HISTAMINE: 226 Adverse Event Reports & Safety Profile

DESCRIPTION The chemical formula for Histamine Phosphate is C 5 H 9 N 3 · 2H 3 PO 4 ; its molecular weight is 307.14. For prick, puncture or scratch testing, the product is a sterile solution that contains 1 mg/mL histamine base (2.75 mg/mL Histamine Phosphate) in Water for Injection; it also contains Glycerin 50% (v/v) as viscosity agent and Phenol 0.4% as preservative. For intracutaneous (intradermal) skin testing, the product is a sterile solution that contains 0.1 mg/mL histamine base (0.275 mg/mL Histamine Phosphate) in Water for Injection and Phenol 0.4% as preservative. The product should be stored refrigerated and protected from light.

INDICATIONS AND USAGE Positive Skin Test Control - Histamine is indicated as an adjunct in allergy skin test for diagnosis, as a positive control to test wheal-flare response of skin for evaluation of skin test response to allergenic extracts.

DOSAGE AND ADMINISTRATION Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

For

Prick, Puncture and Scratch Testing Histamine base 1 mg/mL (Histamine Phosphate 2.75 mg/mL) should be used to give a reaction. (Refer to Interpretation Section.) Prick, Puncture or Scratch Test Techniques The skin in the test area should be cleansed with alcohol and air dried. The histamine control skin test solution should be placed at the same site with the other skin test antigens, either on the patient's back or on the volar surface of the forearm. The patient should be placed in a comfortable position before the testing is begun. For the prick test, a sharp needle is used to puncture the skin, but not to draw blood. If the scratch test is used, carefully break or scratch the skin with a sterile scarifier. Do not draw blood. Each scratch should be about 2 mm - 4 mm in length. A small drop of the histamine base 1 mg/mL (Histamine Phosphate 2.75 mg/mL) is placed on the abraded skin site no closer than 4 or 5 cm from an adjacent test site. Some physicians prefer to place the solution on the test area and then prick through the drop with a sharp needle. Use a separate sterile scarifier or needle for each patient. The test should be read at 15 minutes; if a large wheal reaction occurs before that time the test site should be wiped free of histamine.

Interpretation

The patient's response is based on the size of: erythema (degree of redness) and/or size of wheal (smooth, slightly elevated area) which appear after 10 minutes. For percutaneous testing, 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. For prick, puncture and scratch testing, histamine base 1 mg/mL (Histamine Phosphate 2.75 mg/mL) should be used to give a positive reaction. In a large population, the NHANES II survey reports a mean diameter (average of length and width) wheal of 4.4 mm ± 1.65 mm (± standard deviation) and a mean erythema of 18.4 mm ± 8.55 mm (± standard deviation) when using 25 gauge B-D needle by prick puncture (Pepys) technique. 7 All positive reactions should be interpreted against an appropriate negative control.

For Intradermal Skin Testing

Histamine base 0.1 mg/mL (Histamine Phosphate 0.275 mg/mL) or 0.01 mg/mL should be used to give a reaction. (Refer to Interpretation Section.) Intracutaneously (Intradermal)

Test Techniques

The skin should be cleansed with alcohol and air dried. A sterile one milliliter tuberculin syringe with 26 or 27 gauge needle should be used. A single sterile syringe should be used for each solution to assure sterility. Only the histamine base 0.1 mg/mL (Histamine Phosphate, 0.275 mg/mL) or greater dilution solution should be used. The histamine base skin test solution should be injected at the same site with the other skin test allergens, either on the patient's back or on the arm. The patient should be placed in a comfortable position before the testing is begun. The skin is held tense and the needle is inserted almost parallel to the skin, bevel side up, far enough to cover the beveled portion. Slowly inject 0.01 mL or 0.02 mL, making a small bleb approximately 3 mm - 5 mm in diameter. The test should be read in 15 minutes.

Interpretation

The patient's response is based on the size of: erythema (degree of redness) and/or size of wheal (smooth, slightly elevated area) which appear after 10 minutes. For intradermal skin testing, histamine base 0.1 mg/mL (Histamine Phosphate 0.275 mg/mL) or 0.01 mg/mL should be used to give a positive reaction. The available 0.1 mg/mL concentration must be diluted ten-fold to achieve this dose. All positive reactions should be interpreted against an appropriate negative control. In two successive years of testing, the Committee on Standardization of the American College of Allergy reported positive reactions at histamine base doses of 0.01 mg/mL and higher. Mean sum of wheal diameters was approximately 14 mm ± 4.8 mm and sum of erythema diameter was approximately 52 mm ± 21.6 mm following 0.01 mL intradermal doses of 0.01 mg/mL histamine base.

When

0.01 mL of 0.1 mg/mL histamine base was injected, the sum of cross-diameters of wheal ranged from 15-20 mm and the sum of cross-diameters of erythema ranged from 60-80 mm. 8

CONTRAINDICATIONS Histamine should not be injected into individuals with hypotension, severe hypertension, severe cardiac, pulmonary, or renal disease. Not to be used for diagnosis of pheochromocytoma or to test the ability of the gastric mucosa to secrete hydrochloric acid.

ADVERSE REACTIONS Large doses of histamine may precipitate systemic reactions. These reactions may include flushing, dizziness, headache, bronchial constriction, urticaria, asthma, marked hypotension or hypertension, abdominal cramps, vomiting, metallic taste, local or generalized allergic manifestations. An antihistamine preparation may be given orally, I.M. or I.V. to prevent or ameliorate systemic reactions to the drug. If a systemic or anaphylactic reaction does occur, apply a tourniquet above the site of injection and inject 1:1000 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: 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. Oxygen should be given by mask. Aminophylline or adrenal corticosteroids may be used if necessary after adequate epinephrine and circulatory support has been given. Emergency resuscitation measures and personnel trained in their use should 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 77s (2): p. 271-273, 1986). 16 Rarely are all of the above measures necessary, the tourniquet and epinephrine usually producing prompt responses. However, the physician should be prepared in advance for all contingencies. Promptness in beginning emergency treatment measures is of utmost importance.

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.

Warnings For external use only Do not use

• on wounds or damaged skin
• if you are allergic to ingredients in this product When using this product
• avoid contact with the eyes. If product gets into the eyes, rinse thoroughly with water
• do not bandage tightly or use a heating pad Stop use and ask a doctor if
• rash appears
• condition worsens, or if symptoms persist for more than 7 days, or if symptoms clear up and occur again within a few days If pregnant or breastfeeding, ask a health professional before use. Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center right away.

PRECAUTIONS General A separate sterile needle or other percutaneous testing device should be used for each individual patient to prevent transmission of hepatitis and other infectious agents from one person to another.

Epinephrine

Injection (1:1,000) and injectable antihistamines should be available for immediate use in the event the patient exhibits a severe response. A tourniquet can be applied above the test site to slow absorption if a severe response occurs.

Drug Interactions

Drugs can interfere with the performance of skin tests in general, and specifically with histamine 1 . Antihistamines: Response to histamine 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.

Beta

2 Agonists: Oral terbutaline and parenteral ephedrine, in general, have been shown to decrease allergen induced wheal. Theoretically, this may also reduce whealing capacity to histamine. Dopamine: Intravenous infusion of dopamine has been shown to inhibit skin test responses to histamine.

Beta Blocking

Agents: Propranolol can significantly increase skin test reactivity, including histamine.

Other

Drugs: Short acting steroids, inhaled beta agonists, theophylline and cromolyn do not seem to affect skin test response. Carcinogenesis, Mutagenesis, Impairment of Fertility Animal studies have not been conducted with Histamine.

Nursing

Mothers It is not known if Histamine administered percutaneously or intracutaneously appears in human milk. Because many drugs are excreted in human milk, caution should be exercised when histamine is administered to a nursing woman.

Pregnancy

Category C It is not known whether Histamine can cause fetal harm when administered during pregnancy or whether it can affect reproduction capacity. Histamine should be given during pregnancy only if clearly needed. There are no adequate and well-controlled studies during pregnancy. However, based on histamine's known ability to contract uterine muscle, exposure or repeated doses should be avoided. HISTATROL ® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus or mother.

Pediatric Use

Histamine solutions for percutaneous testing have been given safely in infants and young children. 2,3,4,5 Neonates and infants have lower skin test reactivity to histamines as well as common allergens. 3,4,5,6 About 20% of infants less than six months of age have been observed to have a negative reaction to histamine hydrochloride (1 mg/mL of salt). 4 Skin test reactivity gradually increases to age six and plateaus to age sixty. 2,3 Therefore, small skin test reactions should be anticipated in children under age six.

Drug Interactions Drugs can interfere with the performance of skin tests in general, and specifically with histamine 1 . Antihistamines: Response to histamine 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.

Beta

2 Agonists: Oral terbutaline and parenteral ephedrine, in general, have been shown to decrease allergen induced wheal. Theoretically, this may also reduce whealing capacity to histamine. Dopamine: Intravenous infusion of dopamine has been shown to inhibit skin test responses to histamine.

Beta Blocking

Agents: Propranolol can significantly increase skin test reactivity, including histamine.

Other

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

Active ingredient** (in each pellet)

Histaminum Hydrochloricum

30C HPUS (0.44 mg) The letters "HPUS" indicate that the component in this product are officially monographed in the Homeopathic Pharmacopoeia of the United States.

Inactive Ingredients: Aloe Barbadensis Leaf (Aloe Vera Gel) Juice, Aqua (Deionized Water), Arnica Montana Flower Extract, Beeswax, Boswellia Serrata Extract, Butyrospermum Parkii (Shea) Butter, Cetearyl Alcohol, Cetearyl Olivate, Cetyl Alcohol, Cetyl Myristoleate, Chamomilla Matricaria (Chamomile) Extract, Citric Acid, Cucumis Sativus (Cucumber)

Fruit

Extract, Dimethyl Sulfone (DMSO), Gluconolactone, Glycerin, Glyceryl Stearate, Glycyrrhiza Glabra (Licorice) Extract, Helianthus Annuus (Sunflower) Oil, Hypericum Perforatum (St. John's Wort), Mentha Piperita (Peppermint) Oil, Methylsulfonylmethane (MSM), Olea Europaea (Olive) Oil, Pistacia Lentiscus (Mastic) Oil, Sodium Benzoate, Sodium Laurylglucosides Hydroxypropyl sulfonate, Sorbitan Olivate, Stearic Acid, Xanthan Gum, Zemea (Corn) Propanediol, Zingiber Officinalis (Ginger) Oil.