APPROVED DATA SHEET

TETRAMUNE

Diphtheria and Tetanus Toxoids and Pertussis Vaccine Adsorbed with Haemophilus b Conjugate Vaccine (DTP-HbOC) 0.5 mL and 5.0 mL vials.

 PRESENTATION

Diphtheria and Tetanus Toxoids and Pertussis Vaccine Adsorbed and Haemophilus b Conjugate Vaccine (Diphtheria CRM197 Protein Conjugate), TETRAMUNE (DTP-HbOC) is a sterile combination of PUROGENATED Diphtheria Toxoid aluminium phosphate-adsorbed, PUROGENATED Tetanus Toxoid aluminium phosphate-adsorbed, Pertussis Vaccine (DTP, TRI-IMMUNOL) and a conjugate of oligosaccharides of the capsular antigen of Haemophilus influenzae type b (Haemophilus b) and diphtheria CRM197 protein (HbOC, HibTITER). After shaking, the vaccine is a homogeneous white suspension.

The diphtheria and tetanus toxoids are derived from Corynebacterium diphtheriae and Clostridium tetani, respectively, which are grown in media according to the method of Mueller and Miller and are detoxified by use of formaldehyde. The toxoids are refined by the Pillemer alcohol fractionation method and are diluted with a solution containing sodium phosphate monobasic, sodium phosphate dibasic, glycine and thiomersal (mercury derivative) as a preservative.

Pertussis Vaccine is prepared by growing Phase I 8ordetella pertussis in a modified Cohen-Wheeler broth containing acid hydrolysate of casein. The B. pertussis is inactivated with thiomersal, harvested and then suspended in a solution containing potassium phosphate monobasic, sodium phosphate dibasic, sodium chloride and thiomersal (mercury derivative) as a preservative.

The oligosaccharides are derived from highly purified capsular polysaccharide, polyribosylribitol phosphate, isolated from Haemophilus influenzae type b grown in a chemically defined medium and coupled by reductive amination directly to highly purified CRM197. CRM197 is a nontoxic variant of diphtheria toxin isolated from cultures of C. diphtheriae C7 ( beta 197) grown in a casamino acids and yeast extract based medium. The conjugate is purified by diafiltration to remove unreacted protein, oligosaccharides and reagents, and sterilised by filtration.

The Haemophilus b conjugate component (HibTITER) is combined with the diphtheria and tetanus toxoids and pertussis vaccine adsorbed to produce the final vaccine. As a preservative, thiomersal (mercury derivative) is added to the combination vaccine to a final concentration of 1:10,000. The aluminium content of the final product does not exceed 0.85 mg per 0.5 mL dose by assay. The residual free formaldehyde content by assay is < 0.02%. Each single dose of 0.5 mL TETRAMUNE is formulated to contain 12.5 Lf of diphtheria toxoid, 5 Lf of tetanus toxoid (both toxoids induce not less than 2 units of antitoxin per mL in the guinea pig potency test), 10 ug of purified Haemophilus b saccharide and approximately 25 ug of CRM197 protein. Each 0.5 mL dose of vaccine is formulated to contain less than 16 OPUs of inactivated pertussis cells. The total human immunising dose (the first three 0.5 mL doses given) contains an estimate of 12 units of pertussis vaccine with an estimate of 4 protective units per single human dose. Each component of the vaccine - diphtheria, tetanus, pertussis and Haemophilus b conjugate - meets the required potency standards and contains no other active ingredients.

USES

ACTIONS

Diphtheria is primarily a localised and generalised intoxication caused by diphtheria toxin, an extracellular protein metabolite of toxinogenic strains of C. diphtheriae. The highest case fatality rates are in the very young and in the elderly.

Following adequate immunisation with diphtheria toxoid, it is thought that protection lasts for at least 10 years. Antitoxin levels of at least 0.01 antitoxin units/mL are generally regarded as protective. This significantly reduces both the risk of developing diphtheria and the severity of clinical illness. It does not, however, eliminate carriage of C. diphtheriae in the pharynx or on the skin.

Tetanus is an intoxication manifested primarily by neuromuscular dysfunction caused by a potent exotoxin elaborated by C. tetani. Spores of C. tetani are ubiquitous and there is essentially no natural immunity to tetanus toxin.

Universal primary immunisation with tetanus toxoid with subsequent maintenance of adequate antitoxin levels, by means of timed boosters, is necessary to protect all age groups. Tetanus toxoid is a highly effective antigen and a completed primary series generally induces serum antitoxin levels of at least 0.01 antitoxin units, a level which has been reported to be protective. It is thought that protection persists for at least 10 years.

Pertussis (whooping cough) is a disease of the respiratory tract caused by B. pertussis. This Gram-negative coccobacillus produces a variety of active components including endotoxin and a number of other substances that have been defined primarily on the basis of their biological activity in animals. These active components have been associated with a number of effects, such as lymphocytosis, leucocytosis, sensitivity to histamine, changes in glucose and/or insulin levels, possible neurological effects and adjuvant activity. The roles of each of the different components in either the pathogenesis of, or immunity to, pertussis is not well understood. However, the potency of the pertussis component is measured and shown to be acceptable In the mouse potency test. Serum agglutinin titres have been correlated with protection in clinical trials. The pertussis component induces immunity against pertussis disease in humans.

Most reported illness from B. pertussis occurs in infants and young children; two thirds of reported deaths occur in children less than one year old. Older children and adults, in whom classic signs are often absent, may go undiagnosed and serve as reservoirs of disease.

Haemophilus b disease occurs primarily in children under 5 years of age, in which the incidence peaks between 6 months and 1 year of age. The incidence of invasive Haemophilus b disease is increased in certain children, such as those who are native Americans, black or from lower socioeconomic status and those with medical conditions such as asplenia, sickle-cell disease, malignancies associated with immunosuppression and antibody deficiency syndromes.

The protective activity of antibody to Haemophilus b polysaccharide has been demonstrated by an efficacy study of Haemophilus b polysaccharide PRP vaccine. Data from passive antibody studies indicate that a pre-existinp titre of antibody to PRP of 0.15 ug/mL correlates with protection. A titre of >= 1.0 ug/mL 3 weeks after vaccination is associated with long term protection.

Linkage of Haemophilus b saccharides to a protein such as CRM197 converts the saccharide (HbO) to a T-dependent (HbOC) antigen and results in an enhanced antibody response to the saccharide in young infants that is boostable and predominantly of the IgG class. Laboratory evidence indicates that the native state of the CRM197 protein and the use of oligosaccharides in the formulation of HibTITER Haemophilus b Conjugate Vaccine (HbOC) enhances its immunogenicity. Conjugate vaccines with other carrier proteins will be recognised differently by the immune system. NO DATA ARE AVAILABLE TO SUPPORT THE INTERCHANGEABILITY OF HbOC AND OTHER HAEMOPHILUS b CONJUGATE VACCINES WITH ONE ANOTHER FOR THE PRIMARY SERIES.

HbOC was shown to be effective in a large scale controlled clinical trial. There were no (0) vaccine failures in infants who received 3 doses of HbOC and 12 cases of Haemophilus b disease (6 cases of meningitis) in the control group. The estimate of efficacy is 100% (p = 0.0002); 95% Confidence Intervals (C.l.), 2 tailed, 68%, 100%. Through the end of 1991, with an additional 49,000 person years of follow-up, there were still no cases of H. influenzae type b disease in fully vaccinated infants less than 2 years of age. One case of disease has been reported in a 3.5 year old child who did not receive a booster dose as recommended.

TETRAMUNE has been given to 6,793 children as part of a series of studies to test the safety and immunogenicity of this product when compared to separate administration of DTP and HbOC. The vaccines were given at 2, 4 and 6 months of age or at 15-18 months of age.

The antibody response to each of the components of TETRAMUNE was measured (n=189) and compared to separate administration of the DTP and HbOC vaccines (n=189). After three doses, the antibody response to TETRAMUNE was equal to or higher for all four components; tetanus (IU/mL), diphtheria (IU/mL), pertussis (microagglutination) and H. influenzae b polysaccharide (ug IgG/mL). In addition, responses to specific pertussis antigens (ie pertussis toxin, FHA and 69K protein) were found to be as high or higher in the TETRAMUNE product compared to separate administration of DTP. Therefore, the immunogenicity of the combined vaccine is at least as good as the two vaccines given separately.

INDICATIONS

TETRAMUNE is indicated for the immunisation of children 6 weeks of age up to the seventh birthday for protection against diphtheria, tetanus, pertussis and Haemophilus b disease when indications for immunisation with DTP vaccine and Haemophilus b conjugate vaccine coincide. Typically, this is at 6 weeks, 3, 5 and 15 months of age and over.

DOSAGE AND ADMlNISTRATION

TETRAMUNE is for intramuscular use only.

Parenteral drug products should be inspected visually for particulate matter and discolouration prior to

administration whenever solution and container permit.

For infants beginning at 6 weeks of age, the immunisation series for TETRAMUNE consists of 3 doses of 0.5 mL each at approximately 2 month intervals, followed by a fourth dose of 0.5 mL at approximately 15 months of age.

TETRAMUNE may be substituted for DTP and HibTITER administered separately whenever the recommended schedule for use of these two vaccines coincide (see DTP and HibTITER recommended dosage schedules).

DTP; The primary immunising course for infants and children from 6 weeks of age up to their seventh birthday consists of three doses at 4 to 8 week intervals, followed by a fourth dose 6 to 12 months after the third dose. A booster dose is indicated at age 4 to 6 years, preferably prior to entrance into kindergarten or elementary school. However, if the fourth dose was administered after the fourth birthday, a booster prior to school entry is not considered necessary.

HibTITER: infants 6 weeks to 6 months of age should receive three doses at approximately 2 month intervals. Previously unvaccinated infants 7 to 11 months of age should receive two doses approximately 2 months apart. Previously unvaccinated children 12 to 14 months of age should receive one dose. All vaccinated children should receive a single booster dose at 15 months of age or older, but not less than 2 months after the previous dose. Previously unvaccinated children 15 to 60 months of age should receive a single dose of HibTITER. No data are available to support the interchangeability of HibTITER or other Haemophilus b conjugate vaccines with one another. Therefore, it is recommended that the same conjugate vaccine be used throughout each immunisation schedule, consistent with the data supporting licensure of the vaccine.

Preterm infants may be immunised with TETRAMUNE at the usual chronological age from birth.

Simultaneous administration of DTP, HbOC, oral poliovirus vaccine (OPV) and/or measles-mumps-rubella (MMR) has resulted in seroconversion rates and rates of side effects similar to those observed when the vaccines are administered separately. Therefore, if there is any doubt whether a vaccine recipient will return for further vaccine doses, TETRAMUNE may be given simultaneously with MMR (at separate sites) and OPV if appropriate for the age and previous vaccination status of the recipient.

Interruption of the recommended schedules with a delay between doses does not interfere with the final immunity achieved; nor does it necessitate starting the series over again, regardless of the length of time elapsed between doses.

If a contraindication to the pertussis vaccine component occurs, diphtheria and tetanus toxoids adsorbed (DT) and Haemophilus b conjugate vaccine, HibTITER, should be substituted for each of the remaining doses.

Because this product is a suspension containing an adjuvant, shake vigorously to obtain a uniform suspension prior to withdrawing each dose from the vial. The vaccine should not be used if it cannot be resuspended. The vaccine should be injected intramuscularly. 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 antiseptic.

Atter insertion of the needle, aspirate to help avoid inadvertent injection into a blood vessel.

For either primary or booster immunisation against tetanus and diphtheria of individuals 7 years of age and older, the use of tetanus and diphtheria toxoids adsorbed for adult use (DT) is recommended.

CONTRAINDICATIONS

This product should not be used in individuals 7 years of age or older.

Hypersensitivity to any component of the vaccine, including thiomersal, a mercury derivative, is a contraindication. Immunisation should be deferred during the course of any febrile illness or acute infection. A minor afebrile illness such as a mild upper respiratory infection is not usually reason to defer immunisation.

immunisation with TETRAMUNE is contraindicated it the child has experienced any event following previous

immunisation with a pertussis containing vaccine which is considered to be a contraindication to further doses of pertussis vaccine. These events include:

WARNINGS AND PRECAUTIONS

If any of the following events occur in temporal relation to receipt of DTP, the decision to give subsequent doses of vaccine containing the pertussis component should be carefully considered:

Although these events are considered to be absolute contraindications, 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.

It is also recognised that in certain circumstances, children with stable central nervous system disorders, including well-controlled seizures or satisfactorily explained single seizures, may receive pertussis vaccine. A family history of seizures is not considered to be a contraindication to pertussis vaccine despite studies indicating that a personal or family history of seizures is associated with increased frequency of seizures following pertussis.

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 parent or guardian should be advised of the increased risk involved.

There are no data on whether the prophylactic use of antipyretics can decrease the risk of febrile convulsions.

However, data suggest that the incidence of post-vaccination fever may be reduced by the administration of paracetamol at the time of vaccination and every 4 to 6 hours thereafter to children at higher risk for seizures than the general population.

The clinical judgement of the attending physician should prevail at all times.

If a contraindication to any of the components at this combination vaccine exists, (see CONTRAINDICATIONS) then TETRAMUNE should not be used. For example, if there is a contraindication against the use of a pertussis vaccine component, then diphtheria and tetanus toxoids adsorbed, for paediatric use (DT) and Haemophilus b conjugate vaccine (HibTITER) should be substituted for each of the remaining doses.

TETRAMUNE should be given with caution to infants or children with thrombocytopenia or any coagulation disorder that would contraindicate intramuscular injections (see INTERACTIONS).

As reported with Haemophilus b polysaccharide vaccine, cases of Haemophilus type b disease may occur prior to the onset of the protective effect of this vaccine.

TETRAMUNE will not protect against H. influenzae other than type b strains.

Antigenuria has been detected following receipt of Haemophilus b conjugate vaccine and therefore antigen detection may not have diagnostic value in suspected Haemophilus b disease within 2 weeks of immunisation. Routine immunisation should be deferred during an outbreak of poliomyelitis providing the patient has not sustained an injury that increases the risk of tetanus and providing an outbreak of diphtheria, pertussis or Haemophilus type b disease does not occur simultaneously.

Prior to administration of any dose of TETRAMUNE, the parent or guardian should be asked about the personal history, family history and recent health status. The physician should ascertain previous immunisation history, current health status and occurrence of any symptoms and/or signs at an adverse event after previous immunisations in the child to be immunised, in order to determine the existence of any contraindication to immunisation with TETRAMUNE and to allow an assessment of benefits and risks.

Before the injection of any biological, the physician should take all precautions known for the prevention of allergic or any other adverse reactions. This should include: a review of the patient's history regarding possible sensitivity; the ready availability of adrenaline 1:1000 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 SHIV) infection or other causes, may have reduced antibody response to active immunisation 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 INTERACTIONS).

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

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.

Full protection against the indicated diseases (tetanus, diphtheria, pertussis and haemophilus type b) is based on a full course of immunisation.

CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY

TETRAMUNE has not been evaluated for its carcinogenic or mutagenic potential or for impairment of fertility.

USE IN PREGNANCY

There is no convincing evidence of risk to the foetus from immunisation of pregnant women, using inactivated virus vaccines, bacterial vaccines or toxoids.

USE IN CHILDREN

The safety and effectiveness of TETRAMUNE in children below the age of 6 weeks have not been established. As with any vaccine, TETRAMUNE may not protect 100% of individuals receiving the vaccine.

Children who have recovered from culture-confirmed pertussis need not receive further doses of a vaccine containing pertussis. However, these children should receive additional doses of diphtheria and tetanus toxoids adsorbed as well as Haemophilus b conjugate vaccine as appropriate to complete the series.

Children who have experienced invasive Haemophilus b disease when < 24 months of age should continue immunisation against Haemophilus b. Children whose disease occurred at >= 24 months need not receive further doses of Haemophilus b conjugate vaccine. However, these children should receive additional doses of OTP as appropriate to complete the series.

ADVERSE EFFECTS

The safety of TETRAMUNE has been evaluated in 6,793 children at 2, 4 and 6 months of age or at 15-18 months of age. The percent of doses administered associated with injection site reactions within 72 hours or common systemic symptoms within 4 days is summarised in Table 1.

Table 1

1 within 72 hours of immunisation

2 within 4 days of immunisation

3 data for this study all collected within 24 hours of immunisation

4 percived fever

As with other aluminium-containinq vaccines, a nodule may occasional be palpable at the injection site for several weeks. Although not seen in studies with TETRAMUNE, sterile abscess formation or subcutaneous atrophy at the injection site may also occur.

The following significant adverse events have occurred following administration of DTP vaccines: persistent, inconsolable crying >= 3 hours (1/100 doses), high-pitched, unusual crying (1/1000 doses), fever >= 40.5degC (1/330 doses), transient shock-like (hypotonic, hyporesponsive) episode (1/1750 doses), convulsions (1/1750 doses).

Although DTP may rarely produce symptoms that some have classified as acute encephalopathy, a causal relation between DTP vaccine and permanent brain damage has not been demonstrated. If the vaccine ever causes brain damage, the occurrence of such an event must be exceedingly rare.

The occurrence of sudden infant death syndrome (SIDS) has been reported following administration of DTP. However, a large case-control study in the U.S. revealed no causal relationship between receipt of DTP vaccine and SIDS. A recent study in Northern California found no increase in the rate of SIDS among TETRAMUNE recipients.

Onset of infantile spasms has occurred in infants who have recently received DTP or DT although it has been shown that there is no causal relationship to the administration of preparations containing diphtheria, tetanus and/or pertussis antigens. The incidence of onset of infantile spasms increases at 3-9 months of age, the time period in which the second and third doses of DTP are generally given. Therefore, some cases of infantile spasms can be expected to be related by chance alone to recent receipt of vaccines containing DTP.

Bulging fontanelles has been reported after DTP immunisation, although no cause and effect relationship has been established.

Cardiac effects and respiratory difficulties, including apnoea have been reported rarely following DTP immunisation.

Other events that have been reported following administration of vaccines containing diphtheria, tetanus, pertussis or Haemophilus b antigens include: urticaria, erythema multiforme or other rashes and arthralgias. More rarely, a severe anaphylactic reaction (eg urticaria with swelling of the mouth, difficulty breathing, hypotension or shock) and neurological complications, such as convulsions, encephalopathy and various mono- and polyneuropathies, including Guillain-Barre syndrome have been reported.

INTERACTIONS

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

As with other intramuscular injections, TETRAMUNE should be given with caution to children on anticoagulant therapy.

Tetanus Immune Globulin or Diphtheria Antitoxin, it used, should be given in a separate site with a separate needle and syringe.

It is recommended that influenza virus vaccine should not be administered within 3 days of immunisation with a pertussis containing vaccine since both vaccines may cause febrile reactions in young children.

No impairment of the antibody response to the individual antigens was demonstrated when HibTITER was given at the same time, but at separate sites, as DTP plus Oral Polio Vaccine (OPV) to children 2-20 months of age or Measles, Mumps and Rubella Vaccine (MMR) to children 15 months of age.

No data is available on the concomitant usage with Hepatitis B vaccines.

PHARMACEUTICAL PRECAUTIONS

Store refrigerated away from freezer at 2-8degC.

DO NOT FREEZE.

Multidose vial should be discarded one month after the first dose has been removed.

MEDICINE CLASSIFICATION Prescription Medicine

PACKAGE QUANTITIES

0.5 mL vial (single dose) as single vial or 10 vial pack sizes 5.0 mL vial (10 doses)

FURTHER INFORMATION

Nil

NAME AND ADDRESS

Lederle Laboratories

Division of Wyeth (N.Z.) Limited

477 Great South Road

Penrose

Auckland

New Zealand

Ph (09) 525 7998

â Registered Trademark

Last Text Revision: 080596

Date of Last Revision: 26 June 1996