ADACEL SIDE EFFECTS

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, 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, 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 1. 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 1: 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

The frequency of other solicited adverse events (Days 0-14) are presented in Table 2. 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 2: 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

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).

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

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).