf of diphtheria toxoid, 6 Lf of tetanus toxoid, and 40 mcg pertussis toxoid in each 0.5-mL dose. Each 0.5-mL dose contains 0.5 mg aluminum present as aluminum hydroxide (Rx) [Certiva (thimerosal 1:10,000)]{14}


25 Lf of diphtheria toxoid, 10 Lf of tetanus toxoid, 25 mcg pertussis toxin (PT), 25 mcg filamentous hemagglutinin (FHA), and 8 mcg pertactin in each 0.5-mL dose. Each 0.5-mL dose contains not more than 0.625 mg of aluminum present as aluminum hydroxide (Rx) [Infanrix (2-phenoxyethanol)]{10}

Canada—


25 Lf of diphtheria toxoid, 10 Lf of tetanus toxoid, 25 mcg pertussis toxin (PT), 25 mcg filamentous hemagglutinin (FHA), and 8 mcg pertactin in each 0.5-mL dose. Each 0.5-mL dose contains not more than 0.625 mg of aluminum present as aluminum hydroxide (Rx) [Infanrix (2-phenoxyethanol)]{20}

Note: Lf is the quantity of toxoid as assessed by flocculation.
A hemagglutinating (HA) unit is that amount of material that completely agglutinates chicken red blood cells as measured by the HA assay.


Packaging and storage:
Store between 2 and 8 °C (36 and 46 °F), unless otherwise specified by manufacturer {09} {10} {14} {16} {20}. Protect from freezing {09} {10} {14} {16} {20}.

Preparation of dosage form:
The product should be shaken well immediately before withdrawing each dose, to obtain a uniform suspension {09} {10} {14} {16} {20}. The product should be discarded if it has remaining clumps after vigorous agitation {09} {10} {14} {16} {20}.

Stability:
The vaccine should be kept refrigerated, but should not be frozen, exposed to freezing temperatures, or stored near freezing surfaces {09} {10} {14} {16} {20}.

Auxiliary labeling:
   • Shake well {09} {10} {14} {16} {20}.
   • Do not freeze {09} {10} {14} {16} {20}.


DIPHTHERIA AND TETANUS TOXOIDS AND PERTUSSIS VACCINE ADSORBED USP

Usual adult and adolescent dose
Use is not recommended (see Adolescents section) {19}.

Usual pediatric dose
Children 2 months to 7 years of age
Intramuscular, preferably into the anterolateral aspect of the thigh or the deltoid muscle of the upper arm, 0.5 mL at four- to eight-week intervals for three doses, followed by a fourth dose of 0.5 mL six to twelve months after the third dose {19}. A booster (fifth) dose of 0.5 mL usually is administered at four, five, or six years of age; however, if the fourth dose of the basic immunizing series was administered after the fourth birthday, a booster (fifth) dose is not necessary {19}.

Children 7 years of age and older
Use is not recommended (see Adolescents section) {19}.


Strength(s) usually available
U.S.—


6.7 Limit of flocculation (Lf) of diphtheria toxoid aluminum potassium sulfate adsorbed, 5 Lf of tetanus toxoid aluminum potassium sulfate adsorbed, and 4 Protective Units of pertussis vaccine, in each 0.5-mL dose. Each 0.5-mL dose may contain not more than 250 mcg (0.25 mg) of aluminum in the form of aluminum potassium sulfate (Rx)[Generic](may contain thimerosal)

Canada—


25 Lf of diphtheria toxoid aluminum phosphate adsorbed, 5 Lf of tetanus toxoid aluminum phosphate adsorbed, and 4 to 12 Protective Units of pertussis vaccine, in each 0.5-mL dose. Each 0.5-mL dose may contain 1.5 mg of aluminum phosphate (Rx)[Generic](may contain thimerosal){19}

Note: Lf is the quantity of toxoid as assessed by flocculation.


Packaging and storage:
Store between 2 and 8 °C (36 and 46 °F), unless otherwise specified by manufacturer {19}. Protect from freezing {19}.

Preparation of dosage form:
The product should be shaken well immediately before withdrawing each dose since product contains a bacterial suspension and vigorous agitation may be necessary to resuspend the contents of the vial {19}. The product should be discarded if it has remaining clumps after vigorous agitation {19}.

Stability:
The vaccine should be refrigerated, but should not be frozen, exposed to freezing temperatures, or stored near freezing surfaces {19}. If the vaccine is stored at temperatures below 2 °C (36 °F) or above 25 °C (77 °F) for as little as 24 hours, or if the vaccine is exposed to freezing temperatures or stored near freezing surfaces, subsequent resuspension of the vaccine may be difficult or impossible {19}. Vaccine should not be used if resuspension without any visible clumps cannot be achieved by vigorous shaking {19}.

Auxiliary labeling:
   • Shake well {19}.
   • Do not freeze {19}.



Revised: 02/02/1999



References
  1. Centers for Disease Control and Prevention (CDC). Notice to readers: availability of diphtheria antitoxin through an investigational new drug protocol. MMWR Morb Mortal Wkly Rep 1997; 46(17): 380.
  1. Popovic T, Wharton M, Wenger JD, et al. Are we ready for diphtheria? A report from the Diphtheria Diagnostic Workshop, Atlanta, 11 and 12 July 1994. J Infect Dis 1995; 171: 765-7.
  1. The Committee on Infectious Diseases of the American Academy of Pediatrics (AAP). Immunization of adolescents: recommendations of the Advisory Committee on Immunization Practices, the American Academy of Pediatrics, the American Academy of Family Physicians, and the American Medical Association. Pediatrics 1997; 99(3): 479-88.
  1. American Academy of Pediatrics. Diphtheria. In: Peter G, editor. 1997 Red book: report of the Committee on Infectious Diseases. 24th ed. Elk Grove Village, IL: American Academy of Pediatrics; 1997. p. 191-5.
  1. Wong TP, Groman N. Production of diphtheria toxin by selected isolates of Corynebacterium ulserans and Corynebacterium pseudotuberculosis. Infect Immun 1984; 43(3): 1114-6.
  1. Panel comment, 5/98.
  1. Centers for Disease Control and Prevention (CDC). Recommendations of the Advisory Committee on Immunization Practices: pertussis vaccination—use of acellular pertussis vaccines among infants and young children. MMWR Morb Mortal Wkly Rep 1997; 46(RR-7): 1-25.
  1. American Academy of Pediatrics. Tetanus. In: Peter G, editor. 1997 Red book: report of the Committee on Infectious Diseases. 24th ed. Elk Grove Village, IL: American Academy of Pediatrics; 1997. p. 518-23.
  1. Tripedia package insert (Connaught—US), Rev 9/96, Rec 9/98.
  1. Infanrix package insert (SmithKline Beecham—US), Rev 1/97, Rec 9/98.
  1. Lopez AL, Blumberg DA. An overview of the status of acellular pertussis vaccines in practice. Drugs 1997; 54(2): 189-96.
  1. The Committee on Infectious Diseases of the American Academy of Pediatrics (AAP). Acellular pertussis vaccine: recommendations for use as the initial series in infants and children. Pediatrics 1997; 99(2): 282-8.
  1. Klein DL. Multicenter acellular pertussis vaccine trial: a National Institutes of Health perspective. Pediatrics 1995; 96(3): 547-8.
  1. Certiva package insert (North American Vaccine—US), Rev 5/98, Rec 8/98.
  1. American Academy of Pediatrics. Pertussis. In: Peter G, editor. 1997 Red book: report of the Committee on Infectious Diseases. 24th ed. Elk Grove Village, IL: American Academy of Pediatrics; 1997. p. 394-407.
  1. Acel-Immune package insert (Lederle—US), Rev 3/97, Rec 10/98.
  1. Edwards KM, Meade BD, Decker MD, et al. Comparison of 13 acellular pertussis vaccines: overview and serologic response. Pediatrics 1995; 96(3): 548-57.
  1. Edwards KM, Decker MD. Acellular pertussis vaccines for infants. N Engl J Med 1996; 334(6): 391-2.
  1. Gillis MC, editor. CPS Compendium of pharmaceuticals and specialties. 33rd ed. Ottawa: Canadian Pharmacists Association; 1998. p. 507-8.
  1. Gillis MC, editor. CPS Compendium of pharmaceuticals and specialties. 33rd ed. Ottawa: Canadian Pharmacists Association; 1998. p. 777-8.
  1. Decker MD, Edwards KM, Steinhoff MC, et al. Comparison of 13 acellular pertussis vaccines: adverse reactions. Pediatrics 1995; 96(3): 557-66.
  1. Fisher M. Treatment of acute anaphylaxis. BMJ 1995; 311: 731-3.
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