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Allergen extracts Indications & contraindications

Immunotherapy

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Protocols with one allergen or a mixture of related allergens Protocols with unrelated allergens Switch protocols

Protocols

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Safety aspects and Patient follow-up

Safety aspects Patient follow-up

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Stallergenes' therapeutic ranges

Delivery process Product for sublingual immunotherapy Products for subcutaneous immunotherapy

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Good practices for skin prick tests Methodology Cross-reacting allergens Stallergenes' ranges for skin prick tests

Allergy skin prick tests

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Hymenoptera venom immunotherapy

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Indications Contraindications Special warnings Precautions for use Protocols Adverse effects Stallergenes' ranges

List of available allergen extracts and references

Immunotherapy

I. ALLERGEN EXTRACTS

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1.1

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The quality of allergen extracts is highly dependent on the raw material quality which must meet high standards and be sourced and processed in accordance with regulatory requirements. In this way Stallergenes carries out a careful selection and follow-up of raw material suppliers: highly documented dossiers are required to make sure of the identity, purity and origin of the raw material, hence ensuring its whole traceability as well as maximising safety for the final extract. Regarding mites raw material, Stallergenes has developed and patented a culture medium in line with the European Pharmacopoeia: Stalmite APF®. Stalmite APF®* is a standardised nutritive medium totally free of animal protein, stable in the conditions of temperature and hygrometry favourable to the growth of mites. Hence, Stallergenes ensures the pharmaceutical quality and safety of its mites extracts with the exclusion of any risk of viral or prion contamination as well as the absence of residual allergenicity from the culture medium.

>> Raw material

Raw material & standardisation

1.2

Being of natural origin, the composition and concentration of allergens in the raw material are likely to vary between batches (for example, pollen composition may vary according to the year it is harvested). The standardisation of allergen extracts guarantees the consistency from batch to batch by adjusting inherent variations in biological activity between batches. The standardised allergens are quantified in IR/mL. IR: Index of Reactivity: An allergen extract is attributed a value of 100 IR/mL when it induces a mean 7 mm wheal diameter in a skin prick test using a Stallerpoint® needle in 30 subjects sensitised to the allergen in question. The reactivity of the subjects is also demonstrated by a positive response to a skin prick test with Codeine Phosphate (9%) or Histamine (10 mg/mL).

>> Standardisation: IR: Index of Reactivity

The units used for the standardisation are not universal as each manufacturer of allergen extracts sets up its internal system of standardisation. 1.3

Standardisation of all allergen extracts is not always possible, especially in the case of rare allergens for which it is difficult to find mono-sensitised patients. These allergens are quantified in IC/mL. IC: Index of Concentration: An allergen extract is considered to have a value of 100 IC/mL when the manufacturing parameters result in the same mean dilution ratio as that of standardised extracts from the same group with a value of 100 IR/mL and which are used as reference standards. For groups not having a standardised reference extract, a value of 100 IC/mL corresponds to an extract for which the dilution ratio has been established by clinical experience.

>> IC: Index of Concentration

Allergen extracts are used for diagnosis and specific treatment of allergic diseases.

*APF: Animal Protein Free

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2

Allergens for immunotherapy

WHO POSITION PAPER1: Standardised allergens should be used whenever possible.

>> Already validated by controlled studies :

SPECIFIC IMMUNOTHERAPY POLLENS Grasses Trees Weeds D. pteronyssinus D. farinae Storage mites Blomia Cat Dog Alternaria Cladosporium

MITES

EPITHELIA MOULDS

For other allergens refer to pages 38 to 41.

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Recommendations for allergen mixtures

WHO POSITION PAPER1: Mixtures of unrelated allergens are not recommended.

A - Allergen mixtures

ALLERGENS POLLENS MITES EPITHELIA MOULDS related allergens, mixture possible POLLENS MITES EPITHELIA MOULDS unrelated allergens, mixture not recommended by WHO

1 Source: Bousquet J., Lockey R.F., Malling H-J.; WHO Position paper: Allergen immunotherapy: therapeutic vaccines for allergic diseases. Allergy. 1998; 44, vol.53.

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B - Mixtures with related allergens

A reference can be either a single allergen or a mixture of several related allergens with a high degree of cross-reactivity. Stallergenes does not recommend to mix more than 5 of those references.

>> Stallergenes recommendations:

II. INDICATIONS & CONTRAINDICATIONS

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1.1

Type I allergies (Gell and Coombs classification) mainly comprise rhinitis, conjunctivitis, rhinoconjunctivitis, or asthma of a seasonal or perennial nature. The goal of specific immunotherapy (SIT) is to prevent the clinical consequences of a contact between sensitised subjects and the allergen when aetiological factors have been clearly identified.

>> Therapeutic indications

Indications

1.2

>> Indications in allergic rhinitis: according to ARIA position paper

ARIA POSITION PAPER2 mild intermittent symptoms SPECIFIC IMMUNOTHERAPY Sublingual route Subcutaneous route not recommended

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moderate / severe intermittent symptoms mild persistent symptoms moderate / severe persistent symptoms indicated

1.3

>> Indications in allergic asthma: according to WHO position paper

WHO POSITION PAPER 19983 GRADE OF ASTHMA SEVERITY SPECIFIC IMMUNOTHERAPY Sublingual route Subcutaneous route not recommended indicated not indicated

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GRADE 1: intermittent GRADE 2: mild persistent GRADE 3: moderate persistent GRADE 4: severe persistent

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2 Source: Allergic Rhinitis and its Impact on Asthma (ARIA). Workshop Report. J Allergy Clin Immunol 2001; 108: S147-336. 3 Source: Bousquet J., Lockey R.F., Malling H-J.; WHO Position paper: Allergen immunotherapy: therapeutic vaccines for allergic diseases. Allergy. 1998; 44, vol.53.

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2.1

Contraindications

A - For both subcutaneous and sublingual SIT

Serious immuno-pathological and immunodeficiency diseases; Active cancer (malignancy which has been controlled for some years does not represent a contraindication); Severe psychological disorders; Treatment with -blockers in any form; Severe asthma uncontrolled by pharmacotherapy and/or patients with irreversible airways obstruction (FEV1 is consistently under 70% of predicted values after adequate pharmacological treatment); Significant cardiovascular diseases which increase the risk of side effects from adrenaline; Poor compliance.

>> General contraindications

B - Additional contraindications specific to sublingual SIT

Persistent lesions of the buccal mucosa: ulcers, erosive lichen; Persistent periodontal diseases.

2.2

A - For both subcutaneous and sublingual SIT

Age: children under 5 years of age; Pregnancy is not considered as a contraindication for the continuation of well tolerated immunotherapy but treatment should not be initiated during pregnancy.

>> Relative contraindications

These relative contraindications do not apply to immunotherapy in case of allergy to hymenoptera venom, given its potentially life-threatening nature. 2.3

A - For both subcutaneous and sublingual SIT

Unstable asthma; Any other unstable allergic manifestation (deteriorating rhinitis, generalised urticaria, etc.); Fever; Vaccination (do not administer immunotherapy on the same day).

>> Temporary contraindications

B - Additional temporary contraindications specific to sublingual SIT

Open wound in the mouth; Recent dental extraction / avulsion / care; Bloody gingivitis.

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Protocols

I. PROTOCOLS WITH ONE ALLERGEN OR A MIXTURE OF RELATED ALLERGENS

1 Sublingual immunotherapy (SLIT)

2

The protocols indicated may be adapted to the reactivity of each individual.

1.1

Duration 11 days

>> BUILD-UP PHASE:

10 IR/mL

>> Staloral 300

®

10 doses

For available standardised allergens: 300 IR/mL

8 doses

8 doses

300 IR/mL

6 doses 6 doses

4 doses

4 doses

2 doses 1 dose

Day 1 Day 2 Day 3 Day 4 Day 5 Day 6

2 doses 1 dose

Day 7 Day 8 Day 9 Day 10 Day 11

Recommended minimal maintenance dose: 8 doses 3 times a week or 4 doses every day.

NB: In case of a maintenance dose of 4 doses every day: stop the build-up phase on day 9 and continue directly with the maintenance dose from day 10.

>> MAINTENANCE PHASE:

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1.2

Duration 11 days

>> BUILD-UP PHASE:

>>

Staloral®

For non-standardised allergens, allergens not available in 300 IR/mL and very reactive patients: 100 IR/mL or IC/mL.

10 doses

10 IR/mL or IC/mL

8 doses

100 IR/mL or IC/mL

8 doses

6 doses

6 doses

4 doses

4 doses

2 doses 1 dose

Day 1 Day 2 Day 3 Day 4 Day 5 Day 6

2 doses 1 dose

Day 7 Day 8 Day 9 Day 10 Day 11

Repeat the maximum tolerated dose 3 times a week or every day.

>> MAINTENANCE PHASE:

Stallergenes recommendations for sublingual immunotherapy: BUILD-UP PHASE Pollens:

· Start if possible 3 to 2 months before the pollen season.

MAINTENANCE PHASE Mites, Animal danders & Moulds: Pollens:

· Perennial treatment at least during 3 to 5 years. · During the pollen season it is normally not necessary to reduce the maintenance dose; · Treatment should be maintained during at least 3 to 5 consecutive seasons.

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1.3

>> Pre & co-seasonal protocol for sublingual immunotherapy

with Staloral300 ® to pollens The protocol indicated may be adapted to the reactivity of each patient.

1st year: Start the build-up phase if possible 2 or 3 months before the pollen season according to the build-up phase protocol. Continue the maintenance phase all through the pollen season (2 to 4 months) and stop at the end of the pollen season. 2 the treatment if 2 or 3 restarting with >> doseyear: Reinitiatemaintenance vial.possiblecontinuemonths before the pollen seasonalong the pollen the escalation of the Then, with the maintenance dose all

nd

>>

season (2 to 4 months) and stop at the end of the season.

>> 3

rd

year and eventually 4th and 5th years: Repeat the same protocol as for the 2

nd

year.

Start on Day 1: if possible 2 to 3 months before the pollen season

Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day 9 Day 10 Day 11 10 IR/mL Number of doses 300 IR/mL Number of doses ... and all through the pollen season

Year 1

1

2

4

6

8

10 8 doses 3 times a week or 4 doses every day (stop at the end of the pollen season)

1

2

4

6

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Year 2 - Year 3 and eventually Year 4 and Year 5

Start on Day 1: if possible 2 to 3 months before the pollen season

Day 1 Day 2 Day 3 Day 4 Day 5 300 IR/mL Number of doses ... and all through the pollen season 8 doses 3 times a week or 4 doses every day (stop at the end of the pollen season)

1

2

4

6

8

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2 Subcutaneous immunotherapy (SCIT) Phostal® - Alustal®

The protocols indicated may be adapted to the reactivity of each patient.

>> BUILD-UP PHASE:

1 injection weekly during 3 to 4 months 0.8 mL 0.8 mL 0.8 mL

0.1 IR or IC/mL

0.4 mL

1 IR or IC/mL

0.4 mL

10 IR or IC/mL

0.4 mL

0.6 mL

0.2 mL 0.1 mL

Week 1 Week 2 Week 3 Week 4

0.2 mL 0.1 mL

Week 5 Week 6 Week 7 Week 8

0.2 mL 0.1 mL

Week 9 Week 10 Week 11 Week 12 Week 13

The maximum tolerated dose is renewed every 15 days, then every month or more, though the interval between 2 injections must not exceed 6 weeks. General recommended maintenance dose: 1 injection/ month of the maximal tolerated dose.

>> MAINTENANCE PHASE:

Stallergenes recommendations for SCIT: BUILD-UP PHASE Pollens:

· In case of hypersensitive patients, start the build-up regimen with the 0.01 IR/mL or IC/mL concentration. · Always start the build-up phase at least 4 months before the pollen season.

MAINTENANCE PHASE

· The maintenance phase must be sustained for at least 3 to 5 years; · Interval between 2 maintenance injections must not exceed 6 weeks; · For safety reasons, when starting a new maintenance vial: Inject only half of the usual maintenance dose and, if well tolerated, revert to the full maintenance dose for the next injection.

Pollens:

· During the pollen season: Inject only half of the usual maintenance dose and revert to the full maintenance dose at the end of the pollen season.

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II. PROTOCOLS WITH UNRELATED ALLERGENS

1 Sublingual route

In case of 2 simultaneous SIT courses by sublingual route, and in order to be able to determine which allergen is in cause in the event of an adverse reaction, we recommend to advise your patient to take each treatment on the other day. DAY 1 Allergen A DAY 2 Allergen B

2

Subcutaneous route

In case of 2 simultaneous SIT courses by subcutaneous route, and in order to be able to determine which treatment is in cause in the event of an adverse reaction, we recommend: - to inject the 2 treatments in the 2 different arms; - to wait at least for 30 minutes between the 2 injections.

1st injection Allergen A

2nd injection (on the opposite arm)

30 min after

Allergen B

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III. SWITCH PROTOCOLS

1 From subcutaneous route to sublingual route

SUBCUTANEOUS ROUTE Build-up phase Maintenance phase SUBLINGUAL ROUTE

Switch to the maintenance vial starting from 1 till 8 doses daily and continue following the maintenance protocol.

2

From sublingual route to subcutaneous route

SUBLINGUAL ROUTE Build-up phase Maintenance phase SUBCUTANEOUS ROUTE

Start the subcutaneous protocol from the very beginning.

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Safety aspects and patient follow-up

I. SAFETY ASPECTS

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1.1

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Sublingual immunotherapy

Undesirable effects are rare but may nevertheless signal a need for caution.

>> Side effects >>

1.1.1 Characteristics A - Local reactions

These reactions are common and mainly observed during the build-up phase. Pruritus in the mouth and/or on the lips; A burning feeling around the mouth and lips; Lips or sublingual oedema; Gastrointestinal: abdominal pain and diarrhoea.

B - Systemic reactions

Rhinoconjunctivitis; Asthma.

Both the frequency and the characteristics of side effects are the same in children and adults. 1.1.2

In case of mild local reactions: - For a unique episode with spontaneous improvement: continue with no change; - For repeated episodes: return to the previous well tolerated dose then increase day after day until the full dose. In case of mild-to-moderate local and systemic reactions: - Step back to the previous well tolerated dose for two days, then resume the stepping up procedure. In case of severe local and systemic reactions: - Suspend administration for 48 hours; - If the symptoms regress after discontinuation, resume administration at half the last dose and recommence the step-up procedure; - If the symptoms fail to regress even once the treatment has been discontinued, investigate possible alternative causes because it is unlikely that it is the SIT that is responsible for the reaction. Resume SIT.

>> What to do in case of adverse reaction?

In the event of pruriginous manifestations, prescribe an antihistamine.

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2

Subcutaneous immunotherapy

International recommendations together with Good Medical Practices guidelines stipulate that injection of the allergen extract should be carried out by a physician or by a nurse under the supervision of a physician. There should always be an emergency kit on hand.

2.1

1. 2. 3. 4. 5. 6.

>> Equipment recommended for settings where subcutaneous

immunotherapy is administered

Injectable Adrenaline, HCl 1 mg/mL; Equipment for administering oxygen; Equipment for administering intravenous fluids; Antihistamines: oral and for injection; Salbutamol or terbutaline: in spray form (+ spacer) or in solution for nebulisation; Oral or intravenous corticosteroids.

The proper use of these reagents and equipment by appropriately trained personnel should provide effective initial treatment for most, if not all, systemic reactions to allergen vaccines. The prompt recognition of systemic reactions and the immediate use of adrenaline are the mainstays of therapy.

2.2

>> Good clinical practices

A - Before the injection

Check the emergency kit (see details above) Check the patient's condition: Inquire about: - Any reaction that might have followed the last injection; - Any event that might be relevant (infection or an asthma attack or an exacerbation of allergic symptoms); - Any drugs taken in the interval. Patients taking -blockers (including local treatment) should not receive immunotherapy; - Check that PEFR reading is > 80% of "personal best" for patients with asthma. Check the vial: - Correct allergen composition, concentration and expiry date; - Check the dose to be administered by comparing it to the previous dose and the dosage schedule. When should the maintenance dose be reduced? - When starting a new maintenance vial: Inject only half of the usual maintenance dose and, if well tolerated, revert to the full maintenance dose for the next injection; - During the pollen season: Inject only half of the usual maintenance dose and revert to the full maintenance dose at the end of the pollen season.

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B - The injection itself

Check the interval since last injection; Use a disposable 1 mL syringe (with 1/100 graduations); Shake the vial and, using regular aseptic technique, aspirate the exact volume to be administered; Administration by strict deep subcutaneous route in the lower deltoid region of the arm or in the upper thigh. Always draw back on the syringe to ensure that the needle has not entered a blood vessel.

C - After the injection

Keep the patient under medical observation for 30 minutes after the injection: A longer waiting period is necessary for high-risk patients (e.g. high degree of hypersensitivity); The injection site has to be inspected before the patient leaves the doctor's office / clinic; Advise the patient to avoid strenuous exercise, hot baths and sauna for the rest of the day; Advise the patient to consult the physician or call for emergency assistance in case of severe delayed reaction. Record all the details of the injection in the case notes or desensitisation booklet.

The maintenance phase appears to be associated with fewer systemic reactions than the build-up phase. D - Most current risks with the use of subcutaneous immunotherapy

Errors in dosage; Presence of symptomatic asthma; High degree of hypersensitivity; Injections from new vials; Injections made during periods of exacerbation of symptoms.

E - When postpone an injection ?

(Please refer to page 7 ­ «Temporary contraindications») In case of intercurrent disease: Treat the symptoms and make the SIT injection after recovery. In case of vaccination: Vaccinations against infectious diseases should be scheduled on a different day than SIT injections.

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>> Side-effects 2.3.1 >> Characteristics

2.3 A - Local reactions

Local reactions occur at the injection site: · Flare and oedema; · Subcutaneous nodules (only for extracts adsorbed on Aluminium Hydroxide). They can be divided into reactions that occur within 20-30 min and those that occur later than 30 min after the injection. Local reactions can cause patient discomfort.

Large local reactions do not predict the onset of a subsequent systemic reaction. B - Systemic reactions

Systemic reactions are characterised by generalised signs and/or symptoms occurring away from the injection site. Such reactions usually begin within a few minutes after the injection and more rarely after 30 min.

1) Non-specific reactions: Reactions probably not IgE-mediated; i.e. discomfort, headache, arthralgia, etc. 2) Mild systemic reactions: Mild rhinitis and/or asthma (PEFR - Peak Expiratory Flow Rate - over 60% of expected or of personal best values) responding adequately to antihistamines or inhaled ß2-agonists. 3) Non-life-threatening systemic reactions: Urticaria, angioedema, or severe asthma (PEFR under 60% of expected or of personal best values) responding well to treatment. 4) Anaphylactic shock: Rapidly evoked reaction of itching, flushing, erythema, bronchial obstruction, etc. requiring intensive treatment.

EAACI grading4:

4 Source: Malling H-J., Weeke B. EAACI Position Paper. Immunotherapy. Allergy. 1993; 14, vol. 48: 9-30.

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2.3.2

>> What to do in case of an adverse reaction?

TREATMENT OF THE ADVERSE REACTION WHAT ABOUT SIT CONTINUATION? SMALL LOCAL REACTIONS

TYPE OF REACTION

REACTIONS AT THE SITE OF THE INJECTION

(diameter < to 5 cm in adults or < to 3 cm in children)

Apply an ice-bag on the local reaction.

Continue SIT without any change.

(diameter to 5 cm in adults or to 3 cm in children)

LARGE LOCAL REACTIONS

Oedema and urticaria: Oral corticosteroids: 2 mg/kg up to 60 mg/day for 2 or 3 days; Oral H1-Antihistamines.

Build-up phase: For the next injection: repeat the previous well tolerated dose, and, if there is no adverse reaction, continue the dose escalation for the next injections. Maintenance phase: For the next injection: inject only half of the usual maintenance dose, and, if well tolerated, revert to the full maintenance dose for the next injections.

Moderate rhinitis / Moderate urticaria: Oral corticosteroids: 2 mg/kg up to 60 mg/day for 2 or 3 days; H1-Antihistamines.

MODERATE SYSTEMIC REACTIONS

REACTIONS AWAY FROM THE SITE OF THE INJECTION

Moderate asthma (bronchospasm or a drop 20% in the predictive PEFR associated or not with coughing or respiratory distress): 2 puffs of a short-acting 2-agonist (to be repeated after 5-10 minutes); or nebulisation of a 2-agonist (salbutamol at a dose of 0.02 mL/kg of a 0.5% solution or one vial of terbutaline). Severe urticaria / angioedema: Oral corticosteroids: 2 mg/kg up to 60 mg/day for 2 or 3 days; H1-Antihistamines.

Build-up phase: Control the symptoms; For the next injection: repeat the previous well tolerated dose, and, if there is no adverse reaction, continue the dose escalation for the next injections. Maintenance phase: Control the symptoms; For the next injection: inject only half of the usual maintenance dose, and, if well tolerated, revert to the full maintenance dose for the next injections.

SEVERE SYSTEMIC REACTIONS

Severe asthma: Nebulisation of a 2-agonist (salbutamol at a dose of 0.02 mL/kg of a 0.5% solution or one vial of terbutaline); or 14 puffs of a short-acting 2-agonist (to be repeated after 5-10 minutes); Methylprednisolone: 2 mg/kg IV; Nasal oxygen. Generalised reaction (urticaria + asthma + laryngeal oedema ± drop in blood pressure): Lay the patient down on his/her back with legs in the air, or on his/her side (the safety position in case of vomiting); Adrenaline IM: 0.01 mg/kg which can be repeated after 15 to 30 minutes (weight <20kg dose 0.15 mg / weight>20kg dose 0.30 mg / 2 doses of 0.30 mg in heavy subjects, i.e. 75-80 kg); Nasal oxygen; Intravenous antihistamines; Methylprednisolone: 2 mg/kg IV; Intravenous fluids if the patient is hypotensive. Call for emergency assistance.

Treat the reaction and make sure that symptoms have totally disappeared; Doctors should consider whether to continue subcutaneous SIT with lower doses or to stop it; In case of stop, consider to propose to the patient a sublingual form of SIT, if available.

ANAPHYLACTIC SHOCK

Stop subcutaneous SIT; Doctors could consider whether or not to propose to the patient to follow his/her treatment with a sublingual form of SIT, if available.

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II. PATIENT FOLLOW-UP

1 Efficacy assessment

Efficacy criteria: essentially clinical - Reduction in symptoms; - Reduction in medication use: antihistamines H1; bronchodilators; inhaled steroids; - No biological criteria available. In case of no efficacy: - after 12 months for a perennial allergen; - or after 2 successive pollen seasons in case of a seasonal allergen: The allergen sensitivity and the indication of immunotherapy should be reconsidered.

2

Safety assessment

Sublingual immunotherapy · Based on visits and phone calls from the patient. Subcutaneous immunotherapy · Based on patient diary checked before each injection.

Compliance & Patient Education:

Your patient relies on you for healthcare information. Giving clear instructions and explaining the importance of taking the right dosage at the correct time can help to promote compliance.

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3

Recommendations for patient's follow-up frequency

The doctor is the only person able to define the optimal follow-up frequency according to his/her patient's profile.

3.1

>> Sublingual immunotherapy

A - For a perennial protocol

To reach a good patient's compliance, we recommend seeing the patient every 3 months during the 1st year of treatment and every 4 to 6 months during the following years of treatment.

B - For a pre and co seasonal protocol

To reach a good patient's compliance, we recommend seeing the patient 3 times / year during all the years of the treatment, according to the following scheme: 6 to 4 months before the season: visit for prescription; 1 month after the beginning of the treatment: visit to evaluate safety and compliance; 6 months after the beginning of the treatment: follow-up visit.

3.2

>> Subcutaneous immunotherapy

A - Initial phase

Visit at the doctor's each week for weekly initial injection.

B - Maintenance phase

Visit at the doctor's office once a month for maintenance injection.

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4

Treatment interruption

PHASE

INTERRUPTION

SUBLINGUAL

SUBCUTANEOUS

1 to 2 weeks

Continue the dose escalation without any change.

Repeat the previous dose and continue the build-up phase.

BUILD-UP

PHASE

2 weeks to 1 month

Repeat the previous dose, then continue the build-up phase.

Step back at 0.1 mL with the same concentration, then continue the build-up phase.

More than 1 month

Restart the dose escalation Restart the dose escalation with the 10-fold less with the same vial and continue concentrated vial and continue the build-up phase. the build-up phase.

Less than 1.5 months MAINTENANCE

PHASE

No change in the dosage and concentration.

No change in the dosage and concentration.

1.5 months to 6 months

Reduce the dose by 50%, then continue with the previous well tolerated dose.

Restart with the build-up phase from 0.1 mL of 1 IR or IC/mL vial till the maintenance dose and then continue the treatment.

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Stallergenes' therapeutic ranges

4

I. DELIVERY PROCESS

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II. PRODUCT FOR SUBLINGUAL IMMUNOTHERAPY

1 Staloral®

Sublingual solution of allergen extracts for Specific Immunotherapy. Presentation and method of administration: Vials containing 10 mL of a solution of allergen extracts for sublingual administration. Pump system: 1 vial = 96 doses (remaining doses after pump priming) 1 dose = 0.1mL Available concentrations: CAP COLOR CONCENTRATION IN IR/mL OR IC/mL GREEN* 1 BLUE 10 RED 100 VIOLET** 300 IR/mL

* only for very reactive patients. ** the 300 IR/mL concentration is only available in some countries and for standardised allergens.

2

Precautions of use

Shelf-life: do not use the extract after the expiry date clearly indicated on the vial; Storage: store the vials between +2 and +8°C.

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III. PRODUCTS FOR SUBCUTANEOUS IMMUNOTHERAPY

1 Alustal®

Suspension of allergen extracts for injection. Extracts adsorbed on Aluminium Hydroxide for Specific Immunotherapy. Presentation and method of administration: Vials containing 5 mL of a suspension of allergen extracts adsorbed on Aluminium Hydroxide. Subcutaneous administration only. Available concentrations: CAP COLOR VIAL NUMBER CONCENTRATION IN IR/mL OR IC/mL *only for very reactive patients GREY* 0 0.01 YELLOW 1 0.1 GREEN 2 1 BLUE 3 10

2

Phostal®

Suspension of allergen extracts for injection. Extracts adsorbed on Calcium Phosphate for Specific Immunotherapy. Presentation and method of administration: Vials containing 5 mL of a suspension of allergen extracts adsorbed on Calcium Phosphate. Subcutaneous administration only. Available concentrations: CAP COLOR VIAL NUMBER CONCENTRATION IN IR/mL OR IC/mL GREY* 0 0.01 YELLOW 1 0.1 GREEN 2 1 BLUE 3 10

*only for very reactive patients

3

Precautions of use

Always shake the vial before use, adsorbed extracts are suspensions; Shelf-life: do not use the extract after the expiry date clearly indicated on the vial; Storage: store the vials between +2 and +8°C. Do not freeze because of possible desorption.

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NOTES

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Allergy skin prick tests

Skin prick test: a cornerstone of allergy diagnosis

SKIN PRICK TEST (SPT)

SAFE SENSITIVE EASY TECHNICAL PERFORMANCE IMMEDIATE RESULTS (20 min) LOW COST

5

Skin prick tests can not be performed in case of:

DRUG INHIBITION SKIN DISEASES

Dermographism Eczema Atopic dermatitis

WASH-OUT PERIOD

(before performing the tests)

SERUM SPECIFIC IgE DOSAGE

SAFE NO DRUG INHIBITION DOSAGE WELL-CORRELATED WITH SPT FOR AEROALLERGENS EXPENSIVE

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I. GOOD PRACTICES FOR SKIN PRICK TESTS

1 The patient

Skin prick tests can be performed from the age of 3 months; Make sure that the patient has not taken recently some anti-allergic drugs. In this case a wash out period should be required before performing the skin tests (see table below). Modulatory effects of drugs on skin tests DRUGS GRADE OF INHIBITION Ketotifen ++++ Cetirizine ++++ Levocetirizine ++++ Desloratadine ++++ Loratadine ++++ Chlorpheniramine ++ Corticosteroids (inhaled/oral) / Antileukotriens /

DURATION OF INIHIBITION 10 - 15 days 3 - 10 days 3 - 10 days 3 - 10 days 1 - 3 days / / /

Make sure that the patient has no skin disease (dermographism, atopic dermatitis, eczema) and that no topical corticoid cream was applied there for the last 48 hours. In case of persistent skin diseases (eczema, dermographism, atopic dermatitis), proceed to Specific IgE dosage.

2

The extracts for skin prick tests

Be sure of the quality of the allergen extract tested and use standardised allergens whenever possible. Always use negative and positive controls: - Negative control (diluent of the allergen solution): in case it is positive, suspect a dermographism; - Positive control (Histamine Hydrochloride): in case it is negative, suspect a cutaneous allergy or a drug inhibition (please refer to table page 29 "Interpretation of skin test results").

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II. METHODOLOGY

1 Preparation of the skin prick tests

Check the expiry date of the skin prick test solution; Choose an area of healthy skin: - on the flexor aspect of the forearm, avoiding using the wrist or the antecubital fossa area; - on the back (recommended for children under the age of 5 years). Prepare the skin: clean the skin with cotton with alcohol and let dry; Mark the position of each allergen you wish to test on the forearms or the back, spacing the tests out at about 3 cm.

2

Execution of skin prick tests

Deposit a drop of the extract on the indicated positions; With the help of a standardised prick test needle (Stallerpoint®), prick the skin vertically through each drop, imparting a slight turning movement. Make sure to exert a regular and moderate pressure at each time: usually, a good execution of the test results in the print of the needle's (Stallerpoint®) circumference.

3

Interpretation of the results

Results can be read after at least 20 minutes; Clean the skin with alcohol; Use a thin rollerpoint to circle the wheals; Compare the wheals of the allergen extracts with the wheals of the positive and negative controls; Sensitisation should be considered as positive as soon as the allergen extract's wheal diameter is: - superior to the negative control wheal diameter by at least 3 mm; AND - at least equal to 1/2 of the positive control wheal diameter.

(see table page 29 "Interpretation of skin test results")

In case of doubtful results, proceed to additional allergy tests: provocation tests or laboratory tests (specific IgE dosage).

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Interpretation of skin test results WHEALS CONTROLS VALIDATION OF THE TEST POSITIVE > 3mm NEGATIVE < 3mm POSITIVE > 3mm NEGATIVE > 3mm POSITIVE < 3mm NEGATIVE < 3mm ALLERGENS POSITIVE if > 3mm NEGATIVE if < 3mm ALL > 3mm ALL < 3mm

If DERMOGRAPHISM If DRUG INHIBITION

III. CROSS­REACTING ALLERGENS

Cross reactivities occur when the same amino acid sequences (also called epitopes) are present in different allergen sources. If two species (either animal or plant) are closely related, allergens derived from both may be cross-reactive. It means that an individual who presents a positive skin prick test to one of the pair will possibly also present a positive reaction to the other, even if he or she has never actually encountered the other allergen before. For example, people that are allergic to grass often present a positive skin prick test to related species. Stallergenes has special mixtures gathering different kinds of related cross-reacting allergens.

For more information concerning the cross-reacting allergens, please visit our professional area at www.stallergenes.com.

29

IV. STALLERGENES' RANGES FOR SKIN PRICK TESTS

1 ALYOSTAL® Prick: Allergen extracts solution for prick tests.

Positive controls: Negative control: Presentation: · Histamine Hydrochloride (10 mg/mL). · Phenolated glycero-saline. · 3 mL vials with dropper; · 1 vial 60-75 skin prick tests.

Precautions of use

Shelf-life: do not use after the expiry date which is clearly indicated on the vial; Storage: between +2 and +8°C.

30

2

Stallerpoint®: Single use prick-tests needles.

Presentation: · Stallerpoint® is a Polymethacrylate needle of 1.1 mm length, used to perform prick tests; · 10 needles are held together in a sterile blister. · Prick the skin vertically, imparting a slight turning movement. · Each needle is sterile and therefore used only once (in order to eliminate false positive results caused by previously tested allergens).

Administration method: Shelf-life:

CE 0459

31

Hymenoptera venom immunotherapy

6

I. INDICATIONS

Diagnosis of hypersensitivity to Hymenoptera stings; Specific Immunotherapy of subjects allergic to Hymenoptera stings. The indication lies in the association of a history of severe clinical reactions with positive diagnostic tests as well as the onset of generalised repeated reactions in patients highly exposed or presenting cardiovascular and/or broncho-pulmonar risks.

II. CONTRAINDICATIONS

Unusual (renal, muscular, articular) reactions occurring after Hymenoptera sting; Severe immunodeficiencies.

III. SPECIAL WARNINGS

Patients with associated risk factors such as cardio-vascular and/or broncho-pulmonar pathologies implying a fatal risk in case of Hymenoptera sting can benefit from specific immunotherapy; however because of the increased risk of generalised reaction to injection, SIT should be performed under strict medical surveillance in a hospital setting. Physiological cardiovascular reactions in case of anaphylactic shock can be decreased with intercurrent -blocker treatment. In case of absolute necessity to maintain the -blocker treatment in patients who can benefit from Hymenoptera venom SIT, the risk/ benefit ratio of the indication of SIT should be carefully weighed up and in any case should be performed under strict medical surveillance in a hospital setting. Indications in children are limited to severe generalised reactions considering associated risk factors, notably high exposure risk. Type III allergic reactions and secondary poisoning toxical reactions to multiple stings are not indications for SIT. According to current knowledge, the effect of SIT in patients with cancer or with declared immunodeficiency is not clearly documented. Patients becoming pregnant during the course of SIT in the maintenance phase may continue their treatment, as long as it is well tolerated. It is preferable not to initiate specific immunotherapy in a pregnant patient.

Consequently, for these cases, the risk/benefit ratio of indication of SIT should be carefully weighed up.

32

IV. PRECAUTIONS FOR USE

Any injection for the diagnosis of hypersensitivity or during specific immunotherapy must be performed under medical surveillance and in conditions allowing immediate emergency treatment if required; Before any injection, make sure to have injectable adrenaline at hand in order to treat a possible anaphylactic shock; As for any specific immunotherapy injection, the patient must be kept under medical surveillance for at least 30 minutes after the injection.

Diagnosis of hymenoptera venom allergy

Currently, the intradermal test is preferable to the prick test as it facilitates the production of a sensitivity scale. As some patients are very sensitive to insect venoms, the first dilution tested must be adjusted to each patient, depending on the clinical history presented. It is advisable to begin the intradermal skin test with a low concentration and to successively increase the concentration until it causes an obvious direct reaction. The usual initial injected volume is 0.05 mL of a 0.001 µg/mL concentration. In case of a negative response repeat the injection with serial 10-fold higher concentration until a positive intradermal reaction appears.

33

V. PROTOCOLS

By strict subcutaneous injection. The time to reach the maintenance dose depends on the protocol used. The rush protocols provide more rapid protection, however slow protocols are usually better tolerated. Cluster protocol represents an alternative regimen.

The protocols indicated may be adapted to the reactivity of each patient.

EAACI POSITION PAPER 19935 DAY DAY 1 HOUR 0 0.5 1 1.5 2.5 3.5 0 1 2 3 0 1 2 0 1 2 0 1 0 1

PROTOCOL ULTRA RUSH RUSH CLUSTER CONVENTIONAL dose in µg venom 0.1 1 10 20 30 40 0.01 0.1 1 2 4 8 10 20 40 60 80 100 100 100 0.001 0.01 0.1 0.01 0.1

DAY 2

DAY 3 DAY 4 DAY 8 DAY 15 DAY 22 DAY 29 DAY 36 DAY 43 DAY 50 DAY 57 DAY 64 DAY 71 DAY 78 DAY 85 DAY 92 DAY 99 DAY 106

50 50

100 100 100

1 5 10 20 30 50 50 100 100

1 2 4 8 10 20 40 60 80 100 100 100 100 100

100

100

100

100

100

100

5: Source: Müller U., Mosbech H.. EAACI Position paper: Immunotherapy with Hymenoptera venoms. Allergy. 1993; 14, vol.48: 37-46.

34

The recommended maintenance dose is 100 µg of venom protein, corresponding to about two bee stings and probably many more yellow jacket stings. However, the maintenance dose can be increased up to 200 µg of venom protein, in case of beekeepers who are often stung by several insects at the same time. Further injection of the protective maintenance dose are scheduled every 4 to 6 weeks for at least 3 to 5 years. In particular cases the treatment must be continued for life.

VI. ADVERSE EFFECTS

Local reactions at the injection site, such as urticarial wheal, possibly accompanied by varying degrees of oedema. These reactions appear to be more frequent with the rapid desensitisation method; Systemic manifestations after injection (similar to the reactions observed after a wasp or a bee sting) ranging from general malaise, with or without urticaria, to anaphylactic shock; An important asthenia can be observed in certain patients in the hours following the injection.

VII. STALLERGENES' RANGES

1 Albey® 120 µg

Treatment set composition: · 1 vial containing 120 µg of freeze-dried venom powder; · 1 vial containing 1.8 mL of diluent. · The extract is reconstituted by adding 1.2 mL of diluent to the content of freeze-dried vial to obtain a concentration of 100 µg/mL; · To obtain a tenfold lower concentration (10 µg/mL), inject 0.2 mL of reconstituted extract into a vial of 1.8 mL of diluent. Repeat the operation from the vial obtained in this way (10 µg/mL) to obtain serial tenfold lower concentrations (1 µg/mL, 0.1 µg/mL, etc.).

Reconstitution and dilutions:

35

2

Albey® 550 µg

Treatment set composition: · 1 vial containing 550 µg of freeze-dried venom powder; · 1 vial containing 9 mL of HSA diluent; · 3 vials containing 1.8 mL of diluent. · The extract is reconstituted by adding 5.5 mL of diluent to the content of freeze-dried vial to obtain a concentration of 100 µg/mL; · To obtain a tenfold lower concentration (10 µg/mL), inject 0.2 mL of reconstituted extract into a vial of 1.8 mL of diluent. Repeat the operation from the vial obtained in this way (10 µg/mL) to obtain serial tenfold lower concentrations (1 µg/mL, 0.1 µg/mL, etc.).

Reconstitution and dilution scheme:

5.5 mL

Vial containing 9 ml of HSA diluent

0.2 mL 0.2 mL

9 mL (HSA)

ALBEY 100 µg/mL

Vial containing 550 µg of freeze-dried venom powder

0.2 mL

0.2 mL

0.2 mL

0.2 mL

ALBEY 100 µg/mL Mother Solution

10 µg/mL

1 µg/mL

0.1 µg/mL

0.01 µg/mL

0.001 µg/mL

0.0001 µg/mL

36

3

Available references for Albey® ranges

Honey bee (Apis mellifera) venom; Yellow Jacket (Vespula spp.) venom; Paper wasp (Polistes spp.) venom.

4

Shelf life

Never use after the expiry date which is clearly indicated on the vial. The maximum shelf-life after reconstitution varies according to the concentration of the dilutions. Concentration (µg/mL) 100 10 1 0.1 less than 0.1 Maximum shelf-life 6 months after reconstitution 1 month to be prepared daily

5

Special precautions for storage

Before and after reconstitution, the preparation and its dilutions must be stored between +2 and +8°C (in the refrigerator).

37

List of available allergen extracts and references

7

325 335 314 315 324 317 333 318 350 330 · MITES: Acarus siro Blomia tropicalis Dermatophagoides farinae Dermatophagoides pteronyssinus Glyciphagus domesticus Lepidoglyphus destructor Pyroglyphus africanus Tyrophagus putrescentiae D. pteronyssinus + D. farinae (50/50) Storage mites (Acarus siro, Glyciphagus

Alyostal® Prick Staloral® Alustal® Phostal®

IC IR IR IR IC IC IC IC IC

domesticus, Lepidoglyphus destructor, Tyrophagus putrescentiae)

IC IR* IR* IR* IC IC IC IC IR* IC

IC IR IR IR IC IC IC IC IR IC

IC IR IR IR IC IC IC IC IR IC

400 402 407 409 410 413 447 417 425 426 432 405 401 414 422 446 445

· MOULDS, YEASTS AND DERMATOPHYTES: Alternaria alternata Botrytis cinerea Chaetomium globosum Epicoccum purpurascens Epidermophyton flocosum Helminthosporium halodes Merulius lacrymans Mucor racemosus Pullularia pullulans Rhizopus nigricans Stemphylium botryosum Trichotecium roseum · MOULDS & YEASTS MIXTURES: Aspergillus mix (Aspergillus fumigatus,

A. nidulans, A. niger)

IC IC IC IC IC IC IC IC IC IC IC IC

IC IC IC IC IC IC IC IC IC IC IC IC

IC IC IC IC IC IC IC IC IC IC IC IC

IC IC IC IC IC IC IC IC IC IC IC IC

IC IC IC IC IC

IC IC IC IC IC

IC IC IC IC IC

IC IC IC IC IC

Cladosporium

(Cladosporium (Penicillium digitatum,

cladosporioides, C. herbarum)

Penicillium mix Smut mixture

P. expansum, P. notatum) (Ustilago avenae, U. tritici, U. holci, U. zeae) cerevisiae)

Yeast mixture (Saccharomyces

IR: reference available in IR/mL (Index of Reactivity for standardised extracts) IC: reference available in IC/mL (Index of Concentration for non-standardised extracts) IR*: reference available at 300 IR/mL for Staloral® 38

507 509 506 510 511 516 512 301 303 307

· EPITHELIA: Cat Dog Feather mixture Guinea pig Hamster Horse Rabbit

Alyostal® Prick

Staloral®

Alustal®

Phostal®

(duck, goose, hen)

IR IR IC IC IC IC IC IC IC IC

IR IR IC IC IC IC IC IC IC IC

IR IR IC IC IC IC IC IC IC IC

IR IR IC IC IC IC IC IC IC IC

· INSECTS: Cockroach (Blatella germanica) Corn moth (Ephestia kuehniella) Mosquito (Aedes communis) · POLLENS AND VEGETAL PRODUCTS: Weeds: Alfalfa (Medicago sativa) Dandelion (Taraxacum vulgare) Fat hen (Chenopodium album) Golden rod (Solidago canadensis) Hop (Humulus lupulus) Mugwort (Artemisia vulgaris) Mustard (Brassica nigra) Nettle (Urtica dioica) Ox-eye daisy (Chrysanthemum leucanthemum) Plantain (Plantago) Ragweed (Ambrosia elatior) Rape (Brassica oleifera) Red clover (Trifolium pratense) Rough pigweed (Amaranthus retroflexus) Russian thistle (Salsola kali) Sorrel (Rumex acetosa) Sunflower (Helianthus annuus) Wall pellitory (Parietaria judaica) Wall pellitory (Parietaria officinalis) Chenopodiaceae (Fat hen, Rough pigweed) Compositae (Golden rod, Dandelion,

Ox-eye daisy, Cockelebur)

641 664 623 673 636 605 646 654 643 665 604 625 679 602 710 655 678 708 657 714 719

IC IC IC IC IC IR IC IC IC IC IR IC IC IC IR IC IC IR IR IC IC

IC IC IC IC IC IR* IC IC IC IC IR* IC IC IC IR* IC IC IR* IR* IC IC

IC IC IC IC IC IR IC IC IC IC IR IC IC IC IR IC IC IR IR IC IC

IC IC IC IC IC IR IC IC IC IC IR IC IC IC IR IC IC IR IR IC IC

660 652 601 705 627 624 674 642 630

Grasses and cereals: Bahia grass (Paspalum notatum) Barley (Hordeum vulgare) Bent grass (Agrostis vulgaris) Bermuda grass (Cynodon dactylon) Cocksfoot (Dactylis glomerata) Couch-grass (Agropyron repens) Johnson grass (Sorghum halepense) Maize (Zea mays) Meadow fescue (Festuca elatior)

IC IC IC IR IR IC IC IC IC

IC IC IC IR* IR* IC IC IC IC

IC IC IC IR IR IC IC IC IC

IC IC IC IR IR IC IC IC IC

39

Alyostal® Prick

Staloral®

Alustal®

Phostal®

658 610 671 638 631 661 614 637 701 687 688 762 690 689

Meadow grass (Poa pratensis) Oat (Avena sativa) Rye (Secale cereale) Rye-grass (Lolium perenne) Sweet vernal-grass (Anthoxantum odoratum) Timothy (Phleum pratense) Wheat (Triticum vulgare) Yorkshire fog (Holcus lanatus) 3 Grasses (Cocksfoot, Rye-grass, Timothy) 4 Cereals (Oat, Wheat, Barley, Maize) 5 Grasses (Cocksfoot, Sweet vernal-grass, 5 Grasses / Rye 5 Grasses/4 Cereals 12 Grasses (Bent grass, Bermuda grass,

Bromus, Cocksfoot, Meadow fescue, Meadow grass, Oat grass, Rye-grass, Sweet vernal grass, Timothy, Wild oat, Yorkshire fog) Rye-grass, Meadow grass, Timothy)

IR IC IR IR IR IR IC IC IR IR IR

IR* IC IR* IR* IR* IR* IC IC IR* IR* IR* IR* IR*

IR IC IR IR IR IR IC IC IR IR IR IR IR IR

IR IC IR IR IR IR IC IC IR IR IR IR IR IR

IR

IR*

609 632 635 615 620 716 626 668 675 653 667 649 619 644 634 677 629 648 645 647 621 651 662 666 659

· Trees: Alder (Alnus glutinosa) Ash (Fraxinus excelsior) Beech (Fagus sylvatica) Birch (Betula alba) Chestnut (Castanea vulgaris) Cupressaceae (Juniperus ashei) Cypress (Cupressus sempervirens) Date Palm (Phoenix dactylifera) Elder (Sambucus nigra) Elm (Ulmus campestris) False acacia (Robinia pseudoacacia) Hazel (Corylus avellana) Hornbeam (Carpinus betulus) Horse Chestnut (Aesculus hippocastanum) Juniper (Juniperus communis) Lime (Tilia platyphyllos) Maple (Acer pseudoplatanus) Mesquite (Prosopis glandulosa) Mimosa (Acacia dealbata) Mulberry white (Morus alba) Oak (Quercus robur) Olive (Olea europea) Pine (Pinus sylvestris) Plane (Platanus vulgaris) Poplar (Populus alba)

IR IR IC IR IC IR IC IC IC IC IC IR IR IC IC IC IC IC IC IC IC IR IC IC IC

IR* IR* IC IR* IC IR* IC IC IC IC IC IR* IR* IC IC IC IC IC IC IC IC IR* IC IC IC

IR IR IC IR IC IR IC IC IC IC IC IR IR IC IC IC IC IC IC IC IC IR IC IC IC

IR IR IC IR IC IR IC IC IC IC IC IR IR IC IC IC IC IC IC IC IC IR IC IC IC

IR: reference available in IR/mL (Index of Reactivity for standardised extracts) IC: reference available in IC/mL (Index of Concentration for non-standardised extracts) IR*: reference available at 300 IR/mL for Staloral®

40

680 650 669 702 696 715 717 718

Privet (Ligustrum vulgare) Walnut (Juglans regia) Willow (Salix caprea) Betulaceae (Birch, Alder, Hornbeam, Hazel) Fagaceae (Chestnut, Oak, Beech) Oleaceae (Olive, Privet, Ash) Salicaceae (Poplar, Willow) Tree mixture (Maple, Horse chestnut, Plane,

False acacia, Lime)

Alyostal® Prick

Staloral®

Alustal®

Phostal®

IC IC IC IR IC IC IC IC

IC IC IC IR* IC IC IC

IC IC IC IR IC IC IC

IC IC IC IR IC IC IC

106 903 176

· VEGETAL PRODUCTS: Wheat flour Latex (Hevea brasiliensis) Lupine flour

IC IR IC

IC

IC

IC

41

ONLY FOR PRICK-TESTS (Alyostal ® Prick)

· FOODSTUFF ALLERGENS:

Condiment and seeds: 172 Aniseed 180 Bay laurel 111 Coffee 177 Cumin 178 Curry 176 Lupine

(flour)

Vegetables: 101 Artichoke 128 Bean 112 Carrot 114 Celery 170 Garlic 153 Green Pea 146 Onion 156 Potato 121 Spinach 190 Soya 167 Tomato Fruit and nuts: 171 Almond 155 Apple 169 Apricot 194 Avocado 103 Banana 110 Cocoa 141 Hazel nut 189 Kiwi fruit 117 Lemon

140 Mustard 182 Nutmeg 183 Paprika 184 Pepper 196 Sesame 165 Tea 185 Thyme Cereals: 149 Barley 136 Maize 181 Malt 160 Rice 161 Rye

(flour) (flour)

106 Wheat 105 Wheat

186 Mixture of cereals 195 - amylase Eggs: 143 Egg 144 Egg 145 Egg

(white) (yolk) (whole)

(barley, maize, oat, rice,

188 Mango 137 Melon 147 Olive 148 Orange 187 Passion fruit 151 Peach 109 Peanut 123 Strawberry 142 Walnut

rye, wheat, wheat flour)

Meat: 158 Chicken 157 Pork

· FOODSTUFF ALLERGENS:

42

· FOODSTUFF ALLERGENS:

Fish and seafood: 193 Cod 119 Crab 125 Freshwater fishes (carp, perch, pike) 118 Hake 139 Mussel 131 Oyster 162 Sardine 120 Shrimp 135 Spiny lobster 166 Tuna fish 138 Whiting

· CONTROLS FOR PRICK-TESTS:

Positive control: 2077 Histamine Hydrochloride Negative control: 2069 Phenolated Glycero-Saline

(10 mg/mL)

· STALLERPOINT®:

2144 Box of 100 Stallerpoint

(10 blisters of 10 needles)

2100 Box of 1,000 Stallerpoint (100 blisters of 10 needles)

43

Summary of product characteristics

1. TRADE NAME OF THE MEDICINAL PRODUCT: STALORAL. 2. QUALITATIVE AND QUANTITATIVE COMPOSITION: One vial contains 10 mL of a solution at: 10 ; 100 or 300 IR/mL (standardised extracts) or, 10 or 100 IC/mL (non-standardised extracts), of one of the allergen products listed in the following table. The active substance is the allergen extract. If necessary lower concentrations may be used according to the medical prescription. IR (Index of Reactivity): An allergen extract is said to have a titre of 100 IR/mL if in a prick-test performed using a Stallerpoint® in 30 subjects sensitised to the allergen in question, it produces a wheal measuring 7 mm in diameter (geometric mean). Skin reactivity in these subjects is simultaneously demonstrated by a positive response to a prick-test with codeine phosphate 9% or histamine dihydrochloride 10 mg/mL. IC (Index of Concentration): An allergen extract has an Index of Concentration of 100 IC/mL when its manufacturing parameters lead to the same dilution ratio than those of standardised extracts at 100 IR/mL from the same family, extracts taken as a reference. When the family does not contain any standardised reference extract, the value 100 IC/mL corresponds to an extract whose the dilution ratio is established according to the medical experience. 3. PHARMACEUTICAL FORM: Sublingual solution of allergen extracts for specific immunotherapy. 4. CLINICAL PARTICULARS: 4.1 Therapeutic indications: Type I allergies (Gell and Coombs classification) mainly comprise rhinitis, conjunctivitis, rhinoconjunctivitis or asthma of a seasonal or perennial nature. The goal of specific immunotherapy (SIT) is to prevent the clinical consequences of contact between sensitised subjects and the allergen when aetiological factors have been clearly identified. 4.2 Posology and method of administration: Conditions of use: SIT should be started as soon as the diagnosis has been made. The earlier treatment begins, the greater the efficacy. Thus in children, treatment may begin at the age of 3 to 4 years, but it is preferable to begin at around 5 years. This treatment should be introduced as first-line therapy in children or young adults as soon as warranted by the severity of symptoms. Posology and method of administration: The dosage does not vary according to age but must be adapted in line with the degree of reaction of the individual patient. Therapy comprises 2 phases: an initial treatment phase involving gradual dose increase, a maintenance treatment phase at constant doses. Before the medicine is taken, care should be taken to ensure that the extract being used corresponds to the prescription and the expiry date should be checked. 1. Initial treatment: dose increase: The medicine is taken in the morning fasting. The doses of extract are obtained by exerting a pressure on the pump, placed directly under the tongue and kept under the tongue for two minutes before being swallowed. The medicine is taken daily in rising doses until the maintenance dose is attained. 2. Maintenance treatment: constant dose : Once attained, the maximum dose is taken either every day or three times weekly. The recommended posology is at least 8 doses 3 times weekly or 4 doses daily using the 300 IR/mL concentration. In clinical studies a posology equivalent to 10 doses daily of 300 IR/mL concentration has been well tolerated. Duration of treatment: As a general rule, specific immunotherapy should be continued for 3 to 5 years. It can also last for several seasons in case of seasonnal allergies. 4.3 Contraindications: Serious immunodeficiency, malignant disease, unstable asthma, auto-immune disease. Ongoing treatment with beta-blockers. 4.4 Special warnings and special precautions for use: For patients requiring SIT, symptoms must be controlled prior to therapy by means of suitable treatment where necessary. Standard symptomatic treatment (corticosteroids, beta-2mimetics, histamine H1 antagonists) should be available for patients for whom sublingual administration of allergens has been prescribed. 4.5 Interaction with other medicaments and other forms of interaction: There have been no reports of drug interactions. 4.6 Pregnancy and lactation: Patients becoming pregnant during the course of specific immunotherapy at the maintenance dose (i.e. constant dose) may continue their treatment. If pregnancy occurs during the initial therapy phase (gradual dose increase), it is preferable to withdraw treatment. 4.7 Effects on ability to drive and use machines: No known effect. 4.8 Undesirable effects and overdose: Undesirable effects are rare and are restricted to oropharyngeal discomfort, abdominal pain and moderate syndromic reactions. Oropharyngeal or gastrointestinal discomfort do not necessarily require any change to the dosing regimen but may nevertheless signal a need for caution. Moderate syndromic reactions (urticaria, rhinitis, asthma) may warrant symptomatic treatment with histamine H1 antagonist, beta-2 mimetic or possibly oral corticosteroid. Under these conditions, the prescribing allergy specialist must reassess the benefits of continuing specific immunotherapy. 5. PHARMACOLOGICAL PROPERTIES: Pharmacotherapeutic group: V (Various), C1 Allergy (Desensitisation), P1 Allergens and antigens. ATC code: V01. The precise mechanism of action of allergens administered during the course of specific immunotherapy is not clearly understood. A number of changes can be demonstrated in laboratory parameters: appearance of specific antibodies (IgG) that act as "blocking antibodies", possible decrease in plasma concentrations of specific IgEs, change in behaviour of cells involved in allergic reaction, favourable change in activities of Th2 and Th1 lymphocytes, resulting in production of cytokines (decrease in IL-4 and increase in IFN-) that regulate IgE production. In addition, SIT provokes a lasting immune response via specific immune memory. 6. PHARMACEUTICAL PARTICULARS: 6.1 List of excipients: Mannitol (as a part of active ingredient), Sodium Chloride, Glycerol, Purified water. 6.2 Incompatibilities: None. 6.3 Shelf-life: Never use after the expiry date which is clearly indicated on the vial. 6.4 Special precautions for storage: Staloral solution must be stored between +2°C and +8°C. In case of shift, vials must be maintained in an upright position. When they are transported, vials must be packed in their box fitted with the security ring. In the case of plane travel, do not place the assembled Staloral vial in the luggage room. The vials must be replaced to the refrigerator as soon as possible. 6.5 Nature and content of container: The solution is packaged in 12-mL type-I glass vials, each of which contains 10 mL: Blue capsule: 10 IR/mL or 10 IC/mL. Red capsule: 100 IR/mL or 100 IC/mL. Violet capsule: 300 IR/mL. If required: gold capsule : 0.1 IR/mL or 0.1 IC/mL; green capsule : 1 IR/mL or 1 IC/mL. 6.6 Instructions for use / handling: Refer to the paragraph "Posology and method of administration". Instructions for first use: For reasons of security and integrity, the bottles are hermetically sealed by a plastic and aluminium capsule. When using for the first time, proceed as follows: 1. Remove the plastic coloured part of the capsule. 2. Pull on the metal tab and completely remove the aluminium capsule. 3. Remove the grey stopper. 4. Take the pump from its plastic protector. Place the bottle on a flat surface and, holding it firmly with one hand, fit the pump into place by applying firm pressure. 5. Remove the orange security ring. 6. Prime the pump by successive pressures. After 4 pressures, the pump delivers a complete dose. 7. Place the tip in the mouth, underneath the tongue. Press firmly to obtain the recommended dose. Repeat to administer the number of doses prescribed by the doctor. Keep the product under the tongue for 2 minutes. 8. Clean the mouthpiece after use and re-install the security ring. For the further uses, after having removed the security ring, steps 7 and 8 are the only performed. 7. MANUFACTURER: STALLERGENES S. A. - 6, rue Alexis de Tocqueville 92160 ANTONY ­ France. Update date of the text: September 2003.

Staloral®

44

1. TRADE NAME OF THE MEDICINAL PRODUCT: ALUSTAL, injectable suspension of allergen extract adsorbed onto Aluminium Hydroxide gel for specific immunotherapy. 2. QUALITATIVE AND QUANTITATIVE COMPOSITION: One vial contains: 0.1 - 1 or 10 IR/mL (standardised allergen extract); or 0.1 - 1 or 10 IC/mL (non standardised allergen extract) of one product or a mixture of several products presented in the table enclosed. A 0.01 IR/mL or 0.01 IC/mL is also available for very reactive patients. The active substance is a combination of the allergen extract and Mannitol. The IR unit (Index of Reactivity) is the standardisation unit of Stallergènes. An allergen extract titres 100 IR/mL, when, used by prick-test with a Stallerpoint® on 30 people who are sensitised to this allergen, it gives a weal size of 7 mm diameter (geometric mean). The skin reactivity of these patients is simultaneously shown with 9 % codeine phosphate taken as a positive control. The IC unit (Index of Concentration) is the calibration unit allowing to express the allergen power of non standardised extracts. An allergen extract has an Index of Concentration of 100 IC/mL when its manufacturing parameters lead to the same dilution ratio than those of standardised extracts at 100 IR/mL from the same family extracts taken as a reference. When the family does not contain any standardised reference extract, the value 100 IC/mL corresponds to an extract whose the dilution ratio is established according to the medical experience. For excipients, see section 6.1 "List of excipients". 3. PHARMACEUTICAL FORM: Modified release injectable suspension of allergen extracts adsorbed onto aluminium hydroxide gel for specific immunotherapy, prepared especially for one individual. 4. CLINICAL PARTICULARS. 4.1. Therapeutic indications: Allergies of the Gell and Coombs classification Type I, which are manifest specially by rhinitis, conjunctivitis, rhinoconjunctivitis, asthma, of seasonal or perennial characteristics. When the etiological factors are clearly identified the objective of specific immunotherapy (SIT) is to prevent the clinical consequences of a meeting of the sensitised organ with the allergen. 4.2. Dosage and method of administration: Conditions of use: SIT should be undertaken when indicated. Indeed, it is much more effective when it is started early. Thus in children, it may start from 5 years old. The treatment should begin as first indication when significant symptoms of the child or young adult justify it. Dosage and method of administration: Dosage does not vary with age, but it may be adapted to the special reactivity of each individual. The treatment is in two parts: an initial treatment with progression of doses; a maintenance treatment of constant dosage. Before each injection, check: the expiry date; that the vial to be used corresponds with the prescription (composition, name of the patient, concentration) and shake well before taking the injection volume); respect the usual rules of asepsis; use disposable, "tuberculin" type 1ml syringes graduated to 1/100; inject extremely exactly the fixed dose. The patient should remain under medical supervision for 30 minutes after each injection.Violent exercise after an injection is inadvisable for the rest of the day. 1. Initial treatment: progression of doses: The product is injected only by the deep subcutaneous route, at progressively increasing doses, at one weekly injection until the maximum tolerated dose. For very reactive patients, treatment could be started with a 0.01 IR/mL or 0.01 IC/mL concentration (grey cap). 2. Maintenance treatment: constant dose: The maximum tolerated dose is renewed every 15 days, then every month or more, though the interval between 2 injections must not exceed 6 weeks. Beyond this, the dose must be readjusted. Remember that any therapeutic scheme suggested is only indicative and should be modified according to the condition of the patient and any possible reactions. Decrease the dosage by a half every time vials are changed, and eventually during the pollinic season. Length of treatment: In general, SIT should continue for 3 to 5 years. Desensitisation should be pursued on several seasons when it treats a seasonal allergy. 4.3. Contraindications: Severe immunodeficiency, malignancies, unstable asthma, auto-immune diseases. Current beta-blockers treatment (even local treatment). 4.4. Special warnings and special precautions for use: Patients who are undergoing SIT should have their symptoms controlled beforehand, if necessary, with an adequate treatment. Injections should be suspended if there is a feverish infection. In case of a recent asthma attack, that is confirmed clinically and/or by expiratory peak flow measurement, the treatment should be suspended and restarted after improvement or if necessary after the advice of an allergist. Before every injection, it is essential that, ready to hand, there should be an emergency kit that contains injectable and spray adrenalin, injectable soluble corticosteroid and anti-histamine, beta-2-mimetics. Respect for the procedures of good practice of SIT will avoid possible incidents that are linked to: errors with the vials; errors with the dose; accidental intravascular injections; modifications of the intervals between each injection; bad evaluation of the patient clinical condition. This medicine contains 45 mg of Sodium chloride, take it into account for patients with strict low sodium diet, especially for children. 4.5. Interactions with other medicinal products and other forms of interactions: No reaction with other drugs or medicines has been reported. 4.6 Pregnancy and lactation: A pregnant patient at the maintenance phase (constant dose) of SIT may follow the treatment. At the initial phase (increasing doses), it is preferable to suspend the course. It is also contraindicated to undergo a SIT in pregnant women, due to the foetal risk if a high intolerance reaction occurred. 4.7. Effects on ability to drive or to use machines: No known effect. 4.8 Undesirable effects and overdose: Undesirable effects may be local, syndromic or generalised. A tolerated dose is not necessarily constant. It may vary in time as a function of specific reactivity of the individual and the environment. Local reactions: Local reactions ( 2 to 3 cm in diameter) with erythema, oedema and pruritis are relatively frequent and do not imply modification of the therapeutic scheme. However they should be seen as a warning sign for prudence. A significant local reaction ( 5 cm in diameter) should lead to the administration of an oral antihistamine, lengthening of the supervision of the patient and possible modification of the dosage. Other reactions: Immediate reactions: An asthma attack following an injection requires appropriate bronchodilators, or if necessary injectable corticosteroid. A general reaction may require a treatment with antihistamines-H1 and even corticosteroids. Possible evolution towards a collapse needs an extended and increased supervision in a hospital environment. A laryngeal dyspnea requires a subcutaneous injection of 1/1000 adrenalin (0.25 ml for children under 12 years old and 0.25 to 0.50 ml for adults) and possible hospitalisation. An anaphylactic shock type-reaction urgently needs an intramuscular injection of 0.5 ml of 1/1000 adrenalin (500 micrograms), which can be renewed and possibly combined with an intravenous corticosteroid. A special care in specialised surroundings is required. In every case, the conduct of specific immunotherapy should then be reconsidered by the allergist who suggested it. Delayed reaction : Rarely, a delayed reaction of the « serum sickness » type may follow, with arthralgia, urticaria, nausea, adenopathy and fever. This should terminate the SIT. 4.9 Overdosage: Risk of anaphylaxis or systemic reaction. Medical monitoring in hospital. 5. PHARMACOLOGICAL PROPERTIES: Pharmacotherapeutic group : V (Various), C1 Allergy (Desensitisation), P1 Allergens and antigens. ATC code : V01. The precise mechanism of action of allergens administered during SIT is not known, though some biological modifications have been recorded: appearance of specific antibodies (IgG4), that have a role as « blocking » antibodies; long term reduction of the plasma level of specific IgE; reduction of the reactivity of cells involved in the allergic reaction, shift in lymphocytes Th2 and Th1 responses leading to a favourable production of cytokines (decrease of IL-4 and increase of INF-) which regulates the IgE production; activation of regulator lymphocytes. In addition, SIT provokes an immune response with a long term specific immunological memory. 6. PHARMACEUTICAL PARTICULARS: 6.1. List of excipients: Aluminium Hydroxide; Sodium Chloride; Phenol; Water for injections. 6.2. Incompatibilities: None. 6.3. Shelf life: Never use after the expiry date which is clearly indicated on the vial. 6.4. Special precautions for storage: The injectable suspension ALUSTAL should be stored between + 2 and + 8°C. 6.5. Nature and content of container: The injectable suspension ALUSTAL is packed in a 12 mL type I white glass vial (volume to the neck: 11 mL). Each vial contains 5 ml suspension. Grey cap:0.01 IR/mL or 0.01 IC/mL. Yellow cap: 0.1 IR/mL or 0.1 IC/mL. Green cap: 1 IR/mL or 1 IC/mL. Blue cap: 10 IR/mL or 10 IC/mL. 6.6. Instructions for use/handling: See paragraph 4.1 « Dosage and method of administration ». 7. MANUFACTURER: STALLERGENES S.A. - 6, rue Alexis de Tocqueville - 92160 ANTONY- France. Update date of the text : September 2004. 45

Alustal®

Summary of product characteristics

1. TRADE NAME OF THE MEDICINAL PRODUCT: PHOSTAL. Injectable suspension of allergen extract adsorbed onto Calcium Phosphate gel for specific immunotherapy. 2. QUALITATIVE AND QUANTITATIVE COMPOSITION: A vial contains: 0.01, 0.1, 1 or 10 IR/mL (standardised allergen extract); 0.01, 0.1, 1 or 10 IC/mL (non standardised allergen extract) of one product or a mixture of several products presented in the table enclosed. The IR unit (Index of Reactivity) is the standardisation unit of Stallergenes. An allergen extract titres 100 IR/mL, when, used by prick-test with a Stallerpoint®, on 30 people who are sensitised to this allergen, it gives a weal size of 7 mm diameter (geometric mean). The skin reactivity of these patients is simultaneously shown with 9 % codeine phosphate taken as a positive control. The IC unit (Index of Concentration) is the calibration unit allowing to express the allergen power of non standardised extracts. An allergen extract has an Index of Concentration of 100 IC/mL when its manufacturing parameters lead to the same dilution ratio than those of standardised extracts at 100 IR/mL from the same family extracts taken as a reference. When the family does not contain any standardised reference extract, the value 100 IC/mL corresponds to an extract whose the dilution ratio is established according to the medical experience. 3. PHARMACEUTICAL FORM: Modified release injectable suspension. 4. CLINICAL PARTICULARS: 4.1. Therapeutic indications: Allergies of the Gell and Coombs classification Type I, which are manifest specially by rhinitis, conjunctivitis, rhinoconjunctivitis, asthma, of seasonal or perennial characteristics. When the etiological factors are clearly identified, the objective of specific immunotherapy (SIT) is to prevent the clinical consequences of a meeting of the sensitised organ with the allergen. 4.2. Dosage and method of administration: Conditions of use: SIT should be undertaken when indicated. In effect, it is much more effective when it is started early. Thus in children, it may start from age 3 to 4 years but most often from 5 years old. The treatment should commence as first indication when significant symptoms of the child or young adult justify it. Dosage and method of administration: Dosage does not vary with age, but it may be adapted to the special reactivity of each individual. The treatment is in two parts: - an attack treatment with progression of doses; - a maintenance treatment of constant dosage. Before each injection, check: - the expiry date; - that the vial to be used corresponds with the prescription (composition, name of the patient, concentration; and shake well before taking the injection volume);- respect the usual rules of asepsis;- use disposable, "tuberculin" type 1ml syringes graduated to 1/100; - inject extremely exactly the fixed dose. The patient should remain under medical supervision for 30 minutes after each injection. Violent exercise after an injection is inadvisable for the rest of the day. 1. Attack treatment: progression of doses. The product is injected only by the deep subcutaneous route, at progressively increasing doses, at one weekly injection until the maximum tolerated dose. 2. Maintenance treatment: constant dose. The maximum tolerated dose is renewed every 15 days, then every month or more, though the interval between 2 injections must not exceed 6 weeks. Beyond this, the dose must be readjusted. Remember that any therapeutic scheme suggested is only indicative and should be modified according to the condition of the patient and any possible reactions. Length of treatment: In general, SIT should continue for 3 to 5 years. 4.3. Contra-indications: Severe immunodeficiency, malignancies, unstable asthma, auto-immune diseases. Current beta-blockers treatment. 4.4. Special warnings and special precautions for use: Patients who are undergoing SIT should have their symptoms controlled beforehand, if necessary, with an adequate treatment. Injections should be suspended if there is a feverish infection. In case of a recent asthma attack, that is confirmed clinically and/or by expiratory peak flow measurement, the treatment should be suspended and restarted after improvement or if necessary after the advice of an allergist. Before every injection, it is essential that, ready to hand, there should be an emergency kit that contains injectable and spray adrenalin, injectable soluble corticosteroid and anti-histamine, beta-2mimetics. Respect for the procedures of good practice of SIT will avoid possible incidents that are linked to: - errors with the vials; - errors with the dose; - accidental intravascular injections; - modifications of the intervals between each injection; - bad evaluation of the patient clinical condition. This medicine contains 45 mg sodium chloride, take it into account for patients with strict low sodium diet, especially for children. 4.5. Interactions with other medicinal products and other forms of interactions: No reactions with other drugs or medicines have been reported. 4.6 Pregnancy and lactation: A pregnant patient at the maintenance phase (constant dose) of SIT may follow the treatment. At the attack phase (increasing doses), it is preferable to suspend the course. 4.7. Effects on ability to drive or to use machines: No known effect. 4.8 Undesirable effects and overdose: Undesirable effects may be local, syndromic or generalised. A tolerated dose is not necessarily constant. It may vary in time as a function of specific reactivity of the individual and the environment. Local reactions: Local reactions (2 to 3 cm in diameter) with erythema, oedema and pruritis are relatively frequent and do not imply modification of the therapeutic scheme. However they should be seen as a warning sign for prudence. A significant local reaction ( 5 cm in diameter) should lead to the administration of an oral antihistamine, lengthening of the supervision of the patient and possible modification of the dosage of the supervision of the patient and possible modification of the dosage. Other reactions: Immediate reactions: An asthma attack following an injection requires appropriate bronchodilators, or if necessary injectable corticosteroid. A general reaction may require a treatment with antihistamines-H1 and even corticosteroids. Possible evolution towards a collapse needs an extended and increased supervision in a hospital environment. A laryngeal dyspnea requires a subcutaneous injection of 1/1000 adrenalin (0.25 ml for children under 12 years old and 0.25 to 0.50 ml for adults) and possible hospitalisation. An anaphylactic shock type-reaction urgently needs a subcutaneous or intramuscular injection of 1/1000 adrenalin which can be renewed and possibly combined with an intravenous corticosteroid. A special care in specialised surroundings is required. In every case, the conduct of Specific Immunotherapy should then be reconsidered by the allergist who suggested it. - Delayed reaction: Rarely, a delayed reaction of the " serum sickness " type may follow, with arthralgia, urticaria, nausea, adenopathy and fever. This should terminate the SIT. 5. PHARMACOLOGICAL PROPERTIES: Pharmacotherapeutic group : V (Various), C1 Allergy (Desensitisation), P1 Allergens and antigens. ATC code: V01. The precise mechanism of action of allergens administered during SIT is not known, though some biological modifications have been recorded: - appearance of specific antibodies (IgG), that have a role as " blocking " antibodies; - reduction of the plasma level of specific IgE; - modification of the behaviour of the cells involved in the allergic reaction; - shift in lymphocytes Th2 and Th1 responses leading to a favourable production of cytokines (decrease of IL-4 and increase of INF-) which regulates the IgE production. In addition, SIT provokes an immune response with a long term specific immunological memory. 6. PHARMACEUTICAL PARTICULARS: 6.1. List of excipients: Calcium Phosphate; Sodium chloride; Phenol; Glycerol; Water for injections 6.2. Incompatibilities: None. 6.3. Shelf life: Never use after the expiry date which is clearly indicated on the vial. 6.4. Special precautions for storage: The injectable suspension PHOSTAL should be stored between + 2 and + 8°C. Do not use an extract that has been frozen. 6.5. Nature and content of container: The injectable suspension PHOSTAL is packed in a 11 ml type I white glass vial. 6.6. Instructions for use/handling: See paragraph " Dosage and method of administration ". 7. MANUFACTURER: STALLERGENES S.A.; 6, rue Alexis de Tocqueville; 92160 ANTONY - FRANCE. CONDITIONS OF PRESCRIPTION AND DELIVERY: Only on physician's prescription. UPDATE DATE OF THE TEXT: July 2001.

Phostal®

46

1. TRADE NAME OF THE MEDICINAL PRODUCT: ALBEY Bee venom (Apis mellifera) 120 and 550 µg: freeze-dried powder and solvent for injectable solution. ALBEY Yellow jacket venom (Vespula spp.), 120 and 550 µg: freeze-dried powder and solvent for injectable solution. 2. QUALITATIVE AND QUANTITATIVE COMPOSITION: ALBEY 120 µg: Vial of freeze-dried powder: Bee or Yellow Jacket venom corresponding to 120 µg of proteins, Mannitol 4.8 mg. Solvent: Human Albumin 0.03 g, Sodium Chloride 0.90 g, Phenol 0.40 g, water for injections QSP 100 mL for a vial of 1.8 mL and a vial of 9 mL. ALBEY 550 µg: Vial of freeze-dried powder: Bee or Yellow Jacket venom corresponding to 550 µg of proteins, Mannitol 22 mg. Solvent: Human Albumin 0.03 g, Sodium Chloride 0.90 g, Phenol 0.40 g, water for injections QSP 100 mL for a vial of 1.8 mL and a vial of 9 mL. 3. PHARMACEUTICAL FORM: Powder and solvent for injectable solution. 4. CLINICAL PARTICULARS: 4.1 Indications: Diagnosis of hypersensitivity to Hymenoptera stings. Specific Immunotherapy of subjects allergic to Hymenoptera stings. The indication lies in the association of a history of severe clinical reactions with positive diagnostic tests as well as the onset of generalised repeated reactions in patients highly exposed or presenting cardiovascular and/or broncho-pulmonar risks. 4.2 Dosage and method of administration: Reconstitution and dilutions: The extract is reconstituted by adding 1.2 mL of solvent to the contents of one vial of 120 µg or 5.5 mL of solvent to the contents of one vial of 550 µg (in order to obtain a concentration of 100 µg/mL). To obtain a tenfold lower concentration (10 µg/mL), add 0.2 mL of reconstituted extract into a vial of 1.8 mL of solvent. Repeat the operation from the vial obtained in this way (10 µg/mL) to obtain serial tenfold lower concentrations (1 µg/mL, 0.1 µg/mL, etc.). Use for in vivo diagnosis: For intradermal tests, start by injecting 0.05 mL of a 0.001 µg/mL solution. In the case of a negative response, repeat the injections with serial 10-fold higher concentrations until a positive intradermal reaction is obtained, without exceeding a maximum concentration of 1 µg/mL. For skin prick-tests, the usual concentration is 100 µg/mL. Specific Immunotherapy (SIT): Subcutaneous route only. The protective maintenance dose is 100 µg of venom extract, but it can be increased up to 200 µg of venom in case of beekeepers (bee venom) and in patients insufficiently protected with 100 µg. The protocol used to reach the maintenance dose of 100 µg must be adapted by a physician specialised in allergology, depending on the clinical history and tolerance of the patient. The time taken to reach the maintenance dose depends on the method used: - in few hours (Ultra-Rush) or few days (Rush) in specialised setting only; - in few weeks (conventional method. This maintenance dose is injected every 4 to 6 weeks and specific immunotherapy could be continued for at least 3 to 5 years or a longer period in certain cases. The recommended protocols are identical in adults and in children. 4.3 Contraindications: Unusual (renal, muscular, articular) reactions occurring after Hymenoptera sting. Severe immunodeficiencies. 4.4 Special warnings and special precautions for use: Any injection for the diagnosis of hypersensitivity or during specific immunotherapy must be performed under medical surveillance and in conditions allowing immediate emergency treatment if required. Before any injection, make sure to have injectable adrenaline at hand in order to treat a possible anaphylactic shock. As for any specific immunotherapy injection, the patient must be kept under medical surveillance for at least 30 minutes after the injection. Patients with associated risk factors such as cardio-vascular and/or broncho-pulmonar pathologies implying a fatal risk in case of Hymenoptera sting can benefit from specific immunotherapy; however because of the increased risk of generalised reaction to injection, SIT should be performed under strict medical surveillance in a hospital setting. Physiological cardiovascular reactions in case of anaphylactic shock can be decreased with intercurrent, -blocker treatment. In case of absolute necessity to maintain the, -blocker treatment in patients who can benefit from Hymenoptera venom SIT, the risk/ benefit ratio of the indication of SIT should be carefully weighed up and in any case should be performed under strict medical surveillance in a hospital setting. Indications in children are limited to severe generalised reactions considering associated risk factors, notably high exposure risk. Type III allergic reactions and secondary poisoning toxical reactions to multiple stings are not indications for SIT. According to current knowledge, the effect of SIT in patients with cancer or with declared immunodeficiency is not clearly documented. Consequently, for these cases, the risk/benefit ratio of indication of SIT should be carefully weighed up. 4.5 Interactions with other medicinal products and other forms of interactions: None. 4.6 Pregnancy and lactation: Patients becoming pregnant during the course of SIT in the maintenance phase may continue their treatment, as long as it is well tolerated. It is preferable not to initiate specific immunotherapy in a pregnant patient. 4.7 Effects on ability to use and drive machines: No known effect. 4.8 Undesirable effects: Local reactions at the injection site, such as urticarial wheal, possibly accompanied by varying degrees of oedema. These reactions appear to be more frequent with the rapid desensitisation method. Systemic manifestations after injection (similar to the reactions observed after an Hymenoptera sting) ranging from general malaise, with or without urticaria, to anaphylactic shock. An important asthenia can be observed in certain patients in the hours following the injection. 4.9 Overdose: In case of overdose, the risk of occurrence of a generalised reaction or anaphylactic shock is increased. 5. PHARMACOLOGICAL PROPERTIES: 5.1 Pharmacodynamics properties: Pharmacotherapeutic group: ALLERGENS. ATC Code: V01AA07. The precise mechanism of action of allergens administered during a course of specific immunotherapy is not clearly understood. It has been demonstrated that SIT induces an important decrease in the Th2 reactivity and reorients the immune response towards a more predominant Th1-type. 5.2 Pharmacokinetics properties: No pharmacokinetics study with Hymenoptera venom for subcutaneous specific immunotherapy has been realised. 5.3 Preclinical safety data: None. 6. PHARMACEUTICAL PARTICULARS: 6.1 Incompatibilities: None. 6.2 Special precautions for storage: The preparation, before and after reconstitution, and its dilutions must be stored between +2 and +8°C. The maximum shelf-life after reconstitution varies according to the concentration of the dilutions: Concentration (µg/mL) 100 10 <10 Maximal shelf-life 6 months 1 month To be prepared extemporaneously

Albey®

6.4 Nature and content of container: Powder: 10 mL glass vial containing 120 µg of venom proteins or 10 mL glass vial containing 550 µg of venom proteins. Solvent: 2 mL glass vial containing 1.8 mL solvent or 11 mL glass vial containing 9 mL solvent. 6.5 Instructions for use: No particular requirement. 7. MANUFACTURER: STALLERGENES S.A. - 6, rue Alexis de Tocqueville ­ 92160 Antony (France). UPDATE DATE OF THE TEXT: November 2004.

47

Summary of product characteristics

1. TRADE NAME OF THE MEDICINAL PRODUCT: ALYOSTAL PRICK 100 IR/mL, 100 IC/mL or 1,000 IC/mL. Allergen extracts solution for PRICK test used for the diagnosis of allergic diseases. 2. QUALITATIVE AND QUANTITATIVE COMPOSITION : A vial of solution contains: 100 IR/mL (standardised allergen extracts) or 100 or 1.000 IC/mL (non standardised allergen extracts) of one or several of the products specified in the list enclosed. IR (Index of Reactivity): An allergen extract titres 100 IR/mL when, used by prick-test with a Stallerpoint® on 30 people sensitised to this allergen, it gives a weal size of 7 mm diameter (geometric mean). The skin reactivity of these patients is simultaneously demonstrated by a prick-test using 9 % Codeine Phosphate or Histamine Dihydrochloride 10 mg/mL taken as positive control. IC (Index of Concentration): An allergen extract has an Index of Concentration of 100 IC/mL when its manufacturing parameters lead to the same mean dilution ratio that those of standardised extracts at 100 IR/mL from the same family extracts taken as reference. When the family does not contain any standardised reference extract, the value 100 IC/mL corresponds to an extract whose the dilution ration is established according to the medical experience. When allergens do not induce a sufficient activity, according to the medical experience a concentrated allergen extract can be used at the concentration of 1.000 IC/mL. 3. PHARMACEUTICAL FORM: Cutaneous solution for prick tests (micropuncture). This solution is used with a medical device enabling a very superficial lesion of the skin. 4. CLINICAL PARTICULARS: 4.1. Indications: Detection by skin testing of allergies of Type I in the Gell and Coombs classification, which are manifest mostly by rhinitis, conjunctivitis, rhinoconjunctivitis, asthma, of seasonal or perennial characteristics. Etiological diagnosis requires identification of the allergens that are responsible for the allergic disease. Skin tests are used to confirm type I hypersensitivity, regarding pollens, mites, animal origin allergens, food or other vegetal origin allergens, that is suspected after questioning the patient. 4.2. Dosage and method of administration: The prick-test consists of pricking the arm skin with an adequate medical device, for instance Stallerpoint®, through a drop of concentrated allergen extract. A negative control of diluent and a positive control of Codeine Phosphate or Histamine Hydrochloride are made under the same conditions. It is recommended to do these controls in duplicate to reduce the risk of false positives. The results are read on an average at 20 minutes. Evaluation of the sensitivity is made by comparison of the « weal + erythema » reaction due to the tested allergen with that due to the controls. It is generally agreed that the test is negative when the weal have a diameter less than 3 mm. Greater than this value, the test is considered to be positive. 4.3 Contraindications: In general, there are no contraindications to skin tests, except significant clinical symptoms of the allergic disease and any other current pathologies. 4.4 Special warnings and special precautions for use: Skin tests should be only done and interpreted by physicians. Skin tests should be made on a healthy skin, to avoid uninterpretable results and exacerbation of pre-existing dermatosis. In case of dermographism, it is essential to refer to the control tests because result evaluation is particularly delicate. 4.5. Interactions with others medicines and other forms of interactions: Antihistamine treatments may significantly reduce responses to skin tests. Quick acting antihistamines should be withdrawn for at least 48 hours and hydroxyzine, ketotifen and tricyclic antidepressors for at least 2 weeks. Antihistamines with prolonged action (astemizole) should be withdrawn for at least 6 weeks. The administration of corticosteroids, when the dose is limited to a daily dose equivalent to 30 mg prednisolone, does not significantly modify reaction to skin tests. It is not therefore necessary to stop their administration to proceed to the tests. However, it is preferable to suspend all applications of dermatocorticoids for 2-3 weeks before. 4.6. Pregnancy and lactation: Skin tests should be avoided during pregnancy. 4.7 Effects on ability to drive and to use machines: No known effect. 4.8 Undesirable effects: Tolerance is generally excellent. If the precautions of use are observed, secondary effects are rare. Local oedema, erythema and greater or less pruritis are found in all positive reactions. 4.9. Overdosage: According to the route and the method of administration, a possible overdosage is to be excluded. 5. PHARMACOLOGICAL PROPERTIES: Pharmacological group: Allergens, Immunological tests. ATC code: V01 AA05. Mechanism of action and pharmacodynamic effects: When skin tests are positive, they show the existence of antibodies specific for allergens to which the subject is sensitised. The local reaction that associates oedema, erythema and pruritis (Triad of Lewis) is the result of the in situ release of the mediators of allergy (Histamine, PAF-acether, ECFA, cytokines, etc.) triggered by the antigenantibody reaction. 6. PHARMACEUTICAL PARTICULARS: 6.1. List of excipients: Sodium Chloride, Glycerol, Phenol, Water For Injections; Mannitol (as part of the active substance). 6.2. Incompatibilities: None. 6.3. Shelf life: Never use after the expiry date which is clearly indicated on the vial. 6.4. Special precautions for storage: The Prick-test solution must be kept both between +2 and +8°C. The positive control solution must be stored at + 25°C. 6.5. Nature and contents of containers: ALYOSTAL PRICK is contained in 4.5 ml type I glass vial that is fitted with a dropper applicator, at the rate of 3 ml. 6.6. Instructions for use/handling: See paragraph 4.2 on « Dosage and method of administration ». Clean the forearm skin with alcohol and cotton and let it dry. Mark out with a rollerpoint where prick tests are going to be done. Deposit drops of allergen extracts on the skin then prick through each drop changing the Stallerpoint® each time. The pressure of each prick-test must be regular and moderate, i.e. a skin depression of 2 to 5 mm from Stallerpoint® basis must be observed. A good prick-test is characterized by the Stallerpoint® mark diameter on the skin. Before reading tests, clean well the skin with alcohol or ether to eliminate all phenolated glycerosaline liquid. The reading may be done with tracing paper or weal measure. 7. MANUFACTURER: STALLERGENES S.A. - 6, rue Alexis de Tocqueville ; 92160 ANTONY- France 8. PRESENTATION: Vials of several allergen extracts may be brought together in the same packaging. UPDATE DATE OF THE TEXT: September 2003.

Alyostal Prick®

48

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