TRIPEDIA: Package Insert and Label Information (Page 3 of 4)

Carcinogenesis, Mutagenesis, Impairment of Fertility

Tripedia vaccine has not been evaluated for its carcinogenic or mutagenic potentials or impairment of fertility.

Pregnancy Category C

Animal reproduction studies have not been conducted with Tripedia vaccine. It is not known whether Tripedia vaccine can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Tripedia vaccine is NOT indicated for women of child-bearing age.

Pediatric Use

SAFETY AND EFFECTIVENESS OF TRIPEDIA VACCINE IN INFANTS BELOW SIX WEEKS OF AGE HAVE NOT BEEN ESTABLISHED. (SEE DOSAGE AND ADMINISTRATION SECTION.)

THIS VACCINE IS NOT RECOMMENDED FOR PERSONS 7 YEARS OF AGE AND OLDER. Tetanus and Diphtheria Toxoids Adsorbed For Adult Use (Td) vaccine is to be used in individuals 7 years of age or older.

Geriatric Use

Tripedia vaccine is NOT indicated for adults.

ADVERSE REACTIONS

Over 3,000 US and 12,000 German infants received one or more doses of Tripedia vaccine as part of the primary immunization series in clinical trials conducted by the sponsor and the National Institutes of Health (NIH). A subset of over 1,000 German and US children were monitored for adverse events through a fourth successive dose of Tripedia vaccine. A subset of 580 German children were monitored for adverse events through a fifth successive dose of Tripedia vaccine.

Over 400 children who had received three doses of whole-cell pertussis DTP vaccine were assessed for adverse events following a booster dose of Tripedia vaccine at 15 to 20 months of age.

In a double-blind, comparative US trial, 673 infants were randomized to receive either 3 doses of Tripedia vaccine or Sanofi Pasteur Inc.’s whole-cell pertussis DTP vaccine (TABLE 2).2 Safety data are available for 672 infants, including 505 who received Tripedia vaccine and 167 who received whole-cell pertussis DTP vaccine. Following all three doses, rates for all reported local reactions, fever >101°F, irritability, drowsiness, and anorexia were significantly less in Tripedia vaccine recipients. Reaction rates generally peaked within the first 24 hours, and decreased substantially over the next two days.2,27,28

TABLE 22 ADVERSE EVENTS OCCURRING WITHIN 72 HOURS FOLLOWING THE FIRST THREE DOSES OF TRIPEDIA VACCINE OR WHOLE-CELL PERTUSSIS DTP VACCINE GIVEN TO INFANTS 2 TO 6 MONTHS OF AGE
FREQUENCY
EVENT TRIPEDIA VACCINE REACTION % WHOLE-CELL PERTUSSIS DTP VACCINE REACTION %
Dose 1 Dose 2 Dose 3 Dose 1 Dose 2 Dose 3
No. of Infants * 505 499 490 167 159 152
*
For certain adverse events information was not available for a small number of infants.
p <0.01 when compared to whole-cell pertussis DTP vaccine for all doses.
p <0.05 when compared to whole-cell pertussis DTP vaccine.
Local
Erythema 9.0 9.8 16.9 28.3 32.9 32.9
Erythema >1″ 1.2 1.8 2.2 7.8 8.4 7.4
Swelling 6.4 4.5 6.5 28.3 23.9 27.5
Swelling >1″ 1.4 0.6 1.0 12.7 11.0 11.4
Tenderness 11.8 6.7 7.1 50.6 44.2 42.6
Systemic
Fever >101°F (rectal) 0.4 1.6 3.5 3.6 7.5 11.2
Irritability 35.3 30.1 27.1 72.9 71.8 57.7
Drowsiness 39.4 17.6 15.9 59.6 45.2 25.5
Anorexia 6.0 5.3 5.7 26.5 20.0 18.8
Vomiting 6.0 5.5 3.7 10.8 7.1 2.7
High-pitched cry 2.4 1.0 1.4 10.8 5.8 3.4
Persistent cry 0.2 0.2 0.8 3.0 1.3 2.0

Adverse event data for Tables 2-9 were actively collected using patient diaries, phone call follow-up, and/or by questioning the parent(s) at clinic visits. All data were recorded on standardized case report forms.

A similar reduction in adverse events was seen in a randomized, double-blind, comparative trial conducted in the US by the NIH when Tripedia vaccine was compared to Lederle Laboratories whole-cell pertussis DTP vaccine (TABLE 3).29 Each data point presented in Table 3 is a summary of the frequency of reactions following any of the three primary immunizing doses. Local adverse reactions, which include pain, erythema, swelling, and systemic reactions such as fever, anorexia, vomiting, drowsiness and fussiness may have occurred following any of the three primary vaccinations.

TABLE 329 PERCENT OF INFANTS WHO WERE REPORTED TO HAVE HAD THE INDICATED REACTION BY THE THIRD EVENING AFTER ANY OF THE FIRST THREE DOSES OF TRIPEDIA VACCINE OR WHOLE-CELL PERTUSSIS DTP VACCINE
N * ERYTHEMA SWELLING PAIN FEVER >101°F ANOREXIA VOMITING DROWSINESS FUSSINESS §
*
N = Number of Infants
Moderate or severe = cried or protested to touch or when leg moved.
Rectal Temperatures
§
Moderate or severe = prolonged or persistent crying that could not be comforted and refusal to play.
p <0.01 when compared to whole-cell pertussis DTP vaccine.
Tripedia Vaccine 135 32.6 20.0 9.6 5.2 22.2 7.4 41.5 19.3
Whole-Cell Pertussis DTP Vaccine 371 72.7 60.9 40.2 15.9 35.0 13.7 62.0 41.5

In a multicenter trial conducted by the NIH in the US, the frequency of adverse reactions following each dose in children who received only Tripedia vaccine is shown in Table 4.2,29-31 Of the 135 infants who received Tripedia vaccine at 2, 4, and 6 months of age, a subset of 82 received a fourth dose of Tripedia vaccine and a subset of 18 received a fifth dose of Tripedia vaccine. A trend towards an increased frequency of redness and swelling was noted with successive doses.

TABLE 4 2,29-31 ADVERSE EVENTS (%) OCCURRING WITHIN 72 HOURS FOLLOWING DOSES 1 TO 5 OF TRIPEDIA VACCINE IN CHILDREN WHO RECEIVED TRIPEDIA VACCINE FOR ALL DOSES
PRIMARY BOOSTER
EVENT (N = 135 INFANTS) (N = 82 CHILDREN) (N = 18 CHILDREN)
DOSE 12 Months DOSE 24 Months DOSE 36 Months DOSE 415 to 20 Months DOSE 54 to 6 Years
*
Post-dose 4, percent redness or swelling >20 mm was not available; post-dose 4, 1.2% of subjects had redness >50 mm, and 3.8% had swelling >50 mm.30 Post-dose 5, 5.6% of children had redness >50 mm, and none had swelling that exceeded 50 mm.31
Moderate or severe = cried or protested to touch or when limb moved.
Rectal temperatures for primary series, oral temperatures for Dose 4 and Dose 5. Dose 5 reported as ≥100.1°F.
§
Moderate or severe = prolonged or persistent crying that could not be comforted and refusal to play.
Local
Redness
Any 12.6 12.7 19.1 17.1 33.3
>20 mm 2.2 0 3.8 NA * 22.2*
Swelling
Any 8.8 8.2 10.7 15.9 27.8
>20 mm 0.7 0.7 3.1 NA * 16.7*
Pain 8.1 3.7 2.3 7.3 11.1
Systemic
Fever >101°F 0.7 1.4 3.1 2.4 5.6
Anorexia 8.1 9.7 9.9 8.5 0
Vomiting 5.2 1.5 2.3 2.4 0
Drowsiness 28.9 17.9 4.6 6.1 5.6
Irritability § 8.1 7.4 7.6 3.7 0

A subset of children who participated in a German vaccine efficacy study were vaccinated with a fourth consecutive dose of Tripedia vaccine in the study I92-2923-01 (TABLE 5). Data on the frequency of local and systemic reactions for 72 hours following vaccination was obtained from a diary provided to the parents at the time of vaccination and returned to the investigator by mail.

TABLE 52 FREQUENCY OF ADVERSE EVENTS OCCURRING WITHIN THREE DAYS FOLLOWING VACCINATION WITH TRIPEDIA VACCINE IN CHILDREN 15 TO 18 MONTHS OF AGE WHO PREVIOUSLY RECEIVED THREE DOSES OF TRIPEDIA VACCINE
Event Trial I92-2923-01*4th dose1,010 subjects
*
Subset of 12,514 subjects who received three doses of Tripedia vaccine in a German case control study of vaccine efficacy.
Temperatures measured orally.
Local Reaction
Any 481/1008 (47.7%)
Redness
Any Size 390/1007 (38.7%)
<2.5 cm 257/1007 (25.5%)
>2.5 cm 133/1002 (13.3%)
Swelling, any size 218/1004 (21.7%)
Pain 214/1002 (21.4%)
Systemic Reactions
Temperature >100.4°F 242/968 (25%)
Irritable 250/1005 (24.9%)
Loss of Appetite 146/1003 (14.6%)
Persistent Crying >3 hours 8/1005 (0.8%)

In an open label US study additional safety data are available in 15- to 20-month-old children who had previously received three doses of either Tripedia vaccine (n = 109) or whole-cell pertussis DTP vaccine (n = 30).32 Reaction rates are presented in Table 6.

TABLE 62,32 ADVERSE EVENTS (%) OCCURRING WITHIN 72 HOURS FOLLOWING VACCINATION WITH TRIPEDIA VACCINE IN CHILDREN 15 TO 20 MONTHS OF AGE WHO HAD RECEIVED THREE PREVIOUS DOSES OF TRIPEDIA VACCINE OR THREE DOSES OF WHOLE-CELL PERTUSSIS DTP VACCINE
N * ERYTHEMA≥1 INCH SWELLING≥1 INCH PAIN TEMPERATURE≥101°F IRRITABILITY
*
N = Number of Children
Temperatures measured rectally.
TripediaVaccinePrimed 109 30.3 29.4 19.3 5.5 19.3
Whole-CellpertussisDTP VaccinePrimed 30 23.3 20.0 10.3 3.3 13.3

The frequency of adverse events following a fifth consecutive dose of Tripedia vaccine administered to German children 4 to 6 years of age is shown in Table 7. This fifth dose study was an open label study that enrolled 580 subjects from 24 sites. These subjects were recruited from subjects who had participated in the case-control study of the efficacy of Tripedia vaccine in which more than 12,000 infants received three doses of Tripedia vaccine. In the fifth dose study, information on systemic and local reactions was collected on diary forms for 3 days following vaccination for all subjects, and for 14 days following vaccination for a subset of 241 subjects. For 490 subjects, the actual sizes of local reactions >5 cm, as measured by the parents, was also documented on the diary forms. Local reactions, including those measured as ≥11 cm, typically had an onset within the first three days after vaccination and generally resolved within five days. Three subjects had a local reaction that lasted more than 21 days – one subject had swelling for 25 days, one subject had redness for 26 days, and one subject had redness for 28 days. Twenty-eight (4.8%) of 580 subjects had redness and/or swelling that led to a medical visit. There were no reported permanent sequelae associated with any local reactions. Thirty-two of 490 subjects (6.5%) had swelling reported as ≥11 cm, including 14 subjects (2.9%) who reported swelling of the entire upper arm. Swelling of the entire upper arm was not specifically solicited. Of 32 subjects with swelling reported as ≥11 cm, 19 also reported pain, 30 had redness and 2 had fever >38°C. All cases of swelling ≥11 cm resolved spontaneously without treatment, except for a few subjects who were treated with cool packs. The subjects in the fifth dose study are not necessarily a subset of the 1,010 German children for whom safety data following the fourth dose of Tripedia vaccine are available (TABLE 5). However, children in both the fourth and fifth dose studies were recruited from subjects who had participated in the German case-control study. Available data from these studies suggest an increased frequency and severity of local reactions following the fifth successive dose of Tripedia vaccine compared with the fourth dose.2 Additional safety data in 96 US children who received a fifth dose of Tripedia vaccine following four previous doses of Tripedia vaccine or Tripedia vaccine combined with ActHIB vaccine (TriHIBit vaccine) also demonstrated an increase in the frequency and severity of local reactions following the fifth dose compared with the first three doses.2

TABLE 72 ADVERSE EVENTS (%) OCCURRING WITHIN 72 HOURS FOLLOWING A FIFTH DOSE OF TRIPEDIA VACCINE * IN GERMAN CHILDREN 4 TO 6 YEARS OF AGE WHO PREVIOUSLY RECEIVED FOUR DOSES OF TRIPEDIA VACCINE
EVENT PERCENT (N = 490-580)
*
Note: one child was a protocol violation as he had received four doses of whole-cell DTP vaccine previously.
These subjects are a subset of 12,514 subjects who had received the first three doses of Tripedia vaccine in the German case-control study of vaccine efficacy.
Redness ≥11 cm and swelling ≥11 cm available for 490 subjects and information on other reactions was available for 580 subjects.
§
Moderate or severe = crying or protesting to touch or crying when arm moved.
Temperatures measured orally.
#
Moderate or severe = prolonged irritability, occasional crying and refusal to play or prolonged irritability, frequent crying, bed rest.
Local
Redness (any) 59.8
>5.0 cm 31.0
≥11.0 cm 6.1
Swelling (any) 61.4
>5.0 cm 25.0
≥11.0 cm 6.5
Pain/Tenderness § 20.5
Systemic
Fever >100.4°F 3.8
Loss of Appetite 7.3
Vomiting 2.2
Drowsiness 15.5
Fussiness # 5.9

Table 8 lists the frequency of adverse events in 372 US children who received Tripedia vaccine at 15 to 20 months of age and 240 US children who received Tripedia vaccine at 4 to 6 years of age in a study conducted from 1989-1990. These children had previously received three or four doses of whole-cell pertussis DTP vaccine at approximately 2, 4, 6, and 18 months of age.2

TABLE 82 ADVERSE EVENTS (%) OCCURRING WITHIN 72 HOURS FOLLOWING TRIPEDIA VACCINE IMMUNIZATIONS GIVEN AT 15 TO 20 MONTHS AND 4 TO 6 YEARS OF AGE IN CHILDREN WHO HAD RECEIVED THREE OR FOUR DOSES OF WHOLE-CELL PERTUSSIS DTP VACCINE
EVENT 15 TO 20 MONTHS THREE PREVIOUS WHOLE-CELL PERTUSSIS DTP VACCINE DOSES REACTION %(N = 372 CHILDREN) 4 TO 6 YEARS FOUR PREVIOUS WHOLE-CELL PERTUSSIS DTP VACCINE DOSES REACTION %(N = 240 CHILDREN)
NA Data not collected in this age group.
*
Includes all occurrences of erythema.
Includes all occurrences of swelling.
Temperatures measured rectally for 15- to 20-month-old children and measured orally for 4 to 6 year-old children.
Local
Erythema * 18.3 31.3
Swelling 10.8 27.9
Tenderness 14.2 46.2
Systemic
Fever >101°F 4.7 4.8
Diarrhea 6.3 0.8
Vomiting 2.2 1.7
Anorexia 7.8 5.4
Drowsiness 12.4 15.0
Irritability 21.2 15.8
High-pitched unusual cry 1.1 NA

When Tripedia vaccine was used to reconstitute ActHIB vaccine (TriHIBit vaccine) and administered to children 15 to 20 months of age who had received 3 prior doses of whole-cell pertussis DTP vaccine, the systemic adverse experience profile was comparable to that observed when the two vaccines were given separately. An increase in rates of minor local reactions was observed within the 24-hour period after immunization when compared to the Tripedia vaccine and ActHIB vaccine administered separately. However, local adverse event rates of the combined vaccines were comparable when taking into consideration reactions observed at the ActHIB vaccine site.2 (Refer to ActHIB vaccine package insert.)

The results of an open label, non-controlled clinical study, of 2,457 US children targeted to evaluate less common and more severe adverse events following three doses of Tripedia vaccine in the primary series are shown in Table 9. Data were collected by parental interview at subsequent immunization visits, chart review and telephone calls to the parents 60 days after the third dose.

TABLE 92 MODERATELY SEVERE ADVERSE EVENTS OCCURRING WITHIN 48 HOURS FOLLOWING VACCINATION WITH TRIPEDIA VACCINE AT 2, 4, OR 6 MONTHS OF AGE (N = 7,102 DOSES)
EVENT NUMBER RATE/1,000 DOSES
*
One seizure episode was noted between 48 and 72 hours.
Fever ≥105°F 2 0.28
Hypotonic/Hyporesponsive Episode 1 0.14
Persistent cry ≥3 hours 4 0.56
Convulsions * 0 0

The frequencies of adverse experiences that are more serious and less common than those reported in Table 9 are not known at this time.

In the German case control efficacy study that enrolled 16,780 infants, 12,514 of whom received 41,615 doses of Tripedia vaccine, hospitalization rates and death rates were similar between Tripedia vaccine and DT vaccine recipients. Adverse events were monitored by spontaneous reporting by parents and a medical history obtained at each subsequent vaccination. Adverse events (rates per 1,000 doses) occurring within 7 days following vaccination with Tripedia vaccine included: unusual cry (0.96), persistent cry >3 hours (0.12), febrile seizure (0.05), afebrile seizure (0.02) and hypotonic/hyporesponsive episodes (0.05).2

In the Swedish efficacy trial where 1,419 recipients received the pertussis components in Tripedia vaccine, three deaths due to invasive bacterial infections occurred. Further investigation revealed no evidence for a causal relation between vaccination and altered resistance to invasive disease caused by encapsulated bacteria.33 While the hypothesis that the two variables are related cannot be ruled out in the Swedish trial, deaths due to invasive bacterial infections have been monitored in other trials. In contrast to the Swedish trial, in the German case-control study and US open-label safety study, 14,971 infants received Tripedia vaccine and no deaths due to invasive bacterial infections were reported.

In the German case-control study and US open-label safety study in which 14,971 infants received Tripedia vaccine, 13 deaths in Tripedia vaccine recipients were reported. Causes of deaths included seven SIDS, and one of each of the following: enteritis, Leigh Syndrome, adrenogenital syndrome, cardiac arrest, motor vehicle accident, and accidental drowning. All of these events occurred more than two weeks post immunization.2 The rate of SIDS observed in the German case-control study was 0.4/1,000 vaccinated infants. The rate of SIDS observed in the US open-label safety study was 0.8/1,000 vaccinated infants and the reported rate of SIDS in the US from 1985-1991 was 1.5/1,000 live births.34 By chance alone, some cases of SIDS can be expected to follow receipt of whole-cell pertussis DTP35 or DTaP vaccines.

Additional Adverse Reactions:

  • As with other aluminum-containing vaccines, a nodule may be palpable at the injection sites for several weeks. Sterile abscess formation at the site of injection has been reported.3,36
  • Rarely, an anaphylactic reaction (ie, hives, swelling of the mouth, difficulty breathing, hypotension, or shock) has been reported after receiving preparations containing diphtheria, tetanus, and/or pertussis antigens.3
  • Arthus-type hypersensitivity reactions, characterized by severe local reactions (generally starting 2-8 hours after an injection), may follow receipt of tetanus toxoid.
  • A few cases of peripheral mononeuropathy and of cranial mononeuropathy have been reported following tetanus toxoid administration, although available evidence is inadequate to accept or reject a causal relation.37
  • A review by the Institute of Medicine (IOM) found evidence for a causal relationship between tetanus toxoid and both brachial neuritis and Guillain-Barré syndrome.37
  • A few cases of demyelinating diseases of the CNS have been reported following some tetanus toxoid-containing vaccines or tetanus and diphtheria toxoid-containing vaccines, although the IOM concluded that the evidence was inadequate to accept or reject a causal relationship.37

Adverse events reported during post-approval use of Tripedia vaccine include idiopathic thrombocytopenic purpura, SIDS, anaphylactic reaction, cellulitis, autism, convulsion/grand mal convulsion, encephalopathy, hypotonia, neuropathy, somnolence and apnea. Events were included in this list because of the seriousness or frequency of reporting. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequencies or to establish a causal relationship to components of Tripedia vaccine.2

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