GRAZAX 75,000 SQ-T oral lyophilisate

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 (Phleum pratense) 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. Clinical Particulars

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 1 year 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: 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 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 allergic reactions may be treated with adrenaline. The effects of adrenaline may be potentiated in patients treated with tricyclic antidepressants and 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 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 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

In studies investigating treatment with Grazax 75,000 SQ-T daily in adult patients, 70% of the patients receiving Grazax reported side effects during the first treatment year. This number decreased markedly in the second year of continuous treatment.

Very commonly reported adverse reactions in adult patients, with seasonal grass pollen induced allergic rhinoconjunctivitis, 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.

The following table of undesirable effects is based on data from 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, during the first treatment year.

Adverse reactions are divided into groups according to the MedDRA convention frequencies: Very common (

System Organ Class	Frequency	Adverse Drug Reaction
Cardiac disorders	Uncommon	Palpitations
Infections and infestations	Uncommon	Upper respiratory tract infection, laryngitis
Blood and lymphatic system disorders	Uncommon	Lymphadenopathy
Nervous system disorders	Common	Headache, oral paraesthesia
	Uncommon	Dizziness
Eye disorders	Common	Eye pruritus, conjunctivitis, redness of eyes or tearflow
	Uncommon	Eye swelling
Ear and labyrinth disorders	Very common	Ear pruritus
Respiratory, thoracic and mediastinal disorders	Very common	Throat irritation, sneezing
Common	Cough, asthma, pharyngitis, rhinorrhoea, nasal congestion, nasal passage irritation, rhinitis, throat tightness, dyspnoea, pharyngeal oedema
	Uncommon	Nasopharyngitis, bronchospasm, wheezing, hoarseness, laryngeal discomfort,
Immune system disorders	Uncommon	Systemic allergic reaction
Gastrointestinal disorders	Very common	Oedema mouth, oral pruritus
	Common	Swelling, pain or blistering of oropharynx, dyspepsia and nausea, oral hypoaesthesia or oral discomfort, oral mucosal blistering, swollen tongue or glossodynia. Lip swelling, stomatitis, gastritis, gastro-esophageal reflux, vomiting, diarrhoea
	Uncommon	Lip blister, mouth ulceration, odynophagia, oral pain, , dry mouth and dry throat, tongue disorders, salivary gland disorders, abdominal pain, dysphagia, epigastric discomfort,
Skin and subcutaneous tissue disorders	Common	Pruritus, urticaria,
	Uncommon	Angioneurotic oedema such as swollen face
General disorders and administration site conditions	Common	Fatigue
Uncommon	Chest discomfort, chest pain, chest tightness, feeling hot, malaise, pyrexia, sensation of foreign body

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 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.

Experience in children

Overall, the adverse events profile in children and adolescents treated with Grazax was similar to that observed in adults. Upper respiratory tract infections, abdominal pain, and vomiting were reported more frequently in the paediatric population than in the adult population (all common).

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. Pharmacological Properties

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.

Continuous 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 at one year follow-up).

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 IgG continuously over 3 years of treatment. 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 continuous Grazax treatment (Year 1-3) and 1 year of follow-up (Year 4) are available:

Primary Efficacy Endpoints Years 1-4

	Treatment Year 1	Treatment Year 2	Treatment Year 3	Follow up Year 4
Number of subjects in the analysis A
Grazax	282	172	160	142
Placebo	286	144	127	115
Rhinoconjunctivitis Symptom Score B
Grazax: mean (median)	2.85 (2.6)	2.40 (1.94)	2.56 (2.04)	2.68 (2.27)
Placebo: mean (median)	4.14 (3.8)	3.76 (3.45)	3.59 (3.23)	3.63 (3.27)
Difference in means
Absolute	1.29	1.36	1.04	0.95
[CI 95%]	[0.90; 1.68]	[0.86; 1.86]	[0.52;1.56]	[0.40; 1.50]
Relative to placebo (%)	31%	36%	29%	26%
[CI 95%]	[22%; 41%]	[23%; 49%]	[14%; 43%]	[11%; 41%]
p-value ANOVA	<0.0001	<0.0001	0.0001	0.0007
Difference in medians
Absolute	1.2	1.51	1.19	1.00
Relative to placebo (%)	32%	44%	37%	31%
Rhinoconjunctivitis Medication Score C
Grazax: mean (median)	1.65 (1.0)	1.74 (0.46)	1.82 (0.82)	2.32 (1.23)
Placebo: mean (median)	2.68 (2.2)	3.19 (1.71)	3.04 (2.07)	3.25 (2.58)
Difference in means
Absolute	1.03	1.45	1.22	0.93
[CI 95%]	[0.63; 1.44]	[0.75; 2.16]	[0.52;1.92]	[0.14; 1.72]
Relative to placebo (%)	39%	46%	40%	29%
[CI 95%]	[24%; 54%]	[24%; 68%]	[17%; 63%]	[4%; 53%]
p-value ANOVA	<0.0001	<0.0001	0.0007	0.0215
Difference in medians
Absolute	1.2	1.25	1.25	1.35
Relative to placebo (%)	55%	73%	60%	52%
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 and watery eyes. Rhinoconjunctivitis symptom score range was 0 – 18, the upper value indicates prolonged very severe symptoms in all mentioned categories. In the trial 95% of all recordings were 9 or less. C Medication score: Mean daily rhinoconjunctivitis medication score for each subject for the grass pollen season. Medications that could be used were loratadine (6 points per tablet), olopatadine eye drops (1.5 point per drop) (years 2-4 only), budesonide nasal spray (1 point per puff) and prednisone 5 mg (1.6 point per tablet). ). Rhinoconjunctivitis medication score range was 0 – 36, the upper value indicates prolonged need for high doses of all mentioned substances. In the trial 95% of all recordings were 11 or less.

Secondary Efficacy Endpoints Years 1-4

	Grazax Mean (Median)	Placebo Mean (Median)	Absolute Diff. Mean [CI 95%]	Relative Diff.* [CI 95%]	p-value ANOVA
Secondary Endpoints, Treatment Year 1
Number of subjects A	282	286
Quality of life score B	1.03 (0.9)	1.40 (1.4)	0.37 [0.23; 0.50]	26% [16%; 36%]	<0.0001
Global evaluation C	82%	55%	27% [20%; 34%]	49% [36%; 63%]	<0.0001
Well days D	45% (40%)	33% (22%)	12% [8%; 17%]	38% [23%; 53%]	<0.0001
Percentage of patients with more than 50% well daysD	40%	24%	16% [8%; 24%]	66% [34%; 98%]	<0.0001
Secondary Endpoints, Treatment Year 2
Number of subjects A	172	144
Quality of life score B	0.85 (0.63)	1.26 (1.05)	0.41 [0.23; 0.59]	33% [18%; 49%]	<0.0001
Well days D	49.6% (47.5%)	33.4% (26.5%)	16.2% [9.4% -22.9%]	48% [28%; 69%]	<0.0001
Percentage of patients with more than 50% well daysD	47.1%	28.5%	18.6% [7.5; 29.7]	65% [26%; 104%]	0.0008
Symptom and medication free days F	45.8% (42.6%)	31.7% (24.1%)	14.2% [6.0%; 20.5%]	45% [19%; 65%]	<0.0001
Key Secondary Endpoints, Treatment Year 3
Number of subjects A	160	127
Quality of life score B	0.78 (0.60)	1.01 (0.92)	0.23 [0.07;0.40]	23% [7%; 40%]	0.0058
Well days D	43.0% (41.0%)	30.4% (22.0%)	12.6% [5.6%; 19.7 %]	41% [18 %-65%]	0.0004
Percentage of patients with more than 50% well daysDE	43%	24%	19% (odds ratio¤ 2.4 [1.4; 4.0])	79%	0.0011#
Symptom and medication free days F	34.1% (26.6%)	24.1% (14.8%)	10.0% [3.3%;16.7%]	41.7% [14%;69%]	0.0035
Key Secondary Endpoints, 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 [0.08;0.41]	23% [7%; 38%]