PHARMALGEN WASP VENOM POWDER AND SOLVENT FOR SOLUTION FOR INJECTION - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Pharmalgen Wasp Venom powder and solvent for solution for injection

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

The active ingredient is freeze-dried Vespula spp. (Wasp) venom.

Content of active ingredient in Pharmalgen Wasp Venom is 120 ^g

For a full list of excipients, see 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 wasp venom.

4.2 Posology and method of administration

Diagnosis

Diagnosing allergy to wasp venom using Pharmalgen Wasp 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. For instructions on reconstitution and dilution of the product before administration, see section 6.6.

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. For instructions on reconstitution and dilution of the product before administration, see section 6.6. 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 wasp venom must be confirmed by case history and by in vivo and/or in vitro diagnosis prior to initiating treatment with Pharmalgen Wasp Venom.

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

Initial Phase:

In the Initial Phase, the dose of Pharmalgen Wasp 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 than 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 Ia: Conventional Dosage Schedule

One injection every 3–7 days

*      Dose may be lower, depending on the patient's sen­sitivity.

    To reduce the risk of secondary reactions, each dose of 5–100 pg venom/ml

may be divided into halves and given as 2 injections with an interval of 30 minutes.

Table Ib:

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

Table II: Modified Rush (Clustered) Dosage Schedule

The patient is given 2 – 4 injections per week at intervals of 30 minutes. If necessary this interval may be extended up to 2 weeks.

* Dose may be lower depending on the patient's sen­sitivity.

Table III: Rush Dosage Schedule

The patient is given an injection every 2 hours with a maximum of 4 injections per day. The patient must be hospitalised.

* Dose may be lower depending on the patient's sen­sitivity.

Maintenance Phase:

The recommended concentration for the maintenance dose is 100 ^g 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 wasp stings in patients who have achieved the maximum dose of 100 ^g Pharmalgen Wasp Venom, the dose can be cautiously increased up to 200 ^g.

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.

Dose reduction when systemic reactions are observed

If a severe, systemic reaction occurs after injection (see section 4.8), the treatment with PharmalgenWasp 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.

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 Wasp 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 P-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 Wasp 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 Wasp 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 Wasp 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 Wasp 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 Wasp 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 Wasp Venom should be documented and dosage should be evaluated

The patient’s tolerance of Pharmalgen Wasp 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 Wasp Venom

The patient shows reduced lung function (peak flow or FEV1 < 70% of expected value)

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

Atopic dermatitis has become exacerbated

Other vaccinations have been given in the week before treatment with Pharmalgen Wasp 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 wasp 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 wasp 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 wasp 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 wasp 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 Wasp 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 Wasp 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.

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 reactions 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

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.

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 dose, 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 and dilution with Albumin Diluent:

6.4 Special precautions for storage

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

6.5 Nature and contents of container

Glass vials, chlorobutyl rubber stopper, aluminium cap.

Pharmalgen Wasp Venom is supplied in a package with powder and solvent, 4 × 120 ^g venom + 4 vials containing 5 ml Albumin Diluent.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Before use the product must be reconstituted with Albumin Diluent as described below.

Reconstitution of powder:

1. Extract 1.2 ml Albumin Diluent in a disposable syringe.

2. Carefully inject 1.2 ml Albumin Diluent into the vial with the freeze-dried extract.

3. Carefully turn the vial over 10–20 times; check that all the extract has dissolved. It is now ready for use.

After reconstitution the solution contains 100 ^g/ml of insect venom. The date of the reconstitution and the expiry date must be noted on the label of the vial.

Lower concentrations should be obtained by diluting the solution. Use Albumin Diluent for dilution. To avoid confusion, the vials must be labelled before dilution (minimum information: allergen, concentration, date of dilution and expiry date (see section 6.3)).

Dilution series:

1. 10 gg/ml (1:10): 0.55 ml of the 100 ^g/ml + 5 ml Albumin Diluent

2. 1 gg/ml (1:100): 0.55 ml of the 10 ^g/ml + 5 ml Albumin Diluent

3. 0.1 gg/ml (1:1000): 0.55 ml of the 1 ^g/ml + 5 ml Albumin Diluent

Further dilutions can be prepared using the same method (see figure below).

Please note! Do not use the same sterile syringe to transfer different concentrations. Use a brand new sterile syringe for each dilution stage. To avoid confusion, the vials must be labelled before dilution (minimum information: allergen, concentration, date of dilution and expiry date (see section 6.3)).

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

7 MARKETING AUTHORISATION HOLDER

ALK-Abello A/S

B0ge Allé 6–8

DK-2970 H0rsholm

Denmark

8 MARKETING AUTHORISATION NUMBER(S)

PL 10085/0004

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

17/03/1995 / 07/06/2002