Source: FDA, National Drug Code (US) Revision Year: 2018
There are very few absolute contraindications to this vaccine for those who are at high risk for smallpox. The risk for experiencing serious vaccination complications must be weighed against the risks for experiencing a potentially fatal smallpox infection. See Warnings and Precautions (5) for persons who are at higher risk of experiencing serious vaccination complications.
Severe localized or systemic infection with vaccinia (progressive vaccinia) may occur in persons with weakened immune systems. Individuals with severe immunodeficiency who are not expected to benefit from the vaccine should not receive ACAM2000. These individuals may include individuals who are undergoing bone marrow transplantation or individuals with primary or acquired immunodeficiency who require isolation.
Persons at greatest risk of experiencing serious vaccination complications are often those at greatest risk for death from smallpox. The risk for experiencing serious vaccination complications must be weighed against the risks for experiencing a potentially fatal smallpox infection.
Serious complications that may follow either primary live vaccinia smallpox vaccination or revaccination include: myocarditis and/or pericarditis, encephalitis, encephalomyelitis, encephalopathy, progressive vaccinia (vaccinia necrosum), generalized vaccinia, severe vaccinial skin infections, erythema multiforme major (including Stevens-Johnson syndrome), eczema vaccinatum, blindness, and fetal death in pregnant women. These complications may rarely lead to severe disability, permanent neurological sequelea and death. Based on clinical trials, symptoms of suspected myocarditis or pericarditis (such as chest pain, raised troponin/cardiac enzymes, or ECG abnormalities) occur in 5.7 per 1000 primary vaccinations. This finding includes cases of acute symptomatic or asymptomatic myocarditis or pericarditits or both. Historically, death following vaccination with live vaccinia virus is a rare event; approximately 1 death per million primary vaccinations and 1 death per 4 million revaccinations have occurred after vaccination with live vaccinia virus. Death is most often the result of sudden cardiac death, postvaccinial encephalitis, progressive vaccinia, or eczema vaccinatum. Death has also been reported in unvaccinated contacts accidentally infected by individuals who have been vaccinated.
Estimates of the risks of occurrence of serious complications after primary vaccination and revaccination, based on safety surveillance studies conducted when live vaccinia virus smallpox vaccine (i.e., New York City Board of Health strain, Dryvax) was routinely recommended, are as follows:
Table 1A. Rates of reported complications(a) associated with primary vaccinia vaccinations (cases/million vaccinations)(b):
| Age (yrs) | <1 | 1-4 | 5-19 | ≥20 | Overall rates (h) |
|---|---|---|---|---|---|
| Inadvertent inoculation©§ | 507.0 | 577.3 | 371.2 | 606.1 | 529.2 |
| Generalized vaccinia | 394.4 | 233.4 | 139.7 | 212.1 | 241.5 |
| Eczema vaccinatum | 14.1 | 44.2 | 34.9 | 30.3 | 38.5 |
| Progressive vaccinia(d) | -- (g) | 3.2 | -- (g) | -- (g) | 1.5 |
| Post-vaccinial encephalitis | 42.3 | 9.5 | 8.7 | -- (g) | 12.3 |
| Death(e) | 5 | 0.5 | 0.5 | unknown | -- |
| Total(f) | 1549.3 | 1261.8 | 855.9 | 1515.2 | 1253.8 |
a See article for descriptions of complications.
b Adapted from Lane JM, Ruber FL, Neff JM, Millar JD. Complications of smallpox vaccination, 1968: results of ten statewide surveys. J Infect Dis. 1970; 122:303-309.
c Referenced as accidental implantation.
d Referenced as vaccinia necrosum.
e Death from all complications.
f Rates of overall complications by age group include complications not provided in this table, including severe local reactions, bacterial superinfection of the vaccination site, and erythema multiforme.
g No instances of this complication were identified during the 1968 10 state survey.
h Overall rates for each complication include persons of unknown age.
Table 1B. Rates of reported serious complications(a) associated with vaccinia revaccinations (cases/million vaccinations)(b):
| Age (yrs) | <1 | 1-4 | 5-19 | ≥20 | Overall rates(b) |
|---|---|---|---|---|---|
| Inadvertent inoculation © | (g) | 109.1 | 47.7 | 25 | 42.1 |
| Generalized vaccinia | (g) | (g) | 9.9 | 9.1 | 9 |
| Eczema vaccinatum | (g) | (g) | 2 | 4.5 | 3 |
| Progressive vaccinia (d) | (g) | (g) | (g) | 6.8 | 3 |
| Post-vaccinial encephalitis | (g) | (g) | (g) | 4.5 | 2 |
| Death (e) | -- | -- | -- | -- | -- |
| Total (f) | (g) | 200 | 85.5 | 113.6 | 108.2 |
See Table 1A for explanation of footnotes.
Data on the incidence of adverse events among U.S. military personnel and civilian first responders vaccinated with Dryvax, a licensed live vaccinia virus smallpox vaccine, during vaccination programs initiated in December 2002 are shown below in Table 2. The incidence of preventable adverse events (eczema vaccinatum, contact transmission, and auto-inoculation) were notably lower in these programs when compared with data collected in the 1960s; presumably because of better vaccination screening procedures and routine use of protective bandages over the inoculation site. Myocarditis and pericarditis were not commonly reported following smallpox vaccination in the 1960s, but emerged as a more frequent event based on more active surveillance in the military and civilian programs.
Table 2. Serious adverse events in 2002-20055:
| Adverse event | N a | Incidence/ million | N b | Incidence/million |
|---|---|---|---|---|
| Myo/pericarditis | 86 | 117.71 | 21 | 519.52 |
| Post-vaccinal encephalitis | 1 | 1.37 | 1 | 24.74 |
| Eczema vaccinatum | 0 | 0.00 | 0 | 0.00 |
| Generalized vaccinia | 43 | 58.86 | 3 | 74.22 |
| Progressive vaccinia | 0 | 0.00 | 0 | 0.00 |
| Fetal vaccinia | 0 | 0.00 | 0 | 0.00 |
| Contact transmission | 52 | 71.18 | 0 | 0.00 |
| Auto-inoculation (non-ocular) | 62 | 84.86 | 20 | 494.78 |
| Ocular vaccinia | 16 | 21.90 | 3 | 74.22 |
a Department of Defense program (n=730,580) as of Jan05 where 71% primary vaccination; 89% male; median age 28.5 yr
b Department of Health and Human Services program (n=40,422) as of Jan04 where 36% primary vaccination; 36% male; median age 47.1 yr
In clinical trials involving 2983 subjects who received ACAM2000 and 868 subjects who received Dryvax, ten (10) cases of suspected myocarditis [0.2% (7 of 2983) ACAM2000 subjects and 0.3% (3 of 868) Dryvax subjects] were identified. The mean time to onset of suspected myocarditis and/or pericarditis from vaccination was 11 days, with a range of 9 to 20 days. All subjects who experienced these cardiac events were naïve to vaccinia. Of the 10 subjects, 2 were hospitalized. None of the remaining 8 cases required hospitalization or treatment with medication. Of the 10 cases, 8 were sub-clinical and were detected only by ECG abnormalities with or without associated elevations of cardiac troponin I. All cases resolved by 9 months, with the exception of one female subject in the Dryvax group, who had persistent borderline abnormal left ventricular ejection fraction on echocardiogram. The best estimate of risk for myocarditis and pericarditis is derived from the Phase 3 ACAM2000 clinical trials where there was active monitoring for potential of myocarditis and pericarditis. Among vaccinees naïve to vaccinia, 8 cases of suspected myocarditis and pericarditis were identified across both treatment groups, for a total incidence rate of 6.9 per 1000 vaccinees (8 of 1,162). The rate for the ACAM2000 treatment group were similar: 5.7 (95% CI: 1.9-13.3) per 1000 vaccinees (5 of 873 vaccinees) and for the Dryvax group 10.4 (95% CI: 2.1‑30.0) per 1000 vaccinees (3 of 289 vaccinees). No cases of myocarditis and/or pericarditis were identified in 1819 previously vaccinated subjects. The long-term outcome of myocarditis and pericarditis following ACAM2000 vaccination is currently unknown.
Ischemic cardiac events, including fatalities, have been reported following smallpox vaccination; the relationship of these events, if any, to vaccination has not been established. In addition, cases of non-ischemic, dilated cardiomyopathy have been reported following smallpox vaccination; the relationship of these cases to smallpox vaccination is unknown.
There may be increased risks of adverse events with ACAM2000 in persons with known cardiac disease, including those diagnosed with previous myocardial infarction, angina, congestive heart failure, cardiomyopathy, chest pain or shortness of breath with activity, stroke or transient ischemic attack, or other heart conditions. In addition, subjects who have been diagnosed with 3 or more of the following risk factors for ischemic coronary disease: 1) high blood pressure; 2) elevated blood cholesterol; 3) diabetes mellitus or high blood sugar; 4) first degree relative (for example mother, father, brother, or sister) who had a heart condition before the age of 50; or 5) smoke cigarettes may have increased risks.
Accidental infection of the eye (ocular vaccinia) may result in ocular complications including keratitis, corneal scarring and blindness. Patients who are using corticosteroid eye drops may be at increased risk of ocular complications with ACAM2000.
Severe localized or systemic infection with vaccinia (progressive vaccinia) may occur in persons with weakened immune systems, including patients with leukemia, lymphoma, organ transplantation, generalized malignancy, HIV/AIDS, cellular or humoral immune deficiency, radiation therapy, or treatment with antimetabolites, alkylating agents, high-dose corticosteroids (>10 mg prednisone/day or equivalent for ≥2 weeks), or other immunomodulatory drugs. The vaccine is contraindicated in individuals with severe immunodeficiency [see Contraindications (4)]. Vaccinees with close contacts who have these conditions may be at increased risk because live vaccinia virus can be shed and be transmitted to close contacts.
Persons with eczema of any description such as, atopic dermatitis, neurodermatitis, and other eczematous conditions, regardless of severity of the condition, or persons who have a history of these conditions at any time in the past, are at higher risk of developing eczema vaccinatum. Vaccinees with close contacts who have eczematous conditions, may be at increased risk because live vaccinia virus can shed and be transmitted to these close contacts. Vaccinees with other active acute, chronic or exfoliative skin disorders (including burns, impetigo, varicella zoster, acne vulgaris with open lesions, Darier’s disease, psoriasis, seborrheic dermatitis, erythroderma, pustular dermatitis, etc.), or vaccinees with household contacts having such skin disorders might also be at higher risk for eczema vaccinatum.
ACAM2000 has not been studied in infants or children. The risk of serious adverse events following vaccination with live vaccinia virus is higher in infants. Vaccinated persons who have close contact with infants, e.g., breastfeeding, must take precautions to avoid inadvertent transmission of ACAM2000 live vaccinia virus to infants.
ACAM2000 has not been studied in pregnant women. Live vaccinia virus vaccines can cause fetal vaccinia and fetal death. If ACAM2000 is administered during pregnancy, the vaccinee should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)]. Pregnant women who are close contacts of vaccinees may be at increased risk because live vaccinia virus can shed and be transmitted to close contacts.
ACAM2000 contains neomycin and polymyxin B. Persons allergic to these components may be at higher risk for adverse events after vaccination.
The CDC can assist physicians in the diagnosis and management of patients with suspected complications of vaccinia (smallpox) vaccination. Vaccinia Immune Globulin (VIG) is indicated for certain complications of vaccination live vaccinia virus smallpox vaccine. If VIG and/or other antivirals are needed or additional information is required, physicians should contact the CDC EOC at 770-488-7100.
The most important measure to prevent inadvertent auto-inoculation and contact transmission from vaccinia vaccination is thorough hand washing after changing the bandage or after any other contact with the vaccination site.
Individuals susceptible to adverse effects of vaccinia virus, i.e., those with cardiac disease, eye disease, immunodeficiency states, including HIV infection, eczema, pregnant women and infants, should be identified and measures should be taken to avoid contact between those individuals and persons with active vaccination lesions.
Recently vaccinated healthcare workers should avoid contact with patients, particularly those with immunodeficiencies, until the scab has separated from the skin at the vaccination site. However, if continued contact with patients is unavoidable, vaccinated healthcare workers should ensure the vaccination site is well covered and follow good hand-washing technique. In this setting, a more occlusive dressing may be used. Semipermeable polyurethane dressings are effective barriers to shedding of vaccinia. However, exudate may accumulate beneath the dressing, and care must be taken to prevent viral spread when the dressing is changed. In addition, accumulation of fluid beneath the dressing may increase skin maceration at the vaccination site. Accumulation of exudate may be decreased by first covering the vaccination with dry gauze, then applying the dressing over the gauze. The dressing should be changed every 1‑3 days. [See Self Inoculation and Spread to Close Contacts (17.3) and Care of the Vaccination Site and Potentially Contaminated Materials (17.4)].
Blood and organ donation should be avoided for at least 30 days following vaccination with ACAM2000.
ACAM2000 smallpox vaccine may not protect all persons exposed to smallpox.
The following adverse reactions are discussed in greater detail in other sections of the labeling:
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.
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.
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:
| ACAM2000 N=873(b) n (%) | Dryvax N=289(b) 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 pain(a)* | 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) |
| Nausea(a) | 170 (19) | 65 (22) | 142 (10) | 63 (14) |
| Diarrhea(a) | 144 (16) | 34 (12) | 158 (12) | 77 (17) |
| Constipation(a) | 49 (6) | 9 (3) | 88 (6) | 31 (7) |
| Vomiting(a) | 42 (5) | 10 (3) | 40 (3) | 18 (4) |
| General disorders and administration site conditions | 850 (97) | 288 (100) | 1280 (93) | 434 (97) |
| Injection site pruritus(a) | 804 (92) | 277 (96) | 1130 (82) | 416 (93) |
| Injection site erythema(a) | 649 (74) | 229 (79) | 841 (61) | 324 (72) |
| Injection site pain(a) | 582 (67) | 208 (72) | 505 (37) | 209 (47) |
| Fatigue(a) | 423 (48) | 161 (56) | 468 (34) | 184 (41) |
| Injection site swelling | 422 (48) | 165 (57) | 384 (28) | 188 (42) |
| Malaise(a) | 327 (37) | 122 (42) | 381 (28) | 147 (33) |
| Feeling hot(a) | 276 (32) | 97 (34) | 271 (20) | 114 (25) |
| Rigors(a) | 185 (21) | 66 (23) | 171 (12) | 76 (17) |
| Exercise tolerance decreased(a) | 98 (11) | 35 (12) | 105 (8) | 50 (11) |
| Musculoskeletal and connective tissue disorders | 418 (48) | 153 (53) | 418 (30) | 160 (36) |
| Myalgia(a) | 404 (46) | 147 (51) | 374 (27) | 148 (33) |
| Nervous system disorders | 444 (51) | 151 (52) | 453 (33) | 174 (39) |
| Headache(a) | 433 (50) | 150 (52) | 437 (32) | 166 (37) |
| Respiratory, thoracic, and mediastinal disorders | 134 (15) | 40 (14) | 127 (9) | 42 (9) |
| Dyspnea(a) | 39 (4) | 16 (6) | 41 (3) | 18 (4) |
| Skin and subcutaneous tissue disorders | 288 (33) | 103 (36) | 425 (31) | 139 (31) |
| Erythema(a) | 190 (22) | 69 (24) | 329 (24) | 107 (24) |
| Rash(a) | 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.
b Study 1 Vaccinia Naïve Subjects
c Study 2 Previously Vaccinated Subjects
There are no data evaluating the simultaneous administration of ACAM2000 with other vaccines.
ACAM2000 may induce false-positive tests for syphilis. Positive RPR tests results should be confirmed using a more specific test, such as the FTA assay.
ACAM2000 may induce temporary false-negative results for the tuberculin skin test (purified protein derivative [PPD]) and possibly, blood tests for tuberculosis. Tuberculin testing should be delayed if possible for 1 month following smallpox vaccination.
Pregnancy Category D.
ACAM2000 has not been studied in pregnant women. Live vaccinia virus vaccines can cause fetal harm when administered to a pregnant woman. Congenital infection, principally occurring during the first trimester, has been observed after vaccination with live vaccinia smallpox vaccines, although the risk may be low. Generalized vaccinia of the fetus, early delivery of a stillborn infant, or a high risk of perinatal death has been reported.
The only setting in which vaccination of pregnant women should be considered is when exposure to smallpox is considered likely. If this vaccine is used during pregnancy, or if the vaccinee lives in the same household with or has close contact with a pregnant woman, the vaccinee should be apprised of the potential hazard to the fetus. Healthcare providers, state health departments, and other public health staff should report to the National Smallpox Vaccine in Pregnancy Registry all pregnant women who, from 42 days prior to conception onward, received ACAM2000 or had close contact with a person who received ACAM2000 within the previous 28 days. Civilian women should contact their healthcare provider or state health department for help enrolling in the registry. All civilian and military cases should be reported to the DoD, telephone 619 553-9255, Defense Switched Network (DSN) 553-9255, fax 619 533-7601 or e-mail NHRC-BirthRegistry@med.navy.mil.
ACAM2000 has not been studied in lactating women. It is not known whether vaccine virus or antibodies are secreted in human milk. Live vaccinia virus can be inadvertently transmitted from a lactating mother to her infant. Infants are at high risk of developing serious complications from live vaccinia smallpox vaccination.
The safety and effectiveness of ACAM2000 have not been established in the age groups from birth to age 16. The use of ACAM2000 in all pediatric age groups is supported by evidence from the adequate and well-controlled studies of ACAM2000 in adults and with additional historical data with use of live vaccinia virus smallpox vaccine in pediatrics. Before the eradication of smallpox disease, live vaccinia virus smallpox vaccine was administered routinely in all pediatric age groups, including neonates and infants, and was effective in preventing smallpox disease. During that time, live vaccinia virus was occasionally associated with serious complications in children, the highest risk being in infants younger than 12 months of age [See Warnings and Precautions (5.6)].
Clinical studies of ACAM2000 did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. There are no published data to support the use of this vaccine in geriatric (persons >65 years) populations.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
