10 TREE MIX: Package Insert and Label Information

10 TREE MIX- fraxinus americana pollen, betula nigra pollen, acer negundo pollen, populus deltoides subsp. monilifera pollen, ulmus americana pollen, carya ovata pollen, quercus rubra pollen, platanus occidentalis pollen, black walnut and salix nigra pollen injection, solution
4 WEED MIX- xanthium strumarium pollen, plantago lanceolata pollen, chenopodium album pollen and amaranthus retroflexus pollen injection, solution
BIRCH MIX- betula populifolia pollen and betula nigra pollen injection, solution
MIXED ASPERGILLUS- aspergillus niger var. niger, aspergillus repens, aspergillus flavus var. oryzae and aspergillus terreus injection, solution
MIXED FEATHERS- gallus gallus feather, anas platyrhynchos feather and anser anser feather injection, solution
MIXED MOLDS- alternaria alternata, cladosporium sphaerospermum, aspergillus niger var. niger, aspergillus repens, aspergillus flavus var. oryzae, aspergillus terreus and penicillium chrysogenum var. chrysogenum injection, solution
MIXED PENICILLIUM- penicillium chrysogenum var. chrysogenum injection, solution
ALK-Abello, Inc.

DIRECTIONS FOR USE OF

THERAPEUTIC ALLERGENIC EXTRACTS

WARNING

This product is intended for use by physicians who are experienced in the administration of allergenic extracts and the emergency care of anaphylaxis or for use under the guidance of an allergy specialist.

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 reactions may rarely result in death. Patients should be observed for 20 to 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. Adverse events are to be reported to Med Watch (1-800-FDA-1088), Adverse Event Reporting , Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20852-9787.

This product should not be injected intravenously. Deep subcutaneous routes have proven to be safe. 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 the treatment of shock. Adrenocorticosteroids may be administered parenterally or intravenously.

Refer to WARNINGS, PRECAUTIONS, and ADVERSE REACTIONS sections below.

Port Washington, NY 11050

U.S. Government License No. 1256

DESCRIPTION

Sterile therapeutic extracts are supplied in either Phenol Saline Diluent or in Diluent containing Glycerin 50% (v/v) for subcutaneous injection. Inactive ingredients may include: Sodium Chloride for isotonicity, Glycerin, and Sodium Bicarbonate as buffering agents. These products are compounded and diluted on a w/v or PNU basis. Pollens are individually extracted from pure pollen extracted in a phenol-preserved sodium bicarbonate solution. Short Ragweed and Mixed (Tall and Short) Ragweed extracts are standardized by Antigen E content and so labeled. The Antigen E content of extracts containing Short Ragweed at a concentration more dilute than a weight/volume ratio of 1:10 are obtained by calculating the Antigen E content based on the assay value of more concentrated extract. Pollen extracts are filtered aseptically and, after final packaging, they are tested for sterility and safety. Molds are individually extracted from pure powdered inactivated mold source material extracted in phenol preserved saline. Mold extracts are filtered aseptically and after final packaging are tested for sterility and safety. Molds are present in all inhabited places at all seasons of the year; they are so ubiquitous that they are prevalent at times when common allergic pollens and other inhalants are not. In the home and surroundings, molds are found in upholstered furniture, mattresses, drapes, cellar and storage room dust, woolens, leather goods, fruits, meats, cheeses, garden soil and on plants. Spores, mycelial fragments and mold residues are thus inhaled, contacted and ingested continuously.

Miscellaneous inhalants and epidermals are individually extracted in phenol preserved saline, filtered aseptically and after final packaging are tested for sterility and safety.

CLINICAL PHARMACOLOGY

The 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. 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 extracts. Nevertheless, responses are variable, and in a few studies patients reported no appreciable benefit.

Extracts containing Short Ragweed pollen bear a labeled potency declaration in terms of Antigen E content. Numerous studies have confirmed Antigen E (AgE) as the major antigen associated with Short Ragweed pollinosis.1 Therefore, it is essential that the physician be aware of AgE content of allergenic extract administered for hyposensitization therapy.

Some studies have indicated that for most patients a cumulative Antigen E dosage of less than 0.1 unit is not immunizing (sufficient to stimulate specific IgG antibodies).2 This, however, does not suggest that 0.1 unit is a maximum tolerated dose. Most moderately sensitive patients may tolerate a dosage of ten to fifty times greater. If results with this product are unsatisfactory with exquisitely sensitive patients who cannot tolerate an immunizing dose, the physician should consider alternative therapy.

One well-controlled study demonstrated that standard immunotherapy (gradually increasing doses of antigen given subcutaneously to a maximum tolerated peak dose) using crude ragweed extract of known Antigen E potency, was significantly superior to placebo and low dose immunotherapy (0.1 units AgE cumulative dose) in amelioration of symptoms associated with ragweed hay fever. These patients received a cumulative dose of 18-350 units Antigen E (median = 84.9 units). The maximum single dose ranged from 3.7 to 46.8 units (median = 11.1 units) prior to the ragweed hay fever season.10

Patients for this study were sensitive to Ragweed Antigen E, as determined by intradermal skin testing at a dose of 0.01 units AgE/mL. A series of 24 weekly injections were administered. Forty-seven percent of the patients experienced at least one systemic reaction with an average of 1.2 systemic reactions per patient. None of the patients were able to achieve the expected maximum dose (90 units of Antigen E) in the 24 weekly injection dosage schedule.

10 TREE MIX Indications and Usage

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

Prior to initiation of therapy, the clinical sensitivity 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.

CONTRAINDICATIONS

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 indication 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.3,4,5 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.

WARNINGS

Patients should always be observed for at least 20-30 minutes after any injection. In the event of a marked systemic reaction, application of a tourniquet above the injection site and administration of 0.2 mL to 1 mL (0.01 mg/kg) of Epinephrine Injection (1:1,000) is recommended. Maximal recommended dose for children between 2 and 12 years 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.

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 reaction unresponsive to the above may require cardiopulmonary resuscitation.

DO NOT GIVE INTRAVENOUSLY

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.

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. See PRECAUTIONS AND ADVERSE REACTIONS.

TRANSFER OF PATIENTS

From pyridine extracted alum complexed allergenic extracts to aqueous extracts and glycerinated: In order to avoid untoward reaction, it is recommended that therapy be initiated as though patients were previously untreated. The first dose should be related to the patient’s sensitivity, determined by history and confirmed by skin testing.

From unstandardized aqueous extracts to standardized aqueous extracts and glycerinated: The physician should establish the potency relationship, perhaps by comparative skin testing at equal concentration, prior to injecting the first standardized dose.

From aqueous alum precipitated or modified extracts to aqueous extracts and glycerinated: Since this subject has not been studied, it is recommended that therapy be initiated as if the patient were not previously treated.

PRECAUTIONS

INFORMATION TO 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.

If the protective action of allergenic extract injections is considered essential for the patient’s welfare, appropriate symptomatic therapy with antihistaminic, adrenergic or other drugs might be needed either prior to or in conjunction with the allergenic extract injections.

GENERAL:

  1. Objective assessment of pulmonary function such as Peak Expiratory Flow Rate (PEFR) before allergen administration may be useful in unstable asthmatic to reduce the chances of exacerbation of the patient’s asthma.
  2. Store allergenic extracts between 2° and 8°C 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 WARNINGS).
  5. 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 which can be confirmed by comparative skin testing using end-point titration.
  6. Use standard aseptic precautions when making dilutions. The first dose of the new extract should be reduced to at least 25% of the amount of the dosage from the previous extract.
  7. Extracts in 50% glycerin can cause discomfort at the site of the injection.

PREGNANCY — CATEGORY C:

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.

Controlled studies of hyposensitization with moderate to high doses of allergenic extracts during conception and all trimesters of pregnancy have failed to demonstrate any risk to the fetus or to the mother. However, on the basis of histamine’s known ability to contract uterine muscle, the release of significant amounts of histamine from allergen exposure or hyposensitization overdose should be avoided on theoretical grounds. Therefore, allergenic extracts should be used cautiously in a pregnant woman and only if clearly needed.

PEDIATRIC USE:

Children can receive the same dose as adults, however, to minimize the discomfort associated with dose volume it may be advisable to reduce the volume of the dose by one-half and administer the injection at two different sites.

NURSING MOTHERS:

It is not known if allergens administered subcutaneously appear in human milk. Because many drugs are excreted in human milk, caution should be exercised when allergenic extracts are administered to a nursing woman.

CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY:

Studies in animals have not been performed.

DRUG INTERACTIONS:

Drugs can interfere with the performance of skin tests.6

Antihistamines: Response to mediator (histamine) released by allergens is suppressed by antihistamines. The length of suppression varies and is dependent on individual patient, type of antihistamine and length of time the patient has been on antihistamines. The duration of this suppression may be as little as 24 hours (chlorpheniramine), and can be as long as 40 days (astemizole).

Tricyclic Antidepressants: These exert a potent and sustained decrease of skin reactivity to histamine which may last for a few weeks.

Beta2 Agonists: Oral terbutaline and parenteral ephedrine, in general, have been shown to decrease allergen induced wheal.

Dopamine: Intravenous infusion of dopamine may inhibit skin test responses.

Beta Blocking Agents: Propranolol can significantly increase skin test reactivity (See WARNINGS).

Other Drugs: Short acting steroids, inhaled beta2 agonists, theophylline and cromolyn do not seem to affect skin test response.

ADVERSE REACTIONS

Anaphylaxis and deaths following the injection of mite and other extracts have been reported by The British Committee on Safety in Medicine.7 Fatalities from immunotherapy in the United States since 1945 have been extensively reviewed by Lockey, R. F., et al8 and more recently by Reid, M. ⁠J. et al.9

With careful attention to dosage and administration, such reactions occur infrequently, but it must be remembered that allergenic extracts are highly potent to sensitive individuals and OVERDOSE could result in anaphylactic symptoms. Therefore, it is imperative that physicians administering allergenic extracts understand and be prepared for the treatment of severe reactions.

Local: Reactions at the site of injection may be immediate or delayed. Immediate wheal and erythema reactions are ordinarily of little consequence; but if very large, may be the first manifestation of a systemic reaction. If large local reactions occur, the patient should be observed for systemic symptoms for which treatment is outlined below.

Delayed reactions start several hours after injection with local edema, erythema, itching or pain. They are usually at their peak at 24 hours and usually require no treatment. Antihistamine drugs may be administered orally.

The next therapeutic dose should be reduced to the dose which did not elicit a reaction, and subsequent doses increased more slowly; i.e., use of intermediate dilutions.

Systemic: Systemic reactions are characterized by one or more of the following symptoms: Sneezing, mild to severe generalized urticaria, itching other than at the injection site, extensive or generalized edema, wheezing, asthma, dyspnea, cyanosis, tachycardia, lacrimation, marked perspiration, cough, hypotension, syncope and upper airway obstruction. Symptoms may progress to shock and death. Patients should always be observed for at least 20 to 30 minutes after any injection. Volume expanders and vasopressor agents may be required to reverse hypotension. Inhalational bronchodilators and parenteral aminophylline may be required to reverse bronchospasm. Severe airway obstruction, unresponsive to bronchodilator, may require tracheal intubation and use of oxygen. In the event of a marked systemic reaction, application of a tourniquet above the injection site and the administration of 0.2 mL to 1 mL of Epinephrine Injection (1:1,000) are recommended. Maximal recommended dose for children under 2 years of age is 0.3 mL. Maximal recommended dose for children between 2 and 12 years of age is 0.5 mL. The tourniquet should not be left in place without loosening for 90 seconds every 15 minutes.

The next therapeutic injection of extract should be reduced to the dose which did not elicit a reaction, and subsequent doses increased more slowly; i.e., use of intermediate dilutions.

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