Allergenic Extract, Ragweed Pollen

The sterile Short Ragweed or Giant and Short Ragweed Mix Allergenic Extract in this vial may be supplied for scratch, prick or puncture testing; intradermal testing; treatment; or as a "bulk" extract which is designed primarily for the physician equipped to prepare dilutions and mixtures as required.

Each concentrated lot of Short Ragweed and Giant and Short Ragweed Mix is assayed for Amb a 1 3 (also known as Antigen E) and submitted to the Center for Biologics Evaluation and Research for official release

The Amb a 1 concentrations for dilutions of extracts greater than 1:20 w/v have been obtained by calculation from the assayed value. The following is a brief description of the three expressions of concentration applied to these extracts.

1. Weight to volume (w:v). The amount of allergenic source material added to the extracting fluid. A 1:20 extract indicates that the solution contains the extractable material from one gram of raw material added to each 20 mL of extracting fluid. The amount and composition of extracted materials will vary with the kind of antigen, the extracting fluid, duration of extraction, pH, temperature, and other variables.

2. Protein Nitrogen Units (PNU). One protein nitrogen unit represents 0.00001 mg phosphotungstic acid precipitable protein nitrogen dis solved in one mL of antigen extract. The PNU content of extracts of the same antigen may vary according to the method of measuring the PNU. Thus, the PNU content of extracts from different manufacturers is not comparable unless the PNU method is known to be the same and is reproducible from lot to lot. Also, the amount of protein nitrogen extracted from an antigen is influenced by the same variables as the weight to volume extract. Allergenic materials make up a variable proportion of the total protein of an extract.

3. Of the many allergens from Short Ragweed which have been purified and characterized (Amb a 1, Amb a 2 3 (also known as Antigen K),Ra-34, Ra-4 (BPA-R)5, Ra-56, Ra6, Ra7and Ra87, and cytochrome C 8), Amb a 1 is considered the most important and has been selected as the basis for standardization. Extracts of Short Ragweed containing Amb a 1 are diffused in agar against standard anti-serum to Amb a 1, and compared to the diffusion of standard Amb a 1 solutions. The amount of Amb a 1 is expressed as units of Amb a 1 per mL of extract. Amb a 1 units are approximately equal to micrograms previously used to measure Amb a 1 concentration. The Amb a 1 assay therefore provides an absolute measure of extract potency related to the Amb a 1 antigen in Short Ragweed, rather than only an expression of extract strength.

Ingredients: Active ingredients are the allergen(s) noted on the vial label. Preservative is 50% (v/v) glycerin or 0.4% phenol, as indicated on the vial label. Glycerinated extracts contain 0.5% sodium chloride, 0.275% sodium bicarbonate and 50% glycerin (v/v) as a preservative. Non-glycerinated extracts contain 0.5% sodium chloride, 0.275% sodium bicarbonate and 0.4% phenol (w/v) as a preservative.

20, 21, 22, 23 Allergenic extracts are indicated for use in diagnosis and immunotherapy of patients presenting symptoms of allergy (hay fever, rhinitis, etc.) to specific environmental allergens. The selection of allergenic extracts to be used should be based on a thorough and carefully taken history of hypersensitivity, and confirmed by skin testing.24, 25
The use of mixes of unrelated antigens for skin testing is not recommended since, in the case of a positive reaction, it does not indicate which component of the mix is responsible for the reaction; while, in the case of a negative reaction, it fails to indicate whether the individual antigens at full concentration would give a positive reaction. Utilization of such mixes for compounding a treatment may result, in the former case, in administering unnecessary antigens and, in the latter case, in the omission of a needed antigen.
Statistically controlled blind studies have demonstrated the effectiveness of therapy with Amb a 1.26 However, double blind studies have demonstrated a greater effectiveness for whole Short Ragweed extract when compared to Amb a 1 alone.27 Short Ragweed Extracts, standardized on the basis of Amb a 1 extract, would seem to be a logical choice for immunotherapy.
Allergens to which a patient is extremely sensitive should not be included in treatment mixes with allergens to which there is much less sensitivity, but should be administered separately. This allows individualized and better control of dosage increases, including adjustments in dosage becoming necessary after severe reactions which may occur to the highly reactive allergen.

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, 28, 29, 30, 31

Concentrated extracts must not be injected unless tolerance has been established. Concentrated extracts must be diluted prior to use. See DOSAGE AND ADMINISTRATION for detailed instructions on the dilution of allergenic extracts.

Any evidence of a local or generalized reaction requires a reduction in dosage during the initial stages of immunotherapy, as well as during maintenance therapy. Allergenic extracts diluted with sterile Albumin Saline with Phenol (0.4%) may be more potent than extracts diluted with diluents which do not contain stabilizers. When changing from non-stabilized to stabilized diluent, consider weaker initial dilutions for both intradermal testing and immunotherapy. Dilutions for both intradermal testing and immunotherapy. 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 graduated in 0.01 mL units and with a needle at least 5/8" long should be used to measure each dose from the appropriate dilution. Aseptic techniques should always be employed when injections of allergenic extracts 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 dosage 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. 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 EACH TREATMENT INJECTION. Most severe reactions will occur within this time period, and rapid treatment measures should be instituted. See ADVERSE REACTIONS for these 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 package insert.) 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 to report any symptoms of exposure to the allergen, so the physician can adjust the dosage appropriately.

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.)

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. 32

Topical steroids should be discontinued at the skin test site for at least 2-3 weeks before skin testing.32, 33

Tricyclic antidepressants such as Doxepin should be withheld for at least 7 days before skin testing.34 Topical local anesthetics may suppress flare responses and should be avoided in skin test sites.35

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.

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

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. The physician must carefully consider the benefit-to-risk ratio to both patient and fetus, of performing skin testing or continuing immunotherapy during pregnancy. The recommended precautions (See WARNINGS and PRECAUTIONS) for preventing adverse reactions are especially important in the pregnant patient. Based on the physician's discretion, immunotherapy maintenance doses may be continued during pregnancy if the patient has not experienced adverse side effects. Immunotherapy is generally not initiated during pregnancy due to the risks associated with systemic reactions and their treatment.37

6. Nursing Mothers

There are no current studies on the secretion of allergenic extract components in human milk or their 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 children is the same as for adults,38, 39 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.

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.40

Physicians administering allergenic extract testing or treatment materials should be experienced in the treatment of severe systemic reactions. See WARNINGS box at the beginning of this package insert.

1. Local Reactions
Some erythema, swelling, or pruritus at the site of injection are common, the extent varying with the patient. Such reactions should not be considered significant unless they persist for at least 24 hours.

Local reactions (erythema or swelling) which exceed 4-5 cm in diameter are not only uncomfortable, but also indicate the possibility of a systemic reaction if dosage is increased. In such cases the dosage should be reduced to the last level not causing the reaction and maintained at this level for two or three treatments before cautiously increasing again.

Large, persistent local reactions may be treated by local cold, wet dressings and/or the use of oral antihistamines. They should be considered a warning of possible severe systemic reactions and the need for temporarily reduced dosages.

A mild burning immediately after the injection is to be expected; this usually subsides in 10 to 20 seconds.

2. Systemic Reactions
With careful attention to dosage and administration, systemic reactions occur infrequently, but it cannot be overemphasized that in sensitive individuals any injection could result in anaphylactic shock. Therefore, it is imperative that physicians administering allergenic extracts understand and be prepared for the treatment of severe reactions.

Most severe systemic reactions will begin within a 30 minute time period, but systemic reactions may occur at any time after skin tests or immunotherapy. Symptoms may range from mild to life-threatening (due to anaphylaxis) as described below.

Other possible systemic reaction symptoms which may occur in varying degrees of severity are laryngeal edema, fainting, pallor, bradycardia, hypotension, angioedema, cough, wheezing, conjunctivitis, rhinitis, and urticaria. Adverse reaction frequency data for allergenic extract administration for testing and treatment show that risk is low. 1, 41

If a systemic or anaphylactic reaction does occur, apply a tourniquet above the site of injection and inject 1:1000 epinephrine-hydrochloride intramuscularly into the opposite arm. Loosen the tourniquet at least every 10 minutes. Do not obstruct arterial blood flow with the tourniquet.

EPINEPHRINE DOSAGE
ADULT: 0.3 to 0.5 mL should be injected. Repeat in 5 to 10 minutes if necessary.
PEDIATRIC: The usual initial dose is 0.01 mg (mL) per kg body weight or 0.3 mg (mL) per square meter of body surface area. Suggested dosage for infants to 2 years of age is 0.05 mL to 0.1 mL; for children 2 to 6 years, 0.15 mL; and children 6 to 12 years, 0.2 mL. Single pediatric doses should not exceed 0.3 mg (mL). Doses may be repeated as frequently as every 20 minutes, depending on the severity of the condition and the response of the patient.
After administration of epinephrine, profound shock or vasomotor collapse should be treated with intravenous fluids, and possibly vasoactive drugs. Airway patiency should be insured. Oxygen should be given by mask. Intravenous antihistamine, inhaled bronchodilators, theophylline, and/or adrenal corticosteroids may be used if necessary after adequate epinephrine and circulatory support have been given.
Emergency resuscitation measures and personnel trained in their use must be available immediately in the event of a serious systemic or anaphylactic reaction not responsive to the above measures [Ref. J. Allergy and Clinical Immunology 77(2): p. 271-273, 1986].
Rarely are all of the above measures necessary; the tourniquet and epinephrine usually produce prompt responses. However, the physician should be prepared in advance for all contingencies. Promptness in beginning emergency treatment measures is of utmost importance.
Severe systemic reactions mandate a decrease of at least 50% in the next dose, followed by cautious increases. Repeated systemic reactions, even of a mild nature, are sufficient reason for the cessation of further attempts to increase the reaction-causing dose.

3. Adverse Event Reporting
Report all adverse events to Jubilant HollisterStier LLC, Customer Technical Services Department at 1(800) 992-1120. A voluntary adverse event reporting system for health professionals is available through the FDA MEDWATCH program. Preprinted forms (FDA Form 3500) are available from the FDA by calling 1(800) FDA-1088. Completed forms should be mailed to MEDWATCH, 5600 Fisher Lane, Rockville, MD 20852-9787 or Fax to: 1(800) FDA-0178.

The expiration date is listed on the container label. To insure the maximum potency of Short Ragweed extract and its dilutions, it is recommended that the product be maintained at a temperature of 2° - 8°C at all times, even during use. Dilutions are less stable than the Concentrate. If loss of potency is suspected, the product should be checked by skin testing with equal units of a freshly prepared dilution on known ragweed pollen allergic individuals.

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.