SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

GRAZAX 75,000 SQ-T oral lyophilisate.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Standardised allergen extract of grass pollen from Timothy (Phleumpratense) 75,000 SQ-T* per oral lyophilisate.

* [Standardised Quality units Tablet ( SQ-T)]

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Oral lyophilisate

White to off-white circular oral lyophilisate marked with a debossed image on one side.

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.

Children should be carefully selected for treatment (see section 4.2).

4.2 Posology and method of administration

Posology

The recommended dose for adults and children (5 years or older) is one oral lyophilisate (75,000 SQ-T) daily. Clinical experience on immunotherapy with Grazax in children (younger than 5 years) and the elderly (65 years or older) is lacking.

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

Paediatric population

For treatment of children, physicians should be experienced in treating allergic diseases in children and the patients should be carefully selected considering the expected level of efficacy in this age group (see section 5.1)

Method of administration

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

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

It is recommended to continue treatment with Grazax for a period of 3 years. Data is available for 3 years of treatment and 2 years of follow-up in adults. No data on treatment with Grazax in children beyond one grass pollen season is available.

Clinical effect in the first grass pollen season is expected when treatment is initiated at least 4 months prior to the expected start of the grass pollen season. If treatment is initiated 2-3 months before the season some efficacy may also be obtained.

Grazax is an oral lyophilisate. The oral 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 oral 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: FEVi < 70% of predicted value after adequate pharmacologic treatment, in children: FEVi < 80% of predicted value after adequate pharmacologic treatment) should not be treated with Grazax immunotherapy.

4.4 Special warnings and precautions for use

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 the oral cavity.

In children with concomitant asthma and experiencing an acute upper respiratory tract infection Grazax treatment should be temporarily discontinued until the infection has resolved.

When treated with Grazax the patient is exposed to the allergen that causes the allergic symptoms. Therefore, primarily mild or 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.

In post marketing experience, rare cases of severe systemic allergic reactions have been reported and therefore the medical supervision at start of treatment is an important precaution.

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.

Severe systemic allergic reactions may be treated with adrenaline. The effects of adrenaline may be potentiated in patients treated with tricyclic antidepressants and/or mono amino oxidase inhibitors (MAOIs) with possible fatal consequences; this should be taken into consideration prior to initiating specific immunotherapy.

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.

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.

4.5 Interaction with other medicinal products and other forms of interaction

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 no 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.

Lactation

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.

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

In trials investigating treatment with Grazax 75,000 SQ-T, in adult and paediatric patients, 56% of the patients receiving Grazax reported side effects during the first 3 months of treatment. The number of patients reporting side effects decreased markedly during further treatment.

Very commonly reported adverse reactions in adult and paediatric patients treated with Grazax were local allergic reactions in the mouth which mostly were mild to moderate. In the majority of patients these reactions started early in therapy, lasted from minutes to hours after each intake of Grazax and tended to subside spontaneously within 1 to 7 days.

Tabulated list of adverse reactions

The following table of undesirable effects is based on data from controlled clinical trialsinvestigating Grazax in adult and paediatric patients with seasonal grass-pollen induced rhinoconjunctivitis including patients with mild to moderate co-existing grass-pollen induced asthma.

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	Pharyngitis, rhinitis, upper respiratory tract infection
	Uncommon	Laryngitis
Blood and lymphatic system disorders	Uncommon	Lymphadenopathy
Immune system disorders	Uncommon	Systemic allergic reaction
Nervous system disorders	Common	Headache, paraesthesia
	Uncommon	Dizziness, dysgeusia
Eye disorders	Common	Eye pruritus, conjunctivitis
	Uncommon	Conjunctival hyperaemia, conjunctival irritation, lacrimation increased, eye swelling, eyelid oedema
Cardiac disorder	Uncommon	Palpitation
Ear and labyrinth disorders	Common Uncommon	Ear pruritus
		Ear discomfort, ear pain
Respiratory, thoracic and mediastinal disorders	Very common	Throat irritation
	Common	Sneezing, asthma, cough, dry throat, dyspnoea, nasal discomfort, nasal congestion, oropharyngeal pain, pharyngeal oedema, rhinorrhoea, rhinitis allergic
	Uncommon	Dysphonia, throat tightness, pharyngeal erythema, pharyngeal hypoaesthesia, tonsillar hypertrophy, wheezing, oropharyngeal blistering
	Rare	Bronchospasm
Gastrointestinal disorders	Very common	Oral pruritus
	Common	Oedema mouth, lip swelling, oral discomfort, paraesthesia oral, stomatitis, swollen tongue, dysphagia, abdominal pain, diarrhoea, dyspepsia, nausea, vomiting
	Uncommon	Oral mucosal erythema, oropharyngeal

		discomfort, palatal oedema, dry mouth, lip blister, cheilitis, oral pain, oral disorder, odynophagia, salivary gland enlargement, salivary gland hypersecretion, gingival swelling, gingival pain, aphthous stomatitis, mouth ulceration, tongue blistering, tongue disorder, glossitis, glossodynia, gastritis, gastroesophageal reflux, abdominal discomfort, decreased appetite
Skin and subcutaneous tissue disorders	Common	Pruritus, urticaria, eczema, rash
	Uncommon	Angioedema such as swollen face, erythema, flushing
General disorders and administration site conditions	Common	Fatigue, chest discomfort, pyrexia
	Uncommon	Chest pain, feeling hot, malaise, 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, rare cases of severe systemic allergic reactions have been reported, and therefore the medical supervision at the start of treatment is an important precaution, 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 children and adolescents treated with Grazax was similar to that observed in adults. Non-serious systemic allergic reaction, conjunctival irritation, pharyngeal erythema, lip blister, salivary gland enlargement, erythema, ear pain and chest pain belong to a higher frequency group (common) in the paediatric population than in the table above. 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. Website: www.mhra.gov.uk/yellowcard.

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 reactions or severe local 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.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Allergen extracts, Grass pollen.

ATC code: V01AA02.

Mode of action

Specific immunotherapy with allergen products is the repeated administration of allergens to allergic individuals in order to activate immunomodulatory mechanisms and provide sustained relief of symptoms and less need for medications, and improvement in quality of life during subsequent natural allergen exposure.

Daily treatment with Grazax in adult patients for 3 years resulted in disease modification as demonstrated by a sustained effect after the completion of treatment (effect demonstrated after 1 and 2 years’ follow-up). The magnitude of effect varied over the 5 seasons with a peak in season 2 and a possible trend towards a gradual decrease from season 3 to season 5 (1 additional treatment season +2 treatment free follow-up seasons, see table below). The variation in treatment effect followed the variation in grass pollen exposure. However, it cannot presently be established if the decrease in grass pollen exposure is the sole explanation for the possible trend towards a gradual decrease in treatment effect seen in seasons 3-5.

Grazax is used for disease-modifying treatment of patients with grass pollen induced rhinitis and rhinoconjunctivitis.

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 Grazax has shown to induce a systemic competitive antibody response towards grass, and it induces an increase in specific IgG4 over 3 years of treatment. After 2 years without Grazax treatment the increase in specific IgG4 was still present. The clinical significance of these findings has not been established.

Clinical efficacy in adults

In a placebo controlled, double-blind, randomized multi-national study, the efficacy of Grazax once daily was evaluated in 634 adult patients with grass pollen induced rhinoconjunctivitis. 72% of the patients had positive skin prick tests to one or more allergens other than grass pollen. The efficacy was based on the average daily

rhinoconjunctivitis symptom and medication score during one grass pollen season. Treatment was initiated at least 16 weeks before the anticipated start of the first grass pollen season and was continued all year round.

The efficacy and safety of Grazax has not been established in patients with significant allergic symptoms in the grass pollen season caused by other allergens than grass pollen.

Results after 3 years of daily Grazax treatment (Year 1-3) and 2 years of follow-up (Year 4-5) are available:

Primary Efficacy Endpoints Years 1-5

	Treatment	Treatment	Treatment	Follow up	Follow up
	Year 1	Year 2	Year 3	Year 4	Year 5
Number of subjects in the analysis A Grazax	282	172	160	142	137
Placebo	286	144	127	115	104
Rhinoconjunctivitis Symptom Score B
Grazax: mean (median)	2.85 (2.6)	2.40 (1.94)	2.56 (2.04)	2.68 (2.27)	2.56 (2.18)
Placebo: mean (median)	4.14 (3.8)	3.76 (3.45)	3.59 (3.23)	3.63 (3.27)	3.40 (3.15)
Difference in means
Absolute	1.29	1.36	1.04	0.95	0.84
[CI 95%] Relative to placebo (%)	[0.90; 1.68] 31%	[0.86; 1.86] 36%	[0.52;1.56] 29%	[0.40; 1.50] 26%	[0.28; 1.41] 25%
[CI 95%] p-value ANOVA	[22%; 41%] <0.0001	[23%; 49%] <0.0001	[14%; 43%] 0.0001	[11%; 41%] 0.0007	[9%; 37%] 0.0037
Difference in medians
Absolute	1.2	1.51	1.19	1.00	0.97
Relative to placebo (%)	32%	44%	37%	31%	31%
Rhinoconjunctivitis Medication Score C
Grazax: mean (median)	1.65 (1.0)	1.74 (0.46)	1.82 (0.82)	2.32 (1.23)	2.42 (1.62)
Placebo: mean (median)	2.68 (2.2)	3.19 (1.71)	3.04 (2.07)	3.25 (2.58)	3.04 (2.06)
Difference in means
Absolute	1.03	1.45	1.22	0.93	0.62
[CI 95%] Relative to placebo (%)	[0.63; 1.44] 39%	[0.75; 2.16] 46%	[0.52;1.92] 40%	[0.14; 1.72] 29%	[-0.15; 1.38] 20%
[CI 95%] p-value ANOVA	[24%; 54%] <0.0001	[24%; 68%] <0.0001	[17%; 63%] 0.0007	[4%; 53%] 0.0215	[-8%; 40%] 0.1136
Difference in medians
Absolute	1.2	1.25	1.25	1.35	0.44
Relative to placebo (%)	55%	73%	60%	52%	21%
A The trial was initially planned as a 1-year trial. 546 of the original 634 subjects completed the first year. The trial was extended with 2 more years of treatment and 2 years of follow-up. At inclusion into the extension, 351 subjects chose to enrol (74 were not offered enrolment due to closure of sites), and these were a representative subgroup of the original 634 subjects. The numbers of subjects in the analyses are all subjects providing diary data during the grass pollen seasons. B Symptom score: Mean daily rhinoconjunctivitis symptom score for each subject for the grass pollen season. Rhinoconjunctivitis symptoms included runny nose, blocked nose, sneezing, itchy nose, gritty feeling/red/itchy eyes

Follow-up, Year 4
Number of subjects A	142	115
Quality of life score B	0.82 (0.64)	1.07 (0.97)	0.25 23% 0.0041 [0.08;0.41] [7%; 38%1
Well days D	50.0% (51.9%)	38.1% (31.6%)	11.9% 31% 0.0020 [4.4%;19.4%1 [12%; 50%1
Percentage of patients with more than 50% well days DE	53.1%	34.0%	19.1% 56% 0.0031# (odds ratio0 2.2 [1.3; 3.71)
Symptom and medication free days F	35.2% (25.7%)	27.6% (17.2%)	7.6% 27% 0.0384 [0.41%; 14.8%1 [1%; 54%1
Follow-up, Year 5
Number of subjects A	137	104
Quality of life score B	0.69 (0.56)	0.85 (0.85)	0.16 19% 0.0587 [-0.01; 0.331 [-2%; 38%1
Well days D	49.7% (51.1%)	40.0% (32.9%)	9.74% 24% 0.0203 [1.5%; 17.9%1 [3%; 52%1
Percentage of patients with more than 50% well days DE	49.5%	35.0%	14.5% 41% 0.0280# (odds ratio0 1.8 [1.1; 3.11)
Symptom and medication free days F	33.5% (25.9%)	28.0% (18.2%)	5.5% 20% 0.1737 [-2.4%; 13.4%1 [-8%; 57%1
* Relative difference = Absolute difference|/Placebo; n odds ratio for having excellent control; # p-value for the odds ratio. A The trial was initially planned as a 1-year trial; 546 of the original 634 subjects completed the first year. The trial was extended with 2 more years of treatment and 2 years of follow-up. At inclusion into the extension, 351 subjects chose to enrol (74 were not offered enrolment due to closure of sites), and these were a representative subgroup of the original 634 subjects. The numbers of subjects are all subjects providing diary data during the grass pollen seasons. B Quality of life was assessed by the Rhinoconjunctivitis Quality of Life Questionnaire including 28 items in the domains activity limitation, sleep problems, nose symptoms, eye symptoms, non-nose/eye symptoms, practical problems and emotional function. A higher score is reflecting a worse quality of life. Rhinoconjunctivitis Quality of Life Questionnaire score range was 0 - 6, the upper value indicates prolonged very severe impact on all items. In the trial 95% of all recordings were 4 or less. C Global evaluation: percentage of subjects who noted an improvement in rhinoconjunctivitis symptoms in the treatment season as compared to their recollection of the previous seasons. D Well days: percentage of days where the subjects did not use any rescue medication and had a symptom score not larger than 2. E For year 3 and the 2 follow-up years, analysed by means of the odds ratio for having more than 50% well days during the corresponding grass pollen season. F Symptom and medication free days: percentage of days where the subjects did not use any rescue medication and had no symptoms.

Statistically significant effect was demonstrated for each of the scored rhinoconjunctivitis symptoms (runny nose, blocked nose, sneezing, itchy nose, gritty feeling/red/itchy eyes and watery eyes).

In a trial with shorter pre-treatment, less reductions in symptom and medication scores were found; Grazax treatment approximately 2 months prior to and during the grass pollen season resulted in a symptom score reduction of 16% (p=0.071) and a medication score reduction of 28% (p=0.047) (full analysis set).

Clinical efficacy in children

The efficacy of Grazax has been investigated in children (5-16 years) with grass pollen induced rhinoconjunctivitis with/without asthma in a randomized, doubleblind, placebo controlled study. Patients received treatment prior to the grass pollen season and continued throughout the entire season. Data on the clinical efficacy of Grazax on rhinoconjunctivitis in children are found below.

Efficacy in children

	Grazax	Placebo	Absolute Relative Diff.* Diff. (%) p-value [CI 95%] [CI 95%]
Number of subjects included in the analysis	117	121
Primary endpoints
Rhinoconj unctivitis A symptom score	2.18	2.80	0.62 22% 0.0215 [0.10; 1.15] [4%; 38%]
Rhinoconj unctivitis medication score B	0.78	1.19	0.41 34% 0.0156
Key Secondary endpoints
Rhinoconj unctivitis symptom score A, peak grass pollen season	2.84	3.91	1.07 27% 0.0059 [0.32; 1.81] [9%; 43%]
Rhinoconj unctivitis medication score B, peak grass pollen season	0.87	2.40	1.53 64% 0.0013
Well days C	52%	42%	9% 22% 0.0225 [ 1%; 17%] [3%; 45%]
A Symptom score: Mean daily rhinoconjunctivitis symptom score for each subject for the grass pollen season. Rhinoconjunctivitis symptoms included runny nose, blocked nose, sneezing, itchy nose, gritty feeling/red/itchy eyes and watery eyes. Parametric analysis (square-root-transformed data), relative difference of back-transformed, adjusted means. B Medication score: Median daily rhinoconjunctivitis medication score for each subject for the grass pollen season. Medications used were loratadine tablets, levocabastine eye drops, budesonide nasal spray, prednisolone tablets. Non-parametric analysis, relative difference of medians. C Well days: percentage of days where the subjects did not use any rescue medication and had a symptom score not larger than 2. Parametric analysis (untransformed data), relative difference of adjusted means. *Relative difference = Absolute difference|/Placebo.

5.2 Pharmacokinetic properties

The main part of the allergens in Grazax is polypeptides and proteins, which are expected to be broken down to amino acids and small polypeptides in the lumen of the

gastrointestinal tract and in tissues. It is expected that allergens from Grazax are not absorbed into the vascular system to any significant extent. Thus, no pharmacokinetic studies in animals or clinical studies investigating the pharmacokinetic profile and metabolism of Grazax have been conducted.

5.3 Preclinical safety data

Conventional studies in general toxicity and of toxicity to reproduction in mice revealed no special hazard for humans. In toxicological studies in dogs, daily dosing for 52 weeks was associated with vasculitis / perivasculitis in males, but not in females. It is not expected that there is a risk of developing vasculitis/perivasculitis in humans.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Gelatin (fish source) Mannitol

Sodium hydroxide

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

4 years.

6.4 Special precautions for storage

This medical product does not require any special storage conditions.

6.5 Nature and contents of container

Aluminium blister cards with removable aluminium foil in an outer carton box. Each blister card contains 10 oral lyophilisates.

Pack sizes: 30 (3 x 10) oral lyophilisates, 90 (9 x 10) oral lyophilisates and 100 (10 x 10) oral lyophilisates.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Any unused product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

ALK-Abello A/S Boge Alle 6-8 DK- 2970 Horsholm Denmark

8    MARKETING AUTHORISATION NUMBER(S)

PL 10085/0039

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

14/03/2011

10    DATE OF REVISION OF THE TEXT

10/01/2014