SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Pharmalgen Bee Venom powder and solvent for solution for injection

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

The active ingredient is freeze-dried Apis mellifera (Honey Bee) venom.

Four strengths are available. The vials are distinguished by differently coloured vial caps and number.

Content of active ingredient in Pharmalgen Bee Venom:

Vial 1 0.12 pg Vial 2 1.2 pg Vial 3 12 pg Vial 4 120 pg

For a full list of excipients, se section 6.1

3    PHARMACEUTICAL FORM

Powder and solvent for solution for injection.

4    CLINICAL PARTICULARS

4.1 Therapeutic indications

Diagnosis and treatment of IgE-mediated allergy to bee venom.

4.2 Posology and method of administration

Diagnosis

Diagnosing allergy to bee venom using Pharmalgen Bee Venom should be carried out using either a skin prick test or an intracutaneous test.

Skin prick test:

A concentration of 100 ^g venom/ml is recommended for use in a skin prick test. However, for extremely sensitive patients, testing with a lower concentration (e.g. 1 or 10 ^g venom/ml) is advisable.

Alternatively, an end-point titration test can be used to determine individual starting concentrations for specific immunotherapy. The end-point titration test is performed using concentrations of venom from 0.01 ^g venom/ml. If a positive reaction is observed at 0.01 ^g venom/ml, retesting must be performed using a lower concentration. The lowest concentration resulting in a positive reaction is used as the end-point.

The reaction is read after 15-20 minutes. A reaction is considered positive when a weal with a diameter of more than 3 mm is observed.

Albumin Diluent should be used for dilution and as control.

Intracutaneous test:

The intracutaneous test is 100-1000 times more sensitive than the skin prick test.

The intracutaneous test should always be performed as an end-point titration test. It is recommended to start with a concentration of 0.0001 ^g venom/ml and increase the concentration stepwise by a factor ten every 20 minutes until a positive reaction is observed. If a positive reaction is observed at 0.0001 ^g venom/ml, retesting must be performed using a lower concentration. The lowest concentration causing a positive reaction is taken as the end-point.

Concentrations of > 1 ^g venom/ml are not recommended for the intracutaneous test as these may cause non-specific reactions.

The reaction is read after 15-20 minutes. A reaction is considered positive if a weal with a diameter of more than 5 mm and with erythema is observed.

Albumin Diluent should be used for dilution and as control.

Treatment

IgE-mediated allergy to bee venom must be confirmed by case history and by in vivo and/or in vitro diagnosis prior to initiating treatment with Pharmalgen Bee Venom.

Treatment with Pharmalgen Bee Venom must be performed using subcutaneous injections. Intravenous administration must be avoided due to an increased risk of potentially fatal anaphylactic reactions.

The dosage of Pharmalgen Bee Venom must be individually adjusted. The dosage should depend on the patient's general condition, the allergenic anamnesis and the patient's sensitivity to the specific allergen used.

Treatment with Pharmalgen Bee Venom is in two phases, the Initial Phase and the Maintenance Phase.

Initial Phase:

In the Initial Phase, the dose of Pharmalgen Bee Venom is increased stepwise until the maximum tolerated (maintenance dose) has been reached.

The initial dose is defined as 0.1 ml of the concentration which is 1000 times lower than the end-point concentration obtained in the skin prick test and 10 times lower the end-point concentration obtained in the intracutaneous test.

For every further injection, the dose should be increased by a factor of ten until a final concentration of 0.01 ^g venom/ml has been reached. From this point, further injections should be given according to recommendations shown in Table I, II or III.

Three dosage schedules intended as general guidelines in establishing a maintenance dose are shown in the tables below.

Each dose must be adapted to the individual patient’s reactivity and should only be increased if the previous injection was well tolerated. In all other cases, including interruptions in therapy (infections, vaccinations, holidays, etc.), the dose must be reduced accordingly.

Table Ib:

Recommended dose reduction if an interval between 2 injections has been exceeded while following the Conventional Dosage Schedule.

Exceeding of interval	Recommended dose reduction
> 1 - 2 weeks	Repeat the last administered dose
> 2 - 3 weeks	Reduce dose to 1/2 of the last dose

100	0.9	90
100	1.0	100

* Dose may be lower

epending on the patient's sensitivity.

Maintenance Phase:

The recommended concentration for the maintenance dose is 100 pg venom/ml administered in a volume of 1 ml. However, the strength of the maintenance dose depends on the patient’s sensitivity towards the allergen and should be determined individually on the basis of the patient's response during the Initial Phase.

If allergic reactions are observed after bee stings in patients who have achieved the maximum dose of 100 pg Pharmalgen Bee Venom, the dose can be cautiously increased up to 200 pg.

When the maintenance dose has been attained, the interval between the injections is increased stepwise to two, three and four weeks. The maintenance dose is then administered every four weeks for a period of at least three years.

Table IV: Dose reduction for Maintenance Phase Dosage Schedule

Recommended dose reduction if an interval between two injections has been exceeded while following the Maintenance Phase.

Exceeding of interval	Recommended dose reduction
> 4 - 6 weeks	Reduce dose to 3/4 of last dose
> 6 - 8 weeks	Reduce dose to 1/2 of last dose
> 8 - 10 weeks	Reduce dose to 1/4 of last dose
> 10 weeks	Re-initiate treatment from baseline

Dose reduction when systemic reactions are observed

If a severe, systemic reaction occurs after injection (see section 4.8), the treatment with Pharmalgen Bee Venom should only be continued after careful consideration. If treatment is continued, it may be considered to reduce the following dose to 10% of the dose provoking the reaction.

Dose reduction when large injection site reactions are observed

If an injection site reaction with a diameter of 8 cm or more for adults (5 cm or more for children) occurs and is present for more than 6 hours, the subsequent dose should be reduced according to the table below.

Maximum diameter of swelling
Children	Adults	Recommended dose reduction
< 5 cm	< 8 cm	Continue upward titration according to up-dosing schedule
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

Concomitant treatment of more than one allergy

Pharmalgen venom extracts must not be mixed. Patients who are allergic to more than one type of venom should initiate treatment with one type of venom first. When the maintenance dose has been attained, treatment with the other type of venom may be initiated. The maintenance injections of the two types of venom should be given with an interval of 2 - 3 days.

4.3    Contraindications

Pharmalgen Bee Venom is contraindicated in patients:

•    with hypersensitivity to any of the excipients listed in section 6.1

•    with immune pathologic conditions such as immune complex and immunodeficiency diseases

•    with diseases or conditions preventing the treatment of possible anaphylactic reactions, e.g. chronic heart and lung diseases, severe arterial hypertension and treatment with ^-blockers (see section 4.5)

•    treated with tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs) (see section 4.5)

•    with malignancy

•    with severe chronic or severe seasonal asthma (FEV₁ consistently under 70% of predicted value after adequate pharmacologic treatment)

•    treated with ACE inhibitors (see section 4.5)

4.4    Special warnings and precautions for use

Treatment with Pharmalgen Bee Venom should be administered under supervision of a doctor experienced in specific immunotherapy.

Due to the risk of potentially fatal anaphylactic reactions, treatment with Pharmalgen Bee Venom must be carried out in clinics or hospitals where facilities for cardiopulmonary resuscitation are immediately available for use by adequately trained personnel.

According to national guidelines the patients must be observed for 60 minutes after having received an injection with Pharmalgen Bee Venom. If symptoms of an immediate systemic reaction (e.g. generalised urticaria, angioedema or severe asthma) are observed within this period, symptomatic treatment should be initiated.

Special care should be given to the risk-benefit assessment with regard to 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.

If treatment with Pharmalgen Bee Venom in the Initial Phase is performed according to the Rushed Dosage Schedule, the patient must be hospitalised.

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 (see section 4.5).

Treatment precautions to be taken:

•    The patient’s lung function should be evaluated before treatment with Pharmalgen Bee Venom is initiated (see section 4.3)

•    Patients should be instructed to avoid strenuous physical exercise, hot baths and alcohol on the day of injection

•    Any allergic reactions following previous treatment with Pharmalgen Bee Venom should be documented and dosage should be evaluated

•    The patient’s tolerance of Pharmalgen Bee Venom may change if other anti-allergy medication is altered

•    Prior to each injection check for cloudiness or any indication of contamination, particularly in vials that have already been opened

•    In patients with increased baseline serum tryptase levels and/or mastocytosis, the risk of systemic allergic reactions and the severity of these may be increased

•    Patients suffering from mastocytosis may expect less efficacy compared with the general insect venom allergic population

Adjustment or postponement of dosage is required if:

The patient has fever or shows other clinical signs of acute or chronic infection

•    The patient has experienced allergic symptoms within the last 3-4 days before treatment with Pharmalgen Bee venom

•    The patient shows reduced lung function (peak flow or FEVi < 70% of expected value)

•    The patient has experienced local or systemic reactions during previous treatment with Pharmalgen Bee Venom

•    Atopic dermatitis has become exacerbated

•    Other vaccinations have been given in the week before treatment with Pharmalgen Bee Venom (see section 4.5)

4.5 Interaction with other medicinal products and other forms of interaction

In rare cases ACE inhibitors may exacerbate the response to insect venom, resulting in potentially life threatening allergic reactions to insect stings or venom immunotherapy. Temporary discontinuation of ACE inhibitor treatment (based on the half-life of the ACE inhibitor in question) would avoid this potential risk. However, the risk of discontinuing treatment with an ACE inhibitor should be carefully balanced against the benefit of the allergy immunotherapy in patients with bee venom induced systemic reactions (See section 4.3).

Antihistamines and bronchodilators may increase tolerance. The patient must be consistent in his use of these in the 24 hours before each injection (see section 4.4).

Other vaccines should not be given within 7 days before or after an injection (see section 4.4).

In rare cases patients treated with allergen-specific immunotherapy (including bee venom) experience systemic allergic reactions including anaphylactic reactions. The choice of treatment for anaphylactic reactions is adrenaline.

P-blockers interact with adrenaline and the use of P-blockers is therefore preventing the treatment of possible anaphylactic reactions. Concomitant use of bee venom and P-blockers is contraindicated (see section 4.3).

Tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs) potentiate adrenaline and increase the risk of cardiac arrhythmias (with possible fatal consequence) preventing treatment of possible anaphylactic reactions. Concomitant use of bee venom and tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs) are contraindicated (see section 4.3).

4.6 Fertility, pregnancy and lactation

Pregnancy:

The risk to the mother and the foetus of an anaphylactic reaction must be considered. Treatment should not be initiated during pregnancy.

Lactation:

No clinical data is available on the use of Pharmalgen Bee Venom during lactation.

Fertility:

There is no clinical data with respect to fertility for the use of Pharmalgen.

4.7 Effects on ability to drive and use machines

Delayed general reactions are extremely rare, and the reactions are occurring shortly after injection. Pharmalgen Bee Venom is therefore not presumed to influence on the ability to drive or use machines.

4.8 Undesirable effects

Generally, reactions in connection with the treatment with Pharmalgen are due to an immunological reaction (local and /or systemic) to the respective allergen. Symptoms of an early reaction appear within the first 30 minutes after injection. Symptoms of a delayed reaction normally appear within 24 hours after injection.

Very commonly reported adverse reactions in patients treated with Pharmalgen were local reactions at the injections site.

Adverse reactions are divided into groups according to the MedDRA-convention frequencies: Very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000 to <1/100), rare (>1/10,000 to <1/1,000), very rare (<1/10,000), Frequencies are based on clinical trials with immunotherapy in general. Not known means that the frequency cannot be estimated from the available data and is based on post marketing experience.

System Organ Class	Frequency	Adverse Drug Reaction
Immune system disorders	Uncommon	Anaphylactic reaction
	Rare	Anaphylactic shock
Nervous system disorders	Very common	Headache
	Not known	Dizziness, paraesthesia
Eye disorders	Common	Conjunctivitis
	Not known	Eyelid oedema
Ear and labyrinth disorders	Not known	Vertigo
Cardiac disorders	Not known	Palpitations, tachycardia, cyanosis
Vascular disorders	Common	Flushing
	Not known	Hypotension, pallor
Respiratory, thoracic and mediastinal disorders	Common	Wheezing, cough, dyspnoea
	Not known	Asthma, nasal congestion, allergic rhinitis, sneezing, broncospasms, throat irritation, throat tightness
Gastrointestinal disorders	Common	Diarrhoea, vomiting, nausea, dyspepsia
	Not known	Abdominal pain
Skin and subcutaneous tissue disorders	Common	Urticaria, pruritus, rash
	Not known	Angioedema, erythema
Musculoskeletal and connective tissue disorders	Uncommon	Back pain
	Not known	Joint swelling, arthralgia
General disorders and administration site conditions	Very common	Injection site swelling
	Common	Injection site pruritus, injection site urticaria, discomfort, fatigue
	Not known	Pruritis, chest discomfort, chills, injections site erythema, injection site pain, sensation of foreign body

Local reactions are reactions occurring at the injection site and include injection site swelling, redness, pain, itching, discolouration and haematoma.

Systemic reactions are any symptoms from organs distant from location of injection. Systemic reactions can vary from allergic rhinitis to an anaphylactic shock. Treatment of a severe systemic reaction must be initiated immediately

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the MHRA Yellow Card Scheme at www.mhra.gov.uk/yellowcard. By reporting side effects you can help provide more information on the safety of this medicine.

4.9 Overdose

In case of overdose, the risk of systemic reactions increases. The patient must be observed and any reaction must be treated with the relevant symptomatic and supportive measures. Anaphylactic emergency kit must be immediately available.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: allergen extracts, ATC Code: V01AA07 Skin Test

Superficial injection into the skin of a minute dose of specific allergen will produce a short-lived local reaction in subjects allergic to the allergen.

Treatment

Escalating the dose of Pharmalgen Wasp Venom according to the schedules described in section

4.2    encourages generation of blocking antibodies to such a level that protection from one or several stings may be developed. Resistance is sustained by maintenance doses.

5.2 Pharmacokinetic properties

Not Applicable.

5.3 Preclinical safety data

There are no preclinical data relevant for the prescribing doctor that is not already mentioned in other sections of the SPC.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Powder for solution for injection:

Mannitol

Human serum albumin

This medical product contains less than 1 mmol sodium (23mg) per does, i.e. essentially ‘sodium-free’

Albumin Diluent Human serum albumin Sodium chloride Phenol

Water for injection

6.2    Incompatibilities

This medical product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3    Shelf life

5 years

Shelf life after reconstitution with Albumin Diluent:

Concentration (pg venom/ml)	Shelf life
100	6 months
10	2 weeks
1	1 week
0.1	1 week
< 0.1	1 day

6.4 Special precautions for storage

Pharmalgen Bee Venom vials should be kept in the outer carton. Store in refrigerator (2°C - 8°C). Do not freeze. For storage of the reconstituted medicinal product, see section 6.3.

6.5    Nature and contents of container

Glass vials, chlorobutyl rubber stopper, aluminium cap. Pharmalgen Bee Venom is supplied in two types of packages:

Vial 1 + Albumin Diluent	0.12 pg	0.1 pg/ml	Grey
Vial 2 + Albumin Diluent	1.2 pg	1 pg/ml	Green
Vial 3 + Albumin Diluent	12 pg	10 pg/ml	Orange
Vial 4 + Albumin Diluent	120 pg	100 pg/ml	Red

Maintenance Treatment Set	Content	Concentration		Colour code
4 x (vial 4 + Albumin Diluent)	120 pg	100 pg/ml		Red

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Reconstitution of the freeze-dried substance

Prior to use Pharmalgen should be reconstituted in Albumin Diluent.

Only freeze-dried substance to be used subsequently should be reconstituted. The date for reconstitution and the expiry date for the reconstituted solution should be noted on the vial label.

Dilutions

Series of 10-fold dilutions should be prepared from the reconstituted solution. To obtain a 10-fold dilution 0.55 ml of the reconstituted solution should be injected into a vial containing 5.0 ml of Albumin Diluent. Further dilutions are prepared accordingly. New sterile syringes should be used for each concentration.

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

7 MARKETING AUTHORISATION HOLDER

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

8 MARKETING AUTHORISATION NUMBER(S)

PL 10085/0003

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 17 March 1995 Date of latest renewal: 7 June 2002

DATE OF REVISION OF THE TEXT

04/06/2014