Standardized allergenic extract of grass pollens from Timothy (Phleum pratense), Orchard (Dactylis glomerata), June (Poa pratensis), Red Top (Agrostis alba), Sweet Vernal (Anthoxanthum odoratum), Meadow Fescue (Festuca elatior), Perennial Rye (Lolium perenne), Bermuda Grass (Cynodon dactylon), in the accompanying vial are sterile, and contain glycerin 50% v/v and phenol 0.4% (preservative). Inert ingredients may include sodium chloride for isotonicity and sodium bicarbonate buffer.

Glycerinated pollen extracts, for subcutaneous injection for immunotherapy and/or percutaneous or intracutaneous testing (see Dosage and Administration section), are prepared from defatted dried pollen extracted in glycerinated Coca’s Fluid, filtered aseptically, and dispensed into multiple dose vials. These are subsequently tested for sterility, safety, and potency.

For ease in use and for lot-to-lot consistency, the potency is expressed in Bioequivalent Allergy Units (BAUs) per milliliter. A value of 10,000 BAU/mL is assigned to the CBER reference standard that can be diluted 1:0.5 million to produce intradermal ƩE (sum of Erythema) of 50 mm in highly puncture reactive subjects1. A value of 100,000 BAU/mL is assigned to the CBER reference standard that can be diluted 1:5 million to produce intradermal ƩE (sum of Erythema) of 50 mm in highly puncture reactive subjects. The relative potency of each lot of standardized extract has been compared to the official CBER reference standard by an acceptable assay such as ELISA Inhibition.2 When the potency is equivalent by ELISA Inhibition to the reference, the product is assigned 10,000 BAU/mL or 100,000 BAU/mL. Standardized grass pollen extracts, except for Bermuda, have potency designations of either 10,000 BAU/mL or 100,000 BAU/mL. Bermuda grass pollen extract is only available with a 10,000 BAU/mL potency designation.

In the ELISA Inhibition assay, a competitive binding assay, the wells of microtiter plates are coated using a characterized allergenic extract. Allergic sera is added to each well. The binding of IgE specific for the coating allergen is inhibited by concentrations of a test sample of an extract of the same allergen. The amount of IgE bound to the solid phase allergen (and subsequently the degree of inhibition) is determined using enzyme-labeled anti-human IgE antibodies and the appropriate substrate. The potency relative to a reference is determined using a parallel line bioassay method.

Diagnostically (for skin testing) the allergen combines with IgE antibodies fixed to mast cells in the skin.3 This complexing causes an increase in cellular permeability and degranulation of the mast cells releasing chemical mediators. These mediators (such as histamine) are responsible for a local inflammatory response of wheal and erythema typical of a positive skin test reaction and also, the symptoms commonly associated with allergic disease. The more mediator released, the larger the reaction (wheal and erythema).

Treatment consists of the subcutaneous injection of gradually increasing doses of the allergens to which the patient is allergic. It has been demonstrated that this method of treatment induces an increased tolerance to the allergens responsible for the symptoms on subsequent exposure. Although the exact relationships between allergen, skin-sensitizing antibody (IgE) and the blocking antibody (IgG) have not been precisely established, clinically confirmed immunological studies have adduced evidence of the efficacy of hyposensitization therapy.

Numerous controlled studies have demonstrated the clinical efficacy of immunotherapy with cat, dust mites and some pollen, including grass pollen extracts.4 Nevertheless, responses are variable, and in a few studies patients reported no appreciable benefit.

Puncture test data with 10,000 BAU/mL Grass Pollen Extract CBER reference preparations, in 15 grass allergic patients yielded the following sizes of wheal and erythema (Ʃ = sum of longest diameter and orthogonal cross diameter). 5

A.        Puncture bifurcated needle data with 10,000 BAU/mL CBER Reference Grass Pollen Extract.

The intradermal dose (BAU50) of the CBER (FDA) Grass Pollen Extract Reference Preparation required producing a 50 mm Sum of Erythema was calculated based on titration in sensitive individuals.

B.       Intradermal Dose of CBER Reference Grass Pollen Extracts for 50mm Sum of  Erythema Diameter (BAU50)5.

Indicated use of allergenic extracts is for the diagnosis and treatment (hyposensitization therapy) of patients who experience allergic symptoms due to exposure to grass pollen and who exhibit type I skin sensitivity when tested to those specific allergens.

Hyposensitization (injection) therapy is a treatment for patients exhibiting allergic reactions to seasonal pollens, dust mites, molds, animal danders, and various other inhalants in situations where the offending allergen cannot be avoided.

For previously untreated patients, prior to the initiation of therapy, clinical sensitivity to the standardized grass pollen extract should be established by careful evaluation of the patient's history confirmed by diagnostic skin testing. Hyposensitization should not be prescribed for sensitivities to allergens which can easily be avoided.

10,000 BAU/mL extracts are indicated for percutaneous testing. If negative, the 100,000 BAU/mL dose may be used. Availability of 10,000 and 100,000 BAU/mL dosages facilitate safe switching. Patients who tolerate dilutions prepared from the 10,000 BAU/mL dosage and require a higher dose may be treated with dilutions prepared from the 100,000 BAU/mL dosage.

100,000 BAU/mL concentrations may be especially useful when patients are hyposensitized to numerous allergens. Mixing of allergenic extracts dilutes the potency of each constituent. Using higher concentrations such as 100,000 BAU/mL allows for dilution with other extracts without sacrificing immunizing properties. CAUTION: The final potency of each individual component in a patient mixture should never exceed 10,000 BAU/mL. See also, DOSAGE AND ADMINISTRATION section for discussion of mixture labeling.

A patient should not be immunized with preparations of allergens to which the patient has not demonstrated symptoms, IgE antibodies, positive skin tests, or properly controlled challenge testing. In most cases, immunotherapy is not indicated for those allergens that can be eliminated or minimized by environmental control.

Patients on beta-blockers are not candidates for immunotherapy, as they can be non-responsive to beta-agonists that may be required to reverse a systemic reaction (also see WARNINGS and ADVERSE REACTIONS). In the presence of active symptoms such as rhinitis, wheezing, dyspnea, etc., the indications of immunotherapy must be weighed carefully against the risk of temporarily aggravating the symptoms by the injection itself.

Also, there is some evidence, although inconclusive, that routine immunizations may exacerbate autoimmune diseases. 6,7,8 Hyposensitization should be given cautiously to patients with this predisposition. Patients with severe cardiorespiratory symptoms are at an additional risk during a systemic reaction. The physician must weigh risk to benefit in these cases.

See warnings at the beginning of this package insert.

Patients should always be observed for at least 20 - 30 minutes after any injection. In the event of a marked systemic reaction (for a description of systemic reactions see Adverse Reaction Section), application of a tourniquet above the injection site and intramuscular administration of 0.2 mL to 1.0 mL (0.01 mg/kg) of Epinephrine Injection (1:1000) is recommended. This dose can be repeated after 15 minutes, as needed. Maximal recommended dose for children between 2 and 12 years of age is 0.5 mL. The tourniquet is then gradually released at 15 minute intervals. Patients under treatment with beta-blockers may be refractory to the usual dose of epinephrine. DO NOT GIVE ALLERGENIC EXTRACTS INTRAVENOUSLY.

Volume expanders and vasopressor agents may be required to reverse hypotension. Inhalation bronchodilators and parenteral aminophylline may be required to reverse bronchospasm. In cases of respiratory obstruction, oxygen and intubation may be necessary. Life-threatening reactions unresponsive to the above may require cardiopulmonary resuscitation.

A reduction in starting dose is recommended in the following circumstances:

1. Change to a new lot of extract from the same manufacturer;
   
2. Change to a different manufacturers extract;
   
3. Change in the extract formula;
   
4. Change to an extract bearing a later expiration date;
   
5. When a prolonged lapse in time has occurred since the last injection.

Withhold allergenic extracts temporarily or reduce the dose in patients with any one of the following conditions:

• Severe rhinitis or asthma symptoms;
  
• Infection or flu accompanied by fever;
  
• Exposure to excessive amounts of clinically relevant allergen prior to therapy.

Allergenic extracts slowly become less potent with age. During the course of treatment, it may be necessary to continue therapy with a vial of extract bearing a later expiration date. The initial dose of the extract bearing the later expiration date should be lowered to a safe non-reaction-eliciting level. When switching one standardized extract with another, at least 75% reduction in dose is suggested.

Patients with unstable asthma or steroid dependent asthmatics and patients with underlying cardiovascular disease are at greater risk to a fatal outcome from a systemic allergic reaction12.

See also PRECAUTIONS and ADVERSE REACTIONS.

Information for Patients: Patients should be instructed to describe any active allergic symptoms such as rhinitis, wheezing, dyspnea, etc. prior to injection including any late reactions from previous administration. Patients should be instructed to remain in the office for 20 to 30 minutes after injection to monitor for adverse reactions. Also, see ADVERSE REACTIONS and WARNINGS sections.

General:

1. In the presence of active symptoms such as rhinitis, wheezing, dyspnea, etc., the indications of immunotherapy must be weighed carefully against the risk of temporarily aggravating the symptoms by the injection itself. Objective assessment of pulmonary function such as Peak Expiratory Flow Rate (PEFR) before allergen administration and prior to discharge may be useful in unstable asthmatics to reduce the chances of exacerbation of the patient’s asthma. If the protective action of allergenic extract injections is considered essential for the patient's welfare, appropriate symptomatic therapy with antihistaminic, beta-adrenergic or other drugs might be needed either prior to or in conjunction with the allergenic extract injections.
   
2. Store allergenic extracts between 2o and 8oC at all times, even during use.
   
3. Injections are to be given subcutaneously with the usual sterile precautions using a Tuberculin syringe.
   
4. Care must be taken to avoid injecting into a blood vessel. Pull gently on syringe plunger to determine if a blood vessel has been entered (See boxed Warnings).
   
5. Use standard aseptic precautions when making dilutions.
   
6. Extracts in 50% glycerin can cause discomfort at the site of the injection during the injection. Glycerinated extracts diluted for intradermal testing must be diluted at least twenty-five-fold to less than 2% glycerin (by volume), as glycerin above this level can cause false positive intradermal skin tests. Use of negative control skin test containing an equal concentration of glycerin as the allergen when evaluating intradermal skin tests is recommended.
   
7. Standardized concentrates of allergenic extracts must be diluted prior to initiation of immunotherapy.

Signs and symptoms of overdose are typically local and systemic reactions. For a description and management of overdose reactions, refer to "Adverse Reactions" section above.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

When diluting bulk extracts, use of Sterile Diluent for Allergenic Extracts or Sterile Diluent for Allergenic Extracts Normal Saline with HSA are recommended. Dilutions should be made with sterile disposable syringes using aseptic technique. Commonly 10 fold dilutions are used to achieve a desired concentration for intradermal testing or initiation and continuation of immunotherapy. For example transferring 0.5 mL of a 10,000 BAU/mL extract into 4.5 mL of diluent will yield 5 mL of extract at 1,000 BAU/mL. Prepare as many additional serial dilutions as necessary to reach the appropriate concentration.

Stock mixtures of grass pollen extracts are compounded from individual grass pollen extracts. The total potency per milliliter (mL) of these mixtures is described on the container label, where space permits. The contribution each individual component is expressed in the supplemental labeling accompanying the vial.

For percutaneous testing, 5 mL vial, 10,000 BAU/mL and 100,000 BAU/mL (except Bermuda grass 10,000 BAU/mL only) in glycerin 50% (v/v).

For immunotherapy, 10 mL, 30 mL, and 50 mL vials 10,000 BAU/mL in glycerin 50% (v/v), or 10 mL, 30 mL and 50 mL vials 100,000 BAU/mL in glycerin 50% (v/v). Bermuda is available only at 10,000 BAU/mL.

1Turkeltaub, P. C. et al. 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 ID50EAL method. FDA CBER Methods of the Allergenic Products Testing Laboratory. 1993.

2Miller, CA; Boyle, KT; and Braun, M. ELISA Competition Assay - Quantitative Determination of Relative Potency of Allergenic Extracts. FDA CBER Methods of the Allergenic Products Testing Laboratory. 1993.

3Norman, P. S. The clinical significance of IgE. Hosp. Prac. 1975; 10:41-49.

4Nelson, H.S. Immunotherapy for inhalant allergens. In: Middleton et al. Allergy Principles and Practice 6th Ed. St. Louis: CV Mosby, 2003;1455.

5Data on file at FDA.

6Umetsu, D. T. et al. Serum sickness triggered by anaphylaxis: a complication of immunotherapy. J. Allergy Clin. Immunol. 1985; 76:713.

7Phannphak, P. and Kohler, P. F. Onset of polyarteritis nodosa during allergic hyposensitization treatment. Am. J. Med. 1980; 68:479.

8Frank, M.M. and Hester, C.G. Immune complexes and allergic disease. In: Middleton et al.: Allergy Principles and Practice 6th Ed. St. Louis: CV Mosby, 2003:997.

9Demoly, P., Piette, V., and Bousquet, J. In vivo methods for the study of allergy: skin test, techniques, and interpretation. In: Middleton et al.: Allergy Principles and Practice 6th Ed. St. Louis: CV Mosby, 2003:631.

10Committee on the Safety of Medicines. CSM update: desensitizing vaccines. Brit. Med. J. 1986; 293:948.

11Lockey, R. F. et al. Fatalities from immunotherapy(IT) and skin testing (ST). J. Allergy Clin. Immunol. 1987; 79:660.

12Reid, M. J. et al. Survey of fatalities from skin testing and immunotherapy. 1985-1989. J. Allergy Clin Immunol. 1993; 92:6.

13DuBuske L. M. et al. Special problems regarding Allergen Immunotherapy in Immunology and Allergy Clinics of North America, Greenburger, P.A. Ed. February 1992; 145-149.

14Freedman, SO; Asthma and Allergic Rhinitis II Clinical Aspects. In Freedman and Gold Clinical Immunology, 2nd Ed. Hagerstown, MD: Harper & Row, 1976: 131.

15Bernstein, D I, Wanner M. Borish L, Liss GM: Immunotherapy Committee, American Academy of Allergy, Asthma and Immunology. Twelve-year survey of fatal reactions to allergen injections and skin testing: 1990-2001. J. Allergy Clin Immunol. 2004 Jun; 113(6);1129-36.

Revision: November 2009

©ALK-Abello, Inc. 2009                                           187F

ALLERGENIC EXTRACT
10mL sterile multiple dose vial
STANDARDIZED TIMOTHY GRASS POLLEN

ALLERGENIC EXTRACT
10mL sterile multiple dose vial
STANDARDIZED TIMOTHY GRASS POLLEN

ALLERGENIC EXTRACT
5mL sterile multiple dose vial
FOR PERCUTANEOUS TESTING ONLY
STANDARDIZED TIMOTHY GRASS POLLEN

ALLERGENIC EXTRACT
10mL sterile multiple dose vial
STANDARDIZED SWEET VERNAL GRASS POLLEN

ALLERGENIC EXTRACT
10mL sterile multiple dose vial
STANDARDIZED SWEET VERNAL GRASS POLLEN

ALLERGENIC EXTRACT
5mL sterile multiple dose vial
FOR PERCUTANEOUS TESTING ONLY
STANDARDIZED SWEET VERNAL GRASS POLLEN

ALLERGENIC EXTRACT
10mL sterile multiple dose vial
STANDARDIZED PERENNIAL RYE GRASS POLLEN

ALLERGENIC EXTRACT
50mL sterile multiple dose vial
STANDARDIZED PERENNIAL RYE GRASS POLLEN

ALLERGENIC EXTRACT
5mL sterile multiple dose vial
FOR PERCUTANEOUS TESTING ONLY
STANDARDIZED PERENNIAL RYE GRASS POLLEN

ALLERGENIC EXTRACT
10mL sterile multiple dose vial
STANDARDIZED RED TOP GRASS POLLEN

ALLERGENIC EXTRACT
10mL sterile multiple dose vial
STANDARDIZED RED TOP GRASS POLLEN

ALLERGENIC EXTRACT
5mL sterile multiple dose vial
FOR PERCUTANEOUS TESTING ONLY
STANDARDIZED RED TOP GRASS POLLEN

ALLERGENIC EXTRACT
10mL sterile multiple dose vial
STANDARDIZED ORCHARD GRASS POLLEN

ALLERGENIC EXTRACT
50mL sterile multiple dose vial
STANDARDIZED ORCHARD GRASS POLLEN

ALLERGENIC EXTRACT
5mL sterile multiple dose vial
FOR PERCUTANEOUS TESTING ONLY
STANDARDIZED ORCHARD GRASS POLLEN

ALLERGENIC EXTRACT
10mL sterile multiple dose vial
STANDARDIZED MEADOW FESCUE GRASS POLLEN

ALLERGENIC EXTRACT
10mL sterile multiple dose vial
STANDARDIZED MEADOW FESCUE GRASS POLLEN

ALLERGENIC EXTRACT
5mL sterile multiple dose vial
FOR PERCUTANEOUS TESTING ONLY
STANDARDIZED MEADOW FESCUE GRASS POLLEN

ALLERGENIC EXTRACT
10mL sterile multiple dose vial
STANDARDIZED JUNE GRASS POLLEN

ALLERGENIC EXTRACT
50mL sterile multiple dose vial
STANDARDIZED JUNE GRASS POLLEN

ALLERGENIC EXTRACT
5mL sterile multiple dose vial
FOR PERCUTANEOUS TESTING ONLY
STANDARDIZED JUNE GRASS POLLEN

ALLERGENIC EXTRACT
10mL sterile multiple dose vial
STANDARDIZED BERMUDA GRASS POLLEN

ALLERGENIC EXTRACT
5mL sterile multiple dose vial
FOR PERCUTANEOUS TESTING ONLY
STANDARDIZED BERMUDA GRASS POLLEN

ALLERGENIC EXTRACT
5mL sterile multiple dose vial
FOR PERCUTANEOUS TESTING ONLY
STANDARDIZED JUNE GRASS POLLEN

ALLERGENIC EXTRACT
5mL sterile multiple dose vial
FOR PERCUTANEOUS TESTING ONLY
STANDARDIZED PERENNIAL RYE GRASS POLLEN

ALLERGENIC EXTRACT
5mL sterile multiple dose vial
FOR PERCUTANEOUS TESTING ONLY
STANDARDIZED MEADOW FESCUE GRASS POLLEN

ALLERGENIC EXTRACT
5mL sterile multiple dose vial
FOR PERCUTANEOUS TESTING ONLY
STANDARDIZED SWEET VERNAL GRASS POLLEN

ALLERGENIC EXTRACT
5mL sterile multiple dose vial
FOR PERCUTANEOUS TESTING ONLY
STANDARDIZED ORCHARD GRASS POLLEN

ALLERGENIC EXTRACT
5mL sterile multiple dose vial
FOR PERCUTANEOUS TESTING ONLY
STANDARDIZED TIMOTHY GRASS POLLEN

ALLERGENIC EXTRACT
5mL sterile multiple dose vial
FOR PERCUTANEOUS TESTING ONLY
STANDARDIZED RED TOP GRASS POLLEN

ALLERGENIC EXTRACT
5mL sterile multiple dose vial
FOR PERCUTANEOUS TESTING ONLY
STANDARDIZED PERENNIAL RYE GRASS POLLEN