ALLERGEN PACK BERMUDA GRASS: Package Insert and Label Information

ALLERGEN PACK BERMUDA GRASS-
Alvix Laboratories, LLC

BOXED WARNING

THIS ALLERGENIC PRODUCT IS INTENDED FOR USE BY PHYSICIANS WHO ARE EXPERIENCED IN THE ADMINISTRATION OF ALLERGENIC EXTRACTS AND THE EMERGENCY CARE OF ANAPHYLAXIS, OR FOR USE UNDER THE GUIDANCE OF AN ALLERGY SPECIALIST.

THIS PRODUCT SHOULD NOT BE INJECTED INTRAVENOUSLY.

STANDARDIZED GRASS POLLEN EXTRACTS LABELED IN BIOEQUIVA-LENT ALLERGY UNITS (BAU)/ML ARE NOT INTERCHANGEABLE WITH GRASS POLLEN EXTRACTS LABELED IN ALLERGY UNITS (AU)/ML OR WITH NONSTANDARDIZED GRASS POLLEN EXTRACTS. FOR PREVIOUSLY UNTREATED PATIENTS OR PATIENTS PREVIOUSLYRECEIVING EXTRACTS FROM ANOTHER MANUFACTURER, THE INITIAL DOSE MUST BE BASED ON SKIN TESTING AS DESCRIBED IN THE DOSAGE AND ADMINISTRATION SECTION OF THIS INSERT. PATIENTS BEING SWITCHED FROM OTHER TYPES OF EXTRACTS TO STANDARDIZED EXTRACTS SHOULD BE INSTRUCTED TO RECOGNIZE ADVERSE REACTION SYMPTOMS AND CAUTIONED TO CONTACT THE PHYSICIAN’S OFFICE IF REACTION SYMPTOMS OCCUR. IN CERTAIN INDIVIDUALS THESE REACTIONS COULD BE FATAL. PATIENTS SHOULD BE OBSERVED FOR AT LEAST 20 MINUTES FOLLOWING TREATMENT. PATIENTS WITH LABILE OR STEROID-DEPENDENT ASTHMA ARE “HIGH RISK PATIENTS” WHO REQUIRE SPECIAL CAUTION IN DOSE ADMINISTRATION AND SHOULD REMAIN IN THE OFFICE FOR AT LEAST 30 MINUTES. AIRWAY OBSTRUCTION IN HIGH RISK PATIENTS CAN BE MONITORED BY PEAK FLOW MEASUREMENTS BEFORE AND AFTER ADMINISTRATION OF ALLERGENS. EMERGENCY MEASURES AS WELL AS PERSONNEL TRAINED IN THEIR USE SHOULD BE IMMEDIATELY AVAILABLE IN THE EVENT OF A LIFE THREATENING REACTION. TO REPORT SERIOUS ADVERSE EVENTS, THE FOOD AND DRUG ADMINISTRATION MED-WATCH NUMBER IS 1-800-332-1088. PATIENTS BEING SWITCHED FROM ONE LOT OF EXTRACT TO ANOTHER FROM THE SAME MANUFACTURER SHOULD HAVE THEIR DOSE REDUCED BY 75%.

RISK OF ANAPHYLAXIS SHOULD BE WEIGHED AGAINST BENEFITS: IN PATIENTS RECEIVING BETA BLOCKERS AS THEY MAY NOT BE RESPONSIVE TO BETA ADRENERGIC DRUGS SHOULD ANAPHYLAXIS OCCUR; IN PATIENTS WITH UNSTABLE OR STEROID-DEPENDENT ASTHMA; OR IN PATIENTS WITH CARDIOVASCULAR DISEASE.

REFER ALSO TO THE WARNINGS, PRECAUTIONS, ADVERSE REACTIONS AND OVERDOSAGE SECTIONS BELOW.

DESCRIPTION

Standardized Grass Pollen Allergenic Extracts are supplied as sterile solutions for intracutaneous or subcutaneous administration. Standardized Grass Pollen Allergenic Extracts include Bermuda (Cynodon dactylon), Kentucky Blue (June), (Poa pratensis), Meadow Fescue (Festuca elatior), Orchard (Dactylis glomerata), Perennial Rye (Lolium perenne), Redtop (Agrostis alba), Sweet Vernal (Anthoxanthum odoratum), and Timothy (Phleum pratense). Glycerinated concentrates contain the soluble extractants of the source material with 0.25% sodium chloride, 0.27% sodium bicarbonate, and 50% glycerin v/v. All extracts contain 0.4% phenol as the preservative. Source materials for each extract are the specific pollens collected from the respective plants.

Standardized Grass Pollen Extracts are labeled in Bioequivalent Allergy Units

(BAU)/mL. STANDARDIZED GRASS POLLEN EXTRACTS LABELED IN BAU/ML ARE NOT INTERCHANGEABLE WITH GRASS POLLEN

EXTRACTS LABELED IN AU/ML OR WITH NONSTANDARDIZED

GRASS POLLEN EXTRACTS. Bioequivalent allergy units are assigned based on comparison by enzyme linked immunosorbent assay (ELISA) to references from the U. S. Food and Drug Administration, Center for Biologics Evaluation and Research (CBER). CBER References are assigned unitage based on quantitative skin testing.1-4 CBER references which can be diluted 1:5,000,000 to intradermally elicit a 50 mm sum of erythema diameter response in highly puncture reactive subjects are assigned 100,000 BAU/mL, whereas references diluted 1:500,000 which elicit the same 50 mm sum of erythema diameter response are assigned 10,000 BAU/mL.

KIT CONTAINS

5 x 5mL empty colored vials
1 x 30mL normal saline
1 x 5mL Std. Bermuda Grass Allergen Extract

INDICATIONS AND USAGE

Standardized Grass Pollen Extracts are indicated for the skin-test diagnosis of allergy and immunotherapy treatment of patients with a history of allergy to the respective pollen. The diagnosis of IgE-mediated allergy may be established by the allergy history, clinical evaluation, and skin test reactivity.8,11,15 Extracts at 10,000 BAU/mL are indicated for use in scratch, prick, or puncture skin test diagnosis. Extracts at 100,000 BAU/mL are indicated for use in scratch, prick, or puncture skin test diagnosis in less sensitive subjects, such as those negative or indeterminate upon scratch, prick, or puncture testing at 10,000 BAU/mL. Extracts at 10,000 BAU/mL or 100,000 BAU/mL are indicated for intradermal skin test diagnosis only when appropriately diluted.

Immunotherapy with Standardized Grass Pollen Extracts is indicated when testing and patient history have identified the offending allergens and when it is not possible or practical to avoid these allergens.16-18 Extracts at 10,000 BAU/mL or 100,000 BAU/mL are indicated for immunotherapy only when appropriately diluted. 10,000 BAU/mL extracts are indicated for immunotherapy on previously untreated patients. 100,000 BAU/mL extracts are indicated if a higher dose is needed. (See DOSAGE AND ADMINISTRATION) STANDARDIZED GRASS POLLEN EXTRACTS LABELED IN BAU/mL ARE NOT INTERCHANGEABLE WITH GRASS POLLEN EXTRACTS LABELED IN AU/mL OR WITH NONSTANDARDIZED GRASS POLLEN.

EXTRACTS. The use of Standardized Grass Pollen Extracts for the above purposes should be made only by physicians with special familiarity and knowledge of allergy. (See DOSAGE AND ADMINISTRATION).

CLINICAL PHARMACOLOGY

The allergic reaction is dependent upon the presence of antigen-specific immunoglobulin E (IgE) antibodies that are bound to specific receptors on mast cells and basophils. The presence of IgE antibodies on mast cells and basophils sensitizes these cells and upon interaction with the appropriate allergen-histamine and other mediators are released. IgE antibody has been shown to correlate with atopic diseases such as allergic rhinitis and allergic asthma.5-8 In the skin these mediators are responsible for the characteristic wheal and flare (erythema) reactions upon allergenic extract skin testing in persons with the specific allergies.7-11

Puncture test results with eight US reference extracts at 10,000 BAU/mL (15 grass-specific allergic subjects per extract) are shown in TABLE 1.30 For the eight grass pollens, there was a mean sum-of-diameter wheal of 15.2 mm (SD = 1.8) and a mean sum-of-diameter erythema of 84.0 mm (SD = 5.8).

TABLE 1

Puncture Skin Tests with 10,000 BAU/mL Grass Extracts (Bifurcated Needle)

Reference Puncture Puncture
Pollen Sum of Wheal (mm) Sum of Erythema (mm)
Mean Range Mean Range
Bermuda 15.7 7 — 31 90.3 43 — 123
Kentucky Blue/June 15.9 6 — 28 77.3 47 — 107
Meadow Fescue 11.9 7 — 22 81.1 57 — 115
Orchard 14.1 9 — 19 84.3 57 — 111
Perennial Rye 17.5 6 — 36 92.3 73 — 135
Redtop 14.1 8 — 19 77.1 42 — 98
Sweet Vernal 15.7 8 — 30 81.2 28 — 123

Timothy 16.9 8 — 40 88.3 51 — 109

Intradermal skin tests with eight U.S. reference extracts (TABLE 2) in highly puncture reactive subjects (TABLE 1) indicate that a calculated dose of 0.02 BAU/mL should yield an average sum of erythema reaction of 50 mm, as tested in subjects sensitive to the specific grass pollen extract. However in the more sensitive subjects, the dose was as low as 0.0003 BAU/mL for one grass to 0.002 BAU/mL for several others. Conversely, doses of from 0.1 to 1.9 BAU/mL were calculated to yield the same reaction in the least-sensitive subjects.

TABLE 2

Intradermal Skin Test Doses

(Calculated BAU/mL Required for 50 mm Sum of Erythema)

Bioequivalent

Allergy Units/mL

Reference
Pollen Mean Range

Bermuda

0.02 0.0003 — 0.4
Kentucky Blue/June 0.02 0.004 — 0.1
Meadow Fescue 0.02 0.002 — 0.9
Orchard 0.02 0.002 — 1.9
Perennial Rye 0.02 0.002 — 0.7
Redtop 0.02 0.004 — 0.8
Sweet Vernal 0.02 0.002 — 1.0
Timothy 0.02 0.002 — 0.6

CLINICAL PHARMACOLOGY — CONTINUED

Specific immunotherapy with pollen extracts as employed for many years is helpful in reducing symptoms associated with exposure to the offending allergens. A summary of effectiveness by the Panel on Review of Allergenic Extracts, an advisory committee to the U. S. Food and Drug Administration, has been published.12 Several mechanisms have been proposed to explain the effectiveness of immunotherapy: an increase in antigen-specific IgG antibodies is frequently associated with clinical effectiveness, although correlation is not consistent in all studies; there is a decrease in specific IgE; and IgE production is suppressed during periods of seasonal or high exposure to the antigen.13 Other changes following immunotherapy have been noted including development of auto-anti-idiotypic antibodies, a decrease in blood basophil sensitivity to allergen, a decrease in lymphokine production and lymphocyte proliferation by cells exposed to allergen, and development of allergen-specific suppressor cells.14 The complete mechanisms of immunotherapy are not known and remain the subject of investigation.

Standardized versus nonstandardized extracts: Standardized grass pollen extracts cannot be directly compared to the previously marketed nonstandardized extract concentrates of the same grass pollens such as those labeled at 1:10 w/v or 1:20 w/v or at 20,000 to 40,000 PNU. The potency of the nonstandardized extracts vary from species to species. Some nonstandardized grass pollen concentrates have been from a few thousand BAU/mL to several hundred thousand BAU/mL as measured by in vitro ELISA testing. Extracts of some lots of Greer nonstandardized glycerinated 1:20 w/v extracts such as Meadow Fescue and Redtop have tested over 200,000 BAU/mL. Two Timothy aqueous nonstandardized 1:10 w/v aqueous extract lots were over 200,000 BAU/mL. Several lots of nonstandardized concentrates of Kentucky Blue/June, Orchard, Perennial Rye, and Sweet Vernal varied around 100,000 BAU/mL. Bermuda grass is not as potent. The FDA Bermuda reference is assigned 10,000 BAU/mL, a value similar to that found in several Greer lots of nonstandardized Bermuda. This is the maximum available strength of standardized Bermuda grass pollen extract. See TABLE 3 for examples of BAU potency by in vitro ELISA testing for nonstandardized grass pollen extracts.

TABLE 3

BAU/mL of Previously Marketed, Nonstandardized,

Grass Pollen Extracts BAU/mL Range by In Vitro ELISA*

Pollen

# of Lots

Tested

1:10 w/v Aqueous

# of Lots

Tested

1:20 w/v

glycerinated

Bermuda

1

10,740

5

4,000 to 14,500

Meadow Fescue

3

287,300 to 666,000

4

169,200 to 378,200

Kentucky Blue/June

3

56,100 to 145,400

4

56,100 to 91,500

Orchard

2

134,000 to 139,200

5

71,200 to 110,500

Redtop

3

141,900 to 425,000

4

134,600 to 219,200

Perennial Rye

4

59,100 to 302,000

4

52,900 to 80,400

Sweet Vernal

2

171,900 to 234,800

5

63,900 to 201,200

Timothy

3

186,300 to 291,000

3

63,000 to 104,800

Extracts testing between 67,300 and 148,600 are not statistically different from 100,000 BAU/mL. Extracts which test between 6,730 to 14,860 are not statistically different from 10,000 BAU/mL.

*CAUTION: Only a few lots of each nonstandardized pollen species have been tested by ELISA. The lots tested varied from fresh extracts to extracts more than three years old. Do not assume that these values apply to specific lots that are in distribution. In addition to age, storage temperatures influence potency.

Physicians must exercise care in switching patients from nonstandardized to standardized extracts. As with nonstandardized extracts, dosage with BAU extracts must be derived based on the patient’s sensitivity to the specific pollen. Switching from an extract that was not standardized in BAU cannot be made by a calculated, numerical ratio, but TABLE 3 can be used as a guide. Dose selection can be confirmed by side-by-side testing of nonstandardized and standardized extracts at estimated equal doses. See WARNINGS section.

The potency of nonstandardized grass pollen extracts have varied enough so that the strength of any extract previously used in a specific patient cannot be related to a particular potency in switching to BAU extracts. Therefore, patients being switched from nonstandardized extracts from another manufacturer to extracts standardized in BAU can be reevaluated by diagnostic skin testing to judge the dose to start immunotherapy or to build up to new maintenance dosages.

DOSAGE AND ADMINISTRATION

Diagnostic Testing

For the patient with a suspected diagnosis of allergy to more than one antigen, initial screening skin tests should include the individual extracts. If a screening skin test with a mixture is used, a positive response should be followed by testing with the individual extracts to determine the degree of sensitivity to each and to guide in the selection of extracts and their concentration for immunotherapy if indicated. However, because a negative skin test with a mixture may not be indicative of the absence of allergy to one or more of the components due to their dilution, testing with individual extracts is more precise. False negative responses may occur if serum levels of antihistamines remain from prior medication administration. (See PRECAUTIONS) The use of a histamine positive control is especially recommended for patients on prior medications which may decrease the histamine skin test response.

Skin tests read after 15 to 20 minutes are graded in terms of the induration (wheal) and erythema (flare) response compared to the appropriate controls. Wheal and flare sizes may be recorded by actual measurements. The largest diameter of the wheal and flare may be recorded, or the sum of the largest diameter and the orthogonal (right angle) diameter wheal or flare may be used as in the studies in TABLE 1 and TABLE 2.

Scratch or Prick-puncture Skin Testing:

For puncture, prick, or scratch skin test, the 10,000 BAU/mL strength is recommended and will detect the more sensitive patients. Inconclusive results at 10,000 BAU/mL may be followed by a puncture, prick, or scratch skin test at 100,000. At the higher concentration, some nonspecific positives may occur.

Controls for Scratch, Prick-Puncture Testing:

As a positive control, glycerinated histamine phosphate 5 mg/mL (1.8 mg/mL histamine base) or aqueous histamine phosphate 2.75 mg/mL (1 mg/mL (1:1,000 w/v) histamine base) may be used as a positive control. A 50% glycerosaline solution may be used as the negative control.

Intradermal Skin Testing:

Extracts for intradermal testing must be prepared by diluting the concentrated extract with sterile diluent (such as normal or buffered saline, or normal saline with human serum albumin).

Intradermal skin tests with eight U.S. reference extracts (TABLE 2) indicate that a calculated dose of 0.02 BAU/mL should yield an average sum of erythema reaction of 50 mm, as tested in subjects with similar puncture reactivities described in TABLE 1 to that specific grass pollen extract. However in the more sensitive subjects, the dose was as low as 0.0003 BAU for one grass to 0.002 BAU for several others. Conversely, doses of from 0.1 to 1.9 BAU were calculated to yield the same reaction in the least-sensitive subjects.

Controls for Intradermal Testing:

As a positive control, use glycerinated histamine phosphate diluted to 0.5 mg/mL (0.18 mg/mL histamine base) or aqueous histamine phosphate 0.275 mg/mL (0.1 mg/mL histamine base). As a negative control, use 0.5% to 1% glycerin in 0.9% saline.

A. Patients with a negative scratch or prick-puncture test:

Patients who do not react to a scratch or prick-puncture test should be tested intradermally, using a 26 or 27 gauge 1/4 inch needle, with 0.02 to 0.05 mL of a 50 BAU/mL extract dilution. A negative test should be followed by repeat tests using progressively stronger concentrations until significant wheal and flare reaction sizes are attained or until the maximum recommended strength of 200 BAU/mL is reached. As a positive control, use glycerinated histamine phosphate diluted to 0.5 mg/mL (0.18 mg/mL histamine base) or aqueous histamine phosphate 0.275 mg/mL (0.1 mg/mL histamine base). As a negative control use 0.5% to 1% glycerosaline solution.

B. Patients tested only by the intradermal method:

Since highly reactive individuals may react intracutaneously at doses even smaller than indicated above, it is recommended that intradermal testing be preceded by a puncture test and the dose adjusted accordingly. Other patients suspected of being moderately allergic may be tested with an intradermal test dose of 0.02 to 0.05 mL of a 0.05 BAU/mL dilution. A negative test should be followed by repeat tests using progressively stronger concentrations until the maximum recommended strength of 200 BAU/mL is reached. As a negative control use 0.5% to 1% glycerosaline solution. As a positive control, use glycerinated histamine phosphate diluted to 0.5 mg/mL (0.18 mg/mL histamine base) or aqueous histamine phosphate 0.275 mg/mL (0.1 mg/mL histamine base).

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