Grass Pollen Injection

Standardized allergenic extract is intended for use by physicians who are experienced in the administration of standardized (BAU/mL) allergenic extracts for immunotherapy and the emergency care of anaphylaxis, or for use under the guidance of an allergy specialist. Standardized grass pollen extracts labeled in BAU/mL are not interchangeable with grass pollen extracts labeled in AU/mL or non-standardized grass pollen extracts.  Standardized allergenic extracts are not directly interchangeable with allergenic extracts of the same labeled potency from different manufacturers. For previously untreated patients or patients, switching from non-standardized to standardized, see WARNING section. For previously untreated patients the initial dose of standardized extract must be based on skin testing as described in the warnings, dosage and administration section of this insert. Patients should be instructed to recognize adverse reaction symptoms and cautioned to contact the physician's office if reaction symptoms occur. As with all allergenic extracts, severe systemic reactions may occur. In certain individuals, these life-threatening reactions may be fatal. Patients should be observed for at least 20 - 30 minutes following treatment, and emergency measures, as well as personnel trained in their use, should be immediately available in the event of a life-threatening reaction. 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 reaction.

This product should not be injected intravenously. Deep subcutaneous routes have proven to be safe. See the warnings, precautions, adverse reactions and overdosage sections below.

Sensitive patients may experience severe anaphylactic reactions resulting in respiratory obstruction, shock, coma and/or death. Adverse events are to be reported to MedWatch (1-800-FDA-1088), Adverse Experience Reporting, HFM-210 Center for Biologics Evaluation & Research, Food & Drug Administration, 1401 Rockville Pike, Rockville, MD 20852-1448.

Patients receiving beta-blockers may not be responsive to epinephrine or inhaled bronchodilators. Respiratory obstruction not responding to parenteral or inhaled bronchodilators may require theophylline, oxygen, intubation and the use of life support systems. Parenteral fluid and/or plasma expanders may be utilized for treatment of shock. Adrenocorticosteroids may be administered parenterally or intravenously. Refer to the warnings, precautions and adverse reaction sections below.

See warnings at the beginning of this package insert. Standardized extracts may be more, less, or equivalently potent compared to non-standardized extracts (See table I).

Conversion from non-standardized to standardized Grass Pollen Extracts:

There is no one specific formula to convert immunotherapy patients from non-standardized to standardized extracts. However, you may wish to consider the following as part of your overall plan:

A.       Time your conversion outside of the height of the grass pollen season.

B.       Table I describing potency of non-standardized extracts in CLINICAL PHARMOCOLOGY section can be used as a guide in selection dose.

CAUTION: By the very nature of non-standardized extracts individual lots may vary more than 10-fold from the average value expressed in these tables. Further, you must consider the rapid decline in potency of non-glycerinated concentrates or aqueous dilutions of glycerinated concentrates of grass pollen extract. The BAU/mL expressed in the tables, therefore, may be overstated when compared to actual patient treatment extracts.

1.       Refer to the table in the CLINICAL PHARMACOLOGY section and based on the current w/v or PNU determine an approximate BAU concentration that would be about 1/10 the non-standardized dose that the patient is currently receiving. To compare dose selection by puncture and intradermal testing, compare their wheal and erythema responses. If the reaction to the standardized is equal to or less than the non-standardized, proceed with immunotherapy beginning with 0.05 mL of the standardized extract concentration tested, and proceed to maintenance as described in the DOSAGE AND ADMINISTRATION Section.

2.       If the intradermal reaction to the standardized extract is greater than the non-standardized dose, dilute 10 fold and repeat until skin response to standardized is equal to or less than non-standardized, then proceed with immunotherapy.

C.       From alum precipitated or modified extracts to standardized extracts: It is recommended that therapy be initiated as if the patient were not previously treated.

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.

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.

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.

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 @ 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.

Diagnosis – 

In diagnosing the sensitive individual, the symptom history must be associated with exposure to the allergen. Skin testing is used in conjunction with a definitive history for diagnosing individual sensitivities.

An excellent method of recording results is to cover the skin reaction with transparent tape, outline the erythema first then the wheal with an indelible pen, then remove the tape and transfer it to the patient's permanent record. For preferred results, it is recommended that the actual measurement of the extent of both responses be recorded. This can be accomplished by measuring the longest erythema diameter, then selecting the mid-point of that line and measuring at a 90o angle to that line to determine the orthogonal diameter. The sum of these two measurements is the sum of erythema (ƩE); the sum of wheal diameters is determined in a similar manner.

Patient's response is graded on the basis of the size of erythema and/or wheal.

Prick, scratch, or puncture skin tests should be performed initially using a glycerinated extract at 10,000 BAU/mL.

What follows are general guidelines for percutaneous testing14. Different devices and/or techniques influence the size of the reaction, therefore it is important to refer to the device manufacturer's or distributor's instructions when grading reactions. As a negative control the diluent should be tested and included in the interpretation in the skin test reactions. Use of a positive control such as histamine base at 1 mg/mL should be used to assess skin test reactivity.

Intradermal testing should start with a dilute solution, usually in the range of 0.1 BAU/mL or less.

Glycerinated extracts diluted for intradermal testing may be diluted at least 25-fold to less than 2% glycerin (by volume) as glycerin above this level can cause false positive intradermal skin tests. Use a negative control skin test with glycerin content equal to the glycerin content of the allergen dose used for intradermal testing. Use of a positive control such as histamine base at 0.1 mg/mL or 0.01 mg/mL should be used to test reactivity.

On the forearm or upper outer aspect of the arm, using a 26 - 27 gauge, short bevel needle, inject intradermally 0.05 mL of the intradermal test solution. Skin whealing responses should be observed 10 - 20 minutes after administering the test.

A negative skin test is one where the sum of erythema was 0 or equal to the sum of the wheal. As a negative control, the diluent should be tested and included in the interpretation of the skin reactions. What follows are general guidelines intradermal testing 14.

Immunotherapy -

Starting dose for immunotherapy is related directly to a patient's sensitivity as determined by carefully executed skin testing. Degree of sensitivity can be established by determination of D50 (the intradermal dose, base three, that produces a ƩE = 50 mm).1  

A general rule is to begin at 1/10 of the dose that produces sum of erythema of 50 mm (approximately a 2+ positive skin test reaction). For example, if a patient exhibits a 2+ intradermal reaction to 1 BAU/mL, the first dose should be no higher than 0.05 mL of 0.1 BAU/mL. Dosage may be increased by 0.05 mL each time until 0.5 mL is reached, at which time the next 10-fold more concentrated dilution can be used, beginning with 0.05 mL, if no untoward reaction is observed.

If a tolerated dose of allergenic extract has been established, the initial dose from the new extract should be reduced to 25% of the previously well tolerated dose (see also Precautions).

Interval between doses in the early stages of immunotherapy is no more than once to twice a week, and may gradually be increased to once every two weeks. Generally, maintenance injections may be given as infrequently as once every two weeks to once a month.

Injections are given subcutaneously preferably in the arm. It is advantageous to give injections in alternate arms and routinely in the same area. In some patients, a local tolerance to the allergen may develop thus preventing a possible severe local reaction.

After inserting the needle, but before injecting the dose, pull plunger of the syringe slightly. If blood returns in the syringe, discard the syringe and contents and repeat injection at another site.

Bulk concentrated extracts must be diluted for initial therapy and intradermal skin testing. For recommended diluent, refer to DOSAGE AND ADMINISTRATION section.

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.

Use standard aseptic precautions when making dilutions. The first dose of the new extract should be reduced at least 75% of the amount of the dosage from the previous extract.

Stability studies for diluted and undiluted forms of this product are not complete. Indications are the undiluted product will retain its potency under recommended storage conditions at least until the expiration date on the vial label is reached. It is recommended that minimal amounts of the concentrate be diluted so that the diluted product is used up within a relatively short period of time; i.e., preferably not more than four weeks.

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.

STORAGE:

To maintain stability of allergenic extracts, proper storage conditions are essential. Bulk concentrates and diluted extracts are to be stored at 2o to 8o C even during use. Bulk or diluted extracts are not to be frozen. Do not use after the expiration date shown on the vial label.

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.

4VanMetre, T. E. and Adkinson, N. F. Immunotherapy for aeroallergen disease. In: Middleton et al. Allergy Principles and Practice 3rd Ed. St. Louis: CV Mosby, 1988:1327.

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.

8Kohler, P. F. Immune complexes and allergic disease. In: Middleton et al.: Allergy Principles and Practice 3rd Ed. St. Louis: CV Mosby, 1988:167.

9Bousquet, J. In vivo methods for the study of allergy: skin test, techniques, and interpretation. In: Middleton et al.: Allergy Principles and Practice 3rd Ed. St. Louis: CV Mosby, 1988:167.

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.

Revision: June 2002

©ALK-Abello, Inc. 2002                                           187D