Pentacel (Sanofi Vaccines Canada, Liquid, Powder For Solution) Product Monograph

SUMMARY PRODUCT INFORMATION

Route of Administration

Intramuscular injection

Dosage Form / Strength

Reconstituted product for injection

Each single dose (approximately 0.5 mL) after reconstitution contains:

Active Ingredients:

Purified polyribosylribitol phosphate capsular polysaccharide (PRP) of Haemophilus influenzae type b covalently bound to tetanus protein, diphtheria toxoid, tetanus toxoid, acellular pertussis [pertussis toxoid (PT), filamentous haemagglutinin (FHA), pertactin (PRN), fimbriae types 2 and 3 (FIM)], inactivated poliomyelitis vaccine (IPV) type 1 (Mahoney), type 2 (MEF1) and type 3 (Saukett).

Clinically Relevant Nonmedicinal Ingredients

Excipients: Aluminum phosphate (adjuvant), 2-phenoxyethanol, polysorbate 80, Tris (hydroxymethyl) aminomethane, sucrose.

Manufacturing process residuals: Bovine serum albumin, formaldehyde, glutaraldehyde, neomycin, polymyxin B.

For a complete listing see DOSAGE FORMS, COMPOSITION and PACKAGING section.

DESCRIPTION

PENTACEL^® [Haemophilus b Conjugate Vaccine (Tetanus Protein – Conjugate) Reconstituted with Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed Combined with Inactivated Poliomyelitis Vaccine] is supplied in two vials: one vial containing lyophilized Haemophilus b conjugate vaccine consisting of the Haemophilus influenzae type b capsular polysaccharide PRP covalently bound to tetanus protein, and one vial containing a suspension of diphtheria and tetanus toxoids adsorbed on aluminum phosphate and acellular pertussis vaccine combined with inactivated poliomyelitis vaccine types 1, 2 and 3 and suspended in water for injection. The acellular pertussis vaccine is composed of 5 purified antigens (PT, FHA, PRN and FIM). After reconstitution, the vaccine is a sterile, uniform, cloudy, white to off-white suspension.

INDICATIONS AND CLINICAL USE

PENTACEL^® is indicated for the primary immunization of infants, from the age of 2 months, and in children up to 6 years of age (prior to their 7th birthday), against invasive Haemophilus influenzae type b disease, diphtheria, tetanus, pertussis (whooping cough) and poliomyelitis. (See DOSAGE AND ADMINISTRATION.)

Currently, Haemophilus b conjugate vaccines are not recommended for infants younger than 2 months of age.

According to the National Advisory Committee on Immunization (NACI), children who have had invasive H. influenzae type b (Hib) infection, diphtheria, tetanus or pertussis should still be immunized since these clinical infections do not always confer immunity. (1) For persons who have been exposed to invasive Hib and who are incompletely immunized, refer to the guidelines in the Canadian Immunization Guide.

NACI recommends that Human Immunodeficiency Virus (HIV)-infected persons, both asymptomatic and symptomatic, should be immunized against H. influenzae type b, diphtheria, pertussis, tetanus and poliomyelitis according to standard schedules. (1)

PENTACEL^® is not to be used for the treatment of diseases caused by H. influenzae type b, Corynebacterium diphtheriae, Clostridium tetani, Bordetella pertussis or poliovirus infections.

Pediatrics

PENTACEL^® is not indicated for persons less than 2 months or persons 7 years of age or older.

Geriatrics

PENTACEL^® is not indicated for use in adult and elderly populations.

CONTRAINDICATIONS

Hypersensitivity

NACI recommends that known systemic hypersensitivity reaction to any component of PENTACEL^® or a life-threatening reaction after previous administration of the vaccine or a vaccine containing one or more of the same components are contraindications to vaccination. (1) (2) (3) (See SUMMARY PRODUCT INFORMATION.) Because of uncertainty as to which component of the vaccine may be responsible, none of the components should be administered. Alternatively, such persons may be referred to an allergist for evaluation if further immunizations are considered.

Acute Neurological Disorders

According to ACIP the following events are contraindications to administration of any pertussis-containing vaccine, (2) including PENTACEL^®:

Encephalopathy (e.g., coma, decreased level of consciousness, prolonged seizures) within 7 days of a previous dose of a pertussis-containing vaccine that is not attributable to another identifiable cause.

Progressive neurologic disorder, including infantile spasms, uncontrolled epilepsy, progressive encephalopathy. Pertussis vaccine should not be administered to persons with such conditions until a treatment regimen has been established and the condition has stabilized.

WARNINGS AND PRECAUTIONS

General

Before administration of PENTACEL^®, health-care providers should inform the parent or guardian of the recipient of the benefits and risks of immunization, inquire about the recent health status of the recipient, review the recipient’s history concerning possible hypersensitivity to the vaccine or similar vaccine, previous immunization history, the presence of any contraindications to immunization and comply with any local requirements with respect to information to be provided to the parent or guardian before immunization and the importance of completing the immunization series.

It is extremely important that the parent or guardian be questioned concerning any signs or symptoms of an adverse reaction after a previous dose of vaccine. (See CONTRAINDICATIONS and ADVERSE REACTIONS.)

NACI states that the rates and severity of adverse events in recipients of tetanus toxoid are influenced by the number of prior doses and level of pre-existing antitoxins. (1) (3)

As with any vaccine, PENTACEL^® may not protect 100% of susceptible individuals.

Vaccines that contain Hib antigen do not provide protection against infections with other types of Haemophilus influenzae, or against meningitis of other origin.

Under no circumstances can the tetanus protein contained in conjugate vaccines containing tetanus toxoid as protein carrier be used to replace the usual tetanus vaccination.

Edematous reaction affecting one or both lower limbs has occurred following vaccination with Haemophilus influenzae type b-containing vaccines. When this reaction occurs, it does so mainly after primary injections and is observed within the first few hours following vaccination. Associated symptoms may include cyanosis, redness, transient purpura and severe crying. In reported cases, all events resolved spontaneously without sequelae within 24 hours.

Sudden infant death syndrome (SIDS) has occurred in infants following administration of DTaP vaccines. By chance alone, some cases of SIDS can be expected to follow administration of DTaP, IPV or Hib vaccines. (4)

Administration Route-Related Precautions: Do not administer PENTACEL^® by intravascular injection: ensure that the needle does not penetrate a blood vessel.

Intradermal or subcutaneous routes of administration are not to be utilized.

PENTACEL^® should not be administered into the buttocks.

Febrile or Acute Disease: ACIP recommends that vaccination should be postponed in cases of an acute or febrile disease. (2) (3). However, a disease with low-grade fever should not usually be a reason to postpone vaccination.

If any of the following events occur within the specified period after administration of a whole-cell pertussis vaccine or a vaccine containing an acellular pertussis component, the decision to administer PENTACEL^® should be based on careful consideration of potential benefits and possible risks. (2)

• Temperature of ≥40.5°C (105°F) within 48 hours, not attributable to another identifiable cause;
• Collapse or shock-like state (hypotonic-hyporesponsive episode) within 48 hours;
• Persistent crying lasting ≥3 hours within 48 hours;
• Convulsions with or without fever within 3 days.

Hematologic

Because any intramuscular injection can cause an injection site hematoma in persons with any bleeding disorders, such as hemophilia or thrombocytopenia, or in persons on anticoagulant therapy, intramuscular injections with PENTACEL^® should not be administered to such persons unless the potential benefits outweigh the risk of administration. If the decision is made to administer any product by intramuscular injection to such persons, it should be given with caution, with steps taken to avoid the risk of hematoma formation following injection.

Immune

The possibility of allergic reactions in persons sensitive to components of the vaccine should be evaluated. Hypersensitivity reactions may occur following the use of PENTACEL^® even in persons with no prior history of hypersensitivity to the product components. Cases of allergic or anaphylactic reaction have been reported after receiving some preparations containing diphtheria and tetanus toxoids and/or pertussis antigens. (5)

As recommended by NACI and as with all other products, epinephrine hydrochloride solution (1:1,000) and other appropriate agents should be available for immediate use in case an anaphylactic or acute hypersensitivity reaction occurs. (1) Health-care providers should be familiar with current recommendations for the initial management of anaphylaxis in non-hospital settings including proper airway management. (1) For instructions on recognition and treatment of anaphylactic reactions, see the current edition of the Canadian Immunization Guide or visit the Health Canada website.

According to NACI, immunocompromised persons (whether from disease or treatment) may not obtain the expected immune response. If possible, consideration should be given to delaying vaccination until after the completion of any immunosuppressive treatment. (1) Nevertheless, vaccination of persons with chronic immunodeficiency such as HIV infection is recommended even if the antibody response might be limited. (2)

Neurologic

A review by the US Institute of Medicine (IOM) found evidence for a causal relation between tetanus toxoid and both brachial neuritis and Guillain-Barré syndrome (GBS). (6) ACIP recommends that if GBS occurred within 6 weeks of receipt of prior vaccine containing tetanus toxoid, the decision to give PENTACEL^® or any vaccine containing tetanus toxoid should be based on careful consideration of potential benefits and possible risks .(2)

A few cases of demyelinating diseases of the central nervous system, peripheral mononeuropathies, and cranial mononeuropathies have been reported following vaccines containing tetanus and/or diphtheria toxoids, although the IOM concluded that the evidence is inadequate to accept or reject a causal relation between these conditions and vaccination. (6)

ACIP recommends that for infants or children at higher risk for seizures than the general population, an appropriate antipyretic may be administered (in the dosage recommended in its prescribing information) at the time of vaccination with a vaccine containing an acellular pertussis component (including PENTACEL^®) and for the following 24 hours, to reduce the possibility of post-vaccination fever. (2)

Hypotonic-hyporesponsive episodes (HHEs) rarely follow vaccination with whole-cell pertussis- containing DTP vaccines and occur even less commonly after acellular pertussis-containing DTP vaccines and DT vaccines. NACI states that a history of HHEs is not a contraindication to the use of acellular pertussis vaccines but recommends caution in these cases. (1)

Pregnant Women:

The vaccine should not be administered to pregnant women.

Nursing Women:

The vaccine should not be administered to nursing women.

Pediatrics

The potential risk of apnea and the need for respiratory monitoring for 48 – 72 hours should be considered when administering the primary immunization series to very premature infants (born ≤ 28 weeks of gestation) and particularly for those with a previous history of respiratory immaturity. As the benefit of vaccination is high in this group of infants, vaccination should not be withheld or delayed.

ADVERSE REACTIONS

Clinical Trial Adverse Drug Reactions

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 rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to vaccine use and for approximating rates of those events.

A total of 1,334 doses of PENTACEL^® have been administered to infants and toddlers in 3 clinical trials. In all, 1,005 infants received 3 doses of PENTACEL^®. Of these infants, 296 received 4 doses of PENTACEL^®. Thirty-three toddlers received PENTACEL^® as a 4^th dose at 18 months.

In a randomized, controlled clinical trial conducted in Canada, 335 infants were immunized with PENTACEL^® at 2, 4 and 6 months of age. In addition, 296 of these children were immunized as toddlers at 18 months. (7) Table 1 below provides a summary of the frequency of solicited reactions observed within 24 hours following each dose of PENTACEL^®. Injection site reactions were generally mild. Up to approximately one third of children receiving PENTACEL^® experienced some degree of redness, swelling or tenderness around the injection site. The frequency and duration of severe redness and swelling was higher after the fourth dose in toddlers than in the previous three doses in infants, however severe tenderness did not increase with the fourth dose. Severe systemic reactions were infrequent with PENTACEL^® and experienced by less than 2% of children. No infant immunized with PENTACEL^® and only one toddler immunized with PENTACEL^® experienced a fever >40°C.

Table 1: Frequency (%) of Solicited Reactions Observed 24 Hours Following a Single Dose of PENTACEL^® Administered at 2, 4, 6 and 18 Months of Age

Data from Post-Marketing Experience

The following additional adverse events have been spontaneously reported during the post-marketing use of PENTACEL^® worldwide. Because these events are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to vaccine exposure. Decisions to include these events in labelling were based on one or more of the following factors: 1) severity of the event, 2) frequency of reporting, or 3) strength of causal connection to PENTACEL^®.

Immune system disorders

Anaphylaxis/anaphylactic reaction, hypersensitivity (allergic reactions, such as rash and urticaria).

Psychiatric disorders

Screaming

Nervous system disorders

Somnolence, HHE, depressed level of consciousness, hypotonia, convulsion.

Cardiac disorders

Cyanosis

Vascular disorders

Pallor

Gastrointestinal disorders

Vomiting, diarrhea

General disorders and administration site conditions

Injection site reactions (including inflammation, mass, abscess and sterile abscess), extensive swelling of the injected limb (including swelling that involved adjacent joints), vaccination failure/therapeutic response decreased (invasive H. influenzae type b disease).

Infections and infestations

Meningitis, rhinitis, viral infection

Metabolism and nutrition disorders

Decreased appetite

Respiratory, thoracic and mediastinal disorders

Apnea, cough

Skin and subcutaneous tissue disorders

Erythema, skin discoloration

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 Global Pharmacovigilance Department, Sanofi Pasteur Limited, 1755 Steeles Avenue West, Toronto, ON, M2R 3T4, Canada. 1-888-621-1146 (phone) or 416-667-2435 (fax).

DRUG INTERACTIONS

Vaccine-Drug Interactions

Immunosuppressive treatments may interfere with the development of the expected immune response. (See WARNINGS AND PRECAUTIONS.)

Topical use of lidocaine-prilocaine patches to reduce injection site pain has no adverse effect on antibody response to PENTACEL^®. (8)

Concomitant Vaccine Administration

NACI states that administering the most widely used live and inactivated vaccines during the same patient visit has produced seroconversion rates and rates of adverse reactions similar to those observed when the vaccines are administered separately. (1) NACI recommends that vaccines administered simultaneously should be given using separate syringes at separate sites. (1) (2) Simultaneous administration is suggested, particularly when there is concern that a person may not return for subsequent vaccination. Simultaneous administration of childhood vaccines such as PENTACEL^®, MMR, varicella, pneumococcal conjugate and hepatitis B vaccines, is encouraged for children who are at the recommended age to receive these vaccines and for whom no contraindications exist.

Clinical trials have shown that PENTACEL^® is safe and immunogenic if administered at the same time as other vaccines (including meningococcal C conjugate vaccine (9) and hepatitis B vaccine).

PENTACEL^® should not be mixed in the same syringe with other parenterals.

Vaccine-Laboratory Test Interactions

Antigenuria has been detected in some instances following administration of a vaccine containing Hib antigen. Therefore, urine antigen detection may not have definite diagnostic value in suspected Haemophilus influenzae type b disease within two weeks of immunization. (10)

DOSAGE AND ADMINISTRATION

Recommended Dose

For routine immunization, PENTACEL^® is recommended as a 4-dose series, with a single dose of PENTACEL^® at 2, 4, 6 and 18 months of age.

If for any reason this schedule is delayed, it is recommended that 3 doses be administered with an interval of 2 months between each dose, followed by a fourth dose administered approximately 6 to 12 months after the third dose.

Whenever feasible, PENTACEL^® should be used for all 4 doses in the vaccination series as there are no clinical data to support the use of PENTACEL^® with any other licensed acellular pertussis combination vaccine in a mixed sequence. For situations where a different brand of DTaP, DTaP-IPV or DTaP-IPV/Hib vaccine was originally used, or where the brand is unknown, please refer to the latest edition of the Canadian Immunization Guide.

NACI recommends that premature infants whose clinical condition is satisfactory should be immunized with full doses of vaccine at the same chronological age and according to the same schedule as full-term infants, regardless of birth weight. (1)

Fractional doses (doses <0.5 mL) should not be given. The effect of fractional doses on the safety and efficacy has not been determined.

In compliance with NACI’s recommended immunization schedule, the childhood immunization series should be completed with a single 0.5 mL dose of Sanofi Pasteur Limited’s QUADRACEL^®, [Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed Combined with Inactivated Poliomyelitis Vaccine] between 4 and 6 years of age (i.e., at the time of school entry). Alternatively, ADACEL^® [Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed] and IPV may be administered at separate sites for this booster at 4 to 6 years of age. This booster dose is unnecessary if the fourth dose of PENTACEL^® was administered after the child’s fourth birthday. (1)

A subsequent booster should be administered 10 years later, during adolescence, with ADACEL^® or Td Adsorbed. Thereafter, routine booster immunizations should be with Td at intervals of 10 years.

PENTACEL^® should not be administered to persons less than 2 months or to persons 7 years of age or older. (See INDICATIONS AND CLINICAL USE.)

Administration

Inspect for extraneous particulate matter and/or discolouration before use. If these conditions exist, the product should not be administered.

Reconstitution of Freeze-Dried Product and Withdrawal from Stoppered Vial

Reconstitute Act-HIB^® [Haemophilus b Conjugate Vaccine (Tetanus Protein Conjugate)] with the QUADRACEL^® vaccine. Cleanse the QUADRACEL^® and Act-HIB^® vial stoppers with a suitable germicide before reconstitution. Do not remove from either vial the stoppers or the metal seals holding them in place. Thoroughly but gently shake the vial of QUADRACEL^®, withdraw the entire contents of the liquid vaccine and inject slowly into the vial of lyophilized Act-HIB^®. Swirl the vial now containing PENTACEL^® gently until a uniform, cloudy, white to off-white suspension results. Withdraw the total volume of reconstituted combined vaccine. PENTACEL^® should be used immediately after reconstitution. Refer to Figures 1, 2, 3, 4 and 5.

INSTRUCTIONS FOR RECONSTITUTION OF QUADRACEL^® WITH Act-HIB^®

Aseptic technique must be used. Use a separate sterile needle and syringe, or a sterile disposable unit, for each individual patient to prevent disease transmission. Needles should not be recapped but should be disposed of according to biohazard waste guidelines.

Before injection, the skin over the site to be injected should be cleansed with a suitable germicide. Administer the total volume of reconstituted vaccine intramuscularly (I.M.). In infants younger than 1 year, the anterolateral aspect of the thigh provides the largest muscle and is the preferred site of injection. In older children, the deltoid muscle is usually large enough for injection.

Give the patient 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 should contain the name of the vaccine, date given, dose, manufacturer and lot number.

Overdosage

For management of a suspected drug overdose, contact your regional Poison Control Centre.

ACTION AND CLINICAL PHARMACOLOGY

Diphtheria and Tetanus: Strains of C. diphtheriae that produce diphtheria toxin can cause severe or fatal illness characterized by membranous inflammation of the upper respiratory tract and toxin-induced damage to the myocardium and nervous system. Protection against disease attributable to C. diphtheriae is due to the development of neutralizing antibodies to diphtheria toxin. A serum diphtheria antitoxin level of 0.01 IU/mL is the lowest level giving some degree of protection. ACIP states that antitoxin levels of at least 0.1 IU/mL are generally regarded as protective. (2) (3) Levels of 1.0 IU/mL have been associated with long-term protection. (3)

Tetanus is an acute and often fatal disease caused by an extremely potent neurotoxin produced by C. tetani. The toxin causes neuromuscular dysfunction, with rigidity and spasms of skeletal muscles. Protection against disease attributable to C. tetani is due to the development of neutralizing antibodies to tetanus toxin. ACIP states that a serum tetanus antitoxin level of at least 0.01 IU/mL, measured by neutralization assay, is considered the minimum protective level. (2) (3) A tetanus antitoxin level of at least 0.1 IU/mL as measured by the ELISA used in clinical studies of PENTACEL^® is considered protective for tetanus. Levels of 1.0 IU/mL have been associated with long-term protection.

In a clinical trial in Canada, after 4 doses of PENTACEL^®, 100% (N = 294) of immunized children achieved serum diphtheria and tetanus antitoxin levels of at least 0.01 IU/mL. 99.7% and 100% of these children achieved serum antitoxin levels of at least 0.1 IU/mL for diphtheria and tetanus, respectively.

After completion of the childhood immunization series, circulating antibodies to diphtheria and tetanus toxoids gradually decline but are thought to persist at protective levels for up to 10 years. NACI recommends that Diphtheria and Tetanus Toxoids boosters are recommended every 10 years. (1)

Pertussis: Pertussis (whooping cough) is a respiratory disease caused by B. pertussis. This Gram-negative coccobacillus produces a variety of biologically active components, though their role in either the pathogenesis of, or immunity to, pertussis has not been clearly defined. The mechanism of protection from B. pertussis disease is not well understood. However, in a clinical trial in Sweden (Sweden I Efficacy Trial), pertussis components in PENTACEL^® (i.e., PT, FHA, PRN and FIM) have been shown to prevent pertussis in infants with a protective efficacy of 85.2% using the World Health Organization (WHO) case definition (≥21 consecutive days of paroxysmal cough with culture or serologic confirmation or epidemiological link to a confirmed case). In the same study, the protective efficacy against mild disease was 77.9%.

Minimum serum antibody levels to specific pertussis vaccine components that confer protection against the development of clinical pertussis have not been identified. Nevertheless, a number of studies have demonstrated a correlation between the presence of serum antibody responses to pertussis vaccine components and protection against clinical disease. (11) (12) (13) (14) (15) (16) In a controlled clinical trial in Sweden (Sweden II Trial), the efficacy of a DTaP vaccine with the same formulation of five pertussis antigens as PENTACEL^® was demonstrated to provide a two-fold to three-fold higher protection against pertussis with any cough compared to the vaccine containing three pertussis antigens. The observed difference supports the role of FIM in the protection against colonization of B. pertussis and mild disease.

In a recent publication, Bettinger et al reviewed pertussis cases during 1991-2004 using surveillance data from the Canadian Immunization Monitoring Program, Active (IMPACT), an active surveillance network based in 12 pediatric tertiary-care hospitals across Canada. (17) Overall, the data show declining rates of pertussis during the years in which PENTACEL^® has been used (1999-2004) compared to the period when whole-cell pertussis vaccine was used (1991-1996). Among children 1-4 years of age, incidence of pertussis declined 85%. Data from the Northwest Territories, (18) Newfoundland and Labrador (19) and British Columbia (20) support national and IMPACT data demonstrating a progressive decline of pertussis cases among infants and children through 9 years of age.

Poliomyelitis: Inactivated poliomyelitis vaccine induces the production of detectable levels of neutralizing antibodies against each type of poliovirus. The detection of type-specific neutralizing antibodies has been correlated with protection. (21) A clinical study of PENTACEL^® in 321 Canadian infants showed that, after 4 doses, more than 99.7% of vaccinated children achieved protective antibody levels (titres ≥1:8) to Poliovirus Types 1, 2 and 3 following the primary series. (22)

Haemophilus influenzae type b: The response to the Act-HIB^® component of the vaccine is typical of a T-dependent immune response with induction of immunologic priming and memory. (3) Bactericidal activity against Hib is demonstrated in serum after immunization and correlates with the anti-PRP antibody response induced by Hib conjugate vaccine. In children aged ≥24 months, antibody titres to H. influenzae capsular polysaccharide (anti-PRP) of ≥0.15 μg/mL following vaccination with unconjugated PRP vaccine correlated with protection against invasive H. influenzae type b disease immediately after immunization, whereas titres ≥1.0 μg/mL correlated with protection for at least 1 year. (23) Although the relevance of the 0.15 μg/mL and 1.0 μg/mL thresholds to clinical protection after immunization with conjugate vaccines is not known, these levels have been used to gauge antibody response to vaccination. In a clinical study of PENTACEL^® in 294 Canadian infants, after 4 doses, 100% of vaccinated children achieved protective antibody titres ≥0.15 μg/mL and 99.0% achieved protective antibody levels ≥1.0 μg/mL.

Duration of Effect

To ensure optimal protection during childhood, 4 consecutive doses should be given at 2, 4, 6 and 18 months of age. A booster with a vaccine containing diphtheria, tetanus, acellular pertussis with or without IPV is required at 4 to 6 years.

STORAGE AND STABILITY

Store at 2° to 8°C (35° to 46°F). Do not freeze. Discard product if exposed to freezing.

The vaccine should be used immediately after reconstitution.

Do not use vaccine after expiration date.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Dosage Forms

The stoppers of the vials do not contain latex (natural rubber).

5 dose package containing QUADRACEL^® (5 x 0.5 mL vials) for reconstitution of Act-HIB^® (5 x 1 dose vials).

Composition

After reconstitution, PENTACEL^® is a sterile uniform, cloudy, white to off-white suspension.

Each single dose (approximately 0.5 mL) after reconstitution contains:

Active Ingredients

Purified Polyribosylribitol Phosphate Capsular Polysaccharide (PRP) of Haemophilus influenzae type b covalently bound to 18 – 30 µg of Tetanus Protein 10 µg Diphtheria Toxoid 15 Lf Tetanus Toxoid 5 Lf Acellular Pertussis

Pertussis Toxoid (PT) 20 µg Filamentous Haemagglutinin (FHA) 20 µg Pertactin (PRN) 3 µg Fimbriae Types 2 and 3 (FIM) 5 µg Inactivated Poliomyelitis Vaccine

Type 1 (Mahoney) 40 D-antigen units Type 2 (MEF1) 8 D-antigen units Type 3 (Saukett) 32 D-antigen units

Other Ingredients

Excipients:

Aluminum Phosphate (adjuvant) 1.5 mg 2-phenoxyethanol 0.6% v/v Polysorbate 80 10 ppm (by calculation) Tris (hydroxymethyl) aminomethane 0.6 mg Sucrose 42.5 mg

Manufacturing process residuals:

BSA, formaldehyde, glutaraldehyde, neomycin and polymyxin B are present in trace amounts.

Vaccine Information Service: 1-888-621-1146 or 416-667-2779. Business hours: 8 a.m. to 5 p.m. Eastern Time Monday to Friday.

Full product monograph available on request or visit us at www.sanofipasteur.ca

Product information as of November 2011.

Manufactured by:

Sanofi Pasteur Limited Toronto, Ontario, Canada

and

Sanofi Pasteur SA

Lyon, France

Distributed by:

Sanofi Pasteur Limited

Toronto, Ontario, Canada R8-1111 Canada

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Haemophilus b Conjugate Vaccine (Tetanus Protein Conjugate) Reconstituted with Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed Combined with Inactivated Poliomyelitis Vaccine

Product Characteristics

PENTACEL^® is supplied in two vials: one vial containing lyophilized Haemophilus b conjugate vaccine consisting of the Haemophilus influenzae type b capsular polysaccharide (PRP), covalently bound to tetanus protein, and one vial containing a suspension of diphtheria and tetanus toxoids adsorbed on aluminum phosphate and acellular pertussis vaccine combined with inactivated poliomyelitis vaccine types 1, 2 and 3 and suspended in water for injection. The acellular pertussis vaccine is composed of 5 purified pertussis antigens (PT, FHA, PRN, FIM). After reconstitution, the vaccine is a sterile, uniform, cloudy, white to off-white suspension.

C. diphtheriae is grown in modified Mueller’s growth medium. (24) After purification by ammonium sulphate fractionation, the diphtheria toxin is detoxified with formaldehyde and diafiltered. C. tetani is grown in modified Mueller-Miller casamino acid medium without beef heart infusion. (25) Tetanus toxin is detoxified with formaldehyde and purified by ammonium sulphate fractionation and diafiltration. Diphtheria and tetanus toxoids are individually adsorbed onto aluminum phosphate.

The 5 acellular pertussis vaccine components are produced from B. pertussis cultures grown in Stainer-Scholte medium (26) modified by the addition of casamino acids and dimethyl-beta-cyclodextrin. PT, FHA and PRN are isolated separately from the supernatant culture medium. The FIM components are extracted and copurified from the bacterial cells. The pertussis antigens are purified by sequential filtration, salt-precipitation, ultrafiltration and chromatography. PT is detoxified with glutaraldehyde. FHA is treated with formaldehyde. The residual aldehydes are removed by diafiltration. The individual antigens are adsorbed separately onto aluminum phosphate.

Inactivated poliomyelitis vaccine is a highly purified, inactivated poliovirus vaccine grown in cultures of MRC-5 cells, a line of normal human diploid cells, by the microcarrier technique. (27) (28) The cells are grown in CMRL 1969 medium, supplemented with calf serum. For viral growth, the culture medium is replaced by Medium 199, without calf serum.

After clarification and filtration, viral suspensions are concentrated by ultrafiltration, and purified by two liquid chromatography steps. The monovalent viral suspensions are then inactivated with formaldehyde. After inactivation has been confirmed, one or more lots of inactivated monovalent virus are pooled, concentrated and equilibrated with phosphate buffered saline to produce an inactivated monovalent concentrate. The monovalent concentrates of each type are then combined to produce a trivalent concentrate.

The adsorbed diphtheria, tetanus and acellular pertussis components are combined into an intermediate concentrate. IPV is added and the vaccine is diluted to a final concentration of 2 doses/mL.

Both diphtheria and tetanus toxoids induce at least 2 neutralizing units per mL in the guinea pig potency test. The potency of the acellular pertussis vaccine components is evaluated by the antibody response of immunized guinea pigs to PT, FHA, PRN and FIM as measured by enzyme-linked immunosorbent assay (ELISA). The antigenicity of the IPV is evaluated by the antibody response in rats measured by virus neutralization.

Act-HIB^® is a sterile, lyophilized vaccine that is reconstituted at the time of use with Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed combined with Inactivated Poliomyelitis vaccine. Act-HIB^® consists of the Haemophilus b capsular polysaccharide PRP, a high molecular weight polymer prepared from the H. influenzae type b strain 1482 grown in a semi-synthetic medium, covalently bound to tetanus protein. (29) Act-HIB^® contains no preservative. The tetanus protein is prepared by ammonium sulphate purification, and formalin inactivation of the toxin from cultures of C. tetani (Harvard strain) grown in a modified Mueller and Miller medium. (30) The toxoid is filter sterilized before the conjugation process. Potency of Act-HIB^® is specified on each lot by limits on the content of PRP polysaccharide and protein in each dose and the proportion of polysaccharide and protein that is characterized as high molecular weight conjugate.

CLINICAL TRIALS

Three pivotal clinical trials (Sweden Trial I, Sweden Trial II and PB9502) conducted in Sweden and in Canada, provide the clinical basis for the licensure of PENTACEL^® in Canada. (See Table 2.)

Table 2: Summary of Demographics and Study Design of the Trials with PENTACEL^®

* Number enrolled.

† PEDIACEL^® [Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed Combined with

Inactivated Poliomyelitis Vaccine and Haemophilus b Conjugate Vaccine (Tetanus Protein – Conjugate)] ‡ PENTA™ is a whole-cell DPT-Polio (MRC-5) with lyophilized PRP-T vaccine

§ QUADRACEL^® [Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed Combined with

Inactivated Poliomyelitis Vaccine]

** Act-HIB^® [Haemophilus b Conjugate Vaccine (Tetanus Protein – Conjugate)]

Sweden I Efficacy Trial

A randomized, double-blinded, placebo-controlled efficacy and safety study was conducted in Sweden from 1992 - 1995 (Sweden I Efficacy Trial) under the sponsorship of the National Institute of Allergy and Infectious Diseases (NIAID). (32) A total of 9,829 infants received 1 of 4 vaccines: TRIPACEL^® [Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed], the five-component DTaP vaccine that contains the same antigens (but with a lower content of PT and FHA per dose) present in PENTACEL^® (N = 2,587); a two-component DTaP vaccine (N = 2,566); a whole-cell pertussis DTP vaccine from the U.S. (N = 2,102); or DT vaccine (Swedish National Bacteriological Laboratory) as placebo (N = 2,574). Infants were immunized at 2, 4 and 6 months of age. The mean length of follow-up was 2 years after the third dose of vaccine. The protective efficacy of TRIPACEL^® against pertussis after 3 doses of vaccine using the World Health Organization (WHO) case definition (≥21 consecutive days of paroxysmal cough with culture or serologic confirmation or epidemiologic link to a confirmed case) was 85.2% (95% confidence interval [CI] 80.6 to 88.8). (32) The protective efficacy of TRIPACEL^® against mild pertussis (≥1 day of cough with laboratory confirmation) was 77.9% (95% CI 72.6 to 82.2). (Table 3) Protection against pertussis by TRIPACEL^® was sustained for the 2-year follow-up period. (32) (Table 4)

Table 3: Vaccine Efficacy Against Pertussis Infection of Varying Clinical Severity (7) (32)

Another arm of the trial (7) (32) looked at the persistence of the protection provided by this TRIPACEL^® formulation compared to a placebo. High levels of protection were sustained for TRIPACEL^® over the entire 2-year follow-up period.

Table 4: Duration of Vaccine Efficacy for TRIPACEL^® Compared to Placebo (7) (32)

The incidence of injection site and systemic reactions after administration of TRIPACEL^® was comparable to the DT control group. (7) (32)

A sub-study of this trial looked specifically at immunized children exposed to pertussis from other members of their households. (11) This formulation of TRIPACEL^® was more efficacious than any of the other acellular and whole-cell vaccines studied. There was a correlation between clinical protection and the presence of anti-PRN, anti-FIM and anti-PT antibodies respectively in the serum of immunized children.

Sweden II Efficacy Trial

A second NIAID-sponsored, prospective, randomized, double-blinded efficacy trial was conducted in Sweden (Sweden II Efficacy Trial) from 1993 to 1996. Infants (N = 82,892) were randomized to receive one of four vaccines: a two-component acellular DTaP vaccine (N = 20,697); a three-component acellular DTaP vaccine (n = 20,728); the same formulation of the five-component acellular DTaP vaccine that is contained in PENTACEL^® (N = 20,747); or a European whole-cell DTP vaccine (N = 20,720). (34) Vaccination occurred at 3, 5 and 12 months of age (88% of participants) or at 2, 4 and 6 months of age (12% of participants). The relative risk of typical pertussis (culture-confirmed B. pertussis infection with at least 21 days of paroxysmal cough) was 0.85 and 1.38 among children given the five-component and three-component vaccines, respectively, as compared with those given the whole-cell vaccine. The relative risk of typical pertussis was 0.62 among children given the five-component vaccine as compared with the three-component vaccine. The absolute efficacy of the three-component vaccine, when tested in an earlier double-blinded randomized placebo-controlled trial in Italy was 84% (95% CI, 76-89). (35) Although the absolute efficacy of the five-component vaccine could not be determined in the Sweden II Efficacy Trial because of the lack of a DT control group, based on the relative risk data, it appears that the five-component vaccine demonstrated improved efficacy compared with the 84% absolute efficacy associated with the three-component vaccine. The observed difference supports the role of fimbriae types 2 and 3 (FIM) in the protection against colonization by B. pertussis and mild disease (Table 5). (34)

Table 5: Geometric Mean Titres (GMTs) to Pertussis Antigens Following the Third Dose of TRIPACEL^® (Vaccine Administered at 2, 4 And 6 Months) (7)

Rates of serious adverse events were less than or comparable to the rates in the other acellular pertussis and European whole-cell DTP groups in this study. (7) (34)

Clinical Trial PB9502

In a randomized controlled clinical trial conducted in Canada between 1995 and 1997, 787 infants received PENTACEL^® (N = 335), PEDIACEL^® (N = 339), PENTA™ (N = 112) or QUADRACEL^® and Act-HIB^®, given concomitantly at separate sites (N = 113) at 2, 4, and 6 months of age. Of the 787 children enrolled, 708 received a fourth dose of the same vaccine at 18-20 months of age.

Immunogenicity

In study PB9502, the immunogenicity presented through GMTs of PENTACEL^® antigens did not show any clinically significant differences compared to administration of QUADRACEL^® and Act-HIB^® separately. (See Table 6, Table 7,

Table 8, and Table 9.) (7) Tetanus and diphtheria antitoxin levels were lower in infants receiving PENTACEL^®, but these differences were not clinically significant; after 3 doses, 100% of infants in both groups had obtained the minimal level (≥0.01 EU/mL) of tetanus antibody thought to be protective and 99% of infants in both groups attained the minimal level (≥0.01 IU/mL) of diphtheria antibody thought to be protective. (7) Although the GMT of tetanus antibody was also lower at 19 months in toddlers receiving PENTACEL^®, the difference was not clinically significant. One hundred percent of toddlers in both groups were optimally protected against tetanus (≥0.1 EU/mL) following the fourth dose. (7)

Table 6: Antibody Responses to PRP-T, Diphtheria and Tetanus Toxoids and Poliovirus Types 1, 2 and 3 Measured One Month After the Third Dose of the Primary Series with PENTACEL^® or QUADRACEL^® + Act-HIB^® in Clinical Trial PB9502 (33)

Table 7: Antibody Responses to PRP-T, Diphtheria and Tetanus Toxoids and Poliovirus Types 1, 2 and 3 Measured Immediately Before and One Month After a Fourth Dose at 18 to 19 Months of Age with PENTACEL^® or QUADRACEL^® + Act-HIB^® in Clinical Trial PB9502 (36)

Table 8: Pertussis Antibody Responses Measured One Month After the Third Dose of the Primary Series with PENTACEL^® or QUADRACEL^® + Act-HIB^® in Clinical Trial PB9502 (33)

* Percentage of vaccinees attaining at least a 4-fold increase over their pre-immunization antibody level at 2 months of age.

Table 9: Pertussis Antibody Responses Measured Immediately Before and One Month After a Fourth Dose with PENTACEL^® or QUADRACEL^® + Act-HIB^® in Clinical Trial PB9502 (36)

* Percentage of vaccinees attaining at least a 4-fold increase over their pre-immunization antibody level at 18 to 19 months of age.

Safety

Solicited injection site reactions occurred in 8.7% (redness) to 28.1% (tenderness) of PENTACEL^® vaccinees. Severe injection site reactions were observed in only 0.9% (tenderness) to 7.5% (redness) of PENTACEL^® vaccinees. (See Table 10.) The frequency of reactions at the injection site was generally higher after the fourth dose than in the previous three doses in infants, however, severe tenderness did not increase with the fourth dose. Solicited systemic reactions occurred in 1.8% (vomiting) to 53.4% (fussiness). Except for decreased activity after the first dose (1.2%) and fussiness after the fourth dose (1.0%), severe systemic reactions were uncommon. (See Table 10.) One child immunized with PENTACEL^® experienced a fever ≥40°C. No HHE was observed in this study. One child immunized with PENTACEL^® suffered a febrile seizure. PENTACEL^® differed in solicited reactions from QUADRACEL^® + Act-HIB^® only with respect to tenderness and fever. Redness was less frequent with QUADRACEL^® + Act-HIB^®, whereas fever was milder with PENTACEL^®. (See Table 11.)

Table 10: Frequency (%) of Solicited Reactions Observed Within 24 Hours Following a Single Dose of PENTACEL^® Administered at 2, 4, 6 and 18 Months of Age in Clinical Trial PB9502 (33)

* Cried continuously for ≥3 hrs.

† Sleeping most of the time.

‡ Refused most or all feeds.

§ Multiple liquid stools without any solid consistency. ** Continuously fussy for ≥3 hrs.

†† Baby cries when leg is moved.

‡‡ Frequent vomiting and inability to have any oral intake.

Table 11: Frequency (%) of Solicited Reactions Observed Within 24 Hours Following the Administration of PENTACEL^® or QUADRACEL^® + Act-HIB^® (Q//A) at 2, 4, 6 and 18 Months of Age in Clinical Trial PB9502 (33) (36)

ADDITIONAL RELEVANT INFORMATION

Simultaneous vaccination with combination vaccines during early childhood has been the cornerstone of Canada’s immunization program for many years. PENTACEL^® combines five childhood vaccines and offers protection against diphtheria, tetanus, pertussis, poliomyelitis and invasive Hib disease. Immunization with these antigens has been associated with a striking decrease in the incidence of morbidity and mortality caused by these infections. PENTACEL^® has been licensed in Canada since 1997. Since then it has been licensed in 7 countries around the world. More than 13 million doses of PENTACEL^® have been administered to children in Canada. (7)

Diphtheria and Tetanus: The information provided below is consistent with NACI’s guidelines. Diphtheria is an acute communicable disease caused by exotoxin-producing strains of the bacterium C. diphtheriae. Symptoms result from local infection of the respiratory tract, which may lead to breathing difficulties, or infection of the skin or mucosal surfaces, or from dissemination of diphtheria toxin, which damages the heart and central nervous system. Routine immunization against diphtheria in infancy and childhood has been widely practised in Canada since 1930, resulting in a decline in morbidity and mortality. In Canada, there are 0 to 5 isolates reported each year. The case-fatality rate remains at about 5 – to 10%, with the highest death rates in the very young and elderly. (1) The disease occurs most frequently in unimmunized or partially immunized persons.

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. Between 1980 and 2004, the number of cases reported annually in Canada ranged from 1 to 10, with an average of 4 cases per year. (1)

Both diphtheria and tetanus toxoids are prepared by detoxification of the respective toxins with formaldehyde. Intramuscular injection of diphtheria and tetanus toxoids results in the production of protective antibodies against the toxins and their lethal effects, but it does not preclude local infections by the bacteria. (1) 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. (1) NACI continues to recommend tetanus and diphtheria boosters every 10 years based on concern regarding the decline of antibody levels with age and potential failure of single booster doses to produce protective levels in older individuals. (1)

Pertussis: Pertussis (whooping cough) results from an acute infection of the respiratory tract 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.

Whole-cell pertussis vaccine was first introduced in Canada in 1943. NACI states that over the past 64 years, pertussis incidence has declined by over 90%, although outbreaks of pertussis continue to arise. (1) Because of concerns about the frequency and severity of systemic and injection site adverse reactions with whole-cell pertussis vaccines, acellular pertussis vaccines have replaced whole-cell formulations in Canada. Acellular vaccines provoke significantly fewer injection site reactions, lower rates of fever and fewer episodes of unusual or persistent crying. (7) (32) (34) (37)

PENTACEL^® contains a five-component acellular pertussis vaccine stimulating immune response to PT, FHA, PRN and FIM. In an efficacy trial, five-component acellular pertussis vaccines were significantly more efficacious than other acellular pertussis formulations containing fewer antigens. (7) (32) (38)

Poliomyelitis: Poliomyelitis is caused by infection with one of the three antigenic types of poliovirus. Following introduction of poliovirus vaccine in Canada in 1955, the indigenous disease has been virtually eliminated. (1) However, the persistence of wild virus cases in polio endemic regions of Africa and Asia (39) necessitates that the highest possible level of vaccine-induced immunity be maintained in the Canadian population. IPV is an enhanced formalin-inactivated product, where human diploid cells are used to propagate the three poliovirus types. Clinical studies of infants receiving PENTACEL^® show that more than 99% of children have protective antibody levels (titres ≥1:8) to Poliovirus Types 1, 2 and 3 following the primary series. (7) (22)

Haemophilus influenzae type b: Before the introduction of Haemophilus b conjugate vaccines in Canada, Haemophilus influenzae type b was the most common cause of bacterial meningitis and a leading cause of other serious infections in young children. Four hundred and eighty-five cases were recorded in 1985 before the first vaccine was available. (40) After 1996 when routine infant immunization with the conjugate vaccine found in PENTACEL^® began, only 8 - 10 cases a year were reported. In 1998-99 over 60,000 Canadian infants completed primary immunization with PENTACEL^® and over 200,000 completed a four-dose series including a booster in the second year of life. (41) Only a single case of Hib-infection in a child fully vaccinated with PENTACEL^® was reported to Canada’s nationwide vaccine surveillance system in 1999. (41) In 2000, case reports of Haemophilus b meningitis reached a historical low with only 4 cases reported, a reduction of 99% from pre-vaccine levels. (40)

REFERENCES

1 National Advisory Committee on Immunization. General guidelines. Vaccine safety and adverse events following immunization. Recommended immunization. Diphtheria toxoid. Pertussis vaccine. Poliomyelitis vaccine. Tetanus toxoid. In: Canadian Immunization Guide, 7th ed. Her Majesty the Queen in Right of Canada, represented by the Minister of Public Works and Government Services Canada; 2006. p. 31,73-4,80,82-4,94,113,117-8,126-9,166-78,257-66,277-84,309-16.

2 CDC. General recommendations on immunization. Recommendations of the Advisory

Committee on Immunization Practices (ACIP). MMWR 2006;55(RR-15):1-48. 3 Plotkin SA, Orenstein WA. Diphtheria toxoid. Haemophilus influenzae vaccine. Pertussis vaccine. Tetanus toxoid. In: Vaccines. 4th ed. Philadelphia: Elsevier Inc.; 2004. p. 214,229-68,485,518-19,745-81.

4 Institute of Medicine. Stratton KR, et al, editors. Immunization safety review: Vaccinations and sudden unexpected death in infancy. Washington, DC: The National Academies Press; 2003. p. 13. Available from: URL:http://www.nap.edu/catalog/10649.html 5 CDC. Diphtheria, tetanus and pertussis:recommendations for vaccine use and other preventive measures. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 1991;40(RR-10):1-28.

6 Stratton KR, et al. editors. Adverse events associated with childhood vaccines; evidence bearing on causality. National Academy Press, Washington, DC: 1994. p. 67-117. 7 Data on file at Sanofi Pasteur Limited.

8 Halperin B, et al. Use of lidocaine-prilocaine patch to decrease intramuscular injection pain does not adversely affect the antibody response to diphtheria-tetanus-acellular pertussis-inactivated poliovirus-Haemophilus influenzae type b conjugate and hepatitis B vaccines in infants from birth to six months of age. Pediatr Infect Dis J 2002;21(5):399 405. 9 Halperin S, et al. Simultaneous administration of meningococcal C conjugate vaccine and diphtheria-tetanus-acellular pertussis-inactivated poliovirus-Haemophilus influenzae type b conjugate vaccine in children: a randomized double-blind study. Clin Invest Med 2002;25(6):243-51.

10 Rothstein EP, et al. Comparison of antigenuria after immunization with three Haemophilus influenzae type b conjugate vaccines. Pediatr Infect Dis J 1991;10:311-4. 11 Storsaeter J, et al. Levels of anti-pertussis antibodies related to protection after household exposure to Bordetella pertussis. Vaccine 1998;16(20):1907-16.

12 Cherry JD, et al. A search for serologic correlates of immunity to Bordetella pertussis cough illnesses. Vaccine 1998;16:1901-6.

13 Deen JL, et al. Household contact study of Bordetella pertussis infections. Clin Infect Dis

1995;21(5)1211-9.

14 Preston NW, Stanbridge TN. Efficacy of pertussis vaccines: a brighter horizon. Br Med J

1972;3:448-51.

15 Efficacy of whooping-cough vaccines used in the United Kingdom before 1968. Br Med J

1973;1:259-62.

16 Ramkissoon A, et al. Subclinical pertussis in incompletely vaccinated and unvaccinated infants. S Afr Med J 1995;85(7):662-7.

17 Bettinger JA, et al. The effect of changing from whole-cell to acellular pertussis vaccine on the epidemiology of hospitalized children with pertussis in Canada. Pediatr Infect Dis J 2007;26(1):31-5.

18 Kandola K, et al. A comparison of pertussis rates in the Northwest Territories: pre-and post-acellular pertussis vaccine introduction in children and adolescents. Can J Infect Dis Med Microbiol. 2005;16:271-4.

19 Public Health Agency of Canada. Pertussis in Newfoundland and Labrador: 1991-2004. Can

Comm Dis Rep. 2005;31:1-3.

20 Skowronski DM, et al. The changing age and seasonal profile of pertussis in Canada. J Infect

Dis 2002;185:1448-53.

21 Plotkin SA. Immunologic correlates of protection induced by vaccination. Pediatr Infect Dis J

2001;20:63-75.

22 Mills E, et al. Safety and immunogenicity of a combined five-component pertussis-diphtheria-tetanus-inactivated poliomyelitis-Haemophilus b conjugate vaccine administered to infants at two, four and six months of age. Vaccine 1998;16(6):576 85.

23 Peltola H, et al. Prevention of Haemophilus influenzae type b bacteremic infections with the capsular polysaccharide vaccine. N Engl J Med 1984;310:1561-66.

24 Stainer DW. Production of diphtheria toxin. In: Manclark CR, ed. Proceedings of an informal consultation on the World Health Organization requirements for diphtheria, tetanus, pertussis and combined vaccines. United States Public Health Service, Bethesda, MD. DHHS 91-1174. 1991. p. 7-11.

25 Mueller JH, et al. Variable factors influencing the production of tetanus toxin. J Bacteriol

1954;67(3):271-7.

26 Stainer DW, et al. A simple chemically defined medium for the production of phase I

Bordetella pertussis. J Gen Microbiol 1971;63:211-20.

27 van Wezel AL, et al. Inactivated poliovirus vaccine: current production methods and new developments. Rev Infect Dis 1984;6 (Suppl 2):S335-40.

culture of vero cells on microcarrier. Rev Infect Dis 1984;6 (Suppl 2):S341-4. 29 Chu CY, et al. Further studies on the immunogenicity of Haemophilus influenzae type b and pneumococcal type 6A polysaccharide-protein conjugates. Infect Immun 1983;40:245-56. 30 Mueller JH, et al. Production of diphtheria toxin of high potency (100 Lf) on a reproducible medium. J Immunol 1941;40:21-32.

31 Data on file at Sanofi Pasteur Limited. Gustafsson, et al. Efficacy Trial of Acellular Pertussis

Vaccines: Technical Report Trial 1. Swedish Institute for Infectious Disease Control. 31 Aug 1995.

32 Gustafsson L, et al. A controlled trial of a two-component acellular, a five-component acellular, and a whole-cell pertussis vaccine. N Engl J Med 1996;334:349-55.

33 Data on file at Sanofi Pasteur Limited. Study PB9502. Report on Infant Series. 34 Olin P, et al. Randomised controlled trial of two-component, three-component, and five-component acellular pertussis vaccines compared with whole-cell pertussis vaccine. Lancet 1997;350(9091):1569-77.

35 Greco D, et al. A controlled trial of two acellular vaccines and one whole-cell vaccine against pertussis. N Engl J Med 1996;334:341-8.

36 Data on file at Sanofi Pasteur Limited. Study PB9502. Report on Booster Dose (18-19 months).

37 Decker MD, et al. Comparison of 13 acellular pertussis vaccines: adverse reactions. Pediatrics

1995;96(3):557-66.

38 Cherry JD. Comparative efficacy of acellular pertussis vaccines; an analysis of recent trials.

Pediatr Infect Dis J 1997;16:S90-96.

39 World Health Organization. Polio News. 2002;16:2.

40 Scheifele D, et al. Historic low Haemophilus influenzae type b case tally - Canada 2000.

CCDR 2001;27(18):149-50.

41 Scheifele D, et al. Haemophilus influenzae type b disease control using Pentacel®, Canada,

1998-1999. CCDR 2000;26(11):93-6.

Vaccine Information Service: 1-888-621-1146 or 416-667-2779. Business hours: 8 a.m. to 5 p.m. Eastern Time Monday to Friday.

Full product monograph available on request or visit us at www.sanofipasteur.ca

Product information as of November 2011.

Manufactured by:

Sanofi Pasteur Limited

Toronto, Ontario, Canada

and

Sanofi Pasteur SA

Lyon, France

Distributed by:

Sanofi Pasteur Limited

Toronto, Ontario, Canada R8-1111 Canada