4.1. Therapeutic indications

ITULAZAX is indicated in adults and children (5 years or older) for the treatment of moderate-to-severe allergic rhinitis and/or conjunctivitis induced by pollen from the birch homologous group1. ITULAZAX is indicated in patients with a clinical history of symptoms despite use of symptom-relieving medication and a positive test of sensitisation to a member of the birch homologous group (skin prick test and/or specific IgE).

4.2. Posology and method of administration

Posology

The recommended dose for adults and children (5 years or older) is one sublingual lyophilisate (12 SQ-Bet) daily.

It is recommended that treatment with ITULAZAX should be initiated outside the pollen season and continued during the tree pollen season. Clinical effect during the tree (birch homologous group) pollen season has been demonstrated when treatment is initiated at least 16 weeks prior to the expected start of the tree (birch homologous group) pollen season and continued throughout the season. There are no clinical data available for an in-season treatment start.

International treatment guidelines refer to a treatment period of 3 years for allergy immunotherapy to achieve disease modification. Long-term efficacy has not yet been established. If no improvement is observed during the first year of treatment with ITULAZAX there is no indication for continuing treatment.

Elderly population

Clinical experience in patients ≥65 years of age is limited.

Paediatric population

The posology to be used in children (5-17 years) is the same as in adults. Clinical experience in treatment of allergic rhinitis and/or conjunctivitis with ITULAZAX in children below 5 years of age has not been established. ITULAZAX is not intended for treatment of allergic rhinitis and/or conjunctivitis in children below 5 years of age. Currently available data are described in section 4.8 and 5.1.

Method of administration

ITULAZAX treatment should be initiated by physicians with experience in treatment of allergic diseases. The first sublingual lyophilisate should be taken under medical supervision and the patient should be monitored for at least half an hour to enable discussion and possible treatment of any immediate side effect.

ITULAZAX is a sublingual lyophilisate. The sublingual lyophilisate should be taken with dry fingers from the blister unit immediately after opening the blister and placed under the tongue, where it will disperse. Swallowing should be avoided for approximately 1 minute. Food and beverages should not be taken for the following 5 minutes.

If treatment with ITULAZAX is interrupted for a period of up to 7 days, treatment can be resumed by the patient. If the treatment is interrupted for more than 7 days it is recommended to contact a physician before resuming the treatment.

1 Birch homologous group: Betula verrucosa (birch), Alnus glutinosa (alder), Carpinus betulus (hornbeam), Corylus avellana (hazel), Quercus alba (oak) and Fagus sylvatica (beech).

4.3. Contraindications

Hypersensitivity to any of the excipients (for a full list of excipients, see section 6.1).

Patients with FEV1 <70% of predicted value (after adequate pharmacological treatment) at initiation of treatment.

Patients who have experienced a severe asthma exacerbation within the last 3 months prior to initiation.

Patients with uncontrolled asthma within the last 3 months prior to initiation.

Patients with active systemic autoimmune disorders (unresponsive to treatment) and patients with immune defects, immunodeficiencies or immunosuppression (see section 4.4).

Patients with malignant neoplasia with current disease relevance.

Patients with acute severe oral inflammation or oral wounds (see section 4.4).

4.4. Special warnings and precautions for use

Severe systemic allergic reactions

Treatment should be discontinued and a physician should be contacted immediately in case of severe systemic allergic reactions, severe asthma exacerbation, severe pharyngeal oedema, difficulty in swallowing, difficulty in breathing, changes in voice, hypotension or feeling of fullness in the throat. The onset of systemic symptoms may include flushing, pruritus, sense of heat, general discomfort and agitation/anxiety.

One option for treating severe systemic allergic reactions is adrenaline. The effects of adrenaline may be potentiated in patients treated with tricyclic antidepressants, mono amino oxidase inhibitors (MAOIs) and/or COMT inhibitors with possible fatal consequences. The effects of adrenaline may be reduced in patients treated with beta-blockers.

Patients with cardiac disease may be at increased risk in case of severe systemic allergic reactions. Clinical experience in treatment with ITULAZAX of patients with cardiac disease is limited and allergy immunotherapy should be prescribed with caution in patients with severe cardiovascular disease.

Initiation of ITULAZAX in patients who have previously had a systemic allergic reaction to subcutaneous tree pollen allergy immunotherapy should be carefully considered, and measures to treat potential reactions should be available. This is based on post-marketing experience from a corresponding sublingual tablet product for grass pollen immunotherapy which indicates that the risk of a severe allergic reaction may be increased for patients who have previously experienced a systemic allergic reaction to subcutaneous grass pollen immunotherapy.

Asthma

Asthma is a known risk factor for severe systemic allergic reactions.

Severe asthma exacerbation within the last 12 months is a known risk factor for future exacerbations. Limited data is available with ITULAZAX treatment in this situation.

ITULAZAX has not been studied in patients with severe and/or uncontrolled asthma.

Patients with asthma must be informed of the need to seek medical attention immediately if their asthma deteriorates suddenly.

In patients with asthma experiencing an acute respiratory tract infection, initiation of ITULAZAX treatment should be postponed until the infection has resolved.

Oral inflammation

In patients with severe oral inflammation (e.g. oral lichen planus, mouth ulcers or thrush), oral wounds or following oral surgery, including dental extraction, or following tooth loss, initiation of ITULAZAX treatment should be postponed and ongoing treatment should be temporarily interrupted to allow healing of the oral cavity.

Local allergic reactions

When treated with ITULAZAX the patient is exposed to the allergen that causes the allergic symptoms. Therefore, local allergic reactions are to be expected during the treatment period. These reactions are usually mild or moderate; however, more severe reactions may occur. On the first few days of at-home administration adverse reactions, which were not observed on the first day of treatment, may occur. If the patient experiences significant local adverse reactions from the treatment, allergy pharmacotherapy (e.g. antihistamines) should be considered.

Eosinophilic oesophagitis

Cases of eosinophilic oesophagitis have been reported in association with ITULAZAX treatment. In patients with severe or persistent gastro-oesophageal symptoms such as dysphagia or dyspepsia, ITULAZAX should be interrupted and medical evaluation must be sought.

Autoimmune diseases in remission

Limited data is available on treatment with allergy immunotherapy in patients with autoimmune diseases in remission. ITULAZAX should therefore be prescribed with caution in these patients.

Simultaneous vaccination

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

Fish allergy

ITULAZAX may contain trace amounts of fish protein. Available data have not indicated an increased risk of allergic reactions in patients with fish allergy.

This medicine contains less than 1 mmol sodium (23 mg) per sublingual lyophilisate, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

No interaction trials have been conducted in humans and no potential drug interactions have been identified from any source. Concomitant therapy with symptomatic anti-allergic medications may increase the tolerance level of the patient to immunotherapy. This should be considered at discontinuation of such medications.

4.6. Fertility, pregnancy and lactation

Pregnancy

There is no data on the clinical experience for the use of ITULAZAX in pregnant women. Animal studies do not indicate increased risk to the foetus. Treatment with ITULAZAX should not be initiated during pregnancy. If pregnancy occurs during treatment, the treatment may continue after evaluation of the general condition (including lung function) of the patient and reactions to previous administration of ITULAZAX. In patients with pre-existing asthma close supervision during pregnancy is recommended.

Breastfeeding

No clinical data are available for the use of ITULAZAX during lactation. No effects on the breastfed infants are anticipated.

Fertility

There is no clinical data with respect to fertility for the use of ITULAZAX. In a repeat dose toxicity study in naïve mice no effects were observed in the reproductive organs of both genders.

4.7. Effects on ability to drive and use machines

Treatment with ITULAZAX has no or negligible influence on the ability to drive or use machines.

4.8. Undesirable effects

Summary of the safety profile

Patients taking ITULAZAX should primarily expect mild to moderate local allergic reactions to occur within the first few days of treatment and disappear within a few months (in many cases within a week or two). For the majority of events, the reaction should be expected to start within 10 minutes after intake of ITULAZAX on each day of occurrence and abate within an hour. More severe local allergic reactions may occur (see section 4.4).

Tabulated list of adverse reactions

Adverse reactions associated with ITULAZAX obtained from placebo-controlled clinical trials in adult patients and post-marketing surveillance are tabulated below.

Adverse reactions are divided into groups according to the frequencies: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data).

System Organ Class

Frequency

Adverse Drug Reaction

Immune system disorders

Common

Oral allergy syndrome

Not known

Anaphylactic reaction

Nervous system disorders

Common

Dysgeusia

Ear and labyrinth disorders

Very common

Ear pruritus

Eye disorders

Common

Symptoms of allergic conjunctivitis*

Respiratory, thoracic and mediastinal disorders

Very common

Throat irritation

Common

Cough, dry throat, dysphonia, dyspnoea, oropharyngeal pain, pharyngeal oedema, pharyngeal paraesthesia, rhinitis

Uncommon

Laryngeal oedema, throat tightness

Gastrointestinal disorders

Very common

Oedema mouth, oral pruritus, paraesthesia oral, tongue pruritus

Common

Abdominal pain, diarrhoea, dyspepsia, dysphagia, gastrooesophageal reflux disease, glossodynia, hypoaesthesia oral, lip oedema, lip pruritus, nausea, oral discomfort, oral mucosal blistering, stomatitis, swollen tongue

Uncommon

Glossitis, lip blister, mouth ulceration, oesophageal irritation

Not known

Eosinophilic oesophagitis

Skin and subcutaneous tissue disorders

Common

Urticaria

Uncommon

Angioedema

General disorders and administration site conditions

Common

Chest discomfort, sensation of foreign body

* Symptoms of allergic conjunctivitis typically include conjunctival hyperaemia, eye irritation, eye oedema/swelling, eyelid oedema, eye pruritus, lacrimation increased, and ocular hyperaemia

Description of selected adverse reactions

ITULAZAX allergy immunotherapy involves repeated administration of natural allergen to which the patient is allergic. At initiation of treatment patients should be informed of the adverse reactions they are likely to experience and how to manage these in order to align expectations to treatment and optimise compliance.

Local allergic reactions are manifested in the upper respiratory or gastrointestinal system. Oral pruritus was reported in 38% of the patients, throat irritation in 29% of the patients and tongue pruritus was reported in 13% of the patients.

Systemic allergic reactions, including anaphylactic reactions, are known risks in patients receiving allergy immunotherapy and are considered a class effect.

Symptoms of oral allergy syndrome can occur upon ingestion of certain raw vegetables, fruits or nuts. Treatment with ITULAZAX may worsen the symptoms of existing oral allergy syndrome, and there have been a few new events of oral allergy syndrome reported. Symptoms typically occur at treatment initiation and may resolve with continued treatment.

Paediatric population

The safety profile of ITULAZAX in children (5-17 years) is based on data from double-blind placebo-controlled, multi-regional clinical trials.

Overall, the safety profile in children treated with ITULAZAX was similar to that observed in adult patients. The majority of adverse reactions were mild to moderate in severity and seen with a similar frequency category for children compared to adults.

Anaphylactic reaction was reported with the frequency uncommon (≥1/1,000 to <1/100).

No data from clinical trials on treatment with ITULAZAX in children below 5 years of age exist.

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 Yellow Card Scheme (www.mhra.gov.uk/yellowcard) or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

In a phase I trial, adult subjects with allergic rhinitis and/or conjunctivitis induced by birch pollen were exposed to doses of up to 24 SQ-Bet. For children (5-17 years of age), no data are available for exposure above the recommended daily dose of 12 SQ-Bet.

If doses higher than the recommended daily dose are taken, the risk of side effects may increase, including the risk of severe systemic allergic reactions or local allergic reactions. In case of severe systemic allergic reactions, severe asthma exacerbation, severe pharyngeal oedema, difficulty in swallowing, difficulty in breathing, changes in voice, hypotension or feeling of fullness in the throat, immediate medical evaluation is needed. These reactions should be treated with relevant symptomatic medication.