Drug Information for Pharmalgen (ALK-Abello A S): Dosage and Administration

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  • Reconstitution and Dilution:

    A diluent containing 0.03% human serum albumin (HSA), 0.9% sodium chloride, and 0.4% phenol should be used for reconstituting and diluting these preparations.

    Reconstitute each vial of freeze-dried venom material by drawing the amount of diluent specified on the label into a syringe, and transferring it to the vial of extract using aseptic technique. Swirl or rock the vial gently until all the material has gone into solution. Do not shake the vial or agitate it violently enough to cause the fluid to foam. Note that a needle that has been inserted into a vial of venom must not be re-inserted into a stock bottle of diluent, or into a vial containing another type of extract.

    When reconstituted as directed on the label, the vial will contain 100 µg of venom per ml (300 µg/ml in the case of the mixed vespid preparation). This is the concentration from which the typical maintenance dose is drawn, but it is not suitable for testing or for the initial stages of immunotherapy.

    To obtain the concentrations required for testing or for the initial stages of immunotherapy, prepare serial ten-fold dilutions of the concentrate to achieve the concentrations specified in Table 1.

    Table 1 Dilution Chart for Single-Venom PreparationsNote: For mixed vespid, the concentrations will be 3 times those shown.
    Take This Much VenomAt This ConcentrationAdd It To This Much DiluentTo Get This Much VenomAt This Concentration
    0.2 ml0.2 ml0.2 ml0.2 ml0.2 ml0.2 ml100 µg/ml10 µg/ml1 µg/ml0.1 µg/ml0.01 µg/ml0.001 µg/ml1.8 ml1.8 ml1.8 ml1.8 ml1.8 ml1.8 ml2.0 ml2.0 ml2.0 ml2.0 ml2.0 ml2.0 ml10 µg/ml1 µg/ml0.1 µg/ml0.01 µg/ml0.001 µg/ml0.0001 µg/ml

    The relatively small 0.2 ml volume conserves the original concentrate, and is convenient because sterile diluent is readily available in prefilled 1.8 ml volumes.

    For each vial, record the data of reconstitution or dilution on the label. Then calculate the appropriate shelf life based on the information in Table 4, and write that on the label as well. Note that the calculated shelf life of a dilution must not exceed that of the concentrate from which it was made.

    Skin testing:

    Patients with relevant sting histories should be skin tested with appropriate concentrations of each of the five single Hymenoptera venom preparations (honey bee, yellow jacket, yellow hornet, white faced hornet, wasp).

    The location for testing is usually the flexor surface of the forearm. Use aseptic technique and a separate, sterilized syringe and needle for each extract and each patient. For intradermal testing, introduce the needle into the superficial skin layers until the bevel is completely buried. Slowly inject approximately 0.05 ml.

    The following skin testing protocol can be recommended:

    • Reconstitute each of the five vials of a diagnostic kit using HSA diluent, and prepare serial dilutions such as those in Table 1.
    • Perform a preliminary skin prick test with each preparation at the 1.0 µg/ml concentration, with the diluent as a negative control, and with histamine base at 1 mg/ml as a positive control. For most patients, all tests but the positive control should be negative. Patients reacting to the prick test at 1.0 µg/ml of venom should be considered highly sensitive to the venom, and suitable precautions should be taken. If the positive control is negative, the possibility of skin non-reactivity must be considered.
    • Begin intradermal testing with all venoms, starting at the 0.001 µg/ml dilution for all patients who did not react to the skin prick test, and at the 0.0001 µg/ml for highly sensitive patients.
    • Read the test response after 15 minutes, and determine the degree of response to the injection, in comparison to the negative control. A suggested grading system appears in Table 2.
    Table 2 Skin Test Grading System
    … Mean Diameters (cm) …
    GradeWhealErythema
    0+1+2+3+4+<0.50.5 – 1.00.5 – 1.00.5 – 1.01.0 – 1.5, pseudopodia>1.5, many pseudopodia<0.50.5 – 1.01.1 – 2.02.1 – 3.03.1 – 4.0>4.0
    • If the intradermal reaction is negative at the initial concentration, continue intradermal testing with ten fold increments in the concentration until a clearly positive response has been obtained or a concentration of 1 µg/ml has been tested, whichever occurs first. The use of venom concentrations greater than 1 µg/ml for intradermal testing is not recommended because of the risk of false-positive reactions4. If there is a positive response at concentrations of 0.01µg/ml or less, the patient should be considered highly sensitive to the venom.

    The interpretation of the skin response is based on the size of the wheal, the size of the erythema, and the appearance of irregular, spreading, pseudopod-like projections from the test area. The presence of the latter indicates marked hypersensitivity.

    A patient is considered sensitive to the test extract if there is a reaction of 1+ or greater at a concentration of 1 µg/ml or less, providing that the 1+ reaction is in relation to the negative control.

    If skin tests are negative in a recently stung patient, the skin testing should be repeated after two weeks have elapsed. For patients with negligible response to the histamine control, skin testing should be repeated after 72 hours.

    Treatment:

    An allergic individual should be treated with each venom that provokes a positive skin test. If more than one Hymenoptera venom preparation is indicated, the different preparations should be given by separate injections. The mixed vespid preparation should not be substituted for single-venom treatments unless the patient is allergic to all three of the constituent venoms: yellow jacket, yellow hornet, and white faced hornet.

    Administer the venom solution subcutaneously, using a suitable sterile syringe with a 0.1 ml graduations and a 25-27 gauge 1/4 to 5/8 inch needle. The injections are typically given in the lateral aspect of the upper arm.

  • Dosage Schedule:

  • Dosage of allergenic extracts is a highly individualized matter, and varies according to the degree of sensitivity of the patient, the clinical response, and tolerance of the extract administered previously.

    The dosage schedule in Table 3 is based on the results of a clinical trial involving 103 patients, and is suitable for most patients. It should be noted, however, that the clinical trial incorporated a flexible dosage schedule that utilized guidelines that were somewhat more aggressive in the starting dose and in the dosage increments in the early phases of immunotherapy than those recommended in Table 3 and that no single dosage schedule can be recommended for all patients. See “Precautions”, above.

    The safe administration of venom preparations does not differ in principle from the safe administration of other allergenic extracts. Increasing doses of venom are given at increments dependent on the patient’s ability to tolerate the venoms, until a maintenance dosage is reached and maintained. The prescribed maintenance dosage is 100 µg per venom, and, since the efficacy of lower doses has not been established, it is considered extremely important that the patient be able to reach this dosage.

    During the initial phases of immunotherapy, the patient may receive two or three injections of each venom per visit, spaced at ½ hour intervals, with dosage increments no greater than those shown in Table 3.

    After each injection, the patient’s skin reaction and overall response are evaluated to determine whether the next scheduled dose can be given. The conditions for proceeding to the next dose are as follows:

    • If a single dose results in more than a moderate local reaction (>5.0 cm wheal) within ½ hour, no additional dose of the venom should be given during that visit, and the same dose should be repeated at the next visit – or visits – until the patient has tolerated it.
    • If any systemic manifestation of sensitivity occurs during or following a visit, or if a single dose results in an excessive local reaction (>10 cm wheal) within ½ hour, no additional dose should be administered during the visit and the total dosage for the next visit should be reduced to half of the dose that caused the reaction.
    • Delayed local reactions (occurring 24-48 hours after injection) are relatively common, and do not appear to predict difficulties with future doses. As a rule, therefore, dosage adjustment is not required in most instances. However, at the physician’s discretion and for the comfort of the patient, if delayed large local reactions over 10 cm are reported, the subsequent dose should be held at the same level as the one causing the reaction.

    The figures in Table 3 refer to treatment with a single venom. If a patient requires more than one venom preparation, the number of injections per visit is increased to include the additional venom preparations.

    Table 3 Representative Treatment Schedule Using a Single Venom PreparationFor the mixed vespid preparation, the total venom protein concentration and the total amount of venom protein injected will be triple the amounts shown, with no changes in injection volumes.
    Week No.DayNo.Dose No. Per Dayat ½ Hr. IntervalConcentration of Venom to be Used(µg/ml)Volume to be Injected(ml)Amount of Venom Injected(µg)Conditions for Proceeding to Next Dose:
    111230.010.11.00.10.10.10.0010.010.1If a single dose results in more than a moderate local reaction (>5.0 cm wheal) within ½ hour, an additional dose should not be given during that visit. Repeat the same dose at the next visit – or visits – until tolerated.
    281231.01.0100.10.50.10.10.51.0
    3151231010100.10.51.01510
    422121001000.10.21020If systemic manifestations of sensitivity occur during or following a visit or a single dose results in an excessive local reaction (>10 cm wheal) within ½ hour, do not administer an additional dose during the visit and reduce the total dose for the next visit to half of the total that produced the reaction.
    529121001000.20.32030
    636121001000.30.33030
    743121001000.40.44040
    850121001000.50.55050Delayed (24-48 hrs.) local reactions of <10 cm do not require adjusting the dose; for such reactions that are >10 cm, hold dose at previous level.
    95711001.00100
    Monthly11001.0100 If a patient on maintenance therapy is stung and has any systemic manifestations of sensitivity, his maintenance dosage should be increased to 200 µg for the relevant venom, increasing at no greater than 50 µg increments.

    Weekly visits are continued until the patient has received and tolerated two consecutive maintenance doses of 100 µg. Thereafter, the interval between doses can be increased by increments of one week, to a maximum of four weeks. Thereafter, monthly injections of 100 µg are to be continued indefinitely.

    The use of the Table 3 regimen or a slightly modified dosage schedule may result in some form of mild to moderate allergic reaction in approximately ¼ of the patients, but such reactions are typically not severe enough to warrant stopping the treatment.

    Weekly visits are continued until the patient has received and tolerated two consecutive maintenance doses of 100 µg. Thereafter, the interval between doses can be increased by increments of one week, to a maximum of four weeks. Thereafter, monthly injections of 100 µg are to be continued indefinitely.

    The use of the Table 3 regimen or a slightly modified dosage schedule may result in some form of mild to moderate allergic reaction in approximately ¼ of the patients, but such reactions are typically not severe enough to warrant stopping the treatment.

    The maintenance dose of 100 µg is recommended for both children and adults, and there is no evidence that any lower maintenance dose provides adequate protection. If a patient on maintenance therapy is stung and still has systemic manifestation of sensitivity, the maintenance dosage of the relevant venom should be increased to 200 µg at no than 50 µg increments.

    Duration of Treatment: At the present time it appears necessary to continue maintenance injections indefinitely.

  • Storage:

  • The freeze-dried venom preparations, the diluent, the reconstituted extract, and all diluents should be kept refrigerated at 2-8°C. The maximal storage times for these materials are as shown in

    Table 4.

    Table 4 Recommended Shelf Life
    Venom dosage FormRecommended Shelf Life
    Unreconstituted Freeze-Dried PowderReconstituted in HSA Diluent to a concentration of:As shown on the label
    100 µg/mlTwelve months from date of reconstitution But not to exceed the expiration date of the freeze-dried extract or of the source dilution.
    1.0 – 10 µg/mlOne month from the date of dilution
    0.1 µg/mlTwo weeks from the date of dilution
    <0.1 µg/mlPrepare fresh daily.

    The expiration date of thirty months for the unreconstituted, freeze-dried extract is based on stability data demonstrating that no significant loss of potency occurs after storage at 2-8°C for at least that period of time.

  • Drug Information Provided by National Library of Medicine (NLM).
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