Dermatophagoides Farinae

1 INDICATIONS AND USAGE Greer Standardized Mite ( Dermatophagoides farinae and/or Dermatophagoides pteronyssinus ) Extracts are allergenic extracts indicated for: skin test diagnosis of mite allergy treatment of patients with mite-induced allergic asthma, rhinitis and conjunctivitis. For immunotherapy, patients must show hypersensitivity to Dermatophagoides farinae ( D. farinae ) or Dermatophagoides pteronyssinus ( D. pteronyssinus ) based on their clinical history, allergen exposure history, and skin test reactivity. Greer Standardized Mite Extracts are allergenic extracts indicated for: Diagnosis of skin test reactivity to dust mite allergen (1) Treatment of mite-induced allergic asthma, rhinitis and conjunctivitis in patients that show hypersensitivity to dust mites based on clinical history, allergen exposure history, and skin test reactivity (1)

2 DOSAGE AND ADMINISTRATION Do not inject intravenously. Greer Standardized Mite extracts are diluted with sterile diluent for allergenic extracts when used for intradermal testing or subcutaneous immunotherapy. Dosages vary by mode of administration, and by individual response and tolerance. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Greer Standardized Mite Extracts should be a light brown solution that is free of particulate matter. If particulate matter is observed then the solution should be discarded. 2.1 Diagnostic Testing For diagnosis of a patient with a suspected allergy to either species of dust mite ( D. farinae or D. pteronyssinus ), diagnostic skin testing should include the standardized mite mixture or the single-species mite extracts. If a skin test with the standardized mite mixture elicits a positive reaction, then the single-species mite extracts can be 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)

6 ADVERSE REACTIONS Systemic reactions consist primarily of allergic symptoms, such as generalized skin erythema, urticaria, pruritus, angioedema, rhinitis, wheezing, laryngeal edema, and hypotension. Additional symptoms that are not usually associated with allergy also may occur, such as nausea, emesis, abdominal cramps, and diarrhea. Serious reactions may cause shock, loss of consciousness, and even death. Based on published studies, 7,8 systemic reactions occur in less than 1% of patients receiving conventional immunotherapy to greater than 36% in some studies of patients receiving rush immunotherapy. Local reactions at the injections site are the most commonly occurring reactions (e.g., erythema, itching, swelling, tenderness, pain). Although most adverse systemic reactions occur within 30 minutes of injection (some within minutes of extract exposure), such reactions also can occur up to six hours after skin tests or immunotherapy [see Dosage and Administration (2.2)]. 9 Systemic reactions 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