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The following adverse reactions are discussed in greater detail in other sections of the labeling:

  • Encephalitis, encephalomyelitis, encephalopathy, progressive vaccinia (vaccinia necrosum), generalized vaccinia, severe vaccinial skin infections, erythema multiforme major (including Stevens-Johnson syndrome) and eczema vaccinatum. Severe disability, permanent neurological sequelae, and/or death may occur. Death of unvaccinated individuals who have contact with vaccinated individuals. [See WARNINGS AND PRECAUTIONS].
  • Myocarditis and/or pericarditis, ischemic heart disease and non-ischemic, dilated cardiomyopathy [See WARNINGS AND PRECAUTIONS].
  • Ocular complications and blindness [See WARNINGS AND PRECAUTIONS].

Overall Adverse Reaction Profile

Information regarding the safety of ACAM2000 has been derived from three sources: 1) ACAM2000 clinical trial experience (Phase 1, 2 and 3 clinical trials), 2) data compiled during the era of routine smallpox vaccination using other NYCBH vaccinia vaccines and 3) adverse event data obtained during military and civilian smallpox vaccination programs (2002-2005) that used Dryvax®, a licensed live vaccinia virus smallpox vaccine.

  • General Disorders and Administrative Site Conditions: In the ACAM2000 clinical studies 97% and 92% of vaccinia-naïve and previously vaccinated subjects, respectively, experienced one or more adverse event. Common events included injection site reactions (erythema, pruritus, pain and swelling) and constitutional symptoms (fatigue, malaise, feeling hot, rigors and exercise tolerance decreased). Across all ACAM2000 studies 10% of vaccinia-naïve and 3% of previously vaccinated subjects experienced at least one severe adverse event (defined as interfering with normal daily activities).
  • Nervous System Disorder: Overall, 50% and 34% of vaccinia-naïve subjects and previously vaccinated subjects, respectively, reported headaches in ACAM2000 studies. There have been reports of headache following smallpox vaccination which required hospitalization. Although < 1% of the subjects in the ACAM2000 program experienced severe headaches, none required hospitalization.
    Neurological adverse events assessed among the 2002 - 2005 military (n=590,400) and DHHS (n=64,600) programs temporally associated with smallpox vaccination included headache (95 cases), non-serious limb paresthesias (17 cases) or pain (13 cases) and dizziness or vertigo (13 cases). Serious neurologic adverse events included 13 cases of suspected meningitis, 3 cases of suspected encephalitis or myelitis, 11 cases of Bell palsy, 9 seizures (including 1 death), and 3 cases of Guillain-Barre syndrome. Among these 39 events, 27 (69%) occurred in primary vaccinees and all but 2 occurred within 12 days of vaccination. There have also been cases of photophobia following smallpox vaccination, some of which required hospitalization.
  • Musculoskeletal and Connective Tissue Disorders: Across all ACAM2000 studies, severe, vaccine-related myalgia was seen in 1% of vaccinia-naïve subjects and < 1% of previously vaccinated subjects. Other adverse events included back pain, arthralgia and pain in extremity and none occurred with a frequency of more than 2% in either the vaccinia-naïve or previously vaccinated populations.
  • Blood and Lymphatic System Disorders: The only adverse event occurring at ≥ 5% in the ACAM2000 studies were lymph node pain and lymphadenopathy. The incidence of severe lymph node pain and lymphadenopathy was < 1%.
  • Gastrointestinal (GI) Disorders: Commonly reported GI disorders among ACAM2000-treated subjects included nausea and diarrhea (14%), constipation (6%), and vomiting (4%). Severe abdominal pain, nausea, vomiting, constipation diarrhea and toothache accounted for all the severe adverse events reported and occurred in < 1% of subjects.
  • Skin and Subcutaneous Tissue Disorders: Erythema and rash were noted in 18% and 8% of subjects respectively. In ACAM2000 subjects 1% of vaccinia-naïve and < 1% of previously vaccinated subjects experienced at least one severe adverse event. With the exception of one case of contact dermatitis and one case of urticaria, erythema and rash accounted for all severe events.

Generalized rashes (erythematous, papulovesicular, urticarial, folliculitis, nonspecific) are not uncommon following smallpox vaccination and are presumed to be hypersensitivity reactions occurring among persons without underlying illnesses. These rashes are generally self-limited and require little or no therapy, except among patients whose conditions appear to be toxic or who have serious underlying illnesses.

Inadvertent inoculation at other body sites is the most frequent complication of vaccinia vaccination, usually resulting from autoinoculation of the vaccine virus transferred from the site of vaccination. The most common sites involved are the face, nose, mouth, lips, genitalia and anus. Accidental infection of the eye (ocular vaccinia) may result in ocular complications including, but not limited to, keratitis, corneal scarring and blindness.

Major cutaneous reactions at the site of inoculation, characterized by large area of erythema and induration and streaking inflammation of draining lymphatics may resemble cellulitis. Benign and malignant lesions have been reported to occur at the smallpox vaccination site.

ACAM2000 Clinical Trial Experience

Two randomized, controlled, multi-center Phase 3 trials enrolled 2244 subjects that received ACAM2000 and 737 that received a comparison licensed live vaccinia virus vaccine, Dryvax®. Study 1 was conducted in male (66% and 63% for ACAM2000 and Dryvax®, respectively) and female (34% and 37% for ACAM2000 and Dryvax®, respectively) subjects who previously had not been vaccinated with smallpox vaccine (i.e., vaccinia-naïve subjects). The majority of subjects were Caucasian (76% and 71% for ACAM2000 and Dryvax®, respectively) and the mean age was 23 in both groups with an age range from 18-30 years. Study 2 was conducted in male (50% and 48% for ACAM2000 and Dryvax®, respectively) and female (50% and 52% for ACAM2000 and Dryvax®, respectively) subjects who had been vaccinated with smallpox vaccine > 10 years previously (i.e., previously vaccinated subjects). The majority of subjects were Caucasian (78% for both groups) and the mean age was 49 years in both groups with an age range of 31 to 84 years.

Common Adverse Events Reported In ACAM2000 Clinical Program

Adverse events reported by ≥ 5% of subjects in either the ACAM2000 or the comparison treatment group during Phase 3 studies are presented by type of adverse events, by baseline vaccination status (vaccinia-naïve versus previously vaccinated) and by treatment group. Severe vaccine-related adverse events, defined as interfering with normal daily activities, in vaccinia-naïve subjects were reported by 10% of subjects in the ACAM2000 group and 13% in the comparison group. In the previously vaccinated subjects, the incidence of severe vaccine-related adverse events was 4% for the ACAM2000 groups and 6% for the comparison group.

Table 3 : Adverse Events Reported by ≥ 5% of Subjects in ACAM2000 or Dryvax®

  Study 1 Vaccinia-Naive Subjects Study 2 Previously Vaccinated Subjects
ACAM2000
N=873
n (%)
Dryvax®
N=289
n (%)
ACAM2000
N=1371
n (%)
Dryvax®
N=448
n (%)
At least 1 adverse event 864 (99) 288 (100) 1325 (97) 443 (99)
Blood and lymphatic system disorders 515 (59) 204 (71) 302 (22) 133 (30)
Lymph node paina* 494 (57) 199 (69) 261 (19) 119 (27)
Lymphadenopathy 72 (8) 35 (12) 78 (6) 29 (6)
Gastrointestinal disorders 273 (31) 91 (31) 314 (23) 137 (31)
Nauseaa 170 (19) 65 (22) 142 (10) 63 (14)
Diarrheaa 144 (16) 34 (12) 158 (12) 77 (17)
Constipationa 49 (6) 9 (3) 88 (6) 31 (7)
Vomitinga 42 (5) 10 (3) 40 (3) 18 (4)
General disorders and administration site conditions 850 (97) 288 (100) 1280 (93) 434 (97)
Injection site pruritusa 804 (92) 277 (96) 1130 (82) 416 (93)
Injection site erythemaa 649 (74) 229 (79) 841(61) 324 (72)
Injection site paina 582 (67) 208 (72) 505 (37) 209 (47)
Fatiguea 423 (48) 161 (56) 468 (34) 184 (41)
Injection site swelling 422 (48) 165 (57) 384 (28) 188 (42)
Malaisea 327 (37) 122 (42) 381 (28) 147 (33)
Feeling hota 276 (32) 97 (34) 271 (20) 114 (25)
Rigorsa 185 (21) 66 (23) 171 (12) 76 (17)
Exercise tolerance decreaseda 98 (11) 35 (12) 105 (8) 50 (11)
Musculoskeletal and connective tissue disorders 418 (48) 153 (53) 418 (30) 160 (36)
Myalgiaa 404 (46) 147 (51) 374 (27) 148 (33)
Nervous system disorders 444 (51) 151 (52) 453 (33) 174 (39)
Headachea 433 (50) 150 (52) 437 (32) 166 (37)
Respiratory, thoracic, and mediastinal disorders 134 (15) 40 (14) 127 (9) 42 (9)
Dyspneaa 39 (4) 16 (6) 41 (3) 18 (4)
Skin and subcutaneous tissue disorders 288 (33) 103 (36) 425 (31) 139 (31)
Erythemaa 190 (22) 69 (24) 329 (24) 107 (24)
Rasha 94 (11) 30 (10) 80 (6) 29 (6)
a Event was listed on a checklist included in subject diaries; therefore should be considered solicited. In addition to events listed above the following were also included as part of the checklist: chest pain and heart palpitations, but these events did not occur in ≥ 5% of subjects.