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Honey Bee Hymenoptera V...

Honey Bee Hymenoptera Venom Multidose

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

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

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

Dilutions (see table below) must be made in Sterile Albumin Saline with Phenol (0.4%). They must be made accurately and aseptically, using sterile solutions, vials, syringes, etc., and thoroughly mixed by rocking or swirling. DO NOT SHAKE. Store freeze-dried and reconstituted venom product, and venom dilutions constantly at 2° - 8°C.
Extract Volume Extract Concentration Diluent Volume Dilution Concentration 1 part of 100 µg/mL + 9 parts = 10 µg/mL 1 part of 10 µg/mL + 9 parts = 1 µg/mL 1 part of 1 µg/mL + 9 parts = 0.1 µg/mL 1 part of 0.1 µg/mL + 9 parts = 0.01 µg/mL 1 part of 0.01 µg/mL + 9 parts = 0.001 µg/mL 1 part of 0.001 µg/mL + 9 parts = 0.0001 µg/mL As an example of the preceding dilution table: Extract Volume Extract Concentration Diluent Volume Dilution Concentration 0.2 mL of 100 µg/mL + 1.8 mL = 10 µg/mL 0.2 mL of 10 µg/mL + 1.8 mL = 1 µg/mL 0.2 mL of 1 µg/mL + 1.8 mL = 0.1 µg/mL 0.2 mL of 0.1 µg/mL + 1.8 mL = 0.01 µg/mL 0.2 mL of 0.01 µg/mL + 1.8 mL = 0.001 µg/mL 0.2 mL of 0.001 µg/mL + 1.8 mL = 0.0001 µg/mL NOTE: Mixed Vespid venom protein concentrations will be three times that shown above.
(2) Diagnosis

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

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

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

See DOSAGE AND ADMINISTRATION, Immunotherapy CAUTION.

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

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

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

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

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

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

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

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

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

(3) Immunotherapy:For proper method and route of injection, see WARNINGS, PRECAUTIONS and ADVERSE REACTIONS. The most common site of injection is the lateral aspect of the upper arm. Patients who have multiple venom sensitivities should be given each specific venom injection in a separate site. (Except, if the patient has sensitivities to Yellow Jacket, Yellow Hornet, and White-Faced Hornet venoms concurrently, s/he can be injected with Mixed Vespid venom protein, an equal mixture of these three vespid venoms). Note which venom preparation is injected at a specific site, so that dosage of that venom preparation can be adjusted if an excessive local reaction occurs. In patients receiving more than one venom, there is theoretically a greater risk of systemic reactions.
CAUTION: Sensitivity to venom differs from patient to patient. Thus, it is not possible to provide a dosage schedule suitable for all patients. The Suggested Dose Schedule shown below was used in clinical trials (4) and should be suitable for a majority of patients. IN EXTREMELY SENSITIVE PATIENTS, however, an individualized dose schedule must be employed which will be dictated by the patient's sensitivity. This individualized schedule will probably include weaker dilutions and smaller increments between doses in progressing to the maintenance level (100 µg per venom). In identifying those patients to be classified as extremely sensitive, individuals reacting with significant skin test (wheal greater than 5 mm and erythema greater than 20 mm) at intradermal skin test concentrations of 0.01 µg/mL or less, or those patients experiencing a systemic reaction to any venom skin test concentration, should be considered highly sensitive. Suggested Dose Schedule for a Single Venom: Dose *Volume of No. 1 µg/mL Dose Volume of No. 10 µg/mL Dose Volume of No. 100 µg/mL 1...............0.05 mL 5...............0.05 mL 9.................0.05 mL 2...............0.10 mL 6...............0.10 mL 10................0.10 mL 3...............0.20mL 7...............0.20 mL 11................0.20 mL 4...............0.40 mL 8...............0.40 mL 12................0.40 mL Mixed Vespid venom will containthree times the venom proteinper mL show in this table. 13................0.60 mL * See preceding CAUTION SECTION 14................0.80 mL 15................1.00 mL In proceeding with the Suggested Dose Schedule, or modified schedules (for highly sensitive patients) it is recommended that injections be given at least once per week, as in the clinical studies. (See CLINICAL PHARMACOLOGY and INDICATIONS AND USAGE). When building the dose, it is important that dose intervals not exceed one week since longer intervals may decrease the patienttolerance of the extract. Based on the clinical studies, (4) it is suggested that if a systemic, extremely large local (10 cm or more in duration, or other severe local symptoms), or persistent and severe delayed local reaction occurs during the dose building phase, the dose at the next visit be held constant (or reduced, depending on judgment of the severity of the reaction) as was done at Study Center "A," which reported the least number of systemic reactions during the course of therapy. It must be considered important to achieve the 100 µg per venom maintenance dose (the maintenance dose for Mixed Vespid venom protein is 300 µg), since there are no data on effectiveness of maintenance levels below 100 µg per venom. Following the achievement of maintenance level (100 µg per venom), it is recommended that a second maintenance injection be given at a 1-week interval, and a third maintenance injection at a 2-week interval. Administer the next injection at a 3-week interval, and then monthly for ongoing maintenance. See CLINICAL PHARMACOLOGY and INDICATIONS AND USAGE for further information regarding clinical studies on which the above recommendations are based. The optimum duration for immunotherapy is not known, so current recommendations are that maintenance injections be continued indefinitely, year around, particularly in patients experiencing life-threatening anaphylaxis after insect stings.
Pediatric Use

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

Geriatric Use

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

Standardized Cat Hair

3, 16, 17, 18 (1) General Sterile aqueous diluent containing human serum albumin is recommended when preparing dilutions of the concentrate for intradermal testing or immunotherapy. Dilutions should be made accurately and aseptically, using sterile diluent, vials, syringes, etc. Mix thoroughly and gently by rocking or swirling. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. (2) Diagnosis To identify highly sensitive individuals and as a safety precaution, it is recommended that a prick or puncture test using a drop of the extract concentrate be performed prior to initiating intradermal testing. Prick tests are performed by placing a drop of extract on the skin and piercing through the drop into the skin with a slight lifting motion. Puncture tests are performed by placing a drop of extract on the skin and piercing through the drop perpendicular to the skin with a device such as a Prick Lancetter. After about 1 minute the extract may be wiped away with a dry sponge. The diameter of wheal and erythema reactions are measured 15 minutes after the prick or puncture is made, and the sensitivity class of the patient determined by the table presented at the end of the diagnosis section. Less sensitive individuals (Class 0 to 1+) can be tested intradermally with the recommended dilutions of the extract concentrate (see intradermal testing information below). The skin test concentration of 10,000 BAU/mL (10-19.9 Fel d 1 units/mL) in dropper vials is used for prick or puncture testing. Puncture tests performed on 15 highly sensitive subjects showed the following: Product Mean Sum of Wheal ± Std. Dev. (mm) Mean Sum of Erythema ± 1 Std. Dev. (mm) Standardized Cat Hair 15.1 ± 3.8 73.3 ± 14.3 The sum of a skin response is the sum of the longest diameter and the midpoint orthogonal diameter. Intradermal endpoint titration (IET) tests were completed using the same 15 subjects to determine the mean concentration required to produce a ∑E of 50mm (D 50). That concentration contained 0.049 BAU/mL (range 0.006 to 0.661 BAU/mL). Intradermal extract should be used as follows: Intradermal Tests should be done only on patients with a negative prick or puncture test. Patients who do not react to a valid prick or puncture test should be tested intradermally with 0.02 to 0.05 mL of a 100 BAU/mL extract solution. If this test is negative, a second intradermal test may be performed using a 1,000 BAU/mL extract solution. If the intradermal dilutions were prepared from glycerinated concentrate, the negative control used with this latter dilution should contain 5% glycerol. Skin tests are graded in terms of the wheal and erythema response noted at 15 minutes. Wheal and erythema size may be recorded by actual measurement of the extent of both responses. Refer to the following table to determine the skin test sensitivity class. The corresponding ∑E (sum of the longest diameter and the mid-point orthogonal diameters of erythema) is also presented. Class Wheal Diameter Erythema Diameter Corresponding ∑E 0 < 5 mm <5 mm <10 mm ± 5-10 mm 5-10 mm 10-20 mm 1+ 5-10 mm 11-20 mm 20-40 mm 2+ 5-10 mm 21-30 mm 40-60 mm 3+ 10-15 mm a 31-40 mm 60-80 mm 4+ >15 mm b >40 mm >80 mm a. or with pseudopods b. or with many pseudopods 3) Immunotherapy Allergen extracts should be administered using a sterile syringe with 0.01 mL gradations and a 25-27 gauge x 1/2" to 5/8" needle. The injections are given subcutaneously. The most common sites of injection are the lateral aspect of the upper arm or thigh. Intracutaneous or intramuscular injections may produce large local reactions which may be very painful. Dosage of allergenic extracts is a highly individualized matter and varies according to the degree of sensitivity of the patient, his clinical response, and tolerance to the extract administered during the early phases of an injection regimen. The starting dose should be based on skin tests of the extract to be used for immunotherapy. To prepare dilutions for intradermal and therapeutic use, make a 1:10 dilution by adding 1.0 mL of the concentrate to 9.0 mL of sterile aqueous diluent. Subsequent serial dilutions are made in a similar manner. (See Table I.) To determine the starting dose, begin intradermal testing with the most dilute extract preparation. Inject 0.02 mL and read the reaction after 15 minutes. Intradermal testing is continued with increasing concentrations of the extract until a reaction of 10-20 mm erythema (∑E 20-40 mm) and/or a 5 mm wheal occurs. This concentration at a dose of 0.03 mL then can serve as a starting dose for immunotherapy and be increased by 0.03 mL to as high as 0.12 mL increments each time until 0.3 mL is reached, at which time a dilution 10 times as strong can be used, starting with 0.03 mL. Proceed in this way until a tolerance dose is reached or symptoms are controlled. Suggested maintenance dose is 0.2 mL of the concentrate. Occasionally, higher doses are necessary to relieve symptoms. Special caution is required in administering doses greater than 0.2 mL. The interval between doses normally is 3 to 7 days. This is offered as a suggested schedule for average patients and will be satisfactory in most cases. However, the degree of sensitivity varies in many patients. The size of the dose should be adjusted and should be regulated by the patient’s tolerance and reaction. The size of the dose should be decreased if the previous injection resulted in marked local or the slightest general reaction. Another dose should never be given until all local reactions resulting from the previous dose have disappeared. In some patients, the dosage may be increased more rapidly than called for in the schedule. In seasonal allergies, treatment should be started and the interval between doses regulated so that at least the first 20 doses will have been administered by the time symptoms are expected. Thus, the shorter the interval between the start of immunotherapy and the expected onset of symptoms, the shorter the interval between each dose. Some patients may even tolerate daily doses. A maintenance dose, the largest dose tolerated by the patient that relieves symptoms without producing undesirable local or general reactions is recommended for most patients. The upper limits of dosage have not been established; however, doses larger than 0.2 mL of the glycerinated concentrate may be painful due to the glycerin content. The dosage of allergenic extract does not vary significantly with the respiratory allergic disease under treatment. The size of this dose and the interval between doses will vary and can be adjusted as necessary. Should symptoms develop before the next injection is scheduled, the interval between doses should be decreased. Should allergic symptoms or local reactions develop shortly after the dose is administered, the size of the dose should be decreased. In seasonal allergies, it is often advisable to decrease the dose to one-half or one-quarter of the maximum dose previously attained if the patient has any seasonal symptoms. The interval between maintenance doses can be increased gradually from one week to 10 days, to two weeks, to three weeks, or even to four weeks if tolerated. Repeat the doses at a given interval three or four times to check for untoward reactions before further increasing the interval. Protection is lost rapidly if the interval between doses is more than four weeks. (See WARNINGS Section.) The usual duration of treatment has not been established. A period of two or three years of injection therapy constitutes an average minimum course of treatment. TABLE 1TEN-FOLD DILUTION SERIESStandardized Extracts Labeled 10,000 BAU/mL Dilution Extract + Diluent = BAU/mLConcentration 0 Concentrate +0 mL = 10,000 1 1 mL concentrate +9 mL = 1,000 2 1 mL dilution #1 +9 mL = 100 3 1 mL dilution #2 +9 mL = 10 4 1 mL dilution #3 +9 mL = 1 5 1 mL dilution #4 +9 mL = 0.1 6 1 mL dilution #5 +9 mL = 0.01 7 1 mL dilution #6 +9 mL = 0.001
(4) Pediatric Use

(See PRECAUTIONS)
Positive Skin Test Cont...

Positive Skin Test Control – Histamine

(1) GeneralParenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Prior to testing, clean the skin area with ether or alcohol and allow to dry. The back or the volar surface of the arms are the most satisfactory sites for testing.

Skin of the posterior thighs or abdomen may be used if necessary. Avoid very hairy areas where possible, since the reactions will be smaller and more difficult to interpret there. The most satisfactory areas of the back 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 of the arms are the volar surfaces from the axilla to 2.5 or 5 cm above the wrist, skipping the anti-cubital space.

The histamine test should be applied in the same test area as other allergenic extracts tests, but spaced no closer than 4 to 5 cm from adjacent test sites. Use the same technique or procedure that you use for allergen testing.

The negative control is the diluent used in the extract to be tested (e.g. 50% glycerin, Sterile Albumin Saline with Phenol, Sterile Buffered Saline with Phenol).

With each skin testing method, in order for the reaction to Positive Skin Test Control-Histamine (6 mg/mL Histamine Base) to be considered valid, erythema must be present which exceeds the respective negative control by 4 mm (∑E). A wheal reaction does not have to be elicited unless there is a wheal reaction to the respective negative control. In this case, the wheal of the positive control must exceed the negative control by 4 mm (∑W) in order to be considered appropriate. Record measurement of erythema and wheal diameters.

Tables 1 and 2 summarize skin testing results with histamine base and controls in atopic and non-atopic subjects using four different devices and methods.

(2) Scratch, Prick or Puncture Test: Positive Skin Test Control-Histamine, 6.0 mg/mL Histamine Base.The Scratch, Prick or Puncture test should be read in 15 minutes. If a large wheal reaction occurs before that time, wipe excess histamine solution from test site.
a) Use a sterile scarifier for each patient. Hold the scarifier between the thumb and index finger, press the sharp edge of the instrument against the skin and twirl instrument rapidly. The scratch should disrupt the outer layers of epidermis down to the germinal layer, but should not produce immediate oozing of blood. The amount of pressure needed to produce a satisfactory scratch will vary between patients according to the thickness or fragility of their skin. Apply one drop of Positive Skin Test Control-Histamine to the scratch test site. b) Prick or Puncture Test: Prick tests are performed by placing a drop of extract on the skin and piercing through the drop into the skin with a slight lifting motion. Puncture tests are performed by placing a drop of extract on the skin and piercing through the drop perpendicular to the skin with a device such as a Prick Lancetter. After about 1 minute the extract may be wiped away with a dry sponge.
Standardized Cat Pelt

Standardized Cat Pelt

3, 16, 17 ,18 1. General Sterile aqueous diluent containing human serum albumin is recommended when preparing dilutions of the concentrate for intradermal testing or immunotherapy. Dilutions should be made accurately and aseptically, using sterile diluent, vials, syringes, etc. Mix thoroughly and gently by rocking or swirling. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. 2. Diagnosis To identify highly sensitive individuals and as a safety precaution, it is recommended that a prick or puncture test using a drop of the extract concentrate be performed prior to initiating intradermal testing. Prick tests are performed by placing a drop of extract on the skin and piercing through the drop into the skin with a slight lifting motion. Puncture tests are performed by placing a drop of extract on the skin and piercing through the drop perpendicular to the skin with a device such as a Prick Lancetter. After about 1 minute the extract may be wiped away with a dry sponge. The diameter of wheal and erythema reactions are measured 15 minutes after the prick or puncture is made, and the sensitivity class of the patient determined by the table presented at the end of the diagnosis section. Less sensitive individuals (Class 0 to 1+) can be tested intradermally with the recommended dilutions of the extract concentrate (see Intradermal Testing). The skin test concentration of 10,000 BAU/mL (10-19.9 Fel d 1 Units/mL) in dropper vials is used for prick or puncture testing. Puncture tests performed on 15 highly sensitive subjects showed the following: Product Mean Sum of Wheal± 1 Std. Dev (mm) Mean Sum of Erythema± Std. Dev. (mm) Standardized Cat Pelt 13.9 ± 4.3 67.3 ± 13.3 The sum of a skin response is the sum of the longest diameter and the midpoint orthogonal diameter. Intradermal endpoint titration (IET) tests were completed using the same 15 subjects to determine the mean concentration required to produce a ∑E of 50mm (D 50). That concentration contained 0.042 BAU/mL (range 0.002 to 0.890 BAU/mL). Intradermal extract should be used as follows: Intradermal Tests should be done only on patients with a negative prick or puncture test. Patients who do not react to a valid prick or puncture test should be tested intradermally with 0.02 to 0.05 mL of a 100 BAU/mL extract solution. If this test is negative, a second intradermal test may be performed using a 1,000 BAU/mL extract solution. If the intradermal dilutions were prepared from glycerinated concentrate, the negative control used with this latter dilution should contain 5% glycerol. Skin tests are graded in terms of the wheal and erythema response noted at 15 minutes. Wheal and erythema size may be recorded by actual measurement of the extent of both responses. Refer to the following table to determine the skin test sensitivity class. The corresponding ∑E (sum of the longest diameter and the mid-point orthogonal diameters of erythema) is also presented. Class WhealDiameter ErythemaDiameter Corresponding ∑E 0 <5 mm <5 mm <10 mm ± 5-10 mm 5-10 mm 10-20 mm 1+ 5-10 mm 11-20 mm 20-40 mm 2+ 5-10 mm 21-30 mm 40-60 mm 3+ 10-15 mma 31-40 mm 60-80 mm 4+ >15 mmb >40 mm >80 mm a. or with pseudopods b. or with many pseudopods 3. Immunotherapy Allergen extracts should be administered using a sterile syringe with 0.01 mL gradations and a 25-27 gauge x 1/2" to 5/8" needle. The injections are given subcutaneously. The most common sites of injection are the lateral aspect of the upper arm or thigh. Intracutaneous or intramuscular injections may produce large local reactions which may be very painful. Dosage of allergenic extracts is a highly individualized matter and varies according to the degree of sensitivity of the patient, his clinical response, and tolerance to the extract administered during the early phases of an injection regimen. The starting dose should be based on skin tests of the extract to be used for immunotherapy. To prepare dilutions for intradermal and therapeutic use, make a 1:10 dilution by adding 1.0 mL of the concentrate to 9.0 mL of sterile aqueous diluent. Subsequent serial dilutions are made in a similar manner. (See Table I.) To determine the starting dose, begin intradermal testing with the most dilute extract preparation. Inject 0.02 mL and read the reaction after 15 minutes. Intradermal testing is continued with increasing concentrations of the extract until a reaction of 10-20 mm erythema (∑E 20-40 mm) and/or a 5 mm wheal occurs. This concentration at a dose of 0.03 mL then can serve as a starting dose for immunotherapy and be increased by 0.03 mL to as high as 0.12 mL increments each time until 0.3 mL is reached, at which time a dilution 10 times as strong can be used, starting with 0.03 mL. Proceed in this way until a tolerance dose is reached or symptoms are controlled. Suggested maintenance dose is 0.2 mL of the concentrate. Occasionally, higher doses are necessary to relieve symptoms. Special caution is required in administering doses greater than 0.2 mL. The interval between doses normally is 3 to 7 days. This is offered as a suggested schedule for average patients and will be satisfactory in most cases. However, the degree of sensitivity varies in many patients. The size of the dose should be adjusted and should be regulated by the patient's tolerance and reaction. The size of the dose should be decreased if the previous injection resulted in marked local or the slightest general reaction. Another dose should never be given until all local reactions resulting from the previous dose have disappeared. In some patients, the dosage may be increased more rapidly than called for in the schedule. In seasonal allergies, treatment should be started and the interval between doses regulated so that at least the first 20 doses will have been administered by the time symptoms are expected. Thus, the shorter the interval between the start of immunotherapy and the expected onset of symptoms, the shorter the interval between each dose. Some patients may even tolerate daily doses. A maintenance dose, the largest dose tolerated by the patient that relieves symptoms without producing undesirable local or general reactions is recommended for most patients. The upper limits of dosage have not been established; however, doses larger than 0.2 mL of the glycerinated concentrate may be painful due to the glycerin content. The dosage of allergenic extract does not vary significantly with the respiratory allergic disease under treatment. The size of this dose and the interval between doses will vary and can be adjusted as necessary. Should symptoms develop before the next injection is scheduled, the interval between doses should be decreased. Should allergic symptoms or local reactions develop shortly after the dose is administered, the size of the dose should be decreased. In seasonal allergies, it is often advisable to decrease the dose to one-half or one-quarter of the maximum dose previously attained if the patient has any seasonal symptoms. The interval between maintenance doses can be increased gradually from one week to 10 days, to two weeks, to three weeks, or even to four weeks if tolerated. Repeat the doses at a given interval three or four times to check for untoward reactions before further increasing the interval. Protection is lost rapidly if the interval between doses is more than four weeks. (See WARNINGS Section.) The usual duration of treatment has not been established. A period of two or three years of injection therapy constitutes an average minimum course of treatment. TABLE 1TEN-FOLD DILUTION SERIESStandardized Extracts Labeled 10,000 BAU/mL Dilution Extract + Diluent = BAU/mLConcentration 0 Concentrate +0 mL = 10,000 1 1 mL concentrate +9 mL = 1,000 2 1 mL dilution #1 +9 mL = 100 3 1 mL dilution #2 +9 mL = 10 4 1 mL dilution #3 +9 mL = 1 5 1 mL dilution #4 +9 mL = 0.1 6 1 mL dilution #5 +9 mL = 0.01 7 1 mL dilution #6 +9 mL = 0.001
(4) PEDIATRIC USE
The dose for the pediatric population is the same as for adults. (See PRECAUTIONS.)
(5) GERIATRIC USE
The dose for elderly patients is the same as for adults patients under 65. 28
Honey Bee Hymenoptera V...

Honey Bee Hymenoptera Venom Multidose

(1) General Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Reconstitute and dilute the freeze-dried venom as directed below. Sterile Albumin Saline with Phenol (0.4%) must be used to reconstitute and dilute the venoms for skin testing and treatment. Reconstitute the freeze-dried venoms by adding 5.5 mL Sterile Albumin Saline with Phenol (0.4%) to the vial using a sterile syringe. Swirl or rock the container to dissolve the venom completely. DO NOT SHAKE, since shaking can cause foaming. Dilutions (see table below) must be made in Sterile Albumin Saline with Phenol (0.4%). They must be made accurately and aseptically, using sterile solution, vials, syringes, etc., and thoroughly mixed by rocking or swirling. DO NOT SHAKE. Maintain stock solutions and dilutions constantly at 2° - 8°C. Extract of Volume Extract Concentration Diluent Volume Dilution Concentration 1 part of 100 µg/mL + 9 parts = 10 µg/mL 1 part of 10 µg/mL + 9 parts = 1 µg/mL 1 part of 1µg/mL + 9 parts = 0.1µg/mL 1 part of 0.1 µg/mL + 9 parts = 0.01 µg/mL 1 part of 0.01 µg/mL + 9 parts = 0.001 µg/mL 1 part of 0.001 µg/mL + 9 parts = 0.0001 µg/mL As an example of the above dilution table: Extract of Volume Extract Concentration Diluent Volume Dilution Concentration 0.2mL of 100 µg/mL + 1.8mL = 10 µg/mL 0.2mL of 10 µg/mL + 1.8mL = 1 µg/mL 0.2mL of 1 µg/mL + 1.8mL = 0.1 µg/mL 0.2mL of 0.1 µg/mL + 1.8mL = 0.01 µg/mL 0.2mL of 0.01 µg/mL + 1.8mL = 0.001 µg/mL 0.2mL of 0.001 µg/mL + 1.8mL = 0.0001 µg/mL NOTE: Mixed Vespid Venom Protein concentrations will be three times that shown above. (2) DiagnosisSince the level of insect venom specific IgE may fall to low levels briefly after a reaction to a sting, patients should not be tested until 2 to 4 weeks after any sting. Skin testing should be carried out with all five individual venoms, since many patients have multiple sensitivities .(4)Mixed Vespid venom protein should be used only for therapy - not for diagnosis. Prick testing should be done before intradermal testing to determine appropriate concentration for intradermal testing. See Intradermal Tests below. Skin testing (prick and intradermal) provides information to assist in identifying those patients who are to be classified as extremely sensitive and who may not tolerate the Suggested Dose Schedule. See DOSAGE AND ADMINISTRATION, Immunotherapy CAUTION. In both the prick and intradermal tests, a negative control test with diluent alone must be performed. A histamine positive control test is recommended. The flexor surface of the forearm is the usual location for skin testing. It is important that a separate sterile syringe and needle be used for each extract and each patient. Prick Tests: Prick tests are accomplished using a solution of 1 µg/mL venom protein, by applying one drop of the 1 µg/mL venom protein solution to the forearm, and by pricking the skin through the surface of the drop with a sterile 27 gauge needle. The prick is superficial and should not draw blood. Skin response should be assessed after approximately 15-20 minutes. For prick tests, a positive reaction (reaction greater than diluent control) at the 1 µg/mL concentration indicates a high level of sensitivity to the test venom. Intradermal Tests: Patients showing a positive reaction to the prick test at the 1 µg/mL concentration should begin intradermal tests at concentrations of not more than 0.0001 to 0.001 µg/mL. Patients with negative prick tests may begin intradermal tests at a concentration of 0.001 µg/mL. A 1 mL tuberculin syringe with a short 27-gauge needle should be used to deliver a volume of 0.05 mL for intradermal testing. Introduce the needle into the superficial skin layers, bevel down, until the bevel is completely buried, then slowly inject a 0.05 mL aliquot of the venom dilution, making a small bleb. Start intradermal tests with the most dilute solution. If after 20 minutes no skin reaction is obtained, continue the intradermal testing using ten-fold increments in the concentration until a reaction of 5-10 mm wheal and 11-20 mm erythema is obtained, or until a concentration of 1 µg/mL has been tested, whichever occurs first. A patient should be considered sensitive to the test venom when a skin response of 5-10 mm wheal and 11-20 mm erythema (or greater) occurs at a concentration of 1 µg/mL or less (8), providing that this reaction is greater than that of the diluent control. (3) Immunotherapy For proper method and route of injection, see WARNINGS, PRECAUTIONS and ADVERSE REACTIONS. The most common site of injection is the lateral aspect of the upper arm. Patients who have multiple venom sensitivities should be given each specific venom injection in a separate site. (Except, if the patient has sensitivities to Yellow Jacket, Yellow Hornet, and White-Faced Hornet venoms concurrently, s/he can be injected with Mixed Vespid venom protein, an equal mixture of these three vespid venoms.) Note which venom preparation is injected at a specific site, so that dosage of that venom preparation can be adjusted if an excessive local reaction occurs. In patients receiving more than one venom, there is theoretically a greater risk of systemic reactions. CAUTION: Sensitivity to venom differs from patient to patient. Thus, it is not possible to provide a dosage schedule suitable for all patients. The Suggested Dose Schedule shown below was used in clinical trials (4) and should be suitable for a majority of patients. IN EXTREMELY SENSITIVE PATIENTS, however, an individualized dose schedule must be employed which will be dictated by the patient's sensitivity. This individualized schedule will probably include weaker dilutions and smaller increments between doses in progressing to the maintenance level (100 µg per venom). In identifying those patients to be classified as extremely sensitive, individuals reacting with significant skin test (wheal greater than 5 mm and erythema greater than 20 mm) at intradermal skin test concentrations of 0.01 µg/mL or less, or those patients experiencing a systemic reaction to any venom skin test concentration, should be considered highly sensitive. Suggested Dose Schedule for a single venom: Dose No. *Volume of 1 µg/mL Dose No. Volume of 10 µg/mL Dose No. Volume of 100 µg/mL 1..... ...0.05 mL 5..... ...0.05 mL 9..... ...0.05mL 2..... ...0.10 mL 6..... ...0.10 mL 10.... ...0.10mL 3..... ...0.20 mL 7..... ...0.20 mL 11.... ...0.20mL 4..... ...0.40 mL 8..... ...0.40 mL 12.... ...0.40mL 13.... ...0.60mL 14.... ...0.80mL 15.... ...1.00mL Mixed Vespid Venom will contain three times the venom protein per mL shown in this table. *See preceding CAUTION Section. In proceeding with the Suggested Dose Schedule, or modified schedules (for highly sensitive patients), it is recommended that injections be given at least once per week, as in the clinical studies. (See CLINICAL PHARMACOLOGY and INDICATIONS AND USAGE.) When building the dose, it is important that dose intervals not exceed one week since longer intervals may decrease the patient's tolerance of the extract. Based on the clinical studies (4), it is suggested that if a systemic, extremely large local (10 cm or more in duration, or other severe local symptoms), or persistent and severe delayed local reaction occurs during the dose building phase, the dose at the next visit should be held constant (or reduced, depending on judgment of the severity of the reaction) as was done at Study Center "A" which reported the least number of systemic reactions during the course of therapy. It must be considered important to achieve the 100 µg per venom maintenance dose (the maintenance dose for Mixed Vespid venom protein is 300µg), since there are no data on effectiveness of maintenance levels below 100 µg per venom. Following the achievement of maintenance level (100 µg per venom), it is recommended that a second maintenance injection be given at a 1-week interval, and a third maintenance injection at a 2-week interval. Administer the next injection at a 3-week interval, and then monthly for ongoing maintenance. See CLINICAL PHARMACOLOGY and INDICATIONS AND USAGE for further information regarding clinical studies on which the above recommendations are based. The optimum duration for immunotherapy is not known, so current recommendations are that maintenance injections be continued indefinitely, year around, particularly in patients experiencing life-threatening anaphylaxis after insect stings.
4. PEDIATRIC USE

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

5. GERIATRIC USE

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

Animal Allergens

1. General Parenteral Drug Products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

2. Scratch, Prick or Puncture Testing Methods There are two general methods of skin testing. (1) The skin is scarified first, and the extract is then applied. (2) A drop of extract is put onto the skin, and a prick or puncture is made through the drop. Avoid touching tip of dropper to skin. Either method is satisfactory, but the second requires that the instrument be cleansed between tests or that separate needles be used.

The extracts for scratch, prick or puncture testing are supplied in dropper vials and should be kept in a rack or box in rows of 10 vials corresponding to the rows of tests to be applied to the skin.

All skin tests should be validated by appropriate positive control tests (e.g., histamine) and negative control tests (e.g., Glycerin, Albumin Saline with Phenol (0.4%), or Buffered Saline with Phenol). The negative control test should be the same material as is used as a diluting fluid in the tested extracts. Diluting fluid is used in the same way as an active test extract.

Test sites should be examined at 15 and 30 minutes. To prevent excessive absorption, wipe off antigens producing large reactions as soon as the wheal appears. Record the size of the reaction. Delayed reactions may rarely occur from tests, so it may be helpful to examine the test sites in 24 hours.

Use of Scarifiers and Spacing. Make scarifications at least 2.5 cm apart. Use more space between pollen tests to prevent smearing into adjacent sites. Hold the scarifier between the thumb and index finger, press the sharp edge of the instrument against the skin and twirl instrument rapidly. The scratch should disrupt only the outer layers of epidermis but should not produce immediate oozing of blood. The amount of pressure needed to produce a satisfactory scratch will vary between patients according to the thickness or fragility of their skin. Experience will indicate the proper amount of pressure to exert in making the scratch. If the scarifier is kept sharp and the scratch made quickly, discomfort to the patient is minimized.

Use of Prick Test Needles. The skin is cleaned and single drops of each extract applied to the properly identified test sites. A small, sterile disposable needle, such as a 1/2-inch 26 gauge needle (with the bevel up), a bifurcated vaccinating needle, or a Prick Lancetter™ is inserted through the drop superficially into the skin, the skin lifted slightly and the needle withdrawn. No bleeding should be produced. After about 1 minute the extract may be wiped away.

3. Most Satisfactory Sites for Testing Prior to testing, clean the skin area to be tested with ether or alcohol and allow to dry. Use a sterile instrument for each patient. The back or the volar surface of the arms are the most satisfactory sites for testing. Skin of the posterior thighs or abdomen may be used if necessary. Avoid very hairy areas where possible, since the reactions will be smaller and more difficult to interpret. The most satisfactory areas of the back 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 of the arms are the volar surfaces from the axilla to 2.5 or 5 cm above the wrist, skipping the anti-cubital space.

4. Use of Antigen Mixes The use of complicated mixes of unrelated pollens for testing is not recommended since in the case of a positive reaction, it does not indicate which pollen(s) are responsible, and, in the case of a negative reaction, it fails to indicate whether the individual pollens at full concentration would give a positive reaction.

5. Reading Skin Test Reactions A positive reaction consists of an urticarial wheal with surrounding erythema (resembling somewhat a mosquito bite reaction) larger than the control site. The smallest reaction considered positive is erythema with a central papule at least 5 mm in diameter. In some instances with no reaction at the control site, erythema may be considered an indication of sensitivity. In general, the size of wheal and erythema response correlates directly with the patient’s sensitivity to that allergen.

Standardized Products (a) Mites: The skin test concentration of 30,000 AU/mL in dropper vials is used for scratch, prick or puncture testing. Puncture tests performed on 12 highly sensitive subjects showed the following:
Species Mean Sum of Wheal± Std. Dev. (mm) Mean Sum of Erythema± Std. Dev. (mm) D. farinae 22.4 ± 10.7 82.2 ± 21.7 D. pteronyssinus 24.0 ± 9.9 89.3 ± 24.5
The sum of a skin response is the sum of the longest diameter and the mid-point orthogonal diameter.

(b) Cat Hair and Cat Pelt: The skin test concentration of 10,000 BAU/mL (10-19.9 Fel d 1 Units/mL) in dropper vials is used for prick or puncture testing. Puncture tests performed on 15 highly sensitive subjects showed the following:
Product Mean Sum of Wheal± Std. Dev (mm) Mean Sum of Erythema± Std. Dev (mm) Standardized Cat Hair 15.1 ± 3.8 73.3 ± 14.3 StandardizedCat Pelt 13.9 ± 4.3 67.3 ± 13.3
The sum of a skin response is the sum of the longest diameter and the mid-point orthogonal diameter.

(c) Ragweed pollen (Short Ragweed or Giant and Short Ragweed Mixture) Antigen E Assayed: Short Ragweed extract at 1:20 w/v in 50% glycerin containing approximately 100 to 300 units of Antigen E/mL or Giant and Short Ragweed Mix at 1:20 w/v in 50% glycerin containing approximately 50 to 150 units of Antigen E/mL are usually used for scratch, prick or puncture testing. Refer to the following table to determine the skin test sensitivity grade. The corresponding ∑E (sum of the longest diameter and the mid-point orthogonal diameters of erythema) is also presented.
Grade Erythemamm Papule or Whealmm Correspondingmm ∑E 0 <5 <5 <10 ± 5-10 5-10 10-20 1+ 11-20 5-10 20-40 2+ 21-30 5-10 40-60 3+ 31-40 10-15 (a) 60-80 4+ >40 >15 (b) >80 (a) or with pseudopods (b) or with many pseudopods
A positive skin reaction to any allergen must be interpreted in light of the patient’s history of symptoms, time of the year, known exposures, and eating habits. THE SKIN TESTS ARE IN NO WAY A SUBSTITUTE FOR A CAREFUL ALLERGIC HISTORY. THEY SERVE AS ADDITIONAL INFORMATION TO AID IN IDENTIFYING CAUSATIVE ALLERGENS IN PATIENTS WITH ALLERGIC DISORDERS.

6. Geriatric Use

The dose is the same in patients of all age groups. Because the wheal size in response to allergen skin testing decreases with age, appropriate histamine positive control skin tests must be performed.1

7. Pediatric Use

The dose is the same in patients of all age groups. Wheal size in response to allergen skin testing can be smaller in infants than in adults. Appropriate histamine positive control skin tests must be performed.1
Standardized Mite Mix

Standardized Mite Mix

1. General Sterile aqueous diluent containing human serum albumin [Albumin Saline with Phenol (0.4%)] or diluent of 50% glycerin may be used when preparing dilutions of the concentrate for immunotherapy. For intradermal testing dilutions, Albumin Saline with Phenol is recommended. Dilutions should be made accurately and aseptically, using sterile diluent, vials, syringes, etc. Mix thoroughly and gently by rocking or swirling. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. 2. Diagnosis To identify highly sensitive individuals and as a safety precaution, it is recommended that a scratch, prick or puncture test using a drop of the extract concentrate be performed prior to initiating intradermal testing. Prick tests are performed by placing a drop of extract on the skin and piercing through the drop into the skin with a slight lifting motion. 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 Prick Lancetter. Fifteen minutes after puncture is made the diameter of wheal and erythema reactions are measured, and the sensitivity class of the patient determined by the table presented at end of Diagnosis Section. Less sensitive individuals (Class 0 to 1+) can be tested intradermally with the recommended dilutions of the extract concentrate (See intradermal testing instructions). The skin test concentration of 30,000 AU/mL in dropper vials is used for scratch, prick or puncture testing. Puncture tests performed on 12 selected highly sensitive subjects showed the following: Species Mean ∑ Wheal± Std/ Dev (mm) Mean ∑ Erythema ± Std. Dev (mm) D. farinae 22.4 ± 10.7 82.3 ± 21.7 D. pteronyssinus 24.0 ± 9.9 89.3 ± 24.5 ∑ equals the sum of the longest diameter and the mid-point orthogonal diameter. Extract for intradermal testing should be prepared by diluting the 30,000 AU/mL stock concentrate, provided in multiple-dose vials, with sterile aqueous diluent (refer to the dilution table displayed in the immunotherapy section below). To administer the intradermal strength dilutions, a 1 mL tuberculin syringe with a short 27-gauge needle should be used. The needle is inserted intradermally at a 30° angle, bevel down, and 0.02 to 0.05 mL of the extract is injected. Fifteen minutes following injection, the diameter of wheal and erythema reactions are measured, and the patient's sensitivity class is determined by the table on the following page. Intradermal skin test results in selected highly sensitive subjects are presented for reference purposes: Allergen Number of Persons Mean AU/mL that Elicited∑E = 50mm2 Std. Dev Range D. farinae 12 0.0609 0.0015 - 2.6016 D. pteronyssinus 12 0.0333 0.0003 - 4.0077 Intradermal extract should be used as follows: a. Patients with a negative scratch, prick or puncture test: Patients who do not react to a valid scratch, prick or puncture test should be tested intradermally with 0.02 to 0.05 mL of a 30 AU/mL extract solution. If this test is negative, a second intradermal test may be performed using a 300 AU/mL extract solution. The negative control used with this latter dilution should contain 0.5% glycerin. b. Patients tested only by the intradermal method: Patients suspected of being highly allergic should be tested with 0.02 to 0.05 mL of a solution containing 0.03 AU/mL. A negative test should be followed by repeat tests using progressively stronger concentrations until the maximum recommended strength of 300 AU/mL is reached. The negative control used with this latter dilution should contain 0.5% glycerin. Skin tests are graded in terms of the wheal and erythema response noted at 10 to 20 minutes. Wheal and erythema size may be recorded by actual measurement of the extent of both responses. Refer to the following table to determine the skin test sensitivity class. The corresponding ∑E(sum of the longest diameter and the mid-point orthogonal diameters of erythema) is also presented. Class Wheal Diameter Erythema Diameter Corresponding ∑E 0 <5mm <5mm <10mm ± 5-10mm 5-10mm 10-20mm 1+ 5-10mm 11-20mm 20-40mm 2+ 5-10mm 21-30mm 40-60mm 3+ 10-15mma 31-40mm 60-80mm 4+ >15mmb >40mm >80mm a. or with pseudopods b. or with many pseudopods 3. Immunotherapy Allergen extracts should be administered using a sterile syringe with 0.01 mL gradations and a 25-27 gauge x 1/2"to 5/8" needle. The injections are given subcutaneously. The most common sites of injection are the lateral aspect of the upper arm or thigh. Intracutaneous or intramuscular injections may produce large local reactions which may be very painful. Dosage of allergenic extracts is a highly individualized matter and varies according to the degree of sensitivity of the patient, his clinical response, and tolerance to the extract administered during the early phases of an injection regimen. The starting dose should be based on skin tests of the extract to be used for immunotherapy. To prepare dilutions for intradermal and therapeutic use, make a 1:10 dilution by adding 1.0 mL of the concentrate to 9.0 mL of Sterile Albumin Saline with Phenol (0.4%). Subsequent serial dilutions are made in a similar manner. (See Table I.) To determine the starting dose, begin intradermal testing with the most dilute extract preparation. Inject 0.02 mL and read the reaction after 15 minutes. Intradermal testing is continued with increasing concentrations of the extract until a reaction of 11-20 mm erythema (∑E20-40 mm) and/or a 5 mm wheal occurs. This concentration at a dose of 0.03 mL then can serve as a starting dose for immunotherapy and be increased by 0.03 mL to as high as 0.12 mL increments each time, until 0.3 mL is reached. At this time, a dilution 10 times as strong can be used, starting with 0.03 mL. Proceed in this way until a tolerance dose is reached or symptoms are controlled. Suggested maintenance dose is 0.2 mL of the concentrate. Occasionally, higher doses are necessary to relieve symptoms. Special caution is required in administering doses greater than 0.2 mL. The interval between doses normally is 3 to 7 days. This is offered as a suggested schedule for average patients and will be satisfactory in most cases. However, the degree of sensitivity varies in many patients. The size of the dose should be adjusted and should be regulated by the patient's tolerance and reaction. The size of the dose should be decreased if the previous injection resulted in marked local or the slightest general reaction. Another dose should never be given until all local reactions resulting from the previous dose have disappeared. In some patients, the dosage may be increased more rapidly than called for in the schedule. In seasonal allergies, treatment should be started and the interval between doses regulated, so that at least the first twenty doses will have been administered by the time symptoms are expected. Thus, the shorter the interval between the start of immunotherapy and the expected onset of symptoms, the shorter the interval between each dose. Some patients may even tolerate daily doses. A maintenance dose, the largest dose tolerated by the patient that relieves symptoms without producing undesirable local or general reactions, is recommended for most patients. The upper limits of dosage have not been established; however, doses larger than 0.2 mL of the glycerin concentrate may be painful due to the glycerin content. The dosage of the allergenic extract does not vary significantly with the respiratory allergic disease under treatment. The size of this dose and the interval between doses will vary and can be adjusted as necessary. Should symptoms develop before the next injection is scheduled, the interval between doses should be decreased. Should allergic symptoms or local reactions develop shortly after the dose is administered, the size of the dose should be decreased. In seasonal allergies, it is often advisable to decrease the dose to one-half or one-quarter of the maximum dose previously attained if the patient has any seasonal symptoms. The interval between maintenance doses can be increased gradually from one week to 10 days, to two weeks, to three weeks, or even to four weeks if tolerated. Repeat the doses at a given interval three or four times to check for untoward reactions before further increasing the interval. Protection is lost rapidly if the interval between doses is more than four weeks. (See WARNINGS Section.) The usual duration of treatment has not been established. A period of two or three years of injection therapy constitutes an average minimum course of treatment. TABLE 1TEN-FOLD DILUTION SERIESStandardized Extracts Labeled 30,000 AU/mL Dilution Extract +Diluent = AU/mLConcentration 0 Concentrate +0 mL = 30,000 1 1 mL Concentrate +9 mL = 3,000 2 1 mL dilution #1 +9 mL = 300 3 1mL dilution #2 +9 mL = 30 4 1 mL dilution #3 +9 mL = 3 5 1 mL dilution #4 +9 mL = 0.3 6 1 mL dilution #5 +9 mL = 0.03 7 1 mL dilution #6 +9 mL = 0.003
4. Pediatric Use

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

5. Geriatric Use

The dose for elderly patients is the same as for adult patients under 65.29
Honey Bee Hymenoptera V...

Honey Bee Hymenoptera Venom Venomil Diagnostic Kit Honey Bee Hymenoptera Venom Venomil Maintenance Kit White Faced Hornet Hymenoptera Venom Venomil Diagnostic Kit White Faced Hornet Hymenoptera Venom Venomil Maintenance Kit Yellow Hornet Hymenoptera Venom Venomil Diagnostic Kit Yellow Hornet Hymenoptera Venom Venomil Maintenance Kit Wasp Hymenoptera Venom Venomil Diagnostic Kit Wasp Hymenoptera Venom Venomil Maintenance Kit Yellow Jacket Hymenoptera Venom Venomil Diagnostic Kit Yellow Jacket Hymenoptera Venom Venomil Maintenance Kit Mixed Vespid Hymenoptera Venom Venomil Maintenance Kit

(1) General Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Reconstitute and dilute the freeze-dried venom as directed below. Sterile Albumin Saline with Phenol (0.4%) must be used to reconstitute and dilute the venoms for skin testing and treatment.Reconstitute the freeze-dried venoms by adding 1.2 mL Sterile Albumin Saline with Phenol (0.4%) to the vial using a sterile syringe. Swirl or rock the container to dissolve the venom completely. DO NOT SHAKE, since shaking can cause foaming. Dilutions (see table below) must be made in Sterile Albumin Saline with Phenol (0.4%). They must be made accurately and aseptically, using sterile solutions, vials, syringes, etc., and thoroughly mixed by rocking or swirling. DO NOT SHAKE. Maintain stock solutions and dilutions constantly at 2° - 8°C.
Extract of Volume Extract Concentration Diluent Volume Dilution Concentration 1 part of 100 µg/mL + 9 parts = 10 µg/mL 1 part of 10 µg/mL + 9 parts = 1 µg/mL 1 part of 1µg/mL + 9 parts = 0.1µg/mL 1 part of 0.1 µg/mL + 9 parts = 0.01 µg/mL 1 part of 0.01 µg/mL + 9 parts = 0.001 µg/mL 1 part of 0.001 µg/mL + 9 parts = 0.0001 µg/mL As an example of the above dilution table: Extract of Volume Extract Concentration Diluent Volume Dilution Concentration 0.2mL of 100 µg/mL + 1.8mL = 10 µg/mL 0.2mL of 10 µg/mL + 1.8mL = 1 µg/mL 0.2mL of 1 µg/mL + 1.8mL = 0.1 µg/mL 0.2mL of 0.1 µg/mL + 1.8mL = 0.01 µg/mL 0.2mL of 0.01 µg/mL + 1.8mL = 0.001 µg/mL 0.2mL of 0.001 µg/mL + 1.8mL = 0.0001 µg/mL NOTE: Mixed Vespid Venom Protein concentrations will be three times that shown above. USE OF VENOMIL DIAGNOSTIC SETS The Venomil Diagnostic Sets from Jubilant HollisterStier contain a vial of freeze dried venom protein that when reconstituted as instructed below will contain 100 µg venom or venom protein/mL. To use the Venomil Diagnostic set, follow these steps: 1. Open box and remove contents. Be sure to read the complete package Instruction Sheet paying particular attention to the WARNINGS, PRECAUTIONS, CONTRAINDICATIONS, and ADVERSE REACTIONS. 2. Remove the freeze-dried venom vial and one of the seven vials of diluent from the kit. Withdraw 1.3 mL of Albumin Saline with Phenol (0.4%) from the diluent vial using a 2 or 3 mL disposable syringe. Expel some Albumin Saline with Phenol (0.4%) from the syringe until exactly 1.2 mL are remaining in the syringe. The remaining Albumin Saline with Phenol (0.4%) in the diluent vial may be marked "Control" and used as a negative control for prick testing. 3. Insert the needle of the diluent syringe into the vial of venom and expel the diluent. Remove the syringe. Swirl or rock the vial to dissolve the venom completely. DO NOT SHAKE. Shaking can cause foaming of the extract. At this point, you have completed the reconstitution of the freeze-dried venom. The reconstituted products contain 100 µg of venom or venom protein per mL. DO NOT USE THIS STRENGTH FOR INTRADERMAL SKIN TESTING. DISCARD AFTER THE DILUTIONS HAVE BEEN PREPARED. 4. Remove six vial labels from the kit and mark them: 10 µg/mL, 1 µg/mL, 0.1 µg/mL, 0.01 µg/mL, 0.001 µg/mL and 0.0001 µg/mL. Withdraw 0.2 mL of venom extract in a 1 mL syringe from the vial reconstituted in step #3. Insert the syringe needle into one vial of 1.8 mL Albumin Saline with Phenol (0.4%). Slowly expel the 0.2 mL venom into it. Swirl or rock to mix, and label 10 µg/mL. 5. Withdraw 0.2 mL of the 10 µg/mL venom extract and inject into another vial of 1.8 mL Albumin Saline with Phenol (0.4%). Mix and label 1 µg/mL. 6. The four additional dilutions should be prepared in the same manner. (2) Diagnosis Since the level of insect venom specific IgE may fall to low levels briefly after a reaction to a sting, patients should not be tested until 2 to 4 weeks after any sting. Skin testing should be carried out with all five individual venoms, since many patients have multiple sensitivities. (4) Mixed Vespid venom protein should be used only for therapy - not for diagnosis. Prick testing should be done before intradermal testing to determine appropriate concentration for intradermal testing. See Intradermal Tests. Skin testing (prick and intradermal) provides information to assist in identifying those patients who are to be classified as extremely sensitive and who may not tolerate the Suggested Dose Schedule. See DOSAGE AND ADMINISTRATION, Immunotherapy CAUTION. In both the prick and intradermal tests, a negative control test with diluent alone must be performed. A histamine positive control test is also recommended. The flexor surface of the forearm is the usual location for skin testing. It is important that a separate sterile syringe and needle be used for each extract and each patient. Prick Tests: Prick tests are accomplished by applying one drop of the 1 µg/mL venom extract to the forearm, and by pricking the skin through the surface of the drop with a sterile 27 gauge needle. The prick is superficial and should not draw blood. Skin response should be assessed after approximately 15-20 minutes. For prick tests, a positive reaction (reaction greater than diluent control) at the 1 µg/mL concentration indicates a high level of sensitivity to the test venom. Intradermal Tests: Patients showing a positive reaction to the prick test at the 1 µg/mL concentration should begin intradermal tests at concentrations of not more than 0.0001 to 0.001 µg/mL. Patients with negative prick tests may begin intradermal tests at a concentration of 0.001 µg/mL. A 1 mL tuberculin syringe with a short 27-gauge needle should be used to deliver a volume of 0.05 mL for intradermal testing. Introduce the needle into the superficial skin layers, bevel down, until the bevel is completely buried, then slowly inject a 0.05 mL aliquot of the venom dilution, making a small bleb. Start intradermal tests with the most dilute solution. If after 20 minutes no skin reaction is obtained, continue the intradermal testing using ten-fold increments in the concentration until a reaction of 5-10 mm wheal and 11-20 mm erythema is obtained, or until a concentration of 1 µg/mL has been tested, whichever occurs first. A patient should be considered sensitive to the test venom when a skin response of 5-10 mm wheal and 11-20 mm erythema (or greater) occurs at a concentration of 1 µg/mL or less, (8)providing that this reaction is greater than that of the diluent control. (3) Immunotherapy For proper method and route of injection, see WARNINGS, PRECAUTIONS and ADVERSE REACTIONS. The most common site of injection is the lateral aspect of the upper arm. Patients who have multiple venom sensitivities should be given each specific venom injection in a separate site. (Except, if the patient has sensitivities to Yellow Jacket, Yellow Hornet, and White-Faced Hornet venoms concurrently, s/he can be injected with Mixed Vespid venom protein, an equal mixture of these three vespid venoms). Note which venom preparation is injected at a specific site, so that dosage of that venom preparation can be adjusted if an excessive local reaction occurs. In patients receiving more than one venom, there is theoretically a greater risk of systemic reactions. CAUTION: Sensitivity to venom differs from patient to patient. Thus, it is not possible to provide a dosage schedule suitable for all patients. The Suggested Dose Schedule shown below was used in clinical trials (4)and should be suitable for a majority of patients. IN EXTREMELY SENSITIVE PATIENTS, however, an individualized dose schedule must be employed which will be dictated by the patient's sensitivity. This individualized schedule will probably include weaker dilutions and smaller increments between doses in progressing to the maintenance level (100 µg per venom). In identifying those patients to be classified as extremely sensitive, individuals reacting with significant skin test (wheal greater than 5 mm and erythema greater than 20 mm) at intradermal skin test concentrations of 0.01 µg/mL or less, or those patients experiencing a systemic reaction to any venom skin test concentration, should be considered highly sensitive. Suggested Dose Schedule for a Single Venom: Dose No. *Volume of 1 µg/mL Dose No. Volume of 10 µg/mL Dose No. Volume of 100 µg/mL 1..... ...0.05 mL 5..... ...0.05 mL 9..... ...0.05mL 2..... ...0.10 mL 6..... ...0.10 mL 10.... ...0.10mL 3..... ...0.20 mL 7..... ...0.20 mL 11.... ...0.20mL 4..... ...0.40 mL 8..... ...0.40 mL 12.... ...0.40mL 13.... ...0.60mL 14.... ...0.80mL 15.... ...1.00mL Mixed Vespid Venom will contain three times the venom protein per mL shown in this table. *See preceding CAUTION Section. ALTERNATE MAINTENANCE DOSE SCHEDULE If the above suggested dosage schedule has been followed, Dose #15 will have emptied the third vial of venom. There should now be three vials of freeze-dried venom remaining in the maintenance set. If a smaller volume maintenance dose is desired, then the remaining vials of venom may be reconstituted with 0.6 mL of Sterile Albumin Saline with Phenol (0.4%) instead of the previously recommended 1.2 mL. When 0.6 mL is used for reconstitution, the maintenance dose volume then becomes 0.5 mL instead of 1.0 mL. The 0.5 mL injection will still contain 100 micrograms of venom or venom protein. Precautions should be taken to ensure that maintenance level injections of 0.5 mL are given only from those vials of venom that have been reconstituted with 0.6 mL of diluting fluid. Any other volume used for reconstitution will not give 100 micrograms of venom or venom protein at a dosage of 0.5 mL In proceeding with the Suggested Dose Schedule, or modified schedules (for highly sensitive patients) it is recommended that injections be given at least once per week, as in the clinical studies. (See CLINICAL PHARMACOLOGY and INDICATIONS AND USAGE). When building the dose, it is important that dose intervals not exceed one week since longer intervals may decrease the patient's tolerance of the extract. Based on the clinical studies (4)it is suggested that if a systemic, extremely large local (10 cm or more in duration, or other severe local symptoms), or persistent and severe delayed local reaction occurs during the dose building phase, the dose at the next visit be held constant (or reduced, depending on judgment of the severity of the reaction) as was done at Study Center "A," which reported the least number of systemic reactions during the course of therapy. It must be considered important to achieve the 100 µg per venom maintenance dose (the maintenance dose for Mixed Vespid venom protein is 300 µg), since there are no data on effectiveness of maintenance levels below 100 µg per venom. Following the achievement of maintenance level (100 µg per venom), it is recommended that a second maintenance injection be given at a 1-week interval, and a third maintenance injection at a 2-week interval. Administer the next injection at a 3-week interval, and then monthly for ongoing maintenance. See CLINICAL PHARMACOLOGY and INDICATIONS AND USAGE for further information regarding clinical studies on which the above recommendations are based. The optimum duration for immunotherapy is not known, so current recommendations are that maintenance injections be continued indefinitely, year around, particularly in patients experiencing life-threatening anaphylaxis after insect stings.
PEDIATRIC USE

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

GERIATRIC USE

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

Animal Allergens

1. General Parenteral Drug Products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. 2. Intradermal Testing Methods Cleanse the rubber stopper of the vial with liquid antiseptic before withdrawing extract. A sterile tuberculin syringe with 26-gauge, short-bevel needle should be used for the injection. The anterior surface of the upper and lower arm is preferable for testing. Cleanse the skin with soap and water or wash with alcohol or other antiseptic. Introduce the needle between the superficial layers of the skin and inject 0.02 mL of the extract. Test sites should be at least 2.5 cm apart, and no more than 10 to 20 antigens should be introduced at one time. This group can be followed with additional groups of 10, providing the reactions are not numerous or strong. The same amount of extract should be injected in each site for proper comparison. It is advisable to avoid testing with more than one allergen in the same group in each series, i.e., nuts, fish, epidermals, etc. A site should be injected with 0.02 mL of the control solution. All skin tests should be validated by appropriate positive control tests (e.g., histamine) and negative control tests [e.g., Glycerin, Albumin Saline with Phenol (0.4%), or Buffered Saline with Phenol (0.4%)]. The negative control test should be the same material as is used as a diluting fluid in the tested extracts. Diluting fluid is used in the same way as an active test extract. False positive reactions are sometimes encountered in intradermal testing, and the possibility of irritation reactions should always be taken into consideration. In cases where the patient is known to be quite sensitive, screen testing by scratch, prick or puncture method is recommended, and intradermal testing should be done with caution. The intradermal strength supplied is usually safe for testing patients presenting negative scratch, prick or puncture test reactions. It is recommended that a 1:10 dilution of the stock intradermal strength be used in preliminary testing of patients not previously screened by scratch, prick or puncture tests. 3. Use of Antigen Mixes The use of complicated mixes of unrelated pollens for testing is not recommended since in the case of a positive reaction it does not indicate which pollen(s) are responsible, and in the case of a negative reaction, it fails to indicate whether the individual pollens at full concentration would give a positive reaction. 4. Reading Skin Test Reactions A positive reaction consists of an urticarial wheal with surrounding erythema (resembling somewhat a mosquito bite reaction) larger than the control site. The smallest reaction considered positive is erythema with a central papule at least 5 mm in diameter. In some instances with no reaction at the control site, erythema may be considered an indication of sensitivity. In general, the size of wheal and erythema response correlates directly with the patient's sensitivity to that allergen. Standardized Products (a) Mites: The skin test concentrations of 30 AU/mL and 300 AU/mL in multiple dose vials are used for intradermal testing. Intradermal skin test results in selected highly sensitive subjects are presented for reference purposes: AU/mL that Elicited ∑E = 50 mm Allergen Number ofPersons Mean 2 Std. Dev. Range D. farinae 12 0.0609 0.0015-2.6016 D. pteronyssinus 12 0.333 0.0003-4.0077 Intradermal extracts should be used as follows: (1) Patients with a negative scratch, prick or puncture test: Patients who do not react to a valid scratch, prick or puncture test should be tested intradermally with 0.02 to 0.05 mL of a 30 AU/mL extract solution. If this test is negative, a second intradermal test may be performed using a 300 AU/mL extract solution. The negative control used with this latter dilution should contain 0.5% glycerin. (2) Patients tested only by the intradermal method: Patients suspected of being highly allergic should be tested with 0.02 to 0.05 mL of a solution containing 0.03 AU/mL. A negative test should be followed by repeat tests using progressively stronger concentrations until the maximum recommended strength of 300 AU/mL is reached. The negative control used with this latter dilution should contain 0.5% glycerin. (b) Cat Hair and Cat Pelt: Intradermal endpoint titration (IET) tests were completed with Cat Pelt extract using 15 subjects to determine the mean concentration required to produce a ∑E of 50 (D 50) mm.That concentration contained 0.042 BAU/mL (range 0.002 to 0.890 BAU/mL). IET tests were completed with Cat Hair extract using 15 subjects to determine the mean concentration required to produce a ∑E of 50 mm (D 50). That concentration contained 0.049 BAU/mL (range 0.006 to 0.661 BAU/mL). Intradermal extract should be used as follows: Intradermal Tests should be done only on patients with a negative prick or puncture test. Patients who do not react to a valid prick or puncture test should be tested intradermally with 0.02 to 0.05 mL of a 100 BAU/mL extract solution. If this test is negative, a second intradermal test may be performed using a 1,000 BAU/mL extract solution. If the intradermal dilutions were prepared from glycerinated concentrate, the negative control used with this latter dilution should contain 5% glycerin. Standardized Cat Hair and Cat Pelt products are not interchangeable with each other or any other cat products including those labeled AU/mL. (c) Ragweed pollen (Short Ragweed or Giant and Short Ragweed Mixture) Antigen E Assayed: The intradermal strength for Short Ragweed extract is usually 500 PNU, which by calculation contains approximately 0.7 to 3 units of Antigen E/mL. For Giant and Short Ragweed mix the suggested intradermal strength is 500 PNU, which by calculation contains 0.4 to 1.5 units of Antigen E/mL. These strengths are usually safe for testing patients previously having negative scratch, prick or puncture test reactions. A 1:10 dilution of the stock intradermal strength should be used in preliminary testing of patients not previously screened by scratch, prick, or puncture tests. A study of ragweed sensitive patients9 indicates that intradermal tests, using 0.05 mL of extract, produce positive reactions (1+ to 2+) at Antigen E concentrations of from 2.7x10 -1 to 2.7x10 -6 units per mL. The equivalent PNU range was 100 to 0.001 PNU per mL. Skin tests are graded in terms of the wheal and erythema response noted at 15 minutes. Wheal and erythema size may be recorded by actual measurement of the extent of both responses.
5. Geriatric Use

The dose is the same in patients of all age groups. Because the wheal size in response to allergen skin testing decreases with age, appropriate histamine positive control skin tests must be performed.1

6. Pediatric Use

The dose is the same in patients of all age groups. Wheal size in response to allergen skin testing can be smaller in infants than in adults. Appropriate histamine positive control skin tests must be performed.1

Refer to the following table to determine the skin test sensitivity grade. The corresponding ∑E (sum of the longest diameter and the mid-point orthogonal diameters of erythema) is also presented.
Grade Erythemamm Papule or Whealmm Corespondingmm ∑E 0 <5 <5 <10 ± 5-10 5-10 10-20 1+ 11-20 5-10 20-40 2+ 21-30 5-10 40-60 3+ 31-40 10-15 (a) 60-80 4+ >40 >15 (b) > 80
a or with pseudopods

b or with many pseudopods

A positive skin reaction to any allergen must be interpreted in light of the patient’s history of symptoms, time of year, known exposures, and eating habits. THE SKIN TESTS ARE IN NO WAY A SUBSTITUTE FOR A CAREFUL ALLERGENIC HISTORY; RATHER, THEY SERVE AS ADDITIONAL INFORMATION TO AID IN IDENTIFYING CAUSATIVE ALLERGENS IN PATIENTS WITH ALLERGIC DISORDERS.
Standardized Grass Poll...

Standardized Grass Pollen

1. General Sterile aqueous diluent containing albumin (human) [Albumin Saline with Phenol (0.4%)] or diluent of 50% glycerin may be used when preparing dilutions of the concentrate for immunotherapy. For intradermal testing dilutions, Albumin Saline with Phenol (0.4%) is recommended.Dilutions should be made accurately and aseptically, using sterile diluent, vials, syringes, etc. Mix thoroughly and gently by rocking or swirling.Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

2. Diagnosis Prick or Puncture Test: To identify highly sensitive individuals and as a safety precaution, it is recommended that a prick or puncture test using a drop of 10,000 BAU/mL extract be performed prior to initiating intradermal testing. If this test is negative, a second prick/puncture test may be performed using a 100,000 BAU/mL extract. Prick tests are performed by placing a drop of extract on the skin and piercing through the drop into the skin with a slight lifting motion. Puncture tests are performed by placing a drop of extract concentrate on the skin and piercing the skin through the drop with a small needle such as a Prick Lancetter. Fifteen minutes after puncture is made the diameter of wheal and erythema reactions are measured, and the sensitivity class of the patient determined by Table 3. Less sensitive individuals (Class 0 to 1+) can be tested intradermally with the recommended dilutions of the extract concentrate (See intradermal testing instructions). Intradermal Test: Patients with a negative prick or puncture test should be tested intradermally with 100 BAU/mL. If this test is negative, a second intradermal test may be performed using a 1,000 BAU/mL extract. The negative control should have glycerin concentration equivalent to the glycerin concentration of the intradermal test solution, not to exceed 5% glycerin. It is recommended that patients be tested using the intradermal technique only after screening by prick or puncture test. Extract for intradermal testing should be prepared by diluting the stock concentrate, provided in multiple-dose vials, with Sterile Albumin Saline with Phenol (0.4%) (refer to Table 4 in the Immunotherapy section below). To administer the intradermal strength dilutions, a 1 mL tuberculin syringe with a short 27-gauge needle should be used. The needle is inserted intradermally at a 30° angle, bevel down, and 0.02 to 0.05 mL of the extract is injected. Fifteen minutes following injection, the diameter of wheal and erythema reactions are measured, and the patient's sensitivity class is determined by the table below. Skin tests are graded in terms of the wheal and erythema response noted at 10 to 20 minutes. Wheal and erythema size may be recorded by actual measurement of the extent of both responses. Refer to Table 3 to determine the skin test sensitivity class. The corresponding ∑E (sum of the longest diameter and the mid-point orthogonal diameters of erythema) is also presented.
TABLE 3 Classification of Skin Test Sensitivity for Intradermal and Pick or Puncture Class Wheal Diameter Erythema Diameter Corresponding ∑E 0 < 5 mm <5 mm <10 mm ± 5-10 mm 5-10 mm 10-20 mm 1+ 5-10 mm 11-20 mm 20-40 mm 2+ 5-10 mm 21-30 mm 40-60 mm 3+ 10-15 mm a 31-40 mm 60-80 mm 4+ >15 mm b >40 mm >80 mm a. or with pseudopods b. or with many pseudopods
3. Immunotherapy Allergenic extracts should be administered using a sterile syringe with 0.01 mL gradations and a 25-27 gauge X 1/2" to 5/8" needle. The injections are given subcutaneously. The most common sites of injection are the lateral aspect of the upper arm or thigh. Intracutaneous or intramuscular injections may produce large local reactions which may be very painful. Dosage of allergenic extracts is a highly individualized matter and varies according to the degree of sensitivity of the patient, his clinical response, and tolerance to the extract administered during the early phases of an injection regimen. The starting dose should be based on skin tests of the extract to be used for immunotherapy. To prepare dilutions for intradermal and therapeutic use, make a 1:10 dilution by adding 1.0 mL of the concentrate to 9.0 mL of Sterile Albumin Saline with Phenol (0.4%). Subsequent serial dilutions are made in a similar manner. (See Table 4.) To determine the starting dose, begin intradermal testing with the most dilute extract preparation. Inject 0.02 mL and read the reaction after 15 minutes. Intradermal testing is continued with increasing concentrations of the extract until a reaction of 11-20 mm erythema ∑E 20-40 mm) and/or a 5 mm wheal occurs. This concentration at a dose of 0.03 mL then can serve as a starting dose for immunotherapy and be increased by 0.03 mL to as high as 0.12 mL increments each time until 0.3 mL is reached, at which time a dilution 10 times as strong can be used, starting with 0.03 mL. Proceed in this way until a tolerance dose is reached or symptoms are controlled. Suggested maintenance dose is 0.2 mL of the concentrate. Occasionally, higher doses are necessary to relieve symptoms. Special caution is required in administering doses greater than 0.2 mL. The interval between doses normally is 3 to 7 days. Potencies of 10,000 BAU/mL and 100,000 BAU/mL are available for treatment. The two selections are available to facilitate safe switching by providing flexibility in dosing. For previously untreated patients, initiate treatment using dilutions made from the 10,000 BAU/mL concentrate. If tolerated and symptoms justify a higher dosage, then use of dilutions made from the 100,000 BAU/mL concentrate is warranted. Proceed with caution when using 100,000 BAU/mL in higher doses. When converting a patient who is currently receiving non-standardized grass pollen extracts, it is recommended that skin testing be performed to compare the potency of the new and old extracts. If you choose not to skin test as recommended, but to continue therapy, the maximum first dose of the new allergenic product should not exceed 10% (1/10) of the previous dose. This is offered as a suggested schedule for average patients and will be satisfactory in most cases. However, the degree of sensitivity varies in many patients. The size of the dose should be adjusted and should be regulated by the patient's tolerance and reaction. The size of the dose should be decreased if the previous injection resulted in marked local or the slightest general reaction. Another dose should never be given until all local reactions resulting from the previous dose have disappeared. In some patients, the dosage may be increased more rapidly than called for in the schedule. In seasonal allergies, treatment should be started and the interval between doses regulated so that at least the first twenty doses will have been administered by the time symptoms are expected. Thus, the shorter the interval between the start of immunotherapy and the expected onset of symptoms, the shorter the interval between each dose. Some patients may even tolerate daily doses. A maintenance dose, the largest dose tolerated by the patient that relieves symptoms without producing undesirable local or general reactions, is recommended for most patients. The upper limits of dosage have not been established; however, doses larger than 0.2 mL of the glycerin concentrate may be painful due to the glycerin content. The dosage of allergenic extract does not vary significantly with the respiratory allergic disease under treatment. The size of this dose and the interval between doses will vary and can be adjusted as necessary. Should symptoms develop before the next injection is scheduled, the interval between doses should be decreased. Should allergic symptoms or local reactions develop shortly after the dose is administered, the size of the dose should be decreased. In seasonal allergies, it is often advisable to decrease the dose to one-half or one-quarter of the maximum dose previously attained if the patient has any seasonal symptoms. The interval between maintenance doses can be increased gradually from one week to 10 days, to two weeks, to three weeks, or even to four weeks if tolerated. Repeat the doses at a given interval three or four times to check for untoward reactions before further increasing the interval. Protection is lost rapidly if the interval between doses is more than four weeks. (See WARNINGS Section.) The usual duration of treatment has not been established. A period of two or three years of injection therapy constitutes an average minimum course of treatment.
TABLE 4TEN-FOLD DILUTION SERIESStandardized Extracts Labeled 100,000 BAU/mL Dilution Extract + Diluent = BAU/mL Concentration 0 Concentrate +0 mL = 100,000 1 1 mL Concentrate +9 mL = 10,000 2 1 mL dilution #1 +9 mL = 1,000 3 1 mL dilution #2 +9 mL = 100 4 1 mL dilution #3 +9 mL = 10 5 1 mL dilution #4 +9 mL = 1.0 6 1 mL dilution #5 +9 mL = 0.10 7 1 mL dilution #6 +9 mL = 0.010
(4) PEDIATRIC USE

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

(5) GERIATRIC USE

The dose for elderly patients is the same as for adult patients under 65.4
Pollens – Weeds A...

Pollens – Weeds And Garden Plants

21, 22, 23 1. General Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Sterile aqueous diluent containing human serum albumin [Albumin Saline with Phenol (0.4%)] or diluent of 50% glycerin may be used when preparing dilutions of the concentrate for immunotherapy. For intradermal testing dilutions, Albumin Saline with Phenol (0.4%) is recommended. Dilutions should be made accurately and aseptically, using sterile diluent, vials, syringes, etc. Mix thoroughly and gently by rocking or swirling. Maintain stock solutions and dilutions constantly at 2° - 8°C.

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

3. Geriatric Use The dose for the elderly patients is the same as for adult patients under 65.40

4. Diagnosis A positive reaction consists of an urticarial wheal with surrounding erythema (resembling somewhat a mosquito bite reaction) larger than the control site. The smallest reaction considered positive is erythema with a central papule at least 5 mm in diameter, however certain skin test devices may elicit a smaller positive reaction. Check the device manufacturer's recommendations. In some instances with no reaction at the control site, erythema may be considered an indication of sensitivity.

A positive skin reaction to any allergen must be interpreted in light of the patient's history of symptoms, time of year, and known exposures. THE SKIN TESTS ARE IN NO WAY A SUBSTITUTE FOR A CAREFUL ALLERGIC HISTORY. THEY SERVE AS ADDITIONAL INFORMATION TO AID IN IDENTIFYING CAUSATIVE ALLERGENS IN PATIENTS WITH ALLERGIC DISORDERS.

Skin tests are graded in terms of the wheal and erythema response noted at 15 minutes. Wheal and erythema size may be recorded by actual measurement of the extent of both responses.

Refer to the following table to determine the skin test sensitivity class. The corresponding ∑E (sum of the longest diameter and the mid-point orthogonal diameters of erythema) is also presented.
Class Wheal Diameter Erythema Diameter Corresponding ∑E 0 < 5 mm <5 mm <10 mm ± 5-10 mm 5-10 mm 10-20 mm 1+ 5-10 mm 11-20 mm 20-40 mm 2+ 5-10 mm 21-30 mm 40-60 mm 3+ 10-15 mm a 31-40 mm 60-80 mm 4+ >15 mm b >40 mm >80 mm a. or with pseudopods b. or with many pseudopods a. Scratch, Prick or Puncture Testing To identify highly sensitive individuals and as a safety precaution, it is recommended that a scratch, prick or puncture test using a drop of the extract concentrate be performed prior to initiating intradermal testing. Short Ragweed extract at 1:20 w/v in 50% glycerin containing approximately 100 to 300 units of Amb a 1/mL or Giant and Short Ragweed Mix at 1:20 w/v in 50% glycerin containing approximately 50 to 150 units of Amb a 1/mL are usually used for scratch, prick or puncture testing.
Scratch tests are performed by first scarifying the skin, then applying the extract to the scratch. Prick tests are performed by placing a drop of extract on the skin and piercing through the drop into the skin with a slight lifting motion. The prick is superficial and should not draw blood. Puncture tests are performed by placing a drop of extract on the skin and piercing through the drop perpendicular to the skin with a device such as a Prick Lancetter. After about 1 minute the extract may be wiped away with a dry sponge.

The diameter of wheal and erythema reactions are measured 15 minutes after the scratch, prick or puncture is made, and the sensitivity class of the patient determined by the table presented at the end of the diagnosis section. Less sensitive individuals (Class 0 to 1+) can be tested intradermally with the recommended dilutions of the extract concentrate (see Intradermal Testing )

b. Intradermal Testing

Intradermal tests should be done only on patients with a negative scratch, prick or puncture test. Patients who do not react to a valid scratch, prick or puncture test should be tested intradermally with 0.02 to 0.05 mL of extract solution. The intradermal strength for Short Ragweed extract is usually 500 PNU which by calculation contains approximately 0.7 to 3 units of Amb a 1/mL. For Giant and Short Ragweed mix, the suggested intradermal strength is 500 PNU which by calculation contains 0.4 to 1.5 units of Amb a 1/mL. These strengths are usually safe for testing patients previously having negative scratch, prick or puncture test reactions. A 1:10 dilution of the stock intradermal strength should be used in preliminary testing of patients not previously screened by scratch, prick or puncture tests. If the intradermal dilutions were prepared from glycerinated concentrate, the negative control used with this latter dilution should contain 5% glycerol. A site should be injected with 0.02 mL of the control solution. False positive reactions are sometimes encountered in intradermal testing and the possibility of irritation reactions should always be taken into consideration.
A study of ragweed sensitive patients, 42 indicates that intradermal tests, using 0.05 mL of extract, produce positive reactions (1+ to 2+) at Amb a 1 concentrations of 2.7x10 -1 to 2.7x10 -6 units per mL. The equivalent PNU range was 100 to 0.001 PNU per mL.
5. Immunotherapy Dosage of allergenic extracts is a highly individualized matter and varies according to the degree of sensitivity of the patient, his or her clinical response, and tolerance to the extract administered during the early phases of an injection regimen.

Allergen extracts should be administered using a sterile syringe with 0.01 mL gradations and a 25-27 gauge X 1/2" to 5/8" needle. The injections are given subcutaneously. The most common sites of injection are the lateral aspect of the upper arm or thigh. Intracutaneous or intramuscular injections may produce large local reactions which may be very painful.

To prepare dilutions for intradermal and therapeutic use, make a 1:10 dilution by adding 1.0 mL of the concentrate to 9.0 mL of the sterile aqueous diluent. Subsequent serial dilutions are made in a similar manner.

Following is a suggested schedule for average patients that will be satisfactory in most cases. However, the degree of sensitivity varies in many patients. The size of the dose should be adjusted and should be regulated by the patient's tolerance and reaction. Decrease the size of the dose if the previous injection resulted in marked local or the slightest general reaction. Another dose should never be given until all local reactions resulting from the previous dose have disappeared.

The starting dose should be based on skin tests of the extract to be used for immunotherapy. To determine the starting dose, begin intradermal testing with the most dilute extract preparation. Inject 0.02 mL and read the reaction after 15 minutes. Intradermal testing is continued with increasing concentrations of the extract until a reaction of 10-20 mm erythema (∑E 20-40 mm) and/or a 5 mm wheal occurs. This concentration at a dose of 0.03 mL then can serve as a starting dose for immunotherapy and be increased by 0.03 mL to as high as 0.12 mL increments each time until 0.3 mL is reached, at which time a dilution 10 times as strong can be used, starting with 0.03 mL. Proceed in this way until a tolerance dose is reached or symptoms are controlled. Suggested maintenance dose is 0.2 mL of the concentrate. Occasionally, higher doses are necessary to relieve symptoms. Special caution is required in administering doses greater than 0.2 mL. The interval between doses is normally 3 to 7 days during dose building regimen.

In some patients, the dosage may be increased more rapidly than called for in the schedule. In seasonal allergies, treatment should be started and the interval between doses regulated so that at least the first 20 doses will have been administered by the time symptoms are expected. Thus, the shorter the interval between the start of immunotherapy and the expected onset of symptoms, the shorter the interval between each dose. Some patients may even tolerate daily doses.

Should symptoms develop before the next injection is scheduled, the interval between doses should be decreased. Should allergic symptoms or local reactions develop shortly after the dose is administered, the size of the dose should be decreased. In seasonal allergies, it is often advisable to decrease the dose to one-half or one-quarter of the maximum dose previously attained if the patient has any seasonal symptoms.

A maintenance dose, the largest dose tolerated by the patient that relieves symptoms without producing undesirable local or general reactions, is recommended for most patients. The upper limits of dosage have not been established; however, doses larger than 0.2 mL of the glycerinated concentrate may be painful due to the glycerin content. The dosage of allergenic extract does not vary significantly with the respiratory allergic disease under treatment. The size of this dose and the interval between doses will vary and can be adjusted as necessary.

The interval between maintenance doses can be increased gradually from one week to 10 days, to two weeks, to three weeks, or even to four weeks, if tolerated. Repeat the doses at a given interval three or four times to check for untoward reactions before further increasing the interval. Protection is lost rapidly if the interval between doses is more than four weeks. (See WARNINGS Section.)

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

In two hyposensitization studies using Amb a 1 27, 43 the amount administered over a pre-seasonal course of injections varied from 4 to 2,000 units of Amb a 1. The maximum individual dose attained ranged up to 170 units in one series.
Short Ragweed pollen extracted at 1:20 (w/v) usually assays within a range of 50,000 to 70,000 PNU/mL and 100 to 300 units Amb a 1/mL. Most treatment programs use a w/v concentrate of 1:100 to 1:20 or a PNU/mL concentrate of 20,000 to 40,000. This would approximate a 100 units Amb a 1/mL average concentration of Short Ragweed extract (Giant and Short Ragweed mix would be one-half this value). The following suggested dose schedule is based on this average concentration of 100 Units/mL. The Amb a 1 content of different batches of Short Ragweed extract will vary so it will be necessary to dilute extract concentrate to the same Amb a 1 concentration when using a new lot of antigen. Formula for calculating dilutions: A 1C 1 = A 2C 2 A 1 = Amount of extract you wish to prepare. C 1 = Concentration you wish to prepare. A 2 = Amount of extract you will need for dilution. C 2 = Concentration of extract you will use. Formula for determining diluent required: A 1 minus A 2 = Amount of diluent required.
Animal Allergens

Animal Allergens

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Dosage of allergenic extracts is a highly individualized matter and varies according to the degree of sensitivity of the patient, his clinical response, and tolerance to the extract administered during the early phases of an injection regimen. Allergen extracts should be administered using a sterile syringe with 0.01 mL gradations and a 25-27 gauge x 1/2" to 5/8" needle. The injections are given subcutaneously. The most common sites of injection are the lateral aspect of the upper arm or thigh. Intracutaneous or intramuscular injections may produce large local reactions and may be very painful. Sterile aqueous diluent containing human serum albumin [Albumin Saline with Phenol (0.4%)] or diluent of 50% glycerin may be used when preparing dilutions of the concentrate for immunotherapy. Dilutions should be made accurately and aseptically, using sterile diluent, vials, syringes, etc. Mix thoroughly and gently by rocking or swirling. Maintain stock solutions and dilutions constantly at 2° - 8°C. To prepare dilutions for intradermal and therapeutic use, make a 1:10 dilution by adding 1.0 mL of the Concentrate to 9.0 mL of sterile aqueous diluent. Subsequent serial dilutions are made in a similar manner. Following is a suggested schedule for average patients and will be satisfactory in most cases. However, the degree of sensitivity varies in many patients. The size of the dose should be adjusted according to the patient's tolerance and reaction. Decrease the size of the dose if the previous injection resulted in marked local or the slightest general reaction. Another dose should never be given until all reactions resulting from the previous dose have disappeared. The starting dose should be based on skin tests of the extract to be used for immunotherapy. To determine the starting dose, begin intradermal testing with the most dilute extract preparation. Inject 0.02 mL and read the reaction after 15 minutes. Intradermal testing is continued with increasing concentrations of the extract until a reaction of 10-20 mm erythema ( ∑ E 0-40 mm) and/or a 5 mm wheal occurs. This concentration at a dose of 0.03 mL then can serve as a starting dose for immunotherapy. Subsequent doses can be increased by 0.03 mL to as high as 0.12 mL increments each time until 0.3 mL is reached, at which time a dilution 10 times as strong can be used, starting with 0.03 mL. Proceed in this way until a tolerance dose is reached or symptoms are controlled. Suggested maintenance dose for a pollen extract is 0.2 mL of the Concentrate, while for a non-pollen extract the maximum suggested dose is 0.5 mL of the Concentrate. Occasionally, higher doses are necessary to relieve symptoms. Special caution is required in administering doses greater than 0.2 mL. The interval between doses is normally 3 to 7 days during dose building regimen. Normally immunotherapy can be started with a 1:100,000 dilution of extracts labeled in weight/volume. Certain therapeutic mixtures are labeled as Concentrate, (v/v) dilutions of Concentrate, Amb a 1, Allergy units/mL or Bioequivalent Allergy Units/mL. (See DESCRIPTION.) Strength of each antigen in the mixture is indicated in the product labeling. For beginning treatment, use at least a 1,000-fold dilution of the Concentrate extract for non-pollens, and at least a 10,000-fold dilution of the Concentrate extract for pollens. In some patients, the dosage may be increased more rapidly than recommended above. In seasonal allergies, treatment should be started and the interval between doses regulated so that at least the first twenty doses will have been administered by the time symptoms are expected. Thus, the shorter the interval between the start of immunotherapy and the expected onset of symptoms, the shorter the interval between each dose. Some patients may even tolerate daily doses. Should symptoms develop before the next injection is scheduled, the interval between doses should be decreased. Should allergic symptoms or local reactions develop shortly after the dose is administered, the size of the dose should be decreased. In seasonal allergies, it is often advisable to decrease the dose to one-half or one-quarter of the maximum dose previously attained if the patient has any seasonal symptoms. A maintenance dose, the largest dose tolerated by the patient that relieves symptoms without producing undesirable local or general reactions, is recommended for most patients. The upper limits of dosage have not been established; however, doses larger than 0.2 mL of extract may be painful if glycerin is present. The dosage of allergenic extract does not vary significantly with the respiratory allergic disease under treatment. The size of this dose and the interval between doses will vary and can be adjusted as necessary. The interval between maintenance doses can be increased gradually from one week to 10 days, to two weeks, to three weeks, or even to four weeks, if tolerated. Repeat the doses at a given interval three or four times to check for untoward reactions before further increasing the interval. Protection is lost rapidly if the interval between doses is more than four weeks. (See WARNINGS.) The usual duration of treatment has not been established. A period of two or three years of injection therapy constitutes an average minimum course of treatment.
2. Pediatric Use

The dose for the pediatric population is the same as for adults.

3. Geriatric Use

The dose for elderly patients is the same as for adult patients under 65.36

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