Version May 2024
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 to 13.3) receiving smallpox vaccine.
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.
These risks are increased in vaccinees with the following conditions and may result in severe disability, permanent neurological sequelae and/or death:
Cardiac disease or a history of cardiac disease
Eye disease treated with topical steroids
Congenital or acquired immune deficiency disorders, including those taking immunosuppressive medications
Eczema and persons with a history of eczema or other acute or chronic exfoliative skin conditions
Infants less than 12 months of age
Pregnancy
Smallpox vaccine 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.
Mpox (monkeypox) disease prevention (off-label use):
Percutaneous: Vaccination by scarification (multiple-puncture technique) only; not for IM, intradermal, IV, or SUBQ injection. Note: A trace of blood should appear at vaccination site after 15 to 20 seconds; if no trace of blood is visible, an additional 3 insertions should be made using the same needle, without reinserting the needle into the vaccine bottle.
Use a single drop of vaccine suspension and 15 needle punctures (using the same bifurcated needle) into the superficial skin; if the patient does not have a major cutaneous reaction after the first dose (by day 6 to 8), a second dose (revaccination) from another vial or vaccine lot may be administered. If there is not a reaction to the second dose, consult the CDC or the state or local health department for further guidance.
Note: For postexposure prophylaxis, administration within 4 days of monkeypox virus exposure is the most effective. If given 4 to 14 days after exposure, then the vaccine may reduce symptoms but not prevent disease (CDC 2022a).
Smallpox disease prevention:
Primary vaccination: Vaccination by scarification (multiple-puncture technique) only; not for IM, intradermal, IV, or SUBQ injection. Note: A trace of blood should appear at vaccination site after 15 to 20 seconds; if no trace of blood is visible, an additional 3 insertions should be made using the same needle, without reinserting the needle into the vaccine bottle.
Use a single drop of vaccine suspension and 15 needle punctures (using the same bifurcated needle) into the superficial skin; if the patient does not have a major cutaneous reaction after the first dose (by day 6 to 8), a second dose (revaccination) from another vial or vaccine lot may be administered. If there is not a reaction to the second dose, consult the CDC or the state or local health department for further guidance.
Booster dose: The Advisory Committee on Immunization Practices recommends routine nonemergency revaccination every 3 to 10 years, depending on type of exposure (ACIP [Petersen 2016]). Additional information can be obtained from the Department of Defense and the CDC.
Interchangeability: Smallpox and monkeypox vaccine (Jynneos or Imvamune [Canadian product]) may be used as a booster dose for those persons who received a primary series with the smallpox vaccine (ACAM2000) and who are at continued risk for exposure (CDC/ACIP [Rao 2022]; NACI 2022).
There are no dosage adjustments provided in the manufacturer’s labeling.
There are no dosage adjustments provided in the manufacturer’s labeling.
Refer to adult dosing.
(For additional information see "Smallpox vaccine (live, replication-competent) (United States: Availability limited to health department/Strategic National Stockpile distribution): Pediatric drug information")
Note: Dose is administered percutaneously requiring multiple skin punctures; not for IM, intradermal, IV, or SUBQ injection.
Mpox (monkeypox) disease prevention: Limited data available (CDC 2022a; CDC 2022b; manufacturer's labeling):
Note: Use available for this indication under an expanded access investigational new drug (EA-IND).
Postexposure prophylaxis: Note: Administration within 4 days of monkeypox virus exposure is the most effective. If administered 4 to 14 days after exposure, the vaccine may reduce symptoms but not prevent disease.
Children and Adolescents: ACAM2000: Percutaneous: Vaccination by scarification (multiple-puncture technique): Use a single drop of vaccine suspension (0.0025 mL) and rapidly administer 15 needle punctures using the same bifurcated needle into the superficial skin. A trace of blood should appear at vaccination site.
If the patient does not have a major cutaneous reaction after the first dose (by day 6 to 8), a second dose (revaccination) from another vial or vaccine lot may be administered. If there is not a reaction to the second dose, consult the CDC or the state or local health department for further guidance.
Smallpox disease prevention:
Note: Although only FDA approved in ages ≥16 years, the smallpox vaccine may be used in all ages for postevent exposure or risk of exposure regardless of age. For routine preexposure prophylaxis, smallpox vaccine is not recommended in individuals <18 years of age and is contraindicated in individuals <1 year of age (CDC [Petersen 2015]; CDC/ACIP [Wharton 2003]; manufacturer's labeling).
Primary immunization following exposure or event (CDC [Petersen 2015]; manufacturer's labeling):
Infants, Children, and Adolescents: Limited data available in ages <16 years: ACAM2000: Percutaneous: Vaccination by scarification (multiple-puncture technique): Use a single drop of vaccine suspension (0.0025 mL) and rapidly administer 15 needle punctures using the same bifurcated needle into the superficial skin. A trace of blood should appear at vaccination site.
If the patient does not have a major cutaneous reaction after the first dose (by day 6 to 8), a second dose (revaccination) from another vial or vaccine lot may be administered. If there is not a reaction to the second dose, consult the CDC or the state or local health department for further guidance.
There are no dosage adjustments provided in the manufacturer’s labeling.
There are no dosage adjustments provided in the manufacturer’s labeling.
Cardiovascular effects, including myocarditis and pericarditis potentially leading to cardiomyopathy (nonischemic/dilated), have been reported following smallpox vaccination (Ref). Ischemic heart disease has also been rarely reported following smallpox vaccination.
Mechanism: Unknown; potentially due to autoimmune, noninfectious processes (Ref).
Onset: Myocarditis/pericarditis: Intermediate; in clinical trials, mean time to symptom onset was 11 days (range: 9 to 20 days).
Risk factors:
• Known cardiac disease (ie, previous myocardial infarction, angina, heart failure, cardiomyopathy, chest pain or shortness of breath with activity, stroke or TIA, other heart conditions)
• Risk factors for ischemic coronary disease (ie, hypertension, hyperlipidemia, diabetes mellitus, first-degree relative diagnosed with heart condition before age 50, current smoker)
• History of myopericarditis of any etiology (Ref)
CNS effects, including post-vaccination encephalopathy and encephalitis have been reported following smallpox vaccination. Symptoms may include headache, fever, vomiting, seizures, and coma. Encephalopathy (cerebral damage due to vascular changes) is more frequently reported in patients <2 years of age, while encephalitis more commonly impacts patients ≥2 years of age (Ref). In clinical trials, Guillain-Barré syndrome and Bell palsy have also been rarely reported following smallpox vaccination (Ref).
Mechanism: Unknown; potentially due to autoimmune process (Ref).
Onset: Encephalopathy: Intermediate (6 to 10 days post-vaccination) (Ref). Encephalitis: Intermediate (11 to 15 days post-vaccination) (Ref).
Risk factors:
• Primary vaccination (as compared to revaccination) (Ref)
Ocular complications, including keratitis, corneal scarring, and blindness have been reported following smallpox vaccination secondary to accidental infection of the eye (ocular vaccinia). Most uncomplicated accidental inoculation lesions are self-limiting within ~3 weeks, although severe manifestations may require treatment with topical antivirals or vaccinia immune globulin (Ref).
Mechanism: Autoinoculation (Ref).
Onset: Varied; 7 days to 3 months post-vaccination (Ref).
Risk factors:
• Use of corticosteroid eye drops
• Vaccinee or close contact touching eye and/or immunization site (Ref)
• Contact lens use (Ref)
• History of pruritic eye disease (eg, allergic conjunctivitis, eyelid eczema) (Ref)
Dermatologic complications, including generalized vaccinia, eczema vaccinatum, erythema multiforme, and Stevens-Johnson syndrome, have been reported following smallpox vaccination. Symptoms may include localized or generalized maculopapular, vesicular, pustular, or erosive skin rash. Though most cases are self-limiting, severe cases may be life-threatening and require treatment with vaccinia immune globulin (Ref).
Onset: Intermediate; 4 to 19 days following vaccination (Ref)
Risk factors:
• Primary vaccination (as compared to revaccination) (Ref)
• Eczema vaccinatum: History of atopic dermatitis, neurodermatitis, eczema, or other active acute, chronic or exfoliative skin disorders (eg, burns, impetigo, varicella zoster, acne vulgaris with open lesions, Darier disease, psoriasis, seborrheic dermatitis, erythroderma, pustular dermatitis), or vaccinee with close contact having such skin disorders.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults.
>10%:
Dermatologic: Erythema of skin (18% to 24%), skin rash (6% to 11%; including contact dermatitis [<1%] and urticaria [<1%])
Gastrointestinal: Diarrhea (12% to 16%), nausea (10% to 19%)
Immunologic: Lymph node pain (19% to 57%)
Local: Erythema at injection site (61% to 74%), injection-site pruritus (82% to 92%), pain at injection site (37% to 67%), swelling at injection site (28% to 48%)
Nervous system: Fatigue (34% to 48%), feeling hot (20% to 32%), headache (32% to 50%), malaise (28% to 37%), rigors (12% to 21%)
Neuromuscular & skeletal: Myalgia (27% to 46%)
Miscellaneous: Decreased exercise tolerance (8% to 11%)
1% to 10%:
Gastrointestinal: Constipation (6%), vomiting (3% to 5%)
Hematologic & oncologic: Lymphadenopathy (6% to 8%)
Neuromuscular & skeletal: Arthralgia (≤2%), back pain (≤2%), limb pain (≤2%)
Respiratory: Dyspnea (3% to 4%)
Frequency not defined:
Cardiovascular: Cardiomyopathy (nonischemic/dilated), ischemic heart disease
Gastrointestinal: Abdominal pain, toothache
Local: Injection-site lesion (benign and malignant)
Nervous system: Dizziness, meningitis, pain, peripheral paresthesia, vertigo
Neuromuscular & skeletal: Myelitis
Ophthalmic: Corneal injury (scarring), photophobia
Postmarketing:
Cardiovascular: Myocarditis (Cassimatis 2004), pericarditis (Cassimatis 2004)
Dermatologic: Eczema (vaccinatum) (CDC [Cono 2003]), erythema multiforme (CDC [Cono 2003]), Stevens-Johnson syndrome (CDC [Cono 2003])
Infection: Vaccinia (including generalized, ocular, progressive, skin infection) (CDC [Cono 2003]; Semba 2003)
Nervous system: Bell palsy (Sejvar 2005), encephalitis (Sejvar 2005), encephalopathy (Sejvar 2005), Guillain-Barre syndrome (Sejvar 2005), seizure (Sejvar 2005)
Ophthalmic: Blindness (Semba 2003), keratitis (Semba 2003)
Miscellaneous: Fever (Sejvar 2005)
There are very few absolute contraindications regarding vaccination of individuals at high risk for exposure to smallpox. The decision to vaccinate must be based on a careful analysis of potential benefits and possible risks.
US labeling: Severe immune deficiency (eg, persons undergoing bone marrow transplant, individuals with primary or acquired immunodeficiency requiring isolation) not expected to benefit from the vaccine.
Canadian labeling: Hypersensitivity to the vaccine or any component of the formulation; persons <18 years of age, eczema or other significant exfoliative skin conditions, immunosuppression, pregnancy, breastfeeding, heart disease or ≥3 major cardiac risk factors (ie, hypertension, diabetes, hypercholesterolemia, heart disease at 50 years of age in a first-degree relative, smoking), persons with household or other close contacts with eczema or other exfoliative skin conditions (Smallpox vaccine [Sanofi Pasteur] Canadian product monograph).
ACIP contraindications in a pre-event vaccination program: Serious hypersensitivity to the vaccine or any component of the formulation; history or presence of atopic dermatitis, eczema or other acute, chronic or exfoliative skin conditions (or persons with household contacts with these conditions); immunosuppression (or persons with household contacts who are immunosuppressed); pregnancy or breastfeeding (or persons with household contacts who are pregnant); infants <1 year of age (CDC/ACIP [Wharton 2003]).
ACIP contraindications for non-emergent use in laboratory and health care personnel at risk for occupational exposure to orthopoxviruses, see guidelines for details (ACIP [Petersen 2015]):
Primary vaccines, revaccinees, and household contacts: History or presence of atopic dermatitis, other active exfoliative skin conditions, immunosuppression, pregnancy, and infants
Additional contraindications for primary vaccinees and revaccinees: Breast-feeding, serious vaccine component allergy, and known underlying heart disease.
Additional contraindications for primary vaccines only: 3 or more major cardiac risk factors
ACIP contraindications in a post-event situation: There are no absolute contraindications to vaccination (CDC/ACIP [Rotz 2001]; CDC [Petersen 2015]). The following are relative contraindications:
- Severe immunodeficiency including the following: bone marrow transplant transplantation within the previous 4 months, HIV infection with CD4 <50 cells/mm3 (or AIDS-defining condition if recent CD4 count is unavailable; see guideline for pediatric age specific criteria), severe combined immunodeficiency, complete DiGeorge syndrome, or other severely immunocompromised states requiring isolation (CDC [Petersen 2015])
- High risk for smallpox infection but without known exposure: Hypersensitivity to the vaccine or any component of the formulation, atopic dermatitis, solid organ transplantation within the previous 3 months, bone marrow transplant transplantation within the previous 4 to 24 months, HIV infection with CD4 <50 to 199 cells/mm3 (see guideline for pediatric age specific criteria), active graft-versus-host disease after transplantation, immunosuppressive therapy, or other immunocompromised state (CDC [Petersen 2015]).
Concerns related to adverse effects:
• Anaphylactoid/hypersensitivity reactions: Immediate treatment (including epinephrine 1 mg/mL) for anaphylactoid and/or hypersensitivity reactions should be available during vaccine use (ACIP [Kroger 2023]).
• Syncope: Syncope has been reported with use of injectable vaccines and may result in serious secondary injury (eg, skull fracture, cerebral hemorrhage); typically reported in adolescents and young adults and within 15 minutes of vaccination. Procedures should be in place to avoid injuries from falling and to restore cerebral perfusion if syncope occurs (ACIP [Kroger 2023]).
Disease-related concerns:
• Acute illness: The decision to administer or delay vaccination because of current or recent febrile illness depends on the severity of symptoms and the etiology of the disease. Postpone administration in patients with moderate or severe acute illness (with or without fever); vaccination should not be delayed for patients with mild acute illness (with or without fever) (ACIP [Kroger 2023]). The smallpox vaccine (Sanofi Pasteur) Canadian product monograph recommends postponement of vaccination in persons with acute febrile conditions if used for nonemergency (pre-event) prophylaxis.
• Eczema/exfoliative skin conditions: These patients should not be vaccinated in nonemergency situations, including laboratory and health care personnel at risk for occupational exposure to orthopoxviruses (ACIP [Petersen 2015]; CDC/ACIP [Wharton 2003]).
• Ocular conditions: In a nonemergency situation, the ACIP recommends deferring vaccination in persons with an eye condition requiring steroid treatment until the condition resolves and treatment is complete (CDC/ACIP [Wharton 2003]).
Concurrent drug therapy issues:
• Vaccines: In order to maximize vaccination rates, the ACIP generally recommends simultaneous administration (ie, >1 vaccine on the same day at different anatomic sites) of all age-appropriate vaccines (live or nonlive) for which a person is eligible at a single visit, unless contraindications exist. The ACIP prefers each dose of a specific vaccine in a series come from the same manufacturer when possible (ACIP [Kroger 2023]). For smallpox vaccine: May be given simultaneously with any inactive and most live vaccines. Varicella vaccine should be administered at least 4 weeks before or after smallpox vaccine, to help interpret any postvaccination rashes that may arise. Tuberculosis screening (PPD skin test) should be administered ≥1 month after smallpox vaccination, to avoid temporary false-negative test results.
Special populations:
• Altered immunocompetence: Use in patients with severe immune deficiency may result in progressive vaccinia and is, therefore, contraindicated by the manufacturer. The ACIP recommends that these patients not be vaccinated in nonemergency situations. In general, live vaccines should be administered ≥4 weeks prior to planned immunosuppression and avoided within 2 weeks of immunosuppression when feasible; live vaccines should not be administered for at least 3 months after immunosuppressive therapy (ACIP [Kroger 2023]; IDSA [Rubin 2014]).
Dosage form specific issues:
• Albumin: Some dosage forms may contain human albumin.
• Neomycin: Products may contain neomycin.
• Polymyxin B: Products may contain polymyxin B.
Special handling:
• Biohazard: Use appropriate precautions for handling and disposal. Personnel responsible for preparation and administration should observe appropriate contact precautions to avoid inadvertent inoculation (eg, wear surgical or protective gloves and avoid contact of vaccine with skin, eyes, or mucous membranes). Dispose of all materials for preparation and administration in a biohazard waste container. All materials must be burned, boiled, or autoclaved. Vaccinees should change bandages away from other people and launder their own linens separately to prevent transmission.
Other warnings/precautions:
• Appropriate use: Patients at greatest risk for adverse reactions from the vaccine are also at increased risk for death from smallpox infection. Recommendations for use in response to bioterrorism are periodically updated by the CDC (www.cdc.gov).
• Blood and organ donation: Patients should be advised not to donate blood or organs for 21 to 30 days following vaccination or until the scab has separated; contacts who have inadvertently contracted vaccinia should avoid donating blood for 14 days (CDC/ACIP [Wharton 2003]).
• Effective immunity: Vaccination may not result in effective immunity in all patients. Response depends upon multiple factors (eg, type of vaccine, age of patient) and may be improved by administering the vaccine at the recommended dose, route, and interval (ACIP [Kroger 2023]).
• Transmission of virus: Virus may be cultured from vaccination sites until scab separates from lesion; viral shedding ceases once the lesion is re-epithelialized (~14 to 21 days after vaccination). Individuals should be instructed to avoid contact with patients at high risk of transmission/adverse effects, including persons who are breastfeeding and patients with eczema or immunodeficiency during this time.
In the United States, the currently available live smallpox vaccine (ACAM2000) has not been formally studied in patients <16 years of age; however, live smallpox vaccine was previously used routinely in all pediatric age groups (before the eradication of smallpox disease). Live vaccinia virus has been associated with serious complications in pediatric patients, with the highest risk occurring in ages <2 years, based on experience with the previously available vaccine (Dryvax). Complications may include central nervous system disease, including postvaccinial encephalitis. The live smallpox vaccine is not recommended for routine preexposure prophylaxis in individuals <18 years of age, and it is contraindicated in individuals <1 year of age except for emergency use following exposure (CDC [Petersen 2015]; CDC/ACIP [Wharton 2003]; manufacturer's labeling).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Injection, powder for reconstitution [purified monkey cell source]:
ACAM2000: 1-5 x 108 plaque-forming units per mL [contains polymyxin B, neomycin (trace amounts) and human albumin; packed with diluent, tuberculin syringes for reconstitution, and 100 bifurcated needles for administration]
No
Smallpox vaccine is not available for general public use. Supplies are part of the US federal government's Strategic National Stockpile. See the following for additional information:
CDC Drug Service Formulary: https://www.cdc.gov/laboratory/drugservice/formulary.html.
FDA Smallpox Preparedness and Response Updates: https://www.fda.gov/emergency-preparedness-and-response/mcm-issues/smallpox-preparedness-and-response-updates-fda.
CDC Considerations for Monkeypox Vaccination: https://www.cdc.gov/poxvirus/monkeypox/considerations-for-monkeypox-vaccination.html.
Vaccination should only be performed by health care providers trained in the safe and efficacious administration of the smallpox vaccine. Do not mix with other vaccines or injections; separate needles and syringes should be used for each injection. To prevent syncope related injuries, patients should be vaccinated while seated or lying down (ACIP [Kroger 2023]).
Vaccination by scarification (multiple-puncture technique) only. Administer by percutaneous injection only; not for IM, intradermal, IV, or SUBQ injection. If alcohol is used to clean the skin, allow site to dry completely prior to administration to prevent the inactivation of the vaccine by the alcohol. A single-use bifurcated needle should be dipped carefully into the reconstituted vaccine (following removal of rubber stopper). Visually confirm that the needle picks up a drop of vaccine solution. Using a bifurcated needle, 1 drop of vaccine is introduced into the superficial layers of the skin using a multiple-puncture technique. The skin over the insertion of the deltoid muscle is the preferred site for vaccination. Deposit the drop of vaccine onto clean, dry skin at the vaccination site. Holding the bifurcated needle perpendicular to the skin, punctures are to be made rapidly within a diameter of about 5 mm into the superficial skin of the vaccination site. The puncture strokes should be vigorous enough to allow a trace of blood to appear after approximately 15 to 20 seconds. Wipe off any remaining vaccine with dry sterile gauze. Dispose of all materials in a biohazard waste container; do not reuse the bifurcated needle. All materials must be burned, boiled, or autoclaved.
To prevent transmission of the virus, avoid scratching the vaccination site and cover with gauze (using first aid adhesive tape to keep gauze in place); cover gauze with a semipermeable barrier (eg, semiocclusive dressing) or clothing. Ointment or salves should not be applied to the vaccination site. Good handwashing prevents inadvertent inoculation. Vaccinees should change bandages away from others and launder their own linens separately to prevent transmission.
Percutaneous: Vaccination should only be performed by health care providers trained in the safe and efficacious administration of the smallpox vaccine via the percutaneous route (manufacturer's labeling). Do not mix with other vaccines or injections; separate needles and syringes should be used for each injection (ACIP [Kroger 2023]).
Vaccination by scarification (multiple-puncture technique) only: Administer by percutaneous injection only; not for IM, intradermal, IV, or SUBQ injection. If alcohol is used to clean the skin, allow site to dry completely prior to administration to prevent the inactivation of the vaccine by the alcohol. The skin over the insertion of the deltoid muscle or the posterior aspect of the arm over the triceps are the preferred sites for vaccination.
A single-use bifurcated needle should be dipped carefully into the reconstituted vaccine (following removal of rubber stopper). Visually confirm that the needle picks up a drop of vaccine solution. Using a bifurcated needle, introduce 1 drop of vaccine into the superficial layers of the skin using a multiple-puncture technique. Deposit the drop of vaccine onto clean, dry skin at the vaccination site. Holding the bifurcated needle perpendicular to the skin, 15 punctures are to be made rapidly within a diameter of about 5 mm into the superficial skin of the vaccination site. The puncture strokes should be vigorous enough to allow a trace of blood to appear after approximately 15 to 20 seconds. Wipe off any remaining vaccine with dry sterile gauze. Dispose of all materials in a biohazard waste container; do not reuse the bifurcated needle; all materials must be burned, boiled, or autoclaved.
To prevent transmission of the virus, avoid scratching the vaccination site and cover with gauze (using first aid adhesive tape to keep gauze in place); cover gauze with a semipermeable barrier (eg, semiocclusive dressing) or clothing. Ointment or salves should not be applied to the vaccination site. Good handwashing prevents inadvertent inoculation. Vaccinees should change bandages away from others and launder their own linens to prevent transmission. Soiled and contaminated bandages should be placed in plastic bag for disposal.
An FDA-approved patient medication guide, which is available with the product information and at http://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM142576.pdf, must be dispensed with this medication.
Smallpox disease prevention: Active immunization against smallpox disease in persons determined to be at high risk for smallpox infection.
The Advisory Committee on Immunization Practices (ACIP) recommends routine vaccination for the following (ACIP [Petersen 2016]):
• Laboratory workers who directly handle cultures or animals who are contaminated or infected with replication-competent vaccinia virus, recombinant vaccinia viruses derived from replication-competent vaccinia strains or related orthopoxviruses capable of causing infections in humans (eg, monkeypox virus, cowpox virus, variola virus).
• Consideration may also be given for vaccination of health care personnel who currently treat or anticipate treating patients with vaccinia virus infections or whose contact is limited to contaminated materials or administering ACAM2000 smallpox vaccine; adherence to appropriate infection prevention measures is also necessary.
In a pre-event vaccination program, the ACIP recommends vaccination for the following (CDC/ACIP [Wharton 2003):
• Persons designated by authorities (eg, smallpox response teams) to investigate and follow-up on initial smallpox cases with the likelihood of direct patient contact.
• Hospital-based health care teams who provide patient care for smallpox patients.
• Persons responsible for administering smallpox vaccine.
For post-event vaccination, the ACIP recommends vaccination for the following (CDC [Petersen 2015]):
• Persons directly exposed to an accidental or intentional release of the virus.
• Household family members of a patient with confirmed, probable or suspected smallpox or others spending ≥3 hours in the household since the onset of fever.
• Nonhousehold members with ≥3 hours of close contact (<6.5 feet or <2 meters) with a confirmed or suspected smallpox patient with a rash.
• Persons considered at high risk for smallpox infection (including healthcare workers) as defined by public health authorities.
Mpox (monkeypox) disease prevention
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Acetaminophen: May diminish the therapeutic effect of Vaccines. Management: Consider avoiding routine prophylactic use of acetaminophen before or during vaccine administration when possible. Acetaminophen is still recommended to treat fevers and/or pain that occurs after vaccination. Risk D: Consider therapy modification
Anti-CD20 B-Cell Depleting Therapies: May enhance the adverse/toxic effect of Vaccines (Live). Specifically, the risk of vaccine-associated infection may be increased. Anti-CD20 B-Cell Depleting Therapies may diminish the therapeutic effect of Vaccines (Live). Risk X: Avoid combination
Brincidofovir: May diminish the therapeutic effect of Smallpox Vaccine Live. Risk C: Monitor therapy
Cladribine: May enhance the adverse/toxic effect of Vaccines (Live). Specifically, the risk of vaccine-associated infection may be increased. Cladribine may diminish the therapeutic effect of Vaccines (Live). Risk X: Avoid combination
Corticosteroids (Systemic): May enhance the adverse/toxic effect of Vaccines (Live). Specifically, the risk of vaccine-associated infection may be increased. Corticosteroids (Systemic) may diminish the therapeutic effect of Vaccines (Live). Management: Avoid live vaccines during and for 1 month after therapy with immunosuppressive doses of corticosteroids (equivalent to prednisone > 2 mg/kg or 20 mg/day in persons over 10 kg for at least 2 weeks). Give live vaccines 4 weeks prior to therapy if possible. Risk D: Consider therapy modification
COVID-19 Vaccine (mRNA): Smallpox Vaccine Live may enhance the adverse/toxic effect of COVID-19 Vaccine (mRNA). Specifically, the risk for myocarditis may be increased. Risk C: Monitor therapy
Dimethyl Fumarate: May enhance the adverse/toxic effect of Vaccines (Live). Specifically, Dimethyl Fumarate may increase the risk of vaccinal infection. Dimethyl Fumarate may diminish the therapeutic effect of Vaccines (Live). Management: Non-US labeling for dimethyl fumarate states that live attenuated vaccine administration is not recommended during treatment. US labeling states that safety and effectiveness of live vaccines administered with dimethyl fumarate has not been assessed. Risk C: Monitor therapy
Dupilumab: May enhance the adverse/toxic effect of Vaccines (Live). Risk X: Avoid combination
Elivaldogene Autotemcel: May enhance the adverse/toxic effect of Vaccines. Specifically, there may be a greater risk for contracting an infection from any live vaccine. Elivaldogene Autotemcel may diminish the therapeutic effect of Vaccines. Management: Administration of vaccines is not recommended in the 6 weeks before myeloablative conditioning, and until hematologic recovery after elivaldogene autotemcel treatment. Risk X: Avoid combination
Etrasimod: May enhance the adverse/toxic effect of Vaccines (Live). Specifically, the risk of vaccine-associated infection may be increased. Etrasimod may diminish the therapeutic effect of Vaccines (Live). Risk X: Avoid combination
Immune Globulins: May diminish the therapeutic effect of Vaccines (Live). Management: Live organism vaccination should be withheld for as long as 6 to 11 months following immune globulin administration. Recommendations vary by product and immune globulin dose, see full monograph for details. Risk D: Consider therapy modification
Immunosuppressants (Cytotoxic Chemotherapy): May enhance the adverse/toxic effect of Vaccines (Live). Specifically, the risk of vaccine-associated infection may be increased. Vaccines (Live) may diminish the therapeutic effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination
Immunosuppressants (Miscellaneous Oncologic Agents): May enhance the adverse/toxic effect of Vaccines (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Vaccines (Live). Risk X: Avoid combination
Immunosuppressants (Therapeutic Immunosuppressant Agents): May enhance the adverse/toxic effect of Vaccines (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Vaccines (Live). Risk X: Avoid combination
Leniolisib: May diminish the therapeutic effect of Vaccines (Live). Risk C: Monitor therapy
Methotrexate: May enhance the adverse/toxic effect of Vaccines (Live). Methotrexate may diminish the therapeutic effect of Vaccines (Live). Management: Low-dose methotrexate (0.4 mg/kg/week or less) is not considered sufficiently immunosuppressive to create vaccine safety concerns. Higher doses of methotrexate should be avoided. Risk D: Consider therapy modification
Propacetamol: May diminish the therapeutic effect of Vaccines. Management: Consider avoiding routine prophylactic use of propacetamol before or during vaccine administration when possible. Propacetamol is still recommended to treat fevers and/or pain that occurs after vaccination. Risk D: Consider therapy modification
Rabies Immune Globulin (Human): May diminish the therapeutic effect of Vaccines (Live). Management: Avoid administering the measles vaccine within 4 months after administration of rabies immune globulin. Avoid administering other live vaccines within 3 months after administration of rabies immune globulin. Risk D: Consider therapy modification
Tecovirimat: May diminish the therapeutic effect of Smallpox Vaccine Live. Risk C: Monitor therapy
Teplizumab: May enhance the adverse/toxic effect of Vaccines (Live). Specifically, the risk of vaccines-associated infection may be increased. Teplizumab may diminish the therapeutic effect of Vaccines (Live). Risk X: Avoid combination
Tezepelumab: May enhance the adverse/toxic effect of Vaccines (Live). Risk X: Avoid combination
Tildrakizumab: May enhance the adverse/toxic effect of Vaccines (Live). The risk for contracting an infection from the vaccine may be increased. Tildrakizumab may diminish the therapeutic effect of Vaccines (Live). Risk X: Avoid combination
Tralokinumab: May enhance the adverse/toxic effect of Vaccines (Live). Risk X: Avoid combination
Tuberculin Tests: Vaccines (Live) may diminish the diagnostic effect of Tuberculin Tests. Management: It is preferable to administer live vaccines simultaneously with tuberculin tests. If a live vaccine has been recently administered, the tuberculin skin test should be administered 4 to 6 weeks following the administration of the vaccine. Risk D: Consider therapy modification
Vaccines (Live): May diminish the therapeutic effect of other Vaccines (Live). Management: Two or more injectable or nasally administered live vaccines not administered on the same day should be separated by at least 28 days (ie, 4 weeks). If not, the vaccine administered second should be repeated at least 4 week later. Risk C: Monitor therapy
Varicella Virus Vaccine: Smallpox Vaccine Live may enhance the adverse/toxic effect of Varicella Virus Vaccine. It may be difficult to determine which vaccine caused skin lesions or other adverse effects. Management: Separate the administration of smallpox and varicella vaccines by at least 4 weeks. Risk D: Consider therapy modification
Evaluate pregnancy status prior to vaccination in patients who could become pregnant (CDC/ACIP [Wharton 2003]).
Abstinence or highly effective contraception is recommended following vaccination (CDC/ACIP [Wharton 2003]). Pregnancy should be avoided for at least 4 weeks following vaccination and until the injection site has healed, scabs have fallen off, and a new layer of intact skin has formed (CDC 2022c).
Persons should not donate sperm, oocytes, or embryos for 21 days after smallpox vaccination or until the scab separates spontaneously from the injection site, whichever occurs later. If the scab is removed but not spontaneously separated, donation should be deferred for 2 months. In case of complications from vaccination, donation should be deferred for 14 days after complete resolution of the complications (ASRM/ART 2021).
Outcome data following vaccination with smallpox vaccine during pregnancy are available (Badell 2015; CDC 2003; Conlin 2015; Ryan 2008). Vaccination during any trimester of pregnancy may rarely cause fetal vaccinia which may result in fetal or neonatal death or premature birth (CDC 2003). Fetal vaccinia may present as skin lesions or eruptions resembling smallpox; lesions in the fetal lung and liver have been observed in case reports (Badell 2015). Smallpox vaccination is associated with severe adverse events (encephalitis, encephalomyelitis, encephalopathy, progressive vaccinia, generalized vaccinia, severe vaccinial skin infections, erythema multiforme major, eczema vaccinatum); these risks may be increased in patients who are pregnant.
Smallpox disease during pregnancy is also associated with adverse events. Contracting smallpox while pregnant increases the risk of severe maternal disease (including hemorrhagic smallpox) and death; the fatality rate in unvaccinated pregnant patients can be up to 70%. Pregnant health care workers should avoid direct patient care during an initial emergency response to a smallpox outbreak (CDC [Petersen 2015]).
According to the CDC, vaccination of pregnant patients is contraindicated in a pre-event setting, including laboratory and health care personnel at risk for occupational exposure to orthopoxviruses. Persons living in a household with pregnant patients should also not be vaccinated in a pre-event setting; this includes persons who might have prolonged intimate contact with a vaccinee or who have direct contact with the vaccination site (ACIP [Petersen 2016]; CDC/ACIP [Wharton 2003]). Due to the high maternal and fetal mortality associated with maternal smallpox infection, vaccination is recommended in the post-event setting for pregnant patients exposed to smallpox or at high risk for smallpox infection unless a relative contraindication exists (CDC [Petersen 2015]).
The smallpox vaccine (live) is also available for use against monkeypox virus under an Expanded Use Access IND from the FDA (CDC/ACIP [Rao 2022]; CDC 2022a). Infection with the monkeypox virus may lead to adverse pregnancy outcomes, including spontaneous pregnancy loss, stillbirth, and transmission of the monkeypox virus to the fetus or newborn. When a pregnant patient is diagnosed with mpox (monkeypox), neonatal health care providers should be informed of the diagnosis. When pre- or postexposure vaccination for monkeypox virus is needed during pregnancy, smallpox vaccine (live) should not be used (CDC 2022c).
Data collection to monitor pregnancy and infant outcomes following exposure to smallpox vaccine (live) is ongoing. Health care providers may enroll pregnant patients who were inadvertently vaccinated during pregnancy or from 42 days prior to conception onward, or who were a close contact of a vaccinee within the previous 4 weeks of vaccination, in the CDC pregnancy registry by calling 404-639-8253 (CDC/ACIP [Wharton 2003]). All civilian and military cases should be reported to the Department of Defense (619-553-9255 or [email protected]).
It is not known if the vaccine virus or antibodies are present in breast milk.
According to the CDC, vaccination of a breastfeeding person is contraindicated in a nonemergency situation, including laboratory and health care personnel at risk for occupational exposure to orthopoxviruses (CDC/ACIP [Wharton 2003]). Vaccination is recommended in the post-event setting unless a relative contraindication exists. Following maternal vaccination, inadvertent transmission of live vaccinia virus from the vaccine site to infants is a potential risk during bottle or breastfeeding; proper infection control precautions are recommended. Breastfeeding or infant feeding with expressed breast milk should be discontinued if there is a cutaneous breast lesion suspicious for vaccinia virus infection until the lesion heals (CDC [Petersen 2015]). Persons living in a household with a breastfeeding person may be vaccinated; however, they should observe proper precautions to avoid inadvertent secondary transmission (Garde 2004).
The smallpox vaccine (live) is available for use against monkeypox virus under an Expanded Use Access IND from the FDA (CDC/ACIP [Rao 2022]; CDC 2022a). When pre- or postexposure vaccination for monkeypox virus is needed in a breastfeeding patient, smallpox vaccine (live) should not be used (CDC 2022c).
Monitor for hypersensitivity and syncope for 15 minutes following administration (ACIP [Kroger 2023]). If seizure-like activity associated with syncope occurs, maintain patient in supine or Trendelenburg position to reestablish adequate cerebral perfusion.
Evaluate pregnancy status prior to vaccination in females of reproductive potential (CDC/ACIP [Wharton 2003]).
Primary vaccination: Monitor vaccination site; inspect after 6 to 8 days. Evidence of a major reaction (vesicular or pustular lesion or an area of palpable induration surrounding a central lesion) confirms success of vaccination. An equivocal reaction (all responses other than a major reaction) requires revaccination in patients undergoing primary vaccination only.
Booster dose: Successful vaccination is confirmed when a major cutaneous reaction is observed 6 to 8 days postvaccination. Prior vaccination may reduce the cutaneous response and does not necessarily indicate a vaccination failure.
Vaccinia virus is similar in some respects to the variola (smallpox) virus. By inducing a localized infection with vaccinia virus, immunity to both vaccinia and variola is achieved. Vaccination results in viral replication, production of neutralizing antibodies, immunity, and cellular hypersensitivity.
Onset of action: Neutralizing antibodies appear 15-20 days after vaccination; time to appearance of neutralizing antibodies may be shorter (~7 days) following revaccination (CDC/ACIP [Rotz 2001]).
Duration of action: For 75% of patients, neutralizing antibody titers (>1:10) persisted for 10 years after receiving second doses and <30 years after receiving 3 doses of vaccine (CDC/ACIP [Rotz 2001]).
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