4.1. Therapeutic indications

Disease-modifying treatment of grass pollen induced rhinitis and conjunctivitis in adults and children (5 years or older), with clinically relevant symptoms and diagnosed with a positive skin prick test and/or specific IgE test to grass pollen.

4.2. Posology and method of administration

Posology

The recommended dose for adults and children (5 years or older) is one sublingual lyophilisate (75,000 SQ-T) daily.

Grazax treatment should only be initiated by physicians with experience in treatment of allergic diseases and the capability to treat allergic reactions.

Elderly population

Clinical experience on immunotherapy with Grazax in elderly (65 years or older) is lacking.

Paediatric population

For treatment of children, physicians should be experienced in treating allergic diseases in children. Clinical experience on immunotherapy with Grazax in children younger than 5 years is lacking.

Method of administration

In order to enable patient and physician to discuss any side effects and possible actions it is recommended that the first sublingual lyophilisate is taken under medical supervision (20-30 minutes).

Clinical effect on grass pollen allergic rhinitis and conjunctivitis in the grass pollen season is expected when treatment is initiated at least 4 months prior to the expected start of the grass pollen season and continued throughout the season. If treatment is initiated 2-3 months before the season some efficacy may also be obtained. If no relevant improvement of symptoms is observed during the first pollen season, there is no indication for continuing the treatment. For long term efficacy and disease modifying effect, it is recommended to continue daily treatment for 3 consecutive years.

Grazax is a sublingual lyophilisate. The sublingual lyophilisate should be taken from the blister unit with dry fingers, and placed under the tongue, where it will disperse.

Swallowing should be avoided for about 1 minute. Food and beverage should not be taken for the following 5 minutes.

The sublingual lyophilisate should be taken immediately after opening the blister.

4.3. Contraindications

Hypersensitivity to any of the excipients (for a full list of excipients, see section 6.1). Malignancy or systemic diseases affecting the immune system e.g. autoimmune diseases, immune complex diseases or immune deficiency diseases.

Inflammatory conditions in the oral cavity with severe symptoms such as oral lichen planus with ulcerations or severe oral mycosis.

Patients with uncontrolled or severe asthma (in adults: FEV1 < 70% of predicted value after adequate pharmacologic treatment, in children: FEV1 < 80% of predicted value after adequate pharmacologic treatment) should not be treated with Grazax.

4.4. Special warnings and precautions for use

Severe systemic allergic reactions

In post marketing experience, cases of serious anaphylactic reactions have been reported and therefore the medical supervision at start of treatment is an important precaution. In some cases, the serious anaphylactic reaction has occurred at doses subsequent to the initial dose.

The onset of systemic symptoms may include flushing, intensive itching in palms of hand and soles of the feet, and other areas of the body (like a nettle rash). Sense of heat, general discomfort and agitation/anxiety may also occur. In case of severe systemic 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. In such cases treatment should be discontinued permanently or until otherwise advised by the physician. If patients with concomitant asthma experience symptoms and signs indicating asthma deterioration, treatment should be discontinued, and a physician consulted immediately in order to evaluate the continuation of treatment.

In patients who have previously had a systemic reaction to grass subcutaneous immunotherapy, the risk of experiencing a severe reaction with Grazax may be increased. Initiation of Grazax should be carefully considered and measures to treat reactions should be available.

Serious anaphylactic reactions may be treated with adrenaline. Consider whether your patient would be able to tolerate adrenaline (e.g. treatment with tricyclic antidrepressants, MAOIs, COMTIs and/or beta-blockers) in the rare case of a severe systemic allergic reaction.

Patients with cardiac disease may be at increased risk in case of severe systemic allergic reactions. Clinical experience with treatment with Grazax in patients with cardiac disease is limited.

Local allergic reactions

When treated with Grazax the patient is exposed to the allergen that causes the allergic symptoms. Therefore, primarily mild to moderate local allergic reactions are to be expected during the treatment period. If the patient experiences significant local adverse reactions from the treatment, anti-allergic medication (e.g. antihistamines) should be considered.

Oral conditions

In case of oral surgery, including dental extraction, and shedding of a deciduous tooth in children, treatment with Grazax should be stopped for 7 days to allow healing of oral cavity.

Asthma

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

Grazax has not been studied in patients with severe and 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 and experiencing an acute respiratory tract infection, initiation of Grazax treatment should be postponed until the infection has resolved.

Eosinophilic esophagitis

In post marketing experience, isolated cases of eosinophilic esophagitis have been reported in association with Grazax treatment. In patients with severe or persisting gastro-esophageal symptoms such as dysphagia or dyspepsia, discontinuation of Grazax treatment should be considered.

Simultaneous vaccination

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

Food allergy

Grazax contains fish-derived gelatine. The available data have not indicated an increased risk of allergic reactions in severe fish allergic patients. However, awareness is suggested when initiating treatment with Grazax in these patients.

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 studies investigating drug interactions have been conducted in humans.

Concomitant therapy with symptomatic anti-allergic agents (e.g. antihistamines, corticosteroids and/or mast cell stabilisers) may increase the tolerance level of the patient to immunotherapy.

There are limited data available on possible risks of simultaneous immunotherapy with other allergens during treatment with Grazax.

4.6. Fertility, pregnancy and lactation

Pregnancy

There is no data on the clinical experience for the use of Grazax in pregnant women. Animal studies do not indicate increased risk to the foetus. Treatment with Grazax 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 Grazax. In patients with pre-existing asthma close supervision during pregnancy is recommended.

Breastfeeding

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

Fertility

There is no clinical data with respect to fertility for the use of Grazax. In mice, there was no effect on mating or fertility with Grazax treatment (see section 5.3).

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

Subjects taking Grazax should primarily expect mild to moderate local allergic reactions to occur early in therapy that tend to subside spontaneously within 1 to 7 days. The most commonly reported adverse reactions are oral pruritus, throat irritation and oedema mouth. For the majority of events, the reaction should be expected to start within 5 minutes after intake of Grazax on each day of occurrence and abate after minutes to hours. More severe local or systemic allergic reactions may occur (see section 4.4).

Tabulated list of adverse reactions

Table 1, which shows the adverse reactions, is based on data from placebo-controlled clinical trials investigating Grazax in adult and paediatric patients with seasonal grass-pollen induced rhinoconjunctivitis including patients with mild to moderate co-existing grass-pollen induced 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).

Table 1. Adverse reactions

System Organ Class

Frequency

Adverse Drug Reaction

Immune system disorders

Uncommon

Anaphylactic reaction, systemic allergic reaction

Nervous system disorders

Uncommon

Dysgeusia, paraesthesia

Eye disorders

Common

Eye pruritus, conjunctivitis, eye swelling

Uncommon

Ocular hyperaemia, eye irritation, lacrimation increased

Ear and labyrinth disorders

Very common

Ear pruritus

Uncommon

Ear discomfort, ear pain

Rare

Ear swelling

Cardiac disorder

Uncommon

Palpitations

Respiratory, thoracic and mediastinal disorders

Very common

Throat irritation

Common

Sneezing, cough, dry throat, dyspnoea, oropharyngeal pain, pharyngeal oedema, rhinorrhoea, throat tightness, nasal pruritus

Uncommon

Pharyngeal hypoaesthesia, tonsillar hypertrophy, laryngeal oedema, dysphonia, pharyngeal erythema

Rare

Bronchospasm

Gastrointestinal disorders

Very common

Oral pruritus, oedema mouth

Common

Lip swelling, oral discomfort, paraesthesia oral, stomatitis, dysphagia, abdominal pain, diarrhoea, dyspepsia, nausea, vomiting, oral mucosal erythema, mouth ulceration, oral pain, lip pruritus

Uncommon

Dry mouth, lip blister, cheilitis, odynophagia, salivary gland enlargement, salivary hypersecretion, tongue disorder, glossitis, gastritis, gastroesophageal reflux disease, abdominal discomfort, lip ulceration, oral mucosal blistering

Rare

Eosinophilic oesophagitis

Skin and subcutaneous tissue disorders

Common

Pruritus, urticaria, rash

Uncommon

Angioedema, erythema

General disorders and administration site conditions

Common

Fatigue, chest discomfort

Uncommon

Sensation of foreign body

Description of selected adverse reactions

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

In post marketing experience, cases of serious anaphylactic reactions, including anaphylactic shock have been reported. Medical supervision at start of treatment is therefore an important precaution. In some cases the serious anaphylactic reaction has occurred at doses subsequent to the initial dose. Please refer to section 4.2 and 4.4.

In case of severe systemic 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. In such cases treatment should be discontinued permanently or until otherwise advised by the physician.

Paediatric population

Overall, the adverse events profile in paediatric patients treated with Grazax was similar to that observed in adults. Most events were seen with a similar frequency category for paediatric patients compared to adults. In the paediatric population, eye irritation, ear pain, ear swelling, pharyngeal erythema and oral mucosal blistering are seen at a higher frequency than in table 1: eye irritation, ear pain, pharyngeal erythema and oral mucosal blistering were common and the ear swelling was uncommon. The events were primarily mild to moderate in severity.

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 MHRA 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 grass pollen allergy were exposed to doses up to 1,000,000 SQ-T. No data is available in children regarding exposure to doses above the recommended daily dose of 75,000 SQ-T.

If doses higher than the recommended daily dose are taken, the risk of side effects may increase, 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.

In such cases treatment should be discontinued permanently or until otherwise advised by the physician.