Pollens – Weeds and Garden Plants, Short Ragweed, Ambrosia Artemisiifolia: Package Insert and Label Information (Page 2 of 3)

2. Information for Patients

Patients should be instructed in the recognition of adverse reactions to immunotherapy, and in particular, to the symptoms of shock. (See WARNINGS box at the beginning of this 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 return to the office promptly if symptoms occur after leaving.

Patients should be instructed to report any symptoms of exposure to the allergen, so the physician can adjust the dosage appropriately.

3. Drug Interactions

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.)

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. 32

Topical steroids should be discontinued at the skin test site for at least 2-3 weeks before skin testing.32, 33

Tricyclic antidepressants such as Doxepin should be withheld for at least 7 days before skin testing.34 Topical local anesthetics may suppress flare responses and should be avoided in skin test sites.35

4. 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.

5. Pregnancy

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.

WARNINGS
and PRECAUTIONS) for preventing adverse reactions are especially important in the pregnant patient. Based on the physician’s discretion, immunotherapy maintenance doses may be continued during pregnancy if the patient has not experienced adverse side effects. Immunotherapy is generally not initiated during pregnancy due to the risks associated with systemic reactions and their treatment.37

6. Nursing Mothers

There are no current studies on the secretion of allergenic extract components in human milk or 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.

7. Pediatric Use

Since dosage for children is the same as for adults,38, 39 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.

8. 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.40

ADVERSE REACTIONS

Physicians administering allergenic extract testing or treatment materials should be experienced in the treatment of severe systemic reactions. See WARNINGS box at the beginning of this package insert.

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 the need for temporarily reduced dosages.

A mild burning immediately after the injection is to be expected; this usually subsides 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.

Most severe systemic reactions will begin within a 30 minute time period, but systemic reactions may occur at any time after skin tests or immunotherapy. Symptoms may range from mild to life-threatening (due to anaphylaxis) as described below.

Other possible systemic reaction symptoms 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, 41

If a systemic or anaphylactic reaction does occur, apply a tourniquet above the site of injection and inject 1:1000 epinephrine-hydrochloride intramuscularly into the opposite arm. Loosen the tourniquet at least every 10 minutes. Do not obstruct arterial blood flow with the tourniquet.

EPINEPHRINE DOSAGE

ADULT: 0.3 to 0.5 mL should be injected. Repeat in 5 to 10 minutes if necessary.

PEDIATRIC: 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 mL 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 patiency should be insured. Oxygen should be given by mask. Intravenous antihistamine, inhaled bronchodilators, theophylline, and/or adrenal 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

OVERDOSAGE

See ADVERSE REACTIONS.

DOSAGE AND ADMINISTRATION

21, 22, 23

1. General

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Sterile aqueous diluent containing human serum albumin [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. Maintain stock solutions and dilutions constantly at 2° — 8°C.

2. Pediatric Use

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

3. Geriatric Use

The dose for the elderly patients is the same as for adult patients under 65.40

4. Diagnosis

A positive skin reaction to any allergen must be interpreted in light of the patient’s history of symptoms, time of year, and known exposures. THE SKIN TESTS ARE IN NO WAY A SUBSTITUTE FOR A CAREFUL ALLERGIC HISTORY. THEY SERVE AS ADDITIONAL INFORMATION TO AID IN IDENTIFYING CAUSATIVE ALLERGENS IN PATIENTS WITH ALLERGIC DISORDERS.

Skin tests are graded in terms of the wheal and erythema response noted at 15 minutes. Wheal and erythema size may be recorded by actual measurement of the extent of both responses.

Refer to the following table 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.

Class Wheal Diameter Erythema Diameter Corresponding ∑E
0 < 5 mm <5 mm <10 mm
± 5-10 mm 5-10 mm 10-20 mm
1+ 5-10 mm 11-20 mm 20-40 mm
2+ 5-10 mm 21-30 mm 40-60 mm
3+ 10-15 mm a 31-40 mm 60-80 mm
4+ >15 mm b >40 mm >80 mm

a. or with pseudopods

b. or with many pseudopods

a. Scratch, Prick or Puncture Testing

To identify highly sensitive individuals and as a safety precaution, it is recommended that a scratch, prick or puncture test using a drop of the extract concentrate be performed prior to initiating intradermal testing. Short Ragweed extract at 1:20 w/v in 50% glycerin containing approximately 100 to 300 units of Amb a 1/mL or Giant and Short Ragweed Mix at 1:20 w/v in 50% glycerin containing approximately 50 to 150 units of Amb a 1/mL are usually used for scratch, prick or puncture testing.

Scratch tests are performed by first scarifying the skin, then applying the extract to the scratch. 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. The prick is superficial and should not draw blood. Puncture tests are performed by placing a drop of extract on the skin and piercing through the drop perpendicular to the skin with a device such as a Prick Lancetter. After about 1 minute the extract may be wiped away with a dry sponge.

The diameter of wheal and erythema reactions are measured 15 minutes after the scratch, prick or puncture is made, and the sensitivity class of the patient determined by the table presented at the end of the diagnosis section. Less sensitive individuals (Class 0 to 1+) can be tested intradermally with the recommended dilutions of the extract concentrate (see Intradermal Testing)

b. Intradermal Testing

Intradermal tests should be done only on patients with a negative scratch, prick or puncture test. Patients who do not react to a valid scratch, prick or puncture test should be tested intradermally with 0.02 to 0.05 mL of extract solution. The intradermal strength for Short Ragweed extract is usually 500 PNU which by calculation contains approximately 0.7 to 3 units of Amb a 1/mL. For Giant and Short Ragweed mix, the suggested intradermal strength is 500 PNU which by calculation contains 0.4 to 1.5 units of Amb a 1/mL. These strengths are usually safe for testing patients previously having negative scratch, prick or puncture test reactions. A 1:10 dilution of the stock intradermal strength should be used in preliminary testing of patients not previously screened by scratch, prick or puncture tests. If the intradermal dilutions were prepared from glycerinated concentrate, the negative control used with this latter dilution should contain 5% glycerol. A site should be injected with 0.02 mL of the control solution. False positive reactions are sometimes encountered in intradermal testing and the possibility of irritation reactions should always be taken into consideration.

A study of ragweed sensitive patients, 42 indicates that intradermal tests, using 0.05 mL of extract, produce positive reactions (1+ to 2+) at Amb a 1 concentrations of 2.7×1-1 to 2.7×10-6 units per mL. The equivalent PNU range was 100 to 0.001 PNU per mL.

5. Immunotherapy

Allergen 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.

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 the sterile aqueous diluent. Subsequent serial dilutions are made in a similar manner.

Following is a suggested schedule for average patients that 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. Decrease the size of the dose 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.

The starting dose should be based on skin tests of the extract to be used for immunotherapy. 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 10-20 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 is normally 3 to 7 days during dose building regimen.

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 20 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.

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.

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 glycerinated 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.

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.

In two hyposensitization studies using Amb a 1 27, 43 the amount administered over a pre-seasonal course of injections varied from 4 to 2,000 units of Amb a 1. The maximum individual dose attained ranged up to 170 units in one series.

Short Ragweed pollen extracted at 1:20 (w/v) usually assays within a range of 50,000 to 70,000 PNU/mL and 100 to 300 units Amb a 1/mL. Most treatment programs use a w/v concentrate of 1:100 to 1:20 or a PNU/mL concentrate of 20,000 to 40,000. This would approximate a 100 units Amb a 1/mL average concentration of Short Ragweed extract (Giant and Short Ragweed mix would be one-half this value). The following suggested dose schedule is based on this average concentration of 100 Units/mL

ragweed-table1.jpg
(click image for full-size original)

The Amb a 1 content of different batches of Short Ragweed extract will vary so it will be necessary to dilute extract concentrate to the same Amb a 1 concentration when using a new lot of antigen.

Formula for calculating dilutions:

A1 C1 = A2 C2

A1 = Amount of extract you wish to prepare.

C1 = Concentration you wish to prepare.

A2 = Amount of extract you will need for dilution.

C2 = Concentration of extract you will use.

Formula for determining diluent required:

A1 minus A2 = Amount of diluent required.

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