Summary of medicine characteristics - Pandemrix
1. NAME OF THE MEDICINAL PRODUCT
Pandemrix suspension and emulsion for emulsion for injection. Influenza vaccine (H1N1)v (split virion, inactivated, adjuvanted)
3.75 mic:
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
*
propagated in eggs
**
haemagglutinin
AS03 adjuvant composed of squalene (10.69 milligrams), DL-a-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.
Excipient with known effect
The vaccine contains 5 micrograms thiomers:
3. PHARMACEUTICAL
For the full list of excipients, see secti
Suspension and emulsion for e lsion for injection.
The suspension is a colourless light opalescent liquid.
The emulsion is a whitish to yellowish homogeneous milky liquid.
4.
4.1
Prophylaxis of influenza caused by A (H1N1)v 2009 virus. Pandemrix should only be used if the recommended annual seasonal trivalent/quadrivalent influenza vaccines are 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.
Paediatric population
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 No data are available.
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).
For instructions on mixing of the medicinal product before administration, see section 6.6.
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 listed in section 6.1, 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, immunogenicity or efficacy data to support interchangeability of Pandemrix with other (H1N1)v vaccines.
Epidemiological studies relating to Pandemrix in several European countries have indicated an increased risk of narcolepsy with or without cataplexy in vaccinated as compared with unvaccinated individuals. In children/adolescents (aged up to 20 years), these studies have indicated an additional 1.4 to 8 cases in 100,000 vaccinated subjects. Available epidemiological data in adults aged over 20 years have indicated approximately 1 additional case per 100,000 vaccinated subjects. These data suggest that the excessive risk tends to decline with increasing age at vaccination.
The relationship between Pandemrix and narcolepsy is still under investigation.
Pandemrix should only be used if the recommended annual seasonal trivalent/quadrivalent influenza vaccines are not available and if immunisation against (H1N1)v is considered necessary (see section 4.8).
Paediatric population
There are no safety and immunogenici children aged less than 6 months. Vacc
ty data available from clinical studies with Pandemrix (H1N1)v in hnation is not recommended in this age group.
In children aged 6 to 35 months (
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 >38°C) increased considerably after the second dose. Therefore, monitoring of temperature and measures to lower the fever (such as antipyretic medication as seems clinically necessary) are recommended in young children (e.g. up to approximately 6 years of age) after each dose of Pandemrix.
Syncope
mg) can occur following, or even before, any vaccination especially in adolescents as a
psychogenic response to the needle injection. This can be accompanied by several neurological signs such as transient visual disturbance, paraesthesia and tonic-clonic limb movements during recovery. It is important that procedures are in place to avoid injury from faints.
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. Çj/
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 Fertility, pregnancy and lactation
Pregnancy
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.
Breast-feeding
Pandemrix may be administered in lactating women.
Fertility
No fertility data are available.
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
Summary of the safety profile
Clinical studies have evaluated the incidence of adverse reactions in more than 1,000 subjects 18 years old and above who received Pandemrix (H1N1).
In adults 18 to 60 years of age, the most frequently reported adverse reactions after vaccination were injection site pain (87.8%), fatigue (32.9%), headache (28.1%), arthralgia (17.9%), myalgia (30.0%), shivering (19.4%), injection site swelling (11.5%) and sweating (11.3%).
In subjects > 60 years of age, the most frequently reported adverse reactions after vaccination were injection site pain (59.0%), myalgia (20.6%), fatigue (17.9%), headache (17.6%) and arthralgia (14.3%).
Tabulated list of adverse reactions
Adverse reactions reported are listed per dose according to the following frequency:
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)
in order of decreasing seriousness.
Within each frequency grouping, undesirable effects are pre;
| System Organ Class | Frequency | Adverse reactions |
| Clinical trials | ||
| Blood and lymphatic system disorders | Uncommon | Lymphadenopathy |
| Psychiatric disorders | Uncommon | Insomnia |
| Nervous system disorders | Very common | Headache |
| Uncommon | Paraesthesia, dizziness | |
| Gastrointestinal disorders | Common br | Gastrointestinal symptoms (such as diarrhoea, vomiting, abdominal pain, nausea) |
| Skin and subcutaneous tissue disorders | Very common | Sweating increased |
| Uncommon | Pruritus, rash | |
| Musculoskeletal and connective tissue disorders | Very common | Arthralgia, myalgia |
| General disorders and administration site conditions Ter | Very common | Swelling and pain at the injection site, fatigue, shivering |
| Common | Redness and pruritus at the injection site, fever | |
| Uncommon | induration and warmth at the injection site, influenza like illness, malaise | |
| Post-marketing experience with Pandemrix (H | 1N1)v | |
| Immune system disorders | Anaphylaxis, allergic reactions | |
| Nervous system disorders | Febrile convulsions | |
| Very rare1 | Narcolepsywith or without cataplexy (see section 4.4) | |
| Somnolence2 | ||
| Skin and subcutaneous tissue disorders | Angioedema, generalised skin reactions, urticaria | |
| General disorders and administration site conditions | Injection site reactions (such as inflammation, mass, ecchymosis) | |
| Post-marketing experience with trivalent seasonal influenza vaccines | ||
| Blood and lymphatic system disorders | Rare | Transient thrombocytopenia |
| Nervous system disorders | Rare | Neuralgia |
| Very rare | Neurological disorders, such as encephalomyelitis, neuritis and Guillain Barré syndrome | |
| Vascular disorders | Very rare | Vasculitis with transient renal involvement |
______________________________ _ ____________.____________________________________ement frequency based on estimated attributable risk from epidemiological studies in several European countries (see section 4.4) .
2Reported in patients with narcolepsy and as a temporary event following vaccination
In clinical studies that evaluated reactogenicity in adults aged 18 years and above who received two 0.5 ml doses of Pandemrix (H1N1)v, higher rates of general solicited symptoms (such as fatigue, headache, arthralgia, myalgia, shivering, sweating and fever) were observed after the second dose compared to the first dose.
Paediatric population
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:
| Adverse reactions | 10–17 years | |||
| Half adult dose | Adult dose | |||
| Post dose 1 N=118 | Post dose 2 N=117 | Post dose 1 N=98 | Post dose 2 N=93 | |
| Pain | 73.7% | 68.4% | 92.9% | 96.8% |
| Redness | 22.9% | 31.6% | 21.4% | 28.0% |
| Swelling | 30.5% | 25.6% | 41.8% | 53.8% |
| Shivering | 20.3% | 16.2% | 14.3% | 26.9% |
| Sweating | 7.6% | 6.8% | 5.1% | 7.5% |
| Fever >38°C | 1.7% | 5.1% | 3.1% | 9.7% |
| Fever >39°C | 1.7% | 1.7% | 0.0% | 1.1% |
| Arthralgia | 9.3% | 15.4% | 26.5% | 34.4% |
| Myalgia | 22.0% | 23.1% | 34.7% | 47.3% |
| Fatigue | 28.0% | 27.4% | 40.8% | 51.6% |
| Gastrointestinal | 11.0% | 12.0% | 6.1% | 6.5% |
| Headache | 35.6% | 35.0% | 41.8% | 53.8% |
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:
| Adverse reactions | 3–5 years | 6–9 years | ||||||
| Half adult dose | Adult dose | Half adult dose | Adult dose | |||||
| Post dose 1 | Post dose 2 | Post dose 1 | Post dose 2 | Post dose 1 | Post dose 2 | Post dose 1 | Post dose 2 | |
| N=60 | N=56 | N=53 | N=52 | N=65 | N=63 | N=57 | N=57 | |
| Pain | 60.0% | 55.4% | 75.5% | 84.6% | 63.1% | 65.1% | 94.7% | 96.5% |
| Redness | 26.7% | 41.1% | 28.3% | 34.6% | 23.1% | 33.3% | 24.6% | 33.3% |
| Swelling | 21.7% | 28.6% | 34.0% | 30.8% | 23.1% | 25.4% | 28.1% | 45.6% |
| Shivering | 13.3% | 7.1% | 3.8% | 9.6% | 10.8% | 6.3% | 7.0% | 22.8% |
| Sweating | 10.0% | 5.4% | 1.9% | 7.7% | 6.2% | 7.9% | 1.8% | 7.0% |
| Fever >38°C | 10.0% | 14.3% | 5.7% | 32.6% | 4.6% | 6.4% | 1.8% | 12.3% |
| Fever >39°C | 1.7% | 5.4% | 0.0% | 3.8% | 0.0% | 3.2% | 0.0% | 1.8% |
| Diarrhoea | 5.0% | 5.4% | 1.9% | 5.8% | NA | NA | NA | NA |
| Drowsiness | 23.3% | 17.9% | 15.1% | 28.8% | NA | NA | NA | NA |
| Irritability | 20.0% | 26.8% | 18.9% | 26.9% | NA | NA | NA | NA |
| Loss of appetite | 20.0% | 17.9% | 15.1% | 32.7% | NA | NA | NA | NA |
| Arthralgia | NA | NA | NA | NA | 15.4% | 14.3% | 14.0%. | 22.8% |
| Myalgia | NA | NA | NA | NA | 16.9% | 17.5% | 22.8% | 28.1% |
| Fatigue | NA | NA | NA | NA | 27.7% | 20.6% | 35.1% | 49.1% |
| Gastrointestinal | NA | NA | NA | NA | 13.8% | 7.9% | 15.8% | 14.0% |
| Headache | NA | NA | NA | NA | 21.5% | 20.6% 5 | 42.1% | 45.6% |
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:
| Adverse reactions | Half adult dose | Adult dose | ||
| Post dose 1 N=104 | Post dose 2 N=104 | Post dose 1 N=53 | Post dose 2 N=52 | |
| Pain | 35.6% | 41.3% | 58.5% | 51.9% |
| Redness | 18.3% S | 32.7% | 32.1% | 44.2% |
| Swelling | 11.5% | 28.8% | 20.8% | 32.7% |
| Fever (>38°C) axillary | 6.8% | 41.4% | 7.6% | 46.1% |
| Fever (>39°C) axillary | 1.0% | 2.9% | 1.9% | 17.3% |
| Drowsiness | 16.3% | 33.7% | 20.8% | 42.3% |
| Irritability | 26.9% | 43.3% | 22.6% | 51.9% |
| Loss of appetite | 17.3% | 39.4% | 20.8% | 50.0% |
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).
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in
4.9 Overdose
5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties
5.2 Pharmacokinetic properties
Not applicable.
5.3 Preclinical safety data
Non-clinical data obtained with the mock-up vaccine using a H5N1 vaccine strain reveal no special hazard for humans based on conventional studies of safety pharmacology, acute and repeated dose toxicity, local tolerance, female fertility, embryo-fetal and postnatal toxicity (up to the end of the lactation period).
6. PHARMACEUTICAL PARTICULARS6.1 List of excipients
Suspension vial:
Polysorbate 80
Octoxynol 10
Thiomersal
Sodium chloride (NaCl)
Disodium hydrogen phosphate (Na2HPO4)
Potassium dihydrogen phosphate (KH2PO4)
Potassium chloride (KCl)
Magnesium chloride (MgCl2)
Water for injections
Emulsion vial:
Sodium chloride (NaCl)
Disodium hydrogen phosphate (Na2HPO4)
Potassium dihydrogen phosphate (KH2PO4)
Potassium chloride (KCl)
Water for injections
For adjuvants, see section 2.
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
6.3 Shelf life 2 years.
After mixing, the vaccine should be used within 24 hours. Chemical and physical in-use stability has been demonstrated for 24 hours at 25°C. '
6.4 Special precautions for storage
Store in a refrigerator (2°C – 8°C). Do not freeze.
Store in the original pac
irder to protect from light.
For storage conditions after mixing of the medicinal product, see section 6.3.
6.5 Nature and contents of container
One pack containing:
-
– 4one pack of 50 vials (type I glass) of 2.5 ml suspension with a stopper (butyl rubber).
-
– two packs of 25 vials (type I glass) of 2.5 ml emulsion with a stopper (butyl rubber).
The volume after mixing 1 vial of suspension (2.5 ml) with 1 vial of emulsion (2.5 ml) corresponds to 10 doses of vaccine (5 ml).
6.6 Special precautions for disposal and other handling
Pandemrix consists of two containers: Suspension: multidose vial containing the antigen, Emulsion: multidose vial containing the adjuvant.
Prior to administration, the two components should be mixed.
Instructions for mixing and administration of the vaccine :
-
1. Before mixing the two components, the emulsion (adjuvant) and suspension (antigen) should be brought to room temperature (allow a minimum of 15 minutes); each vial should be shaken and inspected visually for any foreign particulate matter and/or abnormal physical appearance. In the event of either being observed (including rubber particles from the stopper), discard the vaccine.
-
2. The vaccine is mixed by withdrawing the entire contents of the vial containing the adjuvant by means of a 5 ml syringe and by adding it to the vial containing the antigen. It is recommended to equip the syringe with a 23-G needle. However, in the case this needle size would not be available, a 21-G needle might be used. The vial containing the adjuvant should be maintained in upside down position to facilitate the withdrawal of the full content.
-
3. After the addition of the adjuvant to the antigen, the mixture should be well shaken. The mixed vaccine is a whitish to yellowish homogeneous milky liquid emulsion. In the event of other variation being observed, discard the vaccine. f
-
4. The volume of the Pandemrix vial after mixing is at least 5 ml. The vaccine should be administered in accordance with the recommended posology (see section 4.2).
-
5. The vial should be shaken prior to each administration and inspected visually for any foreign particulate matter and/or abnormal physical appearance. In the event of either being observed (including rubber particles from the stopper), discard the vaccine.
-
6. Each vaccine dose of 0.5 ml (full dose) or 0.25 ml (half dose) is withdrawn into a 1 ml syringe for
injection and administered intramuscularly. It is recommended to equip the syringe with a needle gauge not larger than 23-G.
-
7. After mixing, use the vaccine within 24 hours. The mixed vaccine can either be stored in a refrigerator (2°C – 8°C) or at room temperature not exceeding 25°C. If the mixed vaccine is stored in a refrigerator, it should be brought to room temperature (allow a minimum of 15 minutes) before each withdrawal.
7. MARKETING AUTHORISATION HOLDER
.CT
GlaxoSmithKline Biologicals s.a.
rue de l'Institut 89
B-1330 Rixensart, Belgium
8. MARKETING AUTHORISATION NUMBER(S)
EU/1/08/452/001
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 20 May 2008