RxMed: Pharmaceutical Information – QUADRACEL

QUADRACEL™

Connaught

Component Pertussis Vaccine – Diphtheria and Tetanus Toxoids Adsorbed Combined with Inactivated Poliomyelitis Vaccine

Active Immunizing Agent

Action And Clinical Pharmacology: Immunization against diphtheria, tetanus, pertussis and polio has been associated with a striking decrease in the incidence of morbidity and mortality from these diseases. Simultaneous vaccination with a combination vaccine containing pertussis, diphtheria and tetanus toxoids and poliomyelitis vaccines have been used in Canada since 1958.

Diphtheria is a serious communicable disease caused by toxigenic strains of C. diphtheriae. The organism may be harbored in the nasopharynx, skin or other sites of asymptomatic carriers, making eradication of the disease difficult. Routine immunization against diphtheria in infancy and childhood has been widely practised in Canada since 1930, resulting in a decline in morbidity and mortality. Fewer than 5 cases are now reported annually in Canada. The case-fatality rate remains 5 to 10%, with the highest death rates in the very young and elderly. The disease occurs most frequently in unimmunized or partially immunized individuals. Diphtheria toxoid is a cell-free preparation of diphtheria toxin detoxified with formaldehyde. The immunity conferred is antitoxic, not antibacterial, and thus protects against the potentially lethal systemic effects of diphtheria toxin but not directly against local infection.

Tetanus is an acute and often fatal disease caused by an extremely potent neurotoxin produced by C. tetani. The organism is ubiquitous and its occurrence in nature cannot be controlled. Immunization is highly effective, provides long-lasting protection, and is recommended for the whole population. Only 2 to 3 cases of tetanus are now reported annually in Canada. Tetanus toxoid is prepared by detoxification of tetanus toxin with formaldehyde.

Injection of bacterial proteins such as diphtheria and tetanus toxoids results in the production of protective antibodies. A primary series consisting of 2 or more injections is required to prime the immune system and produce a satisfactory protective antibody level. Tetanus antitoxin levels of >0.01 IU/mL are generally accepted as good evidence of immunity from tetanus. Diphtheria antitoxin levels of ³0.01 IU/mL are thought to be the minimal level required for protection. Levels >0.05 IU/mL are considered optimal for protection. After completion of a primary series, circulating antibodies to tetanus and diphtheria toxoids gradually decline but are thought to persist at protective levels for up to 10 years. Tetanus and diphtheria toxoid boosters are recommended every 10 years.

Pertussis (whooping cough) is a highly communicable bacterial disease caused by B. pertussis. Severity and mortality are greatest in infancy, and even infants born to apparently immune mothers are highly susceptible to infection, particularly if maternal immunity was induced by whole cell pertussis vaccine. During the last 30 years, vaccination with whole cell pertussis vaccine has been widely practised in Canada and the incidence and mortality from pertussis have declined remarkably. However, outbreaks of pertussis continue to occur across Canada, with an annual reported rate of 1 000 to 8 000 cases over the past 5 years. Deaths and brain damage from pertussis infections still occur, particularly in young infants who have not been vaccinated. Controversy regarding the safety of whole cell pertussis vaccine during the 1970s led to several studies of the benefits and risks of this vaccination during the 1980s. These epidemiologic analyses clearly indicate that the benefits of the pertussis immunization program outweigh the risks. Acellular pertussis vaccines consisting of purified fractions of the B. pertussis bacterium have been used effectively to control pertussis in children 2 years of age or older in Japan since 1981.

A randomized controlled efficacy study was conducted in Sweden using the formulation of Tripacel which contained lower concentrations of PT, FHA than the current formulation. In this study, 2 500 infants received Tripacel and 2 500 infants received a control vaccine containing diphtheria and tetanus toxoids. Tripacel demonstrated a clinical efficacy of 85% against pertussis disease (defined as 21 days of paroxysmal cough with culture, serologic, or epidemiologic confirmation). The current formulation of Tripacel produced comparable or higher serologic responses to the defined pertussis antigens (PT, FHA, fimbriae and pertactin) when compared to the lower antigen formulation in clinical trials, either as a primary immunizing agent or as a booster vaccine. Tripacel has been shown to have lower rates of local and systemic reactions compared directly against whole cell DPT vaccines when administered to infants and older children.

Poliomyelitis is caused by infection with 1 of the 3 antigenic types of poliovirus. Following introduction of poliovirus vaccine in Canada in 1955, the indigenous disease has been virtually eliminated. The last significant outbreak of poliomyelitis occurred in 1978 to 1979, when there were 11 cases of paralytic disease among unimmunized contacts of imported cases. The last case of poliomyelitis attributed to imported, wild virus occurred in 1988. However, circulation of wild viruses does occur in rare circumstances, and it remains crucial that the highest possible level of vaccine-induced immunity be maintained in the population. Inactivated Poliomyelitis Vaccine (Diploid Cell Origin) – IPV, (sometimes referred to as e-IPV), is an enhanced formalin-inactivated product which has a higher potency than the original IPV. The 3 poliovirus types are propagated in human diploid cells. A primary series induces protective antibody levels in more than 99% of recipients.

In clinical trials conducted in Canada, more than 1 000 children have received Quadracel alone or used to reconstitute Act-HIB, Haemophilus b Conjugate Vaccine (Tetanus Protein-Conjugate). Whether given at 2, 4, 6 months, at 18 to 19 months (fourth dose) or at the 4- to 6-year booster, Quadracel produced comparable antitetanus, diphtheria and polio responses to the DPT Polio Adsorbed control. Anti-PRP responses were comparable as well. Although Quadracel contains 15 Lf of diphtheria toxoid versus the 25 Lf of diphtheria toxoid in DPT Polio Adsorbed, no significant differences in diphtheria antitoxin responses were seen in any of the age groups. Responses to pertussis antigens PT, FHA and pertactin were significantly higher in Quadracel recipients than in recipients of DPT Polio Adsorbed.

With the exception of tetanus, no differences were found in immunogenicity when Quadracel was used to reconstitute Act-HIB or the 2 vaccines were given at separate sites. Anti-PRP responses were comparable. All children were protected against polio. Pertussis responses were not affected by method of administration. Tetanus antitoxin levels were lower in the combined vaccine groups, but all children had protective levels (³0.01 EU*/mL). Following the 18-month dose, all children had tetanus antitoxin levels ³0.10 EU*/mL.

Quadracel was significantly less reactogenic than DPT Polio Adsorbed.

*EU=Elisa Units.

Indications And Clinical Uses: For the primary immunization of infants, at or above the age of 2 months and as a booster in children up to their 7th birthday against diphtheria, tetanus, whooping cough and poliomyelitis.

When both vaccines are indicated, Quadracel may be used to reconstitute Act-HIB (Haemophilus b Conjugate Vaccine Tetanus Protein-Conjugate) for simultaneous administration of all 5 antigens in a single injection. Quadracel must not be mixed in the same syringe with any other vaccines.

Because simultaneous administration of common childhood vaccines is not known to affect the efficacy or safety of any of the routine recommended childhood vaccines, if return of a vaccine recipient for further immunization is doubtful, simultaneous administration of all vaccines appropriate for age and previous vaccination status (including MMR, other H. influenzae type b conjugate vaccines, hepatitis B vaccine) at separate sites with separate syringes is indicated.

Infants born prematurely whose clinical condition is satisfactory should be vaccinated according to their chronological age from birth.

Contra-Indications: General: Immunization with Quadracel should be deferred in the presence of any acute illness, including febrile illness. A minor afebrile illness such as mild upper respiratory infection is not usually reason to defer immunization.

Quadracel should not be administered to children after their 7th birthday or to adults because of the quantity of diphtheria toxoid and because pertussis is less severe in these age groups than in infants and young children.

Absolute Contraindications: Allergy to any component of Quadracel (see Supplied), or an allergic or anaphylactic reaction to a previous dose of DPT Polio Adsorbed are contraindications to vaccination.

Relative Contraindications (based on experience with whole cell pertussis vaccine): Hypotonic-hyporesponsive episodes: No long-term sequelae have been associated with hypotonic-hyporesponsive episodes; however, it may be prudent in areas of low pertussis incidence to withhold the pertussis component and continue immunization with DT Polio Adsorbed in children who have experienced a hypotonic-hyporesponsive episode following a previous dose of pertussis-containing vaccine. Children can continue immunization with Quadracel if the incidence of disease is high in their area.

Deferral: Deferral of the pertussis component of Quadracel should be considered in children with a progressive, evolving, or unstable neurologic condition (including seizures) because administration of the pertussis component may coincide with the onset of overt manifestations of such disorders and result in confusion about causation. It is prudent to delay initiation of immunization with pertussis vaccine until further observation and study have clarified the child’s neurologic status. In addition, the effect of treatment, if any, can be assessed. Immunization with Quadracel should be reinstituted when the condition has resolved, been corrected or controlled.

When immunization with pertussis vaccine is contraindicated or deferred, immunization with diphtheria and tetanus toxoids and poliomyelitis vaccine, when necessary, may be continued using DT Polio Adsorbed.

The use of fractional doses in an attempt to reduce the severity of adverse reactions cannot be recommended because there is insufficient evidence on the safety or efficacy of such smaller doses.

Elective immunization of individuals over 6 months of age should be deferred during an outbreak of poliomyelitis.

Human Immunodeficiency Virus (HIV) Infected Persons: HIV-infected individuals, both asymptomatic and symptomatic, should be immunized against diphtheria, pertussis, tetanus and poliomyelitis according to standard schedules.

Manufacturers’ Warnings In Clinical States: I.M. injections should be given with care in patients suffering from coagulation disorders because of the risk of hemorrhage.

If Quadracel is used in persons with malignancies, receiving immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs, or who are otherwise immunocompromised (including HIV infected individuals), the expected immune response may not be obtained.

Corticosteroid therapy can result in immunosuppression although the exact dose and duration of therapy required to suppress the immune system is not well defined. Persons treated with high doses of systemic steroids, e.g., ³2 mg/kg/day of prednisone orally for more than 2 weeks, should be considered to have a compromised immune system.

As with any vaccine, immunization with Quadracel may not protect 100% of susceptible individuals.

Precautions: General: Care is to be taken by the health care provider for the safe and effective use of Quadracel.

The possibility of allergic reactions in individuals sensitive to components of the vaccine should be evaluated. Epinephrine HCl solution (1:1 000) and other appropriate agents should be available for immediate use in case an anaphylactic or acute hypersensitivity reaction occurs. Health care providers should be familiar with current recommendations for the initial management of anaphylaxis in nonhospital settings.

Before an injection of any vaccine, all appropriate precautions should be taken to prevent adverse reactions. This includes a review of the patient’s history with respect to possible hypersensitivity to the vaccine or similar vaccine, determination of previous immunization history, and the presence of any contraindications to immunization, current health status, and a current knowledge of the literature concerning the use of the vaccine under consideration.

Antipyretic Prophylaxis: Administration of acetaminophen (15 mg/kg/dose) or other appropriate antipyretic at the time of immunization and at 4 and 8 hours after immunization decreases the incidence of febrile and local reactions. Since convulsions after whole cell pertussis vaccine are almost always associated with fever, antipyretic prophylaxis may benefit children at increased risk of seizures. For such children, administration of an antipyretic every 4 to 6 hours for as long as 24 hours after vaccination should be considered. Caregivers should be aware that antipyretic therapy could also obscure fever caused by concomitant, unrelated infection.

Special care should be taken to ensure that the product is not injected into a blood vessel.

A separate, sterile needle and syringe or a sterile disposable unit must be used for each individual patient to prevent the transmission of infectious agents. There have been case reports of transmission of HIV and hepatitis by failure to scrupulously observe sterile technique. In particular, the same needle and/or syringe must never be used to re-enter a multidose vial to withdraw vaccine even when it is to be used for inoculation of the same patient. This may lead to contamination of the vial contents and infection of patients who subsequently receive vaccine from the vial.

Needles should not be recapped and should be disposed of properly.

A family history of convulsions in parents and siblings is not a contraindication to pertussis vaccination and children with such family histories should receive pertussis-containing vaccine according to the recommended schedule. Parents of infants and children with family histories of convulsions should be informed of their children’s increased risk of seizures following administration of any vaccine causing a febrile reaction. Acetaminophen prophylaxis is particularly recommended for children with a personal or family history of convulsions.

Frequent booster doses of tetanus or diphtheria toxoids in the presence of adequate or excessive serum levels of tetanus or diphtheria antitoxins have been associated with increased incidence and severity of reactions and should be avoided.

Before administration of Quadracel, health care personnel should inform the parent or guardian of the patient of the benefits and risks of immunization, and also inquire about the recent health status of the patient to be injected.

Adverse Reactions: In clinical trials done in Canada, Quadracel had consistently lower rates of local and systemic reactions than DPT Polio Adsorbed, whether combined with Act-HIB or given at separate sites. See Tables II and III.

Local Reactions: As with whole cell DPT and DPT Polio, there is a trend for increasing local reaction rates at the fourth and fifth doses, but with Quadracel these are still lower than those observed following whole cell DPT and DPT Polio.

In a clinical trial comparing 3 acellular pertussis and 1 whole cell DPT Vaccine in Sweden 20 745 infants received Tripacel, Component Pertussis Vaccine Combined with Diphtheria and Tetanus Toxoids Adsorbed at 2, 4 and 6 months of age. The following serious adverse events were reported: fever >40°C (within 3 days of immunization) 7; hypotonic-hyporesponsive episode 29; convulsions (within 3 days of immunization) 4; acute severe neurologic event lasting more than 30 minutes 1; infantile spasms 2; invasive bacterial infections 9; deaths 4*.

*Not attributed to the vaccine.

Rates of events were less than or comparable to the rates in the other acellular pertussis vaccine and whole cell DPT groups in this study.

Rarely, an anaphylactic reaction (i.e., hives, swelling of the mouth, difficulty breathing, hypotension, or shock) has been reported after receiving preparations containing diphtheria, tetanus, and/or pertussis antigens.

Arthus-type hypersensitivity reactions, characterized by severe local reactions (generally starting 2 to 8 hours after an injection), may follow receipt of tetanus and diphtheria toxoids. A few cases of peripheral neuropathy have been reported following tetanus toxoid administration, although a causal relationship has not been established.

Persistent nodules at the site of injection have occurred following the use of adsorbed vaccine, but this complication is unusual. Sterile abscess at the site of injection have been reported following use of adsorbed vaccines (6 to 10 per million doses).

Persistent, inconsolable crying lasting 3 or more hours (1%) and high-pitched, unusual screaming (0.1%) have also been reported after whole cell DPT vaccination. The incidence of both of these events is significantly lower with Quadracel. Convulsions and a hypotonic-hyporesponsive state have each been reported to occur at a frequency of about 1:1 750 injections of whole cell DPT. Most convulsions are brief, generalized and self-limited, and are usually associated with fever. Neither febrile nor afebrile convulsions have been shown to be associated with subsequent seizure disorder. Complete recovery, with no persistent sequelae, has been observed on follow-up of children with hypotonic-hyporesponsive episodes or convulsions (see Contraindications and Precautions).

Although there has been a concern about the possible association of severe neurologic illness (including encephalopathy) occurring within 72 hours of the administration of whole cell pertussis-containing vaccines to previously healthy infants, the risk of an association is so small compared to the background rate for these types of events that the question of causation probably cannot be answered.

Reanalysis of the National Childhood Encephalopathy study (NECS) in the United Kingdom has failed to confirm that there was an increased risk of permanent brain damage following acute neurological illness occurring within 7 days of whole cell pertussis vaccination. Additional studies have also failed to demonstrate an association between pertussis vaccine and permanent neurologic sequelae.

Sudden infant death syndrome (SIDS) has been reported in temporal relationship to the administration of vaccines containing diphtheria and tetanus toxoids and pertussis vaccine (DPT). Review of the evidence does not indicate a causal relationship between whole cell DPT vaccine and SIDS. Studies showing a temporal relation between these events are consistent with the expected occurrence of SIDS over the age range in which DPT immunization usually occurs.

Physicians, nurses and pharmacists should report any adverse occurrences temporally related to the administration of the product in accordance with local requirements and report to the Medical Director at Connaught Laboratories Limited, 1755 Steeles Avenue West, Toronto, Ontario, Canada, M2R 3T4.

Dosage And Administration: For primary immunization of infants the following routine immunization schedule is recommended: one 0.5 mL dose administered at 2, 4, 6 and 18 months of age.

If, for any reason this schedule is delayed, it is recommended that 3 doses of 0.5 mL be administered with an interval 4 to 8 weeks between doses, followed by a fourth dose of 0.5 mL administered approximately 1 year following the third dose.

A booster dose of 0.5 mL should be administered between 4 and 6 years of age (i.e., at the time of school entry). This booster dose is unnecessary if the fourth primary immunizing dose has been administered after the fourth birthday.

Thereafter, routine booster immunizations should be with Td, at intervals of 10 years. Persons 7 years of age and older should not be immunized with Quadracel.

Parenteral biological products should be inspected visually for extraneous particulate matter and/or discoloration prior to administration. If these conditions exist, the product should not be administered.

Shake the vial or ampul well to distribute uniformly the suspension before withdrawing each dose. Before withdrawing a dose from an ampul, tap the container first to ensure that any vaccine in the ampul neck falls to the lower portion of the ampul. Once the ampul has been opened, any of its contents not used immediately should be discarded. When administering a dose from a rubber-stoppered vial, do not remove either the rubber stopper or the metal seal holding it in place. Aseptic technique must be used for withdrawal of each dose (see Precautions).

Before injection, the skin over the site to be injected should be cleansed with a suitable germicide.

Administer the vaccine i.m. The preferred site is into the deltoid muscle or into the anterolateral aspect of the mid-thigh (vastus lateralis muscle). In children >1 year of age, the deltoid is the preferred site since use of the anterolateral thigh results in frequent complaints of limping due to muscle pain.

After insertion of the needle, aspirate to ensure that the needle has not entered a blood vessel.

Do not inject i.v.

Each person who is immunized should be given a permanent personal immunization record. In addition, it is essential that the physician or nurse record the immunization history in the permanent medical record of each patient. This permanent office record history should contain the name of the vaccine, date given, dose, manufacturer and lot number.

Availability And Storage: Each 0.5 mL of sterile, cloudy, uniform suspension contains: pertussis toxoid (PT) 20 µg, filamentous hemagglutinin (FHA) 20 µg, fimbriae (agglutinogens 2+3) 5 µg, pertactin (69kDa membrane protein) 3 µg, diphtheria toxoid 15 Lf, tetanus toxoid 5 Lf, aluminum 0.33 mg, purified inactivated poliomyelitis vaccine: Type 1( Mahoney); Type 2 (M.E.F.1); Type 3 (Saukett); and 2-phenoxyethanol 0.6%±0.1% added as preservative. By calculation, the vaccine contains 20 ppm Tween 80 less than 0.05% albumin (human) and less than 1 ppm of bovine serum. Trace amounts of polymyxin B and neomycin may be present from the cell growth medium. Single dose ampuls of 0.5 mL, boxes of 5.

Store between 2 and 8°C. Do not freeze. Product which has been exposed to freezing should not be used. Do not use vaccine after expiration date.

QUADRACEL™ Connaught Component Pertussis Vaccine – Diphtheria and Tetanus Toxoids Adsorbed Combined with Inactivated Poliomyelitis Vaccine Active Immunizing Agent