1. Name Of The Medicinal Product
Pandemrix
Influenza vaccine (H1N1)v (split virion, inactivated, adjuvanted)
2. Qualitative And Quantitative Composition
After mixing, 1 dose (0.5 ml) contains:
Split influenza virus, inactivated, containing antigen* equivalent to:
A/California/07/2009 (H1N1) derived strain used NYMC X-179A 3.75 micrograms**
* propagated in eggs
** haemagglutinin
AS03 adjuvant composed of squalene (10.69 milligrams), DL-α-tocopherol (11.86 milligrams) and polysorbate 80 (4.86 milligrams)
The suspension and emulsion, once mixed, form a multidose vaccine in a vial. See section 6.5 for the number of doses per vial.
Excipients: the vaccine contains 5 micrograms thiomersal
For a full list of excipients see section 6.1.
3. Pharmaceutical Form
Suspension and emulsion for emulsion for injection.
The suspension is a colourless light opalescent liquid.
The emulsion is a whitish homogeneous liquid.
4. Clinical Particulars
4.1 Therapeutic Indications
Prophylaxis of influenza caused by A (H1N1)v 2009 virus. In persons under 20 years of age, Pandemrix should only be used if the recommended annual seasonal trivalent influenza vaccine is not available and if immunisation against (H1N1)v is considered necessary (see sections 4.4 and 4.8).
Pandemrix should be used in accordance with Official Guidance.
4.2 Posology And Method Of Administration
Posology
The dose recommendations take into account the safety and immunogenicity data from clinical studies in healthy subjects
See sections 4.4, 4.8 and 5.1 for details.
No data are available in children aged less than 6 months.
Adults aged 18 years and older:
One dose of 0.5 ml at an elected date.
Immunogenicity data obtained at three weeks after one dose of Pandemrix (H1N1)v suggest that a single dose may be sufficient.
If a second dose is administered there should be an interval of at least three weeks between the first and the second dose.
See section 5.1 regarding immune responses to one and two doses of Pandemrix (H1N1)v, including antibody levels after 6 and 12 months.
Children and adolescents aged 10-17 years
Dosing may be in accordance with the recommendations for adults.
Children aged from 6 months to 9 years
One dose of 0.25 ml at an elected date.
There is a further immune response to a second dose of 0.25 ml administered after an interval of three weeks.
The use of a second dose should take into consideration the information provided in sections 4.4, 4.8 and 5.1.
Children aged less than 6 months
Vaccination is not currently recommended in this age group.
It is recommended that subjects who receive a first dose of Pandemrix should complete the vaccination course with Pandemrix (see section 4.4).
Method of administration
Immunisation should be carried out by intramuscular injection preferably into the deltoid muscle or anterolateral thigh (depending on the muscle mass).
4.3 Contraindications
History of an anaphylactic (i.e. life-threatening) reaction to any of the constituents or trace residues (egg and chicken protein, ovalbumin, formaldehyde, gentamicin sulphate and sodium deoxycholate) of this vaccine.
Immunisation should be postponed in subjects with a severe febrile illness or acute infection.
4.4 Special Warnings And Precautions For Use
The vaccine can only be expected to protect against influenza caused by A/California/07/2009 (H1N1)v-like strains.
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, to thiomersal and to residues (egg and chicken protein, ovalbumin, formaldehyde, gentamicin sulphate and sodium deoxycholate).
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.
Pandemrix should under no circumstances be administered intravascularly.
There are no data with Pandemrix using the subcutaneous route. Therefore, healthcare providers need to assess the benefits and potential risks of administering the vaccine in individuals with thrombocytopenia or any bleeding disorder that would contraindicate intramuscular injection unless the potential benefit outweighs the risk of bleedings.
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 5.1).
There are no safety and immunogenicity data available from clinical studies with Pandemrix (H1N1)v in children aged less than 6 months. Vaccination is not recommended in this age group.
In children aged 6 to 35 months (N=51) who received two doses of 0.25 ml (half of the adult dose) with an interval of 3 weeks between doses there was an increase in the rates of injection site reactions and general symptoms after the second dose (see section 4.8). In particular rates of fever (axillary temperature
There are no safety, immunogenicity or efficacy data to support interchangeability of Pandemrix with other (H1N1)v vaccines.
Epidemiological studies relating to Pandemrix in two countries (Sweden and Finland) have indicated a six to13-fold increased risk of narcolepsy with or without cataplexy in vaccinated as compared with unvaccinated children/adolescents, corresponding to an absolute risk increase of about three to seven additional cases in 100 000 vaccinated subjects. This risk increase has not been found in adults (older than 20 years). A similar risk has not been confirmed but cannot be ruled out in other countries.
The relationship between Pandemrix and narcolepsy is still under investigation.
In persons under 20 years of age, Pandemrix should only be used if the recommended annual seasonal trivalent influenza vaccine is not available and if immunisation against (H1N1)v is considered necessary. (see section 4.8)
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Data obtained on co-administration of Pandemrix (H1N1)v with non-adjuvanted seasonal influenza vaccine (Fluarix, a split virion vaccine) in healthy adults aged over 60 years did not suggest any significant interference in the immune response to Pandemrix (H1N1)v. The immune response to Fluarix was satisfactory.
Co-administration was not associated with higher rates of local or systemic reactions compared to administration of Pandemrix alone.
Therefore the data indicate that Pandemrix may be co-administered with non-adjuvanted seasonal influenza vaccines (with injections made into opposite limbs).
Data obtained on the administration of a non-adjuvanted seasonal influenza vaccine (Fluarix, as above) three weeks before a dose of Pandemrix (H1N1)v in healthy adults over 60 years of age, did not suggest any significant interference in the immune response to Pandemrix (H1N1)v. Therefore the data indicate that Pandemrix may be administered three weeks after the administration of non-adjuvanted seasonal influenza vaccines.
In a clinical study where a non-adjuvanted seasonal influenza vaccine (Fluarix, as above) was administered 3 weeks after the second dose of Pandemrix (two doses were given 21 days apart), a lower immune response to Fluarix was observed as compared to subjects who had not previously received Pandemrix. It is not known whether the observed effects would apply to administration of non-adjuvanted seasonal influenza vaccine after a single dose of Pandemrix or when longer dose intervals have elapsed since administration of Pandemrix. It is preferable that non-adjuvanted seasonal influenza vaccines should be administered before or with the first dose of Pandemrix.
There are no data on co-administration of Pandemrix with other vaccines.
If co-administration with another vaccine is considered, immunisation 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.
Following influenza vaccination, false-positive serology test results may be obtained by the ELISA method for antibody to human immunodeficiency virus-1 (HIV-1), hepatitis C virus and, especially, HTLV-1. In such cases, the Western blot method is negative. These transitory false-positive results may be due to IgM production in response to the vaccine.
4.6 Pregnancy And Lactation
Pandemrix has been administered to women in each trimester of pregnancy. Information on outcomes from estimated more than 200,000 women who have been vaccinated during pregnancy is currently limited. There was no evidence of an increased risk of adverse outcomes in over 100 pregnancies that were followed in a prospective clinical study.
Animal studies with Pandemrix do not indicate reproductive toxicity (see section 5.3).
Data from pregnant women vaccinated with different inactivated non-adjuvanted seasonal vaccines do not suggest malformations or fetal or neonatal toxicity.
Pandemrix may be administered in lactating women.
4.7 Effects On Ability To Drive And Use Machines
Some of the effects mentioned under section 4.8 “Undesirable Effects” may affect the ability to drive or use machines.
4.8 Undesirable Effects
• Clinical trials
Adverse reactions reported are listed according to the following frequency:
Very common (
Common (
Uncommon (
Rare (
Very rare (<1/10,000)
Clinical studies have evaluated the incidence of adverse reactions listed below in approximately 5,000 subjects 18 years old and above who received formulations containing A/Vietnam/1194/2004 (H5N1).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Blood and lymphatic system disorders
Common: lymphadenopathy
Psychiatric disorders
Uncommon: insomnia
Nervous system disorders
Very common: headache
Uncommon: paraesthesia, somnolence, dizziness
Gastrointestinal disorders
Uncommon: gastro-intestinal symptoms (such as diarrhoea, vomiting, abdominal pain, nausea)
Skin and subcutaneous tissue disorders
Common: ecchymosis at the injection site, sweating increased
Uncommon: pruritus, rash
Musculoskeletal and connective tissue disorders
Very common: arthralgia, myalgia
General disorders and administration site conditions
Very common: induration, swelling, pain and redness at the injection site, fever, fatigue
Common: shivering, influenza like illness, injection site reactions (such as warmth, pruritus)
Uncommon: malaise
Additional data on reactogenicity are available from clinical studies in healthy subjects of various age groups from 6 months of age upwards who received Pandemrix (H1N1)v. The available data are as follows:
Adults
A clinical study evaluated the reactogenicity of Pandemrix (H1N1)v in healthy adults aged 18-60 (N=120) and above 60 years (N=120) who received either one or two doses of vaccine. The frequency of adverse reactions was similar between age groups, except for redness (more common in subjects aged >60 years) and shivering and sweating (more common in subjects aged 18-60 years). In the subjects aged 18-60 years, no increase in reactogenicity was observed after the second dose compared to the first dose. In the subjects aged >60 years, arthralgia was reported with a higher frequency after the second dose.
In another clinical study that evaluated reactogenicity in healthy adults aged 18-60 years who received two 0.5 ml doses (21 days apart) of Pandemrix (H1N1)v, there were higher rates of most general solicited symptoms (such as fatigue, headache, arthralgia, shivering, sweating and fever) after the second dose compared to the first dose.
Children aged 10-17 years
In clinical studies that evaluated the reactogenicity in children 10 to 17 years of age who received either two 0.5 ml doses (adult dose) or two 0.25 ml doses (half adult dose) (21 days apart) of Pandemrix (H1N1)v, the per-dose frequency of the following adverse reactions was as shown in the table:
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Children aged 3-9 years
In clinical studies that evaluated reactogenicity in children 3 to 5 and 6 to 9 years of age who received either two 0.25 ml doses (half adult dose) or two 0.5 ml doses (adult dose) (21 days apart) of Pandemrix (H1N1)v, the per-dose frequency of the following adverse reactions was as shown in the table:
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NA= not available
Children aged 6-35 months
In a clinical study that evaluated reactogenicity in children aged 6 to 35 months who received either two 0.25 ml doses (half adult dose) or two 0.5 ml doses (adult dose) (21 days apart) of Pandemrix (H1N1)v there was an increase in injection site reactions and general symptoms after the second dose compared to the first dose particularly in rates of axillary fever (>38°C). The per-dose frequency of the following adverse reactions was as shown in the table:
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• Post-marketing surveillance
Pandemrix (H1N1)v
In addition to the adverse reactions reported in the clinical trials, the following have been reported during post-marketing experience with Pandemrix (H1N1)v:
Immune system disorders
Anaphylaxis, allergic reactions
Nervous system disorders
Febrile convulsions
Very rare1: Narcolepsy2 with or without cataplexy (see section 4.4)
1frequency based on estimated attributable risk from epidemiological studies in Sweden and Finland (see section 4.4)
2 Reported in subjects below 20 years of age.
Skin and subcutaneous tissue disorders
Angioedema, generalised skin reactions, urticaria
Trivalent seasonal influenza vaccines
From Post-marketing surveillance with trivalent seasonal influenza vaccines, the following adverse reactions have also been reported:
Rare:
Neuralgia, transient thrombocytopenia.
Very rare:
Vasculitis with transient renal involvement.
Neurological disorders, such as encephalomyelitis, neuritis and Guillain Barré syndrome.
This medicinal product contains thiomersal (an organomercuric compound) as a preservative and therefore, it is possible that sensitisation reactions may occur (see section 4.4).
4.9 Overdose
No case of overdose has been reported.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Influenza vaccines, ATC Code J07BB02.
Immune response to Pandemrix (H1N1)v
Adults aged 18-60 years
In two clinical studies that evaluated the immunogenicity of Pandemrix in healthy subjects aged 18-60 years. All subjects received two doses of 0.5 ml 21 days apart, except in study D-Pan H1N1-008, in which half of the subjects received only one dose of 0.5 ml. The anti-HA antibody responses were as follows:
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