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Infanrix Side Effects, and Drug Interactions - Diphtheria and Tetanus Toxoids and Acellular Pertussis

Infanrix Side Effects, and Drug Interactions - Diphtheria and Tetanus Toxoids and Acellular Pertussis

SIDE EFFECTS

A total of 92,502 doses of Infanrix has been administered in clinical studies. In these studies, 28,749 infants have received Infanrix as a three-dose primary series, 5,830 children have received Infanrix as a fourth dose following three doses of Infanrix, and 22 children have received Infanrix as a fifth dose following four doses of Infanrix. In addition, 439 children and 169 children have received Infanrix as a fourth or fifth dose following three or four doses of whole-cell DTP vaccine, respectively. In comparative studies, Infanrix has been shown to be followed by fewer of the local and systemic adverse reactions commonly associated with whole-cell DTP vaccination. However, studies have shown that the rate of erythema, swelling and fever increased with successive doses of Infanrix.

In the double-blind, randomized comparative trial in Italy, safety data in a three-dose primary series are available for 4,696 infants who received at least one dose of Infanrix and 4,678 infants who received at least one dose of U.S.-licensed whole-cell DTP vaccine manufactured by Connaught Laboratories, Inc.^13,15 Data were actively collected by parents using standardized diaries for eight consecutive evenings after each vaccine dose with follow-up telephone calls made by nurses after the eighth day. Table 1 lists adverse events reported during the three days after each dose. All common solicited adverse events were less frequent following vaccination with Infanrix as compared to whole-cell DTP after each one of the three doses.

Table 1.¹³ Adverse Events (%) Occurring Within the 3 Days Following Vaccination of Italian Infants with Either Infanrix or Whole-Cell DTP at 2, 4 and 6 Months of Age

	Infanrix			Whole-Cell DTP Vaccine
	Dose 1	Dose 2	Dose 3	Dose 1	Dose 2	Dose 3
No. of infants	4,696	4,560	4,505	4,678	4,474	4,368
Local
Redness	4.8	8.6	16.0	27.1	24.2	28.0
Redness
³ 2.4 cm	1.0	1.3	3.5	12.4	7.3	7.7
Swelling	5.2	8.2	14.5	28.9	23.5	25.8
Swelling
³ 2.4 cm	0.7	1.2	2.9	13.1	7.4	8.0
Tenderness	4.7	4.0	5.2	36.0	26.8	25.9
Systemic
Fever
³ 100.4°F*	7.1	7.9	9.0	46.8	36.1	39.8
Irritability	36.3	34.9	28.8	57.2	50.1	47.2
Drowsiness	34.9	18.8	11.4	54.0	34.1	23.0
Loss of
Appetite	16.5	13.9	11.5	31.2	22.8	19.1
Vomiting	5.8†	4.1†	3.3	6.7	4.7	4.8
Crying
³ 1 Hour	3.9	3.3	2.2	17.3	11.1	8.2

* Rectal temperatures.

† For the comparison of Infanrix and whole-cell DTP vaccine, all adverse events reached statistical significance (p<0.001) at all doses except vomiting at doses 1 and 2, which was not statistically significant at p<0.05.

A similar reduction in adverse events was seen in a randomized, double-blind, comparative trial conducted in the U.S. when Infanrix (Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed) was compared to two U.S.-licensed whole-cell DTP vaccines. Adverse events were actively solicited using standardized diaries with follow-up telephone calls made at days 1, 4 and 8 by blinded study personnel. Table 2 summarizes the frequency of adverse events within 3 days of the three primary immunizing doses. The incidence of redness, swelling, pain, fever (rectal temperature >101^o F), fussiness, drowsiness and poor appetite, were lower following Infanrix than following either whole-cell DTP vaccine.

Table 2.²⁷ Adverse Events (%) Occurring Within the 3 Days Following Vaccination of U.S. Infants with Either Infanrix or Whole-Cell DTP at 2, 4 and 6 Months of Age

	Infanrix			Whole-Cell DTP Vaccine-Lederle			Whole-Cell DTP Vaccine-Connaught
	Dose 1	Dose 2	Dose 3	Dose 1	Dose 2	Dose 3	Dose 1	Dose 2	Dose 3
No. of infants	407	402	395	74	73	73	76	75	74
Local
Redness*	10.6	19.4	25.8	28.4	42.5	39.7	35.5	50.7	50.0
Swelling	7.4†Ά	12.2†Ά	17.5Ά	23.0†	26.0†	27.4	30.3Ά	37.3Ά	31.1Ά
Pain*‡	2.7	2.0	1.5	17.6	15.1	9.6	38.2	17.3	14.9
Systemic
Fever
>101°F§	0.5†Ά	0.7†Ά	5.1	12.2†	8.2†	6.8	14.5Ά	18.7Ά	8.1
Fussiness**	3.9†Ά	3.5†Ά	4.1	25.7†	13.7†	6.8	21.1Ά	16.0Ά	8.1
Drowsiness	26.3†Ά	16.4†Ά	12.9†	51.4†	34.2†	23.3†	52.6Ά	28.0Ά	18.9
Poor	8.1†Ά	7.7	6.6	31.1†	15.1	9.6	19.7Ά	14.7	9.5
Appetite
Vomiting	6.6	3.7	3.8	8.1	4.1	2.7	7.9	2.7	2.7

‡ Moderate or severe = cried or protested to touch or cried when leg moved.

** Moderate or severe = prolonged crying and refusal to play or persistent crying that could not be comforted.

§ Rectal temperatures.

* p<0.05 for the comparison of Infanrix and both whole-cell DTP vaccines.

† p<0.05 for the comparison of Infanrix and whole-cell DTP vaccine-Lederle.

Ά p<0.05 for the comparison of Infanrix and whole-cell DTP vaccine-Connaught.

The frequencies of adverse reactions following each dose in children who received Infanrix at 2, 4 and 6 months of age in a U.S. NIH-sponsored trial are shown in Table 3. Of the 120 infants who received the three-dose primary series, a subset of 76 received a fourth dose of Infanrix at 15 to 20 months of age. Adverse events were actively solicited using standardized diaries with follow-up telephone calls made at day 3 by blinded study personnel.

Table 3.^15,28 Adverse Events (%) Occurring Within the 3 Days Following Vaccination with Infanrix in U.S. Infants and Children in Which All Doses Were Infanrix

	Primary (N=120 infants)			Booster (N=76 children)
Event	Dose 1 (2 months)	Dose 2 (4 months)	Dose 3 (6 months)	Dose 4 (15 to 20 months)
Local
Redness	16.6	15.4	26.3	39.5
Swelling	12.5	15.4	21.0	32.9
Pain*	5.0	5.1	0.9	10.5
Systemic
Fever	0.0	0.9	3.5	6.6
(>101°F)†
Anorexia	7.5	6.0	9.6	11.8
Vomiting	5.8	6.8	3.5	2.6
Drowsiness	37.5	19.7	13.2	6.6
Fussiness‡	3.3	7.7	8.8	9.2

* Moderate or severe = cried or protested to touch or cried when limb moved.

† Rectal temperatures for primary series; oral temperatures for booster.

‡ Moderate or severe = prolonged crying and refusal to play or persistent crying that could not be comforted.

Of 22,505 children who had previously received three doses of Infanrix at 3, 4 and 5 months of age in the large German safety study, 5,361 received a fourth dose at 10 to 36 (mean 20) months of age. Standardized diaries were available on 2,457 children receiving the primary series and 1,809 children receiving the fourth dose. Local and systemic reaction rates within 3 days of vaccination for each dose are reported in Table 4. In this study, the rate of erythema, swelling, pain and fever increased with successive doses of Infanrix.

In another study conducted in Germany, which was double-blinded and randomized, additional safety data are available from 13- to 27-month-old children who received Infanrix (Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed) or whole-cell DTP vaccine, manufactured by Behringwerke, A.G., as a fourth dose. These children had previously received three doses of the same vaccine. The rates of adverse events, which were actively solicited using standardized diaries, are presented in Table 5. The incidence of redness, swelling, severe swelling (greater than 2 cm), pain, fever, severe fever (rectal temperature >103.1°F), restlessness, loss of appetite, vomiting, drowsiness and unusual crying was lower following vaccination with Infanrix compared to whole-cell DTP vaccine.

Table 4.¹⁵ Adverse Events (%) Occurring Within the 3 Days Following Vaccination with Infanrix in German Infants and Children in Which All Doses Were Infanrix

	Primary (N=2,457 infants)			Booster (N=1,809 children)*
Event	Dose 1 (3 months)	Dose 2 (4 months)	Dose 3 (5 months)	Dose 4 (10 to 36 months†)
Local
Redness	8.9	23.6	26.6	45.9
Redness >2 cm	0.0	0.5	1.3	13.8
Swelling	3.9	14.1	18.5	35.4
Swelling >2 cm	0.0	0.3	1.3	11.4
Pain	2.0	2.6	3.7	26.3
Systemic
Fever (=100.4°F)‡	6.3	8.3	13.3	26.4
Fever (>103.1°F)‡	0.0	0.1	0.1	1.1
Loss of Appetite	8.0	7.4	6.5	11.6
Vomiting	4.3	3.9	3.4	2.9
Restlessness	10.3	9.5	8.6	15.9
Unusual Crying	3.9	4.3	4.1	6.4
Diarrhea	6.0	4.9	4.0	11.0

* May not be same children as in primary series.

† Mean = 20 months.

‡ Rectal temperatures.

Table 5.¹⁵ Adverse Events (%) Occurring Within the 3 Days Following Vaccination with Infanrix or Whole-Cell DTP (Fourth Dose) in German Children Who Had Received Three Previous Doses of the Same Vaccine

Event	Infanrix After Infanrix Primary (N=268)	Whole-Cell DTP Vaccine After Whole-Cell DTP Vaccine Primary (N=92)
Local
Redness	32.8	43.5
Redness >2 cm	4.5	3.3
Swelling	22.4	31.5
Swelling >2 cm	3.0	7.6
Pain*	15.7	55.4
Systemic
Fever (=100.4°F)*†	26.9	64.1
Fever (>103.1°F)†‡	0.4	4.3
Restlessness*	12.3	32.6
Loss of Appetite*	10.8	43.5
Vomiting	3.4	7.6
Drowsiness*	10.4	31.5
Unusual Crying*	7.8	33.7

* p<0.0001.

† Rectal temperatures.

‡ p<0.05.

Cases of edematous swelling, generally beginning within 48 hours of vaccination and resolving spontaneously over an average of 4 days without sequelae, have been reported with Infanrix.¹⁵ In the German study in which 5,361 children received a fourth dose of Infanrix (Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed) after three doses of the same vaccine, swelling of the injected thigh was reported spontaneously in 62 vaccinees (1.2%). This swelling was associated with pain upon digital pressure in 53% of cases, with rectal temperature

³ 100.4°F in 45% of cases, and with injection site redness in 71% of cases (redness of the entire thigh was reported in 17% of such cases). The mean difference in the circumference of the thighs in those subjects in whom this was measured (N=17) was 2.2 cm (range: 0.5 to 5 cm). In 1,809 children for whom standardized diaries were available, edematous swelling was observed in 2.5% of vaccinees.

In clinical studies of Infanrix to date, edematous swelling has been seen only with Infanrix as a fourth dose in Infanrix-primed individuals. In other countries where Infanrix has been licensed, limb swelling has been reported rarely following administration of Infanrix at any dose, including the primary series. Edematous swelling has also been reported following administration of other acellular DTP vaccines,²⁹ acellular pertussis vaccine alone (without DT),³⁰ whole-cell DTP vaccine³¹ and other vaccines.³² Table 6 lists the frequency of adverse events in U.S. children who received Infanrix (N=110) or U.S.-licensed whole-cell DTP vaccine (N=55) manufactured by Lederle Laboratories at 15 to 20 months of age³³ and in U.S. children who received Infanrix (N=115) or U.S.-licensed whole-cell DTP vaccine (N=57) manufactured by Lederle Laboratories at 4 to 6 years of age.³⁴ All children had previously received three or four doses of whole-cell DTP vaccine at approximately 2, 4, 6 and 15-18 months of age. Adverse events were actively solicited using standardized diaries with follow-up telephone calls made at days 1, 4 and 8 by blinded study personnel. Significantly fewer solicited local and general adverse events were reported following Infanrix than following whole-cell DTP vaccine when administered as the fourth or fifth dose in those previously primed with three or four doses of whole-cell DTP vaccine.

Table 6.^33,34 Adverse Events (%) Occurring Within the 3 Days Following Vaccination with Infanrix Administered at 15 to 20 Months and 4 to 6 Years of Age in U.S. Children Who Had Previously Received Three or Four Doses of Whole-Cell DTP Vaccine

	15 to 20 months Three Previous Doses of Whole-Cell DTP Vaccine		4 to 6 years Four Previous Doses of Whole-Cell DTP Vaccine
Event	Infanrix (N=110)	Whole-Cell DTP Vaccine (N=55)	Infanrix (N=115)	Whole-Cell DTP Vaccine (N=57)
Local
Redness*	23	45	19	40
Redness† >10	5	31	7	26
mm
Swelling	14	24	15*	33*
Swelling >10 mm	7	15	8	18
Pain†§	5	38	12	40
Systemic
Fever* =99.4°F‡	25	42	23	47
Fever† >100.5°F‡	2	20	1	12
Fussiness	34†	69†	20	30
Drowsiness	9*	24*	11	18
Poor Appetite*	9	20	6	16
Vomiting	2	0	1	4

* p<0.05.

† p<0.0001.

‡ Oral temperatures.

§ Moderate or severe = cried or protested to touch or cried when arm moved.

Severe adverse events reported from the double-blind, randomized comparative Italian study involving 4,696 children administered Infanrix (Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed) or 4,678 children administered whole-cell DTP vaccine (manufactured by Connaught Laboratories, Inc.) as a three-dose primary series are shown in Table 7. The incidence of rectal temperature ³ 104°F, hypotonic-hyporesponsive episodes and persistent crying ³ 3 hours following administration of Infanrix was significantly less than that following administration of whole-cell DTP vaccine.¹³ Hospitalization rates and death rates within 7 days of vaccination were similar between Infanrix and DT vaccine recipients.¹⁵

Table 7.¹³ Severe Adverse Events Occurring Within 48 Hours Following

Vaccination with Infanrix or Whole-Cell DTP in Italian Infants at 2, 4 or 6 Months of Age

	Infanrix (N=13,761 doses)		Whole-Cell DTP Vaccine (N=13,520 Doses)
Event	Number	Rate/1,000 Doses	Number	Rate/1,000 Doses
Fever =104°F*†	5	0.36	32	2.4
Hypotonic Hyporesponsi
ve
Episode‡	0	0	9	0.67
Persistent crying
³ 3 hours*	6	0.44	54	4.0
Seizures**	1§	0.07	3Ά	0.22

* p <0.001.

† Rectal temperatures.

‡ p = 0.002.

§ Maximum rectal temperature within 72 hours of vaccination = 103.1°F.

Ά Maximum rectal temperature within 72 hours of vaccination = 99.5°F, 101.3°F and102.2°F.

**Not statistically significant at p<0.05.

In the large German safety trial that enrolled 22,505 infants (66,867 doses of Infanrix administered as a three-dose primary series), all subjects were monitored for unsolicited adverse events that occurred within 28 days following vaccination using report cards. In a subset of subjects (N=2,457), these cards were standardized diaries which solicited specific adverse events that occurred within 8 days of each vaccination in addition to unsolicited adverse events which occurred throughout the course of the entire trial (from study enrollment until approximately 30 days following the third vaccination). Cards from the whole cohort were returned at subsequent visits and were supplemented by spontaneous reporting by parents and a medical history after the first and second doses of vaccine. In the subset of 2,457, adverse events following the third dose of vaccine were reported via standardized diaries and spontaneous reporting at a follow-up visit. Adverse events in the remainder of the cohort were reported via report cards which were returned by mail approximately 28 days after the third dose of vaccine. Adverse events (rates per 1,000 doses) occurring within 7 days including those events deemed by investigators as related as well as those felt to be unrelated to vaccination included: unusual crying (0.09), febrile seizure (0.0), afebrile seizure (0.13) and hypotonic-hyporesponsive episodes (0.01).

Rates of serious adverse experiences that are less common than those reported in the German safety trial are not known at this time.

In clinical trials involving more than 29,000 infants and children, 14 deaths in Infanrix (Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed) recipients were reported. Causes of deaths included nine cases of Sudden Infant Death Syndrome (SIDS) and one of each of the following: meal aspiration, hepatoblastoma, neuroblastoma, invasive bacterial infection and sudden death in a child greater than 1 year of age. None of these events was determined to be vaccine-related. The rate of SIDS observed in the large German safety study was 0.3/1000 vaccinated infants. The rate of SIDS in the Italian efficacy trial was 0.4/1000 Infanrix-vaccinated infants. The reported rate of SIDS in the U.S. from 1985 to 1991 was 1.5/1000 live births.³⁵ By chance alone, some cases of SIDS can be expected to follow receipt of whole-cell DTP or acellular DTP vaccine.¹⁸ Rarely, an anaphylactic reaction (i.e., hives, swelling of the mouth, difficulty breathing, hypotension, shock) has been reported after receiving preparations containing diphtheria, tetanus and/or pertussis antigens.^1,18 Arthus-type hypersensitivity reactions, characterized by severe local reactions, may follow receipt of tetanus toxoid. A few cases of peripheral mono-neuropathy have been reported following tetanus toxoid administration, although the IOM concluded that the evidence was inadequate to accept or reject a causal relationship.³⁶ A review by the IOM found evidence for a causal relationship between receipt of tetanus toxoid and both brachial neuritis and Guillain-Barré Syndrome.³⁶

Additional Adverse Reactions Evaluated in Conjunction with Whole-Cell DTP Vaccination

Whole-cell DTP vaccine has been associated with acute encephalopathy.²¹ 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 vaccine in the 7 days preceding onset than their age-matched controls. Among children presumed 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 dose, compared to children not receiving DTP vaccine in the 7-day period before onset of their illness, was 3.3 (p<0.001). The attributable risk for all neurologic events was estimated to be 1:140,000 doses of DTP vaccine administered. In this study, a causal relationship between receipt of DTP vaccine and permanent neurologic injury was suggested.^1,37-40 A 10-year follow-up to the NCES demonstrated that children who experience a serious acute neurologic illness following whole-cell DTP vaccine are at increased risk for chronic nervous system dysfunction or death.⁴¹ However, the IOM concluded that the results were insufficient to determine whether DTP vaccine increases the overall risk for chronic nervous system dysfunction in children.^18,22 Subsequent studies have failed to provide evidence in support of a causal relationship between DTP vaccination and either serious acute neurologic illness or permanent neurologic injury.^42-45 The ACIP and AAP continue to recommend the use of DTP vaccine.

Among a subset of children who were participating in the NCES and who had infantile spasms, both DTP and DT vaccination appeared either to precipitate early manifestations of the condition or to lead to its identification by parents.⁴⁶ IOM reviewed this and other studies and concluded that neither vaccine causes the illness.^18,21,45,47 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 vaccine are generally given. Therefore, some cases of infantile spasms can be expected to be temporally associated with receipt of whole-cell DTP or acellular DTP vaccine by chance alone.

SIDS has occurred in infants following administration of whole-cell DTP and acellular DTP vaccine. Large case-control studies of SIDS in the United States have shown that SIDS was not causally related to receipt of DTP vaccine.^48,49 It should be recognized that the first three primary immunizing doses of DTP vaccine are usually administered to infants 2 to 6 months old and that approximately 85% of SIDS cases occur between the ages of 1 and 6 months, with the peak incidence occurring at 6 weeks to 4 months of age. By chance alone, some cases of SIDS can be expected to be temporally related to recent receipt of whole-cell DTP or acellular DTP vaccine. A review by the committee of the IOM concluded that available evidence did not indicate a causal relation between DTP vaccine and SIDS.^18,21 A bulging fontanelle associated with increased intracranial pressure, which occurred within 24 hours following DTP immunization, has been reported, although a causal relationship has not been established.^50-52 As with any vaccine, there is the possibility that broad use of Infanrix (Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed) could reveal adverse reactions not observed in clinical trials.

Reporting Adverse Events

The National Childhood Vaccine Injury Act requires that the manufacturer and lot number of the vaccine administered be recorded by the healthcare provider in the vaccine recipient's permanent medical record, along with the date of administration of the vaccine and the name, address and title of the person administering the vaccine.⁵³ The Act further requires the healthcare provider to report to the U.S. Department of Health and Human Services via VAERS the occurrence following immunization of any event set forth in the Vaccine Injury Table including: anaphylaxis or anaphylactic shock within 4 hours, encephalopathy or encephalitis within 72 hours, or any sequelae thereof (including death).^53,54 In addition, any event considered a contraindication to further doses should be reported.

Drug Interactions

For information regarding simultaneous administration with other vaccines, refer to DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY.

As with other intramuscular injections, Infanrix should not be given to infants or children on anticoagulant therapy unless the potential benefit clearly outweighs the risk of administration (see WARNINGS).

Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs and corticosteroids (used in greater than physiologic doses), may reduce the immune response to vaccines. Although no specific data from studies with pertussis vaccine under these conditions are available, if immunosuppressive therapy will be discontinued shortly, it would be reasonable to defer immunization until the patient has been off therapy for 1 month; otherwise, the patient should be vaccinated while still on therapy (see PRECAUTIONS).¹ If Infanrix is administered to a person receiving immunosuppressive therapy, or a recent injection of immune globulin, or who has an immunodeficiency disorder, an adequate immunologic response may not be obtained.

Tetanus Immune Globulin or Diphtheria Antitoxin, if used, should be given at a separate site, with a separate needle and syringe.

Carcinogenesis, Mutagenesis, Impairment of Fertility

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

Pregnancy: Pregnancy Category C

Animal reproduction studies have not been conducted with Infanrix. It is not known whether Infanrix can cause fetal harm when administered to a pregnant woman or if Infanrix can affect reproductive capacity. Infanrix is not recommended for use in a pregnant woman. Infanrix is not recommended for persons 7 years of age or older.

Pediatric Use

Safety and effectiveness of Infanrix in infants below the age of 6 weeks have not been established (see DOSAGE AND ADMINISTRATION). Infanrix is not recommended for individuals 7 years of age or older. Tetanus and Diphtheria Adsorbed For Adult Use (Td) is to be used in individuals 7 years of age or older.

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