Acel (Vaccination)

ACEL-P™

Wyeth-Ayerst

Acellular Pertussis Vaccine Adsorbed

Active Immunizing Agent

Action And Clinical Pharmacology: Pertussis disease (whooping cough) is caused by a gram-negative coccobacillus, B. pertussis. Acellular pertussis vaccine adsorbed is an acellular pertussis vaccine indicated for primary immunization against disease caused by B. pertussis.

Pertussis (whooping cough) has 3 typical stages (catarrhal, paroxysmal, and convalescent). The second phase is characterized by severe paroxysmal coughing that persists for weeks. The disease primarily affects infants and young children, and morbidity and mortality rates generally are inversely related to age. Infants do not acquire adequate maternal immunity, so they are highly susceptible to infection. Transmission and atypical respiratory infections are known to occur in adults who were immunized as children.

The infection appears to be localized to the cilia of the respiratory tract and the epithelial surfaces of the bronchial tree. The cause of the paroxysmal coughing (the whoop) is uncertain. It may be a result of the tenacious nature of the secretions and the loss of ciliary action.

In the 1940s, a vaccine consisting of whole B. pertussis cells killed by heat or formalin treatment was developed. Based on clinical experience of almost 50 years, the benefits of the whole-cell pertussis vaccines are well established and the vaccine has been shown to be useful in the control of pertussis. However, many children experience discomfort or adverse local reactions from the immunization.

Recently, public acceptance of the whole cell vaccine decreased considerably and, in the late 1970s, the incidence of pertussis disease increased with the decline in use of the whole-cell vaccines. Today, pertussis disease remains a significant contributor to infant mortality in developing countries causing approximately 600 000 deaths annually.

Acellular pertussis vaccines have been used in Japan since 1981, mostly in 2-year-old children. The vaccine used has been of 2 general types: the Takeda (T-type) vaccine and the Biken-type (B-type) vaccine. The Takeda acellular pertussis (T-type) vaccine accounts for 80% of the Japanese market.

Evidence for the efficacy of acellular pertussis vaccines, as a group, is demonstrated by the decline in pertussis disease with their routine use in that country. In addition, a review of epidemiological studies of the Japanese acellular pertussis vaccines estimated that these vaccines, as a group, were 88% efficacious in protecting against clinical pertussis on household exposure, with a 95% confidence interval of 79 to 93%. In 3 Japanese household contact studies which employed retrospective case ascertainment and nonstandard case definitions, the vaccine-specific efficacy of the Takeda vaccine ranged between 89 and 94%, but confidence intervals were wide due to the small number of children in each study. Although there were differences in study methods, these estimates of efficacy are quite comparable to that for whole-cell pertussis vaccine in the United States.

Immunogenicity of the monovalent acellular pertussis vaccine was studied in 249 German children 15 months to 6 years of age who had previously been immunized against diphtheria and tetanus, but had been unvaccinated against pertussis. A 3-dose primary series was administered at 6- to 10-week intervals, and antibody responses against the vaccine antigens were investigated. The antibody responses were pronounced, with 93 to 100% of vaccinees demonstrating at least a 4-fold titer rise above the pre-immunization level after the third dose. In addition, local and systemic reactions were minimal in frequency and severity, and overall reactogenicity was lower than that seen in children of similar ages vaccinated with the same acellular pertussis component in combination with diphtheria and tetanus toxoid as a booster dose. These findings indicated that acellular pertussis vaccine was immunogenic with low reactogenicity, and was therefore appropriate for catch-up immunization in older children who had not previously received pertussis vaccination.

The efficacy of an APDT vaccine containing the Takeda acellular pertussis vaccine component was examined, in particular in a non-blinded household contact study in Japan, conducted by Lederle Laboratories, that included both retrospective and prospective case evaluation. As a consequence of the immunization schedule in Japan at the time of study, none of the vaccinated contacts were less than 2 years of age while some of the unvaccinated contacts were less than 2 years of age. When analysis of results was limited to vaccinated and unvaccinated household contacts 2 years of age and over, efficacy was estimated to be 79% (95% confidence interval, 60 to 89%) for physician-diagnosed pertussis disease. This included respiratory illnesses that may have been mild pertussis. When cases were restricted to disease diagnosed as typical pertussis, omitting mild suspect cases, efficacy was estimated to be 97% (95% confidence interval, 82 to 99%).

When unvaccinated household contacts under 2 years of age are also included in the analysis, efficacy was estimated to be 81% (95% confidence interval, 64 to 90%) against pertussis disease (including mild suspect cases) and 98% (95% confidence interval 84 to 99%) against typical pertussis. While there is some uncertainty with regard to the absolute magnitude of these estimates, the data as a whole demonstrate the efficacy of the Takeda Pertussis Vaccine.

Immunogenicity of an acellular DPT vaccine containing the acellular pertussis vaccine component (Acel-Imune) compared with whole-cell DPT was studied in approximately 1 000 U.S. children receiving these vaccines as a fourth or fifth dose at 17 to 24 months or 4 to 6 years of age. Antibody response following Acel-Imune was similar to whole-cell DPT for LPF, 69kd protein, and agglutinins, and higher than DPT for FHA (the DPT used in these comparative studies was manufactured by Lederle Laboratories). All children achieved protective antibody levels to diphtheria and tetanus toxoids. A serologic correlate to protection against pertussis disease has not been established. Acel-Imune was less reactogenic than the whole-cell DPT vaccine (manufactured by Lederle Laboratories) in these studies with regard to local reactions, including less pain/tenderness, erythema, induration and warmth at the injection site. In addition, there was less drowsiness, fretfulness, fever and antipyretic use following Acel-Imune as compared with DPT. The relative frequency of rare events that may be associated with immunization can only be determined in large post-marketing surveillance studies.

While whole cell pertussis vaccines contain the antigenic components necessary to elicit protective immunity, they may also contain substances irrelevant to protection and possibly related to undesirable side effects of the vaccine. Progress has been made in characterizing the various components of the B. pertussis organism thought to play a role in protective immunity including filamentous hemagglutonin (FHA), lymphocytosis promoting factor (LPF) also known as pertussis toxin (PT), a 69 kilodalton (69Kd) outer membrane protein, and fimbriae (pertussis-specific agglutinogens).

The Takeda acellular pertussis vaccine component used in Acel-P contains inactivated PT, FHA, 69kd outer membrane protein and type 2 fimbriae (pertussis-specific agglutinogen), with minimal endotoxin compared to that in whole-cell pertussis vaccine. The pertussis component induces immunity against pertussis (whooping cough).

Indications And Clinical Uses: For primary immunization of children of 15 months to 6 years of age against disease caused by B. pertussis (whooping cough).

For booster immunization as a 4hdose (completion of the primary immunization) for children older than 15 months who previously received their primary immunization (3 doses) of a whole cell pertussis vaccine.

Contra-Indications: Hypersensitivity to any component of the vaccine, including thimerosal, a mercury derivative, is a contraindication.

Patients exposed to pertussis and likely to become ill with pertussis.

Immunization should be deferred during the course of any febrile illness or acute infection. A minor illness such as mild upper respiratory infection is usually not a reason to defer immunization.

The following recommendations are based on the experience with whole cell vaccines. They should be followed with acellular pertussis vaccine until a wider base of experience is available: Children with progressive neurological illness who manifest frequent convulsions should not be vaccinated. These illnesses are not an absolute contraindication against immunization with pertussis vaccine. However, an increase of the severity of the illness or the occurrence of convulsions might be attributed to the vaccine. On the other hand, with the incidence of pertussis being very high, these patients especially might be at risk. Therefore, the immunizing physician should make a careful assessment of the risks involved. A family history of febrile convulsions and convulsions is not a contraindication.

As fever can trigger a convulsive episode, antipyretics should be used freely in children predisposed to convulsions.

The decision to administer a pertussis-containing vaccine to such children must be made by the physician on an individual basis, with consideration of all relevant factors and assessment of potential risks and benefits for that individual. The physician should review the full text of NACI, ACIP and AAP guidelines prior to considering vaccination for such children. The parent or guardian should be advised of the potential increased risk involved.

If any of the following events occur in temporal relation to receipt of a pertussis vaccine, the decision to give subsequent doses of vaccine containing the pertussis component should be carefully considered: contraindications and precautions to further pertussis vaccination: Contraindication: An immediate anaphylactic reaction.

Precautions: 1. Temperature of 40.5°C within 48 hours not due to another identifiable cause. 2. Collapse or shock-like state (hypotonic – hyporesponsive episode) within 48 hours. 3. Convulsions with or without fever occurring within 3 days.

Although these events were considered absolute contraindications in previous NACI or ACIP recommendations, there may be circumstances, such as a high incidence of pertussis, in which the potential benefits outweigh possible risks particularly because these events are not associated with permanent sequelae.

Manufacturers’ Warnings In Clinical States: Not recommended for use in children below the age of 15 months as the efficacy of the vaccine in children younger than 15 months has not been fully determined.

If the vaccine is used in persons deficient in producing antibody, whether due to genetic defect or immunosuppressive illness or therapy, the expected immune response may not be obtained.

This product is not recommended for immunizing persons on or after their 7th birthday.

As with any vaccine, acellular pertussis vaccine may not protect 100% of individuals receiving the vaccine.

Precautions: If applicable, immunization can be done simultaneously with DT given contra laterally.

Acellular pertussis vaccine is for i.m. use only. The vaccine should not be given intradermally or i.v. since the safety and immunogenicity of these routes have not been evaluated.

Prior to administration of any dose of acellular pertussis vaccine, the parent or guardian should be asked about the personal history, family history and recent health status. The health care provider should ascertain previous immunization history, current health status and occurrence of any symptoms and/or signs of an adverse event after previous immunizations in the child to be immunized to determine the existence of any contraindication to immunization with acellular pertussis vaccine and to allow an assessment of benefits and risks.

Before the injection of any biological, the health care provider should take all precautions known for the prevention of allergic or any other side reactions. This should include: a review of the patient’s history regarding possible sensitivity; the ready availability of epinephrine 1:1 000 and other appropriate agents used for control of immediate allergic reactions; and a knowledge of the recent literature pertaining to use of the biological concerned, including the nature of side effects and adverse reactions that may follow its use.

Children with impaired immune responsiveness, whether due to the use of immunosuppressive therapy (including irradiation, corticosteroids, antimetabolites, alkylating agents, and cytotoxic agents), a genetic defect, human immunodeficiency virus (HIV) infection, or other causes, may have reduced antibody response to active immunization procedures. Deferral of administration of vaccine may be considered in individuals receiving immunosuppressive therapy. Other groups should receive this vaccine according to the usual recommended schedule (see Drug Interactions).

This product is not contraindicated for use in individuals with HIV.

Since this product is a suspension containing an adjuvant, shake vigorously to obtain a uniform suspension prior to withdrawing each dose.

A separate sterile syringe and needle or a sterile disposable unit should be used for each individual patient to prevent transmission of hepatitis or other infectious agents from one person to another. Needles should be disposed of properly and should not be recapped.

Special care should be taken to prevent injection into a blood vessel.

As with other aluminum-containing vaccines, a nodule may occasionally be palpable at the injection site for several weeks. Although not seen in studies with acellular pertussis vaccine, sterile abscess formation or s.c. atrophy at the injection site may also occur.

Children: This product is not recommended for use in children below the age of 15 months.

Pregnancy and Lactation: Not applicable (outside the indication).

Carcinogenesis, Mutagenesis, Impairment of Fertility: Acellular pertussis vaccine has not been evaluated for its carcinogenic, mutagenic potentials or impairment of fertility.

Drug Interactions: Simultaneous immunization is possible with attenuated live vaccines, inactivated vaccines and immunoglobulins if the application is given at separate sites.

Children receiving immunosuppressive therapy may have a reduced response to active immunization procedures.

As with other i.m. injections, acellular pertussis vaccine should be given with caution to children on anticoagulant therapy.

Information to be Provided to the Patient: Prior to administration of this vaccine, health care personnel should inform the parent, guardian, or other responsible adult of the recommended immunization schedule for protection against pertussis and the benefits and risks to the child receiving a vaccine containing an acellular pertussis component. Guidance should be provided on measures to be taken should adverse events occur, such as antipyretic measures for elevated temperatures and the need to report adverse events to the health care provider.

Adverse Reactions: Adverse reactions associated with acellular pertussis vaccine have been evaluated in 249 children 15 months to 6 years receiving this vaccine as the 3-dose primary series.

Adverse reactions associated with acellular pertussis vaccine have occasionally been noted as transient local reactions (e.g., redness, induration and warmth at the injection site).

Occasionally can be seen: fever, sleepiness, fussiness, loss of appetite and vomiting.

Convulsions, unusual sleepiness, rash at the injection site, hypotonic – hyporesponsive episodes and inconsolable crying can occur in particular cases. Neuralgia can occur as with all injections.

As with any injection of biological material, anaphylactic reactions should be expected.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: In case of anaphylactic reactions, the usual procedures for shock therapy apply.

Dosage And Administration: Primary immunization with acellular pertussis vaccine of children not previously immunized against pertussis consists of 3 doses of 0.5 mL each, given at an interval of at least 6 weeks( but not more than 10 weeks) between doses. The dose of 0.5 mL is to be given i.m. only.

The 4th or booster dose of acellular pertussis vaccine given after previous immunization with whole cell pertussis vaccine or as completion of primary immunization with acellular pertussis vaccine, consists of a single dose of 0.5 mL approximately 1 year after the 3rd primary immunization dose.

Administration: Simultaneous administration of live and inactivated vaccines is possible if given at separate sites.

Shake vigorously to obtain a uniform suspension prior to withdrawing each dose from the multiple-dose vial. The vaccine should not be used if it cannot be resuspended.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

The vaccine should be injected i.m. Do not inject s.c. or i.v. (Vaccine applied mistakenly i.v. can result in anaphylactic reactions, including shock.)

The preferred sites are the anterolateral aspect of the thigh or the deltoid muscle of the upper arm. The vaccine should not be injected in the gluteal area or areas where there may be a major nerve trunk. Before injection, the skin at the injection site should be cleansed and prepared with a suitable germicide. After insertion of the needle, aspirate to help avoid inadvertent injection into a blood vessel.

Do not use the vaccine past the expiration date.

Availability And Storage: Each dose (0.5 mL) of white to off-white, cloudy, aqueous suspension contains: adsorbed acellular pertussis vaccine 300 hemagglutinating units (HAU). The pertussis component contains approximately 41 g (but not more than 60 g) pertussis antigens per 0.5 mL dose, including: filamentous hemagglutonin (FHA) approximately 35.9 g (86%), pertussis toxoid (PT) approximately 2.9 g (8%), 69 kilodalton (69kd) outer membrane protein approximately 1.6 g (4%), fimbriae type 2 (pertussis-specific agglutinogen) approximately 0.7 g (2%).

Purification of the acellular pertussis vaccine component is accomplished by ammonium sulfate fractionation steps and a final sucrose density gradient centrifugation. The acellular pertussis vaccine component is detoxified with formaldehyde and thimerosal (mercury derivative) is added as a preservative. Nonmedicinal Ingredients: aluminum gel (aluminum phosphate, aluminum hydroxide), 2-(ethylmercurithio) benzoic acid, sodium salt (thimerosal) and phosphate buffered saline. Thimerosal (mercury derivative) is present in a final concentration of 1:10 000. The final product may also contain gelatin and polysorbate 80 which are used in early stages of the process.

Vials of 0.5 mL (1 dose), packages of 1. Do not freeze. Store refrigerated away from freezer compartment at 2 to 8°C. Product which has been exposed to freezing should not be used. Do not use this vaccine past the expiration date.

ACEL-P™ Wyeth-Ayerst Acellular Pertussis Vaccine Adsorbed Active Immunizing Agent

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