YF-VAX Powder for suspension Ref.[9904] Active ingredients: Yellow fever, live attenuated

Severe Allergic Reactions

Severe allergic reactions (e.g., anaphylaxis) may occur following the use of YF-VAX, even in individuals with no prior history of hypersensitivity to the vaccine components. Appropriate medical treatment and supervision must be available to manage possible anaphylactic reactions following administration of the vaccine.

Yellow fever vaccine-associated vis cerotropic disease

Age greater than 60 years is a risk factor for yellow fever vaccine-associated viscerotropic disease (YEL-AVD) (14) which may present as non-specific multi-organ system failure or can be similar to fulminant yellow fever caused by wild-type yellow fever virus, with liver failure and internal bleeding, leading to death. (See ADVERSE REACTIONS section). Available evidence suggests that the occurrence of this syndrome may depend upon undefined host factors, rather than intrinsic virulence of the yellow fever strain 17D vaccine, based on characterization of vaccine viruses isolated from individuals with YEL-AVD. YEL-AVD has been reported to occur only after the first dose of yellow fever vaccine; there have been no reports of YEL-AVD following booster dose (17). The decision to vaccinate individuals 60 years of age and older needs to weigh the risks and benefits of vaccination and the risk for exposure to yellow fever virus (18) (19) (20) (21).

Yellow fever vaccine-associated neurotropic disease

Age greater than 60 years and immunosuppression are risk factors for post-vaccinal encephalitis, also known as yellow fever vaccine-associated neurotropic disease (YEL-AND) (See ADVERSE REACTIONS section). Almost all cases of YEL-AND have been in first-time vaccine recipients (17). The decision to vaccinate individuals 60 years of age and older and immunosuppressed individuals needs to weigh the risks and benefits of vaccination and the risk for exposure to yellow fever virus.

Data from Clinical Studies

Adverse reactions to YF-VAX include mild headaches, myalgia, low-grade fevers, or other minor symptoms for 5 to 10 days. Local reactions including edema, hypersensitivity, pain or mass at the injection site have also been reported following yellow fever vaccine administration. Immediate hypersensitivity reactions, characterized by rash, urticaria, and/or asthma, occur principally among persons with histories of allergy to eggs or other substances contained in the vaccine.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared to rates in the clinical trials of another vaccine and may not reflect the rates observed in practice.

No placebo-controlled trial has assessed the safety of YF-VAX. However, between 1953 and 1994, reactogenicity of 17D-204 vaccine was monitored in 10 uncontrolled clinical trials. The trials included a total of 3,933 adults and 264 infants greater than 4 months old residing in Europe or in yellow fever endemic areas. Self-limited and mild local reactions consisting of erythema and pain at the injection site and systemic reactions consisting of headache and/or fever occurred in a minority of subjects (typically less than 5%) 5 to 7 days after immunization. In one study involving 115 infants age 4 to 24 months the incidence of fever was as high as 21%. Also in this study, reactogenicity of the vaccine was markedly reduced among a subset of subjects who had serological evidence of previous exposure to yellow fever virus. Only two of the ten studies provided diary cards for daily reporting; this method resulted in a slightly higher incidence of local and systemic complaints. YF-VAX was used as a control in a double-blind, randomized comparative trial with another 17D-204 vaccine, conducted at nine centers in the US. YF-VAX was administered to 725 adults ≥18 years old with a mean age of 38 years. Safety data were collected by diary card for days 1 through 10 after vaccination and by interview on days 5, 11, and 31. Among subjects who received YF-VAX, there were no serious adverse events, and 71.9% experienced non-serious adverse events judged to have been related to vaccination. Most of these were injection site reactions of mild to moderate severity. Four such local reactions were considered severe. Rash occurred in 3.2%, including two subjects with urticaria. Systemic reactions (headache, myalgia, malaise, and asthenia) were usually mild and occurred in 10% to 30% of subjects during the first few days after vaccination. The incidence of non-serious adverse reactions, including headache, malaise, injection site edema, and pain, was significantly lower in subjects >60 years compared to younger subjects. Adverse events were less frequent in the 1.7% of vaccinated subjects who had pre-existing immunity to yellow fever virus, compared to those without pre-existing immunity (8).

Data from Post-marketing Experience

The following additional adverse events have been spontaneously reported during the post-marketing use of YF-VAX worldwide. Because these events are reported voluntarily from a population of uncertain size, it is not possible to estimate their frequency reliably or establish a causal relationship to vaccine exposure. This list includes adverse events based on one or more of the following factors: severity, frequency of reporting, or strength of evidence for a causal relationship to YF-VAX.

General disorders and administration site conditions

Injection-site blisters

Immune System Disorders (14)

Immediate hypersensitivity reactions or anaphylaxis, characterized by rash and/or urticaria and/or respiratory symptoms (e.g., dyspnea, bronchospasm, or pharyngeal edema) occur principally among persons with histories of allergies to egg or other substances contained in the vaccine.

Nervous System Disorders (1) (32) (33) (34)

Isolated cases of Yellow Fever Vaccine-Associated Neurotropic Disease (YEL-AND), sometimes fatal, have been reported to occur within 30 days following vaccination with YF-VAX, and other yellow fever vaccines (See WARNINGS section, Yellow fever vaccine-associated neurotropic disease subsection). Age less than 9 months and congenital or acquired immunodeficiency have been identified as risk factors for this event (See WARNINGS and CONTRAINDICATIONS sections). Twenty-one cases of YEL-AND associated with all licensed 17D vaccines have been reported between 1952 and 2004. Eighteen of these cases were in children or adolescents. Fifteen of these cases occurred prior to 1960, thirteen of which occurred in infants 4 months of age or younger, and two of which occurred in infants six and seven months old. The incidence of vaccine-associated neurologic disease in infants less than 4 months old is estimated to be between 50 and 400 cases per 1,000,000, based on two historical reports where denominators are available (33) (34) (35). A study in Senegal (34) described two fatal cases of encephalitis possibly associated with 17D-204 vaccination among 67,325 children between the ages of 6 months and 2 years, for an incidence rate of 3 per 100,000. The incidence of YEL-AND in the United States is less than 1:100,000 doses administered (17).

Other neurological complications have included Guillain-Barré syndrome (GBS), acute disseminated encephalomyelitis (ADEM), and bulbar palsy.

Infections and infestations

Isolated cases of Yellow Fever Vaccine-Associated Viscerotropic Disease YEL-AVD, formerly described as “Febrile Multiple Organ-System-Failure”, sometimes fatal, have been reported following YF-VAX and other yellow fever vaccines (See WARNINGS section, Yellow fever vaccineassociated viscerotropic disease subsection). In the majority of cases reported, the onset of signs and symptoms was within 10 days after the vaccination. Initial signs and symptoms are non-specific and may include pyrexia, myalgia, fatigue and headache, potentially progressing quickly to liver and muscle cytolysis and possibly to thrombocytopenia, lymphopenia and acute renal failure (18). The pathophysiological mechanism of such reactions has not been established. In some individuals with YEL-AVD a medical history of thymic disease has been reported (36). Age older than 60 has also been identified as a risk factor for this event (9). During surveillance in the U.S. between 1996 and 1998, four individuals (ages 63, 67, 76, and 79) became severely ill 2 to 5 days after vaccination with YFVAX vaccine. Three of these 4 subjects died. The incidence rate for these serious adverse events was estimated at 1 per 400,000 doses of YF-VAX vaccine, based on the total number of doses administered in the U.S. civilian population during the surveillance period (21). YEL-AVD has occurred after yellow fever vaccination in fewer than 1:100,000 U.S. vaccinees, (14) most commonly in individuals 60 years of age and older.

In a CDC analysis of data submitted to the Vaccine Adverse Events Reporting System (VAERS) between 1990 and 1998, the rate of systemic adverse events following vaccination was 2.5-fold higher in the 65 years or older age group (6.2 events per 100,000 doses of vaccine) compared to the 25 to 44 year-old age group (2.5 events per 100,000 doses of vaccine) (31).

Reporting of Adverse Events

To report SUSPECTED ADVERSE REACTIONS, contact the Pharmacovigilance Department, Sanofi Pasteur Inc., Discovery Drive, Swiftwater, PA 18370 at 1-800-822-2463 (1-800-VACCINE) or VAERS at 1-800-822-7967 or https://vaers.hhs.gov.

Patients on Corticosteroid Therapy

Oral Prednisone or other systemic corticosteroid therapy, depending on dose and duration of exposure, may have an immunosuppressive effect on recipients of yellow fever vaccine that potentially decreases immunogenicity and increases the risk of adverse events. Intra-articular, bursal, or tendon injections with corticosteroids should not constitute an increased hazard to recipients of yellow fever vaccine.

Patients with Asymptomatic Human Immunodeficiency Virus (HIV) Infection

The rate of seroconversion following YF-VAX is reduced in individuals with asymptomatic HIV infection and appears to depend on HIV viral load and CD4 + T-cell count (14). Therefore, documentation of a protective antibody response is recommended before travel (See CLINICAL PHARMACOLOGY section). For discussion of this subject and for documentation of the immune response to vaccine where it is deemed essential, contact the CDC at 1-970-221-6400.

Vaccination with YF-VAX may not protect 100% of individuals

Do not administer YF-VAX by intravascular, intramuscular, or intradermal routes.

Use a separate, sterile syringe and needle for each patient to prevent transmission of blood borne infectious agents. Do not recap needles. Dispose of needles and syringes according to biohazard waste guidelines.

Testing for Hypers ensitivity Reactions

Do not administer YF-VAX to an individual with a history of hypersensitivity to egg or chicken protein (See CONTRAINDICATIONS section). However, if an individual is suspected of being an eggsensitive individual, the following test can be performed before the vaccine is administered:

1. Scratch, prick, or puncture test

Place a drop of a 1:10 dilution of the vaccine in physiologic saline on a superficial scratch, prick, or puncture on the volar surface of the forearm. Positive (histamine) and negative (physiologic saline) controls should also be used. The test is read after 15 to 20 minutes. A positive test is a wheal (superficial bump) 3 mm larger than that of the saline control, usually with surrounding erythema. The histamine control must be positive for valid interpretation. If the result of this test is negative, an intradermal (ID) test should be performed.

2. Intradermal test

Inject a dose of 0.02 mL of a 1:100 dilution of the vaccine in physiologic saline. Positive and negative control skin tests should be performed concurrently. A wheal 5 mm or larger than the negative control with surrounding erythema is considered a positive reaction.

If vaccination is considered essential despite a positive skin test, consider desensitization (See DOSAGE AND ADMINISTRATION section, Des ensitization subsection).

Syncope

Syncope can occur following or even before vaccination. Procedures should be in place to prevent falling and injury and to manage syncope.

Prior to administration of YF-VAX, ask potential vaccinees or their parents or guardians about their recent health status and history of yellow fever vaccination. Inform potential vaccinees or their parents or guardians about the benefits and risks of immunization and potential for adverse reactions to YF-VAX administration. Instruct vaccinees or their parents or guardians to report to their health-care providers all serious adverse events that occur up to 30 days post-vaccination.

All travelers should seek information regarding vaccination requirements by consulting with their health care providers. Such requirements may be strictly enforced for entry into certain countries, particularly for persons traveling from Africa or South America to Asia. Additional information is available from local health departments, the Centers for Disease Control and Prevention (CDC), and WHO. Travel agencies, international airlines, and/or shipping lines may also have up-to-date information. The vaccination center should complete, sign, and stamp an International Certificate of Vaccination and provide the certificate to the vaccinee. The immunization record should contain the date, lot number and manufacturer of the vaccine administered. Inform vaccinees that vaccination certificates are valid commencing 10 days after vaccination (14).

Data are limited in regard to the interaction of YF-VAX with other vaccines.

• Measles (Schwartz strain) vaccine, diphtheria and tetanus toxoids and whole cell pertussis vaccine (DTP), (22) Hepatitis A and Hepatitis B vaccines, (5) (14) (23) (24) meningococcal vaccine, Menomune A/C/Y/W-135, and typhoid vaccine, Typhim Vi , (5) (14) (23) have been administered with yellow fever vaccine at separate injection sites.
• The potential for interference between yellow fever vaccine and rabies or Japanese encephalitis vaccines has not been established (14).
• In a prospective study, persons given 5 cc of commercially available immune globulin did not experience alterations in immunologic responses to the yellow fever vaccine (14) (25) (26).
• Although chloroquine inhibits replication of yellow fever vaccine in vitro, it does not appear to adversely affect antibody responses to yellow fever vaccine among persons receiving chloroquine (14) (27).

Animal reproduction studies have not been conducted with YF-VAX. It is also not known whether YF-VAX can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. YF-VAX should be given to a pregnant woman only if clearly needed.

YF-VAX has not been evaluated in pregnant women. However, based on experience of other yellow fever vaccines, the following findings have been determined for safety and effectiveness. A case-control study of Brazilian women found no significant difference in the odds ratio of spontaneous abortion among vaccinated women compared to a similar unvaccinated group (28). In a separate study in Trinidad, 100 to 200 pregnant females were immunized, no adverse events related to pregnancy were reported. In addition, 41 cord blood samples were obtained from infants born to mothers immunized during the first trimester. One of these infants tested positive for IgM antibodies in cord blood. The infant appeared normal at delivery, and no subsequent adverse sequelae of infection were reported. However, this result suggests that transplacental infection with 17D vaccine viruses can occur (29). In another study involving 101 Nigerian women, the majority of whom (88%) were in the third trimester of pregnancy, none of the 40 infants who were delivered in a hospital tested positive for IgM antibodies as a criterion for transplacental infection with vaccine virus. However, the percentage of pregnant women who seroconverted was reduced compared to a non-pregnant control group (38.6% vs. 81.5%) (30).

For further discussion of vaccination with YF-VAX during pregnancy and for documentation of a protective immune response to vaccine where it is deemed essential, contact the CDC at 1-970-221-6400.

Because of the potential for serious adverse reactions in nursing infants from YF-VAX, a decision should be made whether to discontinue nursing or not to administer the vaccine, taking into account the importance of the vaccine to the mother. As of July, 2015, three vaccine-associated neurotropic disease cases have been reported worldwide in exclusively breastfed infants whose mothers were vaccinated with yellow fever vaccines, including one case reported after vaccination with YF-VAX. All three infants were diagnosed with encephalitis and were less than one month of age at the time of exposure (17). Because age less than 9 months is a risk factor for yellow fever vaccine-associated neurotropic disease, YF-VAX is contraindicated in lactating women who are providing breastmilk to infants younger than 9 months of age (See CONTRAINDICATIONS section). Discuss the risks and benefits of vaccination with lactating women who are providing breastmilk to infants 9 months of age and older (14).

Vaccination of infants less than 9 months of age is contraindicated because of the risk of yellow fever vaccine-associated neurotropic disease (See CONTRAINDICATIONS and ADVERSE REACTIONS sections).

There is an increased risk of severe systemic adverse reactions to YF-VAX in individuals 60 years of age and older. Monitor elderly individuals for signs and symptoms of yellow fever vaccine-associated viscerotropic disease, which typically occurs within 10 days post-vaccination (See WARNINGS and ADVERSE REACTIONS sections) (16) (31).