ORALAIR^®

MIMS Revision Date: 01 July 2023

1 Name of Medicine

Oralair Initiation Treatment sublingual tablets 100 IR and 300 IR (allergen pollen extract of 5 grasses).
Oralair Continuation Treatment sublingual tablets 300 IR (allergen pollen extract of 5 grasses).

2 Qualitative and Quantitative Composition

Grass pollen allergen extracts 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 dihydrochloride. The IR unit of Stallergenes is not comparable to the units used by other allergen manufacturers.
One sublingual tablet of 100 IR contains 83.1 - 83.6 mg lactose monohydrate. One sublingual tablet of 300 IR contains 81.8 - 83.1 mg lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Sublingual tablets.
Oralair is presented as a slightly speckled, white to beige tablet. The 100 IR tablet has "100" engraved on both sides and the 300 IR tablets have "300" engraved on both sides.

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 Dose and Method of Administration

Treatment should be initiated each year about 4 months before the expected onset of the pollen season (preseasonal) and must be maintained until the end of the pollen season (coseasonal).
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 is monitored for 30 minutes.
Method of administration. Tablets should be placed under the tongue until complete dissolution (at least 2 minutes) and then swallowed.
It is recommended to take the tablets during the day, in an empty mouth. Food and beverage should not be taken for the following 5 minutes.
Dose regimen in adults, adolescents and children (above the age of 5). The therapy is composed of an initiation treatment (including a 3 day dose escalation) and a continuation treatment.
Initiation treatment. The dose of Oralair should be increased over a three-day period to reach the maintenance dose according to the following scheme (see Table 1).

Maintenance treatment. The dose for adults, adolescents and children is 300 IR daily.
The maintenance treatment should be continued with one Oralair 300 IR sublingual tablet per day 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.
The long-term study, VO53.06, has shown that after preseasonal and coseasonal treatment in adults, over 3 consecutive pollen seasons, efficacy is maintained during the subsequent treatment free pollen season.

4.3 Contraindications

Hypersensitivity to any of the excipients listed, see Section 6.1;
Severe uncontrolled or unstable asthma (FEV₁ < 70% of predicted value) or severe exacerbation of asthma within the previous 3 months;
Patients with active or poorly controlled autoimmune disease, immune defects, immunodeficiencies or immunosuppression or malignant neoplastic diseases with current disease relevance;
Severe oral inflammations (such as oral lichen planus, oral ulcerations or oral mycosis);
Initiation of allergen immunotherapy treatment during pregnancy is contraindicated (see Section 4.6).

4.4 Special Warnings and Precautions for Use

Severe allergic reactions. 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.
Previous systemic allergic reaction to allergen immunotherapy. Initiation of Oralair in patients who have previously had a systemic allergic reaction to previous allergen immunotherapy should be carefully considered, and measures to treat potential reactions should be available.
Asthma. Asthma is a known risk factor for severe systemic allergic reactions. The asthma status should be carefully evaluated before starting therapy (see Section 4.3).
Patients with associated asthma should be controlled at the initiation and during all the duration of Oralair treatment. Abrupt discontinuation of asthma controller medication after initiation of Oralair treatment is not recommended.
Patients with concomitant asthma should be informed of the need to seek medical attention immediately if their asthma deteriorates suddenly.
Cardiovascular diseases. Patients with cardiovascular disease may be at increased risk in case of systemic allergic reactions. This should be taken into consideration prior to initiating Oralair.
Beta-adrenergic blockers. Patients taking beta-adrenergic blockers may be unresponsive to the usual doses of adrenaline used to treat serious systemic reactions, including anaphylaxis. Specifically, beta-adrenergic blockers antagonize the cardio-stimulating and bronchodilating effects of adrenaline.
MAOIs, tricyclic antidepressants and COMT inhibitors. Allergen immunotherapy in patients treated with mono amine oxidase inhibitors (MAOIs), tricyclic antidepressants or catechol-O-methyltransferase (COMT) inhibitors should be considered carefully as these treatments could potentiate the effect of adrenaline.
Mild to moderate local allergic reactions. The treatment consists of exposure to allergens to which the patient is allergic. Therefore, mild or moderate local allergic reactions in the oropharyngeal area (e.g. oral pruritus, throat irritation, ear pruritus) may be expected. If the patient experiences significant application site reactions, symptomatic treatment (e.g. antihistamines) may be considered.
Oral lesions. In case of oral surgery, including dental extraction, initiation of Oralair should be postponed and ongoing treatment should be interrupted until complete healing of the oral cavity.
Eosinophilic oesophagitis. Eosinophilic esophagitis has been reported in association with Oralair. During treatment with Oralair, if severe or persistent gastrointestinal 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.
Autoimmune diseases in remission. In patients with autoimmune disease in remission, Oralair should be prescribed with caution.
Lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption, should not take this medicine.
Use in the elderly. Clinical experience on immunotherapy with Oralair in patients older than 65 years is lacking.
Paediatric use. Clinical experience in younger children < 5 years has 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.
Effects on laboratory tests. No information available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No interaction studies have been performed.
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.
Concomitant therapy with symptomatic anti-allergic medications or anti-IgE medications e.g. omalizumab may increase the tolerance level of the patient to immunotherapy. This should be considered at discontinuation of such medications.
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

Effects on 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 in repeat dose toxicity studies with the 5 grasses pollen extract of Oralair revealed no adverse findings.
Use in pregnancy. (Category B2)
For Oralair no clinical data on exposed pregnancies are available.
Treatment with Oralair should not be initiated during pregnancy (see Section 4.3). If pregnancy occurs during treatment, the treatment may continue, if necessary, but with close supervision.
There was no evidence for embryofetal toxicity, including teratogenicity, following oral administration of Oralair to pregnant rats and rabbits during organogenesis, at exposures at least 76 times greater than the maximum clinical exposure, based on body surface area.
Use in lactation. No clinical data are available for the use of Oralair during lactation. No effects on the breastfed infants are anticipated. It is preferable to avoid initiating allergen immunotherapy during breastfeeding. However, if a patient is under treatment at delivery, she can breastfeed with close supervision. Studies in animals to investigate excretion of Oralair into milk were not conducted.

4.7 Effects on Ability to Drive and Use Machines

Oralair has no known influence on the ability to drive and use machines.

4.8 Adverse Effects (Undesirable Effects)

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.
A total of 1038 adults and 154 children 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 Table 2. 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 nonserious.
Adults, adolescents and children. 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, adverse drug reactions are presented by decreasing seriousness.

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 and eosinophilic esophagitis.
The frequency of these reactions to treatment with Oralair is not known.
Reporting suspected adverse effects. Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

No case of overdose 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 should be consulted immediately.
In the event of an overdose, the adverse effects should be treated symptomatically.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: allergen extract, grass pollen. ATC code: V01AA02.
Mechanism of action. 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 the 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 pollen and induces an increase in specific IgG. The clinical relevance of these findings has not been established.
Clinical trials. Clinical efficacy and safety. VO34.04 study. 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 pollen, as confirmed by cutaneous tests and/or a positive titre of the IgE specific to the grass pollen.
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 the 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).
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 sensitisation status (polysensitised/ monosensitised) and the presence or absence of associated asthma have no impact on the results.
During the first season, 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 (see Tables 3 and 4).

Global evaluation of the efficacy of the treatment by the patient: 119/136 (88%) of patients in the Oralair 300 IR group and 108/148 (73%) of patients in the placebo group noted improvement (moderate to excellent) 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).
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 the placebo group.
VO53.06 study. A long-term, multicentre, multinational, randomised, double blind, placebo controlled study was conducted. The study included 633 adults with seasonal allergic rhinoconjunctivitis caused by grass pollen, as confirmed by cutaneous tests and a positive titre of the IgE specific to the grass pollen.
Patients were randomized to 3 groups: placebo (n = 219), Oralair 300 IR (4M) (n = 207), and Oralair 300 IR (2M) (n = 207). [4M = 4 months preseasonal treatment; 2M = 2 months preseasonal treatment].
Each patient received a sublingual dose once a day for about 4 months before the start of the pollen season, and continuing throughout the pollen season for 3 consecutive pollen seasons.
The fourth pollen season was a treatment free follow-up phase. The efficacy was determined according to the primary endpoint: the average adjusted symptom score AASS at year 3 (see details below). The daily adjusted symptom score (ASS) is a symptom score adjusted for daily rescue medication use. The average ASS (AASS) is the average of the daily adjusted symptom score over the evaluation period.
Results of this study demonstrated a sustained and favourable clinical effect for the 300 IR (4M) treatment group after 3 consecutive treatment periods with a preseasonal and coseasonal administration scheme (4 months before the pollen season until the end of the pollen season). The clinically relevant efficacy shown during the first three years was maintained during the first treatment free follow-up year, indicating post-treatment long-term efficacy.
The efficacy of the 300 IR (4M) group versus the placebo group (number of subjects included in the full analysis set (FAS) population were respectively 188 and 205 in the first year, 160 and 172 in the second year, 149 and 165 in the third year, 143 and 155 in the fourth year) was as follows (see Table 5 and Table 6).
Global evaluation of the efficacy of the treatment by the patient: the first year, 139 patients (74%) in the Oralair 300 IR (4M) group and 127 patients (62%) in the placebo group noted slight to moderate or marked improvement relative to their recollection of the previous pollen season.
The proportions of patients not using rescue medication were 18.1% in the 300 IR (4M) group and 10.7% in the placebo group in the first year; 31.9% in the 300 IR (4M) group and 12.8% in the placebo group in the second year; 43.6% in the 300 IR (4M) group and 20.0% in the placebo group in the third year; 36.4% in the 300 IR (4M) group and 21.9% in the placebo group in the fourth year.
Paediatric population. VO52.06 study. 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 pollen, as confirmed by cutaneous tests and a positive titre of the IgE specific to the grass pollen.
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 the 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).
During the first 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. See Tables 7 and 8.
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).
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 the 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

Genotoxicity. The purified 5 grasses pollen extract contained in Oralair showed no mutagenic or clastogenic potential in a series of in vitro assays (mouse lymphoma TK cells and bacterial reverse mutation).
Moreover, the same less purified extract of five grasses was not genotoxic in vivo in rats, using the two endpoints of chromosomal aberration and unscheduled DNA synthesis, at IP or SC doses resulting in exposures markedly greater than the maximum clinical exposure.
Carcinogenicity. No carcinogenicity studies were conducted in animals.

6 Pharmaceutical Particulars

6.1 List of Excipients

Mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal anhydrous silica, magnesium stearate and lactose monohydrate.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C.
Store in the original package in order to protect from moisture.

6.5 Nature and Contents of Container

Initiation treatment. Pack of 1 x 3 sublingual tablets of 100 IR in a small blister + 1 x 28 sublingual tablets of 300 IR in a blister; and
Pack of 1 x 3 sublingual tablets of 100 IR in a small blister + 1 x 7 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.
Packs of 30, 90 or 100 tablets. Not all pack sizes may be marketed.
Oralair Initiation Treatment sublingual tablets 100 IR and 300 IR (allergen pollen extract of 5 grasses) - (AUST R 167565).
Oralair Continuation Treatment sublingual tablets 300 IR (allergen pollen extract of 5 grasses) - (AUST R 167566).

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Not applicable.

7 Medicine Schedule (Poisons Standard)

Prescription Only Medicine - S4.

Date of First Approval

03 May 2011

Date of Revision

17 May 2023

Summary Table of Changes