re skin testing. topical local anesthetics may suppress flare responses and should be avoided at skin test sites. 7.4 tricyclic antidepressants 1 tricyclic antidepressants can have potent antihistamine effects and will affect skin testing. since use of tricyclics may alter skin test results, dosing for both skin testing and immunotherapy should be done with caution. if tricyclic medication has been recently discontinued, allow 7-14 days prior to skin testing to obviate the antihistamine effect. the risk of anaphylaxis in these patients should be carefully weighed against the risks and benefits of stopping tricyclics. 7.5 other drugs the suppressive action of other drugs should be considered and emphasizes the need for a histamine positive-control test. patients who are receiving beta agonists may be unresponsive to the usual doses of epinephrine used to treat serious systemic reactions, including anaphylaxis (7.1) patients should discontinue medications known to suppress the histamine response prior to skin testing including: antihistamines (7.2), tricyclics (7.4), and topical corticosteroids and topical anesthetics (7.3)

e event. high-risk patients are defined as those patients: with labile or steroid-dependent asthma, particularly in those suffering an exacerbation of their symptoms at the time of extract administration; with extreme sensitivity to a particular allergen(s); who are currently using beta blockers; who are receiving an accelerated immunotherapy build-up schedule (e.g., rush immunotherapy); who are being changed from one allergenic extract to another; who are receiving high doses of allergenic extracts. high risk patients have had fatal reactions. in addition, patients not high-risk but on beta blockers have had fatal reactions because beta blockers interfere with beta adrenergics such as epinephrine used in treatment or anaphylaxis. patients should be kept under observation for a minimum of 30 minutes after receiving allergenic extracts so that any adverse reaction can be observed and properly handled. 2 medications to treat systemic reactions, as well as emergency equipment should be available for immediate use. extracts must only be administered by persons who are aware of the risk of systemic reactions, including anaphylaxis; are capable of handling such reactions; and have the necessary drugs and equipment on hand to do so. 5.2 patients on beta blockers patients receiving beta blockers may be unresponsive to the usual doses of epinephrine used to treat serious systemic reactions, including anaphylaxis. inhalant allergy immunotherapy should be approached with caution in patients taking beta blockers. the risks of anaphylaxis in these patients should be carefully weighed against the benefits of immunotherapy [see drug interactions (7.1)]. 5.3 autoimmune disease immunotherapy should be given cautiously to patients with other immunologic diseases and only if the risk from exposure to the allergen is greater than the risk of exacerbating the underlying disorder. 2 all concentrates of greer standardized mite extracts can cause serious systemic reactions of varying degrees of severity, including anaphylactic shock and death, particularly in patients: with labile or steroid-dependent asthma (5.1) with extreme sensitivity to allergen(s) (5.1) who are currently using beta blockers (5.2) who are on an accelerated immunotherapy build-up schedule (5.1) who are being changed from one allergenic extract to another (5.1) who are receiving high doses of allergen extracts (5.1)

used to determine the degree of sensitivity to each, and to guide in the selection of extracts and their concentration for immunotherapy, if indicated. a positive skin test reaction to any allergen must be interpreted in light of the patient's history of symptoms, the time of year, and known exposure to environmental allergens. 2.1.1 percutaneous skin testing for percutaneous (scratch, prick, or puncture) testing, use 10,000 allergy units/ml greer standardized mite extract stock concentrate in dropper vials. if patient is suspected of having exquisite sensitivity, such as anaphylaxis, to certain foods and drugs, initiate percutaneous testing with several serial 10-fold dilutions of the usual test concentration. for scratch tests, scarify the skin, and then apply one drop of the extract to the scratch. for prick tests, place one drop of extract on the skin and pierce through the drop into the skin with a slight lifting motion. for puncture tests, place one drop of extract on the skin and pierce through the drop perpendicular to the skin. when using percutaneous test devices, follow the directions provided with the test devices. include a positive control to detect false negative responses to skin testing, which may occur if serum levels of antihistamines remain from prior medication administration [see drug interactions (7.2)]. a glycerinated histamine phosphate diluted to 10 mg/ml (6 mg/ml histamine base) may be used as the positive control. include a negative control to detect false positive responses, which can occur when the patient has a non-specific reaction to the diluent. a 50% glycerosaline solution may be used as the negative control. read skin tests 15-20 minutes after exposure. record the induration (wheal) and erythema (flare) response by noting the longest diameter of each, or by the sum of the longest erythema diameter and the mid-point orthogonal diameters of erythema (Σe). percutaneous testing devices often have their own grading systems, as these devices may cause different degrees of trauma to the skin and deliver different volumes of allergenic extract. follow grading instructions for the device used. 2.1.2 intradermal skin testing intradermal tests are commonly used when the reaction to percutaneous testing is negative or equivocal but the patient has a strong clinical history of symptoms triggered by exposure to a specific allergen. because immediate systemic reactions are more common with intradermal testing, prescreening with percutaneous testing is a practical safety measure. 1 dilute the stock concentrate with sterile diluent. use saline with human serum albumin (hsa), buffered saline, or saline. if prescreening is not done, or if patients are expected to be high risk, precautions should be observed since some patients have experienced anaphylaxis and death. patients who do not react to percutaneous skin testing should be tested intradermally at a starting dose of 0.02 to 0.05 ml of a 50 allergy units/ml extract dilution. patients suspected of being highly allergic should first receive a test dose of 0.02 to 0.05 ml of a 0.05 allergy units/ml extract dilution. if the initial dose test is negative, subsequent intradermal tests using increasingly stronger doses may be performed up to the maximum recommended strength of 200 allergy units/ml. if percutaneous skin testing was not performed, include a positive control to detect false negative responses to skin testing, which may occur if serum levels of antihistamines remain from prior medication administration [see drug interactions (7.2)]. a glycerinated histamine phosphate diluted to 0.5 mg/ml (0.18 mg/ml histamine base) or aqueous histamine phosphate 0.275 mg/ml (0.1 mg/ml histamine base) may be used as the positive control. if percutaneous skin testing was not performed, include a negative control to detect false positive responses, which can occur when the patient has a non-specific reaction to the diluent. a 1% glycerin in 0.9% saline solution may be used as the negative control. measure the wheal-and-flare response after 15-20 minutes, which may be graded using variou methods as described in the instructions for the device used. the mean dose of greer dust mite allergen required to elicit a positive intradermal test result (Σe > 50 mm) in a total of 83 mite puncture test positive (Σe > 20 mm) persons is shown in table 1. table 1. intradermal reactivity to mite allergens allergen number of persons dose to elicit 50 mm sum of diameter erythema reaction mean (au*/ml) range (au/ml) d. farinae 46 0.00856 0.00004 - 1.75935 d. pteronyssinus 37 0.00570 0.00002 - 1.36341 ** * allergy units ** data is available on file with greer 2.2 immunotherapy subcutaneous injection only. subcutaneous injections for immunotherapy should be prepared by dilution of stock concentrate based on patient's reactivity. stock concentrations of greer standardized mite extract are available in 5,000 allergy units/ml, 10,000 allergy units/ml, 30,000 allergy units/ ml for immunotherapy. see table 2 for dilution preparation. also see dosage modification guidelines 2.2.1). the initial dose of the extract should be based on the percutaneous test reactivity. in patients who appear to be exquisitely sensitive by history and skin test, the initial dose of the extract should be 0.1 ml of a 0.005 to 0.05 allergy units/ml dilution. patients with lesser sensitivity may be started at a 0.5 to 5 allergy units/ml 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. large local reactions which persist for longer than 24 hours are generally considered an indication for repeating the previous dose or reducing the dose at the next administration. any evidence of a systemic reaction is an indication for a significant reduction (at least 75%) in the subsequent dose. repeated systemic reactions, even of a mild nature, are sufficient reason for the cessation of further attempts to increase the reaction-causing dose. severe reactions require a decrease in the next dose by at least 50%. proceed cautiously in subsequent dosing. a maximum tolerated maintenance dose should be selected based on the patient's clinical response and tolerance. doses larger than 0.2 ml of the concentrate are rarely administered because an extract in 50% glycerin may cause discomfort upon injection. since the two mite species tend to cross-react, consider the total allergy units content in determining the maximum maintenance dose of the mixture. 2.2.1 dosage modifications guidelines for immunotherapy the following conditions may indicate a need to withold or reduce the dosage of immunotherapy. in situations prompting dose reduction, once the reduced dose is tolerated, a cautious increase in dosage can be attempted. immunotherapy should be withheld or reduced in dosage if the following concurrent conditions exist: severe symptoms of rhinitis and/or asthma; infection accompanied by fever; or exposure to excessive amounts of clinically relevant allergen prior to a scheduled injection. changing to a different lot of extract: all extracts lose potency over time. a fresh extract may have an effective potency that is substantially greater than that of older extracts. therefore, the first dose from the fresh vial should not exceed a 25% increase of the previous dose or a 75% reduction of the previous dose, assuming both extracts contain comparable amounts of allergen, defined by allergy units. unscheduled gaps between treatments: patients may lose tolerance for allergen injections during prolonged periods between doses, thus increasing 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, it is customary to repeat or even 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 as a standard operating procedure for the specific clinical setting. similarly, if large unscheduled gaps occur during maintenance therapy, it may be necessary to reduce the dosage. the individual physician should devise a protocol as a standard operating procedure for his or her specific clinical setting in determining how to modify doses of allergen immunotherapy due to unscheduled gaps in treatment. the extract previously used is from another manufacturer: since manufacturing processes and sources of raw materials differ among manufacturers, the interchangeability of extracts from different manufacturers cannot be assured. the starting dose of the extract from a different manufacturer should be greatly decreased even though the extract is the same formula and dilution. in general, a dose reduction of 50-75% 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 dose. the previous extract has expired or is near expiry: the dating period for allergenic extracts indicates the time that they can be expected to remain potent under ideal storage conditions (2 to 8°c) [see how supplied/storage and handling (16)]. some loss of potency occurs even when stored under ideal conditions, therefore extracts should not be stored beyond the expiration date. instead, a new lot of should be used (see "changing to a different lot of extract", above) changing from non-stabilized to human serum albumin (hsa) stabilized diluents: allergenic extracts diluted with hsa and 0.4% phenol are more potent than extracts diluted with diluents that do not contain stabilizers. when switching from a non-stabilized to an hsa stabilized diluent, consider lowering the dose for immunotherapy. 2.2.2 administration of immunotherapy administer immunotherapy by subcutaneous injection in the lateral aspect of the 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 or 2 times per week until the maintenance dose is reached, at which time the injection interval is increased to 2, 3, and finally 4 weeks. because most adverse reactions occur within 30 minutes after injection, patients should be kept under observation for at least 30 minutes. 2 for high risk patients 30 minutes of observation may not be sufficient. 2.3 dilution preparation to prepare dilutions for intradermal testing and immunotherapy, start with a 5,000, 10,000, or 30,000 allergy units/ml stock concetrate, and prepare a 1:10 dilution by adding 0.5 ml of concentrate to 4.5 ml of sterile aqueous diluent. subsequent dilutions are made in a similar manner (see table 2). table 2. ten-fold dilution series for intradermal testing and immunotherapy dilution extract diluent au/ml* au/ml au/ml 0 concentrate 5,000 10,000 30,000 1 0.5 ml concentrate 4.5 ml 500 1,000 3,000 2 0.5 ml dilution 1 4.5 ml 50 100 300 3 0.5 ml dilution 2 4.5 ml 5 10 30 4 0.5 ml dilution 3 4.5 ml 0.5 1 3 5 0.5 ml dilution 4 4.5 ml 0.05 0.1 0.3 6 0.5 ml dilution 5 4.5 ml 0.005 0.01 0.03 * allergy units the extracts are diluted with sterile diluents for allergenic extracts when used for intradermal testing or subcutaneous immunotherapy. dosages vary by mode of administration, and by individual response and tolerance. administered percutaneouslly for diagnostic testing (2.1); stock concentrate 10,000 allergy units/ml (2.1) administered intradermally for diagnostic testing (2.1); stock concentrate 5,000, 10,000, or 30,000 allergy units/ml (2.3) administered subcutaneously for immunotherapy (2.2); stock concentrate of 5,000, 10,000,or 30, 000 allergy units/ml (2.3)

eactions may be fatal or near fatal (6) systemic reactions (e.g. generalized skin erythema, urticaria, pruritus, angioedema, rhinitis, wheezing, laryngeal edema, and hypotension) occur in 4-7% of patients the most common reactions are local reactions at the injection site (e.g., erythema, itching, swelling, tenderness, pain), occuring in 26% to 82% of patients (6) to report suspected adverse reactions, contact greer laboratories, inc., at 1-855-274-1322 or the fda at 1-800-fda-1088 or www.fda.gov/medwatch

re skin testing. topical local anesthetics may suppress flare responses and should be avoided at skin test sites. 7.4 tricyclic antidepressants 1 tricyclic antidepressants can have potent antihistamine effects and will affect skin testing. since use of tricyclics may alter skin test results, dosing for both skin testing and immunotherapy should be done with caution. if tricyclic medication has been recently discontinued, allow 7-14 days prior to skin testing to obviate the antihistamine effect. the risk of anaphylaxis in these patients should be carefully weighed against the risks and benefits of stopping tricyclics. 7.5 other drugs the suppressive action of other drugs should be considered and emphasizes the need for a histamine positive-control test. patients who are receiving beta agonists may be unresponsive to the usual doses of epinephrine used to treat serious systemic reactions, including anaphylaxis (7.1) patients should discontinue medications known to suppress the histamine response prior to skin testing including: antihistamines (7.2), tricyclics (7.4), and topical corticosteroids and topical anesthetics (7.3)

diatric use no studies have systematically examined differences in response to immunotherapy among child and adult patients. children appear to tolerate injections of allergenic extracts very well. 2 very young children (under age 5) can have difficulty cooperating with an immunotherapy program and for this reason, the physician should consider the benefits and risks of immunotherapy and indiviualize treatment in patients under the age of 5 years [see warnings and precautions (5)]. 8.5 geriatric use clinical studies of greer standardized mite extract did not include sufficent numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. other reported clinical experiences has not identified differences in responses between the elderly and younger patients. in general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of concomitant disease or other drug therapy including beta blockers. 2 pregnancy: no human or animal data. use only if clearly needed (8.1) autoimmune disease: immunotherapy may exacerbate the autoimmune disease. use only if clearly needed (5.3) see 17 for patient counseling information. revised: 1/2013

ten correlate closely with clinical (symptom) improvements. specific mechanisms may vary depending on the nature of the allergic disease, the allergenic specificities of patients and populations, extract formulations, route of administration, dose and duration of treatment. 2 subcutaneous administration of allergenic extracts is known to elicit numerous immunological changes that are both time and dose-dependent. many of these changes appear to be related to (or a precursor to) improvements in symptoms and other clinical parameters, as noted above. specific changes found after immunotherapy with dust mite extracts include significant increases in mite-specific igg4 antibodies 12 , interleukin-10-positive t cells, and several t-cell receptors, and significant decreases in serum nitric oxide, eosinophil catonic protein, interleukin-4-positive t cells and ige-mediated basophil histamine release. 13

ls d. farinae / d. pteronyssinus mixture: ndc 22840-0040 15,000 allergy units/ml each species, 10, 30, and 50 ml vials 16.2 storage and handling store dust mite extract at 2 to 8°c (36 to 46°f). keep dust mite extract at 2 to 8°c (36 to 46°f) during office use. dilutions of concentrated extract result in a glycerin content of less than 50% which results in reduced stability of the extracts. 1:100 dilutions should be kept no longer than a month, and more dilute solutions no more than a week. the potency of a dilution can be checked by skin test comparison to a fresh dilution of the extract on a known mite allergic individual.