SUMMARY OF PRODUCT CHARACTERISTICS

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1 SUMMARY OF PRODUCT CHARACTERISTICS 1. NAME OF THE MEDICINAL PRODUCT POLLINEX Quattro 1.0ml 300 SU/ml, 800 SU/ml, 2000 SU/ml Suspension for injection 2. QUALITATIVE AND QUANTITATIVE COMPOSITION POLLINEX Quattro 1.0 ml contains selectively purified allergen extracts of pollen (grass/rye, tree or weed) according to the doctor s prescription. The allergens have been modified into allergoids by treatment with glutaraldehyde and are adsorbed onto L-tyrosine. The allergen extracts are standardised (in SU, Standardised Units) by biochemical methods and characterised, to provide a constant quality of allergen content and allergen activity. Each1.0ml dose contains 50 μg of the adjuvant Monophosphoryl Lipid A/AF (MPL ) Sodium Content This medicinal product contains less than 1mmol Sodium (23mg) per dose, i.e. it is essentially sodium free. For a full list of excipients, please see section 6.1. POLLINEX Quattro 1.0ml is presented as follows: Injection Number Vial No./Colour Dose (Standardised Units (SU)/ml) Total Extractable Volume of Vial 1 1 Green ml 2 2 Yellow ml 3 3 Red ml 4 3 Red ml 3. PHARMACEUTICAL FORM Suspension for injection. A white, opaque suspension. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications POLLINEX Quattro 1.0ml is indicated for the treatment of rhinitis and conjunctivitis in adults, adolescents and children over the age of six caused by an IgE mediated allergy against grass/rye, tree or weed pollen. Pollinex Quattro/SmPC/Version 2/June 2010/General Export text 1

2 This specific immunotherapy (SIT) should be prescribed following diagnosis with a positive skin prick test and/or specific IgE test, and with careful consideration to the patient s history. 4.2 Posology and method of administration Treatment of patients should only be carried out by physicians or nurses (under the supervision of physicians) with experience or expertise in specialist subcutaneous immunotherapy. Epinephrine/adrenaline (1:1000) must always be immediately available. Availability of a suitably equipped, emergency medical kit, which contains adrenaline/epinephrine, must be ensured. In order to prevent an adverse reaction, the patient s history must be fully considered before administration of POLLINEX Quattro 1.0ml. The current health condition of the patient should be checked by taking a careful history. Particular attention should be paid to the following points: Posology Recurrent/current fever or inflammatory conditions Intermittent current infections Tolerability of the previous injection Changes in general health and the use of other medication (particularly symptomatic treatment for allergies) Assessment of lung function in asthmatics, e.g. peak-flow measurement. POLLINEX Quattro 1.0ml should be administered as a course of four 1.0ml injections. One 300 SU/ml injection, one 800 SU/ml injection and two 2000 SU/ml injections, administered subcutaneously prior to the pollen season. The first three injections should be administered in order (Vial 1 through to Vial 3) at 1 to 2 week intervals. The fourth injection (Vial 4) should be administered 1 to 4 weeks after the third injection. At each strength, the maximum dose of 1.0ml suspension should not be exceeded. If one or more doses are missed and the recommended interval between injections is exceeded by more than seven days, the treatment should be started again. Dose adaptation may be required with the occurrence of an adverse event. Should this be necessary follow the dose adaptation guide in 4.2 Method of Administration. On the day of the injection, patients should be advised not eat a heavy meal, drink alcohol or take any strenuous exercise. It is generally accepted in allergy treatment that to achieve a more complete and long term improvement in the allergic symptoms, allergen immunotherapy, should be given in three to five successive years. POLLINEX Quattro 1.0ml is not recommended for use in children below the age of six due to lack of data on the safety and efficacy. Highly Sensitised Populations An adapted posology with a lower dose increment applies in highly sensitised patients (see Injection Interval table indicating alternative posology). Pollinex Quattro/SmPC/Version 2/June 2010/General Export text 2

3 Paediatric Populations Evidence of allergic rhinoconjunctivitis is extremely rare in children under three years of age, with the earliest true presentation occurring around this age. The current clinical practice is to observe child and adolescent patients for one to two periods of seasonal disease to confirm the diagnosis prior to commencement of treatment. Therefore until sufficient clinical data become available, POLLINEX Quattro 1.0ml should not be used to treat children less than six years of age as the safety and efficacy has not yet been established for this age group. For children over the age of six and adolescents the adult posology regimen should be followed. Special precautions to be taken before the injection: For special precautions to be taken prior to the injection, please see section 4.4. Method of Administration POLLINEX Quattro 1.0ml should be warmed to room temperature and then shaken well immediately before injection until all of the sediment is evenly re-suspended (see section 6.6). Injections should be administered at a constant pressure. It is advisable to administer the injection to anxious or potentially unstable patients when they are lying down. POLLINEX Quattro 1.0ml should be administered by subcutaneous injection only to the lateral/posterior aspect of the middle third of the upper arm. The injection sites should be alternated between arms, e.g. 1 st and 3 rd injection in the right arm and 2 nd and 4 th injection in the left arm. Repeated injections at one injection site should be avoided. Aspiration should be carried out to ensure that no blood vessels have been injured. Intramuscular and intravascular injection should be strictly avoided. The patient should also be instructed not to rub the injection site. Injection Intervals If the recommended interval between injections is exceeded by more than seven days, the treatment should be started again (Vial No. 1) for safety reasons. The posology regimen below is suitable for most patients. However, if the patient is highly sensitised, then the posology and the progression from dose to dose, should be adapted to the patient's reactivity according to the clinician s discretion. The first three injections (Vials 1 to 3) should be administered in order (Vial 1 through to Vial 3) at seven to fourteen day intervals. The fourth injection (Vial 4) should be administered seven to twenty eight days after the third injection. Pollinex Quattro/SmPC/Version 2/June 2010/General Export text 3

4 Vial No/Label Colour Recommended Posology 1 Green 1.0ml 300 SU 2 Yellow 1.0ml 800 SU 3 Red 1.0ml 2000 SU Alternative Posology (For highly sensitised patients) 0.5ml 150 SU 1.0ml 300 SU 0.5ml 400 SU 1.0ml 800 SU 0.5ml 1000 SU 1.0ml 2000 SU Interval from Previous Injection (days) Min Max N/A N/A Red 1.0ml 2000 SU N/A 7 28 The next injection should only be given if the previous injection has been well tolerated and the injection intervals have not been exceeded. Dose Adaptation The maximum tolerated dose for an individual may be lower than the maximum dose possible (1.0 ml from Vial No. 3). In case when large local reactions or mild systemic reactions occur, the next recommended dose may be adjusted to reduce the potential for adverse reactions and increase tolerability of the next dose of POLLINEX Quattro 1.0ml. Reaction Local reaction > 10 cm in diameter (swelling) Mild to intense systemic reaction Severe systemic reaction, anaphylactic shock Adjustment No increase in dose, the dose of the previous injection should be repeated, possibly reduce the dose Go back 1 stage in the posology regimen or start again from the beginning The doctor should review the treatment indication If the scheduled repeat dose is tolerated, the full schedule dose (i.e. 1.0ml of Vial 2, or Vial 3 if the reaction occurs after the scheduled injection one or two respectively) will be administered seven to fourteen days later and the dose escalation schedule resumed. No dose adaptation is required after schedule injection three as schedule injection four is of the same concentration. Special Precautions to be taken after the Injection Patients should be kept under medical observation for thirty to sixty minutes after each injection. The period of observation should be extended if mild symptoms or signs of hypersensitivity develop and patients should remain under observation until these have completely resolved. A severe and prolonged adverse reaction may necessitate hospital admission. Pollinex Quattro/SmPC/Version 2/June 2010/General Export text 4

5 The patient should be informed that he/she must contact the doctor or a health care professional immediately if any signs of adverse reactions occur during the observation period or at any time following the injection. In case of severe systemic reaction, continuation of treatment should be re-evaluated. 4.3 Contraindications Hypersensitivity to any of the excipients (for full list of excipients, see section 6.1) POLLINEX Quattro 1.0ml should not be used in the presence of any of the conditions listed below: Chronic or acute infection or inflammation Secondary changes in the affected organ (emphysema, bronchiectasis etc) Asthma Autoimmune disease such as disorders of the liver, kidneys, nervous system or thyroid or rheumatoid disease Immunodeficiency (including that due to immunosuppression regimens (see section 4.5)) Hereditary angiodema Manifest pulmonary or cardiac insufficiency Malignant disease (such as cancer) with current clinical relevance; Beta-blocker therapy (see section 4.5) If administration of adrenaline/epinephrine is contraindicated in the patient Disturbances in tyrosine metabolism, especially in the case of tyrosinaemia and alkaptonuria, POLLINEX Quattro 1.0ml should not be used Pregnancy or pregnancy is confirmed whilst receiving treatment. Less than six years of age (see section 4.2). 4.4 Special warnings and precautions for use Severe anaphylactic reactions/shock may occur. Epinephrine/adrenaline (1:1000) must always be immediately available. Treatment of patients should only be carried out where full facilities for cardio-respiratory resuscitation are immediately available. If the patient has suffered from an acute infection, fever or a severe asthma attack (status asthmaticus), POLLINEX Quattro 1.0ml should not be given until twenty four to forty eight hours after the patient s condition has returned to normal. Vaccinations against viral or bacterial pathogens should be administered at least seven days after the last dose of POLLINEX Quattro 1.0ml, provided that all possible adverse reactions (local or systemic) have completely disappeared (see section 4.5). The next dose should be administered fourteen days after the vaccination date, provided that all possible adverse reactions to the vaccination have completely disappeared. It should be borne in mind that if vaccinations are required whilst the patient is receiving treatment with POLLINEX Quattro 1.0ml the recommended injection intervals may be exceeded. Please refer to section 4.2 Exceeding the recommended injection interval. If the patient is highly sensitised, then an alternative posology regimen is available (see section 4.2). Pollinex Quattro/SmPC/Version 2/June 2010/General Export text 5

6 If the recommended interval for POLLINEX Quattro 1.0ml is exceeded please refer to section 4.2. Patients should be kept under medical observation for thirty to sixty minutes after each injection. This period should be extended even if mild symptoms or signs of hypersensitivity develop and patients should remain under observation until these have completely resolved. A severe and prolonged adverse reaction may necessitate hospital admission. The patient should be informed that he/she must contact the doctor or a representative immediately if any signs of adverse reactions occur during the observation period or at any time following the injection. In case of severe systemic reaction, continuation of treatment should be re-evaluated. High-risk patients (such as patients with an extremely high level of sensitisation) should be monitored more closely (see section 4.8). If the patient is elderly, the increased prevalence of contraindications such as emphysema, bronchiectasis etc. or diseases such as impaired cardiovascular function should be taken into account when prescribing and administering POLLINEX Quattro 1.0ml. If two different hyposensitisation vaccines have to be administered to a patient, they should be administered with a safety interval of two to three days in between. (See section 4.5) Use with caution in patients with impaired cardiovascular and/or pulmonary function. Additional contact with allergens (exogenous or iatrogenic) may lower the threshold of tolerability. Therefore, the patient should be advised to avoid, as far as possible, exposure to their causal and cross reacting allergens (see section 4.5). Concomitant therapy with symptomatic anti-allergic agents (such as antihistamines, corticosteroids or mast cell degranulation inhibitors) may mask the patient s current reactivity status (see section 4.5). Pollinex Quattro/SmPC/Version 2/June 2010/General Export text 6

7 Anaphylactic shock As with any specific immunotherapy there is a risk of anaphylactic shock. Warning symptoms: Tingling, itching and burning sensations on and under the tongue, in the throat and particularly on the palms and soles. This may be immediately followed by shock with cyanosis, hypotension, tachycardia, bronchospasm and unconsciousness. If the patient shows signs of an intense systemic reaction or anaphylactic shock, immediate medical action must be taken in the following order (EAACI, Standards for Practical Allergen Specific Immunotherapy, 2006): 1. Adrenaline/epinephrine (1 mg/ml, mg deeply i.m. or diluted 0.1 mg/ml, mg i.v. (slowly in fractionated doses) may be repeated after mins) 2. i.v. saline 3. Place patient in supine position 4. Oxygen 5-10 l/min 5. Check blood pressure, pulse rate and oxygen saturation 6. Antihistamine clemastine (1 mg/ml, 1-2 ml (1-2 mg, iv.)) 7. Methylprednisolone 80 mg i.v. 8. Hospitalisation necessary because of the risk of delayed shock Monitor pulse and blood pressure continuously. If adrenaline/epinephrine, theophylline, antihistamines or glucocorticoids are administered to children, the doses must be adapted according to the age or weight. Caution must be taken with patients receiving ACE inhibitors as an anaphylactic reaction may be more severe (see sections 4.5 and 4.8). Caution should be exercised in patients receiving tricyclic antidepressants and mono-amineoxidase inhibitors (MAOIs) as the effects of adrenaline may be potentiated. 4.5 Interaction with other medicinal products and other forms of interaction No interaction studies have been performed. Contraindications of concomitant use (See section 4.3): Beta-blockers Immunosuppressant regimen Caution should be exercised with concomitant use of (See section 4.4): Hyposensitisation vaccines Symptomatic anti-allergic agents (e.g. antihistamines, corticosteroids or mast cell degranulation inhibitors) Viral or bacterial pathogen vaccines ACE inhibitors, MAOIs and tricyclic antidepressants (See section 4.4) Additional contact with allergens (exogenous or iatrogenic) may lower the threshold of tolerability. (See section 4.4) Pollinex Quattro/SmPC/Version 2/June 2010/General Export text 7

8 4.6 Pregnancy and lactation POLLINEX Quattro 1.0ml is contraindicated in pregnancy and lactation. (See section 4.3.) Pregnancy There is no data on the clinical experience for use of POLLINEX Quattro 1.0ml in pregnant women. Treatment should not be initiated during pregnancy as severe systemic reactions may be detrimental to the foetus. Lactation No clinical data are available for the use of POLLINEX Quattro 1.0ml during lactation. No effects on the breast fed infant are anticipated. 4.7 Effects on ability to drive and use machines There have been no specific studies performed on the effects on the ability to drive and use machines. POLLINEX Quattro 1.0ml has negligible influence on the effects to drive or operate machinery. If dizziness or fatigue is experienced by the patient they should be advised not to drive or operate machinery until these effects have passed. 4.8 Undesirable effects Adverse reactions ranging from local and mild systemic reactions to intense systemic reactions may occur, even with correct use of POLLINEX Quattro 1.0ml. a) Summary of safety profile The following table contains the adverse reactions which were received from spontaneous reporting. The frequencies are calculated upon the post-marketing patient exposure for POLLINEX Quattro 1.0ml set into relation to spontaneously reported adverse reactions based on the last 5 years safety reporting period. Additionally, serious unexpected adverse reactions reported before this period were considered as well, however a frequency calculation was not feasible. Spontaneous adverse reaction reports were received for 0.03% of patients treated. One fifth of the spontaneously reported adverse reactions are local reactions of mild to moderate intensity at the injection site (e.g. swelling, urticaria, pruritus). One third of the spontaneously reported adverse reactions are typical symptoms caused by the recurrence/exacerbation of the patientspecific allergic symptoms (e.g. nasal, eyes and lung symptoms). One third of the spontaneously reported adverse reactions were reactions of the skin (e.g. rash, pruritus, erythema) and of the respiratory system (e.g. dyspnoea, cough, bronchial obstruction). b) Tabulated summary of adverse reactions Adverse reactions are assigned to organ systems and grouped according to frequency: rare ( 1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). Pollinex Quattro/SmPC/Version 2/June 2010/General Export text 8

9 MedDRA System Order Class (SOC) Frequency MedDRA Preferred Term (PT) Immune system disorders Very rare Anaphylactic shock Psychiatric disorders Not Known Anxiety, Restlessness Nervous system disorders Very rare Loss of consciousness, Paraesthesia (oral), Dizziness, Hypoaesthesia (oral), Dysgeusia, Headache Not known Tremor Eye disorder Very rare Eye oedema, Lacrimation increase, Ocular hyperaemia Not known Optic neuritis, Eye pruritus, Eyelid oedema, Conjunctivitis Ear and labyrinth Very rare Auricular swelling disorders Cardiac disorders Very rare Cardiovascular insufficiency, Cyanosis, Tachycardia Not known Pulse absent, Bradycardia Vascular disorders Very rare Shock, Hypotension, Blood pressure decreased, Hypertension, Flushing/Hot flush, Pallor Not known Vasculitis Respiratory thoracic and Rare Dyspnoea mediastinal disorders Very rare Bronchial obstruction, Cough, Throat irritation, Throat tightness, Nasal congestion Not known Respiratory distress Gastrointestinal disorders Rare Nausea Very rare Vomiting, Swollen tongue, Gastrointestinal disorder, Dysphagia Not known Diarrhoea, Abdominal pain upper, Glossodynia Skin and subcutaneous tissue disorders Very rare Urticaria, Pruritus (generalised), Erythema (generalised), Rash (macular/maculo-papular), Swelling face Musculoskeletal and connective tissue disorders General disorders and administration site conditions Not known Very rare Rare Very rare Not known c) Description of selected adverse reactions Angioedema, Hyperhidrosis Arthralgia, Joint swelling, Sensation of heaviness Injection site reactions (swelling, urticaria, erythema, pruritus, pain) Malaise, Oedema (peripheral), Fatigue, Chills, Feeling abnormal Asthenia, Chest discomfort, Face oedema There have been very rare reports of severe anaphylactic reaction or anaphylactic shock occurring with POLLINEX Quattro 1.0ml. d) Class effects Systemic adverse reactions which are well known to occur with (any) subcutaneous immunotherapy/hyposensitisation therapy are: Pollinex Quattro/SmPC/Version 2/June 2010/General Export text 9

10 Systemic reactions Mild: recurrence or exacerbation of patient-specific allergic signs and symptoms such as itching of the eyes, sneezing, coughing, generalised urticaria, atopic eczema and mild bronchospasm. Fatigue may also occasionally occur after injection of the immunotherapy. Moderate to severe: wheezing, dyspnoea, or Quincke s oedema. Anaphylactic shock/anaphylaxis: although rare, anaphylactic shock may develop a few seconds to minutes after administration of any allergy immunotherapy injection, and frequently before a local reaction has appeared. Typical warning symptoms of anaphylactic shock are: tingling, burning sensations and itching on and under the tongue, in the throat and, particularly, on the palms of the hands and soles of the feet. Anaphylactic shock is clinically characterised by: anxiety, restlessness, dizziness, hypotension, tachycardia, laryngeal oedema with dyspnoea, bronchospasm, shock with cyanosis, nausea and vomiting, unconsciousness, respiratory and cardiac arrest. Severe, delayed reactions: symptoms of serum sickness, such as fever, joint pains, urticaria and swelling of the lymph nodes may occur after several days. These reactions, however, are very rare. Paediatric population Post-marketing experience showed a similar safety profile in children and in adults, including similar frequency of adverse reactions. 4.9 Overdose The likelihood of systemic adverse reactions is increased if the correct time interval is not kept between doses, if the dose is incorrect, or if intramuscular or intravascular injection is used by mistake. In case of an overdose, adverse reactions listed in section 4.8 may occur. Following an overdose the risk of anaphylaxis may be increased. If anaphylaxis occurs refer to section 4.4 for management of the reaction. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties ATC Code V01AA20 Various. POLLINEX Quattro 1.0ml is intended for treatment of patients with specific IgE-mediated allergy with symptoms such as rhinitis and rhinoconjunctivitis caused by grass/rye, tree or weed pollen. The immune system is the target for the pharmacodynamic effect. The intention is to modulate the immune response of the patient, reducing the IgE mediated hypersensitivity response in favour of more normal tolerance to pollens. The precise mechanism of action has not been fully elucidated but there is strong evidence that allergy is a Th2 weighted imbalance in the immune system, manifested in IgE mediated hypersensitivity reactions. Specific immunotherapy or desensitisation is believed to redirect an allergic Th2 biased response in favour of a more normal balanced Th1/Th2 response. The production of allergen specific IgG antibody (especially blocking IgG4 antibody) suppression of specific IgE antibody and decreased mediator (histamine) release from basophils are thought to be important evidence for the redressing of the Th1/Th2 balance. Pollinex Quattro/SmPC/Version 2/June 2010/General Export text 10

11 POLLINEX Quattro 1.0ml contains MPL as an adjuvant. MPL, a microbial cell wall extract, is a Toll-like receptor 4 (TLR-4) agonist that is increasingly used in vaccines. TLRs are major components of the innate immune system, which are highly conserved throughout nature. The innate immune system, which is non-antigen specific, is the primary defence system of the host against any foreign invading organism and many non-self molecules. In addition, the innate system acts to direct the acquired immune system, towards an antigen specific response, which is often dependant on the specific TLRs that are activated. In particular, the specific immune response to an antigen can be directed towards a more Th1, or Th2, response. Addition of a sufficient dose and a suitable duration of exposure to TLR-4 agonists is believed to induce Th1 and Treg cell populations, thus enhancing specific immunotherapy with the modified pollen allergens of POLLINEX Quattro 1.0ml L-tyrosine is a naturally occurring, sparingly soluble, amino acid that is utilised for its adsorbent properties. L-tyrosine acts as a short-term depot adjuvant, thereby extending the bioavailability of allergens and enhancing IgG antibody induction. 5.2 Pharmacokinetic properties Pharmacokinetic studies are not possible for products of specific immunotherapy. Due to the nature of the product plasma levels are not measurable. 5.3 Preclinical safety data Preclinical data for Pollinex Quattro reveal no special hazard for humans based on conventional studies of repeated dose toxicity and carcinogenic potential. Preclinical studies on a product similar to Pollinex Quattro, to determine safety pharmacology, genotoxicity, toxicity to reproduction and development, indicate that there is no special risk to humans. Extensive preclinical studies were also carried out on MPL and revealed no special hazards for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential or toxicity to reproduction and development. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients L-tyrosine Monophosphoryl Lipid A/AF (MPL ) Phenol Sodium Chloride Disodium Phosphate Dodecahydrate Sodium Dihydrogen Phosphate Dihydrate Water for Injections 6.2 Incompatibilities In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. 6.3 Shelf-life The shelf life is 12 months when the product is stored at the recommended storage conditions (see section 6.4). Pollinex Quattro/SmPC/Version 2/June 2010/General Export text 11

12 Chemical and physical in-use stability has been demonstrated for seventy days at 2ºC - 8ºC. From a microbiological point of view, once opened, the product may be stored for a maximum of seventy days at 2ºC - 8ºC. Other in-use storage times and conditions are the responsibility of the user. 6.4 Special precautions for storage Store at 2 C - 8 C (in a refrigerator). Do not freeze. 6.5 Nature and contents of container POLLINEX Quattro 1.0ml is supplied in 3ml clear neutral glass (Type I, Ph. Eur.) vials fitted with a rubber bung closure containing a total fill of 1.9ml drug product. The vials are sealed with an aluminium seal. Vial Number Dose Quantity of Vials in Pack No. 1 (green) 300 SU/ml in 1.9 ml 1 No. 2 (yellow) 800 SU/ml in 1.9 ml 1 No. 3 (Red) 2000 SU/ml in 1.9 ml Special precautions for disposal and other handling Before use, the suspension should be warmed to room temperature and then shaken well until all of the sediment is evenly re-suspended. Any unused product or waste should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER/MANUFACTURER Allergy Therapeutics (UK) Ltd. Dominion Way Worthing, West Sussex, BN14 8SA United Kingdom 8. MARKETING AUTHORISATION NUMBER(S) This product is not licensed and supplied on a named patient basis only. 9. DATE OF FIRST AUTHORISATION Not applicable 10. DATE OF REVISION OF THE TEXT June 2010 Pollinex Quattro/SmPC/Version 2/June 2010/General Export text 12