For percutaneous, intradermal or subcutaneous use only.
The extracts are diluted with sterile diluents when used for intradermal testing or subcutaneous immunotherapy. For percutaneous testing, the extracts are diluted with sterile diluents in patients expected to be at greater risk for systemic allergic reaction. Dosages vary by mode of administration and by individual response.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard solution if either of these conditions exist.
The extracts are diluted with sterile diluents when used for percutaneous and intradermal testing, or for subcutaneous immunotherapy.
Extracts labeled "For Diagnostic Use Only" are intended for percutaneous and intradermal testing only. These extracts have not been shown by adequate data to be safe and effective for therapeutic use. The extracts labeled For Diagnostic Use Only are the foods Barley, Coffee, Oat, Pineapple, Rye, Spinach, Wheat, the insects Flea, House Fly, Mosquito, and the plant and plant parts Cottonseed and Flax.
Undiluted 50% glycerin stock concentrate is used for percutaneous testing. To prepare 10-fold dilutions for percutaneous testing in patients suspected to be at greater risk for systemic allergic reaction, start with the stock concentrate. Proceed as shown in Table 1. The 10-fold dilution series uses 0.5 milliliters of concentrate added to 4.5 milliliters of sterile 50% glycerin diluent. Subsequent dilutions are made in a similar manner.
To prepare 10-fold dilutions for intradermal testing and immunotherapy, start with a 1:10 weight/volume, 1:20 weight/volume, or up to a 40,000 PNU/milliliter stock concentrate. Proceed as shown in Table 1. The 10-fold dilution series uses 0.5 milliliter of concentrate added to 4.5 milliliters of sterile diluent (glycerin-free diluents for intradermal testing, glycerin-free or 10% glycerin-saline diluents for immunotherapy). Subsequent dilutions are made in a similar manner.
*There is no direct potency correlation across the table between PNU/milliliter and w/v.
Undiluted 50% glycerin stock concentrate is used for percutaneous testing. To prepare 5-fold dilutions for percutaneous testing in patients suspected to be at greater risk for systemic allergic reaction, start with the stock concentrate. Proceed as shown in Table 2. The 5-fold dilution series uses 1 milliliter of concentrate added to 4 milliliters of sterile 50% glycerin diluent. Subsequent dilutions are made in a similar manner.
To prepare 5-fold dilutions for intradermal testing or immunotherapy, start with a 1:10 weight/volume, 1:20 weight/volume, or up to a 40,000 PNU/milliliter stock concentrate. Proceed as shown in Table 2. The 5-fold dilution series uses 1 milliliter of concentrate added to 4 milliliters of sterile diluent (glycerin-free diluents for intradermal testing, glycerin-free or 10% glycerin-saline diluents for immunotherapy). Subsequent dilutions are made in a similar manner.
*There is no direct potency correlation across the table between PNU/milliliter and w/v.
Diagnostic testing can be performed via percutaneous or intradermal administration of the Non-Standardized Allergenic Extracts. A positive skin test reaction should be interpreted in relation to the patient's history and known exposure to the specific allergen(s).
For percutaneous testing (prick or puncture), use glycerinated extract; use the extracts at the highest available stock concentration. In patients suspected to be at greater risk for systemic allergic reaction, use 10-fold or 5-fold dilutions of the concentrate.
Prick test: Place one drop of extract with appropriate controls on the skin and with a skin test device, pierce through the drop into the skin with a slight lifting motion. Alternatively, use skin test devices loaded with the extract from the storage trays in a similar manner or in accordance with the device manufacturer's recommendations.
Puncture test: Place one drop of extract or control on the skin and pierce the skin through the drop with a skin test device perpendicular to the skin. Alternatively, use skin test devices loaded with the extract from the storage trays in a similar manner or in accordance with the device manufacturer's recommendations.
When using percutaneous skin test devices, follow the directions provided with the test devices. A glycerinated histamine control solution (6 milligrams/milliliter or 1 milligram/milliliter histamine base) may be used as the positive control. A 50% glycerin-saline solution may be used as the negative control.
Read and record skin test responses 15 to 20 minutes after exposure. Individual patient reactivity can vary with time, allergen potency, and/or immunotherapy, as well as testing technique. The most reliable method of recording a skin test reaction is to measure the largest diameter of both wheal and erythema. While some correlation exists between the size of the skin test reaction and the degree of sensitivity, other factors should be considered in the diagnosis of allergy to specific allergens (see Figure 1 below).
Use a paper or plastic millimeter skin reaction guide as shown below.
Fifteen minutes after application of the skin test, measure the length and midpoint orthogonal width of each flare and wheal from the inner edge of the reaction.
The length of the skin test is defined as the largest diameter and the width of the skin test is defined as the diameter perpendicular to the length at its midpoint. Consider the wheal and flare as separate entities. First, measure the flare and then independently measure the wheal.
The average diameter measurement in the example above of the flare is 26 mm + 36 mm/ 2 = 31 mm and the average diameter of the wheal is 10 mm + 16 mm/2 = 13 mm.
Responses to positive controls should be at least 3 millimeters larger than responses to the negative controls.
Negative controls should elicit no reaction or only reactions of small diameter (less than 2 millimeters wheal, less than 5 millimeters erythema).
If either the positive or negative control response does not meet the above criteria, results for the allergenic extracts tested at the same time should be considered invalid and be repeated.
For intradermal testing, dilute stock concentrate to 1:100 to 1:1000 volume to volume of Non-Standardized Allergenic Extracts stock concentrate solution. Dilute the stock concentrate solution with sterile diluent [see Dosage and Administration (2.1)]. Use normal or buffered saline or normal saline with human serum albumin (HSA) diluent. If the result from the initial test dose is negative, subsequent intradermal tests using increasingly stronger doses may be performed up to the maximum recommended strength of 1:25 volume to volume dilution of the extract concentrate solution.
Inject 0.02 milliliters of the extract solution intradermally according to the algorithms shown in Figure 2.
Figure 2: Algorithm for Dilution of Stock Concentrate Solution of Non-Standardized Allergenic Extracts for Intradermal Skin Testing
1 Corresponds to 1:10,000 - 1:15,625 volume to volume dilution of 1:20 weight/volume glycerinated extract concentrates
2 Corresponds to 1:100 - 1:125 volume to volume dilution of 1:20 weight/volume glycerinated extract concentrates
3 Corresponds to 1:50 - 1:100 volume to volume dilution of 1:20 weight/volume glycerinated extract concentrates
4 Corresponds to 1:25 - 1:100 volume to volume dilution of 1:20 weight/volume glycerinated extract concentrates
Stock concentrates of Non-Standardized Allergenic Extracts are available in aqueous (up to 1:10 weight/volume or 40,000 PNU/milliliter) and 50% glycerin (up to 1:20 weight/volume) strengths for immunotherapy. Stock concentrates are diluted in normal saline, buffered saline, HSA-saline, or 10% glycerin-saline, depending on the patient's reactivity to the diluent. See Table 1 and Table 2 for dilution preparation.
Administer immunotherapy by subcutaneous injection in the lateral aspect of the upper arm or thigh. Avoid injection directly into any blood vessel.
The optimal interval between doses of allergenic extract varies among individuals. Injections are usually given 1 to 2 times per week until the maintenance dose is reached, at which time the injection interval is increased to 2, then 3, and finally 4 weeks. Dosages vary by mode of administration, and by clinical response and tolerance. The minimum course of treatment may be three to five years, depending on the clinical response.
The initial dose of the extract should be based on the skin test reactivity. In patients suspected to be at greater risk for systemic allergic reaction by history and skin test, the initial dose of the extract should be 0.05 milliliter of a 1:20,000,000 to 1:2,000,000 weight/volume extract dilution. Patients not suspected to be at greater risk for systemic allergic reaction may be started at 0.1 milliliter of a 1:200,000 to 1:20,000 weight/volume extract dilution.
The dose of allergenic extract is increased at each injection by no more than 50% of the previous dose, and the next increment is governed by the response to the last injection.
Select the maximum tolerated maintenance dose based on the patient's clinical response and tolerance. Doses larger than 0.2 milliliter of the stock concentrate are rarely administered because an extract in 50% glycerin diluent can cause discomfort upon injection.
Dosage Modification Guidelines for Immunotherapy
The following conditions may indicate a need to withhold or reduce the dosage of immunotherapy.
Any evidence of a systemic reaction is an indication for a significant reduction (at least 75%) in the subsequent dose. Repeated systemic adverse reactions are sufficient reason for the cessation of further attempts to increase the dose.
Local adverse reactions require a decrease in the next dose by at least 50%. Proceed cautiously in subsequent dosing. In situations prompting dose reduction, once the reduced dose is tolerated, a cautious increase in dosage can be attempted.
Changing extract to a different lot or from a different manufacturer: When switching to a different lot of extract, or from another manufacturer's extract, decrease the starting dose. Because manufacturing processes and sources of raw materials differ among manufacturers, the interchangeability of extracts from different manufacturers cannot be assured. In general, a dose reduction of 50 to 75% of the previous dose should be adequate, but each situation must be evaluated separately, considering the patient's history of sensitivity, tolerance of previous injections, and other factors. Dose intervals should not exceed one week when rebuilding the dose.
Unscheduled gaps between treatments: Patients can lose tolerance to allergen injections during prolonged periods between doses, which increases their risk for an adverse reaction. The duration of tolerance between injections varies from patient to patient.
During the build-up phase, when patients receive injections 1 to 2 times per week, repeat or reduce the extract dosage if there has been a substantial time interval between injections. This depends on: 1) the concentration of allergen immunotherapy extract that is to be administered; 2) a previous history of systemic reactions; and 3) the degree of variation from the prescribed interval of time, with longer intervals since the last injection leading to greater reductions in the dose to be administered.
This suggested approach to dose modification, due to unscheduled gaps between treatments during the build-up phase, is not based on published evidence. The individual physician should use this or a similar protocol for the specific clinical setting.
Similarly, if unscheduled gaps occur during maintenance therapy, it may be necessary to reduce the dosage and bring the patient up to maintenance dosing using an established build-up protocol.
Changing from non-stabilized to human serum albumin (HSA) stabilized diluents: Allergenic extracts prepared with diluents containing HSA and 0.4% phenol are more stable than those prepared with diluents that do not contain stabilizers. When switching from a non-stabilized to an HSA-stabilized diluent, consider lowering the dose for immunotherapy.