honey bee hymenoptera venom

Jubilant HollisterStier LLC
Jubilant HollisterStier LLC

INSTRUCTIONS AND DOSAGE SCHEDULE FOR ALLERGENIC EXTRACTS HYMENOPTERA VENOM PRODUCTS Multidose 13.0 mL (Honey Bee, Yellow Jacket, White-Faced Hornet, Wasp, and Mixed Vespid)

FULL PRESCRIBING INFORMATION: CONTENTS*

• WARNINGS
• HONEY BEE HYMENOPTERA VENOM DESCRIPTION
• CLINICAL PHARMACOLOGY
• HONEY BEE HYMENOPTERA VENOM INDICATIONS AND USAGE
• HONEY BEE HYMENOPTERA VENOM CONTRAINDICATIONS
• WARNINGS
• PRECAUTIONS
  • (1) General
  • (2) Information for Patients
  • (3) Drug Interactions
  • (4) Carcinogenesis, Mutagenesis, Impairment of Fertility
  • (5) Pregnancy(12, 21)
  • (6) Nursing Mothers
  • (7) Pediatric Use
  • (8) Geriatric Use
• HONEY BEE HYMENOPTERA VENOM ADVERSE REACTIONS
• OVERDOSAGE
• HONEY BEE HYMENOPTERA VENOM DOSAGE AND ADMINISTRATION
  • Pediatric Use
  • Geriatric Use
• HOW SUPPLIED
• LIMITED WARRANTY
• REFERENCES

FULL PRESCRIBING INFORMATION

HONEY BEE HYMENOPTERA VENOM DESCRIPTION

Hymenoptera Venom Products available are sterile freeze-dried venom of Honey Bee (Apis mellifera) and venom protein of Yellow Jacket (Vespula sp.) and Wasp (Polistes sp.). Mixed Vespid venom protein (Yellow Jacket, Yellow Hornet and White-Faced Hornet) is also available.

The reconstituted single venom products are intended for subcutaneous injection for immunotherapy and percutaneous use for diagnosis. The Mixed Vespid venom protein is for immunotherapy only, not for diagnosis. Diagnosis should be based on individual venoms.

Because of the difficulty in collecting all species of Yellow Jacket and Wasp, the venom raw materials for these two insects may vary in species composition from lot to lot. A listing of the exact species content for any particular lot of Yellow Jacket or Wasp venom protein may be obtained by calling Technical Services at Jubilant HollisterStier LLC, (800) 992-1120.
Final containers of sterile freeze-dried venom products are sealed under vacuum. This will result in the diluting fluid being forcibly drawn into the sealed vial when the syringe needle penetrates the seal during reconstitution. See PRECAUTIONS.

Venom Products Labeled for Reconstitution to 13.0 mL (Multidose 13.0 mL)

When the Multidose 13.0 mL freeze-dried Honey Bee venom is reconstituted with 13.0 mL of fluid, the resulting solution will contain 100 micrograms of venom protein per mL (100 µg/mL) plus 7.7 milligrams of mannitol per mL and trace amounts of sodium chloride. When Multidose 13.0 mL freeze-dried Yellow Jacket and Wasp venom proteins are reconstituted with 13.0 mL of fluid, the resulting solution will contain 100 micrograms of venom protein per mL (100 µg/mL) plus 7.7 milligrams of mannitol per mL and trace amounts of sodium chloride, potassium chloride, acetic acid and beta-alanine. When the Multidose 13.0 mL Mixed Vespid protein is reconstituted with 13.0 mL of fluid, the resulting solution contains 300 micrograms of venom protein per mL (300 µg/mL) plus 23.1 milligrams of mannitol per mL and trace amounts of sodium chloride, potassium chloride, acetic acid and beta-alanine. Mannitol is used as an excipient.

These freeze-dried products can be reconstituted in Sterile Albumin Saline with Phenol (which contains 0.9% NaCl, 0.4% phenol and 0.03% Normal Human Serum Albumin to a concentration of 100 µg/mL (300 µg/mL for Mixed Vespid venom protein). Dilutions of this concentration should be made only with Sterile Albumin-Saline with Phenol (0.4%). See DOSAGE AND ADMINISTRATION for details of dilutions for diagnosis and treatment.

Space is provided on the container label to record the date (month, day, year) venom is reconstituted. Refer to dating period shown under PRECAUTIONS. At the time of reconstitution, write the calculated reconstituted product expiration date (month, day, year) on the vial label in the space provided.

CLINICAL PHARMACOLOGY

Diagnosis

Diluted solutions of stinging insect venom injected intradermally will produce wheal and erythema reactions in patients who have significant IgE-mediated, Type I immediate hypersensitivity to stings of these insects.

Treatment

Repeated injections of increasing doses of insect venom extracts have been shown to ameliorate the intensity of allergic symptoms upon subsequent insect stings. (3,4)

The mechanism by which hyposensitization is achieved is not known completely. IgG antibodies (blocking antibodies) appear in the serum of patients treated with injected venom. No direct relationship has been identified between the level of blocking antibody (or the ratio of blocking antibody to IgE antibody directed to the same venom antigens) and the degree of hyposensitization. However, patients who show protection from symptoms after stings have been found to have significant levels of specific blocking antibody.(3, 4) .
Initially, after a period of immunotherapy with specific venom antigens, levels of IgE antibody may increase.(4) However, from studies carried out with other venom preparations, these levels are reported to decline after a time.(5) After maintenance level has been reached and maintained, symptoms after stings have been shown to decrease considerably.(3, 4)

It is not known if skin-sensitizing antibody can be eradicated or if the patient can be entirely cured, nor is it known how long immunotherapy must be continued.

In a clinical study with Jubilant HollisterStier venom products, injections (using the Suggested Dose Schedule under DOSAGE AND ADMINISTRATION) were given once per week at one study center, and twice or more per week at another center.(4) (For further discussion, see below). It must be considered important to achieve the 100 µg per venom maintenance dose (the maintenance dose for Mixed Vespid venom protein is 300 µg), since there are no data on effectiveness of maintenance levels below 100 µg per venom.

In the clinical trial, 97% of patients at the maintenance dosage (100 µg per venom) showed no systemic reaction following an insect sting challenge.(4)The remaining 3% had a milder reaction than noted prior to treatment. The patients in this study reached maintenance (100 µg per venom) usually within 2 1/2-3 1/2 months after beginning therapy.(4) Whether efficacy of therapy is influenced by the time required to reach maintenance has not yet been determined.

Large local reactions occurred in approximately 60% of the patients given immunotherapy. Some form of systemic response occurred, often repeatedly, in one-third of the patients treated in the clinical trial.(4) Only one systemic response occurred on the first dose given. The rest occurred at various times in the course of immunotherapy. Some systemic manifestations may have occurred because of the patient's apprehension, and did not require treatment. Approximately one-fourth of the patients experiencing systemic responses were given some form of specific therapy (epinephrine, theophylline, or metaproteranol), some on several occasions.(4)

In deciding the criteria for proceeding from dose to dose of the Suggested Dose Schedule (see DOSAGE AND ADMINISTRATION), the results of the clinical study(4) should be considered. A study center "A" reporting the least number of systemic reactions during pre-maintenance treatment held the dose constant in most of the cases where significant local reactions occurred. With the systemic reactions reported, this center held the dose the same in approximately 80% of the incidences. The treatment injections were given at this center usually once per week, and if a patient missed an appointment, the next dose was often the same as the preceding dose (depending on the previous reactivity of the patient). Patients treated at this center reached maintenance in an average of 17-19 visits.

Another study center "B", reporting a higher incidence of systemic reactions, was more regimented in following the Suggested Dose Schedule. This center reduced or held the dose the same in less than 10% of the cases reporting significant local reactions. With the systemic reactions reported, this center held the dose the same or reduced the dosage in approximately 20% of the cases. At this center, more than one injection per week was given at the outset as circumstances and sensitivity allowed. Patients treated at this center reached maintenance in an average of 14 visits.

Following the achievement of maintenance level (100 µg per venom), approximately 80% or more patients were given a second maintenance injection at a 1-week interval. The third maintenance injection was usually (in approximately 60% of the patients) at a 2-week interval. The next injection was usually within 3 weeks, and thereafter, the patients were injected for ongoing maintenance at approximately monthly intervals.(4)

HONEY BEE HYMENOPTERA VENOM INDICATIONS AND USAGE

Insect stings may induce a wide range of allergic symptoms in sensitive patients. A normal sting response is initial burning or stinging pain that may be intense and last several minutes to an hour or more. There is usually some local swelling coming on immediately and persisting for several days. The location of the sting has considerable influence on the intensity of the pain and extent of swelling. Stings on the fingers or feet produce much pain, but less swelling; whereas a sting on the head or face produces extensive swelling with variable pain.

Local reactions coming on rapidly and larger than the usual local reaction, particularly if the swelling spans both adjacent joints on the extremities, can indicate hypersensitivity. Systemic symptoms come on shortly after the sting, often within seconds to minutes. Symptoms may range from generalized flushing, itching, redness, diffuse swelling of the skin or urticarial wheals, abdominal cramps, nausea, vomiting, or incontinence of urine or stool, to faintness, blurring or loss of vision, unconsciousness, seizures, respiratory or cardiac arrest, or death. Later reactions may consist of fever, achiness, malaise, joint swelling, urticaria or other signs of vascular damage typical of serum sickness, a Type III reaction. Typical delayed Type IV reactions may also occur. (6)

Rarely, other types of severe reactions to insect stings have been reported. (6) These include serum sickness, hematologic abnormalities, and neurological disorders commencing some time after a sting, and not associated with anaphylactoid reactions. These patients are not candidates for immunotherapy using insect venoms.

HONEY BEE HYMENOPTERA VENOM CONTRAINDICATIONS

There are no known absolute contraindications to immunotherapy using Hymenoptera Venom Products. See also PRECAUTIONS and WARNINGS.

Patients showing negative intradermal skin tests to specific venoms at 1 µg/mL are not recommended for venom treatment.

WARNINGS

See WARNINGS box at the beginning of this Instruction Sheet. See also PRECAUTIONS. Venom extract must be temporarily withheld from patients or the dose adjusted downward if any of the following conditions exist: (1) severe symptoms of rhinitis and/or asthma; (2) infection or flu accompanied by fever; (3) any evidence of an excessively large local or any generalized reaction during the initial stages of immunotherapy, or during maintenance therapy; and/or (4) insect sting prior to a scheduled injection. Do not administer venom injections during a period of symptoms following an insect sting or on the day the patient received an insect sting, since this could result in an allergen load that exceeds the patient's tolerance.

THE CONCENTRATE MUST NOT BE INJECTED AT ANY TIME UNLESS TOLERANCE HAS BEEN ESTABLISHED. DILUTE CONCENTRATED EXTRACTS WITH STERILE ALBUMIN SALINE WITH PHENOL (0.4%) FOR SKIN TESTING AND IMMUNOTHERAPY.

INJECTIONS MUST NEVER BE GIVEN INTRAVENOUSLY. Subcutaneous injection is recommended. Intracutaneous or intramuscular injections may produce large local reactions or be excessively painful. AFTER INSERTING NEEDLE SUBCUTANEOUSLY, BUT BEFORE INJECTING, ALWAYS WITHDRAW THE PLUNGER SLIGHTLY. IF BLOOD APPEARS IN THE SYRINGE, CHANGE NEEDLE AND GIVE THE INJECTION IN ANOTHER SITE.

Patients with hypersensitivity to insect venom who undergo desensitization treatment while under concomitant therapy with ACE (angiotensin-converting enzyme) inhibitors, may have an increased risk of life-threatening anaphylactic reactions.(9) Patients without insect venom hypersensitivity, who take ACE inhibitors, and are stung by insects, such as bee or wasp, can show such reactions as well.(10)

Two patients undergoing desensitization treatment with Hymenoptera Venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.(11)

Proper selection of the dose and careful injection should prevent most systemic reactions. It must be remembered, however, that allergenic extracts are highly potent in sensitive individuals and that systemic reactions of varying degrees of severity may occur, ranging from mild to life-threatening anaphylaxis, or even death, as described under INDICATIONS AND USAGE and ADVERSE REACTIONS. Patients should be informed of this, and the warnings and precautions should be discussed prior to immunotherapy. See PRECAUTIONS below.
Systemic reactions should be treated as indicated in ADVERSE REACTIONS.

PRECAUTIONS

(1) General

The presence of asthmatic signs and symptoms appear to be an indicator for severe reactions following allergy injections. An assessment of airway obstruction either by measurement of peak flow or an alternate procedure may provide a useful indicator as to the advisability of administering an allergy injection. (1, 12-16)

Concentrated extracts must not be injected unless tolerance has been established.

Diluting fluid should be forcibly drawn into the sealed vial when the syringe needle penetrates the seal during reconstitution. Failure of this to occur for a particular vial indicates possible loss of vacuum. Vials without vacuum should be returned to the manufacturer.

Record date of reconstitution and expiration date of reconstituted product in the space provided on the product label. Date of expiration after reconstitution must not exceed the Final Expiration Date indicated on the container label. (See table below for expiration dates, including dilutions).

A separate sterile syringe should be used for each patient to prevent transmission of hepatitis and other infectious agents from one person to another.

Patient reactions to previous injections should be reviewed before each new injection so that dose can be adjusted accordingly. See ADVERSE REACTIONS and WARNINGS.

Rarely, a patient is encountered who develops systemic reactions to minute doses of allergen and does not demonstrate increasing tolerance to injections after several months of treatment. It is suggested that if systemic reactions or excessive local responses occur persistently at very small doses, efforts at immunotherapy should be stopped.

PATIENTS SHOULD BE OBSERVED IN THE OFFICE FOR AT LEAST 30 MINUTES AFTER SKIN TESTING AND AFTER EACH TREATMENT INJECTION. Most severe reactions will occur within this time period, and rapid treatment measures should be instituted. See ADVERSE REACTIONS for such treatment measures.

(2) Information for Patients

Patients should be instructed in the recognition of adverse reactions to immunotherapy, and in particular, to the symptoms of shock. (See WARNINGS box at the beginning of this Instruction Sheet). Patients should be made to understand the importance of a 30 minute observation period following skin testing or therapeutic injections, and be cautioned to return to the office promptly if symptoms occur after leaving. Patients should be instructed in the use of, and have available, an Emergency Anaphylaxis Kit for self-administration of epinephrine.

Patients must be instructed to report any insect stings that have occurred, since a venom injection should not be given on the same day as the sting, nor during a time when the patient is still experiencing symptoms from the sting.

(3) Drug Interactions

Patients with cardiovascular diseases and/or pulmonary diseases such as symptomatic, unstable, steroid-dependent asthma, and/or those who are receiving cardiovascular drugs such as beta blockers, may be at higher risk for severe adverse reactions. These patients may also be more refractory to the normal allergy treatment regimen. Patients should be treated only if the benefit of treatment outweighs the risks.(1)

Patients on beta blockers may be more reactive to allergens given for testing or treatment and may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.(2)

See WARNINGS section regarding concurrent treatment with ACE inhibitors.

Certain medications may lessen the skin test wheal and erythema responses elicited by allergens and histamine for varying time periods. Conventional antihistamines should be discontinued at least 5 days before skin testing. Long acting antihistamines should be discontinued for at least 3 weeks prior to skin testing.(17) Topical steroids should be discontinued at the skin test site for at least 2-3 weeks before skin testing.(17,18)

Tricyclic antidepressants such as doxepin, should be withheld for at least 7 days before skin testing.(19) Topical local anesthetics may suppress the flare responses and should be avoided on skin test sites.(20)

When using other drugs in patients receiving allergenic extracts, always consult the product labeling of the other drugs to determine any possible interaction with use of allergenic extracts, and specifically with stinging insect (Hymenoptera) venom extracts.

(4) Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been conducted with allergenic extracts to determine their potential for carcinogenicity, mutagenicity, or impairment of fertility.

(5) Pregnancy(12, 21)

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

On the basis of histamine's known ability to contract uterine muscle, theoretically, a systemic reaction, whether occurring from insect sting or from venom skin testing or treatment dose, should be avoided.(3) Therefore, the physician must carefully consider the benefit-to-risk ratio, to both patient and fetus, of continuing venom immunotherapy during pregnancy, or performing venom skin testing, and especially of initiating a venom immunotherapy program where there is a possibility that the patient may not be able to reach the recommended maintenance dose without significant risk of a systemic reaction.

(6) Nursing Mothers

There are no current studies on secretion of the allergenic extract components in human milk or effect on the nursing infant. Because many drugs are excreted in human milk, caution should be exercised when allergenic extracts are administered to a nursing woman.

(7) Pediatric Use

Since dosage for the pediatric population is the same as for adults, the larger volumes of solution may produce excessive discomfort. Therefore, in order to achieve the total dose required, the volume of the dose may need to be divided into more than one injection per visit. A study done in children ages 4 to 17 showed no special problems with venom immunotherapy in this population.(22)

(8) Geriatric Use

The reactions from immunotherapy can be expected to be the same in elderly patients as in younger ones. Elderly patients may be more likely to be on medication that could block the effect of epinephrine which could be used to treat serious reactions, or they could be more sensitive to the cardiovascular side effect of epinephrine because of pre-existing cardiovascular disease.(23)

HONEY BEE HYMENOPTERA VENOM ADVERSE REACTIONS

Physicians administering Hymenoptera Venom testing or treatment materials should be experienced in the treatment of severe systemic reactions (see WARNINGS box at the beginning of this Instruction Sheet).

OVERDOSAGE

See ADVERSE REACTIONS Section.

HONEY BEE HYMENOPTERA VENOM DOSAGE AND ADMINISTRATION

(1) General
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Reconstitute and dilute the freeze-dried venom as directed below. Sterile Albumin Saline with Phenol (0.4%) must be used to reconstitute and dilute the venoms for skin testing and treatment.

Reconstitute the freeze-dried venoms by adding 13.0 mL Sterile Albumin Saline with Phenol (0.4%) to the vial using a sterile syringe. Swirl or rock the container to dissolve the venom completely. DO NOT SHAKE, since shaking can cause foaming.

Dilutions (see table below) must be made in Sterile Albumin Saline with Phenol (0.4%). They must be made accurately and aseptically, using sterile solutions, vials, syringes, etc., and thoroughly mixed by rocking or swirling. DO NOT SHAKE. Store freeze-dried and reconstituted venom product, and venom dilutions constantly at 2° - 8°C.

(2) Diagnosis

Since the level of insect venom specific IgE may fall to low levels briefly after a reaction to a sting, patients should not be tested until 2 to 4 weeks after any sting.

Skin testing should be carried out with all five individual venoms, since many patients have multiple sensitivities.(4) Mixed Vespid venom protein should be used only for therapy - not for diagnosis.

Prick testing should be done before intradermal testing to determine appropriate concentration for intradermal testing. See Intradermal Tests below. Skin testing (prick and intradermal) provides information to assist in identifying those patients who are to be classified as extremely sensitive and who may not tolerate the Suggested Dose Schedule.

See DOSAGE AND ADMINISTRATION, Immunotherapy CAUTION.

In both the prick and intradermal tests, a negative control test with diluent alone must be performed. A histamine positive control test is also recommended.

The flexor surface of the forearm is the usual location for skin testing. It is important that a separate sterile syringe and needle be used for each extract and each patient.

Prick Tests: Prick tests are accomplished by applying one drop of the 1 µg/mL venom protein solution to the forearm, and by pricking the skin through the surface of the drop with a sterile 27 gauge needle. The prick is superficial and should not draw blood.

Skin response should be assessed after approximately 15-20 minutes.

For prick tests, a positive reaction (reaction greater than diluent control) at the 1 µg/mL concentration indicates a high level of sensitivity to the test venom.

Intradermal Tests: Patients showing a positive reaction to the prick test at the 1 µg/mL concentration should begin intradermal tests at concentrations of not more than 0.0001 to 0.001 µg/mL. Patients with negative prick tests may begin intradermal tests at a concentration of 0.001 µg/mL.

A 1 mL tuberculin syringe with a short 27-gauge needle should be used to deliver a volume of 0.05 mL for intradermal testing. Introduce the needle into the superficial skin layers, bevel down, until the bevel is completely buried, then slowly inject a 0.05 mL aliquot of the venom dilution, making a small bleb.

Start intradermal tests with the most dilute solution. If after 20 minutes no skin reaction is obtained, continue the intradermal testing using ten-fold increments in the concentration until a reaction of 5-10 mm wheal and 11-20 mm erythema is obtained, or until concentration of 1 µg/mL has been tested, whichever occurs first.

A patient should be considered sensitive to the test venom when a skin response of 5-10 mm wheal and 11-20 mm erythema (or greater) occurs at a concentration of 1 µg/mL or less,(8) providing that this reaction is greater than that of the diluent control.

(3) Immunotherapy:
For proper method and route of injection, see WARNINGS, PRECAUTIONS and ADVERSE REACTIONS. The most common site of injection is the lateral aspect of the upper arm. Patients who have multiple venom sensitivities should be given each specific venom injection in a separate site. (Except, if the patient has sensitivities to Yellow Jacket, Yellow Hornet, and White-Faced Hornet venoms concurrently, s/he can be injected with Mixed Vespid venom protein, an equal mixture of these three vespid venoms). Note which venom preparation is injected at a specific site, so that dosage of that venom preparation can be adjusted if an excessive local reaction occurs. In patients receiving more than one venom, there is theoretically a greater risk of systemic reactions.

Pediatric Use

The dose for the pediatric population is the same as for adults. (See PRECAUTIONS).

Geriatric Use

The dose for elderly patients is the same as for adult patients under 65.(23) (See PRECAUTIONS).

HOW SUPPLIED

Jubilant HollisterStier LLC sterile freeze-dried Hymenoptera Venom Products are supplied in vacuum-sealed 20 mL vials containing 1300 micrograms (1300 µg) for the single venoms, and 3900 micrograms (3900 µg) per 20 mL vial for the Mixed Vespid venom protein product. Reconstituting fluid [Sterile Albumin Saline with Phenol (0.4%)] is available separately.

Storage: Store freeze-dried and reconstituted venom product, and venom dilutions, at 2° - 8°C, and keep at this temperature range during office use.

LIMITED WARRANTY

A number of factors beyond our control could reduce the efficacy of this product or even result in an ill effect following its use. These include storage and handling of the product after it leaves our hands, diagnosis, dosage, method of administration and biological differences in individual patients. Because of these factors, it is important that this product be stored properly and that the directions be followed carefully during use.

No warranty, express or implied, including any warranty of merchantability or fitness, is made. Representatives of the Company are not authorized to vary the terms or the contents of any printed labeling, including the package insert, for this product except by printed notice from the Company's headquarters. The prescriber and user of this product must accept the terms hereof.

REFERENCES