ACAM2000: Package Insert and Label Information

ACAM2000- vaccinia virus strain new york city board of health live antigen injection, powder, lyophilized, for solution
Emergent Product Development Gaithersburg Inc.

WARNING

Suspected cases of myocarditis and/or pericarditis have been observed in healthy adult primary vaccinees (at an approximate rate of 5.7 per 1000, 95% CI: 1.9-13.3) receiving ACAM2000 [see Warnings and Precautions (5.1)].
Encephalitis, encephalomyelitis, encephalopathy, progressive vaccinia, generalized vaccinia, severe vaccinial skin infections, erythema multiforme major (including STEVENS-JOHNSON SYNDROME), eczema vaccinatum resulting in permanent sequelae or death, ocular complications, blindness, and fetal death have occurred following either primary vaccination or revaccination with live vaccinia virus smallpox vaccines [see Warnings and Precautions (5)].
These risks are increased in vaccinees with the following conditions and may result in severe disability, permanent neurological sequelae and/or death:
o
Cardiac disease or a history of cardiac disease
o
Eye disease treated with topical steroids
o
Congenital or acquired immune deficiency disorders, including those taking immunosuppressive medications
o
Eczema and persons with a history of eczema or other acute or chronic exfoliative skin conditions
o
Infants less than 12 months of age
o
Pregnancy

ACAM2000 is a live vaccinia virus that can be transmitted to persons who have close contact with the vaccinee and the risks in contacts are the same as those for the vaccinee.

The risk for experiencing serious vaccination complications must be weighed against the risks for experiencing a potentially fatal smallpox infection.

1 INDICATIONS AND USAGE

ACAM2000® is indicated for active immunization against smallpox disease for persons determined to be at high risk for smallpox infection.

2 DOSAGE AND ADMINISTRATION

Administer ACAM2000 only after being trained on the safe and effective administration of the vaccine by the percutaneous route (scarification). ACAM2000 should not be injected by the intradermal, subcutaneous, intramuscular, or intravenous route. Provide each patient with the FDA-approved Medication Guide prior to administering the vaccine.

2.1 Instructions for Vaccine Preparation

2.1.1 Reconstitution

ACAM2000 is reconstituted by addition of 0.3 mL of diluent to the vial containing lyophilized vaccine. Note: this 0.3 mL of diluent is not the entire content of the diluent vial. ACAM2000 should only be reconstituted with 0.3 mL of the diluent provided. The vaccine vial should be removed from cold storage and brought to room temperature before reconstitution. The flip cap seals of the vaccine and diluent vials are removed, and each rubber stopper is wiped with an isopropyl alcohol swab and allowed to dry thoroughly. Using aseptic technique and a sterile 1 mL syringe fitted with a 25 gauge x 5/8” needle (provided), draw up 0.3 mL of diluent and transfer the entire content of the syringe to the vaccine vial. Gently swirl to mix but try not to get product on the rubber stopper. The reconstituted vaccine should be a clear to slightly hazy, colorless to straw-colored liquid free from extraneous matter. Reconstituted vaccine should be inspected visually for particulate matter and discoloration prior to administration. If particulate matter or discoloration is observed, the vaccine should not be used and the vial should be disposed safely. [See Preparation / Handling Precautions and Instructions for Disposal (2.2).]

2.1.2 Storage following Reconstitution

After reconstitution, ACAM2000 vaccine may be administered within 6 to 8 hours if kept at room temperature (20-25°C, 68-77°F). Unused, reconstituted ACAM2000 vaccine may be stored in a refrigerator (2-8°C, 36-46°F) up to 30 days, after which it should be discarded as a biohazardous material. [See Preparation / Handling Precautions and Instructions for Disposal (2.2)] Exposure of reconstituted vaccine to room temperature during vaccination sessions should be minimized by placing it in refrigerator or on ice between patient administrations.

2.2 Preparation / Handling Precautions and Instructions for Disposal

Personnel preparing and administering the vaccine should wear surgical or protective gloves and avoid contact of vaccine with skin, eyes or mucous membranes.

The vaccine vial, its stopper, the diluent syringe, the vented needle used for reconstitution, the bifurcated needle used for administration, and any gauze or cotton that came in contact with the vaccine should be discarded in leak-proof, puncture-proof biohazard containers. These containers should then be disposed of appropriately.

2.3 Vaccination Instructions

The reconstituted vaccine should be brought to room temperature prior to administration. Before administration, the vial contents should be visually examined to verify the absence of particulates and gently swirled, without allowing the product to contact the rubber stopper, if necessary to re-dissolve any precipitates that might have formed.

The site of vaccination is the upper arm over the insertion of the deltoid muscle.

No skin preparation should be performed unless the skin at the intended site of vaccination is obviously dirty, in which case an alcohol swab(s) may be used to clean the area. If alcohol is used, the skin must be allowed to dry thoroughly to prevent inactivation of the live vaccine virus by the alcohol.

Remove the vaccine vial cap. Remove bifurcated needle from individual wrapping. Submerge bifurcated end of needle in reconstituted vaccine solution. The needle will pick up a droplet of vaccine (0.0025 mL) within the fork of the bifurcation. Use aseptic technique, i.e., do not insert the upper part of the needle that has been in contact with fingers into the vaccine vial, and never re‑dip the needle into the vaccine vial if the needle has touched skin.

Deposit the droplet of vaccine onto clean, dry skin of the arm prepared for vaccination. The needle is held between thumb and first finger perpendicular to the skin. The wrist of the hand holding the needle of the vaccinator rests against the patient’s arm. Rapidly make 15 jabs of the needle perpendicular to the skin through the vaccine droplet to puncture the skin, within a diameter of about 5 mm. The jabs should be vigorous enough so that a drop of blood appears at the vaccination site.

Any excess droplets of vaccine and blood should be wiped off the skin using a dry gauze pad and discarded in a biohazard container. Discard the needle in a biohazard sharps container. Close the vaccine vial by reinserting the rubber cap and return to a refrigerator or place on ice unless it will be used immediately to vaccinate another subject. [See Storage Following Reconstitution (2.1.2).]

Cover the vaccination site loosely with a gauze bandage, using first aid adhesive tape to keep it in place. This bandage provides a barrier to protect against spread of the vaccinia virus. If the vaccinee is involved in direct patient care, the gauze should be covered with a semipermeable (semiocclusive) dressing as an additional barrier. A semipermeable dressing is one that allows for the passage of air but does not allow for the passage of fluids.

Wash hands with soap and warm water or with alcohol-based hand rubs such as gels or foams after direct contact with the vaccination site, the bandage or clothes, towels or sheets that might be contaminated with virus from the vaccination site. This is vital in order to remove any virus from your hands and prevent contact spread.

Put the contaminated bandages in a sealed plastic bag and throw them away in the trash.

Wash separately clothing, towels, bedding or other items that may have come in direct contact with the vaccination site or drainage from the site, using hot water with detergent and/or bleach. Wash hands afterwards.

Don’t use a bandage that blocks air from the vaccination site. This may cause the skin at the vaccination site to soften and wear away. Use loose gauze secured with medical tape to cover the site.

Don’t put salves or ointments on the vaccination site.

2.4 Instructions for Interpreting Vaccination Response
2.4.1 Primary Vaccinees

In an individual vaccinated for the first time (primary vaccination), the expected response to vaccination is the development of a major cutaneous reaction (characterized by a pustule) at the site of inoculation. The lesion evolves gradually, with appearance of a papule at the site of vaccination after 2-5 days. The papule becomes vesicular, then pustular, and reaches its maximum size at 8-10 days after vaccination. The pustule dries and forms a scab, which usually separates within 14-21 days, leaving a pitted scar. (See Figure 1) Formation of a major cutaneous reaction by day 6-8 is evidence of a successful ‘take’ and acquisition of protective immunity. An equivocal reaction is any reaction that is not a major reaction, and indicates a non-take (vaccination failure) due to impotent vaccine or inadequate vaccination technique.

2.4.2 Previously Vaccinated Individuals (Revaccination)

Successful vaccination in an individual previously exposed to vaccine is confirmed when a major cutaneous reaction [See Primary Vaccinees (2.4.1) and Figure 1] is observed 6 to 8 days post-vaccination. However any prior vaccination may modify (reduce) the cutaneous response upon revaccination (Figure 2) such that the absence of a cutaneous response does not necessarily indicate vaccination failure. Previously vaccinated individuals who do not have a cutaneous response on revaccination do not require revaccination to try to elicit a cutaneous response.

2.4.3 Vaccination Failures

Individuals who are not successfully vaccinated (i.e., vaccination failures) after primary vaccination may be revaccinated again in an attempt to achieve a satisfactory take. The vaccination procedures should be checked, and vaccination repeated with vaccine from another vial or vaccine lot, employing the same technique described in 2.3 [see Vaccination Instructions (2.3)].

If a repeat vaccination is conducted using vaccine from another vial or vaccine lot fails to produce a major reaction, healthcare providers should consult the Centers for Disease Control and Prevention (CDC) Emergency Operations Center (EOC) at 770-488-7100 and their state or local health department before giving another vaccination.

Figure 1: Progression of major cutaneous reaction after primary vaccination1

Day 5 Day 8
Images of the expected cutaneous reaction after primary vaccination showing progression from a vesicle (Day 5) to a pustule (Days 8-10) to a scab (Day 14).
(click image for full-size original)
Day 10 Day 14

Figure 2: Progression of major cutaneous reaction after revaccination1

Day 3 Day 7
Images of the expected cutaneous reaction from Day 3 to Day 14 after revaccination showing modified (reduced) reaction compared to primary vaccination.
(click image for full-size original)
Day 10 Day 14
2.5 Booster Schedule

Persons at continued high risk of exposure to smallpox (e.g., research laboratory workers handling variola virus) should receive repeat ACAM2000 vaccination every three years.

2.6 Smallpox Vaccination Recommendations from US Government Agencies

Additional information may be obtained from U.S. Department of Defense (http://www.esd.whs.mil/Portals/54/Documents/DD/issuances/dodd/620503p.pdf) and U.S. Centers for Disease Control and Prevention (CDC) about smallpox vaccination (https://www.cdc.gov/smallpox/clinicians/vaccination.html).

3 DOSAGE FORMS AND STRENGTHS

After reconstitution of the lyophilized preparation, each vial has approximately 100 doses of 0.0025 mL of vaccinia virus (live) containing 2.5-12.5×105 plaque forming units / dose.

4 CONTRAINDICATIONS

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 Immune Deficiency

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.

5 WARNINGS AND PRECAUTIONS

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.

5.1 Serious Complications and Death

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.

5.1.1 Incidence of Serious Complications in 1968 US Surveillance Studies

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(c) §

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(c)

(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.

5.1.2 Incidence of Serious Complications and Emergence of Myocarditis and/or Pericarditis in 2002-2005

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 2002-2005 5
Adverse event Na Incidence/ million Nb 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
5.1.3 Myocarditis and Pericarditis in the ACAM2000 Clinical Trial Experience

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.

5.2 Cardiac Disease

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.

5.3 Ocular Complications and Blindness

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.

5.4 Presence of Congenital or Acquired Immune Deficiency Disorders

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.

5.5 History or Presence of Eczema and Other Skin Conditions

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.

5.6 Infants (< 12 months of Age) and Children

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.

5.7 Pregnancy

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.

5.8 Allergy to ACAM2000 Smallpox Vaccine or its Components

ACAM2000 contains neomycin and polymyxin B. Persons allergic to these components may be at higher risk for adverse events after vaccination.

5.9 Management of Smallpox Vaccine Complications

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.

5.10 Prevention of Transmission of Live Vaccinia Virus

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).]

5.11 Blood and Organ Donation

Blood and organ donation should be avoided for at least 30 days following vaccination with ACAM2000.

5.12 Limitations of Vaccine Effectiveness

ACAM2000 smallpox vaccine may not protect all persons exposed to smallpox.

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