The safety of ADACEL vaccine was evaluated in 4 clinical studies. A total of 5,841 individuals 11-64 years of age inclusive (3,393 adolescents 11-17 years of age and 2,448 adults 18-64 years) received a single booster dose of ADACEL vaccine.

The principal safety study was a randomized, observer blind, active controlled trial that enrolled participants 11-17 years of age (ADACEL vaccine N = 1,184; Td vaccine N = 792) and 18-64 years of age (ADACEL vaccine N = 1,752; Td vaccine N = 573). Study participants had not received tetanus or diphtheria containing vaccines within the previous 5 years. Observer blind design, ie, study personnel collecting the safety data differed from personnel administering the vaccines, was used due to different vaccine packaging (ADACEL vaccine supplied in single dose vials; Td vaccine supplied in multi-dose vials). Solicited local and systemic reactions were monitored daily for 14 days post-vaccination using a diary card. Participants were monitored for 28 days for adverse events which were not specifically queried on the diary card, ie, unsolicited adverse events, and for 6 months post-vaccination for visits to an emergency room, unexpected visits to an office physician, hospitalization and serious adverse events. Unsolicited adverse event information was obtained either by telephone interview or at an interim clinic visit. Information regarding adverse events that occurred in the 6 month post-vaccination time period was obtained via a scripted telephone interview. Approximately 96% of participants completed the 6-month follow-up evaluation.

In the concomitant vaccination study with ADACEL and Hepatitis B vaccines (see Clinical Studies for description of study design and number of participants), local and systemic adverse events were monitored daily for 14 days post vaccination using a diary card. Local adverse events were only monitored at site/arm of ADACEL vaccine administration. Unsolicited reactions (including immediate reactions, serious adverse events and events that elicited seeking medical attention) were collected at a clinic visit or via telephone interview for the duration of the trial, ie up to six months post-vaccination.

In the concomitant vaccination study with ADACEL vaccine and trivalent inactivated influenza vaccines (see Clinical Studies for description of study design and number of participants), local and systemic adverse events were monitored for 14 days post vaccination using a diary card. All unsolicited reactions occurring through day 14 were collected. From day 14 to the end of the trial, ie, up to 84 days, only events that elicited seeking medical attention were collected.

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.

Serious Adverse Events in All Safety Studies

Throughout the 6-month follow-up period in the principal safety study, serious adverse events were reported in 1.5% of ADACEL vaccine recipients and 1.4% in Td vaccine recipients. Two serious adverse events in adults were neuropathic events that occurred within 28 days of ADACEL vaccine administration; one severe migraine with unilateral facial paralysis and one diagnosis of nerve compression in neck and left arm. Similar or lower rates of serious adverse events were reported in the other trials and there were no additional neuropathic events reported.

Solicited Adverse Events in the Principal Safety Study

The frequency of selected solicited adverse events (erythema, swelling, pain and fever) occurring during Days 0-14 following one dose of ADACEL vaccine or Td vaccine are presented in Table 5. Most of these events were reported at a similar frequency in recipients of both ADACEL vaccine and Td vaccine. Few participants (<1%) sought medical attention for these reactions. Pain at the injection site was the most common adverse reaction occurring in 62-78% of all vaccinees. In addition, overall rates of pain were higher in adolescent recipients of ADACEL vaccine compared to Td vaccine recipients. Rates of moderate and severe pain in adolescents did not significantly differ between the two groups. Rates of pain did not significantly differ for adults. Fever of 38°C and higher was uncommon, although in the adolescent age group, it occurred significantly more frequently in ADACEL vaccine recipients than Td vaccine recipients.⁽¹²⁾

Table 5: Frequencies of Solicited Injection Site Reactions and Fever for Adolescents and Adults, Days 0-14, Following a Single Dose of ADACEL Vaccine or Td Vaccine

		Adolescents		Adults
		11-17 years		18-64 years
		ADACEL	Td	ADACEL	Td
		N = 1,184	N = 792	N = 1,752	N = 573
Adverse	Event*	(%)	(%)	(%)	(%)
Injection Site Pain	Any	77.8†	71	65.7	62.9
	Moderate†	18	15.6	15.1	10.2
	Severe§	1.5	0.6	1.1	0.9
Injection Site Swelling	Any	20.9	18.3	21	17.3
	Moderate†
	1.0 to 3.4 cm	6.5	5.7	7.6	5.4
	Severe§
	≥ 3.5 cm	6.4	5.5	5.8	5.5
	≥ 5 cm (2 inches)	2.8	3.6	3.2	2.7
Injection Site Erythema	Any	20.8	19.7	24.7	21.6
	Moderate†
	1.0 to 3.4 cm	5.9	4.6	8	8.4
	Severe§
	≥ 3.5 cm	6	5.3	6.2	4.8
	≥ 5 cm (2 inches)	2.7	2.9	4	3
Fever	≥ 38.0°C (≥ 100.4°F)	5.0†	2.7	1.4	1.1
	≥ 38.8°C to ≤ 39.4°C (≥ 102.0°F to ≤ 103.0°F)	0.9	0.6	0.4	0.2
	≥ 39.5°C(≥ 103.1°F)	0.2	0.1	0	0.2

* Sample size was designed to detect >10% differences between ADACEL and Td vaccines for events of †Any† intensity.

† ADACEL vaccine did not meet the non-inferiority criterion for rates of †Any Pain† in Adolescents compared to Td Vaccine rates (upper limit of the 95% CI on the difference for ADACEL vaccine minus Td vaccine was 10.7% whereas the criterion was <10%). For †Any† fever the non-inferiority criteria was met, however, †Any† fever was statistically higher in adolescents receiving ADACEL vaccine.

† Interfered with activities, but did not necessitate medical care or absenteeism.

§ Incapacitating, prevented the performance of usual activities, may have/or did necessitate medical care or absenteeism.

The frequency of other solicited adverse events (Days 0-14) are presented in Table 6. The rates of these events following ADACEL vaccine were comparable with those observed with Td vaccine. Headache was the most frequent systemic reaction and was usually of mild to moderate intensity.

Adverse Event		Adolescents		Adults
		11-17 years		18-64years
		ADACEL	Td	ADACEL	Td
		N = 1,184	N = 792	N = 1,752	N = 573
		(%)	(%)	(%)	(%)
Headache	Any	43.7	40.4	33.9	34.1
	Moderate*	14.2	11.1	11.4	10.5
	Severe†	2	1.5	2.8	2.1
Body Ache or Muscle Weakness	Any	30.4	29.9	21.9	18.8
	Moderate*	8.5	6.9	6.1	5.7
	Severe†	1.3	0.9	1.2	0.9
Tiredness	Any	30.2	27.3	24.3	20.7
	Moderate*	9.8	7.5	6.9	6.1
	Severe†	1.2	1	1.3	0.5
Chills	Any	15.1	12.6	8.1	6.6
	Moderate*	3.2	2.5	1.3	1.6
	Severe†	0.5	0.1	0.7	0.5
Sore and Swollen Joints	Any	11.3	11.7	9.1	7
	Moderate*	2.6	2.5	2.5	2.1
	Severe†	0.3	0.1	0.5	0.5
Nausea	Any	13.3	12.3	9.2	7.9
	Moderate*	3.2	3.2	2.5	1.8
	Severe†	1	0.6	0.8	0.5
Lymph Node Swelling	Any	6.6	5.3	6.5	4.1
	Moderate*	1	0.5	1.2	0.5
	Severe†	0.1	0	0.1	0
Diarrhea	Any	10.3	10.2	10.3	11.3
	Moderate*	1.9	2	2.2	2.7
	Severe†	0.3	0	0.5	0.5
Vomiting	Any	4.6	2.8	3	1.8
	Moderate*	1.2	1.1	1	0.9
	Severe†	0.5	0.3	0.5	0.2
Rash	Any	2.7	2	2	2.3

* Interfered with activities, but did not necessitate medical care or absenteeism.

† Incapacitating, prevented the performance of usual activities, may have/or did necessitate medical care or absenteeism.

Local and systemic solicited reactions occurred at similar rates in ADACEL vaccine and Td vaccine recipients in the 3 day post-vaccination period. Most local reactions occurred within the first 3 days after vaccination (with a mean duration of less than 3 days).

Adverse Events in the Concomitant Vaccine Studies

Local and Systemic Reactions when Given with Hepatitis B Vaccine

The rates reported for fever and injection site pain (at the ADACEL vaccine administration site) were similar when ADACEL and Hep B vaccines were given concurrently or separately. However, the rates of injection site erythema (23.4% for concomitant vaccination and 21.4% for separate administration) and swelling (23.9% for concomitant vaccination and 17.9% for separate administration) at the ADACEL vaccine administration site were increased when co-administered. Swollen and/or sore joints were reported by 22.5% for concomitant vaccination and 17.9% for separate administration. The rates of generalized body aches in the individuals who reported swollen and/or sore joints were 86.7% for concomitant vaccination and 72.2% for separate administration. Most joint complaints were mild in intensity with a mean duration of 1.8 days. The incidence of other solicited and unsolicited adverse events were not different between the 2 study groups. ⁽¹²⁾Local and Systemic Reactions when Given with Trivalent Inactivated Influenza Vaccine

The rates of fever and injection site erythema and swelling were similar for recipients of concurrent and separate administration of ADACEL vaccine and TIV. However, pain at the ADACEL vaccine injection site occurred at statistically higher rates following concurrent administration (66.6%) versus separate administration (60.8%). The rates of sore and/or swollen joints were 13% for concurrent administration and 9% for separate administration. Most joint complaints were mild in intensity with a mean duration of 2.0 days. The incidence of other solicited and unsolicited adverse events were similar between the 2 study groups. ⁽¹²⁾

Additional Studies

An additional 1,806 adolescents received ADACEL vaccine as part of the lot consistency study used to support ADACEL vaccine licensure. This study was a randomized, double-blind, multi-center trial designed to assess lot consistency as measured by the safety and immunogenicity of 3 lots of ADACEL vaccine when given as a booster dose to adolescents 11-17 years of age inclusive. Local and systemic adverse events were monitored for 14 days post vaccination using a diary card. Unsolicited adverse events and serious adverse events were collected for 28 days post vaccination. Pain was the most frequently reported local adverse event occurring in approximately 80% of all subjects. Headache was the most frequently reported systemic event occurring in approximately 44% of all subjects. Sore and/or swollen joints were reported by approximately 14% of participants. Most joint complaints were mild in intensity with a mean duration of 2.0 days. ⁽¹²⁾

An additional 962 adolescents and adults received ADACEL vaccine in three supportive Canadian studies used as the basis for licensure in other countries. Within these clinical trials, the rates of local and systemic reactions following ADACEL vaccine were similar to those reported in the four principal trials in the US with the exception of a higher rate (86%) of adults experiencing †any† local injection site pain. The rate of severe pain (0.8%), however, was comparable to the rates reported in the four principal trials. ⁽¹²⁾

Postmarketing Reports

In addition to the data from clinical trials, the following adverse events have spontaneously been reported during the commercial use of ADACEL vaccine in other countries. These adverse events have been very rarely reported (<0.01%), however, incidence rates cannot precisely be calculated. The reported rate is based on the number of adverse event reports per estimated number of vaccinated patients.

General disorders and administration site conditions:

                                   - injection site bruising, sterile abscess

Skin and subcutaneous tissue disorders:

                                   - pruritus, urticaria

Additional Adverse Events

Additional adverse reactions, included in this section, have been reported in conjunction with receipt of vaccines containing diphtheria, tetanus toxoids and/or pertussis antigens.

Arthus-type hypersensitivity reactions, characterized by severe local reactions (generally starting 2-8 hours after an injection), may follow receipt of tetanus toxoid. Such reactions may be associated with high levels of circulating antitoxin in persons who have had overly frequent injections of tetanus toxoid. ⁽¹⁷⁾ (See WARNINGS.)

Persistent nodules at the site of injection have been reported following the use of adsorbed products. ⁽⁵⁾

Cases of allergic or anaphylactic reaction (ie, hives, swelling of the mouth, difficulty breathing, hypotension, or shock) have been reported after receiving some preparations containing diphtheria tetanus toxoids and/or pertussis antigens. ⁽⁵⁾ Death following vaccine-caused anaphylaxis has been reported. ⁽¹⁷⁾

Certain neurological conditions have been reported in temporal association with some tetanus toxoid-containing vaccines or tetanus and diphtheria toxoid-containing vaccines. A review by the Institute of Medicine (IOM) concluded that the evidence favors acceptance of a causal relation between tetanus toxoid and both brachial neuritis and Guillian-Barré syndrome. Other neurological conditions that have been reported include: demyelinating diseases of the central nervous system, peripheral mononeuropathies, cranial mononeuropathies and EEG disturbances with encephalopathy (with or without permanent intellectual and/or motor function impairment). The IOM has concluded that the evidence is inadequate to accept or reject a causal relation between these conditions and vaccines containing tetanus and/or diphtheria toxoids. In the differential diagnosis of polyradiculoneuropathies following administration of a vaccine containing tetanus toxoid, tetanus toxoid should be considered as a possible etiology. ⁽¹⁷⁾

Reporting of Adverse Events

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 of the manufacturer and lot number of the vaccine administered 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. The Act further requires the health-care professional to report to the US Department of Health and Human Services the occurrence following immunization of any event set forth in the Vaccine Injury Table. These include anaphylaxis or anaphylactic shock within 7 days; brachial neuritis within 28 days; an acute complication or sequelae (including death) of an illness, disability, injury, or condition referred to above, or any events that would contraindicate further doses of vaccine, according to this ADACEL vaccine package insert. ^{(16) (18) (19)}

The US Department of Health and Human Services has established the Vaccine Adverse Event Reporting System (VAERS) to accept all reports of suspected adverse events after the administration of any vaccine. Reporting of all adverse events occurring after vaccine administration is encouraged from vaccine recipients, parents/guardians and the health-care provider. Adverse events following immunization should be reported to 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 or visit the VAERS website at http://www.fda.gov/cber/vaers/vaers.htm. ^{(16) (18) (19)}

Health-care providers should also report these events to Pharmacovigilance Department, Aventis Pasteur Inc., Discovery Drive, Swiftwater, PA 18370 or call 1-800-822-2463 (1-800-VACCINE).

Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs and corticosteroids (used in greater than physiologic doses), may reduce the immune response to vaccines. (See PRECAUTIONS, General.)

For information regarding simultaneous administration with other vaccines refer to the CLINICAL PHARMACOLOGY† Concurrently Administered Vaccines, ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION sections.