Honey Bee hymenoptera venom Multidose

Jubilant HollisterStier LLC
Jubilant HollisterStier LLC

Instructions and Dosage Schedule for Allergenic Extracts Hymenoptera Venom Products (Honey Bee, Yellow Jacket, Yellow Hornet, White-Faced Hornet, Wasp, and Mixed Vespid)

FULL PRESCRIBING INFORMATION: CONTENTS*

• WARNINGS
• HONEY BEE HYMENOPTERA VENOM MULTIDOSE DESCRIPTION
• CLINICAL PHARMACOLOGY
• HONEY BEE HYMENOPTERA VENOM MULTIDOSE INDICATIONS AND USAGE
• HONEY BEE HYMENOPTERA VENOM MULTIDOSE CONTRAINDICATIONS
• WARNINGS
• PRECAUTIONS
  • (1) GENERAL
  • (2) INFORMATION FOR PATIENTS
  • (3) DRUG INTERACTIONS
  • (4) CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
  • (5) PREGNANCY
  • (6) NURSING MOTHERS
  • (7) PEDIATRIC USE
  • (8) GERIATRIC USE
• HONEY BEE HYMENOPTERA VENOM MULTIDOSE ADVERSE REACTIONS
• OVERDOSAGE
• HONEY BEE HYMENOPTERA VENOM MULTIDOSE DOSAGE AND ADMINISTRATION
  • 4. PEDIATRIC USE
  • 5. GERIATRIC USE
• HOW SUPPLIED
• LIMITED WARRANTY
• REFERENCES

FULL PRESCRIBING INFORMATION

HONEY BEE HYMENOPTERA VENOM MULTIDOSE DESCRIPTION

Hymenoptera Venom Products available are sterile freeze-dried venom of Honey Bee (Apis mellifera) and venom protein of Yellow Jacket (Vespula sp.), Yellow Hornet (Dolichovespula arenaria), White-Faced Hornet (Dolichovespula maculata) 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.
When the sterile freeze-dried Honey Bee venom is reconstituted with 5.5 mL of sterile fluid, the resulting solution will contain 100 micrograms of venom per mL (100 µg/mL) plus 7.7 milligrams of mannitol per mL. When freeze-dried Yellow Jacket, Yellow Hornet, White-Faced Hornet and Wasp venom proteins are reconstituted with 5.5 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 freeze-dried Mixed Vespid venom protein is reconstituted with 5.5 mL of fluid, the resulting solution contains 300 micrograms of venom protein per mL (300µg/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

HONEY BEE HYMENOPTERA VENOM MULTIDOSE 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.

(1) Diagnosis
Skin testing with insect venoms is useful to demonstrate the presence of IgE antibodies which account for the patient's symptoms.(3) Patients are seldom able to identify the insect which stung them, so skin testing is used to determine the insect culprit. Dilutions of these venom products will help judge the sensitivity of the patient and whether the patient should be treated.(7)
It is not absolutely known what levels (micrograms) of venom, that elicit positive skin tests, are diagnostic of clinical sensitivity. However, patients with a history of reactions (any of three types: generalized urticaria or angioedema; respiratory difficulty due either to laryngeal edema or to bronchospasm; or vascular collapse, with or without loss of consciousness) to previous stings and a positive skin test to a venom intradermal injection of approximately 1 µg/mL had about a 60% chance of reacting again when stung by the same insect. These patients should receive venom immunotherapy.(3)
Patients with a history of reaction (any of the three reaction types described above) to previous stings, but did not demonstrate a positive skin test reaction to venom, were considered in a previous study not to be clinically sensitive, and were not treated.(3) We cannot recommend treatment for such patients.
Another study demonstrated false positive reactions when skin testing with venom concentrations of 10 µg/mL and 100 µg/mL was carried out.(8) Thus there can be a nonspecific skin test reaction potentially due to the pharmacological action of the venom at higher concentrations.
The best statement that can be made, at present, is that patients with significant positive history (reactions of the three types described above) following an insect sting, and who do react with a positive skin test to a venom concentration of 1 µg/mL or less, are recommended for treatment. Patients who have the history described above, but do not react to a 1 µg/mL intradermal venom skin test, cannot be recommended for treatment. At present, the data does not exist to determine whether a patient who might react to a higher concentration, e.g., 2-10 µg/mL, is at risk from a subsequent sting or not. Since it is not known if sting-sensitive patients who subsequently lose their IgE anti-venom antibody can be re-sensitized by further stings, it is advisable to retest these patients after any subsequent stings.(3)However, since the level of venom-specific IgE may fall to low levels briefly after a sting, patients should not be re-tested until 2 to 4 weeks after any sting.

(2) Treatment
Immunotherapy is indicated for those patients diagnosed as sensitive (see Diagnosis above) and is accomplished by using graduated dilutions of the appropriate insect venom or venoms to control the severity of the patient's symptoms from subsequent stings.
Increasing doses of venom are given at intervals, dependent on the patient's ability to tolerate the venom, until a maintenance dosage (100 µg venom is recommended or 300 µg in the case of Mixed Vespid venom protein) is reached and maintained.
Venom sensitivity differs for individual patients, thus it is not possible to provide a dosage schedule that is universally suited to all patients. The dosage schedule shown under DOSAGE AND ADMINISTRATION is a summary of the schedule used in clinical trials of our product and found suitable for the majority of patients. In highly sensitive patients, the physician may be required to use a modified dose schedule, based on the patient's sensitivity to and tolerance of the injections. Lower initial doses and smaller dosage increments than shown under DOSAGE AND ADMINISTRATION may be necessary.

HONEY BEE HYMENOPTERA VENOM MULTIDOSE CONTRAINDICATIONS

WARNINGS

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.)

Maintain stock solutions and dilutions constantly at 2° - 8°C.

Sterile solutions, vials, syringes, etc., should be used and aseptic precautions observed in making dilutions.

To avoid cross-contamination, do not use the same needle to withdraw materials from vials of more than one extract, or extract followed by diluent.

A sterile tuberculin syringe, with a needle at least 5/8" long and graduated in 0.01 mL units, should be used to carefully measure each dose from the appropriate dilution. Aseptic techniques should always be employed when injections are being administered.

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. 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 MULTIDOSE ADVERSE REACTIONS

OVERDOSAGE

See ADVERSE REACTIONS.

HONEY BEE HYMENOPTERA VENOM MULTIDOSE DOSAGE AND ADMINISTRATION