INSTRUCTIONS AND DOSAGE SCHEDULE FOR TREATMENT WITH IMPORTANT ALLERGENIC

INSTRUCTIONS AND DOSAGE SCHEDULE FOR TREATMENT WITH IMPORTANT ALLERGENIC EXTRACTS 385400-H04 WARNINGS This product is intended for use only by physicians who are experienced in the administration of high dose allergy injection therapy and the emergency care of anaphylaxis, or for use under the guidance of an allergist. Allergenic extracts may potentially elicit a severe life-threatening systemic reaction, rarely resulting in death.1 Therefore, emergency measures and personnel trained in their use must be available immediately in the event of such a reaction. Patients should be instructed to recognize adverse reaction symptoms, be observed in the office for at least 30 minutes after skin testing or treatment, and be cautioned to contact the physician’s office if symptoms occur. See ADVERSE REACTIONS. This product is not directly interchangeable with other manufacturers’ products, or with alum-adsorbed products. See WARNINGS section. Reduced dose or extra dilutions may be required under one or more conditions. See WARNINGS section. Consult DOSAGE AND ADMINISTRATION instructions before using this product. This product is not approved for intravenous use, and should never be used intravenously. Patients with cardiovascular diseases and/or pulmonary diseases such as symptomatic unstable, steroid-dependent asthma, and/or those who are receiving cardiovascular drugs such as beta blockers, may be at higher risk for severe adverse reactions. These patients may also be more refractory to the normal allergy treatment regimen. Patients should be treated only if the benefit of treatment outweighs the risks. 1 Patients on beta blockers may be more reactive to allergens given for testing or treatment and may be unresponsive to the usual doses of epinephrine used to treat allergic reactions. 2 See WARNINGS, ADVERSE REACTIONS, and OVERDOSAGE. DESCRIPTION: The extracts supplied in this treatment set or refill have been selected by the patient’s physician on the basis of history and skin tests for an individual patient. The extracts are sterile and intended for subcutaneous injection. Although in some rare cases, an extract will contain only one etiologically specific allergen, usually the extract will contain a mixture of allergens. Source materials utilized in allergenic extract products include pollens, molds, animal epidermals, inhalants, and insects. Pollens are collected using techniques such as waterset or vacuuming, and are cleaned and purified to greater than 99% single species pollen (less than 1% foreign particle presence). Molds are typically grown on synthetic nutrient media and are derived from the surface growth (mycelia). Epidermals include feathers, hair (clippings and/or shavings), or pelt (hair and whole epipunctured severaldescribed if excessive amounts of air are injected from animals deemed dermis), as times on product labeling. Source materials are collected into the vial. To to be healthy at the time of collection by a veterinarian or individual trained and certified by a ringe, and store vial in upright position. veterinarian. Regular process epidermals are extractions of the source material without additional processing (certain materials are defatted). AP Acetone Precipitated Epidermal source materials are derived from the precipitate formed when acetone is added to an aqueous extract. growth (mycelia). Epidermals include feathers, hair (clippings and/or shavings), or pelt (hair and whole epidermis), as described on product labeling. Source materials are collected from animals deemed to be healthy at the time of collection by a veterinarian or individual trained and certified by a veterinarian. Regular process epidermals are extractions of the source material without additional processing (certain materials are defatted). AP Acetone Precipitated Epidermal source materials are derived from the precipitate formed when acetone is added to an aqueous extract. The resulting precipitate is dried, and becomes the source material for the AP product. Standardized Cat Hair and Standardized Cat Pelt are derived from the AP process. Insects are collected in whole body form. Extractions take place as whole body or ground insects. Various other Environmental materials are available as allergenic extracts, and informa tion on these materials can be obtained by contacting our Customer Service Department. The term “Concentrate,” when used in prescription labeling, refers to the allergen manufacturing strength prescribed by the physician and used in the formulation. Should the physician choose to calculate the actual strength of each component in the concentrate mixture, the following formulation may be used: Actual Allergen Strength Allergen Manufacturing % Allergen in Formulation = Strength (by volume or parts) in Concentrate Mixture The following is a brief description of the five methods of describing allergenic product concentration. 1. Weight by volume (w/v) refers to the weight of crude allergen added to the extracting fluid. A 1:10 w/v extract, e.g., indicates that the solution contains the extractable material from one gram of raw material added to each 10 mL of extracting fluid. The amount and composition of extracted materials will vary with the kind of antigen, the extracting fluid, duration of extraction, pH, temperature, and other variables. Pollens are typically extracted at 1:20 (w/v) in Glycero-Coca’s, and at 1:10 (w/v) in Coca’s. Epidermal, environmental, molds and insect products are typically extracted at 1:10 w/v. AP Acetone precipitated epidermal products are prepared at a 1:50 w/v concentration (i.e., 1 gram of dried precipitate in 50 mL of reconstitution fluid). AP Dog Hair-Dander is prepared at 1:100 w/v. (i.e., 1 gram of dried precipitate in 100 mL of reconstitution fluid). 2. Protein Nitrogen Units (PNU) One protein nitrogen unit represents 0.00001 mg phosphotungstic acid precipitable protein nitrogen dissolved in one mL of antigen extract. The PNU content of extracts of the same antigen may vary according to the method of measuring the PNU. Thus, the PNU content of extracts from different manufacturers is not comparable unless the PNU method is known to be the same and is reproducible from lot to lot. The amount of protein nitrogen extracted from an antigen is influenced by such factors as the kind of antigen, the extracting fluid, duration of extraction, pH, temperature and other variables. Allergenic materials make up a variable proportion of the total protein of an extract. Most allergenic extracts are assayed for PNU. This unitage can be obtained for patient prescriptions. 10,000 PNU/mL is typically the strength of each allergen used for treatment formulation (if available). 3. Amb a 1. Of the many allergens from Short Ragweed which have been purified and characterized [Amb a 1 (also known as Antigen E) 3, Amb a 2 (also known as Antigen K) 3, Ra34, Ra4 (BPA-R)5, Ra56, Ra6, Ra7, and Ra8 7, and cytochrome C 8], Amb a 1 is considered the most important and has been selected as the basis for standardization. Extracts of Short Ragweed containing Amb a 1 are diffused in agar against standard anti-serum to Amb a 1, and compared to the diffusion of standard Amb a 1 solutions. The amount of Amb a 1 is expressed as units of Amb a 1 per mL of extract. Amb a 1 units are approximately equal to micrograms previously used to measure Amb a 1 concentration. Amb a 1 assay therefore provides an absolute measure of extract potency related to the Amb a 1 antigen in Short Ragweed, rather than only an expression of extract strength. Each concentrated lot of Short Ragweed and Giant and Short Ragweed Mix is as sayed for Amb a 1 and submitted to the Center for Biologics Evaluation and Research (CBER) for release. The Amb a 1 concentration of any extract which is diluted with a diluent or other allergenic extracts is determined by calculation. The Amb a 1 concentrations for dilutions of extracts greater than 1:20 w/v have been obtained by calculation from the assayed value. 4. Allergy Units (AU/mL). The potency of extracts labeled in Allergy Units (AU/mL) is determined by in vitro comparison to a reference standard established by the Center for Biologics Evaluation and Research (CBER) of the Food and Drug Administration. 5. Bioequivalent Allergy Units (BAU/mL). Other standardized allergenic extracts are labeled in Bioequivalent Allergy Units/mL (BAU/mL) based on their comparison (by ELISA Inhibition or major allergen content) to CBER, FDA Reference Preparations. The FDA reference extracts have been assigned Bioequivalent Allergy Units based on the CBER ID 50EAL technique. 9 Briefly, highly sensitive patients are skin tested to the reference preparation using an intradermal technique employing 3-fold extract dilutions. Depending on the dilution which elicits a summation of erythema diameter of 50, Bioequivalent Allergy Units are assigned as follows: BAU/mL D50 100,000 13-14.9 10,000 11-12.9 1,000 9-10.9 Each lot of Standardized Cat Hair extract is standardized by quantitating the Fel d 1 content based on standards on file with the Center for Biologics Evaluation and Research (CBER) of the U.S. Food and Drug Administration. Test extracts are diffused in agar containing standard anti-serum to Fel d 1, and compared to the diffusion of a reference cat allergen preparation.10 The potency of the extract is expressed as units of Fel d 1 per mL, and extracts containing 10-19.9 Fel d 1 units per mL are labeled at 10,000 BAU/mL. It has been recognized that there are differences in the levels of non Fel d 1 allergens among standardized cat extracts which utilize different source materials. Isoelectric focusing (IEF) patterns have been shown to be predictive of the presence of non Fel d 1 allergens. Therefore, each lot of Standardized Cat Hair is compared by IEF to a Cat Pelt Extract Reference and a Cat Hair Extract Reference on file with the CBER. The labeled name of the cat extract (i.e., Cat Hair Extract or Cat Pelt Extract) must be supported by matching the IEF profile of the corresponding reference. INGREDIENTS: Active ingredients are those allergens listed on the bottom of the package. The strength at which each allergen is added to the Concentrate will also be listed. The standardized mites are grown on a medium of brine shrimp eggs and wheat germ, and are handled and cleaned by a method in which the maximum carryover of the medium components is less than 1%. The medium contains no material of human origin. Preservative is 50% (v/v) glycerin, or 0.4% phenol, as indicated on the product labeling. Additional ingredi ents present in extracting fluids are 0.275% sodium bicarbonate and 0.5% sodium chloride. Vials are diluted from the Concentrate with one of the following diluting fluids. Refer to ingredient list to determine which diluting fluid is used. Sterile Buffered Saline with Phenol (BSP): 0.5% sodium chloride, 0.275% sodium bicarbonate, and 0.4% phenol. Sterile Glycerin Solution (GLY): 50% glycerin. Sterile Albumin Saline with Phenol (ABS): 0.9% sodium chloride, 0.03% albumin (human), and 0.4% phenol. CLINICAL PHARMACOLOGY: 11 The mechanisms by which hyposensitization is achieved are not known completely. It has been shown that repeated injections of appropriate allergenic extracts will ameliorate the intensity of allergic symptoms upon contact with the allergen. 12, 13, 14, 15 Well-controlled clinical studies which demonstrate the efficacy of immunotherapy are available. The allergens which have been studied are cat, mite, and some pollen extracts. 16, 17, 18, 19, 20, 21 Extension of these results to other allergens is generally acceptable. “Blocking antibodies” (IgG), which compete with cell-bound IgE for antigen, appear in the serum as a result of allergen injection. While the level of blocking antibodies is allergen dose related, it does not appear to be related to the relief from symptoms although, as a group, treated patients have higher antibody titers and fewer symptoms than those untreated. IgE antibodies bound to receptors on mast cell membranes are required for the allergic reaction, and their level is probably related to serum IgE concentrations. Initially, serum IgE levels increase with immunotherapy, but continued treatment results in a reduction. The histamine release response of circulating basophils to a specific allergen is reduced in some patients by immunotherapy, but the mechanism of this change is not yet clear. Further study and clarification of the relationships between changes in blocking antibody, reaginic antibody, and mediator-releasing cells, and between these three factors and successful immunotherapy, is needed. INDICATIONS AND USAGE: 11, 22, 23, 24 Allergenic extracts are indicated for use in diagnosis and immunotherapy of patients presenting symptoms of allergy (hay fever, rhinitis, etc.) to specific environmental allergens. The use of graduated doses of specific allergenic extracts followed by maintenance doses of the most concentrated extract tolerated has long been used for immunotherapy of patients presenting symptoms of allergy (hay fever, rhinitis, etc.) to specifically identified materials. The selection of allergenic extracts to be used should be based on a thorough and carefully taken history of hypersensitivity, confirmed by skin testing. 25, 26 While statistically controlled, blind studies on the usefulness of aeroallergens in immunotherapy have been made, for the most part, only for some pollens, extension of these results to other allergens in certain conditions is generally considered acceptable. Avoidance is to be environmental allergens. The use of graduated doses of specific allergenic extracts followed by maintenance doses of the most concentrated extract tolerated has long been used for immunotherapy of patients presenting symptoms of allergy (hay fever, rhinitis, etc.) to specifically identified materials. The selection of allergenic extracts to be used should be based on a thorough and carefully taken history of hypersensitivity, confirmed by skin testing. 25, 26 FOLLOWING A DOSAGE REDUCTION OR EXTRA DILUTIONS ARE REQUIRED IN THE While statistically controlled, blind studies reduction or the need for extra dilutions must CIRCUMSTANCES. The actual amount of dosageon the usefulness of aeroallergens in immunotherapy have been made, for the based part, only for some pollens, extension of these results be determined by the physician most on the clinical situation. Dose should be significantly toless than 50% of in certain conditions is generallythe previous acceptable. Avoidance is be be other allergens the last administered dose from considered extract. Skin testing can to advocatedin determining relative potencybe attained, e.g., allergy to dog dander in kennel owners helpful if possible, but cannot always between two extracts. and employees, more breeders, research workers, veterinarians, etc. as authorized by the 1. If one or dog antigens have been deleted from the mixture Allergens to which a patient is extremely sensitive should not be included in treatment mixes physician. with allergens to which therewas outdated.sensitivity, but should be administered separately. This 2. If the previous extract is much less allows individualized and better control of dosage increases, including adjustments in dosage 3. If prolonged time has elapsed since the last injection. becoming necessary after been made in the refill formula, suchto the highly reactive allergen. 4. If other changes have severe reactions which may occur as redistribution of component parts or percentages, or are no known extracting fluid. CONTRAINDICATIONS: There a difference in absolute contraindications to immunotherapy. See PRECAUTIONSNEW WARNINGS. IMMUNOTHERAPY, OR ESTABLISH INITIAL DOSE BY SKIN INITIATE and COURSE OF Patients FOR THE FOLLOWING SITUATIONS: TITRATIONwith cardiovascular diseases and/or pulmonary diseases such as symptomatic unstable, steroid-dependent asthma, and/or those who are receiving cardiovascular drugs such 1. If blockers, may be at higher risk been added to, or substituted for patients may also as betaone or more new antigens have for severe adverse reactions. Theseantigens in the previous formula as normal allergy treatment regimen. Patients should be treated only if be more refractory to theauthorized by the physician. 2. benefit of treatment outweighsCat Hair to 1Standardized Cat Pelt extracts or vice-versa. Hair the If changing from Standardized the risks. and patients only with allergens to which allergens and are not interchangeable. Treat Pelt extracts differ in their non Fel d 1 they are allergic by skin test reaction, have a 3. If of or more on exposure, and are antigens have been returned to the mixture as history onesymptomspreviously unavailable likely to be exposed again. authorized by including immunotherapy, should be avoided in patients with a bleeding Any injections, the physician. 4. If the tendency. previously used extract was non-standardized or was standardized and labeled in Allergy Units per mL (AU/mL). Patients on beta blockers may be more reactive to allergens given for testing or treatment and 5. If the extract previously usual was from epinephrine used to treat systemic reactions. 2 may be unresponsive to the used doses of another manufacturer. 6. Since there are differences of opinion concerning the possibility of routine immunizations If changing from alum-adsorbed to aqueous or glycerinated extracts. exacerbating autoimmune diseases, immunotherapy should be prevent most systemic reacProper selection of the dose and careful injection should given cautiously to patients with other immunologic diseases and only if that allergenic extracts are highly potent in sensitive tions. It must be remembered, however, the risk from exposure to the allergen is greater than the risk of exacerbating systemic reactions of varying degrees of severity may occur, including individuals, and that the underlying disorder. urticaria, rhinitis,WARNINGS box wheezing, coughing, angioedema, hypotension, bradycardia, WARNINGS: See conjunctivitis, at the beginning of this package insert. See also PRECAUTIONS. pallor, laryngeal edema, fainting, or even anaphylactic shock andor the dose describeddownward Allergenic extracts must be temporarily withheld from patients death, as adjusted under ADVERSEthe following conditionsshould(1) severe symptoms of rhinitis and/or asthma, (2) infection if any of REACTIONS. Patients exist: be informed of this, and the warnings and precautions shouldaccompanied by fever, immunotherapy. (See PRECAUTIONS.) Severe or generalized reaction or flu be discussed prior to (3) any evidence of an excessively large local systemic reactions should be treated stages of immunotherapy REACTIONS. during the initial as indicated in ADVERSE or during maintenance therapy, and/or (4) exposure to excessive amounts of clinically relevant allergen prior to a scheduled injection. Do not start PRECAUTIONS: immunotherapy during a period of symptoms due to exposure. Since the individual components (1) General of the extract are those to which thesigns and allergic, and to which s/hean indicator for severe The presence of asthmatic patient is symptoms appear to be will be exposed, typical allergic symptoms may allergy shortly afterAn assessmentparticularly obstruction either loadmeareactions following follow injections. the injection, of airway when the antigen by from exposure plusof peak flow or an alternate procedure may provide a useful indicator as to the surement the injected antigen exceeds the patient’s antigen tolerance. THE CONCENTRATE MUST NOT BE INJECTED AT ANY TIME UNLESS TOLERANCE HAS BEEN advisability of administering an allergy injection. 1, 27, 28, 29, 30 ESTABLISHED. INJECTIONS MUST NEVER BE GIVEN INTRAVENOUSLY. Sub cutaneous injection Concentrated extracts must not be injected unless tolerance has been established. is recommended. extracts must be diluted prior to injection may produce large local reactions Concentrated Intracutaneous or intramuscular use. See DOSAGE AND ADMINISTRATION or be excessively painful. on the dilution of allergenic extracts. for detailed instructions AFTER INSERTING NEEDLE, BUT BEFOREreaction requires a reduction in dosage during the Any evidence of a local or generalized INJECTING, ALWAYS WITHDRAW THE PLUNGER SLIGHTLY. IF BLOOD APPEARS IN THE well as during maintenance therapy. initial stages of immunotherapy, as SYRINGE, CHANGE NEEDLE AND GIVE THE INJECTION IN ANOTHER SITE. To insure subcutaneous deposition Saline with Phenol (0.4%) diluent may Allergenic extracts diluted with sterile Albumin of the injected material, pinch the skin up between the thumb and forefinger from thediluents which of the upper arm over the triceps be more potent than extracts diluted with outer surface do not contain stabilizers. When muscle. Introduce non-stabilized ato stabilizedto the arm surfaceweaker initial dilutions for to the changing from the needle at 45° angle diluent, consider into the tent, or parallel both armintradermal testing and immunotherapy. selection of the dose and careful injection should surface at the base of the tent. Proper preventSterile systemic reactions. most solutions, vials, syringes, etc., should be used and aseptic precautions observed Systemic reactions may occurprepared should bemay range sterility. exaggeration of the in making dilutions. Dilutions infrequently and tested for from mild patient’s allergiccross-contamination, do rhinitis, conjunctivitis, angioedema, cough, wheezing, To avoid symptoms to urticaria, not use the same needle to withdraw materials from fainting, of morebradycardia, hypotension, or followed by diluent. sensitive individuals, to anavials pallor, than one extract, or extract even, in extremely phylactic sterile and death. syringe, with a needle at least 5/8" risk and the precautions prior to A shock tuberculin Patients should be informed of the long and graduated in 0.01 mL skinunits should be used to measure each systemic reactions should dilution. as indicated in testing and immunotherapy. Severe, dose from the prescribed be treated the ADVERSE REACTIONS section. A SEPARATE STERILE SYRINGE SHOULD BE USED FOR EACH PATIENT TO PREVENT CAUTION: REDUCEDHEPATITIS EXTRA DILUTIONS MAY BE REQUIRED UNDER PERSON THE TRANSMISSION OF DOSE OR AND OTHER INFECTIOUS AGENTS FROM ONE ANY OF TO CONDITIONS NOTED. Injections under any of these conditions could result in an adverse effect ANOTHER. on the Patient reactions to previous injections should be reviewedThe dose should be decreased patient if the usual dose for a new refill is administered. before each new injection and significantly further than the 1/2-dose recommended for starting a new refill.of local responses a conservative dosage schedule followed by the physician until a pattern One or more extra dilutions are generally required. used discussion of specific in dosage. is established which can be See to monitor increases circumstances. The number of dilutions required a patient is encountered whophysician, based upon the patient’s clinical history, Rarely should be determined by the develops systemic reactions to minute doses of including skin test results and previous tolerance oftolerance to injections after several months antigen and does not demonstrate increasing the extracts, and on seasonal allergy factors. Dilutions can be prepared as reactions or excessive AND ADMINISTRATION.persistently at very of treatment. If systemic described in DOSAGE local responses occur small doses, efforts at immunotherapy should be stopped. PATIENTS SHOULD BE OBSERVED IN THE OFFICE FOR AT LEAST 30 MINUTES AFTER EACH TREATMENT INJECTION and instructed to return to the office promptly if symptoms by maintenance doses of the most concentrated extract tolerated has long been used for immunotherapy of patients presenting symptoms of allergy (hay fever, rhinitis, etc.) to specifically identified materials. The selection of allergenic extracts to be used should be based on a thorough and carefully taken history of hypersensitivity, confirmed by skin testing. 25, 26 A DOSAGE REDUCTION OR EXTRA DILUTIONS usefulness of aeroallergens in immunoWhile statistically controlled, blind studies on the ARE REQUIRED IN THE FOLLOWING CIRCUMSTANCES. The actual amount of dosage reduction or the need for extra dilutions must therapy have been made, for the most part, only for some pollens, extension of these results be determined by the physician based is generally situation. acceptable. be significantly to other allergens in certain conditionson the clinicalconsidered Dose should Avoidance is to be less than 50% of the last administered dose from e.g., allergy to dog Skin testing can be advocated if possible, but cannot always be attained,the previous extract.dander in kennel owners helpful in determining relative potency between two extracts. and employees, dog breeders, research workers, veterinarians, etc. 1. Allergens tomore antigens have been deleted from the not be included in treatmentthe If one or which a patient is extremely sensitive should mixture as authorized by mixes with physician.to which there is much less sensitivity, but should be administered separately. This allergens allows the previous extract was outdated. dosage increases, including adjustments in dosage 2. If individualized and better control of becoming necessary after severe reactions whichinjection. to the highly reactive allergen. 3. If prolonged time has elapsed since the last may occur 4. If other changes have been made known absolute contraindications to immunotherapy. CONTRAINDICATIONS: There are no in the refill formula, such as redistribution of componentSee parts or percentages, or a difference in extracting fluid. PRECAUTIONS and WARNINGS. Patients with cardiovascularIMMUNOTHERAPY,pulmonary diseases such as symptomatic INITIATE NEW COURSE OF diseases and/or OR ESTABLISH INITIAL DOSE BY SKIN unstable, steroid-dependent asthma,SITUATIONS: who are receiving cardiovascular drugs such TITRATION FOR THE FOLLOWING and/or those as beta blockers, may be antigens have been added to, or reactions. Theseantigens in thealso 1. If one or more new at higher risk for severe adverse substituted for patients may be more refractory to as authorized by the physician. previous formula the normal allergy treatment regimen. Patients should be treated only if 1 the benefit of treatment outweighs the risks.Standardized Cat Pelt extracts or vice-versa. Hair 2. If changing from Standardized Cat Hair to Treat Pelt extracts differ in their non Fel d 1 allergens allergic by skin test reaction, have a and patients only with allergens to which they are and are not interchangeable. historyone symptomspreviously unavailable likely to be exposed again. to the mixture as of or more on exposure, and are antigens have been returned 3. If Any injections, the physician. authorized by including immunotherapy, should be avoided in patients with a bleeding tendency. previously used extract was non-standardized or was standardized and labeled in 4. If the Patients on beta blockers may be more reactive to allergens given for testing or treatment and Allergy Units per mL (AU/mL). mayIf the extract previously usual was from epinephrine used to treat systemic reactions. 2 5. be unresponsive to the used doses of another manufacturer. 6. Since there are differences of opinion concerning the possibility of routine immunizations If changing from alum-adsorbed to aqueous or glycerinated extracts. exacerbating autoimmune diseases, immunotherapy should be given cautiously to patients with other immunologic diseases and and careful injection should prevent most systemic reac- the Proper selection of the dose only if the risk from exposure to the allergen is greater than risk It must be remembered, however, that tions. of exacerbating the underlying disorder.allergenic extracts are highly potent in sensitive individuals, and that systemic reactions of varying this package severity may occur, including WARNINGS: See WARNINGS box at the beginning of degrees of insert. See also PRECAUTIONS. urticaria, rhinitis, conjunctivitis,temporarily coughing, angioedema,or the dose adjusted downward Allergenic extracts must be wheezing, withheld from patients hypotension, bradycardia, pallor, laryngeal edema, fainting, exist: (1) anaphylactic shock and death, as asthma, (2) infection if any of the following conditions or even severe symptoms of rhinitis and/or described under ADVERSE REACTIONS. Patients should be informed of this, and large local or generalized reaction or flu accompanied by fever, (3) any evidence of an excessively the warnings and precautions should be discussed prior of immunotherapy or during maintenance Severe systemic (4) exposure during the initial stages to immunotherapy. (See PRECAUTIONS.) therapy, and/or reactions should be treated as indicated in ADVERSE REACTIONS. to a scheduled injection. Do not start to excessive amounts of clinically relevant allergen prior immunotherapy PRECAUTIONS: during a period of symptoms due to exposure. Since the individual components of General (1) the extract are those to which the patient is allergic, and to which s/he will be exposed, typical allergic symptoms may follow shortly after thesymptoms particularlybe an the antigen load from The presence of asthmatic signs and injection, appear to when indicator for severe exposure plus the injected antigen exceeds the patient’s antigen tolerance. reactions following allergy injections. An assessment of airway obstruction either by meaTHE CONCENTRATE MUST NOT BE INJECTED AT may provide a useful indicator as to the surement of peak flow or an alternate procedure ANY TIME UNLESS TOLERANCE HAS BEEN ESTABLISHED. of administering an allergy injection. 1,INTRAVENOUSLY. Sub cutaneous injection advisability INJECTIONS MUST NEVER BE GIVEN 27, 28, 29, 30 is recommended. Intracutaneous or not be injected unless may produce large local reactions Concentrated extracts must intramuscular injection tolerance has been established. or be excessivelyextracts must be diluted prior to use. See DOSAGE AND ADMINISTRATION Concentrated painful. AFTER INSERTING NEEDLE, BUT BEFORE INJECTING, ALWAYS for detailed instructions on the dilution of allergenic extracts. WITHDRAW THE PLUNGER SLIGHTLY. evidence ofAPPEARS IN THE SYRINGE, CHANGE NEEDLE AND in dosage during the Any IF BLOOD a local or generalized reaction requires a reduction GIVE THE INJECTION IN ANOTHER SITE. immunotherapy, as well as during maintenance therapy. initial stages of To insure subcutaneous deposition of the injected material, pinch the skin up between the thumb and forefinger from the outer surface of the upper (0.4%) diluenttriceps Allergenic extracts diluted with sterile Albumin Saline with Phenol arm over the may muscle. Introduce the needle at adiluted withto the arm surface into contain stabilizers. When be more potent than extracts 45° angle diluents which do not the tent, or parallel to the arm surface from non-stabilizedtent. Proper selectionconsider weaker initial dilutions forshould changing at the base of the to stabilized diluent, of the dose and careful injection both prevent most systemic and immunotherapy. intradermal testing reactions. Systemic reactions may occur infrequently and be used and from mild exaggeration of the Sterile solutions, vials, syringes, etc., should may range aseptic precautions observed patient’s allergic symptoms to urticaria, rhinitis, conjunctivitis, sterility. in making dilutions. Dilutions prepared should be tested for angioedema, cough, wheezing, fainting, pallor, cross-contamination, do not use thein extremely sensitive individuals, to anaTo avoid bradycardia, hypotension, or even, same needle to withdraw materials from phylacticof moreand death.extract, or extract followed byof the risk and the precautions prior to vials shock than one Patients should be informed diluent. skin testing andtuberculin syringe,Severe, systemic reactions should be graduated in 0.01 mL A sterile immunotherapy. with a needle at least 5/8" long and treated as indicated in the units should be used to section. each dose from the prescribed dilution. ADVERSE REACTIONS measure CAUTION: REDUCED DOSESYRINGE SHOULD BE USED BE REQUIRED UNDER ANY OF THE A SEPARATE STERILE OR EXTRA DILUTIONS MAY FOR EACH PATIENT TO PREVENT CONDITIONS NOTED. Injections under any of these conditions could result in an adverse effect TRANSMISSION OF HEPATITIS AND OTHER INFECTIOUS AGENTS FROM ONE PERSON TO on ANOTHER. if the usual dose for a new refill is administered. The dose should be decreased the patient significantly further than the 1/2-dose recommended be reviewed a new refill. new injection extra Patient reactions to previous injections should for starting before each One or more and dilutions are generally required. See discussionthe specific circumstances. Thelocal responses a conservative dosage schedule followed by of physician until a pattern of number of dilutions established which can be used to monitor increases in dosage. patient’s clinical history, is required should be determined by the physician, based upon the including skin a patient is and previous tolerance of the systemic and on seasonal allergy factors. Rarely test results encountered who develops extracts, reactions to minute doses of Dilutions can bedoes not demonstrate increasing tolerance to injections after several months antigen and prepared as described in DOSAGE AND ADMINISTRATION. of treatment. If systemic reactions or excessive local responses occur persistently at very small doses, efforts at immunotherapy should be stopped. PATIENTS SHOULD BE OBSERVED IN THE OFFICE FOR AT LEAST 30 MINUTES AFTER a conservative dosage schedule followed by the physician until a pattern of local responses is established which can be used to monitor increases in dosage. Rarely a patient is encountered who develops systemic reactions to minute doses of antigen and does not demonstrate increasing tolerance to injections after several months of treatment. If systemic reactions or excessive local responses occur persistently at very (8) Geriatric Use small doses, efforts at immunotherapy should be stopped. The reactions from immunotherapy can be expected to be the same in elderly patients as PATIENTS SHOULD BE OBSERVED IN THE OFFICE FOR AT LEAST 30 MINUTES AFTER in younger ones. Elderly patients may be more likely to be on medication that could block EACH TREATMENT INJECTION and instructed to return to the office promptly if symptoms the effect of epinephrine which could be used to treat serious reactions, or they could be of an allergic reaction or shock occur. Most severe reactions will occur within this time more sensitive to the cardiovascular side effect of epinephrine because of pre-existing period, and rapid treatment measures should be instituted. See ADVERSE REACTIONS for cardiovascular disease. 37 these treatment measures. ADVERSE REACTIONS (2) Information for Patients Physicians administeringbe instructed in the recognition of adverse reactions to immunotherapy, Patients should allergenic extract testing or treatment materials should be experienced in the treatment of severe systemic reactions. See WARNINGS box at at the beginningof this and in particular, to the symptoms of shock. (See WARNINGS box the beginning of this package insert. package insert.) Patients should be made to understand the importance of a 30 minute observation period following skin testing or therapeutic injections, and be cautioned to (1) Local Reactions return to erythema, promptly if symptomsat the site of injection are common, the extent Some the office swelling, or pruritus occur after leaving. Patients the patient. Such reactions should not be considered significant allergen, so varying with should be instructed to report any symptoms of exposure to the unless they the physician leastadjust the dosage appropriately. persist for at can 24 hours. Local reactions (erythema or swelling) which exceed 4-5 (3) cm in Interactions not only uncomfortable, but also indicate the possibility of a systemic Drug diameter are reaction if dosagecardiovascular In such cases the dosage should besuch as symptomatic Patients with is increased. diseases and/or pulmonary diseases reduced to the last level not causing the reaction asthma, and/or those who are receiving cardiovascular drugs unstable, steroid-dependent and maintained at this level for two or three injections before cautiously increasing again. be at higher risk for severe adverse reactions. These patients such as beta blockers, may Large, be more local reactions may be treated by local applications Patients should be may also persistentrefractory to the normal allergy treatment regimen. of cold, wet dressings and/or the the benefit antihistamines. They should risks. 1 treated only if use of oral of treatment outweighs the be considered a warning of possible severe systemic beta blockers may need for temporarily allergens dosages. testing or treatPatients on reactions, and the be more reactive to reduced given for A and may be unresponsive to injection is of epinephrine used to treat allergic mentmild burning immediately after the usual dosesto be expected; this usually leaves in 10 to 20 seconds. Prolonged pain, or pain radiating up the arm, is usually the result of reactions. intramuscular injection, makinglessen the skin testundesirable. Subcutaneous injection is Certain medications may this injection route wheal and erythema responses elicthe preferred route. and histamine for varying time periods. Conventional antihistamines ited by allergens should be discontinued at least 5 days before skin testing. Long acting antihista(2) Systemic Reactions mines should be discontinued for at least 3 weeks prior to skin testing.31 Topical With careful attention to dosage and administration, such reactions occur infrequently, steroids should be discontinued at the skin test site for at least 2-3 weeks before skin but it must be remembered that allergenic extracts are highly potent in sensi tive individuals testing.31,32 and any injection could result in anaphylactic symptoms. Therefore, it is imperative that Tricyclic antidepressants such as Doxepin should be withheld for at least 7 days before physicians administering allergen extracts understand and be prepared for the treatment skin testing. 33 Topical local anesthetics may suppress the flare responses and should be of severe reactions. avoided in skin test sites. 34 Most severe systemic reactions will begin within a 30 minute time period, but systemic When using other drugs in patients receiving allergenic extracts, always consult the reactions may occur at any time after skin tests or immunotherapy. Symptoms may range product labeling of the other drugs to determine any possible interaction with use of alfrom mild to life-threatening (due to anaphylaxis) as described below. lergenic extracts. It cannot be overemphasized that, under certain unpredictable combinations of cir(4) cumstances, anaphylactic shock Impairment of Fertility Other possible systemic reac tion Carcinogenesis, Mutagenesis, is always a possibility. Long-term studies in animals have degrees of severity, are laryngeal edema, to detersymptoms which may occur in varyingnot been conducted with allergenic extracts fainting, mine bradycardia, for carcinogenicity, mutagenicity, or impairment of fertility. pallor, their potentialhypotension, angioedema, cough, wheezing, conjunctivitis, rhinitis and (5) urticaria. Adverse reaction frequency data for allergenic extract administration for testing Pregnancy 35 and Pregnancyshow that risk is low.reproduction studies have not been conducted with altreatment Category C. Animal 1, 38 If a systemic or is also not known whether occur, apply a tourniquet above harm when lergenic extracts. Itanaphylactic reaction doesallergenic extracts can cause fetal the site of injection and inject 1:1000 epinephrine-hydrochloride intramuscularly into the opposite administered to a pregnant woman or can affect reproduction capacity. arm.Allergenic the tourniquet atbe given to a 10 minutes. Do not obstruct arterial blood Loosen extracts should least every pregnant woman only if clearly needed. The flow with the tourniquet. consider the benefit-to-risk ratio to both patient and fetus, of physician must carefully performing skin testing EPINEPHRINE DOSAGE: or continuing immunotherapy during pregnancy. The recommended precautions (See mL should be injected. Repeat for to 10 minutes if necessary. ADULT: 0.3 to 0.5 WARNINGS AND PRECAUTIONS)in 5 preventing adverse reactions are especially important in the pregnant patient. Based on the physician’s discretion, immunotherapy PEDIATRIC: The usual initial dose is 0.01 mg (mL) per kg body weight or 0.3 mg (mL) per maintenance doses may be continued during pregnancy if the patient has not experienced square meter of body surface area. Suggested dosage for infants to 2 years of age is 0.05 adverse side effects. Immunotherapy is generally not initiated during pregnancy due to the mL to 0.1 mL; for children 2 to 6 years, 0.15 mL; and children 6 to 12 years, 0.2 mL. Single risks associated with systemic reactions and their treatment. 36 pediatric doses should not exceed 0.3 mg (mL). Doses may be repeated as frequently as every (6) 20 minutes, depending on the severity of the condition and the response of the patient. Nursing Mothers There are no current epinephrine, profound shock or vasomotor components in After administration of studies on the secretion of allergenic extractcollapse should human milk or intravenous fluids, and infant. vasoactive drugs. are excreted in be treated with their effect on the nursingpossibly Because many drugsAirway patency human milk, caution should be exercised when allergenic extracts are administered to should be insured. Oxygen should be given by mask. Intravenous antihistamine, inhaleda nursing woman. bronchodilators, theophylline and/or adrenal corticosteroids may be used if necessary after (7) adequate epinephrine and circulatory support has been given. Pediatric Use Emergency resuscitation measures and personnel trained in adults. Because be available The dosage for the pediatric population is the same as for their use must of the small immediately child, larger of a serious solution may produce excessive discomfort. Therefore, size of the in the event volumes of systemic or anaphylactic reaction not responsive to the above measures. [Ref. J. Allergy and Clinicalthe volume of the dose may need to be divided in order to achieve the total dose required, Immunology, 77(2): p. 271-273, 1986.] Rarely than of injection measures into moreare allone the above per visit. necessary, the tourniquet and epinephrine usually producing prompt responses. However, the physician should be prepared in advance for all contingencies. Promptness in beginning emergency treatment measures is of utmost importance. a conservative dosage schedule followed by the physician until a pattern of local responses is established which can be used to monitor increases in dosage. Rarely a patient is encountered who develops systemic reactions to minute doses of antigen and does not demonstrate increasing tolerance to injections after several months of treatment. If systemic reactions or excessive local responses occur persistently at very (8) Geriatric Use small doses, efforts at immunotherapy should be stopped. The reactions from immunotherapy can be expected to be the same in elderly patients as PATIENTS SHOULD BE OBSERVED IN THE OFFICE FOR AT LEAST 30 MINUTES AFTER in younger ones. Elderly patients may be more likely to be on medication that could block EACH TREATMENT INJECTION and instructed to return to the office promptly if symptoms the effect of epinephrine which could be used to treat serious reactions, or they could be of an allergic reaction or shock occur. Most severe reactions will occur within this time more sensitive to the cardiovascular side effect of epinephrine because of pre-existing period, and rapid treatment measures should be instituted. See ADVERSE REACTIONS for cardiovascular disease. 37 these treatment measures. ADVERSE REACTIONS (2) Information for Patients Physicians administering allergenic extract testing or treatment materials shouldimmunotherapy, Patients should be instructed in the recognition of adverse reactions to be experienced in the treatment of severe systemic reactions. See WARNINGS box atatthe beginning of this and in particular, to the symptoms of shock. (See WARNINGS box the beginning of this package insert. package insert.) Patients should be made to understand the importance of a 30 minute observation period following skin testing or therapeutic injections, and be cautioned to (1) Local Reactions return to the office promptly ifor pruritus at the after of injection are common, the extent Some erythema, swelling, symptoms occur site leaving. Patients the patient. Such reactions should not be considered significant allergen, so varying with should be instructed to report any symptoms of exposure to the unless they the physician least 24 hours. Local reactions (erythema or swelling) which exceed 4-5 persist for at can adjust the dosage appropriately. (3) cm in Interactions not only uncomfortable, but also indicate the possibility of a systemic Drug diameter are Patients with cardiovascular In such and/or pulmonary diseases reduced to the last reaction if dosage is increased. diseases cases the dosage should besuch as symptomatic unstable, steroid-dependent and maintained at this level for two or three injections drugs level not causing the reactionasthma, and/or those who are receiving cardiovascularbefore such as beta blockers, may cautiously increasing again. be at higher risk for severe adverse reactions. These patients may also persistentrefractory to themay be treated by local applications of cold, wet dressLarge, be more local reactions normal allergy treatment regimen. Patients should be treated only if use of oral antihistamines. They should be considered a warning of possible ings and/or the the benefit of treatment outweighs the risks. 1 Patients on reactions, and the need for temporarily reduced given for severe systemic beta blockers may be more reactive to allergens dosages. testing or treatment mild burning immediately after the usual doses to be expected; this usually leaves in A and may be unresponsive to the injection is of epinephrine used to treat allergic reactions. 10 to 20 seconds. Prolonged pain, or pain radiating up the arm, is usually the result of Certain medications may lessen the skin test wheal and erythema responses elicintramuscular injection, making this injection route undesirable. Subcutaneous injection is ited by allergens the preferred route.and histamine for varying time periods. Conventional antihistamines should be discontinued at least 5 days before skin testing. Long acting antihista(2) Systemic Reactions mines should be discontinued for at least 3 weeks prior to skin testing.31 Topical With careful attention to dosage and administration, such reactions occur infrequently, steroids should be discontinued at the skin test site for at least 2-3 weeks before skin but it must be remembered that allergenic extracts are highly potent in sensi tive individuals testing.31,32 and any injection could result in anaphylactic symptoms. Therefore, it is imperative that Tricyclic antidepressants such as Doxepin should be withheld for at least 7 days before physicians administering allergen extracts understand and be prepared for the treatment skin testing. 33 Topical local anesthetics may suppress the flare responses and should be of severe reactions. avoided in skin test sites. 34 Most severe systemic reactions will begin within a 30 minute time period, but systemic When using other drugs in patients receiving allergenic extracts, always consult the reactions may occur at any time after skin tests or immunotherapy. Symptoms may range product labeling of the other drugs to determine any possible interaction with use of alfrom mild to life-threatening (due to anaphylaxis) as described below. lergenic extracts. It cannot be overemphasized that, under certain unpredictable combinations of cir(4) cumstances, anaphylactic shockImpairmentaof Fertility Other possible systemic reac tion Carcinogenesis, Mutagenesis, is always possibility. Long-term studies occur in varying degrees of severity, are laryngeal edema, to detersymptoms which may in animals have not been conducted with allergenic extracts fainting, mine bradycardia, for carcinogenicity, mutagenicity, or impairment of fertility. pallor,their potentialhypotension, angioedema, cough, wheezing, conjunctivitis, rhinitis and (5) urticaria. Adverse reaction frequency data for allergenic extract administration for testing Pregnancy 35 and Pregnancy show that C. Animal reproduction studies have not been conducted with altreatment Category risk is low. 1, 38 If a systemic It is also not known whether allergenic extracts can cause fetal the site of lergenic extracts.or anaphylactic reaction does occur, apply a tourniquet above harm when injection and to a pregnant woman or can affect reproduction capacity. into the opposite administered inject 1:1000 epinephrine-hydrochloride intramuscularly arm. Loosen the tourniquet at least every 10 minutes. Do not obstruct arterial blood Allergenic extracts should be given to a pregnant woman only if clearly needed. The flow with the tourniquet. consider the benefit-to-risk ratio to both patient and fetus, of physician must carefully performing skin testing or continuing immunotherapy during pregnancy. The recommended EPINEPHRINE DOSAGE: precautions (See mL should be injected. Repeat for to 10 minutes if necessary. ADULT: 0.3 to 0.5WARNINGS AND PRECAUTIONS)in 5 preventing adverse reactions are especially important in the pregnant patient. Based on the physician’s discretion, immunotherapy PEDIATRIC: The usual initial dose is 0.01 mg (mL) per kg body weight or 0.3 mg (mL) per maintenance doses may be continued during pregnancy if the patient has not experienced square meter of body surface area. Suggested dosage for infants to 2 years of age is 0.05 adverse side effects. Immunotherapy is generally not initiated during pregnancy due to the mL to 0.1 mL; for children 2 to 6 years, 0.15 mL; and children 36 to 12 years, 0.2 mL. Single 6 risks associated with systemic reactions and their treatment. pediatric doses should not exceed 0.3 mg (mL). Doses may be repeated as frequently as every (6) 20 minutes, depending on the severity of the condition and the response of the patient. Nursing Mothers There are no current epinephrine, secretion of allergenic extract components in After administration ofstudies on theprofound shock or vasomotor collapse should human milk or intravenous the nursing infant. vasoactive drugs. are excreted in be treated with their effect onfluids, and possibly Because many drugsAirway patency human milk, caution should be exercised when allergenic extracts are administered to a should be insured. Oxygen should be given by mask. Intravenous antihistamine, inhaled nursing woman. bronchodilators, theophylline and/or adrenal corticosteroids may be used if necessary after (7) adequate epinephrine and circulatory support has been given. Pediatric Use Emergency resuscitation measures and personnel trained inadults.use must be the small The dosage for the pediatric population is the same as for their Because of available immediatelychild, larger volumes of solution mayanaphylactic reaction not responsive to the size of the in the event of a serious systemic or produce excessive discomfort. Therefore, above measures. [Ref. J. Allergy and Clinical Immunology,the dose may need to be divided in order to achieve the total dose required, the volume of 77(2): p. 271-273, 1986.] Rarely than one injection measures into more are all of the aboveper visit. necessary, the tourniquet and epinephrine usually producing prompt responses. However, the physician should be prepared in advance for all contingencies. Promptness in beginning emergency treatment measures is of utmost importance. Emergency resuscitation measures and personnel trained in their use must be available immediately in the event of a serious systemic or anaphylactic reaction not responsive to the above measures. [Ref. J. Allergy and Clinical Immunology, 77(2): p. 271-273, 1986.] Rarely are all of the above measures necessary, the tourniquet and epinephrine usually to beproducing in administering allergenic extracts are necessary. be prepared in advance for observed prompt responses. However, the physician should Ten-fold dilutions can be prepared from the extract as follows: all contingencies. Promptness in beginning emergency treatment measures is of utmost Using a sterile syringe and aseptic technique, withdraw 0.5 mL of the extract, add it to a importance. 4.5 mL Severe diluent blank, and rock or swirl to mixof at least 50% in the next dose, followed sterile systemic reactions mandate a decrease thoroughly. Label this and subsequent dilutions with theincreases. Repeated systemic reactions, even of a mild nature, are0.5 mL of by cautious appropriate strength. (See Dilution Tables below). Then withdraw sufficient the new dilution, add it to a second 4.5 mL diluent blank and rock or swirl to mix this additional reason for the cessation of further attempts to reach the reaction-causing dose. dilution thoroughly.Reporting (3) Adverse Event Repeat this procedure until all necessary dilutions Laboratories LLC,using a fresh 4.5 mL Report all adverse events to Hollister-Stier have been made, Customer Technical diluent blank for each dilution. A new syringe andA voluntary adverse eventprepare each dilution. Services Department at 1 (800) 992-1120. needle should be used to reporting system for Do not reaspirate syringe is available through the FDA MEDWATCH program. Preprinted forms health professionals after transferring the extract. EXAMPLE:Form 3500) diluting the Concentrate in by ten-fold1 series, FDA-1088. Completed forms (FDA If you are are available from the FDA a calling (800) the dilution schedule is as follows: should be mailed to MEDWATCH, 5600 Fisher Lane, Rockville, MD 20852-9787 or Fax to: 1 (800) FDA-0178. WITHDRAWAL EXTRACT DILUENT DILUTION OVERDOSAGE: See ADVERSE REACTIONS. + VOLUME STRENGTH VOLUME = STRENGTH DOSAGE AND ADMINISTRATION: 11, 22, 23, 24 + 0.5 mL of Concentrate 4.5 mL = 1:10 v/v of Conc. + 4.5 mL (1)0.5 mL Parenteral drug of Conc. should be inspected visually = 1:100 v/v of Conc. and General: of 1:10 v/v products for particulate matter 0.5 mL of administration whenever solution and container=permit. + 4.5 mL 1:1,000 v/v of Conc. discoloration prior to1:100 v/v of Conc. 0.5 mL of 1:1,000reverse Conc.is offered as 4.5 mL v/v of side + = 1:10,000 v/v ofpatients The dosage chart on the a suggested schedule for average Conc. and will or two doses from the weakest dilution the degree of sensitivity varies in many patient’s be satisfactory in most cases. However, can be administered to determine the individuOne als. IN THESE CASES THE SIZE OF starting dose produces no significant TO BE general symptolerance to the fresh extract. If the THE DOSE AND INTERVAL MAY HAVE local orADJUSTED AND SHOULD BE REGULATED BY THE PATIENT’S TOLERANCE AND REACTION. dose is SHOULD toms, subsequent doses can be increased progressively until a maintenance(A DOSE reached. NEVER product UNTIL ALL for suggested dosage schedule. PREVIOUS DOSE HAVE is small, Refer toBE GIVENinstructions REACTIONS RESULTING FROM A If the change in formulaENTIRELY DISAPPEARED.) The size accelerated may also need to the patient may tolerate an of the dose build-up schedule. be varied depending upon patient’s symptoms of allergy. If symptoms recur before the expiration of the interval between injections, (6) Retesting: subsequent intervals may need to be decreased. After a period on immunotherapy, better tolerance mayPatients ashould be retested and injections, or ashould maintenance dose, or both. permit longer interval between other factors larger be investigated when results are unsatisfactoryindividual components of the extract are those to which the patient is allergic and Since the after a year of treatment. Any coexisting food, non-pollen, or seasonal pollen allergies should be controlled for bestallergic symptoms may follow shortly after the injection, to which he will be exposed, typical results. particularly those experienced by the patient (7) Instructions for Specific Treatment Sets: during exposure when the antigen from the environment plus the injected antigen exceeds the patient’s tolerance to the antigen. In such cases, (a) Pollen: decrease the size of the next scheduled dose by at least one-half of the previous dose. Preseasonal Treatment: 22, 23, largest dose treatment is the patient that relieves symptoms The maintenance level is the 24 Preseasonaltolerated by normally started 8 to 12 weeks prior to expected onset of symptoms or general reactions. AFTER Concentrate (Vial HAS BEEN without producing undesirable local with a 1:5,000 v/v dilution ofIMMUNOTHER APY “5”) of the allergenic extract, or 1:50,000 v/v dilution of BE GIVEN AT WEEKLY prescribed The interval ESTABLISHED, A MAINTENANCE DOSE SHOULDConcentrate (Vial “6”) ifINTERVALS.by physician for a severely sensitive can be Commencing with from one week to 10 days, to 2 weeks, 3 between maintenance dosespatient. increased graduallythe first dose, as listed in the Suggested Dosage Schedule, a dose can be administered every three to five days. In preseasonal check weeks, or even 4 weeks if tolerated. Repeat doses at a given interval three or four times to treatment the interval between doses should be so regulated that at least the first 20 doses will for untoward reactions before increasing the interval further. If large local (or systemic) reactions have been administered increase the interval. Protection is lost rapidly if the interval shorter occur at one interval, do not by the time the hay fever symptoms are expected. Thus, the between the interval between start of WARNINGS section. It may onset of symptoms, patients to doses is more than 4 weeks. Seeimmunotherapy and expectednot be possible for allthe shorter the interval between indicated on the suggested dose schedule. reach the maximum dosedoses. Daily doses may be tolerated by some patients. The dose from 1:5,000 v/v dilution of Concentrate (Vial “5”) should be gradu(2) ally increased until the succeeding dose can be measured from 1:500 v/v dilution of Pediatric Use: The dose for the “4”). Continue in this same as for each Concentrate (Vialpediatric population is the manner with adults. succeeding vial until the (3) doses canUse:measured from the Concentrate (Vial “1”), which is the most concentrated Geriatric be The dose the treatment. When weaker as for adult used, under 65. 0.03 mL and in extract in for elderly patients is the same dilutions arepatientsstart with 37 (4) crease by amounts identical to those shown for 1:5,000 v/v dilution of Concentrate (Vial Determining Initial Dose: “5”). patient 0.3 mL isto be extremely sensitive because of excessively large scratch, prick If a When appears reached, proceed with the next higher strength. In some areas, systemic reactions and require either lower or higher doses; there fore, or puncture reactions, patients may tolerateto testing, severe generalized symptoms during the smaller or larger increments than shown on the schedule mayby aused. After intradermal skin allergy season, or for other reasons, determine the initial dose be series of immunotherapy has been established, MAINTENANCE 1:1,000,000 v/v dilution AT WEEKLY INTERVALS tests. Ten-fold dilutions ofA the antigen to a DOSE SHOULD BE GIVEN of Concentrate, or more, can OR made fresh in IF NECESSARY DURING THE ENTIREwith the most dilute extract, 0.02 the be MORE OFTEN normal or buffered saline. Starting HAY FEVER SEASON. The size of mL maintenance of increasing concentration can be can be every 20 to 30 minutes until a intradermal tests dose will vary with each individual. It applied adjusted as necessary from the maximum5preseasonal and 10 to 20 symptoms develop before expiration of the maintenance reaction of a mm wheal dose. Should mm erythema occurs. This dose and concentration can theninterval, the starting between doses should be decreased. Should allergic symptoms develop serve as a interval dose for immunotherapy, and treatment can be continued according to shortly dose schedules. the outlinedafter the dose is administered, the size of the dose should be reduced. It is often advisable to cut the dose to half or a quarter of the maximum dose attained if the patient (5) has any seasonal symptoms. This lessens the tendency to overdose the patient during the Dilutions: Sterile aqueous season. active pollination diluent containing human serum albumin [Albumin (Human) Saline with Phenol ANOTHER DOSE SHOULD NEVER BEmay be UNDER THESE CONDITIONS: of the con(0.4%)] or diluent of 50% glycerin GIVEN used when preparing dilutions centrate for immunotherapy. Dilutions should be made accurately and aseptically, using sterile 1. vials, syringes, etc. Mix thoroughly and PRESENT, OR diluent, IF SEVERE ALLERGIC SYMPTOMS ARE gently by rocking or swirling. Maintain dilutions constantly at 2° - 8°LOCAL REACTION RESULTING be tested for PREVIOUS DOSE HAS DISAP2. UNTIL ALL C. Dilutions prepared should FROM THE sterility. The usual precautions PEARED. Perennial Treatment: 22, 23, 24 After the symptom period or pollen season has passed, treatment may be continued by increasing the dose to tolerance level and lengthening the interval immediately in the event of a serious systemic or anaphylactic reaction not responsive to the above measures. [Ref. J. Allergy and Clinical Immunology, 77(2): p. 271-273, 1986.] Rarely are all of the above measures necessary, the tourniquet and epinephrine usually producing prompt responses. However, the physician should be prepared in advance for to beall contingencies. Promptness in beginning emergency treatment measures is of utmost observed in administering allergenic extracts are necessary. Ten-fold dilutions can be prepared from the extract as follows: importance. Using a sterile syringe and aseptic technique, withdrawleast 50%of the extract, add it to a Severe systemic reactions mandate a decrease of at 0.5 mL in the next dose, followed 4.5 mL cautious increases. Repeated systemic reactions, even of a Label nature, are sufficient by sterile diluent blank, and rock or swirl to mix thoroughly. mild this and subsequent dilutions with the appropriateof further attempts to reach the below). Then withdraw 0.5 mL of reason for the cessation strength. (See Dilution Tables reaction-causing dose. the new dilution, add it to a second 4.5 mL diluent blank and rock or swirl to mix this additional (3) Adverse Event dilution thoroughly.Reporting Report all adverse events to Hollister-Stier have been made, Customer Technical Repeat this procedure until all necessary dilutions Laboratories LLC,using a fresh 4.5 mL Services Department at 1 (800) 992-1120. voluntary adverse event reporting system for diluent blank for each dilution. A new syringe andAneedle should be used to prepare each dilution. health professionals is available through the FDA MEDWATCH program. Preprinted forms Do not reaspirate syringe after transferring the extract. (FDA Form 3500) are available from the FDA by calling 1 (800) FDA-1088. Completed forms EXAMPLE: If you are diluting the Concentrate in a Lane, Rockville, the dilution schedule is to: should be mailed to MEDWATCH, 5600 Fisher ten-fold series, MD 20852-9787 or Fax as follows: 1 (800) FDA-0178. WITHDRAWAL See ADVERSE REACTIONS. EXTRACT DILUENT DILUTION OVERDOSAGE: VOLUME ADMINISTRATION: 11, 22, 23, 24 + STRENGTH VOLUME = STRENGTH DOSAGE AND 0.5 mL Parenteral drug products should be inspected visually = 1:10 v/v of matter and of Concentrate + 4.5 mL (1) General: for particulate Conc. 0.5 mL of administration whenever solution and container = 1:100 v/v of Conc. + 4.5 mL discoloration prior to1:10 v/v of Conc. permit. 0.5 mL of 1:100 v/v of Conc. is offered as a suggested schedule for average patients + 4.5 mL = 1:1,000 v/v of Conc. The dosage chart on the reverse side 0.5 mL satisfactory in most cases. However, the degreemL sensitivity varies in manyof Conc. of 1:1,000 v/v of Conc. + 4.5 of = 1:10,000 v/v individuand will be als.One THESE CASES THE SIZE weakest DOSE AND INTERVAL MAY HAVEdetermine the patient’s IN or two doses from the OF THE dilution can be administered to TO BE ADJUSTED AND SHOULD BE REGULATED BY THE starting dose produces AND REACTION. or general symptolerance to the fresh extract. If the PATIENT’S TOLERANCE no significant local(A DOSE SHOULD NEVER BE GIVEN doses can be increased progressively until a maintenance dose is reached. toms, subsequentUNTIL ALL REACTIONS RESULTING FROM A PREVIOUS DOSE HAVE ENTIRELY DISAPPEARED.) The size of the dose may also need to be varied depending upon patient’s Refer to product instructions for suggested dosage schedule. If the change in formula is small, symptoms may tolerate an accelerated before schedule. the patient of allergy. If symptoms recurbuild-upthe expiration of the interval between injections, subsequent intervals may need to be decreased. After a period on immunotherapy, better tolerance (6) Retesting:longer interval between injections, or a larger maintenance dose, or both. may permit a Patients individual retested and the factors should be investigated when results are Since the should be components ofotherextract are those to which the patient is allergic and unsatisfactory after a year of typical allergic symptoms may follow shortly or seasonal pollen to which he will be exposed, treatment. Any coexisting food, non-pollen, after the injection, allergies should beexperiencedfor best patient during exposure when the antigen from the enviparticularly those controlled by the results. ronment plus the injected antigen exceeds the (7) Instructions for Specific Treatment Sets: patient’s tolerance to the antigen. In such cases, decrease the size of the next scheduled dose by at least one-half of the previous dose. (a) Pollen: The maintenance level is the 24 largest dose tolerated by the patient that relieves symptoms Preseasonal Treatment: 22, 23, without producing undesirable localPreseasonal reactions. is normally started 8 toAPYweeks BEEN or general treatment AFTER IMMUNOTHER 12 HAS prior to expected MAINTENANCE DOSE SHOULD BE GIVEN AT WEEKLY INTERVALS. “5”) of the ESTABLISHED, Aonset of symptoms with a 1:5,000 v/v dilution of Concentrate (Vial The interval allergenic extract, doses can be increased gradually from one “6”) to 10 days, by weeks, 3 between maintenance or 1:50,000 v/v dilution of Concentrate (Vial week if prescribedto 2physician for a even 4 sensitive patient. Repeat doses at a the first dose, as listed in times to check weeks, orseverelyweeks if tolerated. Commencing with given interval three or four the Suggested Dosage Schedule, before increasing the interval further. If to five days. In preseasonal treatfor untoward reactions a dose can be administered every three large local (or systemic) reactions ment the interval between doses should be so regulated that rapidly if the interval between occur at one interval, do not increase the interval. Protection is lostat least the first 20 doses will have been than 4 weeks. See time the hay fever symptoms are possible for all patients to doses is more administered by theWARNINGS section. It may not beexpected. Thus, the shorter the interval between indicated on the suggested dose schedule. reach the maximum dosestart of immunotherapy and expected onset of symptoms, the shorter the interval between doses. Daily doses may be tolerated by some patients. (2) Pediatric Use:from 1:5,000 v/v dilution of Concentrate (Vial “5”) should be graduThe dose The increased until the succeeding is the same for adults. ally dose for the pediatric population dose can beasmeasured from 1:500 v/v dilution of (3) Concentrate (Vial “4”). Continue in this manner with each succeeding vial until the Geriatric Use: doses canfor elderly patients is theConcentrate (Vial “1”), which is the most concentrated The dose be measured from the same as for adult patients under 65. 37 extract in the treatment. When weaker dilutions are used, start with 0.03 mL and in (4) crease by amounts identical to those shown for 1:5,000 v/v dilution of Concentrate (Vial Determining Initial Dose: If a When appears reached, proceed with the next higher strength. “5”).patient 0.3 mL isto be extremely sensitive because of excessively large scratch, prick or puncture reactions, patients may tolerateto testing, severe generalized symptoms during the In some areas, systemic reactions and require either lower or higher doses; there fore, allergy season,larger increments than shown on the schedule mayby aused. After intradermal skin smaller or or for other reasons, determine the initial dose be series of immunotherapy tests. Ten-fold dilutions ofAthe antigen to a DOSE SHOULD BE GIVENof Concentrate, or more, has been established, MAINTENANCE 1:1,000,000 v/v dilution AT WEEKLY INTERVALS can OR made fresh in IF NECESSARY DURING THE ENTIRE HAYthe most dilute extract, 0.02 the be MORE OFTEN normal or buffered saline. Starting with FEVER SEASON. The size of mL intradermal tests dose will vary with each individual. Itapplied every 20 as necessary from the maintenance of increasing concentration can be can be adjusted to 30 minutes until a reaction of a 5preseasonal and 10 to 20 mm erythema occurs. This dose andof the maintenance maximum mm wheal dose. Should symptoms develop before expiration concentration can theninterval, the starting between doses should be decreased. Should allergic symptoms develop serve as a interval dose for immunotherapy, and treatment can be continued according to the outlinedafter the dose is administered, the size of the dose should be reduced. It is often shortly dose schedules. (5) advisable to cut the dose to half or a quarter of the maximum dose attained if the patient Dilutions: Sterile seasonal symptoms. This human serum albumin [Albumin (Human) during the has anyaqueous diluent containinglessens the tendency to overdose the patient Saline with Phenol (0.4%)] or diluent of 50% glycerin may be used when preparing dilutions of the conactive pollination season. centrate for immunotherapy. Dilutions should be made accurately and aseptically, using sterile ANOTHER DOSE SHOULD NEVER BE GIVEN UNDER THESE CONDITIONS: diluent, vials, syringes, etc. Mix thoroughly ARE gently by rocking or swirling. Maintain dilutions 1. IF SEVERE ALLERGIC SYMPTOMS and PRESENT, OR constantly at 2° - 8° C. Dilutions prepared should be tested for sterility. The usual precautions 2. UNTIL ALL LOCAL REACTION RESULTING FROM THE PREVIOUS DOSE HAS DISAPPEARED. Perennial Treatment: 22, 23, 24 After the symptom period or pollen season has passed, treatment may be continued by increasing the dose to tolerance level and lengthening the interval 1. IF SEVERE ALLERGIC SYMPTOMS ARE PRESENT, OR 2. UNTIL ALL LOCAL REACTION RESULTING FROM THE PREVIOUS DOSE HAS DISAPPEARED. (8) Dilution Series: Perennial Treatment: 22, 23, 24 After have a colored overseal pollen season vial’s dilution. All Treatment vials are numbered and the symptom period or based upon the has passed, treatment may be continued by increasing the dose to tolerance level and lengthening the interval TREATMENTdosesDILUTIONS four weeks. This perennial schedule is maintained until theCOLORof VIAL # SEAL time between VIAL to two or Concentrate 1 Red year symptoms usually occur. Then the interval between doses is decreased to one week and the dosage conc. to 1:10 v/v of conc. treatment Dilution v/v of adjusted according to local reaction and control of symptoms. PerennialYellow 2 may be started at any time of the year continuing from the preseasonal schedule. Dilution weaker than 1:10 v/v of conc.on the Suggested Dosage Chart. 3 Blue See Dosage Schedule noted to 1:100 v/v of conc. Dilution weaker than 1:100 v/v of conc. to 1:1,000 v/v of conc. 4 Green (b) Environmentals / Molds/ Miscellaneous Dilution weaker than 1:1,000 v/v ofDose above. 5 Silver See Determining Initial conc. to 1:10,000 v/v of conc. Treatment is normally of conc. to 1:100,000 v/v dilute set. Beginning with Dilution weaker than 1:10,000 v/vstarted with the most of conc.extract in the 6 Silver the first dose 1:100,000 in the Suggested Dosage conc. Dilution weaker thanas listed v/v of conc. to 1:1,000,000 v/v ofChart, a dose can be administered 7 Silver every three to five days. The doses from 1:1,000 v/v dilution of Concentrate (Vial 5) Dilution weakergradually increased until the succeeding dose can be measured from 1:100 8 Silver should be than 1:1,000,000 v/v of conc. to 1:10,000,000 v/v of conc. HOWv/v dilution of Concentrate (Vial 4). Continue in this manner with Vial 3 and 1:10 v/v SUPPLIED: dilution labeling for actual fill volume(s) of dosage can be measured from Vial 1, which of Concentrate (Vial 2) until the vials. Refer to box is the 5 mL vials of 5 graduated dilutions. Pollens: In Concentrate. When extra dilutions are used, start with the highest numbered vial, which corresponds to the weakest dilution. Environmentals/Molds/Miscellaneous Inhalants and Insects: In 5 mL vials of 4 graduated dilutions. In some areas, some patients may tolerate and require higher doses; therefore, larger Fire increments than showngraduated dilutions. be used. The best results of immunotherapy Ant: In 5 mL vials of 5 in the schedule may occur when the 10 mL is given the largest dose tolerated without excessive local or any Refills: In 5 mL and patient vials at the strength ordered by the physician. systemic symptoms. Diluent or Suggested Dosage Package may include 4.5 mL diluent blanks. If not included, See Extra Dilutions: Chart. or if additional blanks are required, these can be ordered from Hollister-Stier Laboratories (c) preferred, prepared extra dilutions of complete treatment sets may be ordered from LLC. IfFire Ant: See Determining Initial Dose above. If extreme sensitivity is suspected, it is recommended that 0.05 mL of the 1:1,000 v/v Hollister-Stier Laboratories LLC. dilution of Concentrate (Vial 5) be added to a 4.5 mL diluent blank which can be ordered with Custom/Special Product Requests: Refer dilutionproduct Concentrate will result. the set. An approximate 1:100,000 v/v to the of the package label for the number of vials supplied is suggested that an intracutaneous test with 0.02 mL of a 1:100,000 v/v dilution of It and their strengths. the Concentrate be made. Very sensitive individuals such as those who have had nearly fatal See the current Allergy Product Catalog. anaphylactic reactions may not tolerate even 1:100,000 v/v dilution of Concentrate as a starting STORAGE: point. These patients should be testedshown on the label. The diluted antigens are the least The dating period (expiration date) is with a 1:10,000,000 v/v dilution of Concentrate. This dilution can be prepared using sterile normal or buffered saline. Treatment is stable. Consequently, extract and dilutions should be replaced when outdated. started with the dilution that first gives apotency of extracts and their dilutions, it is recommended that they To insure the maximum positive test. An interval temperature of days between doses is adequate. A maintenance dose of 0.3 be maintained at aof four to seven 2° - 8° C, even during use. to 0.4 mL ofregulations requiredilution is period for sterility tests,some patients may develop Government the Concentrate a holding usually attainable but so please allow a minimum systemic symptoms before this dose is reached. When systemic symptoms appear during the of four weeks for delivery when reordering. course of treatment, the subsequent dose must be reduced to a point below the reaction level, LIMITED WARRANTY: increased to a point of maximum tolerance. Extremely sensitive patients and then gradually A number of factors beyond our may not tolerate the Concentrate. control could reduce the efficacy of this product or even result in anSuggestedfollowing Chart. These include storage and handling of the product after See ill effect Dosage its use. it leaves our hands, diagnosis, dosage, method of administration and biologi cal differences in individual patients. THE DILUTION SUPPLIED is important that thisIS OF GREATER POTENCY (d) Refills: IF Because of these factors, it IN THIS PACKAGE product be stored properly andTHAN the directions beIS CURRENTLY RECEIVING, IT SHOULD NOT BE USED WITHOUT that THE PATIENT followed carefully during use. No warranty, express UNLESS including any warranty MIXTURE HAS or fitness, is made. FURTHER DILUTION or implied, TOLERANCE TO THIS of merchantabilityBEEN PREVIOUSLY Representatives of the Company are not authorizedIN vary the terms When contents of to aprinted ESTABLISHED AND IMMUNOTHERAPY IS to PROGRESS. or the changing any fresh labeling, including the package insert, for this product except by printed notice from the Company’s extract of the same formula and dilution, the first dose should not exceed 50% of headquarters. The prescriber and user of this product musttolerated satisfactorily, increase the the last dose from the previous lot. If this first dose is accept the terms hereof. subsequent REFERENCES: doses to the patient’s maintenance level. The maintenance level is the largest 1. dose tolerated F., MD, et al. Fatalities relieves symptoms (IT) and skin testing (ST). J. Allergy local Lockey, Richard by the patient that from immunotherapy without producing undesir able Clin. or general reactions. The interval between maintenance doses can be increased gradually Immunol. 79 (4): 660-667, April 1987. 2. from 1 week to 10 days,W. Rake, Jr., et al. weeks, or anaphylaxis in patients with drug-induced betaJacobs, Robert L., Geoffrey to 2 weeks, 3 Potentiated even 4 weeks if tolerated. Repeat doses at a given blockade. three to four Clin. Immunol., 68for untoward August 1981. adrenergic interval J. Allergy and times to check (2): 125-127, reactions before increasing the 3. interval I.J., J. Pollock, D.G. Klapper, B.L. Rogers reactions occur at one interval, doof Amb a I and Griffith, further. If large local (or systemic) & A.K. Nault,. Sequence Polymorphism not increase Amb a II, the Protection is lost rapidly if the interval Ragweed). Int. Arch. more than Immunol., the interval. Major Allergens in Ambrosia artemisiifolia (Short between doses is Allergy Apply. 4 weeks. 96: WARNINGS section. See 296-304, 1991. 4. Underdown, B.J. & L. Goodfriend. Isolation & characterizationfor an allergen from short ragweed pollen. The accompanying dosage chart may be used of recording the doses and dates Biochem. 8 (3): 980-989, 1969. of maintenance injections. We cannot specify a dose because it is dependent upon 5. the doseB.W. & interval between of a basic protein antigen established and recorded Biochem. Griffiths, and R. Brunet. Isolation injections previously of low ragweed pollen. Can. J. on your 49 (3): treatment original396-400, 1971.schedule. Because of minor variations in the potency of allergens 6. between C.B. & changes in the patient’s reactivity, or weight ragweed allergen: Ra5. Int. Arch. Allergy Lapkoff, lots, L. Goodfriend. Isolation of a low molecular the season of the year, the mainte nance Appl. Immunol. 46 dose for different (2): 215-229, same concentrated antigen may differ to some extent. lots of the 1974. 7. 8. 9. Hussain, R. & D.G. March. Characterization and allergenic activity of ragweed allergens Ra6, Ra7, Ra8. J. Allergy Clin. Immunol. 65 (3): 230, abstr. 218, 1980. Goodfriend, L., A.M. Choudhury, J. Del Carpio and T.P. King. Cytochrome C: New ragweed pollen allergen. Fed. Proc. 38 (3, part II): 1415, abstr. 6261, 1979. Turkeltaub, Paul C., Suresh C. Rastogi, Harold Baer. Office of Biologics Research and Review skin test method for evaluation of subject sensitivity to standardized allergenic extracts and for assignment of allergy units 1. IF SEVERE ALLERGIC SYMPTOMS ARE PRESENT, OR 2. UNTIL ALL LOCAL REACTION RESULTING FROM THE PREVIOUS DOSE HAS DISAPPEARED. (8) Dilution Series: Perennial Treatment: 22, 23, 24 After the symptom period or pollen season has passed, treatAll Treatment vials are numbered and have adose to tolerance basedand lengtheningdilution. ment may be continued by increasing the colored overseal level upon the vial’s the interval between VIAL to two or TREATMENTdosesDILUTIONS four weeks. This perennial schedule is maintained until theCOLORof VIAL # SEAL time year symptoms usually occur. Then the interval between doses is decreased to one week and Concentrate adjusted according to local reaction and control of symptoms. Perennial treatment 1 Red the dosage Dilutionbe started at any time of the year continuing from the preseasonal schedule. 2 Yellow may v/v of conc. to 1:10 v/v of conc. See Dosage Schedule noted to the Suggested Dosage Chart. Dilution weaker than 1:10 v/v of conc.on 1:100 v/v of conc. 3 Blue (b) Environmentals / v/v of conc. to 1:1,000 v/v Dilution weaker than 1:100 Molds/ Miscellaneous of conc. 4 Green See Determining Initial Dose above. Dilution weaker than 1:1,000 v/v of conc. to 1:10,000 v/v of conc. 5 Silver Treatment is normally started with the most dilute extract in the set. Beginning with Dilution weaker thanas listedv/v ofthe Suggested Dosageconc. 6 Silver the first dose 1:10,000 in conc. to 1:100,000 v/v of Chart, a dose can be administered every three to 1:100,000 The doses from 1:1,000 conc. Dilution weaker than five days.v/v of conc. to 1:1,000,000 v/v ofv/v dilution of Concentrate (Vial 5) 7 Silver should be than 1:1,000,000 v/v of conc. the succeeding of conc. Dilution weakergradually increased until to 1:10,000,000 v/v dose can be measured from 1:100 8 Silver v/v dilution of Concentrate (Vial 4). Continue in this manner with Vial 3 and 1:10 v/v HOWdilution of Concentrate (Vial 2) until the dosage can be measured from Vial 1, which SUPPLIED: Referisto box labeling for When extra dilutionsof vials. start with the highest numbered vial, the Concentrate. actual fill volume(s) are used, Pollens: In corresponds to the weakestdilutions. which 5 mL vials of 5 graduated dilution. In some areas, some patients may tolerate and require higher doses; therefore, larger Environmentals/Molds/Miscellaneous Inhalants and Insects: In 5 mL vials of 4 graduated dilutions. increments than shown in the schedule may be used. The best results of immunotherapy Fire Ant: Inwhen the patientgraduated the largest dose tolerated without excessive local or any occur 5 mL vials of 5 is given dilutions. Refills: In 5 mL and 10 mL vials at the strength ordered by the physician. systemic symptoms. See Extra Dilutions: Chart. Diluent or Suggested Dosage Package may include 4.5 mL diluent blanks. If not included, or (c)additional See Determining Initial Dose above.ordered from Hollister-Stier Laboratories if Fire Ant: blanks are required, these can be LLC. IfIfpreferred, sensitivity extra dilutionsitof complete treatment 0.05 mayof the 1:1,000 v/v extreme prepared is suspected, is recommended that sets mL be ordered from Hollister-Stier Concentrate (Vial 5) be added to a 4.5 mL diluent blank which can be ordered with dilution of Laboratories LLC. the set. An approximate 1:100,000 v/v dilution of the Concentrate will result. Custom/Special Product Requests: Refer to the product package label for the number of vials It and their strengths. supplied is suggested that an intracutaneous test with 0.02 mL of a 1:100,000 v/v dilution of the Concentrate be made. Very sensitive individuals such as those who have had nearly fatal See the current Allergy Product Catalog. anaphylactic reactions may not tolerate even 1:100,000 v/v dilution of Concentrate as a starting point. These patients should be tested with a 1:10,000,000 v/v dilution of Concentrate. This STORAGE: dilution canperiod (expiration date) is normal or buffered saline.diluted antigens are the least The dating be prepared using sterile shown on the label. The Treatment is started with the dilution that first extract and dilutions stable. Consequently,gives a positive test. should be replaced when outdated. An interval of four to seven of extracts and their adequate. is recommended that they To insure the maximum potencydays between doses isdilutions, it A maintenance dose of 0.3 to 0.4 mL at a temperature of 2° - 8° is even during use. be maintained of the Concentrate dilution C, usually attainable but some patients may develop systemic symptoms before this dose is reached. for sterility tests, so please appear during the Government regulations require a holding period When systemic symptoms allow a minimum course of treatment, the subsequent dose of four weeks for delivery when reordering. must be reduced to a point below the reaction level, and then gradually LIMITED WARRANTY: increased to a point of maximum tolerance. Extremely sensitive patients may not tolerate the Concentrate. control could reduce the efficacy of this product or even A number of factors beyond our See ill effect Dosage its use. result in anSuggestedfollowing Chart. These include storage and handling of the product after 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. it leaves our hands, diagnosis, dosage, method of administration and biologi cal differences in (d) Refills: IF THE DILUTION SUPPLIED IN THIS PACKAGE IS OF GREATER POTENCY individual patients. Because of these factors, it is important that this product be stored properly THAN THE PATIENT IS CURRENTLY RECEIVING, IT SHOULD NOT BE USED WITHOUT and that the directions be followed carefully during use. FURTHER DILUTION UNLESS TOLERANCE TO THIS MIXTURE HAS BEEN PREVIOUSLY No warranty, express or implied, including any warranty of merchantability or fitness, is made. ESTABLISHED AND IMMUNOTHERAPY IS IN PROGRESS. When changing to a fresh Representatives of the Company are not authorized to vary the terms or the contents of any printed extract of the same formula and dilution, the first dose should not exceed 50% of labeling, including the package insert, for this product except by printed notice from the Company’s the last dose from the previous lot. If this first dose is tolerated satisfactorily, increase the headquarters. The prescriber and user of this product must accept the terms hereof. subsequent doses to the patient’s maintenance level. The maintenance level is the largest REFERENCES: dose tolerated by the patient that relieves symptoms without producing undesir able local 1. or general reactions. The interval between maintenance doses can be increased gradually Lockey, Richard F., MD, et al. Fatalities from immunotherapy (IT) and skin testing (ST). J. Allergy Clin. Immunol. 79 to 10 days, to 1987. from 1 week(4): 660-667, April 2 weeks, 3 weeks, or even 4 weeks if tolerated. Repeat doses 2. at a given interval three to four times al. Potentiated anaphylaxis reactions before increasing the Jacobs, Robert L., Geoffrey W. Rake, Jr., et to check for untoward in patients with drug-induced betaadrenergic blockade. J. Allergy and Clin. Immunol., 68 (2): 125-127, at one interval, do not increase interval further. If large local (or systemic) reactions occur August 1981. 3. the interval.J.Protection is Klapper, B.L. Rogers &interval between doses is more than 4 weeks. Griffith, I.J., Pollock, D.G. lost rapidly if the A.K. Nault,. Sequence Polymorphism of Amb a I and AmbWARNINGS Allergens a II, the See 296-304, Majorsection. in Ambrosia artemisiifolia (Short Ragweed). Int. Arch. Allergy Apply. Immunol., 96: 1991. The accompanying dosage chart may be used for recording the doses and dates 4. Underdown, B.J. & L. Goodfriend. Isolation & characterization of an allergen from short ragweed pollen. of maintenance injections. We cannot specify a dose because it is dependent upon Biochem. 8 (3): 980-989, 1969. the dose and interval between injections previously established and recorded on your 5. Griffiths, B.W. & R. Brunet. Isolation of a basic protein antigen of low ragweed pollen. Can. J. Biochem. original396-400, 1971.schedule. Because of minor variations in the potency of allergens 49 (3): treatment 6. betweenC.B. & changes in the patient’s low molecular weight ragweed allergen: Ra5. Int. Arch. Allergy Lapkoff, lots, L. Goodfriend. Isolation of a reactivity, or the season of the year, the mainte nance dose for different(2): 215-229, same concentrated antigen may differ to some extent. Appl. Immunol. 46 lots of the 1974. 7. 8. 9. Hussain, R. & D.G. March. Characterization and allergenic activity of ragweed allergens Ra6, Ra7, Ra8. J. Allergy Clin. Immunol. 65 (3): 230, abstr. 218, 1980. Goodfriend, L., A.M. Choudhury, J. Del Carpio and T.P. King. Cytochrome C: New ragweed pollen allergen. Fed. Proc. 38 (3, part II): 1415, abstr. 6261, 1979. Turkeltaub, Paul C., Suresh C. Rastogi, Harold Baer. Office of Biologics Research and Review skin test method for evaluation of subject sensitivity to standardized allergenic extracts and for assignment of allergy units Hussain, R. & D.G. March. Characterization and allergenic activity of ragweed allergens Ra6, Ra7, Ra8. J. Allergy Clin. Immunol. 65 (3): 230, abstr. 218, 1980. Goodfriend, L., A.M. Choudhury, J. Del Carpio and T.P. King. Cytochrome C: New ragweed pollen allergen. Fed. Proc. 38 (3, part II): 1415, abstr. 6261, 1979. Turkeltaub, Paul C., Suresh C. Rastogi, Harold Baer. Office of Biologics Research and Review skin test method for evaluation of subject sensitivity to standardized allergenic extracts and for assignment of allergy units to reference preparations using the ID 50 EAL Method (Intradermal Dilution for 50 mm Sum of Erythema Determines the Allergy Unit). Methods of the Allergenic Products Branch Office of Biologics Research and Review, FDA, Bethesda, MD 20892. Revised May 9, 1986. Assay for Cat Allergen I, Manual of Methods, Laboratory of Allergenic Products. Center for Biologics Evaluation and Research, Sept. 1984. Middleton, E., C.E. Reed & E.F. Ellis, editors. Allergy Principles and Practice, C.V. Mosby Co., St. Louis, 1978, pp. 877-898. Lowell, F.C., and W. Franklin. A double-blind study of treatment with aqueous allergenic extracts in cases of allergic rhinitis. J. Allergy, 34 (2): 165-182, 1963. Lowell, F.C., and W. Franklin. A double-blind study of the effectiveness and specificity of injection therapy in ragweed hay fever. N. Eng. J. Med. 273 (13): 675-679, 1965. Zavazal, V., and A. Stainer. Immunologic changes during specific treatment of the atopic state. II. Acta. Allergol. 25 (1): 11-17, 1970. Reisman, R.E., J.I. Wypych, and E.E. Arbesman. Relationship of immunotherapy, seasonal pollen exposure and clinical response to serum concentrations of total IgE and ragweed-specific IgE. Int. Arch. Allergy Appl. Immunol. 48 (6): 721-730, 1975. Taylor, W.W., J.L. Ohman, F.C. Lowell. Immunotherapy in cat-induced asthma; Double-blind trial with evaluation of bronchial responses to cat allergen and histamine. J. Allergy & Clin. Immunol., 61 (5): 283-287, 1978. Smith, A.P. Hyposensitization with Dermatophagoides pteronyssinus antigen: Trial in asthma induced by house dust. Br. Med. J., 4: 204-206, 1971. Chapman, M.D., T.A.E. Platts-Mills, M. Gabriel, H.K. Ng, W.G.L. Allen, L.E. Hill, A.J. Nunn. Antibody response following prolonged hyposensitization with Dermatophagoides pteronyssinus Extract. Int. Arch. Allergy Appl. Immunol., 61: 431-440, 1980. Norman, P.S. Postgraduate course presentation. An overview of immunotherapy, implications for the future. J. Allergy Clin. Immunol., 65 (2): 87-96, 1980. Norman, P.S., W.L. Winkenwerder. Maintenance immunotherapy in ragweed hay fever. J. Allergy, 74: 273282, 1971. Norman, P.S., W.L. Winkenwerder, L.M. Lichtenstein. Immunotherapy of hay fever with ragweed Antigen E; Comparisons with whole pollen extract and placebos. J. Allergy, 42: 93-108, 1968. Sheldon, J.M., R.G. Lovell & K.P. Mathews. A Manual of Clinical Allergy. Second Edition. W.B. Saunders, Philadelphia, 1967, pp. 107-112. Sherman, W.B. Hypersensitivity mechanisms and management. W.B. Saunders, Philadelphia, 1968, pp. 169-172. Swineford, O. Asthma and Hay Fever. Charles C. Thomas, Springfield, IL, 1971, pp. 148-155. Pauli, G., J.D. Bessot, R. Thierry, and A. Lamensons. Correlation between skin tests, inhalation tests and specific IgE in a study of 120 subjects to house dust and D. pteronyssinus. Clin. Allergy 7:337, 1977. Murray, A.B., A.C. Ferguson and B.J. Morrison. Diagnosis of house dust mite allergy in asthmatic children: What constitutes positive history? J. Allergy Clin. Immunol. 71:21, 1983. Reid, M.J., R.F. Lockey, P.C. Turkletaub, T.A.E., Platts-Mills. Survey of fatalities from skin testing and immunotherapy. J. Allergy Clin. Immunol. 92 (1): 6-15, July 1993. Reid, M.J., G. Gurka. Deaths associated with skin testing and immunotherapy. J. Allergy Clin. Immunol. 97(1) Part 3:231, Abstract 195, January 1996. Thompson, R.A., et al, report of a WHO/IUIS working group. The current status of allergen immunotherapy (hyposensitization). Allergy. 44: 369-379, 1989. Malling, H.J., B. Weeke, et al, The European Academy of Allergology and Clinical Immunology. Position Papers. Allergy. 48 (Supplement 14): 9-82, 1993. Pipkorn, Ulf. Pharmacological influence of anti-allergic medication on In Vivo allergen testing. Allergy. 43: 81-86, 1988. Andersson, M. and U. Pipkorn. Inhibition of the dermal immediate allergic reaction through prolonged treatment with topical glucocorticosteroids. Journal Allergy Clinical Immunology. 79 (2): 345-349, February 1987. Rao, Kamineni S., et al. Duration of suppressive effect of tricyclic anti-depressants on histamine induced wheal and flare reactions on human skin. Journal Allergy Clinical Immunology. 82: 752-757, November 1988. Pipkorn, Ulf, and M. Andersson. Topical dermal anesthesia inhibits the flare but not the wheal response to allergen and histamine in the skin prick test. Clinical Allergy. 17: 307-311, 1987. Metzger, W.J., E. Turner & R. Patterson. The safety of immunotherapy during pregnancy. J. Allergy Clin. Immunol. 61 (4): 268-272, 1978. Li, J.T., R.F. Lockey, I.L. Bernstein, J.M. Portnoy, R.A. Nicklas. Allergen Immunotherapy: A Practice Parameter. Ann. Allergy, Asthma & Immunotherapy 90 (1): 26, 2003. Peebles, Ray Stokes, Jr., B. Bochner, Howard J. Zeitz, ed. Anaphylaxis in the elderly. Immunology and Allergy Clinics of North America. 13 (3): 627-646, August 1993. Turkeltaub, Paul C., MD, and Peter J. Gergen, MD. The risk of adverse reactions from percutaneous prickpuncture allergen skin testing, venipuncture, and body measurements: Data from the second National Health and Nutrition Examination Survey 1976-80 (NHANES II). J. Allergy Clin. Immunol. 84 (6): 886-890, Dec. 1989. Printed in U.S.A. 385400-H04 May 2007 *SUGGESTED DOSAGE CHART SCHEDULE FOR IMMUNOTHERAPY THESE DOSAGE REGIMENS ARE NOT BASED ON ADEQUATE AND WELL CONTROLLED TRIALS THAT CONCLUSIVELY ESTABLISH SAFETY AND EFFICACY. Extract Lot No. Exp. Date Physician Patient *This is a suggested dose chart only. Note that one dosage schedule applies to all allergens listed below. Please read instructions before commencing immunotherapy. Observe patients for 30 minutes after injection. Certain individuals may not tolerate this suggested schedule. The physician may need to adjust both the dosage and interval accordingly. The suggested schedule represents typical treatment dilution series prepared by Hollister-Stier Laboratories LLC. For dilution series which differ from those below, the physician may need to modify the schedule as necessary. If it is necessary to begin treatment with weaker dilutions than those shown on schedule, consider the weaker dilution as the beginning bottle for treatment, and the same dosage volume increases should be made. VIALS PROVIDED IN TREATMENT SET Determine the description below at left which matches the prescription formulation. Read across from left to right for most dilute to most concentrated vial strength designations. Select appropriate dosage for each vial strength from column below that strength on chart. Prescription formulation contains: 1:50,000 v/v dilution of Concentrate (Vial 6+) 1:5,000 v/v dilution of Concentrate (Vial 5) 1:10,000 v/v dilution of Concentrate (Vial 5) 1:500 v/v dilution of Concentrate (Vial 4) 1:1,000 v/v dilution of Concentrate (Vial 4) 1:1,000 v/v dilution of Concentrate (Vial 4) 0.03 mL 0.05 0.08 0.12 0.18 0.30 1:50 v/v dilution of Concentrate (Vial 3) 1:100 v/v dilution of Concentrate (Vial 3) 1:100 v/v dilution of Concentrate (Vial 3) 0.03 mL 0.05 0.08 0.12 0.18 0.30 1:5 v/v dilution of Concentrate (Vial 2) 1:10 v/v dilution of Concentrate (Vial 2) 1:10 v/v dilution of Concentrate (Vial 2) 0.03 mL 0.05 0.08 0.12 0.18 0.30 Concentrate (Vial 1) ONE OR MORE POLLENS # FIRE ANT ONLY Concentrate (Vial 1) – NO POLLENS Concentrate (Vial 1) – – DOSAGE SCHEDULE FOR VIALS IN SAME COLUMN ABOVE (Progress top to bottom in each dosage column, and use vials in order shown, Left to Right.) 0.03 mL 0.05 0.08 0.12 0.18 0.30 0.03 mL 0.05 0.08 0.12 0.18 0.30 0.03 mL 0.05 ** 0.08 0.12 0.16 ## 0.20 ##NOTE: Occasionally, higher doses are necessary to relieve symptoms. Special caution is required in administering doses greater than 0.20 mL. **NOTE: Increases from this point on are dependent on patient’s tolerance and amount of allergen content in air. Repeat dose if necessary. Continue immunotherapy entire season regardless of number of doses given. Unsatisfactory results are usually due to improper dosage adjustment. Avoid reactions – Check extract, dilution, and dose – Question the patient about local or systemic reaction to previous injection. # NOTE: If extreme sensitivity is suspected, it is recommended that 0.05 mL of the 1:1,000 v/v dilution of Concentrate (vial 5) be added to a 4.5 mL diluent blank which can be ordered with the set. This will result in an approximate 1:100,000 v/v dilution of Concentrate (91 fold) which may be used for intradermal testing, as well as starting dilution for treatment. See INSTRUCTIONS FOR SPECIFIC TREATMENT SETS. + NOTE: Included by special request only. RECORD DOSE BELOW AS ADMINISTERED DATE VIAL NO. DILUTION DOSE (mL) REMARKS: Reaction to Previous Dose, Relief of Symptoms, etc. PLEASE NOTE: Minor leakage of vial contents may occur after stopper is punctured several times if excessive amounts of air are injected into the vial. To prevent leakage, relieve buildup of air pressure periodically with sterile syringe, and store vial in upright position.