Antigen Laboratories, Inc.

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DOSAGE AND ADMINISTRATION     Refer to “STORAGE” section for proper storage condition for allergenic extract.    Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.  Some allergenic extracts naturally precipitate.    Physicians undertaking immunotherapy should be concerned with patient’s degree of sensitivity.  The initial dilution of allergenic extract, starting dose, and progression of dosage must be carefully determined on the basis of the patient’s history and results of skin tests.  (See “INDICATIONS AND USAGE” section.)  Strongly positive skin tests may be risk factors for systemic reactions.  Less aggressive immunotherapy schedules may be indicated for such patients.    PRICK-PUNCTURE TESTING:  To identify short ragweed sensitive individuals and as a safety precaution, it is recommended that a prick or puncture test be performed prior to initiating very dilute intradermal testing.  Prick (puncture) testing is performed by placing a drop of extract on skin and puncturing skin through the drop with a small needle such as a bifurcated vaccinating needle.  The most satisfactory sites on the back for skin testing are from posterior axillary fold to 2.5 cm from the spinal column, and from the top of the scapula to the lower rib margins.  The best areas on the arms are the volar surfaces from the axilla to 2.5 or 5 cm above the wrist, skipping the anticubital space.  A positive reaction is approximately 10-15 mm erythema with 2.5 mm wheal.    Smaller, less conclusive reactions may be considered positive in conjunction with a definitive history of symptoms on exposure to allergen.  Less sensitive individuals can be tested intradermally with appropriately diluted extract.  (See Intradermal Testing.)    A positive control using histamine phosphate identifies patients whose skin may not react due to medications, metabolic or other reasons.  A negative diluent control would exclude false-positive reactions due to ingredients in diluent or patients who have dermatographism. 

SERIAL DILUTIONSAPPROXIMATE AU/ml RESULTING FROM 1:5 DILUTIONOF ALLERGENIC EXTRACT CONCENTRATE DILUTION # DILUTION EXPONENT 100,000 AU/ml No. 1 5-1 20,000 No. 2 5-2 4,000 No. 3 5-3 800 No. 4 5-4 160 No. 5 5-5 32 No. 6 5-6 6.4 No. 7 5-7 1.28 No. 8 5-8 0.256 No. 9 5-9 0.0512 No. 10 5-10 0.01024 No. 11 5-11 0.002048

SERIAL DILUTIONS APPROXIMATE AU/ml RESULTING FROM 1:10 DILUTION OF ALLERGENIC EXTRACT CONCENTRATE DILUTION # DILUTION EXPONENT 100,000 AU/ml No. 1 10-1 10,000 No. 2 10-2 1,000 No. 3 10-3 100 No. 4 10-4 10 No. 5 10-5 1 No. 6 10-6 0.1 No. 7 10-7 0.01 No. 8 10-8 0.001 No. 9 10-9 0.0001 No. 10 10-10 0.00001

    INTRADERMAL TESTING: Upper or lower arm is the usual location for skin testing. A sterile, disposable syringe and needle is used for each extract tested.  Intracutaneous test dilutions should be made with aqueous diluent.  Three-fold, five-fold or ten-fold dilutions may be prepared from stock concentrates. (1) Start testing with the most dilute allergenic extract concentration.  (2) A volume of 0.01-0.02 ml should be injected slowly into the superficial skin layers making a small bleb (superficial wheal).  (3) An initial skin test with 0.001 AU/ml (10-8 or 5-11 dilution) is considered safe for patients with suspected short ragweed sensitivity.  Reactions to skin testing are graded 0 to 4+ according to size of wheal and erythema produced (refer to chart below).  The reactions should be read after fifteen minutes.

GRADE mm ERYTHEMA mm WHEAL 0 less than 5 less than 5 + 5-10 5-10 1+ 11-20 5-10 2+ 21-30 5-10 3+ 31-40 10-15or with pseudopods 4+ greater than 40 greater than 15or with many pseudopods

    If after twenty minutes no skin reaction is observed, continue testing using increments of the concentration until a reaction of 5-10 mm wheal and 10-30 mm erythema is obtained, or a concentration of 5-2 or 10-1 has been tested.  A positive control of histamine phosphate and a negative control of 50% v/v glycerine diluted with diluent to 5-2 (1:25) or 10-1 (1:10) dilution, should be included in interpretation of intradermal testing.1     INTRADERMAL TESTING--SKIN ENDPOINT TITRATION: Patient’s degree of sensitivity and the initial dose of allergen to be used in immunotherapy can be quantitated using five-fold dilutions of allergenic extract for intracutaneous testing.  A concentration of 0.001 AU/ml (5-11 dilution) is a safe initial dilution.  A sequence of 5-fold dilutions of an allergen are injected intracutaneously (0.01-0.02 ml) to form 4 mm diameter superficial wheals.  After 15 minutes the endpoint is determined by noting the dilution that first produces a wheal and erythema 2 mm larger than dilutions that produce a 5 mm or negative wheal.  The endpoint dilution is used as a starting dose concentration for immunotherapy.    Normally, immunotherapy can be started with 0.15 ml of the dilution of allergenic extract causing the endpoint reaction.  In any allergenic patient, a safe starting dose can be determined by finding the first dose by intradermal skin testing producing a 1+ reaction or the dilution producing the skin endpoint.    Increasing doses of 5-20% increments can be administered providing initial or preceding dose is tolerated without significant local reactions.  The rate of increase in dosage in the early stages of treatment with highly diluted extracts is usually more rapid than the rate of increase possible with more concentrated extracts.  This schedule is intended only as a guide and must be modified to the reactivity of the individual patient.  Physicians must proceed cautiously in the treatment of highly sensitive patients who develop large local or systemic reactions.    Some patients may tolerate larger doses of the allergenic extract depending on patient response.3 Because diluted extract tends to lose activity on storage, the first dose from a more concentrated vial should be the same or less than the previous dose.4,7     Dosages progressively increase according to the tolerance of the patient at intervals of one to seven days until, (1) the maintenance dose is reached (the “optimal” tolerated dose for each individual); (2) the patient achieves relief of symptoms; (3) induration at the site of injection is no larger than 50 mm in 36 to 48 hours.  Maintenance dose may be continued at regular intervals perennially.  It may be necessary to adjust the progression of dosage downward to avoid local and systemic reactions during ragweed pollen season.    The usual duration of treatment has not been established.  A period of two or three years on immunotherapy constitutes an average minimum course of treatment.    Clinical studies indicate the “optimal” immunotherapy dose of 2000 AU/ml (range of 1000-4000 AU/ml) consistently provides clinical relief for short ragweed sensitive patients.  Physician should be forewarned that peak dose in this range is more commonly associated with severe systemic reactions than doses below 1000 AU/ml.  Dose may need adjusting downward for extremely sensitive patients or during periods of increased pollen exposure.  Patients unable to tolerate target dose should be treated with lower immunizing dose.1,17

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DOSAGE AND ADMINISTRATION     The current standard method of immunotherapy dates back to Noon.  Therapy is begun with a low dose which has been shown to be tolerated by both experience and skin testing.  The initial dilution of allergenic extract, starting dose, and progression of dosage must be carefully determined on the basis of the patient’s history and results of skin tests.    The physician who undertakes immunotherapy should be concerned with the degree of sensitivity of the patient.  (See “INDICATIONS AND USAGE”.)  Strongly positive skin tests may be risk factors for systemic reactions.  Less aggressive immunotherapy schedules may be indicated for such patients.    Serial five-fold or ten-fold dilutions of the extract are used to make more dilute extract concentrations.  Other concentrations can be prepared by appropriate dilution.  In brief, the allergist can prepare any dilution of extract that is considered appropriate for the patient.    Prick-Puncture Testing: To identify cat sensitive individuals and as a safety precaution, it is recommended that a prick or puncture test using a drop of the 10,000 BAU/ml extract concentrate be performed prior to initiating very dilute intradermal testing.  Prick (puncture) testing is performed by placing a drop of extract concentrate on the skin and puncturing the skin through the drop with a small needle such as a bifurcated vaccinating needle.  The most satisfactory sites on the back for skin testing are from the posterior axillary fold to 2.5 cm from the spinal column, and from the top of the scapula to the lower rib margins.  The best areas on the arms are the volar surfaces from the axilla to 2.5 or 5 cm above the wrist, skipping the anticubital space.  Glycerinated extracts are recommended for prick testing using the most concentrated dilution.  A positive reaction is approximately 10-15 mm erythema with 2.5 mm wheal.    A positive control using Histamine Phosphate is important to identify those patients whose skin may not be reactive due to medications, metabolic or other reasons.  A diluent control, if negative, would exclude false-positive reactions due to ingredients in the diluent or patients who have dermatographism.    Smaller, less conclusive reactions may be considered positive in conjunction with a definitive history of symptoms on exposure to the allergen.  The more sensitive the patient the higher the probability that he/she will have symptoms related upon natural exposure to the offending Cat allergen.  Hence, the importance of good patient history.  Less sensitive individuals can be tested intradermally with an appropriately diluted extract. (See Intradermal Testing.)

SERIAL DILUTIONS APPROXIMATE BAU/ml RESULTING FROM 1:10 DILUTION OF ALLERGENIC EXTRACT CONCENTRATE Allergenic Extract Concentrate DILUTUION # DILUTION EXPONENT 10,000 BAU/ML 5,000 BAU/ML 1,000 BAU/ML 1 10-1 1,000 500 100 2 10-2 100 50 10 3 10-3 10 5.0 1.0 4 10-4 1 0.5 0.1 5 10-5 0.1 0.05 0.01 6 10-6 0.01 0.005 0.001 7 10-7 0.001 0.0005 0.0001 8 10-8 0.0001 0.00005 0.00001 9 10-9 0.00001 0.000005 0.000001 10 10-10 0.000001 0.0000005 0.0000001 SERIAL DILUTIONS APPROXIMATE BAU/ml RESULTING FROM 1:5 DILUTION OF ALLERGENIC EXTRACT CONCENTRATE Allergenic Extract Concentrate DILUTION # DILUTION EXPONENT 10,000 BAU/ML 5,000 BAU/ML 1,000 BAU/ML 1 5-1 2,000 1,000 200 2 5-2 400 200 40 3 5-3 80 40 8.0 4 5-4 16 8.0 1.6 5 5-5 3.2 1.6 0.32 6 5-6 0.64 0.32 0.064 7 5-7 0.128 0.064 0.0128 8 5-8 0.0256 0.0128 0.00256 9 5-9 0.00512 0.00256 0.000512 10 5-10 0.001024 0.000512 0.0001024

    Intradermal testing: The surface of the upper and lower arm is the usual location for skin testing.  It is important that a new sterile, disposable syringe and needle be used for each extract tested.  Intracutaneous test dilutions should be made with aqueous diluent.  Three-fold, five-fold or ten-fold dilutions may be prepared from stock concentrate extract.  (1) Start testing with the most dilute allergenic extract concentration.  (2) A volume of 0.01-0.02 ml should be injected slowly into the superficial skin layers making a small bleb (superficial wheal).  (3) For patients with a suspected cat sensitivity an allergenic extract dilution of 5-10 (0.005 BAU/ml) or 10-7 (0.001 BAU/ml) dilution should be used for initial skin testing.  Sensitivity of the patient can be expressed only if the minimum concentration required for a 1+ or 2+ reaction (see chart below) is determined by performing a skin test titration.  The reaction should be read after fifteen minutes.EVALUATION OF SKIN REACTIONS

GRADE mm ERYTHEMA mm WHEAL 0 less than 5 less than 5 +/- 5-10 5-10 1+ 11-20 5-10 2+ 21-30 5-10 3+ 31-40 10-15or with pseudopods 4+ greater than 40 greater than 15or with many pseudopods

    If after 20 minutes no skin reaction is obtained, continue the testing using increments in the concentration until a reaction of 5-10 mm wheal and 10-30 mm erythema is obtained, or until the concentration of 5-2 or 10-1 has been tested.  As a negative control the diluent, a concentration of less than 0.5% glycerine (5-3 or 10-3), does not produce positive skin wheal and erythema.  The diluent should be tested and included in the interpretation of the skin reactions.17 INTRADERMAL TESTING--SKIN ENDPOINT TITRATION    The allergenic extract to which the patient is sensitive, the patient’s degree of sensitivity and the initial dose of allergen to be used in immunotherapy can be quantitated using five-fold dilutions of allergenic extract for intracutaneous testing.  The critical variable is the size of the wheal and erythema produced by the intracutaneous injection of 0.01-0.02 ml of the test allergen producing a 4 mm diameter superficial wheal.  For initial screening 5-10 (0.005 BAU/ml) is a safe dilution.  When a sequence of five-fold or ten-fold dilutions of an allergen are injected, the endpoint is detected by noting the dilution that first produces a wheal and erythema (15 minutes after injection) that is 2 mm larger than wheals with erythema produced by weaker, non-reacting dilutions (5 mm negative wheal).  The endpoint dilution is used as a starting dose concentration for immunotherapy.    Normally, immunotherapy with allergenic extracts can be started with 0.15 ml of the endpoint of reaction.  In any allergic patient, a safe starting dose can be determined by finding the first dose by intradermal skin testing producing a 1+ reaction or the dilution producing the skin endpoint.      If the first injection of the initial dilution of extract is tolerated without significant local reaction, increasing doses by 5-20% increments of that dilution may be administered.  The rate of increase in dosage in the early stages of treatment with highly diluted extracts is usually more rapid than the rate of increase possible with more concentrated extracts.  This schedule is intended only as a guide and must be modified according to the reactivity of the individual patient.  Needless to say, the physician must proceed cautiously in the treatment of the highly sensitive patient who develops large local or systemic reactions.     Some patients may tolerate larger doses of the allergenic extract depending on patient response.7  Because dilute extracts tend to lose activity on storage, the first dose from a more concentrated vial should be the same or less than the previous dose.8, 12     Dosages progressively increase thereafter according to the tolerance of the patient at intervals of one to seven days until, (1) the patient achieves relief of symptoms, (2) induration at the site of injection is no larger than 50 mm in 36 to 48 hours, (3) a maintenance dose, the largest dose tolerated by the patient short of aggravating existing symptoms, systemic symptoms, or anaphylaxis, or patient demonstrates untoward reactions that indicate the dose to be excessive.  This maintenance dose may be continued at regular intervals perennially.  It may be necessary to adjust the progression of dosage downward to avoid local and constitutional reactions.

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DOSAGE AND ADMINISTRATION     Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.    Normally, immunotherapy with standardized mite allergenic extracts can be started with 0.15 ml of the endpoint of reaction.     If the first injection of the initial dilution of extract is tolerated without significant local reac­tion, increasing doses by 5-20% increments of that dilution may be administered. The rate of increase in dosage in the early stages of treatment with highly diluted extracts is usually more rapid than the rate of increase possible with more concentrated extracts. This schedule is intend­ed only as a guide and must be modified according to the reactivity of the individual patient. Needless to say, the physician must proceed cautiously in the treatment of the highly sensitive patient who develops large local or systemic reactions.     Some patients may tolerate larger doses of the standardized mite allergenic extract depend­ing on patient response.7 Because dilute extracts tend to lose activity on storage, the first dose from a more concentrated vial should be the same or less than the previous dose.8,12     The physician who undertakes immunotherapy should be concerned with the degree of sen­sitivity of the patient. See "INDICATIONS AND USAGE" section. Strongly positive skin tests may be risk factors for systemic reactions. Less aggressive immunotherapy schedules may be indi­cated for such patients. Maintenance dose potency must be established by the physician's clini­cal observation and experience.6,13     Serial five-fold or ten-fold dilutions of the extract are used to make more dilute extract con­centrations. Other concentrations can be prepared by appropriate dilutions. In brief, the allergist can prepare any dilution of extract that is considered appropriate for the patient.     Dosages progressively increase thereafter according to the tolerance of the patient at inter­vals of one to seven days until, (1) the patient achieves relief of symptoms, (2) induration at site of injection is no larger than 50 mm in 36 to 48 hours, (3) a maintenance dose, the largest dose tolerated by the patient short of aggravating existing symptoms, systemic symptoms, or anaphy­laxis, or demonstrates untoward reactions that indicate the dose to be excessive. This mainte­nance dose may be continued at regular intervals perennially. It may be necessary to adjust the progression of dosage downward to avoid local and constitutional reactions.

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Refer to “STORAGE” section for proper storage condition for allergenic extract. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Some allergenic extracts naturally precipitate.

Physicians undertaking immunotherapy should be concerned with patient’s degree of sensitivity. The initial dilution of allergenic extract, starting dose, and progression of dosage must be carefully determined on the basis of the patient’s history and results of skin tests. Strongly positive skin tests may be risk factors for systemic reactions. Less aggressive immunotherapy schedules may be indicated for such patients.

Precaution is necessary when using extract mixture for skin testing. The diluting effect of individual components within a mixture may cause false negative reactions. Patients extremely sensitive to a common allergen in several components of a mixture may be more likely to experience a systemic reaction than when skin tested individually for each component.9

PRICK-PUNCTURE TESTING: To identify highly sensitive individuals and as a safety precaution, it is recommended that a prick-puncture test using a drop of the extract concentrate be performed prior to initiating very dilute intradermal testing. Prick-puncture testing is performed by placing a drop of extract concentrate on the skin and puncturing the skin through the drop with a small needle such as a bifurcated vaccinating needle. The most satisfactory sites on the back for skin testing are from the posterior axillary fold to 2.5 cm from the spinal column, and from the top of the scapula to the lower rib margins. The best areas on the arms are the volar surfaces from the axilla to 2.5 or 5 cm above the wrist, skipping the anticubital space. A positive reaction is approximately 10-15 mm erythema with 2.5 mm wheal. Smaller, less conclusive reactions may be considered positive in conjunction with a definitive history of symptoms on exposure to the allergen. The more sensitive the patient the higher the probability that he/she will have symptoms related to the exposure of the offending allergen. Hence, the importance of a good patient history. Less sensitive individuals can be tested intradermally with an appropriately diluted extract.

A positive control using histamine phosphate identifies patients whose skin may not react due to medications, metabolic or other reasons. A negative control (50% glycerine for prick-puncture testing) would exclude false-positive reactions due to ingredients in diluent or patients who have dermatographism.

SINGLE DILUTION INTRADERMAL TESTING: The surface of the upper and lower arm is the usual location for skin testing. It is important that a new, sterile, disposable syringe and needle be used for each extract tested. Intracutaneous test dilutions, five-fold or ten-fold, may be prepared from stock concentrate using physiologic saline as a diluent. (1) Start testing with the most dilute allergenic extract concentration. (2) A volume of 0.02-0.05 ml should be injected slowly into the superficial skin layers making a small bleb (superficial wheal). (3) For patients without a history of extreme sensitivity, or a negative or weakly reactive prick-puncture test, the initial dilution for skin testing should be a dilution at least 1:12,500 w/v. This initial dilution can be prepared by diluting 1:20 to 1:50 w/v (2%-5%) extracts five-fold to 5-4 or 1:10 w/v (10%) extracts to 5-5. See “Serial Dilutions Titration Test Dilutions” chart on the next page. Dilute 1:10 w/v (10%) extracts to 10-3 if using ten-fold dilutions. (4) Sensitive patients with a positive prick-puncture test require a further dilution to at least 1:312,500 w/v. This dilution can be prepared by diluting 1:20 to 1:50 w/v (2% - 5%) extracts to 5-6 or 1:10 w/v (10%) extracts to 5-7 (five-fold dilutions). Ten-fold dilution to 10-6 of a 1:10 w/v (10%) extract would be a safe starting dilution. Size of reactions are quantitated based on size of wheal and erythema. For interpretation of skin reactions, refer to chart below. If after 20 minutes no skin reaction is observed, continue testing using increasing increments of the concentration until a reaction of 5-10 mm wheal and 11-30 mm erythema is obtained, or a concentration of 5-2 or 10-1 has been tested. A negative control, 50% glycerine diluted with diluent to 5-2 (1:25) or 10-1 (1:10) dilution and a positive control of histamine phosphate, should be tested and included in interpretation of skin reactions.1, 13

GRADE mm ERYTHEMA mm WHEAL 0 less than 5 less than 5 ± 5-10 5-10 1+ 11-20 5-10 2+ 21-30 5-10 3+ 31-40 10-15 or with pseudopods 4+ greater than 40 greater than 15 or with many pseudopods

INTRADERMAL TESTING-SKIN ENDPOINT TITRATION: The allergenic extracts to which the patient is sensitive, the patient’s degree of sensitivity and the dose of allergen to be used in immunotherapy can be determined through the use of intracutaneous skin tests involving progressive five-fold dilutions of allergenic extracts. Intracutaneously inject 0.01 to 0.02 ml of the test allergen to form a 4 mm diameter superficial skin wheal. For patients demonstrating a negative or weakly reactive prick-puncture skin test, an initial screening dilution of 1:12,500 w/v is safe. For patients demonstrating a positive prick-puncture skin test, an initial screening dilution of 1:312,500 w/v is safe. (See “Serial Dilution Titration Test Dilutions” chart below.) When a sequence of five-fold or ten-fold dilutions of an allergen are injected, the endpoint is determined by noting the dilution that first produces a wheal and erythema (15 minutes after injection) that is 2 mm larger than wheals with erythema produced by weaker, non-reacting dilutions (5 mm negative wheal). The endpoint dilution is used as a starting dose concentration for immunotherapy. An endpoint dose of 0.15 ml is a safe initial dose to be followed by escalation to the optimal maximum tolerated dose for each individual.

Injections should never be given intravenously. A 5/8 inch, 25 gauge needle on a sterile syringe will allow deep subcutaneous injection.

IMMUNOTHERAPY: If the first injection of the initial dilution of extract is tolerated without significant local reaction, increasing doses by 5-20% increments of that dilution may be administered. The rate of increase in dosage in the early stages of treatment with highly diluted extracts is usually more rapid than the rate of increase possible with more concentrated extracts. This schedule is intended only as a guide and must be modified according to the reactivity of the individual patient. Needless to say, the physician must proceed cautiously in the treatment of the highly sensitive patient who develops large local or systemic reactions.6

Some patients may tolerate larger doses of the allergenic extract depending on patient response.7 Because diluted extract tends to lose activity in storage, the first dose from a more concentrated vial should be the same, or less than, the previous dose.8, 12

Dosages progressively increase according to the tolerance of the patient at intervals of one to seven days until, (1) the patient achieves relief from symptoms, (2) induration at the site of injection is no larger than 50 mm in 36 to 48 hours, (3) a maintenance dose is reached (the largest dose tolerated by the patient that relieves symptoms without undesirable local or systemic reactions). This maintenance dose may be continued at regular intervals perennially. It may be necessary to adjust the progression of dosage downward to avoid local and constitutional reactions.

The usual duration of treatment has not been established. A period of two or three years on immunotherapy constitutes an average minimum course of treatment.

SERIAL DILUTION TITRATION TEST DILUTIONS APPROXIMATE ALLERGENIC EXTRACT CONCENTRATION RESULTING FROM 1:5 DILUTION Titration Number Dilution Exponent Weight / Volume Allergenic Extract Concentrate 1:50 (2%) 1:40 (2 1/2%) 1:33 1/3 (3%) 1:20 (5%) 1:10 (10%) No. 1 5-1 1:5 1:250 1:200 1:167 1:100 1:50 No. 2 5-2 1:25 1:1,250 1:1,000 1:835 1:500 1:250 No. 3 5-3 1:125 1:6,250 1:5,000 1:4,175 1:2,500 1:1,250 No. 4 5-4 1:625 1:31,250 1:25,000 1:20,875 1:12,500 1:6,250 No. 5 5-5 1:3,125 1:156,250 1:125,000 1:104,375 1:62,500 1:31,250 No. 6 5-6 1:15,625 1:781,250 1:625,000 1:521,875 1:312,500 1:156,250 No. 7 5-7 1:78,125 1:3,906,250 1:3,125,000 1:2,609,375 1:1,562,500 1:781,250 No. 8 5-8 1:390,625 1:19,531,250 1:15,625,000 1:13,046,875 1:7,812,500 1:3,906,250 No. 9 5-9 1:1,953,125 1:97,656,250 1:78,125,000 1:65,234,375 1:39,062,500 1:19,531,250 No. 10 5-10 1:9,765,625 1:488,281,250 1:390,625,000 1:326,171,875 1:195,312,500 1:97,656,250 No. 11 5-11 1:48,828,125 1:2,441,406,250 1:1,953,125,000 1:1,630,859,375 1:976,562,500 1:488,281,250 No. 12 5-12 1:244,140,625 1:12,207,031,250 1:9,765,625,000 1:8,154,296,875 1:4,882,812,500 1:2,441,406,250

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Refer to “STORAGE” section for proper storage condition for allergenic extract. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Some allergenic extracts naturally precipitate.

Physicians undertaking immunotherapy should be concerned with patient’s degree of sensitivity. The initial dilution of allergenic extract, starting dose, and progression of dosage must be carefully determined on the basis of the patient’s history and results of skin tests. Strongly positive skin tests may be risk factors for systemic reactions. Less aggressive immunotherapy schedules may be indicated for such patients.

Precaution is necessary when using extract mixture for skin testing. The diluting effect of individual components within a mixture may cause false negative reactions. Patients extremely sensitive to a common allergen in several components of a mixture may be more likely to experience a systemic reaction than when skin tested individually for each component.9

PRICK-PUNCTURE TESTING: To identify highly sensitive individuals and as a safety precaution, it is recommended that a prick-puncture test using a drop of the extract concentrate be performed prior to initiating very dilute intradermal testing. Prick-puncture testing is performed by placing a drop of extract concentrate on the skin and puncturing the skin through the drop with a small needle such as a bifurcated vaccinating needle. The most satisfactory sites on the back for skin testing are from the posterior axillary fold to 2.5 cm from the spinal column, and from the top of the scapula to the lower rib margins. The best areas on the arms are the volar surfaces from the axilla to 2.5 or 5 cm above the wrist, skipping the anticubital space. A positive reaction is approximately 10-15 mm erythema with 2.5 mm wheal. Smaller, less conclusive reactions may be considered positive in conjunction with a definitive history of symptoms on exposure to the allergen. The more sensitive the patient the higher the probability that he/she will have symptoms related to the exposure of the offending allergen. Hence, the importance of a good patient history. Less sensitive individuals can be tested intradermally with an appropriately diluted extract.

A positive control using histamine phosphate identifies patients whose skin may not react due to medications, metabolic or other reasons. A negative control (50% glycerine for prick-puncture testing) would exclude false-positive reactions due to ingredients in diluent or patients who have dermatographism.

SINGLE DILUTION INTRADERMAL TESTING: The surface of the upper and lower arm is the usual location for skin testing. It is important that a new, sterile, disposable syringe and needle be used for each extract tested. Intracutaneous test dilutions, five-fold or ten-fold, may be prepared from stock concentrate using physiologic saline as a diluent. (1) Start testing with the most dilute allergenic extract concentration. (2) A volume of 0.02-0.05 ml should be injected slowly into the superficial skin layers making a small bleb (superficial wheal). (3) For patients without a history of extreme sensitivity, or a negative or weakly reactive prick-puncture test, the initial dilution for skin testing should be a dilution at least 1:12,500 w/v. This initial dilution can be prepared by diluting 1:20 to 1:50 w/v (2%-5%) extracts five-fold to 5-4 or 1:10 w/v (10%) extracts to 5-5. See “Serial Dilutions Titration Test Dilutions” chart on the next page. Dilute 1:10 w/v (10%) extracts to 10-3 if using ten-fold dilutions. (4) Sensitive patients with a positive prick-puncture test require a further dilution to at least 1:312,500 w/v. This dilution can be prepared by diluting 1:20 to 1:50 w/v (2% - 5%) extracts to 5-6 or 1:10 w/v (10%) extracts to 5-7 (five-fold dilutions). Ten-fold dilution to 10-6 of a 1:10 w/v (10%) extract would be a safe starting dilution. Size of reactions are quantitated based on size of wheal and erythema. For interpretation of skin reactions, refer to chart below. If after 20 minutes no skin reaction is observed, continue testing using increasing increments of the concentration until a reaction of 5-10 mm wheal and 11-30 mm erythema is obtained, or a concentration of 5-2 or 10-1 has been tested. A negative control, 50% glycerine diluted with diluent to 5-2 (1:25) or 10-1 (1:10) dilution and a positive control of histamine phosphate, should be tested and included in interpretation of skin reactions.1, 13

GRADE mm ERYTHEMA mm WHEAL 0 less than 5 less than 5 ± 5-10 5-10 1+ 11-20 5-10 2+ 21-30 5-10 3+ 31-40 10-15 or with pseudopods 4+ greater than 40 greater than 15 or with many pseudopods

INTRADERMAL TESTING-SKIN ENDPOINT TITRATION: The allergenic extracts to which the patient is sensitive, the patient’s degree of sensitivity and the dose of allergen to be used in immunotherapy can be determined through the use of intracutaneous skin tests involving progressive five-fold dilutions of allergenic extracts. Intracutaneously inject 0.01 to 0.02 ml of the test allergen to form a 4 mm diameter superficial skin wheal. For patients demonstrating a negative or weakly reactive prick-puncture skin test, an initial screening dilution of 1:12,500 w/v is safe. For patients demonstrating a positive prick-puncture skin test, an initial screening dilution of 1:312,500 w/v is safe. (See “Serial Dilution Titration Test Dilutions” chart below.) When a sequence of five-fold or ten-fold dilutions of an allergen are injected, the endpoint is determined by noting the dilution that first produces a wheal and erythema (15 minutes after injection) that is 2 mm larger than wheals with erythema produced by weaker, non-reacting dilutions (5 mm negative wheal). The endpoint dilution is used as a starting dose concentration for immunotherapy. An endpoint dose of 0.15 ml is a safe initial dose to be followed by escalation to the optimal maximum tolerated dose for each individual.

Injections should never be given intravenously. A 5/8 inch, 25 gauge needle on a sterile syringe will allow deep subcutaneous injection.

IMMUNOTHERAPY: If the first injection of the initial dilution of extract is tolerated without significant local reaction, increasing doses by 5-20% increments of that dilution may be administered. The rate of increase in dosage in the early stages of treatment with highly diluted extracts is usually more rapid than the rate of increase possible with more concentrated extracts. This schedule is intended only as a guide and must be modified according to the reactivity of the individual patient. Needless to say, the physician must proceed cautiously in the treatment of the highly sensitive patient who develops large local or systemic reactions.6

Some patients may tolerate larger doses of the allergenic extract depending on patient response.7 Because diluted extract tends to lose activity in storage, the first dose from a more concentrated vial should be the same, or less than, the previous dose.8, 12

Dosages progressively increase according to the tolerance of the patient at intervals of one to seven days until, (1) the patient achieves relief from symptoms, (2) induration at the site of injection is no larger than 50 mm in 36 to 48 hours, (3) a maintenance dose is reached (the largest dose tolerated by the patient that relieves symptoms without undesirable local or systemic reactions). This maintenance dose may be continued at regular intervals perennially. It may be necessary to adjust the progression of dosage downward to avoid local and constitutional reactions.

The usual duration of treatment has not been established. A period of two or three years on immunotherapy constitutes an average minimum course of treatment.

SERIAL DILUTION TITRATION TEST DILUTIONS APPROXIMATE ALLERGENIC EXTRACT CONCENTRATION RESULTING FROM 1:5 DILUTION Titration Number Dilution Exponent Weight / Volume Allergenic Extract Concentrate 1:50 (2%) 1:40 (2 1/2%) 1:33 1/3 (3%) 1:20 (5%) 1:10 (10%) No. 1 5-1 1:5 1:250 1:200 1:167 1:100 1:50 No. 2 5-2 1:25 1:1,250 1:1,000 1:835 1:500 1:250 No. 3 5-3 1:125 1:6,250 1:5,000 1:4,175 1:2,500 1:1,250 No. 4 5-4 1:625 1:31,250 1:25,000 1:20,875 1:12,500 1:6,250 No. 5 5-5 1:3,125 1:156,250 1:125,000 1:104,375 1:62,500 1:31,250 No. 6 5-6 1:15,625 1:781,250 1:625,000 1:521,875 1:312,500 1:156,250 No. 7 5-7 1:78,125 1:3,906,250 1:3,125,000 1:2,609,375 1:1,562,500 1:781,250 No. 8 5-8 1:390,625 1:19,531,250 1:15,625,000 1:13,046,875 1:7,812,500 1:3,906,250 No. 9 5-9 1:1,953,125 1:97,656,250 1:78,125,000 1:65,234,375 1:39,062,500 1:19,531,250 No. 10 5-10 1:9,765,625 1:488,281,250 1:390,625,000 1:326,171,875 1:195,312,500 1:97,656,250 No. 11 5-11 1:48,828,125 1:2,441,406,250 1:1,953,125,000 1:1,630,859,375 1:976,562,500 1:488,281,250 No. 12 5-12 1:244,140,625 1:12,207,031,250 1:9,765,625,000 1:8,154,296,875 1:4,882,812,500 1:2,441,406,250

---

Refer to “STORAGE” section for proper storage condition for allergenic extract. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Some allergenic extracts naturally precipitate.

Physicians undertaking immunotherapy should be concerned with patient’s degree of sensitivity. The initial dilution of allergenic extract, starting dose, and progression of dosage must be carefully determined on the basis of the patient’s history and results of skin tests. Strongly positive skin tests may be risk factors for systemic reactions. Less aggressive immunotherapy schedules may be indicated for such patients.

Precaution is necessary when using extract mixture for skin testing. The diluting effect of individual components within a mixture may cause false negative reactions. Patients extremely sensitive to a common allergen in several components of a mixture may be more likely to experience a systemic reaction than when skin tested individually for each component.9

PRICK-PUNCTURE TESTING: To identify highly sensitive individuals and as a safety precaution, it is recommended that a prick-puncture test using a drop of the extract concentrate be performed prior to initiating very dilute intradermal testing. Prick-puncture testing is performed by placing a drop of extract concentrate on the skin and puncturing the skin through the drop with a small needle such as a bifurcated vaccinating needle. The most satisfactory sites on the back for skin testing are from the posterior axillary fold to 2.5 cm from the spinal column, and from the top of the scapula to the lower rib margins. The best areas on the arms are the volar surfaces from the axilla to 2.5 or 5 cm above the wrist, skipping the anticubital space. A positive reaction is approximately 10-15 mm erythema with 2.5 mm wheal. Smaller, less conclusive reactions may be considered positive in conjunction with a definitive history of symptoms on exposure to the allergen. The more sensitive the patient the higher the probability that he/she will have symptoms related to the exposure of the offending allergen. Hence, the importance of a good patient history. Less sensitive individuals can be tested intradermally with an appropriately diluted extract.

A positive control using histamine phosphate identifies patients whose skin may not react due to medications, metabolic or other reasons. A negative control (50% glycerine for prick-puncture testing) would exclude false-positive reactions due to ingredients in diluent or patients who have dermatographism.

SINGLE DILUTION INTRADERMAL TESTING: The surface of the upper and lower arm is the usual location for skin testing. It is important that a new, sterile, disposable syringe and needle be used for each extract tested. Intracutaneous test dilutions, five-fold or ten-fold, may be prepared from stock concentrate using physiologic saline as a diluent. (1) Start testing with the most dilute allergenic extract concentration. (2) A volume of 0.02-0.05 ml should be injected slowly into the superficial skin layers making a small bleb (superficial wheal). (3) For patients without a history of extreme sensitivity, or a negative or weakly reactive prick-puncture test, the initial dilution for skin testing should be a dilution at least 1:12,500 w/v. This initial dilution can be prepared by diluting 1:20 to 1:50 w/v (2%-5%) extracts five-fold to 5-4 or 1:10 w/v (10%) extracts to 5-5. See “Serial Dilutions Titration Test Dilutions” chart on the next page. Dilute 1:10 w/v (10%) extracts to 10-3 if using ten-fold dilutions. (4) Sensitive patients with a positive prick-puncture test require a further dilution to at least 1:312,500 w/v. This dilution can be prepared by diluting 1:20 to 1:50 w/v (2% - 5%) extracts to 5-6 or 1:10 w/v (10%) extracts to 5-7 (five-fold dilutions). Ten-fold dilution to 10-6 of a 1:10 w/v (10%) extract would be a safe starting dilution. Size of reactions are quantitated based on size of wheal and erythema. For interpretation of skin reactions, refer to chart below. If after 20 minutes no skin reaction is observed, continue testing using increasing increments of the concentration until a reaction of 5-10 mm wheal and 11-30 mm erythema is obtained, or a concentration of 5-2 or 10-1 has been tested. A negative control, 50% glycerine diluted with diluent to 5-2 (1:25) or 10-1 (1:10) dilution and a positive control of histamine phosphate, should be tested and included in interpretation of skin reactions.1, 13

GRADE mm ERYTHEMA mm WHEAL 0 less than 5 less than 5 ± 5-10 5-10 1+ 11-20 5-10 2+ 21-30 5-10 3+ 31-40 10-15 or with pseudopods 4+ greater than 40 greater than 15 or with many pseudopods

INTRADERMAL TESTING-SKIN ENDPOINT TITRATION: The allergenic extracts to which the patient is sensitive, the patient’s degree of sensitivity and the dose of allergen to be used in immunotherapy can be determined through the use of intracutaneous skin tests involving progressive five-fold dilutions of allergenic extracts. Intracutaneously inject 0.01 to 0.02 ml of the test allergen to form a 4 mm diameter superficial skin wheal. For patients demonstrating a negative or weakly reactive prick-puncture skin test, an initial screening dilution of 1:12,500 w/v is safe. For patients demonstrating a positive prick-puncture skin test, an initial screening dilution of 1:312,500 w/v is safe. (See “Serial Dilution Titration Test Dilutions” chart below.) When a sequence of five-fold or ten-fold dilutions of an allergen are injected, the endpoint is determined by noting the dilution that first produces a wheal and erythema (15 minutes after injection) that is 2 mm larger than wheals with erythema produced by weaker, non-reacting dilutions (5 mm negative wheal). The endpoint dilution is used as a starting dose concentration for immunotherapy. An endpoint dose of 0.15 ml is a safe initial dose to be followed by escalation to the optimal maximum tolerated dose for each individual.

Injections should never be given intravenously. A 5/8 inch, 25 gauge needle on a sterile syringe will allow deep subcutaneous injection.

IMMUNOTHERAPY: If the first injection of the initial dilution of extract is tolerated without significant local reaction, increasing doses by 5-20% increments of that dilution may be administered. The rate of increase in dosage in the early stages of treatment with highly diluted extracts is usually more rapid than the rate of increase possible with more concentrated extracts. This schedule is intended only as a guide and must be modified according to the reactivity of the individual patient. Needless to say, the physician must proceed cautiously in the treatment of the highly sensitive patient who develops large local or systemic reactions.6

Some patients may tolerate larger doses of the allergenic extract depending on patient response.7 Because diluted extract tends to lose activity in storage, the first dose from a more concentrated vial should be the same, or less than, the previous dose.8, 12

Dosages progressively increase according to the tolerance of the patient at intervals of one to seven days until, (1) the patient achieves relief from symptoms, (2) induration at the site of injection is no larger than 50 mm in 36 to 48 hours, (3) a maintenance dose is reached (the largest dose tolerated by the patient that relieves symptoms without undesirable local or systemic reactions). This maintenance dose may be continued at regular intervals perennially. It may be necessary to adjust the progression of dosage downward to avoid local and constitutional reactions.

The usual duration of treatment has not been established. A period of two or three years on immunotherapy constitutes an average minimum course of treatment.

SERIAL DILUTION TITRATION TEST DILUTIONS APPROXIMATE ALLERGENIC EXTRACT CONCENTRATION RESULTING FROM 1:5 DILUTION Titration Number Dilution Exponent Weight / Volume Allergenic Extract Concentrate 1:50 2% 1:40 2 1/2% 1:33 1/3 3% 1:20 5% 1:10 10% No. 1 5-1 1:5 1:250 1:200 1:167 1:100 1:50 No. 2 5-2 1:25 1:1,250 1:1,000 1:835 1:500 1:250 No. 3 5-3 1:125 1:6,250 1:5,000 1:4,175 1:2,500 1:1,250 No. 4 5-4 1:625 1:31,250 1:25,000 1:20,875 1:12,500 1:6,250 No. 5 5-5 1:3,125 1:156,250 1:125,000 1:104,375 1:62,500 1:31,250 No. 6 5-6 1:15,625 1:781,250 1:625,000 1:521,875 1:312,500 1:156,250 No. 7 5-7 1:78,125 1:3,906,250 1:3,125,000 1:2,609,375 1:1,562,500 1:781,250 No. 8 5-8 1:390,625 1:19,531,250 1:15,625,000 1:13,046,875 1:7,812,500 1:3,906,250 No. 9 5-9 1:1,953,125 1:97,656,250 1:78,125,000 1:65,234,375 1:39,062,500 1:19,531,250 No. 10 5-10 1:9,765,625 1:488,281,250 1:390,625,000 1:326,171,875 1:195,312,500 1:97,656,250 No. 11 5-11 1:48,828,125 1:2,441,406,250 1:1,953,125,000 1:1,630,859,375 1:976,562,500 1:488,281,250 No. 12 5-12 1:244,140,625 1:12,207,031,250 1:9,765,625,000 1:8,154,296,875 1:4,882,812,500 1:2,441,406,250

---

Refer to “STORAGE” section for proper storage condition for allergenic extract. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Some allergenic extracts naturally precipitate.

Physicians undertaking immunotherapy should be concerned with patient’s degree of sensitivity. The initial dilution of allergenic extract, starting dose, and progression of dosage must be carefully determined on the basis of the patient’s history and results of skin tests. Strongly positive skin tests may be risk factors for systemic reactions. Less aggressive immunotherapy schedules may be indicated for such patients.

Precaution is necessary when using extract mixture for skin testing. The diluting effect of individual components within a mixture may cause false negative reactions. Patients extremely sensitive to a common allergen in several components of a mixture may be more likely to experience a systemic reaction than when skin tested individually for each component.9

PRICK-PUNCTURE TESTING: To identify highly sensitive individuals and as a safety precaution, it is recommended that a prick-puncture test using a drop of the extract concentrate be performed prior to initiating very dilute intradermal testing. Prick-puncture testing is performed by placing a drop of extract concentrate on the skin and puncturing the skin through the drop with a small needle such as a bifurcated vaccinating needle. The most satisfactory sites on the back for skin testing are from the posterior axillary fold to 2.5 cm from the spinal column, and from the top of the scapula to the lower rib margins. The best areas on the arms are the volar surfaces from the axilla to 2.5 or 5 cm above the wrist, skipping the anticubital space. A positive reaction is approximately 10-15 mm erythema with 2.5 mm wheal. Smaller, less conclusive reactions may be considered positive in conjunction with a definitive history of symptoms on exposure to the allergen. The more sensitive the patient the higher the probability that he/she will have symptoms related to the exposure of the offending allergen. Hence, the importance of a good patient history. Less sensitive individuals can be tested intradermally with an appropriately diluted extract.

A positive control using histamine phosphate identifies patients whose skin may not react due to medications, metabolic or other reasons. A negative control (50% glycerine for prick-puncture testing) would exclude false-positive reactions due to ingredients in diluent or patients who have dermatographism.

SINGLE DILUTION INTRADERMAL TESTING: The surface of the upper and lower arm is the usual location for skin testing. It is important that a new, sterile, disposable syringe and needle be used for each extract tested. Intracutaneous test dilutions, five-fold or ten-fold, may be prepared from stock concentrate using physiologic saline as a diluent. (1) Start testing with the most dilute allergenic extract concentration. (2) A volume of 0.02-0.05 ml should be injected slowly into the superficial skin layers making a small bleb (superficial wheal). (3) For patients without a history of extreme sensitivity, or a negative or weakly reactive prick-puncture test, the initial dilution for skin testing should be a dilution at least 1:12,500 w/v. This initial dilution can be prepared by diluting 1:20 to 1:50 w/v (2%-5%) extracts five-fold to 5-4 or 1:10 w/v (10%) extracts to 5-5. See “Serial Dilutions Titration Test Dilutions” chart on the next page. Dilute 1:10 w/v (10%) extracts to 10-3 if using ten-fold dilutions. (4) Sensitive patients with a positive prick-puncture test require a further dilution to at least 1:312,500 w/v. This dilution can be prepared by diluting 1:20 to 1:50 w/v (2% - 5%) extracts to 5-6 or 1:10 w/v (10%) extracts to 5-7 (five-fold dilutions). Ten-fold dilution to 10-6 of a 1:10 w/v (10%) extract would be a safe starting dilution. Size of reactions are quantitated based on size of wheal and erythema. For interpretation of skin reactions, refer to chart below. If after 20 minutes no skin reaction is observed, continue testing using increasing increments of the concentration until a reaction of 5-10 mm wheal and 11-30 mm erythema is obtained, or a concentration of 5-2 or 10-1 has been tested. A negative control, 50% glycerine diluted with diluent to 5-2 (1:25) or 10-1 (1:10) dilution and a positive control of histamine phosphate, should be tested and included in interpretation of skin reactions.1, 13

GRADE mm ERYTHEMA mm WHEAL 0 less than 5 less than 5 ± 5-10 5-10 1+ 11-20 5-10 2+ 21-30 5-10 3+ 31-40 10-15 or with pseudopods 4+ greater than 40 greater than 15 or with many pseudopods

INTRADERMAL TESTING-SKIN ENDPOINT TITRATION: The allergenic extracts to which the patient is sensitive, the patient’s degree of sensitivity and the dose of allergen to be used in immunotherapy can be determined through the use of intracutaneous skin tests involving progressive five-fold dilutions of allergenic extracts. Intracutaneously inject 0.01 to 0.02 ml of the test allergen to form a 4 mm diameter superficial skin wheal. For patients demonstrating a negative or weakly reactive prick-puncture skin test, an initial screening dilution of 1:12,500 w/v is safe. For patients demonstrating a positive prick-puncture skin test, an initial screening dilution of 1:312,500 w/v is safe. (See “Serial Dilution Titration Test Dilutions” chart below.) When a sequence of five-fold or ten-fold dilutions of an allergen are injected, the endpoint is determined by noting the dilution that first produces a wheal and erythema (15 minutes after injection) that is 2 mm larger than wheals with erythema produced by weaker, non-reacting dilutions (5 mm negative wheal). The endpoint dilution is used as a starting dose concentration for immunotherapy. An endpoint dose of 0.15 ml is a safe initial dose to be followed by escalation to the optimal maximum tolerated dose for each individual.

Injections should never be given intravenously. A 5/8 inch, 25 gauge needle on a sterile syringe will allow deep subcutaneous injection.

IMMUNOTHERAPY: If the first injection of the initial dilution of extract is tolerated without significant local reaction, increasing doses by 5-20% increments of that dilution may be administered. The rate of increase in dosage in the early stages of treatment with highly diluted extracts is usually more rapid than the rate of increase possible with more concentrated extracts. This schedule is intended only as a guide and must be modified according to the reactivity of the individual patient. Needless to say, the physician must proceed cautiously in the treatment of the highly sensitive patient who develops large local or systemic reactions.6

Some patients may tolerate larger doses of the allergenic extract depending on patient response.7 Because diluted extract tends to lose activity in storage, the first dose from a more concentrated vial should be the same, or less than, the previous dose.8, 12

Dosages progressively increase according to the tolerance of the patient at intervals of one to seven days until, (1) the patient achieves relief from symptoms, (2) induration at the site of injection is no larger than 50 mm in 36 to 48 hours, (3) a maintenance dose is reached (the largest dose tolerated by the patient that relieves symptoms without undesirable local or systemic reactions). This maintenance dose may be continued at regular intervals perennially. It may be necessary to adjust the progression of dosage downward to avoid local and constitutional reactions.

The usual duration of treatment has not been established. A period of two or three years on immunotherapy constitutes an average minimum course of treatment.

SERIAL DILUTION TITRATION TEST DILUTIONS APPROXIMATE ALLERGENIC EXTRACT CONCENTRATION RESULTING FROM 1:5 DILUTION Titration Number Dilution Exponent Weight / Volume Allergenic Extract Concentrate 1:50 (2%) 1:40 (2 1/2%) 1:33 1/3 (3%) 1:20 (5%) 1:10 (10%) No. 1 5-1 1:5 1:250 1:200 1:167 1:100 1:50 No. 2 5-2 1:25 1:1,250 1:1,000 1:835 1:500 1:250 No. 3 5-3 1:125 1:6,250 1:5,000 1:4,175 1:2,500 1:1,250 No. 4 5-4 1:625 1:31,250 1:25,000 1:20,875 1:12,500 1:6,250 No. 5 5-5 1:3,125 1:156,250 1:125,000 1:104,375 1:62,500 1:31,250 No. 6 5-6 1:15,625 1:781,250 1:625,000 1:521,875 1:312,500 1:156,250 No. 7 5-7 1:78,125 1:3,906,250 1:3,125,000 1:2,609,375 1:1,562,500 1:781,250 No. 8 5-8 1:390,625 1:19,531,250 1:15,625,000 1:13,046,875 1:7,812,500 1:3,906,250 No. 9 5-9 1:1,953,125 1:97,656,250 1:78,125,000 1:65,234,375 1:39,062,500 1:19,531,250 No. 10 5-10 1:9,765,625 1:488,281,250 1:390,625,000 1:326,171,875 1:195,312,500 1:97,656,250 No. 11 5-11 1:48,828,125 1:2,441,406,250 1:1,953,125,000 1:1,630,859,375 1:976,562,500 1:488,281,250 No. 12 5-12 1:244,140,625 1:12,207,031,250 1:9,765,625,000 1:8,154,296,875 1:4,882,812,500 1:2,441,406,250

---

Refer to “STORAGE” section for proper storage condition for allergenic extract. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Some allergenic extracts naturally precipitate.

Physicians undertaking immunotherapy should be concerned with patient’s degree of sensitivity. The initial dilution of allergenic extract, starting dose, and progression of dosage must be carefully determined on the basis of the patient’s history and results of skin tests. Strongly positive skin tests may be risk factors for systemic reactions. Less aggressive immunotherapy schedules may be indicated for such patients.

Precaution is necessary when using extract mixture for skin testing. The diluting effect of individual components within a mixture may cause false negative reactions. Patients extremely sensitive to a common allergen in several components of a mixture may be more likely to experience a systemic reaction than when skin tested individually for each component.9

PRICK-PUNCTURE TESTING: To identify highly sensitive individuals and as a safety precaution, it is recommended that a prick-puncture test using a drop of the extract concentrate be performed prior to initiating very dilute intradermal testing. Prick-puncture testing is performed by placing a drop of extract concentrate on the skin and puncturing the skin through the drop with a small needle such as a bifurcated vaccinating needle. The most satisfactory sites on the back for skin testing are from the posterior axillary fold to 2.5 cm from the spinal column, and from the top of the scapula to the lower rib margins. The best areas on the arms are the volar surfaces from the axilla to 2.5 or 5 cm above the wrist, skipping the anticubital space. A positive reaction is approximately 10-15 mm erythema with 2.5 mm wheal. Smaller, less conclusive reactions may be considered positive in conjunction with a definitive history of symptoms on exposure to the allergen. The more sensitive the patient the higher the probability that he/she will have symptoms related to the exposure of the offending allergen. Hence, the importance of a good patient history. Less sensitive individuals can be tested intradermally with an appropriately diluted extract.

A positive control using histamine phosphate identifies patients whose skin may not react due to medications, metabolic or other reasons. A negative control (50% glycerine for prick-puncture testing) would exclude false-positive reactions due to ingredients in diluent or patients who have dermatographism.

SINGLE DILUTION INTRADERMAL TESTING: The surface of the upper and lower arm is the usual location for skin testing. It is important that a new, sterile, disposable syringe and needle be used for each extract tested. Intracutaneous test dilutions, five-fold or ten-fold, may be prepared from stock concentrate using physiologic saline as a diluent. (1) Start testing with the most dilute allergenic extract concentration. (2) A volume of 0.02-0.05 ml should be injected slowly into the superficial skin layers making a small bleb (superficial wheal). (3) For patients without a history of extreme sensitivity, or a negative or weakly reactive prick-puncture test, the initial dilution for skin testing should be a dilution at least 1:12,500 w/v. This initial dilution can be prepared by diluting 1:20 to 1:50 w/v (2%-5%) extracts five-fold to 5-4 or 1:10 w/v (10%) extracts to 5-5. See “Serial Dilutions Titration Test Dilutions” chart on the next page. Dilute 1:10 w/v (10%) extracts to 10-3 if using ten-fold dilutions. (4) Sensitive patients with a positive prick-puncture test require a further dilution to at least 1:312,500 w/v. This dilution can be prepared by diluting 1:20 to 1:50 w/v (2% - 5%) extracts to 5-6 or 1:10 w/v (10%) extracts to 5-7 (five-fold dilutions). Ten-fold dilution to 10-6 of a 1:10 w/v (10%) extract would be a safe starting dilution. Size of reactions are quantitated based on size of wheal and erythema. For interpretation of skin reactions, refer to chart below. If after 20 minutes no skin reaction is observed, continue testing using increasing increments of the concentration until a reaction of 5-10 mm wheal and 11-30 mm erythema is obtained, or a concentration of 5-2 or 10-1 has been tested. A negative control, 50% glycerine diluted with diluent to 5-2 (1:25) or 10-1 (1:10) dilution and a positive control of histamine phosphate, should be tested and included in interpretation of skin reactions.1, 13

GRADE mm ERYTHEMA mm WHEAL 0 less than 5 less than 5 ± 5-10 5-10 1+ 11-20 5-10 2+ 21-30 5-10 3+ 31-40 10-15 or with pseudopods 4+ greater than 40 greater than 15 or with many pseudopods

INTRADERMAL TESTING-SKIN ENDPOINT TITRATION: The allergenic extracts to which the patient is sensitive, the patient’s degree of sensitivity and the dose of allergen to be used in immunotherapy can be determined through the use of intracutaneous skin tests involving progressive five-fold dilutions of allergenic extracts. Intracutaneously inject 0.01 to 0.02 ml of the test allergen to form a 4 mm diameter superficial skin wheal. For patients demonstrating a negative or weakly reactive prick-puncture skin test, an initial screening dilution of 1:12,500 w/v is safe. For patients demonstrating a positive prick-puncture skin test, an initial screening dilution of 1:312,500 w/v is safe. (See “Serial Dilution Titration Test Dilutions” chart below.) When a sequence of five-fold or ten-fold dilutions of an allergen are injected, the endpoint is determined by noting the dilution that first produces a wheal and erythema (15 minutes after injection) that is 2 mm larger than wheals with erythema produced by weaker, non-reacting dilutions (5 mm negative wheal). The endpoint dilution is used as a starting dose concentration for immunotherapy. An endpoint dose of 0.15 ml is a safe initial dose to be followed by escalation to the optimal maximum tolerated dose for each individual.

Injections should never be given intravenously. A 5/8 inch, 25 gauge needle on a sterile syringe will allow deep subcutaneous injection.

IMMUNOTHERAPY: If the first injection of the initial dilution of extract is tolerated without significant local reaction, increasing doses by 5-20% increments of that dilution may be administered. The rate of increase in dosage in the early stages of treatment with highly diluted extracts is usually more rapid than the rate of increase possible with more concentrated extracts. This schedule is intended only as a guide and must be modified according to the reactivity of the individual patient. Needless to say, the physician must proceed cautiously in the treatment of the highly sensitive patient who develops large local or systemic reactions.6

Some patients may tolerate larger doses of the allergenic extract depending on patient response.7 Because diluted extract tends to lose activity in storage, the first dose from a more concentrated vial should be the same, or less than, the previous dose.8, 12

Dosages progressively increase according to the tolerance of the patient at intervals of one to seven days until, (1) the patient achieves relief from symptoms, (2) induration at the site of injection is no larger than 50 mm in 36 to 48 hours, (3) a maintenance dose is reached (the largest dose tolerated by the patient that relieves symptoms without undesirable local or systemic reactions). This maintenance dose may be continued at regular intervals perennially. It may be necessary to adjust the progression of dosage downward to avoid local and constitutional reactions.

The usual duration of treatment has not been established. A period of two or three years on immunotherapy constitutes an average minimum course of treatment.

SERIAL DILUTION TITRATION TEST DILUTIONS APPROXIMATE ALLERGENIC EXTRACT CONCENTRATION RESULTING FROM 1:5 DILUTION Titration Number Dilution Exponent Weight / Volume Allergenic Extract Concentrate 1:50 (2%) 1:40 (2 1/2%) 1:33 1/3 (3%) 1:20 (5%) 1:10 (10%) No. 1 5-1 1:5 1:250 1:200 1:167 1:100 1:50 No. 2 5-2 1:25 1:1,250 1:1,000 1:835 1:500 1:250 No. 3 5-3 1:125 1:6,250 1:5,000 1:4,175 1:2,500 1:1,250 No. 4 5-4 1:625 1:31,250 1:25,000 1:20,875 1:12,500 1:6,250 No. 5 5-5 1:3,125 1:156,250 1:125,000 1:104,375 1:62,500 1:31,250 No. 6 5-6 1:15,625 1:781,250 1:625,000 1:521,875 1:312,500 1:156,250 No. 7 5-7 1:78,125 1:3,906,250 1:3,125,000 1:2,609,375 1:1,562,500 1:781,250 No. 8 5-8 1:390,625 1:19,531,250 1:15,625,000 1:13,046,875 1:7,812,500 1:3,906,250 No. 9 5-9 1:1,953,125 1:97,656,250 1:78,125,000 1:65,234,375 1:39,062,500 1:19,531,250 No. 10 5-10 1:9,765,625 1:488,281,250 1:390,625,000 1:326,171,875 1:195,312,500 1:97,656,250 No. 11 5-11 1:48,828,125 1:2,441,406,250 1:1,953,125,000 1:1,630,859,375 1:976,562,500 1:488,281,250 No. 12 5-12 1:244,140,625 1:12,207,031,250 1:9,765,625,000 1:8,154,296,875 1:4,882,812,500 1:2,441,406,250

---

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Some allergenic extracts naturally precipitate. This allergenic extract is "For Diagnostic Use Only". (Refer to STORAGE section.)

PRICK-PUNCTURE TESTING: To identify highly sensitive individuals and as a safety precaution, it is recommended that a prick-puncture test using a drop of the extract concentrate be performed prior to initiating very dilute intradermal testing. Prick-puncture testing is performed by placing a drop of extract concentrate on the skin and puncturing the skin through the drop with a small needle such as a bifurcated vaccinating needle. The most satisfactory sites on the back for skin testing are from the posterior axillary fold to 2.5 cm from the spinal column, and from the top of the scapula to the lower rib margins. The best areas on the arms are the volar surfaces from the axilla to 2.5 or 5 cm above the wrist, skipping the anticubital space. Skin testing should include a positive control of histamine phosphate and a negative control of 50% v/v glycerine in buffered saline. A positive reaction is approximately 10-15 mm erythema with 2.5 mm wheal. Smaller, less conclusive reactions may be considered positive in conjunction with a definitive history of symptoms on exposure to the allergen. Less sensitive individuals can be tested intradermally with an appropriately diluted extract (See "INTRADERMAL TESTING").

INTRADERMAL TESTING: The surface of the upper and lower arm is the usual location for skin testing. A sterile, disposable syringe and needle is used for each extract tested. Intracutaneous test dilutions, five-fold or ten-fold, may be prepared from stock concentrate using physiologic saline as a diluent. (1) Start testing with the most dilute allergenic extract concentration. (2) A volume of 0.02-0.05 ml should be injected slowly into the superficial skin layers making a small bleb (superficial wheal). (3) For patients without a history of extreme sensitivity, or a negative or weakly reactive prick-puncture test, the initial dilution for skin testing should be at least 1:12,500 w/v. This initial dilution can be prepared by diluting 1:20 to 1:50 w/v (2%-5%) extracts five-fold to 5-4 or 1:10 w/v (10%) extracts to 5-5. Dilute 1:10 w/v (10%) extracts to 10-3 if using ten-fold dilutions. (4) Sensitive patients with a positive prick-puncture test require a further dilution to at least 1:312,500 w/v. This dilution can be prepared by diluting 1:20 to 1:50 w/v (2%-5%) extracts to 5-6 or 1:10 w/v (10%) extracts to 5-7 (five-fold dilutions). Ten-fold dilution to 10-6 of a 1:10 w/v (10%) extract would be a safe starting dilution. For interpretation of skin reactions, refer to chart below. If after 20 minutes no skin reaction is observed, continue testing using increasing increments of the concentration until a reaction of 5-10 mm wheal and 11-30 mm erythema is obtained, or a concentration of 5-2 or 10-1 has been tested. A negative control, 50% glycerine diluted with diluent to 5-2 (1:25) or 10-1 (1:10) dilution and a positive control of histamine phosphate, should be tested and included in interpretation of skin reactions.2,4

GRADE mm ERYTHEMA mm WHEAL 0 less than 5 less than 5 ± 5-10 5-10 1+ 11-20 5-10 2+ 21-30 5-10 3+ 31-40 10-15 or with pseudopods 4+ greater than 40 greater than 15 or with many pseudopods

INTRADERMAL TESTING–SKIN ENDPOINT TITRATION: The allergenic extracts to which the patient is sensitive and the patient's degree of sensitivity can be determined through the use of intracutaneous skin tests involving progressive five-fold dilutions of allergenic extracts. Intracutaneously inject 0.01 to 0.02 ml of the test allergen to form a 4 mm diameter superficial skin wheal. For patients demonstrating a negative or weakly reactive prick-puncture skin test, an initial screening dilution of 1:12,500 w/v is safe. For patients demonstrating a positive prick-puncture skin test, an initial screening dilution of 1:312,500 w/v is safe (see "Serial Dilution Titration Test Dilutions" chart below).When a sequence of five-fold or ten-fold dilutions of an allergen is injected, the endpoint is determined by noting the dilution that first produces a wheal or erythema (15 minutes after injection) that is 2 mm larger than wheals with erythema produced by weaker, non-reacting dilutions (5 mm negative wheal).

SERIAL DILUTION TITRATION TEST DILUTIONS APPROXIMATE ALLERGENIC EXTRACT CONCENTRATION RESULTING FROM 1:5 DILUTION Titration Number Dilution Exponent Weight / Volume Allergenic Extract Concentrate 1:50 (2%) 1:40 (2 1/2%) 1:33 1/3 (3%) 1:20 (5%) 1:10 (10%) No. 1 5-1 1:5 1:250 1:200 1:167 1:100 1:50 No. 2 5-2 1:25 1:1,250 1:1,000 1:835 1:500 1:250 No. 3 5-3 1:125 1:6,250 1:5,000 1:4,175 1:2,500 1:1,250 No. 4 5-4 1:625 1:31,250 1:25,000 1:20,875 1:12,500 1:6,250 No. 5 5-5 1:3,125 1:156,250 1:125,000 1:104,375 1:62,500 1:31,250 No. 6 5-6 1:15,625 1:781,250 1:625,000 1:521,875 1:312,500 1:156,250 No. 7 5-7 1:78,125 1:3,906,250 1:3,125,000 1:2,609,375 1:1,562,500 1:781,250 No. 8 5-8 1:390,625 1:19,531,250 1:15,625,000 1:13,046,875 1:7,812,500 1:3,906,250 No. 9 5-9 1:1,953,125 1:97,656,250 1:78,125,000 1:65,234,375 1:39,062,500 1:19,531,250 No. 10 5-10 1:9,765,625 1:488,281,250 1:390,625,000 1:326,171,875 1:195,312,500 1:97,656,250 No. 11 5-11 1:48,828,125 1:2,441,406,250 1:1,953,125,000 1:1,630,859,375 1:976,562,500 1:488,281,250 No. 12 5-12 1:244,140,625 1:12,207,031,250 1:9,765,625,000 1:8,154,296,875 1:4,882,812,500 1:2,441,406,250

---

Refer to “STORAGE” section for proper storage condition for allergenic extract. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Some allergenic extracts naturally precipitate.

Physicians undertaking immunotherapy should be concerned with patient’s degree of sensitivity. The initial dilution of allergenic extract, starting dose, and progression of dosage must be carefully determined on the basis of the patient’s history and results of skin tests. Strongly positive skin tests may be risk factors for systemic reactions. Less aggressive immunotherapy schedules may be indicated for such patients.

Precaution is necessary when using extract mixture for skin testing. The diluting effect of individual components within a mixture may cause false negative reactions. Patients extremely sensitive to a common allergen in several components of a mixture may be more likely to experience a systemic reaction than when skin tested individually for each component.9

PRICK-PUNCTURE TESTING: To identify highly sensitive individuals and as a safety precaution, it is recommended that a prick-puncture test using a drop of the extract concentrate be performed prior to initiating very dilute intradermal testing. Prick-puncture testing is performed by placing a drop of extract concentrate on the skin and puncturing the skin through the drop with a small needle such as a bifurcated vaccinating needle. The most satisfactory sites on the back for skin testing are from the posterior axillary fold to 2.5 cm from the spinal column, and from the top of the scapula to the lower rib margins. The best areas on the arms are the volar surfaces from the axilla to 2.5 or 5 cm above the wrist, skipping the anticubital space. A positive reaction is approximately 10-15 mm erythema with 2.5 mm wheal. Smaller, less conclusive reactions may be considered positive in conjunction with a definitive history of symptoms on exposure to the allergen. The more sensitive the patient the higher the probability that he/she will have symptoms related to the exposure of the offending allergen. Hence, the importance of a good patient history. Less sensitive individuals can be tested intradermally with an appropriately diluted extract.

A positive control using histamine phosphate identifies patients whose skin may not react due to medications, metabolic or other reasons. A negative control (50% glycerine for prick-puncture testing) would exclude false-positive reactions due to ingredients in diluent or patients who have dermatographism.

SINGLE DILUTION INTRADERMAL TESTING: The surface of the upper and lower arm is the usual location for skin testing. It is important that a new, sterile, disposable syringe and needle be used for each extract tested. Intracutaneous test dilutions, five-fold or ten-fold, may be prepared from stock concentrate using physiologic saline as a diluent. (1) Start testing with the most dilute allergenic extract concentration. (2) A volume of 0.02-0.05 ml should be injected slowly into the superficial skin layers making a small bleb (superficial wheal). (3) For patients without a history of extreme sensitivity, or a negative or weakly reactive prick-puncture test, the initial dilution for skin testing should be a dilution at least 1:12,500 w/v. This initial dilution can be prepared by diluting 1:20 to 1:50 w/v (2%-5%) extracts five-fold to 5-4 or 1:10 w/v (10%) extracts to 5-5. See “Serial Dilutions Titration Test Dilutions” chart on the next page. Dilute 1:10 w/v (10%) extracts to 10-3 if using ten-fold dilutions. (4) Sensitive patients with a positive prick-puncture test require a further dilution to at least 1:312,500 w/v. This dilution can be prepared by diluting 1:20 to 1:50 w/v (2% - 5%) extracts to 5-6 or 1:10 w/v (10%) extracts to 5-7 (five-fold dilutions). Ten-fold dilution to 10-6 of a 1:10 w/v (10%) extract would be a safe starting dilution. Size of reactions are quantitated based on size of wheal and erythema. For interpretation of skin reactions, refer to chart below. If after 20 minutes no skin reaction is observed, continue testing using increasing increments of the concentration until a reaction of 5-10 mm wheal and 11-30 mm erythema is obtained, or a concentration of 5-2 or 10-1 has been tested. A negative control, 50% glycerine diluted with diluent to 5-2 (1:25) or 10-1 (1:10) dilution and a positive control of histamine phosphate, should be tested and included in interpretation of skin reactions.1, 13

GRADE mm ERYTHEMA mm WHEAL 0 less than 5 less than 5 ± 5-10 5-10 1+ 11-20 5-10 2+ 21-30 5-10 3+ 31-40 10-15 or with pseudopods 4+ greater than 40 greater than 15 or with many pseudopods

INTRADERMAL TESTING-SKIN ENDPOINT TITRATION: The allergenic extracts to which the patient is sensitive, the patient’s degree of sensitivity and the dose of allergen to be used in immunotherapy can be determined through the use of intracutaneous skin tests involving progressive five-fold dilutions of allergenic extracts. Intracutaneously inject 0.01 to 0.02 ml of the test allergen to form a 4 mm diameter superficial skin wheal. For patients demonstrating a negative or weakly reactive prick-puncture skin test, an initial screening dilution of 1:12,500 w/v is safe. For patients demonstrating a positive prick-puncture skin test, an initial screening dilution of 1:312,500 w/v is safe. (See “Serial Dilution Titration Test Dilutions” chart below.) When a sequence of five-fold or ten-fold dilutions of an allergen are injected, the endpoint is determined by noting the dilution that first produces a wheal and erythema (15 minutes after injection) that is 2 mm larger than wheals with erythema produced by weaker, non-reacting dilutions (5 mm negative wheal). The endpoint dilution is used as a starting dose concentration for immunotherapy. An endpoint dose of 0.15 ml is a safe initial dose to be followed by escalation to the optimal maximum tolerated dose for each individual.

Injections should never be given intravenously. A 5/8 inch, 25 gauge needle on a sterile syringe will allow deep subcutaneous injection.

IMMUNOTHERAPY: If the first injection of the initial dilution of extract is tolerated without significant local reaction, increasing doses by 5-20% increments of that dilution may be administered. The rate of increase in dosage in the early stages of treatment with highly diluted extracts is usually more rapid than the rate of increase possible with more concentrated extracts. This schedule is intended only as a guide and must be modified according to the reactivity of the individual patient. Needless to say, the physician must proceed cautiously in the treatment of the highly sensitive patient who develops large local or systemic reactions.6

Some patients may tolerate larger doses of the allergenic extract depending on patient response.7 Because diluted extract tends to lose activity in storage, the first dose from a more concentrated vial should be the same, or less than, the previous dose.8, 12

Dosages progressively increase according to the tolerance of the patient at intervals of one to seven days until, (1) the patient achieves relief from symptoms, (2) induration at the site of injection is no larger than 50 mm in 36 to 48 hours, (3) a maintenance dose is reached (the largest dose tolerated by the patient that relieves symptoms without undesirable local or systemic reactions). This maintenance dose may be continued at regular intervals perennially. It may be necessary to adjust the progression of dosage downward to avoid local and constitutional reactions.

The usual duration of treatment has not been established. A period of two or three years on immunotherapy constitutes an average minimum course of treatment.

SERIAL DILUTION TITRATION TEST DILUTIONS APPROXIMATE ALLERGENIC EXTRACT CONCENTRATION RESULTING FROM 1:5 DILUTION Titration Number Dilution Exponent Weight / Volume Allergenic Extract Concentrate 1:50 (2%) 1:40 (2 1/2%) 1:33 1/3 (3%) 1:20 (5%) 1:10 (10%) No. 1 5-1 1:5 1:250 1:200 1:167 1:100 1:50 No. 2 5-2 1:25 1:1,250 1:1,000 1:835 1:500 1:250 No. 3 5-3 1:125 1:6,250 1:5,000 1:4,175 1:2,500 1:1,250 No. 4 5-4 1:625 1:31,250 1:25,000 1:20,875 1:12,500 1:6,250 No. 5 5-5 1:3,125 1:156,250 1:125,000 1:104,375 1:62,500 1:31,250 No. 6 5-6 1:15,625 1:781,250 1:625,000 1:521,875 1:312,500 1:156,250 No. 7 5-7 1:78,125 1:3,906,250 1:3,125,000 1:2,609,375 1:1,562,500 1:781,250 No. 8 5-8 1:390,625 1:19,531,250 1:15,625,000 1:13,046,875 1:7,812,500 1:3,906,250 No. 9 5-9 1:1,953,125 1:97,656,250 1:78,125,000 1:65,234,375 1:39,062,500 1:19,531,250 No. 10 5-10 1:9,765,625 1:488,281,250 1:390,625,000 1:326,171,875 1:195,312,500 1:97,656,250 No. 11 5-11 1:48,828,125 1:2,441,406,250 1:1,953,125,000 1:1,630,859,375 1:976,562,500 1:488,281,250 No. 12 5-12 1:244,140,625 1:12,207,031,250 1:9,765,625,000 1:8,154,296,875 1:4,882,812,500 1:2,441,406,250

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As a consequence of the discovery of IgE and the development of methods to identify and quantify anti-allergen IgE levels, interest in recent years has centered around the utilization of in vivo and in vitro diagnostic procedures. 7,9

Patients who react to a small quantity of antigen by skin testing can be classified as highly sensitive. Those who react only to large quantities of antigen can be classified as less sensitive. It would appear that there is at least a 50,000-fold range between the most and least sensitive individuals. On the other hand, certain patients who do not appear to have elevated quantities of specific anti-allergen IgE do have positive skin tests and have symptoms of allergic rhinitis. These patients are considerably less sensitive than patients with detectable levels of specific IgE antibody. 10

The current standard method of immunotherapy dates back to the earliest studies by Noon. As adapted for ragweed pollen extract, therapy is begun with a low dose, which has been shown to be tolerated by both experience and skin testing.

The physician who undertakes immunotherapy should be concerned with the degree of sensitivity of the patient. This can be measured by skin test, leukocyte histamine release, or anti-allergen IgE levels. Strongly positive skin tests or high initial ragweed IgE and total IgE may be risk factors for systemic reactions. Less aggressive immunotherapy schedules may be indicated for such patients. Maintenance dose potency must be established by the physician's clinical observation and experience. 10,17

Serial fivefold or tenfold dilutions of the extract are used to make more dilute extract concentrations. Other concentrations can be prepared by appropriate dilution. In brief, the allergist can prepare any dilution of extract that is considered appropriate for the patient.

---

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Some allergenic extracts naturally precipitate. This allergenic extract is "For Diagnostic Use Only". (Refer to STORAGE section.)

PRICK-PUNCTURE TESTING: To identify highly sensitive individuals and as a safety precaution, it is recommended that a prick-puncture test using a drop of the extract concentrate be performed prior to initiating very dilute intradermal testing. Prick-puncture testing is performed by placing a drop of extract concentrate on the skin and puncturing the skin through the drop with a small needle such as a bifurcated vaccinating needle. The most satisfactory sites on the back for skin testing are from the posterior axillary fold to 2.5 cm from the spinal column, and from the top of the scapula to the lower rib margins. The best areas on the arms are the volar surfaces from the axilla to 2.5 or 5 cm above the wrist, skipping the anticubital space. Skin testing should include a positive control of histamine phosphate and a negative control of 50% v/v glycerine in buffered saline. A positive reaction is approximately 10-15 mm erythema with 2.5 mm wheal. Smaller, less conclusive reactions may be considered positive in conjunction with a definitive history of symptoms on exposure to the allergen. Less sensitive individuals can be tested intradermally with an appropriately diluted extract (See "INTRADERMAL TESTING").

INTRADERMAL TESTING: The surface of the upper and lower arm is the usual location for skin testing. A sterile, disposable syringe and needle is used for each extract tested. Intracutaneous test dilutions, five-fold or ten-fold, may be prepared from stock concentrate using physiologic saline as a diluent. (1) Start testing with the most dilute allergenic extract concentration. (2) A volume of 0.02-0.05 ml should be injected slowly into the superficial skin layers making a small bleb (superficial wheal). (3) For patients without a history of extreme sensitivity, or a negative or weakly reactive prick-puncture test, the initial dilution for skin testing should be at least 1:12,500 w/v. This initial dilution can be prepared by diluting 1:20 to 1:50 w/v (2%-5%) extracts five-fold to 5-4 or 1:10 w/v (10%) extracts to 5-5. Dilute 1:10 w/v (10%) extracts to 10-3 if using ten-fold dilutions. (4) Sensitive patients with a positive prick-puncture test require a further dilution to at least 1:312,500 w/v. This dilution can be prepared by diluting 1:20 to 1:50 w/v (2%-5%) extracts to 5-6 or 1:10 w/v (10%) extracts to 5-7 (five-fold dilutions). Ten-fold dilution to 10-6 of a 1:10 w/v (10%) extract would be a safe starting dilution. For interpretation of skin reactions, refer to chart below. If after 20 minutes no skin reaction is observed, continue testing using increasing increments of the concentration until a reaction of 5-10 mm wheal and 11-30 mm erythema is obtained, or a concentration of 5-2 or 10-1 has been tested. A negative control, 50% glycerine diluted with diluent to 5-2 (1:25) or 10-1 (1:10) dilution and a positive control of histamine phosphate, should be tested and included in interpretation of skin reactions.2,4

GRADE mm ERYTHEMA mm WHEAL 0 less than 5 less than 5 ± 5-10 5-10 1+ 11-20 5-10 2+ 21-30 5-10 3+ 31-40 10-15 or with pseudopods 4+ greater than 40 greater than 15 or with many pseudopods

INTRADERMAL TESTING–SKIN ENDPOINT TITRATION: The allergenic extracts to which the patient is sensitive and the patient's degree of sensitivity can be determined through the use of intracutaneous skin tests involving progressive five-fold dilutions of allergenic extracts. Intracutaneously inject 0.01 to 0.02 ml of the test allergen to form a 4 mm diameter superficial skin wheal. For patients demonstrating a negative or weakly reactive prick-puncture skin test, an initial screening dilution of 1:12,500 w/v is safe. For patients demonstrating a positive prick-puncture skin test, an initial screening dilution of 1:312,500 w/v is safe (see "Serial Dilution Titration Test Dilutions" chart below).When a sequence of five-fold or ten-fold dilutions of an allergen is injected, the endpoint is determined by noting the dilution that first produces a wheal or erythema (15 minutes after injection) that is 2 mm larger than wheals with erythema produced by weaker, non-reacting dilutions (5 mm negative wheal).

SERIAL DILUTION TITRATION TEST DILUTIONS APPROXIMATE ALLERGENIC EXTRACT CONCENTRATION RESULTING FROM 1:5 DILUTION Titration Number Dilution Exponent Weight / Volume Allergenic Extract Concentrate 1:50 (2%) 1:40 (2 1/2%) 1:33 1/3 (3%) 1:20 (5%) 1:10 (10%) No. 1 5-1 1:5 1:250 1:200 1:167 1:100 1:50 No. 2 5-2 1:25 1:1,250 1:1,000 1:835 1:500 1:250 No. 3 5-3 1:125 1:6,250 1:5,000 1:4,175 1:2,500 1:1,250 No. 4 5-4 1:625 1:31,250 1:25,000 1:20,875 1:12,500 1:6,250 No. 5 5-5 1:3,125 1:156,250 1:125,000 1:104,375 1:62,500 1:31,250 No. 6 5-6 1:15,625 1:781,250 1:625,000 1:521,875 1:312,500 1:156,250 No. 7 5-7 1:78,125 1:3,906,250 1:3,125,000 1:2,609,375 1:1,562,500 1:781,250 No. 8 5-8 1:390,625 1:19,531,250 1:15,625,000 1:13,046,875 1:7,812,500 1:3,906,250 No. 9 5-9 1:1,953,125 1:97,656,250 1:78,125,000 1:65,234,375 1:39,062,500 1:19,531,250 No. 10 5-10 1:9,765,625 1:488,281,250 1:390,625,000 1:326,171,875 1:195,312,500 1:97,656,250 No. 11 5-11 1:48,828,125 1:2,441,406,250 1:1,953,125,000 1:1,630,859,375 1:976,562,500 1:488,281,250 No. 12 5-12 1:244,140,625 1:12,207,031,250 1:9,765,625,000 1:8,154,296,875 1:4,882,812,500 1:2,441,406,250

---

Refer to “STORAGE” section for proper storage condition for allergenic extract. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Some allergenic extracts naturally precipitate.

Physicians undertaking immunotherapy should be concerned with patient’s degree of sensitivity. The initial dilution of allergenic extract, starting dose, and progression of dosage must be carefully determined on the basis of the patient’s history and results of skin tests. Strongly positive skin tests may be risk factors for systemic reactions. Less aggressive immunotherapy schedules may be indicated for such patients.

Precaution is necessary when using extract mixture for skin testing. The diluting effect of individual components within a mixture may cause false negative reactions. Patients extremely sensitive to a common allergen in several components of a mixture may be more likely to experience a systemic reaction than when skin tested individually for each component.9

PRICK-PUNCTURE TESTING: To identify highly sensitive individuals and as a safety precaution, it is recommended that a prick-puncture test using a drop of the extract concentrate be performed prior to initiating very dilute intradermal testing. Prick-puncture testing is performed by placing a drop of extract concentrate on the skin and puncturing the skin through the drop with a small needle such as a bifurcated vaccinating needle. The most satisfactory sites on the back for skin testing are from the posterior axillary fold to 2.5 cm from the spinal column, and from the top of the scapula to the lower rib margins. The best areas on the arms are the volar surfaces from the axilla to 2.5 or 5 cm above the wrist, skipping the anticubital space. A positive reaction is approximately 10-15 mm erythema with 2.5 mm wheal. Smaller, less conclusive reactions may be considered positive in conjunction with a definitive history of symptoms on exposure to the allergen. The more sensitive the patient the higher the probability that he/she will have symptoms related to the exposure of the offending allergen. Hence, the importance of a good patient history. Less sensitive individuals can be tested intradermally with an appropriately diluted extract.

A positive control using histamine phosphate identifies patients whose skin may not react due to medications, metabolic or other reasons. A negative control (50% glycerine for prick-puncture testing) would exclude false-positive reactions due to ingredients in diluent or patients who have dermatographism.

SINGLE DILUTION INTRADERMAL TESTING: The surface of the upper and lower arm is the usual location for skin testing. It is important that a new, sterile, disposable syringe and needle be used for each extract tested. Intracutaneous test dilutions, five-fold or ten-fold, may be prepared from stock concentrate using physiologic saline as a diluent. (1) Start testing with the most dilute allergenic extract concentration. (2) A volume of 0.02-0.05 ml should be injected slowly into the superficial skin layers making a small bleb (superficial wheal). (3) For patients without a history of extreme sensitivity, or a negative or weakly reactive prick-puncture test, the initial dilution for skin testing should be a dilution at least 1:12,500 w/v. This initial dilution can be prepared by diluting 1:20 to 1:50 w/v (2%-5%) extracts five-fold to 5-4 or 1:10 w/v (10%) extracts to 5-5. See “Serial Dilutions Titration Test Dilutions” chart on the next page. Dilute 1:10 w/v (10%) extracts to 10-3 if using ten-fold dilutions. (4) Sensitive patients with a positive prick-puncture test require a further dilution to at least 1:312,500 w/v. This dilution can be prepared by diluting 1:20 to 1:50 w/v (2% - 5%) extracts to 5-6 or 1:10 w/v (10%) extracts to 5-7 (five-fold dilutions). Ten-fold dilution to 10-6 of a 1:10 w/v (10%) extract would be a safe starting dilution. Size of reactions are quantitated based on size of wheal and erythema. For interpretation of skin reactions, refer to chart below. If after 20 minutes no skin reaction is observed, continue testing using increasing increments of the concentration until a reaction of 5-10 mm wheal and 11-30 mm erythema is obtained, or a concentration of 5-2 or 10-1 has been tested. A negative control, 50% glycerine diluted with diluent to 5-2 (1:25) or 10-1 (1:10) dilution and a positive control of histamine phosphate, should be tested and included in interpretation of skin reactions.1, 13

GRADE mm ERYTHEMA mm WHEAL 0 less than 5 less than 5 ± 5-10 5-10 1+ 11-20 5-10 2+ 21-30 5-10 3+ 31-40 10-15 or with pseudopods 4+ greater than 40 greater than 15 or with many pseudopods

INTRADERMAL TESTING-SKIN ENDPOINT TITRATION: The allergenic extracts to which the patient is sensitive, the patient’s degree of sensitivity and the dose of allergen to be used in immunotherapy can be determined through the use of intracutaneous skin tests involving progressive five-fold dilutions of allergenic extracts. Intracutaneously inject 0.01 to 0.02 ml of the test allergen to form a 4 mm diameter superficial skin wheal. For patients demonstrating a negative or weakly reactive prick-puncture skin test, an initial screening dilution of 1:12,500 w/v is safe. For patients demonstrating a positive prick-puncture skin test, an initial screening dilution of 1:312,500 w/v is safe. (See “Serial Dilution Titration Test Dilutions” chart below.) When a sequence of five-fold or ten-fold dilutions of an allergen are injected, the endpoint is determined by noting the dilution that first produces a wheal and erythema (15 minutes after injection) that is 2 mm larger than wheals with erythema produced by weaker, non-reacting dilutions (5 mm negative wheal). The endpoint dilution is used as a starting dose concentration for immunotherapy. An endpoint dose of 0.15 ml is a safe initial dose to be followed by escalation to the optimal maximum tolerated dose for each individual.

Injections should never be given intravenously. A 5/8 inch, 25 gauge needle on a sterile syringe will allow deep subcutaneous injection.

IMMUNOTHERAPY: If the first injection of the initial dilution of extract is tolerated without significant local reaction, increasing doses by 5-20% increments of that dilution may be administered. The rate of increase in dosage in the early stages of treatment with highly diluted extracts is usually more rapid than the rate of increase possible with more concentrated extracts. This schedule is intended only as a guide and must be modified according to the reactivity of the individual patient. Needless to say, the physician must proceed cautiously in the treatment of the highly sensitive patient who develops large local or systemic reactions.6

Some patients may tolerate larger doses of the allergenic extract depending on patient response.7 Because diluted extract tends to lose activity in storage, the first dose from a more concentrated vial should be the same, or less than, the previous dose.8, 12

Dosages progressively increase according to the tolerance of the patient at intervals of one to seven days until, (1) the patient achieves relief from symptoms, (2) induration at the site of injection is no larger than 50 mm in 36 to 48 hours, (3) a maintenance dose is reached (the largest dose tolerated by the patient that relieves symptoms without undesirable local or systemic reactions). This maintenance dose may be continued at regular intervals perennially. It may be necessary to adjust the progression of dosage downward to avoid local and constitutional reactions.

The usual duration of treatment has not been established. A period of two or three years on immunotherapy constitutes an average minimum course of treatment.

SERIAL DILUTION TITRATION TEST DILUTIONS APPROXIMATE ALLERGENIC EXTRACT CONCENTRATION RESULTING FROM 1:5 DILUTION Titration Number Dilution Exponent Weight / Volume Allergenic Extract Concentrate 1:50 (2%) 1:40 (2 1/2%) 1:33 1/3 (3%) 1:20 (5%) 1:10 (10%) No. 1 5-1 1:5 1:250 1:200 1:167 1:100 1:50 No. 2 5-2 1:25 1:1,250 1:1,000 1:835 1:500 1:250 No. 3 5-3 1:125 1:6,250 1:5,000 1:4,175 1:2,500 1:1,250 No. 4 5-4 1:625 1:31,250 1:25,000 1:20,875 1:12,500 1:6,250 No. 5 5-5 1:3,125 1:156,250 1:125,000 1:104,375 1:62,500 1:31,250 No. 6 5-6 1:15,625 1:781,250 1:625,000 1:521,875 1:312,500 1:156,250 No. 7 5-7 1:78,125 1:3,906,250 1:3,125,000 1:2,609,375 1:1,562,500 1:781,250 No. 8 5-8 1:390,625 1:19,531,250 1:15,625,000 1:13,046,875 1:7,812,500 1:3,906,250 No. 9 5-9 1:1,953,125 1:97,656,250 1:78,125,000 1:65,234,375 1:39,062,500 1:19,531,250 No. 10 5-10 1:9,765,625 1:488,281,250 1:390,625,000 1:326,171,875 1:195,312,500 1:97,656,250 No. 11 5-11 1:48,828,125 1:2,441,406,250 1:1,953,125,000 1:1,630,859,375 1:976,562,500 1:488,281,250 No. 12 5-12 1:244,140,625 1:12,207,031,250 1:9,765,625,000 1:8,154,296,875 1:4,882,812,500 1:2,441,406,250

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As a consequence of the discovery of IgE and the development of methods to identify and quantify anti-allergen IgE levels, interest in recent years has centered around the utilization of in vivo and in vitro diagnostic procedures. 7,9

Patients who react to a small quantity of antigen by skin testing can be classified as highly sensitive. Those who react only to large quantities of antigen can be classified as less sensitive. It would appear that there is at least a 50,000-fold range between the most and least sensitive individuals. On the other hand, certain patients who do not appear to have elevated quantities of specific anti-allergen IgE do have positive skin tests and have symptoms of allergic rhinitis. These patients are considerably less sensitive than patients with detectable levels of specific IgE antibody. 10

The current standard method of immunotherapy dates back to the earliest studies by Noon. As adapted for ragweed pollen extract, therapy is begun with a low dose, which has been shown to be tolerated by both experience and skin testing.

The physician who undertakes immunotherapy should be concerned with the degree of sensitivity of the patient. This can be measured by skin test, leukocyte histamine release, or anti-allergen IgE levels. Strongly positive skin tests or high initial ragweed IgE and total IgE may be risk factors for systemic reactions. Less aggressive immunotherapy schedules may be indicated for such patients. Maintenance dose potency must be established by the physician's clinical observation and experience. 10,17

Serial fivefold or tenfold dilutions of the extract are used to make more dilute extract concentrations. Other concentrations can be prepared by appropriate dilution. In brief, the allergist can prepare any dilution of extract that is considered appropriate for the patient.

---

As a consequence of the discovery of IgE and the development of methods to identify and quantify anti-allergen IgE levels, interest in recent years has centered around the utilization of in vivo and in vitro diagnostic procedures. 7,9

Patients who react to a small quantity of antigen by skin testing can be classified as highly sensitive. Those who react only to large quantities of antigen can be classified as less sensitive. It would appear that there is at least a 50,000-fold range between the most and least sensitive individuals. On the other hand, certain patients who do not appear to have elevated quantities of specific anti-allergen IgE do have positive skin tests and have symptoms of allergic rhinitis. These patients are considerably less sensitive than patients with detectable levels of specific IgE antibody. 10

The current standard method of immunotherapy dates back to the earliest studies by Noon. As adapted for ragweed pollen extract, therapy is begun with a low dose, which has been shown to be tolerated by both experience and skin testing.

The physician who undertakes immunotherapy should be concerned with the degree of sensitivity of the patient. This can be measured by skin test, leukocyte histamine release, or anti-allergen IgE levels. Strongly positive skin tests or high initial ragweed IgE and total IgE may be risk factors for systemic reactions. Less aggressive immunotherapy schedules may be indicated for such patients. Maintenance dose potency must be established by the physician's clinical observation and experience. 10,17

Serial fivefold or tenfold dilutions of the extract are used to make more dilute extract concentrations. Other concentrations can be prepared by appropriate dilution. In brief, the allergist can prepare any dilution of extract that is considered appropriate for the patient.

---

As a consequence of the discovery of IgE and the development of methods to identify and quantify anti-allergen IgE levels, interest in recent years has centered around the utilization of in vivo and in vitro diagnostic procedures. 7,9

Patients who react to a small quantity of antigen by skin testing can be classified as highly sensitive. Those who react only to large quantities of antigen can be classified as less sensitive. It would appear that there is at least a 50,000-fold range between the most and least sensitive individuals. On the other hand, certain patients who do not appear to have elevated quantities of specific anti-allergen IgE do have positive skin tests and have symptoms of allergic rhinitis. These patients are considerably less sensitive than patients with detectable levels of specific IgE antibody. 10

The current standard method of immunotherapy dates back to the earliest studies by Noon. As adapted for ragweed pollen extract, therapy is begun with a low dose, which has been shown to be tolerated by both experience and skin testing.

The physician who undertakes immunotherapy should be concerned with the degree of sensitivity of the patient. This can be measured by skin test, leukocyte histamine release, or anti-allergen IgE levels. Strongly positive skin tests or high initial ragweed IgE and total IgE may be risk factors for systemic reactions. Less aggressive immunotherapy schedules may be indicated for such patients. Maintenance dose potency must be established by the physician's clinical observation and experience. 10,17

Serial fivefold or tenfold dilutions of the extract are used to make more dilute extract concentrations. Other concentrations can be prepared by appropriate dilution. In brief, the allergist can prepare any dilution of extract that is considered appropriate for the patient.

---

As a consequence of the discovery of IgE and the development of methods to identify and quantify anti-allergen IgE levels, interest in recent years has centered around the utilization of in vivo and in vitro diagnostic procedures. 7,9

Patients who react to a small quantity of antigen by skin testing can be classified as highly sensitive. Those who react only to large quantities of antigen can be classified as less sensitive. It would appear that there is at least a 50,000-fold range between the most and least sensitive individuals. On the other hand, certain patients who do not appear to have elevated quantities of specific anti-allergen IgE do have positive skin tests and have symptoms of allergic rhinitis. These patients are considerably less sensitive than patients with detectable levels of specific IgE antibody. 10

The current standard method of immunotherapy dates back to the earliest studies by Noon. As adapted for ragweed pollen extract, therapy is begun with a low dose, which has been shown to be tolerated by both experience and skin testing.

The physician who undertakes immunotherapy should be concerned with the degree of sensitivity of the patient. This can be measured by skin test, leukocyte histamine release, or anti-allergen IgE levels. Strongly positive skin tests or high initial ragweed IgE and total IgE may be risk factors for systemic reactions. Less aggressive immunotherapy schedules may be indicated for such patients. Maintenance dose potency must be established by the physician's clinical observation and experience. 10,17

Serial fivefold or tenfold dilutions of the extract are used to make more dilute extract concentrations. Other concentrations can be prepared by appropriate dilution. In brief, the allergist can prepare any dilution of extract that is considered appropriate for the patient.

---

As a consequence of the discovery of IgE and the development of methods to identify and quantify anti-allergen IgE levels, interest in recent years has centered around the utilization of in vivo and in vitro diagnostic procedures. 7,9

Patients who react to a small quantity of antigen by skin testing can be classified as highly sensitive. Those who react only to large quantities of antigen can be classified as less sensitive. It would appear that there is at least a 50,000-fold range between the most and least sensitive individuals. On the other hand, certain patients who do not appear to have elevated quantities of specific anti-allergen IgE do have positive skin tests and have symptoms of allergic rhinitis. These patients are considerably less sensitive than patients with detectable levels of specific IgE antibody. 10

The current standard method of immunotherapy dates back to the earliest studies by Noon. As adapted for ragweed pollen extract, therapy is begun with a low dose, which has been shown to be tolerated by both experience and skin testing.

The physician who undertakes immunotherapy should be concerned with the degree of sensitivity of the patient. This can be measured by skin test, leukocyte histamine release, or anti-allergen IgE levels. Strongly positive skin tests or high initial ragweed IgE and total IgE may be risk factors for systemic reactions. Less aggressive immunotherapy schedules may be indicated for such patients. Maintenance dose potency must be established by the physician's clinical observation and experience. 10,17

Serial fivefold or tenfold dilutions of the extract are used to make more dilute extract concentrations. Other concentrations can be prepared by appropriate dilution. In brief, the allergist can prepare any dilution of extract that is considered appropriate for the patient.

---

As a consequence of the discovery of IgE and the development of methods to identify and quantify anti-allergen IgE levels, interest in recent years has centered around the utilization of in vivo and in vitro diagnostic procedures. 7,9

Patients who react to a small quantity of antigen by skin testing can be classified as highly sensitive. Those who react only to large quantities of antigen can be classified as less sensitive. It would appear that there is at least a 50,000-fold range between the most and least sensitive individuals. On the other hand, certain patients who do not appear to have elevated quantities of specific anti-allergen IgE do have positive skin tests and have symptoms of allergic rhinitis. These patients are considerably less sensitive than patients with detectable levels of specific IgE antibody. 10

The current standard method of immunotherapy dates back to the earliest studies by Noon. As adapted for ragweed pollen extract, therapy is begun with a low dose, which has been shown to be tolerated by both experience and skin testing.

The physician who undertakes immunotherapy should be concerned with the degree of sensitivity of the patient. This can be measured by skin test, leukocyte histamine release, or anti-allergen IgE levels. Strongly positive skin tests or high initial ragweed IgE and total IgE may be risk factors for systemic reactions. Less aggressive immunotherapy schedules may be indicated for such patients. Maintenance dose potency must be established by the physician's clinical observation and experience. 10,17

Serial fivefold or tenfold dilutions of the extract are used to make more dilute extract concentrations. Other concentrations can be prepared by appropriate dilution. In brief, the allergist can prepare any dilution of extract that is considered appropriate for the patient.

---

As a consequence of the discovery of IgE and the development of methods to identify and quantify anti-allergen IgE levels, interest in recent years has centered around the utilization of in vivo and in vitro diagnostic procedures. 7,9

Patients who react to a small quantity of antigen by skin testing can be classified as highly sensitive. Those who react only to large quantities of antigen can be classified as less sensitive. It would appear that there is at least a 50,000-fold range between the most and least sensitive individuals. On the other hand, certain patients who do not appear to have elevated quantities of specific anti-allergen IgE do have positive skin tests and have symptoms of allergic rhinitis. These patients are considerably less sensitive than patients with detectable levels of specific IgE antibody. 10

The current standard method of immunotherapy dates back to the earliest studies by Noon. As adapted for ragweed pollen extract, therapy is begun with a low dose, which has been shown to be tolerated by both experience and skin testing.

The physician who undertakes immunotherapy should be concerned with the degree of sensitivity of the patient. This can be measured by skin test, leukocyte histamine release, or anti-allergen IgE levels. Strongly positive skin tests or high initial ragweed IgE and total IgE may be risk factors for systemic reactions. Less aggressive immunotherapy schedules may be indicated for such patients. Maintenance dose potency must be established by the physician's clinical observation and experience. 10,17

Serial fivefold or tenfold dilutions of the extract are used to make more dilute extract concentrations. Other concentrations can be prepared by appropriate dilution. In brief, the allergist can prepare any dilution of extract that is considered appropriate for the patient.

---

As a consequence of the discovery of IgE and the development of methods to identify and quantify anti-allergen IgE levels, interest in recent years has centered around the utilization of in vivo and in vitro diagnostic procedures. 7,9

Patients who react to a small quantity of antigen by skin testing can be classified as highly sensitive. Those who react only to large quantities of antigen can be classified as less sensitive. It would appear that there is at least a 50,000-fold range between the most and least sensitive individuals. On the other hand, certain patients who do not appear to have elevated quantities of specific anti-allergen IgE do have positive skin tests and have symptoms of allergic rhinitis. These patients are considerably less sensitive than patients with detectable levels of specific IgE antibody. 10

The current standard method of immunotherapy dates back to the earliest studies by Noon. As adapted for ragweed pollen extract, therapy is begun with a low dose, which has been shown to be tolerated by both experience and skin testing.

The physician who undertakes immunotherapy should be concerned with the degree of sensitivity of the patient. This can be measured by skin test, leukocyte histamine release, or anti-allergen IgE levels. Strongly positive skin tests or high initial ragweed IgE and total IgE may be risk factors for systemic reactions. Less aggressive immunotherapy schedules may be indicated for such patients. Maintenance dose potency must be established by the physician's clinical observation and experience. 10,17

Serial fivefold or tenfold dilutions of the extract are used to make more dilute extract concentrations. Other concentrations can be prepared by appropriate dilution. In brief, the allergist can prepare any dilution of extract that is considered appropriate for the patient.

---

As a consequence of the discovery of IgE and the development of methods to identify and quantify anti-allergen IgE levels, interest in recent years has centered around the utilization of in vivo and in vitro diagnostic procedures. 7,9

Patients who react to a small quantity of antigen by skin testing can be classified as highly sensitive. Those who react only to large quantities of antigen can be classified as less sensitive. It would appear that there is at least a 50,000-fold range between the most and least sensitive individuals. On the other hand, certain patients who do not appear to have elevated quantities of specific anti-allergen IgE do have positive skin tests and have symptoms of allergic rhinitis. These patients are considerably less sensitive than patients with detectable levels of specific IgE antibody. 10

The current standard method of immunotherapy dates back to the earliest studies by Noon. As adapted for ragweed pollen extract, therapy is begun with a low dose, which has been shown to be tolerated by both experience and skin testing.

The physician who undertakes immunotherapy should be concerned with the degree of sensitivity of the patient. This can be measured by skin test, leukocyte histamine release, or anti-allergen IgE levels. Strongly positive skin tests or high initial ragweed IgE and total IgE may be risk factors for systemic reactions. Less aggressive immunotherapy schedules may be indicated for such patients. Maintenance dose potency must be established by the physician's clinical observation and experience. 10,17

Serial fivefold or tenfold dilutions of the extract are used to make more dilute extract concentrations. Other concentrations can be prepared by appropriate dilution. In brief, the allergist can prepare any dilution of extract that is considered appropriate for the patient.

---

As a consequence of the discovery of IgE and the development of methods to identify and quantify anti-allergen IgE levels, interest in recent years has centered around the utilization of in vivo and in vitro diagnostic procedures. 7,9

Patients who react to a small quantity of antigen by skin testing can be classified as highly sensitive. Those who react only to large quantities of antigen can be classified as less sensitive. It would appear that there is at least a 50,000-fold range between the most and least sensitive individuals. On the other hand, certain patients who do not appear to have elevated quantities of specific anti-allergen IgE do have positive skin tests and have symptoms of allergic rhinitis. These patients are considerably less sensitive than patients with detectable levels of specific IgE antibody. 10

The current standard method of immunotherapy dates back to the earliest studies by Noon. As adapted for ragweed pollen extract, therapy is begun with a low dose, which has been shown to be tolerated by both experience and skin testing.

The physician who undertakes immunotherapy should be concerned with the degree of sensitivity of the patient. This can be measured by skin test, leukocyte histamine release, or anti-allergen IgE levels. Strongly positive skin tests or high initial ragweed IgE and total IgE may be risk factors for systemic reactions. Less aggressive immunotherapy schedules may be indicated for such patients. Maintenance dose potency must be established by the physician's clinical observation and experience. 10,17

Serial fivefold or tenfold dilutions of the extract are used to make more dilute extract concentrations. Other concentrations can be prepared by appropriate dilution. In brief, the allergist can prepare any dilution of extract that is considered appropriate for the patient.

---

As a consequence of the discovery of IgE and the development of methods to identify and quantify anti-allergen IgE levels, interest in recent years has centered around the utilization of in vivo and in vitro diagnostic procedures. 7,9

Patients who react to a small quantity of antigen by skin testing can be classified as highly sensitive. Those who react only to large quantities of antigen can be classified as less sensitive. It would appear that there is at least a 50,000-fold range between the most and least sensitive individuals. On the other hand, certain patients who do not appear to have elevated quantities of specific anti-allergen IgE do have positive skin tests and have symptoms of allergic rhinitis. These patients are considerably less sensitive than patients with detectable levels of specific IgE antibody. 10

The current standard method of immunotherapy dates back to the earliest studies by Noon. As adapted for ragweed pollen extract, therapy is begun with a low dose, which has been shown to be tolerated by both experience and skin testing.

The physician who undertakes immunotherapy should be concerned with the degree of sensitivity of the patient. This can be measured by skin test, leukocyte histamine release, or anti-allergen IgE levels. Strongly positive skin tests or high initial ragweed IgE and total IgE may be risk factors for systemic reactions. Less aggressive immunotherapy schedules may be indicated for such patients. Maintenance dose potency must be established by the physician's clinical observation and experience. 10,17

Serial fivefold or tenfold dilutions of the extract are used to make more dilute extract concentrations. Other concentrations can be prepared by appropriate dilution. In brief, the allergist can prepare any dilution of extract that is considered appropriate for the patient.

---

As a consequence of the discovery of IgE and the development of methods to identify and quantify anti-allergen IgE levels, interest in recent years has centered around the utilization of in vivo and in vitro diagnostic procedures. 7,9

Patients who react to a small quantity of antigen by skin testing can be classified as highly sensitive. Those who react only to large quantities of antigen can be classified as less sensitive. It would appear that there is at least a 50,000-fold range between the most and least sensitive individuals. On the other hand, certain patients who do not appear to have elevated quantities of specific anti-allergen IgE do have positive skin tests and have symptoms of allergic rhinitis. These patients are considerably less sensitive than patients with detectable levels of specific IgE antibody. 10

The current standard method of immunotherapy dates back to the earliest studies by Noon. As adapted for ragweed pollen extract, therapy is begun with a low dose, which has been shown to be tolerated by both experience and skin testing.

The physician who undertakes immunotherapy should be concerned with the degree of sensitivity of the patient. This can be measured by skin test, leukocyte histamine release, or anti-allergen IgE levels. Strongly positive skin tests or high initial ragweed IgE and total IgE may be risk factors for systemic reactions. Less aggressive immunotherapy schedules may be indicated for such patients. Maintenance dose potency must be established by the physician's clinical observation and experience. 10,17

Serial fivefold or tenfold dilutions of the extract are used to make more dilute extract concentrations. Other concentrations can be prepared by appropriate dilution. In brief, the allergist can prepare any dilution of extract that is considered appropriate for the patient.

---

As a consequence of the discovery of IgE and the development of methods to identify and quantify anti-allergen IgE levels, interest in recent years has centered around the utilization of in vivo and in vitro diagnostic procedures. 7,9

Patients who react to a small quantity of antigen by skin testing can be classified as highly sensitive. Those who react only to large quantities of antigen can be classified as less sensitive. It would appear that there is at least a 50,000-fold range between the most and least sensitive individuals. On the other hand, certain patients who do not appear to have elevated quantities of specific anti-allergen IgE do have positive skin tests and have symptoms of allergic rhinitis. These patients are considerably less sensitive than patients with detectable levels of specific IgE antibody. 10

The current standard method of immunotherapy dates back to the earliest studies by Noon. As adapted for ragweed pollen extract, therapy is begun with a low dose, which has been shown to be tolerated by both experience and skin testing.

The physician who undertakes immunotherapy should be concerned with the degree of sensitivity of the patient. This can be measured by skin test, leukocyte histamine release, or anti-allergen IgE levels. Strongly positive skin tests or high initial ragweed IgE and total IgE may be risk factors for systemic reactions. Less aggressive immunotherapy schedules may be indicated for such patients. Maintenance dose potency must be established by the physician's clinical observation and experience. 10,17

Serial fivefold or tenfold dilutions of the extract are used to make more dilute extract concentrations. Other concentrations can be prepared by appropriate dilution. In brief, the allergist can prepare any dilution of extract that is considered appropriate for the patient.

---

As a consequence of the discovery of IgE and the development of methods to identify and quantify anti-allergen IgE levels, interest in recent years has centered around the utilization of in vivo and in vitro diagnostic procedures. 7,9

Patients who react to a small quantity of antigen by skin testing can be classified as highly sensitive. Those who react only to large quantities of antigen can be classified as less sensitive. It would appear that there is at least a 50,000-fold range between the most and least sensitive individuals. On the other hand, certain patients who do not appear to have elevated quantities of specific anti-allergen IgE do have positive skin tests and have symptoms of allergic rhinitis. These patients are considerably less sensitive than patients with detectable levels of specific IgE antibody. 10

The current standard method of immunotherapy dates back to the earliest studies by Noon. As adapted for ragweed pollen extract, therapy is begun with a low dose, which has been shown to be tolerated by both experience and skin testing.

The physician who undertakes immunotherapy should be concerned with the degree of sensitivity of the patient. This can be measured by skin test, leukocyte histamine release, or anti-allergen IgE levels. Strongly positive skin tests or high initial ragweed IgE and total IgE may be risk factors for systemic reactions. Less aggressive immunotherapy schedules may be indicated for such patients. Maintenance dose potency must be established by the physician's clinical observation and experience. 10,17

Serial fivefold or tenfold dilutions of the extract are used to make more dilute extract concentrations. Other concentrations can be prepared by appropriate dilution. In brief, the allergist can prepare any dilution of extract that is considered appropriate for the patient.

---

As a consequence of the discovery of IgE and the development of methods to identify and quantify anti-allergen IgE levels, interest in recent years has centered around the utilization of in vivo and in vitro diagnostic procedures. 7,9

Patients who react to a small quantity of antigen by skin testing can be classified as highly sensitive. Those who react only to large quantities of antigen can be classified as less sensitive. It would appear that there is at least a 50,000-fold range between the most and least sensitive individuals. On the other hand, certain patients who do not appear to have elevated quantities of specific anti-allergen IgE do have positive skin tests and have symptoms of allergic rhinitis. These patients are considerably less sensitive than patients with detectable levels of specific IgE antibody. 10

The current standard method of immunotherapy dates back to the earliest studies by Noon. As adapted for ragweed pollen extract, therapy is begun with a low dose, which has been shown to be tolerated by both experience and skin testing.

The physician who undertakes immunotherapy should be concerned with the degree of sensitivity of the patient. This can be measured by skin test, leukocyte histamine release, or anti-allergen IgE levels. Strongly positive skin tests or high initial ragweed IgE and total IgE may be risk factors for systemic reactions. Less aggressive immunotherapy schedules may be indicated for such patients. Maintenance dose potency must be established by the physician's clinical observation and experience. 10,17

Serial fivefold or tenfold dilutions of the extract are used to make more dilute extract concentrations. Other concentrations can be prepared by appropriate dilution. In brief, the allergist can prepare any dilution of extract that is considered appropriate for the patient.

---

As a consequence of the discovery of IgE and the development of methods to identify and quantify anti-allergen IgE levels, interest in recent years has centered around the utilization of in vivo and in vitro diagnostic procedures. 7,9

Patients who react to a small quantity of antigen by skin testing can be classified as highly sensitive. Those who react only to large quantities of antigen can be classified as less sensitive. It would appear that there is at least a 50,000-fold range between the most and least sensitive individuals. On the other hand, certain patients who do not appear to have elevated quantities of specific anti-allergen IgE do have positive skin tests and have symptoms of allergic rhinitis. These patients are considerably less sensitive than patients with detectable levels of specific IgE antibody. 10

The current standard method of immunotherapy dates back to the earliest studies by Noon. As adapted for ragweed pollen extract, therapy is begun with a low dose, which has been shown to be tolerated by both experience and skin testing.

The physician who undertakes immunotherapy should be concerned with the degree of sensitivity of the patient. This can be measured by skin test, leukocyte histamine release, or anti-allergen IgE levels. Strongly positive skin tests or high initial ragweed IgE and total IgE may be risk factors for systemic reactions. Less aggressive immunotherapy schedules may be indicated for such patients. Maintenance dose potency must be established by the physician's clinical observation and experience. 10,17

Serial fivefold or tenfold dilutions of the extract are used to make more dilute extract concentrations. Other concentrations can be prepared by appropriate dilution. In brief, the allergist can prepare any dilution of extract that is considered appropriate for the patient.

---

As a consequence of the discovery of IgE and the development of methods to identify and quantify anti-allergen IgE levels, interest in recent years has centered around the utilization of in vivo and in vitro diagnostic procedures. 7,9

Patients who react to a small quantity of antigen by skin testing can be classified as highly sensitive. Those who react only to large quantities of antigen can be classified as less sensitive. It would appear that there is at least a 50,000-fold range between the most and least sensitive individuals. On the other hand, certain patients who do not appear to have elevated quantities of specific anti-allergen IgE do have positive skin tests and have symptoms of allergic rhinitis. These patients are considerably less sensitive than patients with detectable levels of specific IgE antibody. 10

The current standard method of immunotherapy dates back to the earliest studies by Noon. As adapted for ragweed pollen extract, therapy is begun with a low dose, which has been shown to be tolerated by both experience and skin testing.

The physician who undertakes immunotherapy should be concerned with the degree of sensitivity of the patient. This can be measured by skin test, leukocyte histamine release, or anti-allergen IgE levels. Strongly positive skin tests or high initial ragweed IgE and total IgE may be risk factors for systemic reactions. Less aggressive immunotherapy schedules may be indicated for such patients. Maintenance dose potency must be established by the physician's clinical observation and experience. 10,17

Serial fivefold or tenfold dilutions of the extract are used to make more dilute extract concentrations. Other concentrations can be prepared by appropriate dilution. In brief, the allergist can prepare any dilution of extract that is considered appropriate for the patient.

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Refer to “STORAGE” section for proper storage condition for allergenic extract. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Some allergenic extracts naturally precipitate.

Physicians undertaking immunotherapy should be concerned with patient’s degree of sensitivity. The initial dilution of allergenic extract, starting dose, and progression of dosage must be carefully determined on the basis of the patient’s history and results of skin tests. Strongly positive skin tests may be risk factors for systemic reactions. Less aggressive immunotherapy schedules may be indicated for such patients.

Precaution is necessary when using extract mixture for skin testing. The diluting effect of individual components within a mixture may cause false negative reactions. Patients extremely sensitive to a common allergen in several components of a mixture may be more likely to experience a systemic reaction than when skin tested individually for each component.9

PRICK-PUNCTURE TESTING: To identify highly sensitive individuals and as a safety precaution, it is recommended that a prick-puncture test using a drop of the extract concentrate be performed prior to initiating very dilute intradermal testing. Prick-puncture testing is performed by placing a drop of extract concentrate on the skin and puncturing the skin through the drop with a small needle such as a bifurcated vaccinating needle. The most satisfactory sites on the back for skin testing are from the posterior axillary fold to 2.5 cm from the spinal column, and from the top of the scapula to the lower rib margins. The best areas on the arms are the volar surfaces from the axilla to 2.5 or 5 cm above the wrist, skipping the anticubital space. A positive reaction is approximately 10-15 mm erythema with 2.5 mm wheal. Smaller, less conclusive reactions may be considered positive in conjunction with a definitive history of symptoms on exposure to the allergen. The more sensitive the patient the higher the probability that he/she will have symptoms related to the exposure of the offending allergen. Hence, the importance of a good patient history. Less sensitive individuals can be tested intradermally with an appropriately diluted extract.

A positive control using histamine phosphate identifies patients whose skin may not react due to medications, metabolic or other reasons. A negative control (50% glycerine for prick-puncture testing) would exclude false-positive reactions due to ingredients in diluent or patients who have dermatographism.

SINGLE DILUTION INTRADERMAL TESTING: The surface of the upper and lower arm is the usual location for skin testing. It is important that a new, sterile, disposable syringe and needle be used for each extract tested. Intracutaneous test dilutions, five-fold or ten-fold, may be prepared from stock concentrate using physiologic saline as a diluent. (1) Start testing with the most dilute allergenic extract concentration. (2) A volume of 0.02-0.05 ml should be injected slowly into the superficial skin layers making a small bleb (superficial wheal). (3) For patients without a history of extreme sensitivity, or a negative or weakly reactive prick-puncture test, the initial dilution for skin testing should be a dilution at least 1:12,500 w/v. This initial dilution can be prepared by diluting 1:20 to 1:50 w/v (2%-5%) extracts five-fold to 5-4 or 1:10 w/v (10%) extracts to 5-5. See “Serial Dilutions Titration Test Dilutions” chart on the next page. Dilute 1:10 w/v (10%) extracts to 10-3 if using ten-fold dilutions. (4) Sensitive patients with a positive prick-puncture test require a further dilution to at least 1:312,500 w/v. This dilution can be prepared by diluting 1:20 to 1:50 w/v (2% - 5%) extracts to 5-6 or 1:10 w/v (10%) extracts to 5-7 (five-fold dilutions). Ten-fold dilution to 10-6 of a 1:10 w/v (10%) extract would be a safe starting dilution. Size of reactions are quantitated based on size of wheal and erythema. For interpretation of skin reactions, refer to chart below. If after 20 minutes no skin reaction is observed, continue testing using increasing increments of the concentration until a reaction of 5-10 mm wheal and 11-30 mm erythema is obtained, or a concentration of 5-2 or 10-1 has been tested. A negative control, 50% glycerine diluted with diluent to 5-2 (1:25) or 10-1 (1:10) dilution and a positive control of histamine phosphate, should be tested and included in interpretation of skin reactions.1, 13

GRADE mm ERYTHEMA mm WHEAL 0 less than 5 less than 5 ± 5-10 5-10 1+ 11-20 5-10 2+ 21-30 5-10 3+ 31-40 10-15 or with pseudopods 4+ greater than 40 greater than 15 or with many pseudopods

INTRADERMAL TESTING-SKIN ENDPOINT TITRATION: The allergenic extracts to which the patient is sensitive, the patient’s degree of sensitivity and the dose of allergen to be used in immunotherapy can be determined through the use of intracutaneous skin tests involving progressive five-fold dilutions of allergenic extracts. Intracutaneously inject 0.01 to 0.02 ml of the test allergen to form a 4 mm diameter superficial skin wheal. For patients demonstrating a negative or weakly reactive prick-puncture skin test, an initial screening dilution of 1:12,500 w/v is safe. For patients demonstrating a positive prick-puncture skin test, an initial screening dilution of 1:312,500 w/v is safe. (See “Serial Dilution Titration Test Dilutions” chart below.) When a sequence of five-fold or ten-fold dilutions of an allergen are injected, the endpoint is determined by noting the dilution that first produces a wheal and erythema (15 minutes after injection) that is 2 mm larger than wheals with erythema produced by weaker, non-reacting dilutions (5 mm negative wheal). The endpoint dilution is used as a starting dose concentration for immunotherapy. An endpoint dose of 0.15 ml is a safe initial dose to be followed by escalation to the optimal maximum tolerated dose for each individual.

Injections should never be given intravenously. A 5/8 inch, 25 gauge needle on a sterile syringe will allow deep subcutaneous injection.

IMMUNOTHERAPY: If the first injection of the initial dilution of extract is tolerated without significant local reaction, increasing doses by 5-20% increments of that dilution may be administered. The rate of increase in dosage in the early stages of treatment with highly diluted extracts is usually more rapid than the rate of increase possible with more concentrated extracts. This schedule is intended only as a guide and must be modified according to the reactivity of the individual patient. Needless to say, the physician must proceed cautiously in the treatment of the highly sensitive patient who develops large local or systemic reactions.6

Some patients may tolerate larger doses of the allergenic extract depending on patient response.7 Because diluted extract tends to lose activity in storage, the first dose from a more concentrated vial should be the same, or less than, the previous dose.8, 12

Dosages progressively increase according to the tolerance of the patient at intervals of one to seven days until, (1) the patient achieves relief from symptoms, (2) induration at the site of injection is no larger than 50 mm in 36 to 48 hours, (3) a maintenance dose is reached (the largest dose tolerated by the patient that relieves symptoms without undesirable local or systemic reactions). This maintenance dose may be continued at regular intervals perennially. It may be necessary to adjust the progression of dosage downward to avoid local and constitutional reactions.

The usual duration of treatment has not been established. A period of two or three years on immunotherapy constitutes an average minimum course of treatment.

SERIAL DILUTION TITRATION TEST DILUTIONS APPROXIMATE ALLERGENIC EXTRACT CONCENTRATION RESULTING FROM 1:5 DILUTION Titration Number Dilution Exponent Weight / Volume Allergenic Extract Concentrate 1:50 (2%) 1:40 (2 1/2%) 1:33 1/3 (3%) 1:20 (5%) 1:10 (10%) No. 1 5-1 1:5 1:250 1:200 1:167 1:100 1:50 No. 2 5-2 1:25 1:1,250 1:1,000 1:835 1:500 1:250 No. 3 5-3 1:125 1:6,250 1:5,000 1:4,175 1:2,500 1:1,250 No. 4 5-4 1:625 1:31,250 1:25,000 1:20,875 1:12,500 1:6,250 No. 5 5-5 1:3,125 1:156,250 1:125,000 1:104,375 1:62,500 1:31,250 No. 6 5-6 1:15,625 1:781,250 1:625,000 1:521,875 1:312,500 1:156,250 No. 7 5-7 1:78,125 1:3,906,250 1:3,125,000 1:2,609,375 1:1,562,500 1:781,250 No. 8 5-8 1:390,625 1:19,531,250 1:15,625,000 1:13,046,875 1:7,812,500 1:3,906,250 No. 9 5-9 1:1,953,125 1:97,656,250 1:78,125,000 1:65,234,375 1:39,062,500 1:19,531,250 No. 10 5-10 1:9,765,625 1:488,281,250 1:390,625,000 1:326,171,875 1:195,312,500 1:97,656,250 No. 11 5-11 1:48,828,125 1:2,441,406,250 1:1,953,125,000 1:1,630,859,375 1:976,562,500 1:488,281,250 No. 12 5-12 1:244,140,625 1:12,207,031,250 1:9,765,625,000 1:8,154,296,875 1:4,882,812,500 1:2,441,406,250

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As a consequence of the discovery of IgE and the development of methods to identify and quantify anti-allergen IgE levels, interest in recent years has centered around the utilization of in vivo and in vitro diagnostic procedures. 7,9

Patients who react to a small quantity of antigen by skin testing can be classified as highly sensitive. Those who react only to large quantities of antigen can be classified as less sensitive. It would appear that there is at least a 50,000-fold range between the most and least sensitive individuals. On the other hand, certain patients who do not appear to have elevated quantities of specific anti-allergen IgE do have positive skin tests and have symptoms of allergic rhinitis. These patients are considerably less sensitive than patients with detectable levels of specific IgE antibody. 10

The current standard method of immunotherapy dates back to the earliest studies by Noon. As adapted for ragweed pollen extract, therapy is begun with a low dose, which has been shown to be tolerated by both experience and skin testing.

The physician who undertakes immunotherapy should be concerned with the degree of sensitivity of the patient. This can be measured by skin test, leukocyte histamine release, or anti-allergen IgE levels. Strongly positive skin tests or high initial ragweed IgE and total IgE may be risk factors for systemic reactions. Less aggressive immunotherapy schedules may be indicated for such patients. Maintenance dose potency must be established by the physician's clinical observation and experience. 10,17

Serial fivefold or tenfold dilutions of the extract are used to make more dilute extract concentrations. Other concentrations can be prepared by appropriate dilution. In brief, the allergist can prepare any dilution of extract that is considered appropriate for the patient.

---

As a consequence of the discovery of IgE and the development of methods to identify and quantify anti-allergen IgE levels, interest in recent years has centered around the utilization of in vivo and in vitro diagnostic procedures. 7,9

Patients who react to a small quantity of antigen by skin testing can be classified as highly sensitive. Those who react only to large quantities of antigen can be classified as less sensitive. It would appear that there is at least a 50,000-fold range between the most and least sensitive individuals. On the other hand, certain patients who do not appear to have elevated quantities of specific anti-allergen IgE do have positive skin tests and have symptoms of allergic rhinitis. These patients are considerably less sensitive than patients with detectable levels of specific IgE antibody. 10

The current standard method of immunotherapy dates back to the earliest studies by Noon. As adapted for ragweed pollen extract, therapy is begun with a low dose, which has been shown to be tolerated by both experience and skin testing.

The physician who undertakes immunotherapy should be concerned with the degree of sensitivity of the patient. This can be measured by skin test, leukocyte histamine release, or anti-allergen IgE levels. Strongly positive skin tests or high initial ragweed IgE and total IgE may be risk factors for systemic reactions. Less aggressive immunotherapy schedules may be indicated for such patients. Maintenance dose potency must be established by the physician's clinical observation and experience. 10,17

Serial fivefold or tenfold dilutions of the extract are used to make more dilute extract concentrations. Other concentrations can be prepared by appropriate dilution. In brief, the allergist can prepare any dilution of extract that is considered appropriate for the patient.

---

As a consequence of the discovery of IgE and the development of methods to identify and quantify anti-allergen IgE levels, interest in recent years has centered around the utilization of in vivo and in vitro diagnostic procedures. 7,9

Patients who react to a small quantity of antigen by skin testing can be classified as highly sensitive. Those who react only to large quantities of antigen can be classified as less sensitive. It would appear that there is at least a 50,000-fold range between the most and least sensitive individuals. On the other hand, certain patients who do not appear to have elevated quantities of specific anti-allergen IgE do have positive skin tests and have symptoms of allergic rhinitis. These patients are considerably less sensitive than patients with detectable levels of specific IgE antibody. 10

The current standard method of immunotherapy dates back to the earliest studies by Noon. As adapted for ragweed pollen extract, therapy is begun with a low dose, which has been shown to be tolerated by both experience and skin testing.

The physician who undertakes immunotherapy should be concerned with the degree of sensitivity of the patient. This can be measured by skin test, leukocyte histamine release, or anti-allergen IgE levels. Strongly positive skin tests or high initial ragweed IgE and total IgE may be risk factors for systemic reactions. Less aggressive immunotherapy schedules may be indicated for such patients. Maintenance dose potency must be established by the physician's clinical observation and experience. 10,17

Serial fivefold or tenfold dilutions of the extract are used to make more dilute extract concentrations. Other concentrations can be prepared by appropriate dilution. In brief, the allergist can prepare any dilution of extract that is considered appropriate for the patient.

---

As a consequence of the discovery of IgE and the development of methods to identify and quantify anti-allergen IgE levels, interest in recent years has centered around the utilization of in vivo and in vitro diagnostic procedures. 7,9

Patients who react to a small quantity of antigen by skin testing can be classified as highly sensitive. Those who react only to large quantities of antigen can be classified as less sensitive. It would appear that there is at least a 50,000-fold range between the most and least sensitive individuals. On the other hand, certain patients who do not appear to have elevated quantities of specific anti-allergen IgE do have positive skin tests and have symptoms of allergic rhinitis. These patients are considerably less sensitive than patients with detectable levels of specific IgE antibody. 10

The current standard method of immunotherapy dates back to the earliest studies by Noon. As adapted for ragweed pollen extract, therapy is begun with a low dose, which has been shown to be tolerated by both experience and skin testing.

The physician who undertakes immunotherapy should be concerned with the degree of sensitivity of the patient. This can be measured by skin test, leukocyte histamine release, or anti-allergen IgE levels. Strongly positive skin tests or high initial ragweed IgE and total IgE may be risk factors for systemic reactions. Less aggressive immunotherapy schedules may be indicated for such patients. Maintenance dose potency must be established by the physician's clinical observation and experience. 10,17

Serial fivefold or tenfold dilutions of the extract are used to make more dilute extract concentrations. Other concentrations can be prepared by appropriate dilution. In brief, the allergist can prepare any dilution of extract that is considered appropriate for the patient.

---

As a consequence of the discovery of IgE and the development of methods to identify and quantify anti-allergen IgE levels, interest in recent years has centered around the utilization of in vivo and in vitro diagnostic procedures. 7,9

Patients who react to a small quantity of antigen by skin testing can be classified as highly sensitive. Those who react only to large quantities of antigen can be classified as less sensitive. It would appear that there is at least a 50,000-fold range between the most and least sensitive individuals. On the other hand, certain patients who do not appear to have elevated quantities of specific anti-allergen IgE do have positive skin tests and have symptoms of allergic rhinitis. These patients are considerably less sensitive than patients with detectable levels of specific IgE antibody. 10

The current standard method of immunotherapy dates back to the earliest studies by Noon. As adapted for ragweed pollen extract, therapy is begun with a low dose, which has been shown to be tolerated by both experience and skin testing.

The physician who undertakes immunotherapy should be concerned with the degree of sensitivity of the patient. This can be measured by skin test, leukocyte histamine release, or anti-allergen IgE levels. Strongly positive skin tests or high initial ragweed IgE and total IgE may be risk factors for systemic reactions. Less aggressive immunotherapy schedules may be indicated for such patients. Maintenance dose potency must be established by the physician's clinical observation and experience. 10,17

Serial fivefold or tenfold dilutions of the extract are used to make more dilute extract concentrations. Other concentrations can be prepared by appropriate dilution. In brief, the allergist can prepare any dilution of extract that is considered appropriate for the patient.

---

As a consequence of the discovery of IgE and the development of methods to identify and quantify anti-allergen IgE levels, interest in recent years has centered around the utilization of in vivo and in vitro diagnostic procedures. 7,9

Patients who react to a small quantity of antigen by skin testing can be classified as highly sensitive. Those who react only to large quantities of antigen can be classified as less sensitive. It would appear that there is at least a 50,000-fold range between the most and least sensitive individuals. On the other hand, certain patients who do not appear to have elevated quantities of specific anti-allergen IgE do have positive skin tests and have symptoms of allergic rhinitis. These patients are considerably less sensitive than patients with detectable levels of specific IgE antibody. 10

The current standard method of immunotherapy dates back to the earliest studies by Noon. As adapted for ragweed pollen extract, therapy is begun with a low dose, which has been shown to be tolerated by both experience and skin testing.

The physician who undertakes immunotherapy should be concerned with the degree of sensitivity of the patient. This can be measured by skin test, leukocyte histamine release, or anti-allergen IgE levels. Strongly positive skin tests or high initial ragweed IgE and total IgE may be risk factors for systemic reactions. Less aggressive immunotherapy schedules may be indicated for such patients. Maintenance dose potency must be established by the physician's clinical observation and experience. 10,17

Serial fivefold or tenfold dilutions of the extract are used to make more dilute extract concentrations. Other concentrations can be prepared by appropriate dilution. In brief, the allergist can prepare any dilution of extract that is considered appropriate for the patient.

---

As a consequence of the discovery of IgE and the development of methods to identify and quantify anti-allergen IgE levels, interest in recent years has centered around the utilization of in vivo and in vitro diagnostic procedures. 7,9

Patients who react to a small quantity of antigen by skin testing can be classified as highly sensitive. Those who react only to large quantities of antigen can be classified as less sensitive. It would appear that there is at least a 50,000-fold range between the most and least sensitive individuals. On the other hand, certain patients who do not appear to have elevated quantities of specific anti-allergen IgE do have positive skin tests and have symptoms of allergic rhinitis. These patients are considerably less sensitive than patients with detectable levels of specific IgE antibody. 10

The current standard method of immunotherapy dates back to the earliest studies by Noon. As adapted for ragweed pollen extract, therapy is begun with a low dose, which has been shown to be tolerated by both experience and skin testing.

The physician who undertakes immunotherapy should be concerned with the degree of sensitivity of the patient. This can be measured by skin test, leukocyte histamine release, or anti-allergen IgE levels. Strongly positive skin tests or high initial ragweed IgE and total IgE may be risk factors for systemic reactions. Less aggressive immunotherapy schedules may be indicated for such patients. Maintenance dose potency must be established by the physician's clinical observation and experience. 10,17

Serial fivefold or tenfold dilutions of the extract are used to make more dilute extract concentrations. Other concentrations can be prepared by appropriate dilution. In brief, the allergist can prepare any dilution of extract that is considered appropriate for the patient.

---

As a consequence of the discovery of IgE and the development of methods to identify and quantify anti-allergen IgE levels, interest in recent years has centered around the utilization of in vivo and in vitro diagnostic procedures. 7,9

Patients who react to a small quantity of antigen by skin testing can be classified as highly sensitive. Those who react only to large quantities of antigen can be classified as less sensitive. It would appear that there is at least a 50,000-fold range between the most and least sensitive individuals. On the other hand, certain patients who do not appear to have elevated quantities of specific anti-allergen IgE do have positive skin tests and have symptoms of allergic rhinitis. These patients are considerably less sensitive than patients with detectable levels of specific IgE antibody. 10

The current standard method of immunotherapy dates back to the earliest studies by Noon. As adapted for ragweed pollen extract, therapy is begun with a low dose, which has been shown to be tolerated by both experience and skin testing.

The physician who undertakes immunotherapy should be concerned with the degree of sensitivity of the patient. This can be measured by skin test, leukocyte histamine release, or anti-allergen IgE levels. Strongly positive skin tests or high initial ragweed IgE and total IgE may be risk factors for systemic reactions. Less aggressive immunotherapy schedules may be indicated for such patients. Maintenance dose potency must be established by the physician's clinical observation and experience. 10,17

Serial fivefold or tenfold dilutions of the extract are used to make more dilute extract concentrations. Other concentrations can be prepared by appropriate dilution. In brief, the allergist can prepare any dilution of extract that is considered appropriate for the patient.

---

As a consequence of the discovery of IgE and the development of methods to identify and quantify anti-allergen IgE levels, interest in recent years has centered around the utilization of in vivo and in vitro diagnostic procedures. 7,9

Patients who react to a small quantity of antigen by skin testing can be classified as highly sensitive. Those who react only to large quantities of antigen can be classified as less sensitive. It would appear that there is at least a 50,000-fold range between the most and least sensitive individuals. On the other hand, certain patients who do not appear to have elevated quantities of specific anti-allergen IgE do have positive skin tests and have symptoms of allergic rhinitis. These patients are considerably less sensitive than patients with detectable levels of specific IgE antibody. 10

The current standard method of immunotherapy dates back to the earliest studies by Noon. As adapted for ragweed pollen extract, therapy is begun with a low dose, which has been shown to be tolerated by both experience and skin testing.

The physician who undertakes immunotherapy should be concerned with the degree of sensitivity of the patient. This can be measured by skin test, leukocyte histamine release, or anti-allergen IgE levels. Strongly positive skin tests or high initial ragweed IgE and total IgE may be risk factors for systemic reactions. Less aggressive immunotherapy schedules may be indicated for such patients. Maintenance dose potency must be established by the physician's clinical observation and experience. 10,17

Serial fivefold or tenfold dilutions of the extract are used to make more dilute extract concentrations. Other concentrations can be prepared by appropriate dilution. In brief, the allergist can prepare any dilution of extract that is considered appropriate for the patient.

---

As a consequence of the discovery of IgE and the development of methods to identify and quantify anti-allergen IgE levels, interest in recent years has centered around the utilization of in vivo and in vitro diagnostic procedures. 7,9

Patients who react to a small quantity of antigen by skin testing can be classified as highly sensitive. Those who react only to large quantities of antigen can be classified as less sensitive. It would appear that there is at least a 50,000-fold range between the most and least sensitive individuals. On the other hand, certain patients who do not appear to have elevated quantities of specific anti-allergen IgE do have positive skin tests and have symptoms of allergic rhinitis. These patients are considerably less sensitive than patients with detectable levels of specific IgE antibody. 10

The current standard method of immunotherapy dates back to the earliest studies by Noon. As adapted for ragweed pollen extract, therapy is begun with a low dose, which has been shown to be tolerated by both experience and skin testing.

The physician who undertakes immunotherapy should be concerned with the degree of sensitivity of the patient. This can be measured by skin test, leukocyte histamine release, or anti-allergen IgE levels. Strongly positive skin tests or high initial ragweed IgE and total IgE may be risk factors for systemic reactions. Less aggressive immunotherapy schedules may be indicated for such patients. Maintenance dose potency must be established by the physician's clinical observation and experience. 10,17

Serial fivefold or tenfold dilutions of the extract are used to make more dilute extract concentrations. Other concentrations can be prepared by appropriate dilution. In brief, the allergist can prepare any dilution of extract that is considered appropriate for the patient.

---

As a consequence of the discovery of IgE and the development of methods to identify and quantify anti-allergen IgE levels, interest in recent years has centered around the utilization of in vivo and in vitro diagnostic procedures. 7,9

Patients who react to a small quantity of antigen by skin testing can be classified as highly sensitive. Those who react only to large quantities of antigen can be classified as less sensitive. It would appear that there is at least a 50,000-fold range between the most and least sensitive individuals. On the other hand, certain patients who do not appear to have elevated quantities of specific anti-allergen IgE do have positive skin tests and have symptoms of allergic rhinitis. These patients are considerably less sensitive than patients with detectable levels of specific IgE antibody. 10

The current standard method of immunotherapy dates back to the earliest studies by Noon. As adapted for ragweed pollen extract, therapy is begun with a low dose, which has been shown to be tolerated by both experience and skin testing.

The physician who undertakes immunotherapy should be concerned with the degree of sensitivity of the patient. This can be measured by skin test, leukocyte histamine release, or anti-allergen IgE levels. Strongly positive skin tests or high initial ragweed IgE and total IgE may be risk factors for systemic reactions. Less aggressive immunotherapy schedules may be indicated for such patients. Maintenance dose potency must be established by the physician's clinical observation and experience. 10,17

Serial fivefold or tenfold dilutions of the extract are used to make more dilute extract concentrations. Other concentrations can be prepared by appropriate dilution. In brief, the allergist can prepare any dilution of extract that is considered appropriate for the patient.

---

As a consequence of the discovery of IgE and the development of methods to identify and quantify anti-allergen IgE levels, interest in recent years has centered around the utilization of in vivo and in vitro diagnostic procedures. 7,9

Patients who react to a small quantity of antigen by skin testing can be classified as highly sensitive. Those who react only to large quantities of antigen can be classified as less sensitive. It would appear that there is at least a 50,000-fold range between the most and least sensitive individuals. On the other hand, certain patients who do not appear to have elevated quantities of specific anti-allergen IgE do have positive skin tests and have symptoms of allergic rhinitis. These patients are considerably less sensitive than patients with detectable levels of specific IgE antibody. 10

The current standard method of immunotherapy dates back to the earliest studies by Noon. As adapted for ragweed pollen extract, therapy is begun with a low dose, which has been shown to be tolerated by both experience and skin testing.

The physician who undertakes immunotherapy should be concerned with the degree of sensitivity of the patient. This can be measured by skin test, leukocyte histamine release, or anti-allergen IgE levels. Strongly positive skin tests or high initial ragweed IgE and total IgE may be risk factors for systemic reactions. Less aggressive immunotherapy schedules may be indicated for such patients. Maintenance dose potency must be established by the physician's clinical observation and experience. 10,17

Serial fivefold or tenfold dilutions of the extract are used to make more dilute extract concentrations. Other concentrations can be prepared by appropriate dilution. In brief, the allergist can prepare any dilution of extract that is considered appropriate for the patient.

---

As a consequence of the discovery of IgE and the development of methods to identify and quantify anti-allergen IgE levels, interest in recent years has centered around the utilization of in vivo and in vitro diagnostic procedures. 7,9

Patients who react to a small quantity of antigen by skin testing can be classified as highly sensitive. Those who react only to large quantities of antigen can be classified as less sensitive. It would appear that there is at least a 50,000-fold range between the most and least sensitive individuals. On the other hand, certain patients who do not appear to have elevated quantities of specific anti-allergen IgE do have positive skin tests and have symptoms of allergic rhinitis. These patients are considerably less sensitive than patients with detectable levels of specific IgE antibody. 10

The current standard method of immunotherapy dates back to the earliest studies by Noon. As adapted for ragweed pollen extract, therapy is begun with a low dose, which has been shown to be tolerated by both experience and skin testing.

The physician who undertakes immunotherapy should be concerned with the degree of sensitivity of the patient. This can be measured by skin test, leukocyte histamine release, or anti-allergen IgE levels. Strongly positive skin tests or high initial ragweed IgE and total IgE may be risk factors for systemic reactions. Less aggressive immunotherapy schedules may be indicated for such patients. Maintenance dose potency must be established by the physician's clinical observation and experience. 10,17

Serial fivefold or tenfold dilutions of the extract are used to make more dilute extract concentrations. Other concentrations can be prepared by appropriate dilution. In brief, the allergist can prepare any dilution of extract that is considered appropriate for the patient.