sanofi pasteur Influenza Virus Vaccine, H5N1

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1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use, safely and effectively. See full prescribing information for. Suspension for Intramuscular Injection Initial U.S. Approval: INDICATIONS AND USAGE , is an inactivated monovalent influenza virus vaccine, indicated for active immunization of persons through years of age at increased risk of exposure to the HN influenza virus subtype contained in the vaccine (,., ) DOSAGE AND ADMINISTRATION Immunization consists of two ml (0 μg) intramuscular injections, a ml dose given on day followed by another ml dose given approximately days later (window to days) (,.,.) DOSAGE FORMS AND STRENGTHS Each ml dose contains 0 micrograms (μg) of influenza virus hemagglutinin (HA) of strain A/Vietnam/0/00 (HN, clade ) (.,, ). Suspension in a ml multi-dose vial, contains thimerosal, a mercury derivative (approximately 0 μg mercury/dose), added as a preservative (, ) CONTRAINDICATIONS None () WARNINGS AND PRECAUTIONS History of a hypersensitvity reaction to chicken or egg proteins or life-threatening reactions to previous influenza vaccinations (.). If Guillain-Barré syndrome (GBS) has occurred within six weeks of vaccination with influenza vaccine, the decision to give, should be based on careful consideration of the benefits and risks (.). Immunocompromised persons may have a reduced immune response to (.) ADVERSE REACTIONS Most common (>0%) adverse reactions are pain at injection site, headache, malaise, and myalgia (). To report SUSPECTED ADVERSE REACTIONS, contact Sanofi Pasteur Inc., at (-00-VACCINE) or VAERS at and DRUG INTERACTIONS Do not mix with other vaccines in the same syringe or vial (.). Immunosuppressive therapies may reduce the immune response to (.) USE IN SPECIFIC POPULATIONS Safety and effectiveness have not been established in pregnant or lactating women, and in pediatric and geriatric populations (.,.,.,.). See for PATIENT_COUNSELING_INFORMATION FULL PRESCRIBING INFORMATION: CONTENTS* INDICATIONS AND USAGE DOSAGE AND ADMINISTRATION. Preparation for Administration. Recommended Dose and Schedule DOSAGE FORMS AND STRENGTHS CONTRAINDICATIONS WARNINGS AND PRECAUTIONS. Hypersensitivity. Guillan-Barré Syndrome. Altered Immunocompetence. Preventing and Managing Allergic Reactions ADVERSE REACTIONS. Data from Clinical Studies. Adverse Events Associated with Influenza Vaccines DRUG INTERACTIONS.Concomitant Administration with Other Vaccines. Immunosuppressive Therapies USE IN SPECIFIC POPULATIONS. Pregnancy. Nursing Mothers. Pediatric Use. Geriatric Use DESCRIPTION CLINICAL PHARMACOLOGY. Mechanism of Action NON-CLINICAL TOXICOLOGY. Carcinogenesis, Mutagenesis, Impairment of Fertility CLINICAL STUDIES HOW SUPPLIED STORAGE AND HANDLING. How Supplied.Storage Conditions and Shelf Life PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. Page of

2 FULL PRESCRIBING INFORMATION:. INDICATIONS AND USAGE, is an inactivated monovalent influenza virus vaccine, indicated for active immunization of persons through years of age at increased risk of exposure to the HN influenza virus subtype contained in the vaccine. This indication is based on immune response and not on demonstration of decreased influenza disease after vaccination with Influenza Virus Vaccine, HN. 0. DOSAGE AND ADMINISTRATION.. Preparation for Administration Inspect, vials visually for particulate matter and/or discoloration prior to administration. If either of those conditions exists, the vaccine should not be administered. Shake the multi-dose vial vigorously each time before withdrawing a dose of vaccine. Between uses, return the multi-dose vial to the recommended storage conditions, at to C ( to F). Do not freeze. Discard if the vaccine has been frozen. 0 A separate syringe and needle or a sterile disposable unit should be used for each injection to prevent transmission of infectious agents from one person to another. Needles should be disposed of properly and not recapped. Page of

3 .. Recommended Dose and Schedule, should be administered as a ml dose by intramuscular injection preferably in the lateral aspect of the deltoid muscle of the upper arm. The second ml dose of vaccine should be administered approximately days later (window to days). The vaccine should not be injected in the gluteal region or areas where there may be a major nerve trunk. A needle inch is preferred because needles < inch might be of insufficient length to penetrate the muscle tissue in certain adults. 0. DOSAGE FORMS AND STRENGTHS, is available as a suspension in ml multi-dose vials containing doses. Each ml dose is formulated to contain 0 micrograms (μg) hemagglutinin (HA) of the influenza virus strain A/Vietnam/0/00 (HN, clade ) and not more than. μg of thimerosal (approximately 0 μg of mercury/dose). Thimerosal, a mercury derivative, is added as a preservative.. CONTRAINDICATIONS None 0 Page of

4 . WARNINGS AND PRECAUTIONS.. Hypersensitivity, contains chicken and egg proteins. The decision to give, to persons with known systemic hypersensitivity reactions to egg proteins or life-threatening reactions to previous influenza vaccinations should be based on careful considerations of risks and benefits. 0.. Guillain-Barré Syndrome If Guillan-Barré syndrome has occurred within weeks of receipt of prior influenza vaccine, the decision to give, should be based on careful consideration of the potential benefits and risks... Altered Immunocompetence If, is administered to immunocompromised persons, including individuals receiving immunosuppressive therapy, the expected immune response may not be obtained. 0.. Preventing and Managing Allergic Reactions Prior to administration of, the healthcare provider should review the patient s prior immunization history for possible adverse events, to allow an assessment of benefits and risks. Epinephrine injection (:,000) and other appropriate agents used for the Page of

5 control of immediate allergic reactions must be immediately available should an acute anaphylactic reaction occur.. ADVERSE REACTIONS Adverse event information from clinical trials provides the basis for identifying adverse events that appear to be related to vaccine use and for approximating the rates of these events. However, because clinical trials are conducted under widely varying conditions, adverse event rates observed in the clinical trials of a vaccine cannot be directly compared to rates in the clinical trial of another vaccine, and may not reflect the rates observed in use Data from Clinical Studies A randomized, placebo-controlled, double-blind, multicenter trial was conducted in the US. Healthy adults through years of age were carefully screened for the absence of chronic illnesses. A total number of 0 subjects (mean age:. years; age range through years;. % female, race:.% White, 0.% Black or African American, and.% Asian) received an intramuscular injection of an investigational vaccine formulation of A/Vietnam/0/00 (HN, clade ) containing 0 μg hemagglutinin and no preservative, followed by another injection of the same dose approximately days later. Forty-eight () subjects received 0. ml intramuscular injection of saline placebo. All adverse events were collected following each of the doses. Page of

6 Four serious adverse events (SAEs), all considered unrelated to vaccine, occurred after vaccination including one death and three other SAEs (one each: menorrhagia, cerebrovascular event, and breast cancer). The table below summarizes the frequencies of the solicited adverse reactions that were recorded following any vaccination. Table : Frequencies of Solicited Reactions* within Days After Any Vaccination Percent (%) Placebo. µg µg µg 0 µg (N=) (N=0) (N=0) (N=) (N=0) Local reactions Pain..... Tenderness Erythema/Redness Induration/Swelling Systemic reactions Headache..... Malaise..... Myalgia..... Page of

7 Percent (%) Placebo. µg µg µg 0 µg (N=) (N=0) (N=0) (N=) (N=0) Nausea Fever * All solicited events are considered to be reactions. Note: Immediate reactions are included, except for immediate redness and swelling, as no severity grade was assigned Most of the solicited injection site reactions were of mild to moderate severity and resolved within three days of vaccination. Most of the solicited systemic reactions were also of mild to moderate severity. The table below summarizes the frequencies of the unsolicited adverse events that were recorded throughout the study. Table : Unsolicited Adverse Events* % Reported after any Vaccination Percent (%)* Placebo. µg µg µg 0 µg (N = (N = 0) (N = 0) (N = ) (N = 0) Gastrointestinal disorders Diarrhea Page of

8 Infections and infestations Nasopharyngitis Upper respiratory tract infection Nervous system disorders Headache Respiratory, thoracic and mediastinal disorders Nasal congestion Pharyngolaryngeal pain General disorders and administration site conditions Pyrexia * For unsolicited events, the denominator for percentages is the number of vaccinated subjects for whom safety data are available (safety analysis set)... Adverse Events Associated with Influenza Vaccines Anaphylaxis has been reported after administration of influenza vaccines. Although Influenza Virus Vaccine, HN, contains only a limited quantity of egg protein, this protein can induce immediate hypersensitivity reactions among persons who have severe egg allergy. Allergic reactions include hives, angioedema, allergic asthma, and systemic anaphylaxis. [see WARNINGS AND PRECAUTIONS (.)] Page of

9 The swine influenza vaccine was associated with an increased frequency of Guillain-Barré syndrome (GBS). Evidence for a causal relation of GBS with subsequent vaccines prepared from other influenza viruses is unclear. Neurological disorders temporally associated with influenza vaccination such as encephalopathy, optic neuritis/neuropathy, partial facial paralysis, and brachial plexus neuropathy have been reported. 0 Microscopic polyangitis (vasculitis) has been reported temporally associated with influenza vaccination.. DRUG INTERACTIONS.. Concomitant Administration with Other Vaccines There are no data to assess the concomitant administration of, with other vaccines. If, is to be given at the same time as another injectable vaccine(s), the vaccines should always be administered at different injection sites., should not be mixed with any other vaccine in the same syringe or vial. 0 Page of

10 .. Immunosuppressive Therapies Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs, and corticosteroids (used in greater than physiologic doses), may reduce the immune response to. 0. USE IN SPECIFIC POPULATIONS.. Pregnancy PREGNANCY CATEGORY C Animal reproductive studies have not been conducted with. It is not known whether, can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity., should be given to a pregnant woman only if clearly needed... Nursing Mothers It is not known whether, is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Influenza Virus Vaccine, HN, is administered to a nursing mother. Page 0 of

11 .. Pediatric Use No data are available for the pediatric population (ages less than years). Safety and effectiveness of, in pediatric populations have not been established. 0.. Geriatric Use Clinical studies of, did not include subjects years of age and older to determine whether they respond differently from younger subjects. Other reported clinical experience has identified differences in immune response between the elderly and younger patients to inactivated influenza vaccines. 0. DESCRIPTION, a monovalent type A inactivated vaccine for intramuscular use, is a sterile suspension prepared from influenza virus propagated in embryonated chicken eggs and is supplied in ml multi-dose vials. The virus-containing fluids are harvested and inactivated with formaldehyde. The influenza virus is concentrated and purified in a linear sucrose density gradient solution using a continuous flow centrifuge. The virus is then chemically disrupted using a nonionic surfactant, polyethylene glycol p-isooctylphenyl ether (Triton X-00), producing a split virus. The split virus is then further purified by chemical means and suspended in sodium phosphate-buffered isotonic sodium chloride solution. Page of

12 , is a clear and slightly opalescent suspension formulated to contain 0 µg hemagglutinin (HA) per.0 ml dose of the influenza virus strain A/Vietnam/0/00 (HN, clade ). Porcine gelatin (00 μg/dose) is added as a stabilizer. Thimerosal, a mercury derivative, is added as a preservative. Each.0 ml dose is formulated to contain not more than. µg thimerosal (approximately 0 µg mercury/dose). Each dose may also contain residual amounts of formaldehyde (not more than 00 μg), Polyethylene Glycol p- Isooctylphenyl Ether (not more than 0.0%), and sucrose (not more than.0%). No antibiotics are used in the manufacture of this vaccine. This presentation is latex-free. 0, is available as a suspension in ml multi-dose vials containing doses and should be administered as a ml dose by intramuscular injection. [see DOSAGE AND ADMINISTRATION () and DOSAGE FORMS AND STRENGTHS ()] 0. CLINICAL PHARMACOLOGY.. Mechanism of Action The mechanism of action of type A (HN) influenza virus vaccines is not well understood. Influenza vaccines induce antibodies against the viral hemagglutinin in the vaccine, thereby blocking viral attachment to human respiratory epithelial cells. Specific levels of hemagglutinin inhibition (HI) antibody titer post-vaccination with inactive influenza virus vaccines, including HN influenza virus vaccines, have not been correlated with protection from influenza illness but the antibody titers have been used as a measure of vaccine activity. In some human challenge Page of

13 studies of other influenza viruses, antibody titers of >:0 have been associated with protection from influenza illness in up to 0% of subjects. Antibody against one influenza virus type or subtype confers little or no protection against viruses from other types or subtypes. Furthermore, antibody to one antigenic variant of influenza virus might not protect against a new antigenic variant of the same type or subtype. Frequent development of antigenic variants through antigenic drift is the virological basis for seasonal epidemics and the reason for the usual change of one or more new strains in each year s influenza vaccine. 0 Global surveillance of influenza identifies yearly antigenic variants. An influenza pandemic occurs when humans have little or no immunity to an influenza virus strain and this virus strain is rapidly transmitted from human to human. Antigenic variants of HN viruses have been in circulation in the avian species globally, with rare transmission to humans. However, these avian HN viruses may acquire mutations that facilitate transmission among humans. 0. NON-CLINICAL TOXICOLOGY.. Carcinogenesis, Mutagenesis, Impairment of Fertility, has not been evaluated for carcinogenic or mutagenic potential, or for impairment of fertility. Page of

14 0. CLINICAL STUDIES A prospective, randomized, double-blinded, placebo-controlled, dose-ranging, Phase - study was conducted in healthy subjects through years of age (mean age: 0. years;.% female, race: 0.% White,.% Black or African American, and.% Asian). Vaccine doses contained. µg, µg, µg, or 0 µg no preservative hemagglutinin of the strain A/Vietnam/0/00 (HN, clade ). For the 0 µg dosage, a total of 0 subjects received a dose on day given as a.0 ml intramuscular injection, followed by another injection of the 0 µg dosage approximately days later. Forty-eight () subjects received 0. ml intramuscular injections of saline placebo on the same schedule. The objectives of the study were to assess safety by collecting solicited and unsolicited adverse events, and to assess immunogenicity by measuring neutralizing and hemagglutination inhibition (HAI) antibody titers, and by determining the proportion achieving titer of >:0 twenty-eight days after the second dose. Safety results are summarized in Section.. Immunogenicity results were as follows: Page of

15 Table : Immunogenicity days After Vaccination Dose group Number tested GMT (% CI) Percent Responding (%CI)* Percent achieving a titer of >:0 (% CI) Placebo. (.,.) 0 (0, ) (0, ) 0 µg **. (0.,.0) (, ) (, ) * Response requires both a -fold or greater increase over baseline, and achievement of a :0 titer or greater by HAI ** Blood specimens were not obtained from subjects.. HOW SUPPLIED/STORAGE AND HANDLING.. How Supplied, is supplied in a.0 ml multi-dose vial containing five.0 ml doses. (NDC -00-0) 0.. Storage Conditions and Shelf Life Store in a refrigerator at to C ( to F). Do not freeze. Do not use vaccine after expiration date. Protect from light. Page of

16 . PATIENT COUNSELING INFORMATION Patients, parents or guardians should be fully informed by their health care provider of the benefits and risks of immunization with. When educating vaccine recipients and guardians regarding the potential side effects, clinicians should emphasize that, contains non-infectious particles. Patients, parents or guardians should be instructed to report any serious adverse reaction to their health care provider. 0 Product information as of April 00 Manufactured by: Sanofi Pasteur Inc. Swiftwater PA 0 USA Triton X-00 is a registered trademark of Union Carbide, Co. 0 Page of