Summary of Product Characteristics, Labelling and Package Leaflet

Version 4, 02/2016

SUMMARY OF PRODUCT CHARACTERISTICS, LABELLING AND PACKAGE LEAFLET

SUMMARY OF PRODUCT CHARACTERISTICS

2 1. NAME OF THE MEDICINAL PRODUCT

ORALAIR 100 IR & 300 IR sublingual tablets Initiation treatment

ORALAIR 300 IR sublingual tablets Continuation treatment

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Grass pollen allergen extract from: Cocksfoot (Dactylis glomerata L.), Sweet vernal grass (Anthoxanthum odoratum L.), Rye grass (Lolium perenne L.), Meadow grass (Poa pratensis L.) and Timothy (Phleum pratense L.) …………………...... 100 IR* or 300 IR* per sublingual tablet.

* IR (Index of Reactivity) : The unit IR has been defined to measure the allergenicity of an allergen extract. The allergen extract contains 100 IR/ml when, on a skin prick-test using a Stallerpoint®, it induces a wheal diameter of 7 mm in 30 patients sensitized to this allergen, (geometric mean). The cutaneous reactivity of these patients is simultaneously demonstrated by a positive skin prick-test to either 9 % codeine phosphate or 10 mg/ml histamine. The IR unit of Stallergenes is not comparable to the units used by other allergen manufacturers.

Excipient with known effect: Lactose monohydrate.

One sublingual tablet of 100 IR contains 83.1 – 83.6 mg Lactose monohydrate. One sublingual tablet of 300 IR contains 81.8 – 83.1mg Lactose monohydrate.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Sublingual tablet.

The tablets of 100 IR are slightly speckled white to beige, engraved “100” on both surfaces. The tablets of 300 IR are slightly speckled white to beige, engraved “300” on both surfaces.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Treatment of grass pollen allergic rhinitis with or without conjunctivitis in adults, adolescents and children (above the age of 5) with clinically relevant symptoms, confirmed by a positive cutaneous test and/or a positive titre of the specific IgE to the grass pollen.

4.2 Posology and method of administration

Treatment with ORALAIR should only be prescribed and initiated by physicians with adequate training and experience in the treatment of allergic diseases. In case of paediatric treatment, the physicians should have the corresponding training and experience in children.

The first tablet of ORALAIR should be taken under medical supervision and the patient should be monitored for 30 minutes.

3 Posology

The therapy is composed of an initiation treatment (including a 3-day dose escalation) and a continuation treatment.

The initiation treatment corresponds to the first month of treatment with ORALAIR 100 IR & 300 IR sublingual tablets:

Day 1 1 x 100 IR tablet Small blister Day 2 2 x 100 IR tablets Day 3 1 x 300 IR tablet Day 4 1 x 300 IR tablet Day 5 1 x 300 IR tablet Large blister . . Day 30 1 x 300 IR tablet

From the 2nd month onwards, the continuation treatment must be continued with one ORALAIR 300 IR sublingual tablet per day until the end of the pollen season.

Treatment should be initiated about 4 months before the expected onset of the pollen season and must be maintained until the end of the pollen season.

If no relevant improvement of symptoms is obtained during the first pollen season, there is no indication for continuing the treatment.

In general, if treatment is interrupted for less than 7 days, it is to be continued. Should the interruption period be longer than 7 days, it is recommended to continue the treatment under medical supervision.

Special populations

Clinical experience on immunotherapy with ORALAIR in patients older than 50 years is lacking.

Paediatric population

The safety and efficacy of ORALAIR in children below the age of 5 years have not been established. No data on treatment with ORALAIR in children beyond one grass pollen season are available.

The posology to be used in adolescents and children from 5 years onwards is the same as in adults.

Method of administration

Tablets must be placed under the tongue until complete dissolution (at least 1 minute) and then swallowed. It is recommended to take the tablets during the day, in an empty mouth.

4.3 Contraindications

- Hypersensitivity to any of the excipients listed in section 6.1; - Severe and/or unstable asthma (FEV1 < 70 % of predicted value); - Severe immune deficiency or auto-immune disease; - Malignant diseases (e.g. cancer); - Oral inflammations (such as oral lichen planus, oral ulcerations or oral mycosis).

4.4 Special warnings and precautions for use

In case of oral surgery, including dental extraction, treatment with ORALAIR should be stopped until complete healing.

Specific immunotherapy in patients treated with tricyclic antidepressants and mono amine oxidase inhibitors (MAOIs) should be considered carefully.

Due to the presence of lactose, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Eosinophilic oesophagitis has been reported in association with sublingual tablet immunotherapy. During treatment with Oralair, if severe or persistent gastro-oesophageal symptoms including dysphagia or chest pain occur, Oralair should be interrupted and the patient evaluated by their physician. Treatment should only be resumed upon instruction of the physician.

Patients taking beta-adrenergic blockers may be unresponsive to the usual doses of epinephrine used to treat serious systemic reactions, including anaphylaxis. Specifically, beta-adrenergic blockers antagonize the cardiostimulating and bronchodilating effects of epinephrine.

4.5 Interaction with other medicinal products and other forms of interaction

No interactions were reported in clinical trials with ORALAIR, during which patients were able to take medications to treat allergic symptoms (antihistamines, steroids).

There are no data available on possible risks of simultaneous immunotherapy with other allergens during treatment with ORALAIR.

Severe allergic reactions may be treated with adrenaline. The effects of adrenaline may be potentiated in patients treated with tricyclic antidepressants and mono amine oxidase inhibitors (MAOIs) with possible fatal consequences.

Clinical experience in relation to simultaneous vaccination and treatment with ORALAIR is missing. Vaccination may be given without interrupting treatment with ORALAIR after medical evaluation of the general condition of the patient.

4.6 Fertility, pregnancy and lactation

Pregnancy There are no clinical data from the use of ORALAIR in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid initiating allergen immunotherapy during pregnancy. If pregnancy occurs during treatment, the use of ORALAIR may continue, if necessary, but with close supervision.

Breastfeeding It is unknown whether 5 grass pollen allergen extract is excreted in milk. As a precautionary measure, it is preferable to avoid initiating allergen immunotherapy during Breast- feeding. However, since the systemic exposure of a breast-feeding woman to ORALAIR active substance is negligible, use of ORALAIR may be considered during breast-feeding taking into account the benefit of therapy for the woman and the benefit of breast-feeding for the child.

Fertility There are no fertility data available in humans. No animal fertility studies were conducted with ORALAIR active substance. However, histopathological examination of the male and female reproductive organs revealed no adverse findings in repeat-dose toxicity studies with 5 grass pollen allergen extract.

4.7 Effects on ability to drive and use machines

ORALAIR has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Summary of the safety profile

During treatment with ORALAIR, patients are exposed to allergens that may cause application site reactions and/or systemic allergic symptoms. Application site reactions (e.g. oral pruritus and throat irritation) may therefore be expected during the period of therapy. If a patient experiences an application site reaction, symptomatic treatment (e. g. with antihistamines) may be considered.

As with any allergen immunotherapy, severe allergic reactions including severe laryngopharyngeal disorder or systemic allergic reactions (i.e., acute onset of an illness with involvement of the skin, mucosal tissue, or both, respiratory compromise, persistent gastrointestinal symptoms, or reduced blood pressure and/or associated symptoms) can occur. Inform patients of the associated signs and symptoms and have them seek immediate medical care and discontinue therapy should these occur. Treatment should only be resumed at the instruction of a physician.

Tabulated list of adverse reactions During clinical trials, a total of 1038 adults and 154 paediatrics patients with grass pollen-associated allergic rhinoconjunctivitis were treated with ORALAIR 300 IR once daily in placebo-controlled clinical trials. The undesirable effects reported in these patients are summarized in the table below. The majority of adverse reactions leading to premature study withdrawal were consistent with application site reactions. These were of mild or moderate severity and were non-serious.

Tabulated summary of adverse drug reactions by body system, frequency [Very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥1/10,000, <1/1,000)]. Within each frequency category, serious reactions are presented first.

System Organ Class / Frequency / Adverse Drug Reactions Infections and infestations Common Nasopharyngitis, rhinitis Uncommon Oral herpes, otitis Blood and lymphatic system disorders Uncommon Lymphadenopathy Immune system disorders Uncommon Hypersensitivity, oral allergy syndrome Psychiatric disorders Uncommon Depression Nervous system disorders Very Headache common Uncommon Dysgeusia, somnolence, dizziness Rare Anxiety

Eye disorders Common Eye pruritus, conjunctivitis, lacrimation increased Uncommon Ocular hyperaemia, eye oedema, dry eye Ear and labyrinth disorders Common Ear pruritus Uncommon Ear discomfort Vascular disorders Rare Flushing Respiratory, thoracic and mediastinal disorders Very common Throat irritation Common Asthma, rhinitis allergic (nasal congestion, sneezing, rhinorrhea, nasal discomfort), cough, oropharyngeal pain, pharyngeal oedema, sinus congestion, dyspnea, dysphonia, dry throat, oropharyngeal blistering, oropharyngeal discomfort Uncommon Pharyngeal hypoesthesia, throat tightness, wheezing, laryngeal oedema Gastrointestinal disorders Very common Oral pruritus Common Abdominal pain, diarrhoea, vomiting, mouth oedema, tongue pruritus, lip oedema, paraesthesia oral, dyspepsia, tongue oedema, hypoaesthesia oral, stomatitis, lip pruritus, oral discomfort, nausea, glossodynia, dry mouth, dysphagia Uncommon Oral pain, gingivitis, cheilitis, gastritis, glossitis, salivary gland enlargement, gastro-oesophageal reflux, tongue disorder, salivary hypersecretion, mouth ulceration, oesophageal pain, palatal oedema, oral disorder, odynophagia, eructation Skin and subcutaneous tissue disorders Common Urticaria, pruritus, atopic dermatitis Uncommon Angioedema, rash, acne Rare Face oedema General disorders and administration site conditions

7 Common Chest discomfort Uncommon Lump feeling in throat, asthenia, Influenza like illness Investigations Rare Eosinophil count increased Injury, poisoning and procedural complications Uncommon Excoriation

Compared to adverse reactions reported during the first treatment period, fewer types and lower frequencies of adverse reactions were reported during the second and third treatment periods by adults who were treated with ORALAIR during three consecutive grass pollen seasons in a clinical study.

Description of selected adverse reactions

During treatment with ORALAIR, patients are exposed to allergens that may cause application site reactions and/or systemic allergic symptoms.

Application site reactions (e.g. oral pruritus and throat irritation) may therefore be expected during the period of therapy. If a patient experiences an application site reaction, symptomatic treatment (e. g. with antihistamines) may be considered.

As with any allergen immunotherapy, allergic reactions including severe laryngo-pharyngeal reactions or anaphylactic reactions (i.e., acute onset of an illness with involvement of the skin, mucosal tissue, or both, respiratory compromise, persistent gastrointestinal symptoms, or reduced blood pressure and/or associated symptoms) can occur. Inform patients of the associated signs and symptoms and have them seek immediate medical care and discontinue therapy should these occur. Treatment should only be resumed at the instruction of a physician.

Paediatric population

Overall, the safety profile in the paediatric population is similar to that of adults. The following reactions listed in the tabulated summary were reported at a higher incidence in the paediatric population than in adults: cough, nasopharyngitis, mouth oedema (very common), oral allergy syndrome, cheilitis, glossitis, lump feeling in throat, ear discomfort (common).

In addition to the tabulated summary, the following reactions were reported in children and adolescents who received ORALAIR: tonsillitis, bronchitis, (common), chest pain (uncommon).

Post-marketing

Additionally, the following adverse reactions have been reported during post-marketing surveillance in adults, adolescents and children: asthma exacerbation, systemic allergic reaction, eosinophilic oesophagitis. The frequency of these reactions to treatment with ORALAIR is not known.

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 Appendix V.

4.9 Overdose

No case of overdosing has been reported.

If doses higher than the recommended daily dose are taken, the risk of undesirable effects, including systemic side effects or severe local adverse reactions, is increased. In the case of occurrence of severe symptoms, such as angioedema, difficulty in swallowing, difficulty in breathing, changes in voice, or feeling of fullness in the throat, a physician has to be consulted immediately.

In the event of an overdose, the adverse effects should be treated symptomatically.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Allergen extracts, grass pollen,ATC code: V01AA02

Mechanism of action and pharmacodynamic effects

ORALAIR is used for treatment of patients with specific IgE-mediated allergy symptoms such as rhinitis with or without conjunctivitis caused by grass pollen.

The immune system is the target for the pharmacodynamic effect. The aim is to induce an immune response against the allergen with which the patient is treated. The complete and exact mechanism of action regarding clinical effect of specific immunotherapy is not fully understood and documented. Treatment with ORALAIR has shown to induce a systemic competitive antibody response towards grass and induces an increase in specific IgG. The clinical relevance of these findings has not been established.

Clinical efficacy and safety

Study VO34.04

A European, multicentre, multinational, randomised, double-blind, placebo-controlled study was conducted. The study included 628 adults with seasonal allergic rhinitis and/or rhinoconjunctivitis caused by grass pollens, as confirmed by cutaneous tests and/or a positive titre of the IgE specific to the grass pollens.

Patients were randomized to 4 groups: placebo (n=156), ORALAIR 100 IR/day (n=157), ORALAIR 300 IR/day (n= 155) and ORALAIR 500 IR/day (n=160).

Each patient received a sublingual dose once a day for about 4 months before the start of the pollen season, and continuing throughout one pollen season. Analysis of the results was based on 569 assessable patients (placebo, n=148; ORALAIR 100 IR, n=142; ORALAIR 300 IR, n=136; ORALAIR 500 IR, n=143). The efficacy was determined according to the Rhinoconjunctivitis Total Symptom Score RTSS (see details below) during this one pollen season.

Results of this study showed a comparable efficacy of 500 and 300 IR, with safety data in favour of 300 IR, leading to a recommended dose of 300 IR per day.

The efficacy of the 300 IR group versus the placebo group (number of subjects included in the Intent to Treat (ITT) population were 136 and 148, respectively) showed the following results:

VO34.04 study Efficacy results (during the one pollen season)

Primary endpoint

ORALAIR 300IR Placebo Relative Mean (SD) Mean (SD) Absolute Adjusted Diff Mean VO34.04 study p-value** Mean [CI 95%] Diff.* Median Median % Rhinoconjunctivitis 3.58 (2.98) 4.93 (3.23) -1.39 [-2.09 ; -0.69] 27.3% 0.0001 symptom score A 2.91 4.62 *Relative Mean Difference: Absolute Difference / Placebo ** p-value ANCOVA A Symptom Score: Average daily total rhinoconjunctivitis symptom scores for each patient during the grass pollen season. Rhinoconjunctivitis symptoms included sneezing, runny nose, itchy nose, nasal congestion, watery eyes and itchy eyes (0-18 range of score, the upper value of 18 indicates permanent very severe level in all six symptoms).

Secondary endpoints

ORALAIR Placebo Relative 300IR Absolute Adjusted Mean (SD) Mean VO34.04 study Mean (SD) Diff p-value** Diff.* Median Mean [CI 95%] Median % Rescue Medication 19.7% (24.8) 27.9 % (29.3) - - - use B 10.6% 19.7% Quality of life score 1.08 (0.96) 1.37 (1.01) -0.25 [-0.47 ; -0.04] 21.1% <0.0199 C 0.89 1.20 *Relative Mean Difference: Absolute Difference / Placebo ** p-value ANCOVA B Rescue medication use: Percentage of days per patient with at least one rescue medication intake, p-value 0.0194 NS (Wilcoxon). C Quality of life was assessed at the peak of the pollen season by the Rhinoconjunctivitis Quality of Life Questionnaire RQLQ ( 0-7 range of score, a higher score is reflecting a worse quality of life range) .

Global evaluation of the efficacy of the treatment by the patient: 119/135 patients (88%) in the ORALAIR 300IR group and 108/147 patients (73%) in the placebo group noted slight to moderate or good to excellent improvement relative to their recollection of the previous pollen season.

The ANCOVA results on each of the six individual mean symptom scores ranging from 0 to 3 showed a difference in favour of the 300 IR tablet as compared to placebo for sneezing (-0.19), runny nose (-0.23), itchy nose (-0.23), nasal congestion (-0.28), itchy eyes (-0.24) and watery eyes (-0.21).

The proportion of patients not using rescue medication were 35.3% in the 300 IR group and 27.0% in the placebo group (NS).

Post-hoc endpoints (performed after unblinding):

ORALAIR 300IR Placebo Relative Mean (SD) Mean (SD) Absolute Adjusted Diff Mean VO34.04 study p-value Mean [CI 95%] Diff.* Median Median % Average Adjusted 4.17 (3.39) 5.88 (3.82) -1.84 [-2.66 ; -1.02] 29.1% <0.0001** Symptom Score D 3.57 5.26 Average Rescue 0.31 (0.43) 0.48 (0.53) -0.17 [-0.29 ; -0.05] 35.0% 0.0047** Medication Score E 0.16 0.31

F 43.5% (33.8) 28.7% (30.7) PSCD2-0 - - 0.0001*** 38.6 17.1 25.3% (30.2) 14.9% (23.6) PSFD G - - 0.0006*** 10.9 0.0 *Relative Mean Difference: Absolute Difference / Placebo ** p-value ANCOVA/*** p-value Wilcoxon D Average Adjusted Symptom Score (AASS): Average symptom scores adjusted for rescue medication use (for each patient, using daily symptom scores and daily rescue medication use). E Average Rescue Medication Score: Average daily rescue medication score for each patient during the grass pollen season. Medications used were scored as follows: no rescue medication = 0, antihistamines (oral and/or ocular) = 1, nasal corticosteroids = 2 and oral corticosteroids = 3. F Percentage of Symptom Controlled Days (PSCD2-0): Percentage of days with a symptom score not higher than 2 and without rescue medication. G Proportion of Symptom and rescue medication–Free days (PSFD): Percentage of days without symptoms and without intake of rescue medication.

Sixty-one patients (45%) in the 300 IR group had presented more than 50% Symptom Controlled Days (with a symptom score not higher than 2 and without rescue medication) over the grass pollen season, versus 40 patients (27%) in Placebo group.

Paediatric population

Study VO52.06

A European, multicentre, multinational, randomised, double-blind, placebo-controlled study (VO52.06 study) was conducted. The study included 278 patients aged 5 to 17 years suffering from seasonal allergic rhinitis and/or rhinoconjunctivitis caused by grass pollens, as confirmed by cutaneous tests and a positive titre of the IgE specific to the grass pollens.

Patients were randomized to 2 groups: placebo (n=139) or ORALAIR 300 IR/day (n= 139). Each patient received a sublingual dose once a day for about 4 months before the start of the pollen season, and continuing throughout one pollen season. An incremental dosing scheme was followed for the first 3 days of the treatment phase, where the dose was escalated by 100 IR per day from a starting dose of 100 IR up to daily dose of 300 IR. Analysis of the results was based on 266 assessable patients (placebo, n=135 and ORALAIR 300 IR, n=131). The efficacy was determined according to the Rhinoconjunctivitis Total Symptom Score RTSS (see details below) during this one pollen season.

The efficacy analysis of the 300 IR group versus the placebo group (number of subjects included in the Intent to Treat ITT population were 131and 135 respectively) showed the following results:

VO52.06 study Efficacy results (during the one pollen season):

Primary endpoint

ORALAIR 300IR Placebo Relative Mean (SD) Mean (SD) Absolute Adjusted Diff Mean VO52.06 study p-value** Mean [CI 95%] Diff.* Median Median % Rhinoconjunctivitis 3.25 (2.86) 4.51 (2.93) -1.13 [-1.80 ; -0.46] 28.0% 0.001 symptom score A 2.48 4.08 *Relative Mean Difference: Absolute Difference / Placebo ** p-value ANCOVA A Symptom Score: Average daily total rhinoconjunctivitis symptom scores for each patient during the grass pollen season. Rhinoconjunctivitis symptoms included sneezing, runny nose, itchy nose, nasal congestion, watery eyes and itchy eyes (0-18 range of score, the upper value of 18 indicates permanent very severe level in all 6 symptoms).

Secondary endpoints

ORALAIR 300IR Placebo Relative Mean (SD) Mean (SD) Absolute Adjusted Diff Mean VO52.06 study p-value** Mean [CI 95%] Diff.* Median Median % Average Rescue 0.60 (0.61) 0.79 (0.65) -0.20 [-0.34 ; -0.06] 24.1% 0.0064 Medication Score B 0.39 0.76 Rescue Medication 35.4% (33.2) 46.5% (34.6) - - - use C 26.8% 49.0% *Relative Mean Difference: Absolute Difference / Placebo **p-value ANCOVA B Average Rescue Medication Score: Average daily rescue medication score for each patient during the grass pollen season. Medications used were scored as follows: no rescue medication = 0, antihistamines (oral and/or ocular) = 1, nasal corticosteroids = 2 and oral corticosteroids = 3. C Rescue medication use: Percentage of days per patient with at least one rescue medication intake, p-value 0.0146 NS (Wilcoxon).

Individual Symptom Scores: The ANCOVA results on each of the six individual mean symptom scores ranging from 0 to 3 showed a difference in favour of the 300 IR tablet as compared to placebo for runny nose (-0.16), nasal congestion (-0.26), itchy eyes (-0.33) and watery eyes (-0.21).

The proportion of patients not using rescue medication were 18.3% in the 300 IR group and 14.8% in the placebo group (NS).

Post-hoc endpoints (performed after unblinding):

ORALAIR 300IR Placebo Relative Mean (SD) Mean (SD) Absolute Adjusted Diff Mean VO52.06 study p-value Mean [CI 95%] Diff.* Median Median % Average Adjusted 4.30 (3.57) 6.12 (3.85) -1.64 [-2.51 ; -0.78] 29.8% 0.0002** Symptom Score D 3.33 5.28

E 33.8% (30.0) 23.7% (27.2) PSCD2-0 - - 0.0107*** 30.0 12.2 19.2% (24.9) 10.5% (18.4) PSFD F - - 0.0037*** 5.2 0.0 *Relative Mean Difference: Absolute Difference / Placebo ** p-value ANCOVA/*** p-value Wilcoxon D Average Adjusted Symptom Score (AASS): Average symptom scores adjusted for rescue medication use (for each patient, using daily symptom scores and daily rescue medication use). E Percentage of Symptom Controlled Days (PSCD2-0): Percentage of days with a symptom score not higher than 2 and without rescue medication. F Proportion of symptom and rescue medication-Free Days (PSFD): Percentage of days without symptoms and without intake of rescue medication.

Forty-four patients (34%) in the 300 IR group had presented more than 50% Symptom-Controlled Days (with a symptom score not higher than 2 and without rescue medication) over the grass pollen season, versus 26 patients (19%) patients in Placebo group.

5.2 Pharmacokinetic properties

The majority of allergens in ORALAIR are a mixture of proteins and glycoproteins. There is no direct bioavailability of intact allergens in the blood. Therefore, no pharmacokinetic studies in animals or in humans have been carried out to investigate the pharmacokinetic profile and metabolism of ORALAIR.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of single-dose toxicity, repeated-dose toxicity, genotoxicity, local tolerance and embryofoetal development. In juvenile toxicity study in rats, daily dosing for 10 weeks at the highest dose (300 times the Maximum Human Therapeutic Dose) was associated with significantly shortened APTT (Activated Partial Thromboplastin Time) in males only but neither clinical signs nor histopathological findings were found.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

- Mannitol (E421); - Cellulose, microcrystalline; - Croscarmellose sodium; - Silica, colloidal anhydrous; - Magnesium stearate; - Lactose monohydrate.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

These medicinal products do not require any special temperature storage conditions. Store in the original package in order to protect from moisture. Do not freeze.

6.5 Nature and contents of container

Initiation treatment

1 x 3 sublingual tablets of 100 IR in a small blister + 1 x 28 sublingual tablets of 300 IR in a blister. Each blister (Alu/alu) is composed of a film (polyamide/aluminium/polyvinyl chloride) on one side and a heat-sealed foil (aluminium) coated with a varnish (vinyl) on the other side.

Continuation treatment

1 x 30 sublingual tablets of 300 IR in a blister (Alu/alu) composed of a film (polyamide/aluminium/polyvinyl chloride) on one side and a heat-sealed foil (aluminium) coated with a varnish (vinyl) on the other side. Pack of 1 or 3.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7. MARKETING AUTHORISATION HOLDER

STALLERGENES 6 rue Alexis de Tocqueville 92160 ANTONY France Tel. 0033 (0) 1 55 59 20 00 Fax 0033 (0) 155 59 21 68

8. MARKETING AUTHORISATION NUMBER(S)

Austria ORALAIR 100 IR + 300 IR Sublingualtabletten ZNr. 2 - 00361 ORALAIR 300 IR Sublingualtabletten ZNr. 2 - 00362

Belgium ORALAIR 100 IR & 300 IR BE364515 ORALAIR 300 IR BE364524

Bulgaria ORALAIR 100 IR & 300 IR 20100376 ORALAIR 300 IR 20100374

Czech Republic ORALAIR 100 IR & 300 IR 59/160/10-C ORALAIR 300 IR 59/159/10-C

Estonia ORALAIR 100 IR & 300 IR 672810 ORALAIR 300 IR 672910

France ORALAIR 100 IR & 300 IR, comprimé sublingual 34009 368 951 6 4 ORALAIR 300 IR, comprimé sublingual 34009 368 952 2 5 (30 tablets) 34009 368 953 9 3 (90 tablets)

Germany ORALAIR 100 IR & 300 IR PEI.H.03450.01.1 ORALAIR 300 IR PEI.H.03450.02.1

Hungary ORALAIR 100 IR és 300 IR, nyelvalatti tabletta OGYI-T-21527/01 ORALAIR 300 IR, nyelvalatti tabletta OGYI-T-21527/02 (30 tablets) OGYI-T-21527/03 (90 tablets)

Ireland ORALAIR 100 IR & 300 IR PA2113/001/001 ORALAIR 300 IR PA2113/001/002

Italy ORALAIR 100 IR & 300 IR 039857014 ORALAIR 300 IR 039857026 (30 tablets) 039857038 (90 tablets)

Latvia ORALAIR 100 IR & 300 IR tabletes lietošanai zem mēles 10-0048 ORALAIR 300 IR lietošanai zem mēles 10-0049

Lituania ORALAIR 100 IR & 300 IR poliežuvinės tabletės LT/1/10/2024/001 ORALAIR 300 IR poliežuvinės tabletės LT/1/10/2024/002 (30 tablets) LT/1/10/2024/003 (90 tablets)

Luxembourg ORALAIR 100 IR & 300 IR 2010050081 ORALAIR 300 IR 2010050082

Netherlands ORALAIR 100 IR & 300 IR RVG 105376 ORALAIR 300 IR RVG 105380

Poland ORALAIR 100 IR & 300 IR 16729 ORALAIR 300 IR 16730

Portugal ORALAIR 100 IR / 300 IR 5426440 ORALAIR 300 IR 5426424 (30 tablets) 5426432 (90 tablets)

Romania ORALAIR 100 IR & 300 IR 5858/2013/01 ORALAIR 300 IR 5859/2013/01-02

Spain ORALAIR INICIO 100 IR / 300 IR, comprimidos sublinguales 71953 ORALAIR 300 IR, comprimidos sublinguales 71954

Slovakia ORALAIR 100 IR & 300 IR 59/0853/09-S ORALAIR 300 IR 59/0854/09-S

Slovenia ORALAIR 100 IR in 300 IR podjezične tablete H/10/01187/001 ORALAIR 300 IR podjezične tablete H/10/01187/002 (30 tablets) H/10/01187/003 (90 tablets)

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

[To be completed nationally]

10. DATE OF REVISION OF THE TEXT

September 2019

LABELLING

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CARTON (Initiation treatment)

1. NAME OF THE MEDICINAL PRODUCT

ORALAIR 100 IR & 300 IR Sublingual tablets

Initiation treatment

For use in adults, adolescents and children above the age of 5

Grass pollen allergen extract

2. STATEMENT OF ACTIVE SUBSTANCE(S)

* The IR (Index of Reactivity) expresses the activity and is determined in sensitised patients with a skin test.

3. LIST OF EXCIPIENTS

Contains lactose. See leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

Sublingual tablet 1 blister of 3 tablets of 100 IR 1 blister of 28 tablets of 300 IR

5. METHOD AND ROUTE(S) OF ADMINISTRATION

For sublingual use. Keep the tablet under your tongue until complete dissolution (for at least 1 minute) before swallowing. Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACHOF CHILDREN

Keep out of the sight and reachof children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store in the original package in order to protect from moisture. Do not freeze.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

STALLERGENES 6, rue Alexis de Tocqueville 92160 ANTONY FRANCE

12. MARKETING AUTHORISATION NUMBER(S)

[To be completed nationally]

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

[To be completed nationally]

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE oralair 100 ir & 300 ir

17. UNIQUE IDENTIFIER – 2D BARCODE

Not applicable.

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

Not applicable.

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

BLISTER: 100 IR or 300 IR (Initiation treatment)

1. NAME OF THE MEDICINAL PRODUCT

ORALAIR 100 IR & 300 IR Sublingual tablet

2. NAME OF THE MARKETING AUTHORISATION HOLDER

STALLERGENES

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER

<100 IR> or <300 IR>

< cells are numbered according to the days of intake: - numbers 1 and 2 on the small blister of 100 IR; - numbers from 3 to 30 on the large blister of 300 IR in watermark>

PACKAGE LEAFLET

22 Package leaflet: Information for the user

ORALAIR 100 IR & 300 IR sublingual tablets Initiation treatment

For use in adults, adolescents and children above the age of 5

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or pharmacist. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet 1. What ORALAIR is and what it is used for 2. What you need to know before you take ORALAIR 3. How to take ORALAIR 4. Possible side effects 5. How to store ORALAIR 6. Contents of the pack and other information

1. What ORALAIR is and what it is used for

ORALAIR contains an allergen extract. The treatment with ORALAIR is intended to increase the immunological tolerance towards grass pollens, and thereby reducing the allergic symptoms. ORALAIR is used for the treatment of grass pollen allergy that is characterised by rhinitis (sneezing, runny or itchy nose, nasal congestion) with or without conjunctivitis (itchy and watery eyes) in adults, adolescents and children from the age of 5 years.

Before treatment is started, your allergy will be diagnosed by a doctor with adequate training and experience in allergic diseases, who will perform the appropriate skin and/or blood tests.

2. What you need to know before you take ORALAIR

Do not take ORALAIR - if you are allergic to any of the other ingredients of this medicine (listed in section 6); - if you suffer from severe and/or unstable asthma; - if your immune system is very weakened or if you suffer from a disease that attacks your immune system; - if you suffer from a malignant disease (for example cancer); - if you have any inflammation in your mouth.

Warnings and precautions

Talk to your doctor or pharmacist before taking ORALAIR.

23 If you have to undergo surgery in the mouth or if you are having a tooth pulled, you should stop the treatment with ORALAIR until your oral cavity completely heals.

Talk to your doctor if you have any history of eosinophilic oesophagitis. During treatment, if you have severe or persistent upper abdominal pain, swallowing difficulties or chest pain, please contact your doctor who may reconsider your treatment.

Other medicines and ORALAIR Tell your doctor if you are taking, have recently taken or might take any other medicines.

Tell your doctor especially if you are taking certain medicines against depression (tricyclic antidepressants and mono amine oxidase inhibitors (MAOIs)).

Symptomatic treatment (e.g. antihistamines and/or nasal corticosteroids) may be used with ORALAIR.

Talk to your doctor or pharmacist before taking Oralair: if you are taking a beta blocker (i.e., a class of drugs often prescribed for heart conditions and high blood pressure but also present in some eye drops and ointments), as this drug may decrease the effectiveness of epinephrine used to treat serious systemic reactions.

Pregnancy and breast-feeding

Pregnancy

If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

There is no experience for the use of ORALAIR during pregnancy. Therefore, you should not start an immunotherapy if you are pregnant. If you become pregnant while taking this medicine, speak to your doctor about whether it is appropriate for you to continue the treatment.

Breast-feeding

If you are breast-feeding, ask your doctor or pharmacist for advice before taking this medicine.

There is no experience for the use of ORALAIR during breast-feeding. No effects on infants who are breast-fed during the treatment are anticipated. However, you should not start an immunotherapy if you are breast-feeding. If you wish to breast-feed while undergoing treatment, speak to your doctor about whether it is appropriate for you to continue the treatment.

Driving and using machines

No effect on the capacity to drive or use machines has been observed with ORALAIR.

ORALAIR contains lactose

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.

3. How to take ORALAIR

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure.

ORALAIR is prescribed by doctors with adequate training and experience in treatment of allergy. With prescriptions for children, the doctor has the relevant experience in the treatment of children.

You are advised to take the first tablet under medical supervision. This gives you the possibility of discussing possible side effects with your doctor.

Dosage

The therapy is composed of a treatment initiation phase (including a 3-day dose escalation) and a treatment continuation phase.

This package is to be used for the treatment initiation phase (first treatment month) and contains two blisters: • One small blister with 3 tablets of 100 IR • One large blister with 28 tablets of 300 IR

Use the following dosing scheme:

Always start with the small blister:

Day 1: one tablet of 100 IR

Day 2: two tablets of 100 IR

25 Large blister

From the second month of treatment onwards, continue the therapy with the treatment continuation phase with 300 IR sublingual tablets.

Method of administration

Keep the tablet under your tongue until it completely dissolve (at least 1 minute) before you swallow it. On the second day, put two 100 IR tablets simultaneously under the tongue and then swallow after about 1 minute. It is advisable to take the tablet during the day, in an empty mouth.

Duration of treatment

Start treatment about 4 months before the beginning of the pollen season and continue it until the end of the pollen season.

There is no experience with ORALAIR in patients over 50 years of age.

Use in children and adolescents

There is no experience with ORALAIR in children younger than 5 years of age. There is no experience for more than one pollen season in children. The dosage in adolescents and children from the age of 5 years is the same as in adults.

If you take more ORALAIR than you should

If you take more ORALAIR than you should, you may experience allergic symptoms including local symptoms from mouth and throat. If you experience severe symptoms, immediately contact your doctor.

If you forget to take ORALAIR

Do not take a double dose to make up for a forgotten dose. If you have interrupted the treatment with ORALAIR for less than one week, you can take up treatment where you have left off. If you stopped the treatment for more than 7 days, please ask your doctor how you should restart the treatment.

If you stop taking ORALAIR

If you do not complete the treatment course with ORALAIR, you may not have continued benefit from the treatment. If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

During treatment with ORALAIR, you will be exposed to substances that may cause application site reactions and/or symptoms which may affect the whole body. You may expect application site reactions (such as itching of the mouth and throat irritation). These reactions usually occur at the beginning of therapy, are temporary and generally diminish over time.

Stop taking ORALAIR and contact your doctor immediately if you develop or notice: Severe symptoms affecting the throat or allergic symptoms that affect the whole body (i.e., rapid onset of an illness associated with involvement of the skin and/or mucosa, breathing difficulty, persistent abdominal pain or symptoms related to drop in blood pressure).

Treatment should only be resumed at the physician’s instructions.

Other possible side effects include the following

Very common (affects more than 1 in 10 people) : Throat irritation, itchy mouth, headache.

Common (affects less than 1 in 10 people): Asthma, stomach pain, diarrhoea, vomiting, rhinitis (stuffy nose, runny nose, sneezing, itchy nose, nasal discomfort), inflammation in the eyes, itchy eyes, watery eyes, itchy ears, swelling or itching of lips, swelling or itching or pain of the tongue, mouth disorders (such as dryness, tingling, numbness, inflammation, pain, blistering or swelling), throat disorders (such as dryness, discomfort, pain, blistering or swelling), difficulty in swallowing, hoarseness, cough, chest discomfort, heartburn, upset stomach, nausea, itching, hives, difficulty in breathing, congestion of sinus, persistent skin condition characterised by dryness, redness and itching, skin lesion subsequent to scratching, inflammation of the mouth, nose and throat inflammation.

Uncommon (affects less than 1 in 100 people): Dry eye, eye redness, swelling of the eyes, ear discomfort, ear infection, inflammation of the gums or lips or tongue, tongue ulceration, swollen palate, salivary gland enlargement, overproduction of saliva, throat numbness, throat tightness, foreign body sensation in the throat, allergic reaction with swelling of the face and throat, belching, swollen lymph nodes, rash, acne, cold sores, flu-like illness, altered taste, sleepiness, dizziness, depression, hypersensitivity, sneezing, tiredness, mouth ulceration.

Rare (affects less than 1 in 1000 people) Flushing, facial swelling, increase of eosinophil count, anxiety.

Frequency not known (cannot be estimated from the available data) Additional oesophageal inflammation has been reported.

The number of side effects reported by adults who were treated with ORALAIR during three consecutive grass pollen seasons in a clinical study decreased over the second and third years.

Side effects in children and adolescents

27 The following adverse reactions were more frequent in children and adolescents who received ORALAIR than in adults: cough, nose and throat inflammation, mouth oedema (very common), oral allergy syndrome, lip inflammation, lump feeling in the throat, tongue inflammation, ear discomfort (common). In addition the following adverse reactions were also reported in children and adolescents: bronchitis, tonsillitis (common), chest pain (uncommon).

Additional side effects experience in actual use in adults, adolescents and children (post marketing experience, frequency unknown): Worsening of asthma, systemic allergic reaction.

Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store ORALAIR

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and blister pack after “EXP”. The expiry date refers to the last day of that month.

This medicinal product does not require any special temperature storage conditions. Store in the original package in order to protect from moisture. Do not freeze.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What ORALAIR contains

The active substance is a grass pollen allergen extract from: Cocksfoot (Dactylis glomerata L.), Sweet vernal grass (Anthoxanthum odoratum L.), Rye grass (Lolium perenne L.), Meadow grass (Poa pratensis L.) and Timothy (Phleum pratense L.). One sublingual tablet contains 100 IR or 300 IR.

The IR (Index of Reactivity) expresses the activity and is determined in sensitised patients with a skin test.

The other ingredients are mannitol (E421); cellulose, microcrystalline; croscarmellose sodium; silica, colloidal anhydrous; magnesium stearate and lactose monohydrate.

What ORALAIR looks like and contents of the pack

Sublingual tablet 1 x 3 sublingual tablets of 100 IR in a small blister + 1 x 28 sublingual tablets of 300 IR in a blister

The tablets of 100 IR are slightly speckled white to beige, engraved “100” on both surfaces.

The tablets of 300 IR are slightly speckled white to beige, engraved “300” on both surfaces.

The tablets are supplied in blisters (Alu/Alu) composed of a film (polyamide/aluminium/polyvinyl chloride).

Marketing Authorisation Holder and Manufacturer

[To be completed nationally]

STALLERGENES 6 rue Alexis de Tocqueville 92160 ANTONY France Tel. 0033 (0) 1 55 59 20 00 Fax 0033 (0) 1 55 59 21 68

This medicinal product is authorised in the Member States of the EEA under the following names:

Austria ORALAIR 100 IR + 300 IR Sublingualtabletten Belgium, Bulgaria, Estonia, France, Germany, Hungary, Ireland, Italy, Latvia, Luxembourg, Netherlands, Poland, Portugal, Romania, Slovakia ORALAIR 100 IR & 300 IR Czech republic ORALAIR Spain ORALAIR INICIO 100 IR & 300 IR Lituania ORALAIR 100 IR & 300 IR poliežuvines tabletes Slovenia ORALAIR 100 IR in 300 IR podjezične tablete

This leaflet was last revised in September 2019.