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DTP
(Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed) Intramuscular Injection

DESCRIPTION

Diphtheria and Tetanus Toxoids and Pertussis Vaccine Adsorbed USP (For Pediatric Use) combines diphtheria and tetanus toxoids adsorbed with pertussis vaccine, for intramuscular use, in a sterile isotonic sodium chloride solution containing sodium phosphate buffer to control pH. The vaccine, after shaking, is a turbid liquid, whitish-gray in color. When used to reconstitute Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate), ActHIB ® or OmniHIB, the combined vaccines appear whitish in color.

Corynebacterium diphtheriae cultures are grown in a modified Mueller and Miller medium. 1 Clostridium tetani cultures are grown in a peptone- based medium. Both toxins are detoxified with formaldehyde. The detoxified materials are separately purified by serial ammonium sulfate fractionation and diafiltration.

The pertussis vaccine component is derived from Bordetella pertussis cultures grown on blood-free Bordet Gengou media. The pertussis organisms are harvested and inactivated with thimerosal and resuspended in physiological saline and thimerosal.

The toxoids are adsorbed to aluminum potassium sulfate (alum). The adsorbed diphtheria and tetanus toxoids are combined with pertussis vaccine concentrate, and diluted to a final volume using sterile phosphate-buffered physiological saline. Each 0.5 mL dose contains, by assay, not more than 0.17 mg of aluminum and not more than 100 µg (0.02%) of residual formaldehyde. Thimerosal (mercury derivative) 1:10,000 is added as a preservative.

Each 0.5 mL dose is formulated to contain 6.7 Lf of diphtheria toxoid and 5 Lf of tetanus toxoid (both toxoids induce at least 2 units of antitoxin per mL in the guinea pig potency test).

The total human immunizing dose (the first three 0.5 mL doses administered) contains an estimate of 12 units of pertussis vaccine (4 protective units per single dose). 2 The potency of the pertussis component of each lot of DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) is tested in a mouse protection test.

At the time when Connaught Laboratories, Inc. (CLI) DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) vaccine is used to reconstitute ActHIB ® or OmniHIB, each single dose of the 0.5 mL mixture is formulated to contain 6.7 Lf of diphtheria toxoid, 5 Lf of tetanus toxoid, an estimate of 4 protective units of pertussis vaccine, 10 µg of purified capsular polysaccharide conjugated to 24 µg of inactivated tetanus toxoid, and 8.5% of sucrose.

NOTE: Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate) ActHIB ® is identical to Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate) OmniHIB (distributed by SmithKline Beecham Pharmaceuticals); both products are manufactured by Pasteur Mérieux Sérums & Vaccins S. A.

INDICATIONS

Diphtheria and Tetanus Toxoids and Pertussis Vaccine Adsorbed USP (For Pediatric Use) is recommended for active immunization of children up to age 7 years against diphtheria, tetanus, and pertussis (whooping cough) simultaneously. However, in instances where the pertussis vaccine component is contraindicated, or where the physician decides that pertussis vaccine is not to be administered, DT should be used. Immunization should be started at 6 weeks to 2 months of age and be completed before the seventh birthday. 2,9

Persons recovering from confirmed pertussis do not need additional doses of DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) but should receive additional doses of DT to complete the series. 2

Available data indicate that the appropriate age for institution of immunizations in prematurely born infants is the usual chronological age of 2 months. Vaccine doses should not be reduced for preterm infants. 2,9

If passive immunization is required, Tetanus Immune Globulin (Human) (TIG) and/or equine Diphtheria Antitoxin are the products of choice for tetanus and diphtheria, respectively (see

DOSAGE AND ADMINISTRATION

section).

When CLI DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) vaccine is used to reconstitute ActHIB ® or OmniHIB, the combined vaccines are indicated for the active immunization of infants and children 2 months through 5 years of age for the prevention of invasive diseases caused by diphtheria, tetanus, pertussis and H influenzae type b. 10,11 (Refer to ActHIB ® package insert.)

A single injection containing diphtheria, tetanus, pertussis and Haemophilus b conjugate antigens may be more acceptable to parents and may increase compliance with vaccination programs. Therefore, in those situations where, in the judgment of the physician, it is of benefit to administer a single injection of whole-cell DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) vaccine and Haemophilus b conjugate vaccine concomitantly, only CLI whole-cell DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) vaccine may be used for reconstitution of lyophilized ActHIB ® or OmniHIB. Antibody levels associated with protection may not be achieved earlier than two weeks following the last recommended dose. (See section.)

As with any vaccine, vaccination with DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) or combined vaccines CLI DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) and ActHIB ® or OmniHIB may not protect 100% of susceptible individuals.

NOTE: Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate) ActHIB ® is identical to Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate) OmniHIB (distributed by SmithKline Beecham Pharmaceuticals); both products are manufactured by Pasteur Mérieux Sérums & Vaccins S. A.

This vaccine is NOT to be used for the treatment of diphtheria, tetanus, pertussis or H influenzae type b infection.

This vaccine should NOT be used for immunizing persons 7 years of age and older.

DOSAGE AND ADMINISTRATION

Parenteral drug products should be inspected visually for extraneous particulate matter and or discoloration prior to administration whenever solution and container permit. If these conditions exist, the vaccine should not be administered.

SHAKE VIAL WELL before withdrawing each dose. Vaccine contains a bacterial suspension. Vigorous agitation is required to resuspend the contents of the vial. Discard if vaccine cannot be resuspended.

For Administration of DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) Vaccine Only

The primary series for children less than 7 years of age is four doses of 0.5 mL each given intramuscularly. The customary age for the first dose is 2 months of age but may be given as young as 6 weeks of age and up to the seventh birthday.

Inject 0.5 mL intramuscularly only. The preferred injection sites are the anterolateral aspect of the thigh and the deltoid muscle of the upper arm. The vaccine should not be injected into the gluteal area or areas where there may be a major nerve trunk. During the course of primary immunizations, injections should not be made more than once at the same site.

The use of reduced volume (fractional doses) is not recommended. The effect of such practices on the frequency of serious adverse events and on protection against disease has not been determined.

Do NOT administer this product subcutaneously.

Special care should be taken to ensure that the injection does not enter a blood vessel.

PRIMARY IMMUNIZATION

This vaccine is recommended for children 6 weeks through 6 years (up to the seventh birthday) ideally beginning when the infant is 6 weeks to 2 months of age.

The primary series consists of four doses. For infants 6 weeks through 12 months of age, administer three 0.5 mL doses intramuscularly at least 4 to 8 weeks apart. The fourth dose is administered 6 to 12 months after the third injection.

BOOSTER IMMUNIZATION

For children between 4 and 6 years of age (preferably at time of kindergarten or elementary school entrance), a booster of 0.5 mL should be administered intramuscularly. Those who receive all four primary immunizing doses before their fourth birthday should receive a single dose of DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) just before entering kindergarten or elementary school. This booster dose is not necessary if the fourth dose in the primary series was administered after the fourth birthday. Thereafter, routine booster immunizations should be with Td, at intervals of 10 years. PERSONS 7 YEARS OF AGE AND OLDER SHOULD NOT BE IMMUNIZED WITH DIPHTHERIA AND TETANUS TOXOIDS AND PERTUSSIS VACCINE ADSORBED USP (FOR PEDIATRIC USE) (DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) ).

TABLE 2 2

ROUTINE DIPHTHERIA, TETANUS, AND PERTUSSIS VACCINATION SCHEDULE

Summary For Children

Dose	Customary Age	Age/Interval †	Product
Primary 1	2 Months	6 weeks old or older	DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) †
Primary 2	4 Months	4-8 weeks after first dose*	DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) †
Primary 3	6 Months	4-8 weeks after second dose*	DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) †
Primary 4	15 Months	6-12 months after third dose*	DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) †
Booster	4-6 years old, before entering kindergarten or elementary school (not necessary if fourth primary vaccinating dose administered after fourth birthday)		DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) †
Additional Boosters		Every 10 years after last dose	Td

*Use DT if pertussis vaccine is contraindicated. If the child is ³ 1 year of age at the time that primary dose three is due, a third dose 6 to 12 months after the second dose completes primary vaccination with DT.

†Prolonging the interval does not require restarting series.

Preterm infants should be vaccinated according to their chronological age from birth. 2,9

Interruption of the recommended schedule with a delay between doses does not interfere with the final immunity achieved with D.P. There is no need to start the series over again, regardless of the time elapsed between doses.

Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed (DTaP) can be interchangeably used with DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) for the fourth and fifth doses. However ActHIB ® cannot be reconstituted with DTaP.

The simultaneous administration of D.P. oral poliovirus vaccine (OPV), and measles-mumps-rubella vaccine (MMR) has resulted in seroconversion rates and rates of side effects similar to those observed when the vaccines are administered separately. Simultaneous vaccination (at separate sites with separate syringes) with D.P. MMR, OPV, or inactivated poliovirus vaccine (IPV), and Haemophilus b conjugate vaccine (HbCV) is also acceptable. 2 The ACIP recommends the simultaneous administration, at separate sites with separate syringes, of all vaccines appropriate to the age and previous vaccination status of the recipients including the special circumstance of simultaneous administration of D.P. OPV, HbCV, and MMR at ³15 months of age. 2 If passive immunization is needed for tetanus, TIG is the product of choice. It provides longer protection than antitoxin of animal origin and causes few adverse reactions. The currently recommended prophylactic dose of TIG for wounds of average severity is 250 units intramuscularly. When tetanus toxoid and TIG are administered concurrently, separate syringes and separate sites should be used. The ACIP recommends the use of only adsorbed toxoid in this situation. 2

WHEN RECONSTITUTING HAEMOPHILUS b CONJUGATE VACCINE (TETANUS TOXOID CONJUGATE), ActHIB ® or OmniHIB

NOTE: Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate) ActHIB ® is identical to Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate) OmniHIB (distributed by SmithKline Beecham Pharmaceuticals); both products are manufactured by Pasteur Mérieux Sérums & Vaccins S. A.

CLI whole-cell DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) vaccine also can be used for reconstitution of ActHIB ® or OmniHIB. Cleanse both the DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) and ActHIB ® or OmniHIB vaccine vial rubber barriers with a suitable germicide prior to reconstitution. Thoroughly agitate the vial of CLI wholecell DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) vaccine, then withdraw a 0.6 mL dose and inject into the vial of lyophilized ActHIB ® or OmniHIB. After reconstitution and thorough agitation, ActHIB ® or OmniHIBwill appear whitish in color. Withdraw and administer 0.5 mL dose of DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) /ActHIB ® or OmniHIBvaccines.

When CLI whole-cell DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) vaccine is used to reconstitute ActHIB ® or OmniHIB, administer intramuscularly only. Vaccine should be used within 24 hours after reconstitution.

After reconstitution, each 0.5 mL dose is formulated to contain 6.7 Lf of diphtheria toxoid, 5 Lf of tetanus toxoid, an estimate of 4 protective units of pertussis vaccine, 10 mg of purified capsular polysaccharide conjugated to 24 mg of inactivated tetanus toxoid, and 8.5% of sucrose. (Refer to ActHIB ® package insert.)

Before injection, the skin over the site to be injected should be cleansed with a suitable germicide. After insertion of the needle, aspirate to ensure that the needle has not entered a blood vessel.

Each dose of DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) /ActHIB ® or OmniHIBvaccines is administered intramuscularly in the outer aspect of the vastus lateralis (midthigh) or deltoid. The vaccine should not be injected into the gluteal area or areas where there may be a nerve trunk. During the course of primary immunizations, injections should not be made more than once at the same site.

When CLI DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) vaccine is used to reconstitute ActHIB ® or OmniHIB, the combined vaccines are indicated for infants and children 2 months through 5 years of age for intramuscular administration in accordance with the schedule indicated in Table 3. 10

TABLE 3 10

RECOMMENDED IMMUNIZATION SCHEDULE

For Previously Unvaccinated Children

DOSE	AGE	IMMUNIZATION
First, Second and Third	At 2, 4 and 6 months	DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) or DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) /ActHIB® or DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) /OmniHIBTM
Fourth	At 15 to 18 months	DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) or DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) /ActHIB® or DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) /OmniHIB TM or Acellular Pertussis (DTaP)*
Fifth	At 4 to 6 years	DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) or Acellular Pertussis (DTaP)*

*Acellular Pertussis (DTaP) should NOT be used to reconstitute ActHIB®/OmniHIB. When administering DTaP for the fourth dose, Haemophilus influenzae type b vaccine also should be administered at this time in a separate syringe at a different site.

For Previously Unvaccinated Children

Immunization schedules should be considered on an individual basis for children not vaccinated according to the recommended schedule. Three doses of a product containing D.P. given at approximately 2-month intervals, are required followed by a fourth dose of a product containing DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) or DTaP approximately 12 months later and a fifth dose of a product containing DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) or DTaP at 4 to 6 years of age. If the fourth dose of a pertussis-containing vaccine is not given until after the fourth birthday, no further doses of a pertussis-containing vaccine are necessary.

The number of doses of a product containing H influenzae type b conjugate vaccine indicated depends on the age that immunization is begun. A child 7 to 11 months of age should receive 3 doses of a product containing H influenzae type b conjugate vaccine. A child 12 to 14 months of age should receive 2 doses of a product containing H influenzae type b conjugate vaccine. A child 15 to 59 months of age should receive 1 dose of a product containing H influenzae type b conjugate vaccine.

Preterm infants should be vaccinated according to their chronological age from birth. 9

Interruption of the recommended schedule with a delay between doses should not interfere with the final immunity achieved when CLI DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) vaccine is used to reconstitute ActHIB ® or OmniHIB. There is no need to start the series over again, regardless of the time elapsed between doses.

It is recommended that the same conjugate vaccine be used throughout each immunization schedule, consistent with the data supporting approval and licensure of the vaccine. Since ActHIB ® or OmniHIB are the same vaccine, these may be used interchangeably.

DO NOT INJECT INTRAVENOUSLY

HOW SUPPLIED

DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) Vial, 7.5 mL Product No. 49281-280-84

One 7.5 mL vial of Connaught Laboratories, Inc. Diphtheria and Tetanus Toxoids and Pertussis Vaccine as Diluent packaged with Vial, 1 Dose lyophilized Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate) (10 x 1 Dose vials per package) Product No. 49281-549-10

Administer vaccine within 24 hours after reconstitution.

Storage

Store between 2° 8° C (35° 46° F). DO NOT FREEZE. Temperature extremes may adversely affect resuspendability of this vaccine.

Store lyophilized vaccine packaged with vial containing Diphtheria and Tetanus Toxoids and Pertussis vaccine and reconstituted vaccine, when not in use, between 2° 8° C (35° 46° F). DO NOT FREEZE. Discard vaccine within 24 hours after reconstitution.

REFERENCES

1. Mueller JH, et al. Production of diphtheria toxin of high potency (100 Lf) on a reproducible medium. J Immunol 40: 21- 32, 1941

2. Recommendations of the Immunization Practices Advisory Committee (ACIP). Diphtheria, Tetanus, and Pertussis: Recommendations for vaccine use and other preventive measures. MMWR 40: No. RR- 10, 1991 (NOTE: Articles relevant to reference cited are listed in the MMWR publication.)

3. C.C. Summary of Notifiable Diseases, United States 1992. MMWR 41: No. 55, 1993

4. Department of Health and Human Services, Food and Drug Administration. Biological Products; Bacterial Vaccines and Toxoids; Implementation of Efficacy Review; Proposed Rule. Federal Register Vol 50 No. 240, pp 51002- 51117, 1985

5. Pichichero ME, et al. Pediatric diphtheria and tetanus toxoids- adsorbed vaccine: Immune response to the first booster following the diphtheria and tetanus toxoids vaccine primary series. Pediatr Infec Dis 5: 428- 430, 1986

6. Barkin RM, et al. Pediatric diphtheria and tetanus toxoids (DT) vaccine: Clinical and immunologic response when administered as the primary series. J Pediatr 106: 779- 781, 1985

7. Baraff L, et al. DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) associated reactions: An analysis by injection site, manufacturer, prior reactions and dose. Pediatr 73: 31-36, 1984

8. Centers for Disease Control and Prevention (CDC). Tetanus Surveillance United States, 1989- 1990. Pertussis Surveillance United States, 1989- 1991. MMWR 41: No. SS- 8, 1992

9. American Academy of Pediatrics. In: Peter G, ed. 1994 Red Book: Report of the Committee on Infectious Diseases. 23rd ed. Elk Grove Village, IL 1994

10. Data on file, Pasteur Mérieux Sérums & Vaccins S. A.

11. Data on file, Connaught Laboratories, Inc.

12. Wilson GS. The Hazards of Immunization. Provocation poliomyelitis. 270- 274, 1967

13. Howson CP, et al. Adverse Effects of Pertussis and Rubella Vaccines. National Academy Press, Washington, DC, 1991

14. ACIP. Pertussis immunization: Family history of convulsions and use of antipyretics supplementary ACIP statement. MMWR 36: 281- 282, 1987

15. ACIP. General recommendations on immunization. MMWR 38: 205- 227, 1989

16. C.C. Vaccine Adverse Event Reporting System United States. MMWR 39: 730- 733, 1990

17. C.C. National Childhood Vaccine Injury Act: requirements for permanent vaccination records and for reporting of selected events after vaccination. MMWR 37: 197- 200, 1988

18. Food and Drug Administration. New reporting requirements for vaccine adverse events. FDA Drug Bull 18 (2), 16- 18, 1988

19. Cody CL, et al. Nature and rates of adverse reactions associated with DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) and DT immunizations in infants and children. Pediatr 68: 650- 660, 1981

20. Joffe LS, et al. Diphtheria-tetanus toxoids-pertussis vaccination does not increase the risk of hospitalization with an infectious illness. Pediatr Infect Dis J 11: 730- 735, 1992

21. Rutledge SL, et al. Neurological complications of immunization. J Pediatr 109: 917- 924, 1986

22. Walker AM, et al. Neurologic events following Diphtheria-Tetanus-Pertussis immunization. Pediatr 81: 345- 349, 1988

23. Wilson GS. The Hazards of Immunization. Allergic manifestations: Post- vaccinal neuritis. pp 153- 156, 1967

24. Tsairis P, et al. Natural history of brachial plexus neuropathy. Arch Neurol 27: 109- 117, 1972

25. Blumstein GI, et al. Peripheral neuropathy following tetanus toxoid administration. JAMA 198: 1030- 1031, 1966

26. Stratton KR, et al. Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality. National Academy Press, Washington, DC, 1993

27. Schlenska GK. Unusual neurological complications following tetanus toxoid administration. J Neurol 215: 299- 302, 1977

28. Bellman MH, et al. Infantile spasms and pertussis immunization. Lancet, i: 1031- 1034, 1983

29. Jacob J, et al. Increased intracranial pressure after diphtheria, tetanus and pertussis immunization. Am J Dis Child Vol 133: 217- 218, 1979

30. Mathur R, et al. Bulging fontanel following triple vaccine. Indian Pediatr 18 (6): 417- 418, 1981

31. Shendurnikar N, et al. Bulging fontanel following DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) vaccine. Indian Pediatr 23 (11): 960, 1986

32. C.C. Adverse events following immunization. Surveillance Report No. 3, 1985- 1986, Issued February 1989

33. Griffin MR, et al. Risk of sudden infant death syndrome after immunization with the Diphtheria-Tetanus-Pertussis Vaccine. N Engl J Med 618- 623, 1988

34. Hoffman HJ, et al. Diphtheria-Tetanus-Pertussis immunization and sudden infant death: Results of the National Institute of Child Health and Human Development Cooperative Epidemiological Study of Sudden Infant Death Syndrome Risk Factors. Pediatr 79: 598- 611, 1987

35. Walker AM, et al. Diphtheria-Tetanus-Pertussis immunization and sudden infant death syndrome. Am J Public Health 77: 945-951, 1987

36. Long SS, et al. Longitudinal study of adverse reactions following diphtheria- tetanus- pertussis vaccine in infancy. Pediatr 85: 294- 302, 1990

SIDE EFFECTS

Adverse reactions associated with the use of DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) include local redness, warmth, edema, induration with or without tenderness, as well as urticaria and rash. Some data suggest that febrile reactions are more likely to occur in those who have experienced such responses after prior doses. 6

The frequency of local reactions and fever following DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) vaccination is significantly higher with increasing numbers of doses of D.P. while other mild to moderate systemic reactions (e. g., fretfulness, vomiting) are significantly less frequent. 19 If local redness 2.5 cm occurs, the likelihood of recurrence after another DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) dose increases significantly. 6

Evidence does not indicate a causal relation between DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) vaccine and SIDS. Studies showing a temporal relation between these events are consistent with the expected occurrence of SIDS over the age range in which DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) immunization typically occurs. 13

Deaths due to causes other than SIDS, including deaths due to serious infections, have occurred in infants following the administration of DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) . No association has been shown for hospitalizations due to infectious disease and receipt of DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) . 20

Approximate rates for adverse events following receipt of DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) vaccine (regardless of dose number in the series) are indicated in TABLE 1. 2

TABLE 1 2

ADVERSE EVENTS OCCURRING WITHIN 48 HOURS OF DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) VACCINATIONS

Event	Frequency*
Local
Redness	1/3 doses
Swelling	2/5 doses
Pain	1/2 doses
Systemic
Fever > 38°C (> 100.4° F)	1/2 doses
Drowsiness	1/3 doses
Fretfulness	1/2 doses
Vomiting	1/15 doses
Anorexia	1/5 doses
Persistent, inconsolable crying (duration > 3 hours)	1/100 doses
Fever ³ 40.5°C (³ 105° F)	1/330 doses
Nervous System
Collapse (hypotonic-hyporesponsive episode)	1/1,750 doses
Convulsions (with or without fever)	1/1,750 doses

*Rate per total number of doses regardless of dose number in DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) series.

Body System as a Whole

Mild systemic reactions such as fever, drowsiness, fretfulness, and anorexia, occur quite frequently. These reactions are significantly more common following administration of DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) than following DT, are usually self-limited, and need no therapy other than symptomatic treatment such as acetaminophen. 2

Rarely, an anaphylactic reaction (i. e., hives, swelling of the mouth, difficulty breathing, hypotension, or shock) and death have been reported after receiving preparations containing diphtheria, tetanus, and/or pertussis antigens. 2

Arthus-type hypersensitivity reactions, characterized by severe local reactions (generally starting 2 to 8 hours after an injection), may follow receipt of tetanus toxoid. 2

Moderate to severe systemic events, include high fever (i. e., temperature of >40.5° C [> 105° F]) and persistent, inconsolable crying lasting > 3 hours. These events occur infrequently and appear to be without sequelae. 2 Occasionally, a nodule may be palpable at the injection site of adsorbed products for several weeks. Sterile abscesses at the site of injection have been reported (6 to 10 per million doses). 2

Nervous System

The following neurologic illnesses have been reported as temporally associated with vaccine containing tetanus toxoid: neurological complications 21,22 including cochlear lesion, 23 brachial plexus neuropathies, 23,24 paralysis of the radial nerve, 25 paralysis of the recurrent nerve, 23 accommodation paresis, and EEG disturbances with encephalopathy. 19 The report from the IOM suggests that there is a causal relation between Guillain-Barré syndrome (GBS) and vaccines containing tetanus toxoid. 26 In the differential diagnosis of polyradiculoneuropathies following administration of a vaccine containing tetanus toxoid should be considered as a possible etiology. 19,27

Short-lived convulsions (usually febrile), or collapse (hypotonic-hyporesponsive episode) occur infrequently and appear to be without sequelae. 2

More severe neurologic events, such as a prolonged convulsion, or encephalopathy, although rare, have been reported in temporal association with DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) administration. An analysis of these data failed to show any cause and effect association. 2

In the National Childhood Encephalopathy Study (NCES), a large, case-control study in England, children 2 to 35 months of age with serious, acute neurologic disorders such as encephalopathy or complicated convulsion( s), were more likely to have received DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) in the 7 days preceding onset than their age-, sex-, and neighborhood-matched controls. Among children known to be neurologically normal before entering the study, the relative risk (estimated by odds ratio) of a neurologic illness occurring within the 7-day period following receipt of DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) dose, compared to children not receiving DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) in the 7-day period before onset of their illness, was 3.3 (p

Within this 7-day period, the risk was significantly increased for immunized children only within 3 days of vaccination (relative risk 4.2, p

The methods and results of the NCES have been thoroughly scrutinized since publication of the study. This reassessment by multiple groups has determined that the number of patients was too small and their classification subject to enough uncertainty to preclude drawing valid conclusions about whether a causal relation exists between pertussis vaccine and permanent neurologic damage. Preliminary data from a 10-year follow-up study of some of the children studied in the original NCES study also suggested a relation between symptoms following DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) vaccination and permanent neurologic disability. However, details are not available to evaluate this study adequately, and the same concerns remain about DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) vaccine precipitating initial manifestations of pre-existing neurologic disorders. 2

An IOM report by the Committee to review the adverse consequences of pertussis and rubella vaccines concluded that evidence is consistent with a causal relation between DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) vaccine and acute encephalopathy, defined in the controlled studies reviewed as encephalopathy, encephalitis, or encephalomyelitis. On the basis of a review of the evidence bearing on this relation, the Committee concludes that the range of excess risk of acute encephalopathy following DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) immunization is consistent with that estimated for the NCES: 0.0 to 10.5 per million immunizations. The report also states that there is insufficient evidence to indicate a causal relation between DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) vaccine and permanent neurologic damage. 13

Onset of infantile spasms has occurred in infants who have recently received DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) or DT. Analysis of data from the NCES on children with infantile spasms showed that receipt of DT or DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) was not causally related to infantile spasms. 28 The incidence of onset of infantile spasms increases at 3 to 9 months of age, the time period in which the second and third doses of DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) are generally given. Therefore, some cases of infantile spasms can be expected to be related by chance alone to recent receipt of D.P. 2

A bulging fontanelle associated with increased intracranial pressure which occurred within 24 hours following DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) immunization has been reported. A causal relationship has not been established. 29,30,31

Cardiovascular System

An infant who developed myocarditis several hours after immunization has been reported. 32

Respiratory System

Respiratory difficulties, including apnea, have been observed.

Local

Rash and allergic reactions have been observed. Sudden Infant Death Syndrome (SIDS) has temporally occurred in infants following administration of D.P. A large case-control study of SIDE in the United States showed that receipt of DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) was not causally related to SIDS. 33,34,35 It should be recognized that the first three primary immunizing doses of DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) are usually administered to infants 2 to 6 months of age and that approximately 85% of SIDS cases occur at ages 1 to 6 months, with the peak incidence occurring at 6 weeks to 4 months of age. By chance alone, some SIDE victims can be expected to have recently received D.P. 33,34,35

When CLI whole-cell DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) was administered concomitantly (at separate sites with separate syringes) with ActHIB ® or OmniHIB, the systemic adverse experience profile was not different from that seen when CLI whole-cell DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) vaccine was administered alone. 10,11 (Refer to ActHIB ® package insert.)

In general, the rates of minor systemic reactions after DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) was used to reconstitute ActHIB ® or OmniHIB were comparable to those usually reported after DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) vaccine alone. 6,19,36

When CLI whole-cell DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) was used to reconstitute ActHIB ® or OmniHIB and administered to infants at 2, 4, and 6 months of age, the systemic adverse experience profile was comparable to that observed when the two vaccines were given separately. An increase in the rate of local reactions was observed in some instances within the 24- hour period after immunization. 10,11 (Refer to ActHIB ® package insert.)

Reporting of Adverse Events

Reporting by parents or guardians of all adverse events occurring after vaccine administration should be encouraged. Adverse events following immunization with vaccine should be reported by health-care providers to the US Department of Health and Human Services (DHHS) Vaccine Adverse Event Reporting System (VAERS). Reporting forms and information about reporting requirements or completion of the form can be obtained from VAERS through a toll-free number 1-800-822-7967. 16,17,18

Health-care providers also should report these events to the Director of Medical Affairs, Connaught Laboratories, Inc., a Pasteur Mérieux Connaught Company, Route 611, PO Box 187, Swiftwater, PA 18370 or call 1-800-822-2463.

DRUG INTERACTIONS

If DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) and TIG or Diphtheria Antitoxin are administered concurrently, separate syringes and separate sites should be used.

As with other intramuscular injections, use with caution in patients on anticoagulant therapy. Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs, and corticosteroids (used in greater than physiologic doses), may reduce the immune response to vaccines. Short-term (

If DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) has been administered to persons receiving immunosuppressive therapy, a recent injection of immunoglobulin or having an immunodeficiency disorder, an adequate immunologic response may not be obtained.

WARNINGS

If any of the following events occur in temporal relation to receipt of D.P. the decision to give subsequent doses of vaccine containing the pertussis component should be carefully considered. There may be circumstances, such as a high incidence of pertussis, when the potential benefits outweigh possible risks, particularly since these events are not associated with permanent sequelae. 2

THE FOLLOWING EVENTS WERE PREVIOUSLY CONSIDERED CONTRAINDICATIONS AND ARE NOW CONSIDERED

WARNINGS

: 2

1. Temperature of ³ 40.5° C (105° F) within 48 hours not due to another identifiable cause: Such a temperature is considered a warning because of the likelihood that fever following a subsequent dose of DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) vaccine also will be high. Because such febrile reactions are usually attributed to the pertussis component, vaccination with DT should not be discontinued. 2

2. Collapse or shock-like state (hypotonic- hyporesponsive episode) within 48 hours: Although these uncommon events have not been recognized to cause death nor to induce permanent neurological sequelae, it is prudent to continue vaccination with DT, omitting the pertussis component. 2

3. Persistent, inconsolable crying lasting ³3 hours, occurring within 48 hours: Follow-up of infants who have cried inconsolably following DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) vaccination has indicated that this reaction, though unpleasant, is without long-term sequelae and not associated with other reactions of greater significance. 2 Evidence is insufficient to indicate whether pertussis vaccine-associated protracted, inconsolable, or high-pitched crying or screaming does, or does not, lead to chronic neurologic damage. 13 Inconsolable crying occurs most frequently following the first dose and is less frequently reported following subsequent doses of DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) vaccine. However, crying for > 30 minutes following DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) vaccination can be a predictor of increased likelihood of recurrence of persistent crying following subsequent doses. Children with persistent crying have had a higher rate of local reactions than children who had other DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) -associated reactions (including high fever, seizures, and hypotonic-hyporesponsive episodes), suggesting that prolonged crying was really a pain reaction. 2

4. Convulsions with or without fever occurring within three days: Short-lived convulsions, with or without fever, have not been shown to cause permanent sequelae. Furthermore, the occurrence of prolonged febrile seizures (i. e., status epilepticus any seizure lasting > 30 minutes or recurrent seizures lasting a total of 30 minutes without the child fully regaining consciousness), irrespective of their cause, involving an otherwise normal child does not substantially increase the risk for subsequent febrile (brief or prolonged) or afebrile seizures. The risk is significantly increased (p = 0.018) only among those children who are neurologically abnormal before their episode of status epilepticus. 2 Accordingly, although a convulsion following DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) vaccination has previously been considered a contraindication to further doses, under certain circumstances subsequent doses may be indicated, particularly if the risk of pertussis in the community is high. If a child has a seizure following the first or second dose of D.P. it is desirable to delay subsequent doses until the childs neurologic status is better defined. By the end of the first year of life, the presence of an underlying neurologic disorder has usually been determined, and appropriate treatment instituted. DT vaccine should not be administered before a decision has been made about whether to continue the DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) series. Regardless of which vaccine is given, it is prudent also to administer acetaminophen, 2 15 mg/kg of body weight, at the time of vaccination and every 4 hours subsequently for 24 hours.

Persons who experienced Arthus-type hypersensitivity reactions or a temperature of > 103° F (39.4° C) following a prior dose of tetanus toxoid usually have high serum tetanus antitoxin levels and should not be given even emergency doses of Td more frequently than every 10 years, even if they have a wound that is neither clean nor minor. 2

DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) should not be given to children with any coagulation disorder, including thrombocytopenia, that would contraindicate intramuscular injection unless the potential benefit clearly outweighs the risk of administration.

Recent studies suggest that infants and children with a history of convulsions in first-degree family members (i. e., siblings and parents) have a 3.2- fold increased risk for neurologic events compared with those without such histories. 14 However, the ACIP has concluded that a family history of convulsions in parents and siblings is not a contraindication to pertussis vaccination and that children with such family histories should receive pertussis vaccine according to the recommended schedule. 2

A recent review of all available data by the IOM found evidence is consistent with a causal relation between DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) vaccination and acute encephalopathy, but that there is insufficient evidence to indicate a causal relation between DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) vaccine and permanent neurologic damage. 13

Infants and children with recognized possible or potential underlying neurologic conditions seem to be at enhanced risk for the appearance of manifestations of the underlying neurologic disorder within two or three days following vaccination. 2 Whether to administer DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) to children with proven or suspected underlying neurologic disorders must be decided on an individual basis. Important considerations include the current local incidence of pertussis, the near absence of diphtheria in the United States and the low risk of infection with C. tetani. 2

Although these events were considered absolute contraindications in previous ACIP recommendations, there may be circumstances, such as a high incidence of pertussis, in which the potential benefits outweigh possible risks, particularly because these events are not associated with permanent sequelae. 2

The administration of DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) to children with proven or suspected underlying neurologic disorders that are not actively evolving must be decided on an individual basis.

Only full doses (0.5 mL) of DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) vaccine should be given; if a specific contraindication to DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) exists, the vaccine should not be given. 2 Controversy regarding the safety of pertussis vaccine during the 1970s led to several studies of the benefits and risks of this vaccination during the 1980s. These epidemiologic analyses clearly indicate that the benefits of pertussis vaccination outweigh any risks and have not shown a cause and effect with neurologic illness. 2,9

Deaths have been reported in temporal association with the administration of DTP vaccine (see ADVERSE REACTIONS section). When CLI DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) vaccine is used alone or to reconstitute ActHIB ® or OmniHIB and administered to immunosuppressed persons or persons receiving immunosuppressive therapy, the expected antibody responses may not be obtained. This includes patients with severe combined immunodeficiency, hypogammaglobulinemia, or agammaglobulinemia; altered immune states due to diseases such as leukemia, lymphoma, or generalized malignancy; or an immune system compromised by treatment with corticosteroids, alkylating drugs, antimetabolites or radiation. 15

Administration of DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) and/or Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate) is not contraindicated in individuals with HIV infection. 11

NOTE: Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate) ActHIB ® is identical to Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate) OmniHIB (distributed by SmithKline Beecham Pharmaceuticals); both products are manufactured by Pasteur Mérieux Sérums & Vaccins S. A.

PRECAUTIONS

General

Care is to be taken by the health-care provider for the safe and effective use of D.P.

Epinephrine Injection (1:1000) must be immediately available should an acute anaphylactic reaction occur due to any component of the vaccine.

Prior to an injection of any vaccine, all known precautions should be taken to prevent adverse reactions. This includes a review of the patients history with respect to possible sensitivity and any previous adverse reactions to the vaccine or similar vaccines, previous immunization history, current health status (see CONTRAINDICATIONS;

WARNINGS

sections), and a current knowledge of the literature concerning the use of the vaccine under consideration. Immunosuppressed patients may not respond.

Prior to administration of D.P. health-care personnel should inform the parent or guardian of the patient the benefits and risks of immunization, and also inquire about the recent health status of the patient to be injected.

Special care should be taken to ensure that the injection does not enter a blood vessel.

A separate, sterile syringe and needle or a sterile disposable unit should be used for each patient to prevent transmission of hepatitis or other infectious agents from person to person. Needles should not be recapped and should be properly disposed.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No studies have been performed to evaluate carcinogenicity, mutagenic potential, or impact on fertility.

Pregnancy

THIS VACCINE IS NOT RECOMMENDED FOR PERSONS 7 YEARS OF AGE AND OLDER.

Pediatric Use

SAFETY AND EFFECTIVENESS OF DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) VACCINE OR AT THE TIME WHEN DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) VACCINE IS USED TO RECONSTITUTE ActHIB ® OR OmniHIB IN INFANTS BELOW THE AGE OF SIX WEEKS HAVE NOT BEEN ESTABLISHED. (See DOSAGE AND ADMINISTRATION section.)

This vaccine is recommended for immunizing children 6 weeks of age through 6 years of age (up to the seventh birthday). DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) is the preferred vaccine in this age group, but in those situations where an absolute contraindicationto pertussis vaccination exists, or where in the opinion of the physician the pertussis vaccine should not be administered, DT is the appropriate alternative.

Full protection is achieved upon completion of primary immunization with either four doses of D.P. or three doses of DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) followed by a dose of an approved acellular D.P. A fifth dose of DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) or an approved acellular DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) is required.

THIS VACCINE IS NOT RECOMMENDED FOR PERSONS 7 YEARS OF AGE AND OLDER. For persons 7 years of age and older, the recommended vaccine is Tetanus and Diphtheria Toxoids Adsorbed for Adult Use (Td).

OVERDOSE

No information provided.

CONTRAINDICATIONS

Hypersensitivity to any component of the vaccine, including thimerosal, a mercury derivative, is a contraindication for further use of this vaccine.

It is a contraindication to use this or any other related vaccine after an immediate anaphylactic reaction associated with a previous dose.

It is a contraindication to administer this vaccine in the presence of any evolving neurological condition. Encephalopathy after a previous dose is a contraindication to further use. Immunization should be deferred during the course of an acute illness. Vaccination of infants and children with severe, febrile illness should generally be deferred until these persons have recovered. However, the presence of minor illnesses such as mild upper respiratory infections with or without low-grade fever are not contraindications to further use. 2

Elective immunization procedures should be deferred during an outbreak of poliomyelitis. 12

CLINICAL PHARMACOLOGY

DIPHTHERIA

Corynebacterium diphtheriae may cause both localized and generalized disease. Systemic intoxication is caused by diphtheria exotoxin, an extracellular protein metabolite of toxigenic strains of C. diphtheriae. Protection against disease is due to the development of neutralizing antibodies to diphtheria toxin.

At one time, diphtheria was common in the United States. More than 200,000 cases, primarily among young children, were reported in 1921. Approximately 5% to 10% of cases were fatal; the highest case-fatality ratios were recorded for the very young and the elderly. Reported cases of diphtheria of all types declined from 306 in 1975 to 59 in 1979; most were cutaneous diphtheria reported from a single state. After 1979, cutaneous diphtheria was no longer a notifiable disease. From 1980 to 1989, only 24 cases of respiratory diphtheria were reported; two cases were fatal, and 18 (75%) occurred among persons 20 years of age or older. 2

Diphtheria is currently a rare disease in the United States primarily because of the high level of appropriate vaccination among children (97% of children entering school have received ³ three doses of diphtheria and tetanus toxoids and pertussis vaccine adsorbed [DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) ]) and because of an apparent reduction in the prevalence of toxigenic strains of C. diphtheriae. Most cases occur among unvaccinated or inadequately immunized persons. 2

Both toxigenic and nontoxigenic strains of C. diphtheriaecan cause disease, but only strains that produce toxin cause myocarditis and neuritis. Toxigenic strains are more often associated with severe or fatal illness in noncutaneous (respiratory or other mucosal surface) infections and are more commonly recovered in association with respiratory than from cutaneous infections. 2

A complete vaccination series substantially reduces the risk of developing diphtheria, and vaccinated persons who develop disease have milder illness. Protection lasts at least 10 years. Vaccination does not, however, eliminate carriage of C. diphtheriae in the pharynx or nose or on the skin. 2

TETANUS

Tetanus is an intoxication manifested primarily by neuromuscular dysfunction caused by a potent exotoxin elaborated by Clostridium tetani.

The occurrence of tetanus in the United States has decreased dramatically from 560 reported cases in 1947 to a record low of 48 reported cases in 1987. Tetanus in the United States is primarily a disease of older adults. Of 99 tetanus patients with complete information reported to the Centers for Disease Control and Prevention (CDC) during 1987 and 1988, 68% were ³50 years of age, while only six were

In 4% of tetanus cases reported during 1987 and 1988, no wound or other condition could be implicated. Non-acute skin lesions, such as ulcers, or medical conditions such as abscesses were reported in 14% of cases. 2

Spores of C. tetani are ubiquitous. Serologic tests indicate that naturally acquired immunity to tetanus toxin does not occur in the United States. 2 Thus, universal primary vaccination, with subsequent maintenance of adequate antitoxin levels by means of appropriately timed boosters, is necessary to protect persons among all age-groups. Tetanus toxoid is a highly effective antigen, and a completed primary series generally induces protective levels of neutralizing antibodies to tetanus toxin that persist for > 10 years. 2

The potency of diphtheria and tetanus toxoids was determined on the basis of immunogenicity studies with a comparison to a serological correlate of protection (0.01 I. U./mL) established by the Panel on Review of Bacterial Vaccines & Toxoids. 4

EFFICACY OF DIPHTHERIA AND TETANUS TOXOID VACCINES

Circulating protective levels of neutralizing antibodies to diphtheria and tetanus toxins can be induced by the administration of Diphtheria and Tetanus Toxoids Adsorbed USP (For Pediatric Use) (DT) or D.P.

A clinical study was performed in 20 children under one year of age to determine the serological responses and the adverse reactions when Connaught Laboratories, Inc. (CLI) DT was administered as a primary series of three doses. Protective levels of diphtheria and tetanus antitoxins that were equal to or greater than 0.01 I. U./mL were detected in 100% of the children following two doses of the vaccine. However, maternal antibody may have contributed to the total neutralizing antibody in some of these infants. Protective levels of antitoxin were observed in 100% of these infants following three doses of DT. No local or systemic reactions were observed in approximately half of the infants and only mild or moderate reactions were observed in the remainder of the DT study group. 5

Another clinical study to evaluate serological responses and adverse reactions of CLI DT was performed in 40 children under one year of age. One group of 20 children received 0.5 mL doses of D.P. DT, DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) at two, four and six months of age, respectively. The second group of 20 children received 0.5 mL doses of D.P. DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) , and DT, respectively, at the same ages. The immunologic protection against diphtheria and tetanus as measured by toxin neutralizing antibodies induced by DT was comparable when administered as either a second or third dose. 6 The reaction rates following CLI whole-cell DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) vaccination closely correlated with the rates observed with other commercially available whole-cell DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) vaccines. 7 The incidence of adverse reactions was significantly lower following DT administration (p

PERTUSSIS

Disease caused by Bordetella pertussis was once a major cause of infant and childhood morbidity and mortality in the United States. Pertussis (whooping cough) became a nationally notifiable disease in 1922, and reports reached a peak of 265,269 cases and 7,518 deaths in 1934. The highest number of reported pertussis deaths (9,269) occurred in 1923. The introduction and widespread use of standardized whole-cell pertussis vaccines combined with diphtheria and tetanus toxoids (DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) ) in the late 1940s resulted in a substantial decline in pertussis disease, a decline which continued without interruption for nearly 30 years. 2

By 1970, the annual reported incidence of pertussis had been reduced by 99%. During the 1970s the annual numbers of reported cases stabilized at an average of approximately 2,300 cases each year. During the 1980s, however, the annual numbers of reported cases gradually increased from 1,730 cases in 1980 to 4,517 cases in 1989. An average of eight pertussis-associated fatalities was reported each year throughout the 1980s. 2

From 1989 to 1991, 11,446 cases of pertussis were reported for an unadjusted incidence per 100,000 population of 1.7 in 1989, 1.8 in 1990 and 1.1 in 1991. The incidence for 1992 was 1.6 per 100,000. Age specific incidence and hospitalization rates were highest in the first year of life, decreasing with increasing age. Trends of the past years suggest an increase in reported pertussis since 1976, with the peak year being 1990. 8

During the period 1989 to 1991, of 3,900 reports of hospitalization, 1,115 had developed pneumonia, seizures occurred in 157 cases, encephalopathy was reported for 12, and there were 20 pertussis attributed deaths. These events were more frequently reported in children less than 6 months of age and were generally less frequent with increasing age. 7 Of patients 3 months through 4 years of age, where vaccination status was known, 65% of 4,471 patients had not received the recommended schedule of immunization and 39% had not received any pertussis containing vaccine. 3

Among older children and adults, including those previously vaccinated, B. pertussis infection may result in symptoms of bronchitis or upper-respiratory-tract infection. Pertussis may not be associated with classic signs, especially the inspiratory whoop. Older preschool children and school-age siblings who are not fully vaccinated and who develop pertussis can be important sources of infection for infants

EFFICACY OF PERTUSSIS VACCINE

Although DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) has been evaluated as a control vaccine in a number of clinical trials of Acellular pertussis vaccines, no formal efficacy trial was performed prior to approval. Approval was based on historical and continuing evidence of protection (surveillance) in the population at risk. It was also shown that vaccines with acceptable mouse protection potencies induced protective serum agglutinin antibody titers. 4 The pertussis component of each lot of DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) is tested for potency by a mouse protection test.

In clinical trials, one dose of CLI whole-cell DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) vaccine was used to reconstitute one lyophilized single dose vial of ActHIB ® or OmniHIB with no diminution in anti-PRP response or diphtheria, tetanus and pertussis responses.

PATIENT INFORMATION

As proof of the childs immunization record, the date, lot number and manufacturer of the vaccine administered must be recorded. 16,17,18

The health-care provider should inform the parent or guardian of the patient about the potential for adverse reactions that have been temporally associated with DTP (diphtheria and tetanus toxoids and pertussis vaccine adsorbed usp) administration. Parents or guardians should be instructed to report any serious adverse reactions to their health-care provider.

IT IS EXTREMELY IMPORTANT WHEN THE CHILD RETURNS FOR THE NEXT DOSE IN THE SERIES, T.A. THE PARENT OR GUARDIAN OF THE PATIENT SHOULD BE QUESTIONED CONCERNING OCCURRENCE OF ANY SYMPTOMS AND/OR SIGNS OF AN ADVERSE REACTION AFTER THE PREVIOUS DOSE (SEE CONTRAINDICATIONS; ADVERSE REACTIONS SECTIONS).

The health-care provider should inform the parent or guardian of the patient the importance of completing the immunization series.

The health-care provider should provide the Vaccine Information Materials (VIMs) which are required to be given with each immunization.

The US Department of Health and Human Services has established a Vaccine Adverse Event Reporting System (VAERS) to accept all reports of suspected adverse events after the administration of any vaccine, including but not limited to the reporting of events required by the National Childhood Vaccine Injury Act of 1986. 16 The toll- free number for VAERS forms and information is 1-800-822-7967.

The National Vaccine Injury Compensation Program, established by the National Childhood Vaccine Injury Act of 1986, requires physicians and other health-care providers who administer vaccines to maintain permanent vaccination records and to report occurrences of certain adverse events to the US Department of Health and Human Services. Reportable events include those listed in the Act for each vaccine and events specified in the package insert as contraindications to further doses of the vaccine. 17,18