PENTACEL SIDE EFFECTS

Last updated on MDtodate: 10/10/2022

SIDE EFFECTS

Data From Clinical Studies

Rates of adverse reactions varied by dose number. The most frequent ( > 50% of participants) systemic reactions following any dose were fussiness/irritability and inconsolable crying. The most frequent ( > 30% of participants) injection site reactions following any dose were tenderness and increased circumference of the injected arm.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared to rates in the clinical trials of another vaccine and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to vaccine use and for approximating rates of those events.

The safety of Pentacel vaccine was evaluated in four clinical studies in which a total of 5,980 participants received at least one dose of Pentacel vaccine. In three of the studies, conducted in the US, a total of 4,198 participants were enrolled to receive four consecutive doses of Pentacel vaccine. In the fourth study, conducted in Canada, 1,782 participants previously vaccinated with three doses of Pentacel vaccine received a fourth dose. The vaccination schedules of Pentacel vaccine, Control vaccines, and concomitantly administered vaccines used in these studies are provided in Table 1.

Across the four studies, 50.8% of participants were female. Among participants in the three US studies, 64.5% were Caucasian, 9.2% were Black, 12.9% were Hispanic, 3.9% were Asian, and 9.5% were of other racial/ethnic groups. In the two controlled studies, the racial/ethnic distribution of participants who received Pentacel and Control vaccines was similar. In the Canadian fourth dose study, 86.0% of participants were Caucasian, 1.9% were Black, 0.8% were Hispanic, 4.3% were Asian, 2.0% were East Indian, 0.5% were Native Indian, and 4.5% were of other racial/ethnic groups.

Table 1: Clinical Safety Studies of Pentacel Vaccine: Vaccination Schedules

Study	Pentacel	Control Vaccines	Concomitantly Administered Vaccines
494-01	2, 4, 6 and 15 months	HCPDT + POLIOVAX + ActHIB at 2, 4, 6, and 15 months	7-valent pneumococcal conjugate vaccine* (PCV7) at 2, 4, and 6 months in a subset of participants† Hepatitis B vaccine at 2 and 6 months‡
P3T06	2, 4, 6, and 15-16 months	DAPTACEL + IPOL + ActHIB at 2, 4, and 6 months; and DAPTACEL + ActHIB at 15-16 months	PCV7* at 2, 4, and 6 months Hepatitis B vaccine at 2 and 6 months‡
494-03	2, 4, 6, and 15-16 months	None	PCV7* at 2, 4, and 6 months in all participants; and at 15 months in a random subset of participants Hepatitis B vaccine at 2 and 6 months (if a dose was previously administered)‡ or at 2, 4, and 6 months (if no previous dose) Measles, mumps, rubella vaccine§ (MMR) and varicella§ vaccine at 12 or 15 months in random subsets of participants
5A9908	15-18 months **	None	None
HCPDT: non-US licensed DTaP vaccine that is identical to the DTaP component of Pentacel vaccine. POLIOVAX: US licensed Poliovirus Vaccine Inactivated, Sanofi Pasteur Limited. IPOL: US licensed Poliovirus Vaccine Inactivated, Sanofi Pasteur SA. *PCV7 manufactured by Wyeth Laboratories. †PCV7 was introduced after the study was initiated, and thus, administered concomitantly with Pentacel vaccine in a subset of participants. ‡ The first dose of hepatitis B vaccine (manufacturer not specified) was administered prior to study initiation, from birth to 21 days of age. Subsequent doses were with hepatitis B vaccine manufactured by Merck and Co. § MMR and varicella vaccines were both manufactured by Merck and Co. ** Study participants previously had received three doses of Pentacel vaccine by 8 months of age.

 

Solicited Adverse Reactions

The incidence and severity of selected solicited injection site and systemic adverse reactions that occurred within 3 days following each dose of Pentacel or Control vaccines in Study P3T06 is shown in Table 2. Information on these reactions was recorded daily by parents or guardians on diary cards. In Table 2, injection site reactions are reported for the Pentacel vaccine and DAPTACEL vaccine injection sites.

Table 2: Number (Percentage) of Children with Selected Solicited Adverse Reactions by Severity Occurring within 0-3 days of Pentacel Vaccine or Control Vaccines in Study P3T06

Injection Site Reactions	Pentacel Vaccine				DAPTACEL Vaccine
	Dose 1 N = 465-467 %	Dose 2 N = 451 %	Dose 3 N = 438-440 %	Dose 4 N = 387-396 %	Dose 1 N = 1,400-1,404 %	Dose 2 N = 1,358-1,359 %	Dose 3 N = 1,311-1,312 %	Dose 4 N = 376-380 %
Redness
> 5 mm	7. 1	8.4	8.7	17.3	6.2	7.1	9.6	16.4
> 25 mm	2. 8	1.8	1.8	9.2	1	0.6	1.9	7.9
> 50 mm	0.6	0.2	0	2.3	0.4	0.1	0	2.4
Swelling
> 5 mm	7.5	7.3	5	9.7	4	4	6.5	10.3
> 25 mm	3	2	1.6	3.8	1.6	0.7	1.1	4
> 50 mm	0.9	0	0	0.8	0.4	0.1	0.1	1.3
Tenderness *
Any	47.5	39.2	42.7	56.1	48.8	38.2	40.9	51.1
Moderate or Severe	19.6	10.6	11.6	16.7	20.7	12.2	12.3	15.8
Severe	5.4	1.6	1.4	3.3	4.1	2.3	1.7	2.4
Increase in Arm Circumference
> 5 mm	–	–	–	33.6	–	–	–	30.6
> 20 mm	–	–	–	4.7		–	–	6.9
> 40 mm	–	–	–	0.5	–	–	–	0.8
Systemic Reactions	Pentacel Vaccine				DAPTACEL + IPOL + ActHIB Vaccines			DAPTACEL + ActHIB Vaccines
	Dose 1 N = 466-467 %	Dose 2 N = 451-452 %	Dose 3 N = 435-440 %	Dose 4 N = 389-398 %	Dose 1 N = 1,390-1,406 %	Dose 2 N = 1,346-1,360 %	Dose 3 N = 1,301-1,312 %	Dose 4 N = 379-381 %
Fever†‡
≥ 38.0°C	5.8	10.9	16.3	13.4	9.3	16.1	15.8	8.7
> 38.5°C	1.3	2.4	4.4	5.1	1.6	4.3	5.1	3.2
> 39.5°C	0.4	0	0.7	0.3	0.1	0.4	0.3	0.8
Decreased Activity/Lethargy §
Any	45.8	32.7	32.5	24.1	51.1	37.4	33.2	24.1
Moderate or Severe	22.9	12.4	12.7	9.8	24.3	15.8	12.7	9.2
Severe	2.1	0.7	0.2	2.5	1.2	1.4	0.6	0.3
Inconsolable Crying
Any	59.3	49.8	47.3	35.9	58.5	51.4	47.9	36.2
≥ 1 hour	19.7	10.6	13.6	11.8	16.4	16	12.2	10.5
> 3 hours	1.9	0.9	1.1	2.3	2.2	3.4	1.4	1.8
Fussiness/Irritability
Any	76.9	71.2	68	53.5	75.8	70.7	67.1	53.8
≥ 1 hour	34.5	27	26.4	23.6	33.3	30.5	26.2	19.4
> 3 hours	4.3	4	5	5.3	5.6	5.5	4.3	4.5
Any: Mild, Moderate or Severe; Mild: subject whimpers when site is touched; Moderate: subject cries when site is touched; Severe: subject cries when leg or arm is moved. † Fever is based upon actual temperatures recorded with no adjustments to the measurement route. ‡ Following Doses 1-3 combined, the proportion of temperature measurements that were taken by axillary, rectal or other routes, or not recorded were 46.0%, 53.0%, 1.0%, and 0% respectively, for Pentacel vaccine and 44.8%, 54.0%, 1.0%, and 0.1%, respectively, for DAPTACEL + IPOL + ActHIB vaccines. Following Dose 4, the proportion of temperature measurements that were taken by axillary, rectal or other routes, or not recorded were 62.7%, 34.4%, 2.4% and 0.5%, respectively, for Pentacel vaccine, and 61.1%, 36.6%, 1.7% and 0.5%, respectively, for DAPTACEL + ActHIB vaccines. § Moderate: interferes with or limits usual daily activity; Severe: disabling, not interested in usual daily activity.

 

Hypotonic Hyporesponsive Episodes

In Study P3T06, the diary cards included questions pertaining to HHEs. In Studies 494-01, 494-03, and 5A9908, a question about the occurrence of fainting or change in mental status was asked during post-vaccination phone calls. Across these 4 studies, no HHEs, as defined in a report of a US Public Health Service workshop⁴ were reported among participants who received Pentacel vaccine (N = 5,979), separately administered HCPDT + POLIOVAX + ActHIB vaccines (N = 1,032) or separately administered DAPTACEL + IPOL + ActHIB vaccines (N = 1,455). Hypotonia not fulfilling HHE criteria within 7 days following vaccination was reported in 4 participants after the administration of Pentacel vaccine (1 on the same day as the 1st dose; 3rd on the same day as the 3 dose) and in 1 participant after the administration of DAPTACEL + IPOL + ActHIB vaccines (4 days following the 1st dose).

Seizures

Across Studies 494-01, 494-03, 5A9908 and P3T06, a total of 8 participants experienced a seizure within 7 days following either Pentacel vaccine (4 participants; N = 4,197 for at least one of Doses 1-3; N = 5,033 for Dose 4), separately administered HCPDT + POLIOVAX + ActHIB vaccines (3 participants; N = 1,032 for at least one of Doses 1-3, N = 739 for Dose 4), separately administered DAPTACEL + IPOL + ActHIB vaccines (1 participant; N = 1,455 for at least one of Doses 1-3), or separately administered DAPTACEL + ActHIB vaccines (0 participants; N = 418 for Dose 4). Among the four participants who experienced a seizure within 7 days following Pentacel vaccine, one participant in Study 494-01 had an afebrile seizure 6 days after the first dose, one participant in Study 494-01 had a possible seizure the same day as the third dose, and two participants in Study 5A9908 had a febrile seizure 2 and 4 days, respectively, after the fourth dose. Among the four participants who experienced a seizure within 7 days following Control vaccines, one participant had an afebrile seizure the same day as the first dose of DAPTACEL + IPOL + ActHIB vaccines, one participant had an afebrile seizure the same day as the second dose of HCPDT + POLIOVAX + ActHIB vaccines, and two participants had a febrile seizure 6 and 7 days, respectively, after the fourth dose of HCPDT + POLIOVAX + ActHIB vaccines.

Serious Adverse Events

In Study P3T06, within 30 days following any of Doses 1-3 of Pentacel or Control vaccines, 19 of 484 (3.9%) participants who received Pentacel vaccine and 50 of 1,455 (3.4%) participants who received DAPTACEL + IPOL + ActHIB vaccines experienced a serious adverse event. Within 30 days following Dose 4 of Pentacel or Control vaccines, 5 of 431 (1.2%) participants who received Pentacel vaccine and 4 of 418 (1.0%) participants who received DAPTACEL + ActHIB vaccines experienced a serious adverse event. In Study 494-01, within 30 days following any of Doses 1-3 of Pentacel or Control vaccines, 23 of 2,506 (0.9%) participants who received Pentacel vaccine and 11 of 1,032 (1.1%) participants who received HCPDT + POLIOVAX + ActHIB vaccines experienced a serious adverse event. Within 30 days following Dose 4 of Pentacel or Control vaccines, 6 of 1,862 (0.3%) participants who received Pentacel vaccine and 2 of 739 (0.3%) participants who received HCPDT + POLIOVAX + ActHIB vaccines experienced a serious adverse event.

Across Studies 494-01, 494-03 and P3T06, within 30 days following any of Doses 1-3 of Pentacel or Control vaccines, overall, the most frequently reported serious adverse events were bronchiolitis, dehydration, pneumonia and gastroenteritis. Across Studies 494-01, 494-03, 5A9908 and P3T06, within 30 days following Dose 4 of Pentacel or Control vaccines, overall, the most frequently reported serious adverse events were dehydration, gastroenteritis, asthma, and pneumonia.

Across Studies 494-01, 494-03, 5A9908 and P3T06, two cases of encephalopathy were reported, both in participants who had received Pentacel vaccine (N = 5,979). One case occurred 30 days post-vaccination and was secondary to cardiac arrest following cardiac surgery. One infant who had onset of neurologic symptoms 8 days post-vaccination was subsequently found to have structural cerebral abnormalities and was diagnosed with congenital encephalopathy.

A total of 5 deaths occurred during Studies 494-01, 494-03, 5A9908 and P3T06: 4 in children who had received Pentacel vaccine (N = 5,979) and one in a participant who had received DAPTACEL + IPOL + ActHIB vaccines (N = 1,455). There were no deaths reported in children who received HCPDT + POLIOVAX + ActHIB vaccines (N = 1,032). Causes of death among children who received Pentacel vaccine were asphyxia due to suffocation, head trauma,

Sudden Infant Death syndrome, and neuroblastoma (8, 23, 52 and 256 days post-vaccination, respectively). One participant with ependymoma died secondary to aspiration 222 days following DAPTACEL + IPOL + ActHIB vaccines.

Data From Post-Marketing Experience

The following additional adverse events have been spontaneously reported during the post-marketing use of Pentacel vaccine worldwide, since 1997. Between 1997 and 2007, Pentacel vaccine was primarily used in Canada. Because these events are reported voluntarily from a population of uncertain size, it may not be possible to reliably estimate their frequency or establish a causal relationship to vaccine exposure.

The following adverse events were included based on one or more of the following factors: severity, frequency of reporting, or strength of evidence for a causal relationship to Pentacel vaccine.

Cardiac Disorders

Cyanosis

Gastrointestinal Disorders

Vomiting, diarrhea

General Disorders and Administration Site Conditions

Injection site reactions (including inflammation, mass, abscess and sterile abscess), extensive swelling of the injected limb (including swelling that involved adjacent joints), vaccination failure/therapeutic response decreased (invasive H influenzae type b disease)

Immune System Disorders

Anaphylaxis/anaphylactic reaction, hypersensitivity (such as rash and urticaria)

Infections and Infestations

Meningitis, rhinitis, viral infection

Metabolism and Nutrition Disorders

Decreased appetite

Nervous System Disorders

Somnolence, HHE, depressed level of consciousness

Psychiatric Disorders

Screaming

Respiratory, Thoracic and Mediastinal Disorders

Apnea, cough

Skin and Subcutaneous Tissue Disorders Erythema, Skin Discoloration

Vascular disorders Pallor