4.1. Therapeutic indications

ACARIZAX is indicated in adult patients (18-65 years) diagnosed by clinical history and a positive test of house dust mite sensitisation (skin prick test and/or specific IgE) with at least one of the following conditions:

• persistent moderate to severe house dust mite allergic rhinitis despite use of symptom-relieving medication

• house dust mite allergic asthma not well controlled by inhaled corticosteroids and associated with mild to severe house dust mite allergic rhinitis. Patients' asthma status should be carefully evaluated before the initiation of treatment (see section 4.3).

ACARIZAX is indicated in children (5-17 years) diagnosed by clinical history and a positive test of house dust mite sensitisation (skin prick test and/or specific IgE) with persistent moderate to severe house dust mite allergic rhinitis despite use of symptom-relieving medication.

4.2. Posology and method of administration

Posology

The recommended dose for children and adults (5-65 years) is one sublingual lyophilisate (12 SQ-HDM) daily.

Onset of the clinical effect is to be expected 8-14 weeks after initiation.

International treatment guidelines refer to a treatment period of 3 years for allergy immunotherapy to achieve disease modification. Efficacy data is available for 18 months of treatment with ACARIZAX in adults; no data is available for 3 years of treatment (see section 5.1).

If no improvement is observed during the first year of treatment with ACARIZAX there is no indication for continuing treatment.

Paediatric population

Allergic rhinitis: The posology to be used in children (5-17 years) is the same as in adults. The safety and efficacy of ACARIZAX in children <5 years of age have not been established. No data are available.

Allergic asthma: The efficacy of ACARIZAX in children <18 years of age has not been established. Currently available data are described in section 4.8 and 5.1.

Elderly population

There is no clinical experience on immunotherapy with ACARIZAX in adults >65 years of age.

Method of administration

ACARIZAX 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 effects.

ACARIZAX 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 beverage should not be taken for the following 5 minutes.

If treatment with ACARIZAX is interrupted for a period 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.

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.

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

Patients with active or poorly controlled autoimmune diseases, immune defects, immunodeficiencies, immunosuppression or malignant neoplastic diseases 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

Asthma

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

Patients should be advised that ACARIZAX is not intended to treat acute asthma exacerbations. In the event of an acute asthma exacerbation, a short-acting bronchodilator should be used. If patients find short-acting bronchodilator treatment ineffective or they need more inhalations than usual, medical attention must be sought.

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

ACARIZAX should initially be used as add on therapy and not as a substitute of pre-existing asthma medication. Abrupt discontinuation of asthma controller medication after initiation of ACARIZAX treatment is not recommended. Reductions in asthma controller medication should be performed gradually under the supervision of a physician according to asthma management guidelines.

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, angioedema, 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 systemic allergic reactions. Clinical experience in treatment with ACARIZAX of patients with cardiac disease is limited.

This should be taken into consideration prior to initiating allergy immunotherapy.

Initiation of ACARIZAX in patients who have previously had a systemic allergic reaction to subcutaneous house dust mite 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.

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 ACARIZAX treatment should be postponed and ongoing treatment should be temporarily interrupted to allow healing of the oral cavity.

Local Allergic Reactions

When treated with ACARIZAX 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 oropharyngeal reactions may occur. If the patient experiences significant local adverse reactions from the treatment, anti-allergic medication (e.g. antihistamines) should be considered.

Eosinophilic oesophagitis

Cases of eosinophilic oesophagitis have been reported in association with ACARIZAX treatment. In patients with severe or persisting gastro-oesophageal symptoms such as dysphagia or dyspepsia, ACARIZAX 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. ACARIZAX should therefore be prescribed with caution in these patients.

Food allergy

ACARIZAX 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 ACARIZAX in pregnant women. Animal studies do not indicate increased risk to the foetus.

Treatment with ACARIZAX 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 ACARIZAX. In patients with pre-existing asthma close supervision during pregnancy is recommended.

Breast-feeding

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

Fertility

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

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

Subjects taking ACARIZAX should primarily expect mild to moderate local allergic reactions to occur within the first few days and subsiding again with continued treatment (1-3 months) (see section 4.4). For the majority of events, the reaction should be expected to start within 5 minutes after intake of ACARIZAX on each day of occurrence and abate after minutes to hours. More severe oropharyngeal allergic reactions may occur (see section 4.4).

Isolated cases of severe acute worsening of asthma symptoms have been reported. Patients with known risk factors should not initiate treatment with ACARIZAX (see section 4.3).

Tabulated list of adverse reactions

The following table of adverse reactions is based on data from placebo-controlled clinical trials investigating ACARIZAX in adults and adolescents (more than 2100 patients treated with ACARIZAX) with house dust mite allergic rhinitis and/or allergic asthma and from spontaneous reporting.

Adverse reactions are divided into groups according to the MedDRA convention 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).

System Organ Class

Frequency

Adverse Drug Reaction

Infections and infestations

Very common

Nasopharyngitis

Common

Bronchitis, pharyngitis, rhinitis, sinusitis

Uncommon

Laryngitis

Immune system disorders

Uncommon

Anaphylactic reaction

Nervous system disorders

Common

Dysgeusia

Uncommon

Dizziness, paraesthesia

Eye Disorders

Common

Eye pruritus

Uncommon

Conjunctivitis allergic

Ear and labyrinth disorders

Very common

Ear pruritus

Uncommon

Ear discomfort

Cardiac disorders

Uncommon

Palpitations

Respiratory, thoracic and mediastinal disorders

Very common

Throat irritation

Common

Asthma, cough*, dysphonia, dyspnoea, oropharyngeal pain, pharyngeal oedema

Uncommon

Nasal congestion, nasal discomfort, nasal oedema, pharyngeal erythema, rhinorrhoea, sneezing, throat tightness, tonsillar hypertrophy

Rare

Laryngeal oedema, nasal obstruction, tracheal oedema

Gastrointestinal disorders

Very common

Lip oedema, mouth oedema, oral pruritus

Common

Abdominal pain, diarrhoea, dysphagia, dyspepsia, gastrooesophageal reflux disease, glossodynia, glossitis, lip pruritus, mouth ulceration, oral pain, tongue pruritus, nausea, oral discomfort, oral mucosal erythema, oral paraesthesia, stomatitis, tongue oedema, vomiting

Uncommon

Dry mouth, lip pain, lip ulceration, oesophageal irritation, oral mucosal blistering, salivary gland enlargement, salivary hypersecretion

Rare

Eosinophilic oesophagitis

Skin and subcutaneous tissue disorders

Common

Pruritus, urticaria

Uncommon

Erythema, rash

Rare

Angioedema

General disorders and administration site conditions

Common

Chest discomfort, fatigue

Uncommon

Malaise, sensation of foreign body

Description of selected adverse reactions

If the patient experiences significant adverse reactions from the treatment, anti-allergic medication should be considered.

Cases of serious systemic allergic reactions, including anaphylaxis have been reported post marketing. The medical supervision at first sublingual lyophilisate intake is therefore an important precaution (see section 4.2). However, cases of serious systemic allergic reaction have also occurred at doses subsequent to the initial dose.

In case of acute worsening in asthma symptoms or severe systemic allergic reactions, angioedema, difficulty in swallowing, difficulty in breathing, changes in voice, hypotension or feeling of fullness in the throat a physician should be contacted immediately. Hypertensive crisis has been reported following respiratory distress shortly after intake of ACARIZAX. In such cases treatment should be discontinued permanently or until otherwise advised by the physician.

*In clinical trials cough was observed with the same frequency for ACARIZAX and placebo.

Paediatric population

Adolescents 12-17 years of age

Reported adverse reactions in adolescents have been similar in frequency, type and severity as in adults.

Children 5-11 years of age

Overall, the safety profile in children treated with ACARIZAX was similar to that observed in adults and adolescents. The majority of adverse reactions were mild to moderate in severity and seen with a similar frequency category for children compared to adults/adolescents. The overall safety profile in children with asthma was similar to children without asthma. The safety profile of ACARIZAX in children is primarily based on data from double-blinded, placebo-controlled, multinational clinical trials (approximately 900 children treated with ACARIZAX) with active solicitation of predefined local adverse reactions the first 28 days of treatment.

The following adverse reactions were observed with a higher frequency in the children's studies compared to the adult and adolescent studies:

Abdominal pain, diarrhoea, dysgeusia, glossodynia, mouth ulceration, nausea, pharyngeal oedema and tongue oedema belonged to the frequency category very common (≥1/10). All of these were among the predefined solicited adverse reactions.

Symptoms of allergic conjunctivitis were reported with the frequency common (≥1/100 to <1/10).

Angioedema and eosinophilic oesophagitis were reported with the frequency uncommon (≥1/1,000 to <1/100).

Children <5 years of age

No data on treatment with ACARIZAX in children <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 phase I studies adult patients with house dust mite allergy were exposed to doses up to 32 SQ-HDM. No data are available in children (5-17 years) regarding exposure to doses above the recommended daily dose of 12 SQ-HDM.

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