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Adacel
(Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed)

DESCRIPTION

Adacel vaccine is a sterile isotonic suspension of tetanus and diphtheria toxoids and pertussis antigens adsorbed on aluminum phosphate, for intramuscular injection.

Each 0.5 mL dose contains 5 Lf tetanus toxoid (T), 2 Lf diphtheria toxoid (d), and acellular pertussis antigens [2.5 mcg detoxified pertussis toxin (PT), 5 mcg filamentous hemagglutinin (FHA), 3 mcg pertactin (PRN), 5 mcg fimbriae types 2 and 3 (FIM)].Other ingredients per 0.5 Ml dose include 1.5 mg aluminum phosphate (0.33 mg aluminum) as the adjuvant, ≤ 5 mcg residual formaldehyde, < 50 ng residual glutaraldehyde and 3.3 mg (0.6% v/v) 2-phenoxyethanol (not as a preservative). The antigens are the same as those in DAPTACEL vaccine; however, Adacel vaccine is formulated with reduced quantities of diphtheria and detoxified PT.

The acellular pertussis vaccine components are produced from Bordetella pertussis cultures grown in Stainer-Scholte medium² modified by the addition of casamino acids and dimethylbeta- cyclodextrin. PT, FHA and PRN are isolated separately from the supernatant culture medium. FIM are extracted and co-purified from the bacterial cells. The pertussis antigens are purified by sequential filtration, salt-precipitation, ultrafiltration and chromatography. PT is detoxified with glutaraldehyde, FHA is treated with formaldehyde, and the residual aldehydes are removed by ultrafiltration. The individual antigens are adsorbed onto aluminum phosphate. The tetanus toxin is produced from Clostridium tetani grown in modified Mueller-Miller casamino acid medium without beef heart infusion.3 Tetanus toxin is detoxified with formaldehyde and purified by ammonium sulfate fractionation and diafiltration. Corynebacterium diphtheriae is grown in modified Mueller's growth medium.4 After purification by ammonium sulfate fractionation, diphtheria toxin is detoxified with formaldehyde and diafiltered.

The adsorbed diphtheria, tetanus and acellular pertussis components are combined with aluminum phosphate (as adjuvant), 2-phenoxyethanol (not as a preservative) and water for injection. Adacel vaccine does not contain a preservative.

In the guinea pig potency test, the tetanus component induces at least 2 neutralizing units/mL of serum and the diphtheria component induces at least 0.5 neutralizing units/mL of serum. The potency of the acellular pertussis vaccine components is evaluated by the antibody response of immunized mice to detoxified PT, FHA, PRN and FIM as measured by enzyme-linked immunosorbent assay (ELISA).

Diphtheria and tetanus toxoids are individually adsorbed onto aluminum phosphate.

REFERENCES

2 Stainer DW, et al. A simple chemically defined medium for the production of phase I Bordetella pertussis. J Gen Microbiol 1970;63:211-20.

3 Mueller JH, et al. Variable factors influencing the production of tetanus toxin. J Bacteriol 1954;67(3):271-7.

4 Stainer DW. Production of diphtheria toxin. In: Manclark CR, editor. Proceedings of an informal consultation on the World Health Organization requirements for diphtheria, tetanus, pertussis and combined vaccines. United States Public Health Service, Bethesda, MD. DHHS 91-1174. 1991. p. 7-11.

INDICATIONS

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

DOSAGE AND ADMINISTRATION

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.

When withdrawing a dose from a stoppered vial, do not remove either the stopper or the metal seal holding it in place. Use a separate sterile needle and syringe for each injection. Using a sterile needle and syringe, withdraw the 0.5 mL dose of vaccine from the single-dose vial and administer the vaccine to the individual. Changing needles between withdrawing the vaccine from the vial and injecting it into a recipient is not necessary unless the needle has been damaged or contaminated.

Adacel vaccine should not be combined through reconstitution or mixed with any other vaccine.

Administration, Dose And Schedule

Adacel vaccine is administered as a single 0.5 mL intramuscular injection into the deltoid muscle of the upper arm.

Do not administer this product intravenously, subcutaneously or intradermally. There are no data to support repeat administration of Adacel vaccine.

Five years should have elapsed since the recipient's last dose of tetanus toxoid, diphtheria toxoid and/or pertussis containing vaccine and the administration of Adacel vaccine.

Additional Dosing Information

Primary series

The safety and effectiveness of Adacel vaccine used as a primary series or to complete the primary series, for diphtheria, tetanus, or pertussis has not been demonstrated.

Wound management

If tetanus prophylaxis is needed for wound management, Adacel may be given if no previous dose of any Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine, Adsorbed (Tdap) has been administered.

HOW SUPPLIED

Dosage Forms And Strengths

Adacel vaccine is a suspension for injection (0.5 mL dose) available in 0.5 mL single-dose vials and prefilled syringes. [See DOSAGE AND ADMINISTRATION and Storage And Handling]

Storage And Handling

Syringe, without needle, 1 dose - NDC No. 49281-400-88; in package of 5 syringes, NDC No. 49281-400-15. The tip caps of the prefilled syringes may contain natural rubber latex. No other components are made with natural rubber latex.

Vial, 1 dose - NDC No. 49281-400-58; in package of 5 vials; NDC No. 49281-400-05. The vial stopper is not made with natural rubber latex.

Vial, 1 dose - NDC No. 49281-400-58; in package of 10 vials; NDC No. 49281-400-10. The vial stopper is not made with natural rubber latex.

Adacel vaccine should be stored at 2° to 8°C (35° to 46°F). DO NOT FREEZE. Product which has been exposed to freezing should not be used. Do not use after expiration date shown on the label.

Manufactured by: Sanofi Pasteur Limited, Toronto Ontario Canada. Distributed by: Sanofi Pasteur Inc., Swiftwater PA 18370 USA

SIDE EFFECTS

The safety of Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) 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 dose of Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) vaccine.

The principal safety study was a randomized, observer-blind, active controlled trial that enrolled participants 11-17 years of age (Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) vaccine N = 1,184; Td vaccine N = 792) and 18-64 years of age (Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) vaccine N = 1,752; Td vaccine 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 14-28 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 the participant via telephone. 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 (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) 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, i.e., up to six months post-vaccination.

In the concomitant vaccination study with Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) vaccine and trivalent inactivated influenza vaccine (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, i.e., up to 84 days, only events that elicited seeking medical attention were collected.

In all the studies, participants were monitored for serious adverse events throughout the duration ofthe study.

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 (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) 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 (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) 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 (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) vaccine or Td vaccine are presented in Table 5. Most of these events were reported at a similar frequency in recipients of both Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) 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 63 to 78% of all vaccinees. In addition, overall rates of pain were higher in adolescent recipients of Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) vaccine compared to Td vaccine recipients. Rates of moderate and severe pain in adolescents did not significantly differ between the Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) vaccine and Td vaccine groups. Among adults the rates of pain, after receipt of Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) vaccine 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 (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) vaccine recipients than Td vaccine recipients. (9)

Table 5: Frequencies of Solicited Injection Site Reactions and Fever for Adolescents and Adults, Days 0-14, Following a Single Dose of Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) Vaccine or Td Vaccine

Adverse Event*		Adolescents 11-17 years		Adults 18-64years
		Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) N † = 1,170-1,175 (%)	Td‡ N †= 783-787 (%)	Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) N † =1,688-1,698 (%)	Td‡ N † = 551-561 (%)
Injectiton 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
	Any	20.9	18.3	21.0	17.3
Injection Site Swelling	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
*Sample size was designed to detect > 10% differences between Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) and Td vaccines for events of 'Any' intensity. † N = number of participants with available data. ‡Tetanus and Diphtheria Toxoids Adsorbed For Adult Use manufactured by Sanofi Pasteur Inc., Swiftwater, PA. §Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) 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 (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) 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 (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) 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 (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) vaccine were comparable with those observed with Td vaccine. Headache was the most frequent systemic reaction and was usually of mild to moderate intensity.

Table 6: Frequencies of Other Solicited Adverse Events for Adolescents and Adults, Days 0-14, Following a Single Dose of Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) Vaccine or Td Vaccine

Adverse Event		Adolescents 11-17 years		Adults 18-64 years
		Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) N* =1,174-1,175 (%)	Td † N* = 787 (%)	Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) N* =1,697-1,698 (%)	Td † N* = 560-561 (%)
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
*N = number of participants with available data. † Tetanus and Diphtheria Toxoids Adsorbed For Adult Use 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.

Local and systemic solicited reactions occurred at similar rates in Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) 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).

The rates of unsolicited adverse events reported from days 14-28 post-vaccination were comparable between the two groups, as were the rates of unsolicited adverse events from day 28 through 6 months.

There were no spontaneous reports of whole-arm swelling of the injected limb in this study, nor in the other three studies which contributed to the safety database for Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) vaccine.

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 (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) vaccine administration site) were similar when Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) 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 (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) 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. (9)

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 (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) vaccine and TIV. However, pain at the Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) 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. (9)

Additional Studies

An additional 1,806 adolescents received Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) vaccine as part of the lot consistency study used to support Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) 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 (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) 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 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. (9)

An additional 962 adolescents and adults received Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) 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 (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) 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 four principal trials conducted in the US. (9) 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 (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) vaccine recipients in the supportive Canadian studies.

Postmarketing Reports

The following adverse events have been spontaneously reported during the post-marketing use of Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) vaccine in the US and other countries. Because these events are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to vaccine exposure.

The following adverse events were included based on severity, frequency of reporting or the strength of causal association to Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) vaccine.

General disorders and administration site conditions:

Large injection site reactions ( > 50 mm), extensive limb swelling from the injection site beyond one or both joints.
Injection site bruising, sterile abscess

Nervous system disorders:

Paraesthesia, hypoesthesia, Guillain-Barré syndrome, facial palsy, convulsion, syncope, myelitis

Immune system disorders:

Anaphylactic reaction, hypersensitivity reaction (angioedema, edema, rash, hypotension)

Skin and subcutaneous tissue disorders:

Pruritus, urticaria

Musculoskeletal and connective tissue disorders:

Myositis, muscle spasm

Cardiac disorders:

Myocarditis

Additional Adverse Events

Additional adverse events, 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. (14) (See WARNINGS.)

Persistent nodules at the site of injection have been reported following the use ofadsorbed products. (12)

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 Guillain-Barré syndrome. Other neurological conditions that have been reported include: demyelinating diseases of the central nervous system, peripheral mononeuropathies, and cranial mononeuropathies. 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.

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 (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) vaccine package insert. (15) (16) (17)

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 www.vaers.hhs.gov. (15) (16) (17)

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

DRUG INTERACTIONS

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.

REFERENCES

9 Data on file at Sanofi Pasteur Limited.

12 CDC. Update: vaccine side effects, adverse reactions, contraindications and precautions. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 1996;45(RR-12):1-35.

14 Stratton KR, et al, editors. Adverse events associated with childhood vaccines; evidence bearing on causality. Washington: National Academy Press; 1994. p. 67-117.

15 CDC. Current trends - Vaccine Adverse Event Reporting System (VAERS) United States. MMWR 1990;39(41):730-3.

16 CDC. Current trends - national vaccine injury act: requirements for permanent vaccination records and for reporting of selected events after vaccination. MMWR 1988;37(13):197-200.

17 FDA. New reporting requirements for vaccine adverse events. FDA Drug Bull 1988;18(2):16-8.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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.

Latex

The tip caps of the Adacel prefilled syringe 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]

Guillain-Barre 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-Barre syndrome.1 If Guillain-Barre syndrome occurred within 6 weeks of receipt of prior vaccine containing tetanus toxoid, the risk for Guillain-Barre syndrome may be increased following a dose of Adacel vaccine.

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.

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.

Altered Immunocompetence

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

Syncope

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

REFERENCES

1 Stratton KR, et al, editors. Adverse events associated with childhood vaccines; evidence bearing on causality. Washington: National Academy Press; 1994. p. 67-117.

Use In Specific Populations

Pregnancy

Pregnancy Category C

Animal reproduction studies have not been conducted with Adacel vaccine. It is also not known whether Adacel vaccine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Adacel vaccine should be given to a pregnant woman only if clearly needed.

Animal fertility studies have not been conducted with Adacel vaccine. The effect of Adacel vaccine on embryo-fetal and pre-weaning development was evaluated in two developmental toxicity studies using pregnant rabbits. Animals were administered Adacel vaccine twice prior to gestation, during the period of organogenesis (gestation day 6) and later during pregnancy on gestation day 29, 0.5 mL/rabbit/occasion (a 17-fold increase compared to the human dose of Adacel vaccine on a body weight basis), by intramuscular injection. No adverse effects on pregnancy, parturition, lactation, embryo-fetal or pre-weaning development were observed. There were no vaccine related fetal malformations or other evidence of teratogenesis noted in this study.

Registry of Receipt of Adacel Vaccine During Pregnancy

Sanofi Pasteur Inc. maintains a surveillance registry to collect data on pregnancy outcomes and newborn health status outcomes following vaccination with Adacel vaccine during pregnancy. Women who receive Adacel vaccine during pregnancy are encouraged to contact directly or have their health-care professional contact Sanofi Pasteur Inc. at 1-800-822-2463 (1-800-VACCINE).

Nursing Mothers

It is not known whether Adacel vaccine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Adacel vaccine is given to a nursing woman.

Pediatric Use

Adacel vaccine is not approved for individuals less than 10 years of age. Safety and effectiveness of Adacel vaccine in persons less than 10 years of age have not been established.

Geriatric Use

Adacel vaccine is not approved for use in individuals 65 years of age and older. In a clinical study, individuals 65 years of age and older received a single dose of Adacel vaccine. Based on pre-specified criteria, persons 65 years of age and older who received a dose of Adacel vaccine had lower geometric mean concentrations of antibodies to PT, PRN and FIM when compared to infants who had received a primary series of DAPTACEL® , Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed (DTaP).

OVERDOSE

No information provided.

CONTRAINDICATIONS

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 vaccine. [See DESCRIPTION] 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.

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 vaccine.

CLINICAL PHARMACOLOGY

Mechanism Of Action

Tetanus

Tetanus is a disease manifested primarily by neuromuscular dysfunction caused by a potent exotoxin released by C tetani.

Protection against disease is due to the development of neutralizing antibodies to tetanus toxin. A serum tetanus antitoxin level of at least 0.01 IU/mL, measured by neutralization assay is considered the minimum protective level.5,6

Diphtheria

Diphtheria is an acute toxin-mediated disease caused by toxigenic strains of C diphtheriae. Protection against disease is due to the development of neutralizing antibodies to diphtheria toxin. A serum diphtheria antitoxin level of 0.01 IU/mL is the lowest level giving some degree of protection. Antitoxin levels of at least 0.1 IU/mL are generally regarded as protective.5 Levels of 1.0 IU/mL have been associated with long-term protection.7

Pertussis

Pertussis (whooping cough) is a respiratory disease caused by B pertussis. This Gram-negative coccobacillus produces a variety of biologically active components, though their role in either the pathogenesis of, or immunity to, pertussis has not been clearly defined.

Non-Clinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

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

Clinical Studies

The efficacy of the tetanus toxoid and diphtheria toxoid used in Adacel vaccine was based on the immune response to these antigens compared to a US licensed Tetanus and Diphtheria Toxoids Adsorbed For Adult Use (Td) vaccine manufactured by Sanofi Pasteur Inc., Swiftwater, PA. The primary measures for immune response to the diphtheria and tetanus toxoids were the percentage of participants attaining an antibody level of at least 0.1 IU/mL.

The efficacy of the pertussis antigens used in Adacel vaccine was inferred based on a comparison of pertussis antibody levels achieved in recipients of a single booster dose of Adacel vaccine with those obtained in infants after three doses of DAPTACEL vaccine. In the Sweden I Efficacy Trial, three doses of DAPTACEL vaccine were shown to confer a protective efficacy of 84.9% (95% CI: 80.1%, 88.6%) against WHO defined pertussis (21 days of paroxysmal cough with laboratoryconfirmed B pertussis infection or epidemiological link to a confirmed case). The protective efficacy against mild pertussis (defined as at least one day of cough with laboratory-confirmed B pertussis infection) was 77.9% (95% CI: 72.6%, 82.2%).8

In addition, the ability of Adacel vaccine to elicit a booster response (defined as rise in antibody concentration after vaccination) to the tetanus, diphtheria and pertussis antigens following vaccination was evaluated. The demonstration of a booster response depended on the antibody concentration to each antigen as established based on the 95th percentile of the pre-vaccination antibody concentrations observed in historical clinical trials with Adacel vaccine.

Immunological Evaluation In Adolescents And Adults, 10 Through 64 Years Of Age

Study Td506 was a comparative, multi-center, randomized, observer-blind, controlled trial which enrolled 4,480 participants; 2,053 adolescents (11 through 17 years of age) and 2,427 adults (18 through 64 years of age). Enrollment was stratified by age to ensure adequate representation across the entire age range. Participants had not received a tetanus or diphtheria toxoid containing vaccine within the previous 5 years. After enrollment participants were randomized to receive one dose of either Adacel vaccine or Td vaccine. A total of 4,461 randomized participants were vaccinated. The per-protocol immunogenicity subset included 1,270 Adacel vaccine recipients and 1,026 Td vaccine recipients. Sera were obtained before and approximately 35 days after vaccination. [Blinding procedures for safety assessments are described in ADVERSE REACTIONS(6).]

Demographic characteristics were similar within age groups and between the vaccine groups. A total of 76% of the adolescents and 1.1% of the adults reported a history of receiving 5 previous doses of diphtheria-tetanus-pertussis containing vaccines. Anti-tetanus and anti-diphtheria seroprotection rates ( ≥ 0.1 IU/mL) and booster response rates were comparable between Adacel and Td vaccines. (See Table 3 and Table 4.) Adacel vaccine induced pertussis antibody levels that were non-inferior to those of Swedish infants who received three doses of DAPTACEL vaccine. (See Table 5.) Acceptable booster responses to each of the pertussis antigens were also demonstrated, ie, the percentage of participants with a booster response exceeded the pre-defined lower limit. (See Table 6.)

Table 3: Pre-vaccination and Post-vaccination Antibody Responses and Booster Response Rates to Tetanus Toxoid Following Adacel Vaccine as Compared to Td Vaccine in Adolescents and Adults 11 Through 64 Years of Age

Age Group (years)	Vaccine	N*	Tetanus Antitoxin (IU/mL)
			Pre-vaccination		1 Month Post-vaccination
			% ≥ 0.10 (95% CI)	% ≥ 1.0 (95% CI)	% ≥ 0.10 (95% CI)	% ≥ 1.0 (95% CI)	% Booster†(95% CI)
11-17	Adacel	527	99.6 (98.6, 100.0)	44.6 (40.3, 49.0)	100.0‡ (99.3, 100.0)	99.6§ (98.6, 100.0)	91.7‡(89.0, 93.9)
	Td**	516	99.2 (98.0, 99.8)	43.8 (39.5, 48.2)	100.0 (99.3, 100.0)	99.4 (98.3, 99.9)	91.3 (88.5, 93.6)
18-64	Adacel	742-743	97.3 (95.9, 98.3)	72.9 (69.6, 76.1)	100.0‡(99.5, 100.0)	97.8§ (96.5, 98.8)	63.1‡ (59.5, 66.6)
	Td**	509	95.9 (93.8, 97.4)	70.3 (66.2, 74.3)	99.8 (98.9, 100.0)	98.2 (96.7, 99.2)	66.8 (62.5, 70.9)
* N = number of participants in the per-protocol population with available data. † Booster response is defined as: A four-fold rise in antibody concentration, if the pre-vaccination concentration was equal to or below the cut-off value and a two-fold rise in antibody concentration if the pre-vaccination concentration was above the cut-off value. The cut-off value for tetanus was 2.7 IU/mL. ‡Seroprotection rates at ≥ 0.10 IU/mL and booster response rates to Adacel vaccine were non-inferior to Td vaccine (upper limit of the 95% CI on the difference for Td vaccine minus Adacel vaccine < 10%). § Seroprotection rates at ≥ 1.0 IU/mL were not prospectively defined as a primary endpoint. ** Tetanus and Diphtheria Toxoids Adsorbed for Adult Use manufactured by Sanofi Pasteur Inc., Swiftwater, PA.

Table 4:Pre-vaccination and Post-vaccination Antibody Responses and Booster Response Rates to Diphtheria Toxoid Following Adacel Vaccine as Compared to Td Vaccine in Adolescents and Adults 11 Through 64 Years of Age

Age Group (years)	Vaccine	N*	Diphtheria Antitoxin (IU/mL)
			Pre-vaccination		1 Month Post-vaccination
			% ≥ 0.10 (95% CI)	% ≥ 1.0 (95% CI)	% ≥ 0.10 (95% CI)	% ≥ 1.0 (95% CI)	% Booster1†(95% CI)
11-17	Adacel	527	72.5 (68.5, 76.3)	15.7 (12.7, 19.1)	99.8‡ (98.9, 100.0)	98.7§ (97.3, 99.5)	95.1‡ (92.9, 96.8)
	Td**	515-516	70.7 (66.5, 74.6)	17.3 (14.1, 20.8)	99.8 (98.9, 100.0)	98.4 (97.0, 99.3)	95.0 (92.7, 96.7)
18-64	Adacel	739-741	62.6 (59.0, 66.1)	14.3 (11.9, 17.0)	94.1‡ (92.1, 95.7)	78.0§ (74.8, 80.9)	87.4‡ (84.8, 89.7)
	Td**	506-507	63.3 (59.0, 67.5)	16.0 (12.9, 19.5)	95.1 (92.8, 96.8)	79.9 (76.1, 83.3)	83.4 (79.9, 86.5)
* N = number of participants in the per-protocol population with available data. † Booster response is defined as: A four-fold rise in antibody concentration, if the pre-vaccination concentration was equal to or below the cut-off value and a two-fold rise in antibody concentration if the pre-vaccination concentration was above the cut-off value. The cut-off value for diphtheria was 2.56 IU/mL. ‡ Seroprotection rates at ≥ 0.10 IU/mL and booster response rates to Adacel vaccine were non-inferior to Td vaccine (upper limit of the 95% CI on the difference for Td vaccine minus Adacel vaccine < 10%). § Seroprotection rates at > 1.0 IU/mL were not prospectively defined as a primary endpoint. **Tetanus and Diphtheria Toxoids Adsorbed for Adult Use manufactured by Sanofi Pasteur Inc., Swiftwater, PA.

Table 5: Ratio of Pertussis Antibody Geometric Mean Concentrations (GMCs)Â¥ Observed One Month After a Dose of Adacel Vaccine in Adolescents and Adults 11 Through 64 Years of Age Compared With Those Observed in Infants One Month Following Vaccination at 2, 4 and 6 Months of Age in the Efficacy Trial With DAPTACEL Vaccine

	Adolescents 11-17 Years of Age	Adults 18-64 Years of Age
	Adacel*/DAPTACEL† GMC Ratio (95% CIs)	Adacel‡/DAPTACEL† GMC Ratio (95% CIs)
Anti-PT	3.6(2.8, 4.5)§	2.1(1.6, 2.7)§
Anti-FHA	5.4(4.5, 6.5)§	4.8(3.9, 5.9)§
Anti-PRN	3.2(2.5, 4.1)§	3.2(2.3, 4.4)§
Anti-FIM	5.3(3.9, 7.1)§	2.5(1.8, 3.5)§
Â¥ Antibody GMCs, measured in arbitrary ELISA units were calculated separately for infants, adolescents and adults. * N = 524 to 526, number of adolescents in the per-protocol population with available data for Adacel vaccine. † N = 80, number of infants who received DAPTACEL vaccine with available data post-dose 3 (Sweden Efficacy I). ‡ N = 741, number of adults in the per-protocol population with available data for Adacel vaccine. § GMC following Adacel vaccine was non-inferior to GMC following DAPTACEL vaccine (lower limit of 95% CI on the ratio of GMC for Adacel vaccine divided by DAPTACEL vaccine > 0.67).

Table 6: Booster Response Rates to the Pertussis Antigens Observed One Month After a Dose of Adacel Vaccine in Adolescents and Adults 11 Through 64 Years of Age

	Adolescents 11-17 Years of Age		Adults 18-64 Years of Age		Pre-defined Acceptable Rates * %†
	N‡	% (95% CI)	N‡	% (95% CI)
Anti-PT	524	92.0 (89.3, 94.2)	739	84.4 (81.6, 87.0)	81.2
Anti-FHA	526	85.6 (82.3, 88.4)	739	82.7 (79.8, 85.3)	77.6
Anti-PRN	525	94.5 (92.2, 96.3)	739	93.8 (91.8, 95.4)	86.4
Anti-FIM	526	94.9 (92.6, 96.6)	739	85.9 (83.2, 88.4)	82.4
* The acceptable response rate for each antigen was defined as the lower limit of the 95% CI for the rate being no more than 10% lower than the response rate observed in previous clinical trials. † A booster response for each antigen was defined as a four-fold rise in antibody concentration if the pre-vaccination concentration was equal to or below the cut-off value and a two-fold rise in antibody concentration if the pre-vaccination concentration was above the cut-off value. The cut-off values for pertussis antigens were established based on antibody data from both adolescents and adults in previous clinical trials. The cut-off values were 85 EU/mL for PT, 170 EU/mL for FHA, 115 EU/mL for PRN and 285 EU/mL for FIM. ‡ N = number of participants in the per-protocol population with available data.

Study Td519 assessed the comparative immunogenicity of Adacel administered to adolescents (10 to < 11 years of age and 11 to < 12 years of age) [see ADVERSE REACTIONS] In this study non-inferiority was demonstrated for booster responses to tetanus and diphtheria toxoids, GMCs to the pertussis antigens (PT, FHA, PRN and FIM) and booster responses to the pertussis antigens PT, FHA and PRN. For FIM, non-inferiority was not demonstrated as the lower bound of the 95% CI of the difference in booster response rates (-5.96%) did not meet the predefined criterion ( > - 5% when the booster response in the older age group was > 95%).

Concomitant Hepatitis B Vaccine Administration

The concomitant use of Adacel vaccine and hepatitis B (Hep B) vaccine (Recombivax HB® , 10 mcg per dose using a two-dose regimen, manufactured by Merck and Co., Inc) was evaluated in a multi-center, open-labeled, randomized, controlled study that enrolled 410 adolescents, 11 through 14 years of age inclusive. One group received Adacel and Hep B vaccines concurrently (N = 206). The other group (N = 204) received Adacel vaccine at the first visit, then 4-6 weeks later received Hep B vaccine. The second dose of Hep B vaccine was given 4-6 weeks after the first dose. Serum samples were obtained prior to and 4-6 weeks after Adacel vaccine administration, as well as 4-6 weeks after the 2nd dose of Hep B for all participants. No interference was observed in the immune responses to any of the vaccine antigens when Adacel and Hep B vaccines were given concurrently or separately. [See ADVERSE REACTIONS.]

Concomitant Influenza Vaccine Administration

The concomitant use of Adacel vaccine and trivalent inactivated influenza vaccine (TIV, Fluzone® , manufactured by Sanofi Pasteur Inc., Swiftwater, PA) was evaluated in a multi-center, open-labeled, randomized, controlled study conducted in 720 adults, 19-64 years of age inclusive. In one group, participants received Adacel and TIV vaccines concurrently (N = 359). The other group received TIV at the first visit, then 4-6 weeks later received Adacel vaccine (N = 361). Sera were obtained prior to and 4-6 weeks after Adacel vaccine, as well as 4-6 weeks after the TIV. The immune responses were comparable for concurrent and separate administration of Adacel and TIV vaccines for diphtheria (percent of participants with seroprotective concentration ≥ 0.10 IU/mL and booster responses), tetanus (percent of participants with seroprotective concentration ≥ 0.10 IU/mL), pertussis antigens (booster responses and GMCs except lower PRN GMC in the concomitant group, lower bound of the 90% CI was 0.61 and the pre-specified criterion was ≥ 0.67) and influenza antigens (percent of participants with hemagglutination-inhibition [HI] antibody titer ≥ 1:40 IU/mL and ≥ 4-fold rise in HI titer). Although tetanus booster response rates were significantly lower in the group receiving the vaccines concurrently versus separately, greater than 98% of participants in both groups achieved seroprotective levels of > 0.1 IU/mL. [See ADVERSE REACTIONS ]

REFERENCES

5 FDA. Department of Health and Human Services (DHHS). Biological products bacterial vaccines and toxoids; implementation of efficacy review; proposed rule. Fed Reg 1985;50(240):51002-117.

6 Wassilak SGF, et al. Tetanus toxoid. In: Plotkin SA, Orenstein WA, Offit PA, editors. Vaccines. 5th ed. Philadelphia, PA: WB Saunders Company; 2008. p. 805-39.

7 Vitek CR and Wharton M. Diphtheria toxoid. In: Plotkin SA, Orenstein WA, Offit PA, editors. Vaccines. 5th ed. Philadelphia, PA: W.B. Saunders Company; 2008. p. 139-56.

8 Gustafsson L, et al. A controlled trial of a two-component acellular, a five-component acellular and a whole-cell pertussis vaccine. N Engl J Med 1996;334(6):349-55.

PATIENT INFORMATION

Before administration of Adacel vaccine, health-care providers should inform the patient,-parent or guardian of the benefits and risks of the vaccine and the importance of receiving recommended booster dose unless a contraindication to further immunization exists.

The health-care provider should inform the patient, parent or guardian about the potential for adverse reactions that have been temporally associated with Adacel vaccine or other vaccines containing similar components. The health-care provider should provide the Vaccine Information Statements (VISs) that are required by the National Childhood Vaccine Injury Act of 1986 to be given with each immunization. The patient, parent or guardian should be instructed to report any serious adverse reactions to their health-care provider.

Pregnancy Exposure Registry [See Use In Specific Populations]