Standardized Grass Pollen, Bermuda Grass

PRECAUTIONS

1. GENERAL

The presence of asthmatic signs and symptoms appear to be an indicator for severe reactions following allergy injections. An assessment of airway obstruction either by measurement of peak flow or an alternate procedure may provide a useful indicator as to the advisability of administering an allergy injection.1, 30, 31, 32, 33
Concentrated extracts must be diluted prior to use: See DOSAGE AND ADMINISTRATION Section for detailed instructions on the dilution of standardized glycerinated allergenic extracts.
Allergenic extracts diluted with Albumin Saline with Phenol (0.4%) may be more potent than extracts diluted with diluents which do not contain stabilizers. When switching from non-stabilized to stabilized diluent, consider weaker initial dilutions for both intradermal testing and immunotherapy.
Sterile solutions, vials, syringes, etc. should be used and aseptic precautions observed in making dilutions.
To avoid cross-contamination, do not use the same needle to withdraw materials from vials of more than one extract, or extract followed by diluent.
A sterile tuberculin syringe graduated in 0.01 mL units should be used to measure each dose from the appropriate dilution. Aseptic techniques should always be employed when injections of allergenic extracts are being administered.
A separate sterile syringe should be used for each patient to prevent transmission of hepatitis and other infectious agents from one person to another.
Patient reactions to previous injections should be reviewed before each new injection. A conservative dosage schedule should be 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 allergen and does not demonstrate increasing tolerance to injections after several months 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 EACH TREATMENT INJECTION. Most severe reactions will occur within this time period, and rapid treatment measures should be instituted. See ADVERSE REACTIONS Section for such treatment measures.

2. INFORMATION FOR PATIENTS

Patients should be instructed in the recognition of adverse reactions to immunotherapy, and in particular, to the symptoms of shock. Patients should be made to understand the importance of a 30 minute observation period, and be warned to return to the office promptly if symptoms occur after leaving.

3. CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY

Long-term studies in animals have not been conducted with allergenic extracts to determine their potential for carcinogenicity, mutagenicity or impairment of fertility.

4. PREGNANCY

Pregnancy Category C. Allergenic Extracts. Animal reproduction studies have not been conducted with allergenic extracts. It is also not known whether allergenic extracts can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Allergenic extracts should be given to a pregnant woman only if clearly needed. For women who have been getting maintenance doses of allergen without side effect, the occurrence of pregnancy is not an indication to stop immunotherapy.

5. NURSING MOTHERS

There are no current studies on secretion of the allergenic extract components in human milk, or of their effect on the nursing infant. Because many drugs are excreted in human milk, caution should be exercised when allergenic extracts are administered to a nursing woman.

6. PEDIATRIC USE

Since dosage for the pediatric population is the same as for adults,21 the larger volumes of solution may produce excessive discomfort. Therefore, in order to achieve the total dose required, the volume of the dose may need to be divided into more than one injection per visit.

7. GERIATRIC USE

The reactions from immunotherapy can be expected to be the same in elderly patients as in younger ones. Elderly patients may be more likely to be on medication that could block the effect of epinephrine which could be used to treat serious reactions, or they could be more sensitive to the cardiovascular side effect of epinephrine because of pre-existing cardiovascular disease.4

8. DRUG INTERACTIONS

Patients on non-selective beta blockers may be more reactive to allergens given for diagnosis or treatment, and may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.19
Certain medications may lessen the skin test wheal and erythema responses elicited by allergens and histamine for varying time periods. Conventional antihistamines should be discontinued at least 5 days before skin testing. Long acting antihistamines should be discontinued for at least 3 weeks prior to skin testing.23 Topical steroids should be discontinued at the skin test site for at least 2-3 weeks before skin testing.23, 24 Tricyclic antidepressants such as Doxepin should be withheld for at least 7 days before skin testing.25 Topical local anesthetics may suppress the flare responses and should be avoided in skin test sites.26

STANDARDIZED GRASS POLLEN, BERMUDA GRASS ADVERSE REACTIONS

1. Local Reactions
Some erythema, swelling or pruritus at the site of injection are common, the extent varying with the patient. Such reactions should not be considered significant unless they persist for at least 24 hours. Local reactions (erythema or swelling) which exceed 4-5 cm in diameter are not only uncomfortable, but also indicate the possibility of a systemic reaction if dosage is increased. In such cases the dosage should be reduced to the last level not causing the reaction and maintained at this level for two or three treatments before cautiously increasing again.
Large persistent local reactions may be treated by local cold, wet dressings and/or the use of oral antihistamines. They should be considered a warning of possible severe systemic reactions and an indication of the need for temporarily reduced dosages.
A mild burning immediately after the injection is to be expected. This usually leaves in 10 to 20 seconds.

2. Systemic Reactions
With careful attention to dosage and administration, systemic reactions occur infrequently, but it cannot be overemphasized that in sensitive individuals, any injection could result in anaphylactic shock. Therefore, it is imperative that physicians administering allergenic extracts understand and be prepared for the treatment of severe reactions.
Other possible systemic reactions which may occur in varying degrees of severity are laryngeal edema, fainting, pallor, bradycardia, hypotension, angioedema, cough, wheezing, conjunctivitis, rhinitis, and urticaria. Adverse reaction frequency data for allergenic extract administration for testing and treatment show that risk is low.1, 22
If a systemic or anaphylactic reaction does occur, apply a tourniquet above the site of injection and inject 1:1,000 epinephrine-hydrochloride intramuscularly or subcutaneously into the opposite arm. Loosen the tourniquet at least every 10 minutes. Do not obstruct arterial blood flow with the tourniquet.
EPINEPHRINE DOSAGE
ADULT DOSAGE: 0.3 to 0.5 mL should be injected. Repeat in 5 to 10 minutes if necessary.
PEDIATRIC DOSAGE: The usual initial dose is 0.01 mg (mL) per kg body weight or 0.3 mg (mL) per square meter of body surface area. Suggested dosage for infants to 2 years of age is 0.05 to 0.1 mL; for children 2 to 6 years, 0.15 mL; and children 6 to 12 years, 0.2 mL. Single pediatric doses should not exceed 0.3 mg (mL). Doses may be repeated as frequently as every 20 minutes, depending on the severity of the condition and the response of the patient.
After administration of epinephrine, profound shock or vasomotor collapse should be treated with intravenous fluids, and possibly vasoactive drugs. Airway patency should be insured. Oxygen should be given by mask. Intravenous antihistamines, inhaled bronchodilators, theophylline and/or corticosteroids may be used if necessary after adequate epinephrine and circulatory support have been given. 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 produce prompt responses. However, the physician should be prepared in advance for all contingencies. Promptness in beginning emergency treatment measures is of utmost importance.
Severe systemic reactions mandate a decrease of at least 50% in the next dose, followed by cautious increases. Repeated systemic reactions, even of a mild nature, are sufficient reason for the cessation of further attempts to increase the reaction-causing dose.

3. Adverse Event Reporting
Report all adverse events to Jubilant HollisterStier LLC Customer Technical Services Department at 1 (800) 992-1120. A voluntary adverse event reporting system for health professionals is available through the FDA MEDWATCH program. Preprinted forms (FDA Form 3500) are available from the FDA by calling 1 (800) FDA-1088. Completed forms should be mailed to MEDWATCH, 5600 Fisher Lane, Rockville, MD 20852-9787 or Fax to: 1 (800) FDA-0178.

OVERDOSAGE

See ADVERSE REACTIONS Section.

STANDARDIZED GRASS POLLEN, BERMUDA GRASS DOSAGE AND ADMINISTRATION

1. General
Sterile aqueous diluent containing albumin (human) [Albumin Saline with Phenol (0.4%)] or diluent of 50% glycerin may be used when preparing dilutions of the concentrate for immunotherapy. For intradermal testing dilutions, Albumin Saline with Phenol (0.4%) is recommended.
Dilutions should be made accurately and aseptically, using sterile diluent, vials, syringes, etc. Mix thoroughly and gently by rocking or swirling.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

2. Diagnosis
Prick or Puncture Test: To identify highly sensitive individuals and as a safety precaution, it is recommended that a prick or puncture test using a drop of 10,000 BAU/mL extract be performed prior to initiating intradermal testing. If this test is negative, a second prick/puncture test may be performed using a 100,000 BAU/mL extract. Prick tests are performed by placing a drop of extract on the skin and piercing through the drop into the skin with a slight lifting motion. Puncture tests are performed by placing a drop of extract concentrate on the skin and piercing the skin through the drop with a small needle such as a Prick Lancetter. Fifteen minutes after puncture is made the diameter of wheal and erythema reactions are measured, and the sensitivity class of the patient determined by Table 3. Less sensitive individuals (Class 0 to 1+) can be tested intradermally with the recommended dilutions of the extract concentrate (See intradermal testing instructions).
Intradermal Test: Patients with a negative prick or puncture test should be tested intradermally with 100 BAU/mL. If this test is negative, a second intradermal test may be performed using a 1,000 BAU/mL extract. The negative control should have glycerin concentration equivalent to the glycerin concentration of the intradermal test solution, not to exceed 5% glycerin.
It is recommended that patients be tested using the intradermal technique only after screening by prick or puncture test.
Extract for intradermal testing should be prepared by diluting the stock concentrate, provided in multiple-dose vials, with Sterile Albumin Saline with Phenol (0.4%) (refer to Table 4 in the Immunotherapy section below).
To administer the intradermal strength dilutions, a 1 mL tuberculin syringe with a short 27-gauge needle should be used. The needle is inserted intradermally at a 30° angle, bevel down, and 0.02 to 0.05 mL of the extract is injected. Fifteen minutes following injection, the diameter of wheal and erythema reactions are measured, and the patient's sensitivity class is determined by the table below. Skin tests are graded in terms of the wheal and erythema response noted at 10 to 20 minutes. Wheal and erythema size may be recorded by actual measurement of the extent of both responses. Refer to Table 3 to determine the skin test sensitivity class. The corresponding ∑E (sum of the longest diameter and the mid-point orthogonal diameters of erythema) is also presented.

3. Immunotherapy
Allergenic extracts should be administered using a sterile syringe with 0.01 mL gradations and a 25-27 gauge X 1/2" to 5/8" needle. The injections are given subcutaneously. The most common sites of injection are the lateral aspect of the upper arm or thigh. Intracutaneous or intramuscular injections may produce large local reactions which may be very painful.
Dosage of allergenic extracts is a highly individualized matter and varies according to the degree of sensitivity of the patient, his clinical response, and tolerance to the extract administered during the early phases of an injection regimen. The starting dose should be based on skin tests of the extract to be used for immunotherapy. To prepare dilutions for intradermal and therapeutic use, make a 1:10 dilution by adding 1.0 mL of the concentrate to 9.0 mL of Sterile Albumin Saline with Phenol (0.4%). Subsequent serial dilutions are made in a similar manner. (See Table 4.) To determine the starting dose, begin intradermal testing with the most dilute extract preparation. Inject 0.02 mL and read the reaction after 15 minutes. Intradermal testing is continued with increasing concentrations of the extract until a reaction of 11-20 mm erythema ∑E 20-40 mm) and/or a 5 mm wheal occurs. This concentration at a dose of 0.03 mL then can serve as a starting dose for immunotherapy and be increased by 0.03 mL to as high as 0.12 mL increments each time until 0.3 mL is reached, at which time a dilution 10 times as strong can be used, starting with 0.03 mL. Proceed in this way until a tolerance dose is reached or symptoms are controlled. Suggested maintenance dose is 0.2 mL of the concentrate. Occasionally, higher doses are necessary to relieve symptoms. Special caution is required in administering doses greater than 0.2 mL. The interval between doses normally is 3 to 7 days.
Potencies of 10,000 BAU/mL and 100,000 BAU/mL are available for treatment. The two selections are available to facilitate safe switching by providing flexibility in dosing. For previously untreated patients, initiate treatment using dilutions made from the 10,000 BAU/mL concentrate. If tolerated and symptoms justify a higher dosage, then use of dilutions made from the 100,000 BAU/mL concentrate is warranted. Proceed with caution when using 100,000 BAU/mL in higher doses.
When converting a patient who is currently receiving non-standardized grass pollen extracts, it is recommended that skin testing be performed to compare the potency of the new and old extracts. If you choose not to skin test as recommended, but to continue therapy, the maximum first dose of the new allergenic product should not exceed 10% (1/10) of the previous dose.
This is offered as a suggested schedule for average patients and will be satisfactory in most cases. However, the degree of sensitivity varies in many patients. The size of the dose should be adjusted and should be regulated by the patient's tolerance and reaction. The size of the dose should be decreased if the previous injection resulted in marked local or the slightest general reaction. Another dose should never be given until all local reactions resulting from the previous dose have disappeared.
In some patients, the dosage may be increased more rapidly than called for in the schedule. In seasonal allergies, treatment should be started and the interval between doses regulated so that at least the first twenty doses will have been administered by the time symptoms are expected. Thus, the shorter the interval between the start of immunotherapy and the expected onset of symptoms, the shorter the interval between each dose. Some patients may even tolerate daily doses. A maintenance dose, the largest dose tolerated by the patient that relieves symptoms without producing undesirable local or general reactions, is recommended for most patients. The upper limits of dosage have not been established; however, doses larger than 0.2 mL of the glycerin concentrate may be painful due to the glycerin content. The dosage of allergenic extract does not vary significantly with the respiratory allergic disease under treatment. The size of this dose and the interval between doses will vary and can be adjusted as necessary. Should symptoms develop before the next injection is scheduled, the interval between doses should be decreased. Should allergic symptoms or local reactions develop shortly after the dose is administered, the size of the dose should be decreased. In seasonal allergies, it is often advisable to decrease the dose to one-half or one-quarter of the maximum dose previously attained if the patient has any seasonal symptoms.
The interval between maintenance doses can be increased gradually from one week to 10 days, to two weeks, to three weeks, or even to four weeks if tolerated. Repeat the doses at a given interval three or four times to check for untoward reactions before further increasing the interval. Protection is lost rapidly if the interval between doses is more than four weeks. (See WARNINGS Section.)
The usual duration of treatment has not been established. A period of two or three years of injection therapy constitutes an average minimum course of treatment.

(4) PEDIATRIC USE

The dose for the pediatric population is the same as for adults. (See PRECAUTIONS.)

(5) GERIATRIC USE

The dose for elderly patients is the same as for adult patients under 65.4

HOW SUPPLIED