Package Insert and Label Information: HONEY BEE VENOM

By ALK-Abello A S | Last revised: 9 April 2010

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HONEY BEE VENOM- apis mellifera venom injection, powder, lyophilized, for solution
YELLOW HORNET VENOM PROTEIN- dolichovespula arenaria venom protein injection, powder, lyophilized, for solution
EASTERN YELLOWJACKET VENOM PROTEIN- vespula maculifrons venom protein injection, powder, lyophilized, for solution
WHITE FACED HORNET VENOM PROTEIN- dolichovespula maculata venom protein injection, powder, lyophilized, for solution
COMMON PAPER WASP VENOM PROTEIN- polistes fuscatus venom protein injection, powder, lyophilized, for solution
HYMENOPTERA VENOM DIAGNOSTIC-
ALK-Abello A S

PRESCRIBING INFORMATION

ALLERGENIC EXTRACTS

HYMENOPTERA
VENOM/VENOM PROTEIN

Pharmalgen®

Honey Bee (Apis mellifera)
Yellow Jacket (Vespula spp.)
Yellow Hornet (Dolichovespula arenaria)
White Faced Hornet (Dolichovespula maculata)
Wasp (Polistes spp.)
Mixed Vespid (Yellow Jacket, Yellow Hornet & White Faced Hornet)

ALK-Abelló A/S
DK-2970 Hørsholm, Denmark

WARNING

Hymenoptera venom preparations should be used only by or under the direction of physicians experienced in administering allergens to the maximum tolerated dose and only where adequate means for treating severe systemic reactions are immediately available.

Allergenic extracts may potentially elicit a severe life-threatening systemic reaction, rarely resulting in death¹. Because of the possibility of severe systemic reactions, the patient should be instructed in the recognition of anaphylactic symptoms, observed in the office for at least 30 minutes after each injection, and warned to return to the office if symptoms of an allergic reaction occur.

Patients receiving beta-blockers may not be responsive to epinephrine or inhaled bronchodilators, and the risk of severely complicating the treatment of systemic reactions should be carefully considered before a decision to treat is reached.

Treatment with ACE-inhibitors should be stopped at least 24 hours prior to injection due to an increased risk of anaphylactic reaction based on inhibition of the angiotensin metabolism.

All patients receiving venom immunotherapy should be instructed in the procedure for emergency self-injection of subcutaneous epinephrine. This self treatment might be necessary before patients have reached a maintenance dose of venom, and partially treated patients should be advised to carry an emergency epinephrine kit during the Hymenoptera season.

Before administering these venom preparations, physicians should be thoroughly familiar with the information in this insert, especially the Warnings, Precautions, and Adverse Reactions sections.

Description

Six sterile freeze-dried Hymenoptera preparations are available: honey bee venom, and yellow jacket, yellow hornet, white faced (bald faced) hornet, wasp, and mixed vespid venom protein. The mixed vespid preparation consists of equal amounts of yellow jacket, yellow hornet, and white-faced hornet venom proteins.

Honey bees, yellow hornets, and white faced hornets are present primarily as the single species designated above, and the source material for those extracts is collected only from those species. There are a number of common species of yellow jackets and wasps in the environment, and those extracts reflect that variety and contain venom protein from a number of species. Information concerning the species included in the yellow jacket and wasp preparations is available on request from ALK customer service (1-800-252-9778); in TX and Canada, 1-800-663-0972).

Honey bee venom is obtained from live insects by an electric shock method. The other venoms are obtained from dissected venom sacs, which are crushed in a β-alanine/acetic acid buffer to release the venom. The sac residue is then removed by centrifugation and filtration. Allergenic components in the raw honey bee and yellow jacket venom materials have been described² ^, ³.

These extracts are available in freeze-dried form, and just prior to use, the contents of each vial should be reconstituted with HSA diluent (see How Supplied), using the volume specified on the vial label. When reconstituted as directed, the single-venom preparations will contain 100 µg/ml of venom or venom protein, and the mixed vespid preparation will contain 300 µg/ml of venom protein. This is the concentration from which full maintenance doses are typically drawn. Other ingredients in the solution reconstituted as directed with HSA diluent are 0.06% albumin human USP, 3.0% mannitol, 0.9% sodium chloride, and 0.4% phenol. All these preparations must be diluted before use in diagnosis or in the initial stages of treatment.

Clinical Pharmacology ¹

The mode of action of allergenic extracts is under investigation.

The skin test reaction occurring in previously sensitized individuals is probably related to the interaction of antigen with IgE antibody and the subsequent release of histamine from mast cells. The therapeutic action of allergenic extracts may be related to the production of IgG (blocking) antibodies. Effective immunotherapy with allergenic extracts is usually associated with a rise in serum levels of specific IgG. Immunotherapy also produces an initial rise in specific IgE levels, which then decrease as therapy continues.

HONEY BEE VENOM Indications and Usage

The Pharmalgen venom preparations are indicated for use in the diagnosis and treatment of Hymenoptera sting allergy. The following general considerations should be applied in determining the proper use of these preparations:

Approximately two-thirds of adult patients with a history of sting anaphylaxis and a positive venom skin test but who do not receive immunotherapy will experience a systemic reaction if stung by the implicated insect again. These patients should receive therapy⁴. Children whose reactions have been limited to the skin have an approximately 10% risk of future reactions if stung and not immunized. The nature and severity of these reactions is in general similar to the original reaction and therefore children with this kind of history may not need venom therapy⁵.
The risk of anaphylaxis following a future sting is unknown in patients who have been stung without experiencing a systemic reaction but who are currently venom skin test positive. At this time, no recommendation can be made that such patients receive venom immunotherapy, but they should be counseled on their condition and may benefit from instruction in the self-administration of subcutaneously injected epinephrine. There is an approximately 10% risk of future systemic reactions if prior reactions have consisted of large delayed local reactions⁶. This risk must be considered in deciding whether or not to recommend venom therapy.
Patients with a history of serious systemic reaction to a sting but who are skin test negative to all five venoms are not candidates for therapy. It is not known whether such patients may be resensitized by future stings, and such patients should be retested after any subsequent sting.
A small percentage of patients, who have reached the maintenance dose suggested below, may still experience some degree of allergic response upon being stung by the implicated insect.

Diagnosis: The five individual Hymenoptera venom extracts present in the diagnostic kit (see How Supplied) are indicated for diagnostic skin testing of patients with a history of systemic reactions consistent with insect sting allergy⁷.

Treatment: The Hymenoptera venom extracts are indicated for immunotherapy in patients who have a history of a systemic reaction of any severity to a Hymenoptera sting and a positive skin test to one or more of the venoms. Therapy cannot be recommended in the absence of either of those conditions.

The single-venom extracts are intended for both diagnosis and immunotherapy; the mixed vespid product is intended for immunotherapy only.

Multiple venom preparations are indicated in patients with multiple skin test sensitivities.

Contraindications

No absolute contraindications to venom immunotherapy are known.

However, the risk of serious systemic anaphylactic reactions to venom or any potent allergenic extract suggests a number of preexisting conditions that should be considered relative contraindications. Among those conditions are acute infections, immune disease, severe cardiac disease, and treatment with β-adrenergic antagonist drugs (beta-blockers) and angiotensin inhibitors (ACE-inhibitors). See also Warnings, Precautions, and Adverse Reactions.

Warnings

See additional warnings given in the box at the beginning of this insert.

Some patients are highly sensitive to Hymenoptera venoms and, for such patients, it must be anticipated that even a small skin test dose could result in a serious systemic reaction. Adequate means to treat such reactions must be immediately available, including the following equipment⁸: stethoscope and sphygmomanometer; tourniquets, syringes, hypodermic needles, and large-bore (14 gauge) needles; aqueous epinephrine HCl, 1:1000; oxygen, intravenous fluids, and the equipment for administering them; oral airway; diphenhydramine or similar antihistamine; aminophylline and corticosteroids for intravenous injection; vasopressor.

Patients are most at risk of serious systemic reactions:

During skin testing and the build-up to maintenance dose, before tolerance of the extract is established. Do not begin immunotherapy without establishing the appropriate initial dose by skin testing (see Dosage and Administration), and do not inject the undiluted extract concentrate at any time unless tolerance has been demonstrated.
When changing to a freshly-reconstituted extract; all extracts lose potency over time, and a fresh extract could have an effective potency that is substantially greater than that of the old extract. Reduce the dose by at least 50% when switching a patient to a freshly-reconstituted extract; this is particularly important when the previous extract was near its expiration date.
When changing to an extract from a different manufacturer. Processing and source materials may differ markedly among manufacturers, and extracts from different manufacturers should not be considered interchangeable. Such changes should not be made without establishing the proper dosage by skin testing.
If an error in dosage occurs, take care to properly prepare, label, store, and control all dilutions.

Observe the patient for at least 30 minutes after injection, and be alert for the signs of impending reaction. Make sure the patient understands that serious delayed reactions can occur later on, how to recognize them, and what to do if they occur.

Patients who are receiving beta-blocking medication are high-risk patients for immunotherapy, because systemic reactions to the extract may be more severe in such patients⁹ , and because the beta-blocker may impair the ability to reverse the reaction¹⁰. In such patients, this risk should be carefully weighed before a decision to treat is reached.

Treatment with ACE-inhibitors should be stopped at least 24 hours prior to injection due to an increased risk of anaphylactic reaction based on inhibition of the angiotensin metabolism ¹² ^, ¹³ ^, ¹⁴.

Do not inject this or any allergenic extract intravenously. Before injecting the extract subcutaneously, retract the plunger on the syringe slightly and verify that no blood enters the syringe. If it does, remove the syringe and repeat the procedure at a different site.

This and any allergenic extract should be temporarily withheld or its dosage reduced under any of these conditions¹¹:

When the patient has an unexpectedly severe local or any systemic reaction to the previous dose.
If the patient is experiencing allergic symptoms such as rhinitis or asthma, or is ill with flu or infection accompanied by fever.
If an unusually long time has passed since the previous injection.

Allergic patients differ widely in their sensitivity to this or any allergenic extract, and no single dosage regimen can be recommended for all patients. The treatment schedule described under Dosage and Administration, below, is suitable for the majority of patients, but is based on a rather rapid build-up to the maintenance dosage and will have to be adjusted for sensitive patients. Progression to the next higher dose requires tolerance of the previous one, and the regimen must be modified if any of the conditions described above occur. Such modifications should include weaker dilutions and smaller dosage increments.

Precautions

General:

It is not unusual for patients to be treated with multiple venom preparations simultaneously. Although the majority of patients receiving multiple venoms tolerate treatments as well as patients receiving a single venom, the theoretically greater risk of systemic reactions in patients receiving multiple venoms should be kept in mind.

Do not use the mixed vespid preparations for diagnosis; even though cross-reactivity among those three venoms is common, it is not universal and patients should not be treated with any venom to which they are not demonstrably sensitive.

Patient compliance is an important consideration in the decision to initiate immunotherapy with any potent allergenic extract. Therapy should not be initiated if in the judgment of the physician the patient cannot be depended upon to respond promptly and properly to an impending adverse reaction, or to report such reactions.

Care must be taken to control the preparation, labeling, storage, and use of dilutions. The ramifications of inadvertent over dosage are severe (see Warnings and Adverse Reactions), and so procedural safeguards such as training programs, color-coded labeling, storage controls, and auditing are recommended 11.

As with the administration of any parenteral drug, observe all aspects of good sterile technique. In both testing and treatment, use a separate sterilized needle and syringe for each individual patient, to prevent transmission of hepatitis and other infectious agents from one person to another.

Drug Interaction:

The patient should not take antihistamines in the 72-hour period prior to skin testing, since the pharmacological actions of such drugs might interfere with the skin test response. Also, the concurrent use of an antihistamine might mask an otherwise observable reaction to an injection in patients who are on venom treatment.

Carcinogenesis, mutagenesis, impairment of fertility:

No long term studies with this or any allergenic extract have been carried out to determine their effect on carcinogenesis, mutagenesis, or impairment of fertility.

Pregnancy:

Pregnancy Category C. Animal reproduction studies have not been conducted with allergenic extracts. It is also not known whether allergenic extracts can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Allergenic extracts should be given to a pregnant woman only if clearly needed.

Nursing mothers:

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when allergenic extracts are administered to a nursing woman.

Pediatric use:

The Hymenoptera venom extracts are indicated for immunotherapy in children who have a history of a systemic reaction not confined to the skin, and a positive skin test to one or more of the venoms. The maintenance dose of 100 µg is recommended for both children and adults. If the injection volume is too large for a small child to tolerate comfortably, then the injection volume may be split into multiple injections.

Geriatric Use:

Clinical studies of venom extracts did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Adverse Reactions

Severe anaphylactic reactions to this extract can occur in extremely allergic patients and at any dosage level. Do not use this extract unless you are prepared to deal with these reactions, and until you have read and understood the Warnings, Precautions, and Dosage and Administration sections of this insert.

The most serious systemic reaction that can occur is anaphylactic shock, which, while rare, is life threatening and must be treated immediately. Among other systemic reactions that have occurred are laryngeal edema, fainting, pallor, bradycardia, hypotension, bronchospasm, angioedema, cough, sneezing, conjunctivitis, rhinitis, and urticaria.

Should a serious systemic reaction occur:

Inject 0.3 – 0.5 ml of 1:1000 epinephrine into the opposite arm; this may be repeated every 5 to 10 minutes, as a succession of smaller doses is more effective and less dangerous than a single larger one. Use a smaller dose for infants and children, in the range of 0.01 ml/kg of body weight.
Apply a tourniquet proximal to the injection site; loosen it at least every 10 minutes.
Inject no more than 0.1 ml of 1:1000 epinephrine at the injection site, to delay the absorption of the remaining extract.

These measures will almost always reverse the reaction, but in the rare instances when they do not, then the full armamentarium of emergency medicine may be required, among them: direct laryngoscopy, direct current cardioversion, tracheotomy, and intracardiac injection of drugs⁸.

The occurrence of a severe systemic reaction to an injection of this extract does not contraindicate further therapy, but the next dose given should be reduced by at least 90%, and raised very slowly thereafter. If a pattern of systemic reactions – even very mild ones – appears, then the benefits of continued treatment must be carefully weighed against the substantial demonstrated risk.

Local reactions, even relatively severe but transient redness, swelling and discomfort, are the normal physiologic response to the allergens and to the volume of the fluid injected, and in their milder form is evidence of the effectiveness of the therapy. Local reactions generally subside quickly and do not require treatment, but application of cold to the injection site or other symptomatic measures may be useful.

However, severe local reactions should be considered a warning of potential systemic reaction if that dosage is continued. Always reduce the dose substantially if such a local reaction occurs.