Vaccine Information: Adacel TDaP

ADACEL TDAP- clostridium tetani toxoid antigen (formaldehyde inactivated), corynebacterium diphtheriae toxoid antigen (formaldehyde inactivated), bordetella pertussis toxoid antigen (glutaraldehyde inactivated), bordetella pertussis filamentous hemagglutinin antigen (formaldehyde inactivated), bordetella pertussis pertactin antigen and bordetella pertussis fimbriae 2/3 antigen injection, suspension
Sanofi Pasteur Inc.

1 INDICATIONS AND USAGE

Adacel® is a vaccine indicated for active booster immunization against tetanus, diphtheria and pertussis. Adacel is approved for use in individuals 10 through 64 years of age.

2 DOSAGE AND ADMINISTRATION

For intramuscular injection only.

2.1 Preparation for Administration

Just before use, shake the vial or syringe well until a uniform, white, cloudy suspension results.

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

Withdraw the 0.5 mL dose of vaccine from the single-dose vial using a sterile needle and syringe.

Adacel should not be combined through reconstitution or mixed with any other vaccine. Discard unused portion in vial.

2.2 Administration, Dose and Schedule

Adacel is administered as a single 0.5 mL intramuscular injection.

Routine Booster Vaccination

A first dose of Adacel is administered 5 years or more after the last dose of the Diphtheria and Tetanus Toxoids and Acellular Pertussis (DTaP) series or 5 years or more after a dose of Tetanus and Diphtheria Toxoids Adsorbed (Td). A second dose of Adacel may be administered 8 years or more after the first dose of Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed (Tdap).

Wound Management

Adacel may be administered for tetanus prophylaxis for wound management. For management of a tetanus prone wound, a booster dose of Adacel may be administered if at least 5 years have elapsed since previous receipt of a tetanus toxoid containing vaccine.

3 DOSAGE FORMS AND STRENGTHS

Adacel is a suspension for injection available in 0.5 mL single-dose vials and prefilled syringes. [See HOW SUPPLIED/STORAGE AND HANDLING (16).]

4 CONTRAINDICATIONS

4.1 Hypersensitivity

A severe allergic reaction (eg, anaphylaxis) after a previous dose of any tetanus toxoid, diphtheria toxoid or pertussis containing vaccine or any other component of this vaccine is a contraindication to administration of Adacel. [See DESCRIPTION (11).] Because of uncertainty as to which component of the vaccine may be responsible, none of the components should be administered. Alternatively, such individuals may be referred to an allergist for evaluation if further immunizations are to be considered.

4.2 Encephalopathy

Encephalopathy (eg, coma, prolonged seizures, or decreased level of consciousness) within 7 days of a previous dose of a pertussis containing vaccine not attributable to another identifiable cause is a contraindication to administration of any pertussis containing vaccine, including Adacel.

5 WARNINGS AND PRECAUTIONS

5.1 Management of Acute Allergic Reactions

Epinephrine hydrochloride solution (1:1,000) and other appropriate agents and equipment must be available for immediate use in case an anaphylactic or acute hypersensitivity reaction occurs.

5.2 Latex

For one presentation of Adacel, the tip caps of the prefilled syringes may contain natural rubber latex, which may cause allergic reactions in latex sensitive individuals. The vial stopper is not made with natural rubber latex. [See HOW SUPPLIED/STORAGE AND HANDLING (16).]

5.3 Guillain-Barré Syndrome and Brachial Neuritis

A review by the Institute of Medicine found evidence for acceptance of a causal relation between tetanus toxoid and both brachial neuritis and Guillain-Barré syndrome. (1) If Guillain-Barré syndrome occurred within 6 weeks of receipt of prior vaccine containing tetanus toxoid, the risk for Guillain-Barré syndrome may be increased following a dose of Adacel.

5.4 Progressive or Unstable Neurologic Disorders

Progressive or unstable neurologic conditions are reasons to defer Adacel. It is not known whether administration of Adacel to persons with an unstable or progressive neurologic disorder might hasten manifestations of the disorder or affect the prognosis. Administration of Adacel to persons with an unstable or progressive neurologic disorder may result in diagnostic confusion between manifestations of the underlying illness and possible adverse effects of vaccination.

5.5 Arthus-Type Hypersensitivity

Persons who experienced an Arthus-type hypersensitivity reaction following a prior dose of a tetanus toxoid-containing vaccine should not receive Adacel unless at least 10 years have elapsed since the last dose of a tetanus toxoid containing vaccine.

5.6 Altered Immunocompetence

If Adacel is administered to immunocompromised persons, including persons receiving immunosuppressive therapy, the expected immune response may not be obtained. [See DRUG INTERACTIONS (7.2).]

5.7 Syncope

Syncope (fainting) can occur in association with administration of injectable vaccine, including Adacel. Procedures should be in place to prevent falling injury and manage syncopal reactions.

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

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. As with any vaccine, there is the possibility that broad use of Adacel could reveal adverse reactions not observed in clinical trials.

The safety of a first vaccination with Adacel was evaluated in 5 clinical studies. Three of the studies were conducted in the U.S. and 2 were conducted in Canada. Of the study participants, 86% were Caucasian, 8% Black, 3% Hispanic, 1% Asian and 2% of other ethnic origin. A total of 7,143 individuals 10 through 64 years of age inclusive (4,695 adolescents 10 through 17 years of age and 2,448 adults 18 through 64 years of age) received a single dose of Adacel.

U.S. Adolescent and Adult Study of a First Vaccination with Adacel (Td506)

Clinical study Td506 was a randomized, observer-blind, active-controlled trial that enrolled adolescents 11 through 17 years of age (Adacel N = 1,184; DECAVAC (Tetanus and Diphtheria Toxoids Adsorbed; manufactured by Sanofi Pasteur Inc., Swiftwater, PA) N = 792) and adults 18 through 64 years of age (Adacel N = 1,752; DECAVAC N = 573). Study participants had not received tetanus or diphtheria-containing vaccines within the previous 5 years. Solicited local and systemic reactions and unsolicited adverse events were monitored daily for 14 days post vaccination using a diary card. From days 14 to 28 post vaccination, information on adverse events necessitating a medical contact, such as a telephone call, visit to an emergency room, physician’s office or hospitalization, was obtained via telephone interview or at an interim clinic visit. From days 28 to 6 months post vaccination, participants were monitored for unexpected visits to a physician’s office or to an emergency room, onset of serious illness, and hospitalizations. Information regarding adverse events that occurred in the 6-month post vaccination time period was obtained from participants via telephone contact. At least 96% of participants completed the 6-month follow-up evaluation.

The frequency of selected solicited adverse reactions (erythema, swelling, pain and fever) occurring during days 0 to 14 following vaccination with Adacel or Td vaccine in adolescents 11 through 17 years of age and adults 18 through 64 years of age are presented in Table 1. Most of these reactions were reported at a similar frequency in recipients of both Adacel and Td vaccine. Pain at the injection site was the most common adverse reaction in 62.9% to 77.8% of all vaccinees. In addition, overall rates of pain were higher in adolescent recipients of Adacel compared to Td vaccine recipients. Rates of moderate and severe pain in adolescents did not significantly differ between the Adacel and Td vaccine groups. Among adults, the rates of pain after receipt of Adacel or Td vaccine did not significantly differ. Fever of 38°C and higher was uncommon, although in the adolescent age group it occurred significantly more frequently in Adacel recipients than Td vaccine recipients.

Table 1: Frequencies of Solicited Injection Site Reactions and Fever for Adolescents and Adults, Days 0-14, Following a First Vaccination with Adacel or Td Vaccine in Study Td506
Adverse Reactions * Adolescents11-17 years Adults18-64 years
AdacelN = 1,170-1,175(%) Td N = 783-787 (%) AdacelN = 1,688-1,698(%) Td N = 551-561(%)
*
The study sample size was designed to detect >10% differences between Adacel and Td vaccines for events of ‘Any’ intensity.
N = number of participants with available data.
Tetanus and Diphtheria Toxoids Adsorbed manufactured by Sanofi Pasteur Inc., Swiftwater, PA.
§
Adacel 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 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.
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.
Injection Site Pain Any 77.8§ 71.0 65.7 62.9
Moderate 18.0 15.6 15.1 10.2
Severe # 1.5 0.6 1.1 0.9
Injection Site Swelling Any 20.9 18.3 21.0 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 8.0 8.4
Severe #
≥3.5 cm 6.0 5.3 6.2 4.8
≥5 cm (2 inches) 2.7 2.9 4.0 3.0
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 0.2

The frequency of other solicited adverse reactions (days 0-14) are presented in Table 2. The rates of these reactions following a first vaccination with Adacel were comparable with those observed with Td vaccine. Headache was the most frequent systemic reaction and was usually of mild to moderate intensity.

Table 2: Frequencies of Other Solicited Adverse Reactions for Adolescents and Adults, Days 0-14, Following a First Vaccination with Adacel or Td Vaccine in Study Td506
Adverse Reaction Adolescents 11-17 years Adults 18-64 years
AdacelN * = 1,174-1,175 (%) Td N * = 787 (%) AdacelN * = 1,697-1,698 (%) Td N * = 560-561 (%)
*
N = number of participants with available data.
Tetanus and Diphtheria Toxoids Adsorbed manufactured by Sanofi Pasteur Inc., Swiftwater, PA.
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.
Headache Any 43.7 40.4 33.9 34.1
Moderate 14.2 11.1 11.4 10.5
Severe § 2.0 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 1.0 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 7.0
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 0.6 0.8 0.5
Lymph Node Swelling Any 6.6 5.3 6.5 4.1
Moderate 1.0 0.5 1.2 0.5
Severe § 0.1 0.0 0.1 0.0
Diarrhea Any 10.3 10.2 10.3 11.3
Moderate 1.9 2.0 2.2 2.7
Severe § 0.3 0.0 0.5 0.5
Vomiting Any 4.6 2.8 3.0 1.8
Moderate 1.2 1.1 1.0 0.9
Severe § 0.5 0.3 0.5 0.2
Rash Any 2.7 2.0 2.0 2.3

Injection site and systemic solicited reactions occurred at similar rates in Adacel and Td vaccine recipients in the 3 day post-vaccination period. Most injection site reactions occurred within the first 3 days after vaccination (with a mean duration of less than 3 days). The rates of unsolicited adverse events reported from days 14-28 post-vaccination were comparable between the two vaccine groups, as were the rates of unsolicited adverse events from day 28 through 6 months. There were no spontaneous reports of extensive limb swelling of the injected limb in study Td506, nor in the other three studies which also contributed to the safety database for Adacel.

Adult Study of a Second Vaccination with Adacel (Td537)

In a randomized, observer-blind, active-controlled, multi-center study (Td537), adults 18 through 64 years of age who had received a first dose of Adacel 8-12 years previously were enrolled and randomized to receive either Adacel (N = 1002) or a US licensed Td vaccine, TENIVAC (Tetanus and Diphtheria Toxoids Adsorbed; manufactured by Sanofi Pasteur, Limited) (N = 328). Subjects were recruited from the primary licensure study Td506 and the Canadian general public and had not received Td or Tdap vaccine since their initial Adacel dose. The demographic characteristics for study participants were similar for both vaccine groups. The mean ages were 28.9 years for the Adacel group and 29.2 years for the Td group. Overall, there were more female participants in both the Adacel group and Td group; 64.5% and 64.6%, respectively. In both vaccine groups, greater than 94% of subjects identified as white and 99% as non-Hispanic or Latino.

Safety data were collected from all participants who received the study vaccine (N = 999 for the Adacel group; N = 328 for the Td group). Solicited local and systemic reactions and unsolicited adverse events were monitored for 7 days post-vaccination using a diary card. Unsolicited adverse events were collected for approximately 28 days post-vaccination. Serious adverse events were collected throughout the study period (up to 6 months post-vaccination).

Solicited adverse reactions reported to occur during days 0-7 following vaccination are presented in Table 3.

Table 3: Frequencies of Solicited Adverse Reactions 0-7 Days Following a Second Vaccination with Adacel Compared to Td Vaccine in Study Td537 — Safety Analysis Set
Adverse Reaction Adacel(N=999)(%) Td Adsorbed *(N=328)(%)
N = number of participants with available data
*
Tetanus and Diphtheria Toxoids Adsorbed manufactured by Sanofi Pasteur Limited, Toronto, Ontario, Canada.
Some interference with activity
Significant; prevents daily activity
Injection site pain Any 87.1 87.4
Grade 2 28.5 31.4
Grade 3 3.6 2.8
Injection site erythema Any 6.4 5.5
Grade 2 (≥51 to ≤100 mm) 2.1 2.8
Grade 3 (˃100 mm) 0.2 0.0
Injection site swelling Any 6.9 8.0
Grade 2 (≥51 to ≤100 mm) 2.4 2.2
Grade 3 (˃100 mm) 0.3 0.0
Fever Any 0.9 1.8
Grade 2 (≥38.5°C to ≤38.9°C or ≥101.2°F to ≤102.0°F 0.3 0.6
Grade 3 (≥102.1°F) 0.2 0.3
Headache Any 41.4 39.1
Grade 2 12.4 10.5
Grade 3 2.6 4.0
Malaise Any 33.3 30.8
Grade 2 9.3 9.8
Grade 3 3.0 3.7
Myalgia Any 58.1 58.2
Grade 2 18.7 16.9
Grade 3 3.0 3.1

Adult Study of a Second Vaccination with Adacel (Td518)

Study Td518 was a descriptive, open-label, post-marketing, multi-center study evaluating the safety of Adacel readministration in adults 5 years following a previous dose of Adacel. The mean age of subjects was 31.7 years, there were more females (52.2%) than males (47.8%) and 89.9% of subjects were Caucasian. Solicited adverse reactions were collected for 14 days following vaccination. SAEs were monitored for 6 months following vaccination. A total of 545 subjects 16-69 years of age were enrolled. All participants in this study received a first dose of Adacel vaccine as part of Sanofi Pasteur studies Td501, Td502, or Td505. Approximately 90% of the participants had at least one solicited injection site reaction. The most frequently reported injection site reactions were pain in 87.6% of subjects, followed by erythema/redness in 28.6%, and swelling in 25.6%. Approximately 77% of the participants had at least one solicited systemic reaction. The most frequently reported solicited systemic adverse reactions in subjects who received a second dose of Adacel were myalgia (61%), followed by headache (53.2%), malaise (38.2%), and fever (6.5%).

Injection Site and Systemic Reactions Following Adacel Given Concomitantly with Hepatitis B Vaccine

In the concomitant vaccination study with Adacel (first vaccination) and Hepatitis B vaccine [Recombivax HB] (Td501) [See CLINICAL STUDIES (14)], injection site and systemic adverse events were monitored daily for 14 days post-vaccination using a diary card. Injection site adverse events were only monitored at site/arm of Adacel 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 6 months post-vaccination.

The rates reported for fever and injection site pain (at the Adacel administration site) were similar when Adacel and Hepatitis B vaccine 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 administration site were increased when coadministered. 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.

Injection Site and Systemic Reactions Following Adacel Given Concomitantly with Trivalent Inactivated Influenza Vaccine (TIV)

In the concomitant vaccination study with Adacel (first vaccination) and trivalent inactivated influenza vaccine [Fluzone] (Td502) [See CLINICAL STUDIES (14)], injection site 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.

The rates of fever and injection site erythema and swelling were similar for recipients of concurrent and separate administration of Adacel and TIV. However, pain at the Adacel 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 was similar between the 2 study groups.

Additional Studies

In an additional study (Td505), 1,806 adolescents 11 through 17 years of age received Adacel (first vaccination) as part of the lot consistency study used to support Adacel 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 when given as a booster dose to adolescents 11 through 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 participants. Headache was the most frequently reported systemic event occurring in approximately 44% of all participants. 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.

An additional 962 adolescents and adults received Adacel in three supportive Canadian studies (TC9704, Td9707 and TD9805) used as the basis for licensure in other countries. Within these clinical trials, the rates of local and systemic reactions following the first vaccination with Adacel were similar to those reported in the four principal trials in the U.S. 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 four principal trials conducted in the US. There was one spontaneous report of whole-arm swelling of the injected limb among the 277 Td vaccine recipients, and two spontaneous reports among the 962 Adacel recipients in the supportive Canadian studies.

An additional study (Td519) enrolled 1,302 individuals in an open label, two-arm, multicenter trial (651 participants in each group) to evaluate the safety and immunogenicity of a first vaccination with Adacel administered to persons 10 to <11 years of age compared to persons 11 to <12 years of age. Immediate reactions were monitored for 20 minutes post-vaccination. Solicited local and systemic adverse events were monitored for 7 days post-vaccination using a diary card. Unsolicited and serious adverse events were collected for approximately 30 days post-vaccination. Similar rates of immediate, solicited and unsolicited adverse reactions were reported in each of the two age cohorts. One serious adverse event, not related to vaccination, was reported in the younger age group.

Serious Adverse Events

Throughout the 6-month follow-up period following a first vaccination with Adacel in study Td506, SAEs were reported in 1.5% of Adacel recipients and in 1.4% of Td vaccine recipients. Two SAEs in adults were neuropathic events that occurred within 28 days of Adacel 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 following a first vaccination with Adacel in participants up to 64 years of age and no additional neuropathic events were reported.

In study Td537 when a second vaccination of Adacel was administered 8-12 years following the initial vaccination of Adacel, a total of 8 participants (0.8%) in the Adacel group and 1 participant (0.3%) in the Td group reported SAEs during the 6-month follow-up period. All SAEs were considered by the investigator to be unrelated to the study vaccine.

In study Td518, seven participants experienced an SAE, all of which were considered by the investigator to be unrelated to the study vaccine.

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