Influenza A (H1N1) 2009 Pandemic Monovalent Vaccine (Without Adjuvant) Product Monograph

Indications

Influenza A (H1N1) 2009 Pandemic Monovalent Vaccine (Without Adjuvant) is indicated for the active immunization against the 2009 pandemic H1N1 influenza strain.

This indication is based on experience with the licensed FLUVIRAL^® seasonal influenza vaccine, and limited clinical and nonclinical data available for the pandemic unadjuvanted H1N1 vaccine manufactured by GSK in Dresden, Germany as well as preliminary safety data from studies with the Canadian manufactured vaccine.

Dosage and Administration

There is currently limited clinical experience with Influenza A (H1N1) 2009 Pandemic Monovalent Vaccine (Without Adjuvant), and limited clinical experience with an investigational formulation of an unadjuvanted vaccine manufactured in Dresden, Germany, and Québec, Canada containing the same or a slightly higher amount of antigen derived from A/California/7/2009 (H1N1) (see section Pharmacodynamics) in healthy adults aged 18-60 years. There is no clinical experience yet in the elderly, adolescents or children.

The decision to use Influenza A (H1N1) 2009 Pandemic Monovalent Vaccine (Without Adjuvant) in each age group defined below should take into account the experience with FLUVIRAL®, the extent of the clinical data available with the unadjuvanted H1N1 vaccine, the disease characteristics of the current influenza pandemic and the recommendations of the Public Health Agency of Canada, which may change based on emerging additional data.

The dose recommendations are based on:

• the experience with the trivalent seasonal vaccine, FLUVIRAL®,
• limited immunogenicity data from 2 studies obtained three weeks after administration of a single dose of an investigational formulation of another unadjuvanted H1N1 vaccine manufactured in Dresden, Germany containing either 21 µg or 15 µg HA derived from A/California/7/2009 (H1N1) to healthy adults aged 18-60 years. See section Pharmacodynamics
• as well as preliminary safety data from studies with the Canadian manufactured vaccine.

Adults aged 18-60 years:

One dose of 0.5mL may be administered at an elected date.

The need for a second dose is currently unknown. However, preliminary immunogenicity data obtained at three weeks after administration of an investigational formulation of an unadjuvanted H1N1 vaccine containing either 21 µg or 15 µg HA (in a 0.5mL dose) derived from A/California/7/2009 (H1N1) to a limited number of healthy adults aged 18-60 years suggest that a single dose may be sufficient in this age group. See section Pharmacodynamics.

Elderly (>60 years):

No clinical data are available for Influenza A (H1N1) 2009 Pandemic Monovalent Vaccine (Without Adjuvant) in this age group. One dose of 0.5mL may be administered at an elected date.

Children and adolescents aged 10-17 years:

No clinical data are available for the Influenza A (H1N1) 2009 Pandemic Monovalent Vaccine (Without Adjuvant) in this age group. One dose of 0.5mL may be administered at an elected date.

Children aged 3-9 years:

No clinical data are available for the Influenza A (H1N1) 2009 Pandemic Monovalent Vaccine (Without Adjuvant) in this age group. The use of this vaccine should be considered in light of PHAC recommendations for the A/California/7/2009(H1N1)v-like vaccination. Preliminary data with other similar unadjuvanted vaccines suggest that if used in this age group, a 2-dose regimen (0.5mL with an interval of at least 21 days between doses) is recommended.

Children aged from 6-35 months:

No clinical data are available for the Influenza A (H1N1) 2009 Pandemic Monovalent Vaccine (Without Adjuvant) in this age group. The use of this vaccine should be considered in light of PHAC recommendations for the A/California/7/2009(H1N1)v-like vaccination. Preliminary data with other similar unadjuvanted vaccines suggest that for this age group, unadjuvanted vaccine may not be suitable against this pandemic strain.

Children aged less than 6 months:

Vaccination is not currently recommended in this age group.

For further information, see section Pharmacodynamics.

Method of administration:

Immunization should be carried out by intramuscular injection preferably into the deltoid muscle or anterolateral thigh (depending on muscle mass).

Contraindications

History of an anaphylactic reaction (i.e. life-threatening) to any of the constituents or trace residues of this vaccine.

See also section Warnings and Precautions.

Warnings and Precautions

Caution is needed when administering this vaccine to persons with a known hypersensitivity (other than anaphylactic reaction) to the active substance, to any of the excipients and to residues.

As with all injectable vaccines, appropriate medical treatment and supervision should always be readily available in case of a rare anaphylactic event following the administration of the vaccine.

If the pandemic situation allows, immunization shall be postponed in patients with severe febrile illness or acute infection.

Influenza A (H1N1) 2009 Pandemic Monovalent Vaccine (Without Adjuvant) should under no circumstances be administered intravascularly or intradermally.

Antibody response in patients with endogenous or iatrogenic immunosuppression may be insufficient.

A protective immune response may not be elicited in all vaccinees (see section Pharmacodynamics).

Pregnancy and Lactation

No data have been generated in pregnant or lactating women with Influenza A (H1N1) 2009 Pandemic Monovalent Vaccine (Without Adjuvant). Data from vaccinations with seasonal trivalent influenza vaccines in pregnant or lactating women do not indicate that adverse foetal and maternal outcomes were attributable to the vaccine.

CONSIDERATION SHOULD BE TAKEN OF THE RECOMMENDATIONS MADE BY THE PUBLIC H EALTH AGENCY OF CANADA.

Pediatrics:

No clinical data are available for the Influenza A (H1N1) 2009 Pandemic Monovalent Vaccine (Without Adjuvant) in children less than 10 years of age. For guidance on dosing in this age group, refer to the Dosage and Administration section.

CONSIDERATION SHOULD BE TAKEN OF THE RECOMMENDATIONS MADE BY THE PUBLIC H EALTH AGENCY OF CANADA.

Interactions

No data are available on the concomitant administration of Influenza A (H1N1) 2009 Pandemic Monovalent Vaccine (Without Adjuvant) with other vaccines, including seasonal trivalent influenza vaccines. Such data are in development, and this document will be amended to include them as soon as available. However, if co-administration with another vaccine is indicated, immunization should be carried out on separate limbs. It should be noted that the adverse reactions may be intensified.

The immunological response may be diminished if the patient is undergoing immunosuppressant treatment.

Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed.

Adverse Reactions

H1N1 (A/California/7/2009) Studies:

Preliminary reactogenicity (solicited local and general adverse events reported within 7 days of vaccination) are provided for 2 studies which evaluated the safety of another vaccine manufactured in Dresden, Germany containing HA derived from A/California/7/2009 (H1N1)v-like in healthy subjects aged 18-60 years. In one study, the unadjuvanted vaccine contained a higher amount of antigen (21 µg HA versus 15 µg). In both studies, a group of subjects received the vaccine without the AS03 adjuvant. Pain at the injection site was the most frequently reported solicited adverse events (AE). The frequency of “related” Grade 3 symptoms was 1.5%. Similar safety observations were recently made in another study (Q-Pan-H1N1-001) using the Canadian manufactured vaccine.

Table 2 D-Pan H1N1-021 (Day 0 to Day 6 solicited adverse events following a single dose of 21 µg HA unadjuvanted H1N1 vaccine) - Adverse Events with a causal relationship

Table 3 D-Pan H1N1-007 (Day 0 to Day 6 solicited adverse events following a single dose of 15 µg HA unadjuvanted H1N1 vaccine) - Adverse Events with a causal relationship

Adverse reactions

FLUVIRAL® Studies:

This section is based on the profile observed with FLUVIRAL^® seasonal vaccine and are expected to be applicable to the Influenza A (H1N1) 2009 Pandemic Monovalent Vaccine (Without Adjuvant) as well.

Adverse Drug Reaction Overview

The most commonly reported adverse drug reactions with FLUVIRAL^® are pain and redness at the injection site, fatigue, headache and myalgia. Common reactions are red eyes, sore throat, cough, arthralgia, swelling at the injection site, fever, chills, malaise and chest tightness. Reactions are generally mild and of limited duration. Prophylactic acetaminophen may decrease the frequency of some side effects in adults.

Immediate, allergic-type responses, such as hives, angioedema, allergic asthma, or systemic anaphylaxis occur extremely rarely. These reactions probably result from sensitivity to some vaccine component - most likely residual egg proteins (see CONTRAINDICATIONS).

FLUVIRAL^® was administered to 2,220 adult and elderly subjects in six clinical trials. General symptoms were solicited by a diary aid used by the subjects for 3 days post-vaccination.

Adverse reactions considered possibly related to vaccination have been categorised by frequency as follows.

Very common (≥1/10)

Common (≥1/100 to <1/10)

Uncommon (≥1/1,000 to <1/100)

Rare (≥1/10,000 to <1/1,000)

Very rare (<1/10,000)

Infections and infestations

Uncommon: upper respiratory tract infection

Nervous system disorders

Very common: headache; Uncommon: dizziness

Eye disorders

Common: red eyes*

Respiratory, thoracic and mediastinal disorders

Common: sore throat*, cough*

Gastrointestinal disorders

Uncommon: nausea

Skin and subcutaneous tissue disorders

Uncommon: swelling of the face*

Musculoskeletal and connective tissue disorders

Very common: myalgia; Common: arthralgia

General disorders and administration site conditions

Very common: pain and redness at the injection site, fatigue; Common: swelling at the injection site, fever, chills, malaise, chest tightness*

*These symptoms can be associated to the oculo-respiratory syndrome (ORS). ORS consists of the following signs and symptoms: bilateral red eyes and/or respiratory symptoms (cough, wheeze, chest tightness, difficulty breathing, difficulty swallowing, hoarseness or sore throat) and/or facial swelling. Although not explicitly identified as ORS during the clinical trials, these symptoms were solicited to detect possible cases of that syndrome.

A study was conducted in 130 children aged 3-12 years. The data in the table below show the percentage of reported symptoms to FLUVIRAL^® split-virion vaccine versus a competitor subvirion vaccine. The most frequently reported local reaction was soreness at the injection site and usually resolved in 1-2 days. The most common systemic reactions were headache, loss of appetite and muscle aches. There were no significant differences between the two groups.

Table 4 Percentage of subjects reporting symptoms

Post-Market Adverse Drug Reactions

There have been reports of neurological illnesses, including facial paralysis, encephalitis, encephalopathy, demyelinating disease and labyrinthitis, associated with trivalent inactivated influenza vaccines. Any relationship, other than a temporal one, to the vaccines has not been established. In the 1976 swine influenza vaccine campaign, an apparent association between receipt of the vaccine and subsequent development of Guillain-Barré syndrome was found. Since that time, studies in multiple years with vaccines prepared from other virus strains have failed to show a clear association of influenza vaccines with an increased frequency of Guillain-Barré syndrome. Influenza vaccine is not known to predispose to Reye's syndrome.

Post Marketing Surveillance

From Post-marketing surveillance with seasonal trivalent vaccines (without AS03), the following additional adverse events have been reported:

Blood and lymphatic system disorders

Transient thrombocytopenia.

Immune system disorders

Allergic reactions, in rare cases leading to shock.

Nervous system disorders

Neuralgia, convulsions.

Neurological disorders, such as encephalomyelitis, neuritis and Guillain Barré syndrome.

Vascular disorders

Vasculitis with transient renal involvement.

Skin and subcutaneous tissue disorders

Generalised skin reactions including urticaria

Overdose

Insufficient data are available.

4.0 PHARMACOLOGICAL PROPERTIES

Mechanism of Action

Based on the Fluviral mechanism of action, it is anticipated that Influenza A (H1N1) 2009 Pandemic Monovalent Vaccine (Without Adjuvant), split-virion inactivated influenza vaccine, promotes an active immunization against influenza strain A H1N1 contained in the vaccine. After injection of the vaccine there is an increase in circulating antibody to the viral hemagglutinin and peripheral blood lymphocytes are primed to respond to in vitro stimulation by vaccine antigens. As with other inactivated influenza vaccines, immunization is based on the humoral component of the specific immunological defense system, namely immunoglobulin G (IgG) antibodies against viral hemagglutinin (HA) and neuraminidase antigens. The effectiveness of inactivated influenza vaccines correlates with the age and immunocompetence of the vaccine recipient and the degree of similarity between the virus strains used in the preparation of the vaccines and those prevailing in the population.

Pharmacodynamics

No pharmacodynamic studies and no pharmacokinetics studies have been conducted with FLUVIRAL^®, nor Influenza A (H1N1) 2009 Pandemic Monovalent Vaccine (Without Adjuvant) in accordance with its status as a vaccine.

H1N1 (A/California/7/2009) Studies:

Health Canada will regularly review any new information which may become available and this labelling may be updated if necessary. The following data is currently available with the H1N1 strain with a pandemic potential.

Immune response to an investigational formulation of another vaccine without adjuvant, manufactured in Dresden, Germany, containing 15 µg HA derived from A/California/7/2009 (H1N1) in adults aged 18-60 years

In a clinical study that evaluated the immunogenicity of another vaccine without adjuvant containing 15 µg HA derived from A/California/7/2009 (H1N1)v-like in healthy subjects aged 18-60 years the anti-HA antibody responses post-dose 1 were as follows:

Table 5 Immunogenicity post-dose 1 of another vaccine without adjuvant containing 15 µg HA, in healthy subjects aged 18-60 years

¹ seroprotection rate: proportion of subjects with haemagglutination inhibition (HI) titre ≥1:40; ²seroconversion rate: proportion of subjects who were either seronegative at pre-vaccination and have a protective post-vaccination titre of ≥1:40, or who were seropositive at pre-vaccination and have a 4-fold increase in titre;

³seroconversion factor: ratio of the post-vaccination geometric mean titre (GMT) and the pre-vaccination GMT.

Immune response to an investigational formulation of another vaccine without adjuvant, manufactured in Dresden, Germany, containing 21 µg HA derived from A/California/7/2009 (H1N1) in adults aged 18-60 years

In a clinical study that evaluated the immunogenicity of another vaccine without adjuvant containing 21 µg HA derived from A/California/7/2009 (H1N1)v-like in healthy subjects aged 18-60 years the anti-HA antibody responses post-dose 1 were as follows:

Table 6 Immunogenicity post-dose 1 of another vaccine without adjuvant, containing 21 µg HA, in adults aged 18-60 years

¹ seroprotection rate: proportion of subjects with haemagglutination inhibition (HI) titre ≥1:40; ²seroconversion rate: proportion of subjects who were either seronegative at pre-vaccination and have a protective post-vaccination titre of ≥1:40, or who were seropositive at pre-vaccination and have a 4-fold increase in titre;

³seroconversion factor: ratio of the post-vaccination geometric mean titre (GMT) and the pre-vaccination GMT.

Pharmacokinetics

Evaluation of pharmacokinetic properties is not required for vaccines.

Non-Clinical Data

Preliminary results concerning protection against A/California/7/2009-like H1N1 have been generated in a challenge study in ferrets. Groups of immunologically-naive animals were immunised with one or two doses of AS03-adjuvanted formulations containing from 1.9 to 15 μg HA of antigen (A/California/7/09 strain) manufactured in Germany, two doses of 15μg HA (A/California/7/09 strain) in an unadjuvanted formulation, or phosphate buffered saline (PBS) as control. Following vaccination, the ferrets underwent intratracheal challenge with a high dose of the closely related H1N1v virus A/The Netherlands/602/09.

Initial results indicate that a single vaccination with the AS03-adjuvanted formulations provide better protection than two injections of unadjuvanted antigen or PBS control against macroscopic lung pathology, and resulted in a significant reduction in virus titers in lung tissue. The proportion of lung tissue involved in pathology, and total lung weights, were lowest in animals that received adjuvanted vaccine. These results must be interpreted with caution, given that the animals were immunologically naïve with regard to all H1N1 influenza strains and the route of virus challenge may not represent typical human exposure.

5.0 PHARMACEUTICAL PARTICULARS

The composition of Influenza A (H1N1) 2009 Pandemic Monovalent Vaccine (Without Adjuvant) is:

15 μg HA - A/California/7/2009(H1N1)v-like strain (A/California/7/2009, NYMC X-

179A (H1N1)v).

List of Excipients

The vaccine is formulated with phosphate buffered saline composed of: sodium chloride, potassium chloride, sodium phosphate dibasic heptahydrate, potassium phosphate monobasic and water for injection. Thimerosal 50 μg per 0.5 mL dose is added as a preservative. The vaccine also contains trace residual amounts of egg proteins, formaldehyde, sodium deoxycholate and sucrose. Antibiotics are not used in the manufacture of this vaccine.

Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Shelf Life

Influenza A (H1N1) 2009 Pandemic Monovalent Vaccine (Without Adjuvant) is stable for 18 months.

Do not use vaccine after the expiration date.

Special Precautions for Storage

Store at 2°C to 8°C (in a refrigerator).

Do not freeze. Freezing destroys activity. Do not use vaccine that has been frozen.

Store in the original packaging in order to protect from light.

Once entered, the multidose vial should be discarded after 28 days.

Nature and Contents of Container

Influenza A (H1N1) 2009 Pandemic Monovalent Vaccine (Without Adjuvant) is supplied in 10 mL vials holding 10 x 0.5 mL doses.

Influenza A (H1N1) 2009 Pandemic Monovalent Vaccine (Without Adjuvant) packaging does not contain latex.

Instructions for Use/Handling

Influenza A (H1N1) 2009 Pandemic Monovalent Vaccine (Without Adjuvant) is a translucent to whitish opalescent suspension that may sediment slightly. Inspect Influenza A (H1N1) 2009 Pandemic Monovalent Vaccine (Without Adjuvant) visually for discoloration prior to administration. If this condition exists, the vaccine should not be administered.

Shake the multidose vial vigorously each time before withdrawing a dose of vaccine.

Proper aseptic technique should be used for withdrawal of each dose from the multidose vial. Once entered, return the multidose vial to the recommended storage conditions, between 2°C and 8°C. Once entered, the multidose vial should be discarded after 28 days.

A separate sterile 1-cc syringe and needle or a sterile disposable 1-cc unit should be used for each injection to prevent transmission of hepatitis B, HIV, or other infectious agents from one person to another.

Disinfect the skin at the site of injection with a suitable antiseptic and wipe dry with sterile cotton wool. The injection of Influenza A (H1N1) 2009 Pandemic Monovalent Vaccine (Without Adjuvant) should be given intramuscularly, usually into the deltoid muscle Do not inject influenza vaccine intravenously. No data are available on subcutaneous administration of Influenza A (H1N1) 2009 Pandemic Monovalent Vaccine (Without Adjuvant), nor FLUVIRAL^®.

All vaccines should be observed for about 15 minutes after vaccination. If an anaphylactic reaction develops, sterile epinephrine hydrochloride (1:1000) should be administered.

Any unused product or waste material should be disposed of in accordance with local requirements. Since Influenza A (H1N1) 2009 Pandemic Monovalent Vaccine (Without Adjuvant) is an inactivated vaccine, it presents no risk of contaminating the work area during manipulation.