Product Information Leaflet Arepanrix™ H1N1 AS03-Adjuvanted H1N1 Pandemic Influenza Vaccine This information has been prepared by another organization and is provided as a service to health professionals, consumers and other interested parties. Version 1 approved October 21, 2009 Health Canada has authorized the sale of Arepanrix™ H1N1 based on limited clinical testing in humans under the provision of an Interim Order (IO) issued on October 13, 2009. The authorization is based on the Health Canada review of the available data on quality, safety and immunogenicity, and given the current pandemic threat and its risk to human health, Health Canada considers that the benefit/risk profile of the Arepanrix™ H1N1 vaccine is favourable for active immunization against the H1N1 2009 influenza strain in an officially declared pandemic situation. As part of the authorization for sale for Arepanrix™ H1N1, Health Canada has requested the sponsor agree to post-market commitments. Adherence to these commitments, as well as updates to information on quality, non-clinical, and clinical data will be continuously monitored by Health Canada and the Public Health Agency of Canada. This leaflet will be updated accordingly. Please consult the Health Canada website for the most up-to-date information for this product. Recommendations made by the Public Health Agency of Canada should also be taken into consideration. Table of Contents 1.0 Pharmaceutical Form 2.0 Qualitative and Quantitative Composition 3.0 Clinical Particulars Indications Dosage and Administration Contraindications Warnings and Precautions Interactions Effects on Ability to Drive and Use Machines Adverse Reactions Clinical trials Overdose 4.0 Pharmacological Properties Pharmacodynamics Pharmacokinetics Pre-clinical Safety Data 5.0 Pharmaceutical Particulars List of Excipients Incompatibilities Shelf Life Special Precautions for Storage Nature and Contents of Container Instructions for Use/Handling Consumer Information 1.0 Pharmaceutical Form Arepanrix™ H1N1 (AS03-adjuvanted H1N1 pandemic influenza vaccine) is a two-component vaccine consisting of an H1N1 immunizing antigen (as a suspension), and an AS03 adjuvant (as an oil-in-water emulsion). The H1N1 antigen is a sterile, colorless to slightly opalescent suspension that may sediment slightly in a 10mL vial. The antigen is prepared from virus grown in the allantoic cavity of embryonated hen's eggs. The virus is inactivated with ultraviolet light treatment followed by formaldehyde treatment, purified by centrifugation and disrupted with sodium deoxycholate. The AS03 adjuvant system is a sterile, homogenized, whitish emulsion composed of DL-α-tocopherol (synthetic vitamin E as an anti-oxidant to prevent the squalene from rancidity), squalene (derived from shark liver oil) and polysorbate 80 in a 3mL vial. Immediately prior to use, the full contents of the AS03 vial is withdrawn and added to the antigen vial (mix ratio 1:1). The mixed final product for administration is an emulsion, containing enough product for 10 doses. Top of Page 2.0 Qualitative and Quantitative Composition After combining and mixing the two components, 0.5mL of the resultant emulsion is withdrawn into a syringe for intramuscular injection. The final composition of each vaccine component per 0.5mL dose is as follows: Antigen: Split influenza virus, inactivated, containing antigen* equivalent to: A/California/7/2009 (H1N1)v-like strain (X-179A) 3.75µg HA** per 0.5mL dose * isolated from virus propagated in eggs ** HA = haemagglutinin Preservative content is 5µg Thimerosal (49% mercury) USP per 0.5mL dose or 2.5 micrograms organic mercury (Hg) per 0.5mL dose Adjuvant: DL-α-tocopherol 11.86 milligrams/0.5mL dose Squalene 10.69 milligrams/0.5mL dose, Polysorbate 80 4.86 milligrams/0.5mL dose The suspension and emulsion vials, once mixed, form a multidose vaccine in a vial. See section Nature and Contents of Container for the number of doses per vial. For a full list of excipients, see section List of Excipients under 5.0. Top of Page 3.0 Clinical Particulars Indications Arepanrix™ H1N1 Vaccine is indicated for active immunization against H1N1 influenza strain in an officially declared pandemic situation. (see section 2.0 Qualitative and Quantitative Composition). Dosage and Administration There is currently limited clinical experience with Arepanrix™ H1N1, and limited clinical experience with an investigational formulation of another AS03-adjuvanted vaccine 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 and no clinical experience yet in the elderly, in children or in adolescents. The decision to use Arepanrix™ H1N1 in each age group defined below should take into account the extent of the clinical data available with a version of the vaccine containing H5N1 antigen and the disease characteristics of the current influenza pandemic. The dose recommendations are based on: safety and immunogenicity data available on the administration of AS03-adjuvanted vaccine containing 3.75 µg HA derived from A/Indonesia/5/2005 (H5N1) (Arepanrix™ H5N1) at 0 and 21 days to adults, including the elderly safety and immunogenicity data available on the administration of the adult dose and half of the adult dose to children aged from 3-9 years with anotherAS03-adjuvanted vaccine containing 3.75 µg HA derived from A/Vietnam/1194/2004 (H5N1) at 0 and 21 days limited immunogenicity data from 2 studies obtained three weeks after administration of a single dose of an investigational formulation of another AS03-adjuvanted H1N1 vaccine containing either 5.25 µg or 3.75 µg HA derived from A/California/7/2009 (H1N1) (Pandemrix™) to healthy adults aged 18-60 years. See section Pharmacodynamics. Adults aged 18-60 years: One dose of 0.5mL 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 another AS03-adjuvanted H1N1 vaccine containing either 5.25 µg or 3.75 µg HA derived from A/California/7/2009 (H1N1) (Pandemrix™) 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. If a second dose is needed, it should be given after an interval of at least three weeks. Elderly (>60 years): No clinical data are available for Arepanrix™ H1N1 in this age group. One dose of 0.5mL at an elected date may be considered. The need for a second dose of vaccine is unknown. If a second dose is needed, it should be given after an interval of at least three weeks. See section Pharmacodynamics. Children and adolescents aged 10-17 years: Flying blind!!!~No clinical data are available for any influenza vaccines with AS03 in this age group. Consideration may be given to dosing in accordance with recommendations for adults. Vaccine Roulette = Children aged 3-9 years: Based on limited clinical data available for AS03-adjuvanted H5N1 vaccine containing 3.75 µg HA derived from A/Vietnam/1194/2004 in this age group, 0.25mL of vaccine (i.e. half of the adult dose) at an elected date and a second dose administered at least three weeks later may be considered sufficient. See section Pharmacodynamics. Children aged from 6-35 months: Flying blind! No clinical data are available for influenza vaccines with AS03 in this age group. Consideration may be given to dosing in accordance with the recommendation in children aged 3-9 years. Children aged less than 6 months: Vaccination is not currently recommended in this age group. Why the cut off at 6 months?They don't know!! They're flying blind! 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. How will they know on such short notice??? Will they look???Flying blind!!! 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. Arepanrix™ H1N1 should under no circumstances be administered intravascularly or intradermally. Antibody response in patients with endogenous or iatrogenic immunosuppression may be insufficient. (iatrogenic??? = physician caused!!!) A protective immune response may not be elicited in all vaccinees (see section Pharmacodynamics). (Again!!!Flying blind!!!) Pediatric There is very limited experience with AS03-adjuvanted H5N1 vaccine in children between 3 and 9 years of age, and no experience in children less than 3 years of age or in children and adolescents between 10 and 17 years of age. See sections Dosage and Administration, Adverse Reactions and Pharmacodynamics.<are the parents informed of this fact???> Pregnancy and Lactation No data have been generated in pregnant women with Arepanrix™ H1N1 nor with the prototype AS03 adjuvanted H5N1 vaccine. Data from vaccinations with seasonal trivalent influenza vaccines in pregnant women do not indicate that adverse foetal and maternal outcomes were attributable to the vaccine. Consideration should be taken of any recommendations made by the Public H ealth Agency of Canada. Animal studies have not demonstrated harmful effects with respect to fertility, pregnancy, embryonal/foetal development, parturition or post-natal development (see also the section Non-clinical information). (How long were these studies conducted - Or were they cut off just before any adverse reactions cut in??? No data have been generated in breast-feeding women. No Data??? The S.O.B.'s are Flying blind!!! Interactions No data are available on the concomitant administration of Arepanrix™ H1N1 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 S.O.B.'s are Flying blind!!! The immunological response may be diminished if the patient is undergoing immunosuppressant treatment. The S.O.B.'s are Flying blind!!! Following influenza vaccination, false positive serology test results may be obtained by the ELISA method for antibodies to HIV-1, Hepatitis C, and especially HTLV-1. These transient false-positive results may be due to cross-reactive IgM elicited by the vaccine. For this reason, a definitive diagnosis of HIV-1, Hepatitis C, or HTLV-1 infection requires a positive result from a virus-specific confirmatory test (e.g, Western Blot or immunoblot). The S.O.B.'s are Flying blind!!! You could conceivably be falsely diagnosed as HIV + and have to fight that stigmata for the rest of your life!!! Effects on Ability to Drive and Use Machines??? No studies on the effects on the ability to drive and use machines have been performed. The S.O.B.'s are Flying blind on assumptions!!! Adverse Reactions H1N1 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 AS03-adjuvanted vaccine containing HA derived from A/California/7/2009 (H1N1)v-like (Pandemrix™) in healthy subjects aged 18-60 years. In one study, the vaccine contained a higher amount of antigen (5.25 µg HA). In both studies, a group of subjects received the vaccine without the AS03 adjuvant. Solicited local and general symptoms were generally reported more frequently in the H1N1+AS03 group compared to the H1N1 group. Pain at the injection site was the most frequently reported solicited adverse events (AE). The frequency of ''related' Grade 3 symptoms was low and did not exceed 1.6%. D-Pan H1N1-021 (Day 0 to Day 6 solicited adverse events following a single dose of 5.25µg HA + AS03 H1N1 vaccine [Pandemrix™] versus a single dose of 21 µg HA unadjuvanted H1N1 vaccine) - Adverse Events with a causal relationship D-Pan H1N1-021 (Day 0 to Day 6 solicited adverse events following a single dose of 5.25µg HA + AS03 H1N1 vaccine [Pandemrix™] versus a single dose of 21 µg HA unadjuvanted H1N1 vaccine) - Adverse Events with a causal relationship Adverse reactions H1N1/AS03 N=63 H1N1 N=66 Pain 88.9% 59.1% Redness 31.7% 4.5% Swelling 30.2% 1.5% Fatigue 15.9% 10.6% Headache 14.3% 7.6% Arthralgia 14.3% 3.0% Myalgia 15.9% 4.5% Shivering 3.2% 4.5% Sweating 6.3% 4.5% Fever 0.0% 0.0% D-Pan H1N1-007 (Day 0 to Day 6 solicited adverse events following a single dose of 3.75 µg HA + AS03 vaccine [Pandemrix™] versus a single dose of 15 µg HA unadjuvanted H1N1 vaccine) - Adverse Events with a causal relationship Adverse reactions H1N1/AS03 N=62 H1N1 N=62 Pain 90.3% 37.1% Redness 1.6% 0.0% Swelling 6.5% 0.0% Fatigue 32.3% 25.8% Headache 14.3% 7.6% Arthralgia 11.3% 4.8% Myalgia 33.9% 8.1% Shivering 8.1% 3.2% Sweating 9.7% 8.1% Fever 0.0% 0.0% A total of four serious adverse events (SAEs) have been reported with the H1N1 studies. Three of them were considered by the investigators to be unrelated to the study vaccine (how would they know??) One reported case of hypersensitivity was considered by the investigator to be related to vaccination. H5N1 Studies: Clinical trials Adverse reactions from clinical trials conducted using the mock-up vaccine are listed below. Adults: Clinical studies have evaluated the incidence of adverse reactions listed below in approximately 3,500 subjects 18 years old and above who received Influenza Virus Vaccine containing A/Indonesia/05/2005 (Arepanrix™ H5N1) with at least 3.75 µg HA/AS03. The reactogenicity of vaccination was solicited by collecting adverse events using standardized forms for 7 consecutive days following vaccination with Arepanrix™ H5N1 or placebo (i.e., Day 0 to Day 6). The average frequencies of solicited local and general adverse events reported within 7 days after each vaccination dose are presented below: Percentage of Doses Followed by Solicited Local or General Adverse Events Within 7 Days of Any Vaccination With Arepanrix™ H5N1 (Total Vaccinated Cohort*) Local AREPANRIX™ H5N1 Placebo N=6647 doses N=2209 doses Pain 73.1 12.0 Swelling 6.7 0.4 Redness 5.25 0.4 General N=6639 doses N=2210 doses Muscle Aches 33.3 11.8 Headache 23.4 17.6 Fatigue 23.3 14.1 Joint Pain 16.4 7.4 Shivering 9.8 6.0 Sweating 6.3 4.4 Fever, ≥38.0°C 2.4 1.9 * Total Vaccinated Cohort = all subjects who received at least one dose of vaccine and for whom any safety data were available. Pain at the injection site was the most commonly reported solicited local symptom in both Arepanrix™ H5N1 and placebo groups and was reported at a 6-fold higher frequency (i.e. following 73% of doses) in the Arepanrix™ H5N1 group. Despite the high incidence of injection site pain, the incidence of severe pain was low, with reports occurring after 2.7% of Arepanrix™ H5N1 doses and 0.4% of placebo doses. Overall, severe solicited or unsolicited adverse events of any type occurred in the 7 days after 6.4 to 7.0% of Arepanrix™ H5N1 doses and 3.6% of placebo doses. The most common severe solicited adverse event was local injection site pain; all severe general solicited adverse events occurred after <2% of doses. Other/Additional adverse reactions reported are listed according to the following frequency classification: Very common (≥1/10) | 
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