This information is intended for use by health professionals

1. Name of the medicinal product

ALUTARD SQ Bee Initial Pack (100 SQ U/ml, 1 000 SQ U/ml, 10 000 SQ U/ml and 100 000 SQ U/ml), suspension for injection.

2. Qualitative and quantitative composition

ALUTARDALUTARD SQ Bee contains allergen from honey bee venom (Apis mellifera) adsorbed to aluminium hydroxide, hydrated.

The biological activity of ALUTARD SQ Bee is related to the concentration of the allergen and is expressed in SQ-U/ml.

Table 1: Vial number and strength

Vial No.

(Colour code)

Strength (SQ-U/ml)

Aluminium content in adjuvant (mg/ml)

1 (Grey)

100

0.00113

2 (Green)

1000

0.0113

3 (Orange)

10 000

0.113

4 (Red)

100 000

1.13

For a full list of excipients, see section 6.1.

3. Pharmaceutical form

Suspension for injection.

The suspension is white to faintly brown or green.

4. Clinical particulars
4.1 Therapeutic indications

Allergy immunotherapy for patients with a documented history of generalised and/or systemic IgE-mediated allergic reactions due to sensitisation to honey bee venom (Apis mellifera), confirmed by skin prick test and/or intradermal test and/or specific IgE test.

4.2 Posology and method of administration

Treatment with ALUTARD SQ Bee should be carried out under the supervision of a doctor experienced in specific immunotherapy. After each injection, the patient must be observed for at least 30 minutes.

Posology

The treatment is divided into two phases; an up-dosing phase and a maintenance phase. The aim is to gradually increase the dose until the highest tolerated maintenance dose is reached. The highest recommended maintenance dose is 1 ml of 100 000 SQ-U/ml (vial 4). The dosing of ALUTARD SQ Bee must always be adjusted according to the allergenic anamnesis and the patient's sensitivity to the specific allergen (see 4.4).

Up-dosing phase:

Recommendations for up-dosing are given in table 2, 3 and 4. The recommendations given in the tables are to be considered as a guidance. The patient should be informed that local and general reactions may occur during the up-dosing phase (see section 4.8). The choice of up-dosing schedule depends on the patient's sensitivity since the risk of developing allergic reactions is reduced with a slow up-dosing.

Table 2: 7-week up-dosing (cluster) which is recommended in cases when there is a need for faster protection.

Vial

no

Strength

SQ-U/ml

Week

no

Injection

no

Volume

ml

Dosage

SQ-U

1

100

1

1

0.1

10

2

1 000

2

0.1

100

3

10 000

3

0.1

1 000

10 000

2

4

0.2

2 000

10 000

5

0.2

2 000

10 000

3

6

0.5

5 000

10 000

7

0.5

5 000

4

100 000

4

8

0.2

20 000

100 000

5

9

0.4

40 000

100 000

6

10

0.6

60 000

100 000

7

11

1.0

100 000

Table 3: 15-week up-dosing (conventional) which is suitable for the majority of patients.

Vial

no

Strength

SQ-U/ml

Week

no

Injection

no

Volume

ml

Dosage

SQ-U

1

100

1

1

0.2

20

100

2

2

0.4

40

100

3

3

0.8

80

2

1 000

4

4

0.2

200

1 000

5

5

0.4

400

1 000

6

6

0.8

800

3

10 000

7

7

0.2

2 000

10 000

8

8

0.4

4 000

10 000

9

9

0.8

8 000

4

100 000

10

10

0.1

10 000

100 000

11

11

0.2

20 000

100 000

12

12

0.4

40 000

100 000

13

13

0.6

60 000

100 000

14

14

0.8

80 000

100 000

15

15

1.0

100 000

Table 4: 25-week up-dosing (extended conventional) recommended for sensitive patients.

Vial

no

Strength

SQ-U/ml

Week

no

Injection

no

Volume

ml

Dosage

SQ-U

1

100

1

1

0.2

20

100

2

2

0.4

40

100

3

3

0.8

80

2

1 000

4

4

0.2

200

1 000

5

5

0.4

400

1 000

6

6

0.8

800

3

10 000

7

7

0.1

1 000

10 000

8

8

0.2

2 000

10 000

9

9

0.3

3 000

10 000

10

10

0.4

4 000

10 000

11

11

0.5

5 000

10 000

12

12

0.6

6 000

10 000

13

13

0.7

7 000

10 000

14

14

0.8

8 000

10 000

15

15

0.9

9 000

4

100 000

16

16

0.1

10 000

100 000

17

17

0.2

20 000

100 000

18

18

0.3

30 000

100 000

19

19

0.4

40 000

100 000

20

20

0.5

50 000

100 000

21

21

0.6

60 000

100 000

22

22

0.7

70 000

100 000

23

23

0.8

80 000

100 000

24

24

0.9

90 000

100 000

25

25

1.0

100 000

Maintenance phase:

When the maintenance dose is reached, the interval between injections is gradually increased. The interval is increased from 1 to 2, 4 and 6 to 8 weeks. Subsequently, the injections are given every 6 to 8 weeks. The maintenance treatment is continued for 3-5 years.

If the patient responds with severe allergic reactions during the up-dosing phase, it is possible that the highest recommended dose of 100 000 SQ-U is not reached. A lower dose should then be considered as the maximal tolerated dose for the patient, and this will be the maintenance dose.

Exceeded time interval between two visits

If the recommended time interval between visits has been exceeded, the dosing of the following injection is handled according to the following recommendation:

Table 5: Exceeded time interval between two visits during the up-dosing phase

Weeks between visits

Dosage

Up to 2 weeks

Continue up-dosing according to table 2, 3 or 4

2 - 3 weeks

Repeat previous dose

3 - 4 weeks

Reduce to 50 % of previous dose

4 weeks or more

Restart up-dosing according to table 2, 3 or 4

Table 6: Exceeded time interval between two visits during the maintenance phase

Weeks between visits

Dosage

Up to 8 weeks

Continue with the maintenance dose

8 - 10 weeks

Reduce to 75 % of previous dose

10 - 12 weeks

Reduce to 50 % of previous dose

12 – 14 weeks

Reduce to 25 % of previous dose

14 - 16 weeks

Reduce to 10 % of previous dose

16 weeks or more

Restart up-dosing according to table 2, 3 or 4

In case of a dose reduction in the maintenance phase, the patient must be carefully observed after the injection. Subsequently, up-dose according to the recommendations in table 2, 3 or 4 until the maximal maintenance dose is reached.

Concomitant treatment with more than one allergen

In case of treatment with more than one allergen concomitantly, the injections should be given in different locations on the arm. In order to evaluate possible allergic reactions caused by the specific allergen it is recommended to give the injections with a 30 minute interval.

Dose reduction in case of allergic reactions

Dose reductions in case of local reactions

If an injection site reaction persists for more than 6 hours after the injection, the following dose reduction is recommended depending on the size of the swelling:

Table 7: Recommended dose-reduction in case of local adverse events

Maximum diameter of swelling

Recommended dose reduction

Children

Adults

< 5 cm

< 8 cm

Continue up-ward titration according to schedule (table 2, 3 or 4)

5-7 cm

8-12 cm

Repeat dose last given

7-12 cm

12-20 cm

Reduce dose to dose given the time before last

12-17 cm

>20 cm

Reduce dose to dose given 2 times before last

>17 cm

-

Reduce dose to dose given 3 times before last

Dose reduction in case of systemic reactions

If a serious systemic reaction (see section 4.8) occurs after injection, the treatment should only be continued after careful consideration. If the treatment is continued, the following dose should be reduced to 10% of the dose provoking the reaction.

The chosen reduced dose can be split into two injections given with a 30 minute interval. The patient should be observed after the injections. Subsequently, up-dose according to recommendations in table 2, 3 or 4 until the maximal tolerated dose or 100 000 SQ-U is reached.

Elderly population

No additional dose adjustment is required in the elderly population.

Paediatric population

No additional dose adjustment is required in the paediatric population. See section 4.4.

Method of administration

After each injection, the patient must be observed for at least 30 minutes. On the day of injection the patient must avoid physical exercise, hot baths and alcohol as these co-factors may potentially amplify an anaphylactic reaction.

ALUTARD SQ Bee is administered subcutaneously. The vials must be inverted up and down 10 - 20 times before use. The injection is given either laterally in the distal part of the upper arm or dorsally in the proximal part of the forearm.

Avoid intravascular injection by careful aspiration before injection. Aspiration must be repeated for every 0.2 ml during the injection and the injection must be given slowly. An anaphylactic emergency kit must be available while using ALUTARD SQ Bee. Please refer to section 4.4 for warnings and precaution in relation to treatment.

Precautions in relation to administrations

The injection should be postponed:

- If the patient has a fever or shows other clinical signs of a chronic or acute infection.

- If the patient has an atopic dermatitis that has exacerbated.

- If the patient has had an allergic reaction within the last 3-4 days prior to the injection.

- If other kinds of vaccinations have been given, wait at least a week before treatment with ALUTARD SQ is continued. Other vaccinations should not be given earlier than a week after an ALUTARD SQ injection.

Before injection:

- Double check the allergen, concentration, volume and previous injection date (dosing interval), prior to each injection.

- ALUTARD SQ Bee is intended for subcutaneous injection. Intravenous administration must be avoided due to the increased risk of allergic reactions.

- Allergic reactions (both local and systemic) which occurred during the previous injections should be recorded and the dose should be assessed on the basis of this.

- Pre-treatment with H1 antihistamines should be considered in the up-dosing phase for patients who experience large local reactions or systemic allergic reactions.

- The patient's state of health and allergy status must be evaluated as well as any changes of other medication since the last administered injection (see section 4.4 and 4.5).

- The asthma status, in patients with a medical history of asthma, must be evaluated prior to injection (see section 4.4).

After injection:

- The patient must be advised to consult a doctor or emergency room immediately in case of severe systemic delayed reactions.

- The patient must be advised to observe any local or systemic reactions that may occur subsequently, and to inform the attending doctor at the next visit.

- Any allergic reactions (both local and systemic) should be recorded before the patient leaves the clinic.

4.3 Contraindications

- Hypersensitivity to any of the excipients listed in section 6.1.

- Patients with active or poorly controlled systemic autoimmune diseases and immunodeficiency disorders.

- Patients with disorders or conditions where an induced anaphylactic reaction imply an unacceptable risk such as severe cardiovascular disease.

- Asthma patients at risk of exacerbation and/or with inadequate symptom control defined as the presence of:

loss of symptom control within the last four weeks (e.g. increase in daytime symptoms, nightly wakening, increased need of medication, activity limitations).

4.4 Special warnings and precautions for use

Severe systemic allergic reactions

Due to the risk of serious allergic reactions, immediate access to full resuscitation equipment and drugs must be available, including adrenaline for injection and staff trained in the use thereof. If symptoms of a systemic reaction, such as urticaria, angioedema or severe asthma occur, symptomatic treatment should be initiated immediately (see section 4.2 and 4.8).

Cardiovascular diseases

Patients with cardiac diseases may be at increased risk in case of systemic allergic reactions. Patients with cardiovascular diseases must be sufficiently treated for the underlying condition prior to the initiation of ALUTARD SQ Bee treatment. In connection with the treatment with ALUTARD SQ Bee special attention should be given. See section 4.3. Clinical experience in treatment with ALUTARD SQ Bee of patients with cardiac diseases is limited.

Autoimmune diseases

There are no controlled studies on the influence of autoimmune disorders on the efficacy of allergy immunotherapy (AIT), or on autoimmune disorders as a predisposing factor for severe side effects during AIT. AIT may only be initiated in patients with autoimmune diseases in case of disease remission or well-adjusted therapy. ALUTARD SQ Bee should therefore be prescribed with caution in these patients.

Malignant neoplastic diseases

There are no controlled studies on the influence of malignant neoplastic diseases on the efficacy of AIT, or on malignant neoplastic diseases as a predisposing factor for severe side effects during ALUTARD SQ Bee immunotherapy. AIT may only be initiated when the malignant disease is stable. In case of aggravation treatment with ALUTARD SQ Bee should be discontinued. ALUTARD SQ Bee should therefore be prescribed with caution in these patients.

Mastocytosis

Patients with increased baseline serum tryptase and/or mastocytosis may be at an increased risk of developing systemic allergic reactions and the severity of these may be increased. Patients with mastocytosis should therefore be monitored carefully during treatment with ALUTARD SQ Bee. Patients with mastocytosis may expect less efficacy of treatment compared with the general insect venom allergic population.

Treatment with ACE-inhibitors

Patients simultaneously treated with ACE inhibitors may be at higher risk of developing more severe anaphylactic reactions and should therefore be carefully monitored during the up-dosing phase. Temporarily interrupting the ACE inhibitor treatment (based on the half-life of the ACE inhibitor) should be considered carefully in relation to the advantages of immunotherapy in the individual patient. ACE inhibitors might reduce the effect of ALUTARD SQ Bee.

Treatment with MAO-inhibitors, COMT- inhibitors or beta-blockers

One option for treating severe systemic allergic reactions is adrenaline. The effects of adrenaline may be potentiated in patients treated with tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs) and/or COMT inhibitors with possible fatal consequences. The effects of adrenaline may be reduced in patients treated with beta-blockers. In addition, the effects of adrenaline may exacerbate cardiovascular disease, e.g .cause cardiac arrhythmia. Patients in treatment with beta-blockers should be carefully monitored during the up-dosing phase.

Asthma

Asthma is a known risk factor for severe systemic allergic reactions. In patients with asthma, the asthma symptoms should be adequately controlled prior to the initiation of ALUTARD SQ Bee treatment. In connection with the treatment with ALUTARD SQ Bee special attention should be given. The patient´s asthma condition must be assessed prior to each injection (see section 4.3).

Patients must be informed of the need to seek medical attention immediately if their asthma suddenly deteriorates. Clinical experience in treatment with ALUTARD SQ Bee of patients with asthma is limited.

Other populations (including patients with renal dysfunction)

As ALUTARD SQ Bee contains aluminium, there is a theoretical risk of aluminium accumulation in patients at high risk (e.g. patients with renal dysfunction and patients concomitantly treated with other aluminium containing drugs (e.g. antacids)). This should be considered when initiating therapy with ALUTARD SQ Bee.

Paediatric population

Special care should be given to the risk-benefit assessment with regard to the treatment of children younger than 5 years of age. For children ≥ 5 years of age clinical data of efficacy are sparse, however data on safety do not reveal a higher risk as for adults. A risk-benefit assessment with regard to the treatment of children ≥ 5 years of age is also recommended.

Co-administration with other AIT

No clinical experience on co-administration with other types of allergy immunotherapy is available.

This medicinal product contains less than 1 mmol sodium (23mg) per dose, i.e essentially 'sodium-free'.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been conducted in humans and no potential drug interactions have been identified from any source. Concomitant treatment with symptomatic anti-allergy medications, e. g. antihistamines, corticosteroids and mast cell stabilisers may increase the patient's tolerance level towards the allergen injections. This should be considered at discontinuation of such medications.

For information considering concomitant use of ACE inhibitors, MAOIs, COMT inhibitors, beta-blockers and antacids see section 4.4.

4.6 Fertility, pregnancy and lactation

Pregnancy

There is no clinical experience of the use of ALUTARD SQ Bee during pregnancy. Up-dosing treatment should not be initiated during pregnancy. If pregnancy occurs during maintenance treatment, the maintenance treatment may continue after a careful evaluation of the patient's general condition and reactions to previous injections with ALUTARD SQ Bee.

Breastfeeding

No clinical data is available on the use of ALUTARD SQ Bee during breastfeeding. No effects on the breastfed infants are anticipated.

Fertility

There are no clinical data available related to the effect of ALUTARD SQ Bee on fertility.

4.7 Effects on ability to drive and use machines

ALUTARD SQ Bee may in some cases influence the ability to drive or use machines due to the side effect vertigo.

4.8 Undesirable effects

Summary of the safety profile

Generally, reactions appearing in connection with ALUTARD SQ Bee treatment occur due to an immunological reaction (local and /or systemic) to honey bee venom. Symptoms of an immediate reaction appear within the first 30 minutes after the injection. Symptoms of a delayed reaction appear within the first 24 hours after the injection.

Commonly reported adverse reactions in patients treated with ALUTARD SQ Bee are local reactions at the injection site.

The most serious adverse drug reaction occurring in patients treated with ALUTARD SQ Bee is anaphylactic shock. As it is a life threatening condition, it demands immediate treatment.

Tabulated list of adverse reactions

Data from clinical trials with ALUTARD SQ Bee are limited. Therefore, the following table is based on adverse drug reactions for the product reported spontaneously from the market. The frequency is not known (cannot be estimated from the available data).

System Organ Class

Adverse Drug Reaction

Frequency

Immune system disorders

Systemic allergic reactions including anaphylactic shock

Not known

Nervous system disorder

Headache, dizziness, paraesthesia

Not known

Eye disorders

Eyelid oedema, conjunctivitis, eye pruritus

Not known

Ear and labyrinth disorders

Vertigo

Not known

Cardiac disorders

Tachycardia, palpitations

Not known

Vascular disorders

Hypotension, pallor, flushing

Not known

Respiratory, thoracic and mediastinal disorders

Throat tightness, wheezing, cough, dyspnoea, asthma, throat irritation, nasal congestion

Not known

Gastrointestinal disorders

Dysphagia, diarrhoea, vomiting, nausea, abdominal pain

Not known

Skin and subcutaneous tissue disorders

Urticaria, pruritus, rash, erythema, angioedema, swollen face

Not known

Musculoskeletal and connective tissue disorders

Arthralgia, Joint swelling

Not known

General disorders and administration site conditions

Injection site swelling, injection site urticaria, injection site nodule, injection site pain, injection site granuloma, injection site erythema, injection site pruritus, feeling hot, sensation of foreign body, peripheral swelling, chest discomfort, fatigue, malaise

Not known

Local reactions

Local reactions can be treated with symptomatic medication, e.g. antihistamines.

▪ Injection site reactions consist of one or several of the following symptoms: diffuse swelling, redness, pain, itching and injection site urticaria. These symptoms most often appear within 30 minutes and may also persist after 6 hours. Generalized pruritus may also occur.

▪ Subcutaneous nodules at the injection site have been observed after repeated injections.

The aluminium content may contribute to the occurrence of local adverse effects including positive skin patch test for aluminium.

Systemic allergic reactions

Mild to moderate systemic allergic reactions might occur and can be effectively treated with symptomatic medications, e.g. antihistamines. Literature reporting of systemic reactions associated with the use of ALUTARD SQ Bee and/or ALUTARD SQ Wasp varied from 0% to 25% in the up-dosing phase and from 0% to 16% in the maintenance phase.

Symptoms that may be associated with a systemic allergic reaction may include but are not limited to urticaria, angioedema, dyspnoea, cough, bronchospasm, rhinitis, wheezing, chest tightness, asthma, tachycardia and hypotension. Other symptoms of a systemic allergic reaction can be fatigue, general discomfort, headache, abdominal pain, vomiting, diarrhoea, flushing, rash, pruritus, conjunctivitis or sneezing.

A severe systemic allergic reaction is a potentially life-threatening reaction that usually occurs within a few minutes after the patient has been exposed to the allergen. A severe systemic allergic reaction requires immediate treatment with e.g. adrenalin and/or other anaphylactic treatment.

In case of large local reactions and systemic reactions an evaluation of the treatment must be performed (see section 4.2 and section 4.4).

Atopic dermatitis

Atopic dermatitis may be exacerbated during treatment.

Paediatric population

Limited data from clinical trials on the adverse events in children is available. Available safety data does not indicate additional risks related to the use of ALUTARD SQ in the paediatric population.

Other special populations

No data from clinical trials on the adverse events in other populations available.

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 Yellow Card Scheme (www.mhra.gov.uk/yellowcard) or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

If a higher dose of ALUTARD SQ Bee than intended is injected, the risk of side effects increases including the risk of developing a serious allergic reaction. The patient must be observed and any reaction must be treated with relevant symptomatic medication.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Allergen extracts, insects

ATC-code: V01AA07

Pharmacodynamic effects and mechanism of action

ALUTARD SQ Bee is an allergen specific desensitization immunotherapy. The target organ for the pharmacodynamic effect is the immune system. The aim is to suppress the reaction toward the allergen that the patient is treated with. AIT has various effects on the immune system: The recruitment of T-lymphocytes and eosinophilic granulocytes to the target organ is inhibited, and is followed by a pronounced shift from the production of Th2 cytokines to the production of Th1 cytokines. In addition, the synthesis of IL-10 is increased which may lead to T-lymphocyte anergy. Release of histamine from peripheral blood basophils is decreased, which is a result of the decreased number of recirculating basophils. Serological studies on ALUTARD SQ Bee have found a temporary increase in IgE early during treatment, while there is a substantial longterm rise in IgG.

Clinical efficacy and safety

Due to the potential life-threatening nature of allergic reactions to honey bee stings and for ethical reasons, all available data on efficacy and safety come from clinical studies that have not been placebo controlled. Studies conducted over the past 30 years with a duration of up to 5 years on the efficacy and safety of ALUTARD SQ Bee have demonstrated high clinical efficacy and a favourable safety profile.

Efficacy studies conducted with ALUTARD SQ Bee using controlled in-hospital sting challenge as an endpoint generally demonstrated high clinical efficacy with similar protection rates between studies. The in-hospital sting challenges were performed after 6 to 12 months of treatment, and the fraction of sensitised subjects tolerating a re-sting without experiencing a systemic reaction was 25 out of 30 among subjects receiving ALUTARD SQ Bee (numbers based on 1 clinical trial).

Paediatric population

Paediatric studies on efficacy and safety of venom extracts from honey bee are limited. Clinical data on children below 5 years of age are too limited to draw any conclusions regarding efficacy or safety of ALUTARD SQ.

5.2 Pharmacokinetic properties

Adsorption of the allergen to aluminium hydroxide results in a slow release from the injection site. By subcutaneous injection, the allergen is slowly released which reduces the allergenicity and possibly prolongs the stimulation of the immune system.

5.3 Preclinical safety data

No relevant preclinical safety data is available in addition to the information already included in other sections of the summary of products characteristics.

6. Pharmaceutical particulars
6.1 List of excipients

Sodium chloride

Sodium hydrogen carbonate

Phenol

Water for injection

Sodium Hydroxide (for pH adjustment)

For adjuvants please see section 2.

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf life

3 years

Shelf life after opening of vial is 6 months when used for one individual patient and when stored in refrigerator (2°C – 8°C).

6.4 Special precautions for storage

Store in refrigerator (2°C – 8°C).

Do not freeze.

Store in the original package (sensitive to light).

For storage conditions after first opening of the medicinal product, see section 6.3.

6.5 Nature and contents of container

ALUTARD SQ Bee is supplied in glass vials (type I) fitted with a laminated halobutyl elastomer stopper and sealed with a colour coded aluminium cap with a flip-off centre.

ALUTARD SQ Bee is available in two different packs, an up-dosing pack and a maintenance pack (100 000 SQ U/ml).

Table 9: Up-dosing pack, 4 x 5 ml

Vial no.

Strength (SQ-U/ml)

Colour code

1

100

Grey

2

1 000

Green

3

10 000

Orange

4

100 000

Red

Table 10: Maintenance pack, 5 ml

Vial no.

Strength (SQ-U/ml)

Colour code

4

100 000

Red

6.6 Special precautions for disposal and other handling

The vials must be inverted up and down 10 - 20 times before use.

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 Allé 6 - 8

DK-2970 Hørsholm

Denmark

8. Marketing authorisation number(s)

PL 10085/0055

9. Date of first authorisation/renewal of the authorisation

08/03/2019

10. Date of revision of the text

08/03/2019