Grazax 75 000 SQ-T Frystorkad tablett

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

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Bipacksedel Bipacksedel (PIL)

04-11-2020

Produktens egenskaper Produktens egenskaper (SPC)

26-09-2018

Aktiva substanser:
allergen, timotejpollen
Tillgänglig från:
Orifarm AB
ATC-kod:
V01AA02
INN (International namn):
allergen, timothy pollen
Dos:
75 000 SQ-T
Läkemedelsform:
Frystorkad tablett
Sammansättning:
allergen, timotejpollen 75000 SQ-T Aktiv substans; mannitol Hjälpämne
Receptbelagda typ:
Receptbelagt
Produktsammanfattning:
Förpacknings: Blister, 100 tabletter
Bemyndigande status:
Godkänd
Godkännandenummer:
55257
Tillstånd datum:
2017-03-22

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Bipacksedel: Information till användaren

GRAZAX 75 000 SQ-T frystorkad tablett

Standardiserat allergenextrakt från timotej (

Phleum pratense

Läs noga igenom denna bipacksedel innan du börjar ta detta läkemedel. Den innehåller

information som är viktig för dig.

Spara denna information, du kan behöva läsa den igen.

Om du har ytterligare frågor vänd dig till läkare eller apotekspersonal.

Detta läkemedel har ordinerats enbart åt dig. Ge det inte till andra. Det kan skada dem, även om

de uppvisar sjukdomstecken som liknar dina.

Om du får biverkningar, tala med läkare eller apotekspersonal. Detta gäller även eventuella

biverkningar som inte nämns i denna information. Se avsnitt 4.

I denna bipacksedel finns information om följande:

Vad Grazax är och vad det används för

Vad du behöver veta innan du tar Grazax

Hur du tar Grazax

Eventuella biverkningar

Hur Grazax ska förvaras

Förpackningens innehåll och övriga upplysningar

1.

Vad Grazax är och vad det används för

Grazax innehåller allergenextrakt av gräspollen. Grazax används för att behandla hösnuva (rinit) och

ögoninflammation (konjunktivit) orsakad av gräspollenallergi hos vuxna och barn från fem år. Grazax

påverkar den allergiska sjukdomen genom att öka immunförsvarets tolerans mot gräspollen.

Vid behandling av barn väljs patienterna ut av läkare som har erfarenhet av att behandla allergiska

sjukdomar hos barn.

Läkaren gör en utredning av dina allergiska symtom, och gör ett pricktest eller tar ett blodprov för att

bestämma om du ska bli behandlad med Grazax.

Det rekommenderas att du tar första tabletten på läkarens mottagning. Det är en försiktighetsåtgärd för

att bedöma hur känslig du är för behandlingen och ger dig möjlighet att diskutera eventuella

biverkningar med din läkare.

Grazax förskrivs av läkare med erfarenhet av behandling av allergiska sjukdomar.

2.

Vad du behöver veta innan du tar Grazax

Ta inte Grazax

om du är allergisk mot något annat innehållsämne i detta läkemedel (anges i avsnitt 6)

om du har en sjukdom som påverkar immunsystemet

om du har svår astma (enligt läkares bedömning)

om du har cancer

om du har en kraftig inflammation i munnen

Varningar och försiktighet

Tala med läkare innan du tar Grazax:

om du nyligen dragit ut en tand eller genomgått andra ingrepp i munhålan. Gör då ett avbrott i

behandlingen med Grazax under 7 dagar för att ge munhålan tid att läka

om du har allvarlig fiskallergi

om du tidigare fått en allergisk reaktion i samband med injektion av gräspollenallergen

om du har astma och en pågående akut infektion i de övre luftvägarna. Behandlingen med

Grazax bör avbrytas tillfälligt tills infektionen har avklingat.

Vissa biverkningar kan vara allvarliga och kräver omedelbar medicinsk vård. Se avsnitt 4 för symtom.

Barn

om du har tappat en mjölktand: behandling med Grazax ska upphöra i 7 dagar för att ge

munhålan tid att läka.

Om något av ovanstående stämmer in på dig skall du tala om det för din läkare innan du börjar med

Grazax.

Det finns ingen erfarenhet av behandling med Grazax hos äldre ≥ 65 år.

Andra läkemedel och Grazax

Tala om för läkare eller apotekspersonal om du tar, nyligen har tagit eller kan tänkas ta andra

läkemedel, även receptfria sådana.

Om du tar andra läkemedel mot dina allergiska besvär såsom antihistaminer eller kortikosteroider bör

din doktor utvärdera användningen av dessa läkemedel.

Grazax med mat och dryck

Ät och drick inget under fem minuter efter tablettintaget.

Graviditet, amning och fertilitet

Det finns för närvarande ingen erfarenhet av behandling med Grazax

under graviditet. Behandling med

Grazax bör inte inledas under graviditet. Om du blir gravid under behandlingen kontakta din läkare för

bedömning om fortsatt behandling är lämplig.

Det finns för närvarande ingen erfarenhet av behandling med Grazax

under amning. Grazax förväntas

dock inte påverka barn som ammas. Rådgör med din läkare före användning under amning.

Körförmåga och användning av maskiner

Du är själv ansvarig för att bedöma om du är i kondition att framföra motorfordon eller utföra arbete

som kräver skärpt uppmärksamhet. En av faktorerna som kan påverka din förmåga i dessa avseenden

är användning av läkemedel på grund av deras effekter och/eller biverkningar. Beskrivning av dessa

effekter och biverkningar finns i andra avsnitt. Läs därför all information i denna bipacksedel för

vägledning. Diskutera med din läkare eller apotekspersonal om du är osäker.

Grazax har ingen eller försumbar effekt på förmågan att framföra fordon och använda maskiner.

3.

Hur du tar Grazax

Ta alltid detta läkemedel enligt läkarens anvisningar. Rådfråga läkare eller apotekspersonal om du är

osäker.

Hur mycket Grazax du ska ta

-

Rekommenderad dos är en frystorkad tablett dagligen.

Hur du tar Grazax

-

För bäst effekt ska behandlingen starta minst 4 månader innan gräspollensäsongen förväntas

börja. Rekommenderad behandlingstid med Grazax är 3 år.

Den första dosen av Grazax ska tas på läkarmottagningen.

Det är för att du ska vara under uppsikt av vårdpersonal under cirka en halvtimme efter första

tablettintaget.

Det är en försiktighetsåtgärd för att kontrollera hur känslig du är för läkemedlet.

Det är även ett tillfälle för dig att diskutera eventuella biverkningar med läkaren.

Fortsätt att ta Grazax varje dag - även om det tar ett tag innan din allergi förbättras.

Om dina allergisymtom inte avtar under den första gräspollensäsongen ska du kontakta läkare för att

diskutera den fortsatta behandlingen.

Dina händer måste vara helt torra innan du handskas med tabletterna.

Tabletterna skall tas på följande sätt:

1. Riv av fliken som är markerad med trekanter på toppen av förpackningen.

2. Riv av en ruta från förpackningen längs de streckade linjerna.

3. Vik tillbaka folien från det markerade hörnet och dra sedan av folien.

- Tryck inte tabletten genom folien - den går lätt sönder.

4. Avlägsna försiktigt tabletten från folien och lägg den omedelbart under tungan.

5. Låt tabletten ligga under tungan tills den lösts upp.

- Undvik att svälja under 1 minut.

- Ät eller drick inget under minst 5 minuter efter att du tagit tabletten.

Om du har tagit för stor mängd av Grazax

Om du fått i dig för stor mängd läkemedel eller om t.ex. ett barn fått i sig läkemedlet av misstag

kontakta läkare, sjukhus eller Giftinformationscentralen (tel. 112) för bedömning av risken samt

rådgivning.

Om du tagit för stor mängd Grazax tabletter kan du få allergiska symtom såsom lokala symtom i mun

och hals.

Om du har glömt att ta Grazax

Har du glömt att ta en tablett, kan du ta den senare samma dag. Ta inte dubbel dos för att kompensera

för glömd tablett.

Om du slutar att ta Grazax

Om du inte tar det här läkemedlet som ordinerat är det möjligt att du inte får effekt av behandlingen.

Om du har ytterligare frågor om detta läkemedel kontakta läkare eller apotekspersonal.

4.

Eventuella biverkningar

Liksom alla läkemedel kan detta läkemedel orsaka biverkningar, men alla användare behöver inte få

dem.

Biverkningarna kan vara en allergisk reaktion på det allergen du behandlas med. Reaktionerna varar i

allmänhet minuter till timmar efter intag av

tabletten

och avtar oftast spontant inom en vecka efter det

att behandlingen påbörjats.

Allvarliga biverkningar:

Sluta att ta Grazax och kontakta omedelbart läkare eller sjukhus om du får något av följande symtom

hastigt uppkommen svullnad av ansikte, mun eller hals

svårigheter att svälja

svårigheter att andas

nässelutslag

förändringar av rösten

försämring av existerande astma

svår olustkänsla

Om du får ihållande halsbränna bör du kontakta din läkare.

Andra möjliga biverkningar:

Mycket vanliga (kan förekomma hos fler än 1 av 10 användare):

svullnad i munnen

klåda i munnen eller öronen

irriterande känsla i halsen

Vanliga (kan förekomma hos upp till 1 av 10 användare):

stickande känsla eller domningar i munnen

klåda i ögon, läppar eller näsa

inflammation i ögon eller mun

andnöd, hosta eller nysningar

torrhet i halsen

rinnande näsa

svullnad av ögon eller läppar

sår i munnen

blåsbildning, smärta eller obehag från mun eller hals

magsmärta, diarré, illamående, kräkningar

halsbränna

klåda, utslag eller nässelutslag

trötthet

obehag i bröstet

trånghet i halsen

rodnad i munnen

svårigheter att svälja

Mindre vanliga (kan förekomma hos upp till 1 av 100 användare):

känsla av snabba, kraftiga eller oregelbundna hjärtslag

smakförändring

röda eller irriterade ögon

smärta eller obehag i öronen

känselbortfall i halsen, smärta vid sväljning

förstorade halsmandlar

allvarlig allergisk reaktion

muntorrhet

blåsor på läpparna, läppinflammation, sår på läpparna

förstorade salivkörtlar eller ökad salivproduktion

inflammation i magen, uppstötningar

känsla av främmande föremål i halsen

hudrodnad

svullnad av ansikte

inflammation i tungan

allergisk reaktion

stickande känsla i huden

obehag i magen

svullnad i halsen

tårflöde

heshet

rodnad i halsen

blåsor i munnen

Sällsynta (kan förekomma hos upp till 1 av 1000 användare):

sammandragning av nedre luftvägarna

svullna öron

Ögonirritation, rodnad i halsen, blåsor i munnen, smärta i öronen och svullna öron förekommer oftare

hos barn än hos vuxna.

Om du får besvärliga biverkningar, kontakta din läkare som kan avgöra om du behöver ta

symtomlindrande allergimediciner, t.ex. antihistaminer.

Rapportering av biverkningar

Om du får biverkningar, tala med läkare eller apotekspersonal. Detta gäller även eventuella

biverkningar som inte nämns i denna information. Du kan också rapportera biverkningar direkt (se

detaljer nedan). Genom att rapportera biverkningar kan du bidra till att öka informationen om

läkemedels säkerhet.

Läkemedelsverket

Box 26

751 03 Uppsala

www.lakemedelsverket.se

5.

Hur Grazax ska förvaras

Förvara detta läkemedel utom syn- och räckhåll för barn.

Används före utgångsdatum

som anges på blisterförpackningen och kartongen efter EXP.

Utgångsdatumet är den sista dagen i angiven månad.

Detta läkemedel kräver inga särskilda förvaringsanvisningar.

Läkemedel ska inte kastas i avloppet eller bland hushållsavfall. Fråga apotekspersonalen hur man

kastar läkemedel som inte längre används. Dessa åtgärder är till för att skydda miljön.

6.

Förpackningens innehåll och övriga upplysningar

Innehållsdeklaration

Den aktiva substansen är SQ standardiserat allergenextrakt av pollen från timotej (

Phleum

pratense

). Aktiviteten per tablett uttrycks i enheten SQ-T*, en tablett innehåller 75 000 SQ-T.

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

Övriga innehållsämnen är gelatin (från fisk), mannitol och natriumhydroxid.

Läkemedlets utseende och förpackningsstorlekar

Vit till benvit rund frystorkad tablett märkt med en cirkel på ena sidan.

Blisterförpackningar av aluminium med avdragbar aluminiumfolie i en ytterkartong.

Varje blisterförpackning innehåller 10 frystorkade tabletter.

Följande förpackningar finns: 30 (3x10), 90 (9x10) eller 100 (10x10) frystorkade tabletter.

Eventuellt kommer inte alla förpackningsstorlekar att marknadsföras.

Innehavare av godkännande för försäljning

ALK-Abelló A/S

Bøge Allé 6-8

2970 Hørsholm

Danmark

Tillverkare

ALK-Abelló S.A.

Miguel Fleta 19

28037 Madrid

Spanien

Information lämnas av

ALK Nordic A/S, Danmark Filial

tfn: 0300 – 185 45

e-post: infose@alk.net

Denna bipacksedel ändrades senast 2020-06-08

Läs hela dokumentet

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 (

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.

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.

Grazax treatment should only be initiated by physicians with experience in treatment of allergic diseases

and the capability to treat allergic reactions.

Elderly population

Clincial 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 oral 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 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: FEV

< 70% of predicted value after adequate

pharmacologic treatment, in children: FEV

< 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.

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

Common

Eye pruritus, conjunctivitis, eye swelling

Eye disorders

Uncommon

Ocular hyperaemia, eye irritation, lacrimation increased

Very common

Ear pruritus

Ear and labyrinth

disorders

Uncommon

Ear discomfort, ear pain

Rare

Ear swelling

Cardiac disorder

Uncommon

Palpitations

Respiratory,

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

thoracic and

mediastinal

disorders

Rare

Bronchospasm

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

Gastrointestinal

disorders

Rare

Eosinophilic oesophagitis

Common

Pruritus, urticaria, rash

Skin and

subcutaneous

tissue disorders

Uncommon

Angioedema, erythema

Common

Fatigue, chest discomfort

General disorders

and administration

site conditions

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 national reporting system listed in Appendix V*.

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-

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.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Allergen extracts, Grass pollen.

ATC code: V01AA02.

Mechanism of action

Grazax is allergy immunotherapy. Allergy immunotherapy with allergen products is the repeated

administration of allergens to allergic individuals with the purpose of modifying the immunological

response to the allergen, providing sustained relief of symptoms, less need for medication, and

improvement in quality of life during subsequent natural allergen exposure.

Grazax is disease-modifying treatment of grass pollen induced rhinitis and conjunctivitis for patients with

clinically relevant symptoms. Disease modification in adults and children is demonstrated by sustained

post-treatment effect on rhinoconjunctivitis observed 2 years after 3 years of treatment with Grazax.

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

over 3 years of treatment. 2 years after completed Grazax treatment

the increase in specific IgG

was still present. The clinical significance of these findings has not been

established.

Clinical efficacy and safety in adults

The efficacy of Grazax once-daily on rhinoconjunctivitis was evaluated in a randomised, double-blind,

placebo controlled multi-national trial (GT-08), including 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.

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 of 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). 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.

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) in adults are

available in table 2 and table 3.

Table 2. Primary efficacy endpoints years 1-5 in adults

Treatment

Year 1

Treatment

Year 2

Treatment

Year 3

Follow up

Year 4

Follow up

Year 5

Number of subjects in the

analysis

Grazax

Placebo

Rhinoconjunctivitis Symptom Score

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

[0.90; 1.68]

[0.86; 1.86]

[0.52;1.56]

[0.40; 1.50]

[0.28; 1.41]

Relative to placebo (%)

[22%; 41%]

[23%; 49%]

[14%; 43%]

[11%; 41%]

[9%; 37%]

p-value ANOVA

<0.0001

<0.0001

0.0001

0.0007

0.0037

Difference in medians

Absolute

1.51

1.19

1.00

0.97

Relative to placebo (%)

Rhinoconjunctivitis Medication Score

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

[0.63; 1.44]

[0.75; 2.16]

[0.52;1.92]

[0.14; 1.72]

[-0.15; 1.38]

Relative to placebo (%)

[24%; 54%]

[24%; 68%]

[17%; 63%]

[4%; 53%]

[-8%; 40%]

p-value ANOVA

<0.0001

<0.0001

0.0007

0.0215

0.1136

Difference in medians

Absolute

1.25

1.25

1.35

0.44

Relative to placebo (%)

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.

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.

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 2-5 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.

Table 3. Secondary efficacy endpoints years 1-5 in adults

Grazax

Mean

(Median)

Placebo

Mean

(Median)

Absolute Diff.

Mean

Relative

Diff.*

p-value

ANOVA

Treatment Year 1

Number of subjects

Quality of life score

1.03

(0.9)

1.40

(1.4)

0.37

[0.23; 0.50]

[16%; 36%]

<0.0001

Global evaluation

[20%; 34%]

[36%; 63%]

<0.0001

Well days

(40%)

(22%)

[8%; 17%]

[23%; 53%]

<0.0001

Percentage of patients

with more than 50%

well days

[8%; 24%]

[34%; 98%]

<0.0001

Treatment Year 2

Number of subjects

Quality of life score

0.85

(0.63)

1.26

(1.05)

0.41

[0.23; 0.59]

[18%; 49%]

<0.0001

Well days

49.6%

(47.5%)

33.4%

(26.5%)

16.2%

[9.4% -22.9%]

[28%; 69%]

<0.0001

Percentage of patients

with more than 50%

well days

47.1%

28.5%

18.6%

[7.5; 29.7]

[26%; 104%]

0.0008

Symptom and

medication free days

45.8%

(42.6%)

31.7%

(24.1%)

14.2%

[6.0%; 20.5%]

[19%; 65%]

<0.0001

Treatment Year 3

Number of subjects

Quality of life score

0.78

(0.60)

1.01

(0.92)

0.23

[0.07;0.40]

[7%; 40%]

0.0058

Well days

43.0%

(41.0%)

30.4%

(22.0%)

12.6%

[5.6%; 19.7 %]

[18%; 65%]

0.0004

Percentage of patients

with more than 50%

well days

(odds ratio

2.4 [1.4; 4.0])

0.0011

Symptom and

medication free days

34.1%

(26.6%)

24.1%

(14.8%)

10.0%

[3.3%;16.7%]

41.7%

[14%; 69%]

0.0035

Follow-up, Year 4

Number of subjects

Quality of life score

0.82

(0.64)

1.07

(0.97)

0.25

[0.08;0.41]

[7%; 38%]

0.0041

Well days

50.0%

(51.9%)

38.1%

(31.6%)

11.9%

[4.4%;19.4%]

[12%; 50%]

0.0020

Percentage of patients

with more than 50%

well days

53.1%

34.0%

19.1%

(odds ratio

2.2 [1.3; 3.7])

0.0031

Symptom and

medication free days

35.2%

(25.7%)

27.6%

(17.2%)

7.6%

[0.41%; 14.8%]

[1%; 54%]

0.0384

Follow-up, Year 5

Number of subjects

Quality of life score

0.69

(0.56)

0.85

(0.85)

0.16

[-0.01; 0.33]

[-2%; 38%]

0.0587

Well days

49.7%

(51.1%)

40.0%

(32.9%)

9.74%

[1.5%; 17.9%]

[3%; 52%]

0.0203

Percentage of patients

with more than 50%

well days

49.5%

35.0%

14.5%

(odds ratio

1.8 [1.1; 3.1])

0.0280

Symptom and

medication free days

33.5%

(25.9%)

28.0%

(18.2%)

5.5%

[-2.4%; 13.4%]

[-8%; 57%]

0.1737

* Relative difference = |Absolute difference|/Placebo; ¤ odds ratio for having excellent control; # p-

value for the odds ratio.

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.

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.

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.

Well days: percentage of days where the subjects did not use any rescue medication and had a

symptom score not larger than 2.

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.

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).

Paediatric population

The short term efficacy of Grazax on rhinoconjunctivitis has been investigated in a randomised, double-

blind, placebo controlled trial (GT-12) including 238 children (5–16 years) with grass pollen induced

rhinoconjunctivitis with/without asthma. Patients received treatment prior to the grass pollen season and

continued throughout the entire season (table 4).

The long term efficacy of Grazax has been investigated in a randomised, double-blind, placebo-controlled,

multinational trial (GT-21) including 812 children (5-12 years) with a clinically relevant history of grass

pollen allergic rhinoconjunctivitis and no medical history of asthma.

Daily treatment with Grazax for 3 years resulted in a sustained post-treatment effect on rhinoconjunctivitis

symptoms. The effect on rhinoconjunctivitis symptoms was evident when assessed during the entire 5-

year trial period, during the 2-year follow-up period after completion of treatment and at end of trial. Data

on the clinical efficacy are shown in table 4.

Table 4. Efficacy of Grazax on rhinoconjunctivitis in children

Grazax

Placebo

Absolute

Diff.

[CI

95%

]

Relative Diff.*

(%)

[CI

95%

]

p-value

GT-12

Number of subjects

included in the analysis

Primary endpoints

Rhinoconjunctivitis

symptom score

2.18

2.80

0.62

[0.10; 1.15]

[4%; 38%]

0.0215

Rhinoconjunctivitis

medication score

0.78

1.19

0.41

0.0156

Key Secondary endpoints

Rhinoconjunctivitis

symptom score

, peak

grass pollen season

2.84

3.91

1.07

[0.32; 1.81]

[9%; 43%]

0.0059

Rhinoconjunctivitis

medication score

, peak

grass pollen season

0.87

2.40

1.53

0.0013

Well days

[ 1%; 17%]

[3%; 45%]

0.0225

GT-21

Number of subjects

included in the full

analysis set

Secondary endpoint: Yearly rhinoconjunctivitis symptoms

D

during grass pollen season

Treatment Year 1

19.4

25.5

[2.7; 9.4]

<0.001

Treatment Year 2

20.3

28.8

[5.0; 11.9]

<0.001

Treatment Year 3

21.9

31.1

9.23

[5.7; 12.8]

<0.001

Follow-up, Year 4

23.5

30.3

[3.1; 10.3]

<0.001

Follow-up, Year 5

19.6

25.5

[2.2; 9.4]

0.002

Secondary endpoint: Daily rhinoconjunctivitis symptoms

E

during grass pollen season

Follow-up, Year 5

15.2

19.5

[1.35; 7.40]

0.005

Secondary endpoint: Daily rhinoconjunctivitis medication score

F

during grass pollen season

Follow-up, Year 5

[0.9; 2.7]

<0.001

* Relative difference = |Absolute difference|/Placebo.

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.

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.

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.

Symptoms measured by yearly VAS score: Visual analogue scale score describing ‘how the subject’s

hay fever has been the last week’, on a 100 mm scale from no symptoms to severe symptoms, assessed

once. Parametric analysis, relative difference of adjusted means.

Symptoms measured by daily VAS score: Mean daily visual analogue scale score of ‘how the subject’s

hay fever has been today?’, on a 100 mm scale from no symptoms to severe symptoms, during a 14-day

period. Parametric analysis (square-root-transformed data), relative difference of back-transformed,

adjusted means.

Medication score: Mean daily rhinoconjunctivitis medication score during a 14-day period. Parametric

analysis (square-root-transformed data), relative difference of back-transformed, adjusted means.

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 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. In a

combined fertility and embryo-foetal development study in mice, mating performance and fertility were

unaffected, and there were no adverse foetal findings. In a pre-/postnatal development study, mouse

development was normal.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Gelatine (fish source)

Mannitol

Sodium hydroxide (for pH adjustment)

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

5 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 (3x10) oral lyophilisates, 90 (9x10) oral lyophilisates and 100 (10x10) oral lyophilisates.

Not all pack sizes may be marketed.

6.6

Special precautions for disposal

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

requirements.

7.

MARKETING AUTHORISATION HOLDER

ALK-Abelló A/S

Bøge Alle 6-8

2970 Hørsholm

Denmark

8.

MARKETING AUTHORISATION NUMBER(S)

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

14 March 2006

10.

DATE OF REVISION OF THE TEXT

2020-04-16

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